Performance of PD-L1 immunohistochemistry assays in unresectable - - PowerPoint PPT Presentation

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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. Emens13

1University of California San Francisco Comprehensive Cancer Center, San Francisco, CA, USA; 2Peter MacCallum Cancer Centre, Melbourne, VIC,

Australia; 3NYU Langone Medical Center, New York, NY, USA; 4Barts Cancer Institute, Queen Mary University London, London, UK; 5University Hospital and German Cancer Research Center Heidelberg, Heidelberg, Germany; 6Centro de Pesquisa Clínica, HSL, PUCRS, Porto Alegre, Brazil; 7Aichi Cancer Center Hospital, Nagoya, Japan; 8Department of Medical Oncology, Centre Eugène Marquis, Rennes, France; 9Dana-Farber Cancer Institute, Boston, MA, USA; 10HistoGeneX NV, Antwerp, Belgium; 11Genentech, Inc., South San Francisco, CA, USA; 12University of Milan, European Institute of Oncology IRCCS, Milan, Italy; 13University of Pittsburgh Medical Center Hillman Cancer Center, Pittsburgh, PA, USA

Rugo et al. Abstract 6571 IMpassion130 PD-L1 IHC https://bit.ly/30OmOqz

• 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

Disclosures

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Rugo et al. Abstract 6571 IMpassion130 PD-L1 IHC https://bit.ly/30OmOqz

• IMpassion130 is the first Phase III study of cancer immunotherapy in mTNBC to

demonstrate clinical benefit in PD-L1+ patients1,2

− Atezolizumab + nab-paclitaxel is approved in the United States3 and European Union4 and recommended for the treatment of patients with PD-L1 IC+ mTNBC in the NCCN5 and AGO6 guidelines − PD-L1 expression on IC was evaluated using the VENTANA PD-L1 SP142 IHC assay with a ≥ 1% cutoff1

• The SP142 assay has been clinically validated and FDA-approved to identify patients

with mTNBC for treatment with atezolizumab + nab-paclitaxel3,4

− Dako 22C3a 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

• f clinical activity

Background

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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.

• 1. Schmid New Engl J Med 2018. 2. Schmid ASCO 2019. 3. TECENTRIQ (atezolizumab) USPI 2019. 4. TECENTRIQ (atezolizumab) SmPC 2019.
• 5. NCCN Clinical Practice Guidelines. Breast Cancer. V2.2019. 6. AGO Guidelines. Breast. V2019.1.

Rugo et al. Abstract 6571 IMpassion130 PD-L1 IHC https://bit.ly/30OmOqz

PD-L1 IC status by SP142 predicts PFS and OS benefit with atezolizumab + nab-paclitaxel1,2

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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.

Clinical cutoff date: 2 January 2019.

• 1. Schmid, ASCO 2019. 2. Schmid et al., submitted.

Population Median OS HR (95% CI) A + nP P + nP PD-L1 IC+ 25.0 mo 18.0 mo 0.71 (0.54, 0.93) PD-L1 IC- 19.7 mo 19.6 mo 0.97 (0.78, 1.20) Population Median PFS HR (95% CI) A + nP P + nP PD-L1 IC+ (41%) 7.5 mo 5.3 mo 0.63 (0.50, 0.80) PD-L1 IC- (59%) 5.6 mo 5.6 mo 0.93 (0.77, 1.11)

A + nP (IC+, n = 185) P + nP (IC+, n = 184) A + nP (IC-, n = 266) P + nP (IC-, n = 267)

3 6 9 12 15 18 21 24 27 30 33 36 39 42 3 6 9 12 15 18 21 24 27 30 33 36 39 42 100 90 80 70 60 50 40 30 20 10 100 90 80 70 60 50 40 30 20 10

Overall Survival (%) Progression-Free Survival (%) Months Months

Rugo et al. Abstract 6571 IMpassion130 PD-L1 IHC https://bit.ly/30OmOqz

Efficacy in PD-L1 IC+

PFS OS

Primary Metastatic

PD-L1 status in primary vs metastatic tissues

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a Evaluable population (n = 901). PD-L1 IC+: PD-L1 in ≥ 1% of IC as percentage of tumour area assessed with the VENTANA SP142 assay.

HRs adjusted for prior taxanes, presence of liver metastases, age and ECOG PS. No major differences were observed for clinical benefit in samples collected within 61 days of randomization or beyond that period (Emens, et al, manuscript in preparation). Atezolizumab + nab-paclitaxel Placebo + nab-paclitaxel

HR, 0.61 (95% CI: 0.47, 0.81) HR, 0.55 (95% CI: 0.32, 0.93) HR, 0.79 (95% CI: 0.57, 1.09) HR, 0.69 (95% CI: 0.46, 1.03)

Survival (%) Survival (%) Survival (%) Survival (%) Months Months Months Months

44% 36%

0% 20% 40% 60%

Primary tissue (62%) Metastatic tissue (38%)

P = 0.014 43% 51% 43% 13% 30% 48% 36% 0% 20% 40% 60%

Breast (64%) Lymph node (12%) Lung (6%) Liver (5%) Soft tissue (4%) Skin (2%) Other (6%)

PD-L1 IC+

PD-L1 status by primary vs metastatic tissuea PD-L1 status by anatomical locationa

PD-L1 IC+

• Median time of sample collection to randomization: 61 days

Rugo et al. Abstract 6571 IMpassion130 PD-L1 IHC https://bit.ly/30OmOqz

• Central testing of VENTANA PD-L1 SP142, DAKO 22C3 and VENTANA PD-L1 SP263

IHC assays were performed according to the respective package insertsa

− Each slide was read by a single pathologist out of a panel of 8 pathologistsb − Pathologists were trained and qualified to read IC 1% (SP142 and SP263) and CPS 1 (22C3) cutoffsb

• 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

Methods

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CPS, combined positive score; TC, tumour cells.

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.

Rugo et al. Abstract 6571 IMpassion130 PD-L1 IHC https://bit.ly/30OmOqz

SP142 (IC 1%) and SP263 (IC 1%)

OPAc 69% PPA 98% NPA 45%

SP142 (IC 1%) and 22C3 (CPS 1)

OPAc 64% PPA 98% NPA 34%

PD-L1 IHC assays: prevalence and analytical concordance

7 NPA, negative percentage agreement; OPA, overall percentage agreement; PPA, positive percentage agreement.

a > 97% of SP142+ samples included in 22C3+ or SP263+ samples. b Compared with 41% in ITT (Schmid, New Engl J Med 2018). c ≥ 90% OPA, PPA and NPA required for analytical concordance.

SP142- 22C3- (18%) SP142+ 22C3+ (45%)a SP142- 22C3+ (36%) SP142+ 22C3- (1%) SP142- SP263+ (30%) SP142- SP263- (24%) SP142+ SP263+ (45%)a

PD-L1+ Cases

PD-L1+ prevalence

SP142+ SP263- (1%)

46% 81% 75% 0% 20% 40% 60% 80% 100% SP142 (IC ≥ 1%) 22C3 (CPS ≥ 1) SP263 (IC ≥ 1%)

b

Rugo et al. Abstract 6571 IMpassion130 PD-L1 IHC https://bit.ly/30OmOqz

PD-L1 Status n Median sTILs (IQR) SP142+ SP263+ 274 10% (5-20) SP142- SP263+ 177 5% (2-7) SP142- SP263- 146 3% (1-5)

sTILs (% tumour stroma)

PD-L1 Status n Median sTILs (IQR) SP142+ 22C3+ 274 10% (5-20) SP142- 22C3+ 214 5% (2-7) SP142- 22C3- 109 3% (1-5)

• Within the 22C3+ or SP263+ subgroups, SP142+ patients had numerically higher

sTIL counts compared with SP142- patients

sTILs in PD-L1 subgroups defined by SP142 and 22C3 or SP263

IQR, interquartile range; sTIL, stromal tumour-infiltrating lymphocyte.

** P < 0.01; **** P < 0.0001 by Kruskal-Wallis multiple comparisons test.

Similar results were observed with CD8 IHC staining.

SP142 (IC 1%) and 22C3 (CPS 1) SP142 (IC 1%) and SP263 (IC 1%)

sTILs (% tumour stroma)

** **** **** ** **** ****

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Rugo et al. Abstract 6571 IMpassion130 PD-L1 IHC https://bit.ly/30OmOqz

Population PFS OS

SP142 IC ≥ 1%: 46% (285/614) 22C3 CPS ≥ 1: 81% (497/614) SP263 IC ≥ 1%: 75% (460/614)

Median OS, mo HR (95% CI) A + nP P + nP ∆ 27.3 17.9 9.4 0.74 (0.54, 1.01) Median PFS, mo HR (95% CI) A + nP P + nP ∆ 8.3 4.1 4.2 0.60 (0.47, 0.78)

Clinical outcomes in PD-L1+ populations per SP142 (IC 1%), 22C3 (CPS 1) and SP263 (IC 1%)

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HR adjusted for prior taxanes, presence of liver metastases, age and ECOG PS.

7.5 5.4 2.1 0.68 (0.56, 0.82)

Atezolizumab + nab-paclitaxel Placebo + nab-paclitaxel

7.5 5.3 2.2 0.64 (0.53, 0.79) 21.6 19.2 2.4 0.78 (0.62, 0.99) 22.0 18.7 3.3 0.75 (0.59, 0.96)

Survival (%) Survival (%) Months Months Months Months Survival (%) Survival (%) Survival (%) Survival (%) Months Months

Rugo et al. Abstract 6571 IMpassion130 PD-L1 IHC https://bit.ly/30OmOqz

Population PFS OS

SP142+ 22C3+

(45%; 279/614)

SP142- 22C3+

(36%; 218/614)

SP142- 22C3-

(18%, 111/614)

Median OS, mo HR (95% CI) A + nP P + nP ∆ 27.3 18.0 9.3 0.71 (0.52, 0.98) Median PFS, mo HR (95% CI) A + nP P + nP ∆ 8.3 3.9 4.4 0.60 (0.46, 0.78)

Clinical outcomes in BEP subpopulations defined by SP142 (IC 1%) and 22C3 (CPS 1)

10 Double positive: SP142 IC ≥ 1%, 22C3 CPS ≥ 1; single positive: SP142 IC < 1%, 22C3 CPS ≥ 1; double negative: SP142 IC < 1%, 22C3 CPS < 1. HR adjusted for prior taxanes, presence of liver metastases, age and ECOG PS.

7.3 5.6 1.7 0.81 (0.61, 1.09) 21.3 21.8 −0.5 0.92 (0.64, 1.31) 5.5 5.6 −0.1 1.00 (0.66, 1.51) 14.7 19.6 −4.9 1.08 (0.67, 1.76)

Double positives Single positives Double negatives

Survival (%) Survival (%) Months Months Months Months Survival (%) Survival (%) Survival (%) Survival (%) Months Months

Rugo et al. Abstract 6571 IMpassion130 PD-L1 IHC https://bit.ly/30OmOqz

Population PFS OS

SP142+ SP263+

(45%; 278/614)

SP142- SP263+

(30%; 182/614)

SP142- SP263-

(24%; 147/614)

Median OS, mo HR (95% CI) A + nP P + nP ∆ 27.3 17.9 9.4 0.71 (0.52, 0.97) Median PFS, mo HR (95% CI) A + nP P + nP ∆ 8.3 4.1 4.2 0.61 (0.47, 0.79)

Clinical outcomes in BEP subpopulations defined by SP142 (IC 1%) and SP263 (IC 1%)

11 Double positive: SP142 IC ≥ 1%, SP263 IC ≥ 1%; single positive: SP142 IC < 1%, SP263 IC ≥ 1%; double negative: SP142 IC < 1%, SP263 IC < 1%. HR adjusted for prior taxanes, presence of liver metastases, age and ECOG PS.

7.0 5.4 1.6 0.68 (0.49, 0.94) 21.4 21.0 0.4 0.87 (0.58, 1.29) 5.5 6.9 −1.4 1.13 (0.79, 1.61) 17.9 20.5 −2.6 1.10 (0.72, 1.68)

Double positives Single positives Double negatives

Survival (%) Survival (%) Months Months Months Months Survival (%) Survival (%) Survival (%) Survival (%) Months Months

Rugo et al. Abstract 6571 IMpassion130 PD-L1 IHC https://bit.ly/30OmOqz

In this post hoc exploratory biomarker sub-study of the IMpassion130 trial

• Clinical activity was observed in the SP142 PD-L1 IC+ subgroup, regardless of whether

the sample was from the primary tumour or metastatic tissue

• With overall percentage agreements of 64% (22C3) and 69% (SP263), the analytical

concordance was subpar (< 90%) and the assays are not equivalent − 22C3 (CPS ≥ 1) and SP263 (IC ≥ 1%) PD-L1 assays identified a larger patient population of which SP142+ (IC ≥ 1%) is a subgroup

• The clinical benefit in 22C3+ and SP263+ subgroups was driven by the SP142+ subgroup

− The SP142 assay identified patients with the smallest HR point estimates and longest median PFS and OS from atezolizumab + nab-paclitaxel

• The SP142 assay is the approved diagnostic test used to identify patients with mTNBC

most likely to benefit from the addition of atezolizumab to nab-paclitaxel

Conclusions

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Rugo et al. Abstract 6571 IMpassion130 PD-L1 IHC https://bit.ly/30OmOqz

• The patients and their families
• The investigators and clinical study sites
• Celgene for providing nab-paclitaxel for this study
• This study is sponsored by F. Hoffmann-La Roche, Ltd.
• Medical writing assistance for this oral presentation was provided by

Steffen Biechele, PhD, of Health Interactions, and funded by

• F. Hoffmann-La Roche, Ltd.

Acknowledgements

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