Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma

Abstract

BACKGROUND

Nivolumab plus ipilimumab or nivolumab alone resulted in longer progression-free and overall survival than ipilimumab alone in a trial involving patients with advanced melanoma. We now report 5-year outcomes in the trial.

METHODS

We randomly assigned patients with previously untreated advanced melanoma to receive one of the following regimens: nivolumab (at a dose of 1 mg per kilogram of body weight) plus ipilimumab (3 mg per kilogram) every 3 weeks for four doses, followed by nivolumab (3 mg per kilogram every 2 weeks); nivolumab (3 mg per kilogram every 2 weeks) plus ipilimumab-matched placebo; or ipilimumab (3 mg per kilogram every 3 weeks for four doses) plus nivolumab-matched placebo. The two primary end points were progression-free survival and overall survival in the nivolumab-plus-ipilimumab group and in the nivolumab group, as compared with the ipilimumab group.

RESULTS

At a minimum follow-up of 60 months, the median overall survival was more than 60.0 months (median not reached) in the nivolumab-plus-ipilimumab group and 36.9 months in the nivolumab group, as compared with 19.9 months in the ipilimumab group (hazard ratio for death with nivolumab plus ipilimumab vs. ipilimumab, 0.52; hazard ratio for death with nivolumab vs. ipilimumab, 0.63). Overall survival at 5 years was 52% in the nivolumab-plus-ipilimumab group and 44% in the nivolumab group, as compared with 26% in the ipilimumab group. No sustained deterioration of health-related quality of life was observed during or after treatment with nivolumab plus ipilimumab or with nivolumab alone. No new late toxic effects were noted.

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CONCLUSIONS

Among patients with advanced melanoma, sustained long-term overall survival at 5 years was observed in a greater percentage of patients who received nivolumab plus ipilimumab or nivolumab alone than in those who received ipilimumab alone, with no apparent loss of quality of life in the patients who received

 regimn the past decade, progress in the treatment of advanced melanoma has markedly improved survival outcomes.1 The availability of new systemic therapies — including ipilimumab, an anti–cytotoxic T-lymphocyte–associated antigen 4 monoclonal antibody; anti–programmed death 1 agents (nivolumab and pembrolizumab); nivolumab in combination with ipilimumab; and BRAF and MEK inhibitors (dabrafenib plus trametinib, vemurafenib plus cobimetinib, and encorafenib plus binimetinib) — has transformed the treatment of this disease.1

Initial and follow-up analyses of the phase 3 CheckMate 067 trial, including analyses across clinically relevant subgroups, showed a significantly higher response rate and longer progression-free survival and overall survival with nivolumab plus ipilimumab or nivolumab alone than with ipilimumab alone among patients with advanced melanoma.2-4 Combination therapy with nivolumab plus ipilimumab has also had clinical efficacy in patients with metastatic melanoma and untreated brain metastases.5,6Some patients who have received nivolumab plus ipilimumab have also discontinued therapy without subsequent systemic treatment for melanoma4,7-9; this is one aspect of the value of combination nivolumab plus ipilimumab treatment. In this article, we provide an update of survival outcomes from the CheckMate 067 trial with a minimum of 5 years of follow-up as well as an assessment of the long-term benefit of combination nivolumab plus ipilimumab treatment with respect to outcomes in patients who have not received subsequent systemic treatment for melanoma and with respect to health-related quality of life.

Methods

PATIENTS

Adult patients with previously untreated, unresectable or metastatic histologically confirmed stage III or stage IV melanoma, with known BRAF V600 mutation status, and with an Eastern Cooperative Oncology Group performance-status score of 0 or 1 (on a 5-point scale, with higher scores indicating greater disability) were included in the trial. The full trial eligibility criteria, design, and assessments have been reported previously.4

TRIAL DESIGN AND TREATMENT

Patients were randomly assigned in a 1:1:1 ratio to receive one of the following regimens: nivolumab at a dose of 1 mg per kilogram of body weight every 3 weeks plus ipilimumab at a dose of 3 mg per kilogram every 3 weeks for four doses, followed by nivolumab at a dose of 3 mg per kilogram every 2 weeks; nivolumab at a dose of 3 mg per kilogram every 2 weeks (plus ipilimumab-matched placebo); or ipilimumab at a dose of 3 mg per kilogram every 3 weeks for four doses (plus nivolumab-matched placebo). Randomization was stratified according to BRAF mutation status, metastasis stage defined according to the American Joint Committee on Cancer, and tumor programmed cell death ligand 1 (PD-L1) status.

Treatment was continued until disease progression, the occurrence of unacceptable toxic events, or withdrawal of consent. Patients with clinical benefit and without substantial adverse events could be treated beyond progression according to the investigator’s decision. Minimum follow-up was defined as the time from the date on which the last patient underwent randomization to the clinical cutoff date; the extent of follow-up (for which the median is reported) was defined as the time between the randomization date and the last known date alive (for patients who were alive) or death date (for patients who had died).

The two primary end points were progression-free survival and overall survival, as compared between the nivolumab-plus-ipilimumab group or the nivolumab group and the ipilimumab group. Secondary end points included a comparison of the objective response rate between the nivolumab-containing groups and the ipilimumab group and descriptive efficacy evaluations between the nivolumab-plus-ipilimumab group and the nivolumab group. Additional analyses (survival end points according to subgroup and evaluations of the treatment-free interval and treatment-free status) have been published previously3,4 and are detailed in the Supplementary Methods section in the Supplementary Appendix, available with the full text of this article at NEJM.org. Evaluations of health-related quality of life as determined on the basis of the mean change from baseline analyses with the use of the European Quality of Life 5-Dimensions 3-Level (EQ-5D-3L) questionnaire10,11 are detailed in the Supplementary Methods section.

TRIAL OVERSIGHT

The protocol and amendments for this trial (available at NEJM.org) were reviewed by the institutional review board at each trial site. The trial was conducted in accordance with the Declaration of Helsinki and with Good Clinical Practice guidelines as defined by the International Conference on Harmonisation. All the patients provided written informed consent before enrollment.

The trial was designed by the senior academic authors and the sponsor, Bristol-Myers Squibb. Data were collected by the sponsor and analyzed in collaboration with the authors. The authors vouch for the accuracy and completeness of the data reported and also confirm adherence to the protocol. The initial manuscript was written in collaboration with the first author and the last two authors, who provided direct input into all key sections. All the authors contributed to subsequent drafts and provided final approval to submit the manuscript for publication. Professional medical writing and editorial assistance were paid for by the sponsor. A data and safety monitoring committee provided oversight to assess the risk–benefit profile of nivolumab plus ipilimumab, as described previously.2,3

STATISTICAL ANALYSIS

Efficacy end points were based on the intention-to-treat population. Formal analyses of the two primary end points were conducted at different prespecified time points according to the trial protocol, as described previously.2,3 A 60-month follow-up to assess overall survival, progression-free survival, and the objective response rate with confidence intervals at the 95% level was performed, and updated P values were provided for descriptive purposes. The trial was not designed for a formal statistical comparison between the nivolumab-plus-ipilimumab group and the nivolumab group, but descriptive analyses without formal hypothesis testing were performed. Details of the statistical analysis are provided in the Supplementary Methods section and have been published previously.2-4

Results

PATIENTS AND TREATMENT

From July 2013 through March 2014, a total of 1296 patients were enrolled and 945 underwent randomization (314 to the nivolumab-plus-ipilimumab group, 316 to the nivolumab group, and 315 to the ipilimumab group) (Fig. S1). The baseline characteristics of the patients have been reported previously (Table S1),2-4 and information on drug exposure is provided in Table S2.

At database lock on July 2, 2019, the minimum follow-up from the date on which the last patient underwent randomization was 60 months. The median extent of follow-up was 54.6, 36.0, and 18.6 months for the nivolumab-plus-ipilimumab, nivolumab, and ipilimumab groups, respectively. At the current database lock, most patients were no longer receiving trial therapy, and 36 patients were continuing the trial treatment (12 in the nivolumab-plus-ipilimumab group and 24 in the nivolumab group).

SURVIVAL OUTCOMES

Figure 1.Kaplan–Meier Estimates of Survival in the Overall Population.

Overall survival was longer in the two nivolumab-containing groups than in the ipilimumab group. The median overall survival was more than 60.0 months (median not reached; 95% confidence interval [CI], 38.2 to not reached) in the nivolumab-plus-ipilimumab group, 36.9 months (95% CI, 28.2 to 58.7) in the nivolumab group, and 19.9 months (95% CI, 16.8 to 24.6) in the ipilimumab group (Figure 1A). Overall survival at 5 years was 52% in the nivolumab-plus-ipilimumab group and 44% in the nivolumab group, as compared with 26% in the ipilimumab group.

The median progression-free survival was 11.5 months (95% CI, 8.7 to 19.3) in the nivolumab-plus-ipilimumab group, 6.9 months (95% CI, 5.1 to 10.2) in the nivolumab group, and 2.9 months (95% CI, 2.8 to 3.2) in the ipilimumab group (Figure 1B). Five-year progression-free survival was 36%, 29%, and 8% in the nivolumab-plus-ipilimumab, nivolumab, and ipilimumab groups, respectively.

Figure 2.Kaplan–Meier Estimates of Overall Survival and Progression-free Survival among Patients with or without BRAF Mutations.

Overall survival and progression-free survival were also evaluated in patient subgroups (Fig. S2). Among patients with tumors with BRAF mutations and those with tumors without BRAF mutations, overall survival at 5 years was 60% and 48%, respectively, in the nivolumab-plus-ipilimumab group; 46% and 43% in the nivolumab group; and 30% and 25% in the ipilimumab group (Figure 2). Five-year overall survival among patients with normal lactate dehydrogenase levels was 60%, 53%, and 34% in the nivolumab-plus-ipilimumab, nivolumab, and ipilimumab groups, respectively; among patients with elevated lactate dehydrogenase levels, these rates were 38%, 28%, and 15% (Fig. S3). Tumor PD-L1 expression alone was not predictive of efficacy outcomes (Figs. S4 and S5 and Table S3); this finding was consistent with previous results.4

RESPONSE

Table 1.Response to Treatment.

The rate of objective response among patients who were receiving trial therapy was 58% in the nivolumab-plus-ipilimumab group, 45% in the nivolumab group, and 19% in the ipilimumab group (Table 1). The rate of complete response was 22%, 19%, and 6%, respectively; all these rates of complete response had increased since the previous analysis.4 At database lock, the median duration of response had not been reached in the nivolumab-plus-ipilimumab and nivolumab groups and was 14.4 months in the ipilimumab group, with ongoing responses at 5 years in 62%, 61%, and 40% of the patients with a response, respectively. The duration of response was sustained across stratification subgroups (according to BRAF mutation status, PD-L1 status, and metastasis stage).

OUTCOMES AFTER TREATMENT

As a part of the subsequent therapy received by patients for the management of progressive disease, 21%, 29%, and 40% of patients who were randomly assigned to nivolumab plus ipilimumab, nivolumab, and ipilimumab, respectively, received radiotherapy and 21%, 23%, and 30% underwent surgery. A total of 46%, 59%, and 75% of all patients who were randomly assigned to nivolumab plus ipilimumab, nivolumab, and ipilimumab, respectively, received subsequent systemic therapy (Table S4). Excluding patients who died and had not received subsequent therapy, the median time from randomization to subsequent systemic therapy was more than 60.0 months (median not reached) in the nivolumab-plus-ipilimumab group, 25.2 months in the nivolumab group, and 8.0 months in the ipilimumab group.

Figure 3.Analyses of the Treatment-free Interval and Outcomes after Treatment.

The assessment of the treatment-free interval from the last dose of the trial drug to subsequent systemic therapy or to the last known date alive excluded patients who discontinued trial follow-up or died before receiving subsequent systemic therapy. The median treatment-free interval was 18.1 months in the nivolumab-plus-ipilimumab group, 1.8 months in the nivolumab group, and 1.9 months in the ipilimumab group (Figure 3A). In addition, of the patients who were alive at the time of the current analysis, the percentage who were not receiving trial treatment or subsequent systemic therapy was 74% in the nivolumab-plus-ipilimumab group, 58% in the nivolumab group, and 45% in the ipilimumab group (Figure 3B). Survival outcomes at 5 years of follow-up were similar between patients who discontinued nivolumab plus ipilimumab because of treatment-related adverse events during the induction phase (Fig. S6) and the overall population (Figure 1).

SAFETY

As expected in this long-term follow-up, the results of safety analyses (Tables S5 through S7) were similar to the previously reported results.4 Grade 3 or 4 treatment-related adverse events occurred in 59%, 23%, and 28% of the patients in the nivolumab-plus-ipilimumab, nivolumab, and ipilimumab groups, respectively. The median time to resolution of treatment-related select adverse events in the various categories was generally less than 12 weeks, with the exception of skin-related adverse events in patients who received nivolumab, which resolved by a median of 40.6 weeks, and some events that had not yet resolved (primarily endocrine events, for which long-term hormonal therapy may be warranted). All treatment-related select adverse events that were unresolved at the time of the current analysis (regardless of time of onset) are listed in Table S8. In addition, no new deaths that were considered by the investigator to be related to a trial drug were reported (Table S9).3,4 No previously unreported long-term toxic effects were noted.

HEALTH-RELATED QUALITY OF LIFE

The EQ-5D-3L standardized instrument was used to investigate health-related quality of life in the three treatment groups. Baseline rates of EQ-5D-3L completion were similar among the treatment groups and ranged from 88% to 92% (Table S10). As would be expected from rates of discontinuation of the trial treatment over time,2,3 fewer than 10% of patients who underwent randomization were included in the assessment of health-related quality of life while receiving treatment after 3 years of trial follow-up; however, these patients continued to be followed for survival and would have been included in post-treatment assessments of health-related quality of life (after disease progression or discontinuation of the trial treatment).

According to published estimates for the EQ-5D-3L,11 a change in quality of life was considered to be clinically meaningful if the mean changes from baseline in the index score were above (better) or below (worse) the bounds of 0.08.10,11 For the duration of treatment, time after discontinuation of treatment for any reason, and the treatment-free interval, changes in the index score were generally within the 0.08 boundary in patients in the nivolumab-plus-ipilimumab and nivolumab treatment groups, indicating no meaningful sustained deterioration of health-related quality of life (Fig. S7). During follow-up for survival, deterioration outside the 0.08 boundary occurred more frequently in the ipilimumab monotherapy group than in the other treatment groups.

Discussion

Historically, 5-year survival rates among patients with metastatic melanoma were dismal. Advances in basic science have produced meaningful therapeutic interventions for this disease in the areas of targeted oncogenic pathway inhibition and immune modulation. The current results of the CheckMate 067 trial set a new foundation on which to make improvements in long-term efficacy outcomes with the combination of nivolumab plus ipilimumab.

At 3 years after treatment initiation, a plateau on the survival curve was evident in the groups that received regimens containing nivolumab.3,4 The apparent plateau with nivolumab plus ipilimumab has continued with longer follow-up; this indicates sustained long-term survival in approximately half the population of patients who received nivolumab plus ipilimumab, taking into account that subsequent therapies also had an effect on survival outcomes. Nivolumab plus ipilimumab is also currently the only treatment for metastatic melanoma for which median overall survival has not been reached at 5 years. In addition, complete response rates among patients receiving trial therapy have steadily increased across all groups since the original analysis2; this indicates that the best response can improve over time with immune checkpoint inhibitors. The treatment-free interval continued to lengthen in the nivolumab-plus-ipilimumab group, and the percentage of patients who were alive and not receiving treatment continued to increase across the groups. No new safety signals were observed, and no meaningful, sustained deterioration (i.e., limited fluctuations outside the 0.08 boundary) of health-related quality of life was observed during treatment or after discontinuation of treatment in the nivolumab-plus-ipilimumab and nivolumab monotherapy groups, although health-related quality of life deteriorated after discontinuation of ipilimumab.

This analysis from the CheckMate 067 trial showed that nivolumab-containing regimens were associated with a benefit with respect to overall survival and progression-free survival across patient subgroups. In addition, the analysis confirmed improved long-term clinical outcomes with nivolumab plus ipilimumab (median overall survival, >60.0 months [median not reached]; 5-year overall survival, 60%) and nivolumab (median overall survival, 45.5 months; 5-year overall survival, 46%), as compared with ipilimumab, among patients with tumors with BRAF mutations. The results of a pooled analysis of two phase 3 trials of combined BRAF and MEK inhibition with dabrafenib plus trametinib in patients with advanced melanoma and BRAF mutations were also reported recently. Those results showed a median overall survival of 25.9 months (95% CI, 22.6 to 31.5) and a 5-year overall survival of 34% (95% CI, 30 to 38).12 Comparisons between studies of BRAF inhibitors and immune checkpoint inhibitors are not robust because of the many differences in the trial populations. Overall survival outcomes in the current analysis were also favorable for nivolumab plus ipilimumab and nivolumab in patients with normal lactate dehydrogenase levels and in those with elevated lactate dehydrogenase levels.

Consistent with previous analyses,2-4 both treatments (the nivolumab-plus-ipilimumab combination and nivolumab monotherapy) led to better objective response rates, progression-free survival, and overall survival than ipilimumab, regardless of PD-L1 expression. However, the variations in efficacy results across PD-L1 cutoff values combined with the analysis of the diagnostic usefulness of PD-L1 (i.e., the time-dependent receiver-operating-characteristic analysis) suggest that tumor PD-L1 expression alone is a poor predictive marker of efficacy outcomes in this population, as reported previously.3,4

No new safety signals or additional treatment-related deaths were noted at this 5-year follow-up. As reported previously,4 the incidences of treatment-related adverse events and treatment-related discontinuation of therapy were higher with nivolumab plus ipilimumab than with either nivolumab or ipilimumab alone. However, overall survival and progression-free survival among patients who discontinued nivolumab plus ipilimumab because of a treatment-related adverse event during the induction phase were similar to the respective survival rates in the overall population; this indicates that early discontinuation due to an adverse event does not negatively affect long-term survival among these patients. The majority of treatment-related adverse events leading to discontinuation of nivolumab plus ipilimumab occurred early in treatment2-4; however, given the adoption of checkpoint blockade therapy, long-term follow-up of patients for the appearance of late-onset toxic effects is critical. In addition, studies of alternative dosing regimens involving patients with advanced melanoma are under way13; these studies may help to inform the safety profile of nivolumab plus ipilimumab and may also affect global value.

The evaluation of quality of life in patients receiving therapy for melanoma is also an important factor for both physicians and patients to consider. The EQ-5D-3L results from this 5-year analysis showed no sustained deterioration in health-related quality of life in the nivolumab-plus-ipilimumab or nivolumab monotherapy groups during or after treatment; these findings are consistent with those of previous analyses.14 However, clinically meaningful deterioration was observed more frequently in the ipilimumab group than in the groups receiving nivolumab.

In conclusion, sustained long-term overall survival at 5 years was observed in a greater percentage of patients with advanced melanoma who received nivolumab plus ipilimumab or nivolumab alone than of those who received ipilimumab aloneens containing nivolumab.