Abstract 5237: B-Raf V600E harboring non-melanoma cancers treated with Vemurafenib monotherapy and in combination with Everolimus/Sorafenib/Crizotinib/Paclitaxel+ Carboplatin: A pooled analysis of five phase 1/2 studies
Authors: Nelson Blessie Elizabeth , Roszik Jason , Janku Filip , Hong David , Kato Shumei , Naing Aung , Piha-Paul Sarina , Fu Siqing , Tsimberidou Apostolia , Cabanillas Maria , Busaidy Naifa , Javle Milind , Byers Lauren , Heymach John , Meric-Bernstam Funda , Subbiah Vivek 
Published: June 2022

Abstract
BACKGROUND: BRAF V600 mutations are driver oncogenes in multiple human cancers. Given complex resistance mechanisms beyond combined MEK inhibition, limited data exists to evaluate combinations with CRAF/ARAF/MET/mTOR inhibitors and cytotoxic chemotherapy in sustaining response and overcoming resistance. We explore patient outcomes comparing vemurafenib monotherapy with the above combination therapies in this analysis.
METHODS: A pooled analysis of 5 phase 1/2 clinical trials containing vemurafenib was conducted between January 2012 and October 2020 in BRAF V600E mutant advanced or metastatic tumors. Overall survival (OS) and Progression free survival (PFS) in vemurafenib monotherapy (V) arm compared with vemurafenib + crizotinib (VC), vemurafenib + sorafenib (VS), vemurafenib + everolimus (VE) and vemurafenib + paclitaxel + carboplatin (VPC) arms were assessed. Objective Response Rate (ORR) and Clinical Benefit Rate (CBR=CR+PR+SD≥6 months) and safety profile of combination arms were also explored.
RESULTS: 99 patients were enrolled across 5 studies. Median age was 57 years with 78% of ECOG 1 and M:F ratio at 1:1. Tumor types included NSCLC (13%), Thyroid cancer (12%), Low and High-grade Gliomas (7%), Colorectal cancer (6%), Cholangiocarcinoma (5%) and ECD (3%). V arm derived greatest clinical benefit with median OS at 21 months while addition of PC arm dropped median OS to 2 months. Inferior OS was seen in VPC arm when compared to V arm (p=0.00616). Median PFS peaked at 11 months in VC arm versus 3 months for the VPC arm. Of 85 evaluable patients, 2 complete responses were noted in the V (n=25) and VPC (n=14) arms and 8 Partial Responses (PR) were noted with 5 (18%) patients with NSCLC in V arm followed by 4 PRs in the VC (n=12) arm. PR rates were equally seen in the other arms. ORR (36%) and CBR (40%) rates were the highest for the V arm. G3/G4 treatment related adverse events with neutropenia (63%), thrombocytopenia (50%) and fatigue (63%) were highest in VPC. 1 patient died from G4 thrombocytopenia with intracranial hemorrhage in the VPC arm.
CONCLUSIONS: No significant added clinical benefit was noted when vemurafenib was combined with other targeted agents or cytotoxic therapy. Combinations resulted in poor tolerance and need for dose reductions compromising clinical efficacy. Prospective studies to analyze resistance mechanisms to BRAF inhibitor therapy in BRAF+ tumors and in real time tailoring therapy based on co-occuring alterations is warranted.
Citation Format: Blessie Elizabeth Nelson, Jason Roszik, Filip Janku, David Hong, Shumei Kato, Aung Naing, Sarina Piha-Paul, Siqing Fu, Apostolia Tsimberidou, Maria Cabanillas, Naifa Busaidy, Milind Javle, Lauren Byers, John Heymach, Funda Meric-Bernstam, Vivek Subbiah. B-Raf V600E harboring non-melanoma cancers treated with Vemurafenib monotherapy and in combination with Everolimus/Sorafenib/Crizotinib/Paclitaxel+ Carboplatin: A pooled analysis of five phase 1/2 studies [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 5237.