TY - JOUR
T1 - Phase I Trial of Cetuximab, Radiotherapy, and Ipilimumab in Locally Advanced Head and Neck Cancer
AU - Ferris, Robert L.
AU - Moskovitz, Jessica
AU - Kunning, Sheryl
AU - Ruffin, Ayana T.
AU - Reeder, Carly
AU - Ohr, James
AU - Gooding, William E.
AU - Kim, Seungwon
AU - Karlovits, Brian J.
AU - Vignali, Dario A.A.
AU - Duvvuri, Umamaheswar
AU - Johnson, Jonas T.
AU - Petro, Daniel
AU - Heron, Dwight E.
AU - Clump, David A.
AU - Bruno, Tullia C.
AU - Bauman, Julie E.
N1 - Funding Information:
R.L. Ferris reports personal fees and other support from Achilles Therapeutics, EMD Serono; personal fees from Aduro Biotich, Bicara Therapeutics Inc., Everest Clinical Research Corporation, F. Hoffmann-La Roche Ltd, Genocea Biosciences, Inc., Kowa Research Institute, Inc., Mirati Therapeutics, Inc., Nanobiotix, PPD Development, L.P., Sanofi_Aventis, and Zymeworks; grants from AstraZeneca/Medimmune and Tesaro; grants and other support from Bristol-Myers Squibb and Merck; other support from Hookipa Biotech GmbH, Instil Bio, Inc., Lifescience Dynamics Limited, MacroGenics, Inc., Numab Therapeutics AG, OncoCyte Corporation, Pfizer, Rakuten Medical, Inc., Seagen, Inc., and Vir Biotechnology, Inc.; and grants, personal fees, and other support from Novasenta outside the submitted work. D.A.A. Vignali reports grants and personal fees from Bristol-Myers Squibb; personal fees from Incyte, Bicara, G1 Therapeutics, and Almirall; grants, personal fees, and other support from Tizona, Potenza/Astellas, and Novasenta; personal fees and other support from Apeximmune, T7/ImReg Bio, and Werewolf; other support from Trishula and Oncorus; and personal fees from F-Star outside the submitted work; in addition, D.A.A. Vignali has a patent for LAG3 pending, issued, licensed, and with royalties paid from Bristol-Myers Squibb; a patent for NRP1 pending, issued, licensed, and with royalties paid from Potenza/Astallas; and a patent for IL35 pending and issued. U. Duvvuri reports personal fees from Activ Surgical outside the submitted work; in addition, U. Duvvuri has grant support from the Department of Veterans Affairs, NIH, and private philanthropy. T.C. Bruno reports personal fees from Walking Fish Therapeutics outside the submitted work. No disclosures were reported by the other authors.
Funding Information:
Supported by NCI CTEP, the University of Pittsburgh/UPMC Hillman Cancer Center SPORE in Head and Neck Cancer (grant no. P50 CA097190, to R.L. Ferris), and the Shared Resources of the UPMC Hillman Cancer Center Support Grant (grant no. P30 CA047904).
Publisher Copyright:
© 2022 American Association for Cancer Research.
PY - 2022/4/1
Y1 - 2022/4/1
N2 - Purpose: Concurrent radiotherapy with cetuximab, an anti-EGFR mAb, is a standard treatment for locally advanced head and neck squamous carcinoma (HNSCC). Cytotoxic T lymphocyte antigen-4–positive (CTLA-4þ) regulatory T cells (Treg) dampen cellular immunity and correlate negatively with clinical outcomes. This phase I study added ipilimumab, an anti–CTLA-4 mAb, to cetuximab-radiotherapy. Patients and Methods: A (3 þ 3) design was used to establish the recommended phase II dose (RP2D) of ipilimumab, added at week 5 for four, every-3-week doses to fixed, standard cetuximab-radiotherapy. Eligible subjects had stage III to IVb, high-risk [human papillomavirus–negative (HPV-)] or intermediate-risk HPV-positive (HPVþ)] HNSCC. Dose-limiting toxicity (DLT) was defined as any grade 4 adverse event (AE) except in-field radiation dermatitis or immune-related (ir) AE requiring ≥2 weeks of systemic steroids. Baseline tumor and serial blood specimens were collected for immune correlatives. Results: From July 2013 to May 2016, 18 patients enrolled. Two of 6 in cohort 1 (ipilimumab 3 mg/kg) experienced grade 3 dermatologic DLTs, triggering deescalation of ipilimumab to 1 mg/kg. Dose level -1 was expanded to N = 12 without DLT. irAE included: grade 1, 2, and 3 dermatitis (2, 1, and 3 cases), grade 4 colitis (1), and grade 1 hyperthyroidism (1). Three-year disease-free survival (DFS) and overall survival were 72% [90% confidence interval (CI), 57–92] and 72% (90% CI, 56–92). High expression of coinhibitory receptors PD1/LAG3/CD39 on baseline tumor-infiltrating Treg was associated with worse DFS (HR = 5.6; 95% CI, 0.83–37.8; P = 0.08). Conclusions: The RP2D for ipilimumab plus standard cetuximab–radiotherapy is 1 mg/kg in weeks 5, 8, 11, and 14. The regimen is tolerable and yields acceptable survival without cytotoxic chemotherapy.
AB - Purpose: Concurrent radiotherapy with cetuximab, an anti-EGFR mAb, is a standard treatment for locally advanced head and neck squamous carcinoma (HNSCC). Cytotoxic T lymphocyte antigen-4–positive (CTLA-4þ) regulatory T cells (Treg) dampen cellular immunity and correlate negatively with clinical outcomes. This phase I study added ipilimumab, an anti–CTLA-4 mAb, to cetuximab-radiotherapy. Patients and Methods: A (3 þ 3) design was used to establish the recommended phase II dose (RP2D) of ipilimumab, added at week 5 for four, every-3-week doses to fixed, standard cetuximab-radiotherapy. Eligible subjects had stage III to IVb, high-risk [human papillomavirus–negative (HPV-)] or intermediate-risk HPV-positive (HPVþ)] HNSCC. Dose-limiting toxicity (DLT) was defined as any grade 4 adverse event (AE) except in-field radiation dermatitis or immune-related (ir) AE requiring ≥2 weeks of systemic steroids. Baseline tumor and serial blood specimens were collected for immune correlatives. Results: From July 2013 to May 2016, 18 patients enrolled. Two of 6 in cohort 1 (ipilimumab 3 mg/kg) experienced grade 3 dermatologic DLTs, triggering deescalation of ipilimumab to 1 mg/kg. Dose level -1 was expanded to N = 12 without DLT. irAE included: grade 1, 2, and 3 dermatitis (2, 1, and 3 cases), grade 4 colitis (1), and grade 1 hyperthyroidism (1). Three-year disease-free survival (DFS) and overall survival were 72% [90% confidence interval (CI), 57–92] and 72% (90% CI, 56–92). High expression of coinhibitory receptors PD1/LAG3/CD39 on baseline tumor-infiltrating Treg was associated with worse DFS (HR = 5.6; 95% CI, 0.83–37.8; P = 0.08). Conclusions: The RP2D for ipilimumab plus standard cetuximab–radiotherapy is 1 mg/kg in weeks 5, 8, 11, and 14. The regimen is tolerable and yields acceptable survival without cytotoxic chemotherapy.
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U2 - 10.1158/1078-0432.CCR-21-0426
DO - 10.1158/1078-0432.CCR-21-0426
M3 - Article
C2 - 35091445
AN - SCOPUS:85128000776
VL - 28
SP - 1335
EP - 1344
JO - Clinical Cancer Research
JF - Clinical Cancer Research
SN - 1078-0432
IS - 7
ER -