Abstract P3-23-06: Assessment of select HER2-negative metastatic breast cancer (mBC) agents as a proxy to understand health technology assessment bodies uncertainties in HER2-low mBC agents in Germany, France, Spain, Italy and England
Authors: de Milliano Thom , Harding Tara , Seddik Ahmed , Schmid Peter , Oddsdottir Julia 
Published: March 2022

Abstract
Introduction: Among the molecular subtypes of breast cancer, HER2-negative is the most common, accounting for around ~80% of all cases. Over the last five years, the HER2-negative metastatic breast cancer (mBC) treatment landscape has evolved substantially with European Medicines Agency (EMA) approval of novel therapies for HER2-negative breast cancer as well as with identification of HER2-low disease (HER2 immunohistochemistry 1+ or 2+, but HER2 gene fluorescence in-situ hybridization amplification negative), previously classified as HER2-negative. The majority of new agents targeting HER2-negative/HER2-low breast cancer have been assessed for reimbursement by national health technology assessment bodies (HTABs) in Germany, France, Spain, Italy (EU4) and England. However, paucity/inadequacy of evidence has raised payer concerns over the benefit of these agents leading to restricted or no patient access in some EU markets. This research investigated whether evidence that became available post-launch mitigated HTAB concerns on the evidence base, to support future access to therapies for HER2-low mBC patients. Methods: With the lack of approved HER2-low targeting therapies, an in-depth analysis of the health technology assessments (HTAs) for therapies targeting CDK4/6, PI3K or PARP in HER2-negative mBC was conducted for national HTABs in EU4 and England as a proxy for HER2-low therapies. The analysis included palbociclib, abemaciclib, ribocicblib, alpelisib, talazoparib and olaparib, and focused on HTAB concerns regarding trial design, clinical outcomes, data maturity, safety and health-related quality of life (HRQoL). A targeted literature review (TLR) was conducted to identify evidence published post-HTA submission which addressed priority HTAB concerns and may support clinical outcomes value of future HER2-low mBC agents. Results: Of 53 HTAB recommendations from the 5 included countries, 30% were positive, 23% were positive with restrictions, 17% were negative and 30% received no recommendation. A positive HTAB recommendation opens the path to reimbursement and/or price negotiation depending on the market. In majority of submissions, HTABs questioned relevance of progression- free survival (PFS) as primary endpoint, reliability of median PFS as a surrogate for overall survival (OS) and size of subgroups. Overall, uncertainties around the actual benefit of novel agents were mostly driven by immature OS data at the time of the appraisal and subgroup analyses by molecular factor or prior treatment. The TLR identified studies on the association of PFS to patients’ relevant endpoints, real-world studies validating long-term survival projections and studies confirming the treatment response in subgroups. Conclusions: Majority of HTAB critiques on HER2-negative mBC agents were around study design, selection of endpoints and data maturity and this will likely be the case for upcoming HER2-low therapy launches. In consequence, our research suggests that some uncertainties can be accepted at launch, revealing that post-launch data mitigated some payer concerns. This would ultimately mean that an accelerated access to patients in areas of high unmet need is possible.
Citation Format: Thom de Milliano, Tara Harding, Ahmed Seddik, Peter Schmid, Julia Oddsdottir. Assessment of select HER2-negative metastatic breast cancer (mBC) agents as a proxy to understand health technology assessment bodies uncertainties in HER2-low mBC agents in Germany, France, Spain, Italy and England [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-23-06.