treatment of msi-h/dmmr mcrc - gi connect … · case presentation 18 aes, adverse events; ctla-4:...
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TREATMENT OF MSI-H/DMMR mCRC
Jonathan Mizrahi, MDMD Anderson Cancer Center, Houston, TX
October 18 th, 2019
DISCLAIMER
Dr. Jonathan Mizrahi does not have any relevant financial relationship to disclose.
2
CASE
56 year old female with no significant past medical history presents with recently diagnosed with stage IV adenocarcinoma of the ascending colon with multiple liver and lung metastases
ECOG Performance Status: 1
Review of Systems: 10 lb weight loss in past 4 months, mild fatigue
Family History: No family history of GI, gyn, GU malignancies
Physical Exam: Unremarkable
Labs: Hemoglobin 11.9 g/dL; WBC and platelet counts within normal limits; BMP and liver function tests within normal limits
3BMP, basic metabolic panel; ECOG, Eastern Co-operative Oncology Group; GI, gastrointestinal; GU, genitourinary; gyn, gynaecological; WBC, white blood cell
CASE (CONTINUED)
56 year old female with no significant past medical history presents with recently diagnosed with stage IV adenocarcinoma of the ascending colon with multiple liver and lung metastases
Biopsy from liver metastasis:
• Moderately differentiated adenocarcinoma
• Loss of MLH1 and PMS2 proteins by immunohistochemistry
Molecular results:
• BRAF V600E mutation detected
• KRAS, NRAS wildtype
4BRAF, B-Raf proto-oncogene, serine/threonine kinase ; MLH1, MutL homolog 1; PMS2, PMS1 Homolog 2, mismatch repair system component
HEREDITARY CANCER SCREENING: CRITERIA TO EVALUATE FOR LYNCH SYNDROME
• Known Lynch syndrome in family
• Diagnosis of endometrial or CRC < 50 y/o
• Another Lynch syndrome–related cancer:
– CRC, endometrial, gastric, ovarian, pancreas, upper urinary tract, GBM, biliary tract, small intestine
• dMMR/MSI-H endometrial or CRC
• Family history suggestive of Lynch syndrome
Because of her dMMR status, should she be evaluated for a hereditary cancer syndrome, such as Lynch syndrome?
5CRC, colorectal cancer; GBM, glioblastoma; dMMR, deficient mismatch repair; MSI-H, microsatellite instability high
6
QUESTIONS
• After initial partial response to FOLFOX + bevacizumab followed by stable disease for 9 months, the patient progresses with new and enlarging liver metastases
• Labs, including liver function tests, are still within normal limits
• Her ECOG PS remains at 1
What should we choose as second-line therapy?
7ECOG PS, Eastern Cancer Co-operative Group Performance Status; FOLFOX, folinic acid, fluorouracil and oxaliplatin
NCCN GUIDELINES FOR MSI-H/DMMR CRC
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BRAF, B-Raf proto-oncogene, serine/threonine kinase; CRC, colorectal cancer; dMMR, deficient mismatch repair; FOLFIRI, irinotecan, fluorouracil and folinic acid; KRAS, Kirsten rat sarcoma viral oncogene homolog; MSI-H, micro instability high; NCCN, National Comprehensive Cancer Network; NRAS, neuroblastoma RAS viral oncogene; WT, wild-type
Source: NCCN guidelines Version 2.2019 Colon Cancer
CASE (CONTINUED)
• She was started on nivolumab 240 mg IV every 14 days
• She had a partial response followed by stable disease x 12 months
• Treatment is ongoing with excellent tolerance
9IV, intravenous
TREATMENT OF MSI-H/DMMRMETASTATIC COLORECTAL CANCER
HAO XIE, MD, PHDMayo Clinic College of Medicine, MN
October 18 th, 2019
DISCLOSURE
Dr. Xie Hao does not have any relevant financial relationship to disclose.
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BRAF, B-Raf proto-oncogene, serine/threonine kinase; ECOG, Eastern Cooperative Oncology Group; HER2, human epidermal growth factor receptor 2; IHC, immunohistochemistry; mCRC, metastatic colorectal cancer; MLH1, mutL homolog 1; MSH, mutS protein homolog; PCR, polymerase chain reaction; PMS2, PMS1 homolog 2
• A 57-year-old lady presents with stage IV colon adenocarcinoma (mCRC)– 10 cm cecal mass
– multiple mesenteric implants
– bulky adenopathy at porta hepatis
• Molecular study– IHC: loss of MLH1 and PMS2; retained MSH2
and MSH6
– PCR: not performed
– BRAF V600E, RAS wild-type, no HER2 amplification
• Not surgically resectable
• ECOG performance status 1
• No family history of cancer
CASE PRESENTATION
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13Innocenti, et al. J Clin Oncol. 2019;37(14):1217-1227; Zhang, et al. World J Gastrointest Oncol. 2013;5(2):12-19; Salem, et al. ASCO GI 2017; Abstract 530; Hewish, et al. Nat Rev Clin Oncol. 2010;7(4):197-208.
• 6% of mCRC is MSI-H/dMMR in CALGB/SWOG 80405 study
• MSI-H and tumor mutation burden are highly correlated.
• MSI-H/dMMR CRC: proximal anatomical location, mucinous, signet-ring and medullary features, lymphocytic infiltration, and poorly differentiated, and large
MSI-H/DMMR MCRC
Test HNPCC Sporadic
IHC Loss of MLH1, MSH2, MSH6 Loss of MLH1/PMS2
PCR Positive Positive
hMLH1 methylation Negative Positive
BRAF V600E mutation Negative Positive
Germline mutation in MMR genes Positive Negative
BRAF, B-Raf proto-oncogene, serine/threonine kinase; CALGB, Cancer and Leukemia Group B; dMMR, mismatch repair deficient; hMLH1, human mutL homolog 1; HNPCC, hereditary nonpolyposis colorectal cancer; IHC, immunohistochemistry; mCRC, metastatic colorectal cancer; MLH1, mutL homolog 1; MMR, mismatch repair; MSH, mutS protein homol; MSI-H, microsatellite instability high; PCR, polymerase chain reaction; SWOG, Southwest Oncology Group
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dMMR, mismatch repair deficient; mCRC, metastatic colorectal cancer; MSI-H, microsatellite instability high; ORR, objective response rate; PFS, progression-free survival
Le, et al. N Eng J Med. 2015;372(26):2509-2520; Le, et al. Science. 2017;357(6349):409-413; Overman, et al. Lancet Oncol. 2017;18(9):1182-1191; Overman, et al. JCO. 2018;36(8):773-779
• For MSI-H/dMMR mCRC progressed after fluoropyrimidine, irinotecan, and oxaliplatin
• Pembrolizumab
– ORR: 53%, 2-year PFS rate: 53%
• Nivolumab
– ORR: 31.1%, 1-year PFS rate: 50%
• Nivolumab + ipilimumab
– ORR: 55%, 1-year PFS rate: 71%
APPROVED IMMUNE CHECKPOINT INHIBITORS (ICI) IN mCRC
15dMMR, mismatch repair deficient; MSI-H, microsatellite instability high
Source: Le, et al. N Eng J Med. 2015;372(26):2509-2520. (each bar represents one patient)
CLINICAL RESPONSES OF MSI-H/DMMRTUMORS TO PEMBROLIZUMAB
16dMMR, mismatch repair deficient; MSI-H, microsatellite instability high
Source: Overman, et al. JCO. 2018;36(8):773-779.
CLINICAL RESPONSES OF MSI-H/DMMRTUMORS TO NIVOLUMAB + IPILIMUMAB
17CT, computerized tomography; irAEs, immune-related adverse events
• Pembrolizumab 200 mg every 3 weeks was started
• CT scan after 12 weeks
– Complete resolution of bulky adenopathy at porta hepatis
– Partial response elsewhere
• Completion of 20-month pembrolizumab
– Stable disease
– No irAEs
CASE PRESENTATION
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AEs, adverse events; CTLA-4: cytotoxic T-lymphocyte-associated protein 4; EGFR, epidermal growth factor receptor; ICI, immune checkpoint inibitors; PD1, programmed cell death-1
Innocenti F, et al. J Clin Oncol. 2019;37(14):1217-1227. Clinicaltrials.gov identifier: NCT02563002
• Time to introduce ICI– First line: better AEs, durable response
– Second line or later: no first line data
• No study of ICI in combination with chemotherapy
• Treatment duration– Stop treatment after disease control for 2 years
– Possibly add ipilimumab (monoclonal antibody CTLA-4) after failure of anti-PD1 alone
• Treatment consideration after ICI– MSI-H benefit more from bevacizumab compared to anti-EGFR (cetuximab)
• Ongoing trials– KEYNOTE-177: pembrolizumab vs. chemotherapy
DISCUSSION
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