Im Immuno-Onc Oncolo logy: gy: Be Beyon ond PD1 D1 Single Agent Michael Overman, MD Professor Gastrointestinal Medical Oncology MD Anderson Cancer Center moverman@mdanderson.org
Agenda/Disclosures • Agenda • The Challenge • Status of CTLA-4 Inhibition In GI Cancers • Combinations in dMMR CRC • Combinations in pMMR CRC • Disclosures • Consulting: • Merrimack, BMS, Roche, AstraZeneca • Research Funding: • Roche, Merck, Celgene, Medimmune, BMS, Amgen
Anti-PD1 Therapy in 20 Tumor Types (Pembrolizumab)
Rationale Combinations: How Do We Do It? Im Immunogram: : Quantifying A Patient’s Cancer- Immune Interaction Blank + Shumacher et al. Science 2016, Melero et al. Nat Rev 2015
Immune Checkpoints and Tumor Immune Microenvironment
Status of CTLA-4 Inhibition In GI Cancers
Nivolumab + Ipilimumab in MSS Metastatic CRC • Nivo 1 mg/kg + Ipi 3 mg/kg (Q3W x 4 doses) • Then Nivo 3 mg/kg (Q2W) • Nivo 1 mg/kg + Ipi 1 mg/kg Tolerable N = 10 • Third-line or (Q3W x 4 doses) later colon non- 1:1 • Then Nivo 3 mg/kg (Q2W) MSI-H • Nivo 3 mg/kg + Ipi 1 mg/kg (Q3W x 4 doses) ≥ 6 weeks • ECOG PS of 0-1 N ≥ 3 • Then Nivo 3 mg/kg (Q2W) N = 10 Nivolumab 1 mg/kg + Nivolumab 3 mg/kg + Ipilimumab 3 mg/kg Ipilimumab 1 mg/kg (n = 10) (n = 10) ORR, n (%) 1 (10) 0 Median PFS, mo (95% CI) 2.28 (0.62, 4.40) 1.31 (0.89, 1.71) Median OS, mo (95% CI) 11.53 (0.62, NE) 3.73 (1.22, 5.62) NE = not estimable Overman et al. ASCO 2016
Pancreas and Gastroesophageal Cancer 83% gastric 65 Pancreas Pts (12% PD-L1 high) • • 17% gastroesophageal Junction Durvalumab +/- Tremiliumab Ipilimumab 2017 Bang et al CCR; O’Reilly GI ASCO 2018
Ongoing CTLA-4 Phase II/III Trials Trial Phase Stage Arm1 Arm2 Arm3 Gastroesophageal CheckMate649 III IV Nivo/Ipi folfox/xelox nivo + folfox/xelox Checkmate648 III IV Nivo/Ipi Cis/5fu nivo +Cis/5FU NCT02340975 II IV Durva/Tremi Tremi Durva Neuroendocrine NCT02923934 II IV Nivo/Ipi NCT03420521 II IV Nivo/Ipi Pancreas NCT03190265 II IV Nivo/Ipi/GVAX Nivo/Ipi NCT03404960 II IV Nivo/Ipi/Niraparib NCT02879318 II IV Gem/Abrax/Durva/Tremi Gem/Abrax Colon Cancer The Niche Trial II I-III Nivo/Ipi/Celecoxib Nivo/Ipi NCT02870920 II IV Durva/Tremi BSC NCT03442569 II IV Pan/Nivo/Ipi NCT03271047 II IV Binimetinib/Nivo/Ipi Binimetinib/Nivo NCT03122509 II IV Durva/Tremi + Xrt or Abl NCT03007407 II IV Durva/Tremi + Xrt CT03202758 II IV Durva/Tremi/FOLFOX Biliary NCT03101566 II IV GemCis/Nivo Nivo/Ipi NCT03482102 II IV Dura/Tremi/Xrt IMMUNCHEC II IV Druva/Tremi/GemCis Durva/Tremi/Gem GemCis HCC HIMALAYA III CP-A Durva/Tremi Durva Sorafenib NCT03638141 II CP-A Durva/Tremi/TACE NCT03482102 II CP-A Dura/Tremi/Xrt
Combinations in dMMR CRC
dMMR CRC Nivolumab vs. Nivolumab/Ipilimumab: Checkmate 142 ORR 31% ≥12wk DCR 69% 12m PFS 48% Nivolumab, N=77 1.0 Progression-free Survival 0.8 Probability of 0.6 0.4 NIVO 3 mg/kg Q2W 0.2 NIVO 3 mg/kg + IPI 1 mg/kg Q3W Nivolumab/Ipilimumab, N=84 0.0 0 3 6 9 12 15 18 21 24 Time (Months ) No.at Risk NIVO 74 48 22 14 12 10 7 3 NIVO + IPI 84 65 35 17 13 8 1 0 ORR 55% ≥12wk DCR 79% 12m PFS 77% Overman et al. Lancet Onc 2017 and Overman et al. JCO 2018
Efficacy for NI Refractory vs. Frontline Cohorts Progression-free Survival Frontline Refractory Frontline Refractory Overall Survival Overman JCO 2018, Heinz-Lenz ESMO 2018
Treatment-Related Adverse Events for Nivolumab and Ipilimumab Frontline (N=45) Refractory (N =119 Nivolumab (3 mg/kg, Q3W) + Nivolumab (3 mg/kg, Q2W) ipilimumab (1 mg/kg, Q3W x 4 + ipilimumab (1 mg/kg, doses) then Nivolumab (3mg/kg, Q6W) Q2W) Patients, n (%) Any gr An grade Gr Grad ade 3–4 Any TRAE 35 (78) 7 (16) 49 (41) 32 (27) Any serious TRAE 6 (13) 3 (7) 27 (23) 24 (20) Any TRAE leading to 3 (7) 1 (2) 15 (13) 12 (10) discontinuation TRAEs reportined in >10% of pts 11 (24) 0 20 (17) 0 Puritis 8 (18) 1 (2) 16 (14) 1 (1) Hypothyroidism 7 (16) 1 (2) 21 (18) 2 (2) Asthenia 6 (13) 0 <10% 0 Anthralgia 5 (11) 0 <10% 0 Lipase increased 5 (11) 0 <10% 0 Nausea 5 (11) 0 13 (11) 2 (2) Rash <10% 1 (2) 26 (22) 2 (2) Diarrhea Overman JCO 2018, Heinz-Lenz ESMO 2018
Nivolumab/Ipilimumab post PD-1 progression 26 y/o with metastatic dMMR/MSI-high CRC treated with pembrolizumab x 4 • cycles from 5/2/2018 to 6/28/2018 with PET/CT progression • Treated with nivolumab (3 mg/kg) and ipilimumab (1 mg/kg) x 3 cycles 09/14/2018 06/26/2018 nivolumab (3 mg/kg) and ipilimumab (1 mg/kg) x 3 cycles Case per Alexis Leal, UColorado
NICHE Clinical Trial: dMMR cohort Chalabi et al ESMO 2018
Anti-PD1 for Locally Advanced dMMR CRC: Pathological Complete Response CASE 1 2/2018 12/2017 • Local lymph node recurrence Pembro x4 treated with irinotecan/cetuximab and then capox/panitumumab • In 2/2017 the patient was treated with pembrolizumab x 4 cycles CASE 2 9/7/17 7/2/17 Locally advanced primary • Nivo x 6 treated with FOLFOX with progression Then Nivolumab x 6 cycles •
Neoadjuvant Therapy for dMMR Primary Endpoint: pCR Surgery Additional pembrolizumab (~20pts) x6 cycles (18 weeks) Neoadjuvant pembrolizumab x2 cycles (6 weeks) Recommend surgical resection, Responding though option for continued therapy per Pt/MD High risk locally Secondary advanced dMMR Endpoint: resectable and Organ intact Continue therapy ctDNA at 3 weeks unresectable tumor survival at 1 for a total of one year (n=40) year (~10pts) Non- Surgical ctDNA pre-tx responding Statistics resection Primary Endpoint: pCR rate (20 patient cohort estimated 70% pCR provides 95% CI Planned opening 1/2019 of 50% to 90%)
MSI-high CRC and intrinsic resistance to PD1 Blockade Pre-treatment 2months later MLH-1 methylation Nivolumab x3 600 500 MDACC Cohort: 400 No HLA mutations StrongBind 300 in HLA A/B/C WeakBind 200 NoBind 100 0 S211 S266 S1696 S660 S767 S6 Non-Responders Responders
619 CRC cases from NHS and HPFS (173,230pts) HLA mutation - no./total no. (%) MSS POLE wild MSI-high POLE TIL type (N =418) mutant (N=177) TIL score 0 4/340 (1) 9/77 (12) TIL score 1 5/56 (9) 20/55 (36) TIL score 2+ 5/22 (23) 22/45 (49) 29% Giannakis et al. Cell Report 2016
Primary Resistance to PD-1 Blockade: HLA Processing and JAK1/2 Loss of Function Mutations MDACC Cohort: No HLA mutations in HLA A/B/C N=16 MSI-high CRCs treated with Pembrolizumab Shin + Ribas et al. Can Dis 2016
• 1535 melanoma and NSCLC patients treated with immune checkpoint therapy • Analyzed for HLA class I genotype Chowell et al. Science 2018
Combinations in pMMR CRC
Negative Phase III Trials in CRC: Imblaze 270 and MODUL Atezolizumab + Cobimetinib Atezolizumab + Bevacizumab Bendell et al. GI ESMO 2018, Grothey ESMO 2018
Trametinib and T-cell Recruitment CT26 (syngeneic mouse CRC model) TIL quantificaiton, day 7 Baseline Cobi+Atezo CD8 0.03% 1.72% Bendell et al. ASCO 2016 and GI ASCO 2018, Liu et al. CCR 2015
CRC Tumor Immune Infiltrate in Response to PD1/CTLA4 blockade Mandatory Approximately 4wks Approximately 4wks Liver Biopsy Metastatic Durvalumab 1500 mg+ CRC with Durvalumab Surgical tremelimumab 75mg 1500 mg IV Resectable Resection IV x1 Liver disease q4 wks x 4 (N = 35) Baseline CD 45 CD 3 CD4 PD1 ICOS CD8 On-treatment CD4 PD1 ICOS CD8 PI Overman
CRC Tumor Immune Infiltrate in Response to PD1/CTLA4 blockade 1 0 0 1 0 0 + ce lls B a s e lin e + n o n -T re g c e lls CD8 CD4 O n -T re a tm e n t 8 0 8 0 + C D 8 6 0 6 0 + C D 3 4 0 4 0 % o f C D 4 5 % o f C D 4 2 0 2 0 0 0 + + + + + + + + + + + + + + + + + + + + + + P D 1 + T im 3 C D 7 3 IC O S + IC O S 4 1 B B T im 3 G IT R O X 4 0 C T L A 4 L a g 3 1 + T im 3 3 S + IC O S B 3 R 0 4 3 D 7 4 A g O m T B D X I L a P i C 1 G T L C O T I 4 C P D 1 P D 1 1 1 D D P P T re g (C D 2 5 + F o x p 3 + ) 1 0 0 + c e lls 2 0 + cells 8 0 B a s e lin e 1 5 + F o x p 3 + C D 4 O n - T r e a t m e n t 1 0 6 0 + C D 3 + C D 2 5 5 % o f C D 4 5 4 0 0 % o f C D 4 2 0 -5 B a s e lin e O n -T re a tm e n t 0 + + + + + + + + + P D 1 C D 7 3 IC O S 4 1 B B T im 3 G IT R O X 4 0 C T L A 4 L a g 3
NICHE Trial Chalabi et al ESMO 2018
Macrophages in CRC - 23 primary MSI-high tumors - 45 primary MSS tumors - 34 untreated liver metastases PD-L1 CD3 CD8 PD1 DAPI CD68 AE1/AE3 Pancytokeratin Overman unpublished
CSF1R in Clinic Cannarile JITC 2017
Thank You Michael Overman moverman@mdanderson.org
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