ADDING ATEZOLIZUMAB (Tecentriq) to a fluoropyrimidine plus bevacizumab (Avastin) did not improve outcomes for patients with BRAF wild-type metastatic colorectal cancer enrolled in the umbrella MODUL trial.¹

Axel Grothey, MD

“Despite activity in other, immune-responsive tumor types, there was no improvement in progression-free survival or overall survival with the addition of atezolizumab as maintenance therapy,” said Axel Grothey, MD, a consultant at West Cancer Center, University of Tennessee, Memphis, who presented the findings at the European Society for Medical Oncology (ESMO) 2018 Congress. The results come from the largest randomized umbrella maintenance study in the first-line metastatic colorectal cancer setting and the largest chemoimmunotherapy study reported to date, he said.

In metastatic colorectal cancer, molecular screening approaches and biomarkers are being evaluated for their ability to characterize tumors and identify patients likely to benefit from targeted therapies. That is the foundation of the phase II MODUL study (ClinicalTrials.gov identifier NCT02291289), which is “highly adaptable and signal-seeking, permitting the modification or addition of new targeted treatments based on biomarker signals observed during the study,” Dr. Grothey said.

MODUL follows an umbrella design: patients with unresectable, previously untreated metastatic colorectal cancer receive 16 weeks of induction treatment with FOLFOX (fluoropyrimidine, leucovorin, oxaliplatin) plus bevacizumab followed by maintenance with fluoropyrimidine plus bevacizumab (the control arm) or experimental treatment in 1 of the 4 cohorts.

Dr. Grothey reported the results of cohort 2, which included patients with BRAF wild-type disease treated with fluoropyrimidine/bevacizumab with or without the anti–programmed cell death ligand 1 (PD-L1) agent atezolizumab. The primary endpoint was progression-free survival per investigator assessment.

Rationale for Regimen

DR. GROTHEY explained the rationale for combining a programmed cell death protein 1 (PD-1)/PD-L1 inhibitor with a vascular endothelial growth factor (VEGF) inhibitor. He noted that, as single agents, PD-1/PD-L1 antibodies have not shown meaningful activity in mismatch repair–proficient/microsatellite stable (MSS) tumors, which account for 95% of patients with metastatic colorectal cancer. Preclinical and clinical studies in other tumors have shown this combination is effective, he said.

“Despite activity in other, immune-responsive tumor types, there was no improvement in progression-free survival or overall survival with the addition of atezolizumab as maintenance therapy.”

— Axel Grothey, MD

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Atezolizumab promotes T-cell activation and restores anticancer immunity. Bevacizumab promotes dendritic cell maturation, normalizes the tumor vasculature (increasing T-cell infiltration), and hampers the activity of immunosuppressive cells. The activity of atezolizumab is further enhanced through this VEGF-mediated immunomodulatory effect.

“The idea is that combining PD-1/PD-L1 inhibition with VEGF inhibition may reverse VEGF-mediated immune suppression and promote T-cell infiltration into the tumor,” he said.

MODUL Design

IN THE MODUL STUDY, 696 patients received induction treatment; then 445 patients with BRAF wild-type tumors (cohort 2) were randomly assigned to maintenance treatment: 148 received fluoropyrimidine/bevacizumab and 297 received the same plus atezolizumab until disease progression.

After a median follow-up of 10.5 months, the primary endpoint was not met. Median progression-free survival was 7.39 months in the control arm and 7.13 months in the atezolizumab arm (hazard ratio [HR] = 0.92, P = .48), Dr. Grothey reported.

The response rate, disease control rate, time to disease progression, and duration of response showed small numerical differences favoring the experimental treatment, and trends were observed among some subgroups, Dr. Grothey reported. He added that one patient with a microsatellite instability–high tumor had a complete response. Overall survival at the time of this primary analysis was immature.

“We saw a split in the Kaplan-Meier curve for progression-free survival, which could indicate a subgroup of patients who benefit from atezolizumab, so we mandated longer follow-up. However, after an additional 8 months, these differences completely washed out,” he said.

At 18.7 months, the progression-free survival outcome remained unchanged at 7.39 months in the control arm and 7.20 months in the atezolizumab arm (HR= 0.96, P = .727). With 51% of patients experiencing an event, the overall survival endpoint was mature, and no differences were observed. Median overall survival was 21.91 months and 22.05 months in the control and atezolizumab arms, respectively (HR = 0.86, P = .283).

The safety profiles observed were consistent with previous findings, with no new safety signals identified. “But almost all patients in this analysis had MSS tumors,” Dr. Grothey emphasized. “Further efforts are required to find new strategies to circumvent the complex underlying immune escape mechanisms in patients with MSS colorectal cancer.” ■

DISCLOSURE: Dr. Grothey has been a consultant/advisor (with honoraria going to his institution) for Guardant Health, Genentech/Roche, Bayer, Bristol-Myers Squibb, Lilly, Boston Biomedical, Amgen, and Array BioPharma; has received institutional research funding from Boehringer Ingelheim, Genentech/Roche, Bayer, Pfizer, Eisai, Sanofi, Lilly, and Boston Biomedical; and has received reimbursement for travel/ accommodations/expenses from Genentech/Roche, Bayer, Bristol-Myers Squibb, Boston Biomedical, Merck Sharp & Dohme, Amgen, and Boehringer Ingelheim.

REFERENCE

1. Grothey A, Tabernero J, Arnold D, et al: Fluoropyrimidine and bevacizumab plus or minus atezolizumab as first-line treatment for BRAF wild type metastatic colorectal cancer: Findings from the MODUL trial of biomarker-driven maintenance. ESMO 2018 Congress. Abstract LBA19. Presented October 22, 2018.