COMMIT: Triplet regimen extends PFS in select CRC patients

In the phase III COMMIT* trial, a combination of mFOLFOX6 (FFX), atezolizumab, and bevacizumab significantly improves progression-free survival (PFS) in patients with deficient mismatch repair or microsatellite instability-high metastatic colorectal cancer (dMMR/MSI-H mCRC).

The median PFS with the triplet regimen was 24.5 months at a median follow-up of 3.5 years; with atezolizumab alone, it was just 5.3 months. A comparison between arms yielded a hazard ratio (HR) of 0.439 (p=0.0103). [ASCO GI 2026, abstract 14]

“The p-value crossed the prespecified O’Brien Flemming boundary in this interim analysis. Hence, this meets the statistical criteria defined in the protocol,” said Dr Caio Max Sao Pedro Rocha Lima from the Atrium Health Wake Forest University Baptist Comprehensive Medical Center, Winston-Salem, North Carolina, US, at ASCO GI 2026.

Exploratory subgroup analysis

The HRs consistently favoured the combo in patients with clinically high-risk features such as those aged ≥60 years (0.40) and those who have BRAF V600E mutation (0.23), right-sided primary tumours (0.39), and had prior adjuvant therapy (0.28), as well as those with higher baseline disease burden (0.37 and 0.43 for tumour diameters ≥6 cm and carcinoembryonic antigen ≥5.3, respectively).

“Taken together, these suggest that the combination may be particularly helpful in patients with more aggressive biology and/or higher tumour volume,” Rocha Lima said.

Other efficacy outcomes, safety

The combination yielded higher objective response rate (ORR; 86.1 percent) and disease control rate (DCR; 64.7 percent) than atezolizumab alone (46 percent and 32.4 percent, respectively).

The rates of complete (36.1 percent vs 18.9 percent) and partial (50 percent vs 27 percent) responses were twice as high with the combo as with atezolizumab monotherapy, whereas the rate of progressive disease was substantially lower (2.8 percent vs 32.4 percent).

At the time of this analysis, there was no difference in the 24-month overall survival between the combination and monotherapy arms (67 percent for both; HR, 1.04; p=0.90).

The combination was associated with more grade 3–5 adverse events (AEs; n=34 vs 18) and deaths (n=4 vs 1) than the comparator. The most common grade 3–4 AEs with the combo were neutropenia, infection, and hypertension (26.8, 26.8, and 19.5 percent, respectively).

There were four grade 5 events in the combo arm: one disease progression, one fatal hepatic haemorrhage following liver surgery, and two sudden deaths after prolonged exposure to treatment. The rates of immune-related AEs were similarly low (<5 percent) between arms.

Patients progress within a year despite Tx

“Although checkpoint inhibitor monotherapy has transformed MSI-H mCRC management, nearly half of patients still progress within a year,” said Rocha Lima. “This highlights the need for strategies to improve the effectiveness of PD-1/PD-L1 monotherapy.”

Early-phase data show that the FFX, bevacizumab, and atezolizumab combination is feasible and active, with no unexpected safety signals. [J Clin Oncol 2015;33:704]

COMMIT comprised 102 dMMR/MSI-H mCRC patients who had not received systemic treatment for metastatic disease. They were randomized 1:1:1 to the triplet regimen**, atezolizumab alone, or bevacizumab with chemo. Given the favourable KEYNOTE-177 results, the third arm was closed in June 2020, leaving 82 evaluable participants (median age 63 years, 52 percent women). Most participants had BRAF wild-type or unknown status (77 percent), right-sided or transverse tumours (72 percent), and extrahepatic metastatic disease (>80 percent).

“Future efforts are needed to characterize the subsets of dMMR/MSI-H CRC that require intensification of therapy beyond single-agent PD-1/PD-L1 therapy,” Rocha Lima said. “Ongoing correlative analyses will hopefully provide deeper mechanistic interpretation of the differential outcomes across treatment arms.”

A potential game changer

“The chemo, atezolizumab, and bevacizumab combination could be a game changer for the 1L Tx of dMMR/MSI-H mCRC,” commented Dr Vishwanath Sathyanarayanan from the Apollo Hospitals, Bangalore, India, in the ASCO press release. “The encouraging ORR, DCR, and median PFS … establish the combination as a potential new treatment option [in this setting].”