The HER2-RADiCAL study (Response ADaptive CAre pLan) - tailoring treatment for HER2 positive early breast cancer

Research question: HER2-RADiCAL seeks to reduce the burden of toxicity and NHS cost of treating HER2-positive (HER2+) early breast cancer (EBC) by testing the hypothesis that for certain patients systemic anti-cancer therapy can be adapted (reduced) without loss of efficacy, based on histopathological response of primary breast cancer to therapy prior to surgery (neoadjuvant). Background: HER2+ EBC is treated with curative intent by surgery plus systemic anticancer therapy intended to eliminate occult disseminated disease that may give rise to incurable metastatic recurrence. Chemotherapy, typically containing both anthracycline and taxane cytotoxics, is administered with 1 year dual anti-HER2 therapy (trastuzumab and pertuzumab). Whilst effective, these treatments are associated with significant toxicities, including cardiac toxicity, and substantial healthcare costs. Delivery of neoadjuvant therapy provides individualised actionable prognostic information gained by histopathological assessment of response in the primary tumour and ipsilateral lymph nodes. The absence of residual invasive disease (so-called pathological complete response or pCR) identifies a population with excellent outcomes who are potentially suitable for therapy de-escalation to ensure the balance of toxicity and financial burden is proportionate to absolute clinical benefit. Aims & objectives: HER2-RADiCAL will assess long-term efficacy and cost effectiveness of response-adapted therapy in patients with HER2+ EBC of good prognosis defined by pCR (ypT0/is ypN0) following non-anthracycline containing neoadjuvant chemotherapy and dual anti-HER2 therapy. Methods: HER2-RADiCAL is a response-directed interventional cohort (single arm) study embedded within a real world data driven clinical pathway model. Eligible patients with HER2+ EBC with locally-determined pCR after standard of care taxane based (non-anthracycline) neoadjuvant chemotherapy, trastuzumab and pertuzumab will receive response adapted therapy comprising i) completion of trastuzumab after 6 rather than 12 months and ii) no further pertuzumab or adjuvant chemotherapy. The primary clinical endpoint will be relapse free interval (RFI) at 3 years. 720 participants will provide 90% power to exclude an event rate >6.5% at 3 years. Secondary endpoints include relapse free survival (RFS), overall survival (OS), treatment pathway adherence and cost-effectiveness. Health economic modelling will compare the protocol driven study cohort with two comparator pathways: a non-response adapted maximum therapy pathway (the standard clinical pathway prior to the study) and a real world representative pathway taken from 4 nation NHS data at the beginning and end of the study period. Timelines for delivery: The anticipated total duration of the study is 102 months with participants recruited from Nov-21 to Sep-24 and followed up for a minimum of 3 years until primary analysis and a further 2 thereafter for event rate monitoring. Results of the primary analysis will be available in Q4 2027. Anticipated impact and dissemination: HER2-RADiCAL seeks to generate practice-changing evidence for pathological response adapted de-escalation of systemic therapy in HER2+ EBC. Uniquely, dual anti-HER2 therapy and chemotherapy will be de-escalated, substantially reducing NHS costs. It has been designed to maximise impact through the delivery of relevant and timely data that is less sensitive to ongoing evolution of treatment pathways.