Ivonescimab Under Priority Review by China’s NMPA for Frontline PD-L1–Positive NSCLC

A supplemental new drug application (sNDA) for a first-in-class PD-1/VEGF bispecific immunotherapy agent ivonescimab (AK112) has been granted priority review by the National Center for Drug Evaluation of the State Drug Administration of the People's Republic of China for the frontline treatment of patients with PD-L1–positive locally advanced or metastatic non–small cell lung cancer (NSCLC).¹

The sNDA was supported by findings from the phase 3 HARMONi-2 (AK112-303) trial. At a prespecified interim analysis conducted by an independent data monitoring committee, findings showed that ivonescimab elicited a statistically significant and clinically meaningful progression-free survival (PFS) improvement per blinded independent central review vs pembrolizumab (Keytruda), and a news release from Akeso stated that the HR was “significantly better than expected.” This PFS benefit was shown across all clinical subgroups, including in patients with low PD-L1 expression, those with high PD-L1 expression, those with squamous histologies, those with nonsquamous histologies, and those with other high-risk features.²

The news release also notes that there are no other known head-to-head phase 3 clinical trials that have shown a statistically significant PFS improvement for a treatment vs pembrolizumab in this setting.¹

This is the second indication for which ivonescimab has been granted priority review in China. In May 2024, the drug was approved in China through the priority review program for patients with EGFR-mutant, nonsquamous NSCLC that has progressed after EGFR TKI therapy. Ivonescimab has also been granted 3 breakthrough therapy designations by the Center for Drug Evaluation for the treatment of patients with lung cancer.

The HARMONi-2 Trial

HARMONi-2 enrolled patients at least 18 years of age with histologically or cytologically confirmed stage IIIB/C or IV NSCLC.3 Patients needed to have a life expectancy of at least 3 months; an ECOG performance status (PS) of 0 or 1; measurable disease per RECIST 1.1 criteria; and positive PD-L1 expression in tumor tissue. Patients were also required to have adequate organ function and to recover from the effects of any prior surgery or radiotherapy.

Patients were excluded if they had disease with any histologically confirmed small cell component; harbored EGFR mutations or ALK gene translocations; received prior systemic antitumor therapy for locally advanced or metastatic NSCLC; had known active central nervous system metastases; or had an active infection requiring systemic therapy.

Patients were randomly assigned to receive intravenous ivonescimab monotherapy at the selected dose or intravenous pembrolizumab monotherapy at 200 mg every 3 weeks. The primary end point was PFS. Key secondary end points included overall survival (OS), overall response rate, duration of response, disease control rate, and time to response.

The HARMONi-3 Trial

The ongoing phase 3 HARMONi-3 trial (NCT05899608) is enrolling patients at least 18 years of age with metastatic NSCLC that is histologically or cytologically confirmed to be squamous.4 Patients need to have an ECOG PS of 0 or 1, a life expectancy of at least 3 months, a tumor proportion score showing PD-L1 expression, and at least 1 measurable noncerebral lesion per RECIST 1.1 criteria.

Patients will be excluded if they have histologic or cytopathologic evidence of small cell lung carcinoma or nonsquamous NSCLC; known actionable genomic alterations in EGFR, ALK, ROS1, or other genes for which frontline therapies are approved; received any prior therapy for metastatic NSCLC; or had tumor invasion, encasement of organs, or encasement of major blood vessels, if deemed to pose a significantly increased risk of bleeding.

Patients are being randomly assigned to receive ivonescimab plus chemotherapy or pembrolizumab plus chemotherapy. OS in the intention-to-treat population serves as the trial’s primary end point. Key secondary end points include PFS per RECIST 1.1 criteria, as well as the incidence and severity of adverse effects and clinically significant laboratory test abnormalities.

References

1. Ivonescimab (PD-1/VEGF) received priority review from China’s NMPA for first-line treatment of PD-L1 positive NSCLC. News release. Akeso, Inc. August 15, 2024. Accessed August 15, 2024. https://www.akesobio.com/en/media/akeso-news/240815/
2. Ivonescimab monotherapy decisively beats pembrolizumab monotherapy head-to-head, achieves statistically significant superiority in PFS in first-line treatment of patients with PD-L1 positive NSCLC in China. News release. Summit Therapeutics. May 30, 2024. Accessed August 15, 2024.https://www.smmttx.com/pressrelease/ivonescimab-monotherapy-decisively-beats-pembrolizumab-monotherapy-head-to-head-achieves-statistically-significant-superiority-in-pfs-in-first-line-treatment-of-patients-with-pd-l1-positive-nsclc-in/
3. AK112 in advanced non-small cell lung cancer. ClinicalTrials.gov. Updated September 21, 2023. Accessed August 15, 2024. https://classic.clinicaltrials.gov/ct2/show/NCT05499390
4. Clinical study of ivonescimab for first-line treatment of metastatic squamous NSCLC patients. ClinicalTrials.gov. Updated June 14, 2024. Accessed August 15, 2024. https://clinicaltrials.gov/study/NCT05899608