Background: BRAF mutations occurring in 1%e5% of patients with non-small-cell lung cancer (NSCLC) are therapeutic targets for these cancers but the impact of the exact mutation on clinical activity is unclear. The French National Cancer Institute (INCA) launched the AcSé vemurafenib trial to assess the efficacy and safety of vemurafenib in cancers with various BRAF mutations. We herein report the results of the NSCLC cohort. Patients and methods: Tumour samples were screened for BRAF mutations in INCA-certified molecular genetic centres. Patients with BRAF-mutated tumours progressing after 1 line of treatment were proposed vemurafenib 960 mg twice daily. Between October 2014 and July 2018, 118 patients were enrolled in the NSCLC cohort. The primary outcome was the objective response rate (ORR) assessed every 8 weeks (RECIST v1.1). A sequential Bayesian approach was planned with an inefficacy bound of 10% for ORR. If no early stopping occurred, the treatment was of interest if the estimated ORR was 30% with a 90% probability. Secondary outcomes were tolerance, response duration, progression-free survival (PFS), and overall survival (OS). Results: Of the 118 patients enrolled, 101 presented with a BRAF V600 mutation and 17 with BRAF nonV600 mutations; the median follow-up was 23.9 months. In the BRAF nonV600 cohort, no objective response was observed and this cohort was stopped. In the BRAF V600 cohort, 43/96 patients had objective responses. The mean Bayesian estimated success rate was 44.9% [95% confidence intervals (CI) 35.2%e54.8%]. The ORR had a 99.9% probability of being 30%. Median response duration was 6.4 months, median PFS was 5.2 months (95% CI 3.8e6.8), and OS was 10 months (95% CI 6.8e15.7). The vemurafenib safety profile was consistent with previous publications. Conclusion:Routine biomarker screening of NSCLC should include BRAF V600 mutations. Vemurafenib monotherapy is effective for treating patients with BRAF V600 -mutated NSCLC but not those with BRAF nonV600 mutations. Trial registration: ClinicalTrials.gov identifier: NCT02304809.

2579 Background: Targeting tumor associated macrophages is an emerging strategy to increase the responsiveness of PDAC and CRC to anti-PD(L)1. Pexidartinib (P) is an orally active, small-molecule kinase inhibitor that targets the colony-stimulating factor-1 receptor (CSF1R) on macrophages. Methods: Adult pts with advanced/ metastatic PDAC or CRC were treated with a fixed dose of D (1500mg q4w, IV) and ascending doses of P (400, 600, 800 and 1000mg/d, orally). Dose escalation was conducted according to a Likelihood Continual Reassessment Method with a 28-day window to evaluate dose-limiting toxicity (DLT), a stopping rule advised dose escalation termination in case of a high probability ( > 90%) for the next 6 pts to be assigned to the same dose. Following the determination of RP2D, 14 pts with PDAC and 14 pts with CRC who consented to serial tumor biopsies were enrolled in expansion cohorts to assess preliminary anti-tumor activity and biomarkers. Results: 19 pts (12M, 7F, median age, 56 y [range, 43-76y]) were enrolled in 4 dose escalation cohorts (P 400, 600 and 800mg/d: 3 pts each and P 1000mg/d: 10 pts). Pharmacokinetic analysis showed dose-dependent increase in the exposure of P from 400 to 1000 mg. Two DLTs (AST/ALT elevations including one with bilirubin increase) were seen at dose level P 1000mg/d. The most frequent ( > 2pts) related (to either D, P or both) AEs were: fatigue, maculopapular rash/pruritus/dry skin, hair color changes, anorexia, edema (periorbital, limbs or face), AST/ALT increases, bilirubin increases, nausea, vomiting and diarrhea. The most frequent (≥2pts) Grade ≥ 3 AEs related to P were: AST/ALT increase, ALP increase, neutrophil or white blood cell count decrease, and fatigue. Clinical benefit rate at 2 months was 21% (4 SD /19pts), 2 pts with MSI-H CRC had SD for more than 6 months including 1 pt still receiving single agent D after > 18 months. The RP2D for the combination was P 800mg/d + D 1500mg q4w. Enrolment in the expansion cohorts was completed in January 2019. Conclusions: Toxicity was consistent with the expected profiles of the individual drugs and no unexpected events were seen with the combination. Updated data will be presented at the meeting. Clinical trial information: NCT02777710.

Background Vismodegib specifically inhibits Sonic Hedgehog (SHH). We report results of a Phase I/II evaluating vismodegib + temozolomide in immunohistochemically defined SHH recurrent/refractory adult medulloblastoma. Methods Temozolomide naïve patients were randomized 2:1 to receive vismodegib + temozolomide (Arm A) or temozolomide (Arm B). Patients previously treated with temozolomide were enrolled in an exploratory cohort of vismodegib (Arm C). If the safety run showed no excessive toxicity, a Simon’s two-stage Phase II design was planned to explore the 6-month progression free survival (PFS-6). Stage II was to proceed if arm A PFS-6 was ≥3/9 at the end of Stage I. Results A total of 24 patients were included: Arm A (10), Arm B (5), and Arm C (9). Safety analysis showed no excessive toxicity. At the end of Stage I, the PFS-6 of arm A was 20% (2/10 patients, 95% Unilateral Lower Confidence Limit: 3.7%) and the study was prematurely terminated. The overall response rates (ORR) were 40% [95% CI: 12.2; 73.8] and 20% [95% CI: 0.5; 71.6] in arm A and B, respectively. In arm C, PFS-6 was 37.5% (95% CI: 8.8; 75.5) and ORR was 22.2% [95% CI: 2.8; 60.0]. Among 11 patients with an expected sensitivity according to NGS, 3 had partial response (PR), 4 remained stable (SD) while out of 7 potentially resistant patients, 1 had PR and 1 SD. Conclusion Addition of vismodegib to temozolomide did not add toxicity but failed to improve PFS-6 in SHH recurrent/refractory medulloblastoma. Prediction of sensitivity to vismodegib needs further refinements.

Background: Carboplatin-paclitaxel is standard of care for recurrent/advanced EC for which surgery AE radiation are not curative. Dostarlimab is an antieprogrammed cell death 1 (PD-1) humanized monoclonal antibody that showed antitumor activity and an acceptable safety profile in patients (pts) with recurrent or advanced EC in the GARNET trial. Niraparib is a PARP inhibitor (PARPi) approved as 1L maintenance therapy in pts with advanced ovarian cancer following response to platinum-based chemo. Based on mechanism of action and preclinical findings, PARPi are being investigated for use in EC. RUBY part 2 will evaluate the efficacy and safety of Annals of Oncology abstracts S770Volume 32 -Issue S5 -2021

TPS5604 Background: Gynecological carcinosarcomas (CS) are rare and highly aggressive tumors with a 5-year overall survival (OS) < 10%. After initial treatment majority of patients (pts) relapse and receive diverse chemotherapies (CT) producing modest benefits. The median PFS in relapse after platinum based CT is less than 4 months and median OS less than 1 year. New innovative strategies are urgently needed. Since CS showed high DNA damage response activity and potentially a high tumor mutation load resulting in neo-antigens, a synergy between PARPi and anti-PD1 is expected. Methods: ROCSAN is a multicentric, randomized, open-label, integrated Phase II/III study. In the Phase II, 63 pts with recurrent or progressing endometrial or ovarian CS after at least a first line of platinum-based CT will be randomized (2:2:1) to receive either niraparib in monotherapy, niraparib in combination with dostarlimab or standard CT (paclitaxel, doxorubicine, gemcitabine, topotecan). Stratification factors include the number of previous CT lines (1 vs 2-3), FIGO stage at diagnosis (I-II vs III-IV), CS localisation (ovarian vs endometrial), and performance status (0-1 vs 2). The primary objective of the Phase II is to select the best experimental strategy between niraparib and dostarlimab/niraparib combination based on Response Rate at 4 months (RR-4M by RECIST1.1). A single stage design with a 10% unacceptable RR-4M and a 30% targeted RR-4M was used to determine Phase II sample size, assuming a 10% one sided alpha for each comparison and more than 90% power. A pick-the-winner selection design could be used in case of promising efficacy in each experimental arm. At the interim analysis, an Independent Data Monitoring Committee will make recommendation for the selection of the optimal experimental arm. The Steering committee could then support to continue enrolment for the international Phase III which is calibrated to detect an improvement in median OS from 7 months (Standard CT) to 11.7 months (best experimental arm). Assuming a 5% alpha level and 80% power, 133 additional pts could be randomized (2:1). Secondary endpoints include safety, PFS, PFS2, TTST, ORR, duration of response, patient report outcomes (assessed via EORTC QLQ-C30 OV28, HADS, PRO-CTCAE). A translational program supported by European Community is associated to the clinical study to identify predictive biomarkers of response/resistance to study treatments, to correlate with immune environment, a special focus on genetic instability and the EMT process will be included. Trial is currently recruiting only in France for the phase II part, the first pt was randomized in July 2020. Clinical trial information: NCT 03651206.

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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.

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