Elevated serum activin A and PD-L1 and survival in the CCTG MA.31 phase III trial (trastuzumab vs. lapatinib) in first-line HER2+ metastatic breast cancer.

person Prashanth Reddy Moku Penn State Hershey College of Medicine, Hershey, PA info_outline Prashanth Reddy Moku, Lois E. Shepherd, Suhail Ali, Kim Leitzel, Wendy R. Parulekar, Liting Zhu, Shakeel Virk, Dora Nomikos, Samuel Aparicio, Karen A. Gelmon, Joseph Drabick, Leah Cream, Scott Halstead, Hyma Vani Polimera, Ashok Maddukuri, Aamnah Ali, Joyson Poulose, Howard Spiegel, Bingshu E. Chen, Allan Lipton

Authors person Prashanth Reddy Moku Penn State Hershey College of Medicine, Hershey, PA info_outline Prashanth Reddy Moku, Lois E. Shepherd, Suhail Ali, Kim Leitzel, Wendy R. Parulekar, Liting Zhu, Shakeel Virk, Dora Nomikos, Samuel Aparicio, Karen A. Gelmon, Joseph Drabick, Leah Cream, Scott Halstead, Hyma Vani Polimera, Ashok Maddukuri, Aamnah Ali, Joyson Poulose, Howard Spiegel, Bingshu E. Chen, Allan Lipton Organizations Penn State Hershey College of Medicine, Hershey, PA, Canadian Cancer Trials Group, Kingston, ON, Canada, Penn State Hershey Medical Center, Hershey, PA, NCIC Clinical Trials Group, Queen's University, Kingston, ON, Canada, Queen's University, Canadian Cancer Trials Group, Kingston, ON, Canada, NCIC Clinical Trials Group, Kingston, ON, Canada, British Columbia Cancer Agency, Vancouver, BC, Canada, BC Cancer Agency, Vancouver, BC, Canada, Penn State Cancer Institute, Hershey, PA, ProteinSimple, San Jose, CA Abstract Disclosures Research Funding Other Background: In MA.31 the trastuzumab-taxane combination led to longer PFS than lapatinib-taxane in HER2+ metastatic breast cancer (MBC). In MA.31 we previously reported the prognostic/predictive utility of pretreatment serum PD-L1 (SABCS 2018, PD3-10) and serum activin A (SABCS 2016, P6-07-06) separately; here we evaluate them combined. Methods: MA.31 accrued 652 centrally and/or locally-identified HER2-positive patients, and pretreatment serum was available for 382 patients (184 in trastuzumab arm, 198 in lapatinib arm) . The ELLA immunoassay platform (ProteinSimple, San Jose, CA) was used to quantitate serum PD-L1, and ELISA for activin A (R&D Systems, Minneapolis, MN). Results: In correlation analysis, pretreatment serum PD-L1 was moderately correlated with serum activin A (r = 0.21, p = 0.004). In univariate analysis for OS, the combination of higher serum PD-L1 and higher serum activin A (median cutpoints) (vs. both low) was significant for shorter OS in the trastuzumab arm (HR 6.62, p=0.0005) and in the lapatinib arm (HR 3.25, p=0.0003)(table). In multivariate analysis for OS (17 covariates included), elevated serum activin A/PD-L1 combination remained the most significant independent covariate in the trastuzumab arm (HR 12.40, p=0.001), and in the lapatinib arm (HR 5.2, p=0.0001). Conclusions: In the CCTG MA.31 trial, elevated pretreatment serum activin A (TGF-B superfamily) and PD-L1 was associated with a shorter OS to HER2-targeted treatment. Multiple mechanisms, including immune evasion, may decrease the effectiveness of HER2-targeted therapy. Elevated serum activin A and PD-L1 may identify HER2-positive MBC patients who would benefit from inhibitors of the HER2, PD-1, and activin A pathways. Univariate analysis of OS of serum activin A and PD-L1 combined. Serum biomarker (ActA & PD-L1) TRAS arm 1 LAPT arm 2 HR CI (95%) # Pts HR CI (95%) # Pts both high vs both low 6.62 2.27 - 19.32 54 3.25 1.65 - 6.42 62 ActA high / PD-L1 low vs both low 4.15 1.34 - 12.87 39 2.62 1.26 - 5.44 37 ActA low / PD-L1 high vs both low 3.16 0.95 - 10.51 36 0.93 0.36 - 2.35 34 both low* 1 * 55 1 * 65 * Referent cohort 1 p = 0.0012 2 p = 0.0003