Immunotherapy for Colorectal Cancer

Michael Overman, MDMD Anderson Cancer Center

Gastrointestinal Medical Oncology

Immune Infiltrate and Prognosis in Primary CRC: Immunoscore

JCO 2006 Pages et al., NEJM 2005 Pages et al.

411 stage I and II CRC

Deficient mismatch repair (dMMR) or microsatellite instability-high (MSI-H)

Tejpar BJC 2009; Koopman BJC 2009

• Mutations in MMR (inherited) or loss of MMR by methylation (acquired) results in microsatellite instability (MSI)

– Increased duplication of tandem dinucleotide repeats (microsatellites)– Resulting increased mutations rate and higher risk of colon cancer– Unique clinicopathological features (lymphocytic infiltrate, Crohn’s-like

reaction, varigated histology, poor differentiation, right sided)

Anti-CD3

MSI-high CRC ≈3% HNPCC

≈12% sporadic

Universal Testing for HNPCC

1158 (31.5)

992(27)

2125 (57.8)

2394(65.2)

3671(100)

No Tested (%)

Moreira et al. JAMA 2012

Revised Bethesda criteria:1. CRC <50y/o2. Synchronous, metachronous CRC or other HNPCC cancer3. CRC with MSI-high histology in <60y/o4. CRC in ≥1 1st-degree relative with hnpcc cancer with 1 cancer diagnosed <50yrs5. CRC in ≥2 1st or 2nd-degree relatives with hnpcc cancer regardless of age

Jerusalem criteria: all CRC <70 years old

dMMR or MSI-H Have Better Outcomes (Prognostic Effect)

0102030405060708090

100

0 1 2 3 4 5Years

% D

isea

se F

ree

HR: 0.51 (0.29-0.89)p=0.009

Untreated (N=515)

MSI-H 80%MSS 56%

5 yr DFS

Sargent, et al. ASCO 2008 and ASCO 2014; Tejpar BJC 2009; Koopman BJC 2009

Stage MSI-H

II 22%

III 12%

IV 3.5%

5-year OS HR 95% OS P-value dMMR pMMR Stage II

Surgery alone (n=307) 90% 78% 0.27 0.10 - 0.74 0.011

Stage III

Surgery alone (n=264) 59% 54% 0.69 0.35 – 1.36 0.283

ACCENT database

14 phase III adjuvant studies

Metastatic MSI-high CRC

Retrospective reivew of 55 metastatic MSI-H pts from MDACC + Royal Melbourne

Hospital, Australia – 14 BRAF V600E (25%)

Goldstein + Overman AoO 2014

BRAF V600E

Somatic mutation frequencies CRC

Nature 2012Colon TCGA

CRC TCGA

Nature 2012Colon TCGA

Mutational Rates Across Tumors

Lawrence Nature 2013

Schreiber et al. Science 2011

Tumor Antigens:Differentiation (melanocyte differentiation antigens…)Overexpressed (HER-2…)Viral (HPV proteins…)Cancer/testis (MAGE, NY-ESO-1…)Mutational (p53…)

Immunity and Cancer

Matsushita A et al. Nature (2012); 482 (7385); 400-4

Immunogenic methylcholantherene-induced sarcoma cell

lines from Rag2-/- mice demonstrate ≈20% tumor

rate in naïve wildtype mice

Spectirn β-2 R913L mutation predicted and

cloned from TIL

MHC class I

Corbiere et al. Can Res 2012; Robbins J Exp Med 1996; Gaudin et al. J Immun 1999

Peptide In silico HLA nM affinity

A0201SLFEGIDFYT 11SLFEGIDIYT 18

A2403 SYLDSGIHS 5646SYLDSGIHF6

A0201ILDKVLVHP 16730ILDKVLVHL 42

BMS-936550RR: 0/18 CRC

TremelimumabRR: 1/45 CRC

(response duration 15m)

NivolumabRR: 0/19 CRC

NivolumabRR: 1/14 CRC

(response duration >21m, MSI-H pt)

Immune Checkpoint Agents in CRC

CMS 400 MSI-high CRC patient

Immune Escape Mechanisms in MSI-high CRC

Llosa et al. Cancer Discovery 2014

Invasive FrontStroma

TIL

Le DT, et al. NEJM. 2015: 372: 2509-20.

Pembrolizumab 10 mg/kg every 14 days

Pembrolizumab: Response Rate

Pembrolizumab: Additional Efficacy Endpoints

CEA response Progression-free survival

Immune Infiltrate

PDL1 expression

CD8 density

CD8 density and response

Ongoing Anti-PD1 or Anti-PDL1 Clinical Trials with MSI-high CRC Subsets

• NCT01876511: Phase 2 study of MK-3475 in patients with microsatellite unstable (MSI) tumors– MSI-high CRC, MSS CRC, MSI-high non-CRC

• NCT02060188: A study of nivolumab and nivolumab plus ipilimumab in recurrent and metastatic colon cancer (CheckMate 142)

– MSI-high CRC, MSS CRC

• NCT02227667: Evaluate the Efficacy of MEDI4736 in Immunological Subsets of Advanced Colorectal Cancer– MSI-high CRC, TIL high CRC

• NCT02404411: phase I/II study of PDR001 in patients with advanced malignancies– MSI-high CRC, other tumors

• NCT01633970: A phase 1b study of MPDL3280A (an engineered anti-PDL1 antibody) in combination with bevacizumab and/or chemotherapy in patients with advanced or metastatic solid tumors

– MSI-high CRC, other tumors

• A phase 1, open-label study of GSK3174998 administered alone and in combination with anticancer agents including Pembrolizumab in subjects with selected advanced solid tumors

– MSI-high CRC, other tumors

Immune checkpoint in melanoma

Ipilimumab in advanced melanoma

Wolchok et al. Lancet Oncol 2010

Nivolumab/Ipilimumab: Chort 2a (n=16):Nivolumab 3mg/kg + ipilimumab 1mg/kgClinical benefit of 73%G3/4 immmune Aes: 11

Wolchok et al. NEJM 2013

What about combo data in MSI-high CRC?

Nivolumab in frontline melanoma

Robert et al. NEJM 2014

CheckMate 142 Study Design

Responses seen

Limited activity

Overman, PI

Nivolumab single agentMSI-High CRC

Pre-rectal Xrt Pre-tx Restaging at 4months

Cap/xrt to rectum Nivolumab

Pre-tx Restaging at 4months

Nivolumab

Patient #1

Patient #2

Nivolumab single agentMSI-High Gastric Cancer

Pre-tx11/13/2013

Restaging6/10/2015

Conclusion

• Test for MSI-high– As universal testing approach for HNPCC– For prognostic relevance in stage II– For clinical trial options in metastatic patients

• Clinical trials of immune-checkpoints in MMR deficient (MSI-high) CRC should be engaged upon

• Targeting PD1/L1 and/or CTLA-4 have demonstrated limited to no activity in MMR proficient CRC