Highlights from the WCLC 2023 – Targeting MET Alterations

The 2023 World Conference on Lung Cancer (WCLC 2023) was held in Singapore, on 10–12 September. The meeting covered some exciting developments in the field of lung cancer, with a focus on multidisciplinary approaches in diagnosis, treatment, research, and care. Novel targeted therapies for patients with specific molecular characteristics and targetable oncogenic driver alterations were discussed. Highlights included new data in novel targets, biomarkers, targeted therapy of MET Exon 14 skipping mutation (METex14) and MET amplification (METamp), and the use of MET inhibitors in non-small cell lung cancer (NSCLC).

First-Line Savolitinib Showed Encouraging Efficacy in METex14 Mutated NSCLC in a Phase 3b Study

Savolitinib, a potent and highly selective oral MET tyrosine kinase inhibitor (TKI) has shown preliminary efficacy in patients with METex14 NSCLC. The phase 3b study (NCT04923945) was a single-arm, multi-cohort, multi-center, open-label study. At WCLC 2023, Prof. Shun Lu presented new data focusing on patients in cohort 2 (1L) with at least 6 months follow-up or end of treatment (OA21.03). 

Cohort 2 (1L) comprised patients with advanced or metastatic treatment-naïve METex14 NSCLC. The results showed encouraging efficacy of 1L savolitinib. In the tumor-response-evaluable set (n=84), the objective response rate (ORR) assessed by independent review committee (IRC) was 60.7% (95% CI: 49.5.6, 71.2) and the disease control rate (DCR) was 95.2% (95% CI: 88.3%, 98.7%). All subtypes of METex14 NSCLCs demonstrated efficacy with 1L savolitinib. In the full analysis set (n=87), the ORR assessed by IRC was 58.6% (95% CI: 47.6, 69.1), the median duration of response (mDOR) was not reached [NR] (95% CI: 9.7, NR), the median time to response (mTTR) was 1.4 months (95% CI: 1.4, 1.5), and the DCR was 92.0% (95% CI: 84.1, 96.7). The median progression-free survival (mPFS) was 13.8 months (95% CI: 9.7, NR) with a median follow-up of 11.1 months (95% CI: 11.0, 13.7) and the 6-month PFS rates were 76.4% (95% CI: 65.6, 84.3). The median overall survival (mOS) was NR (95% CI: 17.4, NR) with a median follow-up of 15.0 months (95% CI: 13.2, 15.4).

The safety profile was tolerable and no new safety signals were found. Prof. Shun Lu concluded that the data indicate a potential use of 1L savolitinib in patients with treatment-naïve METex14 NSCLC. 

CHRYSALIS: Amivantamab Demonstrated Antitumor Activity in Primary METex14 Advanced NSCLC

Amivantamab, a bispecific EGFR-MET antibody, is approved for the treatment of advanced NSCLC with EGFR exon 20 insertion mutations after prior platinum-based chemotherapy. An earlier study showed encouraging antitumor activity of amivantamab in patients with advanced, METex14 NSCLC. At WCLC 2023, Natasha B. Leighl presented updated results from the study, which included a larger population of patients with advanced METex14 NSCLC (OA21.04).

CHRYSALIS (NCT02609776) is an ongoing phase 1 study of amivantamab monotherapy in patients with primary advanced METex14 NSCLC whose disease had progressed on, or who had declined, the current regional standard-of-care. As of June 19, 2023, 97 patients were enrolled in the METex14 NSCLC cohort.

Amivantamab demonstrated antitumor activity with a median follow-up of 10.0 months in patients with primary METex14 advanced NSCLC, including patients who failed on MET inhibitors: the ORR was 33% in the overall population, the mPFS was 5.4 months (95% CI: 4.3, 7.0), and the mOS was 15.8 months (95% CI: 13.1, 21.8). The ORR in treatment-naïve patients was 50%; for patients with no prior MET inhibitors and those with prior MET inhibitors, the ORRs were 46% and 21%, respectively. Amivantamab also showed durable clinical benefits. The mDOR was 11.2 months (95% CI: 5.3, 19.0) with a DOR ≥ 6 months in 47% of responders, and 38% (12/32) remain on treatment. The overall clinical benefit rate (CBR) and the CBRs for cohorts of patients with treatment-naïve, no prior MET inhibitor and prior MET inhibitors were 70% (95% CI: 60, 79), 88% (95% CI: 62, 98), 64% (95% CI: 44, 81) and 68% (95% CI: 54, 80), respectively.

The safety profile was consistent with the prior report in EGFR-driven NSCLC. Rash (78.4%), infusion-related reaction (72.2%), and paronychia (48.5%) were the most common treatment-emergent adverse events (TEAEs). No new safety signals were found. A clinical trial (NCT05488314) investigating amivantamab plus capmatinib (MET inhibitor) in patients with METex14 or METamp NSCLC is ongoing.

Liquid Biopsy Analysis from the VISION Trial: Tepotinib in METex14 NSCLC

Tepotinib has shown robust and durable efficacy in patients with METex14 NSCLC. Liquid biopsy (LBx) biomarkers (NGS and circulating MET-related markers) were analyzed for potential prognostic, predictive, or pharmacodynamic relevance (data cut-off: Nov 20, 2022). ctDNA next generation sequencing (NGS) (Guardant360®) or enzyme-linked immunosorbent assay (ELISA) were used to analyze baseline, on-treatment and/or end-of-treatment (EOT) LBx from the VISION study for shed MET (sMET) and hepatocyte growth factor (HGF). The results were presented at WCLC 2023 (OA21.06).

The correlation between outcomes and baseline and on-treatment biomarkers was evaluated. Patients with high baseline HGF (>upper quartile [1.67 ng/mL], n=58) had numerically shorter mDOR and mPFS compared with low HGF (≤upper quartile, n=175): 13.4 months (95% CI: 6.6, not estimable [NE]) vs 19.4 months (95% CI: 10.8, NE) and 8.0 months (95% CI: 4.1, 11.0) vs 13.7 months (95% CI: 11.0, 19.7), respectively. Baseline sMET levels had no correlation with response status (CR/PR, SD, or PD). However, for patients with baseline and ≥1 on-treatment sMET measurement, relative change from baseline triggered numerically higher ORR, mPFS and mOS in low sMET change (≤lower quartile, n=61) compared with high (>lower quartile, n=183). For 165 patients with baseline LBx NGS profiles, 114 were positive for METex14 (L+) and 51 were negative (L-). ORRs were comparable between L+ and L- patients, but L- patients had longer mDOR and mPFS.

In analyses of outcomes according to baseline oncogenic alterations detected by NGS, patients with TP53 mutations (73/165, 44%) and patients with wild-type TP53 had comparable ORR, but mPFS was shorter for the TP53 mutated (8.2 months [95% CI: 6.8, 11.0] vs 11.3 months [95% CI: 8.5, 19.7]). Among the 81 L+ patients with two consecutive on-treatment samples, patients with confirmed molecular response (MR, n=65) had better clinical outcomes than patients with molecular progression (MP, n=12): mDOR, 18.5 months (95% CI: 9.0, 46.4) vs 6.2 months (95% CI: 4.1, NE); mPFS, 11.2 months (95% CI: 9.5, 19.7) vs 4.2 months (95% CI: 1.4, 8.2).

Acquired resistance was identified in post-progression EOT samples. 9 of 73 patients had acquired MET kinase domain mutations and 7 of them had PR as best response. Off-target alterations in KRAS (mutation and amplification), EGFR (mutation and amplification), MYC (amplification), BRAF (amplification), RB1 (mutation), and ERBB2 (amplification) were observed in 9/73 (12%) patients, whichpotentially contributed to acquired resistance together with the on-target secondary MET mutations.

INSIGHT-2:  Tepotinib + Osimertinib Demonstrated Promising Efficacy in METamp EGFRm NSCLC

INSIGHT-2 (NCT03940703) is an open-label Phase II study of tepotinib in combination with osimertinib in patients with EGFR-mutant MET amplification (EGFRm METamp) NSCLC following 1L osimertinib. At WCLC 2023, Tae Min Kim presented the primary analysis (>9 months follow-up, data-cut on March 28, 2023) of the entire population and patients enrolled in Asia (OA21.05).

The combination of tepotinib and osimertinib demonstrated clinically meaningful efficacy outcomes in the studied cohort and the subset in Asia. The primary endpoint was ORR by IRC in patients with central fluorescence in situ hybridization (FISH)+ METamp. In 98 patients with FISH+ METamp receiving tepotinib and osimertinib, ORR was 50.0% (95% CI: 39.7, 60.3) which was consistent across patient subgroups; mDOR was 8.5 months (95% CI: 6.1, NE); mPFS and mOS were clinically meaningful, 5.6 months (95% CI: 4.2, 8.1) and 17.8 months (95% CI: 11.1, NE), respectively.

Of 76 Asian patients, 52 had confirmed FISH+ METamp. ORR in this subgroup was 59.6% (95% CI: 45.1, 73.0). The mDOR, mPFS and mOS were 7.3 months (95% CI: 4.7, NE), 6.9 months (95% CI: 5.4, 8.4), and 19.8 months (95% CI: 13.6, NE), respectively. Efficacy outcomes were also clinically meaningful in 31 patients with LBx NGS METamp and 19 patients with brain metastases at baseline (TBx FISH), ORRs were 54.8% (95% CI: 36.0, 72.7) and 57.9% (95% CI: 33.5, 79.7), respectively.

The combination demonstrated a manageable safety profile. The health-related quality of life (HRQoL) was maintained. A similar safety profile was reported among Asian patients. Tae Min Kim concluded that tepotinib plus osimertinib provided a potential chemotherapy-sparing oral targeted treatment option for patients with EGFRm NSCLC with METamp following 1L osimertinib, who have a high unmet need for treatment.

Activating MET Tyrosine Kinase Domain Mutations as De Novo Oncogenic Drivers in NSCLC

Activating MET tyrosine kinase domain (TKD) mutation was identified to be the sole oncogenic driver in a small but significant subset of NSCLC and was a potential target of the currently available MET TKIs (OA19.05). The study collected MET TKD mutations and other genomic data from > 11,000 NSCLC patients in two cohorts. MET TKD mutations were further divided into two subtypes, i.e., “oncogenic-likely oncogenic” and “unknown biological function”. Cohort #1 focused on the GENIE, China Pan-Cancer, TCGA, DFCI, MSKCC, and cohort #2 was defined as the Foundation Medicine Pan-Cancer cohort.

In cohort #1, 0.2% (44/23,195) of patients, and 0.14% (129/92,406) of patients in cohort #2, had “oncogenic-likely oncogenic” MET TKD mutations without concurrent METex14 alterations. The most common mutations were amino acid substitutions at positions H1094, D1228, L1195, Y1230, and M1250. “Oncogenic-likely oncogenic mutations” were identified as the sole driver mutation in 45% (20/44) of patients in cohort #1 and 60% (78/129) in cohort #2.

Importantly, two patients who had lung adenocarcinoma harboring MET TKD mutations as a sole driver were enrolled in a clinical trial with elzovantinib (TPX-0022), a MET inhibitor, and both experienced substantial tumor shrinkage. Preclinical models showed that a majority of “oncogenic-likely oncogenic” mutations and some with currently “unknown biological function” had the potential to transform Ba/F3 cells. Ba/F3 cells expressing MET TKD mutations demonstrated differential sensitivity to currently available type I and type II MET TKIs. In conclusion, activating MET TKD mutation was identified as the sole oncogenic mutation in a small but significant subset of NSCLC and was potentially targetable with currently available MET TKIs.