Cu Curr rrent t and Em Emerging Rol ole of of Immune Ch - PowerPoint PPT Presentation

Cu Curr rrent t and Em Emerging Rol ole of of Immune Ch Checkpoi oint t Inhibitor ors s in th the Ma Management t of of mCR CRC Michael J Overman, MD Professor Department of Gastrointestinal Medical Oncology Division of Cancer Medicine The University of Texas MD Anderson Cancer Center Houston, Texas

Immune checkpoint inhibitors MSI-high disease • Sequencing and selection of treatment • Autoimmune toxicity • Treatment discontinuation Microsatellite-stable disease • Regorafenib/nivolumab

Immune checkpoint inhibitors MSI-high disease • Sequencing and selection of treatment • Autoimmune toxicity • Treatment discontinuation Microsatellite-stable disease • Regorafenib/nivolumab

Immune checkpoint inhibitors MSI-high disease • Sequencing and selection of treatment • Autoimmune toxicity • Treatment discontinuation Microsatellite-stable disease • Regorafenib/nivolumab

Cu Curr rrent t and Em Emerging Rol ole of of Immune Ch Checkpoi oint t Inhibitor ors s in th the Ma Management t of of mCR CRC Michael J Overman, MD Professor Department of Gastrointestinal Medical Oncology Division of Cancer Medicine The University of Texas MD Anderson Cancer Center Houston, Texas

Disclosures Array BioPharma Inc, AstraZeneca Pharmaceuticals LP, Bristol-Myers Squibb Company, CatalYm, Consulting Agreements Gritstone Oncology, Promega Corporation, Roche Laboratories Inc Apexigen, AstraZeneca Pharmaceuticals LP, Bristol- Contracted Research Myers Squibb Company, Merck, Nouscom, Roche Laboratories Inc.

dMMR or MSI-H CRC: Frameshift Neoantigens MSI-high N=141 N=619 CRC Giannakis et al. Cell Report 2016; Kloor et al. Trends in Cancer 2016; Chalmers et al. Genomic Medicine 2017; 2013 Kim et al. Cell

dMMR Testing Next- generation Sequencing Immunohisto- Polymerase Chain Reaction chemistry Complete loss of expression in one of the MMR proteins = MSI-high Intact Loss of expression expression Panel of 5 or more microsatellites with allelic shift in 2 (>30%) or more markers = MSI-high Latham + Stadler et al. JCO 2018

TCGA Analysis: 39 cancer types; 11,139 tumors TOP 15 Uterine Endometrial Carcinoma Colon Adenocarcinoma Stomach Adenocarcinoma Rectal Adenocarcinoma Adrenocortical Carcinoma Uterine Carcinosarcoma Cervical Wilms Tumor Mesothelioma Esophageal Carcinoma Breast Carcinoma Renal Clear Cell Ovarian Cholangiocarcinoma Thymoma Bonneville et al., JCO PO 2017

dMMR and Pembrolizumab Pembrolizumab ORR 53% 100 M M R -p ro fic ie n t C R C M M R -d e fic ie n t C R C Keynote 16 % C h a n g e fro m B a s e lin e S L D 50 0 ORR 34% ORR 32% -50 -100 Keynote 164 cohort B Keynote 158 Le et al. NEJM 2015; Le et al. Science 2017; Marabelle JCO 2019; Le ASCO 2018 a3514

dMMR and Nivolumab, Nivolumab/Ipilimumab Nivolumab and Nivolumab Ipilimumab ORR 55% ORR 31% Checkmate 142 Checkmate 142 Overman Lancet Onc 2017; Overman JCO 2018

Efficacy for NI Refractory vs Frontline Cohorts Progression-free Survival Frontline (n=45) (median 19.9m f/u) Frontline Refractory Refractory (n=119) Overall Survival Refractory Frontline Overman JCO 2018, Heinz-Lenz ESMO 2018 and GI ASCO 2020

NICHE Clinical Trial • Ipilimumab 1mg/kg Day1 • Nivolumab 3mg/kg Day 1 + 15 • Median duration from first tx to surgery 32 days (IQR: 28-35) Chalabi et al ESMO 2018

non-CRC dMMR Nivolumab Pembrolizumab Lee et al Science 2017, Pembrolizumab FDA label; Azad + Overman JCO 2019

Frontline Metastatic N=315 Enrollment Completed 2/2018 mFOLFOX6/Bevacizumab N=270 NRG- GI004/SWOG- KEYNOTE 177 mFOLFOX6/Bevacizumab R Atezolizumab 1610 MSI-high R MSI-high mCRC mCRC mFOLFOX6/Bevacizumab Pembrolizumab PI: Michael Overman and + Atezolizumab PI: Luis Diaz Caio Max S. Rocha Lima Stage III Adjuvant N=402 N=700 mFOLFOX6 + Atezolizumab (12 cycles) Avelumab x 6 months POLEM then Atezolizumab x 6 months Alliance 021502 Resected MSI-H R (ATOMIC) or POLE Stage III R Resected MSI-H mFOLFOX6 (12 cycles) observation post adjuvant tx Stage III PI: Tony Dhillon PI: Frank Sinicrope

Novel Phase IIs NCT03832569 N=48 NCT04082572 N=40 MSI-H Placebo High risk locally ctDNA+ post advanced dMMR curative Pembrolizumab x R Resection resectable or Pembrolizumab x 12m surgery/adjuv 6m unresectable ant tx Primary endpoint: Primary endpoint: Path CR tumor PI: Yelena Janjigian ctDNA clearance at 12m PI: Michael Overman

Are There Response Predictors ? Cohen et al. 2019 Jama Onc, Mandal et al. 2019 Science

Negative anti-PD1/PDL1 trials in MSS CRC CHECKMATE 142 (MSS CRC) KEYNOTE-028 (PDL-1+ CRC) Nivo 1/ Ipi 3 Nivo 3/ Ipi 1 (n = 10) (n = 10) ORR, n (%) 1 (10) 0 Median PFS 2.28 1.31 The only MSI-high pt was the one responder (95% CI), mo (0.62, 4.40) (0.89, 1.71) IMBLAZE 270 PFS Atezolizumab + Atezolizumab + Cobimetinib Bevacizumab Atezolizumab Bendell et al. GI ESMO 2018, Grothey ESMO 2018, O’Neil et al. ESMO 2015

High TMB as a Marker for Response in MSS CRC? CO.26 Durvalumab/Tremelimumab in MSS CRC TAPUR: Pembrolizumab in high TMB (≥9) CRC GuardantOMNI cfDNA panel: 500 genes, 2.1MB Number of pts 27 Median Age, yrs 59 (34-79) ≥3 Prior systemic 78 regimens, % DC rate, % (OR or 28 (16, 45) SD16+) (90% CI) OR rate, % (95%) 4 (0, 19) Median PFS, wks 9.3 (7.3, 16.1) (95% CI) 1 year OS, % 45.6 (22.2,66.3) 2.9% (95% CI) HTMB ranged from 9 to 54 Muts/Mb FoundationOne data Fabrizio J of Gastro Onc 2018; Chen ASCO 2019; Meriri et al. GI ASCO 2020 a133

Regorafenib and Nivolumab Regorafenib 80mg/d 21on/7off Nivolumab 3mg/kd q2wks Fukuoka et al. a2522 ASCO 2019

Treatment-Related Adverse Events for N/I Frontline (N=45) Refractory (N =119) Nivolumab (3 mg/kg, Q3W) + ipilimumab (1 Nivolumab (3 mg/kg, Q2W) mg/kg, Q3W x 4 doses) then Nivolumab + ipilimumab (1 mg/kg, (3mg/kg, Q2W) Q6W) Patients, n (%) Any grade Grade 3–4 Any grade Grade 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 reported in >10% of patients 20 (17) 0 Pruritus 11 (24) 0 16 (14) 1 (1) Hypothyroidism 8 (18) 1 (2) 21 (18) 2 (2) Asthenia 7 (16) 1 (2) <10% 0 Anthralgia 6 (13) 0 <10% 0 Lipase increased 5 (11) 0 <10% 0 Nausea 5 (11) 0 13 (11) 2 (2) Rash 5 (11) 0 26 (22) 2 (2) Diarrhea <10% 1 (2) Overman JCO 2018, Heinz-Lenz ESMO 2018