Abstract CT212: A phase III randomized study of paclitaxel (T) and trastuzumab (H) versus T, H and lapatinib (L) in first line treatment of HER2+ metastatic breast cancer (MBC)
Authors: Crown John , Jacot William , Collins Denis M. , Coate Linda , Saetersdal Anna , Kennedy M John , Kelly Catherine , De Ibarguen Blanca Cantos Sanchez , Conejero Raquel Andrés , Costa Luis , Brito Margarida , Keane Maccon , Rovira Pedro Sanchez , Martin Miguel , O'Connor Miriam , Vazquez Manuel Ramos , Alvarez Elena , O'Reilly Seamus , Mattson Johanna , Lopez Laura Jolis , Lescure Alvaro Rodriguez , Blanco Esperanza , Muino Coralia Bueno , Moulton Brian , O'Donovan Norma , Hernando Andres , Nolan Marc , Parker Imelda , Gullo Giuseppe , Hennessy Bryan 
Published: September 2020

Abstract
Background: The addition of H to chemotherapy improved disease outcome in HER2+ MBC. The combination of H and L with chemotherapy improved event free survival (EFS) in the neo-adjuvant setting but not in the adjuvant setting. However, improved EFS did not translate to overall survival benefit. This international trial (ICORG (CTRIAL-IE) 11-10/NCT01526369) compared the efficacy of TH vs. THL in first line treatment of HER2+ MBC. The primary aim of this study was to assess any benefit for the addition of L to TH in an advanced HER2+ breast cancer patient population. Target accrual was not met due to changes to standard of care mid-study. Methods: Patients (Pts) (n= 75 enrolled, randomized 1:1) received weekly T (80mg/m², for 3 weeks of a 4 week cycle) + H (8mg/kg loading dose on cycle 1 day 1 and 4mg/kg every 2 weeks) + L (1,000 mg daily)) until disease progression, unacceptable toxicity or consent withdrawal. The primary outcome measure was progression free survival (PFS). Secondary outcome measure was overall survival (OS). Eligibility criteria included: Female &gt; 18 years, invasive MBC, measurable disease by RECIST criteria V1.1, HER2+ by testing of the primary tumour and if available the biopsied metastatic lesion. No prior systemic therapy for metastatic disease (except one line of hormonal therapy for metastatic disease without H). No recurrence within 12 months (mo) from completion of adjuvant chemotherapy to the development of metastatic disease. No recurrence within 6 mo from completion of adjuvant H to the development of metastatic disease and no prior L treatment. Results: Of the 75 pts enrolled, n=65 (TH n=34, THL n=31) were included in the PFS analysis. Median PFS (95% CI) was numerically higher, but not statistically significant, in THL (24.0 mo (9.5, 34.5)) vs TH (19.3 mo (8.7, 22.7)), HR 0.827, p= 0.601. For OS analysis, n=69 (TH n=35 and THL n=34) were included. 41/69 (59.4%) had no prior therapy. No statistically significant, clinically meaningful improvement in OS (Median (95% CI)) was observed (TH 53.8 mo (41.8, -) vs. THL 45.6 mo (29.7, -), HR 1.048, p=0.891). Analysis of the safety set (n=70 (TH n= 36, THL n=34)) revealed a higher incidence of Grade 3/4 AEs in THL (61.8%) vs. TH (50%), p=0.322. There were 2 on-treatment fatalities due to adverse events (AEs) in the THL arm, one due to respiratory failure, the other due to central nervous system metastasis. There were no on-treatment fatalities in the TH arm. GI disorders were the most prevalent AE, with the incidence of diarrhea significantly higher in the THL arm (88% vs. 42%, p &lt;0.0001). Conclusions: The addition of a HER2-targeted TKI to TH was tolerated with GI toxicity emerging as the predominant AE. While underpowered, this study indicates a numerical advantage in PFS that does not reach statistical significance for the addition of L to TH. This may indicate that the addition of a HER2-targeted TKI to H-containing chemotherapy regimens warrants investigation in HER2+ MBC.
Citation Format: John Crown, William Jacot, Denis M. Collins, Linda Coate, Anna Saetersdal, M John Kennedy, Catherine Kelly, Blanca Cantos Sanchez De Ibarguen, Raquel Andrés Conejero, Luis Costa, Margarida Brito, Maccon Keane, Pedro Sanchez Rovira, Miguel Martin, Miriam O'Connor, Manuel Ramos Vazquez, Elena Alvarez, Seamus O'Reilly, Johanna Mattson, Laura Jolis Lopez, Alvaro Rodriguez Lescure, Esperanza Blanco, Coralia Bueno Muino, Brian Moulton, Norma O'Donovan, Andres Hernando, Marc Nolan, Imelda Parker, Giuseppe Gullo, Bryan Hennessy. A phase III randomized study of paclitaxel (T) and trastuzumab (H) versus T, H and lapatinib (L) in first line treatment of HER2+ metastatic breast cancer (MBC) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT212.