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.

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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

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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