Immunotherapy and Targeted Therapy Triplet Active in Microsatellite Stable mCRC

The triplet regimen of nivolumab (Opvido), ipilimumab (Yervoy), and panitumumab (Vectibix) has shown antitumor activity among patients with previously treated metastatic colorectal cancer (mCRC) that is microsatellite stable (MSS) and KRAS, NRAS, and BRAF wild-type, according to findings from a phase 2 LCCC1632 study (NCT03442569).

“The combination of panitumumab, ipilimumab, and nivolumab met its primary end point with a 35% 12-week response rate and demonstrated promising activity in previously treated KRAS, NRAS, and BRAF wild-type, microsatellite stable, metastatic colorectal cancer,” Michael Sangmin Lee, MD, an assistant professor at The University of Texas MD Anderson Cancer Center, said during a presentation at the 2021 Gastrointestinal Cancers Symposium.

The multicenter Simon’s 2-stage phase 2 trial enrolled patients with unresectable and/or metastatic CRC who had KRAS, NRAS, and BRAF wild-type, MSS, or mismatch repair proficient (pMMR) disease and who had received 1 to 2 prior treatment regimens, not including an EGFR inhibitor or immune checkpoint inhibitor.

In the study, patients were administered 6 mg/kg of intravenous panitumumab every 2 weeks with 240 mg intravenous nivolumab every 2 weeks and 1 mg/kg intravenous ipilimumab every 6 weeks.

The primary end point was the 12-week response rate and secondary end points included overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and toxicity.

The trial included a safety run-in phase of 6 patients who were assessed for tolerability; no dose-limiting toxicities were observed in 12 weeks. Then 26 patients were included in stage I, in which 7 responses were required to justify continued enrollment; 9 responses were observed in this stage. Then in stage II, 24 more patients were enrolled, and 17 responses were required to justify further study of the treatment regimen.

With an α of 0.10, the study was statistically designed with 80% power to detect an improvement in response rate from a null hypothesis of 22% to an alternative hypothesis of 35%, Lee explained.

Of the total patient population across the stages of the study, the median age was 56 years (range, 36-74), 66% were male, 77% were White, 52% had an ECOG performance status of 1, and 50% had left-sided colon tumors.

Among 49 patients evaluable for response, the response rate at 12 weeks was 35%, consisting of all partial responses and meeting the primary end point of the trial. An additional 43% of patients achieved stable disease (SD) and 22% had progression.

The ORR was 20% with confirmed responses in 18% (95% CI, 10%-31%). SD was noted in 39% of patients and disease progression in 20%. Seven patients were still on treatment. A majority of patients did achieve a reduction in their tumor size from baseline.

The median PFS was 5.7 months (95% CI, 5.5-7.9) and the median OS was 27 months (95% CI, 14.5-not evaluable), although these OS data are not yet mature.

Common grade 3 to 5 treatment-related adverse events (TRAEs) included hypomagnesemia (11%), rash acneiform (11%), lipase increase (9%), amylase increase (7%), and alanine aminotransferase increase, aspartate aminotransferase increase, diarrhea, hypophosphatemia, and maculopapular rash (5% each). The 2 grade 5 events included myocarditis, which was possibly related to treatment, and colon perforation, which was not considered to be likely related to treatment.

“Though toxicities were of course observed, they were consistent overall with the expected adverse event profiles of anti-EGFR therapy and combination ipilimumab and nivolumab,” Lee commented.

He noted that correlative studies are ongoing using archival specimens and limited on-treatment biopsies.

_Reference:

_{Lee MS, Loehrer PJ Sr, Imanirad I, 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). J Clin Oncol. 2021;39(suppl 3):7. doi: 10.1200/JCO.2021.39.3_suppl.7}