Association between pertuzumab-associated diarrhea/rash and survival outcomes

Authors and affiliations:
Arlindo R. Ferreira^1,2,3,a, Sofia Ferreira^1,4,a, Matteo Lambertini^1,5,6, Christian Maurer^1,7, Samuel Martel^1,8, Luis Costa², Noam Ponde^1,9,b, Evandro de Azambuja1,b

^a - Co-first authors

^b - Co-last authors

¹ - Institut Jules Bordet, L’Université Libre de Bruxelles (U.L.B), Belgium

² - Hospital de Santa Maria and Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Portugal

³ - Breast Unit, Champalimaud Clinical Center, Champalimaud Foundation, Portugal

⁴ - Instituto Português de Oncologia de Lisboa Francisco Gentil, Portugal

⁵ - IRCCS Ospedale Policlinico San Martino, Genova, Italy

⁶ - University of Genova, Genova, Italy

⁷ - Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf and University of Cologne, Germany

⁸ - CISSS Montérégie-centre/Hôpital Charles-Lemoyne, Canada

⁹ - AC Carmargo Cancer Center, São Paulo, Brazil

Abstract:
Background: Skin rash and diarrhoea are known side-effects of pertuzumab. Studies with other anti-HER2 agents suggested that adverse events correlate with patient outcomes. In this exploratory cohort of patients with metastatic HER2-positive breast cancer included in the CLEOPATRA trial we evaluated the value of rash and diarrhoea as prognostic markers and as predictors of pertuzumab benefit. Methods: This is a retrospective analysis of the multicenter, prospective, randomised CLEOPATRA trial. We defined two analytic cohorts: cohort 1 (C1) included patients from treatment initiation, and cohort 2 (C2) included patients after discontinuation of docetaxel. A landmark analysis was introduced to deal with immortal-time bias. Study endpoints were progression-free survival (PFS) and overall survival (OS). Univariable and multivariable Cox proportional hazards models were used. Results: Of the 808 patients and after application of the landmark analysis, C1 and C2 included 777 and 518 patients, respectively. In C1, rash occurred in 271 patients (34.9%) and diarrhoea in 470 (60.5%). Rash was prognostic for PFS and OS (C1: adjusted hazard ratio [aHR] = 0.66 [95% CI = 0.48–0.91], p = 0.010]; C2: aHR 0.52 [95% CI = 0.30–0.89], p = 0.018) in both cohorts, while diarrhoea was only prognostic for PFS in cohort 2 (aHR = 0.65 [95% CI = 0.46–0.91], p = 0.011). Rash and diarrhoea were not predictive of pertuzumab benefit (in terms of PFS/OS) in the two cohorts. Conclusions: In patients treated with pertuzumab, trastuzumab, and docetaxel, rash is prognostic whenever it occurs during treatment, while diarrhoea only has prognostic value when occurring after docetaxel discontinuation. However, neither rash nor diarrhoea predict pertuzumab benefit.

Journal: European Journal of Cancer

Link: https://www.ejcancer.com/article/S0959-8049(20)31360-5/fulltext