Dr Buchbinder on the Potential Role for RP1 Plus Nivolumab in Melanoma After PD-1 Progression

“A lot of patients are undergoing TIL therapy now when they've progressed after immunotherapy. [However,] having something like an effective injection therapy, in combination with nivolumab, that we could use in this space would give us another option, particularly for those patients [who perhaps] can't [receive] TIL therapy or have even [progressed on prior] TIL therapy.

Elizabeth Buchbinder, MD, assistant professor, Medicine, Harvard Medical School, senior physician, Medical Oncology, Dana-Farber Cancer Institute, discusses the potential implications of the FDA's decision to grant breakthrough therapy designation to RP1 (vusolimogene oderparepvec) plus nivolumab (Opdivo) for the treatment of adult patients with advanced melanoma.

a biologics license application (BLA) was submitted to the FDA for accelerated approval

 of RP1 (vusolimogene oderparepvec) in combination with nivolumab (Opdivo) for the treatment of adult patients with advanced melanoma who have previously received a regimen containing a PD-1 inhibitor. This combination concurrently received breakthrough therapy designation from the FDA for the same indication. Both the BLA submission and breakthrough designation are supported by data from the anti-PD-1–progressed melanoma cohort (n = 156) of the phase 1/2 IGNYTE trial (NCT03767348).

After a median follow-up of 15.4 months, the overall response rate (ORR) in this cohort was 32.7%, including complete response (CR) and partial response (PR) rates of 14.7% and 17.9%, respectively. Among patients who had previously received anti–PD-1 monotherapy (n = 82), the ORR was 37.8%, with CR and PR rates of 22.0% and 15.9%, respectively. In those previously treated with both PD-1 and CTLA-4 inhibitors (n = 74), the ORR was 27.0%, with CR and PR rates of 6.8% and 20.3%, respectively.

Based on these data, the confirmatory phase 3 IGNYTE-3 trial (NCT06264180) is currently enrolling patients with advanced melanoma who have progressed on PD-1 and CTLA-4 therapy or are ineligible for CTLA-4 therapy. The primary endpoint of this trial is overall survival (OS), with secondary endpoints including progression-free survival (PFS) and ORR.

The current treatment landscape for advanced melanoma is evolving with the use of targeted therapies and tumor-infiltrating lymphocyte (TIL) therapy, both of which are becoming more prevalent, particularly for patients who have progressed after immunotherapy, Buchbinder says. However, the introduction of a combination like RP1 plus nivolumab offers a new and valuable option, she states. This combination could be particularly beneficial for patients who are ineligible for TIL therapy, have progressed on TIL therapy, or lack viable targeted therapy options, Buchbinder says. Additionally, patients who are not candidates for other clinical trials may find this combination to be an effective alternative, she notes. The availability of this option provides an important opportunity to expand treatment choices for advanced melanoma, potentially leading to improved outcomes for patients with limited options, Buchbinder concludes.

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Elizabeth Buchbinder, MD, discusses the implications of the FDA's decision to grant breakthrough therapy designation to RP1 plus nivolumab in melanoma.


Treatment With Nivolumab Maintenance Following irAEs in Melanoma

Dr Buchbinder on Treatment With Nivolumab Maintenance Following irAEs in Melanoma

Elizabeth Buchbinder, MD, assistant professor, Medicine, Harvard Medical School, senior physician, Medical Oncology, Dana-Farber Cancer Institute, discusses the investigation of treatment with nivolumab (Opdivo) maintenance therapy in patients with melanoma who experienced severe immune-related adverse effects (irAEs) associated with combination therapy with nivolumab and ipilimumab (Yervoy).

Data from a retrospective analysis that were presented at the 

revealed practice discrepancies that were unrelated to patient factors but influenced by physician considerations. The study demonstrated a 68% reduction in the risk of death among patients who resumed nivolumab monotherapy (n = 46) compared with those who did not (n = 76; HR, 0.32; 95% CI, 0.12-0.84). Among patients who resumed treatment, 26% (n = 12) encountered any-grade irAEs, with 5 patients experiencing grade 3 irAEs. However, no grade 4 or 5 irAEs were reported. The observed irAE rates and improved survival in patients resuming maintenance nivolumab indicate the potential benefit of administering additional immunotherapy following the resolution of initial severe irAEs. 

Buchbinder explains that these outcomes emphasize the need

 for additional prospective investigation of this topic.

Because this is a retrospective study, it's crucial to prospectively validate these data or include significantly larger numbers before considering changes in practice, Buchbinder begins. Nevertheless, the findings are intriguing and prompt thoughtful consideration, she states. Notably, there are observable variations in how providers globally approach the continuation of nivolumab, Buchbinder explains.

Although much work remains in this domain, initiating dialogue about this topic may catalyze further research, Buchbinder continues. The initial step involves building upon the findings from the retrospective analysis by assembling a more extensive dataset from other institutions to explore whether these trends persist with a broader patient cohort, she notes. However, given the retrospective nature of this research, prospective validation would be desirable for more robust confirmation of the findings, Buchbinder concludes.

Elizabeth Buchbinder, MD, discusses the investigation of treatment with nivolumab maintenance therapy in patients with melanoma who experienced severe immune-related adverse effects associated with combination therapy with nivolumab and ipilimumab.


Elizabeth Buchbinder, MD, assistant professor, Medicine, Harvard Medical School, senior physician, Medical Oncology, Dana-Farber Cancer Institute, discusses the rationale for investigating nivolumab (Opdivo) maintenance therapy in patients with melanoma who experienced severe immune-related adverse effects (irAEs) due to combination therapy with nivolumab and ipilimumab (Yervoy), and details the findings of this investigation.

Many patients with metastatic melanoma who are treated with the combination of ipilimumab and nivolumab in the frontline develop toxicity following only a few doses, Buchbinder begins. Typically, this means that treatment is stopped, and the patient will then receive steroids or another immunosuppressive therapy, followed by the decision of whether to resume immunotherapy, she says. Notably, these patients will have residual disease on the scan, Buchbinder explains.

To combat this difficult decision, some patients in this situation will be treated with nivolumab alone, Buchbinder expands. Many of the irAEs could stem from the combination of these therapies, leading to the decision to treat with nivolumab alone. However, some clinicians will opt for observation until patients experience disease progression before deciding on another treatment, Buchbinder says. Based on these varying practice patterns, investigators further examine each approach, Buchbinder emphasizes.

A retrospective analysis presented at the 2023 ASCO Annual Meeting found differences in practice that weren't based on patient factors; rather, they were based on physician factors, Buchbinder continues. Findings showed that patients who resumed nivolumab monotherapy (n = 46) experienced a 68% reduction in the risk of death compared with those who did not resume nivolumab (n = 76; HR, 0.32; 95% CI, 0.12-0.84). Among patients who resumed treatment, 26% (n = 12) experienced any-grade irAEs, and 5 patients had grade 3 irAEs. No grade 4 or 5 irAEs were reported.

Given the rates of irAEs and improved survival for patients who resumed maintenance nivolumab, these data suggest that giving more immunotherapy following the resolution of initial severe irAEs could be beneficial and should be prospectively studied, she concludes.

Elizabeth Buchbinder, MD, discusses the rationale for investigating nivolumab  maintenance therapy in patients with melanoma who experienced severe immune-related adverse effects due to combination therapy with nivolumab and ipilimumab, and details the findings of this investigation.


Elizabeth Buchbinder, MD,

Articles

Dr Buchbinder on the Potential Role for RP1 Plus Nivolumab in Melanoma After PD-1 Progression

Dr Buchbinder on Treatment With Nivolumab Maintenance Following irAEs in Melanoma

Dr Buchbinder on Treatment Decisions After Severe irAEs With Nivolumab/Ipilimumab in Melanoma