NCI9673 (Part B): ETCTN Randomized Phase II Study of Nivolumab With or Without Ipilimumab in Refractory, Metastatic Squamous Cell Carcinoma of the Anal Canal

Author(s): Van K. Morris, MD1; Kristen K. Ciombor, MD2; Lianchun Xiao, MS1; Joshua K. Ochieng, PhD1; Enrica Marmonti, PhD1; Blase Polite, MD3; Benjamin A. Weinberg, MD4; John C. Krauss, MD5; John Hays, MD, PhD6; Sarbajit Mukherjee, MD7; Olivia Aranha, MD8; Syma Iqbal, MD9; Tony Shields, MD10; Al B. Benson, MD11; Syed Kazmi, MD12; Christopher Lieu, MD13; Howard Hochster, MD14; Jennifer Whisenant, PhD2; Cara Haymaker, PhD1; Cathy Eng, MD2;
Source: J Clin Oncol 44, 497-507(2026)Volume 44, Number 6DOI: 10.1200/JCO-25-00929
Original Article
Professional photo of Maem Hussein, MD

Dr. Maen Hussein's Thoughts

DON’T… more toxic, no benefit.

PURPOSE

In the previously completed NCI9673 (part A) single-arm study, the antiprogrammed death (PD)–ligand-1 antibody nivolumab demonstrated efficacy for patients with metastatic anal cancer. In NCI9673 (Part B), we evaluated the anticytotoxic T-cell lymphocyte antigen-4 (CTLA-4) antibody ipilimumab in combination with nivolumab for patients with incurable anal cancer.

METHODS

In this phase II NCI ETCTN trial, 100 patients with refractory, incurable anal cancer were randomly assigned to receive nivolumab (480 mg IV once every 4 weeks) alone or with ipilimumab (1 mg/kg IV once every 8 weeks). The primary end point was progression-free survival (PFS). Secondary endpoints included radiographic response, overall survival (OS), and grade ≥3 adverse events. A log-rank test was used to compare survival between arms, with a one-sided alpha of 0.1 and power of 90%. Immune biomarkers were analyzed from baseline and on treatment tissue and blood collections.

RESULTS

The median PFS for nivolumab versus nivolumab plus ipilimumab were 2.9 months (90% CI, 1.9 to 3.8) and 3.7 months (90% CI, 2.0 to 5.6), respectively (hazard ratio [HR], 0.86 [95% CI, 0.60 to 1.23]; P = .25). Response rates were similar for nivolumab (17.4%) and nivolumab plus ipilimumab (21.5%; P = .89). The median OS was 15.9 months for nivolumab and 20.0 months for nivolumab plus ipilimumab (HR, 0.98 [90% CI, 0.63 to 1.51]). Grade ≥3 treatment-related AEs occurred in 6 patients (12%) receiving nivolumab alone and in 12 patients (25%) receiving nivolumab plus ipilimumab. week 9, circulating TIGIT+ CD8+ cells (P < .001) increased with nivolumab plus ipilimumab treatment relative to baseline.

CONCLUSION

The addition of ipilimumab to nivolumab did not statistically improve overall response rate, PFS, or OS but may harbor increased toxicity. Paired blood samples identified TIGIT expression on peripheral T cells as a compensatory change unique to dual PD-1 plus CTLA-4 blockade.

Author Affiliations

1University of Texas—MD Anderson Cancer Center, Houston, TX; 2Vanderbilt-Ingram Cancer Center, Nashville, TN; 3University of Chicago, Chicago, IL; 4Georgetown University, Washington, DC; 5University of Michigan, Ann Arbor, MI; 6The Ohio State University, Columbus, OH; 7Baptist Miami Cancer Institute, Miami, FL; 8Washington University School of Medicine, St. Louis, MO; 9University of Southern California, Los Angeles, CA; 10Karmanos Cancer Institute, Detroit, MI; 11Northwestern University, Chicago, IL; 12The University of Texas Southwestern Medical Center, Dallas, TX; 13University of Colorado, Aurora, CO; 14Rutgers University, Newark, NJ

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