Adjuvant Ipilimumab Outplays High-Dose Interferon For High-Risk Melanoma

Author: By Shreeya Nanda, Senior medwireNews Reporter

medwireNews: High-dose interferon α-2b should no longer be the standard adjuvant treatment option for patients with resected high-risk melanoma, say phase III trial researchers who demonstrated a significant overall survival (OS) benefit with ipilimumab 3 mg/kg (ipi3) over interferon in these patients.

There was no significant difference in relapse-free survival (RFS) between the ipi3 and interferon groups, and the toxicity profile was “roughly comparable”, they add, highlighting that the data “support the use of ipi3”.

The team also evaluated ipilimumab 10 mg/kg (ipi10), which is the dose currently approved by the US FDA for the adjuvant treatment of stage III melanoma, but found no significant improvement in either OS or RFS versus high-dose interferon, with more toxicity.

Editorialists Allison Betof Warner, from Memorial Sloan Kettering Cancer Center in New York, USA, and Michael Postow, from Weill Cornell Medical College in New York, write in a related piece: “Given the OS benefit of ipi3 compared with [high-dose interferon], we agree with the authors that if patients have access to immune checkpoint blockade, [high-dose interferon] is no longer an acceptable standard adjuvant therapy.

“Yet given [the] superiority and lower toxicity of adjuvant nivolumab over ipilimumab in the CheckMate238 study and similarly promising adjuvant data for pembrolizumab over observation in the KEYNOTE-054 study, the role of adjuvant ipi3 remains unclear and […] limited to selected settings where patients have already progressed on anti-PD1 therapy.”

The E1609 trial recruited 1670 patients who had undergone resection of stage IIIB–IV melanoma and randomly assigned them to receive adjuvant ipi3 (n=523) or ipi10 (n=511) every 3 weeks for four doses and then every 12 weeks for a further four doses, or to receive high-dose interferon (n=636).

As reported in the Journal of Clinical Oncology, the co-primary endpoint of OS was significantly prolonged with ipi3 versus interferon, with a hazard ratio (HR) for death of 0.78 and 5-year rates of 72% and 67%, respectively.

The other primary outcome – RFS – was also better with ipi3 than interferon, with an HR of 0.85 in favour of the CTLA-4 inhibitor and corresponding median RFS durations of 4.5 and 2.5 years, but this did not reach statistical significance, which the study authors suspect may be due to the sample size.

The comparison of ipi10 and interferon also showed trends towards improvements with ipi10 in OS (HR=0.88) and RFS (HR=0.84), but again these were not statistically significant.

Of note, the OS advantage with ipi3 was seen despite a significantly greater use of salvage ipilimumab, either alone or alongside anti-PD-1 agents, by interferon-treated patients than their counterparts given ipi3 or ipi10.

Ahmad Tarhini, from the H Lee Moffitt Comprehensive Cancer Center in Tampa, Florida, USA, and co-researchers therefore suggest that “it is likely that our results represent a conservative estimate of ipi3 benefits.”

Adverse events (AEs) of at least grade 3 were observed in 38.6% of patients in the ipi3 group, 57.9% of those in the ipi10 group and 78.8% of those in the high-dose interferon group. Fatal AEs that were considered at least possibly related to treatment occurred in three, eight and two patients, respectively.

The investigators note that the adverse events (AEs) were “consistent with the known toxicity profiles of these agents”, and the greater toxicity of ipi10 versus ipi3 “was expected and consistent with what is known in metastatic melanoma, although the rates seem to be higher in the adjuvant setting than in the metastatic setting.”

And the team concludes: “E1609 supports the survival value of adjuvant immune checkpoint blockade, demonstrating significant OS benefit in comparison with the active control [high-dose interferon], previously shown to benefit OS and RFS.”

References

Tarhini AA, Lee SJ, Hodi FS, et al. Phase III study of adjuvant ipilimumab (3 or 10 mg/kg) versus high-dose interferon alfa-2b for resected high-risk melanoma: North American Intergroup E1609. J Clin Oncol; Advance online publication 27 December 2019.
doi: 10.1200/JCO.19.01381

Betof Warner A, Postow MA. Another victory for immune checkpoint blockade in melanoma: Adjuvant ipilimumab over interferon. J Clin Oncol; Advance online publication 27 December 2019.
doi: 10.1200/JCO.19.02988