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CHICAGO -- An investigational bispecific antibody targeting PD-1 and VEGF significantly decreased the risk of disease progression or death in patients with metastatic EGFR-mutant non-small cell lung cancer (NSCLC) who progressed on targeted agents, a randomized study from China showed.

In primary results of the HARMONi-A trial, median progression-free survival (PFS) improved from 4.8 months with standard platinum-based chemotherapy plus placebo to 7.1 months with chemotherapy plus ivonescimab (HR 0.46, 95% CI 0.34-0.62, P<0.001), reported Li Zhang, MD, of Sun Yat-sen University Cancer Center in Guangzhou.

The PFS benefit was consistent across all molecular and clinical subgroups, including patients with brain metastases and those who received a third-generation EGFR tyrosine kinase inhibitor (TKI) such as osimertinib (Tagrisso), Zhang said at the American Society of Clinical Oncology (ASCO) meeting here.

"Moreover, there is a trend toward an overall survival benefit, with a separation of the curves that has been sustained over time," he added. "The safety profile was generally manageable without any unexpected safety events and a lower rate of treatment discontinuation."

Findings of the double-blind phase III trial were simultaneously published in .

"The regimen could become another standard-of-care treatment option for EGFR-mutant non-small cell lung cancers progressing on a TKI," said ASCO-designated discussant William William Jr., MD, of Grupo Oncoclínicas in São Paulo, Brazil, though he added that he was less enthusiastic if patients had received the FLAURA-2 regimen (osimertinib plus chemotherapy) as their initial treatment.

Doublet platinum-based chemotherapy, as used in HARMONi-A, is recommended by the National Comprehensive Cancer Network for NSCLC patients who progress on EGFR TKIs, but multiple trials have attempted to improve on outcomes with the addition of PD-1/L1 blockade, VEGF inhibitors, or other drugs.

Adding nivolumab (Opdivo) or pembrolizumab (Keytruda) monotherapy to the standard chemotherapy failed to improve PFS or overall survival (OS) in the and KEYNOTE-789 trials, respectively. Inclusion of both anti-VEGF and checkpoint blockade with chemotherapy has yielded PFS improvements, but those benefit.

"HARMONi-A is the only study where there seems to be a potential benefit for overall survival, although the data is still immature," said William.

With 52% of recorded events, median OS reached 17.1 months in the ivonescimab arm versus 14.5 months in the control arm (HR 0.80, 95% CI 0.59-1.08), a difference that did not reach significance.

The MARIPOSA-2 trial also showed promise in this setting, William noted. In that study, amivantamab (Rybrevant) -- an EGFR- and MET-directed bispecific antibody -- improved PFS and showed a trend toward an OS benefit when added to chemotherapy compared with chemotherapy alone. Those phase III data are with the FDA.

A potential hurdle for ivonescimab's approval is that the FDA has recently been turning away PD-1 inhibitors and other cancer drugs developed exclusively in China, though it has made exceptions when the drug would fill an unmet need.

"I hope the fact that the study was only done in Asia is not a limiting factor for regulatory agencies worldwide to approve this regimen," said William.

Zhang noted that the trial is being expanded globally and will enroll patients in North America and Europe.

Ivonescimab is already approved in China and made a splash ahead of the ASCO meeting when its drugmaker that first-line use of the bispecific antibody alone improved PFS over pembrolizumab alone in a head-to-head trial () of PD-L1-positive NSCLC.

Zhang presented primary analysis data for the , which randomized 322 patients with previously treated EGFR-mutant nonsquamous NSCLC to carboplatin-pemetrexed chemotherapy plus either ivonescimab (AK112/SMT112) or placebo at 55 centers across China. Patients were required to have a good performance status and were stratified by previous receipt of a third-generation EGFR inhibitor and by the presence of brain metastases at baseline.

Participants had a median age of about 60, and a slight majority were women. More than 97% of patients had stage IV disease, with brain metastases in 22% and liver metastases in 12%. Most (86%) had received third-generation EGFR inhibitors (osimertinib in 59%) -- as first-line therapy for about one-third of the patients and as second-line therapy for a little more than half.

Prespecified subgroup analyses of the primary endpoint of PFS showed a similar benefit for patients who had received third-generation EGFR inhibitors (HR 0.48, 95% CI 0.35-0.66), those with brain metastases (HR 0.40, 95% CI 0.22-0.73), and across molecular subtypes:

• Exon 19 deletion: HR 0.48 (95% CI 0.32-0.73)
• L858R: HR 0.43 (95% CI 0.27-0.67)

Overall response rates were 50.6% in the ivonescimab arm and 35.4% in the placebo arm (P=0.006), with a median duration of response of 6.6 and 4.2 months, respectively.

Safety data showed more grade ≥3 adverse events (AEs) in the ivonescimab arm (61.5% vs 49.1% in the placebo arm), with the most common including decreases in neutrophil counts, white blood cell counts, and platelet counts; and anemia. Chemotherapy was responsible for most of the AEs, said Zhang.

The ivonescimab regimen was also associated with more serious AEs versus placebo (41% vs 25.2%) but generally low rates of grade ≥3 immune-related AEs (6.2% vs 2.5% in the placebo arm) or VEGF-related AEs (3.1% vs 2.5%, respectively). AEs leading to discontinuation of either ivonescimab or placebo occurred in 5.6% and 2.5%.

William said the biggest limitation of the trial was the decision not to include anti-VEGF in the control arm, making it unclear if the benefit seen is related to VEGF inhibition alone or the combination of VEGF and PD-1 inhibition.