Real-world outcomes with immuno-oncology therapies in advanced melanoma: final results of the OPTIMIzE registry study.

Aim: The OPTIMIzE registry study evaluated real-world outcomes in patients with advanced melanoma receiving immuno-oncology therapies. Materials and methods: Data were collected for patients treated with anti-programmed death 1 (PD-1) monotherapy (nivolumab or pembrolizumab; n = 147) or nivolumab plus ipilimumab (n = 81) from 2015-2017 and followed for ≥3 years. Results: Nivolumab plus ipilimumab versus anti-PD-1 monotherapy was associated with a nonsignificantly lower risk of death (adjusted HR: 0.83; 95% CI: 0.54-1.28; p = 0.41), higher disease control rate (72 vs 56%; p = 0.04), and stable quality of life, but more grade 3-4 treatment-related adverse events (54 vs 26%; p < 0.0001). Conclusion: These results support the use of immuno-oncology therapy in advanced melanoma.

Melanoma is a serious form of skin cancer that develops from melanocytes, which are pigment cells that give the skin, hair, and other tissues their color. At advanced stages of spread, melanoma can be life-threatening. However, immunotherapy, a type of therapy that helps the body's immune system to destroy cancer cells, allows some patients with advanced melanoma to live longer. The OPTIMIzE study looked at how well patients with advanced melanoma did when treated with different immunotherapies. These patients were treated in a real-world setting, such as a doctor's office, and were not participating in a clinical trial. Compared with clinical trials, real-world studies like the OPTIMIzE study may include a more varied group of patients because of the less selective study enrollment requirements. In the OPTIMIzE study, patients were treated with either a single immunotherapy (nivolumab or pembrolizumab alone) or a combination of two immunotherapies (nivolumab plus ipilimumab). Both single and combination immunotherapies were effective and tolerable. Patients receiving nivolumab plus ipilimumab had greater tumor shrinkage than patients receiving nivolumab or pembrolizumab alone, but with more side effects from their treatment. Despite the occurrence of side effects with both single and combination immunotherapies, patients reported that their quality of life remained stable while being treated. The OPTIMIzE study shows that immunotherapy is effective and tolerable for patients with advanced melanoma in the real-world setting. This information may help doctors with selecting treatments for their patients with advanced melanoma. Clinical Trial Registration: NCT02780089 (ClinicalTrials.gov).

Adjuvant Nivolumab versus Ipilimumab in Resected Stage III/IV Melanoma: 5-Year Efficacy and Biomarker Results from CheckMate 238.

PURPOSE: In the phase III CheckMate 238 study, adjuvant nivolumab significantly improved recurrence-free survival (RFS) and distant metastasis-free survival versus ipilimumab in patients with resected stage IIIB-C or stage IV melanoma, with benefit sustained at 4 years. We report updated 5-year efficacy and biomarker findings. PATIENTS AND METHODS: Patients with resected stage IIIB-C/IV melanoma were stratified by stage and baseline programmed death cell ligand 1 (PD-L1) expression and received nivolumab 3 mg/kg every 2 weeks or ipilimumab 10 mg/kg every 3 weeks for four doses and then every 12 weeks, both intravenously for 1 year until disease recurrence, unacceptable toxicity, or withdrawal of consent. The primary endpoint was RFS. RESULTS: At a minimum follow-up of 62 months, RFS with nivolumab remained superior to ipilimumab (HR = 0.72; 95% confidence interval, 0.60-0.86; 5-year rates of 50% vs. 39%). Five-year distant metastasis-free survival (DMFS) rates were 58% with nivolumab versus 51% with ipilimumab. Five-year overall survival (OS) rates were 76% with nivolumab and 72% with ipilimumab (75% data maturity: 228 of 302 planned events). Higher levels of tumor mutational burden (TMB), tumor PD-L1, intratumoral CD8+ T cells and IFNγ-associated gene expression signature, and lower levels of peripheral serum C-reactive protein were associated with improved RFS and OS with both nivolumab and ipilimumab, albeit with limited clinically meaningful predictive value. CONCLUSIONS: Nivolumab is a proven adjuvant treatment for resected melanoma at high risk of recurrence, with sustained, long-term improvement in RFS and DMFS compared with ipilimumab and high OS rates. Identification of additional biomarkers is needed to better predict treatment outcome. See related commentary by Augustin and Luke, p. 3253.

Sensitivity of treatment-free survival to subgroup analyses in patients with advanced melanoma treated with immune checkpoint inhibitors.

Patients with advanced melanoma treated with immune checkpoint inhibitors can experience ongoing disease control after treatment discontinuation without subsequent systemic anticancer therapy. We previously defined a novel outcome, treatment-free survival (TFS), as the time between protocol therapy cessation and subsequent therapy initiation/death. We assessed the effect of established prognostic variables [lactate dehydrogenase (LDH), programmed death ligand 1 status, BRAF mutation status, performance status, and sex] on TFS in different treatment scenarios: treatment until toxicity/progression with frequent early cessation (nivolumab plus ipilimumab), treatment until toxicity/progression with a well-tolerated regimen (nivolumab), and treatment for a short fixed duration (ipilimumab). Data were pooled from 1077 patients with advanced melanoma treated in the CheckMate 069 and 067 trials. TFS was defined as the area between the Kaplan-Meier curves for time to therapy cessation and time to subsequent therapy initiation/death. TFS was estimated by restricted mean (r-mean) survival time at 36 months since randomization. Clinically meaningful TFS (r-mean TFS 3.7-12.7 months) was observed across all patient subgroups. TFS was longest in patients treated with nivolumab plus ipilimumab. The largest differences in r-mean TFS were observed with LDH in the nivolumab plus ipilimumab and ipilimumab treatment groups (TFS difference 4.7 and 4.9 months, respectively). In the nivolumab group, there was little difference in TFS across subgroups (r-mean TFS 3.7-5.5 months). TFS was sensitive to prognostic subgroup differences; however, duration of treatment affected the sensitivity of TFS. These results provide further support for TFS as a clinical outcome measure.

Long-Term Outcomes With Nivolumab Plus Ipilimumab or Nivolumab Alone Versus Ipilimumab in Patients With Advanced Melanoma.

PURPOSE: In the phase III CheckMate 067 trial, durable clinical benefit was demonstrated previously with nivolumab plus ipilimumab and nivolumab alone versus ipilimumab. Here, we report 6.5-year efficacy and safety outcomes. PATIENTS AND METHODS: Patients with previously untreated unresectable stage III or stage IV melanoma were randomly assigned 1:1:1 to receive nivolumab 1 mg/kg plus ipilimumab 3 mg/kg once every 3 weeks (four doses) followed by nivolumab 3 mg/kg once every 2 weeks (n = 314), nivolumab 3 mg/kg once every 2 weeks (n = 316), or ipilimumab 3 mg/kg once every 3 weeks (four doses; n = 315). Coprimary end points were progression-free survival and overall survival (OS) with nivolumab plus ipilimumab or nivolumab versus ipilimumab. Secondary end points included objective response rate, descriptive efficacy assessments of nivolumab plus ipilimumab versus nivolumab alone, and safety. Melanoma-specific survival (MSS; descriptive analysis), which excludes deaths unrelated to melanoma, was also evaluated. RESULTS: Median OS (minimum follow-up, 6.5 years) was 72.1, 36.9, and 19.9 months in the combination, nivolumab, and ipilimumab groups, respectively. Median MSS was not reached, 58.7, and 21.9 months, respectively; 6.5-year OS rates were 57%, 43%, and 25% in patients with BRAF-mutant tumors and 46%, 42%, and 22% in those with BRAF-wild-type tumors, respectively. In patients who discontinued treatment, the median treatment-free interval was 27.6, 2.3, and 1.9 months, respectively. Since the 5-year analysis, no new safety signals were observed. CONCLUSION: These 6.5-year CheckMate 067 results, which include the longest median OS in a phase III melanoma trial reported to date and the first report of MSS, showed durable, improved clinical outcomes with nivolumab plus ipilimumab or nivolumab versus ipilimumab in patients with advanced melanoma and, in descriptive analyses, with the combination over nivolumab monotherapy.

Long-term outcomes of patients with active melanoma brain metastases treated with combination nivolumab plus ipilimumab (CheckMate 204): final results of an open-label, multicentre, phase 2 study.

BACKGROUND: Combination nivolumab plus ipilimumab was efficacious in patients with asymptomatic melanoma brain metastases (MBM) in CheckMate 204, but showed low efficacy in patients with symptomatic MBM. Here, we provide final 3-year follow-up data from the trial. METHODS: This open-label, multicentre, phase 2 study (CheckMate 204) included adults (aged ≥18 years) with measurable MBM (0·5-3·0 cm in diameter). Asymptomatic patients (cohort A) had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and no neurological symptoms or baseline corticosteroid use; symptomatic patients (cohort B) had an ECOG performance status of 0-2 with stable neurological symptoms and could be receiving low-dose dexamethasone. Nivolumab 1 mg/kg plus ipilimumab 3 mg/kg was given intravenously every 3 weeks for four doses, followed by nivolumab 3 mg/kg every 2 weeks for up to 2 years, until disease progression or unacceptable toxicity. The primary endpoint was intracranial clinical benefit rate (complete responses, partial responses, or stable disease lasting ≥6 months) assessed in all treated patients. Intracranial progression-free survival and overall survival were key secondary endpoints. This study is registered with ClinicalTrials.gov, NCT02320058. FINDINGS: Between Feb 19, 2015, and Nov 1, 2017, 119 (72%) of 165 screened patients were enrolled and treated: 101 patients were asymptomatic (cohort A; median follow-up 34·3 months [IQR 14·7-36·4]) and 18 were symptomatic (cohort B; median follow-up 7·5 months [1·2-35·2]). Investigator-assessed intracranial clinical benefit was observed in 58 (57·4% [95% CI 47·2-67·2]) of 101 patients in cohort A and three (16·7% [3·6-41·4]) of 18 patients in cohort B; investigator-assessed objective response was observed in 54 (53·5% [43·3-63·5]) patients in cohort A and three (16·7% [3·6-41·4]) patients in cohort B. 33 (33%) patients in cohort A and three (17%) patients in cohort B had an investigator-assessed intracranial complete response. For patients in cohort A, 36-month intracranial progression-free survival was 54·1% (95% CI 42·7-64·1) and overall survival was 71·9% (61·8-79·8). For patients in cohort B, 36-month intracranial progression-free survival was 18·9% (95% CI 4·6-40·5) and overall survival was 36·6% (14·0-59·8). The most common grade 3-4 treatment-related adverse events (TRAEs) were increased alanine aminotransferase and aspartate aminotransferase (15 [15%] of 101 patients each) in cohort A; no grade 3 TRAEs occurred in more than one patient each in cohort B, and no grade 4 events occurred. The most common serious TRAEs were colitis, diarrhoea, hypophysitis, and increased alanine aminotransferase (five [5%] of each among the 101 patients in cohort A); no serious TRAE occurred in more than one patient each in cohort B. There was one treatment-related death (myocarditis in cohort A). INTERPRETATION: The durable 3-year response, overall survival, and progression-free survival rates for asymptomatic patients support first-line use of nivolumab plus ipilimumab. Symptomatic disease in patients with MBM remains difficult to treat, but some patients achieve a long-term response with the combination. FUNDING: Bristol Myers Squibb.

Treatment-free survival over extended follow-up of patients with advanced melanoma treated with immune checkpoint inhibitors in CheckMate 067.

BACKGROUND: Treatment-free survival (TFS) characterizes disease control after discontinuation of immune checkpoint inhibitors (ICIs) until subsequent therapy or death. We previously evaluated TFS in a pooled analysis of the CheckMate 067 and CheckMate 069 trials of the ICIs nivolumab and ipilimumab, alone or in combination, in patients with advanced melanoma after minimum follow-up of 36 months. This analysis investigated TFS differences between treatments in CheckMate 067 after a minimum follow-up of 60 months, and their relation to overall survival (OS) differences. METHODS: Data were from 937 patients who initiated treatment (nivolumab plus ipilimumab, nivolumab, or ipilimumab) in CheckMate 067 (NCT01844505). TFS was defined as the area between the Kaplan-Meier curves for time to protocol therapy cessation and time to subsequent systemic therapy initiation or death, each measured from randomization. TFS was partitioned as time with and without toxicity. Toxicity included persistent and late-onset grade ≥2 select treatment-related adverse events (ie, those of potential immunologic etiology). The area between Kaplan-Meier curves was estimated by the difference in 60-month restricted-mean times of the endpoints. Between-group differences were estimated with bootstrapped 95% CIs. RESULTS: At 60 months from randomization, 39%, 24%, and 11% of patients assigned to treatment with nivolumab plus ipilimumab, nivolumab, and ipilimumab, respectively, had survived and were treatment-free. The 60-month mean TFS was approximately twice as long with the combination (19.7 months) than with nivolumab (9.9 months; absolute difference, 9.8 (95% CI 6.7 to 12.8)) or ipilimumab (11.9 months; absolute difference, 7.8 (95% CI 4.6 to 11.0)). In the respective groups, mean TFS represented 33% (8% with and 25% without toxicity), 17% (2% and 14%), and 20% (3% and 17%) of the 60-month period. Compared with 36-month estimates, mean TFS over the 60-month period represented slightly greater percentages of time in the nivolumab-containing regimen groups and a lesser percentage in the ipilimumab group. TFS differences between the combination and either monotherapy increased with longer follow-up. CONCLUSIONS: Along with improved long-term OS with the nivolumab-containing regimens versus ipilimumab, TFS without toxicity was sustained with nivolumab plus ipilimumab versus either monotherapy, demonstrating larger between-group differences with extended follow-up.

First-line immunotherapy versus targeted therapy in patients with BRAF-mutant advanced melanoma: a real-world analysis.

Aim: To compare effectiveness of nivolumab + ipilimumab (NIVO + IPI) versus BRAF + MEK inhibitors (BRAFi + MEKi) in patients with BRAF-mutant advanced melanoma in the real-world setting. Materials & methods: This study used the Flatiron Health electronic medical record database. Results: After adjusting for differences in baseline characteristics, NIVO + IPI was associated with a 32% reduction in risk of death versus BRAFi + MEKi. At a mean follow-up of 15-16 months, 64% of NIVO + IPI patients and 43% of BRAFi + MEKi patients were alive; subsequent therapy was administered to 33 and 41% of patients, respectively. After first-line NIVO + IPI, 20% of patients died before subsequent therapy, whereas 32% died after first-line BRAFi + MEKi. Conclusion: In this real-world study, patients treated with first-line NIVO + IPI showed significant survival benefit versus those receiving first-line BRAFi + MEKi.

Treatment-Free Survival: A Novel Outcome Measure of the Effects of Immune Checkpoint Inhibition-A Pooled Analysis of Patients With Advanced Melanoma.

PURPOSE: Outcome measures that comprehensively capture attributes of immuno-oncology agents, including prolonged treatment-free time and persistent treatment-related adverse events (TRAEs), are needed to complement conventional survival end points. METHODS: We pooled data from the CheckMate 067 and 069 clinical trials of nivolumab and ipilimumab, as monotherapies or in combination, for patients with advanced melanoma. Treatment-free survival (TFS) was defined as the area between Kaplan-Meier curves for two conventional time-to-event end points, each defined from random assignment: time to immune checkpoint inhibitor (ICI) protocol therapy cessation and time to subsequent systemic therapy initiation or death. TFS was partitioned as time with and without toxicity by a third end point, time to cessation of both ICI therapy and toxicity. Toxicity included persistent and late-onset grade 3 or higher TRAEs. The area under each Kaplan-Meier curve was estimated by the 36-month restricted mean time. RESULTS: At 36 months, many of the 1,077 patients who initiated ICI therapy were surviving free of subsequent therapy initiation (47% nivolumab plus ipilimumab, 37% nivolumab, 15% ipilimumab). The restricted mean TFS was longer for nivolumab plus ipilimumab (11.1 months) compared with nivolumab (4.6 months; difference, 6.5 months; 95% CI, 5.0 to 8.0 months) or ipilimumab (8.7 months; difference, 2.4 months; 95% CI, 0.8 to 4.1 months); restricted mean TFS represented 31% (3% with and 28% without toxicity), 13% (1% and 11%), and 24% (less than 1% and 23%) of the 36-month period, respectively, in the three treatment groups. TFS without toxicity was longer for nivolumab plus ipilimumab than nivolumab (difference, 6.0 months) or ipilimumab (difference, 1.7 months). CONCLUSION: The analysis of TFS between ICI cessation and subsequent therapy initiation revealed longer TFS without toxicity for patients with advanced melanoma who received nivolumab plus ipilimumab compared with nivolumab or ipilimumab. Regardless of treatment, a small proportion of the TFS involved grade 3 or higher TRAEs.

Comparative efficacy of combination immunotherapy and targeted therapy in the treatment of BRAF-mutant advanced melanoma: a matching-adjusted indirect comparison.

AIM: Comparison of clinical outcomes of nivolumab + ipilimumab versus BRAF + MEK inhibitors (dabrafenib + trametinib or vemurafenib + cobimetinib) in BRAF-mutant advanced melanoma. METHODS: Matching-adjusted indirect comparisons were conducted between nivolumab + ipilimumab (CheckMate 067/069 studies) and BRAF + MEK inhibitors (COMBI-d, COMBI-v and coBRIM studies). Overall survival (OS), progression-free survival and objective response rates were assessed. RESULTS: After adjusting, nivolumab + ipilimumab showed improved OS versus dabrafenib + trametinib (hazard ratio [HR] = 0.64; 95% CI: 0.46-0.89) or vemurafenib + cobimetinib (HR = 0.56; 95% CI: 0.36-0.89); OS outcomes were similar at 1 year, with benefits emerging after 12 months; progression-free survival and objective response rates were similar. Grade 3/4 adverse events occurred in 54.1% with nivolumab + ipilimumab, 31.6% with dabrafenib + trametinib and 59.5% with vemurafenib + cobimetinib. CONCLUSION: Nivolumab + ipilimumab had significantly improved clinical outcomes versus BRAF + MEK inhibitors, with benefits increasing after longer follow-up. Ongoing randomized trials directly comparing these treatments are necessary to prospectively validate these findings.

Clinical and economic outcomes associated with treatment sequences in patients with BRAF-mutant advanced melanoma.

AIM: The cost-effectiveness of treatment sequences in BRAF-mutant advanced melanoma. MATERIALS & METHODS: A discrete event simulation model was developed to estimate total costs and health outcomes over a patient's lifetime (30 years). Efficacy was based on the CheckMate 067/069 trials and a matching-adjusted-indirect comparison between immuno-oncology and targeted therapies. Safety, cost (in US dollars; US third-party payer perspective) and health-related quality-of-life inputs were based on published literature. RESULTS: Estimated survival gain was higher for sequences initiating with anti-PD-1 + anti-CTLA-4 than for anti-PD-1 monotherapy or BRAF+MEK inhibitors. The incremental cost-effectiveness ratio per QALY gained for first-line anti-PD-1 + anti-CTLA-4 was US$54,273 versus first-line anti-PD-1 and $79,124 versus first-line BRAF+MEK inhibitors. CONCLUSION: Initiating treatment with anti-PD-1 + anti-CTLA-4 was more cost-effective than initiation with anti-PD-1 monotherapy or BRAF+MEK inhibitors.

Sequential treatment approaches in the management of BRAF wild-type advanced melanoma: a cost-effectiveness analysis.

AIM: To evaluate the cost-effectiveness of treatment sequences with checkpoint inhibitors in patients with BRAF wild-type melanoma. MATERIALS & METHODS: Using a discrete event simulation model, cost and health outcomes were estimated. Pooled data from CheckMate 067/069 trials were used to calculate survival outcomes including treatment-free interval extrapolated over a patient's lifetime. Costs accounted for treatment, administration, toxicity, and disease management. RESULTS: First-line anti-PD-1 + anti-CTLA-4 initiating sequences had the highest estimated mean survival gain (7.6-7.7 years), driven by a longer estimated mean treatment-free interval (5.3 years). Incremental costs per incremental quality-adjusted life year gained for anti-PD-1 + anti-CTLA-4 followed by chemotherapy were US$30,955 versus anti-PD-1 initiating sequences, within the willingness-to-pay threshold. CONCLUSION: Anti-PD-1 + anti-CTLA-4 initiating sequences for BRAF wild-type melanoma are cost-effective versus anti-PD-1.