Immunotherapy combination improves PFS in pretreated melanoma
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Key takeaways:
- A combination of ipilimumab and nivolumab improved PFS by 37% compared with ipilimumab alone.
- Researchers also observed a higher objective response rate among patients who received the combination.
The combination of ipilimumab and nivolumab extended PFS compared with ipilimumab alone as second-line therapy for patients with advanced melanoma resistant to PD-1 inhibitors, according to study results published in Nature Medicine.
“Notably, this is the first randomized study in any tumor type to report ... that continuation of a PD-1 inhibitor beyond progression can result in a PFS benefit when combined with another therapy as opposed to that other therapy alone,” Ari VanderWalde, MD, MPH, FACP, director of clinical research at West Cancer Center & Research Institute, told Healio. “[Although] many early studies in development have been relying on the assumption that this can work, this is the first study to validate that assumption. This can have significant impact on the field of clinical cancer research and drug development efforts.”
Background and methods
Anti-PD-1 antibodies are a widely used standard first-line treatment for metastatic melanoma.
The ideal treatment for patients who do not respond to frontline single-agent anti-PD-1 therapy has not been established, according to study background.
VanderWalde and colleagues hypothesized that absence of pre-existing intratumor T-cell infiltrates the key mechanism to lack of response to PD-1 blockade — may help reverse treatment resistance.
They conducted a randomized phase 2 study that included 91 patients with metastatic melanoma whose disease progressed after frontline anti-PD-1/anti-PD-L1 therapy.
Researchers compared treatment with an anti-CTLA-4 antibody with or without continuation of PD-1 blockade
They assigned 68 patients to ipilimumab (Yervoy, Bristol Myers Squibb) plus nivolumab (Opdivo, Bristol Myers Squibb). The other 23 received ipilimumab alone.
PFS served as the primary endpoint. Secondary endpoints included OS, objective response rate, difference in CD8 T-cell infiltrate among responding and nonresponding tumors, and toxicity.
Results
Results showed a 37% improvement in PFS in the combination group (HR = 0.63; 90% CI, 0.41–0.97).
Researchers also reported a higher ORR in the combination group (28% vs. 9%; one-sided P = .05).
A higher percentage of patients assigned the combination experienced grade 3 or higher treatment-related adverse events (57% vs. 35%). Toxicity profiles for both ipilimumab and nivolumab appeared consistent with the known profiles of each agent, according to investigators.
Results showed no significant change in intratumoral CD8 T-cell density.
Next steps
The findings suggest the ipilimumab-nivolumab combination may reverse primary resistance to PD-1 blockade therapy for some patients with metastatic melanoma, researchers wrote.
“The most obvious and important take-home message is that patients who do not respond to anti-PD-1 therapy in the first line who have not previously received an anti-CTLA 4 inhibitor should now receive the combination of ipilimumab and nivolumab in the second line,” VanderWalde told Healio. “Even beyond this, however, this study can potentially even change the approach to first-line therapy.
“The combination of ipilimumab and nivolumab are often used in the first-line setting but [this has] a very high toxicity risk,” VanderWalde added. “Given the high response rate and PFS benefit in our study, it might be reasonable to reserve ipilimumab and its associated toxicity only for those relatively small number of patients who don’t respond to PD-1 therapy alone.”
References:
- VanderWalde A, et al. Nat Med. 2023;10.1038/s41591-023-02498-y.
- Immunotherapy drug combo helps extend the lives of patients with metastatic melanoma (press release). Available at: https://www.uclahealth.org/news/immunotherapy-drug-combo-helps-extend-lives-patients-with. Published Aug. 17, 2023. Accessed Aug. 23, 2023.
For more information:
Ari VanderWalde can be reached at avanderwalde@westclinic.com.
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