The Food and Drug Administration ( FDA ) has approved Keytruda ( Pembrolizumab ), the 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 Keytruda is approved based on tumor 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 Keytruda.
The approval is based on data from the KEYNOTE-012 study, which included patients with recurrent or metastatic HNSCC who had disease progression on or after Platinum-containing chemotherapy or following Platinum-containing chemotherapy administered as part of induction, concurrent, or adjuvant therapy and ECOG performance status ( PS ) of zero or one.
The data showed an objective response rate ( ORR ) of 16% ( 95% CI: 11, 22 ), complete response rate of 5%, with responses of six months or longer observed in 82% ( n=23/28 ) of the responding patients.
ORR and duration of response were similar regardless of human papilloma virus ( HPV ) status.
Immune-mediated adverse reactions occurred with Keytruda including pneumonitis, colitis, hepatitis, endocrinopathies, and nephritis. Based on the severity of the adverse reaction, Keytruda should be withheld or discontinued and corticosteroids administered.
Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. Female patients of reproductive potential should be advised of the potential hazard to a fetus.
KEYNOTE-012 was 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.
Head and neck cancer is a complex disease that historically has been associated with high recurrence rates and poor long-term outcomes, highlighting the critical need for new treatment options.
Pembrolizumab is a humanized monoclonal antibody that works by increasing the ability of the body’s immune system to help detect and fight tumor cells. Pembrolizumab blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells.
The accelerated FDA approval was based on a multicenter, nonrandomized, open-label, multi-cohort phase 1b study, KEYNOTE-012, that evaluated safety in 192 patients with recurrent or metastatic HNSCC and ECOG PS of zero or one; 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 tumor 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 Keytruda 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 Keytruda could be reinitiated for subsequent disease progression and administered for up to one additional year.
The primary efficacy outcome measures were ORR according to Response Evaluation Criteria in Solid Tumors ( RECIST ) v1.1, as assessed by blinded independent central review ( BICR ), 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 Keytruda. The most frequent serious adverse reactions reported in at least 2% of patients were pneumonia, dyspnea, confusional 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 dyspnea ( 20% ).
Adverse reactions in patients with HNSCC were generally similar to those occurring in patients with melanoma and non-small cell lung cancer ( NSCLC ), with the exception of increased incidences of facial edema ( 10% all Grades; 2.1% Grades 3-4 ) and new or worsening hypothyroidism. ( Xagena )
Source: Merck, 2016