NMPA Approval Sought for Frontline Cadonilimab Plus Chemo in Gastric or GEJ Adenocarcinoma

Michelle Yu Xia, PhD

China’s National Medical Products Administration (NMPA) has accepted the supplemental new drug application (sNDA) seeking the approval of cadonilimab (AK104) plus capecitabine and oxaliplatin (Xelox) for use in the first-line treatment of patients with unresectable locally advanced, recurrent, or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma.¹

The application was supported by data from the phase 3 AK104-302 trial (NCT05008783) in which the addition of cadonilimab to chemotherapy resulted in a significant overall survival (OS) improvement compared with chemotherapy alone in this population, meeting the primary end point of the trial.² The survival benefit derived with the cadonilimab regimen was observed regardless of PD-L1 status, and was seen in those with a combined positive score of 5 or more or less than 5. Safety data aligned with what has previously been reported with the agent. No new safety signals were observed.

“There is a significant need to enhance overall effectiveness, particularly among patients with low PD-L1 expression,” Professor Ji Jiafu, MD, PhD, of the Peking University Cancer Hospital, stated in a press release.¹ “This addresses the limitations of current single-target immunotherapy in clinical settings, effectively showcasing the synergistic mechanism of ‘PD-1+CTLA-4’ dual immune therapy. It is expected to overcome the shortcomings of current immune treatment strategies for advanced gastric cancer and represents a potentially superior immunotherapeutic approach for this condition.”

The randomized, double-blind, multicenter, phase 3 study included patients with histopathologically confirmed gastric or GEJ adenocarcinoma who were between the ages of 18 and 75 years and who had at least 1 measurable lesion by RECIST v1.1 criteria.³ Although previous treatment for locally advanced or metastatic disease was not allowed, prior curative-intent neoadjuvant or adjuvant chemotherapy or chemoradiation was permitted if at least 6 months passed between progressive disease and the least treatment.

Those with HER2-positive gastric or GEJ adenocarcinoma, and those with squamous cell carcinoma, sarcoma, or undifferentiated carcinoma, were excluded. Other key exclusion criteria included receipt of palliative local therapy for non-target lesions, systemic nonspecific immunomodulatory therapy, or Chinese herbal medicine or traditional Chinese medical products with antitumor indications within 2 weeks before receipt of first study dose. Patients could not have known active or untreated brain metastases, meningeal metastases, spinal cord compression, or leptomeningeal disease.

Participants were randomized to placebo or cadonilimab given on day 1 of each 3-week cycle. Patients on both arms received intravenous oxaliplatin at 130 mg/m2 once every 3 weeks combined with oral capecitabine at 1000 mg/m2 twice daily. Following 6 cycles of chemotherapy, patients received maintenance placebo or cadonilimab once every 3 weeks.

In addition to the primary end point of OS in the intention-to-treat population, key secondary end points comprised disease control rate, overall response rate, duration of response, time to response, progression-free survival (PFS), and safety.

In June 2022, the NMPA approved cadonilimab for use in patients with relapsed or metastatic cervical cancer that had progressed on or following platinum-based chemotherapy.⁴ In November 2023, the phase 3 AK104-303 trial (NCT04982237) was reported to meet its primary end point when the first-line combination of cadonilimab and platinum-based chemotherapy with or without bevacizumab (Avastin) improved PFS by blinded independent central review and RECIST v1.1 criteria vs placebo plus chemotherapy with or without bevacizumab in this population.⁵ The P value was less than .0001. The PFS benefit was experienced irrespective of PD-L1 status. Moreover, there was a trend for improved OS with cadonilimab vs placebo.

“Since its approval for cervical cancer treatment in 2022, cadonilimab has garnered recognition from both clinicians and patients due to its remarkable efficacy and safety,” Yu Xia, PhD, founder, chairwoman, president, and chief executive officer of Akeso, stated in a press release.¹ “We eagerly anticipate the approval of its new indication for gastric cancer, as it will revolutionize the clinical treatment approach for advanced gastric cancer and introduce a new era of immunotherapy options for patients.”

References

1. Supplemental new drug application for Akeso’s cadonilimab (PD-1/CTLA-4) accepted by NMPA for first-line treatment of gastric cancer. News release. Akeso, Inc. January 5, 2024. Accessed January 8, 2024. https://www.prnewswire.com/news-releases/supplemental-new-drug-application-for-akesos-cadonilimab-pd-1ctla-4-accepted-by-nmpa-for-first-line-treatment-of-gastric-cancer-302027004.html
2. Akeso's cadonilimab (PD-1/CTLA-4) phase III trial meets primary endpoint at interim analysis demonstrating strong overall survival benefit as first-line treatment in all-comer patients with gastric cancer or gastroesophageal junction adenocarcinoma (GC/GEJC). News release. Akeso. November 7, 2023. Accessed January 8, 2024. https://www.prnewswire.com/news-releases/akesos-cadonilimab-pd-1ctla-4-phase-iii-trial-meets-primary-endpoint-at-interim-analysis-demonstrating-strong-overall-survival-benefit
3. A study of AK104 in the first-line treatment of locally advanced unresectable or metastatic G/​GEJ adenocarcinoma. ClinicalTrials.gov. Updated October 18, 2023. Accessed January 8, 2024. https://clinicaltrials.gov/study/NCT05008783
4. Akeso’s cadonilimab (PD-1/CTLA-4), the first dual immune checkpoint inhibitor to treat cancer, approved for marketing in China. Akeso. News release. June 29, 2022. Accessed January 8, 2024. https://www.akesobio.com/en/media/akeso-news/20220629/
5. Cadonilimab (PD-1/CTLA-4 bispecific antibody) met primary endpoint of progression-free survival in phase III trial for first-line treatment of recurrent/metastatic cervical cancer in all-comer patients. News release. Akeso, Inc. November 27, 2023. Accessed January 8, 2024. https://www.prnewswire.com/news-releases/cadonilimab-pd-1ctla-4-bispecific-antibody-met-primary-endpoint-of-progression-free-survival-in-phase-iii-trial-for-first-line-treatment-of-recurrentmetastatic-cervical-cancer-in-all-comer-patients-301996677.html