Immunotherapy combination shows antitumor activity in PD-1-refractory melanoma
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The combination of pembrolizumab and low-dose ipilimumab appeared tolerable and led to significant antitumor activity among patients with advanced melanoma who previously failed prior immunotherapy, according to phase 2 study results.
“Front-line pembrolizumab [Keytruda, Merck] plus ipilimumab [Yervoy Bristol Myers Squibb] has an incrementally higher response rate than anti-PD-1 alone in patients with melanoma but with severe immune-related toxicity in more than 50% of patients,” Jason J. Luke, MD, FACP, director of the Cancer Immunotherapeutics Center and associate professor of medicine at UPMC Hillman Cancer Center and University of Pittsburgh School of Medicine, told Healio. “Ipilimumab in the second-line setting is associated historically with a 13% response rate, although previous studies have suggested an ability of ipilimumab to drive new T cells into the tumor microenvironment. We hypothesized that continuing anti-PD-1 therapy after progression on monotherapy might enhance low-dose ipilimumab, leading to a higher response rate as well as lower rates for severe immune-related adverse events.”
Luke and colleagues evaluated the efficacy and safety of 1 mg/kg ipilimumab plus 200 mg pembrolizumab once every 3 weeks for four doses, followed by 200 mg pembrolizumab alone every 3 weeks for up to 2 years, among 70 patients (median age, 64 years; 67% men) with advanced melanoma who had progressed on immediate prior therapy with an anti-PD-1 antibody alone (n = 60) or anti-PD-1/L1 antibody-based combinations (n = 10). Most patients (89%) had cutaneous melanoma, 29% had BRAF V600 mutations, 49% had M1c or M1d disease and 31% had elevated serum lactate dehydrogenase concentrations.
Median time on prior anti-PD-1/L1 therapy was 4.8 months, and 13 patients experienced progression during prior adjuvant treatment.
Response rate by immune-related RECIST served as the primary endpoint. PFS and safety served as secondary endpoints.
Median follow-up was 12 months.
The majority (76%) of patients received four or more doses of pembrolizumab plus low-dose ipilimumab. The other patients received a median two cycles of therapy. Reasons for treatment discontinuation included progressive disease (n = 11), adverse events (n = 4) and death (n = 2). Median number of cycles was nine among those who continued pembrolizumab monotherapy.
Results showed an overall response rate of 29% (95% CI, 18.4-40.6), including five (7.2%) complete responses and 15 (21.4%) partial responses.
Median PFS was 5 months (95% CI, 2.8-8.3), median OS was 24.7 months (95% CI, 15.2 to not reached) and median duration of response was 16.6 months (95% CI, 7.9 to not reached).
Researchers observed responses among 15% of patients who had progressed on an anti-PD-1 antibody in the adjuvant setting, 17% of patients who had liver metastases and previously treated brain metastases and 27% of patients with elevated lactate dehydrogenase at baseline.
Grade 3 to grade 4 treatment-associated adverse events occurred among 27% of patients, including diarrhea, rash and transaminase elevations. There were no treatment-associated deaths.
“These data, in conjunction with the international retrospective study on the same topic, suggest that an anti-CTLA-4 antibody should no longer be given as a monotherapy but rather combined with anti-PD-1 antibody and given as a low dose as a second-line treatment for melanoma,” Luke said. “Anti-PD-1 antibody with low-dose ipilimumab is now considered a backbone regimen from which to develop combination regimens. We are now investigating the combination of BRAF with and without MEK inhibitors in combination with anti-PD-1 therapy and low-dose ipilimumab for extremely high-risk patients with advanced BRAF-mutant melanoma.”
In an accompanying editorial, Laura A. Huppert, MD, and Adil I. Daud, MD, MBBS, both researchers at University of California, San Francisco, reiterated the importance of awaiting randomized results of an anti-PD-1 and anti-CTLA-4 antibody combination after anti-PD-1 antibody failure to definitively establish the superiority of this combination regimen.
“Nonetheless, this study provides compelling evidence that the combination of PD-1 and CTLA-4 blockade is a safe and effective treatment approach in the PD-1-refractory patient population,” the editorial authors wrote.
For more information:
Jason J. Luke, MD, FACP, can be reached at UPMC Hillman Cancer Center, 5150 Centre Ave., Room 563, Pittsburgh, PA 15232; email: lukejj@upmc.edu.
References:
Huppert LA and Daud AI. J Clin Oncol. 2021;doi:10.1200/JCO.21.00943.
Olson DJ, et al. J Clin Oncol. 2021;doi:10.1200/JCO.21.00079.
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