Abstract P1-11-09: Five year follow up of a randomized phase II comparison of neo-adjuvant docetaxel, carboplatin, trastuzumab with or without lapatinib in HER-2 positive breast cancer
Authors: Crown John , Collins Denis M. , Eustace Alex J. , Keane Maccon , Coate Linda , Kennedy John , O’Reilly Seamus , Kelly Catherine , O’Connor Miriam , Martin Michael J. , Murphy Conleth , Duffy Karen , Walshe Janice , Mahgoub Thamir , Gullo Giuseppe , Moulton Brian , Alvarez-Iglesias Alberto , Parker Imelda , Hennessy Bryan 
Published: March 2023

Abstract
Background: The addition of trastuzumab (H) to pre-operative chemotherapy in HER2+ breast cancer (H+BC) increases the rate of pathological complete response (pCR). TCH is a widely used adjuvant regimen in early stage H+BC. Lapatinib (L) is a small molecule HER2 antagonist that produces responses following H failure, and has been reported to augment H activity in combination in vitro. We compared neo-adjuvant docetaxel, carboplatin (TC) + H v TCL v TCHL in pts with H+BC.
Methods: Pts with stages Ic–III H+BC were randomized to receive neo-adjuvant TCH, TCL or TCHL (ICORG/CTRIAL-IE 10-05, NCT01485926 www.clinicaltrials.gov). Pts subsequently underwent surgery and received H post-operatively for 1 year from the first dose of H. The primary endpoint of the trial was pCR. Secondary objectives were overall survival (OS) and relapse-free survival (RFS) and molecular and pharmacological markers of response. This study was supported by GSK, Novartis, The Cancer Clinical Research Trust and The Caroline Foundation.
Results: When the NCIC CTG MA.31 trial reported inferior outcomes for L compared to H, we discontinued the TCL arm. This abstract reports data on the 76 pts recruited to the TCH and TCHL arms only, who included stage II (69.7%; n=53) or stage III disease (21.1%; n=16, with stage unknown for 9.2% (n=7). The final analysis set numbered 75 pts. Clinicopathological characteristics were well balanced between arms. The pCR rate of the two arms TCHL and TCH were virtually identical at 51.6% and 52.8% respectively (Fisher’s test p-value: 1.000). TCHL pts had significantly superior 5 year relapse-free survival (relative risk (RR) 0.171, 95% CI 0.041 – 0.713; log-rank test p-value = 0.009). OS was comparable between the TCH and TCHL groups (RR 0.205, 95% CI 0.025 – 1.675); log-rank test p-value = 0.2). Median RFS and OS were not reached. The most frequent serious adverse event was diarrhoea which occurred in 21.3% (n=16/75) pts (Grade 3 diarrhoea 13/16). One pt (TCH arm) who did not have protocol-mandated prophylactic G-CSF had a Grade 5 toxicity. One TCHL pt had a self-limiting diverticular perforation. There was a significantly higher frequency of severe diarrhoea in pts who received the TCHL regimen (Grade 3+, 32.4% vs 10.5%, p=0.038). The use of prophylactic loperamide reduced the frequency of diarrhoea in both the TCHL arm (86.2% vs 44.4%, p=0.004) and in the TCH arm (58.8% vs 24%, p=0.009). A post lock audit with minimum 9-year follow-up showed relapse rates of 15% TCHL vs 33% TCH.
Conclusions: The study did not meet its primary pCR endpoint possibly due to a high TCH pCR rate, and small numbers. TCHL produced a statistically significant improvement in RFS compared to TCH. TCHL produced a higher rate of gastro-intestinal toxicity, but the use of loperamide significantly reduced the frequency of diarrhoea. These data suggest that anti-HER2 TKIs merit further investigation in the neo-adjuvant treatment of early stage H+BC.
Table 1. pCR rates, 5 year RFS and OS results for ICORG/CTRIAL-IE 10-05 (NCT01485926) study pts. * significant, p&lt;0.05.
Citation Format: John Crown, Denis M. Collins, Alex J. Eustace, Maccon Keane, Linda Coate, John Kennedy, Seamus O’Reilly, Catherine Kelly, Miriam O’Connor, Michael J. Martin, Conleth Murphy, Karen Duffy, Janice Walshe, Thamir Mahgoub, Giuseppe Gullo, Brian Moulton, Alberto Alvarez-Iglesias, Imelda Parker, Bryan Hennessy. Five year follow up of a randomized phase II comparison of neo-adjuvant docetaxel, carboplatin, trastuzumab with or without lapatinib in HER-2 positive breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-11-09.