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Review

New Generations of Tyrosine Kinase Inhibitors in Treating NSCLC with Oncogene Addiction: Strengths and Limitations

Division of Thoracic Oncology, European Institute of Oncology IRCCS, Via G. Ripamonti 435, 20141 Milan, Italy
*
Author to whom correspondence should be addressed.
Cancers 2023, 15(20), 5079; https://doi.org/10.3390/cancers15205079
Submission received: 29 September 2023 / Revised: 17 October 2023 / Accepted: 17 October 2023 / Published: 20 October 2023

Abstract

:

Simple Summary

This manuscript focuses on improving the treatment of non-small cell lung cancer, with actionable gene alterations. The aim is to understand how the treatment with Tyrosine Kinase Inhibitors (TKIs) can be used and improved. Newer generations of TKIs have better results in controlling the disease and extending patient survival. These drugs also work better in the brain, which is crucial for patients with brain metastases. However, there are challenges. The use of newer TKIs may limit the role of older ones, and resistance to the drugs can emerge. The considerations from this manuscript suggest that understanding the biology of the tumor and the properties of the drugs could help develop new treatment strategies and ultimately benefit patients with this type of lung cancer.

Abstract

Tyrosine kinase inhibitors (TKIs) revolutionized the treatment of patients with advanced or metastatic non-small cell lung cancer (NSCLC) harboring most driver gene alterations. Starting from the first generation, research rapidly moved to the development of newer, more selective generations of TKIs, obtaining improved results in terms of disease control and survival. However, the use of novel generations of TKIs is not without limitations. We reviewed the main results obtained, as well as the ongoing clinical trials with TKIs in oncogene-addicted NSCLC, together with the biology underlying their potential strengths and limitations. Across driver gene alterations, novel generations of TKIs allowed delayed resistance, prolonged survival, and improved brain penetration compared to previous generations, although with different toxicity profiles, that generally moved their use from further lines to the front-line treatment. However, the anticipated positioning of novel generation TKIs leads to abolishing the possibility of TKI treatment sequencing and any role of previous generations. In addition, under the selective pressure of such more potent drugs, resistant clones emerge harboring more complex and hard-to-target resistance mechanisms. Deeper knowledge of tumor biology and drug properties will help identify new strategies, including combinatorial treatments, to continue improving results in patients with oncogene-addicted NSCLC.

1. Introduction

Lung cancer remains one of the most prevalent and deadly malignancies worldwide, with non-small cell lung cancer (NSCLC) constituting the majority of cases diagnosed [1]. Over the past few decades, significant strides have been made in understanding the molecular underpinnings of NSCLC, leading to the identification of driver gene alterations that have, in turn, transformed the landscape of treatment for this disease. Among these remarkable advancements, the advent of tyrosine kinase inhibitors (TKIs) has emerged as a paradigm-shifting approach, offering newfound hope and extended survival to patients with advanced or metastatic NSCLC harboring specific genetic alterations [2,3].
The landscape of medical oncology has witnessed a revolution triggered by these targeted therapies, as they have the potential to halt the progression of the disease with greater efficacy and fewer adverse effects compared to conventional chemotherapy. Understanding the historical evolution and ongoing developments of TKIs is crucial for both clinicians and researchers in the field of medical oncology.
The inception of TKIs in NSCLC therapy began with the first generation of these agents. Initially designed to target the epidermal growth factor receptor (EGFR), this class of drugs showed unprecedented promise in a subset of NSCLC patients harboring EGFR mutations [4]. It was a watershed moment, offering personalized treatment options and substantially improving outcomes for these individuals. However, the first-generation TKIs, such as erlotinib and gefitinib, brought with them their own set of limitations, including the emergence of resistance mechanisms like the p.T790M mutation [5].
Recognizing the need for more potent and selective therapies, researchers swiftly moved forward in the development of subsequent generations of TKIs. These newer iterations promised enhanced specificity for their respective targets and a greater ability to circumvent resistance mechanisms [6].
Despite these remarkable advancements, the utilization of novel generations of TKIs is not without its complexities and challenges. Resistance remains a persistent issue, necessitating ongoing research into more effective treatment strategies [7,8,9]. Additionally, the optimal sequencing of these agents and their integration into the treatment landscape of NSCLC requires careful consideration (Figure 1). The identification of predictive biomarkers and the management of adverse effects associated with TKI therapy are also areas of active investigation [10].
This review manuscript will provide a thorough analysis of the strengths and limitations associated with the use of TKIs in NSCLC with oncogene addiction. We will explore the pivotal clinical trials that have shaped the current treatment paradigm and shed light on the emerging therapies currently under investigation. Furthermore, we will delve into the intricate biology underlying the potential strengths and limitations of these agents, unraveling the complex interplay between oncogenic signaling pathways and therapeutic interventions.

2. Novel Generations of TKIs for NSCLC in Clinical Practice

2.1. Efficacy

Since the advent of the first-generation TKIs, erlotinib and gefitinib, for the treatment of patients with EGFR-sensitizing mutations, an enduring paradigm shift towards precision oncology has guided the development of more potent and specific TKIs to overcome intrinsic and acquired resistance mechanisms responsible to treatment failure (efficacy results of novel generation TKIs in clinical practice are shown in Table 1).
Second-generation TKIs afatinib and dacomitinib improved clinical outcomes compared to platinum-based chemotherapy (PBC) and first-generation TKIs in patients with EGFR-sensitizing mutations [11,12,13,14,15,16]. Moreover, in a pooled analysis of the LUX-Lung trials, afatinib was also active in tumors with uncommon EGFR mutations, although the clinical benefit was lower in patients with de novo T790M and exon-20 insertion mutations [17]. However, after these molecules entered clinical practice, the occurrence of severe adverse events (AEs), mostly skin rash and diarrhea, due to the inhibition of wild-type EGFR narrowed the therapeutic window that was needed to effectively overcome acquired resistance mechanisms, especially the T790M mutation. To address this shortcoming, the third-generation osimertinib was developed to specifically target the EGFR-T790M mutation while retaining activity against initial activating mutations and selectivity over wild-type EGFR. Osimertinib received its first approval from the Food and Drug Administration (FDA) for the treatment of EGFR-T790M-positive NSCLC based on a 6-month improvement in progression-free survival (PFS) compared to PBC in the AURA3 trial and a hazard ratio (HR) for overall survival (OS) of 0.54 after adjustment for the high crossover rate in the study [18,19]. Subsequently, in the FLAURA trial, osimertinib outperformed first-generation TKIs in PFS (18.9 vs. 10.2 months, HR 0.46) and OS (38.6 vs. 31.8 months, HR 0.80), regardless of the T790M mutation, with better tolerability, establishing the role of first-line osimertinib as the gold-standard [20,21]. Despite these results, the emergence of resistance ultimately leads to treatment failure. Resistance mechanisms are highly complex and multifaceted, including the emergence of the C797S mutation, the loss of T790M, small cell lung cancer (SCLC) transformation, and MET amplification; thus, tumor biopsy upon disease progression should be considered whenever feasible to optimize treatment strategies [22,23].
Although relatively rare, accounting for 2–3% of cases, EGFR-exon 20 insertion mutations confer resistance to TKIs, requiring treatment with PBC. The oral TKI Mobocertinib was active and led to sustained responses in PBC-treated patients with EGFR-exon 20 insertion mutations. Based on these results, despite gastrointestinal and dermatological AEs hampering their clinical utility, mobocertinib was granted FDA accelerated approval [24,25]. However, the confirmatory trial EXCLAIM-2 ended prematurely in July 2023 as first-line mobocertinib monotherapy failed to improve PFS compared to PBC [26]. Therefore, it is still to be determined whether the approval will remain intact, particularly given the PFS improvement observed with the combination of first-line amivantamab, an EGFR-MET bispecific antibody, and PBC over PBC alone in the phase III PAPILLON trial [27].
In the realm of HER2-mutation-positive NSCLC, phase 2 trials have investigated the role of small molecule TKIs, pyrotinib and poziotinib. These agents showed only modest activity and severe gastrointestinal and cutaneous AEs, owing to EGFR inhibition, that hindered further development [28,29,30]. Current research is focusing on novel HER2-selective TKIs that lack activity against other HER/ERBB family members, aiming for enhanced activity and improved safety. Notably, in the phase 2 study DESTINY-Lung01 the antibody drug-conjugate (ADC) trastuzumab-deruxtecan (TDXd) yielded durable activity in previously treated patients and was generally well-tolerated, though interstitial lung disease (ILD) required prompt diagnosis and management [31], and the ongoing DESTINY-Lung-04 will determine its superiority over PBC as first-line (NCT05048797).
Following the approval of the first-in-class ALK-TKI, crizotinib [32], there was a compelling need for more potent therapeutic alternatives to overcome resistance. Owing to an inhibitory activity against several crizotinib or ceritinib-resistant ALK mutations, alectinib first improved PFS and intracranial objective response rate (ORR) in crizotinib-resistant patients compared to PBC, with an acceptable safety profile [33]. Subsequently, the ALEX trial established the superiority of first-line alectinib compared to crizotinib, with a 24-month PFS improvement (HR 0.32) and higher CNS activity (59% vs. 26%) [34,35]. First-line brigatinib also improved long-term outcomes over crizotinib in the ALTA 1L study and stands as a viable treatment option in this setting [36]. The third-generation lorlatinib, initially developed to overcome resistance mechanisms responsible for progression to second-generation TKIs, significantly improved PFS (HR 0.28) compared to crizotinib in the CROWN trial [37,38]. Treatment with lorlatinib was associated with an acceptable toxicity profile, as grade 3–4 AEs were mostly represented by altered lipid levels [38]. Interestingly, some compound mutations that confer resistance to lorlatinib might re-sensitize tumoral cells to crizotinib, making molecularly guided treatment a potentially valuable therapeutic strategy in some cases [39].
In the context of ROS1-fusion-positive NSCLC, crizotinib is associated with a median PFS of approximately 19 months [40], yet treatment failure and CNS progression generally occur within 2 years of treatment [41]. Lorlatinib demonstrated activity in crizotinib-resistant, ROS1-positive NSCLC in a Phase I-II trial, achieving an ORR of 35% [42]. Recently, in a pooled analysis of the phase I-II trials, ALKA-372-001, STARTRK-1, and STARTRK-2 entrectinib achieved an ORR of 67%, with a median duration of response (DoR) of almost 16 months, thereby supporting the choice of this agent for first-line treatment. Although generally well tolerated, severe AEs occurring at a low frequency, including cardiac and CNS AEs, need to be carefully monitored as they might require dose modifications in some instances [43,44].
Persistent efforts in the structural analyses of KRAS, a protein that has been historically deemed “undraggable”, paved the way for the development of KRASG12C-selective inhibitors sotorasib and adagrasib, that, although not in the class of TKIs, are worth mentioning as they have been both approved for clinical use following at least one prior line of systemic therapy. Sotorasib demonstrated activity in the phase I/II CodeBreaK-100 trial, with an ORR of 41%. The most common AEs included diarrhea and elevation in transaminases. However, in the phase III CodeBreaK-200 trial, the PFS improvement was small compared with docetaxel (5.6 vs. 4.5 months, HR 0.66), and OS was similar in the two arms (10.6 vs. 11.3 months) [45]. Similarly, adagrasib achieved an ORR of 43% in phase I/II KRYSTAL-1 trial, with durable responses and grade ≥3 AEs in 45% of patients [46,47], while its efficacy as second-line compared to docetaxel and as first-line is currently under investigation (KRYSTAL-12, NCT04685135; KRYSTAL-7, NCT04613596).
Traditionally, MET gene alterations have been treated with crizotinib [48], and other multikinase inhibitors, with limited efficacy and significant toxicity. Selective MET-TKIs capmatinib and tepotinib have revolutionized the treatment landscape for patients with a MET-exon-14-skipping mutation, leading to high and durable responses in both previously treated (ORR 40–51%) and treatment-naïve patients (ORR 56–67%) in the GEOMETRY mono-1 and VISION trials, respectively [49,50]. Noteworthy, common AEs associated with these agents include peripheral edema, increased creatinine levels, and gastrointestinal events. Another specific MET-TKI, Savolitinib, was only approved in the People’s Republic of China in 2021 [51]. Notably, MET-TKIs have yet to receive approval for high-level MET amplification, although preliminary data warrant further investigation, and the ideal methodology for determining the level of amplification and appropriate cutoffs for treatment is still an active area of research.
In RET-fusion positive NSCLC, the RET-selective TKIs selpercatinib and pralsetinib earned approval in 2021, as strong clinical activity was observed in the phase I/II LIBRETTO-001 and ARROW studies, both in treatment-naïve (ORR 84% and 72%, respectively) and previously treated patients (ORR 61% and 59%, respectively) [52,53]. Common AEs for selpercatinib include hypertension and increased liver enzymes, while it is crucial to monitor the occurrence of ILD associated with pralsetinib [54,55].
For BRAF-V600E-mutant NSCLC, the combination of oral serine/threonine kinase inhibitors dabrafenib and trametinib obtained significant responses in both the first (ORR 68%) and second (ORR 64%) line in the phase II BRF113928 study, and it is considered standard of care [56]. Recently, encorafenib plus binimetinib showed comparable efficacy, with an ORR of 75% in treatment-naïve and 46% in pretreated patients, and this combination might emerge as a new therapeutic option [57].
Lastly, larotrectinib and entrectinib have received tumor-agnostic approval based on their efficacy in basket trials enrolling patients with neurotrophic tyrosine receptor kinases (NTRK) fusion-positive tumors. The phase I/II NAVIGATE trial and the pooled analysis of the STARTRK-1, STARTRK-2, and ALKA-372-001 studies demonstrated ORRs of 73 and 63%, respectively, in patients with NTRK-fusion-positive NSCLC. The incidence of grade 3–4 AEs, dose reductions, and discontinuations was low [58,59,60].
Table 1. Efficacy results in registrational trials for 2nd and 3rd generation TKIs and KRAS-inhibitors in clinical practice.
Table 1. Efficacy results in registrational trials for 2nd and 3rd generation TKIs and KRAS-inhibitors in clinical practice.
OncogeneTKIRegistrational TrialN° of PatientsControl ArmPrimary EPEfficacy ResultsCNS Activity in Patients with Evaluable Lesions
EGFR exon 19 deletions and exon 20 L858RAfatinibPhase IIB LUX-Lung-7 [14,61]319GefitinibPFSMedian PFS 11.0 vs. 10.9 months
(HR 0.74; 95% CI, 0.57–0.95; p = 0.0178)
NA
DacomitinibPhase III ARCHER 1050 [15,16]452GefitinibPFSMedian PFS 14.7 vs. 9.2 months
(HR 0.59; 95% CI, 0.47–0.74; p < 0.0001)
-
OsimertinibPhase III FLAURA [20,21,62]556Gefitinib or ErlotinibPFSMedian PFS 18.9 vs. 10.2 months
(HR 0.46; 95% CI, 0.37–0.57; p < 0.001)
icORR 91% vs. 68%
icDoR 15.2 vs. 18.8 months
ALKCeritinibPhase III ASCEND-4 [63]376PBCPFSMedian PFS 16.6 vs. 8.1 months
(HR 0.55; 95% CI, 0.42–0.73; p < 0.00001)
icORR 72.7% vs. 27.3%
icDoR 16.6 months vs. NE
AlectinibPhase III ALEX [34,35]303CrizotinibPFSMedian PFS 34.8 vs. 10.9 months
(HR 0.43; 95% CI 0.32–0.58, p = 0.0001)
icORR 81% vs. 50%
icDoR 17.3 vs. 5.5 months
BrigatinibPhase III ALTA 1L [36] 275CrizotinibPFSMedian PFS 24.0 vs. 11.1 months
(HR 0.48, 95% CI 0.35–0.66, log-rank p < 0.0001)
icORR 78% vs. 26%
icDoR 27.9 vs. 9.2 months
LorlatinibPhase III CROWN [37,38,64]296CrizotinibPFSMedian PFS NR vs. 9.3 months
(HR 0.28; 95% CI 0.19–0.41, p < 0.001)
icORR 83% vs. 23%
icDoR NR vs. 10.2 months
ROS1EntrectinibPhase I-II ALKA-372-001, STARTRK-1, and STARTRK-2 [43,44]161-ORR
DoR
ORR 67.1% (95% CI 59.3–74.3)
Median DoR 15.7 months (95% CI 13.9–28.6)
icORR 79.2%
icDoR 12.9 months
MET Exon 14 skippingTepotinibPhase II VISION trial [50,65] 111, 1L T+
(cohort C + A)
-ORRORR 56.8% (95% CI, 47.0–66.1)icORR 55%
icDoR 9.5 months
97, ≥2L
(cohort C + A)
ORR 49.5% (95% CI, 39.2–59.8)
CapmatinibPhase II
GEOMETRY-mono-1 trial [49,66,67,68]
28 Treatment-naïve
(cohort 5b)
-ORRORR 67.9% (95% CI, 47.6–84.1)iORR 67.9%
32 Treatment-naïve
(expansion cohort 7)
ORR 65.6% (95% CI, 46.8–81.4)
69 pretreated 2/3L
(cohort 4)
ORR 40.6% (95% CI, 28.9–53.1)iORR 40.6%
31 pretreated 2L
(expansion cohort 6)
ORR 51.6% (95% CI, 33.1–69.8)
KRAS G12CSotorasibPhase II CodeBreaK 100 [69]174-ORRORR 40.7% (95% CI, 33.3–48.4)icORR NR
icDoR NR
Phase III CodeBreak 200 [45]345DocetaxelPFSMedian PFS 5.6 vs. 4.5 months
(HR 0.66; 95% CI 0.51–0.86, p = 0.0017)
icORR 33%
AdagrasibPhase I/II KRYSTAL-1 [47,70]116-ORRORR 42.9% (95% CI, 34.5–52.6)icORR 42%
icDoR 12.7 months
RETSelpercatinibPhase I/II LIBRETTO-001 [54,71]69 Treatment-naïve-ORRORR 84% (95% CI, 73–92)icORR 82%
icDoR 9.4 months
247 PPPORR 61% (95% CI, 55–67)
PralsetinibPhase I/II ARROW [55]75 Treatment-naïve-ORRORR 72% (95% CI, 60–82)icORR 78%
136 PPPORR 59% (95% CI, 50–67)
BRAF
V600E
Dabrafenib/
Trametinib
Phase II
BRF113928 [56]
36 Treatment-naïve (Cohort C)-ORRORR 63.9% (95% CI, 46.2–79.2)NA
57 Pretreated
(Cohort B)
-ORR 68.4% (95% CI, 54.8–80.1)
NTRKLarotrectinibPhase I/II NAVIGATE [58]20 NSCLC-ORRORR 73% (95% CI, 45–92)icORR 63%
EntrectinibPhase I/II STARTRK-1; STARTRK-2; ALKA-372–001 [59,60]22 NSCLC-ORRORR 63.6% (95% CI, 40.7–82.8)icORR 67%
CI: confidence interval; CNS: central nervous system; DoR: duration of response; EP: end point; HR: hazard ratio; icDCR: intracranial disease control rate; icDoR: intracranial duration of response; icORR: intracranial ORR; NA: not available; NE: not estimable; NR: not reached; NSCLC: non-small cell lung cancer; OR: odds ratio; ORR: objective response rate; OS: overall survival; PPP: platinum-pretreated patients; PFS: progression-free survival; T+: MET ex14 skipping positive in tissue biopsy; TKI: tyrosine kinase inhibitor; TTF: time-to-treatment failure.

2.2. CNS Activity

As a result of the specific and potent oncogene inhibition with novel TKIs, leading to improved extracranial disease control and prolonged survival, approximately 20–40% of patients ultimately develop CNS metastases. Brain metastases are associated with poor long-term outcomes, and few therapeutic options are available. Conventional local therapies include whole-brain radiation therapy, rarely curative and burdened by neurocognitive toxicity, and stereotactic radiosurgery, whereas poor performance status and disease burden often preclude neurosurgery. Furthermore, few chemotherapy agents have the ability to cross the blood–brain barrier (BBB), while, in contrast, novel generation TKIs have been specifically engineered to improve their intracranial permeability and activity, eventually leading to better intracranial outcomes.
While first- and second-generation EGFR-TKIs exhibit intracranial efficacy at some level, their concentrations in the cerebrospinal fluid (CSF) only reach 1–5% of the serum concentrations [72,73,74,75,76]. In contrast, osimertinib not only reaches higher intracranial concentrations but also demonstrates substantial intracranial efficacy at its standard daily dose of 80 mg [77,78]. In the FLAURA trial, the median CNS-PFS was not achieved with osimertinib, compared to 13.9 months in patients treated with first-generation TKIs (HR 0.48; 95% CI 0.26–0.86). Additionally, the incidence of CNS progression was lower in the osimertinib arm (6% vs. 15%), regardless of the presence of baseline CNS involvement [20]. Among patients with evaluable brain metastases, the intracranial response rate was substantially higher with osimertinib (91% vs. 68%) [62,79].
In the natural history of ALK-translocated NSCLC, most patients develop CNS metastases. First-line alectinib or brigatinib have improved intracranial ORR compared to crizotinib, with intracranial ORRs of approximately 80% and durable intracranial responses [34,35,36]. In cross-study comparisons, ceritinib showed lower CNS penetration, with an intracranial ORR of 72% observed in the ASCEND-4 trial [63]. The third-generation lorlatinib outperformed the intracranial activity of crizotinib in the CROWN trial (83% vs. 23%), with complete responses in 71% of patients treated with lorlatinib. Moreover, the 12-month rate of CNS progression in patients with and without baseline brain metastases was improved in the experimental arm (7% vs. 72% and 1% vs. 18%, respectively) [38,64].
For patients with ROS-rearranged NSCLC, the intracranial activity of entrectinib further enforces its use in treatment-naïve patients, with this agent leading to intracranial ORRs of approximately 80%, alongside a median intracranial PFS of 12.0 months and a median intracranial DoR of 12.9 months [44].
Similarly, both tepotinib and capmatinib have shown intracranial activity in patients with MET exon-14 skipping, and an intracranial ORR of 68% was observed in treatment-naïve patients treated with capmatinib in the GEOMETRY-Mono-1 study [49,50].
In the LIBRETTO-001 trial, CNS responses with selpercatinib were documented in 85% of patients, regardless of previous systemic treatment and/or radiotherapy, with a median DoR of 9.4 months [71]. Pralsetinib also led to an intracranial ORR of 78% in the ARROW trial [55].
Notably, several targeted agents have shown efficacy in patients with leptomeningeal disease, including lorlatinib and alectinib for ALK-positive cancers and selpercatinib in RET-fusion NSCLC [80,81]. For those with an EGFR mutation and leptomeningeal disease, osimertinib has demonstrated significant intracranial activity against brain metastases at a dose of 80 to 160 mg daily [82].

3. Novel Generations of Small Molecule Inhibitors in Clinical Development

3.1. EGFR

Beyond osimertinib, several third-generation TKIs have been developed, and three of them (lazertinib, almonertinib, furmonertinib) have already been approved with the same indications of osimertinib in Korea and China [83,84,85,86,87]. Table 2 summarizes their principal features, their main clinical results, and, where available, their approval indications.
Similarly to osimertinib, they have proven to be active towards EGFR-T790M resistance mutation and showed superiority to 1st or 2nd generation TKI. Moreover, they share the same risk of developing rare and severe toxicity (ILD and QTc prolongation) and are inactive toward EGFR p.C797S mutation. In the absence of any head-to-head comparison results, the real advantage taken from more similar drugs available in the market will be the potential improvement in the cost-effectiveness of these drugs [88,89,90].
Table 2. 3rd generation EGFR TKIs beyond osimertinib.
Table 2. 3rd generation EGFR TKIs beyond osimertinib.
Lazertinib aAlmonertinib bFurmonertinib cTY-9591SH-1028Limertinib dAbivertinib eBefotertinib fRezivertinib g
Structure
Respect
To Osi
pyrimidine and on phenyl ringscyclopropyl group on the indole grouptphenyl ring and methyl groupNot releasedindole ringIndole and pyrimidine ringpyrimidine and on phenyl ringsNot releasedoxygen replacing on phenyl ring
IC50 nM
(T790M+)
1.850.37Not releasedNot
released
0.550.30.18Not releasedGI50 22 nM
RP2D240 mg110 mg80 mg160 mg200 mg160 mg BID300 mg BID75–100 mg180 mg
MTDNot reachedNot reachedNot reachedunpublishedunpublishedunpublishedNot reachedNot reachedNot reached
Approved
for
T790M+
Korea 18 January 2021China 18 March 2020China 3 March 2021------
TrialPhase I/II
Lee 2020 [84]
Apollo
Lu 2020 [91]
Phase I/II
Shi 2021 [92]
NCT04204473
Ongoing
Phase I/II
Xiong 22 [93]
Phase IIb
Li 2022 [94]
Phase I/II
Zhou 2022 [95]
Phase I/II
Lu 2022 [96]
Phase I
Shi 2022 [97]
ORR
(T790M+)
58%69%74%-60.4%68.8%56.5%67.6%60.5%
mPFS
mos
(T790M+)
1112.39.6-12.6118.516.69.7
Approved
for
1st line
Korea 30 June 2023 China 4 December 2021China 28 June 2022------
Vs 1st TKILASER301
Cho 2023 [85]
AENEAS
Lu 2022 [98]
FURLONG
Shi 2022 [99]
-NCT04239833
Ongoing
NCT04143607
Ongoing
AEGIS-1
Ongoing
NCT04206072
Lu 2023 [100]
REZOR
Ongoing
mPFS
(mos)
20.6 vs. 9.719.3 vs. 9.920.8 vs. 11.1----21.1 vs. 13.8-
ILD3%1%1%NR0NRNR2%NR
Ongoing
trials
MARIPOSA
Lazertinib
vs.
Osimertinib
vs.
Lazertinib/
amivantamab
--FLETEO
TY-9591
vs.
osimertinib
-----
Abbreviations: IC50 = Half-maximal inhibitory concentration; RP2D = recommended phase 2 dose; ORR = overall response rate; mPFS = median progression-free survival. a. Lazertinib, also known as (AKA) GNS-1480/YH25448/JNJ-73841937; b. almonertinib AKA aumolertinib or HS-10296; c. fulmonertinib AKA Alflutinib/AST2818; d. Limertinib, also known as (AKA) = ASK120067; e. abivertinib AKA AC0010/Avitinib/STI-6565; f. befotertinib AKA D-0316; g. rezivertinib AKA BPI-7711.
To overcome EGFR-C797X mediated resistance, several 4th generation TKIs have been designed and are at difference stages of clinical research (Table S1) [101]. The first developed drugs (EAI045, JBJ-04-125-02, BLU-701) were rapidly withdrawn since their activity depends on combination with other drugs or lack of efficacy [102,103,104]. In the same line, BLU-945 is also being investigated in combination with osimertinib to improve the activity against EGFR-sensitizing mutations [105]. Further, fourth-generation EGFR-TKIs, which have demonstrated proof of activity in cancer models harboring C797S with or without T790M, are being experimented in phase I trials (Table S1) [106,107,108,109,110,111,112,113,114].
With concern on the EGFR and HER2 Exon 20 insertion mutations that are intrinsically resistant to available EGFR-TKIs, different drugs with similar properties are currently evaluated in clinical research (Tables S2 and S3) [115,116,117,118,119,120,121]. The main issue in the development of TKIs targeting EGFR or HER2 exon 20 insertions consists of achieving high selectivity over wild-type receptors in order to increase their therapeutic window [114]. With regard to uncommon EGFR mutations, few studies are investigating the efficacy of specific TKIs or combinations: phase II trials of furmonertinib (NCT05548348), sutetinib (NCT05168566) and the afatinib/bevacizumab combination (NCT05267288), phase III trial of almonertinib over standard chemotherapy (NCT04951648).

3.2. KRAS

The efficacy of KRAS-G12C inhibitors is tempered by the RAS pathway complexity, the concomitant presence of other gene mutations, such as KEAP1, and the acquired secondary mutations on the switch pocket II of KRAS [122,123]. New KRAS inhibitors have been designed to inhibit this target more potently and selectively (Table 3 and Table S4). Among them, divarasib and JDQ433 are on more advanced clinical development. Divarasib (GDC-6036) has been designed to inhibit covalently, selectively, and with more potency KRAS G12C compared to sotorasib and adagrasib [124]. JDQ443 has been designed to overcome resistance mechanisms observed with other KRAS G12C inhibitors since it acts through a novel binding mechanism that forms novel interactions with KRAS under the switch II pocket, irreversibly trapping KRAS in the inactive, GDP-bound state reaching the residue C12 without interfering with residue H95 [125].

3.3. BRAF and MET

The novel encorafenib and binimetinib combination, already approved for BRAF-mutated melanoma, has been investigated in two different phase II trials (ENCO-BRAF, OCEANII) for NSCLC patients. Several trials are experimenting with novel (pan)-RAF inhibitors alone or in combination with MEK, FAK, RAS, or SHP-2 inhibitors in patients with BRAF-V600E solid tumors, including NSCLC refractory to BRAK/MEK-inhibitors or harboring other RAF alterations (BRAF class II and III mutations, RAF gene fusions or amplification) [127] (Table S5).
Despite the development of acquired MET mutations seems to be related to the type of MET-inhibitors, at present, no clinical trial has been designed to investigate the re-sensitiveness of these patients to a novel class of MET TKIs, with the exception of a small phase II trial of capmatinib in crizotinib-resistant NSCLC patients, which showed discouraging results [128]. At the state-of-the-art, only the bifunctional anti-EGFR and MET antibody amivantamab have shown modest activity (ORR 17%) in MET-TKI-resistant patients in the Chrysalis trial [129]. Preliminary results were presented from the phase I SHIELD trial of elzovantinib, a MET, SRC, and CSF1R inhibitor, in 52 patients with MET dysregulated solid tumors, including 30 patients with MET-altered NSCLC (20 MET-ex14 skipping mutations, 8 MET amplified, 2 other MET mutations) [130]. Among the eleven TKI naïve NSCLC patients, the ORR was 36% regardless of dose modifications (Table S6).

3.4. Fusion Genes

Novel 3rd and 4th ALK-TKIs are underway in clinical research. APG-2449 is a novel FAK inhibitor and a third-generation ALK/ROS1-TKI that has shown potent activity towards a range of ALK-resistant mutations and brain penetrant capacity in pre-clinical NSCLC tumor models. An ongoing phase I trial is evaluating patients with second-generation TKIs-resistant ALK/ROS1-positive NSCLC. Preliminary results have shown an ORR of 28.5% among 14 patients with ALK-TKI refractory NSCLC [131]. TPX-0131 and NVL-655 are the 4th generation ALK-Is. The clinical development of TPX-0131 has been withdrawn due to safety issues; meanwhile, phase I/II of NVL-655 is ongoing [132,133] (Table S7). Tables S8 and S9 show the ongoing clinical trials of new ROS1 and NTRK inhibitors (taletrectinib, repotrectinib, NVL-520 among the others for ROS1 and repotrectinib, VMD-928 and XZP-928 for NTRK) with high BBB penetrance and activity towards secondary single or double mutations.
Novel RET inhibitors have been designed to cover acquired resistance mutations while sparing the inhibition of other targets, such as VEGFR2, to augment their therapeutic window (Table 4).

4. Combination Treatments with New Generation TKIs

4.1. EGFR

After the encouraging results of the Japanese phase III trial NEJ009 [140] and phase II OPAL trial [141], the FLAURA-2 trial confirmed the benefit of combining PBC to the third generation TKI osimertinib in 586 treatment naïve EGFR+ NSCLC patients, as the combination led to a PFS improvement in 8 months (HR 0.62) [142]. Table 5 depicts trials of the TKI-CT combination for a selected population of patients (p53 mutant or other tumor suppressor genes, lack of circulating DNA clearance, brain metastases). In the post-TKI setting, the COMPEL phase III trial is investigating the role of adding a TKI to standard second-line chemotherapy in order to prevent CNS progression [143].
Histologic transformation into SCLC has been observed in 3–14% of EGFR+ NSCLC patients treated with first-generation EGFR-TKIs (gefitinib or erlotinib), frequently mediated by p53/RB1 loss of function [144]. An ongoing phase II trial is evaluating the combination of olaparib and durvalumab in this setting (NCT04538378).
Another important line of research is represented by the development of bispecific antibodies. In the CHRYSALIS study (NCT02609776), the combination of amivantamab plus lazertinib was tested in 20 treatment-naïve Asian patients with EGFR-mutant NSCLC, attaining an ORR of 100%. Interestingly, after a median duration of treatment of 33.5 months, median DOR, PFS, and OS have not yet been reached [145].
The phase 3 MARIPOSA study is further investigating the lazertinib/amivantamab combination versus lazertinib or osimertinib alone in 1074 treatment-naïve NSCLC patients with EGFR-common mutations, and positive results have been preliminarily announced [146]. Indeed, in the MARIPOSA2 phase III trial, the combination of amivantamab alone or plus lazertinib with standard PBC has led to a PFS improvement in NSCLC patients harboring common EGFR-mutations after failure of treatment with osimertinib [147].
Among the different TKI-TKI combinations, the major interest is focused on MET inhibition. Alongside the first-line combination of savolitinib plus osimertinib (FLOWERS, NCT05163249; NCT04743505), major efforts are being oriented towards the post-3rd generation TKI setting. Based on the results of preliminary trials with gefitinib plus capmatinib and osimertinib plus savolitinib [148], phase II and III trials have been designed to confirm the efficacy of these combinations [149,150]. Moreover, the ORCHARD trial is a biomarker-directed phase II platform study evaluating the optimal treatment for individual patients with EGFR-mutant NSCLC [151] (Table 5, Table S10).

4.2. Other Driver Gene Mutations

Table S11 summarizes ongoing TKI-based combinations with chemotherapy, antiangiogenics, multitargeted drugs, or immune-modulating agents for NSCLC patients with EGFR or HER2 exon 20 insertion mutations.
Several combinations have been designed and are under development in clinical trials to overcome resistance to KRAS inhibitors (Table S12). Indeed, trials have been designed to investigate the MEK-inhibitors and ICI combinations in solid tumors, BRAF or KRAS mutated NSCLC on the basis of preclinical data and case reports suggesting that MEK inhibition can modulate CTLA-4 expression and potentially increase the efficacy of ICI [152,153] (Table S13).
Few clinical trials are ongoing with TKI-based combinations of drugs (TKI plus MEK-I or ICI plus amivantamab), aiming to overcome the occurrence of resistance to MET inhibitors (Table S14).

4.3. Fusion Genes

Several trials are experimenting with the feasibility of different ALK, ROS1, or RET TKI-based combinations plus different classes of drug: chemotherapy, antiangiogenesis, multi-targeted kinase inhibitors (lenvatinib, crizotinib, apatinib), or selective inhibitors towards different targets (MEK, MET, or SHP-2), ICI, or immunomodulators (Tables S15 and S16).

5. The Issue of Sequencing Treatments with New Generation TKIs

In the dynamic landscape of targeted therapy for driver gene alterations in cancer, the introduction of novel generations of TKIs has ushered in a new era of treatment paradigms. These advancements have conferred delayed resistance, prolonged overall survival, and enhanced CNS penetration compared to their predecessors [20,64,154,155]. This transformative impact has often led to the relocation of these novel agents from later lines of therapy to the front-line treatment setting. While these innovations represent a substantial leap forward in cancer care, they raise a significant and somewhat paradoxical challenge: the potential obsolescence of TKI treatment sequencing and the diminished role of previous TKI generations.
However, this progress comes with its own set of complexities, particularly in terms of toxicity profiles. While the safety and tolerability of these novel agents are generally manageable, they often differ from those of their predecessors, requiring new learning curves for medical oncologists on the management of novel and peculiar adverse events in clinical practice (e.g., cognitive effects with lorlatinib and entrectinib, the management of interstitial lung disease occurring at different rates with different drugs) [59,156].
This strategic shift towards the front-line adoption of novel TKIs raises a critical question regarding the sequencing of TKI treatments. Historically, the sequencing of TKIs was a vital aspect of managing drug resistance and optimizing patient outcomes. Patients who developed resistance to an earlier generation of TKI often had the option to switch to a subsequent generation with a different mechanism of action, thereby extending the duration of disease control [18,33]. However, the ascendancy of novel TKIs as first-line therapies has effectively closed this avenue. With the superior efficacy of these agents, previous generations have become less relevant in the treatment algorithm, relegating them to a historical perspective rather than a therapeutic option. As such, whereas TKI sequencing from first- to novel generations relegated chemotherapy options at the end of the treatment sequence, anticipating novel TKI generations in the front-line setting made the role of the ‘old’ chemotherapy options being revived as a necessary second-line treatment option, outside clinical trials [2].
Nonetheless, this paradigm shift underscores the imperative for continuous innovation and adaptation in oncology as the field continues to evolve to meet the ever-changing needs of patients with driver gene alterations.

6. The Issue of Resistance: Selective Pressure on Resistant Clones

Resistance to cancer therapies is a formidable challenge in the field of medical oncology, and a crucial aspect of this challenge is the selective pressure imposed on resistant clones within heterogeneous tumors [7,157]. Molecular heterogeneity, a pervasive feature of most cancers, lies at the heart of acquired resistance development. Tumors, even when sharing similar clinical characteristics, are composed of a mosaic of molecular clones, each characterized by unique genetic and phenotypic traits [158]. This inherent diversity within tumors provides fertile ground for the emergence of drug-resistant clones, each endowed with specific survival advantages and resistance mechanisms [7]. Particular subgroups referred to as Drug-Tolerant Persister (DTP) cells, have the capacity to endure high-dose treatments [159]. Intriguingly, these sub-clones possess distinctive stem cell markers and can adapt their characteristics in response to therapy-induced selective pressure [159]. DTPs, along with de novo mutations and preexisting resistance mechanisms, are among the potential strategies employed by cancers to evade the pressures exerted by anticancer drugs [157,158].
The consequence of this molecular diversity is that therapeutic interventions, while initially effective against a subset of tumor cells, inadvertently create an environment conducive to the survival and proliferation of drug-resistant clones. The selective pressure imposed by treatments favors the outgrowth of these resistant populations over time, ultimately leading to therapeutic failure [158]. This selective pressure is a dynamic process in which sensitive tumor cells are progressively eliminated, allowing resistant clones to dominate [160].
The role of druggable driver mutations further underscores the complexity of acquired resistance development. In cases where tumors harbor well-defined driver mutations, resistance mechanisms are often intricately linked to these drivers. However, the potency of the therapeutic agent employed can significantly influence the nature of resistance. High-potency drugs, as novel generations of TKIs are, can exert more substantial selective pressure, potentially driving the development of resistance mechanisms that are independent of the drug’s primary target [157,161].
A notable example is observed in the treatment of EGFR-mutant lung cancers, where the use of different generations of tyrosine kinase inhibitors (TKIs) leads to distinct resistance patterns [161]. First-generation TKIs like gefitinib and erlotinib are associated with a high incidence of the p.T790M resistance mutation. In contrast, second-generation TKIs such as afatinib have a reduced incidence of p.T790M mutations, while third-generation TKIs like osimertinib exhibit even lower rates of EGFR-dependent resistance mechanisms [23,162]. Instead, under the selective pressure of more potent drugs like osimertinib, alternative resistance mechanisms such as MET amplification can become prevalent [163]. Similarly, the different structure and potency among first-, second-, and third-generation ALK TKIs lead to a different selection of resistance mutations [164,165]. In addition, the sequential use of subsequent generations of TKIs may lead to the emergence of compound resistance patterns [166].
Indeed, under the selective pressure of more potent compounds, as novel generations of TKIs, resistant clones emerge, harboring more complex and hard-to-target resistance mechanisms [7,167]. Understanding the interplay between selective pressure, molecular heterogeneity drug potency, binding affinity, and structure is critical for devising effective strategies to overcome drug resistance and improve treatment outcomes in cancer patients.

7. Conclusions and Future Directions

From the humble beginnings of the first-generation TKIs, exemplified by erlotinib and gefitinib in EGFR-mutant disease, to the cutting-edge third-generation agents such as osimertinib and extending the application of TKI treatment to other oncogene-driven diseases, we have witnessed a remarkable transformation in the therapeutic landscape of NSCLC [168]. These targeted therapies have not only prolonged the lives of countless patients but have also provided a blueprint for precision medicine in oncology.
As we conclude our exploration of the strengths and limitations of novel generations of TKIs in NSCLC, it is evident that these agents have significantly improved disease control and survival rates among patients harboring specific genetic alterations. However, it is equally clear that challenges persist, and there is much work yet to be done to optimize their use and expand treatment options. One notable limitation is the development of resistance mechanisms, which underscores the need for ongoing research into novel therapeutic strategies.
One promising avenue lies in the realm of Antibody-Drug Conjugates (ADCs). These innovative biopharmaceuticals combine the specificity of monoclonal antibodies with the cytotoxic potency of chemotherapy drugs (payload), offering a new approach to target oncogenic pathways in NSCLC [169]. ADCs have the potential to overcome some of the limitations of TKI therapy, particularly in cases of resistance and heterogeneous tumor populations. To date, different ADCs are being investigated in driver-mutant NSCLCs after the failure of standard TKI treatment [170]. In a future perspective, these agents can be designed to target specific driver mutations, either by direct antibodies or even using TKIs as pharmaceutical components (as payload or instead of monoclonal antibody) of the ADCs, providing a level of precision therapy that was previously unthinkable [169].
In addition, combination treatments represent another potential strategy. The intricate biology of NSCLC, characterized by the crosstalk between multiple signaling pathways, necessitates a multifaceted approach to therapy. Combinations of TKIs with chemotherapy agents as recently demonstrated in the FLAURA-2 trial with osimertinib plus platinum-doublet, have shown promise in enhancing antitumor responses and delaying the emergence of resistance [142]. Furthermore, rational combinations of TKIs with other targeted therapies, such as MET inhibitors [171], are being actively investigated to address resistance mechanisms and broaden the scope of effective treatment options.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/cancers15205079/s1, Table S1. 4th generation EGFR TKIs properties compared to those of Osimertinib; Table S2. Summary of EGFR Ex20ins TKi inhibitors; Table S3. Summary of HER2ex20 ins TKIs; Table S4. Ongoing clinical trials of RAS inhibitors; Table S5. Ongoing clinical trials of RAF inhibitors; Table S6. Ongoing clinical trials of novel MET inhibitors in MET dysregulated NSCLC or solid tumors; Table S7. Ongoing clinical trials of novel ALK TKIs; Table S8. Ongoing clinical trials of novel ROS1 TKIs; Table S9. Ongoing clinical trials of novel NTRK inhibitors; Table S10. Ongoing clinical trials of novel RET TKIs; Table S11. Ongoing trials of TKI-based combinations in EGFR or HER2 Exon 20 insertions; Table S12. Ongoing clinical trials of KRAS inhibitor-based combinations; Table S13. ICI-TKI based combinations in BRAF mutated NSCLC patients; Table S14. Ongoing clinical trials of TKI-based combination in MET dysregulated NSCLC patients; Table S15. Ongoing clinical trials of TKI-based in ALK+ or ROS1+ NSCLC patients; Table S16. Ongoing combinations in RET+ NSCLC.

Author Contributions

Conceptualization, I.A. and A.P.; methodology, I.A., C.C. and G.S.; data curation, I.A., C.C. and G.S.; writing—original draft preparation, I.A., C.C. and G.S.; writing—review and editing, I.A., C.C., G.S., E.D.S., P.T.A. and A.P.; visualization, I.A.; supervision, A.P. and F.d.M.; All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Acknowledgments

This work was partially supported by the Italian Ministry of Health with “Ricerca Corrente” and “5 × 1000” funds.

Conflicts of Interest

A. P. reports personal fees as speaker bureau or advisor for AstraZeneca, Agilent/Dako, Boehringer Ingelheim, Bristol-Myers Squibb, Eli-Lilly, Merck Sharp and Dohme, Janssen, Novartis, Pfizer and Roche Genentech, outside the submitted work; U. Malapelle has received personal fees, as consultant and/or speaker bureau, from Boehringer Ingelheim, Roche, MSD, Amgen, Thermo Fisher Scientific, Eli Lilly, Diaceutics, GSK, Merck and AstraZeneca, unrelated to the current work. F.d.M. received honoraria or consulting fees from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Merck Sharp and Dohme, Pfizer, Novartis, Takeda, Xcovery, and Roche. The other authors declare no conflict of interest.

References

  1. Siegel, R.L.; Miller, K.D.; Wagle, N.S.; Jemal, A. Cancer statistics, 2023. CA Cancer J. Clin. 2023, 73, 17–48. [Google Scholar] [CrossRef] [PubMed]
  2. Hendriks, L.E.; Kerr, K.M.; Menis, J.; Mok, T.S.; Nestle, U.; Passaro, A.; Peters, S.; Planchard, D.; Smit, E.F.; Solomon, B.J.; et al. Oncogene-addicted metastatic non-small-cell lung cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann. Oncol. 2023, 34, 339–357. [Google Scholar] [CrossRef] [PubMed]
  3. Pottier, C.; Fresnais, M.; Gilon, M.; Jérusalem, G.; Longuespée, R.; Sounni, N.E. Tyrosine Kinase Inhibitors in Cancer: Breakthrough and Challenges of Targeted Therapy. Cancers 2020, 12, 731. [Google Scholar] [CrossRef] [PubMed]
  4. Mok, T.S.; Wu, Y.-L.; Thongprasert, S.; Yang, C.-H.; Chu, D.-T.; Saijo, N.; Sunpaweravong, P.; Han, B.; Margono, B.; Ichinose, Y.; et al. Gefitinib or Carboplatin–Paclitaxel in Pulmonary Adenocarcinoma. N. Engl. J. Med. 2009, 361, 947–957. [Google Scholar] [CrossRef] [PubMed]
  5. Attili, I.; Karachaliou, N.; Conte, P.; Bonanno, L.; Rosell, R. Therapeutic approaches for T790M mutation positive non-small-cell lung cancer. Expert Rev. Anticancer Ther. 2018, 18, 1021–1030. [Google Scholar] [CrossRef]
  6. Herrera-Juárez, M.; Serrano-Gómez, C.; Bote-de-Cabo, H.; Paz-Ares, L. Targeted therapy for lung cancer: Beyond EGFR and ALK. Cancer 2023, 129, 1803–1820. [Google Scholar] [CrossRef]
  7. Attili, I.; Del Re, M.; Guerini-Rocco, E.; Crucitta, S.; Pisapia, P.; Pepe, F.; Barberis, M.; Troncone, G.; Danesi, R.; de Marinis, F.; et al. The role of molecular heterogeneity targeting resistance mechanisms to lung cancer therapies. Expert Rev. Mol. Diagn. 2021, 21, 757–766. [Google Scholar] [CrossRef]
  8. Ullah, A.; Leong, S.W.; Wang, J.; Wu, Q.; Ghauri, M.A.; Sarwar, A.; Su, Q.; Zhang, Y. Cephalomannine inhibits hypoxia-induced cellular function via the suppression of APEX1/HIF-1α interaction in lung cancer. Cell Death Dis. 2021, 12, 490. [Google Scholar] [CrossRef]
  9. Gerritse, S.L.; Labots, M.; ter Heine, R.; Dekker, H.; Poel, D.; Tauriello, D.V.F.; Nagtegaal, I.D.; Van Den Hombergh, E.; Van Erp, N.; Verheul, H.M.W. High-Dose Intermittent Treatment with the Multikinase Inhibitor Sunitinib Leads to High Intra-Tumor Drug Exposure in Patients with Advanced Solid Tumors. Cancers 2022, 14, 6061. [Google Scholar] [CrossRef]
  10. Moes-Sosnowska, J.; Szpechcinski, A.; Chorostowska-Wynimko, J. Clinical significance of TP53 alterations in advanced NSCLC patients treated with EGFR, ALK and ROS1 tyrosine kinase inhibitors: An update. Tumour Biol. 2023; preprint. [Google Scholar] [CrossRef]
  11. Sequist, L.V.; Yang, J.C.; Yamamoto, N.; O’Byrne, K.; Hirsh, V.; Mok, T.; Geater, S.L.; Orlov, S.; Tsai, C.M.; Boyer, M.; et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 2013, 31, 3327–3334. [Google Scholar] [CrossRef] [PubMed]
  12. Wu, Y.L.; Zhou, C.; Hu, C.P.; Feng, J.; Lu, S.; Huang, Y.; Li, W.; Hou, M.; Shi, J.H.; Lee, K.Y.; et al. Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with advanced non-small-cell lung cancer harbouring EGFR mutations (LUX-Lung 6): An open-label, randomised phase 3 trial. Lancet Oncol. 2014, 15, 213–222. [Google Scholar] [CrossRef]
  13. Yang, J.C.; Wu, Y.L.; Schuler, M.; Sebastian, M.; Popat, S.; Yamamoto, N.; Zhou, C.; Hu, C.P.; O’Byrne, K.; Feng, J.; et al. Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-Lung 3 and LUX-Lung 6): Analysis of overall survival data from two randomised, phase 3 trials. Lancet Oncol. 2015, 16, 141–151. [Google Scholar] [CrossRef] [PubMed]
  14. Paz-Ares, L.; Tan, E.H.; O’Byrne, K.; Zhang, L.; Hirsh, V.; Boyer, M.; Yang, J.C.; Mok, T.; Lee, K.H.; Lu, S.; et al. Afatinib versus gefitinib in patients with EGFR mutation-positive advanced non-small-cell lung cancer: Overall survival data from the phase IIb LUX-Lung 7 trial. Ann. Oncol. 2017, 28, 270–277. [Google Scholar] [CrossRef] [PubMed]
  15. Mok, T.S.; Cheng, Y.; Zhou, X.; Lee, K.H.; Nakagawa, K.; Niho, S.; Lee, M.; Linke, R.; Rosell, R.; Corral, J.; et al. Improvement in Overall Survival in a Randomized Study That Compared Dacomitinib with Gefitinib in Patients with Advanced Non-Small-Cell Lung Cancer and EGFR-Activating Mutations. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 2018, 36, 2244–2250. [Google Scholar] [CrossRef] [PubMed]
  16. Mok, T.S.; Cheng, Y.; Zhou, X.; Lee, K.H.; Nakagawa, K.; Niho, S.; Chawla, A.; Rosell, R.; Corral, J.; Migliorino, M.R.; et al. Updated Overall Survival in a Randomized Study Comparing Dacomitinib with Gefitinib as First-Line Treatment in Patients with Advanced Non-Small-Cell Lung Cancer and EGFR-Activating Mutations. Drugs 2021, 81, 257–266. [Google Scholar] [CrossRef] [PubMed]
  17. Yang, J.C.; Sequist, L.V.; Geater, S.L.; Tsai, C.M.; Mok, T.S.; Schuler, M.; Yamamoto, N.; Yu, C.J.; Ou, S.H.; Zhou, C.; et al. Clinical activity of afatinib in patients with advanced non-small-cell lung cancer harbouring uncommon EGFR mutations: A combined post-hoc analysis of LUX-Lung 2, LUX-Lung 3, and LUX-Lung 6. Lancet Oncol. 2015, 16, 830–838. [Google Scholar] [CrossRef]
  18. Mok, T.S.; Wu, Y.L.; Ahn, M.J.; Garassino, M.C.; Kim, H.R.; Ramalingam, S.S.; Shepherd, F.A.; He, Y.; Akamatsu, H.; Theelen, W.S.; et al. Osimertinib or Platinum-Pemetrexed in EGFR T790M-Positive Lung Cancer. N. Engl. J. Med. 2017, 376, 629–640. [Google Scholar] [CrossRef]
  19. Papadimitrakopoulou, V.A.; Mok, T.S.; Han, J.Y.; Ahn, M.J.; Delmonte, A.; Ramalingam, S.S.; Kim, S.W.; Shepherd, F.A.; Laskin, J.; He, Y.; et al. Osimertinib versus platinum-pemetrexed for patients with EGFR T790M advanced NSCLC and progression on a prior EGFR-tyrosine kinase inhibitor: AURA3 overall survival analysis. Ann. Oncol. 2020, 31, 1536–1544. [Google Scholar] [CrossRef]
  20. Soria, J.C.; Ohe, Y.; Vansteenkiste, J.; Reungwetwattana, T.; Chewaskulyong, B.; Lee, K.H.; Dechaphunkul, A.; Imamura, F.; Nogami, N.; Kurata, T.; et al. Osimertinib in Untreated EGFR-Mutated Advanced Non-Small-Cell Lung Cancer. N. Engl. J. Med. 2018, 378, 113–125. [Google Scholar] [CrossRef]
  21. Ramalingam, S.S.; Vansteenkiste, J.; Planchard, D.; Cho, B.C.; Gray, J.E.; Ohe, Y.; Zhou, C.; Reungwetwattana, T.; Cheng, Y.; Chewaskulyong, B.; et al. Overall Survival with Osimertinib in Untreated, EGFR-Mutated Advanced NSCLC. N. Engl. J. Med. 2020, 382, 41–50. [Google Scholar] [CrossRef]
  22. Thress, K.S.; Paweletz, C.P.; Felip, E.; Cho, B.C.; Stetson, D.; Dougherty, B.; Lai, Z.; Markovets, A.; Vivancos, A.; Kuang, Y.; et al. Acquired EGFR C797S mutation mediates resistance to AZD9291 in non-small cell lung cancer harboring EGFR T790M. Nat. Med. 2015, 21, 560–562. [Google Scholar] [CrossRef] [PubMed]
  23. Passaro, A.; Jänne, P.A.; Mok, T.; Peters, S. Overcoming therapy resistance in EGFR-mutant lung cancer. Nat. Cancer 2021, 2, 377–391. [Google Scholar] [CrossRef] [PubMed]
  24. Riely, G.J.; Neal, J.W.; Camidge, D.R.; Spira, A.I.; Piotrowska, Z.; Costa, D.B.; Tsao, A.S.; Patel, J.D.; Gadgeel, S.M.; Bazhenova, L.; et al. Activity and Safety of Mobocertinib (TAK-788) in Previously Treated Non-Small Cell Lung Cancer with EGFR Exon 20 Insertion Mutations from a Phase I/II Trial. Cancer Discov. 2021, 11, 1688–1699. [Google Scholar] [CrossRef] [PubMed]
  25. Zhou, C.; Ramalingam, S.S.; Kim, T.M.; Kim, S.W.; Yang, J.C.; Riely, G.J.; Mekhail, T.; Nguyen, D.; Garcia Campelo, M.R.; Felip, E.; et al. Treatment Outcomes and Safety of Mobocertinib in Platinum-Pretreated Patients with EGFR Exon 20 Insertion-Positive Metastatic Non-Small Cell Lung Cancer: A Phase 1/2 Open-label Nonrandomized Clinical Trial. JAMA Oncol. 2021, 7, e214761. [Google Scholar] [CrossRef]
  26. Takeda’s Exkivity Sputters in Lung Cancer Trial, with Accelerated Approval on the Line. Available online: https://www.fiercepharma.com/pharma/takedas-exkivity-sputters-lung-cancer-trial-accelerated-approval-and-jj-rivalry-line (accessed on 1 October 2023).
  27. Treatment with RYBREVANT® (amivantamab-vmjw) Plus Chemotherapy Resulted in Statistically Significant and Clinically Meaningful Improvement in Progression-Free Survival in Patients with Newly Diagnosed EGFR Exon 20 Insertion Mutation-Positive Non-Small Cell Lung Cancer. Available online: https://www.jnj.com/treatment-with-rybrevant-amivantamab-vmjw-plus-chemotherapy-resulted-in-statistically-significant-and-clinically-meaningful-improvement-in-progression-free-survival-in-patients-with-newly-diagnosed-egfr-exon-20-insertion-mutation-positive-non-small-cell-lung-cancer (accessed on 1 October 2023).
  28. Neal, J.; Doebele, R.; Riely, G.; Spira, A.; Horn, L.; Piotrowska, Z.; Costa, D.; Zhang, S.; Bottino, D.; Zhu, J.; et al. P1.13-44 Safety, PK, and Preliminary Antitumor Activity of the Oral EGFR/HER2 Exon 20 Inhibitor TAK-788 in NSCLC. J. Thorac. Oncol. 2018, 13, S599. [Google Scholar] [CrossRef]
  29. Zhou, C.; Li, X.; Wang, Q.; Gao, G.; Zhang, Y.; Chen, J.; Shu, Y.; Hu, Y.; Fan, Y.; Fang, J.; et al. Pyrotinib in HER2-Mutant Advanced Lung Adenocarcinoma After Platinum-Based Chemotherapy: A Multicenter, Open-Label, Single-Arm, Phase II Study. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 2020, 38, 2753–2761. [Google Scholar] [CrossRef]
  30. Le, X.; Cornelissen, R.; Garassino, M.; Clarke, J.M.; Tchekmedyian, N.; Goldman, J.W.; Leu, S.Y.; Bhat, G.; Lebel, F.; Heymach, J.V.; et al. Poziotinib in Non-Small-Cell Lung Cancer Harboring HER2 Exon 20 Insertion Mutations After Prior Therapies: ZENITH20-2 Trial. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 2022, 40, 710–718. [Google Scholar] [CrossRef]
  31. Li, B.T.; Smit, E.F.; Goto, Y.; Nakagawa, K.; Udagawa, H.; Mazières, J.; Nagasaka, M.; Bazhenova, L.; Saltos, A.N.; Felip, E.; et al. Trastuzumab Deruxtecan in HER2-Mutant Non-Small-Cell Lung Cancer. N. Engl. J. Med. 2022, 386, 241–251. [Google Scholar] [CrossRef]
  32. Shaw, A.T.; Kim, D.W.; Nakagawa, K.; Seto, T.; Crinó, L.; Ahn, M.J.; De Pas, T.; Besse, B.; Solomon, B.J.; Blackhall, F.; et al. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N. Engl. J. Med. 2013, 368, 2385–2394. [Google Scholar] [CrossRef]
  33. Novello, S.; Mazières, J.; Oh, I.J.; de Castro, J.; Migliorino, M.R.; Helland, Å.; Dziadziuszko, R.; Griesinger, F.; Kotb, A.; Zeaiter, A.; et al. Alectinib versus chemotherapy in crizotinib-pretreated anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer: Results from the phase III ALUR study. Ann. Oncol. 2018, 29, 1409–1416. [Google Scholar] [CrossRef] [PubMed]
  34. Peters, S.; Camidge, D.R.; Shaw, A.T.; Gadgeel, S.; Ahn, J.S.; Kim, D.-W.; Ou, S.-H.I.; Pérol, M.; Dziadziuszko, R.; Rosell, R.; et al. Alectinib versus Crizotinib in Untreated ALK-Positive Non–Small-Cell Lung Cancer. N. Engl. J. Med. 2017, 377, 829–838. [Google Scholar] [CrossRef] [PubMed]
  35. Mok, T.; Camidge, D.R.; Gadgeel, S.M.; Rosell, R.; Dziadziuszko, R.; Kim, D.W.; Pérol, M.; Ou, S.I.; Ahn, J.S.; Shaw, A.T.; et al. Updated overall survival and final progression-free survival data for patients with treatment-naive advanced ALK-positive non-small-cell lung cancer in the ALEX study. Ann. Oncol. 2020, 31, 1056–1064. [Google Scholar] [CrossRef] [PubMed]
  36. Camidge, D.R.; Kim, H.R.; Ahn, M.J.; Yang, J.C.H.; Han, J.Y.; Hochmair, M.J.; Lee, K.H.; Delmonte, A.; Garcia Campelo, M.R.; Kim, D.W.; et al. Brigatinib Versus Crizotinib in ALK Inhibitor-Naive Advanced ALK-Positive NSCLC: Final Results of Phase 3 ALTA-1L Trial. J. Thorac. Oncol. 2021, 16, 2091–2108. [Google Scholar] [CrossRef] [PubMed]
  37. Shaw, A.T.; Bauer, T.M.; de Marinis, F.; Felip, E.; Goto, Y.; Liu, G.; Mazieres, J.; Kim, D.W.; Mok, T.; Polli, A.; et al. First-Line Lorlatinib or Crizotinib in Advanced ALK-Positive Lung Cancer. N. Engl. J. Med. 2020, 383, 2018–2029. [Google Scholar] [CrossRef] [PubMed]
  38. Solomon, B.J.; Bauer, T.M.; Mok, T.S.K.; Liu, G.; Mazieres, J.; de Marinis, F.; Goto, Y.; Kim, D.W.; Wu, Y.L.; Jassem, J.; et al. Efficacy and safety of first-line lorlatinib versus crizotinib in patients with advanced, ALK-positive non-small-cell lung cancer: Updated analysis of data from the phase 3, randomised, open-label CROWN study. Lancet Respir. Med. 2023, 11, 354–366. [Google Scholar] [CrossRef]
  39. Shaw, A.T.; Friboulet, L.; Leshchiner, I.; Gainor, J.F.; Bergqvist, S.; Brooun, A.; Burke, B.J.; Deng, Y.L.; Liu, W.; Dardaei, L.; et al. Resensitization to Crizotinib by the Lorlatinib ALK Resistance Mutation L1198F. N. Engl. J. Med. 2016, 374, 54–61. [Google Scholar] [CrossRef]
  40. Shaw, A.T.; Ou, S.H.; Bang, Y.J.; Camidge, D.R.; Solomon, B.J.; Salgia, R.; Riely, G.J.; Varella-Garcia, M.; Shapiro, G.I.; Costa, D.B.; et al. Crizotinib in ROS1-rearranged non-small-cell lung cancer. N. Engl. J. Med. 2014, 371, 1963–1971. [Google Scholar] [CrossRef]
  41. Gainor, J.F.; Tseng, D.; Yoda, S.; Dagogo-Jack, I.; Friboulet, L.; Lin, J.J.; Hubbeling, H.G.; Dardaei, L.; Farago, A.F.; Schultz, K.R.; et al. Patterns of Metastatic Spread and Mechanisms of Resistance to Crizotinib in ROS1-Positive Non-Small-Cell Lung Cancer. JCO Precis. Oncol. 2017, 1, 1–13. [Google Scholar] [CrossRef]
  42. Shaw, A.T.; Solomon, B.J.; Chiari, R.; Riely, G.J.; Besse, B.; Soo, R.A.; Kao, S.; Lin, C.C.; Bauer, T.M.; Clancy, J.S.; et al. Lorlatinib in advanced ROS1-positive non-small-cell lung cancer: A multicentre, open-label, single-arm, phase 1-2 trial. Lancet Oncol. 2019, 20, 1691–1701. [Google Scholar] [CrossRef]
  43. Drilon, A.; Siena, S.; Dziadziuszko, R.; Barlesi, F.; Krebs, M.G.; Shaw, A.T.; de Braud, F.; Rolfo, C.; Ahn, M.J.; Wolf, J.; et al. Entrectinib in ROS1 fusion-positive non-small-cell lung cancer: Integrated analysis of three phase 1-2 trials. Lancet Oncol. 2020, 21, 261–270. [Google Scholar] [CrossRef] [PubMed]
  44. Dziadziuszko, R.; Krebs, M.G.; De Braud, F.; Siena, S.; Drilon, A.; Doebele, R.C.; Patel, M.R.; Cho, B.C.; Liu, S.V.; Ahn, M.J.; et al. Updated Integrated Analysis of the Efficacy and Safety of Entrectinib in Locally Advanced or Metastatic ROS1 Fusion-Positive Non-Small-Cell Lung Cancer. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 2021, 39, 1253–1263. [Google Scholar] [CrossRef] [PubMed]
  45. de Langen, A.J.; Johnson, M.L.; Mazieres, J.; Dingemans, A.-M.C.; Mountzios, G.; Pless, M.; Wolf, J.; Schuler, M.; Lena, H.; Skoulidis, F.; et al. Sotorasib versus docetaxel for previously treated non-small-cell lung cancer with KRASG12C mutation: A randomised, open-label, phase 3 trial. Lancet 2023, 401, 733–746. [Google Scholar] [CrossRef] [PubMed]
  46. Ou, S.I.; Jänne, P.A.; Leal, T.A.; Rybkin, I.I.; Sabari, J.K.; Barve, M.A.; Bazhenova, L.; Johnson, M.L.; Velastegui, K.L.; Cilliers, C.; et al. First-in-Human Phase I/IB Dose-Finding Study of Adagrasib (MRTX849) in Patients with Advanced KRAS(G12C) Solid Tumors (KRYSTAL-1). J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 2022, 40, 2530–2538. [Google Scholar] [CrossRef]
  47. Jänne, P.A.; Riely, G.J.; Gadgeel, S.M.; Heist, R.S.; Ou, S.I.; Pacheco, J.M.; Johnson, M.L.; Sabari, J.K.; Leventakos, K.; Yau, E.; et al. Adagrasib in Non-Small-Cell Lung Cancer Harboring a KRAS(G12C) Mutation. N. Engl. J. Med. 2022, 387, 120–131. [Google Scholar] [CrossRef] [PubMed]
  48. Drilon, A.; Clark, J.W.; Weiss, J.; Ou, S.I.; Camidge, D.R.; Solomon, B.J.; Otterson, G.A.; Villaruz, L.C.; Riely, G.J.; Heist, R.S.; et al. Antitumor activity of crizotinib in lung cancers harboring a MET exon 14 alteration. Nat. Med. 2020, 26, 47–51. [Google Scholar] [CrossRef]
  49. Wolf, J.; Seto, T.; Han, J.Y.; Reguart, N.; Garon, E.B.; Groen, H.J.M.; Tan, D.S.W.; Hida, T.; de Jonge, M.; Orlov, S.V.; et al. Capmatinib in MET Exon 14-Mutated or MET-Amplified Non-Small-Cell Lung Cancer. N. Engl. J. Med. 2020, 383, 944–957. [Google Scholar] [CrossRef]
  50. Paik, P.K.; Felip, E.; Veillon, R.; Sakai, H.; Cortot, A.B.; Garassino, M.C.; Mazieres, J.; Viteri, S.; Senellart, H.; Van Meerbeeck, J.; et al. Tepotinib in Non-Small-Cell Lung Cancer with MET Exon 14 Skipping Mutations. N. Engl. J. Med. 2020, 383, 931–943. [Google Scholar] [CrossRef]
  51. Lu, S.; Fang, J.; Li, X.; Cao, L.; Zhou, J.; Guo, Q.; Liang, Z.; Cheng, Y.; Jiang, L.; Yang, N.; et al. Once-daily savolitinib in Chinese patients with pulmonary sarcomatoid carcinomas and other non-small-cell lung cancers harbouring MET exon 14 skipping alterations: A multicentre, single-arm, open-label, phase 2 study. Lancet Respir. Med. 2021, 9, 1154–1164. [Google Scholar] [CrossRef]
  52. Drilon, A.; Oxnard, G.R.; Tan, D.S.W.; Loong, H.H.F.; Johnson, M.; Gainor, J.; McCoach, C.E.; Gautschi, O.; Besse, B.; Cho, B.C.; et al. Efficacy of Selpercatinib in RET Fusion-Positive Non-Small-Cell Lung Cancer. N. Engl. J. Med. 2020, 383, 813–824. [Google Scholar] [CrossRef]
  53. Subbiah, V.; Velcheti, V.; Tuch, B.B.; Ebata, K.; Busaidy, N.L.; Cabanillas, M.E.; Wirth, L.J.; Stock, S.; Smith, S.; Lauriault, V.; et al. Selective RET kinase inhibition for patients with RET-altered cancers. Ann. Oncol. 2018, 29, 1869–1876. [Google Scholar] [CrossRef]
  54. Drilon, A.; Subbiah, V.; Gautschi, O.; Tomasini, P.; de Braud, F.; Solomon, B.J.; Shao-Weng Tan, D.; Alonso, G.; Wolf, J.; Park, K.; et al. Selpercatinib in Patients with RET Fusion-Positive Non-Small-Cell Lung Cancer: Updated Safety and Efficacy from the Registrational LIBRETTO-001 Phase I/II Trial. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 2023, 41, 385–394. [Google Scholar] [CrossRef]
  55. Griesinger, F.; Curigliano, G.; Thomas, M.; Subbiah, V.; Baik, C.S.; Tan, D.S.W.; Lee, D.H.; Misch, D.; Garralda, E.; Kim, D.W.; et al. Safety and efficacy of pralsetinib in RET fusion-positive non-small-cell lung cancer including as first-line therapy: Update from the ARROW trial. Ann. Oncol. 2022, 33, 1168–1178. [Google Scholar] [CrossRef] [PubMed]
  56. Planchard, D.; Besse, B.; Groen, H.J.M.; Hashemi, S.M.S.; Mazieres, J.; Kim, T.M.; Quoix, E.; Souquet, P.J.; Barlesi, F.; Baik, C.; et al. Phase 2 Study of Dabrafenib Plus Trametinib in Patients with BRAF V600E-Mutant Metastatic NSCLC: Updated 5-Year Survival Rates and Genomic Analysis. J. Thorac. Oncol. 2022, 17, 103–115. [Google Scholar] [CrossRef] [PubMed]
  57. Riely, G.J.; Smit, E.F.; Ahn, M.J.; Felip, E.; Ramalingam, S.S.; Tsao, A.; Johnson, M.; Gelsomino, F.; Esper, R.; Nadal, E.; et al. Phase II, Open-Label Study of Encorafenib Plus Binimetinib in Patients with BRAF(V600)-Mutant Metastatic Non-Small-Cell Lung Cancer. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 2023, 41, 3700–3711. [Google Scholar] [CrossRef] [PubMed]
  58. Drilon, A.; Tan, D.S.W.; Lassen, U.N.; Leyvraz, S.; Liu, Y.; Patel, J.D.; Rosen, L.; Solomon, B.; Norenberg, R.; Dima, L.; et al. Efficacy and Safety of Larotrectinib in Patients with Tropomyosin Receptor Kinase Fusion-Positive Lung Cancers. JCO Precis. Oncol. 2022, 6, e2100418. [Google Scholar] [CrossRef]
  59. Demetri, G.D.; De Braud, F.; Drilon, A.; Siena, S.; Patel, M.R.; Cho, B.C.; Liu, S.V.; Ahn, M.J.; Chiu, C.H.; Lin, J.J.; et al. Updated Integrated Analysis of the Efficacy and Safety of Entrectinib in Patients with NTRK Fusion-Positive Solid Tumors. Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res. 2022, 28, 1302–1312. [Google Scholar] [CrossRef]
  60. Doebele, R.C.; Drilon, A.; Paz-Ares, L.; Siena, S.; Shaw, A.T.; Farago, A.F.; Blakely, C.M.; Seto, T.; Cho, B.C.; Tosi, D.; et al. Entrectinib in patients with advanced or metastatic NTRK fusion-positive solid tumours: Integrated analysis of three phase 1–2 trials. Lancet Oncol. 2020, 21, 271–282. [Google Scholar] [CrossRef]
  61. Park, K.; Tan, E.H.; O’Byrne, K.; Zhang, L.; Boyer, M.; Mok, T.; Hirsh, V.; Yang, J.C.; Lee, K.H.; Lu, S.; et al. Afatinib versus gefitinib as first-line treatment of patients with EGFR mutation-positive non-small-cell lung cancer (LUX-Lung 7): A phase 2B, open-label, randomised controlled trial. Lancet Oncol. 2016, 17, 577–589. [Google Scholar] [CrossRef]
  62. Reungwetwattana, T.; Nakagawa, K.; Cho, B.C.; Cobo, M.; Cho, E.K.; Bertolini, A.; Bohnet, S.; Zhou, C.; Lee, K.H.; Nogami, N.; et al. CNS Response to Osimertinib Versus Standard Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Patients with Untreated EGFR-Mutated Advanced Non-Small-Cell Lung Cancer. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 2018, 36, 3290–3297. [Google Scholar] [CrossRef]
  63. Soria, J.C.; Tan, D.S.W.; Chiari, R.; Wu, Y.L.; Paz-Ares, L.; Wolf, J.; Geater, S.L.; Orlov, S.; Cortinovis, D.; Yu, C.J.; et al. First-line ceritinib versus platinum-based chemotherapy in advanced ALK-rearranged non-small-cell lung cancer (ASCEND-4): A randomised, open-label, phase 3 study. Lancet 2017, 389, 917–929. [Google Scholar] [CrossRef] [PubMed]
  64. Solomon, B.J.; Bauer, T.M.; Ignatius Ou, S.H.; Liu, G.; Hayashi, H.; Bearz, A.; Penkov, K.; Wu, Y.L.; Arrieta, O.; Jassem, J.; et al. Post Hoc Analysis of Lorlatinib Intracranial Efficacy and Safety in Patients with ALK-Positive Advanced Non-Small-Cell Lung Cancer from the Phase III CROWN Study. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 2022, 40, 3593–3602. [Google Scholar] [CrossRef]
  65. Thomas, M.; Garassino, M.; Felip, E.; Sakai, H.; Le, X.; Veillon, R.; Smit, E.; Mazieres, J.; Cortot, A.; Raskin, J.; et al. OA03.05 Tepotinib in Patients with MET Exon 14 (METex14) Skipping NSCLC: Primary Analysis of the Confirmatory VISION Cohort C. J. Thorac. Oncol. 2022, 17, S9–S10. [Google Scholar] [CrossRef]
  66. Wolf, J.; Garon, E.B.; Groen, H.J.M.; Tan, D.S.-W.; Robeva, A.; Mouhaer, S.L.; Carbini, M.; Chassot-Agostinho, A.; Heist, R.S. Capmatinib in MET exon 14-mutated, advanced NSCLC: Updated results from the GEOMETRY mono-1 study. J. Clin. Oncol. 2021, 39, 9020. [Google Scholar] [CrossRef]
  67. Vansteenkiste, J.F.; Smit, E.F.; Groen, H.J.M.; Garon, E.B.; Heist, R.S.; Hida, T.; Nishio, M.; Kokowski, K.; Grohe, C.; Reguart, N.; et al. 1285P Capmatinib in patients with METex14-mutated advanced non-small cell lung cancer who received prior immunotherapy: The phase II GEOMETRY mono-1 study. Ann. Oncol. 2020, 31, S830. [Google Scholar] [CrossRef]
  68. Garon, E.B.; Heist, R.S.; Seto, T.; Han, J.-Y.; Reguart, N.; Groen, H.J.; Tan, D.S.; Hida, T.; de Jonge, M.J.; Orlov, S.V.; et al. Abstract CT082: Capmatinib in METex14-mutated (mut) advanced non-small cell lung cancer (NSCLC): Results from the phase II GEOMETRY mono-1 study, including efficacy in patients (pts) with brain metastases (BM). Cancer Res. 2020, 80, CT082. [Google Scholar] [CrossRef]
  69. Skoulidis, F.; Li, B.T.; Dy, G.K.; Price, T.J.; Falchook, G.S.; Wolf, J.; Italiano, A.; Schuler, M.; Borghaei, H.; Barlesi, F.; et al. Sotorasib for Lung Cancers with KRAS p.G12C Mutation. N. Engl. J. Med. 2021, 384, 2371–2381. [Google Scholar] [CrossRef]
  70. Negrao, M.V.; Spira, A.I.; Heist, R.S.; Jänne, P.A.; Pacheco, J.M.; Weiss, J.; Gadgeel, S.M.; Velastegui, K.; Yang, W.; Der-Torossian, H.; et al. Intracranial Efficacy of Adagrasib in Patients from the KRYSTAL-1 Trial with KRASG12C–Mutated Non–Small-Cell Lung Cancer Who Have Untreated CNS Metastases. J. Clin. Oncol. 2023, 41, 4472–4477. [Google Scholar] [CrossRef]
  71. Subbiah, V.; Gainor, J.F.; Oxnard, G.R.; Tan, D.S.W.; Owen, D.H.; Cho, B.C.; Loong, H.H.; McCoach, C.E.; Weiss, J.; Kim, Y.J.; et al. Intracranial Efficacy of Selpercatinib in RET Fusion-Positive Non-Small Cell Lung Cancers on the LIBRETTO-001 Trial. Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res. 2021, 27, 4160–4167. [Google Scholar] [CrossRef]
  72. Zeng, Y.D.; Liao, H.; Qin, T.; Zhang, L.; Wei, W.D.; Liang, J.Z.; Xu, F.; Dinglin, X.X.; Ma, S.X.; Chen, L.K. Blood-brain barrier permeability of gefitinib in patients with brain metastases from non-small-cell lung cancer before and during whole brain radiation therapy. Oncotarget 2015, 6, 8366–8376. [Google Scholar] [CrossRef]
  73. Deng, Y.; Feng, W.; Wu, J.; Chen, Z.; Tang, Y.; Zhang, H.; Liang, J.; Xian, H.; Zhang, S. The concentration of erlotinib in the cerebrospinal fluid of patients with brain metastasis from non-small-cell lung cancer. Mol. Clin. Oncol. 2014, 2, 116–120. [Google Scholar] [CrossRef] [PubMed]
  74. Togashi, Y.; Masago, K.; Fukudo, M.; Terada, T.; Fujita, S.; Irisa, K.; Sakamori, Y.; Kim, Y.H.; Mio, T.; Inui, K.; et al. Cerebrospinal fluid concentration of erlotinib and its active metabolite OSI-420 in patients with central nervous system metastases of non-small cell lung cancer. J. Thorac. Oncol. 2010, 5, 950–955. [Google Scholar] [CrossRef] [PubMed]
  75. Tamiya, A.; Tamiya, M.; Nishihara, T.; Shiroyama, T.; Nakao, K.; Tsuji, T.; Takeuchi, N.; Isa, S.I.; Omachi, N.; Okamoto, N.; et al. Cerebrospinal Fluid Penetration Rate and Efficacy of Afatinib in Patients with EGFR Mutation-positive Non-small Cell Lung Cancer with Leptomeningeal Carcinomatosis: A Multicenter Prospective Study. Anticancer Res. 2017, 37, 4177–4182. [Google Scholar] [CrossRef]
  76. Ballard, P.; Yates, J.W.; Yang, Z.; Kim, D.W.; Yang, J.C.; Cantarini, M.; Pickup, K.; Jordan, A.; Hickey, M.; Grist, M.; et al. Preclinical Comparison of Osimertinib with Other EGFR-TKIs in EGFR-Mutant NSCLC Brain Metastases Models, and Early Evidence of Clinical Brain Metastases Activity. Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res. 2016, 22, 5130–5140. [Google Scholar] [CrossRef] [PubMed]
  77. Nanjo, S.; Hata, A.; Okuda, C.; Kaji, R.; Okada, H.; Tamura, D.; Irie, K.; Okada, H.; Fukushima, S.; Katakami, N. Standard-dose osimertinib for refractory leptomeningeal metastases in T790M-positive EGFR-mutant non-small cell lung cancer. Br. J. Cancer 2018, 118, 32–37. [Google Scholar] [CrossRef]
  78. Yang, J.C.H.; Kim, S.W.; Kim, D.W.; Lee, J.S.; Cho, B.C.; Ahn, J.S.; Lee, D.H.; Kim, T.M.; Goldman, J.W.; Natale, R.B.; et al. Osimertinib in Patients with Epidermal Growth Factor Receptor Mutation-Positive Non-Small-Cell Lung Cancer and Leptomeningeal Metastases: The BLOOM Study. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 2020, 38, 538–547. [Google Scholar] [CrossRef]
  79. Wu, Y.L.; Ahn, M.J.; Garassino, M.C.; Han, J.Y.; Katakami, N.; Kim, H.R.; Hodge, R.; Kaur, P.; Brown, A.P.; Ghiorghiu, D.; et al. CNS Efficacy of Osimertinib in Patients with T790M-Positive Advanced Non-Small-Cell Lung Cancer: Data from a Randomized Phase III Trial (AURA3). J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 2018, 36, 2702–2709. [Google Scholar] [CrossRef]
  80. Bauer, T.M.; Shaw, A.T.; Johnson, M.L.; Navarro, A.; Gainor, J.F.; Thurm, H.; Pithavala, Y.K.; Abbattista, A.; Peltz, G.; Felip, E. Brain Penetration of Lorlatinib: Cumulative Incidences of CNS and Non-CNS Progression with Lorlatinib in Patients with Previously Treated ALK-Positive Non-Small-Cell Lung Cancer. Target. Oncol. 2020, 15, 55–65. [Google Scholar] [CrossRef]
  81. Gadgeel, S.M.; Gandhi, L.; Riely, G.J.; Chiappori, A.A.; West, H.L.; Azada, M.C.; Morcos, P.N.; Lee, R.M.; Garcia, L.; Yu, L.; et al. Safety and activity of alectinib against systemic disease and brain metastases in patients with crizotinib-resistant ALK-rearranged non-small-cell lung cancer (AF-002JG): Results from the dose-finding portion of a phase 1/2 study. Lancet Oncol. 2014, 15, 1119–1128. [Google Scholar] [CrossRef]
  82. Lee, J.; Choi, Y.; Han, J.; Park, S.; Jung, H.A.; Su, J.M.; Lee, S.H.; Ahn, J.S.; Park, K.; Ahn, M.J. Osimertinib Improves Overall Survival in Patients with EGFR-Mutated NSCLC with Leptomeningeal Metastases Regardless of T790M Mutational Status. J. Thorac. Oncol. 2020, 15, 1758–1766. [Google Scholar] [CrossRef]
  83. Ahn, M.-J.; Han, J.-Y.; Lee, K.H.; Kim, S.-W.; Kim, D.-W.; Lee, Y.-G.; Cho, E.K.; Kim, J.-H.; Lee, G.-W.; Lee, J.-S.; et al. Lazertinib in patients with EGFR mutation-positive advanced non-small-cell lung cancer: Results from the dose escalation and dose expansion parts of a first-in-human, open-label, multicentre, phase 1–2 study. Lancet Oncol. 2019, 20, 1681–1690. [Google Scholar] [CrossRef] [PubMed]
  84. Cho, B.C.; Han, J.Y.; Kim, S.W.; Lee, K.H.; Cho, E.K.; Lee, Y.G.; Kim, D.W.; Kim, J.H.; Lee, G.W.; Lee, J.S.; et al. A Phase 1/2 Study of Lazertinib 240 mg in Patients with Advanced EGFR T790M-Positive NSCLC After Previous EGFR Tyrosine Kinase Inhibitors. J. Thorac. Oncol. 2022, 17, 558–567. [Google Scholar] [CrossRef] [PubMed]
  85. Cho, B.C.; Ahn, M.J.; Kang, J.H.; Soo, R.A.; Reungwetwattana, T.; Yang, J.C.; Cicin, I.; Kim, D.W.; Wu, Y.L.; Lu, S.; et al. Lazertinib Versus Gefitinib as First-Line Treatment in Patients with EGFR-Mutated Advanced Non-Small-Cell Lung Cancer: Results from LASER301. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 2023, 41, 4208–4217. [Google Scholar] [CrossRef] [PubMed]
  86. Yang, J.C.; Camidge, D.R.; Yang, C.T.; Zhou, J.; Guo, R.; Chiu, C.H.; Chang, G.C.; Shiah, H.S.; Chen, Y.; Wang, C.C.; et al. Safety, Efficacy, and Pharmacokinetics of Almonertinib (HS-10296) in Pretreated Patients with EGFR-Mutated Advanced NSCLC: A Multicenter, Open-label, Phase 1 Trial. J. Thorac. Oncol. 2020, 15, 1907–1918. [Google Scholar] [CrossRef] [PubMed]
  87. Lu, S.; Wang, Q.; Zhang, G.; Dong, X.; Yang, C.; Song, Y.; Chang, G.; Lu, Y.; Pan, H.; Chiu, C.; et al. OA02.03 The Third Generation EGFR Inhibitor (EGFR-TKI) HS-10296 in Advanced NSCLC Patients with Resistance to First Generation EGFR-TKI. J. Thorac. Oncol. 2019, 14, S208–S209. [Google Scholar] [CrossRef]
  88. Park, S.; Ku, B.M.; Jung, H.A.; Sun, J.M.; Ahn, J.S.; Lee, S.H.; Park, K.; Ahn, M.J. EGFR C797S as a Resistance Mechanism of Lazertinib in Non-small Cell Lung Cancer with EGFR T790M Mutation. Cancer Res. Treat. 2020, 52, 1288–1290. [Google Scholar] [CrossRef]
  89. Zhang, Y.C.; Chen, Z.H.; Zhang, X.C.; Xu, C.R.; Yan, H.H.; Xie, Z.; Chuai, S.K.; Ye, J.Y.; Han-Zhang, H.; Zhang, Z.; et al. Analysis of resistance mechanisms to abivertinib, a third-generation EGFR tyrosine kinase inhibitor, in patients with EGFR T790M-positive non-small cell lung cancer from a phase I trial. EBioMedicine 2019, 43, 180–187. [Google Scholar] [CrossRef]
  90. Wang, F.; Adjei, A.A. Does the Lung Cancer Field Need Another Third-Generation EGFR Tyrosine Kinase Inhibitor? J. Thorac. Oncol. 2020, 15, 881–883. [Google Scholar] [CrossRef]
  91. Lu, S.; Wang, Q.; Zhang, G.; Dong, X.; Yang, C.-T.; Song, Y.; Chang, G.-C.; Lu, Y.; Pan, H.; Chiu, C.-H.; et al. Abstract CT190: A multicenter, open-label, single-arm, phase II study: The third generation EGFR tyrosine kinase inhibitor almonertinib for pretreated EGFR T790M-positive locally advanced or metastatic non-small cell lung cancer (APOLLO). Cancer Res. 2020, 80, CT190. [Google Scholar] [CrossRef]
  92. Shi, Y.; Hu, X.; Zhang, S.; Lv, D.; Wu, L.; Yu, Q.; Zhang, Y.; Liu, L.; Wang, X.; Cheng, Y.; et al. Efficacy, safety, and genetic analysis of furmonertinib (AST2818) in patients with EGFR T790M mutated non-small-cell lung cancer: A phase 2b, multicentre, single-arm, open-label study. Lancet Respir. Med. 2021, 9, 829–839. [Google Scholar] [CrossRef]
  93. Xiong, A.; Ren, S.; Liu, H.; Miao, L.; Wang, L.; Chen, J.; Li, W.; Li, R.; Wang, X.; Lu, Z.; et al. Efficacy and Safety of SH-1028 in Patients with EGFR T790M-Positive NSCLC: A Multicenter, Single-Arm, Open-Label, Phase 2 Trial. J. Thorac. Oncol. 2022, 17, 1216–1226. [Google Scholar] [CrossRef]
  94. Li, B.; Wu, L.; Pan, Y.; Pan, Z.; Liu, Y.; Fan, Y.; Ji, Y.; Fang, J.; Shi, Q.; Li, K.; et al. Efficacy and safety of ASK120067 (limertinib) in patients with locally advanced or metastatic EGFR T790M-mutated non–small cell lung cancer: A multicenter, single-arm, phase IIb study. J. Clin. Oncol. 2022, 40, 9106. [Google Scholar] [CrossRef]
  95. Zhou, Q.; Wu, L.; Hu, P.; An, T.; Zhou, J.; Zhang, L.; Liu, X.Q.; Luo, F.; Zheng, X.; Cheng, Y.; et al. A Novel Third-generation EGFR Tyrosine Kinase Inhibitor Abivertinib for EGFR T790M-mutant Non-Small Cell Lung Cancer: A Multicenter Phase I/II Study. Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res. 2022, 28, 1127–1135. [Google Scholar] [CrossRef]
  96. Lu, S.; Zhang, Y.; Zhang, G.; Zhou, J.; Cang, S.; Cheng, Y.; Wu, G.; Cao, P.; Lv, D.; Jian, H.; et al. Efficacy and Safety of Befotertinib (D-0316) in Patients with EGFR T790M-Mutated NSCLC That Had Progressed After Prior EGFR Tyrosine Kinase Inhibitor Therapy: A Phase 2, Multicenter, Single-Arm, Open-Label Study. J. Thorac. Oncol. 2022, 17, 1192–1204. [Google Scholar] [CrossRef]
  97. Shi, Y.; Zhao, Y.; Yang, S.; Zhou, J.; Zhang, L.; Chen, G.; Fang, J.; Zhu, B.; Li, X.; Shu, Y.; et al. Safety, Efficacy, and Pharmacokinetics of Rezivertinib (BPI-7711) in Patients with Advanced NSCLC with EGFR T790M Mutation: A Phase 1 Dose-Escalation and Dose-Expansion Study. J. Thorac. Oncol. 2022, 17, 708–717. [Google Scholar] [CrossRef]
  98. Lu, S.; Dong, X.; Jian, H.; Chen, J.; Chen, G.; Sun, Y.; Ji, Y.; Wang, Z.; Shi, J.; Lu, J.; et al. AENEAS: A Randomized Phase III Trial of Aumolertinib Versus Gefitinib as First-Line Therapy for Locally Advanced or MetastaticNon-Small-Cell Lung Cancer with EGFR Exon 19 Deletion or L858R Mutations. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 2022, 40, 3162–3171. [Google Scholar] [CrossRef]
  99. Shi, Y.; Chen, G.; Wang, X.; Liu, Y.; Wu, L.; Hao, Y.; Liu, C.; Zhu, S.; Zhang, X.; Li, Y.; et al. Furmonertinib (AST2818) versus gefitinib as first-line therapy for Chinese patients with locally advanced or metastatic EGFR mutation-positive non-small-cell lung cancer (FURLONG): A multicentre, double-blind, randomised phase 3 study. Lancet Respir. Med. 2022, 10, 1019–1028. [Google Scholar] [CrossRef] [PubMed]
  100. Lu, S.; Zhou, J.; Jian, H.; Wu, L.; Cheng, Y.; Fan, Y.; Fang, J.; Chen, G.; Zhang, Z.; Lv, D.; et al. Befotertinib (D-0316) versus icotinib as first-line therapy for patients with EGFR-mutated locally advanced or metastatic non-small-cell lung cancer: A multicentre, open-label, randomised phase 3 study. Lancet Respir. Med. 2023, 11, 905–915. [Google Scholar] [CrossRef] [PubMed]
  101. Jia, Y.; Yun, C.H.; Park, E.; Ercan, D.; Manuia, M.; Juarez, J.; Xu, C.; Rhee, K.; Chen, T.; Zhang, H.; et al. Overcoming EGFR(T790M) and EGFR(C797S) resistance with mutant-selective allosteric inhibitors. Nature 2016, 534, 129–132. [Google Scholar] [CrossRef]
  102. Wang, S.; Song, Y.; Liu, D. EAI045: The fourth-generation EGFR inhibitor overcoming T790M and C797S resistance. Cancer Lett. 2017, 385, 51–54. [Google Scholar] [CrossRef]
  103. To, C.; Jang, J.; Chen, T.; Park, E.; Mushajiang, M.; De Clercq, D.J.H.; Xu, M.; Wang, S.; Cameron, M.D.; Heppner, D.E.; et al. Single and Dual Targeting of Mutant EGFR with an Allosteric Inhibitor. Cancer Discov. 2019, 9, 926–943. [Google Scholar] [CrossRef] [PubMed]
  104. Conti, C.; Campbell, J.; Woessner, R.; Guo, J.; Timsit, Y.; Iliou, M.; Wardwell, S.; Davis, A.; Chicklas, S.; Hsieh, J.; et al. Abstract 1262: BLU-701 is a highly potent, brain-penetrant and WT-sparing next-generation EGFR TKI for the treatment of sensitizing (ex19del, L858R) and C797S resistance mutations in metastatic NSCLC. Cancer Res. 2021, 81, 1262. [Google Scholar] [CrossRef]
  105. Shum, E.; Elamin, Y.Y.; Piotrowska, Z.; Spigel, D.R.; Reckamp, K.L.; Rotow, J.K.; Tan, D.S.-W.; Lim, S.M.; Kim, T.M.; Lin, C.-C.; et al. A phase 1/2 study of BLU-945 in patients with common activating EGFR-mutant non–small cell lung cancer (NSCLC): SYMPHONY trial in progress. J. Clin. Oncol. 2022, 40, TPS9156. [Google Scholar] [CrossRef]
  106. Liu, L.; Qiu, C.; Liu, X.; Lian, Y.; Chen, H.; Song, X.; Shen, Q.; Du, G.; Guo, J.; Yan, D.; et al. Abstract 5462: BPI-361175, a 4th generation EGFR-TKI for the treatment of non-small cell lung cancer (NSCLC). Cancer Res. 2022, 82, 5462. [Google Scholar] [CrossRef]
  107. Zheng, S.; Deng, W.; Zheng, Q.; Yang, Y.; Li, N.; Pang, T.; Feng, X.; Taylor, S.; Ma, L.; Wu, Y.; et al. Abstract 5457: QLH11811, a selective 4th-generation EGFR inhibitor for osimertinib-resistant EGFR-mutant NSCLC. Cancer Res. 2022, 82, 5457. [Google Scholar] [CrossRef]
  108. Jin, T.J.; Kang, S.-U.; Kim, C.; Brenneman, J.; Song, M.; Printsev, P.; Seo, B.-B.; Lee, Y.-H.; Lee, S.-Y. Abstract 3346: BBT-207, a novel, 4th generation, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) with broad-spectrum activity to both treatment-emergent and drug-naïve mutants for the treatment of NSCLC. Cancer Res. 2022, 82, 3346. [Google Scholar] [CrossRef]
  109. Kasuga, H.; Kataoka, Y.; Yamamoto, F.; Mizutani, T.; Tsuji, S.; Tanaka, S.; Mizuarai, S. Abstract 3259: TAS3351 is a 4th-generation EGFR-TKI overcoming T790M and C797S-mediated resistance in NSCLC with EGFR common mutations. Cancer Res. 2022, 82, 3259. [Google Scholar] [CrossRef]
  110. Yun, M.R.; Yu, M.R.; Duggirala, K.B.; Lee, K.; Lim, S.M.; Jo, A.; Seah, E.; Kim, C.; Cho, B.C. 999P JIN-A02, a fourth-generation, highly effective tyrosine kinase inhibitor with intracranial activity, targeting EGFR C797S mutations in NSCLC. Ann. Oncol. 2022, 33, S1010–S1011. [Google Scholar] [CrossRef]
  111. Lim, S.M.; Fujino, T.; Kim, C.; Lee, G.; Lee, Y.H.; Kim, D.W.; Ahn, J.S.; Mitsudomi, T.; Jin, T.; Lee, S.Y. BBT-176, a Novel Fourth-Generation Tyrosine Kinase Inhibitor for Osimertinib-Resistant EGFR Mutations in Non-Small Cell Lung Cancer. Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res. 2023, 29, 3004–3016. [Google Scholar] [CrossRef]
  112. Huang, W.; Zhu, L.; Yan, X.; Huang, X.; Hao, J.; Li, S.; Li, X.; Chen, Z.; Jia, Y.; Li, H.; et al. Abstract 5461: H002: A wide spectrum, highly selective fourth-generation EGFR inhibitor overcoming resistance harboring C797S mutation in NSCLC. Cancer Res. 2022, 82, 5461. [Google Scholar] [CrossRef]
  113. Lucas, M.C.; Merchant, M.; O’Connor, M.; Smith, S.; Trombino, A.; Zhang, W.Y.; Simon, J.; Eathiraj, S.; Waters, N.; Buck, E. 27MO BDTX-1535, a CNS penetrant, irreversible inhibitor of intrinsic and acquired resistance EGFR mutations, demonstrates preclinical efficacy in NSCLC and GBM PDX models. Ann. Oncol. 2022, 33, S14. [Google Scholar] [CrossRef]
  114. Johnson, M.L.; Henry, J.T.; Spira, A.I.; Battiste, J.; Alnahhas, I.; Ahluwalia, M.S.; Barve, M.A.; Edenfield, W.J.; Nam, D.-H.; Eathiraj, S.; et al. A phase 1 study to assess BDTX-1535, an oral EGFR inhibitor, in patients with glioblastoma or non–small-cell lung cancer. J. Clin. Oncol. 2023, 41, TPS9156. [Google Scholar] [CrossRef]
  115. Robichaux, J.P.; Elamin, Y.Y.; Tan, Z.; Carter, B.W.; Zhang, S.; Liu, S.; Li, S.; Chen, T.; Poteete, A.; Estrada-Bernal, A.; et al. Mechanisms and clinical activity of an EGFR and HER2 exon 20–selective kinase inhibitor in non–small cell lung cancer. Nat. Med. 2018, 24, 638–646. [Google Scholar] [CrossRef]
  116. Le, X.; Goldman, J.W.; Clarke, J.M.; Tchekmedyian, N.; Piotrowska, Z.; Chu, D.; Bhat, G.; Lebel, F.M.; Socinski, M.A. Poziotinib shows activity and durability of responses in subgroups of previously treated EGFR exon 20 NSCLC patients. J. Clin. Oncol. 2020, 38, 9514. [Google Scholar] [CrossRef]
  117. Yu, H.A.; Tan, D.S.W.; Smit, E.F.; Spira, A.I.; Soo, R.A.; Nguyen, D.; Lee, V.H.F.; Yang, J.C.H.; Velcheti, V.; Wrangle, J.M.; et al. Phase (Ph) 1/2a study of CLN-081 in patients (pts) with NSCLC with EGFR exon 20 insertion mutations (Ins20). J. Clin. Oncol. 2022, 40, 9007. [Google Scholar] [CrossRef]
  118. Wang, M.; Yang, J.C.H.; Mitchell, P.L.; Fang, J.; Camidge, D.R.; Nian, W.; Chiu, C.H.; Zhou, J.; Zhao, Y.; Su, W.C.; et al. Sunvozertinib, a Selective EGFR Inhibitor for Previously Treated Non-Small Cell Lung Cancer with EGFR Exon 20 Insertion Mutations. Cancer Discov. 2022, 12, 1676–1689. [Google Scholar] [CrossRef]
  119. Han, B.; Zhou, C.; Wu, L.; Yu, X.; Li, Q.; Liu, F.; Shen, C. 1210P Preclinical and preliminary clinical investigations of furmonertinib in NSCLC with EGFR exon 20 insertions (20ins). Ann. Oncol. 2021, 32, S964. [Google Scholar] [CrossRef]
  120. Liu, S.V.; Villaruz, L.C.; Lee, V.H.F.; Zhu, V.W.; Baik, C.S.; Sacher, A.; McCoach, C.E.; Nguyen, D.; Li, J.C.; Pacheco, J.M.; et al. LBA61 First analysis of RAIN-701: Study of tarloxotinib in patients with non-small cell lung cancer (NSCLC) EGFR Exon 20 insertion, HER2-activating mutations & other solid tumours with NRG1/ERBB gene fusions. Ann. Oncol. 2020, 31, S1189. [Google Scholar]
  121. Oguchi, K.; Araki, H.; Tsuji, S.; Nakamura, M.; Miura, A.; Funabashi, K.; Osada, A.; Tanaka, S.; Suzuki, T.; Kobayashi, S.S.; et al. TAS2940, a novel brain-penetrable pan-ERBB inhibitor, for tumors with HER2 and EGFR aberrations. Cancer Sci. 2023, 114, 654–664. [Google Scholar] [CrossRef]
  122. Zhao, Y.; Murciano-Goroff, Y.R.; Xue, J.Y.; Ang, A.; Lucas, J.; Mai, T.T.; Da Cruz Paula, A.F.; Saiki, A.Y.; Mohn, D.; Achanta, P.; et al. Diverse alterations associated with resistance to KRAS(G12C) inhibition. Nature 2021, 599, 679–683. [Google Scholar] [CrossRef]
  123. Awad, M.M.; Liu, S.; Rybkin, I.I.; Arbour, K.C.; Dilly, J.; Zhu, V.W.; Johnson, M.L.; Heist, R.S.; Patil, T.; Riely, G.J.; et al. Acquired Resistance to KRASG12C Inhibition in Cancer. N. Engl. J. Med. 2021, 384, 2382–2393. [Google Scholar] [CrossRef] [PubMed]
  124. Sacher, A.; LoRusso, P.; Patel, M.R.; Miller, W.H., Jr.; Garralda, E.; Forster, M.D.; Santoro, A.; Falcon, A.; Kim, T.W.; Paz-Ares, L.; et al. Single-Agent Divarasib (GDC-6036) in Solid Tumors with a KRAS G12C Mutation. N. Engl. J. Med. 2023, 389, 710–721. [Google Scholar] [CrossRef] [PubMed]
  125. Weiss, A.; Lorthiois, E.; Barys, L.; Beyer, K.S.; Bomio-Confaglia, C.; Burks, H.; Chen, X.; Cui, X.; de Kanter, R.; Dharmarajan, L.; et al. Discovery, Preclinical Characterization, and Early Clinical Activity of JDQ443, a Structurally Novel, Potent, and Selective Covalent Oral Inhibitor of KRASG12C. Cancer Discov. 2022, 12, 1500–1517. [Google Scholar] [CrossRef] [PubMed]
  126. Tan, D.S.; Shimizu, T.; Solomon, B.; Heist, R.S.; Schuler, M.; Luken, M.J.D.M.; Gazzah, A.; Wermke, M.; Dooms, C.; Loong, H.H.; et al. Abstract CT033: KontRASt-01: A phase Ib/II, dose-escalation study of JDQ443 in patients (pts) with advanced, KRAS G12C-mutated solid tumors. Cancer Res. 2022, 82, CT033. [Google Scholar] [CrossRef]
  127. Drilon, A.; Sharma, M.R.; Johnson, M.L.; Yap, T.A.; Gadgeel, S.; Nepert, D.; Feng, G.; Reddy, M.B.; Harney, A.S.; Elsayed, M.; et al. SHP2 Inhibition Sensitizes Diverse Oncogene-Addicted Solid Tumors to Re-treatment with Targeted Therapy. Cancer Discov. 2023, 13, 1789–1801. [Google Scholar] [CrossRef] [PubMed]
  128. Dagogo-Jack, I.; Moonsamy, P.; Gainor, J.F.; Lennerz, J.K.; Piotrowska, Z.; Lin, J.J.; Lennes, I.T.; Sequist, L.V.; Shaw, A.T.; Goodwin, K.; et al. A Phase 2 Study of Capmatinib in Patients with MET-Altered Lung Cancer Previously Treated with a MET Inhibitor. J. Thorac. Oncol. 2021, 16, 850–859. [Google Scholar] [CrossRef]
  129. Krebs, M.; Spira, A.I.; Cho, B.C.; Besse, B.; Goldman, J.W.; Janne, P.A.; Ma, Z.; Mansfield, A.S.; Minchom, A.R.; Ou, S.-H.I.; et al. Amivantamab in patients with NSCLC with MET exon 14 skipping mutation: Updated results from the CHRYSALIS study. J. Clin. Oncol. 2022, 40, 9008. [Google Scholar] [CrossRef]
  130. Hong, D.S.; Catenacci, D.; Bazhenova, L.; Cho, B.C.; Ponz-Sarvise, M.; Heist, R.; Moreno, V.; Falchook, G.; Zhu, V.W.; Swalduz, A.; et al. Abstract P225: Preliminary interim data of elzovantinib (TPX-0022), a novel inhibitor of MET/SRC/CSF1R, in patients with advanced solid tumors harboring genetic alterations in MET: Update from the Phase 1 SHIELD-1 trial. Mol. Cancer Ther. 2021, 20, P225. [Google Scholar] [CrossRef]
  131. Zhao, H.; Chen, J.; Song, Z.; Zhao, Y.; Guo, Y.; Wu, G.; Ma, Y.; Zhou, W.; Yu, X.; Gao, F.; et al. First-in-human phase I results of APG-2449, a novel FAK and third-generation ALK/ ROS1 tyrosine kinase inhibitor (TKI), in patients (pts) with second-generation TKI-resistant ALK/ROS1+ non–small cell lung cancer (NSCLC) or mesothelioma. J. Clin. Oncol. 2022, 40, 9071. [Google Scholar] [CrossRef]
  132. Murray, B.W.; Zhai, D.; Deng, W.; Zhang, X.; Ung, J.; Nguyen, V.; Zhang, H.; Barrera, M.; Parra, A.; Cowell, J.; et al. TPX-0131, a Potent CNS-penetrant, Next-generation Inhibitor of Wild-type ALK and ALK-resistant Mutations. Mol. Cancer Ther. 2021, 20, 1499–1507. [Google Scholar] [CrossRef]
  133. Pelish, H.E.; Tangpeerachaikul, A.; Kohl, N.E.; Porter, J.R.; Shair, M.D.; Horan, J.C. Abstract 1468: NUV-655 (NVL-655) is a selective, brain-penetrant ALK inhibitor with antitumor activity against the lorlatinib-resistant G1202R/L1196M compound mutation. Cancer Res. 2021, 81, 1468. [Google Scholar] [CrossRef]
  134. Drilon, A.E.; Zhai, D.; Rogers, E.; Deng, W.; Zhang, X.; Ung, J.; Lee, D.; Rodon, L.; Graber, A.; Zimmerman, Z.F.; et al. The next-generation RET inhibitor TPX-0046 is active in drug-resistant and naïve RET-driven cancer models. J. Clin. Oncol. 2020, 38, 3616. [Google Scholar] [CrossRef]
  135. Schoffski, P.; Cho, B.C.; Italiano, A.; Loong, H.H.F.; Massard, C.; Rodriguez, L.M.; Shih, J.-Y.; Subbiah, V.; Verlingue, L.; Andreas, K.; et al. BOS172738, a highly potent and selective RET inhibitor, for the treatment of RET-altered tumors including RET-fusion+ NSCLC and RET-mutant MTC: Phase 1 study results. J. Clin. Oncol. 2021, 39, 3008. [Google Scholar] [CrossRef]
  136. Zhao, H.; Wei, X.; Huang, Y.; Yang, Y.; Fang, W.; Ma, Y.; Chen, L.; Chen, D.; Wang, F.; Peng, R.; et al. 1329P A single-arm, open-label, multi-center, phase I study of HA121-28 in patients with advanced solid tumors. Ann. Oncol. 2021, 32, S1018. [Google Scholar] [CrossRef]
  137. Odintsov, I.; Kurth, R.I.; Ishizawa, K.; Delasos, L.; Lui, A.J.W.; Khodos, I.; Hagen, C.J.; Chang, Q.; Mattar, M.S.; Vojnic, M.; et al. Abstract P233: TAS0953/HM06 is effective in preclinical models of diverse tumor types driven by RET alterations. Mol. Cancer Ther. 2021, 20, P233. [Google Scholar] [CrossRef]
  138. Zhou, C.; Li, W.; Zhang, Y.; Song, Z.; Wang, Y.; Huang, D.; Ye, F.; Wang, Q.; Sun, Y. A first-in-human phase I, dose-escalation and dose-expansion study of SY-5007, a highly potent and selective RET inhibitor, in Chinese patients with advanced RET positive solid tumors. J. Clin. Oncol. 2023, 41, 9111. [Google Scholar] [CrossRef]
  139. Niu, C.; Zheng, M.; Wang, H.; Ji, K.; Li, M.; Wang, G.; Ni, R.; Liang, A.; Gong, A.; Zhang, Y.; et al. Abstract 3419: TY-1091, a highly selective and potent second-generation RET inhibitor, demonstrates superior antitumor activity in multiple RET-mutant models. Cancer Res. 2023, 83, 3419. [Google Scholar] [CrossRef]
  140. Hosomi, Y.; Morita, S.; Sugawara, S.; Kato, T.; Fukuhara, T.; Gemma, A.; Takahashi, K.; Fujita, Y.; Harada, T.; Minato, K.; et al. Gefitinib Alone Versus Gefitinib Plus Chemotherapy for Non-Small-Cell Lung Cancer with Mutated Epidermal Growth Factor Receptor: NEJ009 Study. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 2020, 38, 115–123. [Google Scholar] [CrossRef]
  141. Saito, R.; Sugawara, S.; Ko, R.; Azuma, K.; Morita, R.; Maemondo, M.; Oizumi, S.; Takahashi, K.; Kagamu, H.; Tsubata, Y.; et al. Phase 2 study of osimertinib in combination with platinum and pemetrexed in patients with previously untreated EGFR-mutated advanced non-squamous non-small cell lung cancer: The OPAL Study. Eur. J. Cancer 2023, 185, 83–93. [Google Scholar] [CrossRef]
  142. Tagrisso plus Chemotherapy Extended Median Progression-Free Survival by Nearly 9 Months in EGFR-Mutated Advanced Lung Cancer in FLAURA2 Phase III Trial. 2023. Available online: https://www.astrazeneca.com/media-centre/press-releases/2023/tagrisso-plus-chemotherapy-extended-median-progression-free-survival-by-nearly-9-months-in-egfr-mutated-advanced-lung-cancer-in-flaura2-phase-iii-trial.html (accessed on 1 October 2023).
  143. Sequist, L.V.; Peled, N.; Tufman, A.; Servidio, L.; Li, J.; Taylor, R.; Zhao, J. P47.11 COMPEL: Chemotherapy with/without Osimertinib in Patients with EGFRm Advanced NSCLC and Progression on First-Line Osimertinib. J. Thorac. Oncol. 2021, 16, S1101. [Google Scholar] [CrossRef]
  144. Oser, M.G.; Niederst, M.J.; Sequist, L.V.; Engelman, J.A. Transformation from non-small-cell lung cancer to small-cell lung cancer: Molecular drivers and cells of origin. Lancet Oncol. 2015, 16, e165–e172. [Google Scholar] [CrossRef]
  145. Cho, B.C.; Lee, S.H.; Han, J.Y.; Cho, E.K.; Lee, J.S.; Lee, K.H.; Curtin, J.C.; Gao, G.; Xie, J.; Schnepp, R.W.; et al. P1.16-01 Amivantamab and Lazertinib in Treatment-Naive EGFR-Mutant Non-Small Cell Lung Cancer (NSCLC). J. Thorac. Oncol. 2022, 17, S126. [Google Scholar] [CrossRef]
  146. 2023. Available online: https://www.prnewswire.com/news-releases/landmark-phase-3-mariposa-study-meets-primary-endpoint-resulting-in-statistically-significant-and-clinically-meaningful-improvement-in-progression-free-survival-for-rybrevant-amivantamab-vmjw-plus-lazertinib-versus-osimertinib--301941646.html (accessed on 1 October 2023).
  147. 2023. Available online: https://www.janssen.com/phase-3-mariposa-2-study-meets-dual-primary-endpoint-resulting-statistically-significant-and (accessed on 1 October 2023).
  148. Hartmaier, R.J.; Markovets, A.A.; Ahn, M.J.; Sequist, L.V.; Han, J.Y.; Cho, B.C.; Yu, H.A.; Kim, S.W.; Yang, J.C.; Lee, J.S.; et al. Osimertinib + Savolitinib to Overcome Acquired MET-Mediated Resistance in Epidermal Growth Factor Receptor-Mutated, MET-Amplified Non-Small Cell Lung Cancer: TATTON. Cancer Discov. 2023, 13, 98–113. [Google Scholar] [CrossRef] [PubMed]
  149. Ahn, M.j.; De Marinis, F.; Bonanno, L.; Cho, B.C.; Kim, T.M.; Cheng, S.; Novello, S.; Proto, C.; Kim, S.W.; Lee, J.S.; et al. EP08.02-140 MET Biomarker-based Preliminary Efficacy Analysis in SAVANNAH: Savolitinib+osimertinib in EGFRm NSCLC Post-Osimertinib. J. Thorac. Oncol. 2022, 17, S469–S470. [Google Scholar] [CrossRef]
  150. Mazieres, J.; Kim, T.M.; Lim, B.K.; Wislez, M.; Dooms, C.; Finocchiaro, G.; Hayashi, H.; Liam, C.K.; Raskin, J.; Tho, L.M.; et al. LBA52 Tepotinib + osimertinib for EGFRm NSCLC with MET amplification (METamp) after progression on first-line (1L) osimertinib: Initial results from the INSIGHT 2 study. Ann. Oncol. 2022, 33, S1419–S1420. [Google Scholar] [CrossRef]
  151. Yu, H.A.; Goldberg, S.B.; Le, X.; Piotrowska, Z.; Goldman, J.W.; De Langen, A.J.; Okamoto, I.; Cho, B.C.; Smith, P.; Mensi, I.; et al. Biomarker-Directed Phase II Platform Study in Patients with EGFR Sensitizing Mutation-Positive Advanced/Metastatic Non-Small Cell Lung Cancer Whose Disease Has Progressed on First-Line Osimertinib Therapy (ORCHARD). Clin. Lung Cancer 2021, 22, 601–606. [Google Scholar] [CrossRef] [PubMed]
  152. Poon, E.; Mullins, S.; Watkins, A.; Williams, G.S.; Koopmann, J.O.; Di Genova, G.; Cumberbatch, M.; Veldman-Jones, M.; Grosskurth, S.E.; Sah, V.; et al. The MEK inhibitor selumetinib complements CTLA-4 blockade by reprogramming the tumor immune microenvironment. J. Immunother. Cancer 2017, 5, 63. [Google Scholar] [CrossRef] [PubMed]
  153. Hellmann, M.D.; Kim, T.W.; Lee, C.B.; Goh, B.C.; Miller, W.H., Jr.; Oh, D.Y.; Jamal, R.; Chee, C.E.; Chow, L.Q.M.; Gainor, J.F.; et al. Phase Ib study of atezolizumab combined with cobimetinib in patients with solid tumors. Ann. Oncol. 2019, 30, 1134–1142. [Google Scholar] [CrossRef]
  154. Nishino, M.; Soejima, K.; Mitsudomi, T. Brain metastases in oncogene-driven non-small cell lung cancer. Transl. Lung Cancer Res. 2019, 8, S298–S307. [Google Scholar] [CrossRef]
  155. Yun, M.R.; Kim, D.H.; Kim, S.Y.; Joo, H.S.; Lee, Y.W.; Choi, H.M.; Park, C.W.; Heo, S.G.; Kang, H.N.; Lee, S.S.; et al. Repotrectinib Exhibits Potent Antitumor Activity in Treatment-Naïve and Solvent-Front-Mutant ROS1-Rearranged Non-Small Cell Lung Cancer. Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res. 2020, 26, 3287–3295. [Google Scholar] [CrossRef]
  156. Mazieres, J.; Iadeluca, L.; Shaw, A.T.; Solomon, B.J.; Bauer, T.M.; de Marinis, F.; Felip, E.; Goto, Y.; Kim, D.W.; Mok, T.; et al. Patient-reported outcomes from the randomized phase 3 CROWN study of first-line lorlatinib versus crizotinib in advanced ALK-positive non-small cell lung cancer. Lung Cancer 2022, 174, 146–156. [Google Scholar] [CrossRef] [PubMed]
  157. Crucitta, S.; Cucchiara, F.; Mathijssen, R.; Mateo, J.; Jager, A.; Joosse, A.; Passaro, A.; Attili, I.; Petrini, I.; van Schaik, R.; et al. Treatment-driven tumour heterogeneity and drug resistance: Lessons from solid tumours. Cancer Treat. Rev. 2022, 104, 102340. [Google Scholar] [CrossRef]
  158. Lim, Z.F.; Ma, P.C. Emerging insights of tumor heterogeneity and drug resistance mechanisms in lung cancer targeted therapy. J. Hematol. Oncol. 2019, 12, 134. [Google Scholar] [CrossRef] [PubMed]
  159. Sharma, S.V.; Lee, D.Y.; Li, B.; Quinlan, M.P.; Takahashi, F.; Maheswaran, S.; McDermott, U.; Azizian, N.; Zou, L.; Fischbach, M.A.; et al. A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations. Cell 2010, 141, 69–80. [Google Scholar] [CrossRef] [PubMed]
  160. Passaro, A.; Malapelle, U.; Del Re, M.; Attili, I.; Russo, A.; Guerini-Rocco, E.; Fumagalli, C.; Pisapia, P.; Pepe, F.; De Luca, C.; et al. Understanding EGFR heterogeneity in lung cancer. ESMO Open 2020, 5, e000919. [Google Scholar] [CrossRef]
  161. Del Re, M.; Crucitta, S.; Gianfilippo, G.; Passaro, A.; Petrini, I.; Restante, G.; Michelucci, A.; Fogli, S.; de Marinis, F.; Porta, C.; et al. Understanding the Mechanisms of Resistance in EGFR-Positive NSCLC: From Tissue to Liquid Biopsy to Guide Treatment Strategy. Int. J. Mol. Sci. 2019, 20, 3951. [Google Scholar] [CrossRef]
  162. Oxnard, G.R.; Hu, Y.; Mileham, K.F.; Husain, H.; Costa, D.B.; Tracy, P.; Feeney, N.; Sholl, L.M.; Dahlberg, S.E.; Redig, A.J.; et al. Assessment of Resistance Mechanisms and Clinical Implications in Patients with EGFR T790M-Positive Lung Cancer and Acquired Resistance to Osimertinib. JAMA Oncol. 2018, 4, 1527–1534. [Google Scholar] [CrossRef]
  163. Schmid, S.; Früh, M.; Peters, S. Targeting MET in EGFR resistance in non-small-cell lung cancer-ready for daily practice? Lancet Oncol. 2020, 21, 320–322. [Google Scholar] [CrossRef]
  164. Shaw, A.T.; Solomon, B.J.; Besse, B.; Bauer, T.M.; Lin, C.C.; Soo, R.A.; Riely, G.J.; Ou, S.I.; Clancy, J.S.; Li, S.; et al. ALK Resistance Mutations and Efficacy of Lorlatinib in Advanced Anaplastic Lymphoma Kinase-Positive Non-Small-Cell Lung Cancer. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 2019, 37, 1370–1379. [Google Scholar] [CrossRef]
  165. McCoach, C.E.; Le, A.T.; Gowan, K.; Jones, K.; Schubert, L.; Doak, A.; Estrada-Bernal, A.; Davies, K.D.; Merrick, D.T.; Bunn, P.A., Jr.; et al. Resistance Mechanisms to Targeted Therapies in ROS1(+) and ALK(+) Non-small Cell Lung Cancer. Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res. 2018, 24, 3334–3347. [Google Scholar] [CrossRef]
  166. Shiba-Ishii, A.; Johnson, T.W.; Dagogo-Jack, I.; Mino-Kenudson, M.; Johnson, T.R.; Wei, P.; Weinrich, S.L.; McTigue, M.A.; Walcott, M.A.; Nguyen-Phuong, L.; et al. Analysis of lorlatinib analogs reveals a roadmap for targeting diverse compound resistance mutations in ALK-positive lung cancer. Nat. Cancer 2022, 3, 710–722. [Google Scholar] [CrossRef] [PubMed]
  167. Yeo, M.-K.; Kim, Y.; Lee, D.H.; Chung, C.; Bae, G.E. Cosuppression of NF-&kappa;B and AICDA Overcomes Acquired EGFR-TKI Resistance in Non-Small Cell Lung Cancer. Cancers 2022, 14, 2940. [Google Scholar]
  168. Mongre, R.K.; Mishra, C.B.; Shukla, A.K.; Prakash, A.; Jung, S.; Ashraf-Uz-Zaman, M.; Lee, M.-S. Emerging Importance of Tyrosine Kinase Inhibitors against Cancer: Quo Vadis to Cure? Int. J. Mol. Sci. 2021, 22, 11659. [Google Scholar] [CrossRef] [PubMed]
  169. Drago, J.Z.; Modi, S.; Chandarlapaty, S. Unlocking the potential of antibody-drug conjugates for cancer therapy. Nat. Rev. Clin. Oncol. 2021, 18, 327–344. [Google Scholar] [CrossRef] [PubMed]
  170. Passaro, A.; Jänne, P.A.; Peters, S. Antibody-Drug Conjugates in Lung Cancer: Recent Advances and Implementing Strategies. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 2023, 41, 3747–3761. [Google Scholar] [CrossRef]
  171. Sequist, L.V.; Han, J.Y.; Ahn, M.J.; Cho, B.C.; Yu, H.; Kim, S.W.; Yang, J.C.; Lee, J.S.; Su, W.C.; Kowalski, D.; et al. Osimertinib plus savolitinib in patients with EGFR mutation-positive, MET-amplified, non-small-cell lung cancer after progression on EGFR tyrosine kinase inhibitors: Interim results from a multicentre, open-label, phase 1b study. Lancet Oncol. 2020, 21, 373–386. [Google Scholar] [CrossRef]
Figure 1. Current treatment options in advanced NSCLC according to molecular gene testing. Novel generations of TKIs, where available, were initially positioned in a therapeutic sequence, but they are established as front-line treatments across driver mutations. Drug classes: Tyrosine kinase inhibitors: Osimertinib, gefitinib, erlotinib, afatinib, dacomitinib, mobocertinib, alectinib, brigatinib, lorlatinib, ceritinib, crizotinib, entrectinib, selpercatinib, pralsetinib, capmatinib, tepotinib, larotrectinib|small molecule inhibitors: dabrafenib, trametinib, sotorasib, adagrasib|bispecific antibodies: amivantamab|Antibody-drug conjugates: trastuzumab-deruxtecan|Abbreviations: CT = chemotherapy; Atezo = atezolizumab; Pembro = pembrolizumab; Nivo = nivolumab|Ipi = ipilimumab|beva = bevacizumab.
Figure 1. Current treatment options in advanced NSCLC according to molecular gene testing. Novel generations of TKIs, where available, were initially positioned in a therapeutic sequence, but they are established as front-line treatments across driver mutations. Drug classes: Tyrosine kinase inhibitors: Osimertinib, gefitinib, erlotinib, afatinib, dacomitinib, mobocertinib, alectinib, brigatinib, lorlatinib, ceritinib, crizotinib, entrectinib, selpercatinib, pralsetinib, capmatinib, tepotinib, larotrectinib|small molecule inhibitors: dabrafenib, trametinib, sotorasib, adagrasib|bispecific antibodies: amivantamab|Antibody-drug conjugates: trastuzumab-deruxtecan|Abbreviations: CT = chemotherapy; Atezo = atezolizumab; Pembro = pembrolizumab; Nivo = nivolumab|Ipi = ipilimumab|beva = bevacizumab.
Cancers 15 05079 g001
Table 3. Summary of the novel KRAS inhibitors most advanced in clinical research.
Table 3. Summary of the novel KRAS inhibitors most advanced in clinical research.
DrugIC50Clinical Trial(s)ResultsSafety ProfileOngoing Clinical Trial(s)
Divarasib
(GDC-6036)
400 mg OD
0.0029 nMPhase I/II
GO42144
Sacher 2023 [124]
ORR 53.4%
mPFS 13.1 months
AE rate 93%
G ≥ 3: 12%
Most common AEs
nausea (74%),
diarrhea (61%), and vomiting (58%)
NAUTIKA1
NCT04302025
Biomarker-driven Neoadjuvant platform
JDQ443
200 mg BID
0.012 nMPhase I–II
KontRast-01
Tan 2022 [126]
Phase III KontRASt-02
NCT05132075
Ongoing
ORR 57%
mDoR 4 months
AE rate 71.8%
G ≥ 3: 12.8%
Most common AEs
fatigue (30.8%)
nausea (17.9%)
edema (15.4%)
diarrhea (12.8%) vomiting (12.8%)
KontRASt-04
JDQ433C12301
1stline JDQ433 + TNO155 vs. CT + ICI
STRIDER
NCT05999357 Ph II BM +
KontRASt-06
NCT05445843 1st line PD-L1 neg or PD-L1+/SKT11+
Abbreviations: IC50 = Half-maximal inhibitory concentration; OD = once daily; BID = two times a day; nM = nanomolar; ORR = overall response rate; mPFS = median progression-free survival; mDoR = median duration of response; AE(s) = adverse event(s); G = grade; Ph = phase; CT = chemotherapy; ICI immune-checkpoint inhibitor; Tx = treatment.
Table 4. Summary of clinical results of novel RET inhibitors.
Table 4. Summary of clinical results of novel RET inhibitors.
DrugEC/IC50 CCDC6RET
Ratio
IC50G810RClinical TrialResultsOngoing Clinical Trial
TPX-0046 [134]IC50 < 10 nM+
17 nM
Phase I/II
NCT04161391
Terminated (Adverse change in the risk/benefit)Drug
withdrawn
Zeteletinib
(BOS172738)
150 mg OD
IC50 < 1 nMNot releasedPhase I/II
Schöffski 2021 [135]
ORR 33% mDoR not reachedPhase I/II
Schöffski 2021
HA121-28
600 mg OD
Data not releasedData not
released
Phase I/II
Zhao 2021 [136]
Post-CT ORR 41% mPFS not reachedNCT05117658
Ph II trial
Post-CT
TAS0953/HM06 [137]IC50 0.02–s0.1 µM+MARGARET
Phase I/II
NCT04683250
OngoingMARGARET
Phase I/II
NCT04683250
SY-5007
160 or 200 mg BID
IC50 < 1 nMNot releasedPhase I/II
Zhou 2023 [138]
ORR 75% mDoR not reachedNCT06031558
Ph III trial
Single arm
TY-1091 [139]IC50 < 1 nM ++
9.5 nM
Phase I/II
NCT05675605
OngoingPhase I/II
NCT05675605
Abbreviations: IC50 = Half-maximal inhibitory concentration; OD = once daily; BID = two times a day; nM = nanomolar; ORR = overall response rate; mPFS = median progression-free survival; mDoR = median duration of response; AE(s) = adverse event(s); G = grade; Ph = phase; CT = chemotherapy; ICI immune-checkpoint inhibitor; Tx = treatment.
Table 5. Main TKI-based combinations either in tx naïve or previously TKI pretreated EGFR-mutant NSCLC.
Table 5. Main TKI-based combinations either in tx naïve or previously TKI pretreated EGFR-mutant NSCLC.
CTAntiangiogenicsBispecific AntibodiesADCs or TKIs
First line TxFLAURA-2
[NCT04035486]
Osimertinib +/− CT
(K-I common)
TRIAL HAS RESULT
[NCT05263947]
Icotinib + bevacizumab
(K-I L858R)
CHRYSALIS [NCT02609776]
Lazertinib+ amivantamab
(cohort TKI naive)
[NCT05007938]
Befotertinib +
icotinib
TOP
[NCT04695925]
Osimertinib +/− CT
(K-I EGFR/p53+)
[NCT04181060]
Osimertinib +/− bevacizumab
(K-I sensitizing mutations)
OSTARA
[NCT05801029]
Lazertinib+ amivantamab
(K-I common)
METLUNG
[NCT05445791]
1st or 2nd TKI +metformin
(KI sensitizing mutations)
[NCT04552613]
Standard TKI+/−CT
(K-I EGFR/concomitant genes+)
[NCT05507606]
Osimertinib +/− bevacizumab
(K-I EGFR/p53+)
MARIPOSA [NCT04487080]
Lazertinib+ amivantamab
(K-I common)
[NCT05880706]
Osimertinib+BL-B01D1
(KI common mutations)
[NCT04410796]
Osimertinib +/− CT
(K-I ctDNA+ at C2)
[NCT04988607]
Osimertinib +/− bevacizumab
(K-I L858R)
PACE-Lung
[NCT05281406]
Osimertinib +CT
(K-I ctDNA+ at wk3)
AUTOMAN
[NCT04770688]
Osimertinib + anlotinib
(KI common mutations)
[NCT05209256]
Furmonertinib+/− CT
(K-I sensitizing mutations)
[NCT03909334]
Osimertinib+/− ramucirumab
(KI common mutations)
[NCT04923906]
Almonertinib+/− CT
(K-I sensitizing mutations)
FOCUS-A
[NCT04895930]
furmonertinib+anlotinib
(KI common EGFR)
ACROSS1
[NCT04500704]
Almonertinib+/− CT
(K-I common mutations)
[NCT05271916]
Dacomitinib+anlotinib
(KI phI common; Ph II L858R)
ACROSS2
[NCT04500717]
Almonertinib+/− CT
(K-I common mutations/Suppressor Genes+)
BELLA
[NCT04575415]
Bevacizumab + EGFRTKIs
(observational study)
[NCT03992885]
Icotinib + CT
(KI sensitizing mutations)
[NCT03904823]
Almonertinib + famitinib
(K-I sensitizing mutations)
[NCT05778149]
Almonertinib + anlotinib
(K-I common mutations/p53)
ACTIVE/CTONG1706
[NCT02824458]
Gefitinib +/− apatinib
(KI common mutations)
MET-based FLOWERS (NCT05163249) osimertinib+/− savolitinib (K-I sensitizing/MET+°)
NCT04743505
Osimertinib +/− savolitinib (K-I sensitizing)
Post-3rd gen EGFR TKI CHRYSALIS [NCT02609776]
Lazertinib+ amivantamab
(cohort post-TKIs)
Lung-MAP Sub-Study [NCT05642572]
Osimertinib+capmatinib +/− ramucirumab
(K-I sensitizing MET AMP)
CHRYSALIS 2
NCT04077463
Lazertinib+ amivantamab+/− CT
(cohort post-osimertinib)
CHRYSALIS 2
NCT04077463
Lazertinib+ amivantamab+/− CT
(cohort post-osimertinib)
INSIGHT 2
[NCT03940703]
Tepotinib +osimertinib
(K-I common/MET+ç)
MARIPOSA-2
[NCT04988295]
CT+/+ amivantamab +/− lazertinib
(KI common postosimertinib)
MARIPOSA-2
[NCT04988295]
CT+/+amivantamab+/lazertinib
(KI common postosimertinib)
SAVANNAH
(NCT03778229)
Savolitinib+/-osimertinib
(K-I common/MET+§)
PALOMA
[NCT04606381]
Sc amivantamab
(KI solid tumors Common EGFR NSCLC post-TKIs)
SACHI
[NCT05015608]
CT vs. Osimertinib+ savolitinib
(K-I common/MET+@)
SAFFRON
[NCT05261399]
CT vs. osimertinib+savolitinib
(K-I common/MET+§)
PALOMA2
[NCT05498428]
Sc Amivantamab+several regimens
(KI Solid Tumors Including txnaive or POSTTKIs common EGFR EGFRex20ins tx naïve)
SAFFRON
[NCT05261399]
CT vs. osimertinib+savolitinib (K-I common/MET+§)
PALOMA-3
[NCT05388669]
Lazertinib + sc vs. ev amivantamab
(k-I common post CT and osimertinib)
[NCT05821933]
Furmonertinib+RC108 +/- Toripalimab
(k-I sensitizing/MET OE post-TKIs)
AMAZE-lung [NCT05601973]
Lazertinib amivantamab bevacizumab
(KI post osimertinib or Lazertinib).
AMAZE-lung [NCT05601973]
Lazertinib amivantamab bevacizumab
(KI post osimertinib or Lazertinib).
[NCT04965090] Amivantamab/lazertinib
(KI common after3rdTKI and BM+)
PolyDamas
[NCT05908734] amivantamab+cetrilumab
(KI post osimertinib/CT)
NCT03797391
EMB-01
(KI EGFR or MET+)
[NCT05498389]
EMB-01+ osimertinib
(KI postTKIs)
[NCT04868877]
MCLA-129+osimertinib
(k-I NSCLC/solid tumours)
Abbreviations: CT = chemotherapy; ADC(s) = Antibody(ies) drug conjugated; TKI(s) = Tyrosine kinase inhibitor(s); Tx = treatment; KI = key inclusion criteria; Ph = phase; C = cycle; wk = week; ctDNA = circulating DNA; NSCLC = Non-Small-Cell Lung Cancer; EGFR Epidermal Growth Factor Receptor; EGFREx20ins = EGFR eson 20 insertions; MET OE = MET overexpressed; ç MET+ = gene copy number ≥ 5 and/or MET/CEP7 ≥ 2; § MET+ = MET-Overexpressed (IHC90+) and/or Amplified (GCN≥ 10); @ MET+ = GCN not reported cutoff; ° MET+ = IHC 3+ in ≥75% of tumor cells; MET gene copy ≥ 5 or MET/CEP7 ratio ≥ 2; HER 2 AMP = Her2 amplified; EGFREx20ins = EGFR exon 20 insertions; BL-B01D1 is a bifunctional antibody anti-EGFR/HER3 conjugated to a topoisomerase-I; Famitinib is a multitargeted agent which inhibits stem cell factor receptor (c-Kit; SCFR), vascular endothelial growth factor receptor (VEGFR) 2 and 3, platelet-derived growth factor receptor (PDGFR) and FMS-like tyrosine kinases Flt1 and Flt3; RC108 = ADC anti MET; MCLA-129 is a Human Anti-EGFR and Anti-c-MET Bispecific Antibody.
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Attili, I.; Corvaja, C.; Spitaleri, G.; Del Signore, E.; Trillo Aliaga, P.; Passaro, A.; de Marinis, F. New Generations of Tyrosine Kinase Inhibitors in Treating NSCLC with Oncogene Addiction: Strengths and Limitations. Cancers 2023, 15, 5079. https://doi.org/10.3390/cancers15205079

AMA Style

Attili I, Corvaja C, Spitaleri G, Del Signore E, Trillo Aliaga P, Passaro A, de Marinis F. New Generations of Tyrosine Kinase Inhibitors in Treating NSCLC with Oncogene Addiction: Strengths and Limitations. Cancers. 2023; 15(20):5079. https://doi.org/10.3390/cancers15205079

Chicago/Turabian Style

Attili, Ilaria, Carla Corvaja, Gianluca Spitaleri, Ester Del Signore, Pamela Trillo Aliaga, Antonio Passaro, and Filippo de Marinis. 2023. "New Generations of Tyrosine Kinase Inhibitors in Treating NSCLC with Oncogene Addiction: Strengths and Limitations" Cancers 15, no. 20: 5079. https://doi.org/10.3390/cancers15205079

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