Individualised neoantigen therapy mRNA-4157 (V940) plus pembrolizumab versus pembrolizumab monotherapy in resected melanoma (KEYNOTE-942): a randomised, phase 2b study
(1) Weber JS (2) Carlino MS (3) Khattak A (4) Meniawy T (5) Ansstas G (6) Taylor MH (7) Kim KB (8) McKean M (9) Long GV (10) Sullivan RJ (11) Faries M (12) Tran TT (13) Cowey CL (14) Pecora A (15) Shaheen M (16) Segar J (17) Medina T (18) Atkinson V (19) Gibney GT (20) Luke JJ (21) Thomas S (22) Buchbinder EI (23) Healy JA (24) Huang M (25) Morrissey M (26) Feldman I (27) Sehgal V (28) Robert-Tissot C (29) Hou P (30) Zhu L (31) Brown M (32) Aanur P (33) Meehan RS (34) Zaks T
Weber et al. evaluated the addition of personalized neoantigen vaccines (mRNA-4157) to pembrolizumab in a phase IIb clinical with 157 patients, and found that it resulted in a clinical benefit, prolonging recurrence-free survival and distant metastasis-free survival, with the benefit becoming more apparent over longer periods of time. The combination treatment showed a manageable safety profile, consistent with the addition of a second agent to immune checkpoint blockade. Patients with circulating tumor DNA had worse outcomes regardless of treatment group, and neither TMB nor PD-L1 at baseline were not predictive of outcomes.
(1) Weber JS (2) Carlino MS (3) Khattak A (4) Meniawy T (5) Ansstas G (6) Taylor MH (7) Kim KB (8) McKean M (9) Long GV (10) Sullivan RJ (11) Faries M (12) Tran TT (13) Cowey CL (14) Pecora A (15) Shaheen M (16) Segar J (17) Medina T (18) Atkinson V (19) Gibney GT (20) Luke JJ (21) Thomas S (22) Buchbinder EI (23) Healy JA (24) Huang M (25) Morrissey M (26) Feldman I (27) Sehgal V (28) Robert-Tissot C (29) Hou P (30) Zhu L (31) Brown M (32) Aanur P (33) Meehan RS (34) Zaks T
Weber et al. evaluated the addition of personalized neoantigen vaccines (mRNA-4157) to pembrolizumab in a phase IIb clinical with 157 patients, and found that it resulted in a clinical benefit, prolonging recurrence-free survival and distant metastasis-free survival, with the benefit becoming more apparent over longer periods of time. The combination treatment showed a manageable safety profile, consistent with the addition of a second agent to immune checkpoint blockade. Patients with circulating tumor DNA had worse outcomes regardless of treatment group, and neither TMB nor PD-L1 at baseline were not predictive of outcomes.
BACKGROUND: Checkpoint inhibitors are standard adjuvant treatment for stage IIB-IV resected melanoma, but many patients recur. Our study aimed to evaluate whether mRNA-4157 (V940), a novel mRNA-based individualised neoantigen therapy, combined with pembrolizumab, improved recurrence-free survival and distant metastasis-free survival versus pembrolizumab monotherapy in resected high-risk melanoma. METHODS: We did an open-label, randomised, phase 2b, adjuvant study of mRNA-4157 plus pembrolizumab versus pembrolizumab monotherapy in patients, enrolled from sites in the USA and Australia, with completely resected high-risk cutaneous melanoma. Patients with completely resected melanoma (stage IIIB-IV) were assigned 2:1 to receive open-label mRNA-4157 plus pembrolizumab or pembrolizumab monotherapy. mRNA-4157 was administered intramuscularly (maximum nine doses) and pembrolizumab intravenously (maximum 18 doses) in 3-week cycles. The primary endpoint was recurrence-free survival in the intention-to-treat population. This ongoing trial is registered at ClinicalTrials.gov, NCT03897881. FINDINGS: From July 18, 2019, to Sept 30, 2021, 157 patients were assigned to mRNA-4157 plus pembrolizumab combination therapy (n=107) or pembrolizumab monotherapy (n=50); median follow-up was 23 months and 24 months, respectively. Recurrence-free survival was longer with combination versus monotherapy (hazard ratio [HR] for recurrence or death, 0á561 [95% CI 0á309-1á017]; two-sided p=0á053), with lower recurrence or death event rate (24 [22%] of 107 vs 20 [40%] of 50); 18-month recurrence-free survival was 79% (95% CI 69á0-85á6) versus 62% (46á9-74á3). Most treatment-related adverse events were grade 1-2. Grade ³3 treatment-related adverse events occurred in 25% of patients in the combination group and 18% of patients in the monotherapy group, with no mRNA-4157-related grade 4-5 events. Immune-mediated adverse event frequency was similar for the combination (37 [36%]) and monotherapy (18 [36%]) groups. INTERPRETATION: Adjuvant mRNA-4157 plus pembrolizumab prolonged recurrence-free survival versus pembrolizumab monotherapy in patients with resected high-risk melanoma and showed a manageable safety profile. These results provide evidence that an mRNA-based individualised neoantigen therapy might be beneficial in the adjuvant setting. FUNDING: Moderna in collaboration with Merck Sharp & Dohme, a subsidiary of Merck & Co, Rahway, NJ, USA.
Author Info:
(1) Laura and Isaac Perlmutter Cancer Center at NYU Langone Health, New York, NY, USA. Electronic address: Jeffrey.Weber@nyulangone.org. (2) Westmead and Blacktown Hospitals, Melan
oma Institute Australia, Sydney, NSW, Australia. (3) Hollywood Private Hospital, Perth, WA, Australia; Edith Cowan University, Perth, WA, Australia. (4) Saint John of God Subiaco Hospital, Subiaco, WA, Australia. (5) Washington University School of Medicine, St Louis, MO, USA. (6) Earle A Chiles Research Institute, Providence Cancer Institute, Portland, OR, USA. (7) California Pacific Medical Center Research Institute, San Francisco, CA, USA. (8) Sarah Cannon Research Institute at Tennessee Oncology, Nashville, TN, USA. (9) Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia; Royal North Shore and Mater Hospitals, Sydney, NSW, Australia. (10) Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. (11) The Angeles Clinic and Research Institute, a Cedars-Sinai affiliate, Los Angeles, CA, USA. (12) Smilow Cancer Center at Yale New Haven Hospital, New Haven, CT, USA. (13) Texas Oncology PA, Dallas, TX, USA. (14) Hackensack University Medical Center, Hackensack, NJ, USA. (15) The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA. (16) University of Arizona, Tucson, AZ, USA. (17) University of Colorado Cancer Center, Aurora, CO, USA. (18) Princess Alexandra Hospital, Brisbane, QLD, Australia. (19) Georgetown-Lombardi Comprehensive Cancer Center, Washington, DC, USA. (20) UPMC Hillman Cancer Center, Pittsburgh, PA, USA. (21) Orlando Health Kuhl Avenue, Orlando, FL, USA. (22) Dana-Farber Cancer Institute, Boston, MA, USA. (23) Merck & Co, Rahway, NJ, USA. (24) Merck & Co, Rahway, NJ, USA. (25) Moderna, Cambridge, MA, USA. (26) Moderna, Cambridge, MA, USA. (27) Moderna, Cambridge, MA, USA. (28) Moderna, Cambridge, MA, USA. (29) Moderna, Cambridge, MA, USA. (30) Moderna, Cambridge, MA, USA. (31) Moderna, Cambridge, MA, USA. (32) Moderna, Cambridge, MA, USA. (33) Moderna, Cambridge, MA, USA. (34) Moderna, Cambridge, MA, USA.
