Pembrolizumab for previously treated advanced anal squamous cell carcinoma: results from the non-randomised, multicohort, multicentre, phase 2 KEYNOTE-158 study

Marabelle, Aurélien; Cassier, Philippe; Fakih, Marwan; Kao, Steven; Nielsen, Dorte L.; Italiano, Antoîne; Guren, Tormod Kyrre; Dongen, Marloes G J van; Spencer, Kristen; Bariani, Giovanni M.; Ascierto, Paolo A.; Santoro, Armando; Shah, Manisha H.; Asselah, Jamil; Iqbal, Syma; Takahashi, Shunji; Piha‐Paul, Sarina A.; Ott, Patrick A.; Chatterjee, Arkendu; Jin, Fan; Norwood, Kevin; Delord, Jean‐Pierre

doi:10.1016/s2468-1253(21)00382-4

Cited by 43 publications

(32 citation statements)

References 14 publications

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“…Importantly, responses in the POD1UM-202 study were observed regardless of PD-L1 expression, liver metastases, or HIV status; retifanlimab was well-tolerated with a low incidence (2.1%) of treatment discontinuation because of immune-related adverse events ( 20 ). Retifanlimab response in locally advanced and/or metastatic SCAC results is supported by the results with other single-agent PD-(L)1 inhibitors ( 21 – 24 ), with the reported median PFS and OS of 4.1 and 11.5 months for nivolumab ( 21 ), 2.0 and 13.9 months for avelumab ( 24 ), and up to 3.0 and 11.9 months for pembrolizumab ( 22 , 23 ), respectively.…”

Section: Introductionmentioning

confidence: 65%

“…The current preferred first-line regimen for unresectable locally advanced or metastatic SCAC is carboplatin–paclitaxel, with the reported PFS and OS of 8.1 and 20.0 months, respectively ( 20 ). Although new treatment options have been investigated ( 23 , 24 ), there have been no approved therapies for SCAC in recent years. POD1UM-303 is one of the largest well-controlled, randomized trials of a novel therapeutic in locally inoperable or metastatic SCAC.…”

Section: Discussionmentioning

confidence: 99%

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POD1UM-303/InterAACT 2: A phase III, global, randomized, double-blind study of retifanlimab or placebo plus carboplatin–paclitaxel in patients with locally advanced or metastatic squamous cell anal carcinoma

Jones

Bowman

et al. 2022

Front. Oncol.

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BackgroundSquamous carcinoma of the anal canal (SCAC) is a human papillomavirus (HPV)-driven cancer with poor prognosis in locally advanced or recurrent settings. Carboplatin–paclitaxel is the preferred first-line regimen for unresectable locally advanced or metastatic SCAC, with the reported median progression-free survival (PFS) and overall survival (OS) of 8.1 and 20.0 months, respectively. Immune checkpoint blockade (ICB) demonstrates improved survival in HPV-driven cervical and head and neck cancers. Retifanlimab (INCMGA00012) is an investigational humanized, hinge-stabilized, immunoglobulin G4κ monoclonal antibody targeting programmed cell death-1 (PD-1), with characteristics common to the ICB class. In POD1UM-202, retifanlimab showed substantial clinical activity and an expected safety profile in patients with advanced SCAC who progressed on platinum-based chemotherapy. Based on these encouraging results, POD1UM-303/InterAACT 2 (NCT04472429), a phase III, double-blind, randomized, multiregional study, investigates the addition of retifanlimab to the standard of care (SOC) carboplatin–paclitaxel in patients with inoperable locally recurrent or metastatic SCAC not previously treated with systemic chemotherapy.Methods and analysisPatients ≥18 years with inoperable locally recurrent or metastatic SCAC, measurable disease per RECIST v1.1, and no prior systemic chemotherapy or PD-(L)1-directed therapy will be enrolled and stratified by PD-L1 expression, region, and extent of disease. Patients with well-controlled human immunodeficiency virus infection are eligible. Planned enrollment is approximately 300 patients worldwide, with a 1:1 randomization to retifanlimab or placebo. Patients will receive up to six induction cycles (24 weeks) of carboplatin (area-under-the-curve 5 on day 1) and paclitaxel (80 mg/m2 on days 1, 8, and 15) every 28 days per SOC. Concurrently, retifanlimab 500 mg or placebo will be administered intravenously in a blinded fashion on day 1 of each 28-day cycle for up to 13 cycles (1 year) in the absence of unacceptable toxicity, disease progression, withdrawal of consent, loss to follow-up, or premature discontinuation. Crossover to open-label retifanlimab will be allowed for patients assigned to placebo upon verification of progression by blinded independent central radiographic review (BICR). The primary study endpoint is PFS per RECIST v1.1 by BICR. Secondary endpoints are OS, objective response rate, duration of response, disease control rate, safety, and retifanlimab pharmacokinetics. The study is currently recruiting.Clinical Trial Registrationhttps://clinicaltrials.gov/ct2/show/NCT04472429; https://clinicaltrialsregister.eu/ctr-search/search?query=2020-000826-24

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Section: Introductionmentioning

confidence: 65%

Section: Discussionmentioning

confidence: 99%

POD1UM-303/InterAACT 2: A phase III, global, randomized, double-blind study of retifanlimab or placebo plus carboplatin–paclitaxel in patients with locally advanced or metastatic squamous cell anal carcinoma

Jones

Bowman

et al. 2022

Front. Oncol.

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“…and were also evaluated in SCCA, as well as other anti-PD1 antibodies (nivolumab, retifanlimab) (51), and showed a promising result in a subgroup of patients (52)(53)(54).…”

Section: Discussionmentioning

confidence: 99%

Prognostic role of HPV integration status and molecular profile in advanced anal carcinoma: An ancillary study to the epitopes-HPV02 trial

et al. 2022

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Squamous Cell Carcinoma of the Anal canal (SCCA) is a rare disease associated with a Human Papillomavirus (HPV) infection in most cases, predominantly the HPV16 genotype. About 15% of SCCA are diagnosed in metastatic stage and some will relapse after initial chemoradiotherapy (CRT). Treatment of patients by Docetaxel, Cisplatin and 5-fluorouracil (DCF) has been recently shown to improve their complete remission and progression-free survival. The aim of this retrospective study was to explore the impact of HPV infection, HPV DNA integration, TERT promoter mutational status and somatic mutations of oncogenes on both progression-free (PFS) and overall survivals (OS) of patients treated by DCF. Samples obtained from 49 patients included in the Epitopes-HPV02 clinical trial, diagnosed with metastatic or non-resectable local recurrent SCCA treated by DCF, were used for analyses. Median PFS and OS were not associated with HPV status. Patients with episomal HPV had an improved PFS compared with SCCA patients with integrated HPV genome (p=0.07). TERT promoter mutations were rarely observed and did not specifically distribute in a subset of SCCA and did not impact DCF efficacy. Among the 42 genes investigated, few gene alterations were observed, and were in majority amplifications (68.4%), but none were significantly correlated to PFS. As no biomarker is significantly associated with patients’ survival, it prompts us to include every patient failing CRT or with metastatic disease in DCF strategy.

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“… 25 Immune checkpoint blockade for SCAC is a promising approach based on the biologic and clinical similarities to HPV-driven cancers, such as cervical cancer and some squamous cell cancers of the head and neck, where PD-(L)1 inhibitor therapy has proven to be effective. 26 , 27 , 28 , 29 As such, restoring immune function via treatment with PD-1 inhibitors such as nivolumab 30 and pembrolizumab 31 , 32 has shown promising activity in advanced SCACs.…”

Section: Introductionmentioning

confidence: 99%

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)

Anandappa

Capdevila³

et al. 2022

ESMO Open

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Pembrolizumab for previously treated advanced anal squamous cell carcinoma: results from the non-randomised, multicohort, multicentre, phase 2 KEYNOTE-158 study

Cited by 43 publications

References 14 publications

POD1UM-303/InterAACT 2: A phase III, global, randomized, double-blind study of retifanlimab or placebo plus carboplatin–paclitaxel in patients with locally advanced or metastatic squamous cell anal carcinoma

POD1UM-303/InterAACT 2: A phase III, global, randomized, double-blind study of retifanlimab or placebo plus carboplatin–paclitaxel in patients with locally advanced or metastatic squamous cell anal carcinoma

Prognostic role of HPV integration status and molecular profile in advanced anal carcinoma: An ancillary study to the epitopes-HPV02 trial

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)

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