Phase 3 HARMONi Trial Meets PFS Endpoint in EGFR-Mutated NSCLC

The phase 3 HARMONi trial has met its progression-free survival (PFS) endpoint and “showed a positive trend” in overall survival, which is the other primary endpoint of the study, officials from Summit Therapeutics Inc announced.

The multiregional, double-blinded, placebo-controlled study is evaluating ivonescimab plus platinum-doublet chemotherapy compared to placebo plus platinum-doublet chemotherapy in patients with EGFR-mutated, locally advanced or metastatic non-squamous non-small cell lung cancer (NSCLC) who have progressed after treatment with a 3rd generation EGFR tyrosine kinase inhibitor (TKI).

At the prespecified primary data analysis, ivonescimab plus chemotherapy “demonstrated a statistically significant and clinically meaningful improvement” in PFS, with a hazard ratio of 0.52 (95% CI: 0.41 – 0.66; P<0.00001). The PFS was measured by a blinded independent central radiology review committee (BICR) and compared to a placebo in combination with chemotherapy.

“A clinically meaningful hazard ratio was observed in both Asia and ex-Asia sub-populations,” officials explained in the announcement. “The primary analysis demonstrated the consistency of the magnitude of the PFS benefit between patients [randomly assigned] in Asia and ex-Asia, as well as the consistency in a single-region study (HARMONi-A) with this multiregional study.”

Officials also announced that the company intends to file a Biologics License Application (BLA) to seek approval for ivonescimab plus chemotherapy in this setting.

“Based on discussions with the United States Food & Drug Administration (FDA), under our determination and subject to our review, Summit will consider the timing of the filing of this BLA,” officials said in a news release. “The FDA noted that a statistically significant overall survival benefit is necessary to support marketing authorization, which will weigh into Summit’s considerations regarding the timing of a potential BLA .”

Ivonescimab plus chemotherapy also showed a “positive trend in OS in the primary analysis” but it did not achieve a statistically significant benefit, showing a hazard ratio of 0.79 (95% CI: 0.62 – 1.01; P=0.057). This trend was demonstrated in Asian and North American patients and the results of the primary analysis in this multiregional study “were consistent with that of the single-region HARMONi-A study, which demonstrated an overall survival hazard ratio of 0.80 at 52% data maturity in a similar patient population,” officials said.

Company officials noted that the study median follow-up time for western patients was less than the median overall survival at the time of the analysis, and these patients “may continue to be followed for long-term outcomes.”

However, this OS “trend provides further support” for the use of ivonescimab plus chemotherapy in second-line and later EGFR-mutated NSCLC, “a setting where high unmet need continues to exist with limited approved options in the U.S. and other western territories,” officials said in the news release, noting that “there are no current FDA-approved regimens that have demonstrated a statistically significant overall survival benefit in this patient setting.”

“The evidence of a consistent benefit in PFS for both Asian and western patients, as well as the consistent overall survival results between the single-region HARMONi-A study and our global HARMONi study demonstrates the potential benefit ivonescimab has to bring to patients around the world, including the U.S.,” Robert W. Duggan, Chairman and Co-Chief Executive Officer of Summit, said in a statement.

Officials noted that no new safety signals were observed in this study, with grade 3 or higher treatment-emergent adverse events reported for 56.9% of patients in the ivonescimab plus chemotherapy arm versus 50% with chemotherapy alone.

Fatal TEAEs, excluding disease progression, were reported for 1.8% of patients in the ivonescimab plus chemotherapy arm versus 2.8% in those patients receiving chemotherapy alone. The safety profile of ivonescimab plus chemotherapy was acceptable and manageable in the context of the observed clinical benefit.

A complete data presentation from the clinical study is intended to be shared at a future major medical conference, officials said.

“Our conviction in the promise that this therapy holds for patients continues to be validated: we believe that ivonescimab has the potential to make a meaningful difference for the betterment of patients’ lives,” Dr. Maky Zanganeh, President and Co-CEO of Summit, said in a news release.