OA12.05 Vemurafenib in Patients Harboring V600 and Non V600 BRAF Mutations: Final Results of the NSCLC Cohort from the AcSé Trial.

Abstract

Background: MET exon 14 alterations occur in w3% of non-squamous non-small cell lung cancer (NSCLCs) and 20e30% of sarcomatoid lung carcinomas. Here we present updated antitumor activity for crizotinib in patients with advanced NSCLC whose tumors are positive for MET exon 14 alterations (hereafter MET exon 14-positive NSCLC), including updated biomarker analyses in circulating tumor DNA (ctDNA). Method: Patients with MET exon 14-positive NSCLC by local molecular profiling were treated with 250 mg crizotinib BID in an expansion cohort of the ongoing PROFILE 1001 study (NCT00585195). Responses were based on derived investigator assessment per RECIST v1.0. Prospective plasma profiling for MET exon 14 alterations in plasma ctDNA was performed (Plasma-SELECT-R64; Personal Genome Diagnostics, Boston, MA). Result: As of Jan 31, 2018, 69 patients (65 response-evaluable) with MET exon 14positive NSCLC had been treated. Median age was 72 y (range: 34, 91). Tumor histology was: 84% adenocarcinoma, 9% sarcomatoid adenocarcinoma, 4% squamous cell carcinoma and 3% adenosquamous carcinoma. 61% were former-smokers, 38% never-smokers and 1% a current smoker. Median duration of treatment was 7.4 mo (95% CI: 5.5, 9.1), with 29% of patients ongoing. Confirmed responses were 3 CRs and 18 PRs (ORR, 32% [95% CI: 21, 45]); 29 patients had SD as their best overall response (Figure). Median time to response was 7.6 weeks (range: 3.7, 16.3). Median DOR was 9.1 mo (95% CI: 6.4, 12.7). Median PFS was 7.3 mo (95% CI: 5.4, 9.1). MET exon 14 alterations were detected in ctDNA from 18/37 (49%) patients with analyzable samples. Conclusion: In patients with MET exon 14-positive advanced NSCLC, crizotinib treatment led to objective responses that were rapid and durable, with CRs in some cases. Plasma ctDNA profiling detected MET exon 14 alterations in a subset of patients who harbor MET exon 14 alterations by tumor testing.

Circulating Tumor DNA Genomics Reveal Potential Mechanisms of Resistance to BRAF-Targeted Therapies in Patients withBRAF-Mutant Metastatic Non–Small Cell Lung Cancer

“…Although BRAF-TT may provide tumor control in patients with BRAF-mutant advanced NSCLC (3,6,23,24), acquired resistance ultimately develops through mechanisms that are largely unknown. A detailed understanding of the molecular alterations associated with resistance to BRAF-TT may help inform future therapeutic strategies in subsequent treatment lines.…”

Advanced-Stage Non–Small Cell Lung Cancer: Advances in Thoracic Oncology 2018

“…The combination of dabrafenib (a BRAF TKI) and trametinib (a MEK TKI) is the SoC treatment according to the FDA and EMA in patients with BRAF V600E-mutant NSCLC regardless of prior treatment, 114,115 as BRAF TKI monotherapy has been reported to have limited efficacy, such as in AcSé trial (RR ¼ 45%, PFS ¼ 5.2 months, and OS ¼ 9.3 months [ Table 6]). [114][115][116][117][118][119][120][121][122][123][124][125][126][127][128][129][130][131][132] The recent functional classification of BRAF mutations (class I, V600 mutations; class II, non-V600 mutations; and class III, ERK-signaling amplification) demonstrated that class II and III tumors have unfavorable prognosis and suggested that class-specific therapies are necessary. 133 BRAF-mutant NSCLC overlaps with PD-L1 expression in 60% of cases (45% with PD-L1 expression !50%), low or intermediate TMB, and microsatellite-stable status, 134 but ICI efficacy is similar to that in patients with wild-type BRAF.…”

The Evolution of BRAF Activation in Non-Small-Cell Lung Cancer

“…A case report have also shown that dMPAKi is also benefit for patients harboring a dual G469A and W604C BRAF mutations and the response is more than 15 months (65). However, other studies found vemurafenib is not effective in NSCLC patients with BRAF non-V600 mutation (44,66).…”