Performance of PD-L1 immunohistochemistry assays in unresectable locally advanced or metastatic triple-negative breast cancer: post hoc analysis of IMpassion130 Hope S. Rugo, 1 Sherene Loi, 2 Sylvia Adams, 3 Peter Schmid, 4 Andreas Schneeweiss, 5 Carlos H. Barrios, 6 Hiroji Iwata, 7 Véronique Diéras, 8 Eric P. Winer, 9 Mark M. Kockx, 10 Dieter Peeters, 10 Stephen Y. Chui, 11 Jennifer C. Lin, 11 Anh Nguyen Duc, 11 Giuseppe Viale, 12 Luciana Molinero, 11 Leisha A. Emens 13 1 University of California San Francisco Comprehensive Cancer Center, San Francisco, CA, USA; 2 Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; 3 NYU Langone Medical Center, New York, NY, USA; 4 Barts Cancer Institute, Queen Mary University London, London, UK; 5 University Hospital and German Cancer Research Center Heidelberg, Heidelberg, Germany; 6 Centro de Pesquisa Clínica, HSL, PUCRS, Porto Alegre, Brazil; 7 Aichi Cancer Center Hospital, Nagoya, Japan; 8 Department of Medical Oncology, Centre Eugène Marquis, Rennes, France; 9 Dana-Farber Cancer Institute, Boston, MA, USA; 10 HistoGeneX NV, Antwerp, Belgium; 11 Genentech, Inc., South San Francisco, CA, USA; 12 University of Milan, European Institute of Oncology IRCCS, Milan, Italy; 13 University of Pittsburgh Medical Center Hillman Cancer Center, Pittsburgh, PA, USA esmo.org
Disclosures 2 Research support for the parent study and editorial support from F. Hoffman-La Roche, Ltd. Research support to the University of California, San Francisco from Immunomedics, Daiichi Sankyo, Eisai, Eli Lilly, Genentech, Inc./F. Hoffmann-La Roche, Ltd, MacroGenics, Merck, Novartis, OBI and Pfizer Travel support from Daiichi Sankyo, Genentech, Inc./F. Hoffmann-La Roche, Ltd, MacroGenics, Mylan, Novartis, Pfizer and PUMA Rugo et al. Abstract 6571 IMpassion130 PD-L1 IHC https://bit.ly/30OmOqz
Background 3 IMpassion130 is the first Phase III study of cancer immunotherapy in mTNBC to demonstrate clinical benefit in PD-L1+ patients 1,2 Atezolizumab + nab -paclitaxel is approved in the United States 3 and European Union 4 and − recommended for the treatment of patients with PD-L1 IC+ mTNBC in the NCCN 5 and AGO 6 guidelines − PD-L1 expression on IC was evaluated using the VENTANA PD-L1 SP142 IHC assay with a ≥ 1% cutoff 1 The SP142 assay has been clinically validated and FDA-approved to identify patients with mTNBC for treatment with atezolizumab + nab -paclitaxel 3,4 Dako 22C3 a and VENTANA SP263 are 2 other commercially available PD-L1 IHC assays approved − for non-TNBC indications In this exploratory post hoc IMpassion130 substudy, 22C3 and SP263 PD-L1 IHC assays were evaluated for PD-L1 prevalence, analytical concordance with SP142 and estimates of clinical activity AGO, Arbeitsgemeinschaft Gynäkologische Onkologie; IC, tumour-infiltrating immune cells; IHC, immunohistochemistry; NCCN, National Comprehensive Cancer Network. a Commercialized by Merck to support the use of pembrolizumab. Rugo et al. Abstract 6571 1. Schmid New Engl J Med 2018. 2. Schmid ASCO 2019. 3. TECENTRIQ (atezolizumab) USPI 2019. 4. TECENTRIQ (atezolizumab) SmPC 2019. IMpassion130 PD-L1 IHC 5. NCCN Clinical Practice Guidelines. Breast Cancer. V2.2019. 6. AGO Guidelines. Breast. V2019.1. https://bit.ly/30OmOqz
PD-L1 IC status by SP142 predicts PFS and OS 4 benefit with atezolizumab + nab -paclitaxel 1,2 Median PFS Median OS HR HR Population Population (95% CI) (95% CI) A + nP P + nP A + nP P + nP 0.63 0.71 100 100 Progression-Free Survival (%) PD- L1 IC+ (41%) 7.5 mo 5.3 mo PD-L1 IC+ 25.0 mo 18.0 mo (0.50, 0.80) (0.54, 0.93) 90 90 0.93 0.97 PD-L1 IC- (59%) 5.6 mo 5.6 mo PD-L1 IC- 19.7 mo 19.6 mo 80 Overal l Survival (%) 80 (0.78, 1.20) (0.77, 1.11) 70 70 60 60 50 50 40 40 30 30 20 20 10 10 0 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 Months Months A + nP (IC+, n = 185) P + nP (IC+, n = 184) A + nP (IC-, n = 266) P + nP (IC-, n = 267) A + nP, atezolizumab + nab -paclitaxel; HR, hazard ratio; ITT, intention to treat; OS, overall survival; P + nP, placebo + nab -paclitaxel; PFS, progression-free survival. PD-L1 IC+: PD- L1 in ≥ 1% of IC as percentage of tumour area assessed with the VENTANA SP142 assay. NCT02425891. Stratification factors: prior taxane use, liver metastases and PD-L1 IC status. Co-primary endpoints in ITT and PD-L1 IC+: PFS and OS. Rugo et al. Abstract 6571 Clinical cutoff date: 2 January 2019. IMpassion130 PD-L1 IHC 1. Schmid, ASCO 2019. 2. Schmid et al., submitted. https://bit.ly/30OmOqz
PD-L1 status in primary vs metastatic tissues 5 Efficacy in PD-L1 IC+ PD-L1 status by primary vs metastatic tissue a PFS OS Primary tissue 44% HR, 0.61 (95% CI: 0.47, 0.81) HR, 0.79 (95% CI: 0.57, 1.09) (62%) P = 0.014 Primary Survival (%) Survival (%) Metastatic tissue 36% (38%) 0% 20% 40% 60% PD-L1 IC+ Months Months HR, 0.69 (95% CI: 0.46, 1.03) HR, 0.55 (95% CI: 0.32, 0.93) PD-L1 status by anatomical location a Metastatic Breast (64%) 43% Survival (%) Survival (%) Lymph node (12%) 51% Lung (6%) 43% Liver (5%) 13% Soft tissue (4%) 30% Months Months Skin (2%) 48% Atezolizumab + nab -paclitaxel Other (6%) Placebo + nab -paclitaxel 36% Median time of sample collection to randomization: 61 days 0% 20% 40% 60% PD-L1 IC+ a Evaluable population (n = 901). PD-L1 IC+: PD- L1 in ≥ 1% of IC as percentage of tumour area assessed with the VENTANA SP142 ass ay. Rugo et al. Abstract 6571 HRs adjusted for prior taxanes, presence of liver metastases, age and ECOG PS. No major differences were observed for clinical benefit in samples collected IMpassion130 PD-L1 IHC within 61 days of randomization or beyond that period (Emens, et al, manuscript in preparation). https://bit.ly/30OmOqz
Methods 6 Central testing of VENTANA PD-L1 SP142, DAKO 22C3 and VENTANA PD-L1 SP263 IHC assays were performed according to the respective package inserts a − Each slide was read by a single pathologist out of a panel of 8 pathologists b − Pathologists were trained and qualified to read IC 1% (SP142 and SP263) and CPS 1 (22C3) cutoffs b PD-L1 IC algorithm (SP142 and SP263) − Presence of discernible PD- L1 staining of any intensity in IC covering ≥ 1% of tumour area occupied by TC, associated intratumoural and continuous peritumoural stroma PD-L1 CPS algorithm (22C3) − Number of PD-L1–stained cells (TC, lymphocytes and macrophages) divided by the total number of viable TC, multiplied by 100 The biomarker-evaluable population (BEP) in this retrospective exploratory analysis comprised 614 patients (68% of ITT) with samples tested with the 3 PD -L1 assays − Prevalence of PD- L1 IC+ status according to SP142 was higher in the BEP (46%) than the ITT (41%). All other evaluated baseline characteristics were balanced between BEP and ITT − PFS outcome with A + nP in the BEP slightly overperformed compared with PFS outcome in the ITT Rugo et al. Abstract 6571 CPS, combined positive score; TC, tumour cells. IMpassion130 PD-L1 IHC a Using respective platforms. b SP142: 5 pathologists trained for TNBC; 22C3: 2 pathologists trained for non-TNBC; SP263: 3 pathologists trained for non-TNBC. https://bit.ly/30OmOqz
PD-L1 IHC assays: prevalence and 7 analytical concordance PD-L1+ SP142 (IC 1%) SP142 (IC 1%) prevalence and 22C3 (CPS 1) and SP263 (IC 1%) 100% SP142+ SP142+ 22C3- SP263- 81% (1%) (1%) 80% 75% SP142+ SP142+ PD-L1+ Cases 22C3+ SP263+ 60% (45%) a (45%) a b 46% 40% SP142- SP142- 22C3+ SP263+ SP142- SP142- 20% (36%) (30%) 22C3- SP263- (18%) (24%) 0% OPA c 64% OPA c 69% SP142 22C3 SP263 (IC ≥ 1%) (CPS ≥ 1) (IC ≥ 1%) PPA 98% PPA 98% NPA 34% NPA 45% NPA, negative percentage agreement; OPA, overall percentage agreement; PPA, positive percentage agreement. Rugo et al. Abstract 6571 a > 97% of SP142+ samples included in 22C3+ or SP263+ samples. b Compared with 41% in ITT (Schmid, New Engl J Med 2018). IMpassion130 PD-L1 IHC c ≥ 90% OPA, PPA and NPA required for analytical concordance. https://bit.ly/30OmOqz
sTILs in PD-L1 subgroups defined by 8 SP142 and 22C3 or SP263 SP142 (IC 1%) and 22C3 (CPS 1) SP142 (IC 1%) and SP263 (IC 1%) PD-L1 Median sTILs PD-L1 Median sTILs Status n (IQR) Status n (IQR) SP142+ 10% SP142+ 10% 274 274 SP263+ (5-20) 22C3+ (5-20) **** **** SP142- 5% SP142- 5% 214 177 **** **** 22C3+ (2-7) SP263+ (2-7) ** ** SP142- 3% SP142- 3% 109 146 22C3- (1-5) SP263- (1-5) sTILs (% tumour stroma) sTILs (% tumour stroma) Within the 22C3+ or SP263+ subgroups, SP142+ patients had numerically higher sTIL counts compared with SP142- patients IQR, interquartile range; sTIL, stromal tumour-infiltrating lymphocyte. Rugo et al. Abstract 6571 ** P < 0.01; **** P < 0.0001 by Kruskal-Wallis multiple comparisons test. IMpassion130 PD-L1 IHC Similar results were observed with CD8 IHC staining. https://bit.ly/30OmOqz
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