For patients with PD-L1-positive advanced non-small cell lung cancer (NSCLC), frontline treatment via ivonescimab resulted in a 49% reduction in the risk of disease progression or death when compared to treatment with Keytruda (pembrolizumab), study findings have shown.
Findings from the primary analysis of the phase 3 HARMONi-2 trial were presented at the 2024 IASLC World Conference on Lung Cancer.
At a median follow-up of 8.67 months, the median progression-free survival (PFS; the time a patient lives without their disease spreading or worsening) was 11.14 months among patients treated with ivonescimab (198 patients) versus 5.82 months for those treated with Keytruda (200 patients), meaning there was a 49% lower risk of progression or death with ivonescimab. The nine-month PFS rates with ivonescimab and Keytruda were 56% and 40%, respectively.
Study Highlights
- Ivonescimab, a novel drug, has shown a clinically significant improvement in efficacy compared to Keytruda (pembrolizumab) in frontline treatment of PD-L1-positive advanced NSCLC.
- Patients treated with ivonescimab experienced a 49% lower risk of disease progression or death compared to those treated with Keytruda.
- Median progression-free survival (PFS) was significantly longer for patients treated with ivonescimab (11.14 months) compared to those treated with Keytruda (5.82 months).
- The improvement in PFS with ivonescimab was observed regardless of PD-L1 tumor proportion score, indicating its effectiveness across different patient populations.
“This is the first randomized phase 3 study to demonstrate a clinically significant improvement in efficacy with a novel drug compared with [Keytruda] in advanced NSCLC,” Dr. Caicun Zhou, 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 (the microscopic study of tissues and cells). In patients with a PD-L1 tumor proportion score (TPS) between 1% and 49% and 50% or greater, the risks of disease progression or death were 46% and 54% lower, respectively.
A PD-L1 test, according to the American Lung Association, measures the percentage of cells in a tumor that express PD-L1. PD-L1, according to the National Cancer Institute, is a protein that works to control the body’s immune cell responses.
A subgroup analysis showed that patients with clinical stage 3B/C disease were the only population who did not derive benefit from ivonescimab.
“HARMONI-2 is a well-designed randomized phase 3 study comparing ivonescimab with [Keytruda] in the frontline, PD-L1 TPS [of at least] 1% setting in China,” Dr. John V. Heymach, 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% to 49% group, [Keytruda] monotherapy is approved but would not be the preferred comparator in the U.S. 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.
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.
Bispecific antibodies work by bringing healthy T cells, part of the body’s immune system, close to cancer cells with the goal of helping the T cells kill the cancer cells.
Prior findings from the phase 1b/2 HARMONi-5 trial demonstrated that ivonescimab led to an objective response rate (ORR; patients who responded partially or completely to treatment) of 60% and a disease control rate (DCR; patients whose disease disappeared, shrunk or is stable from treatment) of 93.3% in efficacy evaluable patients treated at the 20-miligrams per kilogram every-three-week dose level (15 patients), which was the dose level selected for this phase 3 trial. Median follow-up at the time of the analysis was 10.4 months.
Findings from HARMONi-5 served as the basis for the randomized, double-blind HARMONi-2 trial.
Eligible patients had stage 3B to 4 advanced NSCLC with an ECOG performance status of 0 or 1 (meaning patients may be restricted in strenuous activity but are able to carry out daily tasks) 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 to receive 20 milligrams per kilogram of ivonescimab every three weeks or 200 mg of Keytruda every three weeks. Treatment was continued for up to 24 months or loss of clinical benefit or unacceptable toxicity, whichever came first.
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%), 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 4 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%).
The baseline characteristics in the ivonescimab arm were generally similar to those of patients in the Keytruda arm.
Additional results indicated that the ORR was higher with ivonescimab versus Keytruda, at 50% versus 38.5%, respectively. The DCR was 89.9% with ivonescimab and 70.5% with Keytruda. The median duration of response was not reached in either arm. Of note, when the median duration of response is not reached in a clinical trial, this suggests that a significant number of patients are still experience a response to the treatment, even after a prolonged period.
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 [side effects] were predominantly proteinuria (high protein levels in the urine), hypertension and laboratory abnormalities,” he added.
Grade 3 (severe) or greater treatment-related side effects occurred in 29.4% of patients who received at least one dose of ivonescimab (197 patients). The most common side effects that occurred in at least 10% of patients in the ivonescimab arm were proteinuria (31.5%), increased aspartate aminotransferase levels (indicative of liver disease, 19.8%), hypercholesterolemia (high cholesterol, 16.2%), increased blood bilirubin levels (15.7%), hypertension (high blood pressure; 15.7%), increased alanine aminotransferase levels (a sign of liver damage, 14.7%), hypothyroidism (14.2%), anemia (low red blood cell count, 13.2%), hypoalbuminemia (low albumin levels in the blood, 11.7%), increased amylase levels (potentially indicative of pancreas issues, 11.2%), hyperglycemia (high blood sugar, 11.2%), increased blood and uric acid levels (10.7%), arrhythmia (irregular heartbeat; 10.2%), hypertriglyceridemia (high levels of triglycerides, 10.2%) and rash (7.6%).
Overall treatment-related side effects led to ivonescimab discontinuation in 1.5% of patients and death in 0.5% of patients.
In the population with squamous histology (90 patients), grade 3 or greater treatment-related side effects occurred in 22.2% of patients; 2.2% of patients discontinued ivonescimab because of treatment-related side effects and no treatment-related side effects led to death in this subset.
With regard to immune-related side effects, any-grade toxicities occurred in 29.9% of patients who received ivonescimab (grade 3 or higher, 7.1%), but none led to treatment discontinuation or death. Possible VEGF-related AEs occurred in 47.7% of patients treated with ivonescimab (grade or higher, 10.2%). Grade 3 hemorrhage (bleeding) occurred in two patients with nonsquamous disease in the ivonescimab arm.
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 results in the EGFR-mutated population, supports the possible superiority of ivonescimab to [Keytruda] in frontline NSCLC. [We await] OS results and confirmatory studies outside of China,” Heymach said in conclusion.
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