Abstract P2-13-08: Combined Peri-Operative Lapatinib and Trastuzumab in Early HER2-positive Breast Cancer - Long Term Results of the Randomized UK EPHOS-B Trial

Background: EPHOS-B is a multi-centre randomized trial designed to investigate whether anti-HER2 therapy given 11 days pre-surgery inhibited proliferation and/or increased apoptosis in HER2-positive early breast cancer. Significant differences in Ki67 response (≥30% change between baseline and surgery) were observed between treatment groups and control, although no significant increases in apoptosis were seen [1]. We report here 5-year outcomes and their association with peri-operative response, including post-hoc exploratory analyses on stromal tumour infiltrating lymphocytes (TILs). Methods: Patients were randomized (1:2:2) to no treatment (control), trastuzumab or lapatinib (Part-1), and (1:1:2) to control, trastuzumab, or lapatinib and trastuzumab combination (Part-2). Relapse free survival (RFS) is defined as the time from randomisation to local, regional, or distant tumour recurrence or death from any cause, with second primary cancers censored. Five-year RFS rates were estimated by Kaplan-Meier across treatment and peri-operative response groups, and compared by Log-Rank tests. Central scoring of stromal tumour infiltrating lymphocytes (TILs) on scanned H&E baseline and surgery slides was conducted post-hoc according to the International TILs Working Group. Baseline TILs (bTILS) were explored across treatment groups, and associated with trial outcomes. Changes in TILS in patients without pathological regression were correlated with Ki67 changes and RFS. Results: Overall, 257 patients were randomized (Part-1: control 22, trastuzumab 57, lapatinib 51; Part-2: control 29, trastuzumab 32, trastuzumab+lapatinib 66). Central pathology review identified six patients achieving complete pathological response (pCR), and 13 RCB1 (as per the Residual Cancer Burden score), all but two in the combination group. After 6 years median follow-up, 28 women (11%) had recurrence, and 19 (7%) died; no differences between groups were found (Table). No recurrences were observed amongst pCR patients; only 1 local recurrence observed amongst RCB1. Patients with Ki67 falls ≥50% had better RFS than those with modest falls or no falls (Table). In patients with no evidence of disease regression at surgery, those with higher TILs (≥20%) at surgery had better RFS than those with lower TILs. Conclusions: Early response (pCR/RCB1 or Ki67 reductions >50%) after 11 days pre-operative anti-HER2 dual therapy identifies cancers dependent on the HER2 pathway and provides a strategy for individualising treatment, including de-escalation of therapy. [1] Bundred N, Cameron D, Amstrong A et al (2016) Effects of perioperative lapatinib and trastuzumab, alone and in combination, in early HER2+ breast cancer − the UK EPHOS-B trial (CRUK/08/002) European Journal of Cancer;57:S1-S8. Table - Relapse-free survival by treatment and by peri-operative responseN randomisedNRFS event5-year RFS95%CILog-rank p-valueRandomised treatmentTrastuzumab (P1)577 (12.3%)88%76-94%T vs L p=0.75Lapatinib (P1)515 (9.8%)90%77-96%L vs C p=0.41Control (P1)221 (4.6%)95%92-99%Trastuzumab (P2)327 (21.9%)87%69-95%T vs T+L p=0.048Combination (P2)665 (7.6%)92%83-97%T+L vs C p=0.64Control (P2)293 (10.3%)90%71-97%%Ki67 change:>50% decrease722 (2.8%)99%90-100%0.002>10% decrease7717 (22.1%)80%69-88%<10% or no decrease827 (8.5%)91%83-96%Disease responseRCB060100%-0.63RCB1131 (7.7%)92%57-99RCB2/3/no evidence of regression23626 (11%)90%85-93Baseline TILS<=20%18023 (13%)89%83-930.10>20%502 (4%)96%85-99Surgery TILS (only RCB2/3)<=20%12220 (16.4%)86%78-910.021>20%653 (4.6%)95%86-98Change in TILS (only RCB2/3)No significant increase15221 (13.8%)88%81-920.16Increase >20%352 (5.7%)94%79-99 Citation Format: Nigel Bundred, Nuria Porta, Adrian Murray Brunt, Angela Cramer, Andrew Hanby, Abeer Shaaban, Emad Rakha, Anne Armstrong, Ramsey Cutress, David Dodwell, Marie Emson, Abigail Evans, Sue Hartup, Kieran Horgan, Stuart McIntosh, Jay Naik, Samkaran Narayanan, Jane Oii, Anthony Skene, David Cameron, Judith Bliss. Combined peri-operative lapatinib and trastuzumab in early HER2-positive breast cancer - Long term results of the randomized UK EPHOS-B trial [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 P2-13-08.