OBJECTIVES: This study examined the use of pathological complete response (pCR) as a surrogate primary endpoint in the approval process and reimbursement recommendations of drugs for the treatment of neoadjuvant early breast cancer (eBC) in the European Union (EU).

METHODS: We searched the European Medicines Agency (EMA) website to identify the Marketing Authorization (MA) submissions of breast cancer drugs. Published European public assessment reports (EPAR) of approved drugs since 1995 were examined for the primary endpoint used in pivotal trials. We then examined Health Technology Assessment (HTA) reports to explore reimbursement decisions in France, Germany, England, Spain and Italy.

RESULTS: Of the 30 MA granted for breast cancer drugs, 11 were indicated for eBC and 5 approved in neoadjuvant treatment of eBC. We identified one novel drug (pertuzumab) and three trastuzumab biosimilars (Ontruzant®, Herzuma®, Kanjinti®) that had been approved based on pCR as a primary endpoint in the pivotal trials whereas Herceptin® had been previously approved based on disease-free survival (adjuvant indication followed by neoadjuvant). HTA bodies of England (NICE) and Spain (AEMPS) recommended pertuzumab for reimbursement in neoadjuvant setting, whereas HTA bodies in Germany (GBA), Italy (AIFA) and France (HAS) did not recommend reimbursement. The biosimilars, whose similarity recognition was based on pCR, may however be automatically reimbursed as they often do not require a new HTA process.

CONCLUSIONS: Although the EMA has approved a drug in neoadjuvant eBC based on demonstration of statistical significant increase in pCR rate, HTA bodies have received this evidence with more scepticism, as shown by the heterogeneous reimbursement decisions of pertuzumab in neoadjuvant eBC in EU5 countries. Despite the EMA efforts in issuing the guideline EMA/CHMP/151853/2014 on pCR, further research seems to be required to establish the validity of pCR as a surrogate endpoint, from a payer perspective.