Updates in Oncogene-Driven NSCLC from WCLC

The treatment landscape for advanced non-small cell lung cancer (NSCLC) is changing rapidly and becoming increasingly biomarker driven. Advances in molecular diagnostics have expanded the number of targetable oncogenic driver alterations and led to the development and approval of new targeted treatment options. At the 2022 World Conference on Lung Cancer (WCLC) held in Vienna, Austria, during 6 – 9 August, new data related to the diagnosis and management of lung cancer were presented, including data on targeted therapy for MET exon 14 (METex14) skipping mutations, KRAS G12C mutation, and EGFR tyrosine kinase inhibitor (TKI) resistance.

Targeting METex14 Skipping Mutations

METex14 skipping mutation is an oncogenic driver occurring in 3 – 4% of NSCLC patients, who are typically elderly (≥70 years) and therefore challenging to treat due to comorbidities. An important advance in the management of patients harboring METex14 skipping mutation has been the development of MET TKIs, and two highly selective MET TKIs, capmatinib and tepotinib, were recently approved in many countries. These approvals were based on durable responses observed in phase II trials: Cohort A of the VISION trial1 (tepotinib) and the GEOMETRY Mono-1 trial2 (capmatinib). Among data presented at 2022 WCLC on METex14, results from the confirmatory cohort of the VISION trial (OA03.05)3 are particularly clinically relevant.

Confirmation of robust and durable efficacy with tepotinib

Primary analysis (>9 months follow-up) from the independent confirmatory cohort C of the VISION trial (n=161) was presented by Michael Thomas, MD (Translational Lung Research Center in Heidelberg University Hospital, Germany). Patients included in the VISION trial had METex14 skipping mutation detected by liquid and/or tissue biopsy and received tepotinib 500 mg once daily. In cohort C, patients had a median age of 71 years, most had adenocarcinoma histology, around half were male, and about half had a smoking history. The overall response rate (ORR) with tepotinib was 54.7%, with a median duration of response (mDoR) of 20.8 months. Median progression-free survival (mPFS) was 13.8 months, and median overall survival (mOS) was 18.8 months. This “robust and durable efficacy” was seen across all treatment lines, but was particularly meaningful in treatment-naïve patients enrolled by tissue biopsy. In addition, promising intracranial activity was seen in patients with brain metastases. Among 43 patients with brain target and non-target lesions (cohorts A and C) intracranial disease control rate was 88.4%, with intracranial PFS of 20.9 months. Tepotinib was generally well tolerated: grade ≥3 treatment-related adverse events (TRAEs) occurred in 34.2% of patients, with peripheral edema being the most common (10.9%). Dose reduction was required in 33.5% and treatment interruptions in 42.5% of patients, while permanent discontinuation due to TRAEs was needed in 14.7% of patients. Importantly, patients who required treatment interruptions or dose reductions were able to continue benefiting from treatment with tepotinib. Dr. Thomas concluded that the VISION trial was the largest clinical trial of MET TKIs in METex14 skipping NSCLC, and results from cohort C provide convincing evidence of durable efficacy.

Real-world data and ongoing strategies in NSCLC with METex14 skipping mutations

Real-world data from a retrospective, multicenter analysis of 81 patients with METex14 skipping mutated NSCLC treated with capmatinib in an early-access program (RECAP; EP08.02-122)4 confirmed the durable systemic and intracranial activity indicated in the GEOMETRY Mono-1 trial,2 also corroborating the VISION trial findings supporting use of selective MET TKIs in these patients.

In addition, the ongoing multinational MOMENT registry (EP08.02-126),5 which aims to prospectively collect high-quality clinical data from patients with advanced METex14-mutant NSCLC, will provide important information on the management of these patients in routine clinical practice and will serve as a source for future research to optimize patient care in patients with this rare molecular subtype of NSCLC.

Looking to the future, other strategies including MET-directed antibodies, and antibody-drug conjugates that target MET are in early-phase trials; it will be interesting to see the data as these trials proceed.

Targeting KRAS G12C in Advanced NSCLC

KRAS gene mutations are among the most common driver alterations in NSCLC. Among the different known KRAS mutations, KRAS G12C occurs in 13% of patients with lung adenocarcinoma and has been found to be druggable, with direct inhibitors targeting KRAS G12C. Sotorasib is the first specific and irreversible KRAS G12C inhibitor approved for patients with previously treated KRAS G12C mutated advanced NSCLC, based on results from the phase I/II CodeBreaK100/101 trial. Another KRAS G12C inhibitor, adagrasib, is currently under review for approval based on results from the KRYSTAL-1 trial. Both agents showed similar efficacy with ORR of about 40% and median OS around 12.5 months. However, there are major challenges with current KRAS G12C inhibitors, including complex resistance mechanisms, efficacy limitations, optimal dosing, CNS penetration, and targeting of other KRAS mutations. Ongoing research is addressing these challenges.

Early results of sotorasib combinations and new KRAS G12C inhibitors not yet convincing

In an evaluation of the combination of sotorasib plus immunotherapy (pembrolizumab or atezolizumab), the concurrent combination of sotorasib and immunotherapy was found to be relatively toxic, with hepatotoxicity being a significant adverse event. The data were presented by Bob T. Li, MD (Memorial Sloan Kettering Cancer Center, New York, US) (OA03.06).6 The results showed that a lead-in strategy with low-dose sotorasib had better tolerability than concurrent sotorasib and immunotherapy. The ORR was 29% with lead-in sotorasib plus pembrolizumab, with a mDoR of 17.9 months in responding patients. The mOS for sotorasib with any immunotherapy was 15.7 months. Notably, however, the majority of patients had received prior immunotherapy. Based on the findings, further evaluation is planned to assess the benefit-risk ratio of low-dose, lead-in sotorasib followed by immunotherapy as first-line treatment for immunotherapy-naïve patients with advanced NSCLC.

Other combination strategies include sotorasib plus the small-molecule SHP2 inhibitor, RMC-4630 (OA.03.03).7 In preclinical models, the combination of sotorasib and SHP inhibitor impaired receptor tyrosine kinase signaling and enhanced antitumor efficacy of sotorasib. Early-phase trial data of the combination with sotorasib showed that the combination was safe and well-tolerated in KRAS G12C mutant NSCLC, with the most promising clinical activity (ORR: 50%) in KRAS G12C inhibitor-naïve patients.

In addition, encouraging clinical activity and a favorable toxicity profile were reported for GDC-6036, an oral, highly potent, and selective KRAS G12C inhibitor (OA03.04).8 Phase I data showed a confirmed ORR of 46%. D-1553, another novel KRAS G12C inhibitor, also demonstrated activity in a phase I trial, with an ORR of 37.8% and disease control rate of 91.9%, although the toxicity profile had some features that could prove limiting (OA03.07).9

Overcoming Resistance to Osimertinib

A third-generation TKI, osimertinib, has become the preferred standard first-line therapy for EGFR-mutant NSCLC, based on the survival benefit seen in the FLAURA trial when compared with first-generation EGFR TKIs (gefitinib/erlotinib). It is also the treatment of choice for patients initially treated with other EGFR TKIs, who subsequently develop EGFR T7090M resistance mutation. However, developing acquired resistance to osimertinib is also inevitable. Resistance mechanisms are heterogeneous and include EGFR-dependent as well as EGFR-independent mechanisms. On disease progression with osimertinib, it is of paramount importance that patients are retested for alterations that may be targeted for therapeutic benefit.

Evolution of acquired resistance to osimertinib over time

Interesting real-world data from a retrospective, observational study using a clinical genomic database, presented by Suresh Ramalingam, MD (Emory University School of Medicine, Atlanta, Georgia, US), showed that for patients treated with osimertinib in the first-line setting, MET amplification was the most common initial resistance mechanism in the first year of osimertinib treatment. However, MET amplification became less frequent over time, while the incidence of EGFR C797X mutation increased substantially and was the most frequent mutation in patients after a year of osimertinib treatment. Cumulatively, EGFR C797X mutations were 1.25 times more common than MET amplification after first-line osimertinib and 2.4 times more common after second-line osimertinib (MA07.03).10 These data highlight the complex nature of osimertinib resistance, indicating the need for novel targeted therapy to address resistance mechanisms in patients who progressed on osimertinib, with EGFR C797X, MET amplification, and CCNE1 amplification having the highest incidence.

Targeting MET amplification in osimertinib-resistant EGFR-mutated NSCLC: Ongoing MET and EGFR co-inhibition strategy

Preliminary efficacy data from the ongoing phase II SAVANNAH trial of the MET TKI savolitinib with osimertinib indicate the importance of appropriate MET biomarker-based patient selection (EP08.02-140).11 In the study, MET overexpression was detected by immunohistochemistry (IHC) (3+ in ≥50% of tumor cells [IHC50+]) and MET amplification by fluorescence in situ hybridization (FISH) (MET copy number ≥5 and/or MET: CEP7 signal ratio ≥2 [FISH5+]). The efficacy of savolitinib (300 mg) plus osimertinib (80 mg) was assessed in the overall population (n=193) defined by IHC 50% and/or FISH 5+, in a subgroup of patients defined by exploratory, high cut-off levels: IHC 3+ staining in ≥90% tumor cells (IHC90+) and/or MET copy number ≥10 (FISH10+) (n=108) and in those without IHC90+ and/or FISH10+ status (n=79). Improved outcomes were observed in patients with IHC90+ and/or FISH10+, with an ORR of 49%, mDoR of 9.3 months and mPFS of 7.1 months, compared with the total population (ORR: 32%; mDoR: 8.3 months; mPFS: 5.3 months), and particularly versus the subgroup without IHC90+ and/or FISH10+ status (ORR: 9%; median DoR: 6.9 months; mPFS: 2.8 months). The combination of savolitinib and osimertinib is being evaluated further versus chemotherapy, post-osimertinib, in the phase III SAFFRON trial (EP08.02-138).12

Further data supporting MET-TKI and EGFR-TKI combinations emerge from a real-world case series of 12 patients with EGFR-mutant, MET-amplified NSCLC (EP08.02-162).13 After developing MET amp resistance on EGFR TKI, patients received the MET inhibitor tepotinib through compassionate use request. A total of 11 patients had clinical benefit with tepotinib plus EGFR TKI (including osimertinib) per the treating physician’s assessment, with 8 considered as having a partial response. Of note, the clinical activity with the combination was also observed in patients with several lines of prior treatment. The combination of tepotinib plus osimertinib is being evaluated formally in the ongoing phase II INSIGHT 2 trial14 in patients with MET-amplified EGFR-mutant NSCLC with acquired resistance to first-line osimertinib.

Insights from other strategies targeting EGFR TKI resistance mechanisms

In the small phase I/Ib CHRYSALIS trial, a combination of EGFR-MET bispecific antibody, amivantamab, plus third-generation EGFR TKI, lazertinib, with platinum-based chemotherapy in heavily pretreated advanced EGFR-mutant NSCLC yielded an ORR of 50% (including in patients with brain metastases). Responses were durable, with adverse events consistent with previous reports (MA 07.04).15

Also, novel fourth-generation EGFR-TKIs are under evaluation as potential targeted therapy for C797S-resistant mutation, including JIN-A02 (MA07.08)16 and BBT-176 (MA07.09).17 These agents have shown positive data preclinically and in early clinical trials (BBT-176), including for triple-mutant EGFR (ex19del/T790M/C797S) tumors, and will be interesting to follow over the next years.

Taken together, these data on oncogene-driven NSCLC presented at WCLC indicate the importance of broad molecular testing at the time of diagnosis of advanced NSCLC, as well as at progression, to detect oncogenic drivers or resistance mechanisms, which will enable to provide patients with optimal standard-of-care for patients, or inclusion in one of the numerous biomarker-driven ongoing clinical trials. Among the presented data, confirmatory efficacy results from the VISION trial are reassuring for clinical practice, supporting the use of a MET inhibitor, such as tepotinib, as the preferred treatment choice in patients diagnosed with advanced NSCLC with MET exon 14 skipping mutation. Strategies to enhance the activity of the currently available KRAS G12C inhibitor (sotorasib) are promising but not yet convincing, and sotorasib remains the standard second-line targeted therapy for KRAS G12C mutant NSCLC. While data for targeting acquired MET amplification resistance are emerging, strategies to target C797S are still in their infancy.

References:

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