Ivonescimab Improves PFS Vs Pembrolizumab in Advanced PD-L1+ NSCLC

"This is the first randomized phase 3 study to demonstrate a clinically significant improvement in efficacy with a novel drug compared with pembrolizumab in advanced NSCLC,” according to lead study author Caicun Zhou, MD, PhD.

The risk of disease progression or death decreased with frontline ivonescimab compared with pembrolizumab (Keytruda) among those with PD-L1–positive advanced non–small cell lung cancer (NSCLC), according to primary analysis data from the phase 3 HARMONi-2 trial (AK112-303; NCT05499390) presented at the IASLC 2024 World Conference on Lung Cancer (WCLC).¹

At a median follow-up of 8.67 months, the median progression-free survival (PFS) was 11.14 months (95% CI, 7.33-not estimable [NE]) among patients treated with ivonescimab (n = 198) vs 5.82 months (95% CI, 5.03-8.21) for those treated with pembrolizumab (n = 200; stratified HR, 0.51; 95% CI, 0.38-0.69; P <.0001). The 9-month PFS rates with ivonescimab and pembrolizumab were 56% (95% CI, 47%-64%) and 40% (95% CI, 32%-48%), respectively.

“This is the first randomized phase 3 study to demonstrate a clinically significant improvement in efficacy with a novel drug compared with pembrolizumab in advanced NSCLC,” Caicun Zhou, MD, PhD, lead study author and director of the Department of Oncology at Shanghai Pulmonary Hospital in China, said in a presentation of the data.

Moreover, the PFS improvement with ivonescimab was seen regardless of PD-L1 expression or histology. In patients with a PD-L1 tumor proportion score (TPS) between 1% and 49% and 50% or greater, the stratified HRs were 0.54 (95% CI, 0.37-0.79) and 0.46 (95% CI, 0.28-0.75), respectively. The HRs for patients with squamous and nonsquamous histology were 0.48 (95% CI, 0.31-0.74) and 0.54 (95% CI, 0.36-0.82), respectively. A subgroup analysis showed that patients with clinical stage IIIB/C disease (HR, 1.01; 95% CI, 0.29-3.51) were the only population who did not derive benefit from ivonescimab.

“HARMONI-2 is a well-designed randomized phase 3 study comparing ivonescimab with pembrolizumab in the frontline, PD-L1 TPS ≥1% setting in China,” John V. Heymach, MD, PhD, discussant and chair of the Department of Thoracic/Head and Neck Medical Oncology at The University of Texas MD Anderson Cancer Center in Houston, said. “For the PD-L1 TPS 1%-49% group, pembrolizumab monotherapy is approved but would not be the preferred comparator in the US and the rest of the world,” he added, noting that a different study design likely will be required before changes are made to current practices.¹

The Origins of the HARMONi-2 Trial

The frontline standard of care for patients with oncogene driver–negative, PD-L1–positive advanced NSCLC is PD-(L)1 inhibitors alone or in combination with chemotherapy. However, clinical benefit is modest for patients treated with current immune monotherapies. Ivonescimab is a novel bispecific antibody targeting PD-1 and VEGF that has proven clinical benefit and safety in this population.

Prior findings from the phase 1b/2 HARMONi-5 trial (AK112-202; NCT04900363) demonstrated that ivonescimab led to an objective response rate (ORR) of 60.0% and a disease control rate (DCR) of 93.3% in efficacy evaluable patients treated at the 20-mg/kg every-3-week dose level (n = 15), which was the dose level selected for this phase 3 trial. Median follow-up at the time of the analysis was 10.4 months (range, 8.4-10.9).²

Findings from HARMONi-5 served as the basis for the randomized, double-blind HARMONi-2 trial, which was designed to provide 90% power to detect a HR of 0.67 with an approximate sample size of 388 patients and 264 PFS events. Per the study protocol, an interim PFS analysis was planned when 185 (70%) of independent radiology review committee (IRRC)–assessed PFS events occurred.1

Eligible patients had stage IIIB to IV advanced NSCLC with an ECOG performance status of 0 or 1 and PD-L1 TPS of at least 1%. Patients who received prior systemic therapy or had a documented EGFR mutation or ALK rearrangement were excluded.

A total of 398 patients were randomly assigned 1:1 to receive 20 mg/kg of ivonescimab every 3 weeks or 200 mg of pembrolizumab every 3 weeks. Treatment was continued for up to 24 months or loss of clinical benefit or unacceptable toxicity, whichever came first. Patients were stratified by clinical stage (IIIB/C vs IV), histology (squamous vs nonsquamous), and PD-L1 TPS (≥50% vs 1%-49%).

The primary end point of the study was PFS by blinded IRRC per RECIST 1.1 criteria. Secondary end points included overall survival (OS), investigated-assessed PFS, ORR, duration of response (DOR), time to response, and safety. Quality of life served as an exploratory end point.

The Makeup of the HARMONi-2 Trial Population and Additional Data

Baseline characteristics of the ivonescimab population revealed that most patients were at least 65 years of age (51.0%), male (82.8%), and had an ECOG performance status of 1 (87.4%). Most patients were also former smokers (60.6%) and had clinical stage IV disease (92.4%), nonsquamous histology (54.5%), and a PD-L1 TPS between 1% and 49% (58.1%). The minority of patients had liver (12.6%) and brain (16.7%) metastases. Per pathology, most patients’ tumors were centrally located (72.2%) although some had tumors that were encasing a large blood vessel (6.7%) or had cavitation/necrosis (10.0%). The baseline characteristics in the ivonescimab arm were generally similar to those of patients in the pembrolizumab arm.

Additional results indicated that the ORR was higher with ivonescimab vs pembrolizumab, at 50% (95% CI, 42.8%-57.2%) vs 38.5% (95% CI, 31.7%-45.6%), respectively. The DCR was 89.9% (95% CI, 84.8%-93.7%) with ivonescimab and 70.5% (95% CI, 63.7%-76.7%) with pembrolizumab. The median duration of response was not reached in either arm.

Zhou noted that the OS data were not mature at the time of the presentation having not met the required number of events, and the data will be reported in the future.

Safety Findings With Bispecific Blockade of PD-1/VEGF

“The safety profile of ivonescimab was consistent with prior studies and well tolerated, including in patients with squamous NSCLC,” Zhou said. “The differences in adverse effects [AEs] were predominantly proteinuria, hypertension, and laboratory abnormalities,” he added.

Grade 3 or greater treatment-related AEs (TRAEs) occurred in 29.4% of patients who received at least one dose of ivonescimab (n = 197). The most common AEs that occurred in at least 10% of patients in the ivonescimab arm were proteinuria (31.5%), increased aspartate aminotransferase levels (19.8%), hypercholesterolemia (16.2%), increased blood bilirubin levels (15.7%), hypertension (15.7%), increased alanine aminotransferase levels (14.7%), hypothyroidism (14.2%), anemia (13.2%), hypoalbuminemia (11.7%), increased amylase levels (11.2%), hyperglycemia (11.2%), increased blood and uric acid levels (10.7%), arrhythmia (10.2%), hypertriglyceridemia (10.2%), and rash (7.6%).

Overall TRAEs led to ivonescimab discontinuation in 1.5% of patients and death in 0.5% of patients. In the population with squamous histology (n = 90), grade 3 or greater TRAEs occurred in 22.2% of patients; 2.2% of patients discontinued ivonescimab because of TRAEs and no TRAEs led to death in this subset.

With regard to immune-related AEs, grade 3 or greater toxicities occurred in 29.9% of patients who received ivonescimab (grade ≥3, 7.1%), but none led to treatment discontinuation or death. Possible VEGF-related AEs occurred in 47.7% of patients treated with ivonescimab (grade ≥3, 10.2%). Grade 3 hemorrhage occurred in 2 patients with nonsquamous disease in the ivonescimab arm.

Ivonescimab also appeared to provide a “comparable, numerically better” time to deterioration in global health status vs pembrolizumab according to the EORTC QLQ-C30; the median value was not reached (95% CI, 9.63-NE) with ivonescimab vs 9.92 months (95% CI, 8.02-NE) with pembrolizumab (stratified HR, 0.92; 95% CI, 0.63-1.33).

Trial Conclusions

“Ivonescimab is a novel frontline treatment for patients with advanced NSCLC and positive PD-L1 [expression],” Zhou said.

“The magnitude of benefit, coupled with the previously reported [phase 3] HARMONi-A [NCT05184712] results in the EGFR-mutated population, supports the possible superiority of ivonescimab to pembrolizumab in frontline NSCLC. [We await] OS results and confirmatory studies outside of China,” Heymach said in conclusion.

Disclosures: Zhou cited receiving honoraria for serving as a speaker for Lilly China, Sanofi, BI, Roche, MSD, Qilu, Hengrui, Innovent Biologics, C-Stone, LUYE Pharma, TopAlliance Biosciences Inc., Amoy Diagnostics; and for serving as an advisor for Innovent Biologics, Hengrui, Qilu, and TopAlliance Biosciences Inc.

Heymach reported serving as a consultant for AbbVie, AnHeart Therapeutics, ArriVent Biopharma, AstraZeneca, BioCurity Pharmaceuticals, BioNTech AG, Blueprint Medicines, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly & Co, EMD Serono, Genentech, GlaxoSmithKline, Janssen Pharmaceuticals, Mirati Therapeutics, Novartis Pharmaceuticals, Regeneron Pharmaceuticals, Sanofi, Spectrum Pharmaceuticals, and Takeda. He has received grant/research support from AstraZeneca, Boehringer Ingelheim, Spectrum, Mirati, Bristol Myers Squibb, and Takeda; and licensing/royalties from Spectrum.

References

1. Zhou C, Chen J, Wu L, et al. Phase 3 study of ivonescimab (AK112) vs. pembrolizumab as first-line treatment for PD-L1-positive advanced NSCLC: HARMONi-2. Presented at: 2024 IASLC World Conference on Lung Cancer; September 7-10, 2024; San Diego, California. Abstract PL02.04.
2. Wang L, Luo Y, Ren S, et al. A phase 1b study of ivonescimab, a programmed cell death protein-1 and vascular endothelial growth factor bispecific antibody, as first- or second-line therapy for advanced or metastatic immunotherapy-naive NSCLC. J Thorac Oncol. 2024;19(3):465-475. doi:10.1016/j.jtho.2023.10.014