Meeting NewsPerspective

Nivolumab shows durable benefit for advanced melanoma

Jeffrey S. Weber

CHICAGO — Patients with surgically resected stage III or stage IV melanoma at high risk for recurrence maintained longer RFS after adjuvant treatment with nivolumab then standard ipilimumab, according to long-term efficacy results from the CheckMate 238 clinical trial presented at ASCO Annual Meeting.

“These more mature data continue to demonstrate durable clinical benefit with nivolumab and further support its use for resected stage III or IV melanoma,” Jeffrey S. Weber, MD, PhD, deputy director of Perlmutter Cancer Center at NYU Langone Health, said during his presentation.

CheckMate 238 is the first trial designed to compare nivolumab (Opdivo, Bristol-Myers Squibb), an anti-PD-1 antibody, and ipilimumab (Yervoy, Bristol-Myers Squibb), a CTLA-4 antibody, as adjuvant therapy for patients with resected stage III or stage IV melanoma at high risk for recurrence, defined as greater than 50% risk for relapse over 5 years.

Both agents are approved for treatment of advanced melanoma. Ipilimumab also is approved in the United States for treatment of resected stage III melanoma.

Earlier results of CheckMate 238 demonstrated prolonged RFS with nivolumab compared with standard ipilimumab in this patient population. For this analysis, Weber and colleagues reported on long-term efficacy results with an additional 6 months of follow-up.

The analysis included 906 patients aged 15 years or older. The majority (81%) of patients had stage III disease, 32% had ulcerated primary melanoma, 48% had macroscopic lymph node involvement and 42% harbored BRAF mutations.

Researchers randomly assigned patients to 3 mg/kg nivolumab via IV every 2 weeks (n = 453; median age, 56 years) or 10 mg/kg ipilimumab every 3 weeks for four doses, then every 12 weeks from week 24 up to 1 year (n = 453; median age, 54 years).

Treatment continued until disease recurrence or unacceptable toxicity. RFS in the intent-to-treat population served as the primary endpoint. Secondary endpoints included OS, safety and tolerability, RFS by PD-L1 tumor expression and health-related quality of life.

Minimum follow-up was 2 years.

A total 171 recurrent events occurred among patients who received nivolumab and 221 for patients who received ipilimumab. The RFS benefit with nivolumab compared with ipilimumab persisted with longer follow-up (30.8 months vs. 24.1 months; HR = 0.66; P < .0001).

The 2-year RFS rate was higher among patients who received nivolumab than ipilimumab in subgroups defined by disease stage (stage IIIB, 70.8% vs. 60.7%; stage IIIC, 58% vs. 45.4%; stage IV, 58% vs. 44.3%), PD-L1 expression ( 5%, 75.5% vs. 58.4%; < 5%, 55.2% vs. 45.5%) and BRAF mutation status (mutated, 61.9% vs. 51.7%; wild type, 63.5% vs. 46.2%).

Distant metastatic-free survival at 2 years also continued to be significantly longer with nivolumab than with ipilimumab (70.5% vs. 63.7%; HR = 0.76; P = .034).

Researchers administered subsequent therapies to 31.1% of patients who received nivolumab and 41.1% who received ipilimumab.

No deaths were reported among the nivolumab group compared with five in the ipilimumab group.

“The numbers are very small and is an interesting trend, but it will take an awful lot of follow-up to see enough deaths to be able to make any statistical assessment of whether there really is a difference in survival,” Weber said.

Per protocol, there was no additional safety assessment for the long-term analysis because patients stopped treatment more than 100 days prior to previous data cutoff. – by Melinda Stevens

Reference:

Weber JS, et al. Abstract 9502. Presented at: ASCO Annual Meeting; June 1-5, 2018; Chicago.

Disclosures: Weber reports stock and other ownership interests in, consultant/advisory roles with, research funding to his institution from, or travel expenses from AbbVie, Altor BioScience, Amgen, Astellas Pharma, AstraZeneca, Biond, Bristol-Myers Squibb, cCam Biotherapeutics, Celldex, CytomX Therapeutics, Daiichi Sankyo, Eisai, Genentech, GlaxoSmithKline, Ichor Medical Systems, Incyte, Lion Biotechnologies, Medivation, Merck, Nektar, Novartis, Pieris Pharmaceuticals, Roche, Sellas Life Sciences and WindMIL. He also is named on a patent from Biodesix for a PD-1 antibody biomarker, and on a patent submitted by Moffitt Cancer Center for an ipilimumab (Yervoy, Bristol-Myers Squibb) biomarker. Please see the abstract for all other authors’ relevant financial disclosures.

Jeffrey S. Weber

CHICAGO — Patients with surgically resected stage III or stage IV melanoma at high risk for recurrence maintained longer RFS after adjuvant treatment with nivolumab then standard ipilimumab, according to long-term efficacy results from the CheckMate 238 clinical trial presented at ASCO Annual Meeting.

“These more mature data continue to demonstrate durable clinical benefit with nivolumab and further support its use for resected stage III or IV melanoma,” Jeffrey S. Weber, MD, PhD, deputy director of Perlmutter Cancer Center at NYU Langone Health, said during his presentation.

CheckMate 238 is the first trial designed to compare nivolumab (Opdivo, Bristol-Myers Squibb), an anti-PD-1 antibody, and ipilimumab (Yervoy, Bristol-Myers Squibb), a CTLA-4 antibody, as adjuvant therapy for patients with resected stage III or stage IV melanoma at high risk for recurrence, defined as greater than 50% risk for relapse over 5 years.

Both agents are approved for treatment of advanced melanoma. Ipilimumab also is approved in the United States for treatment of resected stage III melanoma.

Earlier results of CheckMate 238 demonstrated prolonged RFS with nivolumab compared with standard ipilimumab in this patient population. For this analysis, Weber and colleagues reported on long-term efficacy results with an additional 6 months of follow-up.

The analysis included 906 patients aged 15 years or older. The majority (81%) of patients had stage III disease, 32% had ulcerated primary melanoma, 48% had macroscopic lymph node involvement and 42% harbored BRAF mutations.

Researchers randomly assigned patients to 3 mg/kg nivolumab via IV every 2 weeks (n = 453; median age, 56 years) or 10 mg/kg ipilimumab every 3 weeks for four doses, then every 12 weeks from week 24 up to 1 year (n = 453; median age, 54 years).

Treatment continued until disease recurrence or unacceptable toxicity. RFS in the intent-to-treat population served as the primary endpoint. Secondary endpoints included OS, safety and tolerability, RFS by PD-L1 tumor expression and health-related quality of life.

Minimum follow-up was 2 years.

A total 171 recurrent events occurred among patients who received nivolumab and 221 for patients who received ipilimumab. The RFS benefit with nivolumab compared with ipilimumab persisted with longer follow-up (30.8 months vs. 24.1 months; HR = 0.66; P < .0001).

The 2-year RFS rate was higher among patients who received nivolumab than ipilimumab in subgroups defined by disease stage (stage IIIB, 70.8% vs. 60.7%; stage IIIC, 58% vs. 45.4%; stage IV, 58% vs. 44.3%), PD-L1 expression ( 5%, 75.5% vs. 58.4%; < 5%, 55.2% vs. 45.5%) and BRAF mutation status (mutated, 61.9% vs. 51.7%; wild type, 63.5% vs. 46.2%).

Distant metastatic-free survival at 2 years also continued to be significantly longer with nivolumab than with ipilimumab (70.5% vs. 63.7%; HR = 0.76; P = .034).

Researchers administered subsequent therapies to 31.1% of patients who received nivolumab and 41.1% who received ipilimumab.

No deaths were reported among the nivolumab group compared with five in the ipilimumab group.

“The numbers are very small and is an interesting trend, but it will take an awful lot of follow-up to see enough deaths to be able to make any statistical assessment of whether there really is a difference in survival,” Weber said.

Per protocol, there was no additional safety assessment for the long-term analysis because patients stopped treatment more than 100 days prior to previous data cutoff. – by Melinda Stevens

Reference:

Weber JS, et al. Abstract 9502. Presented at: ASCO Annual Meeting; June 1-5, 2018; Chicago.

Disclosures: Weber reports stock and other ownership interests in, consultant/advisory roles with, research funding to his institution from, or travel expenses from AbbVie, Altor BioScience, Amgen, Astellas Pharma, AstraZeneca, Biond, Bristol-Myers Squibb, cCam Biotherapeutics, Celldex, CytomX Therapeutics, Daiichi Sankyo, Eisai, Genentech, GlaxoSmithKline, Ichor Medical Systems, Incyte, Lion Biotechnologies, Medivation, Merck, Nektar, Novartis, Pieris Pharmaceuticals, Roche, Sellas Life Sciences and WindMIL. He also is named on a patent from Biodesix for a PD-1 antibody biomarker, and on a patent submitted by Moffitt Cancer Center for an ipilimumab (Yervoy, Bristol-Myers Squibb) biomarker. Please see the abstract for all other authors’ relevant financial disclosures.

    Perspective

    What is remarkable about all of these data for the immune checkpoint blocking agents as adjuvant therapy in melanoma is that they maintain the superiority over the control, which was not the case when all we had was interferon. So, there is a space between the curves that continues over time and will become a plateau eventually that will turn into an overall survival difference.

    With the difference between the curves for adjuvant therapy it would be very hard, even therapy given for patients who relapse, to catch up with it.

    In a lot of diseases, and certainly in early data for melanoma when we didn’t have checkpoint inhibitors in the adjuvant setting but we did have it in the advanced disease setting, you always had to worry that even if you gave a highly effective adjuvant therapy that delayed relapse and lowered rate of relapse at a particular landmark point, patients who relapsed could go on to benefit from the treatment of advanced disease with effective therapy.  This phenomenon would potentially dilute or eradicate any survival difference that might have been attributable to adjuvant therapy. In this case, if you use the best treatment as adjuvant therapy and it really delays or reduces relapse, then you don’t have to use that therapy, or you can’t use it when they relapse, that will mean the most definitive thing you could do for those patients was pre-relapse. What we have to do now is find which patients are being impacted by the effectiveness of the active adjuvant therapy, so the others can be spared the risk, toxicities and expense.

    • Kim A. Margolin, MD
    • City of Hope

    Disclosures: Margolin reports a consultant/advisory role with Iovance, ad hoc consultant roles with ImaginAb and Nektar, and participation on a data safety monitoring board for ImaginAb.

    See more from ASCO Annual Meeting