Three-drug combination active in metastatic colorectal cancer subset
Click Here to Manage Email Alerts
A three-drug combination demonstrated activity for patients with microsatellite-stable, BRAF V600E-positive metastatic colorectal cancer, according to study results presented at ASCO Gastrointestinal Cancers Symposium.
The regimen — which consisted of encorafenib (Braftovi, Pfizer), cetuximab (Erbitux, Eli Lilly) and nivolumab (Opdivo, Bristol Myers Squibb) — also appeared well-tolerated.
“If [these results are] validated in future efforts, we could potentially identify a successful combination immunotherapy approach for a subset of patients with microsatellite-stable metastatic colorectal cancer, for which immunotherapy alone has been historically ineffective,” researcher Van K. Morris, MD, assistant professor of gastrointestinal medical oncology at The University of Texas MD Anderson Cancer Center, told Healio. “In doing so, our goal here is to offer durable and improved survival for this subset of patients with colorectal cancer who otherwise experience shorter survival because of their underlying aggressive oncologic phenotype.”
Patients with BRAF V600E-positive metastatic colorectal cancer often experience rapid progression, and their disease tends not to be as responsive to standard chemotherapy, Morris said.
Encorafenib is an oral small molecule kinase inhibitor that targets BRAF V600E. Cetuximab is an epidermal growth factor receptor inhibitor.
A previous study showed the combination of these agents extended survival compared with traditional therapy for patients with BRAF V600E-positive metastatic colorectal cancer. However, median time on study was about 4 months, and only 20% of patients responded to treatment, Morris said.
“Therefore, [although] progress is being made in the treatment of patients with BRAF-mutated metastatic colorectal cancer, we still need to do better in terms of offering more durable and effective treatment options for this population,” Morris said.
BRAF V600E-positive, microsatellite-stable colorectal cancer is characterized by higher baseline tumor mutation burden and higher immune activation than microsatellite-stable, BRAF wild-type disease.
A prior laboratory study conducted in Italy showed microsatellite-stable, BRAF V600E-posiitive colorectal cancer cells treated with therapies that target BRAF plus EGFR changed in phenotype to microsatellite instability-high status, Morris said.
“Based on this collective rationale, it is possible that these tumors may then be primed for benefit with the combination of encorafenib plus cetuximab with immunotherapy with agents like nivolumab,” Morris said.
Morris and colleagues conducted a single-institution, single-arm phase 1/phase 2 trial to assess the three-drug combination for patients with treatment-refractory microsatellite-stable, BRAF V600E-positive metastatic colorectal cancer.
Researchers enrolled 26 patients (median age, 58 years; range, 32-85; 58% female). Thirteen patients (50%) had ECOG performance status of 1 and 16 (62%) had received one prior line of therapy; however, none had received prior BRAF inhibitors, anti-EGFR antibody treatment or immunotherapy.
Patients received 300 mg oral encorafenib daily, 500 mg/m2 cetuximab via IV every 14 days, and 480 mg nivolumab via IV every 28 days.
Overall response rate and safety/tolerability served as primary endpoints. Investigators also assessed PFS and OS.
Researchers observed no dose-limiting toxicities.
Four patients (15%) experienced grade 3 or grade 4 treatment-related adverse events. Grade 3 adverse events included one case each of colitis, maculopapular rash, leukocytosis and elevated amylase/lipase. One patient experienced grade 4 myositis.
“Overall, this regimen was safe and well-tolerated,” Morris said. “There were no unexpected or surprising toxicities from the combination.”
The response analysis included 22 patients. Median follow-up was 16.3 months.
Researchers reported an ORR of 50% (95% CI, 28-72) and a disease control rate of 96% (95% CI, 77-100), with median PFS of 7.4 months (95% CI, 5.6-not reached) and median OS of 15.1 months (95% CI, 7.7-not reached). Median duration of response was 7.7 months (95% CI, 3.8-not reached).
“We are very pleased with the initial findings in our study,” Morris said. “The [PFS and OS results] are encouraging and suggest the potential for benefit by the addition of immunotherapy to the standard of care — encorafenib plus cetuximab — in this population.”
Two patients remain on the study after more than 70 weeks, Morris said.
A randomized phase 2 trial designed to evaluate the combination of encorafenib and cetuximab with or without nivolumab for patients with microsatellite-stable, BRAF V600E-positive metastatic colorectal cancer is expected to begin this year.
“One limitation to our study is that it is a single-institution study for which patients were healthy enough to travel to/from Houston,” Morris said. “To overcome this caveat, a randomized phase 2 trial through SWOG will activate across the United States in the coming months and will test more formally whether ... the addition of nivolumab improves survival outcomes when added to encorafenib/cetuximab [for] patients with microsatellite-stable, BRAF V600E metastatic colorectal cancer. Data from this trial will be critical to understand better if nivolumab offers meaningful benefit, as we cannot draw definitive conclusions from a single-institution, single-arm trial alone.”
Collapse
Morris VK, et al. Abstract 12. Presented at: ASCO Gastrointestinal Cancers Symposium; Jan. 20-22, 2022; San Francisco.
Click Here to Manage Email Alerts