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Talimogene Laherparepvec and Pembrolizumab in Recurrent Or Published OnlineFirst July 15, 2020; DOI: 10.1158/1078-0432.CCR-20-1170 CLINICAL CANCER RESEARCH | CLINICAL TRIALS: IMMUNOTHERAPY Talimogene Laherparepvec and Pembrolizumab in Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck (MASTERKEY-232): A Multicenter, Phase 1b Study Kevin J. Harrington1, Anthony Kong2,3, Nicolas Mach4, Jason A. Chesney5, Beatriz Castelo Fernandez6, Danny Rischin7, Ezra E.W. Cohen8, Hoi-Shen Radcliffe9, Burak Gumuscu10, Jonathan Cheng10, Wendy Snyder11, and Lillian L. Siu12 ABSTRACT ◥ Purpose: The prognosis for patients with recurrent or metastatic follow-up was 5.8 months (range, 0.3–24.2). One DLT of head and neck squamous cell carcinoma (R/M HNSCC) is poor, and T-VEC–related fatal arterial hemorrhage was reported. Twenty only a minority of patients benefit from checkpoint immunother- (55.6%) and 21 (58.3%) patients experienced adverse events apy. Talimogene laherparepvec (T-VEC), an oncolytic immuno- (AE) related to T-VEC and pembrolizumab, respectively. therapy approved for advanced melanoma, in combination with Besides the DLT, there were no treatment-related fatal AEs. pembrolizumab may yield enhanced antitumor activity over either Aconfirmed partial response was observed in 5 (13.9%) patients. agent alone. Ten (27.8%) patients were unevaluable for response due to early Patients and Methods: This was a phase Ib/III, multicenter trial death. Median PFS and OS were 3.0 months [95% confidence testing intratumoral T-VEC combined with intravenous pembro- interval (Cl), 2.0–5.8] and 5.8 months (95% Cl, 2.9–11.4), lizumab in R/M HNSCC refractory to platinum-based chemother- respectively. apy. For phase Ib, primary endpoint was incidence of dose-limiting Conclusions: The combination of T-VEC and pembrolizumab toxicity (DLT). Key secondary endpoints included objective demonstrated a tolerable safety profile in R/M HNSCC. The efficacy response rate and progression-free survival per irRECIST, overall with the combination was similar to that with pembrolizumab survival, and safety. monotherapy in historical HNSCC studies. Phase III part of this Results: Thirty-six patients were enrolled into the phase Ib study was not further pursued (ClinicalTrials.gov Identifier: study. The data cut-off date was August 28, 2018. Median NCT02626000). Introduction num-based agents, fluorouracil, and cetuximab in various combina- tions, depending on the patient’s performance status, comorbidities, Squamous cell carcinoma of the head and neck (HNSCC) is a prior treatments, and geographical variations in therapies supported common and frequently lethal malignancy, with approximately by different health care systems (2, 3). The median overall survival 800,000 newly diagnosed cases and 400,000 deaths worldwide in (OS) was 7.4 months with chemotherapy and 10.1 months with 2018 (1). For most patients with recurrent or metastatic (R/M) chemotherapy plus cetuximab in the first-line setting. (3) Checkpoint HNSCC, the previous first-line treatment options included plati- inhibitor immunotherapies are now approved as a single agent (first- line or second-line) or in combination with chemotherapy (first-line) – 1The Institute of Cancer Research, Royal Marsden Hospital, London, United in these patients (4 6). Kingdom. 2Institute of Cancer and Genomic Science, University of Birmingham, The programmed death 1 (PD-1) receptor is expressed on activated Birmingham, United Kingdom. 3Comprehensive Cancer Centre, King’s College T cells and interacts with its ligands, PD-L1 and PD-L2, to prevent London, United Kingdom. 4Department of Oncology, University Hospital of healthy cells from autoimmune attacks. Excessive expression of PD-L1 5 Geneva, Geneva, Switzerland. James Graham Brown Cancer Center, University or PD-L2 on tumor or stromal cells can result in immune evasion, 6 of Louisville, Louisville, Kentucky. Medical Oncology Department, University leading to recurrence and metastasis of the tumor (7). Pembrolizumab Hospital La Paz, Madrid, Spain. 7Peter MacCallum Cancer Centre, Melbourne, Australia. 8Moores Cancer Center UC San Diego Health, La Jolla, California. is a humanized, monoclonal PD-1 antibody that has demonstrated fi 9Amgen Limited, Uxbridge, United Kingdom. 10Merck & Co., Inc., Kenilworth, antitumor activity and a tolerable safety pro le in multiple tumor New Jersey. 11Amgen, Inc., Thousand Oaks, California. 12Princess Margaret types. It is currently approved as a single agent or in combination with Cancer Centre, Toronto, Ontario, Canada. platinum and fluorouracil, with certain restrictions based on PD-L1 Note: Supplementary data for this article are available at Clinical Cancer combined positive score (CPS) in some jurisdictions, for the first-line Research Online (http://clincancerres.aacrjournals.org/). treatment of patients with R/M HNSCC, replacing the previous use of fl K.J. Harrington and A. Kong contributed equally to this article. EXTREME regimen (platinum and uorouracil chemotherapy with cetuximab) in this setting; single-agent pembrolizumab is also Corresponding Author: Kevin J. Harrington, The Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, United Kingdom. Phone: 207-153-5030; approved for the treatment of patients with disease progression on Fax: 207-808-2235; E-mail: [email protected] or after platinum-based chemotherapy (5, 8, 9). In the phase III KEYNOTE-048 trial comparing pembrolizumab alone or with plat- Clin Cancer Res 2020;26:5153–61 inum and fluorouracil chemotherapy versus cetuximab with chemo- doi: 10.1158/1078-0432.CCR-20-1170 therapy in patients with previously untreated R/M HNSCC, the Ó2020 American Association for Cancer Research. objective response rate (ORR) with pembrolizumab was 17% in the AACRJournals.org | 5153 Downloaded from clincancerres.aacrjournals.org on October 2, 2021. © 2020 American Association for Cancer Research. Published OnlineFirst July 15, 2020; DOI: 10.1158/1078-0432.CCR-20-1170 Harrington et al. T-VEC in combination with ipilimumab, which blocks cytotoxic Translational Relevance T lymphocyte–associated antigen 4, met its primary endpoint: intra- Recurrent or metastatic squamous cell carcinoma of the head tumoral T-VEC plus systemic ipilimumab resulted in a significantly and neck (R/M HNSCC) represents a disease setting with consid- higher ORR without additional safety signals than ipilimumab alone in erable clinical complexity and a poor prognosis. In this phase Ib patients with advanced melanoma (39% vs. 18%, P ¼ 0.002; ref. 17). study, we tested a novel combination of talimogene laherparepvec, The treatment effect of T-VEC as a monotherapy or in combination a genetically modified herpes simplex virus-1–based oncolytic with checkpoint inhibitors has been observed in both injected and immunotherapy, and pembrolizumab, a humanized mAb against uninjected (including visceral) melanoma lesions, indicating that a PD-1, in R/M HNSCC. We hypothesized that combining these two systemic antitumor immune response was triggered (18, 19). These agents with complementary roles in activating antitumor immune results suggest that T-VEC may improve the efficacy of checkpoint responses might augment the activity of either agent alone. This inhibitor immunotherapies by changing the tumor microenvironment combination demonstrated manageable toxicities and antitumor and support the rationale that combining immunotherapies with efficacy comparable with that with single-agent pembrolizumab in complementary mechanisms of action may yield augmented antitu- historical HNSCC studies. Responses were durable, with most mor responses. responders having responses still ongoing at data cutoff. Even The objective of this study was to evaluate the safety and preliminary though the response to the combination did not appear to be efficacy of the combination of intratumoral injection of T-VEC and superior to previous reports of pembrolizumab monotherapy, this intravenous pembrolizumab in patients with R/M HNSCC. study provides insights into the design of future trials testing combinatorial immunotherapeutic regimens. Patients and Methods Patients Eligible patients had an age of 18 years or older; Eastern Cooperative total population, 23% in the population with PD-L1 CPS of ≥20, and Oncology Group (ECOG) performance status of 0 or 1; histologically 19% in the population with PD-L1 CPS of ≥1. Pembrolizumab alone or confirmed R/M HNSCC of the oral cavity, oropharynx, hypopharynx, with chemotherapy improved OS versus cetuximab with chemother- or larynx that was not suitable for curative surgical resection; disease apy in the CPS of ≥20 and CPS of ≥1 populations. In the total progression after treatment with a platinum-based regimen, defined as population, the median OS associated with pembrolizumab plus one of the following: (i) disease progression or recurrence between 3 chemotherapy was significantly longer than that associated with and 6 months of prior curatively intended multimodal therapy, which cetuximab plus chemotherapy [13.0 months vs. 10.7 months; HR ¼ includes platinum therapy, for locoregionally advanced HNSCC (this 0.77 (95% confidence interval (CI), 0.63–0.93); P ¼ 0Á0034; ref. 6]. In criterion was applicable only to patients who had not received treat- the phase II KEYNOTE-055 and phase III KEYNOTE-040 HNSCC ment in the R/M setting), or (ii) disease progression or recurrence after trials of pembrolizumab that required disease progression during or prior platinum-based therapy in the R/M setting; disease suitable for after platinum-based chemotherapy, the ORR was 16% and 14.6%, intratumoral
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