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Study Finds Immune-Related Adverse Events Herald Benefit With Adjuvant Pembrolizumab in Melanoma


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In the EORTC 1325/KEYNOTE-054 trial of adjuvant pembrolizumab in patients with stage III melanoma, recurrences were reduced by 44% in the immunotherapy arm, vs placebo, but this benefit increased to a 63% reduction in risk among patients developing an immune-related adverse event on treatment.1

Alexander M.M. Eggermont, MD, PhD

Alexander M.M. Eggermont, MD, PhD

“This study shows that for patients who have an immune-related adverse event with pembrolizumab, outcomes are almost twice as good as for those who do not,” said Alexander M.M. Eggermont, MD, PhD, of Gustave Roussy Cancer Centre and the Université Paris-Saclay in France.

EORTC 1325/KEYNOTE-054 included 1,019 adults with complete resection of cutaneous melanoma metastatic to lymph node(s), classified as stage IIIA, IIIB, or IIIC. Consistent with the main analysis in the intent-to-treat population,2 recurrence-free survival for patients starting treatment was longer in the pembrolizumab arm than in the placebo arm (hazard ratio [HR] = 0.56). At 2 years, 75.5% of the pembrolizumab arm was recurrence-free, compared with 61.1% of the placebo arm, Dr. Eggermont reported.

The cumulative incidence of immune-related adverse events after 15 months of  treatment was 37.3% with pembrolizumab and 9.0% with placebo. These disorders were primarily endocrine disorders, which were observed in 23.4% and 5.0%, respectively; all but approximately 4% and 1%, respectively, were thyroid disorders. Vitiligo and rash were seen in about 5% of patients in the pembrolizumab arm.

The occurrence of an immune-related adverse event was significantly associated with a longer recurrence-free survival in the pembrolizumab arm, whereas no such association was found among patients on the placebo arm. This was true for both men and women as well as regardless of disease stage.

Compared with the placebo arm, the reduction in the hazard of recurrence or death in the pembrolizumab arm was greater after onset of an immune-related adverse event (HR = 0.37) than without one or before one (HR = 0.61), which Dr. Eggermont considered a “significant” difference (P = .028).

Adjuvant Therapy for Melanoma

  • In the EORTC 1325/KEYNOTE-054 phase II trial of patients with stage III melanoma, adjuvant pembrolizumab reduced recurrences by 44% over placebo.
  • The benefit increased to a 63% reduction in risk for patients who developed immune-related adverse events on treatment. Most events were treatable endocrine disorders.
  • In the 7-year follow-up of the phase III ipilimumab study (EORTC 18071), a 10% absolute benefit was maintained, vs placebo, in recurrence-free, distant metastasis–free, and overall survival.

Adjuvant Ipilimumab in Melanoma

In the long-term (7-year) follow-up of EORTC 18071, treatment of patients who have high-risk stage III melanoma with adjuvant ipilimumab provided a sustained improvement in recurrence-free, distant metastasis–free, and overall survival, despite a 53% rate of treatment discontinuation due to toxicity, in the latest analysis of the trial, also presented at the Annual Meeting by Dr. Eggermont.3

The phase III trial randomly assigned 951 patients to ipilimumab at 10 mg/kg or placebo given for 4 doses, then every 2 months for up to 3 years. The benefits, as assessed by local investigators, “were long-lasting, with almost a 10% difference observed vs placebo at 7 years, and were consistent across subgroups,” Dr. Eggermont stated.

The 7-year estimate of recurrence-free survival was 39.2% in the ipilimumab group and 30.9% in the placebo group (HR = 0.75; P < .001). Distant metastasis–free survival was 44.5% and 36.9%, respectively (HR = 0.76; P = .002), and overall survival was 60.0% and 51.3%, respectively (HR = 0.73; P = .002).

“This study confirms that the overall survival benefit of adjuvant ipilimumab is real, because it’s seen at 5, 6, 7, and 8 years.”
— Alexander M.M. Eggermont, MD, PhD

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“This study confirms that the overall survival benefit of adjuvant ipilimumab is real, because it’s seen at 5, 6, 7, and 8 years,” he said. “The difference in absolute terms at every time point is 8% to 10%, regardless of stopping therapy. Half the patients went off treatment after 4 doses, so you don’t need maintenance therapy. It’s all driven by 4 doses of ipilimumab, just like we see in advanced disease.” 

DISCLOSURE: Dr. Eggermont has served on scientific advisory boards for and/or received honoraria or travel support from Actelion, Agenus, Amgen, Bayer, Biocad, BioInvent, BMS, Catalym, CellDex, Ellipses, Gilead, GSK, HalioDx, Incyte, IO Biotech, ISA Pharmaceuticals, Medimmune, MSD, Novartis, Pfizer, Polynoma, Regeneron, Sanofi, Sellas, and Skyline Dx; has stock in RiverDx, SkylineDx, and Theranovir; and has had speaker engagements with MSD and Novartis.

REFERENCES

1. Eggermont AMM, Kicinski M, Blank CU, et al: Prognostic and predictive value of an immune-related adverse event among stage III melanoma patients included in the EORTC 1325/KEYNOTE-054 pembrolizumab vs placebo trial. 2019 ASCO Annual Meeting. Abstract 2517. Presented June 1, 2019.

2. Eggermont AMM, Blank CU, Mandala M, et al: Adjuvant pembrolizumab versus placebo in resected stage III melanoma. N Engl J Med 378:1789-1801, 2018.

3. Eggermont AMM, Chiarion-Sileni V, Grob JJ, et al: Ipilimumab versus placebo after complete resection of stage III melanoma. 2019 ASCO Annual Meeting. Abstract 2512. Presented June 1, 2019.


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