An update of results of the phase III CheckMate 067 trial at 5 years presented by Larkin et al at the European Society for Medical Oncology (ESMO) 2019 Congress showed that both nivolumab in combination with ipilimumab and nivolumab alone provided significant improvements in overall survival, progression-free survival, and objective response rate over ipilimumab alone in patients with advanced melanoma (Abstract LBA68). The findings were simultaneously published in The New England Journal of Medicine.

“This 5-year analysis represents the longest phase III follow-up for checkpoint inhibitor combination therapy and demonstrates long-term survival with both nivolumab-containing arms vs ipilimumab. In descriptive analyses, nivolumab/ipilimumab was associated with improved survival and a higher likelihood of being alive and treatment-free compared with nivolumab alone, both without loss of quality of life.”

— Larkin et al

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Methods

In the study, 945 treatment-naive patients with stage III or IV treatment-naive melanoma were randomly assigned to receive either nivolumab at 1 mg/kg plus ipilimumab at 3 mg/kg every 3 weeks for four doses followed by nivolumab at 3 mg/kg every 2 weeks (n = 314); nivolumab at 3 mg/kg every 2 weeks plus ipilimumab-matched placebo (n = 316); or ipilimumab at 3 mg/kg every 3 weeks for four doses plus nivolumab-matched placebo (n = 315) until disease progression or unacceptable toxicity occurred. The patients were stratified by programmed cell death ligand 1 (PD-L1) status, BRAF mutation status, and disease stage.

The co-primary endpoints were overall survival and progression-free survival. Since the study was not powered to compare the nivolumab treatment arms, descriptive analyses were performed to evaluate efficacy between nivolumab/ipilimumab and nivolumab monotherapy, as well as treatment-free status and health-related quality of life assessed using the EQ-5D-3L utility index.

Results

The long-term data showed that patients with melanoma treated with nivolumab—delivered either as monotherapy or in combination with ipilimumab—continued to show improved overall survival, progression-free survival, and response rates vs treatment with ipilimumab alone.

With a minimum of 60 months of follow-up, median overall survival in the nivolumab/ipilimumab, nivolumab, and ipilimumab arms was > 60 months (not reached; 95% confidence interval [CI] = 38.2–not reached), 36.9 months (95% CI = 28.2–58.7), and 19.9 months (95% CI = 16.8–24.6), respectively; 5-year overall survival rates were 52% (95% CI = 46–57), 44% (95% CI = 39–50), and 26% (95% CI = 22–31), respectively.

Median progression-free survival was 11.5 months (95% CI = 8.7–19.3) for patients treated with nivolumab/ipilimumab, 6.9 months (95% CI = 5.1–10.2) for those treated with nivolumab, and 2.9 months (95% CI = 2.8–3.2) for those treated with ipilimumab; 5-year progression-free survival rates were 36% (95% CI = 31–42), 29% (95% CI = 24–35), and 8% (95% CI = 5–12), respectively.

In the respective treatment arms, objective response rates were 58%, 45%, and 19%. The median duration of response was not reached in both the nivolumab combination and monotherapy arms, compared with 14.4 months in the ipilimumab arm.

The median time from randomization to administration of subsequent systemic therapy was not reached (95% CI = 59.6– not reached) with nivolumab plus ipilimumab, 25.2 months (95% CI = 16.0–43.2) with nivolumab alone, and 8.0 months (95% CI = 6.5–8.7) with ipilimumab alone.

At 60 months, among patients who were alive and followed on study, 112 of 151 (74%) of those treated with nivolumab/ipilimumab, 75 of 130 (58%) of those receiving nivolumab alone, and 30 of 67 (45%) receiving ipilimumab alone remained free from subsequent systemic therapy, respectively.

Overall survival was improved in both the nivolumab-containing arms vs the ipilimumab arm, irrespective of BRAF status. Five-year overall survival rates in patients with BRAF mutations were 60% with nivolumab/ipilimumab, 46% with nivolumab alone, and 30% with ipilimumab alone; and 48%, 43%, and 25% with the respective treatments in patients with wild-type BRAF mutations.

Similarly, improved overall survival was observed with nivolumab-based treatment irrespective of baseline lactate dehydrogenase (LDH) levels: in patients with LDH levels at or under the upper limit of normal, 5-year overall survival rates with the respective treatments were 60%, 53%, and 34%; and in patients with LDH levels above the upper limit of normal, those rates were 38%, 28%, and 15%.

Improved overall survival with the respective treatments was seen in patients with PD‑L1 expression ≥ 5%, among whom 5-year overall survival rates were 57%, 51%, and 33%; rates were 51%, 43%, and 24% in patients with PD-L1 expression < 5%.

No sustained deterioration of health-related quality of life was observed during or after treatment with nivolumab/ipilimumab or with nivolumab alone, and no new late toxic effects were noted.

The researchers concluded, “This 5-year analysis represents the longest phase III follow-up for checkpoint inhibitor combination therapy and demonstrates long-term survival with both nivolumab-containing arms vs ipilimumab. In descriptive analyses, nivolumab/ipilimumab was associated with improved survival and a higher likelihood of being alive and treatment-free compared with nivolumab alone, both without loss of quality of life.”

Disclosure: CheckMate 067 was funded by Bristol-Myers Squibb. For full disclosures of the study authors, visit esmo.org or nejm.org.