Immune checkpoint blockade in lung cancer

Transcription

1 Immune checkpoint blockade in lung cancer Raffaele Califano Department of Medical Oncology The Christie and University Hospital of South Manchester, Manchester, UK

2 Outline Background Overview of the data Conclusions

3 Immunogenicity of NSCLC Lawrence, et al. Nature 213,

4 NSCLC and SCLC are highly mutated Lung Cancers from smokers have 1x somatic mutations vs non-smokers Vogelstein, et al. Science 213

5 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

6 Nivolumab (Anti PD-1 antibody)

7 Phase I Study 8-wk treatment cycle Rapid PD or clin. deterioration Off Study Day SCANS BMS 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

8 Activity ISEL BR.21 Brahmer, et al,. ASCO 214, abs 8112

9 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 (%) year OS = 24% 3-year OS = 18% Weeks since treatment initiation Time Since First Dose (Months) ASCO 214, Abstract 8112 CMSTO 214, Abstract 3428

10 Phase II in Squamous (Checkmate-63) ORR 15% Rizvi et al, Lancet Oncology 215

11 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

12 Overall Survival mos mo, (95% CI) Nivolumab n = (7.3, 13.3) Docetaxel n = (5.1, 7.3) 7 # events OS (%) yr OS rate = 42% HR =.59 (95% CI:.44,.79), P =.25 Nivolumab 3 2 Docetaxel 1 1-yr OS rate = 24% Number of Patients at Risk Time (months) Nivolumab Docetaxel Brahmer, et al, NEJM July 215

13 Progression-Free Survival Nivolumab n = 135 Docetaxel n = 137 PFS (%) mpfs, mo (95% CI) 3.5 (2.1, 4.9) 2.8 (2.1, 3.5) HR =.62 (95% CI:.47,.81); P = yr PFS rate = 21% 2 Nivolumab 1 1-yr PFS rate = 6.4% Docetaxel Number of Patients at Risk Time (months) Nivolumab Docetaxel Brahmer, et al, NEJM July 215

14 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 NR (2.9, 21+) 2.2 (1.6, 12) (1.4+, 15+) 2.1 (1.8, 9.5) Brahmer, et al, NEJM July 215

15 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 Time (Weeks) Brahmer, et al, NEJM July 215

16 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) Nivolumab Docetaxel Brahmer, et al, NEJM July 215

17 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 Median number of doses was 8 (range, 1 48) for nivolumab and 3 (range, 1 29) for docetaxel Brahmer, et al, NEJM July 215

18 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 Licensed in Europe 2 as second-line 2 for Squamous 2 NSCLC 1 1 Pulmonary, % Pneumonitis Lung infiltration Interstitial lung disease Renal,% Blood creatinine increased Tubulointerstitial nephritis Skin,% Hypersensitivity/Infusion reaction, % Hypersensitivity Infusion-related reaction b 1 b Brahmer, et al, NEJM July 215

19 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

20 Overall Survival Nivolumab (n = 292) Docetaxel (n = 29) mos, mo HR =.73 (96% CI:.59,.89); P =.15 OS (%) yr OS rate = 39% 1-yr OS rate = 51% Nivolumab 2 1 Docetaxel Number of Patients at Risk Time (months) 27 Nivolumab Docetaxel Paz Ares, ASCO 215

21 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 % (9, 17) Best overall response, % Complete response Partial response Stable disease Progressive disease Unable to determine < 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, % Paz Ares, ASCO 215

22 Progression-Free Survival 1 9 PFS (%) Nivolumab (n = 292) Docetaxel (n = 29) mpfs, mo HR =.92 (95% CI:.77, 1.11); P = yr PFS rate = 19% Nivolumab 1 1-yr PFS rate = 8% Time (months) Number of Patients at Risk Docetaxel 27 Nivolumab Docetaxel Paz Ares, ASCO 215

23 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

24 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% 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, % Treatment-related SAEs, % Treatment-related AEs leading to discontinuation, % Treatment-related deaths, % <1

25 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, % Fatigue Nausea Decreased appetite Asthenia 1 < Diarrhea Peripheral edema 3 1 <1 Myalgia 2 <1 11 Anemia 2 <1 2 3 Alopecia <1 25 Neutropenia < Febrile neutropenia 1 1 Leukopenia 1 8

26 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 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 < <1 3 3 <1 Paz Ares, ASCO 215

27 Pembrolizumab (Anti PD-1 antibody)

28 Keynote - 1 N= % of patients received 2 lines of treatment Garon et al, NEJM 215

29 Objective Response Rate Garon et al, NEJM 215

30 Outcome in all treated patients Garon et al, NEJM 215

31 Examples of PD-L1 IHC staining Garon et al, NEJM 215

32 ORR by PD-L1 proportion score Pts with measurable disease Garon et al, NEJM 215

33 PFS by PD-L1 expression Garon et al, NEJM 215

34 OS by PD-L1 expression Garon et al, NEJM 215

35 Atezolizumab (Anti PD-L1 antibody)

36 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

37 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

38 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

39 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%) Median OS (95% CI), mo Atezolizumab Docetaxel n = 144 n = (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 = (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

40 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

41 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%) Median PFS (95% CI), mo Atezolizumab Docetaxel n = 144 n = (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 = (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

42 Overall Response and Duration of Response 5 ORR (confirmed; RECIST v1.1), % 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

43 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

44 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

45 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

46 BIRCH: Atezolizumab in PD-L % 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

47 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

48 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

49 What is PD-L1 Positivity?

50 Small cell Lung Cancer

51 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

52 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) Progressive disease, % Treatment-related AEs, % 7.5 a 11 b Deaths, % Treatment-related deaths, % 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

53 Efficacy Nivolumab (n = 4) Nivolumab + Ipilimumab a (n = 46) ORR, % Complete response, % 2.2 Partial response, % Stable disease, % Disease control rate, % 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 NR (1.5, NR) A Antonia et al. J Clin Oncol 215; 33 (suppl): abstr 753

54 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 Fatigue Diarrhea Nausea Vomiting Decreased appetite Pruritus Rash Rash maculopapular Hypothyroidism Hyperthyroidism AST increased Amylase increased Lipase increased Pneumonitis Courtesy of S. Antonia Antonia et al. J Clin Oncol 215; 33 (suppl): abstr 753

55 Tumor response and PD-L1 expression Best reduction from baseline in target lesion (%) Nivolumab 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

56 Overall survival 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 (%) Nivolumab + Ipilimumab Nivolumab 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

57 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

58 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

59 Antitumor Activity a (RECIST v1.1, Investigator Review) Best Overall Response n % 95% CI Complete response Partial response Stable disease Progressive disease No assessment b Disease control rate c : 33.3% (95% CI, ) 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.

60 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

61 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, % 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.

62 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!