Immunotherapies for Advanced NSCLC: Current State of the Field. H. Jack West Swedish Cancer Institute Seattle, Washington

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1 Immunotherapies for Advanced NSCLC: Current State of the Field H. Jack West Swedish Cancer Institute Seattle, Washington

2 Nivolumab in Squamous NSCLC Chemo-pretreated (1 st line) Adv squamous NSCLC N = 272 Primary Endpoint: Overall Survival R A N D Nivolumab 3 mg/kg IV q14 d until PD Docetaxel 75 mg/m 2 IV q21 d until PD Brahmer J, et al. N Engl J Med. 2015;373(2):

3 Overall Survival Benefit With Nivolumab Brahmer J, et al. N Engl J Med. 2015;373(2):

4 Toxicity Differences Strongly Favor Nivolumab Treatment-Related Adverse Events Reported in at Least 5% of Patients Brahmer J, et al. N Engl J Med. 2015;373(2):

5 Nivolumab in Nonsquamous NSCLC Chemo-pretreated (1 st line) Adv nonsquamous NSCLC N = 582 Primary Endpoint: Overall Survival R A N D Nivolumab 3 mg/kg IV q14 d until PD Docetaxel 75 mg/m 2 IV q21 d until PD Borghaei H, et al. N Engl J Med. 2015;373(17):

6 Overall Survival Benefit With Nivolumab in Nonsquamous NSCLC Borghaei H, et al. N Engl J Med. 2015;373(17):

7 Responses to Nivolumab vs Docetaxel in Nonsquamous Advanced NSCLC Borghaei H, et al. N Engl J Med. 2015;373(17):

8 Progression-Free Survival Benefit With Nivolumab in Nonsquamous NSCLC Is there a subgroup who really do better with docetaxel? Should we do PD-L1 testing to individualize treatment recommendations? Borghaei H, et al. N Engl J Med. 2015;373(17):

9 Should We Be Selecting Nonsquamous Patients for Nivolumab Based on PD-L1 Expression? Paz-Ares L, et al. J Clin Oncol. 2015;33(suppl): Abstract LBA109.

10 Nivolumab in Previously Treated Advanced NSCLC Nivolumab 2 mg/kg IV q14 days FDAapproved for pretreated squamous and nonsquamous NSCLC No requirement for PD-L1 testing, either in guidelines or by payers Optimal duration of therapy unknown

11 Pembrolizumab (MK3475) in NSCLC Expansion Cohorts: KEYNOTE-001 Nonrandomized (N = 33) PD-L1+ tumors 2 previous therapies Nonrandomized (N = 40) PD-L1- tumors 2 previous therapies Randomized (N = 144) PD-L1+ tumors 1 previous therapy Randomized (N = 45) PD-L1+ tumors Treatment naïve Nonrandomized (N = 45) PD-L1+ tumors 1 previous therapy R (3:2) R (1:1) Pembro 10 mg/kg q3w Pembro 10 mg/kg q2w Pembro 10 mg/kg q3w Pembro 10 mg/kg q2w Pembro 2 mg/kg q3w Pembro 10 mg/kg q3w Pembro 10 mg/kg q2w Pembro 2 mg/kg q3w Response assessment Primary measure: ORR by RECIST v1.11 per independent central review Secondary measure: immune-related response criteria 2 per investigator assessment Pembrolizumab was given until disease progression, unacceptable toxicity, or death Garon EB, et al. N Engl J Med. 2015;372(21):

12 Pembrolizumab in First-Line or Previously Treated Advanced NSCLC Progression-Free Survival Overall Survival Garon EB, et al. N Engl J Med. 2015;372(21):

13 KEYNOTE-10: Pembrolizumab vs Docetaxel As 2 nd -Line Therapy in PD-L1+ Advanced NSCLC Chemo-pretreated (1 st line) PD-L1+ (>1% by IHC) adv NSCLC (squam/nonsquam) N = 1034 R A N D Pembrolizumab 2 mg/kg IV q21 days until PD Pembrolizumab 10 mg/kg IV q21 days until PD Docetaxel 75 mg/m2 IV q21 days until PD Primary Endpoints: Overall Survival and Progression-Free Survival Looking at 1) all pts and 2) subset with >50% PD-L1+ Herbst RS, et al. Lancet. 2016;387(10027):

14 KEYNOTE-10: Pembrolizumab vs Docetaxel, Overall Survival All (PD-L1+) Patients PD-L1 >50% Patients ORR, % Pembrolizumab 2 mg/kg (n = 139) PD-L1 TPS 50% 30 (P<.0001*) PD-L1 TPS 1% 18 (P<.0005*) Herbst RS, et al. Lancet. 2016;387(10027): Pembrolizumab 10 mg/kg (n = 151) 29 (P<.0001*) 18 (P<.0002*) Docetaxel (n = 152) 8 9

15 KEYNOTE-10: Pembrolizumab vs Docetaxel, Overall Survival Older patients benefited from pembro Higher PD-L1 expression correlates with greater benefit from pembro, but lower PD-L1+ also benefit Archival tissue comparable to fresh Both adeno & squamous histologies show comparable benefit for pembro Herbst RS, et al. Lancet. 2016;387(10027):

16 KEYNOTE-10: Pembrolizumab vs Docetaxel, Progression-Free Survival Does Dose Matter for Pembrolizumab? PD-L1 >50% Patients All (PD-L1+) Patients Dose doesn t matter for PD-L1 > 50% subgroup, but emerges for all patients I would infer that dose likely does matter for lower PD -L1 expression subset Herbst RS, et al. Lancet. 2016;387(10027):

17 KEYNOTE-10: Pembrolizumab vs Docetaxel, Toxicities Herbst RS, et al. Lancet. 2016;387(10027):

18 Pembrolizumab in Previously Treated Advanced NSCLC Pembrolizumab FDA approved (at 2 mg/kg dose every 3 weeks) for pretreated PD-L1-positive (by companion diagnostic) advanced NSCLC independent of NSCLC histology (based on 61 pts treated at 10 mg/kg dose) Definition of PD-L1 positive is debatable: specific test defines positive as 50% staining KEYNOTE 10 data corroborate benefit of pembro over docetaxel, benefit (but not FDA approval) extends beyond PD-L1 >50% to any PD-L1+

19 PD-L1 Expression on Tumor Cells (TC) and Immune Cells (IC) as Marker for Atezolizumab Response Spira AI, et al. J Clin Oncol. 2015;33(suppl): Abstract Fehrenbacher L, et al. Lancet. 2016;387(10030):

20 Phase II POPLAR Trial: Atezolizumab vs Docetaxel in Previously Treated NSCLC Chemo-pretreated (1-2 lines) Adv NSCLC (squam/nonsquam) N = 287 Stratification: PD-L1 expression 0/1 vs 2/3 nonsquamous vs squamous 2 nd line vs 3 rd line R A N D Atezolizumab 1200 mg IV q21d until PD Docetaxel 75 mg/m2 IV q21d until PD Primary endpoint: OS in PD-L1 selected and ITT populations Secondary endpoints: overall safety as well as PFS, ORR, DoR in PD-L1 selected and ITT populations Fehrenbacher L, et al. Lancet. 2016;387(10030):

21 POPLAR Trial: Overall Survival All Patients (ITT), Including by PD-L1 Expression Higher PD-L1 expression (on tumor cells, immune cells, or both) correlates with greater benefit from atezolizumab No benefit with atezo in 32% of pts with neg PD-L1 expression on TCs or ICs Fehrenbacher L, et al. Lancet. 2016;387(10030):

22 Phase III OAK Trial: Atezolizumab vs Docetaxel in Previously Treated NSCLC Chemo-pretreated (1-2 lines) Adv NSCLC (squam/non-squam) N = 1100 Stratification: PD-L1 expression 0/1 vs 2/3 nonsquamous vs squamous 2 nd line vs 3 rd line R A N D Atezolizumab 1200 mg IV q21d until PD Docetaxel 75 mg/m2 IV q21d until PD Primary endpoint: OS Secondary endpoint: ORR, PFS, DoR, Safety National Institutes of Health. Available at: Accessed August 23, 2016.

23 Gravitational Pull of First-Line Immunotherapy: KEYNOTE-024 Stage IV NSCLC (squamous/nonsquam) PD-L1 + (>50%) N = 305 R A N D Primary Endpoint: Progression-Free Survival Pembrolizumab 200 mg IV every 3 weeks Carbo/paclitaxel or Cisplatin or carbo/pemetrexed or Cisplatin or carbo/gemcitabine IV every 3 weeks Press release 6/16/2016: Significant improvement in PFS, also improvement in OS Pembrolizumab 200 mg IV every 3 weeks National Institutes of Health. Available at: Accessed August 23, 2016.

24 CheckMate 026: Similar Trial, Different Outcome Stage IV NSCLC (squamous/nonsquam) PD-L1 + ( 5%) N = 541 R A N D Primary Endpoint: Progression-Free Survival Nivolumab 2 mg/kg IV every 2 weeks Carbo/paclitaxel (squam) cisplatin or carbo/gemcitabine (squam) or Cisplatin or carbo/pemetrexed (nonsquam) IV every 3 weeks Press release 8/5/2016: No significant improvement in PFS Nivolumab 2 mg/kg IV every 2 weeks National Institutes of Health. Available at: Accessed August 23, 2016.

25 Why Different Results From Single-Agent Immunotherapy vs First-Line Chemo? Clinically significant differences among PD-1/PD- L1 checkpoint inhibitors/pembrolizumab is significantly more effective than nivolumab Significant difference in tested populations 28% of tested patients vs 41% of patients From cancergrace.org press release, 6/16/16 22C3 antibody for pembro is significantly better discriminator than 28-8 antibody for nivolumab

26 A Roadmap of Immunotherapy- Tumor Interactions 4 Trafficking of T cells to tumors Priming and activation Anti-CTLA4 Anti-CD137 (agonist) Anti-OX40 (agonist) Anti-CD27 (agonist) IL-2 IL Infiltration of T cells into tumors Anti-VEGF Cancer antigen presentation Vaccines IFN-α GM-CSF Anti-CD40 (agonist) TLR agonists 2 6 Recognition of cancer cells by T cells CARs Release of cancer cell antigens Chemotherapy Radiation therapy Targeted therapy 1 7 Killing of cancer cells Anti PD-L1 Anti PD-1 IDO inhibitors Chen DS, et al. Immunity. 2013;39(1):1-10.

27 Should Immunotherapy Be Added to Conventional Chemotherapy? IMpower 132 Stage IV Non-squamous NSCLC Any PD-L1 N = 680 R A N D Cisplatin or carboplatin/pemetrexed + Atezolizumab 1200 mg IV every 3 weeks Cisplatin or carboplatin/pemetrexed IV every 3 weeks Primary Endpoint: Progression-Free Survival National Institutes of Health. Available at: Accessed August 23, 2016.

28 CTLA-4 and PD-1/PD-L1 Checkpoint Blockade for Cancer Treatment CTLA-4 mabs: Ipilimumab Tremelimumab PD-1 mabs: Nivolumab Pembrolizumab Pidilizumab PD-L1 mabs: Atezolizumab Avelumab Durvalumab Ribas A. N Engl J Med. 2012;366(26):

29 Efficacy by PD-L1 Status Hellmann MD, et al. J Clin Oncol. 2016;34(suppl): Abstract 3001.

30 Response Rate to Nivo/Ipi (pooled) by PD-L1 Status Hellmann MD, et al. J Clin Oncol. 2016;34(suppl): Abstract 3001.

31 Safety of Nivo/Ipi Combo vs Nivo Alone Hellmann MD, et al. J Clin Oncol. 2016;34(suppl): Abstract 3001.

32 Immunotherapy Monotherapy or Doublet vs Standard Chemotherapy CheckMate-227 Trial Stage IV NSCLC Squamous or Nonsquamous No Restriction by PD-L1 Expression N = 1980 R A N D Primary Endpoints: Overall Survival & Progression-Free Survival Nivolumab q2 weeks Nivo q3 weeks + Ipilimumab q3 weeks x 4 treatments Cisplatin or Carboplatin + pemetrexed (nonsquam) or gemcitabine (squam) Nivo q2 weeks National Institutes of Health. Available at: Accessed August 23, 2016.

33 Chinese Menu for Immunotherapy Trials in First Line Advanced NSCLC Choose 1 from column A Choose 1 from column B Choose any number from column C Choose 1-2 from column D Choose 1 from column E All NSCLC - driver mutns Nonsquam Squamous EGFR mut+ ALK+ No PD-L1 requirement PD-L1+ PD-L1 High R A N D Std Rx Std Rx + Bev PD1/PD-L1 inhib Std Rx + PD1/PD-L1 inhib Fixed duration Treat until progression Crossover No crossover Primary Endpoint: PFS PD1/PD-L1 + CTLA4 inhib

34 Immune Checkpoint Inhibitors in NSCLC: The Present (What We Know) Nivolumab (regardless of PD-L1 expression) & pembrolizumab (in PD-L1+) FDA approved in treated advanced NSCLC Efficacy and side effect profiles of other PD-1 and PD- L1 inhibitors more similar than different (All) checkpoint inhibitors demonstrate greater efficacy in PD-L1+ patients Greater expression correlated with greater benefit, but PD-L1+ is neither necessary nor sufficient for response Optimal test, threshold, all still unknown Non-testing currently preferred for 2 nd line = nivo/pembro Pembro superior to chemo first line in high PD-L1+

35 Immune Checkpoint Inhibitors in NSCLC: The Future (What We Don t Know) Is PD-1/PD-L1 superior to standard 1 st -line Rx in any pts other than those with high PD-L1 expression? Is combo of immunotx w/std therapy (concurrent) superior to sequential? Are combinations of PD-1/PD-L1 w/ctla-4 inhib superior to PD1/PD-L1 as monotherapy? Does that depend on PD-L1 expression? Is there a group in whom immunotx is ineffective enough to favor not treating at any time? Will any specific antibody/form of testing for PD-L1 emerge as best/std? Will another predictive assay prove superior or add to utility of PD-L1? Will we define a point of diminishing returns for duration of therapy? How will many very similar agents differentiate themselves in market space? If efficacy & safety overlap, will economic issues guide choices?

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