Munich, Germany, 22 October 2018 - Immunotherapy with pembrolizumab improves survival in patients with head and neck cancer that has recurred or metastasised, according to late-breaking results from the KEYNOTE-048 study reported at the ESMO 2018 Congress in Munich. (1)
The current standard treatment for metastatic or recurrent head and neck cancer is platinum-based chemotherapy (5-fluorouracil (5-FU) with cisplatin or carboplatin) plus the EGFR inhibitor cetuximab. Around 35% of patients respond to treatment, which leads to a median survival of just over ten months.
The phase III KEYNOTE-048 study examined whether the anti-PD-1 monoclonal antibody pembrolizumab could prolong survival and slow cancer growth compared to standard treatment. KEYNOTE-048 enrolled patients with head and neck cancer who had not received prior chemotherapy or biologic therapy for recurrent or metastatic disease. Patients were randomly allocated in a 1:1:1 ratio to: 1) standard treatment with platinum-based chemotherapy (5-FU with cisplatin or carboplatin) and cetuximab (the control group); 2) pembrolizumab alone; or 3) a novel combination of pembrolizumab and platinum-based chemotherapy.
At ESMO 2018 researchers presented results on pembrolizumab alone compared to standard treatment in patients expressing PD-L1, a marker of immune activity, and on the novel combination compared to standard treatment in all patients regardless of PD-L1 expression.
In the first comparison, 301 patients received pembrolizumab and 300 patients had standard treatment, with median follow up of 11.7 and 10.7 months, respectively. The patient demographics and disease characteristics were similar between the treatment arms.
In patients with tumour and/or surrounding cells expressing PD-L1 (combined positive score [CPS] >20), overall survival was significantly longer with pembrolizumab (14.9 months) than standard treatment (10.7 months, hazard ratio [HR] 0.61, p=0.0007). Some 23.3% responded to pembrolizumab and 36.1% responded to standard treatment. Median response duration was longer with pembrolizumab (20.9 months) than standard therapy (4.5 months). There was no difference in progression-free survival between groups (HR 0.99, 95% confidence interval [CI] 0.75-1.29).
"Patients with PD-L1 expression live longer when they have initial treatment with pembrolizumab," said first author Prof Barbara Burtness, Yale School of Medicine and Co-Director, Development Therapeutics Research Program, Yale Cancer Center, New Haven, US.
The results were similar in patients with a lower cut point of PD-L1 expression (CPS >1). Overall survival was significantly longer with pembrolizumab (12.3 months) compared to standard care (10.3 months, HR 0.78, p=0.0086). Some 19.1% on pembrolizumab responded to treatment compared to 34.9% on standard chemotherapy. Median response duration was longer with pembrolizumab (20.9 months) than standard chemotherapy (4.5 months). There was no difference in progression-free survival between groups (HR 1.16, 95% CI 0.75-1.29).
In the second comparison, 281 patients received the novel combination of pembrolizumab and platinum-based chemotherapy and 278 received standard treatment, with median follow-up of 13.0 and 10.7 months, respectively. (2) Patient demographics and disease characteristics were similar between treatment arms. Overall survival was prolonged with the combination (13.0 months) versus standard care (10.7 months, HR 0.77, p=0.0034). Response rates were 35.6% for the pembrolizumab combination and 36.3% for standard treatment. There was no difference in progression-free survival between groups (HR 0.92, 95% CI 0.77-1.10).
Side effects in the three treatment groups were as expected. Pembrolizumab alone was less toxic than standard treatment. Pembrolizumab combined with chemotherapy and standard treatment had similar toxicity.
Burtness noted that compared to standard care, pembrolizumab alone had a lower response rate and numerically shorter progression-free survival, but significantly longer overall survival. She said: "Pembrolizumab appears to prolong life even when the cancer continues to grow, suggesting that it should be a first line therapy in recurrent and metastatic head and neck cancer. Whether pembrolizumab is given alone or with chemotherapy may depend on PD-L1 expression and we are conducting analyses to answer this question."
Commenting on the findings for ESMO, Dr Tanguy Seiwert, Head and Neck Cancer Programme Director, and Assistant Professor of Medicine at the University of Chicago Medicine, Chicago, US, said: "This is the first study to show superior overall survival over the decade-old standard of care, platinum-based chemotherapy and cetuximab, and establishes PD-L1 CPS as a valid marker for head and neck cancer that should be routinely measured in these patients."
But he added: "The challenge is that treatment benefit is not equally distributed but depends on a biomarker. Hence, PD-L1 CPS expression will likely inform our choice between the two new options - pembrolizumab alone, with a favourable side effect profile, and pembrolizumab combined with chemotherapy, which may be used in a larger group of patients. Higher PD-L1 expression is associated with more benefit but the exact cut points have to be determined, and individual patient characteristics will play an important role as well. Separate analyses are needed in patients who have tumours with low or absent PD-L1 expression, where there is potentially less benefit."
Regarding the need for further research, Seiwert said: "The usefulness of other biomarkers to select patients for treatment, such as tumour mutational burden, should also be examined."
Notes to Editors
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This press release contains information provided by the authors of the highlighted abstracts and reflects the content of those abstracts. It does not necessarily reflect the views or opinions of ESMO who cannot be held responsible for the accuracy of the data. Commentators quoted in the press release are required to comply with the ESMO Declaration of Interests policy and the ESMO Code of Conduct.
References and notes
- Abstract LBA8_PR 'First-line pembrolizumab for recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC): interim results from the phase 3 KEYNOTE-048 study' will be presented by Barbara Burtness during the Presidential Symposium 3 on Monday, 22 October, 16:30 to 18:00 CEST in Room 18 - Hall A2. Annals of Oncology, Volume 29 Supplement 8 October 2018
- There are fewer patients in the novel combination part of the trial because there was a brief accrual hold due to safety.
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LBA8_PR - KEYNOTE-048: Phase III study of first-line pembrolizumab (P) for recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC)
B. Burtness1, K.J. Harrington2, R. Greil3, D. Soulieres4, M. Tahara5, G. De Castro Jr.6, A. Psyrri7, N. Baste Rotllan8, P.C. Neupane9, A. Bratland10, T. Fuereder11, B.G.M. Hughes12, R. Mesia13, N. Ngamphaiboon14, T. Rordorf15, W.Z. Wan Ishak16, A. Roy17, J. Cheng18, F. Jin18, D. Rischin19
1Internal Medicine, Yale University School of Medicine, New Haven, CT, USA, 2Targeted Therapy, The Institute of Cancer Research/The Royal Marsden NHS Foundation Trust, National Institute of Health Research Biomedical Research Centre, London, UK, 3III Medical Department, Salzburg Cancer Research Institute, Cancer Cluster Salzburg, Paracelsus Medical University Salzburg, Salzburg, Austria, 4Department of Medicine - Department of Hemato-Oncology, Centre Hospitalier de l'Universite Montreal, Montreal, QC, Canada, 5Head and Neck Medical Oncology, National Cancer Center Hospital East, Kashiwa, Japan, 6Clinical Oncology, ICESP - Instituto do Cancer do Estado de Sao Paulo, Sao Paulo, Brazil, 7Internal Medicine/Medical Oncology, Attikon University Hospital, Athens, Greece, 8Department of Head and Neck Surgical & Medical Oncology, Gustave Roussy Institute, Villejuif, France, 9Medicine/Oncology, University of Kansas Medical Center, Kansas City, KS, USA, 10Oncology, Oslo University Hospital, Oslo, Norway, 11Department of Medicine I, Clinical Division of Oncology & Comprehensive Cancer Center, Medizinische Universitaet Wien, Vienna, Austria, 12Cancer Care Services, Royal Brisbane and Women's Hospital and University of Queensland, Brisbane, Australia, 13Servicio de Oncologia Medica, Catalan Institut of Oncology, Hospitalet de Llobregat, Barcelona, Spain, 14Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand, 15Oncology, University Hospital Zurich, Zurich, Switzerland, 16Clinical Oncology Unit, University Malaya, Kuala Lumpur, Malaysia, 17BARDS, Merck & Co., Inc., Kenilworth, NJ, USA, 18MRL, Merck & Co., Inc., Kenilworth, NJ, USA, 19Medical Oncology, Peter MacCallum Cancer Center, Melbourne, Australia
Background: KEYNOTE-048 was an open-label, randomized phase 3 study of P or P + chemotherapy (C) vs EXTREME (E) as first-line systemic therapy for R/M HNSCC (NCT02358031).
Methods: Patients (pts) with R/M HNSCC not curable by local therapy and with no prior systemic therapy (R/M setting) who provided a tumor sample for PD-L1 testing were randomized to P 200 mg Q3W, P + C (cisplatin 100 mg/m2 or carboplatin AUC 5 Q3W + 5-FU 1000 mg/m2/d for 4 d Q3W), or E (cetuximab 400 mg/m2 loading/250 mg/m2 QW + C) given until PD, unacceptable toxicity, 6 cycles (C), or 24 mo (P). Primary end points for P vs E and P + C vs E were PFS and OS in the PD-L1 combined positive score (CPS) greater than or equal to 20 and greater than or equal to 1 and total populations (pop). Cutoff date for this final PFS/interim OS analysis was Jun 13, 2018 (minimum follow-up, ~17 mo).
Results: 882 pts were randomized: 301 to P, 281 to P + C, 300 to E. P was superior to E for OS in CPS greater than or equal to 20 (N = 255; median 14.9 vs 10.7 mo; HR 0.61 [95% CI 0.45-0.83]; P = 0.0007) and greater than or equal to 1 (N = 512; median 12.3 vs 10.3 mo; HR 0.78 [95% CI 0.64-0.96]; P = 0.0086); OS for P was non-inferior to E in the total pop (N = 601). P did not prolong PFS in CPS greater than or equal to 20 (P = 0.5); per the analysis plan, no further PFS testing was done for P vs E. Confirmed ORR (P vs E) was 23% vs 36% for CPS greater than or equal to 20, 19% vs 35% for CPS greater than or equal to 1, and 17% vs 36% for the total pop; median DOR was 20.9 vs 4.2 mo, 20.9 vs 4.5 mo, and 20.9 vs 4.5 mo. Gr 3-5 drug-related AE rates were 17% (P) vs 69% (E). P + C was non-inferior and superior to E for OS in the total pop (N = 559; median 13.0 vs 10.7 mo; HR 0.77 [95% CI 0.63-0.93]; P = 0.0034); OS for P + C was not significantly superior to E in CPS greater than or equal to 20 and greater than or equal to 1 at this interim analysis. PFS was not prolonged with P + C (P = 0.2). For P + C vs E, confirmed ORR was 36% vs 36%, median DOR was 6.7 vs 4.3 mo, and gr 3-5 drug-related AE rates were 71% vs 69%.
Conclusions: For first-line R/M HNSCC, P significantly improved OS over E in the PD-L1 CPS greater than or equal to 20 and greater than or equal to 1 populations and was noninferior in the total population with favorable safety. P + C significantly improved OS in the total population with safety comparable to E. P and P + C responses were durable. These data support pembrolizumab and pembrolizumab + platinum + 5-FU as new first-line standards of care for R/M HNSCC. The study continues to the final OS analysis.
Clinical trial identification: NCT0235803; Trial initiation, February 6, 2015
Editorial Acknowledgement: Medical writing and editorial assistance was provided by Melanie Leiby, an employee of Merck & Co., Inc., Kenilworth, NJ, USA
Legal entity responsible for the study: Merck & Co., Inc
Funding: Merck & Co., Inc.
Disclosure: B. Burtness: Advisory board member: Merck, Astra-Zeneca, Bristol-Myers Squibb, Aduro, Amgen, Genentech; Research funding: Merck, Advaxis, Bristol-Myers Squibb; Honoraria: IDDI; Travel expenses, including accommodations: Boehringer Ingelheim.
K.J. Harrington: Advisory board member, honoraria, travel expenses: MSD, Merck-Serono, Bristol-Myers Squibb, AstraZeneca, Pfizer; Speakers' bureau: MSD, Merck-Serono, Bristol-Myers Squibb, AstraZeneca; Research funding: MSD, AstraZeneca.
R. Greil: Advisory board member: Celgene, Novartis, Roche, Bristol-Myers Squibb, Takeda, Abbvie, AstraZeneca; Honoraria: Celgene, Roche, Merck, Takeda, AstraZeneca, Novartis, Amgen, Bristol-Myers Squibb, MSD, Sandoz.
D. Souliere: Advisory board member: Merck, Bristol-Myers Squibb, Pfizer, AstraZeneca; Research funding: Merck, Bristol-Myers Squibb, Pfizer, Novartis.
M. Tahara: Advisory board member: Ono Pharmaceutical, Bristol-Myers Squibb, MSD, Bayer, AstraZeneca, Pfizer, Aspyrian; Honoraria: Ono Pharmaceutical, Bristol-Myers Squibb, MSD, Bayer, AstraZeneca, Eisai.
G. De Castro Jr.: Advisory board member: MSD, Bristol-Myers Squibb; Speakers' bureau, honoraria, travel expenses: MSD, Bristol-Myers Squibb, Merck-Serono.
N. Baste Rotllan: Advisory board member: Bristol-Myers Squibb, Merck Serono, Nanobiotix
T. Fuereder: Advisory board member and research funding: MSD, Merck KGgA; Honoraria: MSD, Merck KGgA, Roche, Pfizer, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb.
B.G.M. Hughes: Advisory board member: MSD, Bristol-Myers Squbb, Roche, AstraZeneca, Pfizer, Boehringer Ingelheim, Eisai; Research funding: Amgen; Travel expenses: Boehringer Ingelheim.
R. Mesia: Advisory board member: MSD, Bristol-Myers Squibb, Merck KGaA, AstraZeneca, Roche; Speakers bureau: Bristol-Myers Squibb, Merck KGaA; Travel expenses: Merck KGaA, Bristol-Myers Squibb.
N. Ngamphaiboon: Advisory board: Roche, MSD, Amgen, Novartis, Taiho; Speakers' bureau: AstraZeneca, Roche, MSD, Eli Lilly; Research funding: Pfizer, MSD, Roche; Honoraria: Roche, MSD, Amgen, Novartis, Taiho; Travel expenses: Merck, Roche, Eisai, Taiho, Amgen.
T. Rordorf: Honoraria for advisory boards: MSD, Bristol-Myers Squibb, Amgen.
W.Z. Wan Ishak: Advisory board member: MSD, Roche, Eli Lilly; Speakers' bureau: Roche, Pfizer, Eli Lilly, Eisai; Research funding: Roche, MSD, Amgen; Honoraria: Eli Lilly, AstraZeneca, Eisai, Pfizer; Travel: Eisai, Pfizer, Eli Lilly, AstraZeneca, MSD.
A. Roy, J. Cheng, F. Jin: Employee and stock owner: Merck & Co., Inc.
D. Rischin: Advisory board member (all uncompensated): Merck, Bristol-Myers Squibb, Amgen; Research funding: Merck, Bristol-Myers Squibb, Regeneron, Amgen, Genentech-Roche, GlaxoSmithKline; Travel expenses: Merck.
All other authors have declared no conflicts of interest.