Adjuvant low-dose ipilimumab extends OS vs. high-dose interferon alfa-2b in metastatic melanoma
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Adjuvant ipilimumab dosed at 3 mg/kg significantly improved OS compared with high-dose interferon alfa-2b among patients with metastatic unresectable melanoma, according to results of the phase 3 E1609 trial published in Journal of Clinical Oncology.
“Following the regulatory approval of 3 mg/kg ipilimumab [Yervoy, Bristol-Myers Squibb] for metastatic unresectable melanoma and the later approval of 10 mg/kg adjuvant ipilimumab, the relative safety and efficacy of ipilimumab at the two dose levels became important to evaluate compared with high-dose interferon alfa-2b [Intron A, Merck],” Ahmad A. Tarhini, MD, PhD, senior member and director of cutaneous clinical and translational research at Moffitt Comprehensive Cancer Center and Research Institute, told Healio.
“For the first time in melanoma adjuvant therapy, we have shown significant improvement in OS against an active control regimen,” he added.
Tarhini and colleagues randomly assigned 1,670 patients with metastatic unresectable melanoma in a 1:1:1 fashion to 3 mg/kg ipilimumab (n = 523; median age, 54 years; 62.7% men), 10 mg/kg ipilimumab (n = 511; median age, 52 years; 66.9% men) or high-dose interferon alfa-2b (n = 636; median age, 54 years; 62.1% men).
The study involved a two-step hierarchic approach in which researchers first evaluated 3 mg/kg ipilimumab, and then 10 mg/kg ipilimumab, vs. high-dose interferon alfa-2b.
OS and RFS served as primary endpoints.
Median follow-up was 57.4 months (range, 0.03-86.6).
Results showed a 5-year OS rate of 72% (95% CI, 68-76) with 3 mg/kg ipilimumab vs. 67% (95% CI, 62-72) with high-dose interferon alfa-2b. An intent-to-treat analysis of 1,051 concurrently randomly assigned patients showed a significant OS benefit with 3 mg/kg ipilimumab vs. high-dose interferon alfa-2b (HR = 0.78; 95.6% repeated CI, 0.61-0.99).
Median RFS was 4.5 years (95% CI, 2.6 to not reached) with 3 mg/kg ipilimumab vs. 2.5 years (95% CI, 1.7-3.3) with high-dose interferon alfa-2b (HR for RFS = 0.85; 99.4% CI, 0.66-1.09).
Results of the second step of the trial showed a 5-year OS rate of 70% (95% CI, 65-74) with 10 mg/kg ipilimumab vs. 65% (95% CI, 60-70) with high-dose interferon alfa-2b, and median RFS of 3.9 years (95% CI, 2.9 to not reached) vs. 2.4 years (95% CI, 1.6-3). Although the OS and RFS trends favored 10 mg/kg ipilimumab, they did not reach statistical significance.
Grade 3 or higher adverse events occurred among 78.8% (95% CI, 75.1-82.3) of patients who received high-dose interferon alfa-2b, 57.9% (95% CI, 53.4-62.2) of patients in the 10 mg/kg ipilimumab cohort and 38.6% (95% CI, 34.3-42.9) of patients in the 3 mg/kg ipilimumab cohort.
“An OS benefit was seen despite a post-protocol salvage pattern that significantly favored the use of more active agents known to impact survival on the high-dose interferon alfa-2b arm,” Tarhini told Healio. “The currently approved adjuvant ipilimumab dose of 10 mg/kg was more toxic and not clearly superior in efficacy to high-dose interferon alfa-2b or ipilimumab dose of 3 mg/kg. Based on our results, high-dose interferon alfa-2b is no longer an acceptable form of adjuvant therapy for patients with high-risk melanoma.”
The researchers plan to present an in-depth analysis of the immune-related adverse events with CTLA-4 blockade experienced during this study at this year’s ASCO-SITC Clinical Immuno-Oncology Symposium.
“We are also currently conducting the quality-of-life analysis based on data collected during the study’s conduct and we plan to present this data at this year’s ASCO Annual Meeting,” Tarhini told Healio. “In addition, we are in the completion phase of a biomarker analysis of predictors of clinical benefit and toxicity risk, as well as other mechanistic studies that may help plan the next phase of studies based on this trial.”
By demonstrating that adjuvant high-dose interferon alfa-2b no longer has a role in the immune checkpoint blockade era, Tarhini and colleagues answered a key question in the melanoma field, Allison Betof Warner, MD, PhD, and Michael A. Postow, MD, medical oncologists at Memorial Sloan Kettering Cancer Center, wrote in an accompanying editorial.
“We congratulate the investigators on their diligence to complete this study while so many changes were occurring in the treatment of unresectable [late-stage] melanoma and where appropriate adjustments to study arms and analyses were needed as other data in the field emerged,” they wrote. “We can use this study as an example of the need to remain as flexible as possible, within an appropriate statistical framework, in our ongoing adjuvant and neoadjuvant studies to ensure that the questions being asked are as clinically relevant as possible in the rapidly changing melanoma landscape.” – by Jennifer Southall
For more information:
Ahmad A. Tarhini, MD, PhD, can be reached at Moffitt Comprehensive Cancer Center and Research Institute, 10920 McKinley Drive, Tampa, FL 33612; email: ahmad.tarhini@moffitt.org.
Disclosures: The study was funded by Bristol-Myers Squibb, NCI and NIH. The study authors report no relevant financial disclosures. Betof Warner reports honoraria from LG Chem Life Sciences Innovation Center and research funding from Leap Therapeutics. Postow reports consultant/advisory roles with Aduro Biotech, Array BioPharma, Bristol-Myers Squibb, Incyte, Merck, New Link Genetics and Novartis; honoraria from Bristol-Myers Squibb and Merck; and institutional research funding from Array BioPharma, AstraZeneca/MedImmune, Bristol-Myers Squibb, Infinity Pharmaceuticals, Merck, Novartis and Rgenix.
Perspective
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Sanjiv S. Agarwala, MD
This trial underwent several modifications due to the changing landscape of melanoma therapy and eventually adopted a two-step hierarchic approach, first evaluating adjuvant ipilimumab at 3 mg/kg vs. high-dose interferon followed by ipilimumab at 10 mg/kg vs. high-dose interferon.
Unfortunately, the data provided by this trial are more or less irrelevant to clinical practice today. Ipilimumab at 10 mg/kg proved to be inferior to adjuvant nivolumab (Opdivo, Bristol-Myers Squibb) in the CheckMate 238 trial, and high-dose interferon is almost never used as adjuvant therapy for melanoma in the modern era. Although 10 mg/kg ipilimumab was not superior to high-dose interferon for either of the primary endpoints in the E1609 trial, it is hard to conceive that this is due to superiority of 3 mg/kg ipilimumab over 10 mg/kg ipilimumab — the study was not designed to compare these two doses and, as the researchers point out, toxicity, crossover and sample size could account for this finding.
In an era of new and emerging data for melanoma on a regular basis, it will be necessary for the practicing clinician to make deductions based on the available information. For instance, if 3 mg/kg ipilimumab is superior to high-dose interferon and nivolumab is superior to 10 mg/kg ipilimumab, it is logical to assume that nivolumab is superior to high-dose interferon. For the patient with a BRAF mutation, the COMBI-AD trial showed that the BRAF/MEK inhibitor combination of dabrafenib (Tafinlar, Novartis) and trametinib (Mekinist, Novartis) is superior to placebo. We await the results of the Checkmate 915 trial that tested the combination of ipilimumab and nivolumab vs. nivolumab in high-risk melanoma.
The results of the E1609 trial do not provide any new insights in the modern era of adjuvant therapy. The unanswered questions remain: What is the best option for patients who harbor a BRAF mutation? Is combination immunotherapy with nivolumab and ipilimumab superior to nivolumab alone? What will be the impact of the paradigm shift of no longer performing completion lymphadenectomy for patients with a positive sentinel lymph node?
The good news for our patients is that we have more effective therapies available with substantially less toxicity than high-dose interferon for patients with high-risk, surgically resected melanoma. As better biological markers and insights emerge, the future will depend upon selecting the best patient for the most appropriate treatment to maximize clinical benefit.
References:
Hauschild A, et al. LBA6_PR. Presented at: European Society for Medical Oncology Congress; Sept. 8-12, 2017; Madrid.
Weber JS, et al. Abstract 9502. Presented at ASCO Annual Meeting; June 1-5, 2018; Chicago.
Temple University
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