The U.S. Food and Drug Administration (FDA) has approved the humanized IgG1 monoclonal anti–PD-1 antibody penpulimab-kcqx with cisplatin or carboplatin and gemcitabine for the first-line treatment of adults with recurrent or metastatic nonkeratinizing nasopharyngeal carcinoma (NPC). The FDA also approved penpulimab as a single agent for adults with metastatic nonkeratinizing NPC with disease progression on or after platinum-based chemotherapy and at least one other prior line of therapy.
Study AK105-304 and AK105-202
Efficacy of penpulimab with cisplatin or carboplatin and gemcitabine was evaluated in Study AK105-304 (ClinicalTrials.gov identifier NCT04974398), a randomized, double-blind, multicenter trial in 291 patients with recurrent or metastatic NPC who had not received previous systemic chemotherapy for recurrent or metastatic disease. Patients were randomly assigned 1:1 to receive either penpulimab with cisplatin or carboplatin and gemcitabine, followed by penpulimab, or placebo with cisplatin or carboplatin and gemcitabine, followed by placebo.
The primary efficacy outcome measure was progression-free survival as assessed by a blinded independent review committee according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1; overall survival was a key secondary endpoint. Median progression-free survival was 9.6 months (95% confidence interval [CI] = 7.1–12.5 months) in the penpulimab arm and 7.0 months (95% CI = 6.9–7.3 months) in the placebo arm (hazard ratio [HR] = 0.45, 95% CI = 0.33, 0.62, two-sided P < .0001), with 31% and 11% of patients alive and progression-free after 12 months of follow-up in the penpulimab and placebo arms, respectively. Although overall survival results were immature, with 70% of prespecified deaths for the final analysis reported, no detrimental trend was observed.
Efficacy of single-agent penpulimab was evaluated in Study AK105-202 (NCT03866967), an open-label, multicenter, single-arm trial conducted in a single country. The trial included a total of 125 patients with unresectable or metastatic nonkeratinizing NPC who had disease progression after platinum-based chemotherapy and at least one other line of therapy. Patients received penpulimab until disease progression or unacceptable toxicity, for a maximum of 24 months.
The major efficacy outcome measures were objective response rate and duration of response according to RECIST version 1.1 as assessed by an independent radiology review committee. The objective response rate was 28% (95% CI = 20%–37%), and the median duration of response was not reached (95% CI = 9.2 months to not estimable).
Immune-mediated adverse reactions were reported with penpulimab, including pneumonitis, colitis, hepatitis, endocrinopathies, nephritis with renal dysfunction, and skin adverse reactions. The most common adverse reactions for penpulimab with cisplatin or carboplatin and gemcitabine—occurring in at least 20% of patients—were nausea, vomiting, hypothyroidism, constipation, decreased appetite, decreased weight, cough, COVID-19 infection, fatigue, rash, and pyrexia; the most common adverse reactions for single-agent penpulimab were hypothyroidism and musculoskeletal pain. Fatal adverse reactions occurred in 1% of patients, including a case each of pneumonitis, septic shock, colitis, and hepatitis.
The recommended penpulimab dose with cisplatin or carboplatin and gemcitabine is 200 mg every 3 weeks until disease progression or unacceptable toxicity for a maximum of 24 months. The recommended single-agent penpulimab dose for previously treated patients with NPC is 200 mg every 2 weeks until disease progression or unacceptable toxicity for a maximum of 24 months.
This review used the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment. This application was granted Fast Track designation, Breakthrough Therapy designation, and Orphan Drug designation.
