Nivolumab Alone, With Ipilimumab Maintains Improved Outcomes in Advanced Melanoma in Long-Term Follow-Up

Jedd D. Wolchok, MD, PhD, FASCO

Nivolumab (Opdivo) monotherapy or in combination with ipilimumab (Yervoy) continued to show durable improvements in overall survival (OS) compared with ipilimumab alone in patients with previously untreated advanced melanoma, according to 6.5 years of follow-up from the phase 3 CheckMate-067 trial that were presented during the 2021 ASCO Annual Meeting.^1,2

The long-term data showed that the median OS with the combination was 72.1 months (95% CI, 38.2–not reached [NR]) and 36.9 months (95% CI, 28.2-58.7) with nivolumab alone, compared with 19.9 months (95% CI, 16.8-24.6) with ipilimumab alone.

The 6.5-year OS rates were 49%, 42%, and 23%, for nivolumab/ipilimumab, nivolumab alone, and ipilimumab alone, respectively.

Additionally, the 6.5-year progression-free survival (PFS) rate was 34% with nivolumab and ipilimumab and the median PFS was 11.5 months (95% CI, 8.7-19.3). The rates were 29% and 7% with nivolumab and ipilimumab as single agents, respectively; the median PFS was 6.9 months (95% CI, 5.1-10.2) and 2.9 months (95% CI, 2.8-3.2), respectively.

“These mature 6.5-year CheckMate-067 results with the combination of nivolumab plus ipilimumab include the longest median overall survival of 72.1 months in a phase 3 study of patients with advanced melanoma,” said lead study author Jedd D. Wolchok, MD, PhD, FASCO, chief of the Immuno-Oncology Service, Human Oncology and Pathogenesis Program, at Memorial Sloan Kettering Cancer Center. “Durable clinical benefit was observed across clinically relevant subgroups, including BRAF mutation and baseline liver metastasis status.”

Wolchok is also a 2014 Giant of Cancer Care® winner in Melanoma.

In 2015, the FDA approved the combination of nivolumab and ipilimumab for the treatment of patients with metastatic melanoma, based on earlier findings from CheckMate-067. Nivolumab is also approved for use as a single agent in this patient population.

In the double-blind, phase 3 CheckMate-067 study, investigators randomized patients with previously untreated unresectable advanced (stage III or IV) melanoma 1:1:1 to receive the combination of nivolumab at 1 mg/kg and ipilimumab at 3 mg/kg for 4 doses, followed by nivolumab at 3 mg/kg every 2 weeks (n = 314), nivolumab alone at 3 mg/kg every 2 weeks plus placebo (n = 316), or ipilimumab alone at 3 mg/kg every 3 weeks for 4 doses plus placebo (n = 315). Treatment was administered until disease progression or unacceptable toxicity.

Patients were stratified by level of PD-L1 expression (<5% vs ≥5%), BRAF mutation status, and metastasis stage.

The co-primary end points were PFS and OS; secondary end points were objective response rate (ORR), descriptive efficacy assessments, and safety.

At the 6.5-year analysis, 49% of patients were alive and in follow-up. Of this percentage, 77% of patients who were treated with nivolumab plus ipilimumab were reported to be off of therapy and did not receive subsequent systemic treatment at a median follow-up of 80.8 months (range, 74.0-86.3); 18% received subsequent systemic therapy and 5% remain on treatment. Sixty-nine percent of those on nivolumab alone, and 43% of those on single-agent ipilimumab also have been off of treatment and did not require subsequent systemic therapy, at a median follow-up of 80.8 months (range, 76.4-85.3) and 81.0 months (range, 77.0-85.6), respectively. Twenty-five percent of patients on nivolumab received subsequent therapy and 7% are still on treatment with the PD-1 inhibitor; 57% on the ipilimumab arm received subsequent systemic therapy.

The median treatment-free intervals following study therapy discontinuation for those on nivolumab/ipilimumab was 27.6 months (95% CI, 0.0-83.0), 2.3 months (95% CI, 0.2-81.6) for patients on nivolumab, and 1.9 months (95% CI, 0.1-81.9) for those on the ipilimumab arm. The median duration of treatment was 3.6 months (range, 0-80.1), 8.6 months (range, 0-79.8), and 3.7 months (range, 0-49.9), respectively.

In the nivolumab/ipilimumab arm, the ORR was 58% (95% CI, 53%-64%), with a complete response (CR) was 23% and the partial response (PR) was 36%. Additionally, the stable disease (SD) rate was 12% and 24% of patients had progressive disease (PD). Six percent of patients had unknown responses.

In the single-agent nivolumab arm, the ORR was 45% (95% CI, 39%-51%), which comprised a 19% CR rate and a 26% PR rate. Nine percent of patients had SD and 38% had PD; 8% of patients had unknown responses.

In the ipilimumab-alone arm, the ORR was 19% (95% CI, 15%-24%), which included a 6% CR rate and a 13% PR rate. The SD, PD, and unknown response rates were 22%, 50%, and 9%, respectively.

These response data were not markedly different from the 5-year analysis, Wolchok noted.

The clinical benefit was sustained and observed with both nivolumab/ipilimumab and nivolumab alone across relevant key subgroups, which included those with BRAF-mutant and BRAF wild-type tumors, and patients with baseline liver metastases.

For those with BRAF-mutant disease, the median PFS was 16.8 months (95% CI, 8.3-32.0), 5.6 months (95% CI, 2.8-9.5), and 3.4 months (95% CI, 2.8-5.2) for nivolumab/ipilimumab, nivolumab alone, and ipilimumab alone (nivolumab/ipilimumab vs ipilimumab, HR, 0.44; 95% CI, 0.31-0.62; nivolumab vs ipilimumab, HR, 0.71; 95% CI, 0.51-0.98; nivolumab/ipilimumab vs nivolumab, HR, 0.62; 95% CI, 0.44-0.89). The 6.5-year PFS rates were 37%, 23%, and 9% for nivolumab plus ipilimumab, single-agent nivolumab, and single-agent ipilimumab, respectively.

Also, in the BRAF-mutant subgroup, the median OS was NR (95% CI, 50.7-NR), 45.5 months (95% CI, 26.4-NR), and 24.6 months (95% CI, 17.9-31.0) with nivolumab/ipilimumab, nivolumab alone, and ipilimumab alone, respectively (nivolumab/ipilimumab vs ipilimumab, HR, 0.43; 95% CI, 0.30-0.60; nivolumab vs ipilimumab, HR, 0.63; 95% CI, 0.44-0.90; nivolumab/ipilimumab vs nivolumab, HR, 0.68; 95% CI, 0.46-1.0). The 6.5-year OS rates were 57%, 43%, and 25%, respectively.

In patients with BRAF wild-type melanoma, the median PFS with nivolumab plus ipilimumab was 11.2 months (95% CI, 7.0-18.1), 8.2 months (95% CI, 5.1-19.6) with nivolumab monotherapy, and 2.8 months (95% CI, 2.8-3.1) with ipilimumab monotherapy (nivolumab/ipilimumab vs ipilimumab, HR, 0.41; 95% CI, 0.33-0.52; nivolumab vs ipilimumab, HR, 0.47; 95% CI, 0.38-0.59; nivolumab/ipilimumab vs nivolumab, HR, 0.88; 95% CI, 0.69-1.12).The 6.5-year PFS rates were 33%, 31%, and 6%, respectively.

Here, the median OS was 39.1 months (95% CI, 27.5-NR), 34.4 months (24.1-59.2), and 18.5 (95% CI, 14.1-22.7) months for nivolumab/ipilimumab, nivolumab alone, and ipilimumab alone, respectively (nivolumab/ipilimumab vs ipilimumab, HR, 0.58; 95% CI, 0.45-0.74; nivolumab vs ipilimumab, HR, 0.63; 95% CI, 0.50-0.80; nivolumab/ipilimumab vs nivolumab, HR, 0.92; 95% CI, 0.71-1.18). The 6.5-year OS rate was 46% in those who received the combination, 42% for nivolumab alone, and 22% for ipilimumab alone.

“These data support ongoing equipoise with a question of optimal first-line therapy for patients with BRAF-mutated melanoma,” said Wolchok.

In those with liver metastases, the median OS was 28.2 months (95% CI, 15.2-71.9) with nivolumab/ipilimumab, 18.2 months (95% CI, 8.1-32.3) with nivolumab alone, and 13.1 months (95% CI, 9.6-18.4) with ipilimumab alone (nivolumab/ipilimumab vs ipilimumab HR, 0.66; 95% CI, 0.46-0.93; nivolumab vs ipilimumab HR, 0.81; 95% CI, 0.58-1.14; nivolumab/ipilimumab vs nivolumab HR, 0.81; 95% CI, 0.56-1.16). Additionally, the OS rates were 38%, 31%, and 22% for the combination, nivolumab monotherapy, and ipilimumab monotherapy, respectively.

For patients without liver metastases, the median OS in the nivolumab/ipilimumab, single-agent nivolumab, and single-agent ipilimumab arms was NR (95% CI, 50.7-NR), 52.7 months (95% CI, 36.0-NR), and 23.5 months (95% CI, 18.6-29.4), respectively (nivolumab/ipilimumab vs ipilimumab HR, 0.47; 95% CI, 0.37-0.60; nivolumab vs ipilimumab HR, 0.56; 95% CI, 0.44-0.71; nivolumab/ipilimumab HR, 0.84; 95% CI, 0.64-1.09). The 6.5-year OS rates were 54%, 47%, and 23%, respectively.

In the combination arm, as well as in the single-agent nivolumab arm, the median duration of response (DOR) has still not yet been reached; the median DOR was 19.2 months for those on the ipilimumab arm.

Melanoma-specific survival (MSS) was also explored as part of a post hoc analysis. Here, the median MSS was not reached (95% CI, 7.1–NR) with the combination arm, 58.7 months (95% CI, 35.9–NR) with single-agent nivolumab, and 21.9 months (95% CI, 18.1-27.4) with single-agent ipilimumab. The HR for the combination against ipilimumab was 0.48 (95% CI, 0.39-0.60) and was 0.81 when compared with nivolumab alone (95% CI, 0.64-1.03). The HR for MSS was 0.59 (95% CI, 0.48-0.73) when comparing nivolumab with ipilimumab. The 6.5-year MSS rates were 56%, 48%, and 27%, respectively.

Regarding safety, the profile of nivolumab and ipilimumab combined was found to be consistent with prior data of the regimen and no new safety signals were observed. No additional treatment-related deaths had occurred since the 36-month analysis of CheckMate-067.

Grade 3/4 treatment-related adverse events (TRAEs) occurred in 59% of patients on the nivolumab/ipilimumab arm, in 24% on the nivolumab-alone arm, and in 28% of patients on the ipilimumab arm. Grade 3/4 TRAEs leading to treatment discontinuation occurred in 31%, 8%, and 13% of patients, respectively.

“These results build upon our decade-long legacy in treating melanoma, which began when the average life expectancy following a diagnosis of metastatic melanoma was roughly six months and less than 10% of patients survived beyond five years,” stated Gina Fusaro, development lead, melanoma, Bristol Myers Squibb.2 “With some of the longest follow-up with immunotherapies to date, Opdivo and Yervoy have consistently demonstrated durable, long-term survival benefits for patients diagnosed with advanced melanoma.”

Previously, 5-year follow-up findings from CheckMate-067, which were published in the New England Journal of Medicine, showed that the median OS with nivolumab/ipilimumab was not reached and was 36.9 months with nivolumab alone, compared with 19.9 months with ipilimumab alone (HR, 0.52 for nivolumab/ipilimumab vs ipilimumab; HR, 0.63 for nivolumab vs ipilimumab).³ The 5-year OS rates were 52%, 44%, and 26%, respectively. In those with BRAF-mutated tumors, the rates were 60%, 46%, and 30%. The median follow-up was 60 months.

At 5 years, the OS rate was 52% with nivolumab plus ipilimumab, 44% with nivolumab alone, and 26% with ipilimumab alone.

References

1. Wolchok JD, Chiarion-Sileni V, Gonzalez R, et al. CheckMate 067: 6.5-year outcomes in patients (pts) with advanced melanoma. J Clin Oncol. 2021;39(suppl 15):9506. doi:10.1200/JCO.2021.39.15_suppl.9506
2. Six-and-a-half-year outcomes for Opdivo (nivolumab) in combination with Yervoy (ipilimumab) continue to demonstrate durable long-term survival benefits in patients with advanced melanoma. News release. Bristol Myers Squibb. May 19, 2021. Accessed June 6, 2021. https://bit.ly/3pnRufC
3. Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Five-year survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med. 2019;381(16):1535-1546. doi:10.1056/NEJMoa1910836