FDA NewsPerspective

FDA approves Keytruda for first-line treatment of head and neck squamous cell carcinoma

The FDA approved pembrolizumab for the first-line treatment of patients with metastatic or unresectable recurrent head and neck squamous cell carcinoma.

The approval includes two indications: for use in combination with platinum and fluorouracil for all patients, and as a single agent for patients whose tumors express PD-L1 — with a combined positive score of 1 or greater — as determined by an FDA-approved test. The FDA also expanded its approval of PD-L1 IHC 22C3 pharmDx kit (Agilent) to include use as a companion diagnostic to select patients for treatment for this indication.

Pembrolizumab (Keytruda, Merck) is now the first anti-PD-1 therapy approved in the first-line setting as monotherapy for patients whose tumors express PD-L1 or in combination with chemotherapy regardless of PD-L1 expression for patients with metastatic or unresectable, recurrent HNSCC. The agent also is the first anti-PD-1 therapy to demonstrate a statistically significant improvement in OS for this population.

“This approval is a very exciting milestone in the treatment of head and neck cancer and has the potential to transform the way we treat patients with this debilitating disease by offering important new therapeutic options,” Barbara Burtness, MD, professor of medicine at Yale School of Medicine and co-director of the Development Therapeutics Research Program at Yale Cancer Center, as well as a HemOnc Today Editorial Board Member, said in a press release. “Metastatic or recurrent head and neck cancer has been an area of significant unmet need, so it is encouraging to have immunotherapy regimens available for patients in the first-line setting.”

FDA based the approval, in part, on data from the phase 3 KEYNOTE-048 trial, which compared pembrolizumab with the standard EXTREME regimen (cetuximab [Erbitux, Eli Lilly] with carboplatin or cisplatin plus fluorouracil) among 882 patients (median age, 61 years; range, 20-94; men, 83%; white, 73%) with previously untreated metastatic HNSCC or with recurrent disease considered incurable by local therapies.

Researchers stratified patients according to PD-L1 expression, HPV status and ECOG performance status, and then randomly assigned them 1:1:1 to one of three groups:

  • 200 mg IV pembrolizumab every 3 weeks;
  • 200 mg IV pembrolizumab every 3 weeks, 5 mg/mL/min IV carboplatin every 3 weeks or 100 mg/m2 IV cisplatin every 3 weeks and 1,000 mg/m2 daily fluorouracil over 96 hours every 3 weeks; or
  • an initial 400-mg/m2 dose of IV cetuximab followed by 250 mg/m2 IV once weekly, 5 mg/mL/min IV carboplatin every 3 weeks or 100 mg/m2 IV cisplatin every 3 weeks and 1,000 mg/m2 daily fluorouracil over 96 hours every 3 weeks.

OS and PFS served as the main efficacy outcomes.

Results showed pembrolizumab significantly improved OS both as monotherapy in the PD-L1-positive group with a combined positive score of at least 1 (median OS, 12.3 months vs. 10.3 months; HR = 0.78; 95% CI, 0.64-0.96) and in combination with chemotherapy in the total study population (median OS, 13 months vs. 10.7 months; HR = 0.77; 95% CI, 0.63-0.93). When used in combination with chemotherapy, pembrolizumab showed benefit for patients with combined positive score of 20 of higher (HR = 0.69; 95% CI, 0.51-0.94) and 1 or higher (HR = 0.71; 95% CI, 0.57-0.88).

Among patients with a PD-L1 combined positive score of 20 of higher, the median OS was 14.9 months for those assigned pembrolizumab monotherapy compared with 10.7 months for cetuximab plus chemotherapy (HR = 0.61; 95% CI: 0.45-0.83).

The interim analysis did not show a significant difference in OS between the pembrolizumab monotherapy arm and the cetuximab-plus-chemotherapy arm for the overall population.
“Head and neck squamous cell carcinoma has historically presented many challenges to physicians and patients, including limited treatment options and physical and functional issues caused by the disease and its treatment,” Jonathan Cheng, MD, vice president of clinical research at Merck Research Laboratories, said in a press release. “This approval is an important advance in the management of this devastating cancer. The results of KEYNOTE-048, which support this approval, demonstrated that pembrolizumab monotherapy for patients whose tumors expressed PD-L1 CPS greater than or equal to 1 and pembrolizumab in combination with chemotherapy regardless of PD-L1 expression significantly prolonged survival for patients with metastatic or with unresectable, recurrent head and neck squamous cell carcinoma in the first-line setting.”

Common adverse events associated with pembrolizumab monotherapy included fatigue, constipation and rash. Adverse events associated with pembrolizumab in combination with chemotherapy included nausea, fatigue, constipation, vomiting, mucosal inflammation, diarrhea, decreased appetite, stomatitis and cough.

Pembrolizumab initially received accelerated approval in 2016 for patients with recurrent or metastatic HNSCC with disease progression on or after platinum-containing chemotherapy based on the phase 1b KEYNOTE-012 trial. These data from KEYNOTE-048 supported converting the accelerated approval to full approval.

 

The FDA approved pembrolizumab for the first-line treatment of patients with metastatic or unresectable recurrent head and neck squamous cell carcinoma.

The approval includes two indications: for use in combination with platinum and fluorouracil for all patients, and as a single agent for patients whose tumors express PD-L1 — with a combined positive score of 1 or greater — as determined by an FDA-approved test. The FDA also expanded its approval of PD-L1 IHC 22C3 pharmDx kit (Agilent) to include use as a companion diagnostic to select patients for treatment for this indication.

Pembrolizumab (Keytruda, Merck) is now the first anti-PD-1 therapy approved in the first-line setting as monotherapy for patients whose tumors express PD-L1 or in combination with chemotherapy regardless of PD-L1 expression for patients with metastatic or unresectable, recurrent HNSCC. The agent also is the first anti-PD-1 therapy to demonstrate a statistically significant improvement in OS for this population.

“This approval is a very exciting milestone in the treatment of head and neck cancer and has the potential to transform the way we treat patients with this debilitating disease by offering important new therapeutic options,” Barbara Burtness, MD, professor of medicine at Yale School of Medicine and co-director of the Development Therapeutics Research Program at Yale Cancer Center, as well as a HemOnc Today Editorial Board Member, said in a press release. “Metastatic or recurrent head and neck cancer has been an area of significant unmet need, so it is encouraging to have immunotherapy regimens available for patients in the first-line setting.”

FDA based the approval, in part, on data from the phase 3 KEYNOTE-048 trial, which compared pembrolizumab with the standard EXTREME regimen (cetuximab [Erbitux, Eli Lilly] with carboplatin or cisplatin plus fluorouracil) among 882 patients (median age, 61 years; range, 20-94; men, 83%; white, 73%) with previously untreated metastatic HNSCC or with recurrent disease considered incurable by local therapies.

Researchers stratified patients according to PD-L1 expression, HPV status and ECOG performance status, and then randomly assigned them 1:1:1 to one of three groups:

  • 200 mg IV pembrolizumab every 3 weeks;
  • 200 mg IV pembrolizumab every 3 weeks, 5 mg/mL/min IV carboplatin every 3 weeks or 100 mg/m2 IV cisplatin every 3 weeks and 1,000 mg/m2 daily fluorouracil over 96 hours every 3 weeks; or
  • an initial 400-mg/m2 dose of IV cetuximab followed by 250 mg/m2 IV once weekly, 5 mg/mL/min IV carboplatin every 3 weeks or 100 mg/m2 IV cisplatin every 3 weeks and 1,000 mg/m2 daily fluorouracil over 96 hours every 3 weeks.
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OS and PFS served as the main efficacy outcomes.

Results showed pembrolizumab significantly improved OS both as monotherapy in the PD-L1-positive group with a combined positive score of at least 1 (median OS, 12.3 months vs. 10.3 months; HR = 0.78; 95% CI, 0.64-0.96) and in combination with chemotherapy in the total study population (median OS, 13 months vs. 10.7 months; HR = 0.77; 95% CI, 0.63-0.93). When used in combination with chemotherapy, pembrolizumab showed benefit for patients with combined positive score of 20 of higher (HR = 0.69; 95% CI, 0.51-0.94) and 1 or higher (HR = 0.71; 95% CI, 0.57-0.88).

Among patients with a PD-L1 combined positive score of 20 of higher, the median OS was 14.9 months for those assigned pembrolizumab monotherapy compared with 10.7 months for cetuximab plus chemotherapy (HR = 0.61; 95% CI: 0.45-0.83).

The interim analysis did not show a significant difference in OS between the pembrolizumab monotherapy arm and the cetuximab-plus-chemotherapy arm for the overall population.
“Head and neck squamous cell carcinoma has historically presented many challenges to physicians and patients, including limited treatment options and physical and functional issues caused by the disease and its treatment,” Jonathan Cheng, MD, vice president of clinical research at Merck Research Laboratories, said in a press release. “This approval is an important advance in the management of this devastating cancer. The results of KEYNOTE-048, which support this approval, demonstrated that pembrolizumab monotherapy for patients whose tumors expressed PD-L1 CPS greater than or equal to 1 and pembrolizumab in combination with chemotherapy regardless of PD-L1 expression significantly prolonged survival for patients with metastatic or with unresectable, recurrent head and neck squamous cell carcinoma in the first-line setting.”

Common adverse events associated with pembrolizumab monotherapy included fatigue, constipation and rash. Adverse events associated with pembrolizumab in combination with chemotherapy included nausea, fatigue, constipation, vomiting, mucosal inflammation, diarrhea, decreased appetite, stomatitis and cough.

Pembrolizumab initially received accelerated approval in 2016 for patients with recurrent or metastatic HNSCC with disease progression on or after platinum-containing chemotherapy based on the phase 1b KEYNOTE-012 trial. These data from KEYNOTE-048 supported converting the accelerated approval to full approval.

 

    Perspective
    Dan P. Zandberg

    Dan P. Zandberg

    The randomized phase 3 KEYNOTE-048 trial compared both pembrolizumab monotherapy and pembrolizumab plus platinum/5-FU with the EXTREME regimen — which consists of platinum/5-FU plus cetuximab — for frontline treatment of recurrent/metastatic HNSCC.

    The trial compared each experimental arm with EXTREME for the total population, those with PD-L1 combined positive score (CPS) greater than 1, and those with PD-L1 CPS greater than 20.

    Interim results presented at European Society for Medical Oncology Congress in 2018 showed significant improvement in OS with pembrolizumab monotherapy for those with CPS greater than 1 and CPS greater than 20, and significant OS improvement with platinum/5-FU plus pembrolizumab for the total population.

    Data on the superiority of pembrolizumab monotherapy in the total population was pending at that time; however, updated and final analysis of the trial presented at this year’s ASCO Annual Meeting showed pembrolizumab monotherapy did not improve OS in the total population compared with EXTREME. This led to FDA approval of platinum/5-FU plus pembrolizumab for all patients, and pembrolizumab monotherapy for patients whose tumors express PD-L1 (PD-L1 CPS >1) for first-line treatment of recurrent/metastatic HNSCC. 

    This landmark trial changes the standard of care for this patient population. Consistent with the goal of a more personalized treatment approach, PD-L1 by CPS is the first required biomarker for standard-of-care treatment selection in HNSCC. For those who qualify, pembrolizumab monotherapy represents an efficacious and less toxic treatment that is critically important to our patients with relapsed/metastatic disease, many of whom have persistent toxicity from upfront definitive therapy.

    However, several important questions remain. Improvement in survival for the total population with platinum/5-FU plus pembrolizumab is not the same as the benefit for a patient with PD-L1-negative disease. In practice, we will know the PD-L1 status of our patients. Given that 85% of patients in KEYNOTE-048 had a PD-L1 CPS greater than 1, the question remains whether the addition of pembrolizumab to chemotherapy is of benefit for those with PD-L1 CPS less than 1.

    With 44% of PD-L1-expressing patients having had CPS greater than 20, an additional question is whether this group drove the OS benefit observed with pembrolizumab monotherapy for all patients who had CPS greater than 1. If a patient has a PD-L1 CPS score between 1 and 19, is pembrolizumab monotherapy enough or do we need to give platinum/5-FU with pembrolizumab? Further subgroup analysis would be exploratory but — if conducted — it may shine light on these questions, which not only will have importance in everyday practice but also in defining target populations for future clinical trial design in the frontline setting.

    Platinum/5-FU plus pembrolizumab is the only standard-of-care option for patients with PD-L1 CPS less than 1. For a PD-L1-expressing patient, my decision about whether to use monotherapy or add platinum/5-FU is based on an assessment of their likelihood of tolerance of chemotherapy, as well as the balance of the need for response versus increased toxicity of adding chemotherapy. Although not compared directly, platinum/5-FU plus pembrolizumab was associated with a numerically higher response rate than pembrolizumab monotherapy among patients with CPS greater than 1 (36% vs. 19%), and among those with CPS greater than 20 (43% vs 23%). Therefore, for a PD-L1-expressing patient who can tolerate chemotherapy and has bulky and/or symptomatic disease — where the benefit of a greater chance of response outweighs the toxicity — I discuss platinum/5-FU plus pembrolizumab, especially for those with PD-L1 CPS between 1 and 19.

    In summary, the positive results of KEYNOTE-048 change the standard of care for frontline therapy for patients with recurrent/metastatic HNSCC. This trial represents great progress — both for the field and for our patients — and serves as the new benchmark for continuing to improve outcomes for this patient population through scientific discovery and innovative clinical trials.


    • Dan P. Zandberg, MD
    • HemOnc Today Next Gen Innovator
      UPMC Hillman Cancer Center

    Disclosures: Zandberg reports institutional research funding from Merck.

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