A phase Ib study of the safety and efficacy of atezolizumab (atezo) + bevacizumab (bev) + cobimetinib (cobi) in patients (pts) with metastatic colorectal cancer (mCRC)

Abstract

Background: mCRC is a non-immunogenic tumour type with poor response to checkpoint inhibitors, hypothetically due to low tumour T-cell levels and incomplete blockade of MAPK-mediated growth factor signalling. Combining the anti-tumour immunity effects of the anti–PD-L1 Ab (atezo), MEK inhibitor (cobi) and anti-VEGF Ab (bev) in pts with mCRC may improve response. Atezo enhances T-cell priming/activation, cobi decreases tumour growth and increases tumour antigen presentation via MHC I and bev increases T-cell infiltration. Therefore, bev + atezo + cobi may enhance immune recognition of mCRC. This report is the primary analysis of a Phase Ib study of this combination. Methods: This study assessed the safety and activity of atezo (840 mg q2w IV) + bev (5 mg/kg q2w IV) + cobi (60 mg qd 21 on/7 off oral) in pts with mCRC who progressed on ≥ 1 prior line of treatment (tx) containing 5-FU and oxaliplatin/irinotecan. After safety run-in, dose-expansion and biopsy cohorts were enrolled. The primary objective was to assess safety. Results: In the primary analysis (Sep 21, 2018, cutoff), 49 pts were evaluated. Median safety follow-up was 7.8 mo (range, 1.4-25.4 mo). Median prior lines of tx was 2 (range, 1-7). 33 pts (67%) had RAS-mutant tumours. 45 pts (92%) had microsatellite stable disease; 4 pts (8%) had unknown microsatellite status. 48 pts (98%) had tx-related AEs (TRAEs), 30 pts (61%) had G3-5 TRAEs and 1 pt (2%) had bev-related G5 GI necrosis. AEs led to tx withdrawal in 9 pts (18%). Most common AEs were diarrhoea (78%), acneiform dermatitis (51%), fatigue (49%), rash (41%) and CPK increase (35%). Confirmed ORR was 8% in the overall population. See Table for activity by tx line and RAS status. Conclusions: Atezo + bev + cobi had an acceptable safety profile with manageable AEs with improved activity over that reported with SOC in 2L+ mCRC. A greater benefit trend was seen in pts with a RAS mutation vs wild-type tumours. [Table presented] Clinical trial identification: NCT02876224. Editorial acknowledgement: Chris Lum, PhD, of Health Interactions, funded by F. Hoffmann-La Roche, Ltd. Legal entity responsible for the study: F. Hoffmann-La Roche, Ltd. Funding: F. Hoffmann-La Roche, Ltd. Disclosure: J. Bendell: Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Gilead; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche/Genentech; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (institution): Five Prime; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Lilly; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Merck; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: MedImmune; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Celgene; Research grant / Funding (institution): EMD Serono; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Taiho; Advisory / Consultancy, Research grant / Funding (institution): Macrogenics; Advisory / Consultancy, Research grant / Funding (institution): GSK; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Novartis; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: OncoMed; Advisory / Consultancy, Research grant / Funding (institution): LEAP; Advisory / Consultancy, Research grant / Funding (institution): TG Therapeutics; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: BI; Advisory / Consultancy, Research grant / Funding (institution): Daiichi Sankyo; Advisory / Consultancy, Research grant / Funding (institution): Bayer; Advisory / Consultancy, Research grant / Funding (institution): Incyte; Advisory / Consultancy, Research grant / Funding (institution): Apexigen; Research grant / Funding (institution): Koltan; Research grant / Funding (institution): SynDevRex; Research grant / Funding (institution): Forty Seven; Research grant / Funding (institution): AbbVie; Advisory / Consultancy, Research grant / Funding (institution): Array; Research grant / Funding (institution): Onyx; Advisory / Consultancy, Research grant / Funding (institution): Sanofi; Research grant / Funding (institution): Takeda; Research grant / Funding (institution): Eisai; Research grant / Funding (institution): Celldex; Research grant / Funding (institution): Agios; Research grant / Funding (institution): Cytomx; Research grant / Funding (institution): Nektar; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: ARMO; Research grant / Funding (institution): Boston Biomedical; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Ipsen; Advisory / Consultancy, Research grant / Funding (institution): Merrimack; Research grant / Funding (institution): Tarveda; Research grant / Funding (institution): Tyrogenex; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Oncogenex; Research grant / Funding (institution): Marshall Edwards; Research grant / Funding (institution): Pieris; Research grant / Funding (institution): Mersana; Research grant / Funding (institution): Calithera; Research grant / Funding (institution): Blueprint; Research grant / Funding (institution): Evelo; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: FORMA; Research grant / Funding (institution): Jacobio; Research grant / Funding (institution): Effector; Research grant / Funding (institution): Novocare; Research grant / Funding (institution): Arrys; Research grant / Funding (institution): Tracon; Research grant / Funding (institution): Sierra; Advisory / Consultancy, Research grant / Funding (institution): Arch Oncology; Advisory / Consultancy, Research grant / Funding (institution): Prelude Oncology; Research grant / Funding (institution): Unum Therapeutics; Research grant / Funding (institution): Vyriad; Research grant / Funding (institution): Harpoon; Research grant / Funding (institution): ADC; Advisory / Consultancy, Research grant / Funding (institution): Amgen; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Millennium; Research grant / Funding (institution): Imclone; Research grant / Funding (institution): Acerta Pharma; Research grant / Funding (institution): Rgenix; Research grant / Funding (institution): Bellicum; Advisory / Consultancy: Phoenix Bio; Advisory / Consultancy: Cyteir; Advisory / Consultancy: Molecular Partners; Advisory / Consultancy: Innate; Advisory / Consultancy: Torque; Advisory / Consultancy: Tizona; Advisory / Consultancy: Janssen; Advisory / Consultancy: Tolero; Advisory / Consultancy: TD2 (Translational Drug Development); Advisory / Consultancy: Seattle Genetics; Advisory / Consultancy: Moderna Therapeutics; Advisory / Consultancy: Tanabe Research Laboratories; Advisory / Consultancy: Beigene; Advisory / Consultancy: Continuum Clinical; Advisory / Consultancy: Agios. C. Lieu: Honoraria (self): Foundation Medicine. K.P.S. Raghav: Honoraria (self): Genentech, Inc.; Honoraria (self): Bayer, Inc.; Travel / Accommodation / Expenses: Tracon, Inc. G. Argilés: Full / Part-time employment: VHIO; Research grant / Funding (institution): Bayer; Research grant / Funding (self): Spains Society Against Cancer; Honoraria (self), Travel / Accommodation / Expenses: Roche; Honoraria (self), Travel / Accommodation / Expenses: Amgen; Honoraria (self), Travel / Accommodation / Expenses: Merck Serono; Honoraria (self): BMS; Honoraria (self), Travel / Accommodation / Expenses: Servier; Honoraria (self), Travel / Accommodation / Expenses: Bayer. A. Cubillo: Advisory / Consultancy, Research grant / Funding (institution): Servier; Research grant / Funding (institution): Adacap; Research grant / Funding (institution): Merck; Advisory / Consultancy: Amgen. X. Qu: Shareholder / Stockholder / Stock options, Full / Part-time employment: Genentech Inc. Y. Yan: Shareholder / Stockholder / Stock options, Full / Part-time employment: Genentech/Roche. M. Merchant: Full / Part-time employment: Genentech/Roche. H. Zeuner: Full / Part-time employment: Roche. J.D. Gallo: Shareholder / Stockholder / Stock options, Full / Part-time employment: Genentech Inc. N.H. Segal: Advisory / Consultancy, Research grant / Funding (institution): Roche/Genentech; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy, Research grant / Funding (institution): Merck; Advisory / Consultancy, Research grant / Funding (institution): BMS; Advisory / Consultancy, Research grant / Funding (institution): MedImmune/AstraZeneca; Research grant / Funding (institution): Incyte; Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy: Pieris; Advisory / Consultancy: PsiOxus; Advisory / Consultancy: Synlogic; Advisory / Consultancy: Aduro; Advisory / Consultancy: Kyn Therapautics; Advisory / Consultancy: Pure Tech Ventrures; Advisory / Consultancy: Horizon Pharma; Advisory / Consultancy: EMD Serono; Advisory / Consultancy: Gritstone Oncology; Advisory / Consultancy: Chugai; Advisory / Consultancy: TRM Oncology; Advisory / Consultancy: IFM Therapeutics; Advisory / Consultancy: Cstone Pharmaceuticals.