Inmunoterapia en cáncer de pulmón. Mariano Provencio Servicio de Oncología Médica Hospital Universitario Puerta de Hierro

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1 Inmunoterapia en cáncer de pulmón Mariano Provencio Servicio de Oncología Médica Hospital Universitario Puerta de Hierro

2 Current Therapeutic Landscape for NSCLC Current treatment strategies in NSCLC Various chemotherapy regimens based on histologic diagnosis Targeted therapy options available for specific molecular mutations Anti-EGFR targeted therapy for patients with EGFR mutations ALK inhibitors for patients with ALK translocations ROS, Her2, Even with various personalized approaches, the 5-yr survival rate for patients with NSCLC (all stages) is only 17% The role of immunotherapy in lung cancer have historically been associated with disappointing results 1. American Cancer Society. Cancer facts and figures 2013.

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4 Anti-CTLA-4 Blockade In preclinical mouse models, CTLA4 blockade in combination with various chemotherapeutic agents was synergistic in inducing tumor regression and elicited prolonged anti-tumor effects and induction of a memory immune response

5 ED-SCLC naive Were randomized 1:1:1 Concurrent regimen: 4 doses of ipilimumab/paclitaxel/carbo followed by 2 doses of carbo/paclitaxel Phased-ipilimumab regimen: 2 doses placebo/carbo/taxol followed 4 doses of ipilimumab/taxol/carbo Control regimen: Up to six doses of placebo/taxol/carbo Ipilimumab: 10mg/Kg; taxol: 175mg/m2; carbo (AUC:6), every 3 weeks Primary end point: immune-relatedpfs. Secondary: mwho-pfs;os, OPP, iborr Reck M et al. Ann Oncol 2013;24:75-83

6 Efficay Phased-regimen improved irpfs compared control HR, 0.64; p:0.03 Median 5.3 vs 6.4 m Reck M et al. Ann Oncol 2013;24:75-83

7 mwho-pfs: 5.2 m vs 5.2 m control OS: phased: 12.9 m vs 9.9 m (HR:0.75) Reck M et al. Ann Oncol 2013;24:75-83

8 Tumor response rates appeared to favor phased ipi, the differences being greater when assessed by irc Reck M et al. Ann Oncol 2013;24:75-83

9 Discontinuation were similar across arms: control 9%; concurrent 7% and phased: 5% Overall incidence grade 3 / 4 AES 9% control 21% concurrent 17% phased Reck M et al. Ann Oncol 2013;24:75-83 A phase III clinical trial is currently ongoing to evaluated the efficacy of ipilimumab in addition to chemotherapy with platinum/etoposide in patients with ES-SCLC with the primary endpoint of OS (NCT )

10 204 patients chemotherapy-naive NSCLC were randomly 1:1:1 Primary end point: irpfs Other end points: PFS, ORR, irorr, OS and safety

11 Kaplan-Meier plots for progression-free survival per immune-related response criteria (irpfs). Phased ipilimumab regimen improved irpfs significantly compared with control HR: 0.72; p: 0.05 Median irpfs: 4.6 m control 5.7 m phased 5.5 m concurrent Median WHO-PFS: 4.2 m control 5.1 m phased 4.1 concurrent Lynch T J et al. JCO 2012;30: by American Society of Clinical Oncology

12 Lynch T J et al. JCO 2012;30: Kaplan-Meier plots for overall survival (OS). In phased regimen irpfs greater in patients with squamous histology: HR: 0.55 (95% CI, ) also in WHO-PFS ( HR: 0.40 (95% CI, ) Median OS phased ipili was: 12.2 m vs 8.3 m control (> 3.9m) HR: 0.87, p:0.23 in squamous/phased regimen: HR: 0.48 ( ) vs nonsquamous HR: 1.17

13 PD-1 and PD-L1 Antibodies Agent Anti PD-L1 MPDL3280A (Genetech) MEDI-4736 (Astra) BMS (BMS) MSB C (Merck) Anti PD 1 Nivolumab (BMS) MK-3475 Pembrolizumab (Merck) Pidilizumab (CureTch) AMP 224 (Glaxo) AMP 514 (Astra)

14 Blockade of PD-1 Binding to PD-L1 (B7-H1) and PD-L2 (B7-DC) Revives T Cells IFN-γ mediated upregulation of tumor PD-L1 IFN-γ Tumor-associated fibroblast Stromal PD-L1 modulation of T cells Can you generate tumor-killing T cells? Antigen priming IFN-γR Can the T cells get to the tumor? T-cell trafficking Tumor cell Other NFκB P13K CD8+ cytoxic T lymphocyte M2 macrophage PD-L1/PD-1 mediated inhibition of tumor cell killing T reg cell IL-4/13 Can the T cells see the tumor? Peptide-MHC expression T h 2 T cell TGF-β Dendritic cell T-cell polarization Priming and activation of T cells Immune cell modulation of T cells PD-L2 mediated inhibition of T H 2 T cells Can the T cells be turned off? Inhibitory cytokines Can the T cells be turned off? PD-L1 expression on tumor cells PD-L1 expression on tumor cells is induced by γ-interferon In other words, activated T cells that could kill tumors are specifically disabled by those tumors PD-1 PD-L1 PD-L2 T-cell receptor MHC-1 CD28 Shp-2 B7.1 Reprinted from Clinical Cancer Research. 2013;19(5): Sznol M, et al. Antagonist antibodies to PD-1 and B7-H1 (PD-L1) in the treatment of advanced human cancer.

15 Phase I Nivolumab Multidose Regimen Eligibility: advanced melanoma, NSCLC, RCC, CRC, or CRPC with PD after 1-5 systemic therapies Brahmer JR. Phase I study of single-agent anti-programmed death-1 (MDX- 1106) JCO 2010; 28: NSCLC Expansion Cohort: Pts randomized to 3 dose levels of nivolumab (1, 3, or 10 mg/kg) 8-wk treatment cycle Day 1* 15* 29* 43* 57 Rapid PD or clinical deterioration Unacceptable toxicity Off study Follow-up q8w x 6 (48 wks) CR/PR/SD or PD but clinically stable *Dose administered IV q2w. Scans done at baseline and following each 8-wk treatment cycle. Brahmer JR, et al. WCLC 2013/ JCO 2013, abs Treat to confirmed CR, worsening PD, unacceptable toxicity, or 12 cycles (96 wks)

16 Efficacy of Nivolumab Monotherapy in Patients With NSCLC (N=129) Heavily preteated (55% had received three or more prior lines of therapy) Dose, mg/kg ORR, % (n/n) Median DOR, Wks (Range) SD Rate 24 Wks, % (n/n) Median PFS, Mos (95% CI) Median OS, Mos (95% CI) All doses 17.1% (22/129) 74.0 (6.1+, ) 10.1 (13/129) 2.3 ( ) 9.6 ( ) 1 mg/kg 3.0 % (1/33) 63.9 (63.9, 63.9) 15.2 (5/33) 1.9 ( ) 9.2 ( ) 3 mg/kg 24.3 % (9/37) 74.0 (16.1+, ) 8.1 (3/37) 1.9 ( ) 14.9 (9.5-NE) 10 mg/kg 20.3 % (12/59) 83.1 (6.1+, ) 8.5 (5/59) 3.6 ( ) 9.2 ( ) Durable responses: responses are ongoing in 45% of patients (10/22) Rapid responses: 50% of responding pts had response at first assessment (8 wks) 7/16 responders who discontinued for reasons other than disease progression responded for 16 wks; 6/7 remain in response Responses in PD-L1 negative Similar OS by PDL1 or molecular status (EGFR or KRAS) Brahmer JR, et al. WCLC 2013/ JCO 2013, abs 8030.

17 Nonsquamous Squamous Proportion Survival Nivolumab: Duration of Response and OS 1-yr OS: 44% and 41% squamous and non-squamous histology NSCLC Responders by Histology 1.0 All Treated Subjects With NSCLC 0.8 Died/Treated Median OS (95% CI) 94/ ( ) yr OS: 42% (48 pts at risk) Duration of response up to discontinuation of therapy Ongoing response Time to response Response duration following discontinuation of therapy Wk yr OS: 24% (20 pts at risk) Mos Since Initiation of Treatment Pts at Risk, n Brahmer JR, et al. WCLC Abstract MO18.03/JCO 2013

18 Select AEs ( 1%) Occurring in Pts With NSCLC Treated With Nivolumab (N = 129) Drug-related pneumonitis (any grade) occurred in 8 NSCLC pts (6%) vs 12 pts (4%) in the overall study population 3 pts (2%) with NSCLC had grade 3/4 pneumonitis Treatment-Related Select AE, % (n) Any Grade* Grade 3/4* Any treatment-related select AE 41 (53) 5 (6) Skin 16 (20) 0 Gastrointestinal 12 (15) 1 (1) Pulmonary 7 (9) 2 (3) Endocrinopathies 6 (8) 0 Hepatic 5 (6) 1 (1) Infusion reaction 4 (5) 1 (1) Renal 3 (4) 0 *AE severity was graded based on the Common Terminology Criteria for Adverse Events, v3.0. Brahmer JR, et al. ASCO Abstract Brahmer JR, et al. WCLC Abstract MO18.03.

19 1 st -line nivolumab monotherapy (3mg/kg q 2 wks): Safety, efficacy, and correlation with PD-L1 status (n=20) Responders by histology ORR 30% 22% SCC, 36% Non-SCC Responders by PDL-1 Key results Overall ORR 30% (2 CR,1 SCC, 1 non-scc) Response at first assessment (11 weeks) in 83% (5/6 pts) PD-L1 expression status correlate with response (50% in PD-L1+; 0 PD-L1-) PFS rate at 24 weeks was 60%, 1-year OS 75% Grade 3 4 treatment-related AEs 20% ASCO 2014 Gettinger 14, poster, abstr 8024

20 Unprecedented RR seen in patients with heavily pretreated NSCLC Ongoing Nivolumab Clinical Trials in Patients With NSCLC Line of therapy Phase PD-L1 Selection Comparator Single agent Nivolumab 1st line [1] III Yes Chemotherapy maintenance 2nd line, squamous [2] III No Docetaxel 2nd line, adeno [3] III Yes Docetaxel 2nd line, squamous [4] II No NA Combination Nivolumab 2nd line [5] I No + LAG3 2nd line [6] I No + lirilumab (KIR) 1st line [7] I No Single agent; + chemotherapy; + bevacizumab; + erlotinib; + ipilimumab 1. ClinicalTrials.gov. NCT ClinicalTrials.gov. NCT ClinicalTrials.gov. NCT ClinicalTrials.gov. NCT ClinicalTrials.gov. NCT ClinicalTrials.gov. NCT ClinicalTrials.gov. NCT

21 KEYNOTE-001: MK-3475 for Patients With NSCLC Screening -28 Days MK-3475 C1D1 Mandatory Biopsy CR or PR, SD PD, unacceptable toxicity, or investigator decision Continue dosing & assessments q9w* Off study Treatment: administered IV 2 mg/kg q3w, 10 mg/kg q3w, or 10 mg/kg q2w Tumor assessment: Imaging q9w Primary: RECIST v1.1 (independent central review) Secondary: immune-related response criteria (investigator assessed) Tumor biopsy A new tumor biopsy within 60 days prior to the first dose of MK-3475 was required *Until progression, unacceptable toxicity, or investigator decision. Garon EB, et al. WCLC Abstract MO Reprinted with permission.

22 Response Rate (%) Response Rate (%) PD-L1 Identifies Pts With NSCLC Most Likely to Benefit From MK n/n: 25/129 15/41 7/46 RR-RECIST / n/n: 28/ /44 4/53 4/49 RR-irRC Total 1%-49% PD-L1 staining 50% PD-L1 staining PD-L1 negative Strong PD-L1 positive staining was considered 50% of tumor cells, and weak was defined as staining between 1% to 49% of positively staining tumor cells. Negative had no tumor staining for PD-L1. Gandhi L, et al. AACR Abstract CT105.

23 Examples of PD-L1 NSCLC Sample Immunohistochemical Staining* Staining Intensity PD-L1 Positivity, % PD-L1 Negative PD-L1 Positive *Clinical trial assay. Gandhi L, et al. AACR Abstract CT105

24 KEYNOTE-001: MK-3475 AEs in Patients With NSCLC Adverse Event All Grades, n (%) Grades 3-5, n (%) Rash 8 (21) 0 (0) Pruritis 7 (18) 0 (0) Fatigue 6 (16) 0 (0) Diarrhea 5 (13) 0 (0) Arthralgia 4 (11) 0 (0) Back pain 2 (5) 0 (0) Cough 2 (5) 0 (0) Decreased appetite 2 (5) 0 (0) 20 patients (53%) experienced 1 drug-related AE of any grade Drug-related AEs of interest: grade 2 hyperthyroidism (n = 1), grade 2 hypothyroidism (n = 1), grade 2 pneumonitis (n = 1), and grade 3 pulmonary edema (n = 1) No patient experienced treatment-related death Garon EB, et al. WCLC Abstract MO18.02.

25 Ongoing MK-3475 Clinical Trials in Patients With NSCLC Line of Therapy Phase PD-L1 Selection Single-agent MK-3475 Comparator 1st line; 2nd line [1,2] I/II Both NA 2nd line [3] III Yes Docetaxel 1st line [4] III Yes Chemotherapy Combination MK-3475 NA [5] I/II No Single agent; + chemotherapy; + pemetrexed; + gefitinib; + erlotinib; + ipilimumab 1. ClinicalTrials.gov. NCT ClinicalTrials.gov. NCT ClinicalTrials.gov. NCT ClinicalTrials.gov. NCT ClinicalTrials.gov. NCT

26 BMS : PD-L1 antibody 207 patients with advanced solid organ malignancies was given every 2 weeks 75 p with NSCLC 49 evaluable for response 5 objective responses (4 non-squamous and 1 squamous) Brahmer JR NEJM 2012; 366:

27 Phase I Study of MPDL3280A in NSCLC MPDL3280A: anti PD-L1 antibody engineered for enhanced safety and efficacy Specifically engineered to block the PD1/PD-L1 interaction Patients with metastatic solid tumors EGFR and KRAS status assessed at baseline Study design: MPDL3280A IV every 3 wks x 16 cycles ( 1 yr) Primary endpoint: safety Secondary endpoint: ORR by RECIST v1.1 Characteristics n = 85* Median age, yrs (range) 60 (24-84) Sex, male/female, n (%) 48 (56)/37 (44) ECOG PS, 0 / 1, n (%) 27 (32)/58 (68) Histology, n (%) Squamous 20 (24) Nonsquamouss 65 (76) Characteristics, n (%) n = 85* Previous systemic regimens 1 or 2 36 (42) 3 47 (55) Smoking status Current/previous 68 (80) Never 17 (20) *Safety evaluable patients (n = 85) with NSCLC. Data cutoff April 30, Systemic regimens administered in the metastatic, adjuvant or neoadjuvant setting. 3% of patients had no previous systemic regimens. Horn L, et al. WCLC Abstract MO18.

28 MPDL3280A in NSCLC: Best Response by PD-L1 Status and DOT/DOR PD-L1 Status* (N = 53) IHC 3 (n = 6) IHC 2 and 3 (n = 13) IHC 1/2/3 (n = 26) All patients (IHC 0/1/2/3 and 7 patients with diagnostic unknown; N = 53) ORR, % (n/n) 83 (5/6) 46 (6/13) 31 (8/26) 23 (12/53) Pts With PD, % (n/n) 17 (1/6) 23 (3/13) 38 (10/26) 40 (21/53) Histology IHC NS IHC 0 S IHC 3 NS IHC 0 NS IHC 1 NS IHC 0 S IHC 2 NS IHC 3 S IHC 3 NS IHC 3 NS IHC 0 NS IHC 3 NS IHC 1 Duration of Treatment and Response *PD-LI status determined using proprietary Genentech Roche IHC. Wk ORR includes investigator-assessed unconfirmed and confirmed (u/c) PR per RECIST 1.1. Patients first dosed at 1-20 mg/kg by October 1, Data cutoff April 30, Horn L, et al. WCLC Abstract MO18/Spigel DR. JCO abstract On study, on treatment On study, post treatment Treatment discontinued Ongoing response First response First PD

29 Pts With PR (%) Pts With PR (%) Pts With PR (%) MPDL3280A Phase Ia: Response by Smoking and Mutational Status Current/Former: 20/75: 27% ORR Never: 0/13 ESMO 2014 Former/ Current Smokers Smoking Status (NSCLC; n = 53) 81% 19% Never Smokers 50 Response by Smoking Status (ORR*) % 20 10% 10 11/43 1/10 0 Former/Current Smokers Never Smokers EGFR Status (NSCLC; n = 53) EGFR WT 76% 13% 11% Unknown EGFR Mutant Response by EGFR Status (ORR*) 23% 17% 9/40 1/6 EGFR WT EGFR Mutant KRAS Status (NSCLC; n = 53) 50 Response by KRAS Status (ORR*) 40 Unknown 30% 30% 30 KRAS WT 20 51% 10% 19% 10 KRAS 8/27 1/10 0 Mutant KRAS WT KRAS Mutant *ORR includes investigator-assessed u/c PR by RECIST 1.1. Patients first dosed at 1-20 mg/kg by October 1, Data cutoff April 30, Horn L, et al. WCLC Abstract MO18. ASCO/JCO

30 [TITLE] Calles ESMO 2014

31 MPDL3280A: Treatment-Related Adverse Events in Patients With NSCLC Majority of AEs were grade 1/2 and did not require intervention No MTD or dose-limiting toxicities No grade 3-5 pneumonitis observed Treatment-related death (cardiorespiratory arrest) in 1 patient with sinus thrombosis and large tumor mass invading the heart at baseline Immune-related grade 3.4 AEs: 1 patient with large-cell neuroendocrine NSCLC (diabetes mellitus, 1%) Adverse Event (n = 85) Treatment Related, % (n) Any Grade* Grade 3/4 Any AE 66 (56) 11 (9) Fatigue 20 (17) 2 (2) Nausea 14 (12) 1 (1) Decreased appetite 12 (10) 0 Dyspnea 9 (8) 1 (1) Diarrhea 8 (7) 0 Asthenia 7 (6) 0 Headache 7 (6) 0 Rash 7 (6) 0 Pyrexia 6 (5) 0 *AEs occurring in 5% of patients. Grade 3/4 treatment-related AEs listed include treatmentrelated AEs for which the any grade occurrence was 5% of patients. Data cutoff April 30, Vomiting 6 (5) 1 (1) Upper respiratory tract infection 5 (4) 0 Horn L, et al. WCLC Abstract MO18. Reprinted with permission.

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33 Vaccine therapy Vaccine Antigen Specific MAGE 3 present in numerous tumors JCO 2013 MAGE-A3 ESMO 2014 Phase trial stage/pop Proof-of-concept MAGE A3 positive Stage IB Phase II vaccine vs placebo MAGRIT Stage IB, II and IIIA + MAGE-3 gene placebo vs vaccine Nº Trial design Results 122 Recurrence 35% MAGE A3 arm vs 43% placebo Disease Free Interval: HR: 0.75; p:0.25 Disease Free Survival: HR: 0.76; p:0.24 OS: HR: 0.81; p: Stopped Did not meet primary end points, including DFS

34 Vaccine MUC-1 Membrane-associated Glycoprotein MUC-1 is increased in cancer cell 60% NSCLC Role not clear Peptide based vaccine- Liposomal BLP-25 (L-BLP25) Butts C. JCO 2005 MUC-1 L-BLP-25 Phase trial stage/pop Phase II IIIB and IV stable after ChT or RT START Stage III unresectable vaccine vs ctx vs placebo Nº Results 171 Eight weekly sc imm L-BLP25 vs BSC Median Survival: 17.4 m vs 13 m (HR: 0.73; p: 0.11) 3-year survival rate was: 31% L-BLP25 vs 17% (p:0.035) A post hoc analysis: benefit in stage IIIB (3-y: 49% vs 27%; p: 0.07) 1513 After ChemoRT; placebo vs Vaccine Did not meet primary end point OS: 0.88; median OS: 25.6 vs 22.3; p:0.123

35 Vaccine TG 4010 glycoprotein based pox virus Encoding for MUC-1 and IL-2 Ramlau R. JTO 2008 TG4010 MUC positive Lancet Oncol 2011 TG 4010 glycoprotein MUC-1 Phase trial stage/pop Phase II Stage IIIB/IV 1st line with CDDP-VNR Phase IIB IIIB/IV cis-gem alone vs Cht + vaccine Stage IV Nº Results 67 Concurrent arm: 35% and OS: PFS: TG40101: 43.2% ChT: 35.1% (p:0.307) ong oing OS: TG4010: 10.7 m ChT: 10.3 m placebo vs vaccine Primary end point: OS

36 Vaccine CIMAvax EGF Recombinat Human Epidermal Growth Factor Neninger E. JCO 2008 Bec2 combined with BCG anti-idiotypic antibody GD3 JCO 2005 Belagenpumatucel antisense gene TGF-B2 AACR 2013 Phase trial stage/pop Phase II Stage IIIB/IV 1st line following BSC vs vaccine Phase III SCLC after induction Phase II Stage IV Nº Results 80 Median OS: 11.7m with good EGFR antibody response 551 No improvement in OS, PFS or QoL OS median 16.4 vs 14.3 m 75 OS: 44.4 m

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38 Immunocompetent Mice Reject Tumors Originating in Immunodeficient Mice In other words, competent immune systems force the tumors to figure out how to survive in hostile environments Shankaran V, et al. Nature. 2001;410:

39 Conclusions Next frontier of treatment of lung cancer

40 The cytotoxic T-lymphocyte antigen-4 (CTLA-4) inhibitory checkpoint pathway is important in regulating early T-cell activation. Brahmer J R JCO 2013;31: by American Society of Clinical Oncology

41 Safety and response with nivolumab/erlotinib in p with advanced mutant EGFR (NCT ) Key patient inclusion criteria Stage IIIB/IV NSCLC Non-squamous EGFR+ CT naïve (n=21) Key results: 21 p (20 prior treatment with erlotinib) nivolumab 3 mg/kg q2w + erlotinib 150 mg/day Grade 3 AEs occurred in 24% of p (no grade 4 reported) ORR 19% / 45% SD PFS 29.4 weeks ( ), OS NR ( ) PD Rizvi 14, poster, abstr 8022