1085O - Atezolizumab, bevacizumab, and cobimetinib (TACo) in patients (pts) with PD1 refractory melanoma brain metastases (MBM)

Background

Combination immune checkpoint blockade (ICB) achieves frequent durable responses in pts with untreated MBM. However, systemic treatments (tx) after ICB failure are limited, especially in BRAF wild-type pts. We investigated the novel TACo regimen in ICB- refractory MBM based on biological insights that (1) VEGF can drive ICB resistance, and (2) MEK inhibition can increase MHC I expression and T cell infiltration to potentially synergize with ICB. We hypothesized this regimen would be safe and demonstrate efficacy in pts with MBM.

Methods

In this single-center phase II study evaluating TACo in pts with MBM (NCT03175432), primary objectives included safety and efficacy (intracranial response rate (ICRR) by modified RECIST 1.1). Secondary objectives included IC clinical benefit rate (ICCBR), progression free (PFS) and overall survival (OS), and duration on tx (DoT). Prior PD1 tx and ≥1 non irradiated lesion (5-30mm) were required. BRAF mutated pts were allowed after BRAF/MEK tx (3-month washout). Pts on ≤4m/day PO of dexamethasone or equivalent were allowed. Tx schedule: atezolizumab 840mg IV every 2 weeks (wks), bevacizumab 5mg/kg every 2 wks, cobimetinib 60mg PO daily for 3 wks followed by 1 wk off. MRIs were obtained prior to cycles 1-3, and 5.

Results

Of the 20 pts treated, 70% were male, median age 59.5 yrs (34-78), and 2 pts were BRAFV600E mutated. 11 pts had ≥ 1 prior tx for MBM. Median follow up was 8.2 mos (0.4-39.2). Median DoT was 8 wks (0.6-63.8). 18 pts experienced tx related adverse events (AEs), most commonly rash (70%), diarrhea (D) (55%), hypertension (HTN) (25%), proteinuria (25%). 35% pts had gr 3/4 AEs: HTN (15%), D (10%) were most common. 2 pts stopped tx due to toxicity. 18 pts were evaluable for IC response: ICRR was 39% (1 CR, 6 PR) and ICCBR was 56% (+SD). Median PFS was 2.7 mos (95% CI 0.9,7.3) and median OS was 9.3 (95% CI 3.8,20.9). 7 (35%) pts continued on tx post progression for ≥ 3 wks (3-55 wks).

Conclusions

In this heavily pretreated MBM pt population with no available standard systemic therapy options, TACo regimen was tolerable, demonstrated IC clinical benefit, and provided clinical benefit beyond progression, warranting further evaluation.

Clinical trial identification

NCT03175432.

Editorial acknowledgement

Legal entity responsible for the study

MD Anderson Cancer Center - PI Hussein Tawbi.

Funding

Genentech.

Disclosure

V. Honaker: Financial Interests, Institutional, Full or part-time Employment, Research nurse: MD Anderson Cancer Center; Financial Interests, Personal, Stocks/Shares: Pfizer. I.C. Glitza: Financial Interests, Personal, Speaker, Consultant, Advisor: BMS, Array, Novartis, Sintetica; Financial Interests, Institutional, Research Funding: BMS, Merck, Pfizer. R. Amaria: Financial Interests, Personal, Advisory Board: Iovance Biotherapeutics, Novartis, Erasca; Financial Interests, Institutional, Coordinating PI: Merck, Bristol Myers Squibb, Novartis; Financial Interests, Institutional, Local PI: Iovance, Roche; Financial Interests, Institutional, Trial Chair: Obsidian. S. Patel: Financial Interests, Personal, Advisory Board: TriSalus, Cardinal Health, Castle Biosciences, Novartis, BMS, Pfizer, Immatics; Financial Interests, Personal, Other, Consultant for educational materials: Advance Knowledge in Healthcare; Financial Interests, Personal, Advisory Board, Advisory Board and Corporate Day speaker (unbranded): Delcath; Financial Interests, Personal, Other, Independent Data Monitoring Committee: Immunocore; Financial Interests, Personal, Other, Consultant: Guidepoint Global; Financial Interests, Institutional, Trial Chair: Provectus Biopharmaceuticals, Bristol Myers Squibb; Financial Interests, Institutional, Local PI: Lyvgen, InxMed, Foghorn Therapeutics, IDEAYA, Novartis, Seagen, Syntrix Bio; Financial Interests, Institutional, Steering Committee Member: TriSalus Life Sciences; Non-Financial Interests, Member: ASCO, AACR, International Society of Ocular Oncology, Society for Melanoma Research; Non-Financial Interests, Leadership Role: SWOG. A. Diab: Financial Interests, Institutional, Research Funding: BMS. M. Wong: Financial Interests, Personal, Speaker, Consultant, Advisor: Merck, Pfizer, BMS, Regeneron, EMD Serono, ExiCure, Castle Biosciences. J. Mcquade: Financial Interests, Personal, Speaker, Consultant, Advisor: BMS, Merck, Roche. C. Chung: Financial Interests, Personal, Officer, Vice-Chair: Quantitative Imaging Biomarker Alliance RSNA; Financial Interests, Institutional, Coordinating PI, Research funding: Siemens Healthineers; Financial Interests, Institutional, Coordinating PI, Research and Co-development Funding: RaySearch Laboratories; Non-Financial Interests, Leadership Role, Co-Chair of ICRU committee report: International Commission on Radiation Units and Measures (ICRU). J.S. Wefel: Financial Interests, Personal, Advisory Board: Bayer; Financial Interests, Institutional, Other, Neurocognitive outcomes consultant: GT Medical Technologies, Novocure; Non-Financial Interests, Advisory Role: American Brain Tumor Association; Non-Financial Interests, Leadership Role: International Cognition and Cancer Task Force. M. Davies: Financial Interests, Personal, Advisory Board: Roche, Pfizer, Novartis, BMS, Sanofi-Aventis, GSK, Vaccinex, Apexigen, Eisai, Iovance, Merck, ABM Therapeutics; Financial Interests, Institutional, Coordinating PI: Pfizer; Financial Interests, Institutional, Research Grant: ABM Therapeutics, Lead Pharma, Genentech, GSK, Sanofi-Aventis, Merck, Oncothyreon; Financial Interests, Research Grant: Myriad. H.A. Tawbi: Financial Interests, Personal, Advisory Board: Bristol Myers Squibb, Merck, Novartis, Genentech, Eisai, Karyopharm, Iovance, Pfizer, Jazz Pharmaceuticals; Financial Interests, Institutional, Trial Chair: Bristol Myers Squibb; Financial Interests, Institutional, Local PI: Merck, RAPT Pharmaceuticals; Financial Interests, Institutional, Steering Committee Member: Novartis, Genentech; Financial Interests, Institutional, Funding: GSK, Eisai. All other authors have declared no conflicts of interest.