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Adjuvant immunotherapy prolongs recurrence-free survival in resected stage II B/C melanoma

News Release

Adjuvant immunotherapy prolongs recurrence-free survival in resected stage II B/C melanoma

ESMO Congress 2021, 16-21 September

Reports and Proceedings

European Society for Medical Oncology

Lugano, Switzerland, 18 September 2021 – The first randomised phase III clinical trial in stage II melanoma has shown a 35% reduction in the risk of recurrence with adjuvant pembrolizumab compared with placebo. The late breaking results of the KEYNOTE-716 trial are presented at the ESMO Congress 2021. (1)

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Patients with stage IIB and IIC melanoma have a deep or ulcerated primary tumor. These patients occur in similar numbers, and have the same risk of recurrence and death, as those with stage IIIA and IIIB melanoma. Despite the equivalent risk, the current standard of care is observation for stage II B/C and adjuvant therapy for stage III A/B melanoma.

Medical Comments on finds

Commenting on the findings, Dr. Omid Hamid, Chief of Research/Immuno-Oncology, The Angeles Clinic and Research Institute, a Cedars-Sinai Affiliate, Los Angeles, US, chair of the congress’s melanoma and other skin tumours track said: “The US Food and Drug Administration (FDA) is now examining this drug for the adjuvant treatment of stage IIB and IIC melanoma which, if approved, means we would be introducing immunotherapy earlier in the patient journey. This has the potential to spare patients recurrence and metastases. It is important to note that the trial included not just adults but also children and adolescents aged 12 years and older.”

KEYNOTE-716 randomly allocated to 976 patients with complete resection of cutaneous stage IIB or IIC melanoma and no lymph node involvement to the PD-1 inhibitor pembrolizumab or placebo for up to one year. At a median follow-up of 14.4 months, pembrolizumab significantly prolonged recurrence-free survival compared to placebo, with a hazard ratio of 0.65.

Finding will change Treatment

“These results are set to substantially change the population of melanoma patients who get treated in the adjuvant setting,” said study author Dr. Jason J. Luke, Director, Cancer Immunotherapeutics Center, UPMC Hillman Cancer Center, Pittsburgh, US. “Historically we have defined high-risk patients after surgery as those with lymph node positive disease. This trial suggests that the depth of the primary tumour and the ulceration status provide substantial information about the risk of recurrence and metastases and whether or not we might pursue adjuvant therapy. In future we will need to reconsider how we incorporate sentinel lymph node biopsy into our risk stratification.”

During the 14.4-month follow-up, 54 (11.1%) patients on pembrolizumab had a recurrence compared with 82 (16.8%) on placebo, while distant recurrences were nearly halved with pembrolizumab (23 events) versus placebo (38 events). Luke pointed out: “There has been a belief that early-stage melanoma doesn’t recur very fast and that these patients don’t develop metastatic disease. These data clearly disprove that and show that patients with high-risk stage II melanoma recur quickly and distantly, just the same as patients with stage IIIA and IIIB. Treatment with pembrolizumab reduced that in a meaningful and statistically significant way, indicating that these stage II patients should be offered adjuvant therapy.”

Luke highlighted that the potential for side-effects may have been one reason for withholding adjuvant treatment in the stage II setting: “When the only available therapies were high-dose interferon and ipilimumab, both of which were associated with more than 50% rates of severe adverse events, that just wasn’t tolerable for patients with early stage disease. But now with anti-PD-1 treatment it’s a much more attractive risk/benefit scenario and given the results of this trial, I think we should be offering this to our patients.”

Luke said the trial has established a benchmark for future studies: “In a world of financial constraints and personalised medicine, we’d ultimately like to know exactly who we need to treat. This trial provides a platform from which to do those molecular studies. In addition, as patients who recur in the placebo arm cross over to the pembrolizumab group, we will eventually get an answer about whether it is more effective to treat right after surgery or to wait until the melanoma comes back.”

Hamid noted that the dose frequency and duration of adjuvant therapy in stage II B/C melanoma should also be evaluated: “Studies of adjuvant therapy in other stage II solid tumours have suggested that a shorter time course of therapy can provide the best risk/benefit ratio – although these were not immunotherapies. Patients in KEYNOTE-716 were treated for one year and while the incidence of grade 3 or 4 toxicity was minimal, side-effects could potentially have a significant impact on the lifestyle of these patients.”

He added that longer follow-up is required to find out if there is an overall survival benefit with anti-PD-1 therapy in these patients. “We also need to determine what giving adjuvant anti-PD-1 therapy in stage II B/C means for stage III patients who recur and would currently receive this treatment,” said Hamid. “I foresee that some of the regimens we now use in the metastatic setting may move up earlier in stage III disease. Ongoing clinical trials are examining novel combinations in the stage III setting – for example, VEGF targeted therapies or pegylated IL-2 or anti-LAG-3 antibody plus anti-PD-1 therapy – versus standard single agent anti-PD-1 therapy.”

This press release contains information provided by the author of the highlighted abstract and reflects the content of this abstract. It does not necessarily reflect the views or opinions of ESMO who cannot be held responsible for the accuracy of the data. Commentators quoted in the press release are required to comply with the ESMO Declaration of Interests policy and the ESMO Code of Conduct.

1 LBA3_PR ‘Pembrolizumab versus placebo after complete resection of high-risk stage II melanoma: Efficacy and safety results from the KEYNOTE-716 double-blind phase III trial‘ will be presented by Jason J. Luke during Presidential Symposium 1 on Saturday, 18 September, 15:05 to 16:35 (CEST) on Channel 1. Annals of Oncology, Volume 32, 2021 Supplement 5

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LBA3_PR – Pembrolizumab versus placebo after complete resection of high-risk stage II melanoma: Efficacy and safety results from the Keynote 716 double-blinded phase III trial  

J.J. Luke1, P. Rutkowski2, P. Queirolo3, M. Del Vecchio4, J. Mackiewicz5, V. Chiarion Sileni6, L. de la Cruz Merino7, M.A. Khattak8, D. Schadendorf9, G.V. Long10, P.A. Ascierto11, M. Mandala12, F. De Galitiis13, V. Sondak14, R.A. Scolyer15, J.M. Kirkwood16, K. Chen17, N. Ibrahim17, S. Ahsan17, A.M.M. Eggermont18

1Medical Oncology, UPMC Hillman Cancer Center, Pittsburgh, United States of America, 2Department Of Soft Tissue/bone Sarcoma And Melanoma, Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland, 3Melanoma And Sarcoma Medical Treatment Unit, IEO – Istituto Europeo di Oncologia, Milan, Italy, 4Medical Oncology Department, Fondazione IRCCS – Istituto Nazionale dei Tumori, Milan, Italy, 5Department Of Medical And Experimental Oncology, Department Of Diagnostics And Cancer Immunology, Poznan University of Medical Sciences, Greater Poland Cancer Centre, Poznan, Poland, 6Clinical And Experimental Oncology Dept., IOV – Istituto Oncologico Veneto IRCCS, Padova, Italy, 7Medical Oncology, Hospital Universitario Virgen Macarena, Seville, Spain, 8Oncology, Fiona Stanley Hospital and Edith Cowan University, Perth, Australia, 9Department Of Dermatology, University Hospital Essen & German Cancer Consortium Partner Site, Essen, Germany, 10Melanoma Institute Australia, The University Of Sydney, Royal North Shore and Mater Hospitals, Sydney, Australia, 11Melanoma, Cancer Immunotherapy And Development Therapeutics Unit, Istituto Nazionale Tumori – IRCCS – Fondazione Pascale, Napoli, Italy, 12Medical Oncology Unit, University of Perugia, Perugia, Italy, 13Oncology Dept., IDI – Istituto dermopatico dell’immacolata – IRCCS, Rome, Italy, 14Cutaneous Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, United States of America, 15Pathology, Melanoma Institute and Royal Prince Alfred Hospital and NSW Health Pathology, Sydney, Australia, 16Melanoma Program, UPMC Hillman Cancer Center, Pittsburgh, United States of America, 17Clinical Development, Merck Sharp & Dohme Corp., Kenilworth, United States of America, 18University Medical Center Utrecht, & Princess Máxima Center, Utrecht, Netherlands

Background: Current standard of care for patients (pts) after resection of high-risk stage II melanoma is observation. In the phase 3 double-blind KEYNOTE-716 trial we evaluated pembrolizumab (pembro) versus placebo in pts with resected AJCC-8 stage IIB or IIC melanoma. We present results of the first recurrence-free survival (RFS) interim analysis.

Methods: Eligible pts aged ≥12 years with complete resection of cutaneous stage IIB or IIC melanoma with negative sentinel lymph node biopsy were randomized 1:1 to pembro 200 mg (2 mg/kg for pediatric pts) or placebo Q3W for 17 cycles (up to 1 year). Randomization was stratified by T category 3b, 4a, 4b (adults) with a separate stratum for pediatric pts. Treatment continued until disease recurrence or unacceptable toxicity. The primary endpoint was RFS per investigator assessment. Safety was also evaluated. The data cutoff date for the interim analysis was December 4, 2020.

Results: Overall, 976 pts (64% stage IIB; 34.8% stage IIC) were randomized (487 pembro; 489 placebo). At median follow-up of 14.4 months, pembro significantly prolonged RFS vs placebo (HR 0.65, 95% CI 0.46-0.92; P=0.00658; median not reached for both). 54 (11.1%) vs 82 (16.8%) pts had a recurrence with almost halving of distant recurrence events in the pembro (23) vs placebo (38) group. The 12-month RFS rate was 90.5% vs 83.1%. Grade ≥3 any-cause AEs occurred in 125 (25.9%) vs 83 (17.1%) pts in the pembro vs placebo group. Grade ≥3 drug-related AEs occurred in 78 (16.1%) vs 21 (4.3%) pts; 74 (15.3%) vs 12 (2.5%) discontinued due to a drug-related AE. No deaths due to any-cause AE or drug-related AEs occurred with pembro; four deaths due to any-cause AEs occurred with placebo. Immune-mediated AEs occurred in 36.2% vs 8.4%, most commonly hypothyroidism (15.7% vs 3.5%) and hyperthyroidism (10.4% vs 0.6%). Most were grade 1-2 in severity.

Conclusions: Adjuvant pembrolizumab for resected stage IIB and IIC melanoma decreased the risk of disease recurrence or death by 35% compared with placebo and was associated with significantly prolonged RFS and a favorable benefit-risk profile.

Clinical trial identification: Identifier: NCT03553836. EudraCT Number: 2018-000669-35. First posted: June 12, 2018.
Editorial acknowledgement: Editoral assistance was provided by Luana Atherly-Henderson, PhD, CMPP an employee of Merck Sharp & Dohme, Corp.
Legal entity responsible for the study: Merck Sharp & Dohme Corp.
Funding: Pharmaceutical, biotech, or other commercial company – Merck Sharp & Dohme Corp.