Optimizing the Use of Checkpoint Inhibitors in Recurrent or Metastatic Head and Neck Cancer

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The management of recurrent and/or metastatic head and neck cancer is complex. Historically, patients with squamous cell carcinoma of the head and neck with local or regional recurrence were considered for salvage surgery or reirradiation (in high-volume centers or centers of expertise), with an eye toward a cure, according to Robert I. Haddad, MD, Division Chief of Head and Neck Oncology at Dana-Farber Cancer Institute. For many patients, surgery or reirradiation is not an option, and immunotherapy is currently the standard of care for these patients.

Robert I. Haddad, MD

Robert I. Haddad, MD

“Unfortunately, most patients are not candidates for curative intent therapy and are treated with palliative intent with immunotherapy, chemotherapy, cetuximab, or enrollment on clinical trials,” he said at the 2021 Winship Cancer Institute of Emory University Symposium: Updates in the Management of Head and Neck Cancer.1

The ‘Old’ Standard of Care vs Immunotherapy

In the first-line treatment of patients with recurrent or metastatic head and neck cancer, the EXTREME regimen (fluorouracil/platinum/cetuximab) was the standard of care for over a decade. In the EXTREME trial, the addition of cetuximab to chemotherapy improved survival from 7.4 months to 10.1 months,2 and this remained the standard of care until the publication of the KEYNOTE-048 trial. Now, checkpoint blockade has become the new standard of care for combined positive score (CPS)-positive recurrent metastatic squamous cell carcinoma.

The KEYNOTE-048 study demonstrated the superiority of pembrolizumab in the first-line metastatic setting.3 In the trial, patients were randomly assigned to one of three arms: pembrolizumab as a single agent, pembrolizumab/chemotherapy followed by pembrolizumab maintenance, or the EXTREME regimen. Approximately 40% of patients on the trial had a CPS ≥ 20, and the majority (85%) had a CPS ≥ 1.

In patients with a CPS ≥ 20, pembrolizumab plus chemotherapy led to a significant median overall survival benefit compared with the EXTREME regimen: 14.7 months vs 11.0 months. In patients with a CPS ≥ 1, pembrolizumab plus chemotherapy led to a median overall survival of 13.6 months, compared with 10.4 months with the EXTREME regimen. In the total patient population, median overall survival was 13 months with pembrolizumab/chemotherapy vs 10.7 months with EXTREME.

According to Dr. Haddad, these findings naturally led to one question in clinical practice: In the first-line setting, can head and neck oncologists forgo chemotherapy and rely instead on a checkpoint inhibitor as a single agent?

A ‘Game-Changer’ in Advanced Disease

In the KEYNOTE-048 trial, single-agent pembrolizumab led to a statistically significant improvement in overall survival compared with the EXTREME regimen. In patients with a CPS ≥ 20, overall survival was 14.8 months vs 10.7 months; in patients with a CPS ≥ 1, overall survival was 12.3 vs 10.3 months.

“With one agent compared with three agents, we saw no need for chemotherapy, with a significant improvement in overall survival,” Dr. Haddad said. “This was a game-changer in the field of recurrent or metastatic head and neck cancer, establishing what is currently considered the standard of care for these patients.”

The data now support both pembrolizumab plus platinum-based chemotherapy and pembrolizumab monotherapy as new first-line standard-of-care therapies for recurrent or metastatic squamous cell carcinoma of the head and neck. However, for patients with a CPS of 0, the EXTREME regimen is preferred, commented Dr. Haddad, reserving checkpoint inhibitors (either nivolumab or pembrolizumab) for the second line.

“And for patients with a CPS ≥ 1, I often use single-agent pembrolizumab, reserving pembrolizumab plus chemotherapy for those who are in need of an immediate response and tumor debulking,” Dr. Haddad shared.

Immunotherapy Combination Active,
but Data Skewed

Presented at the European Society for Medical Oncology Congress this year by Dr. Haddad and colleagues, the international phase III CheckMate 651 trial compared nivolumab and ipilimumab with the EXTREME regimen in the first-line treatment of recurrent or metastatic squamous cell carcinoma of the head and neck.4 As in the KEYNOTE-048 study, about 40% of patients in this trial had a CPS ≥ 20, and around 75% had a CPS ≥ 1.

In patients with a PD-L1 CPS ≥ 20 or a CPS ≥ 1, nivolumab/ipilimumab showed evidence of significant clinical benefit vs EXTREME, as seen in prolonged overall survival and duration of response. Median overall survival was 17.6 months vs 14.6 months (CPS ≥ 20) and 15.7 vs 13.2 months (CPS ≥ 1), respectively. Although it did not reach statistical significance, “the overall survival of 17.6 months with nivolumab/ipilimumab is the best we’ve seen in a randomized phase III trial for that group of patients,” he noted. “A large percentage—almost half of the patients enrolled on the ‘EXTREME’ arm—received a checkpoint inhibitor in second-line treatment,and this has profoundly impacted the overall survival in the trial,” Dr Haddad pronounced.


  • Checkpoint blockade is the new standard of care for patients with CPS-positive recurrent or metastatic head and neck cancer.
  • Nivolumab plus ipilimumab shows activity in this patient population, although significant crossover to checkpoint inhibitors in the CheckMate 651 trial kept the experimental arm from reaching statistical significance.
  • Use of the combination of a checkpoint inhibitor and cetuximab needs further study.

With nivolumab/ipilimumab, more than half of responders were still in response at 18months in both patient populations. The checkpoint inhibitor combination also tended to delay symptom deterioration; it also clinically improved overall health status vs the EXTREME regimen in the population with a CPS ≥ 20. The safety profile was also favorable compared with EXTREME.

Novel Uses of Checkpoint Inhibitors
in the Advanced Setting

In patients with recurrent disease who have had definitive therapy but still have a surgical option, the combination of nivolumab and the investigational anti-KIR monoclonal antibody lirilumab showed promise, according to Dr. Haddad. “Think of your patients with laryngeal cancer who have been treated with radiation and chemotherapy, who now have recurrent disease and will have a laryngectomy,” he explained.

In a phase II study, patients with recurrent head and neck cancer who were deemed to have a surgical option were given one cycle of nivolumab/lirilumab followed by surgery, then 6 months of the same regimen.5 Reirradiation was not allowed.

The 1-year disease-free survival in these patients was 55%. “We feel this is a promising regimen worthy of further study,” he said. “One of the important endpoints we looked for was whether surgery would be delayed, but there was no delay in salvage surgery; within 2 weeks of the first dose of immunotherapy, we were able to get patients to surgery.”

Another recently published trial noted by Dr. Haddad examined pembrolizumab plus cetuximab in first-line treatment of recurrent or metastatic head and neck cancer.6 The overall response rate was 45%, and nearly half of the patients enrolled on the trial had a low PD-L1 CPS < 1.

“This is much higher than the response rate you will see with single-agent pembrolizumab in this setting,” he added. “Frankly, this was a surprising result to me and to many of us in the field. These data are very promising and worthy of further study.” 

DISCLOSURE: Dr. Haddad has received research funding from BMS, Merck, -Pfizer, Genentech, and Kura; and has served as a consultant to Merck, BMS, Eisai, Pfizer, AstraZeneca, Genentech, Loxo, Glenmark, Immunomic Therapeutics, and GSK.


1. Haddad RI: Optimizing the use of check point inhibitors in recurrent metastatic SCCHN. 2021 Updates in the Management of Head & Neck Cancer. Presented November 6, 2021.

2. Vermorken JB, Mesia R, Rivera F, et al: Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med. 359:1116-1127, 2008.

3. Burtness B, Harrington KJ, Greil R, et al: Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): A randomised, open-label, phase 3 study. Lancet 394:1915-1928, 2019.

4. Argiris A, Harrington K, Tahara M, et al: Nivolumab + ipilimumab vs -EXTREME regimen as first-line treatment for recurrent/metastatic squamous cell carcinoma of the head and neck: Final results of CheckMate 651. ESMO Congress 2021. Abstract LBA36. Presented September 20, 2021.

5. Hanna GJ, ONeill A, Shin KY, et al: Neoadjuvant and adjuvant nivolumab and lirilumab in patients with recurrent, resectable squamous cell carcinoma of the head and neck. Clin Cancer Res. October 19, 2021 (early release online).

6. Sacco AG, Chen R, Worden FP, et al: Pembrolizumab plus cetuximab in patients with recurrent or metastatic head and neck squamous cell carcinoma. Lancet Oncol 6:883-892, 2021.

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