Rozeman et al. presented long-term survival and biomarker data following neoadjuvant CTLA-4 plus PD-1 blockade in Stage III melanoma. Histological comparison of biopsies taken prior to blockade therapy initiation and following surgical resection revealed >77% pathological response rate (pRR, defined as <50% viable tumor cells in tumor bed). Relapse-free survival at 36 months was highly correlated with pRR (97% in pRR versus 36% in pRR-, p<0.0001). RNA sequencing and plasma proteomics identified markers associated both with response (e.g., IFNγ) and with non-response (e.g., VEGFR-2).
Contributed by Margot O’Toole
ABSTRACT: Neoadjuvant ipilimumab plus nivolumab showed high pathologic response rates (pRRs) in patients with macroscopic stage III melanoma in the phase 1b OpACIN ( NCT02437279 ) and phase 2 OpACIN-neo ( NCT02977052 ) studies1,2. While the results are promising, data on the durability of these pathologic responses and baseline biomarkers for response and survival were lacking. After a median follow-up of 4 years, none of the patients with a pathologic response (n = 7/9 patients) in the OpACIN study had relapsed. In OpACIN-neo (n = 86), the 2-year estimated relapse-free survival was 84% for all patients, 97% for patients achieving a pathologic response and 36% for nonresponders (P < 0.001). High tumor mutational burden (TMB) and high interferon-gamma-related gene expression signature score (IFN-γ score) were associated with pathologic response and low risk of relapse; pRR was 100% in patients with high IFN-γ score/high TMB; patients with high IFN-γ score/low TMB or low IFN-γ score/high TMB had pRRs of 91% and 88%; while patients with low IFN-γ score/low TMB had a pRR of only 39%. These data demonstrate long-term benefit in patients with a pathologic response and show the predictive potential of TMB and IFN-γ score. Our findings provide a strong rationale for a randomized phase 3 study comparing neoadjuvant ipilimumab plus nivolumab versus standard adjuvant therapy with antibodies against the programmed cell death protein-1 (anti-PD-1) in macroscopic stage III melanoma.
Author Info: (1) Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands. (2) Department of Molecular Oncology and Immunology, Netherlands Cancer Institute, Ams
Author Info: (1) Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands. (2) Department of Molecular Oncology and Immunology, Netherlands Cancer Institute, Amsterdam, the Netherlands. (3) Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia. (4) Department of Surgery, Mater Hospital, Sydney, New South Wales, Australia. )5) Department of Surgery, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia. (6) Oncode Institute, Utrecht, the Netherlands. (7) Department of Biometrics, Netherlands Cancer Institute, Amsterdam, the Netherlands. (8) Department of Pathology, Netherlands Cancer Institute, Amsterdam, the Netherlands. (9) Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden. (10) Department of Oncology/Skin Cancer Center, Theme Cancer, Karolinska University Hospital, Stockholm, Sweden. (11) Genomics Core Facility, Netherlands Cancer Institute, Amsterdam, the Netherlands. (12) Core Facility Molecular Pathology and Biobanking, Netherlands Cancer Institute, Amsterdam, the Netherlands. (13) Department of Surgical Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands. (14) Breast and Melanoma Surgery Unit, Royal North Shore hospital, Sydney, New South Wales, Australia. (15) Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital and New South Wales Health Pathology, Sydney, New South Wales, Australia. (16) Department of Medical Oncology, Royal North Shore and Mater Hospitals, Sydney, New South Wales, Australia. (17) Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands. c.blank@nki.nl. (18) Department of Molecular Oncology and Immunology, Netherlands Cancer Institute, Amsterdam, the Netherlands. c.blank@nki.nl.
#Contributed equally.
