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Combining immunotherapeutic agents Paolo A. Ascierto, MD Unit Melanoma, Cancer Immunotherapy and Innovative Therapies Istituto Nazionale Tumori – Fondazione “G. Pascale”, Napoli, Italy Disclosure • Employment or Leadership Position: None • Consultant/Advisory Role: Bristol-Meyers Squibb, Roche-Genentech, Merck Sharp & Dohme, Novartis, Amgen, Array, Merck Serono • Stock Ownership: None • Research Funding: Bristol-Meyers Squibb, RocheGenentech, Array • Expert Testimony: None • Other Remuneration: None The goals for treatments …… early and fast responses Long-term benefit cure the patients Ascierto ESMO 2016 Two different drugs... Two different concepts immunotherapy slow acting, but possibility to reach long-term benefit Oct-2010 Ascierto ESMO 2016 Jun-2011 target therapy fast acting, rapid metabolic shutdown, unfortunately resistance Day 0 Day 15 Istituto Nazionale Tumori Fondazione “G. Pascale”, Naples, Italy Raising the bar …… Targeted therapy Combination? Percent alive Percent alive Percent alive Immunotherapy 0 1 2 Years 3 0 1 2 Years 3 0 1 2 3 Years Figure modified from Ribas et al., Clin Cancer Res. 2012. Raising the bar …… Chemotherapy Radiotherapy Combination approaches Immunotherapy Targeted therapy Ascierto ESMO 2016 Raising the bar …… Chemotherapy Radiotherapy Combination approaches Immunotherapy + Immunotherapy Targeted therapy Ascierto ESMO 2016 Components of eliciting a clinically relevant immune response Abrogate immuno-suppressive networks T-regs B-regs Turn on NK cell Turn on T-cell activate IDO • • • • CD137 CD40 CD137 VEGF chemotherapy radiation therapy vaccine intratumoral arginine CTLA4 sMICB – oncolytic virus – cytokines – TLR agonists PD-1 OX40 M2 MO LAG-3 GITR CD27 BTLA T & NK cell trafficking and infiltration into the tumor PGE2 TIM-3 Fc/CD16 sMICA IL-2 TGF-β NKG2D Prime system a-KIR MDSC inhibit IL-15 exosomes adenosine IL-10 SMR 2014 BMS scientific symposium Targeting CTLA-4 and PD-1 pathways Periphery Tumour microenvironment Activation (cytokines, lysis, proliferation, migration to tumour) MHC Dendritic cell B7 B7 TCR TCR +++ +++ CD28 CTLA-4 +++ --- T cell Anti-CTLA-4 MHC T cell PD-1 PD-L1 --- Tumour cell Anti-PD-1/PD-L1 PD-1 PD-L2 --Anti-PD-1 CTLA-4 pathway PD-1 pathway Wolchock J, et al. JCO 2013 Volume 31, Issue 15_suppl ; abstr 9012^ CA209-067 study: ORR and PFS Larkin et al. NEJM 2015 Wholchok et al ASCO 2016 CA209-069 study: PFS and OS Postow et al AACR 2016 Hodi et al. Lancet Oncol. 2016 Sep 9 KEYNOTE-029: Study Design Dose Expansion (Part 1B) Dose Run-In (Part 1A) Patients • Advanced MEL, ≥0 prior therapies OR • Advanced RCC, ≥1 prior therapy Pembro 2 mg/kg Q3W up to 24 months + Ipi 1 mg/kg Q3W x 4 doses Tolerable based on DLT rate? No Stop development Combination tolerable based on DLT rate and AE profile1,2 Yes Patients • Advanced MEL • ≥0 prior therapies • No prior anti–CTLA-4, PD-1, or PD-L1 • ECOG PS 0 or 1 Primary end point: Safety Secondary end points: ORR, DOR, PFS, OS ClinicalTrials.gov, NCT02089685. Long G et al ASCO 2016 Keynote 029: Best Change From Baseline in Tumor Size Change From Baseline, % (RECIST v1.1, investigator review) 100 80 60 40 20 0 -20 -40 -60 -80 -100 PD-L1 positive PD-L1 negative PD-L1 unknown 81% ORR = 57% Median change: –54.5% Data cutoff date: Mar 17, 2016. Long et al. ASCO 2016 Keynote 029: AE Summary Category Treatment Related N = 153 Immune Mediateda N = 153 Any grade 145 (95%) 89 (58%) Grade 3-4 64 (42%) 38 (25%) 0 0 16 (10%) 12 (8%) 11 (7%) 6 (4%) 16 (10%) 11 (7%) Led to death Led to ipilimumab discontinuation only Led to pembrolizumab discontinuationb Led to ipilimumab and pembrolizumab discontinuationc Long et al. ASCO 2016 CA209-511: Study Design Phase IIIb/IV, Randomized, Double Blinded, Study of Nivolumab 3 mg/kg in Combination with Ipilimumab 1 mg/kg vs Nivolumab 1 mg/kg in Combination with Ipilimumab 3 mg/kg in Subjects with Previously Untreated, Unresectable or Metastatic Melanoma Double Blinded Part 1 6 weeks* Open-label Part 2*** Arm A (n = 173) Previously Untreated Unresectable Stage III-IV Melanoma Randomize (N = 346) 1:1 Stratify by • PD-L1 expression • M stage nivolumab 3 mg/kg IV + ipilimumab 1 mg/kg IV Nivolumab Flat Dose 480 mg Every 4 weeks Every 3 weeks for 4 doses Arm B (n = 173) nivolumab 1 mg/kg IV + ipilimumab 3 mg/kg IV Nivolumab Flat Dose 480 mg Every 4 weeks Every 3 weeks for 4 doses *6 weeks from last dose in part 1 to Part 2 monotherapy flat dose **Treatment beyond initial investigator-assessed RECIST 1.1-defined progression will be considered in subjects experiencing investigator assessed clinical benefit and tolerating study therapy. Such subjects must discontinue therapy when further progression is documented. *** The treatment arm assigned in Part 1 will no be revealed until the end of the study Treat until progression** or unacceptable toxicity Changes in Target Lesions: Nivo/Ipi and Pembro/Epacadostat nivolumab + ipilimumab pembrolizumab + epacadostat 1 mg/kg nivolumab + 3 mg/kg ipilimumab 300 Change in target lesions from baseline (%) 200 First occurrence of new lesion 100 80 60 40 20 0 –20 –40 –60 –80 –100 0 10 20 30 40 50 60 70 80 90 100 110 Weeks since treatment initiation Wolchok JD, et al. J Clin Oncol 2013;31(suppl): abstract 9012^; Sznol M, et al. J Clin Oncol 2013;31(suppl): abstract CRA9006^ Hamid et al. SMR November 21, 2015 T-VEC + ipilimumab Puzanov et al JCO 2016; 34:2619-2626 T-VEC + pembrolizumab Long et al SMR 2015 MASTERKEY-265 Phase 3 Study Design N = 330 N = 660 T-VEC Intralesional • Unresectable stage III or IV melanoma • Treatment naive – Prior BRAFi allowed • Injectable lesions Pembrolizumab 200mg IV Q3W R 1:1 T-VEC placebo Intralesional Pembrolizumab 200mg IV Q3W N = 330 Primary Endpoints: PFS and OS NCT02263508 Long et al SMR 2015 Mozzillo N, Simeone E, et al.Oncoimmunology 2015 in press Survival results All cohort 6 months-OS was 93,3 % and 1 y-OS was 86,2% 9/9 (100%) responder patients were alive at a median follow up of 16,2 months. Mozzillo N, Simeone E, et al.Oncoimmunology 2015 Heppt et al. Cancer Immunol Immunother. 2016 Aug;65(8):951-9 Rationale for investigating opportunities to combine immunotherapy with other therapeutic modalities Multiple mechanisms of potential synergy between the different treatment modalities Radiation Adhesion molecules (CAM-1) and death receptors (FAS) Peptide pools CD8 T cell Upregulation of MHCI Uploading of antigen processing machinery Chemotherapy Targeted therapies Vascular normalisation T cell initiation Effector immune infiltrate Release of tumour antigens (cascade) Cytokine release Translocation of calreticulin CD8 T cells TAA crosspresentation Dendritic cell MDSC Tregs M2 macrophages TAA Upregulates MHCI Adhesion molecules/ death receptors APM CD8 T cells (homeostatic peripheral expansion) MDSC CD8 T cells T cell function Tregs Activation of apoptosis Blockage of cell cycle 1. Adapted from Hodge JW. Semin Oncol 2012;39:323–39; 2. Drake CG Ann Oncol 2012;23 Suppl 8:viii41–6; 3. Ménard C, et al. Cancer Immunol Immunother 2008;57:1579-87; 4. Hannani D, et al. Cancer J 2011;17:351–58; 5. Ribas A at al. Curr Opin Immunol 2013:25:291–96. Raising the bar …… Chemotherapy Radiotherapy Combination approaches Immunotherapy Targeted therapy Radiotherapy modifies the immune system interaction with cancer Lymphocytepoor Lymphocyterich Demaria & Formenti, Front Oncol 2012 Radiation + ipilimumab • A patient with melanoma received ipilimumab and radiotherapy • The target and other lesions regressed • Regression of distant lesions may be due to an enhanced systemic response Figure adapted from Postow M, et al. N Engl J Med 2012; 366(10): 925–931. Abscopal Effects of Radiotherapy in Melanoma Patients Progressing After Ipilimumab (cont’d) • Patient survival according to abscopal responses 100 OS (%) 80 Abscopal response Median OS, months (95% CI): 22.4 (2.5–50.3) No abscopal response Median OS, months (95% CI): 8.3 (7.6–9.0) 60 40 20 0 0 6 12 18 Months 24 30 36 • Abscopal response was present in 11 patients and absent in 10 patients • Groups were compared using the log-rank test; p=0.002 Grimaldi AM, et al. Oncoimmunology 2014;3:e28780 Abscopal Effects of Radiotherapy in Melanoma Patients Progressing After Ipilimumab Baseline Post ipilimumab Post radiotherapy • 54-year old patient • Received 4 cycles of ipilimumab 3 mg/kg • Followed by palliative whole brain radiotherapy • Post RT follow-up CT scans indicative of abscopal response Grimaldi AM, et al. Oncoimmunology 2014;3:e28780 799 patients randomized RT Site: bone mets Dose : 8 Gy, single fraction Study powered to detect a 4 month difference in median overall survival (15.8 versus 12 months) Time: RT within 2 days from IPI, then anytime during IPI Raising the bar …… Chemotherapy Radiotherapy Combination approaches Immunotherapy Targeted therapy Combining Ipilimumab with Chemotherapy Summary of Efficacy Results in Melanoma Randomised phase 2 trial of ipilimumab 3 mg/kg + DTIC vs ipilimumab alone Randomised phase 3 trial of ipilimumab 10 mg/kg + DTIC vs DTIC alone Treatment-naïve Treatment-naïve Patient population Ipi + DTIC Patients, n Median OS, months 1-year OS, % Median PFS, months Best overall response rate, % Median duration of response, months 35 14.3 62 Ipi Ipi + DTIC DTIC 37 11.4 45 250 11.2 47.3 252 9.1 36.3 Not reported 14.3 5.4 Not reported (durable CRs and PRs of 20+ months) 24% reduction in the risk of progression with ipi + DTIC Single arm phase 2 trial of ipilimumab 10 mg/kg + fotemustine Single arm phase 2 trial of ipilimumab 10 mg/kg + temozolomide Pretreated and Treatment-naïve Treatment-naïve 86 13.3 52.6 64 Not reached 68 5.3 5.1 15.2 10.3 29.1 30 19.3 8.1 Not reached 12+ Caution is warranted when comparing across trials Robert C, et al. N Engl J Med 2011;364(26):2517–26 Di Giacomo AM, Lancet Oncol 2012;13(9):879–86 Patel SP, et al. Presented at ESMO 2012. P1126 Langer et al ESMO 2016 Phase 2 trial to evaluate CTLA-4 T cell checkpoint inhibition with ipilimumab in combination with chemotherapy (carboplatin/paclitaxel) in lung cancer 1.0 NSCLC (Phased) Events/ Median OS, patients months 95% CI HR P value 0.8 Control 56/66 4.63 4.14–5.52 0.6 Concurrant Ipilimumab 55/70 5.52 4.17–6.74 0.81 0.13 0.4 0.2 irPFS (probability) irPFS (probability) NSCLC (Concurrent) 0 4 6 8 10 Time (months) Control 66 59 55 41 38 28 17 13 11 5 Ipilimumab 70 62 48 44 40 34 29 20 18 9 4 8 12 14 0.8 0.6 95% CI HR P value Control 56/66 4.63 4.14–5.52 Phased Ipilimumab 54/68 5.68 4.76–7.79 0.72 0.05 0.4 0.2 16 0 3 2 3 1 1 1 1 0 1 0 0 0 6 8 10 Time (months) 4 4 12 3 3 3 3 14 3 3 1 1 16 1 1 1 1 0 0 ED-SCLC (Phased) 1.0 Events/ Median OS, patients months 0.6 4 Control 66 59 55 41 38 28 17 13 11 5 Ipilimumab 66 59 55 41 38 28 17 13 11 5 ED-SCLC (Concurrent) 0.8 2 No. at risk 3 6 95% CI HR P value Control 40/45 5.26 4.67–5.72 Concurrant Ipilimumab 37/43 5.68 5.19–6.87 0.75 0.4 0.2 0 0.11 irPFS (probability) 2 No. at risk irPFS (probability) Events/ Median OS, patients months 0 0 1.0 Events/ Median OS, patients months 95% CI HR P value 0.8 Control 40/45 5.26 4.67–5.72 0.6 Phased Ipilimumab 38/42 6.44 5.29–7.75 0.64 0.4 0.2 0 0 No. at risk 1.0 2 4 6 8 10 12 14 Time (months) 16 18 20 22 Control 45 44 42 38 36 26 11 10 7 5 4 3 2 2 2 2 1 0 0 0 0 0 0 0 Ipilimumab 43 38 36 31 29 26 16 12 11 10 9 9 8 5 4 3 3 2 2 2 2 2 1 0 Data from trial CA184-041. aStatistically significant per protocol-stipulated one-sided =0.1; P values not adjusted for multiple comparisons. HR = hazard ratio; Ipi = ipilimumab; irPFS = PFS by immune-related response criteria (irRC); mWHO-PFS = PFS by modified WHO criteria (mWHO); Pbo = placebo; PFS = progression-free survival. 1. Lynch TJ, et al. J Clin Oncol. 2012;30:2046–2054; 2. Reck M, et al. Ann Oncol. 2013;24:75–83. 0 No. at risk 2 4 6 8 10 12 14 Time (months) 16 18 20 22 Control 45 44 42 38 36 26 11 10 7 5 4 3 2 2 2 2 1 0 0 0 0 0 0 Ipilimumab 42 42 40 37 35 31 22 18 10 7 7 6 6 6 5 5 5 3 2 1 1 1 0 0.03 Raising the bar …… Chemotherapy Radiotherapy Combination approaches Immunotherapy Targeted therapy Summary of Published Data of Immunotherapy in Combination with Targeted Agents • The combination of ipilimumab with targeted agents could in theory result in synergistic effects Jang, S, Atkins M. Lancet Oncol 2013;14:e60–9 Ribas A, et al. N Engl J Med 2013;368:1365–6 Effect of BRAF inhibitors on the immune system BRAF inhibition is associated with increased melanoma antigen expression in tumours of patients with metastatic melanoma Antitumour activity of combined BRAFi+MEKi plus anti-PD-13 CD4+ and CD8+ increase in responder lesion and decrease in lesions which progressed ↑ MHC and melanoma antigen expression3 BRAF inhibition is associated with increased CD8+ T-cell infiltrate in tumours of patients with metastatic melanoma Wilmott JS, et al. Clin Cancer Res 2011;18:1386–94, Reprinted from Clinical Cancer Research 2012, with permission from AACR Frederick DT, et al. Clin Cancer Res 2013;19:1225–31, Reprinted from Clinical Cancer Research 2013, with permission from AACR 3. From Hu-Lieskovan S et al. Sci Transl Med 2015;7:279ra41., Reprinted with permission from AAAS Summary of Published Data of Immunotherapy in Combination with Targeted Agents • The combination of ipilimumab with targeted agents could in theory result in synergistic effects • Concurrent administration of vemurafenib and ipilimumab may not be feasible – Increased incidence of hepatotoxicity observed in a phase 1 safety study – Toxicity may preclude adequate dosing Jang, S, Atkins M. Lancet Oncol 2013;14:e60–9 Ribas A, et al. N Engl J Med 2013;368:1365–6 Summary of Published Data of Immunotherapy in Combination with Targeted Agents • The combination of ipilimumab with targeted agents could in theory result in synergistic effects • Concurrent administration of vemurafenib and ipilimumab may not be feasible – Increased incidence of hepatotoxicity observed in a phase 1 safety study – Toxicity may preclude adequate dosing Jang, S, Atkins M. Lancet Oncol 2013;14:e60–9 Ribas A, et al. N Engl J Med 2013;368:1365–6 Summary of Published Data of Immunotherapy in Combination with Targeted Agents • The combination of ipilimumab with targeted agents could in theory result in synergistic effects • Concurrent administration of vemurafenib and ipilimumab may not be feasible – Increased incidence of hepatotoxicity observed in a phase 1 safety study – Toxicity may preclude adequate dosing • Phase 1 data show that combinations of dabrafenib + ipilimumab with or without trametinib are not associated with hepatotoxicity Jang, S, Atkins M. Lancet Oncol 2013;14:e60–9 Ribas A, et al. N Engl J Med 2013;368:1365–6 Puzanov I, et al. J Clin Oncol 2014;32(suppl 5s): abstract 2511 Summary of Published Data of Immunotherapy in Combination with Targeted Agents • The combination of ipilimumab with targeted agents could in theory result in synergistic effects • Concurrent administration of vemurafenib and ipilimumab may not be feasible – Increased incidence of hepatotoxicity observed in a phase 1 safety study – Toxicity may preclude adequate dosing • Phase 1 data show that combinations of dabrafenib + ipilimumab with or without trametinib are not associated with hepatotoxicity • The triplo combo ipilimumab/dabrafenib/trametinib is not feasible due to the increase of gastro-intestinal toxicity (bowel perforation) Jang, S, Atkins M. Lancet Oncol 2013;14:e60–9 Ribas A, et al. N Engl J Med 2013;368:1365–6 Puzanov I, et al. J Clin Oncol 2014;32(suppl 5s): abstract 2511 Summary of Published Data of Immunotherapy in Combination with Targeted Agents • The combination of ipilimumab with targeted agents could in theory result in synergistic effects • Concurrent administration of vemurafenib and ipilimumab may not be feasible – Increased incidence of hepatotoxicity observed in a phase 1 safety study – Toxicity may preclude adequate dosing • Phase 1 data show that combinations of dabrafenib + ipilimumab with or without trametinib are not associated with hepatotoxicity • The triplet combo ipilimumab/dabrafenib/trametinib is not feasible due to the increase of gastro-intestinal toxicity (bowel perforation) • Sequential treatment with ipilimumab and targeted therapies may be a more appropriate therapeutic approach Ackerman A, et al. J Clin Oncol 2012; 30 (suppl): abstract 8569 Ascierto PA, et al. J Transl Med 2012;10: Epub ahead of print Jang, S, Atkins M. Lancet Oncol 2013;14:e60–9 Ribas A, et al. N Engl J Med 2013;368:1365–6 Puzanov I, et al. J Clin Oncol 2014;32(suppl 5s): abstract 2511 Summary of Published Data of Immunotherapy in Combination with Targeted Agents • What about the combo anti-PD-1/PD-L1 with Target Therapy ? Summary of Published Data of Immunotherapy in Combination with Targeted Agents • What about the combo anti-PD-1/PD-L1 with Target Therapy ? • We know that anti-PD-L1can be combined with BRAFi Sullivan R et al SMR 2015 Summary of Published Data of Immunotherapy in Combination with Targeted Agents • What about the combo anti-PD-1/PD-L1 with Target Therapy ? • We know that anti-PD-L1can be combined with BRAFi Sullivan R et al SMR 2015 Summary of Published Data of Immunotherapy in Combination with Targeted Agents • What about the combo anti-PD-1/PD-L1 with Target Therapy ? • We know that anti-PD-L1can be combined with BRAFi • What about the triplet ? Summary of Published Data of Immunotherapy in Combination with Targeted Agents • • • • What about the combo anti-PD-1/PD-L1 with Target Therapy ? We know that anti-PD-L1can be combined with BRAFi What about the triplet ? It’s feasible ! Ribas et al. ASCO 2015 Summary of Published Data of Immunotherapy in Combination with Targeted Agents • • • • What about the combo anti-PD-1/PD-L1 with Target Therapy ? We know that anti-PD-L1can be combined with BRAFi What about the triplet ? It’s feasible ! Hwu P et al. ESMO 2016 KEYNOTE-022 Phase 2 Trial Design Advanced melanoma • BRAFi/MEKi , antiPD-1/L1, IPI naïve • N=120 Pembrolizumab + Dabrafenib + Trametinib 1:1 Placebo + Dabrafenib + Trametinib • Primary endpoint: PFS • Interim Analysis for early efficacy signal Clinicaltrials.gov NCT02130466 PFS curves may predict long-term benefit … % Progression-Free 100 Anti-PD-1 Combo target 50 1 2 Years Ascierto & Long. Lancer Oncol. 2016 PFS curves may predict long-term benefit … % Progression-Free 100 Anti-PD-1 Combo Target 50 1 2 Years Ascierto & Long. Lancer Oncol. 2016 Via Mariano Semmola, 80131, Napoli, Italy Tel. +39 081 5903 431; Fax +39 081 5903 841 Email: [email protected]