Atezolizumab Is a Humanized Anti-PDL1 Antibody That Inhibits the Binding of PD-L1 to PD-1 and B7.1

Transcription

1 Phase II, Single-Arm Trial (BIRCH) of Atezolizumab as First-Line or Subsequent Therapy for Locally Advanced or Metastatic PD-L1-Selected Non-Small Cell Lung Cancer (NSCLC) Abstract 16LBA Besse B, Johnson ML, Jänne PA, Garassino MC, Eberhardt W, Peters S, Toh CK, Kurata T, Li Z, Kowanetz M, Mocci S, Shankar G, Sandler A, Rizvi NA

2 Atezolizumab Is a Humanized Anti-PDL1 Antibody That Inhibits the Binding of PD-L1 to PD-1 and B7.1 High rates of somatic mutations in lung cancer may contribute to increased immunogenicity, 1 making immunotherapy a viable treatment approach Inhibiting PD-L1/PD-1 and PD-L1/B7.1 interactions can restore anti-tumor T-cell activity and enhance T-cell priming Targeting PD-L1 leaves the PD-L2/PD-1 interaction intact, thereby potentially preserving peripheral immune homeostasis Atezolizumab (MPDL3280A; anti-pdl1) has demonstrated promising response rates in NSCLC that correlated with PD-L1 expression on tumor cells (TC) and/or tumor-infiltrating immune cells (IC) 2,3 1 Chen DS, et al. Clin Cancer Res. 2012;18(24): Horn L, et al. J Clin Oncol. 2015;33(suppl): Abstract Spira AI, et al. J Clin Oncol. 2015;33(suppl): Abstract 8010.

3 BIRCH: Phase II Trial of Atezolizumab in PD-L1-Selected Advanced NSCLC Locally advanced or metastatic NSCLC Tumor PD-L1 expression by IHC (TC2/3 and/or IC2/3) ECOG PS 0 or 1 No brain mets N = 667 Cohort 1 (1L) No prior chemo N = 142 Cohort 2(2L) 1 prior platinum chemo N = 271 Cohort 3 (3L+) 2 prior chemos (including 1 platinum) n = 254 PD Until loss of clinical benefit Atezolizumab dosed at 1200 mg IV q3w in all cohorts Primary endpoint: Objective response rate assessed by Independent Review Facility (IRF- assessed ORR) per RECIST v1.1 Secondary endpoints: IRF-assessed progression-free survival (PFS), duration of response (DOR) per RECIST v1.1 INV-assessed ORR, PFS, DOR per RECIST v1.1 and modified RECIST Overall survival (OS) Safety

4 BIRCH: PD-L1 TC and IC Selection Criteria TC2/3 IC2/3 Intrinsic PD-L1 expression in tumor cells (TC) 34% of screened patients between Jan and Dec Adaptive PD-L1 expression in tumor-infiltrating immune cells (IC) BIRCH enrolled patients with tumors that were PD-L1 TC2/3 or IC2/3 VENTANA SP142 IHC assay was used to determine PD-L1 expression on both TC and IC Archival or freshly collected tumor specimens were required for PD-L1 testing at a central laboratory PD-L1 as a predictive biomarker: PD-L1 expression on TC and IC was independently predictive of response in patients with previously treated NSCLC (ie, POPLAR) 1,2 TC3 or IC3 = TC > 50% or IC >10% PD-L1+ cells; TC2/3 or IC2/3 = TC or IC > 5% PD-L1+ cells, respectively 1 Horn L, et al. J Clin Oncol. 2015;33(suppl): Abstract Vansteenkiste J, et al. Eur J Cancer. 2015;51(Suppl 3): Abstract 14LBA.

5 BIRCH: Hierarchical Testing Procedure The primary efficacy analyses compared IRF-assessed ORRs in the prespecified subgroups to historical controls using the following sequence: Line of Therapy (Ordered by the testing procedure) PD-L1 Status 3L+ (cohort 3) TC3 or IC3 2L+ (cohorts 2/3) TC3 or IC3 3L+ TC3 or IC2/3 3L+ TC2/3 or IC2/3 2L+ TC3 or IC2/3 2L+ TC2/3 or IC2/3 All lines (all 3 cohorts) TC3 or IC3 Prespecified historical control rates: 5% for 3L+, 7% for 2L+, 15% for all lines

6 BIRCH: Baseline Characteristics All Treated Patients Median age (range), y 3L+ (n = 253) 64.0 (38-84) 2L (n = 267) 63.0 (28-83) 1L (n = 139) 67.0 (35-88) All Patients (n = 659) Male, % ECOG PS 1, % Current/previous tobacco use, % Non-squamous histology, % EGFR mutation a 64.0 (28-88) n Positive 14 (11%) 15 (12%) 10 (14%) 39 (12%) KRAS mutation a n Positive 24 (32%) 21 (34%) 14 (35%) 59 (33%) TC3 or IC3 status, % a Mutational status not required at enrollment; limited data available.

7 BIRCH: IRF-Assessed ORR by Line of Therapy TC3 or IC3 and TC2/3 or IC2/3 Subgroups BIRCH met its primary endpoint in all predefined subgroups per protocol-specified criteria Majority of responses were ongoing (>61% in TC3 or IC3) Median DOR was 7 mo in 3L+, NR in 1L/2L in TC3 or IC3, although follow-up is limited IRF- and INV-assessed ORRs (per RECIST v1.1) were similar. In TC3 or IC3, eg, 27% vs 29% in 3L+; 24% vs 25% in 2L; and 26% vs 31% in 1L, respectively

8 BIRCH: Overall Survival by Line of Therapy TC2/3 or IC2/3 No. of Patients at Risk 1L L L

9 BIRCH: Overall Survival by Line of Therapy TC3 or IC3 No. of Patients at Risk 1L L L

10 BIRCH: PFS by Line of Therapy TC2/3 or IC2/3 No. of Patients at Risk 1L L L

11 BIRCH: PFS by Line of Therapy TC3 or IC3 No. of Patients at Risk 1L L L

12 BIRCH: Safety Summary All Treated Patients Number of Patients with 1 AE 3L+ (n = 253) 2L (n = 267) 1L (n = 139) All Patients (n = 659) All-cause AEs 96% 92% 91% 94% All-cause Grade 3-4 AEs 39% 37% 40% 38% Treatment-related AEs 69% 63% 57% 64% Treatment-related Grade 3-4 AEs 11% 12% 9% 11% AE leading to withdrawal of atezolizumab a 4% 6% 6% 5% AE of special interest 28% 28% 20% 26% Treatment-related Grade 5 AE 0.4% b % Treatment duration, median (range) 4.1 mo (0-14) 4.1 mo (0-15) 4.9 mo (0-14) 4.2 mo (0-15) a Causes of atezolizumab withdrawal (all cohorts): pneumonitis (0.6%), pneumonia (0.5%), pneumonia aspiration (0.3%), septic shock (0.3%), cerebrovascular accident (0.3%), sudden death (0.3%), thrombocytopenia (0.3%) b One grade 5 treatment-related event (pneumonia)

13 BIRCH: Treatment-Related AEs 5% of Treated Patients a a Treatment-related AEs that occurred during and up to 30 days from last day of atezolizumab administration

14 BIRCH: Adverse Events of Special Interest (AESI) All Treated Patients

15 BIRCH: Summary BIRCH demonstrated clinically meaningful efficacy with atezolizumab monotherapy in PD-L1-selected patients with advanced NSCLC The majority of responses are still ongoing OS data not yet mature 6-month OS rate is consistent with POPLAR results for 2/3L+ Safety profile is consistent with previous atezolizumab monotherapy trials, with no unexpected signals or differences in toxicity across cohorts Higher PD-L1 expression correlates with higher responses and may allow identification of NSCLC patients who are likely to benefit from atezolizumab therapy

16 Ongoing Atezolizumab Development in NSCLC Phase 1b trial of atezolizumab with chemotherapy showed 67% preliminary ORR and tolerable safety in unselected patients with NSCLC (NCT ) 1,2 Multiple Phase III 1L trials in NSCLC studies IMpower 150, NCT IMpower 130, NCT IMpower 131, NCT IMpower 110, NCT IMpower 111, NCT Phase III 2L+ NSCLC trial OAK, NCT Atezolizumab + chemotherapy (unselected) Atezolizumab vs chemotherapy (PD-L1 selected) 1 Giaccone G, et al. Eur J Cancer. 2015;51(Suppl 3): Abstract Camidge R, et al. Presented at: World Conference Lung Cancer; September 7, 2015; Denver, Colorado. Abstract ORAL02.06.