Assessment of Capecitabine and Bevacizumab With or Without Atezolizumab for the Treatment of Refractory Metastatic Colorectal Cancer: A Randomized Clinical Trial

Abstract

Importance: Cotargeting vascular endothelial growth factor and programmed cell death 1 or programmed cell death ligand 1 may produce anticancer activity in refractory metastatic colorectal cancer (mCRC). The clinical benefit of atezolizumab combined with chemotherapy and bevacizumab remains unclear for the treatment of mCRC.

Objectives: To assess whether the addition of atezolizumab to capecitabine and bevacizumab therapy improves progression-free survival (PFS) among patients with refractory mCRC and to perform exploratory analyses among patients with microsatellite-stable (MSS) disease and liver metastasis.

Design, setting, and participants: This double-blind phase 2 randomized clinical trial enrolled 133 patients between September 25, 2017, and June 28, 2018 (median duration of follow-up for PFS, 20.9 months), with data cutoff on May 4, 2020. The study was conducted at multiple centers through the Academic and Community Cancer Research United network. Adult patients with mCRC who experienced disease progression while receiving fluoropyrimidine, oxaliplatin, irinotecan, bevacizumab, and anti-epidermal growth factor receptor antibody therapy (if the patient had a RAS wild-type tumor) were included.

Interventions: Patients were randomized (2:1) to receive capecitabine (850 or 1000 mg/m2) twice daily on days 1 to 14 and bevacizumab (7.5 mg/kg) on day 1 plus either atezolizumab (1200 mg; investigational group) or placebo (placebo group) on day 1 of each 21-day cycle.

Main outcomes and measures: The primary end point was PFS; 110 events were required to detect a hazard ratio (HR) of 0.65 with 80% power (1-sided α = .10). Secondary end points were objective response rate, overall survival (OS), and toxic effects.

Results: Of 133 randomized patients, 128 individuals (median age, 58.0 years [IQR, 51.0-65.0 years]; 77 men [60.2%]) were assessed for efficacy (82 in the investigational group and 46 in the placebo group). Overall, 15 patients (11.7%) self-identified as African American or Black, 8 (6.3%) as Asian, 1 (0.8%) as Pacific Islander, 101 (78.9%) as White, 1 (0.8%) as multiple races (Asian, Native Hawaiian/Pacific Islander, and White), and 2 (1.6%) as unknown race or unsure of race. Microsatellite-stable disease was present in 110 patients (69 in the investigational group and 41 in the placebo group). Median PFS was 4.4 months (95% CI, 4.1-6.4 months) in the investigational group and 3.6 months (95% CI, 2.2-6.2 months) in the placebo group (1-sided log-rank P = .07, a statistically significant result; HR, 0.75; 95% CI, 0.52-1.09). Among patients with MSS and proficient mismatch repair, the HR for PFS was 0.66 (95% CI, 0.44-0.99). The most common grade 3 or higher treatment-related adverse events in the investigational vs placebo groups were hypertension (6 patients [7.0%] vs 2 patients [4.3%]), diarrhea (6 patients [7.0%] vs 2 patients [4.3%]), and hand-foot syndrome (6 patients [7.0%] vs 2 patients [4.3%]). One treatment-related death occurred in the investigational group. In the investigational group, the response rate was higher among patients without liver metastasis (3 of 13 individuals [23.1%]) vs with liver metastasis (4 of 69 individuals [5.8%]). The benefit of atezolizumab for PFS and OS was greater among patients without vs with liver metastasis (primary analysis of PFS: HR, 0.63 [95% CI, 0.27-1.47] vs 0.77 [95% CI, 0.51-1.17]; OS: HR, 0.33 [95% CI, 0.11-1.02] vs 1.14 [95% CI, 0.72-1.81]).

Conclusions and relevance: In this randomized clinical trial, the addition of atezolizumab to capecitabine and bevacizumab therapy provided limited (ie, not clinically meaningful) clinical benefit. Patients with MSS and proficient mismatch repair tumors and those without liver metastasis benefited more from dual inhibition of the vascular endothelial growth factor and programmed cell death 1 or programmed cell death ligand 1 pathways.

Trial registration: ClinicalTrials.gov Identifier: NCT02873195.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Mettu reported receiving grants and personal fees from Genentech Inc during the conduct of the study; grants from Amgen, Amphivena Therapeutics, ARMO BioSciences, AstraZeneca, BioMed Valley Discoveries, Bristol Myers Squibb, Erytech Pharma, Incyte Corp, the Lustgarten Foundation, Merck Sharp & Dohme, Mereo Biopharma, the National Institutes of Health, OncoMed Pharmaceuticals, Repare Therapeutics, Revolution Medicines, and Syros Pharmaceuticals outside the submitted work. Dr Halfdanarson reported receiving grants from Advanced Accelerator Applications, Agios Pharmaceuticals, Basilea Pharmaceutica, Ipsen, Thermo Fisher Scientific, and Turnstone Biologics and personal fees from Advanced Accelerator Applications, ITM Isotope Technologies, Lexicon Pharmaceuticals, and TerSera Therapeutics outside the submitted work. Dr Lenz reported receiving personal fees from Bayer, Genentech Inc, and Merck KGaA during the conduct of the study and personal fees from Amgen, Bristol Myers Squibb, Fulgent Genetics, and Oncocyte Corp outside the submitted work. Dr Boland reported receiving grants from Genentech Inc during the conduct of the study; grants from AbbVie, Athenex, Boehringer Ingelheim, Ipsen, MacroGenics, Merck & Co, Processa Pharmaceuticals, and Taiho Pharmaceutical Co; and personal fees from Bayer, Celgene Corp, and Ipsen outside the submitted work. Dr Crysler reported receiving grants from AstraZeneca, Bristol Myers Squibb, Genentech Inc, and MedImmune outside the submitted work. Dr Wu reported receiving grants from Boston Biomedical, FLX Bio, Ibhibrx, Lycera Corp, Seagen, RAPT Therapeutics, Seagen, Symphogen, and Vaccinex and personal fees from Array BioPharma, Daiichi Sankyo, PrecisCa, and Signatera outside the submitted work. Dr Nixon reported receiving grants from Genentech Inc, HTG Molecular Diagnostics, MedImmune, MedPacto, Promega Corp, and Seagen and personal fees from AdjuVolt, Eli Lilly and Company, GlaxoSmithKline, Leap Therapeutics, the National Cancer Institute, and Promega Corp during the conduct of the study; grants from Genentech Inc, HTG Molecular Diagnostics, MedImmune, MedPacto, OncoMed Pharmaceuticals, Promega Corp, Seagen, and TRACON Pharmaceuticals; and personal fees from Eli Lilly and Company, GlaxoSmithKline, Leap Therapeutics, and Promega Corp outside the submitted work. Dr Hurwitz reported owning employee shares in Genentech Inc during the conduct of the study. Dr Fakih reported receiving grants from Amgen, AstraZeneca, Bristol Myers Squibb, Novartis, and Verastem Oncology and personal fees from Amgen, Array BioPharma, Bayer, GlaxoSmithKline, Guardant Health, HalioDx, Mirati Therapeutics, Pfizer, Seagen, Taiho Pharmaceutical Co, and Zhuhai Yufan Biotechnologies outside the submitted work. Dr Ou reported receiving grants from Genentech Inc during the conduct of the study. Dr Bekaii-Saab reported receiving grants from AbGenomics Corp, Agios Pharmaceuticals, Amgen, Arcus Biosciences, Arrys Therapeutics, Atreca, Bayer, Boston Biomedical, Bristol Myers Squibb, Celgene Corp, Clovis Oncology, Eli Lilly and Company, Genentech Inc, Incyte, Ipsen, Merck & Co, Merus, Mirati Therapeutics, Novartis, Pfizer, and Seagen and personal fees from 1Globe Health Institute, AbbVie, Arcus Biosciences, Array BioPharma, AstraZeneca, Bayer, BeiGene, Boehringer Ingelheim, Celularity, Daichii Sankyo, Eisai Co, Eli Lilly and Company, Exact Sciences Corp, Exelixis, FibroGen, Foundation Medicine, Genentech Inc, Immuneering Corp, Imugene, Incyte, Ipsen, Janssen Pharmaceuticals, Kanaph Therapeutics, Merck & Co, Natera, the Pancreatic Cancer Action Network, Pfizer, Seagen, Swedish Orphan Biovitrum, Stemline Therapeutics, Sun BioPharma, Suzhou Kintor Pharmaceuticals, Treos Bio, and Xilis outside the submitted work. No other disclosures were reported.

Figures

Figure 1.. Study Flow Diagram

mCRC indicates metastatic colorectal cancer.

Figure 2.. Progression-Free and Overall Survival

Patients in the investigational group received capecitabine and bevacizumab with atezolizumab, and patients in the placebo group received capecitabine and bevacizumab with placebo. Plus sign (+) indicates time of censor. A, Among 82 patients in the investigational group, 78 progression-free survival (PFS) events occurred (median, 4.4 months [95% CI, 4.1-6.4 months]; 6-month estimate, 43.9% [95% CI, 34.4%-56.1%]; 12-month estimate, 15.2% [95% CI, 9.1%-25.6%]). Among 46 patients in the placebo group, 45 PFS events occurred (median, 3.6 months [95% CI, 2.2-6.2 months]; 6-month estimate, 36.7% [95% CI, 25.1%-53.8%]; 12-month estimate, 6.9% [95% CI, 2.3%-20.5%]). B, Among 82 patients in the investigational group, 61 overall survival (OS) events occurred (median, 10.3 months [95% CI, 8.3-15.2 months]; 6-month estimate, 75.6% [95% CI, 66.9%-85.5%]; 12-month estimate, 44.5% [95% CI, 34.7%-57.1%]). Among 46 patients in the placebo group, 35 OS events occurred (median, 10.2 months [95% CI, 8.5-16.6 months]; 6-month estimate, 68.8% [95% CI, 56.5%-83.8%]; 12-month estimate, 42.0% [95% CI, 29.4%-59.9%]). HR indicates hazard ratio.

Figure 3.. Best Percentage Change in Tumor Measurement From Baseline and Swimmer Plot

A and B, Dashed line indicates 30% reduction in tumor measurement compared with baseline. C, Swimmer plot shows response and progression among patients with microsatellite stable (MSS) and proficient mismatch repair (pMMR) disease. Patients in the investigational group received capecitabine and bevacizumab with atezolizumab, and patients in the placebo group received capecitabine and bevacizumab with placebo. The tan lines (after blue or orange) indicate the follow-up period. dMMR indicates deficient mismatch repair; and MSI-H, microsatellite instability high.

Figure 4.. Survival End Points of Investigational vs Placebo Groups by Presence and Absence of Liver Metastasis

HR indicates hazard ratio; OS, overall survival; and PFS, progression-free survival.