FDA Approval of Penpulimab Expands Treatment Options in Recurrent/Metastatic Non-Keratinizing NPC

Aditya Shreenivas, MD, MS

The FDA approval of penpulimab-kcqx in combination with chemotherapy represents a significant advancement in the first-line treatment landscape for patients with recurrent or metastatic non-keratinizing nasopharyngeal carcinoma (NPC), a rare malignancy with historically limited therapeutic options in the United States, according to Aditya Shreenivas, MD.

On April 24, 2025, the FDA approved penpulimab in combination with cisplatin or carboplatin and gemcitabine for adult patients with recurrent or metastatic non-keratinizing NPC. The agent also received approval as a monotherapy for patients with metastatic disease that has progressed on or after platinum-based chemotherapy and at least 1 additional line of therapy.1 These regulatory decisions were supported by data from the phase 3 Study AK105-304 (NCT04974398) and the phase 2 Study AK105-202 (NCT03866967), respectively.

Results from Study AK105-304 presented at the 2025 AACR Annual Meeting showed that at a median follow-up of 19.1 months (range, 0-31.5), patients treated with penpulimab plus chemotherapy (n = 144) achieved a median progression-free survival (PFS) of 9.6 months (95% CI, 7.1-12.5) compared with 7.0 months (95% CI, 6.9-7.3) for those treated with placebo plus chemotherapy (n = 147; HR, 0.45; 95% CI, 0.33-0.62; P < .0001).1,2

"The AK105-304 study evaluating penpulimab supported its potential as the second FDA-approved agent for use in the first-line treatment of non-keratinizing NPC, with a reasonably tolerable safety profile,” Shreenivas explained in an interview with OncLive®.

In the interview, Shreenivas detailed the significance of the FDA approval of penpulimab plus chemotherapy for the frontline treatment of recurrent or metastatic non-keratinizing NPC; expanded on the key data from Study AK105-304 supporting the regimen’s approval; and highlighted future directions for research with penpulimab.

Shreenivas is an assistant professor in the Department of Medical Oncology & Therapeutics Research at City of Hope in Duarte, California.

OncLive: What made Study AK105-304 unique compared with prior studies investigating first-line treatment for recurrent or metastatic NPC?

Shreenivas: Recurrent or metastatic NPC is a highly aggressive disease with limited treatment options for those patients. In first-line setting, standard of care is chemotherapy with immunotherapy. Studies that have been done in the past have primarily been based in Asia; they have not been global. Study AK105-304 was truly a global study, because it involved patients outside of Asia in South America, Canada, and the United States.

What was the design of Study AK105-304?

This was a randomized, double-blind, phase 3 study with 1:1 randomization between penpulimab plus chemotherapy vs chemotherapy plus placebo. The study was designed with a crossover, so patients who progressed in the placebo [arm] were allowed to cross over to the penpulimab arm. Initially, patients got chemotherapy with placebo or penpulimab, then after 6 cycles, they moved to penpulimab or placebo monotherapy for up to 2 years or until disease progression.

The primary end point was blinded independent central review–assessed PFS, and there were other secondary end points, such as overall survival [OS], overall response rate [ORR], and others that were assessed. The study was unique because the other studies did not have the crossover design.

What efficacy and safety data were reported from this analysis?

The median PFS was statistically significant in the experimental arm with penpulimab at 9.6 months vs 7.0 months in the placebo arm. The duration of response for patients who responded was 9.8 months [95% CI, 7.0-17.5] in the penpulimab arm vs 5.7 months [95% CI, 5.5-6.7] in the placebo arm. The ORR was similar in both arms at 68.1% [95% CI, 59.8%-75.6%] and 63.9% [95% CI, 55.6%-71.7%], respectively.

The [adverse] effect [AE] profile was also manageable, [and] that dovetails into the unique [mechanism of] action of penpulimab. It is an IgG1 monoclonal antibody but has an Fc malfunction, which limits the immune-related AEs that are associated with agents like these. That's why the [rate of] immune related AEs, especially grade 3 and above, was relatively lower than some of the other agents that have been used in this space. [Penpulimab showed a] manageable toxicity profile outside of the hematological toxicities [that] are quite common with these combinations [with chemotherapy]

How does the FDA approval affect the NPC treatment paradigm?

[Currently,] the only other drug approved by the FDA is toripalimab-tpzi [Loqtorzi], based on the phase 3 JUPITER-02 study [NCT03581786]. There are other drugs that are approved outside of the United States, including tislelizumab [Tevimbra] based on the phase 3 RATIONALE 309 study [NCT03924986], and other drugs like camrelizumab.

Study AK105-304 [brings a] second drug in the first-line space [in the United States] with a reasonably tolerable safety profile, and it would allow for the development of other trials in different settings.

What are the next steps for assessing the activity of this agent?

[In this analysis] we saw the benefit of this agent across different subgroups. [Moving forward], it would be nice to do some additional subgroup analyses to look at biomarkers for response, because PD-L1 status was not necessarily the only biomarker that led to an improved response. Looking at different biomarkers at different metastatic sites and differential response in those sites [would also be of interest]. Also, we have to keep in mind that OS data are still being analyzed. They were still immature [at this analysis], and we are looking forward to that OS data once they are [available].

References

1. FDA approves penpulimab-kcqx for non-keratinizing nasopharyngeal carcinoma. FDA. April 23, 2025. Accessed May 14, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-penpulimab-kcqx-non-keratinizing-nasopharyngeal-carcinoma
2. 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.