The Novel Bispecific Antibody Ivonescimab May be Poised to Change the SOC in NSCLC

Ivonescimab (AK112; SMT112) stood out at the 2024 IASLC World Conference on Lung Cancer (WCLC) when data presented were the first from a randomized, phase 3 study to demonstrate a clinically significant improvement in efficacy with a novel drug vs pembrolizumab (Keytruda) in patients with advanced non–small cell lung cancer (NSCLC).1 In the phase 3 HARMONi-2 trial (NCT05499390), frontline treatment with ivonescimab significantly improved independent radiology review committee (IRRC)–assessed progression-free survival (PFS) vs pembrolizumab in patients with advanced disease and a PD-L1 tumor proportion score (TPS) of at least 1% (HR, 0.51; 95% CI, 0.38-0.69; P < .0001).

Encouraging data from HARMONi-2 supported the August 2024 priority review granted by China’s National Center for Drug Evaluation of the State Drug Administration to the supplemental new drug application seeking the approval of ivonescimab for the frontline treatment for patients with PD-L1–positive locally advanced or metastatic NSCLC.2 Additionally, based on data from the phase 3 HARMONi-A trial (NCT05184712), the FDA granted fast track designation to ivonescimab plus platinum-based chemotherapy for the treatment of adult patients with locally advanced or metastatic EGFR-mutant NSCLC who experience disease progression following EGFR-TKI therapy.3

“Ivonescimab is a PD-1/VEGF bispecific antibody with this cooperative binding property that has the potential to move the bar forward in both oncogene-driven and non-oncogene–driven squamous and nonsquamous advanced NSCLC. However, we need trials in a more diverse patient population, which are ongoing, to prove that [benefit],” Jonathan Wesley Riess, MD, MS, said in an interview with OncLive®. Riess is medical director of thoracic oncology and an associate professor of medicine at UC Davis Comprehensive Cancer Center in Sacramento, California.

As HARMONi-2 was conducted at a single location at Shanghai Pulmonary Hospital in China, investigators are awaiting confirmatory data on ivonescimab’s efficacy in the PD-L1–positive setting.4 Notably, the manufacturer of ivonescimab, Akeso Biopharma, highlighted that 2 global, multiregional clinical trials and 4 registrational trials evaluating ivonescimab vs anti–PD-1 therapies are being conducted; these are all phase 3 trials.5

Drilling Down on the First-in-Class Agent: Ivonescimab Bests Pembrolizumab

Findings from HARMONi-2 showed that at a median follow-up of 8.67 months, patients who received ivonescimab (n = 198) achieved a median PFS of 11.14 months (95% CI, 7.33-not estimable) compared with 5.82 months (95% CI, 5.03-8.21) among those treated with pembrolizumab (n = 200).1 The PFS benefit observed with ivonescimab vs pembrolizumab was consistent across major clinical subgroups; overall survival (OS) data were not mature at the time of the primary analysis data presentation given at WCLC.

“Particularly, [there was] a PFS benefit in the 1% to 49% PD-L1 expression subgroup, as well as the 50% or above expression subgroup. Also, [a benefit was seen regarding] histology in patients with squamous and nonsquamous disease. This was particularly noteworthy because the phase 3 KEYNOTE-042 trial [NCT02220894] looked at PD-L1 expression [of] 1% or more with pembrolizumab, [and] the benefit was really driven by the 50% or more subgroup,” Riess noted.

PFS benefits with the first-in-class bispecific antibody targeting PD-1 and VEGF vs pembrolizumab were seen in the PD-L1–low expression group with a TPS of 1% to 49% (stratified HR, 0.54; 95% CI, 0.37-0.79), the PD-L1–high expression group with a TPS of at least 50% (stratified HR, 0.46; 95% CI, 0.28-0.75), the squamous histology population (stratified HR, 0.48; 95% CI, 0.31-0.74), and the nonsquamous histology population (stratified HR, 0.54; 95% CI,0.36-0.82).1

“Anti-angiogenesis agents such as bevacizumab [Avastin] can’t be given in squamous lung cancer. You can give ramucirumab [Cyramza] but not bevacizumab, and [the fact] that you’re able to deliver [ivonescimab] in the first-line setting in patients with squamous disease is also noteworthy. Notably, for the 1% to 49% [TPS] subgroup, the comparator [arm] of pembrolizumab is not standard of care [SOC]. For PD-L1–high [tumors with a TPS of] 50% or more, [pembrolizumab] is a SOC, but our SOC for patients with 1% to 49% [expression] is chemotherapy plus a PD-1 agent. [In the HARMONi-2 trial, the comparator arm] wasn’t quite the SOC that we would have [used] in the United States [US]; this was a Chinese-specific clinical trial that will need to be replicated in the US and in more diverse patient populations.”

In HARMONi-2, patients with stage IIIB to IV advanced NSCLC without EGFR or ALK rearrangements and a PD-L1 TPS of at least 1% were enrolled. Patients were stratified by clinical stage (IIIB/C vs IV), histology (squamous vs nonsquamous), and PD-L1 TPS (≥50% vs 1%-49%). PFS was the primary end point; patients were randomly assigned 1:1 to receive ivonescimab at 20 mg/kg every 3 weeks vs pembrolizumab at 200 mg every 3 weeks until no clinical benefit, unacceptable toxicity, or up to 24 months.

The baseline patient characteristics were generally well balanced between arms, and most patients were male (83.7%), had stage IV disease (92.2%), did not have liver metastases (86.7%), did not have brain metastases (81.9%), and had an ECOG performance of 1 (87.2%) rather than 0 (12.8%). Additionally, patients had nonsquamous (54.5%) and squamous (45.5%) histology, with most squamous tumors located centrally (67.4%). More patients had a PD-L1 TPS of 1% to 49% (57.8%) than 50% or more (42.2%).

Further Examining Ivonescimab: Next Steps, Safety, and More

“VEGF is a key cytokine in the development of normal blood vessels, but also in the development of vessels, tumors, and other tissues undergoing abnormal angiogenesis. By blocking that, you can modify the tumor microenvironment—in some sense, the tumor immune microenvironment—and inhibit angiogenesis and this abnormal vascular growth,” Riess said.

“[Ivonescimab is a] bispecific antibody, so you [target] PD-1 as well, [and] it’s acting as an immune checkpoint inhibitor. One can say, ‘Why not combine a VEGF antibody like bevacizumab and a PD-1 antibody like pembrolizumab; wouldn’t you have the same thing?’ What’s interesting is that this bispecific antibody [has] exhibited cooperative binding properties where binding to one target increases the affinity for binding to another. We’ve seen that with ivonescimab as well as other bispecific antibodies in development, and that’s a unique functional property that one could hypothesize would make it favorable to test in patients with lung cancers and other cancers.”

Furthermore, in the phase 3 HARMONi-A trial, ivonescimab plus chemotherapy (n = 161) elicited a median PFS per IRRC assessment of 7.1 months (95% CI, 5.9-8.7) in patients with EGFR-mutant nonsquamous NSCLC who progressed on prior EGFR TKIs vs 4.8 months (95% CI, 4.2-5.6) in those who received placebo plus chemotherapy (n = 161; HR, 0.46; 95% CI, 0.34-0.62; P < .001); this met the primary end point of the study.6 At 52% data maturity, there was also a favorable trend seen regarding OS (HR, 0.80; 95% CI, 0.59-1.08).

Riess also noted that ivonescimab has a shorter half-life, which may allow for a more tolerable safety profile compared with other agents. The agent’s safety profile was manageable in HARMONi-2, which was consistent with what was observed in previous studies, according to investigators.1

Patients in the safety population of HARMONi-2 treated with ivonescimab (n = 197) vs pembrolizumab (n = 199) experienced grade 3 or higher treatment-related adverse effects (TRAEs; 29.4% vs 15.6%), serious TRAEs (20.8% vs 16.1%), and TRAEs leading to discontinuation (1.5% vs 3.0%), respectively. TRAEs led to death in 1 patient who received ivonescimab and 2 patients who received pembrolizumab. HARMONi-2 investigators noted that the differences seen regarding AEs were predominantly with proteinuria (any-grade, 31.5% vs 10.1%) and hypertension (15.7% vs 2.5%).

When asked where ivonescimab could have the biggest impact, Riess said, “There are 2 settings that come to mind. One is in those EGFR oncogene driver–type subsets of lung cancer, which [represents] a significant portion of our population [where I practice in Northern California]. There’s still not an effective PD-1 agent for that patient population, and bringing something that has activity to those patients would be noteworthy and a step forward. The other settings [could be in patients with] PD-L1–high [expression] as a single agent, PD-L1–lower [expression with] potential combinations with chemotherapy, and squamous [disease] as well. There are several settings where ivonescimab has the potential to move the bar forward.”

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. Ivonescimab (PD-1/VEGF) received priority review from China’s NMPA for first-line treatment of PD-L1 positive NSCLC. News release. Akeso Biopharma. August 15, 2024. Accessed December 20, 2024. https://www.akesobio.com/en/media/akeso-news/240815/
3. Summit Therapeutics announces completion of enrollment in its phase III HARMONi trial in 2L+ EGFRm NSCLC. News release. News release. Summit Therapeutics. October 3, 2024. Accessed December 20, 2024. https://www.smmttx.com/pressrelease/promising-anti-tumor-activity-and-safety-of-ivonescimab-in-combination-therapies-in-crc-tnbc-and-hnscc-featured-at-esmo-2024-3/
4. AK112 in advanced non-small cell lung cancer. ClinicalTrials.gov. Updated September 21, 2023. Accessed December 20, 2024. https://clinicaltrials.gov/study/NCT05499390
5. Two ivonescimab (PD-1/VEGF) results including phase 3 monotherapy versus pembrolizumab monotherapy in first-line treatment for PD-L1 positive NSCLC to be presented at WCLC 2024. News release. Akeso Biopharma. August 11, 2024. Accessed December 20, 2024. https://www.akesobio.com/en/media/akeso-news/240810/
6. Zhang L, Fang W, Zhao Y, et al. Ivonescimab combined with chemotherapy in patients with EGFR-mutant non-squamous non-small cell lung cancer who progressed on EGFR tyrosine-kinase inhibitor treatment (HARMONi-A): A randomized, double-blind, multi-center, phase 3 trial. J Clin Oncol. 2024;42(suppl 16):8508. doi:10.1200/JCO.2024.42.16_suppl.8508