METex14 Skipping Research Articles

Programmed Cell Death Protein 1 Inhibitors and MET Targeted Therapies in NSCLC With MET Exon 14 Skipping Mutations: Efficacy and Toxicity as Sequential Therapies

IntroductionNSCLC with MET exon 14 skipping mutation (METex14) is associated with poor outcomes. Integration of novel targeted therapies is challenging because of barriers in testing and drug access. We, therefore, sought to characterize the treatment patterns, outcomes, and emerging issues of treatment sequencing in patients with METex14-mutant NSCLC. MethodsWe reviewed all NSCLC cases with METex14 alterations between 2014 and 2020 across four Canadian cancer centers. Demographics, disease characteristics, systemic therapy, overall response rates (ORRs), survival, and toxicity were summarized. ResultsAmong 64 patients with METex14-mutant NSCLC, the median overall survival was 23.1 months: 127.0 months in stage 1, 27.3 months in resected stage 2 and 3, and 16.6 months in unresectable stage 3 or 4 disease, respectively. In patients with advanced disease, 22% were too unwell for systemic treatment. MET tyrosine kinase inhibitors (TKIs) were administered to 28 patients with an ORR of 33%, median progression-free survival of 2.7 months, and 3.8 months for selective TKIs. Programmed cell death protein-1 (PD-1) inhibitors were given to 25 patients—the ORR was 44% and progression-free survival was 10.6 months. No responses were seen with subsequent MET TKIs after initial TKI treatment. Grade 3 or higher toxicities occurred in 64% of patients who received MET TKI after PD-1 inhibitors versus 8% in those who did not receive PD-1 inhibitors. ConclusionsMany patients with advanced METex14 NSCLC were too unwell to receive treatment. PD-1 inhibitors seem effective as an initial treatment, although greater toxicity was seen with subsequent MET TKIs. Thus, timely testing for METex14 skipping and initial therapy are imperative to improving patient survival.

ABN401 in patients with NSCLC with MET exon 14 (METex14) skipping: Result from the pilot expansion study.

e21148 Background: c-MET alterations, specifically exon 14 skipping mutations occur in ~ 4% of NSCLC cases and are now considered an actionable biomarker in the metastatic setting1. In addition to its pathophysiological role, c-MET alterations have also been implicated as a major resistance mechanism to targeted therapies against EGFR and vascular EGFR. These findings have widened the research on c-MET-altered NSCLCs and driven a new era of MET inhibitors. ABN401, a highly selective MET kinase inhibitor, has demonstrated an acceptable safety profile and promising preliminary antitumor activity in patients (pts) with advanced solid tumors2. Here, results are reported from the pilot expansion part of phase 1 evaluating ABN401 in pts with NSCLC harboring c-MET dysregulation. Methods: Pts with c-MET dysregulation in NSCLC were enrolled in the phase 1 pilot expansion cohort. ABN401 was orally administered daily in a 21-day cycle at the recommended phase 2 dose (RP2D) of 800mg, which was established in the dose escalation cohort. The primary objective was to evaluate the safety and tolerability of ABN401 and determine the dose-limiting toxicity (DLT) and the maximum tolerated dose (MTD) according to CTCAE v5. Secondary objectives included pharmacokinetic assessments and preliminary evaluations of efficacy. Tumor assessments were performed using the Response Evaluation Criteria in Solid Tumors (RECIST 1.1) in pts with c-MET dysregulation in NSCLC. Results: c-MET dysregulated (overexpression, amplification, and METex14 skipping) NSCLC pts were enrolled and received a daily dose of 800 mg ABN401 without experiencing any dose-limiting toxicities (DLTs). As of January 31, 2023, four pts are still on treatment. The safety profile of ABN401 was consistent with previous reports2 and the most common treatment-related adverse events were nausea, vomiting, and diarrhea (grade 1, mild). All pts in this cohort tolerated the treatment well at a dose of 800mg QD. Among all, 4 pts had METex14 skipping mutations, out of which 2 pts demonstrated partial responses to the therapy, and one patient had SD. One patient with MET amplification is now in SD and has been receiving treatment for approximately 16 months. Conclusions: The ABN401 pilot expansion part of phase 1 demonstrated promising anti-tumor effects and safety in NSCLC pts with c-MET dysregulation, providing support for further evaluation of ABN401 in the METex14 skipping cohort (cohort-1) of the global phase 2 study (NCT05541822). Enrollment is currently ongoing. References National Comprehensive Cancer Network: Non-small cell lung cancer (version 2.2021). https://www.nccn.org/professionals/physician_gls/default.aspx#nscl . Dae Ho Lee, et al. Journal of Clinical Oncology 2022 40:16_suppl, 3105-3105. Clinical trial information: NCT04052971 .

Biomarkers to predict the efficacy of immune checkpoint inhibitors in patients with non-small-cell lung cancer with actionable genetic alterations.

e21175 Background: Although the efficacy of immune checkpoint inhibitors (ICI) in patients with actionable genetic alterations (AGAs) in non-small-cell lung cancer (NSCLC) has been known to be modest, some patients demonstrated improved survival. Thus, this study aimed to find predictive biomarkers for ICI in patients with NSCLC with various AGAs and to identify the predictive biomarkers for ICI efficacy. Methods: We compared the progression-free survival (PFS) of 324 advanced NSCLC patients who received ICI monotherapy (as over second-line therapy) by different AGAs from January 2018 and July 2022 at the Samsung Medical Center. To identify predictive markers of ICI, we adjusted the impacts on PFS of ICI in smoking status, PD-L1 expression, TP53, KEAP, STK11 mutation status, and steroid use during ICI monotherapy. Results: The median age was 63.1 years (range, 27.8–84.8) and 53.1% of patients was male, and 46.3% of patients was an ex-/or current smoker. A total of 324 patients were included with the following AGAs: EGFR mutation (n = 149, 46.0%), ALK rearrangement, (n = 12, 3.7%), KRAS mutation (n = 72, 22.2%), HER2 mutation or amplification (n = 34, 10.5%), and MET ex14 skipping or amplification (n = 32, 9.9%), ROS1 rearrangement (n = 9, 2.8%), BRAF V600E (n = 9, 2.8%), and RET rearrangement (n = 7, 2.2%). The median PFS was 2.0 months (95% confidence interval, 1.8–2.2) in the total AGA group. The 6-month PFS rate was 25.8% (19.5–34.3) in the group with KRAS/ BRAF V600E/ MET/ HER2 and 12.8% (8.6–19.1) in the group with EGFR/ ALK/ ROS1/ RET (P < 0.01). In the group with KRAS/ BRAF V600E/ MET/ HER2, KEAP, or STK11 wild-type (P = 0.03), PD-L1 (≥1%) (P < 0.01) and steroid use during ICI monotherapy due to immune-related adverse events (IRAE) (P < 0.01) were related to a favorable PFS of ICI; however, no statistical significance was found for TP53 mutation and smoking status for PFS of ICI. In the group with EGFR/ ALK/ ROS1/ RET, PD-L1(≥ 50%) was the only factor that was related to a favorable PFS, and not TP53 mutation status, KEAP, or STK11. Conclusions: This study showed a difference in PFS among each type of AGAs. Although there are limitations due to the small number of patients, the KRAS/ BRAF V600E/ MET/ HER2 group had a favorable PFS compared with the EGFR/ ALK/ ROS1/ RET group . KEAP/STK11/PD-L1 status and steroid use due to IRAE predicted favorable PFS of ICI in the KRAS/ BRAF V600E/ MET/ HER2 group .

Response to neoadjuvant immune checkpoint inhibitor (ICI)-based therapy in oncogene-driven resectable non-small cell lung cancer (NSCLC).

8523 Background: Neoadjuvant (NEO) chemotherapy (chemo) plus nivolumab (nivo) has received FDA approval for treatment of resectable NSCLC, demonstrating superior event-free survival compared to chemo alone. However, outcomes of NEO ICI-based therapies in patients (pts) with oncogene-driven (OD)-NSCLC remains an unanswered question. Methods: We conducted a retrospective secondary analysis of pts enrolled in the clinical trial NCT02259621 with clinical stage I-IIIA NSCLC, treated with NEO ICI-based therapies: nivo alone, nivo+ipilimumab (ipi), or nivo+chemo followed by surgery. Pts underwent baseline genomic profiling using NGS. Pts with KRAS, EGFR, MET, BRAF, ALK, HER2, ROS1, RET or NTRK alterations were identified as OD-NSCLC. STK11 and KEAP1 mutations (muts) were also recorded. For pts who underwent definitive resection (DR) and baseline NGS testing, association of OD-status and clinical outcomes, including major pathologic response (MPR) and recurrence-free survival (RFS) are reported. Proportions are reported with exact 95% binomial confidence intervals (CI). Binomial probabilities are compared with Chi-square or Fisher’s exact tests. RFS and median follow-up (f/u) are reported using the Kaplan-Meier (KM) and reverse KM methods, respectively. Results: 61 pts received NEO ICI-based therapy: 60% treated with nivo alone, 15% with ipi+nvo and 25% with chemo+nivo. 92% of pts underwent DR. Pathologic complete response (pCR) and MPR rates were, 12.5% and 37.5%, respectively. Baseline NGS testing was available for 47 pts, of whom, 49% had OD-NSCLC, with the majority (78%) harboring a KRAS mut. Additional OD alterations included non-classical EGFR (9%), METex14 skipping (9%) and ROS1 fusion (4%), of whom, 3/5 pts had a MPR after NEO-ICI. STK11 muts were noted in 16% pts, and co-altered with KRAS in 9%. Median f/u for OD-NSCLC was 42.58 months. Pts with OD-NSCLC had comparable RFS after NEO-ICI compared to those with non-OD-NSCLC (HR 0.64, CI 0.19-2.13, p=0.5), including those with KRAS+ disease (HR 0.73, CI 0.2-2.73, p=0.6). Pts with co-mut KRAS+ STK11+ trended toward shorter RFS compared to KRAS+ STK11- (HR 6.36, CI 0.56-72.82, p=0.1). STK11+ also trended toward shorter RFS without reaching statistical significance (HR 2.51, CI 0.67-9.35, p=0.17). No significant associations between OD-status and MPR rates were seen, however KRAS+ (4/18) vs. Kras- (13/29) trended toward lower MPR rate (p=0.1). Four of 5 pts with disease progression preventing DR harbored an STK11 or KEAP1 mut. Conclusions: Findings from this cohort treated with various NEO ICI-based therapies, suggests comparable RFS, regardless of OD status- with the majority harboring KRAS muts. Lower MPR rates were observed for pts with KRAS+ tumors. STK11 mut and KRAS+ STK11+ co-mut status both trended toward shorter RFS, though definitive conclusions are limited by cohort size and treatment heterogeneity.

Effects of mutations in SWI/SNF subunits on context-specific prognosis in driver positive and driver negative NSCLC.

9039 Background: Mutations(mt) in the Switch/Sucrose-Nonfermentable chromatin remodeling complex (SWI/SNF) are commonly found in NSCLC and have been associated with worse prognosis. However, the overall prognostic role of the individual SWI/SNF subunits in all NSCLCs and in oncogenic driver-positive (D+) and driver-negative (D-) groups remains unclear. Our study attempts to clarify the prognostic role of SWI/SNF subunit alterations in these populations. Methods: 42,379 NSCLC tumor specimens were tested at Caris Life Sciences (Phoenix, AZ) with NextGen Sequencing (NGS) of DNA (592-gene panel or whole-exome sequencing). Based on the observed frequency of likely pathogenic/pathogenic (LP/P) mts, the four most commonly-altered SWI/SNF subunits – ARID1A (8.29%), SMARCA4 (6.29%), ARID2 (3.05%) and PBRM1 (1.98%) – were further analyzed. We divided the cohort by driver mts. D+ tumors possessed at least one of the following alterations: LP/P mts in KRAS, EGFR, BRAF, ERBB2 or MET; METex14 skipping; ERBB2 amplification, LP/P fusions in ALK (including IHC overexpression), RET, ROS1, NTRK (1-3) & NRG1. D- tumors were devoid of mts/amplifications/fusions in all genes mentioned above. Kaplan-Meier analysis was performed on real world survival data (n = 24685) obtained from insurance claims. Statistical significance was determined using chi-square and Mann-Whitney U test adjusted for multiple comparisons (q < 0.05). Results: Of the SWI/SNF genes, only SMARCA4mts were associated with worse survival in the overall (HR = 1.46), D+ (HR = 1.984) and D- (HR = 1.224) cohorts (all p < 0.01). While SMARCA4mt was associated in the D- cohort with KEAP1 and STK11 mts, the worse prognosis persisted even in their absence (HR = 1.41, p < 0.001). To understand the role of SWI/SNF mts in the context of driver co-mts, we compared the survival of D+ vs D- tumors for each SWI/SNF subunit. As expected, D+ tumors were associated with better survival in SWI/SNF wild-type (wt) tumors (HRs 0.76-0.78, p < 0.00001). There was no survival effect of ARID1A, ARID2 or PBRM1 mts (HRs = 0.9-1, p = ns). In contrast, in SMARCA4mts, D+ tumors had much worse survival than D- (HR = 1.295, p = 0.003). This effect is driven by the KRASmt cohort, as KRASmt/SMARCA4mt tumors had significantly worse survival compared with D- tumors (HR = 1.882, p < 0.001). Of note, KRASmts are enriched in the D+/SMARCA4mt subgroup (78% of all oncogenic drivers). When KRASmts were removed from the D+ group, no survival difference was observed between D+ and D- SMARCA4mt tumors (HR = 0.938, p = ns). Conclusions: In this largest-ever retrospective cohort of NSCLC patients with SWI/SNF mutations, SMARCA4mt is the only SWI/SNF alteration broadly associated with worse survival. SMARCA4mt is associated with particularly short survival in KRASmt tumors. These data suggest underlying biology which may inform further investigation and therapeutic development.

Phase Ib study of neoadjuvant concurrent chemoradiation plus durvalumab followed by surgery and adjuvant durvalumab for resectable stage III NSCLC.

8556 Background: The use of neoadjuvant and adjuvant immunotherapy in resectable non-small cell lung cancer (NSCLC) has become a standard of care. However, the integration of immunotherapy into a trimodality treatment regimen has not been widely explored. We hypothesized that adding durvalumab to neoadjuvant concurrent chemoradiation and surgery would not increase treatment-related adverse events (TRAE) during neoadjuvant period. Methods: This was a prospective, single center, single-arm, open-label phase Ib study. Patients with resectable, stage III N2 NSCLC received concurrent chemoradiation [weekly paclitaxel (45mg/m2)/carboplatin (AUC 2.0) for 5 weeks with radiotherapy 45Gy] and durvalumab 1,500mg Q4W for 2 cycles followed by surgical resection and adjuvant durvalumab for 1 year. The primary endpoint was the frequency of patients who experience grade 3 or more TRAE during neoadjuvant therapy based on CTCAE 4.03. Results: Of 30 patients (median age 65.5 years; 67% male), 56.7% had squamous histology and 60.0% had stage IIIA. Any grade AEs and TRAEs (neoadjuvant/adjuvant) were reported in 83.3%/76.7% and 70.0%/63.3% of patients, respectively. Grade 3 or more AEs and TRAEs (neoadjuvant/adjuvant) were reported in 10.0/3.3% and 10.0%/0.0%, respectively. Grade 3 or more TRAE reported during neoadjuvant treatment were neutropenia, anemia, and nausea, one each; no Grade 5 AEs occurred. Surgical resection was not performed in three patients: two due to treatment-related adverse events (AEs) and one due to patient refusal. Among 27 patients who received complete resection, the pathologic complete response (pCR) rate and major pathologic response (MPR) rate were 40.7% (95% CI, 22.4 – 61.2) and 74.1% (95% CI, 53.7 – 88.9), respectively. Excluding four patients with EGFR, ALK, KRAS G12C, or MET ex14skipping mutations, the pCR rate was 47.8% (95% CI, 26.8 – 69.4) and MPR rate was 87.0% (95% CI, 66.4 – 97.2). Overall, pathologic downstaging was achieved in 70.4% (95% CI, 49.8 – 86.2). Objective response rate according to RECIST v1.1 was 50.0% (95% CI, 31.3 – 68.7). One patient delayed the schedule for surgical resection due to radiation pneumonitis (G2), unrelated to the drug administered. Otherwise, there were no peri-operative mortality or morbidity. All patients who underwent surgery, except one whose disease progressed immediately after resection, received at least one dose of adjuvant durvalumab; 61.5% completed 1-year treatment, 11.5% were continuing treatment, 11.5% discontinued due to AE, and 11.5% discontinued due to disease progression at the time of data cutoff. Grade 3 or more TRAE reported during adjuvant treatment were radiation pneumonitis and proteinuria, one each. Conclusions: This study confirms the manageable safety profile of adding durvalumab to neoadjuvant concurrent chemoradiation for treatment of resectable stage III NSCLC. Clinical trial information: NCT03694236 .

EE146 Cost-effectiveness of Tepotinib for Patients With Previously Treated Advanced Non-Small Cell Lung Cancer Harboring Metex14 Skipping Alterations in Spain

We evaluated the cost-effectiveness of tepotinib vs. alternatives considered the standard of care in Spain in previously treated patients with advanced non-small-cell lung cancer harboring METex14 skipping alterations (aNSCLC METex14) from the payer perspective.

Savolitinib versus crizotinib for treating MET positive non-small cell lung cancer.

The c-MET protein, encoded by the mesenchymal-epithelial transition factor (MET) gene, can regulate cell proliferation, migration and invasion. Studies have shown that it is one of the essential driver genes for non-small cell lung cancer (NSCLC). Currently, several clinical studies have carried out objective assessments on the efficacy and safety of different types of MET tyrosine kinase inhibitors (TKIs). However, direct cross-sectional comparisons between different agents are still not available. Our study was a single-center retrospective clinical study, which collected the data from MET positive NSCLC patients treated with MET TKIs at the Lung Cancer Center of Peking Union Medical College Hospital. We explored the efficacy and safety of crizotinib versus savolitinib in patients with METex14 skipping and MET amplification, separately. Patients with METex14 skipping (median PFS=10.7months) had a better clinical response to MET TKIs than MET amplification patients (median PFS=4.1months). In the METex14 skipping subgroup, savolitinib did not show better survival benefit with significance than crizotinib (p > 0.05). In the MET amplification subgroup, savolitinib (median PFS=7.1months) demonstrated a better progression-free survival benefit than crizotinib (median PFS=1.4months), p=0.05. The most common adverse effects of both MET TKIs were peripheral edema (41.2%), gastrointestinal reactions (23.5%), and liver injury (14.7%). The incidence rate of peripheral edema was higher in savolitinib than crizotinib. In METex14 skipping NSCLC patients,the efficacy of savolitinib and crizotinib did not show significant difference. In MET amplification patients, savolitinib showed better efficacy than crizotinib.

MET Exon 14 Variants in Non-Small Cell Lung Carcinoma: Prevalence, Clinicopathologic and Molecular Features

Somatic MET exon 14 skipping mutations (MET ex14) are targetable driver mutations for non-small cell lung cancer (NSCLC), responsive to MET inhibitors. Objective: This study seeks to further characterize the clinicopathologic features and mutational profile of MET ex14 variant NSCLC. Design: Retrospective review of all MET ex14 tested NSCLC. Testing for selected BRAF, EGFR, HER2, KRAS, and MET mutations was performed using a clinically validated NGS assay, followed by MiSeq sequencing. Variants were classified as significant (Tier1/2) or variants of uncertain significance (VUS) per 2017 AMP/ASCO/CAP Joint Consensus Guidelines. PD-L1 expression was assessed by immunohistochemistry. Results: Of 2296 NSCLCs tested between 2017-7/2019, MET ex14 variants were present in 44 (1.9%). A total of 32 of 44 variants were MET exon 14 skipping, while the other 12 mutations were significant missense (3) or VUS (9). Of nine VUS, five were adjacent to the canonical splice site and likely to impact splicing. Four cases had concomitant mutations. Of 35 cases with known clinical staging, stage 1–2 = 20 (57%), stage 3 = 3 (9%), and stage 4 = 12 (34%). Of 19 resected NSCLSs, histological types and growth pattern included 7 lepidic pattern-predominant. A high percentage of tumors with MET ex14 mutations are positive for PD-L1, and the percentage of cases with PD-L1 expression >50% trends higher in more advanced disease. Conclusions: Most MET variants identified in our cohort (73%) are MET ex14 skipping. The prevalence of MET ex14 variants is 1.9%, and a large percentage of tumors has lower clinical stage and less aggressive pathologic features.

Robust Performance of the Novel Research-Use-Only Idylla GeneFusion Assay Using a Diverse Set of Pathological Samples with a Proposed 1-Day Workflow for Advanced NSCLC Evaluation.

A range of different techniques are available for predictive biomarker testing for non-small-cell lung cancer (NSCLC) clinical management. International guidelines suggest next-generation sequencing (NGS) as the preferred procedure, but other reverse transcriptase-polymerase chain reaction (RT-PCR)-based methods are rapidly evolving. In this study, we evaluated the reliability and accuracy of the IdyllaTM GeneFusion assay, a rapid and fully automated platform able to simultaneously detect ALK, ROS1, RET and NTRK1/2/3 and MET ex14 skipping mutations and compared its performance with routine reference methods. The cohort included thirty-seven NSCLCs plus two parotid gland carcinomas, previously characterized for the above alterations through either IHC, FISH, RT-PCR or NGS. In 36 of 39 cases, the Idylla GeneFusion assay and the reference methods were concordant (overall agreement: 92.3%). Tumor sections stored at room temperature for up to 60 days and 17 cases older than 2 years were successfully characterized. Our results suggest that the Idylla GeneFusion assay is a reliable tool to define gene fusion status and may be a valuable stand-alone diagnostic test when time efficiency is needed or NGS is not feasible.

Identification of Novel MET Exon 14 Skipping Variants in Non-Small Cell Lung Cancer Patients: A Prototype Workflow Involving in Silico Prediction and RT-PCR.

HighlightsMET exon 14 skipping is an oncogenic targetable driver mutation in lung cancer. Two novel non-canonical splice site variants identified in MET genome.Predicted splicing strength using in silico splicing prediction tools.Tested routine cytological smear slides for RNA-based molecular diagnostics.RT-PCR and Sanger sequencing analysis confirmed MET exon 14 skipping. Simple SummaryNon-small Cell Lung cancer (NSCLC) contributes to 85% of total lung cancer diagnoses in the United States. With the discovery of various targetable genetic markers and FDA approval of drugs against these markers, genetic testing has become a routine part of the diagnosis and staging process of NSCLC. MET gain of function mutations have been of particular interest as FDA has recently approved two MET inhibitors for the treatment of NSCLC patients with MET exon 14 skipping (METex14) mutations. However, an effective workflow for the classification of various METex14 mutations in the clinical testing laboratory has not been explored. In this report, we reveal two novel METex14 variants and propose a cost-effective and robust workflow for molecular diagnosis of MET variants contributing to exon 14 skipping with the use of readily available specimen sources.Background and aims: The MET exon 14 skipping (METex14) is an oncogenic driver mutation that provides a therapeutic opportunity in non-small cell lung cancer (NSCLCs) patients. This event often results from sequence changes at the MET canonical splicing sites. We characterize two novel non-canonical splicing site variants of MET that produce METex14. Materials and Methods: Two variants were identified in three advanced-stage NSCLC patients in a next-generation sequencing panel. The potential impact on splicing was predicted using in silico tools. METex14 mutation was confirmed using reverse transcription (RT)-PCR and a Sanger sequencing analysis on RNA extracted from stained cytology smears. Results: The interrogated MET (RefSeq ID NM_000245.3) variants include a single nucleotide substitution, c.3028+3A>T, in intron 14 and a deletion mutation, c.3012_3028del, in exon 14. The in silico prediction analysis exhibited reduced splicing strength in both variants compared with the MET normal transcript. The RT-PCR and subsequent Sanger sequencing analyses confirmed METex14 skipping in all three patients carrying these variants. Conclusion: This study reveals two non-canonical MET splice variants that cause exon 14 skipping, concurrently also proposes a clinical workflow for the classification of such non-canonical splicing site variants detected by routine DNA-based NGS test. It shows the usefulness of in silico prediction to identify potential METex14 driver mutation and exemplifies the opportunity of routine cytology slides for RNA-based testing.

21P Analytical performance of FusionPlex Dx

FusionPlex Dx (FP Dx) is a 2-part multimodal next-generation sequencing (NGS)-based in vitro diagnostic kitted device that detects structural alterations and oncogenic isoforms in RNA derived from formalin-fixed, paraffin-embedded (FFPE) samples from solid tumors using proprietary Anchored Multiplex PCR (AMP™) chemistry. FP Dx is approved as a companion diagnostic for five indications: METex14 skipping events, ALK, RET, ROS1 gene fusions to guide therapy in non-small cell lung cancer and NTRK1/2/3 gene fusions for all solid tumors.

MA05.07 Intertumoral Molecular Heterogeneity of Non-small Cell Lung Cancer with MET Exon 14 Skipping

MET exon 14 skipping, as a rare driver for non-small cell lung cancer (NSCLC), can be successfully targeted by MET specific tyrosine kinase inhibitors (TKI) like Savolitinib, Tepotinib, and Capmatinib. Recent clinical trials of MET selective TKIs displayed encouraging clinical efficacy. While nearly half of NSCLC patients with MET exon 14 skipping did not benefit from MET-TKI treatment, which indicated biological heterogeneity in NSCLCs driven by METex14 skipping. This study aims to disclose the intertumoral heterogeneity of METex14 skipping positive NSCLCs at the functional level.

1182P US real-world (RW) patient characteristics with METex14 skipping advanced non-small cell lung cancer (aNSCLC)

We evaluated the characteristics of adult patients (pts) with METex14 skipping aNSCLC using RW data predating the FDA approval of the two MET tyrosine kinase inhibitors (TKIs), tepotinib and capmatinib.

Oncogene Overlap Analysis of Circulating Cell-free Tumor DNA to Explore the Appropriate Criteria for Defining MET Copy Number–Driven Lung Cancer

IntroductionDefining clinically relevant MET amplification levels in non-small cell lung cancer (NSCLC) remains challenging. We hypothesize that oncogene overlap and MET amplicon size decline with increase in MET plasma copy number (pCN), thus enriching for MET-dependent states. Patients and MethodsWe interrogated cell-free DNA NGS results of 16,782 patients with newly diagnosed advanced NSCLC to identify those with MET amplification as reported using Guardant360. Co-occurring genomic mutations and copy number alterations within each sample were evaluated. An exploratory method of adjusting for tumor fraction was also performed and amplicon size for MET was analyzed when available. ResultsMET amplification was detected in 207 (1.2%) of samples. pCN ranged from 2.1 to 52.9. Of these, 43 (20.8%) had an overlapping oncogenic driver, including 23 (11.1%) METex14 skipping or other MET mutations. The degree of (non-MET) oncogene overlap decreased with increases in pCN. Patients with MET pCN ≥ 2.7 had lower rates of overlapping drivers compared to those with MET pCN < 2.7 (6.1% vs. 16.3%, P = .033). None of the 7 patients with pCN > 6.7 had an overlapping driver. After adjusting for tumor fraction, adjusted pCN (ApCN) was also lower for those with overlapping drivers than those without (median ApCN 4.9 vs. 7.3, P =.024). There was an inverse relationship between amplicon size and pCN. ConclusionsWe propose that a high MET pCN and/or ApCN, together with the absence of overlapping oncogenic drivers and small MET amplicon size, will enrich for patients most likely to derive benefit from MET targeted therapy.

Exposure–response analyses for the MET inhibitor tepotinib including patients in the pivotal VISION trial: support for dosage recommendations

PurposeTepotinib is a highly selective MET inhibitor approved for treatment of non-small cell lung cancer (NSCLC) harboring METex14 skipping alterations. Analyses presented herein evaluated the relationship between tepotinib exposure, and efficacy and safety outcomes.MethodsExposure–efficacy analyses included data from an ongoing phase 2 study (VISION) investigating 500 mg/day tepotinib in NSCLC harboring METex14 skipping alterations. Efficacy endpoints included objective response, duration of response, and progression-free survival. Exposure–safety analyses included data from VISION, plus four completed studies in advanced solid tumors/hepatocellular carcinoma (30–1400 mg). Safety endpoints included edema, serum albumin, creatinine, amylase, lipase, alanine aminotransferase, aspartate aminotransferase, and QT interval corrected using Fridericia’s method (QTcF).ResultsTepotinib exhibited flat exposure–efficacy relationships for all endpoints within the exposure range observed with 500 mg/day. Tepotinib also exhibited flat exposure–safety relationships for all endpoints within the exposure range observed with 30–1400 mg doses. Edema is the most frequently reported adverse event and the most frequent cause of tepotinib dose reductions and interruptions; however, the effect plateaued at low exposures. Concentration-QTc analyses using data from 30 to 1400 mg tepotinib resulted in the upper bounds of the 90% confidence interval being less than 10 ms for the mean exposures at the therapeutic (500 mg) and supratherapeutic (1000 mg) doses.ConclusionsThese analyses provide important quantitative pharmacologic support for benefit/risk assessment of the 500 mg/day dosage of tepotinib as being appropriate for the treatment of NSCLC harboring METex14 skipping alterations.Registration NumbersNCT01014936, NCT01832506, NCT01988493, NCT02115373, NCT02864992.

EE160 Tepotinib for the Treatment of Adult Patients with Metastatic Non-Small Cell Lung Cancer Harboring METEX14 Skipping Alterations: A US Cost-Effectiveness Analysis

This study compared the cost-effectiveness, from the US Medicare perspective, of tyrosine kinase inhibitors tepotinib and capmatinib for treating line-agnostic adult patients with metastatic non-small cell lung cancer (mNSCLC) harboring mesenchymal-epithelial transition factor gene exon 14 (METex14) skipping alterations.

Abstract 5737: Precision oncology driven real world clinical genomics data mining of MET alterations, TMB, and PDL-1 to empower indication agnostic patient enrollment and combination strategies

Abstract Background: Following MET inhibitor and checkpoint inhibitor approvals, it is essential to identify cancer indications that harbor molecular alterations of interest and a thorough real-world molecular genomics based characterization of those tumors would allow to expand cancer specific indications that might benefit from MET and checkpoint inhibitors and shed light on exploring clinically efficacious combo strategies. Importantly, such an approach provides the end-to-end solutions that shall significantly contribute to clinical translation and/or back translation strategies for innovative cancer therapies. Methods: We systemically interrogated FoundationInsights®, a dataset of real-world molecular genomic tumor profiling from North American patients, and investigated the prevalence of MET amplifications, METex14 skipping and MET fusions prevalence in 62110 unique patient samples across five indications (lung adenocarcinoma [LUAD], esophageal/gastroesophageal-junction/stomach adenocarcinoma [Eso/GEJ/Sto], papillary renal cell carcinoma, hepatocellular carcinoma [HCC] and glioblastoma). MET alteration prevalence was further categorized based on tumor cell PD-L1 IHC status (22C3 pharmDx) and TMB status. Additionally, comprehensive text mining from clinicaltrials.gov and landscape overview were conducted. Results: MET amplification was the most frequent MET alteration examined with a prevalence ranging from 1.4% in HCC to 4.8% in Eso/GEJ/Sto. In HCC and LUAD, MET amplification prevalence was higher in tumors with high TMB (≥10 mutations/megabase, P&amp;lt;0.05). In Eso/GEJ/Sto and LUAD, MET amplification occurrence was higher in PD-L1-high tumor vs. PD-L1-low or PD-L1-neg tumors (P&amp;lt;0.05). METex14 skipping mutations were observed in LUAD (2.3%), rarely in the other five tumor types analyzed (≤0.1%). Lastly in LUAD, METex14 skipping mutations were more frequent in PD-L1 high tumors but not those with high TMB (P&amp;lt;0.05). Text mining results indicate that- while most trials use MET amplification for patient stratification- there is a distinct tendency for MET inhibitor trials to increasingly include METex14 skipping as a major selection criterion as well. Conclusions: Real world genomics corroborated MET amplification as a predominant MET alteration across various indication. The potential clinical benefit to combine MET inhibitors with PD-1/PD-L1 blockades in specific indications and specific subsets of patients is further recognized. Collectively, the comprehensive molecular profiling &amp; text mining approaches will continue to guide application of precision medicine in clinical trial design based on appropriate biomarker selection. Citation Format: Zheng Feng, Jean-Christophe Pignon, Radwa Sharaf, Natalie Romanov, Julien Doudement, Lee A. Albacker, Noriaki Kurata, Neil R. Smith, Nobutoshi Matsushita, Juergen Scheuenpflug. Precision oncology driven real world clinical genomics data mining of MET alterations, TMB, and PDL-1 to empower indication agnostic patient enrollment and combination strategies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5737.

A cell-free RNA-based next-generation sequencing (NGS) assay for the detection of actionable gene fusions in patients with non–small cell lung cancer (NSCLC).

3040 Background: Gene fusions and alternate RNA splice forms represent clinically actionable driver and resistance-conferring alterations in NSCLC and other cancers. Where tissue samples are inadequate for molecular testing, liquid biopsies could address the gap in detection of clinically relevant gene fusions. Targeted cell-free (cf) DNA-based NGS methods are typically used for non-invasive blood-based testing of gene fusions, but have limited sensitivity if fusion breakpoints involve long intronic regions or repetitive sequences (e.g. NTRKs and NRG1). RNA-based approaches are not affected by introns, can identify expressed fusion genes and can discriminate splicing. We developed an NGS assay optimized for cfRNA analyte for the detection of actionable gene fusions and exon deletion/skipping events in liquid biopsies. Methods: A highly multiplexed molecular-barcoded primer panel was designed for cfRNA-based detection of actionable fusion genes in NSCLC ( ALK, BRAF, FGFR2, FGFR3, MET (including exon 14 skipping), NRG1, NTRK1/2/3, RET and ROS1) covering &gt; 90% of reported driver and partner gene exons in COSMIC database. The panel also targets housekeeping genes as endogenous sample controls. We developed a custom bioinformatics pipeline to call fusions and exon skipping based on split and spanning reads. Results: In initial analytical validation using fragmented RNA from pre-characterized reference material (representing 32 unique fusions at known copy numbers), the assay could detect as low as 10 fusion copies with a sensitivity of 97.6% and a specificity of 100%. For clinical testing, cfRNA co-eluted with cfDNA in nucleic acid extracts from plasma was used. In plasma samples (n = 103) from advanced NSCLC, 76% (15/21) of fusions (5 ALK, 3 RET, 2 ROS1, 5 MET ex14 skipping, 1 FGFR3-TACC3) detected in a clinically validated cfDNA assay (LiquidHALLMARK) were also detected in corresponding cfRNA. In a subset of samples that were driver-negative untreated or tyrosine kinase-inhibitor treated, the cfRNA assay yielded 9 gene fusions or breakpoints (1 CD74-NRG1, 4 BRAF, 2 MET, 2 FGFR3-TACC3 fusions) that could not be detected by the cfDNA assay. This represents an increase of 8.7% (9/103) of actionable alterations (driver or resistance) identified using cfRNA. Together cfRNA and cfDNA resulted in 30 fusion events to be detected compared to 21 by the cfDNA assay alone, representing a 42.8% (9/21) increase in fusion-specific detection of the combined assay. Conclusions: This novel cfRNA assay can detect actionable gene fusions and exon skipping events in liquid biopsies with high sensitivity. Combining cfRNA with more routine cfDNA testing can increase the total actionable diagnostic information from non-invasive testing in NSCLC patients where tissue samples are lacking, especially for gene fusions not amenable to detection in cfDNA.

Genomic profile by liquid biopsy of Peruvian patients with lung cancer.

e15027 Background: The optimal treatment of advanced NSCLC patients is currently led by genomic profiling with the goal of detecting actionable mutations with an approved targeted therapy. However, tissue DNA samples are not always available to perform this assays. In this context, liquid biopsy has emerged as a valuable tool for providing the best treatment option. Methods: Retrospective study held at Instituto Nacional de Enfermedades Neoplasicas (INEN), Lima - Peru, between January 2019 and September 2021 to assess the genomic profile of 190 newly diagnosed advanced NSCLC patients through liquid biopsy. Blood samples were profiled with the FoundationOne Liquid Biopsy assay. We describe frequency of pathogenic and targetable genetic alterations, as well as the survival outcomes. Genomic and clinical data were recorded from clinical files. Results: The median age was 63 years (26-90), 66.3% were women, 15.3% smokers, 26.3% had exposure to biomass, 22.6% had a first-degree family history of cancer. The most frequent histological type was adenocarcinoma (86.8%). Regarding genomic profile, 183 patients (96.3%) had at least one pathogenic genetic alteration, the most frequent altered genes were TP53 (54.7%), EGFR (50.5%), DNMT3A (17.9%), KRAS (9.5%) and NF1 (6.8%). 116 patients (61%) had a targetable mutation: EGFR Ex19del/ins (27.4%), EGFR L858R/L861Q (17.9%), ALK rearrangements (5.8%), BRAF V600E (3.2%), RET fusions (1.6%), METex14 skipping (1.6%), KRAS G12C (1.6%), ROS 1 (1.1%), and NTRK (0.5%). Of these, 71 patients (65.5%) were able to access target therapy. For the latter, estimated median PFS and OS were 14.0 months (9.3 – 18.6) and 17.8 months (8.2 – 27.4), respectively. Conclusions: Peruvian NSCLC patients represent a population with a high frequency of pathogenic and targetable mutations, being EGFR mutations and ALK rearrangements the most prevalent ones. Despite limited access, a great proportion of patients received target therapy, achieving remarkable survival.