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The combination of regorafenib (Stivarga) plus nivolumab (Opdivo) in patients with mismatch repair–proficient (pMMR)/microsatellite stable (MSS) colorectal cancer (CRC) showed a discrepancy in efficacy between the Japanese and North American Population, according to results of a single-arm phase 2 study presented at the 2021 ASCO Annual Meeting.1
The benefit and efficacy of immunotherapy for the treatment of pMMR/MSS metastatic CRC has yet to be established. However, a recent Japanese phase 1b trial found that the combination of regorafenib plus nivolumab had encouraging activity and a manageable safety profile,2 putting it at odds with a study of this combination in North America.
“The Japanese REGONIVO phase 1b trial showed that the combination of the multi-kinase inhibitor regorafenib plus nivolumab had encouraging activity with an objective responserate of 33% in patients with microsatellite stable metastatic colorectal cancer and had manageable safety. Our single-arm
phase 2 study assessed the safety and efficacy of this combination in patients from North America,” said Marwan G. Fakih, MD, a professor in the Department of Medical Oncology & Therapeutics Research, associate director for clinical sciences, medical director of the Judy & Bernard Briskin Center for Clinical Research, and co-director of the Gastrointestinal Cancer Program at the City of Hope Comprehensive Cancer Center.
This phase 2 study (NCT04126733) enrolled patients 18 years of age and older who had received 2 lines or less of prior therapy for extended RAS-mutant disease or 3 or less prior lines of therapy for extended RAS wild type (WT). Prior lines of therapy were required to include fluoropyrimidines, irinotecan, oxaliplatin, VEGF-targeted therapy, and if extended RAS WT, an EGFR-targeted therapy. Additionally, patients had to have an ECOG performance status of 0 or 1.
During the study, patients received a starting dose of daily regorafenib 80 mg for 3 weeks on, 1 week off. Patients then progressed up to 120 mg for the next cycle and beyond, following the same 3 weeks on, 1 week off schedule. Patients also received 480 mg of intravenous nivolumab every 4 weeks.
The primary end point of the study is overall response rate. Secondary end points include duration of response (DoR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. Pharmacokinetic and biomarker analyses were also performed.
At the time of data cutoff on November 11, 2020, 10% of patients were still undergoing treatment and 90% had discontinued treatment. The most common cause for discontinuation was disease progression (81%). Other reasons included adverse events (AEs; 11%) and physician’s decision (5%).
Of the 70 patients included in the analysis, 59% were male. The median age was 57 (range, 34-85). White patients made up 71% of the cohort, Black or African American patients made up 14% of the cohort, Asian patients made up 10% of the cohort, Native Hawaiian or Other Pacific Islander patients made up 1% of the cohort, and 3% did not report their race. Over half (51%) had an ECOG performance status of 0 and 49% had an ECOG score of 1. The primary cancer site for 36% of patients was the right colon, the left colon for 47% of patients, and the rectum for 17% of patients. Liver metastases were reported at baseline in 67% of patients and lung metastases in 73%.
In terms of mutations, 31% of patients had either BRAF, KRAS, NRAS wild type, 61% had a KRAS or NRAS mutation, 4% had a BRAF mutation, and 3% could not be evaluated for mutations. Ninety-three percent of patients had adenocarcinoma not otherwise specified and 7% had mucinous adenocarcinoma.
Four percent of patients had received just 1 prior line of therapy, 43% had 2 prior lines of therapy, 26% had 3 prior lines of therapy, and 27% had 4 or more prior lines of therapy. Additionally, 100% of patients were treated with fluoropyrimidines and irinotecan. Ninety-nine percent of patients received oxaliplatin, 94% were exposed to a VEGF inhibitor, and 33% to an EGFR inhibitor. Under a quarter of patients (24%) had received prior radiotherapy. The median time from diagnosis of metastases was 24 months (range, 1-141).
For regorafenib, the median duration of treatment was 2.2 months and the median number of cycles was 3. Of the patients, 41% were able to progress to 120 mg. For nivolumab, the median treatment duration was 1.9 months and the median number of cycles was 3.
Of the 7% of patients who had a partial response, none had liver metastases. Of the patients with liver metastases, 30% had stable disease, 57% had progressive disease, and 13% were not evaluable. Thirty percent had their disease controlled for 8 or more weeks, and the median duration of stable disease was 21 weeks. For patients without liver metastases, 22% had a partial response, 35% had stable disease, 39% had progressive disease, and 4% were not evaluable. The ORR was 22% and the DCR at 8 or more weeks was 57%. The median duration of stable disease was 30 weeks. For all patients, 31% achieved stable disease, 51% had progressive disease, and 10% were not evaluable. The ORR was 7%, the DCR at 8 weeks or more was 39%, and the median duration of stable disease was 30 weeks.
The median OS for patients without liver metastases was 11.9 months, 10.7 months for those with liver metastases, and 11.9 months for all patients. The median PFS for patients with liver metastases was 3.5 months, 1.8 months for those without liver metastases, and 1.8 months for all patients.
In terms of safety, the majority of treatment-emergent AEs (TEAEs) were grade 1 or 2. The most common grade 3 or 4 drug-related TEAEs were maculopapular rash, fatigue, pneumonia, and increased bilirubin. Drug-related TEAEs occurred in 34% and serious cases presented in 9% of patients.
Any-grade TEAEs occurred in 99% of patients. Grade 1 or 2 TEAEs occurred in 31% of patients, grade 3 TEAEs occurred in 53% of patients, grade 4 TEAEs occurred in 10%, grade 5 TEAEs occurred in 4% of patients, and serious TEAEs occurred in 47% of patients. TEAEs led to regorafenib dose interruption in 56% of patients and nivolumab interruptions in 20% of patients. Regorafenib led to dose reduction in 16% of patients. TEAEs led to permanent discontinuation of either drug in 11% of patients.
The most common grade 3 TEAE was maculopapular rash, occurring in 14% of patients. Grade 3 pneumonia occurred in 4% of patients and grade 4 pneumonia occurred in 1% of patients. Grade 3 blood bilirubin increase was reported in 3% of patients and grade 4 blood bilirubin increase occurred in 3% of patients.
“The efficacy of combination treatment with regorafenib plus nivolumab in the North American population was not consistent with the results in the Japanese population”said Fakih.
“The objective response rate was 7%. For the subgroup of patients without liver metastases, the overall response rate was 22%. Overall, adverse events were generally consistent with the known safety profile of regorafenib and/or nivolumab. The level of antitumor activity of the combination may warrant further analysis of subgroups of patients with clinical characteristics or biomarkers that could be indicative of response.”