Title: The HER2-RADiCAL study (Response ADaptive CAre pLan) - tailoring treatment for HER2 positive early breast cancer
Funder: Department of Health and Social Care

Abstract: AIM: Our aim is to reduce the burden of treatment and the risk of serious long-term side effects for some patients with the “HER2-positive” type of early breast cancer (HER2+EBC). We want to find out if we can adjust the amount of drug treatment given to patients after surgery according to the way the cancer initially responds to drug treatment before surgery. _x000D_ BACKGROUND: Patients with HER2+EBC usually receive a course of drug treatment as well as surgery. This drug treatment improves chances of cure by destroying any breast cancer cells that might have already begun to spread. _x000D_ Drug treatment is made up of chemotherapy, along with two antibody drugs (trastuzumab and pertuzumab). It is now common to start drug treatment before surgery (neoadjuvant treatment). This means that tests on tissue removed at surgery can show if the patient's cancer is responding to the treatment. If these tests do not find any cancer cells in the breast or lymph glands from the armpit, this predicts a very high chance of cure for the patient, and is called a pathological complete response (pCR). _x000D_ This study will test whether patients who have pCR can safely receive less trastuzumab and pertuzumab after surgery, and avoid receiving a type of drug called an anthracycline as part of their chemotherapy._x000D_ This is important as the side effects of anthracyclines include a small risk of leukaemia and heart muscle damage. Longer courses of antibody therapy also increase the risk of heart muscle damage._x000D_ This reduction of drug treatment may not only benefit the patient, but also save NHS resources._x000D_ DESIGN & METHODS: HER2-RADiCAL is a study for patients with HER2+EBC treated with neoadjuvant chemotherapy, pertuzumab and trastuzumab, who have a pCR at surgery. Eligible patients must not have received an anthracycline as part of their neoadjuvant treatment. All patients who enter the study will stop treatment with pertuzumab and will receive no more chemotherapy. Treatment with trastuzumab will stop at 6 months rather than the current standard of 12 months’ duration. 720 patients will enter the study and be followed up in clinic. _x000D_ We expect recurrences of cancer to be rare in this group of patients (~1% of patients per year) and this will be monitored throughout the study. If the number of patients with a recurrence is higher than expected the study will be stopped. If the rate of recurrences is as low as we expect the study will be analysed once patients have been followed up for 3 years._x000D_ PATIENT & PUBLIC INVOLVEMENT: Patients have helped design and develop this study through: _x000D_ • several national meetings_x000D_ • discussion with patients who are members of Independent Cancer Patients' Voice (ICPV)_x000D_ • attending an international focus group on reducing treatment burden in patients with pCR. _x000D_ Patient advocates have worked closely with the study team to develop HER2-RADiCAL. They will continue to be involved throughout the study, and will work with the team on patient documents, study management and communicating results._x000D_ COMMUNICATING RESULTS: This research is of international interest. HER2-RADiCAL addresses the question to which most breast clinicians and patients want the answer. It will be reported in UK and international meetings and journals. Summaries of the results will be reported to patients and the public via breast cancer organisations and charities. HER2-RADiCAL aims to be practice changing.

Lay abstract: 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)._x000D_ 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._x000D_ 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._x000D_ 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. _x000D_ 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. _x000D_ 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.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS