Panitumumab Combo Elicits Response in mCRC Subset

Results met the study's predetermined threshold of patient response to necessitate further research.

The addition of ipilimumab (Yervoy) and nivolumab (Opdivo) to standard-of-care (SOC) panitumumab (Vectibix) showed an acceptable response rate including durable responses as a second or later line of therapy for patients with KRAS/NRAS/BRAF wild-type, microsatellite stable (MSS), metastatic colorectal cancer (mCRC).

Findings from the phase 2 trial, which were published in JCO Oncology Advances, also showed responses in patients with liver metastases.

The response rate for the combination therapy was 32.1% (n = 18; 95% CI, 21.4%-45.2%) by RECIST criteria, reaching the predetermined threshold of patient response (n ≥ 17) for further investigation.

“These results add to a growing body of literature supporting the efficacy of immune checkpoint inhibitor therapy in MSS CRC, particularly for patients without liver metastases,” wrote Hanna K Sanoff, MD, of the University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, and co-authors of the study.

Results

Additionally, at 12 weeks, the response rate was 19 of 56 (34%; 95% CI, 23%-47%) by irRECIST criteria. The median duration of response was 5 months (95% CI, 3.3-9). The best response rate was 36% (n = 20; 95% CI, 24%-49%). The median overall survival (OS), calculated by date of death from any cause or last contact, was 17.6 months (95% CI, 14.2-27.5).

Median progression-free survival (PFS) was 6 months (95% CI, 5.5-7.4) for the patient population, 6 months (95% CI, 0.7-10.6) for patients with liver metastases, and 8.2 months (95% CI, 5.5-28.3) for patients without liver metastases.

Researchers noted that the rate of survival may be because of favorable clinical characteristics of the patient population, including 50% of patients having tumors of the left colon and 50% of patients receiving study treatment as a second line of therapy.

Five patients discontinued therapy due to clinical progression, and 2 patients died during the trial period and were considered to have progressed. The median duration of therapy was 5.7 months.

Safety

Two grade 5 toxicities occurred, including 1 patient who possibly developed treatment-related myocarditis without pericardial effusion and 1 who developed disease-related colonic perforation without a complete response to treatment.

The most frequent grade 3 or higher adverse effects (AEs) were maculopapular, acneiform, or desquamating rash (n = 11; 20%), hypomagnesemia (n = 6; 11%), elevated lipase (n = 5; 9%), elevated amylase (n = 4; 7%), diarrhea (n = 3; 5%), AST/ALT elevation (n = 3; 5%), and hypophosphatemia (n = 3; 5%). Other grade 3 or 4 treatment-related AEs each occurred in 1 or 2 patients, respectively.

Trial Design

In this multicenter, Simon’s 2-stage, phase 2 trial, researchers assessed data from 56 patients who were enrolled from March 2018 to June 2020, all of whom had KRAS/NRAS/BRAF wild-type, MSS, or proficient mismatch repair (MMR) mCRC. Patients were given 6 mg/kg of panitumumab every 2 weeks, 1 mg/kg of ipilimumab every 6 weeks, and 240 mg of nivolumab every 2 weeks, each administered intravenously.

Patients had received 1 (n = 28) or 2 (n = 28) prior lines of therapy but had not received epidermal growth factor receptor (EGFR), PD-1/PD-L1, or CTLA-4 blockades. The median patient age was 56 years (range, 36-74), and most patients (78.6%, n = 44) had liver metastases.

The trial started with a 6-patient safety run-in, which would follow stage I of the trial if there were no dose-limiting toxicities at the 12-week mark. Researchers aimed to accrue 26 additional patients and required 7 responses to justify stage II of the trial. In stage II, researchers would accrue 24 additional patients. Patients were treated until disease progression, unacceptable adverse events, or cessation of therapy. The primary outcome of the trial was the overall response rate at 12 weeks by RECIST criteria.

Of note, 26 and 29 patients had an ECOG performance statuses of 0 and 1, respectively. ECOG status was not available for 2 patients. Nineteen patients (33%) were female.

Background

Panitumumab is a monoclonal antibody that targets EGFR. According to the study, previous findings associated the use of EGRF blockades with increased PD-L1 and CTLA-4 expression and T-cell infiltration. Ipilimumab is anti-cytotoxic T-cell lymphocyte-4, and nivolumab is an immune checkpoint inhibitor that targets PD-L1.

“With the evolution of the mCRC paradigm to administer EGFR inhibitors in the first-line setting, future combination studies with dual checkpoint blockade should also be considered in the first-line setting,” observed the researchers. “…Despite the small sample size, the efficacy readout still supports further evaluation of [immunotherapy] combinations with EGFR blockade in a larger, randomized study.”

As noted by the authors, the study was limited by a lack of control arm and limited representation of race and ethnicity, with 43 out of 56 patients (77%) being White.

Reference

Somasundaram A, Moore DT, Turk AA, et al. Phase II study of ipilimumab, nivolumab, and panitumumab in patients with KRAS/NRAS/BRAF wild-type microsatellite stable metastatic colorectal cancer. JCO Oncol Adv. 2025;2:1-8. doi:10.1200/OA-24-00086