Caicun Zhou, MD, PhD
In a phase III study conducted in China, the bispecific antibody ivonescimab demonstrated a statistically significant and clinically meaningful improvement in progression-free survival compared with the PD-1 inhibitor pembrolizumab as a first-line treatment of PD-L1–positive advanced non–small cell lung cancer (NSCLC), according to Zhou et al. These findings from the HARMONi-2 study were presented by Caicun Zhou, MD, PhD, of Shanghai Pulmonary Hospital, at the International Association for the Study of Lung Cancer (IASLC) 2024 World Conference on Lung Cancer.1
About HARMONi-2
Ivonescimab is a bispecific antibody targeting both PD-1 and the vascular endothelial growth factor (VEGF). It showed activity as front-line therapy in the phase II AK112-202 study.2
The phase III HARMONi-2 trial randomly assigned 398 patients from 55 centers in China to receive either ivonescimab (20 mg/kg) or pembrolizumab (200 mg) every 3 weeks. Patients had untreated locally advanced or metastatic NSCLC, and their tumors were PD-L1–positive (tumor proportion score [TPS] ≥ 1%) but negative for EGFR mutations or ALK rearrangements.
Patient Subgroups
At the planned interim analysis, with a median follow-up of 8.7 months, patients treated with ivonescimab achieved a median progression-free survival of 11.14 months compared with 5.8 months observed with pembrolizumab, representing a 49% reduction in the risk of disease progression or death (hazard ratio [HR] = 0.51; P < .0001). At 9 months, the progression-free survival rate was 56% with ivonescimab vs 40% with pembrolizumab.
The drug’s benefit was consistent across various patient subgroups, as demonstrated by robust hazard ratios: PD-L1–low (TPS = 1%–49%), HR = 0.54; PD-L1–high (TPS ≥ 50%), HR = 0.46; nonsquamous histology, HR = 0.54; squamous histology, HR = 0.48. Objective response rates were 50.0% with ivonescimab and 38.5% with pembrolizumab. Disease control rates were 89.9% and 70.5%, respectively, according to study data.
Safety Profiles
Safety profiles for both treatments were comparable, with no new safety signals identified for ivonescimab. Treatment-related serious adverse events were reported in 20.8% of patients receiving ivonescimab and 16.1% of those receiving pembrolizumab. Grade ≥ 3 immune-related adverse events were also similar between the two groups. In patients with squamous cell carcinoma, grade ≥ 3 toxicities were comparable between the two groups, approximately 20%. Ivonescimab produced slightly more proteinuria, hypertension, and laboratory abnormalities. All VEGF-related adverse events were grades 1 to 3 in both arms. Ivonescimab was associated with a numerically longer time to deterioration of global status, whose median was not reached with ivonescimab and was about 10 months with pembrolizumab.
Investigators indicated that the findings from HARMONi-2 support the use of ivonescimab as a first-line treatment option for patients with PD-L1–positive advanced NSCLC.
EXPERT POINT OF VIEW
John V. Heymach, MD
The invited discussant of HARMONi-2 was John V. Heymach, MD, Chair of Thoracic/Head and Neck Medical Oncology and the David Bruton Endowed Chair in Cancer Research at The University of Texas MD Anderson Cancer Center, Houston. He said the study was well designed, with “striking results” that were “remarkably consistent” across subgroups. “They exceeded my expectations going in,” he added.
However, he noted the enrollment of Chinese subjects alone and questioned whether pembrolizumab monotherapy is the appropriate comparator for ivonescimab. “Yes, pembrolizumab is approved in this population, but it is not the treatment of choice for patients with a good performance status in the United States and, I think, much of the world,” he commented. Focusing on the PD-L1–low subset, he noted, KEYNOTE-042 found minimal benefit in overall survival with pembrolizumab compared with chemotherapy among patients with a tumor proportion score (TPS) of 1%–49% (hazard ratio = 0.92).3 However, he acknowledged that KEYNOTE-189 found “substantial” survival benefit (hazard ratio = 0.55) for adding pembrolizumab to chemotherapy in patients with a TPS of 1% to 49% and nonsquamous histology.4
“The magnitude of benefit, coupled with the previously reported HARMONi-A results in the EGFR-mutant population,2 supports the possible superiority of ivonescimab to pembrolizumab in first-line non–small cell lung cancer [NSCLC],” he concluded. However, overall survival results and confirmatory studies outside China are needed.
Questions Still in Need of Answers
Several key initial questions need to be addressed, Dr. Heymach suggested:
- Is there a need for yet another PD-1/L1 inhibitor?
- Is there a mechanistic reason to expect ivonescimab to be much different from other PD-1/L1 inhibitors or other PD-1/VEGF pathway inhibitor combinations?
- Does ivonescimab have greater activity than the combination of separate VEGF and PD-1 antibodies?
To this last question, Dr. Heymach offered a “maybe,” predicting the single agent may indeed trump combinations of its target inhibitors. As he explained, VEGF helps drive tumor invasiveness through angiogenesis, and it can also suppress the tumor microenvironment.
“It’s important to draw a distinction: Ivonescimab blocks VEGF-alfa. VEGF-alfa binds to both VEGF receptor-1 and VEGF receptor-2. For tumor angiogenesis, VEGF receptor- 2 is the primary driver, but the antiimmune effects are mediated by VEGF receptor-1. This is important because drugs that block VEGF receptor-2 alone may not have the same immunomodulatory effects,” he pointed out. Although other combinations of anti–PD-1/VEGF have shown some promise, he added, their benefits do not achieve the “striking extent in terms of progression-free survival we see in this study.”
All things considered, Dr. Heymach shared these concluding remarks: “HARMONi-2, along with other recent studies, supports the broad potential benefit of PD-1/VEGF pathway blockade across major NSCLC subgroups.” If the benefit seen in this trial can be confirmed in other studies, he added, “it is possible that the therapeutic harmony we’ve had in this first-line space may finally come to an end. It’s this disharmony we should all be rooting for.”
DISCLOSURE: Dr. Zhou reported no conflicts of interest. Dr. Heymach has served as a consultant to AbbVie, AnHeart Therapeutics, ArriVent Biopharma, AstraZeneca, BioCurity Pharmaceuticals, BioNTech AG, Blueprint Medicines, Boehringer Ingelheim, BMS, Eli Lilly, EMD Serono, Genentech, GlaxoSmithKline, Janssen Pharmaceuticals, Mirati Therapeutics, Novartis Pharmaceuticals, Regeneron Pharmaceuticals, Sanofi, Spectrum Pharmaceuticals, and Takeda and has licensing/royalty agreements with 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: Primary analysis of HARMONi-2. 2024 World Conference on Lung Cancer. Abstract PL02.04. Presented September 8, 2024.
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 19:465-475, 2024.
3. Mok TSK, Wu YL, Kudaba I, et al: Pembrolizumab versus chemotherapy for previously untreated, PD-L1–expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): A randomised, open-label, controlled, phase 3 trial. Lancet 393:1819-1830, 2019.
4. Gandhi L, Rodríguez-Abreau D, Gadgeel S, et al: Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med 378:2078-2092, 2018.
