First-Line Ivonescimab Plus Chemo Improves PFS in Advanced Squamous NSCLC

Squamous NSCLC |
Image Credit: © catalin
– stock.adobe.com

Treatment with the PD-1– and VEGF-directed bispecific antibody ivonescimab (SMT112) in combination with chemotherapy resulted in a statistically significant and clinically meaningful progression-free survival (PFS) improvement vs tislelizumab (Tevimbra) in patients with advanced squamous non–small cell lung cancer (NSCLC), meeting the primary end point of the phase 3 HARMONi-6 trial (NCT05840016).1

In findings from a first pre-specified interim analysis, the ivonescimab regimen led to clinically meaningful improvements in PFS in both the PD-L1–positive and –negative populations. These findings support the potential role of ivonescimab as a novel first-line treatment option for patients with advanced squamous NSCLC, regardless of PD-L1 expression status.

"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 NSCLC but also marks a significant milestone in global oncology immunotherapy," Shun Lu, MD, PhD, director of Shanghai Lung Cancer, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, and principal investigator of the HARMONi-6 study, stated in a news release.

Regarding safety, no new safety signals were reported with ivonescimab, and the rates of grade 3 or higher bleeding adverse effects were comparable between the 2 arms. Full data are expected to be presented at an upcoming medical meeting in 2025.

"The interim analysis results from the HARMONi-6 study show that ivonescimab in combination with chemotherapy significantly prolonged PFS compared to tislelizumab with chemotherapy,” Lu continued. “In patients with up to 63% central squamous carcinoma, ivonescimab demonstrated a safety profile comparable [with] the control group. This highlights its potential to overcome the limitations of bevacizumab [Avastin] in treating squamous NSCLC, 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.”

The HARMONi-6 trial enrolled a total of 532 patients across 66 clinical research centers in China. Approximately 63% of patients enrolled had centrally located squamous cell carcinoma, a distribution consistent with real-world patient populations.

The randomized, controlled, multicenter study included patients at least 18 years of age with histologically or cytologically confirmed stage IIIB/C or IV squamous NSCLC who received no prior systemic therapy in the locally advanced or metastatic setting.2 Other key inclusion criteria included an ECOG performance status of 0 to 1, measurable disease per RECIST 1.1 criteria, adequate organ function, and a life expectancy of at least 3 months.

Investigators excluded patients with nonsquamous NSCLC, along with those harboring EGFR mutations, ALK translocations, ROS1 rearrangements, MET exon 14 skipping mutations, or RET gene fusions. Active central nervous system metastases also excluded patients from participation.

Patients were randomly assigned to receive ivonescimab once every 3 weeks or tislelizumab at 200 mg once every 3 weeks. Patients in both arms also received 4 cycles of chemotherapy comprising carboplatin at area under the curve 5 once every 3 weeks and paclitaxel at 175 mg/m2 once every 3 weeks.

Along with the primary end point of PFS, secondary end points included overall survival, overall response rate, duration of response, disease control rate, time to response, and safety.

"Today, we are incredibly excited to announce the third significant positive result for ivonescimab in a phase 3 study. PD-1 combined with chemotherapy remains the global standard of care for first-line treatment of NSCLC. Ivonescimab has once again demonstrated its breakthrough clinical value and market competitiveness as a next-generation cancer therapy through compelling clinical data," Xia Yu, PhD, founder, chairwoman, president, and chief executive officer of Akeso, added in a news release.1

Previously, findings from the phase 3 HARMONi-2 trial (NCT05499390) demonstrated a PFS benefit in patients with locally advanced or metastatic, PD-L1–positive NSCLC.3

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. Akeso. April 23, 2025. Accessed April 23, 2025. https://www.akesobio.com/en/media/akeso-news/250423/
2. AK112 in combination with chemotherapy in advanced squamous non-small cell lung cancer. ClinicalTrials.gov. Updated August 23, 2023. Accessed April 23, 2025. https://clinicaltrials.gov/study/NCT05840016
3. 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 April 23, 2025. https://www.businesswire.com/news/home/20240530536730/en content/uploads/2024/05/2024_PR_0530_Ivonescimab-AK112-303-Data-_-FINAL.pdf