Update on the development of immune checkpoint inhibitors

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1 Update on the development of immune checkpoint inhibitors Jean-Pascal Machiels Department of Medical Oncology Laboratory of Medical Oncology Cliniques universitaires Saint-Luc Université catholique de Louvain, UCL, Brussels

2 Presentation outline Clinical activity Further developments: Anti-PD1/PD-L1 + anti-ctla-4 Combination with chemotherapy Combination with radiotherapy

TCR = T-cell receptor; PD-L1 = programmed

3 Priming phase Effector phase Dendritic cell T cell T cell Tumor cell MHC Lymph node TCR TCR Peripheral tissue MHC Activation signals B7 CD28 Inhibitory signals Negative signals PD-1 PD-L1 B7 Antibody CTLA-4 CD28 Antibody Antibody TCR = T-cell receptor; PD-L1 = programmed death-ligand1. Ribas A. N Engl J Med. 2012;366:

4 Targeting the PD-1/PD-L1 pathway Design Population Nivolumab (Checkmate 141) Anti-PD-1 Phase III Progressive diseasewith six months of platinum therapy Pembrolizumab (Keynote-012) Anti-PD-1 Single arm (Phase 1b) PD-L1 positive Pembrolizumab (Keynote-012) Anti-PD-1 Single arm (Phase 1b) Unselected for PD-L1 Pembrolizumab (Keynote-055) Anti-PD-1 Single arm (Phase 2) Unselected for PD-L1, after progression on platinum and cetuximab therapy Durvalumab (study 1108) Anti-PD-L1 Single arm Unselected for PD-L1 Seiwertet al. Lancet Oncol. 2016, Chow et al. J. Clin. Oncol. 2016, Bauml et al. ASCO 2016, SegalASCO 2015, Ferris RL et al. NEJM 2006

5 Targeting the PD-1/PD-L1 pathway Design Population Nivolumab (Checkmate 141) Anti-PD-1 Phase III Progressive diseasewith six months of platinum therapy Pembrolizumab (Keynote-012) Anti-PD-1 Single arm (Phase 1b) PD-L1 positive Pembrolizumab (Keynote-012) Anti-PD-1 Single arm (Phase 1b) Unselected for PD-L1 Pembrolizumab (Keynote-055) Anti-PD-1 Single arm (Phase 2) Unselected for PD-L1, after progression on platinum and cetuximab therapy Durvalumab (study 1108) Anti-PD-L1 Single arm Unselected for PD-L1 Seiwertet al. Lancet Oncol. 2016, Chow et al. J. Clin. Oncol. 2016, Bauml et al. ASCO 2016, SegalASCO 2015, Ferris RL et al. NEJM 2006

Phase 3 Checkmate 141 study design Key Eligibility Criteria R/M SCCHN of the oral

platinum-based therapy Irrespective of number of prior lines of therapy

of PD-L1 status Stratification factor Prior cetuximab treatment R 2:1 Nivolumab 3

mg/m² IV weekly Cetuximab 400 mg/m² IV once, then 250 mg/m² weekly Primary endpoint

6 Phase 3 Checkmate 141 study design Key Eligibility Criteria R/M SCCHN of the oral cavity, pharynx, or larynx Progression on or within 6 months of last dose of platinum-based therapy Irrespective of number of prior lines of therapy Documentation of p16 to determine HPV status (oropharyngeal cancer only) Regardless of PD-L1 status Stratification factor Prior cetuximab treatment R 2:1 Nivolumab 3 mg/kg IV Q2W Investigator s Choice Methotrexate 40 mg/m² IV weekly Docetaxel 30 mg/m² IV weekly Cetuximab 400 mg/m² IV once, then 250 mg/m² weekly Primary endpoint OS Other endpoints PFS ORR Safety DOR Biomarkers Patient-reported quality of life Clinicaltrials.gov NCT

7 Demographics (2) Patient s characteristics Nivolumab (n = 240) n (%) Investigator s Choice (n = 121) n (%) Total (N = 361) n (%) ECOG performance status 0 49 (20.4) 23 (19.0) 72 (19.9) (78.8) 94 (77.7) 283 (78.4) 2 1 (0.4) 3 (2.5) 4 (1.1) Not reported 1 (0.4) 1 (0.8) 2 (0.6) Number of prior lines of systemic cancer therapy (43.8) 58 (47.9) 163 (45.2) 2 81 (33.8) 45 (37.2) 126 (34.9) 3 54 (22.5) 18 (14.9) 72 (19.9) Site of primary tumor Oral cavity 108 (45.0) 67 (55.4) 175 (48.5) Pharynx 92 (38.3) 36 (29.8) 128 (35.5) Larynx 34 (14.2) 15 (12.4) 49 (13.6) Other 6 (2.5) 3 (2.5) 9 (2.5)

8 Treatment Administration Patient s characteristics Nivolumab (n = 240) Investigator s Choice (n = 121) Total (N = 361) Patients receiving 1 dose, n (%) 236 (98.3) 111 (91.7) 347 (96.1) Investigator s choice therapy, n (%) Methotrexate 46 (38.0) Docetaxel 52 (43.0) Cetuximab 13 (10.7) Median time on therapy, mo (95% CI) 1.9 ( ) 1.9 ( ) Median duration of follow-up, mo (range) 5.3 (0 16.8) 4.6 (0 15.2) Number of deaths, n (%) 133 (55.4) 85 (70.2) 218 (60.4) Ongoing treatment, n (%) 41 (17.4) 3 (2.7) 44 (12.7)

9 Overall survival Overall Survival (% of patients) Median OS, mo (95% CI) HR (97.73% CI) Nivolumab (n = 240) 7.5 ( ) 0.70 Investigator s Choice (n = 121) 5.1 ( ) ( ) Months 1-year OS rate (95% CI) 36.0% ( ) 16.6% ( ) No. at Risk Nivolumab Investigator s Choice p-value

10 Treatment-related AEs in > 10% of patients Event Any grade n (%) Nivolumab (n = 236) Grade 3 4 n (%) Investigator s Choice (n = 111) Any grade n (%) Grade 3 4 n (%) Any a 139 (58.9) 31 (13.1) 86 (77.5) 39 (35.1) Fatigue 33 (14.0) 5 (2.1) 19 (17.1) 3 (2.7) Nausea 20 (8.5) 0 23 (20.7) 1 (0.9) Diarrhea 16 (6.8) 0 15 (13.5) 2 (1.8) Anemia 12 (5.1) 3 (1.3) 18 (16.2) 5 (4.5) Asthenia 10 (4.2) 1 (0.4) 16 (14.4) 2 (1.8) Mucosal inflammation 3 (1.3) 0 14 (12.6) 2 (1.8) Alopecia (12.6) 3 (2.7) a One Grade 5 event (hypercalcemia) in the nivolumab arm and one Grade 5 event (lung infection) in the investigator s choice arm were reported. A second death occurred in the nivolumab arm subsequent to pneumonitis.

11 Treatment-related select AEs Event Any grade n (%) Nivolumab (n = 236) Grade 3 4 n (%) Investigator s Choice (n = 111) Any grade n (%) Grade 3 4 n (%) Skin 37 (15.7) 0 14 (12.6) 2 (1.8) Endocrine 18 (7.6) 1 (0.4) 1 (0.9) 0 Gastrointestinal 16 (6.8) 0 16 (14.4) 2 (1.8) Hepatic 5 (2.1) 2 (0.8) 4 (3.6) 1 (0.9) Pulmonary 5 (2.1) 2 (0.8) 1 (0.9) 0 Hypersensitivity/Infusion reaction 3 (1.3) 0 2 (1.8) 1 (0.9) Renal 1 (0.4) 0 2 (1.8) 1 (0.9) Select AEs: AEs with potential immunologic etiology that requires monitoring/intervention

12 Targeting the PD-1/PD-L1 pathway Design Population Nivolumab (Checkmate 141) Anti-PD-1 Phase III Progressive diseasewith six months of platinum therapy Pembrolizumab (Keynote-012) Anti-PD-1 Single arm (Phase 1b) PD-L1 positive Pembrolizumab (Keynote-012) Anti-PD-1 Single arm (Phase 1b) Unselected for PD-L1 Pembrolizumab (Keynote-055) Anti-PD-1 Single arm (Phase 2) Unselected for PD-L1, after progression on platinum and cetuximab therapy Durvalumab (study 1108) Anti-PD-L1 Single arm Unselected for PD-L1 Seiwertet al. Lancet Oncol. 2016, Chow et al. J. Clin. Oncol. 2016, Bauml et al. ASCO 2016, SegalASCO 2015, Ferris RL et al. NEJM 2006

13 Pembrolizumab in recurrent head and neck cancer Pembrolizumab (Keynote-012) Pembrolizumab (Keynote-012) Pembrolizumab (Keynote-055) Anti-PD-1 Anti-PD-1 Anti-PD-1 Design Population N ORR % Survival Single arm (Phase 1b) Single arm (Phase 1b) Single arm (Phase 2) PD-L1 positive 60 Overall: 18% HPV- : 14% HPV+: 25% Unselected for PD-L1 132 Overall: 18% HPV- : 14% HPV+: 32% PD-L1 +: 22% Unselected for PD-L1, after progression on platinum and cetuximab therapy 171 Overall: 16% 13 months 8 months Seiwertet al. Lancet Oncol. 2016, Chow et al. J. Clin. Oncol. 2016, Bauml et al. ASCO 2016

14 Pembrolizumab in PD-L1 selected R/M SCCHN No. at Risk KEYNOTE-012 B Cohort (Pembrolizumab in PD-L1 Selected R/M SCCHN) 2.2 months Time, mo Probability of Remaining Progression Free Phase 2 Cetuximab Monotherapy in Platinum-Refractory R/M SCCHN 2.3 months ITT/safety IRC-PD Time to Progression, d Seiwertet al. Lancet Oncol. 2016, Vermorken et al. J. Clin. Oncol. 2007

15 Treatment-related adverse events Any Grade With Incidence 5% N = 171 n (%) Any 109 (64) Fatigue 30 (18) Hypothyroidism 16 (9) Nausea 11 (6) Aspartate aminotransferase increase 11 (6) Diarrhea 10 (6) Appetite decrease 9 (5) Rash 9 (5) Pruritus 8 (5) Grade 3-5 in 2 Patients N = 171 n (%) Any 26 (15) Aspartate aminotransferase increase 4 (2) Anemia 3 (2) Pneumonitis 2 (1) Alkaline phosphatase increase 1 death due treatment-related pneumonitis 7 (4%) discontinuations due to TRAEs Immune-mediated adverse events (any grade): o Hypothyroidism (n = 27; 16%) o Pneumonitis (n = 7; 4%) o Hyperthyroidism (n = 4; 2%) 2 (1) Haddad et al. ESMO 2016

16 Targeting the PD-1/PD-L1 pathway Design Population Nivolumab (Checkmate 141) Anti-PD-1 Phase III Progressive diseasewith six months of platinum therapy Pembrolizumab (Keynote-012) Anti-PD-1 Single arm (Phase 1b) PD-L1 positive Pembrolizumab (Keynote-012) Anti-PD-1 Single arm (Phase 1b) Unselected for PD-L1 Pembrolizumab (Keynote-055) Anti-PD-1 Single arm (Phase 2) Unselected for PD-L1, after progression on platinum and cetuximab therapy Durvalumab (study 1108) Anti-PD-L1 Single arm Unselected for PD-L1 Seiwertet al. Lancet Oncol. 2016, Chow et al. J. Clin. Oncol. 2016, Bauml et al. ASCO 2016, SegalASCO 2015, Ferris RL et al. NEJM 2006

17 Durvalumab in recurrent head and neck cancer Patients with R/M HNSCC, progressive disease at study entry, an ECOG PS of 0 or 1, and no prior anti-pd-1/pd-l1 exposure are eligible Durvalumab 10 mg/kg every 2 weeks x 1 year HNSCC (n=62 patients) Dose expansion Primary endpoint Safety and tolerability Key secondary endpoints ORR per RECIST v1.1; DCR; DoR; PFS; OS Exploratory endpoint PD-L1 expression on tumour cells and tumour infiltrating immune cells Tumour assessments conducted at Weeks 6, 12, 16 then every 8 weeks during treatment period

18 Selected drug-related AEs of interest System organ class Event Durvalumab 10 mg/kg q2w (N=62) All grades n (%) Endocrine Hypothyroidism 2 (3) 0 Gastrointestinal Diarrhoea 5 (8) 0 Investigations Aspartate aminotransferase increased 2 (3) 0 Grade 3 n (%) Blood thyroid-stimulating hormone decreased 1 (2) 0 Respiratory Pneumonitis 2 (3) 0 Skin Erythema 3 (5) 0 Pruritus 4 (7) 0 Rash 4 (7) 0 Rash erythematous 2 (3) 1 (2) Rash generalised 1 (2) 0 Rash maculo-papular 4 (7) 0 Rash pruritic 1 (2) 1 (2)

19 Objective response rate All patients RECIST response (ORR), n/n (%) 95% CI DCR 12 weeks, n/n (%) 95% CI 7/62 (11%) /62 (29)

20 Objective response rate PD-L1 high = 25% of tumour cells with membrane staining PD-L1 low/negative = <25% of tumour cells with membrane staining All patients PD-L1 high PD-L1 low/negative RECIST response (ORR), n/n (%) 95% CI 7/62 (11) /22 (18) /37 (8) DCR 12 weeks, n/n (%) 95% CI 18/62 (29) /22 (32) /37 (27)

21 Objective response rate PD-L1 high = 25% of tumour cells with membrane staining PD-L1 low/negative = <25% of tumour cells with membrane staining All patients PD-L1 high PD-L1 low/negative HPV + HPV RECIST response (ORR), n/n (%) 95% CI 7/62 (11) /22 (18) /37 (8) /25 (4) /25 (16) DCR 12 weeks, n/n (%) 95% CI 18/62 (29) /22 (32) /37 (27) /25 (24) /25 (24)

22 Objective response rate PD-L1 high = 25% of tumour cells with membrane staining PD-L1 low/negative = <25% of tumour cells with membrane staining All patients PD-L1 high PD-L1 low/negative HPV + HPV RECIST response (ORR), n/n (%) 95% CI 7/62 (11) /22 (18) /37 (8) /25 (4) /25 (16) DCR 12 weeks, n/n (%) 95% CI 18/62 (29) /22 (32) /37 (27) /25 (24) /25 (24) Responses are rapid PRs as early as the first assessment (7 weeks) Responses appear durable Among 7 responders, 6 had DoR 12 months Most responses occurred in the first 16 weeks

23 Change in target lesion size from baseline by PD-L1 Patients with PD-L1high tumours Patients with PD-L1 low/negative tumours 100 Subjects with confirmed CR/PR Other subjects New lesion 100 Subjects with confirmed CR/PR Other subjects New lesion Change from baseline (%) Change from baseline (%) Time (months) Time (months) Data cutoff: 29 April,

24 Presentation outline Clinical activity Further developments: Anti-PD1/PD-L1 + anti-ctla-4 Combination with chemotherapy Combination with radiotherapy

27 Durvalumab and Tremelimumab Setting Regimen PDL1 Status Rationale Phase 2 HAWK 1 2L SCCHN postplatinum in R/M setting Durvalumab mono PD-L1+ N = 112 Accelerated approval of the monotherapy in PD-L1+ Zandberg Durvalumab + tremelimumab PD-L1- n = 120 Phase 2 CONDOR 2 2L SCCHN post-platinum in R/M setting Durvalumab mono Tremelimumab mono PD-L1- n = 60 PD-L1- n = 60 Accelerated approval of the combination in PD-L1- Establishes individual component contribution to combination in PD-L1- Siu Phase 3 EAGLE 3 2L SCCHN post-platinum 1L patients who progressed 6 mo of multimodal tx with platinum in LA setting Durvalumab + tremelimumab Durvalumab mono SOC PD-L1+ n = 100 PD-L1+ n = 100 PD-L1+ n = 100 PD-L1- n = 140 PD-L1- n = adaptive 140 PD-L1- n = 140 Confirmatory trial Combination approval in all-comers Ferris and Licitra

28 Nivolumab + ipilimumab in newly diagnosed R/M head and neck Phase 2, randomized study Patients with recurrent/metastatic SCCHN Tumor sample must be available for analysis of PD- L1 and HPV (oropharynx only) ECOG PS 0-1 R Nivolumab + ipilimumab Nivolumab + placebo Primary endpoint: ORR in platinum-refractory subgroup Secondary endpoints: ORR in platinum-eligible subgroup, PFS, OS

29 Presentation outline Clinical activity Further developments: Anti-PD1/PD-L1 + anti-ctla-4 Combination with chemotherapy Combination with radiotherapy

30 Pembrolizumab + chemotherapy in NSCLC Cisplatin-alimta +/-pembrolizumab (n=123) Median PFS 13 vs 8.9 months Langer et al. Lancet Oncology 2016

31 Pembrolizumab versus chemotherapy in NSCLC (PD-L1>50%) in tumor cells ORR Chemotherapy 27.8% Pembrolizumab 44.8% Reck et al. NEJM 2016

32 Recurrent/metastatic SCCHN: first-line Pembrolizumab Cisplatin/5FU/Pembrolizumab Cisplatin/5FU/Cetuximab

33 Presentation outline Clinical activity Further developments: Anti-PD1/PD-L1 + anti-ctla-4 Combination with chemotherapy Combination with radiotherapy

34 PD-1/PD-L1 inhibitors synergize with RT RT + Anti PD-1 RT + Anti PD-L1 Survival, % a b Survival, % a b c c Days After Time Tumor After Tumor Implantation Implantation, Days NT 5x2 Gy RT αpd-1 mab 10 mg/kg 5x2 Gy RT + α PD-1 mab Days After Tumor Implantation a P <.001, log-rank (Mantel-Cox) test vs control mice. b P <.001, log-rank (Mantel-Cox) test vs monotherapy. c Significance when compared with control mice.. 1. Dovedi SJ et al. Cancer Res. 2014;74:

35 PHASE I TRIAL OF CETUXIMAB, IMRT, AND IPILIMUMAB IN PREVIOUSLY UNTREATED, LOCALLY ADVANCED HEAD AND NECK SQUAMOUS CELL CARCINOMA Julie E. Bauman, David A. Clump, James Ohr, William E. Gooding, Seungwon Kim, Brian J. Karlovits, Umamaheswar Duvvuri, Jonas T. Johnson, Daniel Petro, Dwight E. Heron, Robert L. Ferris esmo.org

36 Study design PROTOCOLTHERAPY IMRT Gy, standard fractionation Cetuximab 400 mg/m 2 load then 250 mg Ipilimumab Cohort -1: Cohort 1 (start): Cohort 2: 1 mg/kg 3 mg/kg 10 mg/kg Week of Treatment X X X X X X X X X X X X X X X X X X X DOSE-LIMITING TOXICITY: Any grade 4 toxicity (except in-field radiation dermatitis or asymptomatic, correctable lab abnormality) Any grade 3 immunerelated AE (irae) requiring 2 weeks of systemic immunosuppression Any toxicity at least partially attributable to ipilimumab resulting in the delay of IMRT completion by 10 fractions

37 DOSE-LIMITING TOXICITY Two of 6 patients in Cohort 1 (ipilimumab 3 mg/kg) experienced dermatologic immunerelated AEs qualifying as DLTs A. Perforating Folliculitis B. Autoimmune Dermatitis

38 Checkpoint inhibitors +/- (chemo) radiation in locally advanced Head and neck cancer Avelumab Nivolumab (RTOG 3504) Pembrolizumab... Concurrent versus sequential Post-operative and primary treatment

39 Conclusions PD-1 monoclonal antibodies are standard of care in patients that progress on or after platinum therapy Time now to investigate anti-pd1 therapy in the curative setting (RT, CRT, neoadjuvant) Does adding checkpoint inhibitors to (chemo)radiation improve survival? Can checkpoint inhibitors replace CT in certain settings? What about toxicities when combined with (chemo)radiation?

40 Conclusions To identify biomarker(s): PD-L1 expression Presence of non-synonymous mutations Interferon-gamma signature T-cell infiltrations Combine with other immunotherapy strategies Oncolytic virus Anti-EGFR therapies Vaccines IDO Etc..

41 This is only the beginning months We have to fill this gap Time, mo No. at Risk Seiwert et al. Lancet Oncology 2016

Immunotherapy for the Treatment of Head and Neck Cancers. Robert F. Taylor, MD Aurora Health Care

Immunotherapy for the Treatment of Head and Neck Cancers Robert F. Taylor, MD Aurora Health Care Disclosures No relevant financial relationships to disclose I will be discussing non-fda approved indications