Abstract PD3-10: Higher serum PD-L1 predicts for increased overall survival to lapatinib vs trastuzumab in the phase 3 CCTG MA.31 trial
Authors: Moku PR , Shepherd LE , Ali SM , Leitzel K , Parulekar WE , Zhu L , Virk S , Nomikos D , Aparicio S , Gelmon KA , Drabick JJ , Cream L , Halstead SE , Umstead T , Mckeone D , Maddukuri A , Polimera HV , Ali A , Poulose J , Pancholy N , Spiegel H , Nagabhairu V , Chen BE , Lipton A 
Published: May 2019

Background: In the CCTG (Canadian Clinical Trials Group) MA.31 randomized phase 3 trial, the trastuzumab-taxane combination led to longer PFS than lapatinib-taxane in HER2-positive metastatic breast cancer (MBC). We previously reported the prognostic utility of pretreatment serum PD-L1 in the trastuzumab arm of MA.31 (ASCO 2018, #1031), and here we evaluate serum PD-L1 in the lapatinib arm, and in the whole trial. Higher serum PD-L1 has been reported to be associated with reduced response to treatment with the immune checkpoint inhibitors in melanoma and lung cancer.

Methods: MA.31 accrued 652 centrally and/or locally-identified HER2-positivepatients; 186 in the trastuzumab arm, and 202 in the lapatinib armhad pretreatment serum available. TheELLA immunoassay platform (ProteinSimple, San Jose, CA) was used to quantitate serum PD-L1. Step-wise forward Cox multivariate analysis was used for PFS and OS, and testing for treatment-biomarker interaction was based on the local partial-likelihood method (Liu Y, Jiang W, and Chen BE, Statistics in Medicine 34, 3516-3530, 2015).

Results: In the total study population, pretreatment serum PD-L1 concentration had a median of 86.2 pg/ml, and 25% and 75% interquartiles of 64.1 and 134.3 pg/ml, respectively. In univariate analysis in the whole trial, and within both treatment arms, serum PD-L1 was not a significant biomarker for PFS. For OS, higher serum PD-L1 (as a continuous variable) was significant for shorter OS within the trastuzumab arm (HR=3.84, p=0.04), but was not associated with OS in the lapatinib arm (p=0.37). In the whole trial, in multivariate analysis for OS [15 covariates included: age, race, ECOG status, anthracyclines, other chemo, endocrine, radio, other prior adjuvant therapy, disease status, ER status, PR status, Ki67 (log transformed), CK5, EGFR, treatment arm, and serum PD-L1 (with median cut point)], serum PD-L1 remained a significant independent covariate (HR= 2.27, p= 0.001 (Table).There was significant interaction between treatment arm and continuous serum PD-L1 (Bootstrap method, p=0.0025); above 214.2 pg/ml serum PD-L1 (89% percentile), higher pretreatment serum PD-L1 was associated with a shorter OS to trastuzumab treatment, but longer OS to lapatinib treatment.

Conclusions: In the CCTG MA.31 trial, serum PD-L1 was a significant predictive factor: higher pretreatment serum PD-L1 was associated with a shorter OS to trastuzumab treatment, but longer OS to lapatinib treatment. Immune evasion may decrease the effectiveness of trastuzumab therapy. Further evaluation of elevated serum PD-L1 in the advanced breast cancer setting is warranted to identify HER2-positive MBC patients who may benefit from novel immune-targeted therapies in addition to trastuzumab.

Multivariate Analysis (whole trial): Significant Independent CovariatesCovariateP-ValueHRLower 95% CIHigher 95% CISerum PD-L1 (pretreatment) (&gt;median vs &lt;median)0.0012.271.403.68EGFR Status (continuous IHC score)0.0031.0121.0041.019Other Chemotherapy (yes vs no)0.0081.911.193.07Treatment Arm (trastuzumab vs. lapatinib)0.0100.530.330.86ECOG Performance Status (0 vs 1 or 2)0.0250.590.370.94Ki67 (log)0.0461.451.0062.081

Citation Format: Moku PR, Shepherd LE, Ali SM, Leitzel K, Parulekar WE, Zhu L, Virk S, Nomikos D, Aparicio S, Gelmon KA, Drabick JJ, Cream L, Halstead SE, Umstead T, Mckeone D, Maddukuri A, Polimera HV, Ali A, Poulose J, Pancholy N, Spiegel H, Nagabhairu V, Chen BE, Lipton A. Higher serum PD-L1 predicts for increased overall survival to lapatinib vs trastuzumab in the phase 3 CCTG MA.31 trial [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD3-10.