Im Immuno-Onc Oncolo logy: gy: Be Beyon ond PD1 D1 Single - - PowerPoint PPT Presentation

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Im Immuno-Onc Oncolo logy: gy: Be Beyon ond PD1 D1 Single - - PowerPoint PPT Presentation

Aug 01, 2023 893 likes •1.22k views

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

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SLIDE 1

Im Immuno-Onc Oncolo logy: gy: Be Beyon

  • nd PD1

D1 Single Agent

Michael Overman, MD Professor Gastrointestinal Medical Oncology MD Anderson Cancer Center moverman@mdanderson.org

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SLIDE 2

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
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SLIDE 3

Anti-PD1 Therapy in 20 Tumor Types

(Pembrolizumab)

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SLIDE 4

Rationale Combinations: How Do We Do It?

Blank + Shumacher et al. Science 2016, Melero et al. Nat Rev 2015

Im Immunogram: : Quantifying A Patient’s Cancer- Immune Interaction

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SLIDE 5

Immune Checkpoints and Tumor Immune Microenvironment

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SLIDE 6

Status of CTLA-4 Inhibition In GI Cancers

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SLIDE 7

Nivolumab + Ipilimumab in MSS Metastatic CRC

Nivolumab 1 mg/kg + Ipilimumab 3 mg/kg (n = 10) Nivolumab 3 mg/kg + Ipilimumab 1 mg/kg (n = 10) ORR, n (%) 1 (10) 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

  • Nivo 1 mg/kg + Ipi 3 mg/kg (Q3W x 4 doses)
  • Then Nivo 3 mg/kg (Q2W)

N = 10

  • Third-line or

later colon non- MSI-H

  • ECOG PS of 0-1

Tolerable ≥ 6 weeks

  • Nivo 1 mg/kg + Ipi 1 mg/kg

(Q3W x 4 doses)

  • Then Nivo 3 mg/kg (Q2W)

N ≥ 3

  • Nivo 3 mg/kg + Ipi 1 mg/kg (Q3W x 4 doses)
  • Then Nivo 3 mg/kg (Q2W)

N = 10 1:1

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SLIDE 8

Pancreas and Gastroesophageal Cancer

2017 Bang et al CCR; O’Reilly GI ASCO 2018

  • 83% gastric
  • 17% gastroesophageal Junction

65 Pancreas Pts (12% PD-L1 high) Ipilimumab Durvalumab +/- Tremiliumab

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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

Ongoing CTLA-4 Phase II/III Trials

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SLIDE 10

Combinations in dMMR CRC

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SLIDE 11

Overman et al. Lancet Onc 2017 and Overman et al. JCO 2018

dMMR CRC Nivolumab vs. Nivolumab/Ipilimumab: Checkmate 142

ORR 55% ≥12wk DCR 79% 12m PFS 77% Nivolumab/Ipilimumab, N=84 ORR 31% ≥12wk DCR 69% 12m PFS 48% Nivolumab, N=77

Probability of Progression-free Survival

1.0 0.8 0.6 0.4 0.2 0.0 3 6 9 12 15 18 21 24 74 48 22 14 12 10 7 3

Time (Months)

No.at Risk NIVO

84 65 35 17 13 8 1

NIVO + IPI

NIVO 3 mg/kg Q2W NIVO 3 mg/kg + IPI 1 mg/kg Q3W

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SLIDE 12

Efficacy for NI Refractory vs. Frontline Cohorts

Frontline Refractory Progression-free Survival Overall Survival Frontline Refractory

Overman JCO 2018, Heinz-Lenz ESMO 2018

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SLIDE 13

Treatment-Related Adverse Events for Nivolumab and Ipilimumab

Frontline (N=45) Refractory (N =119

Nivolumab (3 mg/kg, Q2W) + ipilimumab (1 mg/kg, Q6W) Nivolumab (3 mg/kg, Q3W) + ipilimumab (1 mg/kg, Q3W x 4 doses) then Nivolumab (3mg/kg, Q2W)

Patients, n (%) An Any gr 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 discontinuation 3 (7) 1 (2) 15 (13) 12 (10) TRAEs reportined in >10% of pts Puritis Hypothyroidism Asthenia Anthralgia Lipase increased Nausea Rash Diarrhea 11 (24) 8 (18) 7 (16) 6 (13) 5 (11) 5 (11) 5 (11) <10% 1 (2) 1 (2) 1 (2) 20 (17) 16 (14) 21 (18) <10% <10% <10% 13 (11) 26 (22) 1 (1) 2 (2) 2 (2) 2 (2)

Overman JCO 2018, Heinz-Lenz ESMO 2018

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Nivolumab/Ipilimumab post PD-1 progression

09/14/2018 06/26/2018 nivolumab (3 mg/kg) and ipilimumab (1 mg/kg) x 3 cycles

  • 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

Case per Alexis Leal, UColorado

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NICHE Clinical Trial: dMMR cohort

Chalabi et al ESMO 2018

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Anti-PD1 for Locally Advanced dMMR CRC: Pathological Complete Response

  • Local lymph node recurrence

treated with irinotecan/cetuximab and then capox/panitumumab

  • In 2/2017 the patient was

treated with pembrolizumab x 4 cycles

12/2017 2/2018

Pembro x4 Nivo x 6

7/2/17 9/7/17

  • Locally advanced primary

treated with FOLFOX with progression

  • Then Nivolumab x 6 cycles

CASE 1 CASE 2

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SLIDE 17

Neoadjuvant Therapy for dMMR

High risk locally advanced dMMR resectable and unresectable tumor (n=40) Responding Non- responding Surgery Surgical resection Primary Endpoint: pCR (~20pts) Neoadjuvant pembrolizumab x2 cycles (6 weeks) Additional pembrolizumab x6 cycles (18 weeks) ctDNA pre-tx ctDNA at 3 weeks Recommend surgical resection, though option for continued therapy per Pt/MD Continue therapy for a total of one year Secondary Endpoint: Organ intact survival at 1 year (~10pts)

Statistics Primary Endpoint: pCR rate

(20 patient cohort estimated 70% pCR provides 95% CI

  • f 50% to 90%)

Planned opening 1/2019

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SLIDE 18

MSI-high CRC and intrinsic resistance to PD1 Blockade

S1696 S660 S767 S6

StrongBind WeakBind NoBind

100 200 300 400 500 600 S211 S266

Responders Non-Responders 2months later Pre-treatment MLH-1 methylation Nivolumab x3 MDACC Cohort: No HLA mutations in HLA A/B/C

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619 CRC cases from NHS and HPFS (173,230pts)

Giannakis et al. Cell Report 2016

TIL MSS POLE wild type (N =418) MSI-high POLE 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)

HLA mutation - no./total no. (%) 29%

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Primary Resistance to PD-1 Blockade:

HLA Processing and JAK1/2 Loss of Function Mutations

Shin + Ribas et al. Can Dis 2016

N=16 MSI-high CRCs treated with Pembrolizumab MDACC Cohort: No HLA mutations in HLA A/B/C

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SLIDE 21

Chowell et al. Science 2018

  • 1535 melanoma

and NSCLC patients treated with immune checkpoint therapy

  • Analyzed for HLA

class I genotype

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SLIDE 22

Combinations in pMMR CRC

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SLIDE 23

Negative Phase III Trials in CRC: Imblaze 270 and MODUL

Bendell et al. GI ESMO 2018, Grothey ESMO 2018

Atezolizumab + Cobimetinib Atezolizumab + Bevacizumab

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SLIDE 24

Trametinib and T-cell Recruitment

CT26 (syngeneic mouse CRC model)

TIL quantificaiton, day 7

Bendell et al. ASCO 2016 and GI ASCO 2018, Liu et al. CCR 2015

CD8 Baseline Cobi+Atezo

0.03% 1.72%

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SLIDE 25

CRC Tumor Immune Infiltrate in Response to PD1/CTLA4 blockade

Metastatic CRC with Resectable Liver disease (N = 35) Surgical Resection Durvalumab 1500 mg+ tremelimumab 75mg IV x1 Approximately 4wks Mandatory Liver Biopsy Approximately 4wks Durvalumab 1500 mg IV q4 wks x 4

Baseline On-treatment

CD 45 CD8 CD 3 PD1 PD1 ICOS ICOS CD8 CD4 CD4

PI Overman

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CRC Tumor Immune Infiltrate in Response to PD1/CTLA4 blockade

B a s e lin e O n -T re a tm e n t

  • 5

5 1 0 1 5 2 0

T re g (C D 2 5 +F o x p 3 +)

% o f C D 4 5

+ C D 3 + C D 4 + cells

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

+

2 0 4 0 6 0 8 0 1 0 0

% o f C D 4

+ C D 2 5 + F o x p 3 + c e lls

B a s e lin e O n - T r e a t m e n t

P D 1

+

P D 1

+T im 3 +

C D 7 3

+

I C O S

+

P D 1

+IC O S +

4 1 B B

+

T i m 3

+

G I T R

+

O X 4

+

C T L A 4

+

L a g 3

+

2 0 4 0 6 0 8 0 1 0 0

% o f C D 4 5

+ C D 3 + C D 8 + ce lls

P D 1

+

P D 1

+T im 3 +

C D 7 3

+

IC O S

+

P D 1

+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

+

2 0 4 0 6 0 8 0 1 0 0

% o f C D 4

+ n o n -T re g c e lls

B a s e lin e O n -T re a tm e n t

CD8 CD4

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SLIDE 27

NICHE Trial

Chalabi et al ESMO 2018

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Macrophages in CRC

  • 23 primary MSI-high tumors
  • 45 primary MSS tumors
  • 34 untreated liver metastases

Overman unpublished

PD-L1 CD3 CD8 PD1 CD68 DAPI AE1/AE3 Pancytokeratin

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CSF1R in Clinic

Cannarile JITC 2017

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Thank You Michael Overman moverman@mdanderson.org

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