First-Line Penpulimab Plus Chemo Extends PFS in Recurrent or Metastatic Nasopharyngeal Carcinoma

Image Credit: © lertsakwiman– stock.adobe.com

Penpulimab administered in combination with gemcitabine and platinum-based chemotherapy generated an improvement in progression-free survival (PFS) compared with placebo plus chemotherapy in the first-line treatment ofpatients with recurrent or metastatic nasopharyngeal carcinoma (NPC), according to data from the phase 3 Study AK105-304 (NCT049743980).1

Findings presented at the 2025 AACR Annual Meeting showed that at a median follow-up of 19.1 months (range, 0-31.5), patients treated in the penpulimab arm (n = 144) achieved a median PFS of 9.6 months (95% CI, 7.1-12.5) compared with 7.0 months (95% CI, 6.9-7.3) in patients treated in the placebo arm (HR, 0.45; 95% CI, 0,33-0.62; P < .0001). In the experimental arm, the 12- and 24-month PFS rates were 44.2% (95% CI, 34.9%-53.0%) and 22.8% (95% CI, 13.1%-34.0%), respectively. In the control arm, these respective rates were 15.4% (95% CI, 9.4%-22.7%) and 5.5% (95% CI, 1.6%-13.0%).

“Penpulimab and chemotherapy provides another option for [the] first-line treatment of recurrent or metastatic NPC, which is a highly aggressive disease. The primary end point of the study was met,” lead study author Aditya Shreenivas, MD, MS, an assistant professor in Head & Neck Medical Oncology at City of Hope in Duarte, California, said in a presentation of the data. “Key secondary end point data, [including] the overall survival [OS] data, [are] still being calculated. Median OS both arms have not been reached.”

On April 23, 2025, the FDA approved penpulimab-kcqx in combination with cisplatin or carboplatin and gemcitabine for the first-line treatment of adult patients with recurrent or metastatic non-keratinizing NPC, based on data from Study AK105-304.2

Notably, the regulatory agency simultaneously approved penpulimab monotherapy for adult patients with metastatic non-keratinizing NPC with disease progression on or after platinum-based chemotherapy and at least 1 other prior line of therapy. The single-agent approval was supported by findings from the phase 2 Study AK105-202 (NCT03866967).

Study AK105-304 Overview

The global, multicenter, randomized, double-blind trial enrolled patients with recurrent or metastatic NPC who received no prior lines of systemic therapy, had an ECOG performance status of 0 to 1, and had adequate organ function.1

Investigators randomly assigned patients 1:1 to receive penpulimab at 200 mg or placebo in combination with chemotherapy once every 3 weeks for 6 cycles, followed by penpulimab or placebo alone once every 3 weeks for up to 24 months or until progression disease or loss of clinical benefit. Notably, patients in the placebo arm were allowed to cross over to receive penpulimab upon disease progression.

In both arms, chemotherapy comprised cisplatin at 80 mg/m2 or carboplatin at area under the curve 5 once every 3 weeks in combination with gemcitabine at 1000 mg/m2 on day 1 and day 8 of each 21-day cycle.

PFS per blinded independent central review served as the trial’s primary end point. OS was a key secondary end point. Other secondary end points comprised investigator-assessed PFS, overall response rate (ORR), disease control rate (DCR), and safety.

Baseline Characteristics

The median age in the penpulimab arm (n = 144) and placebo arm (n = 147) was 51.0 years (range, 31-75) and 50.0 years (range, 23-68), respectively. The majority of patients in both arms were male (penpulimab, 82.6%; placebo, 81.0%), from Asian countries (95.8%; 96.6%), had an ECOG performance status of 1 (64.6%; 63.3%), had recurrent disease (68.8%; 66.7%), received prior anticancer therapies (69.4%; 66.7%), did not have liver metastases (59.7%; 59.2%), had undifferentiated non-keratinizing squamous cell carcinoma (77.8%; 75.5%), had a PD-L1 tumor proportion score of under 50% or unknown (57.6%; 58.5%), had Epstein-Barr virus DNA levels of at least 500 copies/mL (60.4%; 66.7%), and received cisplatin during the study (97.9%; 97.3%).

Among 144 treated patients in the penpulimab arm, 124 had reached the end of treatment due to radiographic disease progression (n = 62), patients request (n = 18), completing 24 months of treatment (n = 14), initiation of new antitumor therapy (n = 8), investigator decision (n = 3), adverse effects (AEs; n = 5), death (n = 5), clinical disease progression without radiographic confirmation (n = 2), and other (n = 7).

In the placebo arm, 144 of 147 enrolled patients received treatment, and 135 had reached the end of treatment due to radiographic disease progression (n = 104), patient request (n = 9), completing 24 months of treatment (n = 3), initiation of new antitumor therapy (n = 1), investigator decision (n = 6), AEs (n = 2), death (n = 2), clinical disease progression without radiographic confirmation (n = 3), withdrawal of consent (n = 1), and other (n = 4). In this arm, 46.3% of patients crossed over to receive penpulimab.

Additional Efficacy and Safety Data

Shreenivas noted that the PFS benefit was consistent across key subgroups.

In the penpulimab arm, the ORR was 68.1% (95% CI, 59.8%-75.6%) compared with 63.9% (95% CI, 55.6%-71.7%) in the placebo arm. The complete response, partial response, stable disease, and progressive disease rates in the experimental arm were 18.1%, 50.0%, 22.9%, and 2.1%, respectively. These respective rates were 8.8%, 55.1%, 27.9%, and 2.0% in the placebo arm. The DCR was 91.0% (95% CI, 85.1%-95.1%) in the penpulimab arm vs 91.8% (95% CI, 86.2%-95.7%) in the placebo arm.

The median DOR was 9.8 months (95% CI, 7.0-17.5) in the penpulimab group vs 5.7 months (95% CI, 5.5-6.7) in the placebo group (HR, 0.40; 95% CI, 0.27-0.59; P < .0001).

Regarding safety, any-grade treatment-related AEs (TRAEs) occurred in all patients penpulimab arm vs 98.6% of patients in the placebo arm. The rates of grade 3 or higher TRAEs were 89.0% and 85.9%, respectively. Any-grade TRAEs led to treatment interruption and permanent discontinuation in 62.3% and 11.0% of patients, respectively, in the penpulimab; these respective rates were 56.3% and 8.5% in the placebo arm.

Serious TRAEs occurred in 43.8% of patients in the penpulimab arm vs 40.1% of patients in the control arm. TRAEs led to death in 1.4% of patients in the penpulimab group vs none in the placebo group. The rates of infusion-related reactions were 3.4% and 0.7%, respectively.

The most common AEs reported in at least 20% of patients treated with penpulimab plus chemotherapy included nausea, vomiting, hypothyroidism, constipation, decreased appetite, decreased weight, cough, COVID-19 infection, fatigue, rash, and pyrexia.2

Disclosures: Shreenivas reported serving as an advisory board member for Lilly and Taiho; a steering committee member for Bayer; and receiving research support from Foundation One. He did not have any financial relationships to disclose.

References

1. Hu C, Chen X, Xu T, et al. Penpulimab versus placebo in combination with chemotherapy as first-line treatment for recurrent or metastatic nasopharyngeal carcinoma: a global, multicenter, randomized, double-blind, phase 3 trial (AK105-304). Presented at: 2025 AACR Annual Meeting; April 25-30, 2025; Chicago, IL. Abstract CT011.
2. FDA approves penpulimab-kcqx for non-keratinizing nasopharyngeal carcinoma. FDA. April 23, 2025. Accessed April 27, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-penpulimab-kcqx-non-keratinizing-nasopharyngeal-carcinoma