Novartis Launches First Head-to-Head Phase III Trial Comparing Kisqali and Ibrance in HER2-Enriched HR+/HER2- Advanced Breast Cancer

On September 19, Novartis announced a collaboration with the SOLTI Innovative Cancer Research Center to conduct a Phase III study codenamed Harmonia, designed to perform a head-to-head comparison of the efficacy of Kisqali versus Ibrance in combination with endocrine therapy for HER2-enriched (HER2E), HR+/HER2- advanced breast cancer.

HER2E refers to the presence of HER2 gene amplification without corresponding enhanced HER2 protein-mediated signaling activity at the transcriptional level. According to estimates by the National Cancer Institute, 30% to 40% of breast cancer patients with the HER2E subtype are clinically HER2-negative.

The Harmonia study is the first prospective Phase III trial to enroll patients with specific tumor molecular subtypes identified via RNA-level testing, as well as the first head-to-head clinical trial comparing CDK4/6 inhibitors in patients with HR+/HER2- advanced breast cancer. The Harmonia study is scheduled to launch in Q1 2022 and will be conducted across 80 centers in Spain, Portugal, and the United States, with progression-free survival (PFS) as the primary endpoint. Additionally, the study will evaluate whether Kisqali alters tumor biology to achieve a superior tumor response compared to Ibrance.

Novartis conducted this "head-to-head" comparison primarily because its competitor Ibrance, leveraging its first-mover advantage, has captured over 70% of the market share in the CDK4/6 inhibitor segment. Although Kisqali is the only CDK4/6 inhibitor to demonstrate an overall survival (OS) benefit over endocrine therapy alone for patients with HR+/HER2- advanced breast cancer across three pivotal clinical trials (MONALEESA-7, MONALEESA-3, and MONALEESA-2), it has not reversed the situation of being overshadowed by Ibrance in the market.

Although Ibrance sales continue to slow, with the drug even losing U.S. market share in the first two quarters of 2021, this trend is primarily attributable to the competitive impact of Eli Lilly’s Verzenio (abemaciclib). In comparable trials evaluating adjuvant combination endocrine therapy versus endocrine therapy alone for early HR+/HER2- breast cancer, Pfizer encountered a setback, while Eli Lilly reported positive results in its interim analysis. Novartis is also conducting a similar Phase III trial (NATALEE, NCT03701334); although results have not yet been disclosed, the study is likewise garnering high attention from the industry.

Although Kisqali currently appears to trail Verzenio in market momentum, the three-way rivalry in the CDK4/6 inhibitor landscape is poised to intensify. For Novartis, achieving success in a direct head-to-head comparison against Ibrance would fundamentally alter the competitive landscape. The Overall Survival (OS) advantage demonstrated in clinical trials would be substantially amplified, ultimately reshaping physicians' prescribing practices.

This may be the rationale behind Novartis's plan to conduct the Harmonia study, which aims to help patients with HR+/HER2-negative advanced breast cancer of the aggressive HER2-enriched (HER2E) molecular subtype determine the optimal treatment choice between Kisqali and Ibrance.

Note: The original text has been abridged.