Late-breaking results from the KEYNOTE-048 study (NCT02358031) reported at the annual congress of the European Society for Medical Oncology – ESMO 2018, in Munich, Germany, show that immunotherapy with pembrolizumab (Keytruda?; Merck Sharp & Dohme, a subsidiary of Merck & Co), a humanized IgG4 isotype antibody targeting the programmed cell death 1 receptor (also known as PD-1 and CD279) and blocks a protective mechanism of cancer cells, improves survival in patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC). [1]

These interim results were presented today during the ESMO 2018 Presidential Symposium.

Head and neck
Head and neck cancer describes a number of different tumors that develop in or around the throat, larynx, nose, sinuses and mouth. Most head and neck cancers are squamous cell carcinomas that begin in the flat, squamous cells that make up the thin surface layer of the structures in the head and neck. The leading modifiable risk factors for head and neck cancer include tobacco and heavy alcohol use. Other risk factors include infection with certain types of human papillomaviruses (HPV).

Worldwide, an estimated 835,000 new head and neck cancer cases will be diagnosed in 2018, and an estimated 431,000 people will die from the disease this year. In the United States, there were an estimated 63,000 new cases diagnosed in 2017.

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 epidermal growth factor receptor (EGFR-) inhibitor cetuximab (Erbitux; Lilly & Co; in Europe Merck Group/Merck KGaA). Around 35% of patients respond to treatment, which leads to a median survival of just over ten months.

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KEYNOTE-048 study
The phase III KEYNOTE-048 study (NCT023580310) 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.

Trial results
The 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 tumor 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).

Photo 1.0: Barbara Burtness, MD is Professor of Medicine (Medical Oncology) at the Yale University School of Medicine and Yale Cancer Center. She serves as Co-Leader of the Developmental Therapeutics Program and the Disease Aligned Research Team Leader for Head and Neck Cancer. Burtness is internationally recognized for her research in head and neck cancer. She chairs the Eastern Cooperative Oncology Group Head and Neck Cancer Committee, and leads national and international trials of targeted therapy in head and neck cancer. She comes to Yale from Fox Chase Cancer Center, where she co-led the Developmental Therapeutics Program, was Chief of Head and Neck Oncology and served as Associate Director for Clinical Research.

?Patients with PD-L1 expression live longer when they have initial treatment with pembrolizumab,? said first author Barbara Burtness, MD, 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).

Adverse events
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.

?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,? Burtness said.

Superior overall survival
?[Pembrolizumab] is the first anti-PD-1 therapy to show superior overall survival as first-line treatment compared to the EXTREME regimen*, the current standard of care in patients with recurrent or metastatic head and neck cancer,? said Roy Baynes, MD, PhD, senior vice president and head of Global Clinical Development, chief medical officer, Merck Research Laboratories.

?Recurrent or metastatic head and neck cancer is a very challenging disease… [This] study, helps to advance our understanding of the potential for [Pembrolizumab] and PD-1 inhibition in the first-line setting.?

Biomarker dependent
?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,? said Tanguy Seiwert, MD, Head and Neck Cancer Programme Director, and Assistant Professor of Medicine at the University of Chicago Medicine, Chicago, Illinois.

?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 favorable 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 tumors with low or absent PD-L1 expression, where there is potentially less benefit,? he added.

?The usefulness of other biomarkers to select patients for treatment, such as tumour mutational burden, should also be examined,? Seiwert said, commenting on the need for further research.

Clinical trials
A Study of Pembrolizumab (MK-3475) for First Line Treatment of Recurrent or Metastatic Squamous Cell Cancer of the Head and Neck (MK-3475-048/KEYNOTE-048) – NCT02358031

[1] 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

*The EXTREME regimen was an open-label, randomized (1:1), multicenter, controlled clinical trial conducted outside the United States using European Union-approved cetuximab as the clinical trial material. This trial compared cetuximab + platinum-based therapy (cisplatin or carboplatin) with 5-fluorouracil (CT) vs CT alone; choice of cisplatin or carboplatin was at the discretion of the treating physician. The regimen including cetuximab at a loading dose (400 mg/m2 IV) followed by weekly doses (250 mg/m2 IV) in combination with cisplatin (100 mg/m2 IV Q3W) or carboplatin (AUC 5 IV Q3W) plus 5-FU (1000 mg/m2/day IV) continuous from Day 1-4 Q3W (maximum six cycles), followed by additional cetuximab monotherapy maintenance therapy until progression of disease or toxicity (n=300).

Last Editorial Review: October 23, 2018

Featured Image: Attendees during the Presidential Session at the ESMO 2018 Congress Doctor. Courtesy: ? 2010 ? 2018 European Society for Medical Oncology. Used with permission.

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