Dual checkpoint blockade improves PFS as first-line treatment of advanced melanoma
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The addition of relatlimab to nivolumab conferred a significant PFS benefit among treatment-naive patients with advanced melanoma, according to results of the phase 2/phase 3 RELATIVITY-047 study presented at the virtual ASCO Annual Meeting.
The data showed the combination of relatlimab (BMS-986016, Bristol Myers Squibb), a human IgG4 lymphocyte-activation gene 3 (LAG-3)-blocking antibody, plus the anti-PD-1 agent nivolumab (Opdivo, Bristol Myers Squibb), was well-tolerated and had a manageable safety profile.
Despite improvements made over the last decade in the treatment of advanced melanoma, only approximately 35% of patients benefit from single-agent anti-PD-1 therapy and approximately 55% benefit from the combination of anti-PD-1 with anti-CTLA-4 therapy, with that combination causing severe toxicity among more than 50% of patients, Hussein A. Tawbi, MD, PhD, deputy chair of and professor in the department of melanoma medical oncology, director of melanoma clinical research and early drug development and director of personalized cancer therapy in the department of melanoma medical oncology at The University of Texas MD Anderson Cancer Center, told Healio.
“So, this leaves about half of our patients with metastatic melanoma patients who need novel agents, and also ideally combinations that improve upon single-agent anti-PD-1 without the increased toxicity,” he said. “Nivolumab plus relatlimab offers exactly this; we have improved PFS with a 25% reduced risk for progression and a toxicity profile that is in keeping with single-agent anti-PD-1.”
LAG-3, which is upregulated in melanoma and other cancer types, regulates an immune checkpoint pathway that inhibits T-cell activity. Relatlimab restores effector function of exhausted T cells and, when used with nivolumab, can enhance antitumor immune responses.
“To build on [prior] success and to develop novel regimens that are safe and effective, we combined relatlimab, which blocks another immune checkpoint called LAG-3, with nivolumab, which blocks PD-1,” Evan J. Lipson, MD, associate professor of oncology at Johns Hopkins Kimmel Cancer Center and Bloomberg-Kimmel Institute for Cancer Immunotherapy, said during a press conference. “Although these drugs work through distinct pathways, they have a common goal, which is to unleash an attack by immune T cells against cancer.”
Researchers chose to evaluate this combination in the first-line setting for two reasons, Tawbi told Healio.
“First, it has a well-defined standard of care (single-agent anti-PD-1 or combination anti-PD-1 plus anti-CTLA-4), whereas there is no established standard in the second line,” he said. “Secondly, the mechanism of action of relatlimab is well-suited to first-line combination, whereas phase 1 data from the second line was encouraging but still not promising enough for phase 3 in that setting.”
The analysis included data of 714 patients with previously untreated unresectable or metastatic melanoma who received 480 mg IV nivolumab every 4 weeks alone (n = 359) or with 160 mg relatlimab (n = 355). Patients assigned the combination received a fixed dose of nivolumab plus relatlimab, meaning the agents were prepared together in the same vial and administered as a single IV infusion to reduce preparation and infusion times and risk for administration errors, according to Lipson.
PFS, assessed by a blinded independent central review, served as the study’s primary endpoint. OS and objective response rate served as secondary endpoints.
Median follow-up was 13.2 months.
Patients assigned the combination demonstrated median PFS of 10.12 months, more than double the 4.63-month median PFS observed in the nivolumab-alone group (HR = 0.75; 95% CI, 0.62-0.92). Researchers also reported a higher rate of 1-year PFS in the combination group (47.7% vs. 36%).
“I was very pleased to see the results and truly excited for our [patients with] melanoma to have a new option that improves the risk-benefit profile of combination immune checkpoint inhibitors,” Tawbi said. “A decreased risk for progression by 25% and almost doubling of the median PFS are definitely clinically meaningful and indicate that nivolumab plus relatlimab should likely become the new standard of care in first-line advanced melanoma.”
Grade 3 to grade 4 treatment-related adverse events occurred among 18.9% of patients assigned the combination compared with 9.7% of patients assigned nivolumab alone. The most common of these included fatigue (1.1% vs. 0.3%), rash (0.8% vs. 0.6%), arthralgia (0.8% vs. 0.3%) and diarrhea (0.8% vs. 0.6%).
Treatment-related adverse events that led to discontinuation occurred among 14.6% of patients assigned the combination and 6.7% of those assigned nivolumab alone.
“In general, treatment-related adverse events that were associated with relatlimab plus nivolumab were manageable and reflected the safety profile that we typically see with immune checkpoint inhibitors,” Lipson said. “Although the incidence of grade 3 to grade 4 treatment-related adverse events was higher with relatlimab plus nivolumab than with nivolumab alone, these adverse events occurred at a lower rate than has been observed with other immunotherapy combinations.”
Three treatment-related deaths occurred in the combination group — due to hemophagocytic lymphohistiocytosis, acute edema of the lung and pneumonitis — and two, due to sepsis and myocarditis, and worsening pneumonia, occurred in the monotherapy group.
“Importantly, this is the first phase 3 study to validate inhibition of the LAG-3 immune checkpoint as a therapeutic strategy for patients with cancer, and it established the LAG-3 pathway as the third immune checkpoint pathway in history, after CTLA-4 and PD-1, for which blockade appears to have clinical benefit,” Lipson said.
Because this analysis excluded patients with brain metastases, that is a group that should be explored in future evaluations of this combination, Tawbi said.
“We also need longer term follow-up, and a deeper look at the biomarkers of response,” he said. “It also will be critical to evaluate existing therapies like anti-PD-1plus anti-CTLA-4 after failure of nivolumab plus relatlimab. This combination should also be considered in the adjuvant setting.”
Perspective
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Julie R. Gralow, MD, FACP, FASCO
As multiple approvals of immune checkpoint inhibitors as single agents, or sometimes in combination with chemotherapy, occurred, we began exploring treatment with combinations of immunotherapy drugs that target different sites of immune checkpoints. Relatlimab is a novel agent with a new target, LAG-3, and the RELATIVITY-047 study found that adding relatlimab to an anti-PD-1 inhibitor in melanoma, or using two immunotherapy agents blocking different places in the immune system, extended time to disease progression compared with using the PD-1 inhibitor alone for patients with previously untreated metastatic melanoma. These results provide validation of the LAG-3 immune checkpoint as a therapeutic target in patients with cancer, specifically melanoma in this study, and they also support combination treatment with immunotherapies that act on different parts of the immune system.
Perspective
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Philip Friedlander, MD, PhD
The immune system maintains complex regulation through multiple positive and negative checkpoints. Inhibition of the PD-1 checkpoint has demonstrated significant efficacy in patients with stage IV melanoma.
The need to build upon the efficacy conferred by anti-PD-1 immunotherapy has led to the development of strategies that target multiple immune checkpoints. The RELATIVITY-047 phase 3 study assessed efficacy of dual pathway inhibition through concomitant blockade of the PD-1 and LAG-3 checkpoints. LAG-3 inhibits T-cell activity and is upregulated in melanoma.
The results demonstrate that dual inhibition of the LAG-3 and PD-1 checkpoints through treatment with relatlimab and nivolumab leads to longer PFS when used first line to treat patients with advanced melanoma. This represents an important therapeutic advance and holds significant promise. However, as the median follow-up is only 13.2 months, the survival data need to mature and, currently, it is not clear if the PFS benefit translates into OS benefit in the overall study population or in specific subgroups.
The PFS benefit conferred by the addition of relatlimab needs to be analyzed in the context of standard-of-care first-line immunotherapy. Currently, patients are treated with either anti-PD-1 monotherapy or with dual PD-1 and CTLA-4 checkpoint inhibition using nivolumab plus ipilimumab (Yervoy, Bristol Myers Squibb).
The CheckMate 067 study randomly assigned patients with unresectable stage III or stage IV melanoma to treatment with ipilimumab, nivolumab or combination therapy. With a minimum of 60-month follow-up, median PFS durations were 6.9 months with nivolumab monotherapy, 2.9 months with ipilimumab monotherapy, and 11.5 months with ipilimumab plus nivolumab. Median OS was not reached in the ipilimumab-plus-nivolumab group, with 50.2% of patients alive at 5 years. Median OS for nivolumab monotherapy was 36.9 months.
Although it is difficult to compare data across different trials, the 10.1-month median PFS conferred by relatlimab plus nivolumab is numerically comparable to the 11.5 months conferred by ipilimumab plus nivolumab. A limitation of the RELATIVITY-047 study is the lack of comparison to treatment with ipilimumab plus nivolumab, which limits ability to compare rigorously the relative survival benefits.
When selecting treatment for a given patient with advanced melanoma, the benefit-risk profile needs to be considered. In CheckMate 067, treatment-related grade 3 or grade 4 adverse events occurred among 59% of patients treated with nivolumab plus ipilimumab and 23% of patients treated with nivolumab monotherapy. A significant limitation of ipilimumab-plus-nivolumab treatment is that most patients develop high-grade treatment-related toxicity. In RELATIVITY-047, high-grade treatment-related adverse events developed among 18.9% of patients treated with relatlimab plus nivolumab. Therefore, there appears to be a favorable safety profile as defined by the rate of high-grade toxicity when adding relatlimab, as opposed to ipilimumab, to nivolumab therapy. As efficacy data mature from RELATIVITY-047, the relative benefit-risk profiles can be defined more accurately to help decide the most appropriate checkpoints to modulate in a given patient.
Reference:
Larkin J, et al. N Engl J Med. 2019;doi:10.1056/NEJMoa1910836.
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Tawbi H, et al. Abstract 9503. Scheduled for presentation at: ASCO Annual Meeting (virtual meeting); June 4-8, 2021.
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