Ivonescimab/Chemo Prolongs PFS in 1L Advanced Squamous NSCLC

Ivonescimab plus chemotherapy prolonged PFS in the phase 3 HARMONi-6 trial where 63% of patients had centrally located squamous cell carcinoma.

Ivonescimab, a first-in-class PD-1/VEGF bispecific antibody, in combination with chemotherapy, demonstrated statistically significant and clinically meaningful results in untreated advanced squamous non–small cell lung cancer (NSCLC) at the first pre-specified interim analysis of the phase 3 HARMONi-6 trial (NCT05840016), according to a press release from the developer, Akeso.¹

The treatment combination met the trial’s primary end point of progression-free survival (PFS). In the intention-to-treat population, invonescimab plus chemotherapy “decisively beat” treatment of tislelizumab-jsgr (Tevimbra) plus chemotherapy with regards to PFS. Meaningful PFS benefits were also observed in patients with PD-L1–positive and PD-L1–negative disease.

More complete results from the HARMONi-6 trial are planned to be shared at an upcoming medical conference.

Previously, the combination elicited prolonged PFS in patients with NSCLC who progressed after EGFR tyrosine kinase inhibitors in the phase 3 HARMONi-A trial (NCT05184712).² The combination also demonstrated anti-tumor activity and tolerability in advanced NSCLC in the phase 2 AK112-202 trial (NCT04900363) and the phase 2 AK112-201 study (NCT04736823) trial.³

“The interim analysis results from the HARMONi-6 study show that ivonescimab in combination with chemotherapy significantly prolonged PFS compared with tislelizumab with chemotherapy. In patients with up to 63% central squamous carcinoma, ivonescimab demonstrated a safety profile comparable with the control group,” Lu Shun, MD, director of Shanghai Lung Cancer, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, and lead investigator of the HARMONi-6 trial, stated in the release.¹ “This highlights its potential to overcome the limitations of bevacizumab in treating squamous non–small cell lung cancer, ultimately enhancing the clinical benefits of immunotherapy for NSCLC. With its combined immune and antiangiogenic mechanisms, ivonescimab offers a promising new treatment option for patients with advanced squamous carcinoma.”

HARMONi-6 is a randomized, controlled trial evaluating the efficacy and safety of ivonescimab with chemotherapy vs tislelizumab with chemotherapy in patients with advanced squamous NSCLC.⁴ The trial enrolled a total of 532 patients, of whom 63% had centrally located squamous cell carcinoma. The developer noted that this patient population was resemblant of real-world populations.

Eligible patients were 18 years or older with histologically or cytologically confirmed stage IIIB/C or IV squamous NSCLC and no receipt of prior systemic anti-tumor therapy for locally advanced or metastatic NSCLC. Additionally, patients had an ECOG performance status of 0 or 1, measurable disease per RECIST v1.1, adequate organ function, and a life expectancy of 3 months or more.

Exclusion criteria include EGFR-sensitive mutations or ALK gene translocations; known ROS1 rearrangement, MET exon 14 skipping mutation, or were RET gene fusion positive; immunodeficiency or receipt of systemic steroid therapy within 2 years of first study dose; surgery within 30 days of study; active central nervous system metastases; and active infection requiring systemic therapy.

Treatment in the experimental arm consisted of ivonescimab administered via intravenous infusion at the selected dose every 3 weeks, carboplatin administered via intravenous infusion at area under the curve 5 once every 3 weeks, and 175 mg/m² of paclitaxel via intravenous infusion for every 3 weeks for 4 cycles. In the control arm, 200 mg of tislelizumab was administered intravenously every 3 weeks, and chemotherapy was the same as listed above.

The primary trial end point was PFS assessed by an independent regulatory review committee. Secondary end points include overall survival, overall response rate, number of patients with detectable anti-drug antibodies, PD-L1 expression, and safety.

The safety profile of ivonescimab plus chemotherapy in this population was favorable, with no new safety signals identified. The treatment-related serious adverse events incidence and bleeding events, of grade 3 or higher, with the experimental treatment were similar to the control group.

“It is a great honor for us to witness ivonescimab once again successfully challenge the optimal standard of care. This breakthrough not only advances the treatment of non-small cell lung cancer but also marks a significant milestone in global oncology immunotherapy,” said Shun.¹

References

1. Ivonescimab in combination with chemotherapy demonstrates statistically significant and strongly positive results in first-line treatment of squamous non-small cell lung cancer (sq-NSCLC) vs. tislelizumab in combination with chemotherapy. News release. Akesobio. April 22, 2025. Accessed April 23, 2025. https://tinyurl.com/3r7379fu
2. Fang W, Zhao Y, Luo Y, et al. Ivonescimab plus chemotherapy in non–small cell lung cancer with EGFR variant: a randomized clinical trial. JAMA. Published online May 31, 2024. doi:10.1001/jama.2024.10613
3. Zhang L, Zhou C, Fang W, et al. Intracranial activity of ivonescimab alone or in combination with platinum doublet chemotherapy in patients with advanced non-small cell lung cancer and brain metastases. Presented at the 2024 European Lung Cancer Congress; March 20-23, 2024; Prague, Czech Republic. Abstract 174P.
4. AK112 in combination with chemotherapy in advanced squamous non-small cell lung cancer. ClinicalTrials.gov. Updated August 23, 2023. Accessed April 23, 2025. https://tinyurl.com/35y9hur5