First-line penpulimab plus chemo offers survival benefits for R/M nasopharyngeal carcinoma

The use of penpulimab, in combination with gemcitabine and cisplatin or carboplatin, as first-line treatment for recurrent or metastatic (R/M) nasopharyngeal carcinoma (NPC) provides statistically significant and clinically meaningful benefit, according to a study presented at AACR 2025.

In addition, penpulimab plus chemotherapy has a manageable safety profile, providing a new treatment option in the first-line setting for patients with R/M NPC.

“Penpulimab combined with gemcitabine and cisplatin or carboplatin demonstrates a favourable efficacy and tolerability profile, offering a new beneficial treatment option for R/M NPC patients globally,” said study co-author and presenter Dr Aditya Shreenivas from City of Hope in Los Angeles, California, US.

Shreenivas and his team conducted the phase III AK105-304 trial across 46 sites worldwide. They randomized 291 patients to receive either penpulimab (200 mg, day 1; n=144) plus chemotherapy (gemcitabine 1,000 mg/m2, day 1 and 8; cisplatin 80 mg/m2, day 1 or carboplatin AUC5, day 1) or placebo (200 mg, day 1; n=147) plus chemotherapy every 3 weeks (Q3W) for up to 6 cycles, followed by maintenance therapy with penpulimab or placebo (200 mg, Q3W). 

Eligible participants were aged 18–75 years and had previously nonsystemically treated R/M NPC, stratified by disease stage (de novo metastases vs recurrent), ECOG (0 vs 1), and liver metastasis (present vs absent). Those in the placebo arm were allowed to crossover to receive penpulimab monotherapy (200 mg, Q3W) upon confirmed disease progression by blinded independent centre review (BICR).

At baseline, patient characteristics were generally balanced between the two treatment groups. The median follow-up time was 19.1 months.

Survival

The median PFS per BICR assessment, the primary outcome, was longer in the penpulimab arm (9.6 months, 95 percent confidence interval [CI], 7.1–12.5) than the placebo arm (7.0 months, 95 percent CI, 6.9–7.3; hazard ratio [HR], 0.45, 95 percent CI, 0.33–0.62; two-sided p<0.0001). [AACR 2025, abstract CT011]

For the secondary outcomes, the confirmed objective response rate (ORR) was 68.1 percent with penpulimab plus chemotherapy and 63.9 percent with placebo plus chemotherapy, while the median duration of response (DoR) was 9.8 months (95 percent CI, 7.0–17.5) vs 5.7 months (95 percent CI, 5.5–6.7), respectively (HR, 0.4, 95 percent CI, 0.27–0.59).

Data on overall survival (OS), the key secondary endpoint, was not yet complete, with 48 deaths recorded in the penpulimab arm and 49 in the placebo arm (HR, 0.94, 95 percent CI, 0.63–1.40).

After adjusting for patients who crossed over to penpulimab from placebo, a more perceptible OS benefit was seen: Rank Preserving Structural Failure Time model (HR, 0.62, 95 percent CI, 0.41–0.94), Inverse Probability of Censoring Weighting method (HR, 0.75, 95 percent CI, 0.43–1.30), and two-stage Accelerated Failure Time model (HR, 0.78, 95 percent CI, 0.52–1.17).

Safety profile

With regard to safety, grade ≥3 treatment-related adverse events (AEs) occurred in 89.0 percent of patients in the penpulimab arm and 85.9 percent in the placebo arm. Serious AEs occurred in 50.7 percent and 48.6 percent, respectively. 

Immune-related (ir)AEs were also observed in 30.8 percent of penpulimab-treated patients vs 8.5 percent in those treated with placebo. Grade ≥3 irAEs were noted in 4.1 percent vs 0 percent, respectively.

“The safety profile of penpulimab plus chemotherapy was manageable and consistent with previous reports, with no new safety signals,” Shreenivas said.

Penpulimab is a humanized anti-PD1 IgG1 monoclonal antibody with a modified Fc segment. It has a more stable structure, lower antigen-binding dissociation rate, and higher receptor occupancy rate compared with other anti-PD1 agents. [Front Immunol 2022;13:924542; Drugs 2021;81:2159-2166; Cancer Cell 2015;28:285-295]

“These characteristics may enhance efficacy and safety, as demonstrated in clinical trials across multiple tumour types, including ... nonsmall cell lung cancer, hepatocellular carcinoma, and NPC,” Shreenivas said. [Lancet Respir Med 2024;12:355-365; Front Oncol 2021;11:684867]

Recently, the FDA approved penpulimab-kcqx with gemcitabine and cisplatin or carboplatin for the first-line treatment of adults with R/M nonkeritinizing NPC on 23 April 2025. [https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-penpulimab-kcqx-non-keratinizing-nasopharyngeal-carcinoma]