Ivonescimab Tops Pembrolizumab in PD-L1-Positive, Advanced NSCLC

Ivonescimab — a novel first-in-class PD-1/VEGF bispecific antibody — led to clinically meaningful improvement in progression-free survival (PFS) compared with pembrolizumab (Keytruda) as first-line therapy for PD-L1-positive, advanced non-small cell lung cancer (NSCLC) in a Chinese trial.

In the phase III study, ivonescimab achieved a median PFS of 11.14 months compared with 5.82 months with pembrolizumab, translating into a 49% reduction in the risk of progression or death (HR 0.51, 95% CI 0.38-0.69, P<0.0001).

Nine-month PFS was 56% with ivonescimab versus 40% with pembrolizumab, as Caicun Zhou, MD, PhD, of Shanghai Pulmonary Hospital reported at a session at the World Conference on Lung Cancer in San Diego.

“This is the first randomized phase III trial to demonstrate a significant improvement in efficacy [compared with] pembrolizumab in advanced non-small cell lung cancer,” Zhou said.

Invited discussant John Heymach, MD, PhD, of the University of Texas MD Anderson Cancer in Houston, said results of the trial “really are striking, and exceed my expectations going into this study,” adding that the data, along with previously reported results, supported the possible superiority of ivonescimab to pembrolizumab in first-line NSCLC.

“But of course we’re awaiting the overall survival results, and we’re awaiting additional studies done outside China,” he said.

He also cautioned that pembrolizumab may not be a relevant comparator for the intermediate PD-L1 population (PD-L1 tumor proportion score [TPS] 1-49%), which made up more than half of the total study cohort.

Heymach pointed out that the KEYNOTE-042 study showed no significant overall survival benefit with pembrolizumab in the intermediate group compared with chemotherapy, whereas KEYNOTE-189, which evaluated adding pembrolizumab to chemotherapy, did find a significant overall survival benefit with pembrolizumab in the intermediate PD-L1 subgroup with nonsquamous histology.

“So, yes, pembrolizumab is approved in this population, but it would not be the treatment of choice for a good performance-status patient in the U.S., and I think in much of the rest of the world,” he said.

In the HARMONi-2 trial, 398 patients from 55 centers in China were randomized to receive either ivonescimab (20 mg/kg) or pembrolizumab (200 mg) every 3 weeks. To be eligible for the trial, patients had to have untreated locally advanced or metastatic NSCLC, ECOG performance status 0-1, and be PD-L1 positive (TPS ≥1%) but negative for EGFR mutations or ALK rearrangements.

About 42% of patients in the study had PD-L1 high (≥50%) expression, 13% had liver metastases, and 18% brain metastases.

Over the median follow-up of 8.7 months, the PFS benefit of ivonescimab over pembrolizumab was consistent across pre-specified subgroups, including patients with:

• Squamous NSCLC (HR 0.50, 95% CI 0.33-0.76)
• Non-squamous NSCLC (HR 0.55, 95% CI 0.36-0.84)
• PD-L1 TPS 1-49% (HR 0.54, 95% CI 0.37-0.78)
• PD-L1 TPS ≥50% (HR 0.48, 95% CI 0.29-0.79)
• Liver metastases (HR 0.47, 95% CI 0.23-0.98)

The effect was also directionally consistent, albeit not statistically significant, in the subgroup of patients with brain metastases (HR 0.55, 95% CI 0.28-1.05).

The overall response rate was 50% with ivonescimab versus 38.5% with pembrolizumab, while disease control rates were 89.9% and 70.5%, respectively.

Treatment-related adverse events (TRAEs) of all grades occurred in 89.8% of patients in the ivonescimab group and 81.9% of those in the pembrolizumab group, with grade 3 or worse TRAEs occurring in 29.4% and 15.6% of the two groups, respectively.

While ivonescimab roughly doubled grade 3 or worse TRAEs, there were fewer TRAEs leading to discontinuations with the drug (1.5% vs 3.0%) and one death as compared with two in the pembrolizumab arm.

Treatment-related serious adverse events were observed in 20.8% of patients in the ivonescimab arm and 16.1% in the pembrolizumab arm. Grade 3 or worse immune-related AEs occurred in 7.1% and 8.0%, respectively.

In his discussion, Heymach observed that the treatment landscape of first-line metastatic NSCLC without a driver mutation has been relatively stable over the last several years.

If the benefits from HARMONi-2 are confirmed with other studies, he said that “it is possible that the therapeutic harmony that we’ve had in this first-line space may finally come to an end, and I think that’s a disharmony that we all should be rooting for.”

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