Ipilimumab-pembrolizumab combination appears promising for advanced melanoma
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Pembrolizumab plus low-dose ipilimumab demonstrated antitumor activity among patients with advanced melanoma who failed prior treatment, according to phase 2 study results presented during the ASCO20 Virtual Scientific Program.
The regimen — administered immediately after patients progressed on PD-1 antibody therapy — also appeared tolerable.
Pembrolizumab plus low-dose ipilimumab demonstrated antitumor activity when administered to patients with advanced melanoma immediately after they progressed on PD-1 antibody therapy.
“Treatment options for patients [after anti-PD-1] antibody failure are limited,” Daniel Olson, MD, oncology fellow at The University of Chicago Comprehensive Cancer Center, said during a presentation. “In KEYNOTE-006, ipilimumab [Yervoy, Bristol-Myers Squibb] appeared to result in similar efficacy in front-line vs. second-line treatment, and in CheckMate 067, ipilimumab combined with a PD-1 antibody improved outcomes but resulted in high toxicity. It has been hypothesized that using low-dose ipilimumab could result in fewer high-grade toxicities. Observations that combined checkpoint therapy provides a clinical benefit and that low-dose ipilimumab may make the regimen more tolerable provided the basis for the current trial.”
The study included 70 patients (median age, 64 years; range, 27-87; 67% men) with advanced melanoma and no prior CTLA-4 antibodies for metastatic disease who progressed on PD-1 antibody therapy.
Sixty patients had been treated with a PD-1 antibody alone and 10 patients had been treated with PD-1 antibody-based combinations. Ten patients had progressed in the adjuvant setting. Median time on a prior PD-1 antibody was 4.8 months.
Immediately after progression, patients received 1 mg/kg ipilimumab plus 200 mg pembrolizumab (Keytruda, Merck) every 3 weeks for four cycles, followed by pembrolizumab alone for up to 2 years.
Immune-related response per immune-related RECIST (irRECIST) served as the primary endpoint. Safety, PFS, OS and biomarkers served as secondary outcomes.
Overall, four patients achieved complete response, 17 achieved partial response and 16 had stable disease.
“Nine patients came off study prior to their first restaging scans, which was due primarily to early objective clinical progression in those patients who then came off study without formal measurements. [Although] all 70 patients were included in the denominator for [response rate], per the irRECIST criteria, we only included those patients with confirmed [response rate], which gave us an irRECIST [response rate] of 27%,” Olson said.
Median duration of response was 18.5 months (95% CI, 10.6 to undetermined).
Median PFS was 5 months (95% CI, 2.8-8.3) and median OS was 24.7 months (95% CI, 15.2 to undetermined).
About one-quarter (27%) of patients experienced grade 3 to grade 4 treatment-associated adverse events, including diarrhea, rash and transaminase elevation.
Given the heterogeneity of patients, Olson and colleagues assessed responses among different subgroups of patients, including those with liver or central nervous system disease (30%), those with PD-1 antibodies whose disease progressed (15%) and those with noncutaneous melanoma (14%).
Results showed response rates of 42% among those with elevated lactate dehydrogenase, 26% among those with BRAF mutations, 31% among those with BRAF wild-type disease, 17% among those with PD-L1-positive disease and 38% among those with PD-L1-negative disease.
“The responses observed in some of these higher-risk patients and the responses observed in PD-L1-negative tumors suggest that we may be capturing atypical responders with pembrolizumab plus ipilimumab,” Olson said. “We also found that pembrolizumab plus ipilimumab appeared effective in patients with non-T-cell inflamed tumors.”
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Olson D, et al. Abstract 10004. Presented at: ASCO20 Virtual Scientific Program; May 29-31, 2020.
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