Adjuvant Nivolumab/Ipilimumab Fails to Significantly Improve RFS in High-Risk Melanoma

Sabine Maier, MD

The dual immunotherapy combination comprised of nivolumab (Opdivo) and ipilimumab (Yervoy) failed to lead to a statistically significant improvement in recurrence-free survival (RFS) when used as an adjuvant treatment in the intent-to-treat (ITT) population of patients with resected stage IIIB/C/D or stage IV melanoma, according to updated results from the phase 3 CheckMate-915 trial (NCT03068455).¹

However, the trial reinforced the benefit of nivolumab monotherapy as a standard of care in the adjuvant setting, according to Bristol Myers Squibb, the manufacturer of the PD-1 and CTLA-4 inhibitors. Moreover, the toxicity profiles of single-agent nivolumab and the immunotherapy combination proved to be consistent with what has previously been reported when used at the dose and schedule examined in the trial, with no new signals observed.

The company plans to complete a full assessment of the findings from CheckMate-915 and will collaborate with investigators to share the data at an upcoming medical meeting.

“We are proud of our legacy in melanoma with both [nivolumab] and [ipilimumab]. They have each brought significant benefit as monotherapies for appropriate [patients with] melanoma in the adjuvant setting, and as a dual immunotherapy regimen in the metastatic setting,” Sabine Maier, MD, vice president and head of Oncology Clinical Development at Bristol Myers Squibb, stated in a press release.

“In CheckMate-915, we evaluated adding [ipilimumab] to [nivolumab] against [nivolumab] – an established, active comparator and current standard of care in the adjuvant setting,” added Maier. “We designed this study to determine if dual immunotherapy has the potential to bring additional benefits to patients in this setting, understanding the high benchmark we would need to exceed with this trial.”

Previously, in November 2019, the company reported that the combination did not result in a statistically significant PFS improvement compared with nivolumab alone when used in the adjuvant setting for patients with resected stage IIB/C/D or stage IV melanoma and whose tumors expressed PD-L1 of less than 1%, missing the co-primary end point of the trial.² However, at that time, the Data Monitoring Committee recommended that the study continue as planned.

In the placebo-controlled, double-blind phase 3 trial, investigators set out to examine nivolumab at a dose of 240 mg every 2 weeks in combination with ipilimumab at 1 mg/kg every 6 weeks compared with nivolumab alone at 480 mg every 4 weeks for 1 year in a total of 1943 patients with completely resected stage IIIB/C/D or stage IV melanoma.

To be eligible for participation, patients could not have received previous treatment with an anticancer therapy for melanoma, with the exception of surgery for disease lesions and/or adjuvant radiation following neurosurgical resection for central nervous system lesions. Moreover, patients with a history of uveal melanoma, those who had active or known autoimmune disease, had received previous treatment with interferon or another antibody or drug targeting T-cell costimulation or checkpoint pathway were not permitted.

The primary end point of the trial was RFS, while key secondary end points included overall survival (OS) and PD-L1 expression.

Earlier data presented during the 2017 World Congress on Melanoma showed a 3-year sustained RFS benefit with nivolumab/ipilimumab when used in patients with high-risk, resected stage IIIC/IV disease.³ Specifically, in a single-center trial that enrolled a total of 40 patients, the combination given in the adjuvant setting resulted in a 3-year RFS of 71%.

Participants with stage IIIC/IV melanoma that had been rendered to be disease free were included on the trial. The 20 patients in cohort A received an induction regimen of nivolumab at 1 mg/kg plus ipilimumab at 3 mg/kg every 3 weeks for 4 doses; this was followed by maintenance nivolumab at 3 mg/kg every 2 weeks for 2 years. The 20 patients in cohort B were given an induction regimen comprised of nivolumab at 3 mg/kg plus ipilimumab at 1 mg/kg every 3 weeks for 4 doses; this was followed by the same maintenance regimen and schedule that cohort A received. The primary end point of this trial was treatment tolerability. Secondary end points of the trial included RFS and OS.

Fifty percent of patients in cohort A completed their induction regimen, with an average of 3 cycles, and 30% completed induction therapy plus 2 years of maintenance treatment, with an average of 34.8 cycles. Sixty-five percent of patients in cohort B completed their induction regimen, with an average of 3.6 cycles, and 30% completed induction plus 2 years of maintenance treatment, with an average of 36.3 cycles.

Results showed that the median RFS had not been reached at a median follow-up of 2.9 years. The median follow-up for cohort A was 3.4 years, while it was 2.5 years for cohort B. The RFS rate at 3 years for cohort A was 70% (95% CI, 45-85) versus 75% (95% CI, 50-89) for cohort B. The RFS at 2 years in cohorts A and B were 80% (95% CI, 55-92) and 75% (95% CI, 50-89), respectively.

Moreover, the median follow-up was 2.9 years for patients with stage IV disease across both cohorts (n = 20). In this subgroup, the 3- and 2-year RFS rates were 74% (95% CI, 48-88) and 80% (95% CI, 55-92), respectively. One patient death was reported. The median OS had not been reached.

With regard to safety, both cohorts experienced elevated aspartate transaminase/alanine transaminase, endocrine disorders, and nausea; however, these effects were found to be significantly higher in cohort A. Eighteen patients in cohort A experienced grade 3 or 4 treatment-related toxicities, and 11 discontinued treatment due to these effects. Fourteen patients in cohort B reported grade 3 or 4 treatment-related adverse effects, with 9 patients stopping treatment.

“We remain committed to continued research in melanoma, both to further understand the potential benefit of [ipilimumab] in combination with [nivolumab] to treat [patients with] high-risk melanoma in the earlier stages of disease, as well as to study additional novel combinations in various settings,” added Maier.

References

1. Bristol Myers Squibb announces update on CheckMate -915 evaluating Opdivo (nivolumab) plus Yervoy (ipilimumab) versus Opdivo in resected high-risk melanoma patients. News release. Bristol Myers Squibb. October 2, 2020. Accessed October 5, 2020. https://bit.ly/3niBavd.
2. Bristol-Myers Squibb announces update on CheckMate -915 for Opdivo (nivolumab) plus Yervoy (ipilimumab) versus Opdivo alone in patients with resected high-risk melanoma and PD-L1 <1%. News release. Bristol-Myers Squibb. November 20, 2019. Accessed October 5, 2020. https://bit.ly/2D3mU3n.
3. Eroglu, Z. Mature results of combination nivolumab (NIVO) plus ipilimumab (IPI) as adjuvant therapy in stage IIIC/IV melanoma (MEL). Presented at: 2017 World Congress of Melanoma; October 18-21, 2017; Brisbane, Australia. Presentation SMR09-6.