Abstract P4-10-09: Association between pertuzumab (P) induced diarrhea and skin rash and survival outcomes in patients (pts) with HER2-positive metastatic breast cancer enrolled in the CLEOPATRA trial
Authors: Ferreira Arlindo R. , Pondé Noam , Lambertini Matteo , Maurer Christian , Martel Samuel , Costa Luis , De Azambuja Evandro 
Published: March 2020

Introduction: P and trastuzumab (T) are approved for the treatment of early and advanced breast cancer (BC) pts. Skin rash and diarrhea are frequent adverse events (AE) with P. With the use of lapatinib, we demonstrated that early development of rash correlates with pathologic complete response in the NeoALTTO trial and is both a prognostic and predictive marker in the ALTTO trial. In this subanalysis of the CLEOPATRA trial, we investigated if incidence of rash and diarrhea associates with progression free survival (PFS) or overall survival (OS) and if it can predict the benefit of P+T. Methods: In the CLEOPATRA phase III trial, advanced HER2-positive BC pts where randomized between first-line T vs P+T with at least 6 cycles of docetaxel. We evaluated whether rash (any grade) and/or diarrhea (any grade or grade ≥3) were prognostic in pts receiving P+T and/or predictive of benefit from P+T vs T. To deal with immortal-time bias, we performed a landmark analysis removing pts progressing/dying before a minimum of 46 days (median time to rash/diarrhea occurrence) after treatment initiation (cohort 1), and after end of docetaxel treatment (cohort 2). Survival endpoints were PFS and OS according to study definition. We also investigated if age (&lt;50 or ≥50 years) influences the incidence of diarrhea or rash and if the 2 AEs are associated with one another. For both AEs, the earliest event was considered for analysis. Results: Of the 808 patients in the CLEOPATRA study, cohort 1 included 777 pts (T: 379; P+T: 398) and cohort 2 included 518 pts (T: 232; P+T: 286). The table summarizes the incidence and impact of rash and diarrhea by treatment arm and their effect on outcomes after a median PFS and OS follow-up of 43.6 (IQR 22.9-50.5) and 48.4 (IQR 43.5-55.0) months, respectively, in cohort 1. It shows that rash is prognostic for both PFS and OS (P+T treated) but not predictive of P+T benefit vs T; while diarrhea is not prognostic but predicts P+T PFS benefit. In cohort 2, diarrhea and rash were prognostic for PFS (rash, HR 0.42 [95% CI 0.29-0.60], p&lt;0.001; diarrhea 0.48 [0.35-0.65], p&lt;0.001) and only rash for OS (rash, 0.50 [0.29-0.86], p=0.013; diarrhea, 0.64 [0.39-1.03], p=0.064), but neither were predictive of P+T benefit for PFS (rash, p for interaction of any grade x treatment [pint]=0.695; diarrhea, pint=0.194) nor OS (rash, pint=0.841; diarrhea, pint=0.155). Younger age (&lt;50 years) was not associated with diarrhea (OR 1.01 [95% CI 0.76-1.35], p=0.932), rash (1.07 [0.79-1.45], p=0.69) or both (0.92 [0.67-1.27], p=0.635). Having diarrhea (any grade) was associated with having rash (any grade; p&lt;0.001, Cramér’s V 0.24).Conclusion: Rash is prognostic both for PFS and OS, but not predictive of pertuzumab benefit. Conversely, diarrhea predicts PFS benefit of P when occurring during docetaxel administration but is prognostic only after docetaxel withdrawal. These results may be used to reassure pts experiencing these AEs during treatment.

Incidence and Impact of Diarrhea and/or Rash on PFS and OS in cohort 1Patients, n (%)PFS, % at 2 yrsOS, % at 2 yrsPrognostic role (pertuzumab treated)RashYes, any grade169 (42.5)48.587.3No, any grade229 (57.5)37.478.0HR (95% CI), p-value (any grade vs. no)NA0.71 (0.56-0.91), p&lt;0.0060.66 (0.48-0.91), p&lt;0.001DiarrheaYes, any grade238 (59.8)42.683.5No, any grade160 (40.2)41.679.6Yes, grade ≥337 (9.3)50.480.8No, grade ≥3361 (90.7)41.482.1HR (95% CI), p-value (any grade vs. no)NA0.97 (0.77-1.24), p&lt;0.8340.93 (0.68-1.28), p=0.677Predictive role (overall cohort 1)RashYes, any grade271 (34.9)45.584.6No, any grade506 (65.1)28.872.0pintNAp=0.477p=0.711DiarrheaYes, any grade406 (52.2)39.479.3No, any grade371 (47.8)29.673.4Yes, grade ≥357 (7.3)40.574.8No, grade ≥3720 (92.7)34.376.7pint (any grade vs. no)NAp=0.049p=0.564

Citation Format: Arlindo R. Ferreira, Noam Pondé, Matteo Lambertini, Christian Maurer, Samuel Martel, Luis Costa, Evandro De Azambuja. Association between pertuzumab (P) induced diarrhea and skin rash and survival outcomes in patients (pts) with HER2-positive metastatic breast cancer enrolled in the CLEOPATRA trial [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P4-10-09.