OVERALL SURVIVAL IN KATE2 (NCT02924883): A PHASE 2 STUDY OF PD-L1 - - PowerPoint PPT Presentation

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OVERALL SURVIVAL IN KATE2 (NCT02924883): A PHASE 2 STUDY OF PD-L1 INHIBITOR ATEZOLIZUMAB + TRASTUZUMAB EMTANSINE (T-DM1) VS PLACEBO + T-DM1 IN PREVIOUSLY TREATED HER2-POSITIVE ADVANCED BREAST CANCER

Leisha A. Emens,1Francisco Esteva,2 Mark Beresford,3 Cristina Saura,4 Michelino De Laurentiis,5 Sung-Bae Kim,6 Seock-Ah Im,7 Yifan Wang,8 Aruna Mani,9 Jigna Shah,9 Haiying Liu,9 Sanne de Haas,10 Monika Patre,10 Sherene Loi11

1University of Pittsburgh Medical Center Hillman Cancer Center, Pittsburgh, PA; 2Perlmutter Cancer Center at NYU Langone Medical

Center, New York, NY; 3Royal United Hospital, Bath, UK; 4Vall d’Hebron University Hospital, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain; 5IRCCS Istituto Nazionale Tumori Fondazione Pascale, Napoli, Italy;

6Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea; 7Seoul National University Hospital, Seoul, Korea; 8Roche

(China) Holding Ltd, Shanghai, China; 9Genentech, Inc., South San Francisco, CA; 10F. Hoffmann-La Roche, Basel, Switzerland; 11Peter MacCallum Cancer Centre, Melbourne, Australia

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DISCLOSURES

Advisory roles: AbbVie, Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Celgene, Genentech, Gritstone, Lilly, Macrogenics, Medimmune, Molecuvax, Novartis, Peregrine, Replimune, Roche, Syndax, Vaccinex Royalties: Aduro Biotech Grants: Aduro Biotech, AstraZeneca, Breast Cancer Research Foundation Stocks: None Others: Research funding: Aduro Biotech, AstraZeneca, Breast Cancer Research Foundation, Corvus, Department of Defense, EMD Serono, Genentech, HeritX, Inc., Maxcyte, Merck, National Cancer Institute, NSABP Foundation, Roche, Translational Breast Cancer Research Consortium

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KATE2: BACKGROUND

• T-DM1 is indicated for the treatment of HER2-positive

metastatic breast cancer previously treated with trastuzumab and a taxane

• In addition to its cytotoxic activity, T-DM1 may potentiate

tumour immunity

• Combining T-DM1 with atezolizumab, an anti-PD-L1 antibody

that restores anti-cancer immunity,1,2 may result in greater clinical activity than either drug alone

• In KATE2 (NCT02924883), there was no statistically significant

difference in PFS in patients with HER2-positive advanced breast cancer treated with atezolizumab + T-DM1 vs placebo + T-DM1 in the ITT population (median PFS 8.2 vs 6.8 m), but PFS was numerically longer with combination treatment in patients with PD-L1 IC+ disease (median PFS 8.5 vs 4.1 m)3

• Here we present the final analysis of safety and clinical activity

DC, dendritic cell; IC, tumour-infiltrating immune cell; ITT, intention-to-treat.

• 1. Chen DS, Mellman I. Immunity 2013;39:1-10; 2. Herbst RS, et al. Nature.

2014;515:563-567; 3. Emens LA, et al. San Antonio Breast Cancer Symposium; Dec 4-8, 2018; San Antonio, TX. Abstract PD3-01.

Atezolizumab: Promotes T-cell activation T-DM1: Targets the HER2 receptor and promotes tumour cell death Atezolizumab: Restores anti-cancer immunity, with activity further enhanced by chemotherapy-induced antigen exposure Activated T cells DC Tumour antigen s Tumour cells Access slides at: https://bit.ly/2NGiaqZ

• Data cutoff for primary analysis: 11 December 2017
• Data cutoff for OS analysis: 11 December 2018

Stratification factors:

• Tumour PD-L1 IC status (IC0 [<1%] vs IC1/2/3 [≥1%])a
• World region (Western Europe vs North America vs rest of world)
• Presence of liver metastases (yes or no)

aDetermined using VENTANA SP142.

Primary endpoint:

• Investigator-assessed PFS

Secondary endpoints:

• OS
• Objective response rate
• Duration of response

Exploratory endpoints:

• PFS in patients with PD-L1+

disease

• Exploratory biomarker

subgroups (PD-L1, PIK3CA mutation status, HER2 expression, immune-related [TILs, CD8 IHC expression]) Post hoc endpoint:

• OS in PD-L1 subgroups

IC, tumour-infiltrating immune cell; IHC, immunohistochemistry; ITT, intention-to-treat; LABC, locally advanced breast cancer; MBC, metastatic breast cancer; OS, overall survival; PD, progressive disease; PFS, progression-free survival; TIL, tumour-infiltrating lymphocyte.

HER2+ LABC or MBC

• Prior taxane and

trastuzumab

• Progression on

metastatic therapy

• r within 6 months
• f adjuvant therapy
• Measurable

disease

(n=202)

T-DM1 3.6 mg/kg q3w + Atezolizumab 1200 mg q3w Survival Follow-Up

Until PD per RECIST 1.1

R

2 1

T-DM1 3.6 mg/kg q3w + Placebo 1200 mg q3w

Until loss of clinical benefit

KATE2: STUDY DESIGN Efficacy endpoints in the ITT population

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PRIMARY ANALYSIS RESULTS OF KATE2: PFS IN ITT AND PD-L1 IC+ POPULATIONS

11 December 2017 cutoff date

ITT PD-L1 IC+

HR, hazard ratio; IC, tumour-infiltrating immune cell; ITT, intention-to-treat; NE, not estimable; PFS, progression-free survival. Emens LA, et al. San Antonio Breast Cancer Symposium; Dec 4-8, 2018; San Antonio, TX. Abstract PD3-01. T-DM1 + Atezolizumab T-DM1 + Placebo

• No. of Patients at Risk

133 69 118 54 90 42 59 31 42 23 25 15 15 7 131 66 100 46 74 33 46 25 26 18 21 14 3 1

PFS Rate (%) 100 80 60 40 20 2 4 6 8 10 12 14 Months Median PFS (range) T-DM1 + atezolizumab: 8.5 mo (5.7–NE) T-DM1 + placebo: 4.1 mo (2.7–11.1) Stratified HR=0.60 (95% CI: 0.32–1.11)

T-DM1 + Atezolizumab T-DM1 + Placebo

• No. of Patients at Risk

T-DM1 + Atezolizumab (n=57) T-DM1 + Placebo (n=27)

57 27 51 20 40 15 24 10 16 8 9 6 6 1 56 26 44 16 31 11 19 9 9 7 8 6 2

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PFS Rate (%) 100 80 60 40 20 Months Median PFS (range) T-DM1 + atezolizumab: 8.2 mo (5.8–10.7) T-DM1 + placebo: 6.8 mo (4.0–11.1) Stratified HR=0.82 (95% CI: 0.55–1.23) P=0.3332 2 4 6 8 10 12 14 T-DM1 + Atezolizumab (n=133) T-DM1 + Placebo (n=69)

6-month PFS rate 58% 51% 12-month PFS rate 38% 34%

KATE2: BASELINE DEMOGRAPHICS

T-DM1 + Atezolizumab (n=133) T-DM1 + Placebo (n=69) PD-L1+ diseasea 57 (43%) 27 (39%) Median age, y (range) 54 (29–78) 55 (28–77) Aged <65 y 118 (89%) 58 (84%) Sex, female 131 (98%) 69 (100%) Race White 72 (54%) 44 (64%) Asian 49 (37%) 23 (33%) Other 12 (9%) 2 (3%) ECOG PSb 93 (70%) 40 (58%) 1 39 (29%) 28 (41%) Liver metastases 44 (33%) 22 (32%) Visceral involvement 95 (71%) 48 (70%)

ECOG PS, Eastern Cooperative Oncology Group performance status; ER, oestrogen receptor; MBC, metastatic breast cancer; PR, progesterone receptor.

aPositive defined as IHC IC 1/2/3. bThere was one patient with unknown ECOG status in each study arm.

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T-DM1 + Atezolizumab (n=133) T-DM1 + Placebo (n=69) Hormone receptor status ER− and PR− 48 (36%) 29 (42%) ER+ and/or PR+ 79 (59%) 38 (55%) Unknown 6 (5%) 2 (3%) Prior lines of therapy for MBC 15 (11%) 6 (9%) 1 68 (51%) 40 (58%) 2 23 (17%) 9 (13%) ≥3 27 (20%) 14 (20%)

KATE2: PATIENT DISPOSITION IN THE ITT POPULATION

T-DM1 + Atezolizumab (n=133) T-DM1 + Placebo (n=69) On-study, as of data cutoff date (11 December 2018) 81 (61%) 35 (51%) Alive on study treatment 25 (19%) 8 (12%) Alive in survival follow-up 56 (42%) 27 (39%) Discontinued study 52 (39%) 34 (49%) Deatha 29 (22%) 18 (26%) Withdrawal by subject 21 (16%) 15 (22%) Otherb 2 (2%) 1 (1%)

a Some patients agreed to provide survival status after withdrawal from the study, so the number of patients who discontinued from study due to death is smaller than the total

number of deaths.

b One protocol deviation, one lost to follow-up, one other.

ITT, intention-to-treat.

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T-DM1 + Atezolizumab T-DM1 + Placebo Median follow -up (mo) 19.0 18.2 Patients w ith OS event, n (%) 32 (24.1) 20 (29.0) Median OS (mo) NE NE Stratified HR (95% CI) 0.74 (0.42–1.30) 1-year survival rate (%) 89.1 89.0

11 December 2018 cutoff date

Overall Survival (%) 100 80 60 40 20 3 6 9 12 15 18 21 24 27 Time (mo)

133 69 129 64 122 61 116 58 111 54 101 47 78 35 44 16 21 8 6 1 T-DM1 + Atezolizumab T-DM1 + Placebo

• No. of Patients at Risk

131 67 130 66 126 63 122 62 121 61 118 60 116 55 114 54 111 51 104 48 98 45 86 37 66 29 56 23 42 14 34 12

CI, confidence interval; HR, hazard ratio; NE, not estimable; ITT, intention-to-treat; OS, overall survival.

KATE2: OS IN ITT POPULATION

• With 52 OS events reported, median OS was not reached in either arm
• 1-year OS was similar in both arms

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T-DM1 + Atezolizumab (n=133) T-DM1 + Placebo (n=69) Censored

A tezolizumab + T-DM1 Placebo + T-DM1 Patients with OS ev ent, n (%) 11 (19.3) 8 (29.6) Median OS (mo) NE NE Stratif ied HR (95% CI) 0.55 (0.22–1.38) 1-y ear surv iv al rate (%) 94.3 87.9 A tezolizumab + T-DM1 Placebo + T-DM1 Patients with OS ev ent, n (%) 21 (27.6) 12 (28.6) Median OS (mo) NE NE Stratif ied HR (95% CI) 0.88 (0.43–1.80) 1-y ear surv iv al rate (%) 85.1 89.7

11 December 2018 cutoff date

Overall Survival (%) 100 80 60 40 20 3 6 9 12 15 18 21 24 27 Time (mo) Overall Survival (%) 100 80 60 40 20 3 6 9 12 15 18 21 24 27 Time (mo) T-DM1 + Atezolizumab (n=57) T-DM1 + Placebo (n=27) Censored T-DM1 + Atezolizumab (n=76) T-DM1 + Placebo (n=42) Censored

• In the PD-L1 IC+ subgroup, the 1-year OS rate was numerically higher in the atezolizumab + T-DM1 arm

than in the placebo + T-DM1 arm

CI, confidence interval; HR, hazard ratio; IC, tumour-infiltrating immune cell; NE, not estimable; OS, overall survival.

KATE2: OS IN PD-L1 IC+ AND PD-L1 IC− SUBGROUPS

OS in PD-L1 IC+ Subgroup (IC 1/2/3) OS in PD-L1 IC− Subgroup (IC 0)

57 27 56 23 54 23 52 22 49 21 45 18 33 15 18 6 9 2 56 26 56 25 55 23 54 23 54 23 52 23 52 21 50 21 49 19 45 19 44 18 37 16 27 11 23 8 17 5 13 4 2 T-DM1 + Atezolizumab T-DM1 + Placebo

• No. of Patients at Risk

76 42 73 41 68 38 64 36 62 33 56 29 45 20 26 10 12 6 75 41 74 41 71 40 68 39 67 38 66 37 64 34 64 33 62 32 59 29 54 27 49 21 39 18 33 15 25 9 21 8 4 1 T-DM1 + Atezolizumab T-DM1 + Placebo

• No. of Patients at Risk

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KATE2: BASELINE BIOMARKER DEMOGRAPHICS

T-DM1 + Atezolizumab (n=133) T-DM1 + Placebo (n=69) PD-L1 IHC expression Positive (IC 1/2/3) 57 (43%) 27 (39%) HER2 IHC status IHC 3+ 103 (77%) 56 (81%) IHC 2+ 27 (20%) 12 (17%) IHC 0/1+ 3 (2%) 1 (1%) HER2 gene ratio (n=127) (n=64) 2 to <4 37 (29%) 21 (33%) ≥4 90 (71%) 43 (67%) PIK3CA mutation status n=109 n=52 Mutated 33 (30%) 20 (38%) Non-mutated 76 (70%) 32 (62%)

IC, tumour-infiltrating immune cell, IHC, immunohistochemistry. Note: Biomarker assays were performed on the primary tumour (T-DM1+atezolizumab, 54%; T-DM1, 65%) or a metastatic (T-DM1+ atezolizumab, 36%; T-DM1, 32%) or locally advanced (T-DM1+ atezolizumab, 10%; T-DM1, 3%) tumour.

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IC, tumour-infiltrating immune cell, IHC, immunohistochemistry; Teff; T effector cell; TIL, tumour infiltrating lymphocyte.

ALL BIOMARKERS OF T CELL ACTIVATION/QUANTITY WERE ENRICHED IN THE PD-L1 IC+ SUBGROUP

PD-L1 proteina vs PD-L1 gene expression

a PD-L1 protein was measured by IHC. b The Teff signature included PD-L1, IFNγ, CXCL9, GZMB, and CD8A. c TILs were scored according to www.tilsinbreastcancer.org; The median for stromal TILs was 5%.

PD-L1 protein vs CD8 gene expression PD-L1 protein vs Teff signatureb gene expression PD-L1 protein vs TILsc

PD-L1 RNA 2 –2 –4 IC0 IC1/2/3 PD-L1 IHC IC0 IC1/2/3 PD-L1 IHC IC0 IC1/2/3 PD-L1 IHC IC0 IC1/2/3 PD-L1 IHC CD8 RNA 2 –2 Teff Signature 2 1 –1 TIL (%) 80 60 40 20 –2

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KATE2: OS BY OTHER IMMUNE BIOMARKER SUBGROUPS IS CONSISTENT WITH PD-L1 IC+ SUBGROUP DATA

CI, confidence interval; HR, hazard ratio; OS, overall survival; TIL, tumour-infiltrating cell; Teff, T effector cell. Baseline Risk Factors All Patients PD-L1 RNA Expression ≤Median >Median CD8A RNA Expression ≤Median >Median Teff Signature ≤Median >Median TILs <5% ≥5% n 69 25 23 26 22 26 22 25 40 Events 20 9 7 11 5 9 7 5 13 1-Year Survival (%)a 89.0 86.5 89.7 87.1 89.5 87.1 89.5 100 83.5 T-DM1 + Placebo (n=69) n 133 48 49 47 50 47 50 45 80 Events 32 14 11 11 14 12 13 13 17 1-Year Survival (%)a 89.0 84.5 89.6 84.8 89.4 86.7 87.6 84.2 90.8 T-DM1 + Atezolizumab (n=133) HR (95% CI) 0.74 (0.43–1.30) 0.77 (0.33–1.78) 0.57 (0.22–1.49) 0.46 (0.20–1.07) 1.09 (0.39–3.04) 0.64 (0.27–1.53) 0.70 (0.28–1.75) 1.43 (0.51–4.01) 0.55 (0.26–1.12) T-DM1 + Atezolizumab Better T-DM1 + Placebo Better 0.01 0.1 1 10 100

a One-year survival is included since median OS was not estimable in most subgroups.

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KATE2: SAFETY SUMMARY (SAFETY POPULATION)

Incidence T-DM1 + Atezolizumab (n=133) T-DM1 + Placebo (n=67) Any AE 132 (99%) 65 (97%) Grade ≥3 70 (53%) 30 (45%) Grade 5 2 (1.5%)a 1 (1.5%)b Any serious AEc 48 (36%) 14 (21%) AE leading to discontinuation of any study treatment 39 (29%) 10 (15%)

a Death from haemophagocytic syndrome in one patient and brain haemorrhage due to accidental fall in one patient. b Cardiac failure in one patient, deemed T-DM1–related by the investigator, with outcome of death 1 year after the last dose. c SAEs occurring in ≥2% of patients, with ≥2% difference between treatment arms were pyrexia (8%), ALT increased (2%), AST increased (2%), and vomiting (2%) in the

T-DM1 + atezolizumab arm and abdominal pain (3%) and seizure (3%) in the T-DM1 + placebo arm. 11 December 2018 cutoff date

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ALT, alanine aminotransferase; AST, aspartate aminotransferase.

KATE2: GRADE ≥3 AEs OCCURRING IN ≥2% OF PATIENTS, WITH ≥2% DIFFERENCE BETWEEN TREATMENT ARMS (SAFETY POPULATION)

Grade ≥3 AEs T-DM1 + Atezolizumab (n=133) T-DM1 + Placebo (n=67) Thrombocytopenia 17 (13%) 3 (4%) AST Increased 12 (9%) 2 (3%) Anaemia 11 (8%) ALT Increased 8 (6%) 2 (3%) Pyrexia 4 (3%) Diarrhoea 3 (2%) Urinary Tract Infection 2 (2%) 3 (4%) Abdominal Pain 1 (1%) 3 (4%)

ALT, alanine aminotransferase; AST, aspartate aminotransferase. 11 December 2018 cutoff date

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KATE2: T-DM1–SELECTED AND IMMUNE-RELATED AEs (SAFETY POPULATION)

AE Categories T-DM1 + Atezolizumab (n=133) T-DM1 + Placebo (n=67) All grade Grade 3–5 All grade Grade 3–5 T-DM1–Selected AEs IRR/Hypersensitivity (Type 1) 70 (53%) 5 (4%) 22 (33%) Hepatotoxicitya 56 (42%) 18 (14%) 20 (30%) 4 (6%) Thrombocytopenia 45 (34%) 18 (14%) 14 (21%) 4 (6%) Peripheral Neuropathy 41 (31%) 3 (2%) 19 (28%) 2 (3%) Haemorrhage 39 (29%) 3 (2%) 15 (22%) 1 (1%) Pulmonary Toxicity 6 (5%) 2 (2%) 3 (4%) 1 (1%) Cardiac Dysfunction 1 (1%) 4 (6%) 1 (1%) Immune-related AEs

b,c

Immune-related Rash 43 (32%) 2 (2%) 10 (15%) Immune-related Hypothyroidism 21 (16%) 5 (7%) Immune-related Pancreatitis 5 (4%) 1 (1%) 1 (1%)

a Includes liver laboratory abnormalities; b Immune-related hepatitis, pneumonitis, and IRR/hypersensitivity are presented in the respective categories in T-DM1–selected AEsas

they are overlapping toxicities, and the wider MedDRA search criteria were used for overlapping toxicities; c Immune-related vasculitis, diabetes, myositis, and nephritis were reported in one patient each in the experimental arm and in none in the control arm. Immune-related colitis and ocular inflammatory toxicity were reported in two patients each in the experimental arm and in none in the control arm. Immune-related hyperthyroidism was reported in one patient in the experimental arm and in one patient in the control arm. 11 December 2018 cutoff date

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KATE2: SUMMARY AND CONCLUSIONS

• At the second planned OS analysis, OS numerically favoured the atezolizumab + T-DM1

arm (stratified HR=0.74; 95% CI: 0.42–1.30)

• Although the number of events is small, the data suggest an OS benefit with

atezolizumab + T-DM1 in PD-L1 IC+ patients (1-year survival rate of 94% vs 88%)

– All biomarkers of T cell activation/quantity were enriched in the PD-L1 IC+ subgroup

• Overall, the safety profile of the combination was consistent with the known safety profile
• f each drug
• Based on these results, further study of HER2-targeted agents plus atezolizumab in

previously treated HER2-positive, PD-L1 IC+ advanced breast cancer is warranted

HR, hazard ratio; OS, overall survival; TIL, tumour-infiltrating lymphocyte.

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ACKNOWLEDGEMENTS

• The patients and their families
• The KATE2 investigators and clinical study sites
• The independent data monitoring committee
• TILs were scored in haematoxylin and eosin slides by Dr Roberto Salgado,

according to the guidelines of the International Immuno-Oncology Biomarker Working Group on Breast Cancer

• This trial was sponsored by F. Hoffmann-La Roche Ltd
• Medical writing assistance for this presentation was provided by Twist Medical and

was funded by F. Hoffmann-La Roche, Ltd

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TIL, tumour-infiltrating lymphocyte.