Abstract PD1-07: Exploratory analytical harmonization of PD-L1 immunohistochemistry assays in advanced triple-negative breast cancer: A retrospective substudy of IMpassion130
Authors: Rugo Hope , Loi Sherene , Adams Sylvia , Schmid Peter , Schneeweiss Andreas , Barrios Carlos H , Iwata Hiroji , Diéras Véronique , Winer Eric P , Kockx Mark M , Peeters Dieter , Chui Stephen Y , Lin Jennifer C , Duc Anh Nguyen , Viale Guiseppe , Molinero Luciana , Emens Leisha A 
Published: March 2020

Background: In the Phase 3 IMpassion130 (NCT02425891) trial in metastatic triple-negative breast cancer (mTNBC), first-line atezolizumab + nab-paclitaxel (A+nP) significantly improved PFS vs placebo + nab-paclitaxel (P+nP) in the intent-to-treat (ITT) and PD-L1+ (PD-L1-stained immune cells [IC] ≥ 1% of the tumor area by VENTANA PD-L1 SP142 assay) populations. SP142 is currently the only validated assay for selecting patients who may derive benefit with A+nP. In post-hoc analyses of IMpassion130 (Rugo, ESMO 2019, submitted), PD-L1 status was also evaluated by Dako 22C3 and VENTANA SP263 assays. The SP142+ population (IC ≥ 1%; 46% prevalence) was captured within the 22C3 (CPS ≥ 1, 81% prevalence) and SP263 (IC ≥ 1%, 75% prevalence) subgroups, which identified more patients (pts) with PD-L1+ tumors. A+nP clinical activity was highest in pts identified as PD-L1+ by both SP142 and 22C3/SP263. HRs for clinical activity were lower in pts identified as PD-L1+ by 22C3/SP163, but PD-L1- by SP142. There was no suggestion of clinical benefit in pts identified as PD-L1- by both SP142 and 22C3/SP263. In the current retrospective exploratory analysis, we attempted to harmonize the PD-L1 assays by identifying cutoffs for 22C3 or SP263 that replicate the SP142 IC ≥ 1% population. Methods: Samples from IMpassion130 were assessed by a central laboratory for PD-L1 expression using VENTANA SP142 or SP263 IHC assays or Dako 22C3 IHC assay. Optimal cutoffs for 22C3 and SP263 were identified as those that maximize the analytical concordance (defined as overall percentage agreement; OPA) with the clinically validated SP142 IC 1% cutoff as the reference standard. Association with clinical activity was analyzed in the biomarker-evaluable population (BEP) in tumor samples from pts evaluated by the three PD-L1 assays. Results: In the BEP (n = 614; 68% of ITT), the intraclass correlation index (Spearman r) between SP142 IC and 22C3 CPS or SP263 IC was 0.57 and 0.69, respectively. The model-derived cutoffs with highest OPA (75%) for SP142 IC ≥ 1% were CPS 10 for 22C3 and IC 4% for SP263. Compared with our previous analyses at standard cutoffs (22C3 CPS 1; SP263 IC 1%), model-derived cutoffs resulted in negative percentage agreement increases from 45% to 74% (22C3) and from 34% to 77% (SP263), accompanied by positive percentage agreement reductions from 98% to 74% (22C3) and to 73% (SP263). These data suggest that the SP142 assay may identify a different population from the 22C3 or SP263 assays. For 22C3 at CPS 10, 36% of pts were SP142+/22C3+, but 10% were SP142+/22C3-, and 17% SP142-/22C3+. For SP263 at IC 4%, 34% of pts were SP142+/SP263+, but 12% were SP142+/SP263-, and 12% SP142-/SP263+. See table for prevalences, medians and HR point estimates for PFS and OS with the model-derived cutoffs. Conclusions: The suboptimal OPAs achieved with the model-derived cutoffs indicate that the assays could not be harmonized. Differences in SP142+ vs 22C3+ or SP263+ populations at model-derived cutoffs suggest that SP142, 22C3 and SP263 may not identify the same tumor biology. Additional data are required to understand these differences. Findings from these hypothesis-generating, post-hoc exploratory analyses based on mathematical modeling should be interpreted with caution. Currently, the VENTANA PD-L1 SP142 IHC assay (IC ≥ 1%) is the only clinically validated companion assay to select pts with mTNBC for A+nP treatment.

Populationn (%)Median PFS, moPFS HRMedian OS, moOS HRA+nPP+nP(95% CI)A+nPP+nP(95% CI)BEP614 (100)7.45.40.7221.119.20.84(0.61, 0.86)(0.68, 1.03)SP142IC ≥ 1%285 (46)8.34.10.627.317.90.74(0.47, 0.78)(0.54, 1.01)IC &lt; 1%329 (54)5.75.60.8620.820.70.95(0.68, 1.09)(0.72, 1.27)22C3CPS ≥ 10325 (53)7.55.50.712218.70.77(0.56, 0.91)(0.57, 1.03)CPS &lt; 10289 (47)5.85.40.7320.219.40.94(0.57, 0.93)(0.69, 1.26)SP263IC ≥ 4%286 (47)8.75.50.6428.919.60.71(0.49, 0.83)(0.51, 0.98)

Citation Format: Hope Rugo, Sherene Loi, Sylvia Adams, Peter Schmid, Andreas Schneeweiss, Carlos H Barrios, Hiroji Iwata, Véronique Diéras, Eric P Winer, Mark M Kockx, Dieter Peeters, Stephen Y Chui, Jennifer C Lin, Anh Nguyen Duc, Guiseppe Viale, Luciana Molinero, Leisha A Emens. Exploratory analytical harmonization of PD-L1 immunohistochemistry assays in advanced triple-negative breast cancer: A retrospective substudy of IMpassion130 [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 PD1-07.