Immune checkpoint blockade in lung cancer Raffaele Califano Department of Medical Oncology The Christie and University Hospital of South Manchester, Manchester, UK
Outline Background Overview of the data Conclusions
Immunogenicity of NSCLC Lawrence, et al. Nature 213,
NSCLC and SCLC are highly mutated Lung Cancers from smokers have 1x somatic mutations vs non-smokers Vogelstein, et al. Science 213
PD-1/PD-L1 inhibitors Agent Type of mab Company Phase Anti PD-1 Nivolumab Fully Human IgG4 BMS Phase III Pembrolizumab Humanized IgG4 MSD Phase III Anti PD-L1 Atezolizumab Engineered Human IgG1 Roche Phase III Durvalumab Engineered Human IgG1 Medimmune/AZ Phase III
Nivolumab (Anti PD-1 antibody)
Phase I Study 8-wk treatment cycle Rapid PD or clin. deterioration Off Study Day 1 15 29 43 57 SCANS BMS-936558 iv Q2wk Doses for NSCLC: 1, 3, 1 mg/kg N=129 Unacceptable toxicity CR/PR/SD or PD but clinically stable Follow-up every 8 wks x 6 (48 wks) Treat to confirmed CR, worsening PD, unacceptable toxicity, or 12 cycles Brahmer, et al,. ASCO 214, abs 8112
Activity ISEL BR.21 Brahmer, et al,. ASCO 214, abs 8112
Duration of Response and Overall Survival Efficacy NSCLC Responders by Histology All Treated Subjects with NSCLC 1 9 Squamous 8 7 Non-squamous Time to and duration of response while on treatment Ongoing response Time to response Response duration following latest reported dose of therapy OS (%) 6 5 4 3 2 2-year OS = 24% 3-year OS = 18% 1 16 32 48 64 8 96 112 128 144 16 Weeks since treatment initiation 6 12 18 24 3 36 42 48 54 6 66 Time Since First Dose (Months) ASCO 214, Abstract 8112 CMSTO 214, Abstract 3428
Phase II in Squamous (Checkmate-63) ORR 15% Rizvi et al, Lancet Oncology 215
CheckMate 17 - Squamous Stage IIIb/IV SQ NSCLC 1 prior platinum doublet-based chemotherapy ECOG PS 1 Pre-treatment (archival or fresh) tumor samples required for PD-L1 analysis N = 272 Randomize 1:1 Nivolumab 3 mg/kg IV Q2W until PD or unacceptable toxicity n = 135 Docetaxel 75 mg/m 2 IV Q3W until PD or unacceptable toxicity n = 137 Primary Endpoint: OS Additional Endpoints: Investigator-assessed ORR Investigator-assessed PFS Correlation between PD-L1 expression and efficacy Safety Quality of life (LCSS) 83% of patients had quantifiable PD-L1 expression Brahmer, et al, NEJM July 215
Overall Survival 1 9 8 mos mo, (95% CI) Nivolumab n = 135 9.2 (7.3, 13.3) Docetaxel n = 137 6. (5.1, 7.3) 7 # events 86 113 OS (%) 6 5 4 1-yr OS rate = 42% HR =.59 (95% CI:.44,.79), P =.25 Nivolumab 3 2 Docetaxel 1 1-yr OS rate = 24% 3 6 9 12 15 18 21 24 Number of Patients at Risk Time (months) Nivolumab Docetaxel 135 113 86 69 52 31 15 7 137 13 68 45 3 14 7 2 Brahmer, et al, NEJM July 215
Progression-Free Survival 1 9 8 7 Nivolumab n = 135 Docetaxel n = 137 PFS (%) 6 5 4 mpfs, mo (95% CI) 3.5 (2.1, 4.9) 2.8 (2.1, 3.5) HR =.62 (95% CI:.47,.81); P =.4 3 1-yr PFS rate = 21% 2 Nivolumab 1 1-yr PFS rate = 6.4% Docetaxel 3 6 9 12 15 18 21 24 Number of Patients at Risk Time (months) Nivolumab Docetaxel 135 68 48 33 21 15 6 2 137 62 26 9 6 2 1 Brahmer, et al, NEJM July 215
Response Rate Nivolumab n = 135 Docetaxel n = 137 ORR, % (95% CI) 2 (14, 28) P-value a.83 9 (5, 15) Best overall response, % Complete response Partial response Stable disease Progressive disease Unable to determine Median DOR, c mo (range) Median time to response, c mo (range) 1 b 19 29 41 1 NR (2.9, 21+) 2.2 (1.6, 12) 9 34 35 22 8.4 (1.4+, 15+) 2.1 (1.8, 9.5) Brahmer, et al, NEJM July 215
Response Characteristics of Confirmed Responders 63% (17/27) of patients had ongoing response RECIST v1.1 Responders Nivolumab Time to first response On treatment (nivolumab) On treatment (docetaxel) Off treatment Ongoing response Docetaxel 33% (4/12) of patients had ongoing response 8 16 24 32 4 48 56 64 72 8 88 96 14 Time (Weeks) Brahmer, et al, NEJM July 215
OS and PFS by PD-L1 Expression Survival benefit with nivolumab was independent of PD-L1 expression level PD-L1 positive expression PD-L1 negative expression Not quantifiable PD-L1 expression was measured in pre-treatment tumor biopsies (DAKO automated IHC assay).125.25.5 1. 2. Nivolumab Docetaxel Brahmer, et al, NEJM July 215
Treatment and Safety Summary Treatment-related AEs, % Treatment-related AEs leading to discontinuation, % Treatment-related deaths, % Any Grade Nivolumab n = 131 Grade 3 5 Any Grade Docetaxel n = 129 Grade 3 5 58 7 86 57 3 2 1 7 2 Median number of doses was 8 (range, 1 48) for nivolumab and 3 (range, 1 29) for docetaxel Brahmer, et al, NEJM July 215
Selected Adverse Events Endocrine, % Hypothyroidism Gastrointestinal, % Diarrhea Colitis Hepatic, a % ALT increased AST increased Nivolumab n = 131 Docetaxel n = 129 Any Grade Grade 3 4 Any Grade Grade 3 4 4 4 8 8 1 Licensed in Europe 2 as second-line 2 for 1 2 1 1 Squamous 2 NSCLC 1 1 Pulmonary, % Pneumonitis Lung infiltration Interstitial lung disease Renal,% Blood creatinine increased Tubulointerstitial nephritis 5 5 1 3 3 1 Skin,% 9 9 2 Hypersensitivity/Infusion reaction, % Hypersensitivity Infusion-related reaction 1 1 1 1 1 1 1 1 2 2 1 b 1 b 2 2 2 2 1 2 2 1 1 Brahmer, et al, NEJM July 215
CheckMate 57 Non Squamous Stage IIIB/IV non-sq NSCLC Pre-treatment (archival or recent) tumor samples required for PD-L1 ECOG PS 1 Failed 1 prior platinum doublet Prior maintenance therapy allowed Prior TKI therapy allowed for known ALK translocation or EGFR mutation N = 582 Randomize 1:1 Nivolumab 3 mg/kg IV Q2W until PD or unacceptable toxicity n = 292 Docetaxel 75 mg/m 2 IV Q3W until PD or unacceptable toxicity n = 29 Primary Endpoint OS Additional Endpoints ORR PFS Safety Efficacy by tumor PD-L1 expression Quality of life (LCSS) PD-L1 expression measured using the Dako/BMS automated IHC assay Paz Ares, ASCO 215
Overall Survival 1 9 8 7 6 Nivolumab (n = 292) Docetaxel (n = 29) mos, mo 12.2 9.4 HR =.73 (96% CI:.59,.89); P =.15 OS (%) 5 4 3 1-yr OS rate = 39% 1-yr OS rate = 51% Nivolumab 2 1 Docetaxel 3 6 9 12 15 18 21 24 Number of Patients at Risk Time (months) 27 Nivolumab Docetaxel 292 232 194 169 146 123 62 32 9 29 244 194 15 111 88 34 1 5 Paz Ares, ASCO 215
Response Rate ORR (95% CI) Nivolumab (n = 292) Docetaxel (n = 29) 19% (15, 24) Odds Ratio (95% CI) 1.72 (1.1, 2.6) P-value a.246 12% (9, 17) Best overall response, % Complete response Partial response Stable disease Progressive disease Unable to determine 1 18 25 44 11 <1 12 42 29 16 Median time to response, mo (range) 2.1 (1.2, 8.6) 2.6 (1.4, 6.3) Median DOR, mo (range) 17.2 (1.8, 22.6+) 5.6 (1.2+, 15.2+) Ongoing response, % 52 14 Paz Ares, ASCO 215
Progression-Free Survival 1 9 PFS (%) 8 7 6 5 4 Nivolumab (n = 292) Docetaxel (n = 29) mpfs, mo 2.3 4.2 HR =.92 (95% CI:.77, 1.11); P =.3932 3 2 1-yr PFS rate = 19% Nivolumab 1 1-yr PFS rate = 8% 3 6 9 12 15 18 21 24 Time (months) Number of Patients at Risk Docetaxel 27 Nivolumab Docetaxel 292 128 82 58 46 35 17 7 2 29 156 87 38 18 6 2 1 1 Paz Ares, ASCO 215
Efficacy by PD-L1 expression Increasing PD-L1 expression (>1%): Longer OS vs Docetaxel Higher RR than Docetaxel In PD-L1 negative pts: No difference Paz Ares, ASCO 215
Treatment and Safety Summary Nivolumab (n = 287) Docetaxel (n = 268) Median number of doses received (range) 6 (1, 52) 4 (1, 23) Relative dose intensity, 9% 83 66 Patients continuing treatment, % 15 Patients who received subsequent systemic therapy, % Any Grade 42 5 Grade 3 4 Any Grade Grade 3 4 Treatment-related AEs, % 69 1 88 54 Treatment-related SAEs, % 7 5 2 18 Treatment-related AEs leading to discontinuation, % 5 4 15 7 Treatment-related deaths, % <1
Treatment-related Adverse Events Total patients with an event Nivolumab (n = 287) Docetaxel (n = 268) Any Grade, % Grade 3 4, % Any Grade, % Grade 3 4, % 69 1 88 54 Fatigue 16 1 29 5 Nausea 12 1 26 1 Decreased appetite 11 16 1 Asthenia 1 <1 18 2 Diarrhea 8 1 23 1 Peripheral edema 3 1 <1 Myalgia 2 <1 11 Anemia 2 <1 2 3 Alopecia <1 25 Neutropenia <1 31 27 Febrile neutropenia 1 1 Leukopenia 1 8
Treatment-related Select AEs Nivolumab (n = 287) Docetaxel (n = 268) Any Grade Grade 3 4 a Any Grade Grade 3 4 a Endocrine, % Hypothyroidism 7 Gastrointestinal, % Diarrhea 8 1 23 1 Hepatic, % ALT increased AST increased 3 1 NON-SQUAMOUS 3 <1 NSCLC 1 Pulmonary, % Pneumonitis 3 1 <1 <1 Skin, % Rash Pruritus Erythema Hypersensitivity/Infusion reaction, % Infusion-related reaction NOT LICENSED FOR 9 8 1 <1 3 1 4 <1 3 3 <1 Paz Ares, ASCO 215
Pembrolizumab (Anti PD-1 antibody)
Keynote - 1 N= 495 65% of patients received 2 lines of treatment Garon et al, NEJM 215
Objective Response Rate Garon et al, NEJM 215
Outcome in all treated patients Garon et al, NEJM 215
Examples of PD-L1 IHC staining Garon et al, NEJM 215
ORR by PD-L1 proportion score Pts with measurable disease Garon et al, NEJM 215
PFS by PD-L1 expression Garon et al, NEJM 215
OS by PD-L1 expression Garon et al, NEJM 215
Atezolizumab (Anti PD-L1 antibody)
POPLAR Study Metastatic or locally advanced NSCLC (2L/3L) Disease progression on a prior platinum therapy N = 287 R 1:1 Stratification Factors PD-L1 IC expression ( vs 1 vs 2 vs 3) a Histology (squamous vs non-squamous) Prior chemotherapy regimens (1 vs 2) a Archival or fresh tissue required for pre-dose testing Atezolizumab 12mg IV q3w until loss of clinical benefit Docetaxel 75mg/m 2 IV q3w until disease progression Phase 2. Primary endpoint: OS in ITT and PD-L1 expression subgroups Analysis is based on 173 events with a minimum follow-up 13 months Vansteenkiste et al, ECC 215
PD-L1 expression on TC and IC Intrinsic PD-L1 expression in tumour cells (TC) SP142 IHC assay is sensitive and specific for PD-L1 expression in both TC and IC Distinct TC and IC sub-populations exist at each of four cutoff levels a Adaptive PD-L1 expression in tumour-infiltrating immune cells (IC) IC=immune cells; TC=tumour cell PD-L1 expression levels evaluated in POPLAR a TC scored as % of tumour cells and IC scored as % of tumour area: TC3 or IC3 = TC 5% or IC 1% PD-L1+ TC2/3 or IC2/3 = TC or IC 5% PD-L1+ TC1/2/3 or IC1/2/3 = TC or IC 1% PD-L1+ TC and IC = TC and IC < 1% PD-L1+ Vansteenkiste et al, ECC 215
OS in ITT population Minimum follow up = 13 months HR =.73 (.53,.99) P value =.4 Median 9.7 mo (8.6, 12.) Median 12.6 mo (9.7, 16.4) + Atezolizumab Docetaxel Censored Vansteenkiste et al, ECC 215
POPLAR: OS by PD-L1 Expression Subgroup TC3 or IC3 TC2/3 or IC2/3 TC1/2/3 or IC1/2/3 TC and IC n (%) 47 (16%) 15 (37%) 198 (68%) 92 (32%).49.54.59 1.4 Median OS (95% CI), mo Atezolizumab Docetaxel n = 144 n = 143 15.5 (9.8, NE) 15.1 (8.4, NE) 15.5 (11., NE) 9.7 (6.7, 12.) 11.1 (6.7, 14.4) 7.4 (6., 12.5) 9.2 (7.3, 12.8) 9.7 (8.6, 12.) ITT N = 287.73 12.6 (9.7, 16.4) 9.7 (8.6, 12.).2 1 2,1 1 1 Hazard Ratio a In favor of atezolizumab In favor of docetaxel Vansteenkiste et al, ECC 215
Both TC and IC are independent predictors of survival improvement TC1/2/3 and IC (33/287; 11%) a TC1/2/3 and IC1/2/3 (76/287; 26%) a IC1/2/3 and TC (86/287; 3%) a PD-L1 in TC only PD-L1 in IC only PD-L1 status OS HR b (95% CI) TC1/2/3 and IC.37 (.12,1.13) IC1/2/3 and TC.63 (.36,1.12) TC1/2/3 and IC1/2/3.6 (.34, 1.8) TC1/2/3 or IC1/2/3.59 (.4,.85) Vansteenkiste et al, ECC 215
PFS by PD-L1 Expression Subgroup TC3 or IC3 TC2/3 or IC2/3 TC1/2/3 or IC1/2/3 TC and IC n (%) 47 (16%) 15 (37%) 198 (68%) 92 (32%).6.72.85 1.12 Median PFS (95% CI), mo Atezolizumab Docetaxel n = 144 n = 143 7.8 (2.7, 12.3) 3.4 (1.4, 6.9) 2.8 (2.6, 5.5) 1.7 (1.4, 4.2) 3.9 (1.9, 5.7) 2.8 (1.9, 3.9) 3. (2.8, 4.1) 4.1 (2.7, 5.6) ITT N = 287.94 2.7 (2., 4.1) 3. (2.8, 4.1).2 1 2,1 1 1 Hazard Ratio a In favor of atezolizumab In favor of docetaxel Vansteenkiste et al, ECC 215
Overall Response and Duration of Response 5 ORR (confirmed; RECIST v1.1), % 38 25 13 38 13 22 15 18 17 8 1 15 15 Atezolizumab (n = 144) Docetaxel (n = 143) TC3 or IC3 TC2/3 or IC2/3 TC1/2/3 or IC1/2/3 TC and IC ITT ITT Atezolizumab (n = 21) Docetaxel (n = 21) Median duration of response, mo (95% CI) 14.3 (11.6, NE) 7.2 (5.6, 12.5) HR a (95% CI).41 (.18,.96) P value b.33 Responders with ongoing response, n (%) 12 (57%) 5 (24%) Median DOR in atezolizumab not mature; majority of responses are ongoing Vansteenkiste et al, ECC 215
Safety Atezolizumab n = 142 Docetaxel n = 135 Median treatment duration 3.7 mo 2.1 mo Patients treated beyond progression per RECIST v1.1 4% 2% All Grade AEs, any cause 96% 96% Treatment-related AEs 67% 88% Grade 3-4 AEs, any cause 4% 53% Treatment-related Grade 3-4 AEs 11% 39% Grade 5 AEs, any cause 4% 4% Treatment-related Grade 5 AEs 1% 2% Patients withdrawing from treatment due to AEs 8% 22% Grade 5 event terms Atezolizumab (n = 6): Cardiac failure, pneumonia, ulcer hemorrhage, pneumothorax, pulmonary embolism, embolism Docetaxel (n = 5): Sepsis (n = 2), death (n = 2), acute respiratory distress syndrome Vansteenkiste et al, ECC 215
Adverse Events AEs more frequent with docetaxel AEs more frequent with atezolizumab Alopecia Nausea Diarrhea Asthenia Myalgia Neutropenia Neuropathy peripheral Peripheral sensory neuropathy Febrile neutropenia Decreased appetite Dyspnea Pyrexia Arthralgia Insomnia Musculoskeletal Pain Pneumonia Hypothyroidism Grade 1-2 AEs Grade 3-4 AEs Grade 1-2 AEs Grade 3-4 AEs 4% 3% 2% 1% 1% 2% 3% 4% Docetaxel Atezolizumab For atezolizumab, other immune-mediated AEs (any grade) included: AST increased (4%), ALT increased (4%), Pneumonitis (3%), Colitis (1%), Hepatitis (1%) Vansteenkiste et al, ECC 215
BIRCH: Atezolizumab in PD-L1+ Locally advanced or metastatic NSCLC Tumor PD-L1 expression by IHC (TC2/3 and/or IC2/3) ECOG PS 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 12 mg IV q3w in all cohorts. Phase 2. Primary endpoint: ORR by Independent Review Besse et al, ECC 215
BIRCH: Atezolizumab in PD-L1+ 3 27% 24% 26% TC2/3 or IC2/3 TC3 or IC3 ORR, % 2 17% 17% 19% 1 n = 253 n = 115 n = 267 n = 122 n = 139 n = 65 3L+ 2L 1L BIRCH met its primary endpoint in all predefined subgroups per protocol-specified criteria Besse et al, ECC 215
OS by Line of Therapy TC2/3 or IC2/3 Subgroup Median OS, mo (95% CI) 6-mo OS, % 1L (Cohort 1) 14. (14., NE) 82% 2L (Cohort 2) NE (11.2, NE) 76% 3L+ (Cohort 3) NE (8.4, NE) 71% Median follow up: 8.8 mo (1L), 7.9 mo (2L) and 8.6 mo (3L+) Besse et al, ECC 215
OS by Line of Therapy TC3 or IC3 Subgroup Median OS, mo (95% CI) 6-mo OS, % 1L (Cohort 1) NE (1.4, NE) 79% 2L (Cohort 2) NE (1.6, NE) 8% 3L+ (Cohort 3) NE (NE, NE) 75% Median follow up: 8.8 mo (1L), 7.9 mo (2L) and 8.6 mo (3L+) Besse et al, ECC 215
What is PD-L1 Positivity?
Small cell Lung Cancer
CheckMate 32 Key patient inclusion criteria SCLC Progressive disease 1 prior therapy including first-line platinum-based therapy Unselected by PD-L1 expression (n=128) Primary endpoint ORR Nivolumab 3 mg/kg IV q2w (n=4) Nivolumab 1 mg/kg + ipilimumab 1 mg/kg IV q3w for 4 cycles (n=3) Nivolumab 1 mg/kg + ipilimumab 3 mg/kg IV q3w for 4 cycles (n=47) Nivolumab 3 mg/kg + ipilimumab 1 mg/kg IV q3w for 4 cycles (n=38) Nivolumab 3 mg/kg IV q2w Antonia et al. J Clin Oncol 215; 33 (suppl): abstr 753
Exposure to study drugs Nivolumab 3 (n = 4) Nivolumab 1 + Ipilimumab 1 (n = 3) Nivolumab 1 + Ipilimumab 3 (n = 47) Median number of infusions, n (range) Patients not continuing treatment, % 3 (1 3) Nivolumab: 9 (1 1) Ipilimumab: 4 (1 4) Nivolumab: 3 (1 23) Ipilimumab: 3 (1 4) 8 67 57 Progressive disease, % 65 33 34 Treatment-related AEs, % 7.5 a 11 b Deaths, % 65 67 34 Treatment-related deaths, % 2.1 1 death due to myasthenia gravis in the nivolumab 1/ipilimumab 3 arm Courtesy of S. Antonia Antonia et al. J Clin Oncol 215; 33 (suppl): abstr 753
Efficacy Nivolumab (n = 4) Nivolumab + Ipilimumab a (n = 46) ORR, % 18 32.6 Complete response, % 2.2 Partial response, % 18 3.4 Stable disease, % 2 3.4 Disease control rate, % 38 63 Progressive disease, % 53 b 37 Death prior to first response assessment, % Not evaluable (no tumor assessment follow-up), % Median time to objective response, mos Median DOR, mos (95% CI) Range Courtesy of S. Antonia 1 6.5 2.2 1.6 2.2 NR 4.1 11+ 6.9 (1.5, NR) 1.5 11.1+ A Antonia et al. J Clin Oncol 215; 33 (suppl): abstr 753
Adverse Events Nivolumab 3 (n = 4) Any Grade, % Grade 3 4, % Nivolumab 1 + Ipilimumab 3 (n = 47) Any Grade, % Grade 3 4, % Total Treatment-related AEs 53 15 77 34 Fatigue 18 2.5 21 Diarrhea 13 23 8.5 Nausea 1 13 2.1 Vomiting 2.5 8.5 4.3 Decreased appetite 1 4.3 Pruritus 7.5 19 2.1 Rash 2.5 21 4.3 Rash maculopapular 13 4.3 Hypothyroidism 2.5 15 Hyperthyroidism 2.5 13 AST increased 5. 4.3 Amylase increased 2.5 2.5 6.4 2.1 Lipase increased 11 6.4 Pneumonitis 5. 2.1 2.1 Courtesy of S. Antonia Antonia et al. J Clin Oncol 215; 33 (suppl): abstr 753
Tumor response and PD-L1 expression Best reduction from baseline in target lesion (%) 15 125 1 75 5 25 25 5 75 1 Nivolumab 15 125 1 75 5 25 25 5 75 1 Nivolumab + Ipilimumab <1% PD-L1 1% PD-L1 Not evaluable* Confirmed responders Evaluable samples (4 of 96) PD-L1 expression level, n (%) <1% 1% Nivolumab (n=22) 15 (68) 7 (32) Nivolumab + ipilimumab (n=18) 12 (67) 6 (33) Courtesy of S. Antonia Antonia et al. J Clin Oncol 215; 33 (suppl): abstr 753
Overall survival 1 9 8 7 mos, mos (95% CI) Nivolumab (n = 4) 4.4 (2.9, 9.4) Nivolumab + Ipilimumab a (n = 5) 8.2 (3.7, NR) 6 OS (%) 5 4 3 Nivolumab + Ipilimumab Nivolumab 2 1 3 6 9 12 15 Time (months) a Combined data for nivolumab 1 + ipilimumab 1 and nivolumab 1 + ipilimumab 3 cohorts Courtesy of S. Antonia Antonia et al. J Clin Oncol 215; 33 (suppl): abstr 753
KEYNOTE 28 Key patient inclusion criteria SCLC PD-L1 positivity Failure of standard therapy 1 measurable lesion ECOG PS or 1 Absence of autoimmune disease or interstitial lung disease (n=24) Pembrolizumab 1 mg/kg q2w CR, PR or SD Confirmed PD/ toxicity Treat for 24 months or until PD/toxicity Discontinue pembrolizumab Primary endpoints Response assessment ORR, safety Courtesy of P. Ott Ott et al. J Thorac Oncol 215; 1 (suppl 2): ORAL1.4
Analysis of PD-L1 expression Samples: archival or newly obtained core or excisional biopsy of a nonirradiated lesion Immunohistochemistry: performed at a central laboratory using a prototype assay and the 22C3 antibody clone (Merck) Positivity: membranous PD-L1 expression in 1% of tumor and associated inflammatory cells or positive staining in stroma SCLC cohort: of 147 evaluable samples, 42 PD-L1 positive (28.6%) Examples of PD-L1 Staining in SCLC Specimens from KEYNOTE-28 PD-L1 Negative Courtesy of P. Ott PD-L1 Positive Ott et al. J Thorac Oncol 215; 1 (suppl 2): ORAL1.4
Antitumor Activity a (RECIST v1.1, Investigator Review) Best Overall Response n % 95% CI Complete response.-14.2 Partial response 7 29.2 12.6-51.1 Stable disease 1 4.2.1-21.1 Progressive disease 1 41.7 22.1-63.4 No assessment b 6 25. 9.8-46.7 Disease control rate c : 33.3% (95% CI, 15.6 55.3) a Both confirmed and unconfirmed responses are included. Response was assessed by RECIST v1.1 per investigator review. b Includes patients who died or discontinued for clinical progression before the first imaging assessment (n = 3) or who had not reached the first imaging assessment at data cutoff (n = 3). c Patients with CR, PR, or SD of any duration. Data cutoff date: June 24, 215.
Treatment-Related Adverse Events Any Grade, Occurring in 2 Patients Any N = 24 n (%) 15 (62.5) Arthralgia 4 (16.7) Asthenia 4 (16.7) Nausea 2 (8.3) Fatigue 2 (8.3) Hyperlacrimation 2 (8.3) Myalgia 2 (8.3) Rash 2 (8.3) No cases of pneumonitis Grade 3-5, Occurring in 1 Patient N = 24 n (%) Any 2 (8.3) Asthenia a 1 (4.2) Blood bilirubin increased 1 (4.2) Colitis a 1 (4.2) Intestinal ischemia a 1 (4.2) AEs of Interest Based on Immune Etiology Occurring in 1 Patient Autoimmune thyroiditis (grade 2) N = 24 n (%) 1 (4.2) Colitis a (grade 5) 1 (4.2) a Occurred in the same patient. Data cutoff date: June 24, 215. Courtesy of P. Ott
PD-L1 Expression and Response Using prototype IHC assay, no relationship between level of PD-L1 expression on tumor and immune cells within tumor nests and frequency of response One-sided P =.235 by logistic regression C e ll s W it h P D - L 1 E x p r e s s i o n, % 1 8 6 4 2 Responder Nonresponder Courtesy of P. Ott Patients were eligibile for enrollment if they had PD-L1 expression in 1% of tumor or immune cells in tumor nests or staining in the stroma. Data cutoff date: June 24, 215.
Take Home Message Incredibly exciting and effective drugs! Biomarker not really there yet Is it right to exclude PD-L1 neg patients? Data from large phase 3 studies awaited!