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IMMUNED Confirms OS Benefit For Nivolumab–Ipilimumab After Initial Stage IV Melanoma Treatment

Patients without evidence of disease after stage IV melanoma surgery or radiotherapy have significantly better overall survival with adjuvant use of nivolumab plus ipilimumab versus placebo
20 Sep 2022
Immunotherapy
Melanoma

Author: By Lynda Williams, Senior medwireNews Reporter 

medwireNews: The final analysis of the IMMUNED trial demonstrates significant recurrence-free survival (RFS) and overall survival (OS) benefits with the use of adjuvant nivolumab plus ipilimumab in patients who are at high risk of recurrence after treatment for stage IV melanoma. 

The phase II double-blind, placebo-controlled study was published in The Lancet to coincide with its presentation at the ESMO Congress 2022 in Paris, France, by Dirk Schadendorf, from University Hospital Essen in Germany. 

He reported that after a median 49.2 months of follow-up, the primary endpoint of RFS was significantly higher for patients with no evidence of disease after surgery or radiotherapy who were given nivolumab plus ipilimumab or nivolumab alone compared with those given placebo. Median RFS for these groups was unreached, 12.3 months and 6.3 months, respectively. 

The hazard ratios (HRs) for recurrence were 0.25 for the combination versus placebo, and 0.60 for nivolumab monotherapy versus placebo. The 4-year RFS rates were a corresponding 64.2%, 31.4% and 15.0%. 

The RFS benefits of nivolumab plus ipilimumab versus placebo occurred across all patient subgroups, including by age, sex, melanoma stage, PD-L1 expression, BRAF and NRAS status, and prior receipt of radiotherapy, the researchers comment. 

Moreover, exploratory analysis suggested RFS was statistically superior with combination therapy versus nivolumab alone (HR=0.41) and across all patient subgroups assessed. 

Median OS was unreached in all three arms with 4-year OS rates of 83.8% in patients given nivolumab plus ipilimumab, 72.6% for those treated with nivolumab alone and 63.1% for the placebo-treated controls. 

But the HR for OS only reached significance for use of the combination versus placebo (HR=0.41) and not for nivolumab monotherapy versus placebo. The OS benefit with the combination versus placebo was “consistently observed across all subgroups” and exploratory post-hoc subgroup analyses “demonstrated a favourable effect for nivolumab plus ipilimumab over nivolumab for most subgroups”, say Dirk Schadendorf and co-authors. 

By contrast, subgroup analysis suggested a “more inconsistent” benefit for nivolumab versus placebo, although the researchers note that this analysis may be “affected by subsequent therapy as the protocol permitted patients in the placebo control group to switch over to nivolumab monotherapy in case of disease recurrence.” 

Post-hoc analysis of the 19 patients who crossed over to nivolumab indicated that the median progression-free survival or RFS after beginning their second study treatment was unreached at the time of analysis. 

“The recurrence-free and overall survival benefit of nivolumab plus ipilimumab over placebo reinforces the change of practice already initiated for the treatment of patients with stage IV melanoma with no evidence of disease”, the investigators summarise. 

However, they caution that the significant RFS and OS benefit of the combination treatment “must be balanced against the high rate of treatment-related grade 3–4 adverse events”, which affected 71% of patients in the combination arm versus 29% of patients given only nivolumab. Treatment was discontinued because of any side effects at this severity in 53% and 9% of patients, respectively, versus 2% of controls. 

The authors of an accompanying comment describe the OS benefit in the IMMUNED study participants given nivolumab plus ipilimumab as “impressive” and say it “supports this strategy in clinical practice”, adding that the results “set a high bar for future studies exploring novel combinations to treat patients with stage IV melanoma with no evidence of disease.”  

James Smithy and Michael Postow, both from Memorial Sloan Kettering Cancer Center in New York, USA, conclude: “Future studies should define the best duration of therapy; how to monitor minimal residual disease; and whether certain patients with resected stage IV melanoma, such as patients with brain metastases, stand to benefit most from adjuvant nivolumab plus ipilimumab compared with nivolumab alone.” 

References 

784O - Schadendorf D, Hassel JC, Fluck M, et al. Adjuvant nivolumab alone or in combination with ipilimumab versus placebo in stage IV melanoma with no evidence of disease: Overall survival results of IMMUNED, a randomized, double-blind multicentre phase II DeCOG trial. Ann Oncol 2022; 33 (suppl_7): S356–S409. Doi: 10.1016/annonc/annonc1059

Livingstone E, Zimmer L, Hassel JC, et al. Adjuvant nivolumab plus ipilimumab or nivolumab alone versus placebo in patients with resected stage IV melanoma with no evidence of disease (IMMUNED): final results of a randomised, double-blind, phase 2 trial. Lancet; Advance online publication 10 September 2022. DOI: https://doi.org/10.1016/S0140-6736(22)01654-3

Smithy JW, Postow MA. Adjuvant checkpoint blockade following complete local therapy for melanoma metastases. Lancet; Advance online publication 10 September 2022. DOI: https://doi.org/10.1016/ S0140-6736(22)01654-3

medwireNews is an independent medical news service provided by Springer Healthcare Ltd. © 2022 Springer Healthcare Ltd, part of the Springer Nature Group

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