A phase II study of retifanlimab (INCMGA00012) in patients with squamous carcinoma of the anal canal who have progressed following platinum-based chemotherapy (POD1UM-202)

S Rao, G Anandappa, J Capdevila, L Dahan, L Evesque, S Kim, M P Saunders, D C Gilbert, L H Jensen, E Samalin, K-L Spindler, S Tamberi, A Demols, M G Guren, D Arnold, M Fakih, T Kayyal, M Cornfeld, C Tian, M Catlett, M Smith, J-P Spano, S Rao, G Anandappa, J Capdevila, L Dahan, L Evesque, S Kim, M P Saunders, D C Gilbert, L H Jensen, E Samalin, K-L Spindler, S Tamberi, A Demols, M G Guren, D Arnold, M Fakih, T Kayyal, M Cornfeld, C Tian, M Catlett, M Smith, J-P Spano

Abstract

Background: Locally advanced or metastatic squamous carcinoma of the anal canal (SCAC) has poor prognosis following platinum-based chemotherapy. Retifanlimab (INCMGA00012), a humanized monoclonal antibody targeting programmed death protein-1 (PD-1), demonstrated clinical activity across a range of solid tumors in clinical trials. We present results from POD1UM-202 (NCT03597295), an open-label, single-arm, multicenter, phase II study evaluating retifanlimab in patients with previously treated advanced or metastatic SCAC.

Patients and methods: Patients ≥18 years of age had measurable disease and had progressed following, or were ineligible for, platinum-based therapy. Retifanlimab 500 mg was administered intravenously every 4 weeks. The primary endpoint was overall response rate (ORR) by independent central review. Secondary endpoints were duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety.

Results: Overall, 94 patients were enrolled. At a median follow-up of 7.1 months (range, 0.9-19.4 months), ORR was 13.8% [95% confidence interval (CI) 7.6% to 22.5%], with one complete response (1.1%) and 12 partial responses (12.8%). Responses were observed regardless of human immunodeficiency virus or human papillomavirus status, programmed death ligand 1 (PD-L1) expression, or liver metastases. Stable disease was observed in 33 patients (35.1%) for a DCR of 48.9% (95% CI 38.5% to 59.5%). Median DOR was 9.5 months (range, 5.6 months-not estimable). Median (95% CI) PFS and OS were 2.3 (1.9-3.6) and 10.1 (7.9-not estimable) months, respectively. Retifanlimab safety in this population was consistent with previous experience for the PD-(L)1 inhibitor class.

Conclusions: Retifanlimab demonstrated clinically meaningful and durable antitumor activity, and an acceptable safety profile in patients with previously treated locally advanced or metastatic SCAC who have progressed on or are intolerant to platinum-based chemotherapy.

Keywords: INCMGA00012; PD-(L)1 inhibitor; anal cancer; clinical trial; phase II; retifanlimab.

Conflict of interest statement

Disclosure SR reports being an advisor or receiving honoraria from Amgen, Celgene, and Shire; travel grants from Bayer, Celgene, and Incyte Corporation. JC reports scientific consultancy role (speaker and advisory roles) for Advanced Accelerator Applications, Amgen, Bayer, Eisai, Eli Lilly, Exelixis, Hutchison MediPharma, Ipsen, Isotopen Technologien München, Merck Serono, Novartis, Pfizer, and Sanofi; research support/grants from Advanced Accelerator Applications, AstraZeneca, Bayer, Eisai, Novartis, and Pfizer. LD reports honoraria from Amgen, Sanofi, and Servier. LE reports honoraria from Merck and Servier. SK reports research funding from Bioprojet Pharma, Boehringer Ingelheim, Bristol Myers Squibb, Novartis, Pfizer, Roche, and Sanofi; advisor or honoraria from Incyte Corporation, Ipsen, Merck Sharp & Dohme, Sanofi, and Servier. MPS reports being an advisor or receiving honoraria from Amgen, Merck, and Servier. ES reports honoraria from or serves on the advisory board for Amgen, Bristol Myers Squibb, Merck Sharp & Dohme, Pierre Fabre Oncology, Roche, Sandoz, and Servier. KLS reports honoraria from Boston Scientific. AD reports consultant and advisory role for AstraZeneca, Basilea Pharmaceutica, Bayer, and Servier; research funding from Bayer. DA reports consultant or advisory role, and/or presentation honoraria from AstraZeneca, Boston Scientific, Bristol Myers Squibb, Eli Lilly, Merck Sharp & Dohme, Pierre Fabre Oncology, Sanofi, Servier, and Terumo. MF reports consultant or advisory role for Amgen, Array BioPharma, GlaxoSmithKline, Incyte Corporation, Pfizer, Seattle Genetics, and Taiho Pharmaceutical; speakers’ bureau for Guardant Health; research funding (institutional) from Amgen, AstraZeneca, Bristol Myers Squibb, and Novartis. MCo, CT, and MS report employment and stock ownership in Incyte Corporation. MCa reports former employment and stock ownership in Incyte Corporation. JPS reports honoraria from AstraZeneca, Biogaran, Bristol Myers Squibb, Eli Lilly, Gilead Sciences, Leo Pharma, Mylan, Myriad Genetics, Novartis, Pfizer, and Pierre Fabre; consulting or advisory role for Merck Sharp & Dohme and Roche; grant from MSD Avenir. All other authors have declared no conflicts of interest. Data sharing Incyte Corporation (Wilmington, DE, USA) is committed to data sharing that advances science and medicine while protecting patient privacy. Qualified external scientific researchers may request anonymized datasets owned by Incyte Corporation for the purpose of conducting legitimate scientific research. Researchers may request anonymized datasets from any interventional study (except phase I studies) for which the product and indication have been approved on or after 1 January 2020 in at least one major market (e.g. US, EU, JPN). Data will be available for request after the primary publication or 2 years after the study has ended. Information on Incyte Corporation’s clinical trial data sharing policy and instructions for submitting clinical trial data requests are available at: https://www.incyte.com/Portals/0/Assets/Compliance%20and%20Transparency/clinical-trial-data-sharing.pdf?ver=2020-05-21-132838-960

Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.

Figures

Figure 1
Figure 1
(A) Best percentage change from baseline in target lesion size (sum of diameters) for individual patients,a and (B) percentage change from baseline over time in sum of longest diameter of target lesions in responders and patients with SD. Confirmed best objective response is shown for each patient in the figure. Upper limit of dotted line indicates criteria for PD (≥20% increase in sum of target lesion diameters), and lower limit indicates criteria for PR (≥30% decrease in sum of target lesion diameters). CR, complete response; DCR, disease control rate; ICR, independent central radiographic review; PD, progressive disease; PFS, progression-free survival; PR, partial response; SD, stable disease. aOut of 94 patients enrolled in the study, 7 patients are not shown as they had missing baseline or postbaseline target lesion assessments.
Figure 2
Figure 2
Duration of treatment and best objective responsesa by ICR according to RECIST version 1.1 (full analysis set). Confirmed best objective response is shown for each patient in the figure. ICR, independent central radiographic review. aOut of 94 patients enrolled in the study, 5 patients are not shown, as they had missing postbaseline target lesion assessments.
Figure 3
Figure 3
Kaplan–Meier estimate of (A) progression-free survival and (B) overall survival. CI, confidence interval; NE, not estimable; Q4W, every 4 weeks.

References

    1. Islami F., Ferlay J., Lortet-Tieulent J., Bray F., Jemal A. International trends in anal cancer incidence rates. Int J Epidemiol. 2017;46(3):924–938.
    1. Shiels M.S., Kreimer A.R., Coghill A.E., Darragh T.M., Devesa S.S. Anal cancer incidence in the United States, 1977-2011: distinct patterns by histology and behavior. Cancer Epidemiol Biomarkers Prev. 2015;24(10):1548–1556.
    1. Sung H., Ferlay J., Siegel R.L., et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209–249.
    1. Moureau-Zabotto L., Vendrely V., Abramowitz L., et al. Anal cancer: French Intergroup Clinical Practice Guidelines for diagnosis, treatment and follow-up (SNFGE, FFCD, GERCOR, UNICANCER, SFCD, SFED, SFRO, SNFCP) Dig Liver Dis. 2017;49(8):831–840.
    1. Nelson R.A., Levine A.M., Bernstein L., Smith D.D., Lai L.L. Changing patterns of anal canal carcinoma in the United States. J Clin Oncol. 2013;31(12):1569–1575.
    1. Arbyn M., de Sanjosé S., Saraiya M., et al. EUROGIN 2011 roadmap on prevention and treatment of HPV-related disease. Int J Cancer. 2012;131(9):1969–1982.
    1. Bansal A., Singh M.P., Rai B. Human papillomavirus-associated cancers: a growing global problem. Int J Appl Basic Med Res. 2016;6(2):84–89.
    1. Eng C. Anal cancer: current and future methodology. Cancer Invest. 2006;24(5):535–544.
    1. Gunderson L.L., Winter K.A., Ajani J.A., et al. Long-term update of US GI intergroup RTOG 98-11 phase III trial for anal carcinoma: survival, relapse, and colostomy failure with concurrent chemoradiation involving fluorouracil/mitomycin versus fluorouracil/cisplatin. J Clin Oncol. 2012;30(35):4344–4351.
    1. James R.D., Glynne-Jones R., Meadows H.M., et al. Mitomycin or cisplatin chemoradiation with or without maintenance chemotherapy for treatment of squamous-cell carcinoma of the anus (ACT II): a randomised, phase 3, open-label, 2 × 2 factorial trial. Lancet Oncol. 2013;14(6):516–524.
    1. NCCN Clinical Practice Guidelines in Oncology: Anal Carcinoma. Version 2.2020. 2020. Available at.
    1. Sclafani F., Rao S. Systemic therapies for advanced squamous cell anal cancer. Curr Oncol Rep. 2018;20(7):53.
    1. Rao S., Guren M.G., Khan K., et al. Anal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2021;32(9):1087–1100.
    1. Rao S., Sclafani F., Eng C., et al. International rare cancers initiative multicenter randomized phase II trial of cisplatin and fluorouracil versus carboplatin and paclitaxel in advanced anal cancer: InterAAct. J Clin Oncol. 2020;38(22):2510–2518.
    1. Kim S., Francois E., Andre T., et al. Docetaxel, cisplatin, and fluorouracil chemotherapy for metastatic or unresectable locally recurrent anal squamous cell carcinoma (Epitopes-HPV02): a multicentre, single-arm, phase 2 study. Lancet Oncol. 2018;19(8):1094–1106.
    1. Kim S., Meurisse A., Spehner L., et al. Pooled analysis of 115 patients from updated data of Epitopes-HPV01 and Epitopes-HPV02 studies in first-line advanced anal squamous cell carcinoma. Ther Adv Med Oncol. 2020;12
    1. Saint A., Evesque L., Falk A.T., et al. Mitomycin and 5-fluorouracil for second-line treatment of metastatic squamous cell carcinomas of the anal canal. Cancer Med. 2019;8(16):6853–6859.
    1. NCCN Clinical Practice Guidelines in Oncology: Cancer in People with HIV. Version 1.2021. 2021. Available at.
    1. Daling J.R., Madeleine M.M., Johnson L.G., et al. Human papillomavirus, smoking, and sexual practices in the etiology of anal cancer. Cancer. 2004;101(2):270–280.
    1. Frisch M., Glimelius B., van den Brule A.J., et al. Sexually transmitted infection as a cause of anal cancer. N Engl J Med. 1997;337(19):1350–1358.
    1. Jiménez W., Paszat L., Kupets R., Wilton A., Tinmouth J. Presumed previous human papillomavirus (HPV) related gynecological cancer in women diagnosed with anal cancer in the province of Ontario. Gynecol Oncol. 2009;114(3):395–398.
    1. Sunesen K.G., Nørgaard M., Thorlacius-Ussing O., Laurberg S. Immunosuppressive disorders and risk of anal squamous cell carcinoma: a nationwide cohort study in Denmark, 1978-2005. Int J Cancer. 2010;127(3):675–684.
    1. Tulay P., Serakinci N. The role of human papillomaviruses in cancer progression. J Cancer Metastasis Treat. 2016;2:201–213.
    1. Westrich J.A., Warren C.J., Pyeon D. Evasion of host immune defenses by human papillomavirus. Virus Res. 2017;231:21–33.
    1. Wang Y., Wang H., Yao H., Li C., Fang J.-Y., Xu J. Regulation of PD-L1: emerging routes for targeting tumor immune evasion. Front Pharmacol. 2018;9:536.
    1. Ferris R.L., Blumenschein G., Jr., Fayette J., et al. Nivolumab for recurrent squamous-cell carcinoma of the head and neck. N Engl J Med. 2016;375(19):1856–1867.
    1. Cohen E.E.W., Soulières D., Le Tourneau C., et al. Pembrolizumab versus methotrexate, docetaxel, or cetuximab for recurrent or metastatic head-and-neck squamous cell carcinoma (KEYNOTE-040): a randomised, open-label, phase 3 study. Lancet. 2019;393(10167):156–167.
    1. Colombo N., Dubot C., Lorusso D., et al. Pembrolizumab for persistent, recurrent, or metastatic cervical cancer. N Engl J Med. 2021;385:1856–1867.
    1. Tewari K.S., Monk B.J., Vergote I., et al. EMPOWER-Cervical 1/GOG-3016/ENGOT-cx9: interim analysis of phase III trial of cemiplimab vs. investigator’s choice (IC) chemotherapy (chemo) in recurrent/metastatic (R/M) cervical carcinoma. Ann Oncol. 2021;32(7):P940–P941. Abs VP944-2021.
    1. Morris V.K., Salem M.E., Nimeiri H., et al. Nivolumab for previously treated unresectable metastatic anal cancer (NCI9673): a multicentre, single-arm, phase 2 study. Lancet Oncol. 2017;18(4):446–453.
    1. Ott P.A., Piha-Paul S.A., Munster P., et al. Safety and antitumor activity of the anti-PD-1 antibody pembrolizumab in patients with recurrent carcinoma of the anal canal. Ann Oncol. 2017;28(5):1036–1041.
    1. Marabelle A., Cassier P.A., Fakih M., et al. Pembrolizumab for previously treated advanced anal squamous cell carcinoma: results from the non-randomised, multicohort, multicentre, phase 2 KEYNOTE-158 study. Lancet Gastroenterol Hepatol. 2022;7(5):446–454.
    1. Chen X., Wang P., Kaul S., Sumrow B., Yeleswaram S. Assessment of flat dosing strategy for INCMGA00012 in patients with advanced tumors. Cancer Res. 2019;79(suppl 13) Abs LB-268.
    1. Condamine T., Owens S., Feldman P., et al. Pharmacodynamic correlates in a phase I study of INCMGA00012, a PD-1 antagonistic monoclonal antibody. Cancer Res. 2019;79(13) Abs CT085.
    1. La Motte-Mohs R., Shah S., Brown J.G., et al. Preclinical characterization of MGA012, a novel clinical-stage PD-1 monoclonal antibody. J ImmunoTher Cancer. 2017;5(87) Abs P336.
    1. Mehnert J.M., Joshua A., Lakhani N., et al. First-in-human phase 1 study of INCMGA00012 in patients with advanced solid tumors: interim results of the cohort expansion phase. J Immunother Cancer. 2018;6(suppl 1) Abs P669.
    1. Sodergren S.C., Johnson C.D., Gilbert A., et al. Phase I-III development of the EORTC QLQ-ANL27, a health-related quality of life questionnaire for anal cancer. Radiother Oncol. 2018;126(2):222–228.
    1. Brahmer J.R., Lacchetti C., Schneider B.J., et al. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol. 2018;36(17):1714–1768.
    1. Tumeh P.C., Hellmann M.D., Hamid O., et al. Liver metastasis and treatment outcome with anti-PD-1 monoclonal antibody in patients with melanoma and NSCLC. Cancer Immunol Res. 2017;5(5):417–424.
    1. Mehnert J.M., Paz Ares L., Pikiel J., et al. A phase 1 study of INCMGA00012, a PD-1 inhibitor, in patients with advanced solid tumors: preliminary results for patients with advanced cervical cancer (POD1UM-101) J Immunother Cancer. 2019;7(suppl 1) Abs P394.
    1. Bauml J., Seiwert T.Y., Pfister D.G., et al. Pembrolizumab for platinum- and cetuximab-refractory head and neck cancer: results from a single-arm, phase II study. J Clin Oncol. 2017;35(14):1542–1549.
    1. Chung H.C., Ros W., Delord J.P., et al. Efficacy and safety of pembrolizumab in previously treated advanced cervical cancer: results from the phase II KEYNOTE-158 study. J Clin Oncol. 2019;37(17):1470–1478.
    1. Ferris R.L., Haddad R., Even C., et al. Durvalumab with or without tremelimumab in patients with recurrent or metastatic head and neck squamous cell carcinoma: EAGLE, a randomized, open-label phase III study. Ann Oncol. 2020;31(7):942–950.
    1. Rischin D., Gil-Martin M., González-Martin A., et al. PD-1 blockade in recurrent or metastatic cervical cancer: data from cemiplimab phase I expansion cohorts and characterization of PD-L1 expression in cervical cancer. Gynecol Oncol. 2020;159(2):322–328.
    1. Andersen A.S., Koldjaer Sølling A.S., Ovesen T., Rusan M. The interplay between HPV and host immunity in head and neck squamous cell carcinoma. Int J Cancer. 2014;134(12):2755–2763.
    1. de Vos van Steenwijk P.J., Heusinkveld M., Ramwadhdoebe T.H., et al. An unexpectedly large polyclonal repertoire of HPV-specific T cells is poised for action in patients with cervical cancer. Cancer Res. 2010;70(7):2707–2717.
    1. TECENTRIQ (atezolizumab) [package insert] Genentech Inc; San Francisco, CA: October 2021. Available at.
    1. KEYTRUDA (pembrolizumab) [package insert] Merck & Co., Inc; Whitehouse Station, NJ: January 2020. Available at.
    1. OPDIVO (nivolumab) [package insert] Bristol-Myers Squibb Company; Princeton, NJ: March 2022. Available at.
    1. Marabelle A., Cassier P.A., Fakih M., et al. Pembrolizumab for advanced anal squamous cell carcinoma (ASCC): results from the multicohort, phase II KEYNOTE-158 study. J Clin Oncol. 2020;38(suppl 4) Abs 1.
    1. Lonardi S., Pietrantonio F., Prete A.A., et al. Final results of the CARACAS study: randomized phase II trial of avelumab alone or with cetuximab for unresectable, locally advanced or metastatic squamous cell anal carcinoma progressed to at least one line of treatment. Ann Oncol. 2020;31(suppl 4):S412. Abs 402MO.
    1. Marabelle A., Cassier P.A., Fakih M., et al. Pembrolizumab for previously treated advanced anal squamous cell carcinoma: pooled results from the KEYNOTE-028 and KEYNOTE-158 studies. J Clin Oncol. 2020;38(suppl 15):Abs 4020.
    1. Haanen J., Carbonnel F., Robert C., et al. Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2017;28(suppl 4):iv119–iv142.
    1. Mattos B.R.S., Camandaroba M.P.G., Ruiz-Garcia E., et al. Outcomes of patients with metastatic anal cancer according to HIV infection: a multicenter study by the Latin American Gastrointestinal Oncology Group (SLAGO) Clin Colorectal Cancer. 2021;20(4):299–304.
    1. Uldrick T.S., Ison G., Rudek M.A., et al. Modernizing clinical trial eligibility criteria: recommendations of the American Society of Clinical Oncology–Friends of Cancer Research HIV Working Group. J Clin Oncol. 2017;35(33):3774–3780.
    1. Marabelle A., Fakih M., Lopez J., et al. Association of tumour mutational burden with outcomes in patients with advanced solid tumours treated with pembrolizumab: prospective biomarker analysis of the multicohort, open-label, phase 2 KEYNOTE-158 study. Lancet Oncol. 2020;21(10):1353–1365.
    1. Cristescu R., Mogg R., Ayers M., et al. Pan-tumor genomic biomarkers for PD-1 checkpoint blockade-based immunotherapy. Science. 2018;362(6411):eaar3593.

Source: PubMed

Sponsors et collaborateurs

Les conditions médicales

Interventions en matière de drogue

3
S'abonner