Higher Serum PD-L1 Level Predicts Increased OS With Lapatinib vs Trastuzumab in CCTG MA.31 Study

Findings from the retrospective, randomized, phase 3 Canadian Cancer Trials Group (CCTG) MA.31 trial, published in Cancer, suggested a higher serum PD-L1 level was a significant predictive factor for a better response to lapatinib (Tykerb) than trastuzumab (Herceptin) in patients with HER2-positive metastatic breast cancer.

Moving forward, researchers indicated that further evaluation of elevated serum PD-L1 in advanced breast cancer is necessary to determine which patients with HER2-positive metastatic breast cancer may benefit from novel immune-targeted therapies in addition to trastuzumab.

“Our goal here was to evaluate the role of pretreatment serum PD-L1 as a prognostic and predictive biomarker in the Canadian Cancer Trials Group (CCTG) MA.31 randomized phase 3 trial of lapatinib versus trastuzumab in patients with HER2-positive [metastatic breast cancer],” the authors explained. “In this trial, it was previously reported that patients on trastuzumab had significantly longer PFS than patients on lapatinib.”

In this study, researchers enrolled 652 patients with metastatic breast cancer who were HER2-positive, including 387 with serum available. Of those with serum available, 185 were randomized to the trastuzumab arm and 202 to the lapatinib arm.

Among the entire trial population, continuous pretreatment serum PD-L1 levels were not associated with overall survival (OS). Within the trastuzumab arm though, a higher continuous pretreatment serum PD-L1 level was found to be significant for shorter OS (HR, 3.85; P = .04); pretreatment serum PD-L1 was not associated with OS in the lapatinib arm (P = .37).

Further, in a multivariable analysis for OS, serum PD-L1 (median cut point) remained a significant independent covariate for the entire study population (HR, 2.38; P = .001). Moreover, there was a significant interaction between treatment arm and continuous serum PD-L1 (bootstrap method; P = .0025), with serum PD-L1 being associated with significantly shorter OS with trastuzumab treatment versus lapatinib treatment at or above 214.2 pg/mL (the 89th percentile).

“This study concluded that the addition of pembrolizumab (Keytruda) to trastuzumab yielded better outcomes in the tumor tissue–positive PD-L1 cohort,” the authors noted. “On the basis of our data showing that patients with high pretreatment serum PD-L1 levels were relatively resistant to trastuzumab therapy, we hypothesize that serum PD-L1 may identify a subgroup of patients with HER2-positive [metastatic breast cancer] who may benefit the most from the addition of novel immunotherapies to trastuzumab.”

The researchers went on to note that because higher pretreatment serum PD-L1 levels predict a reduced outcome with trastuzumab in breast cancer and with immune checkpoint inhibitor therapy in many solid tumor types, the hypothesis outlined in this study might apply to all cancer types treated with any immunotherapy. However, further research is required to validate this theory.

“Because there are currently no FDA-approved predictive circulating biomarkers for determining patient outcomes with immunotherapy, circulating PD-L1 analysis is warranted in all clinical trials of any immunotherapy,” the authors wrote. “Further evaluation of circulating PD-L1 may lead to better selection of additional therapy combinations with immunotherapy in future clinical trials.”

Reference:

Moku P, Shepherd L, Ali SM, et al. Higher Serum PD-L1 Level Predicts Increased Overall Survival With Lapatinib Versus Trastuzumab in the CCTG MA.31 Phase 3 Trial. Cancer. doi: 10.1002/cncr.33149