Abstract CT011: 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)

Abstract Background: Studies have shown that the combination of PD-1 inhibitors with chemotherapy exhibits promising efficacy as a first-line treatment for Asian patients with recurrent or metastatic nasopharyngeal carcinoma (R/M NPC). This presentation reports the results of a global phase 3 clinical trial with ethnically diverse patients treated with penpulimab plus chemotherapy vs. placebo plus chemotherapy as the first-line therapy for R/M NPC (NCT04974398). Methods: AK105-304 trial was conducted across 46 sites worldwide. Participants aged 18-75 years with previously non-systemically treated R/M NPC, stratified by disease stages (de novo metastases vs. recurrent), ECOG (0 vs. 1), liver metastasis (present vs. absent), were randomized (1:1) to receive penpulimab or placebo (200mg, Day1) in combination with gemcitabine (1000mg/m2, Day 1 and 8) and cisplatin (80mg/m2, Day1) or carboplatin (AUC5, Day1) every 3 weeks (Q3W) for up to 6 cycles, followed by maintenance therapy with penpulimab or placebo (200mg, Q3W). Placebo-arm patients were allowed to crossover to receive penpulimab monotherapy (200 mg, Q3W) upon confirmed disease progression by blinded independent center review (BICR). Primary endpoint was PFS assessed by BICR, and key secondary endpoint was OS. Other secondary endpoints included ORR, DoR and safety. Results: 291 patients were randomized to penpulimab arm (n=144) or placebo arm (n=147). Baseline characteristics were generally balanced between treatment arms. By April 29, 2024, median follow-up time was 19.1 months. Per BICR assessment, median PFS was 9.6 months (95% CI: 7.1, 12.5) and 7.0 months (95% CI: 6.9, 7.3), respectively, for penpulimab+chemo and placebo+chemo (HR=0.45, 95% CI: 0.33, 0.62, two-sided P < 0.0001). Confirmed ORR was 68.1% vs. 63.9%, and median DoR was 9.8 months (95% CI: 7.0, 17.5) vs. 5.7 months (95% CI: 5.5, 6.7) (HR=0.4, 95%CI: 0.27, 0.59). OS was not mature, with 48 deaths in penpulimab arm and 49 in placebo arm (HR=0.94, 95% CI: 0.63, 1.40). After adjusting for crossover of patients from placebo to penpulimab upon PD, OS benefit became more evident, with HR of 0.62 (0.41, 0.94) by Rank Preserving Structural Failure Time (RPSFT) model, 0.75 (0.43, 1.30) by Inverse Probability of Censoring Weighting (IPCW) method, and 0.78 (0.52, 1.17) by two-stage Accelerated Failure Time (AFT) model. The incidence of Grade ≥3 TRAEs was 89.0% vs. 85.9%; SAEs was 50.7% vs. 48.6%; irAEs was 30.8% vs. 8.5%; Grade ≥3 irAEs was 4.1% vs. 0. Conclusions: Penpulimab combined with gemcitabine and cisplatin or carboplatin demonstrated statistically significant and clinically meaningful benefit with a manageable safety profile, and provides a new beneficial treatment option in the first-line treatment for R/M NPC patients globally. Citation Format: Chaosu Hu, Xiaozhong Chen, Tingting Xu, Shuang Huang, Feng Liu, Song Qu, Lisha Chen, Ping Zhou, Shenhong Qu, Xiaohong Ai, Yong Chen, Meilian Liu, Rensheng Wang, Kelvin KW Chan, Peng Zhang, Chunhong Hu, Jiyu Wen, Jian Zhang, Qin Lin, Xiaojiang Li, Kangsheng Gu, Li Xiang, Dongxia Wang, Jingao Li, Daren Lin, Desheng Hu, Jianwu Ding, Siyang Wang, Xiaoming Huang, Lin Wang, Feng Jin, David G. Pfister, Milena Perez Mak, Pedro Rafael Martins de Marchi, Yi Jiang, Haihua Yang, Xiaoye Hu, Tianrun Liu, Dehua Wu, Aditya Shreenivas, Thiago Bueno de Oliveira, Carlos Eduardo Baston Silva, Gustavo Vasconcelos Alves, Xianming Li, Zhifang Yao, Dongmei Lu, Mingxiu Hu, Zhongmin Maxwell Wang, Baiyong Li, Michelle Xia. 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) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT011.

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Journal
Cancer Research
Published
2025-04-25
DOI
https://doi.org/10.1158/1538-7445.am2025-ct011
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5
Primary Topic
Head and Neck Cancer Studies
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article
Field-Weighted Citation Impact
9.24
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Abstract CT011: 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)

Michelle Xia, Yong Chen, David G. Pfister, Meilian Liu et al.
5 citations
Cancer Research
Head and Neck Cancer Studies
9.24
article

Abstract CT011: 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)

Michelle Xia, Yong Chen, David G. Pfister, Meilian Liu, Kelvin Chan, Pedro Rafael Martins De Marchi, Lin Wang, Carlos Eduardo Baston Silva, Xiaozhong Chen, Shenhong Qu, Gustavo Vasconcelos Alves, Xiaohong Ai, Zhongmin Maxwell Wang, Ping Zhou, Thiago Bueno de Oliveira, Dehua Wu, Tianrun Liu, Baiyong Li, Jiyu Wen, Haihua Yang, Chaosu Hu, Milena Perez Mak, Aditya Varnam Shreenivas, Lisha Chen, Qin Lin, Xiang Li, Peng Zhang, Jian Zhang, Tingting Xu, Chunhong Hu, Xiaojiang Li, Kangsheng Gu, Shuang Huang, Siyang Wang, Daren Lin, Zhifang Yao, Desheng Hu, Dongmei Lu, Jian-Wu Ding, Xianming Li, Rensheng Wang, Dongxia Wang, Feng Jin, Jingao Li, Yi Jiang, Feng Liu, Xiao-Ming Huang, Xiaoye Hu, Song Qu, Mingxiu Hu
article en
5 citations

Abstract

Abstract Background: Studies have shown that the combination of PD-1 inhibitors with chemotherapy exhibits promising efficacy as a first-line treatment for Asian patients with recurrent or metastatic nasopharyngeal carcinoma (R/M NPC). This presentation reports the results of a global phase 3 clinical trial with ethnically diverse patients treated with penpulimab plus chemotherapy vs. placebo plus chemotherapy as the first-line therapy for R/M NPC (NCT04974398). Methods: AK105-304 trial was conducted across 46 sites worldwide. Participants aged 18-75 years with previously non-systemically treated R/M NPC, stratified by disease stages (de novo metastases vs. recurrent), ECOG (0 vs. 1), liver metastasis (present vs. absent), were randomized (1:1) to receive penpulimab or placebo (200mg, Day1) in combination with gemcitabine (1000mg/m2, Day 1 and 8) and cisplatin (80mg/m2, Day1) or carboplatin (AUC5, Day1) every 3 weeks (Q3W) for up to 6 cycles, followed by maintenance therapy with penpulimab or placebo (200mg, Q3W). Placebo-arm patients were allowed to crossover to receive penpulimab monotherapy (200 mg, Q3W) upon confirmed disease progression by blinded independent center review (BICR). Primary endpoint was PFS assessed by BICR, and key secondary endpoint was OS. Other secondary endpoints included ORR, DoR and safety. Results: 291 patients were randomized to penpulimab arm (n=144) or placebo arm (n=147). Baseline characteristics were generally balanced between treatment arms. By April 29, 2024, median follow-up time was 19.1 months. Per BICR assessment, median PFS was 9.6 months (95% CI: 7.1, 12.5) and 7.0 months (95% CI: 6.9, 7.3), respectively, for penpulimab+chemo and placebo+chemo (HR=0.45, 95% CI: 0.33, 0.62, two-sided P < 0.0001). Confirmed ORR was 68.1% vs. 63.9%, and median DoR was 9.8 months (95% CI: 7.0, 17.5) vs. 5.7 months (95% CI: 5.5, 6.7) (HR=0.4, 95%CI: 0.27, 0.59). OS was not mature, with 48 deaths in penpulimab arm and 49 in placebo arm (HR=0.94, 95% CI: 0.63, 1.40). After adjusting for crossover of patients from placebo to penpulimab upon PD, OS benefit became more evident, with HR of 0.62 (0.41, 0.94) by Rank Preserving Structural Failure Time (RPSFT) model, 0.75 (0.43, 1.30) by Inverse Probability of Censoring Weighting (IPCW) method, and 0.78 (0.52, 1.17) by two-stage Accelerated Failure Time (AFT) model. The incidence of Grade ≥3 TRAEs was 89.0% vs. 85.9%; SAEs was 50.7% vs. 48.6%; irAEs was 30.8% vs. 8.5%; Grade ≥3 irAEs was 4.1% vs. 0. Conclusions: Penpulimab combined with gemcitabine and cisplatin or carboplatin demonstrated statistically significant and clinically meaningful benefit with a manageable safety profile, and provides a new beneficial treatment option in the first-line treatment for R/M NPC patients globally. Citation Format: Chaosu Hu, Xiaozhong Chen, Tingting Xu, Shuang Huang, Feng Liu, Song Qu, Lisha Chen, Ping Zhou, Shenhong Qu, Xiaohong Ai, Yong Chen, Meilian Liu, Rensheng Wang, Kelvin KW Chan, Peng Zhang, Chunhong Hu, Jiyu Wen, Jian Zhang, Qin Lin, Xiaojiang Li, Kangsheng Gu, Li Xiang, Dongxia Wang, Jingao Li, Daren Lin, Desheng Hu, Jianwu Ding, Siyang Wang, Xiaoming Huang, Lin Wang, Feng Jin, David G. Pfister, Milena Perez Mak, Pedro Rafael Martins de Marchi, Yi Jiang, Haihua Yang, Xiaoye Hu, Tianrun Liu, Dehua Wu, Aditya Shreenivas, Thiago Bueno de Oliveira, Carlos Eduardo Baston Silva, Gustavo Vasconcelos Alves, Xianming Li, Zhifang Yao, Dongmei Lu, Mingxiu Hu, Zhongmin Maxwell Wang, Baiyong Li, Michelle Xia. 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) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT011.

Cancer ResearchVol. 85(8_Supplement_2)
Sunnybrook Health Science Centre (CA), Memorial Sloan Kettering Cancer Center (US), Central South University (CN), Nanchang University (CN), Guiyang Medical University (CN), Sun Yat-sen University (CN), Guangxi Medical University (CN), Guilin Medical University (CN), Guangdong Medical College (CN), University of Toronto (CA), Anhui Medical University (CN), Wenzhou Medical University (CN), AC Camargo Hospital (BR), Shantou University (CN), Kettering University (US), Affiliated Hospital of Southwest Medical University (CN), First Affiliated Hospital of Xiamen University (CN), Instituto do Câncer do Estado de São Paulo (BR), Cancer Hospital of Shantou University Medical College (CN), Hospital de Câncer de Barretos (BR), Fudan University Shanghai Cancer Center (CN), Sixth Affiliated Hospital of Sun Yat-sen University (CN), Jiangxi Provincial Cancer Hospital (CN), Sun Yat-sen Memorial Hospital (CN), Zhejiang Cancer Hospital (CN), Nanfang Hospital (CN), ShenZhen People’s Hospital (CN), Second Affiliated Hospital of Nanchang University (CN), Affiliated Hospital of Guizhou Medical University (CN), City of Hope (US), Fifth Affiliated Hospital of Sun Yat-sen University (CN), Hunan Cancer Hospital (CN), The People's Hospital of Guangxi Zhuang Autonomous Region (CN), Hospital Nossa Senhora da Conceição (BR), Sichuan Cancer Hospital (CN), Zhujiang Hospital (CN), Dongguan People’s Hospital (CN), First Affiliated Hospital of GuangXi Medical University (CN), Hainan General Hospital (CN), The First Affiliated Hospital, Sun Yat-sen University (CN), First Affiliated Hospital of Anhui Medical University (CN), First Affiliated Hospital of University of South China (CN), Jiangmen Central Hospital (CN), Second Xiangya Hospital of Central South University (CN), Zhejiang Taizhou Hospital (CN), Hubei Cancer Hospital (CN), Hangzhou Cancer Hospital (CN), Southern Medical University (CN), Hainan Medical University (CN), University of South China (CN), Guangzhou Medical University (CN)
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