Treatment combinations based on immune checkpoint inhibitors (ICIs) are showing promise in improving survival outcomes for patients with microsatellite stable (MSS) metastatic colorectal cancer (mCRC), a challenging subtype to treat. Two recent studies highlight the potential of ICI-based regimens in both heavily pretreated and first-line settings.
ICI Combinations in Heavily Pretreated MSS mCRC
A retrospective study published in the American Journal of Cancer Research investigated the efficacy and safety of ICI-based regimens in heavily pretreated MSS mCRC patients. The study, conducted at Renmin Hospital of Wuhan University in China, included 143 patients who had received at least second-line treatment. The primary endpoint was progression-free survival (PFS) and overall survival (OS).
The results showed that patients treated with ICI plus a tyrosine kinase inhibitor (TKI), either with or without chemotherapy, experienced meaningful survival improvements. The median OS was 11.8 months (95% CI, 10.2-13.4), and the median PFS was 4.6 months (95% CI, 4.1-5.1). The objective response rate (ORR) in the intention-to-treat population was 11.2% (95% CI, 6.7-17.8), and the disease control rate (DCR) was 72.7% (95% CI, 64.5-79.7).
Notably, patients who had cross-line therapy showed a significant improvement in OS compared to those who did not (15.8 months vs 10.2 months). However, liver metastasis was found to be a negative prognostic factor for both OS (HR, 1.77; 95% CI, 1.06-2.96) and PFS (HR, 2.35; 95% CI, 1.54-3.59).
While the shortest median PFS was observed in patients receiving ICI alone (2.5 months; 95% CI, 0.0-4.9), combinations of ICI plus TKI and ICI plus large molecular targeted drugs plus chemotherapy yielded a median PFS of 4.4 months. The median OS was 14.3 months (95% CI, 4.6-24.1) in patients treated with ICI plus TKI and chemotherapy compared to those who received ICI plus chemotherapy.
The safety profile of the ICI-based regimens was generally manageable, with most adverse events being grades 1 and 2. Treatment-related adverse events were observed in 93.9% of patients, and immune-related adverse events occurred in 42.0%.
The researchers concluded that ICI plus TKI, with or without chemotherapy, demonstrated meaningful survival improvement in this patient population. "This real-world clinical outcome may provide reliable data support for further clinical studies of immunotherapy rechallenge in patients with MSS CRC," the authors wrote.
Personalized Neoantigen Targeting in First-Line MSS mCRC
In a separate development, updated data from the phase 2 GO-010 trial (NCT05141721) showed a trend of improved progression-free survival (PFS) with a maintenance therapy consisting of the individualized neoantigen targeting GRANITE (GRT-C901/GRT-R902), atezolizumab (Tecentiq), ipilimumab (Yervoy), bevacizumab (Avastin), and fluoropyrimidine compared with bevacizumab plus fluoropyrimidine alone in patients with first-line MSS mCRC.
The findings, presented at the October 2024 data cutoff, indicated that the GRANITE-based regimen reduced the risk of death by 27% compared to the control regimen (HR, 0.73; 90% CI, 0.44-1.21). At data cutoff, 28% of patients in the GRANITE arm (n = 39) remained progression-free compared with 13% of patients in the control arm (n = 30). Notably, an increased PFS benefit was observed in the subgroup of patients with low levels of circulating tumor DNA (ctDNA; n = 31; HR, 0.50; 90% CI, 0.20-1.28) compared to those with high levels of ctDNA (n = 30; HR, 0.78; 90% CI, 0.39-1.58).
Andrew Allen, MD, PhD, co-founder, president, and chief executive officer of Gritstone bio, stated, "Our encouraging phase 2 data for GRANITE in MSS CRC continue to mature and demonstrate durable benefit over time. With 2 additional months of follow-up, relative PFS has further improved in the analysis of all patients treated with GRANITE, and most notably, in those with a lower tumor burden at study baseline."
The GO-101 trial was an open-label, randomized study that enrolled patients with histologically confirmed metastatic CRC who had received less than 30 days of first-line treatment with a standard-of-care (SOC) chemotherapy regimen in combination with bevacizumab. After 24 weeks of induction therapy, patients were randomized to receive either the GRANITE-based regimen or a fluoropyrimidine and bevacizumab alone.
The primary endpoint in phase 2 was the rate of molecular responses, defined as at least a 30% decrease from baseline in ctDNA. Secondary end points included safety, PFS, overall survival (OS), overall response rate, duration of response, clinical benefit rate, and deepening of response.
OS data remained immature and are expected to read out in the second half of 2025. Safety data showed GRANITE was tolerable.
Implications for MSS mCRC Treatment
These studies provide further evidence for the potential of immunotherapy-based approaches in MSS mCRC, a subtype that has historically been less responsive to immunotherapy compared to microsatellite instability-high (MSI-H) tumors. The findings suggest that combining ICIs with other agents, such as TKIs or personalized neoantigen vaccines, may overcome resistance mechanisms and improve outcomes for patients with MSS mCRC. Further research is needed to validate these findings and identify predictive biomarkers that can help guide treatment decisions.
