MADRID-Adjuvant therapy with the PD-1 inhibitor nivolumab-already approved for treating metastatic melanoma-had a statistically and clinically significant benefit over treatment with the current standard of care, the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor ipilimumab, in patients with high-risk completely resected stage IIIB, IIIC, and IV melanoma in the CheckMate 238 study reported at the ESMO 2017 Congress (LBA8_PR).
"Not only was nivolumab more clinically effective than ipilimumab, but the toxicity was considerably less. And it was better tolerated-by any parameter of toxicity-any treatment-related adverse event, grade 3-4 treatment-related adverse event or-what's most important to me as an oncologist-the proportion of patients who discontinued because of treatment-related toxicity," said first author Jeffrey Weber, MD, PhD, Deputy Director of the Laura and Isaac Perlmutter Cancer Center, and Professor of Oncology in the Department of Medicine at NYU Langone Health.
Fewer Discontinuations
Ten percent of the patients stopped because of side effects in the nivolumab group compared to more than 40 percent for the ipilimumab group. When asked to assess the overall impact of the findings, Weber said he had "high hopes" the FDA would approve nivolumab as adjuvant therapy for resected high-risk disease. "I think this is clearly an impressive result that I hope will generate a new standard of care in the adjuvant mode for patients with both BRAF wild-type and BRAF-mutated melanoma."
He said the patients studied had on average a 50 percent risk of progression within 5 years and a 50 percent risk of death within 10 years. After complete resection, adjuvant nivolumab was compared with the existing standard of care in the U.S.-adjuvant ipilimumab. The superiority of nivolumab was, therefore, in comparison to an agent that had already proven to delay progression and extend life.
In the CheckMate 238 study, 906 patients were randomized double-blind-453 to nivolumab and 453 to ipilimumab-after complete resection of their tumors. The study was stopped early because of a benefit favoring nivolumab in the primary endpoint-relapse-free survival (RFS). Weber said the hazard ratio for RFS was 0.65 with a "p value" of 0.0001 amounting to a 35 percent risk reduction for relapse. Overall survival was a secondary endpoint, but calculation of any impact on overall survival was expected to be complicated because patients were allowed to cross over to the other drug upon relapse.
Overall toxicity was lower with nivolumab. Fourteen percent of patients had grade 3 or 4 treatment-related adverse events with nivolumab compared to 46 percent in those treated with ipilimumb. Adverse events of any grade led to discontinuation in 10 patients in the nivolumab arm and 43 percent of those receiving standard ipilimumab therapy.
The superiority of nivolumab was seen across all subgroups, Weber said, irrespective of BRAF or PD-L1 status or disease stage. And he said that distant metastasis-free survival-which he thought was likely to be associated with overall survival-was also superior with nivolumab compared to ipilimumab.
Change Tumor Biology
If the agent were approved, Weber expected large numbers of patients with high-risk resected melanoma would soon get nivolumab. "This may change the biology of the disease because now most patients who have relapsed melanoma who need treatment for metastatic disease will have seen nivolumab or the BRAF MEK [inhibitor combination] dabrafenib-trametinib," he noted.
Exposing patients to immunotherapy with checkpoint inhibitors like ipilimumab or targeted agents like dabrafenib and trametinib would drive resistance via genetic, epigenetic, and RNA-expression changes, he explained. "So, if you treat patients and they develop resistance and relapse, it's going to have a different identity than the tumor prior to treatment."
John Haanen, MD, PhD, Head of the Division of Medical Oncology at the Netherlands Cancer Institute in Amsterdam, said the results of CheckMate 238 were very exciting. "They show for the first time that an anti-PD-1 drug is superior in the adjuvant setting and, because of its lower toxicity, nivolumab is much easier to give than ipilimumab."
This mirrored the situation in the metastatic setting, Haanan said, where anti-PD-1 treatment was more efficacious and had a much better safety profile and replaced ipilimumab as first-line treatment.
Anti PD-1 Standard of Care?
Haanen awaited clinical trial findings with another anti-PD-1 drug, pembrolizumab, being tested as adjuvant therapy against placebo in patients with resected stage III melanoma in a phase III European Organisation for Research and Treatment of Cancer trial. "If relapse-free survival is better with pembrolizumab, it is likely that adjuvant anti-PD-1 will become standard of care for high-risk melanoma in the near future provided an overall survival benefit is also shown."
Olivier Michielin, MD, PhD, Medical Oncologist and Consultant in Dermato-Oncology and Melanoma at Lausanne University Hospital in Switzerland, stated that CheckMate 238 was a groundbreaking study showing that nivolumab was able to increase the benefit very significantly over treatment with ipilimumab.
He was optimistic the drug would be approved in this setting soon. "As soon as we can action this treatment in our patients we will do that. Clearly for us the benefit and the better toxicity profile speak highly in favor of going for nivolumab," he said.
Reinhard Dummer, MD, Professor and Clinic Director of the Dermatology Clinic and Consultant at the Skin Cancer Center in the University Hospital, Zurich, Switzerland, spoke bluntly about the findings Weber had presented. "Ipilimumab is 'out' for adjuvant therapy. Nivolumab is the new standard," he stated.
Dummer emphasized that findings from CheckMate 238 along with the benefits of BRAF and MEK inhibition with dabrafenib and trametinib (reported in the same session of the ESMO 2017 Congress) required a complete updating of melanoma adjuvant therapy. "All of these patients deserve a discussion about adjuvant therapy. At earlier times, we have discussed about ipilimumab or interferons. This will stop. We will now discuss targeted therapy and nivolumab," he concluded.
Peter M. Goodwin is a contributing writer.