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Clinical Trial
. 2021 Jun;22(6):883-892.
doi: 10.1016/S1470-2045(21)00136-4. Epub 2021 May 11.

Pembrolizumab plus cetuximab in patients with recurrent or metastatic head and neck squamous cell carcinoma: an open-label, multi-arm, non-randomised, multicentre, phase 2 trial

Assuntina G Sacco  1 , Ruifeng Chen  2 , Francis P Worden  3 , Deborah J L Wong  4 , Douglas Adkins  5 , Paul Swiecicki  3 , Wanxing Chai-Ho  4 , Peter Oppelt  5 , Debanjali Ghosh  6 , Julie Bykowski  7 , Alfredo Molinolo  6 , Emily Pittman  6 , M Valeria Estrada  6 , Kathryn Gold  6 , Gregory Daniels  6 , Scott M Lippman  6 , Amanda Natsuhara  6 , Karen Messer  2 , Ezra E W Cohen  6
Affiliations
Clinical Trial

Pembrolizumab plus cetuximab in patients with recurrent or metastatic head and neck squamous cell carcinoma: an open-label, multi-arm, non-randomised, multicentre, phase 2 trial

Assuntina G Sacco et al. Lancet Oncol. 2021 Jun.

Abstract

Background: Pembrolizumab (PD-1 inhibitor) and cetuximab (EGFR inhibitor) are active as single agents and in combination with cytotoxic chemotherapy for recurrent or metastatic head and neck squamous cell carcinoma (HNSCC). Given each drug's single agent activity and unique mechanism of action, we aimed to evaluate the anti-tumour activity of PD-1 blockade with EGFR inhibition in recurrent or metastatic HNSCC.

Methods: This study is an open-label, non-randomised, multi-arm, phase 2 trial done at four academic centres in the USA. Participants were required to have platinum-resistant or platinum-ineligible, recurrent or metastatic HNSCC, be at least 18 years old, have an Eastern Cooperative Oncology Group performance status 0-1, have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, and to have received no previous immunotherapy or EGFR inhibition. All participants received pembrolizumab 200 mg intravenously every 3 weeks, combined with an initial loading dose of cetuximab 400 mg/m2 intravenously followed by 250 mg/m2 intravenously weekly (21 day cycle). The primary endpoint was overall response rate defined as the proportion of participants with a partial or complete responses (per RECIST version 1.1) by 6 months in the intention-to-treat population. The safety population included all participants who received at least one dose of pembrolizumab. Herein, the final analysis of cohort 1 (no previous PD-1, PD-L1, or EGFR inhibition for recurrent or metastatic HNSCC) is reported. Three additional cohorts (two for participants with a previous response to immunotherapy followed by relapse or progression, with or without previous cetuximab exposure, and one for cutaneous HNSCC) will be reported separately once fully accrued. This study is registered with ClinicalTrials.gov, NCT03082534, and remains open as the three additional cohorts are actively accruing participants.

Findings: Between March 22, 2017, and July 16, 2019, 33 participants were enrolled to cohort 1. All 33 participants received at least one dose of pembrolizumab. Median follow-up duration was 7·3 months (IQR 3·9-10·9). By 6 months, the overall response rate was 45% (95% CI 28-62), with 15 of 33 participants achieving a partial response. The most common grade 3-4 treatment-related adverse event was oral mucositis (three [9%] of 33 participants), and serious treatment-related adverse events occurred in five (15%) participants. No treatment-related deaths occurred.

Interpretation: Pembrolizumab combined with cetuximab shows promising clinical activity for recurrent or metastatic HNSCC, and merits further investigation.

Funding: Merck Sharp & Dohme.

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Conflict of interest statement

Declaration of interests AGS reports institutional research funding from Merck for the study presented in the article. FPW reports honoraria outside of the submitted work from Merck and Eli Lilly for advisory boards, and support for attending meetings or travel, or both, from Merck outside the submitted work. DJLW reports institutional research funding from Merck, Sharp & Dohme and Eli Lilly, outside the submitted work. DA reports institutional research funding from Merck for the study presented in the Article; institutional grants or contracts outside the submitted work from Aduro, Celgene (Bristol Myers Squibb), Novartis, AstraZeneca, Atara Biio, Blueprint Medicine, Celldex, Kura, Exelixis, Innate, Sensei, Matrix Biomed, Hookipa, CoFactor, Cue Biopharma, Medimmune, Shanghai Denovo, Eli Lilly, and Pfizer; and participation on a data safety monitoring board or advisory board outside the submitted work for Merck, Cue Biopharma, Pfizer, Celgene (Bristol Myers Squibb), and Eli Lilly. PS reports grants or contracts outside the submitted work from Pfizer and Ascentage Pharma, applications for provisional patents for companion diagnostics outside the submitted work, and participation on a data safety monitoring board or advisory board outside the submitted work for Prelude Therapeutics and Regeneron. PO reports honoraria for speaker bureaus in which he provided lectures from Merck and Bristol Myers Squibb for speaker bureaus outside the submitted work. KG reports institutional research funding from Pfizer and Pharmacyclics outside the submitted work, and personal consulting fees (advisory boards) from AstraZeneca, Takeda, Rakuten, and Regeneron outside the submitted work. EEWC reports personal consulting fees from Merck and Merck Sharp & Dohme outside the submitted work. All other authors declare no competing interests.

Figures

Figure 1:
Figure 1:. Trial profile for cohort 1
HPV=human papillomavirus. *Each participant could have multiple reasons for discontinuing treatment.
Figure 2:
Figure 2:. Waterfall plot of best response and spider plot of overall response
(A) Waterfall plot of best overall response and (B) spider plot of overall response based on target lesions only. For both plots, 25 (76%) of 33 participants are included. Seven participants only had baseline imaging available for Response Evaluation Criteria in Solid Tumors, and were therefore classified as having progressive disease in the primary analysis. One additional participant did not have any measurable target lesions at baseline but did have non-target lesions, which were measured on serial imaging. Dashed lines at 20% increase: a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. Dashed lines at 30% decrease: a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. HPV=human papillomavirus.
Figure 3:
Figure 3:. Swimmer plot of participant outcomes over time
Swimmer plot denoting outcomes (overall response based on target and non-target lesions per Response Evaluation Criteria in Solid Tumors version 1.1) and observation time (n=33). HPV=human papillomavirus.
Figure 4:
Figure 4:. Progression-free survival and overall survival
(A) Progression-free survival. (B) Overall survival. Tick marks represent censored participants and grey shading represents 95% confidence bands.
See this image and copyright information in PMC

References

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