Ipilimumab, nivolumab and panitumumab for chemorefractory KRAS/NRAS/BRAF wild-type, microsatellite stable metastatic colorectal cancer

Results of a phase II study presented at ASCO GI 2021 indicates promising clinical activity of a triplet combination consisting of the immune checkpoint inhibitors ipilimumab and nivolumab and the anti-EGFR agent panitumumab in previously treated patients with microsatellite stable metastatic colorectal cancer (mCRC).

Introduction

Panitumumab is an anti-epidermal growth factor receptor (EGFR) antibody that has previously been shown to produce a response rate of 22% and a median PFS of 4.1 months in KRAS wild-type chemorefractory metastatic colorectal cancer. Anti-EGFR therapy causes immunogenic, tumor-specific apoptosis mediated through an adaptive immune response. However, anti-EGFR resistance eventually develops in the vast majority of patients and is associated with an increase in expression of CTLA-4 and PD-L1. This observation forms the rationale to combine anti-EGFR therapy with inhibitors of these immune checkpoints

In the presented phase II trial, a combination of the CTLA-4 inhibitor ipilimumab, the PD-1 inhibitor nivolumab and panitumumab was evaluated in patients with microsatellite stable, mCRC. In this trial, a total of 56 patients with KRAS/NRAS/BRAF wild-type mCRC were treated with ipilimumab at a dose of 1 mg/kg every 6 weeks, nivolumab at a dose of 240 mg every 2 weeks and panitumumab 6 mg/kg every 2 weeks until disease progression, unacceptable toxicity or patient withdrawal. Eligible participants were required to have microsatellite stability or proficient mismatch repair disease. Patients were allowed to have received no more than 2 prior lines therapy and had be anti-EGFR naive. The primary endpoint of this study was 12-week response rate, with secondary objective including overall response rate (ORR), progression-free survival (PFS), overall survival (OS) and safety. 

Treatment combination produces a median progression free survival of 5.7 months

During a 12-week run-in period, including 6 patients, no dose-limiting toxicities occurred, and the subsequent first stage of the trial with 26 patients yielded a satisfactory response rate to warrant full enrollment of the trial. The median age of the 56 patients in the study was 56 years, two thirds were male and 77% were male. Overall. 79% of participants had a right-sided colon or rectal primary tumor. At the time of the analysis, 49 were evaluable for response. After 12 weeks (primary endpoint), no complete responses were seen, but 17 patients (35%) did experience a partial response. In addition, 21 (43%) patients had disease stabilization, for a disease control rate of 76%.

Seven patients remained on treatment at time of analysis. The median PFS reported in this trial was 5.7 months. Data for OS were not yet mature but indicate a median PS of 27 months.

Unfortunately, two grade 5 adverse events were reported: one case of myocarditis (possibly related) and one patient suffering a colonic perforation (unlikely related). The most common grade 3/4 treatment-related adverse events included hypomagnesemia (11%), rash (11%), an increased lipase level (9%), an increased level of amylase (7%), increased ALT and AST (both 5%) and diarrhea (5%).

Conclusion

In conclusion, this study met its primary endpoint with 35% of patients having a partial response after 12 weeks of therapy. Furthermore, the safety profile observed was consistent with the expected AEs of anti-EGFR therapy. As such, panitumumab, ipilimumab and nivolumab demonstrated promising activity in previously treated MSS KRAS/NRAS/BRAF wild type mCRC patients.

Reference

Sangmin Lee M et al., Phase II study of ipilimumab, nivolumab, and panitumumab in patients with KRAS/NRAS/BRAF wild-type (WT) microsatellite stable (MSS) metastatic colorectal cancer (mCRC). Presented at ASCO GI 2021; Abstract 7.