FDA Approves Pembrolizumab for Patients with Recurrent or Metastatic HNSCC with Disease Progression on or After Platinum-Containing Chemotherapy

PD-L1 testing is not needed prior to use of pembrolizumab in HNSCC patients

On 8 August, 2016, Merck, known as MSD outside the United States and Canada, announced that the US Food and Drug Administration (FDA) has approved pembrolizumab (KEYTRUDA®), the company’s anti-PD-1 (programmed death receptor-1) therapy, at a fixed dose of 200 mg every three weeks, for the treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) with disease progression on or after platinum-containing chemotherapy.

Under the FDA’s accelerated approval regulations, this indication for pembrolizumab is approved based on tumour response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. For HNSCC patients, PD-L1 testing is not needed prior to use of pembrolizumab.

The accelerated FDA approval is based on data from the KEYNOTE-012 study, the first clinical study to investigate the role of a PD-1 inhibitor in patients with recurrent or metastatic HNSCC with disease progression on or after platinum-containing chemotherapy.

A multicentre, non-randomised, open-label, multi-cohort phase Ib study, KEYNOTE-012, evaluated safety in 192 patients with recurrent or metastatic HNSCC and ECOG performance status of 0 or 1. Efficacy was evaluated in 174 of these patients who had disease progression on or after platinum-containing chemotherapy administered for recurrent or metastatic HNSCC or following platinum-containing chemotherapy administered as part of induction, concurrent, or adjuvant therapy.

Patients were enrolled regardless of tumour human papilloma virus (HPV) status (33% were HPV-positive). The median number of prior lines of therapy administered for the treatment of HNSCC was two. Nearly all (95%) of the patients enrolled had prior radiation therapy.

Patients received pembrolizumab at a dose of 10 mg/kg every two weeks (n=53) or a 200 mg fixed dose every three weeks (n=121) until unacceptable toxicity or disease progression. Patients without disease progression were treated for up to 24 months. Treatment with pembrolizumab could be reinitiated for subsequent disease progression and administered for up to one additional year.

The primary efficacy outcome measures were overall response rate (ORR) according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, as assessed by blinded independent central review, and duration of response.

Efficacy analysis showed an ORR of 16% (95% CI: 11, 22) with a complete response rate of 5%. The median follow-up time was 8.9 months. Among the 28 responding patients, the median duration of response had not been reached (range 2.4+ to 27.7+ months), with 23 patients having responses of six months or longer. The ORR and duration of response were similar irrespective of dosage regimen (10 mg/kg every 2 weeks or 200 mg every 3 weeks) or HPV status.

In HNSCC, serious adverse reactions occurred in 45% of patients receiving pembrolizumab. The most frequent serious adverse reactions reported in at least 2% of patients were pneumonia, dyspnoea, confusion state, vomiting, pleural effusion, and respiratory failure. The incidence of adverse reactions, including serious adverse reactions, was similar between dosage regimens (10 mg/kg every 2 weeks or 200 mg every 3 weeks). The most common adverse reactions (reported in at least 20% of patients) were fatigue (46%), decreased appetite (22%), and dyspnoea (20%). Adverse reactions in patients with HNSCC were generally similar to those occurring in patients with melanoma and non-small cell lung cancer, with the exception of increased incidences of facial oedema (10% all grades; 2.1% grades 3-4) and new or worsening hypothyroidism.

Merck currently has a large clinical development programme, including multiple registration-enabling studies in head and neck cancer, and is conducting research investigating pembrolizumab as a monotherapy, as well as in combination with chemotherapy compared to the current standard of care.