immunotherapy in metastatic colorectal cancer … · unresectable or metastatic colorectal cancer...
TRANSCRIPT
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IMMUNOTHERAPY IN METASTATIC COLORECTAL CANCER (mCRC)
SHASHANK CINGAM, MDUNM Comprehensive Cancer Center,
Albuquerque, NM
October 18 th, 2019
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DISCLAIMER
Dr. Shashank Cingam does not have any relevant financial relationship to disclose.
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mCRC, metastatic colorectal cancer; SEER, Surveillance, Epidemiology, and End Results; 1American Cancer Society. Key statistics for colorectal cancer. https://www.cancer.org/cancer/colon-rectal-cancer/about/key-statistics.html. Accessed November 10, 2019; 2Crooke H, et al J Clin Oncol. 2018;36(4)_suppl:587-587
• Third leading cause of cancer related mortality in both men/women in US1
• Approximate 51,020 deaths during 20191
• Poor 5 year survival with mCRC (SEER data –14.2%- <65 years ; 7.4% ->65 years )2
• Paucity of targetable / actionable mutations
• Limited options after failure of standard chemotherapy
WHY THE NEED FOR NEWER/ INVESTIGATIONAL THERAPIES IN mCRC?
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A2aR, adenosine 2a receptor; A2bR, adenosine 2b receptor; PD-1, Programmed cell death protein 1; PD-L1, Programmed death-ligand 1; IDO1, Indoleamine-pyrrole 2,3-dioxygenase; LAG3, Lymphocyte-activation gene 3; TLR-9, Toll-like receptor 9
• Immune checkpoint inhibitors (PD-1/PD-L1 inhibitors, CTLA-4 inhibitors, IDO1 inhibitors, anti-LAG3 antibodies)
• Immune stimulatory (anti-OX40 agonists, TLR-9 agonists)
• Vaccines
• Oncolytic viruses
• Other agents (dual A2aR/A2bR antagonists )
IMMUNOTHERAPY
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mCRC, metastatic colorectal cancer; PD-1, Programmed cell death protein 1; PD-L1, Programmed death-ligand 1;O’Neil BH et al. PLoS One 2017;12(12):e0189848.; Le DT et al. New England Journal of Medicine 2015;372(26):2509-20.; Overman MJ et al. The Lancet Oncology 2017;18(9):1182-91.
• Available agents for commercial use:
– PD-1 inhibitors Nivolumab, Pembrolizumab; Cemiplimab
– PD-L1 inhibitors Atezolizumab, Durvalumab, Avelumab
• Poor response in Nivolumab and Pembrolizumab in unselected mCRC patients in Phase 1 studies
• Better responses in patients with Microsatellite Instability-High (MSI-H) or Mismatch Repair Deficient (dMMR)
CHECKPOINT INHIBITORS
NCT01876511: clinical responses to Pembrolizumab treatment
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ONGOING mCRC PD-1/PD-L1 INHIBITOR TRIALS AS MONOTHERAPY/ ADJUVANT SETTING
Title Identifier Phase MMR/ MSI status
Therapy Line Treatment Arms
Study of Pembrolizumab (MK-3475) vs Standard Therapy in Participants With Microsatellite Instability-High (MSI-H) or Mismatch Repair Deficient (dMMR) Stage IV Colorectal Carcinoma (KEYNOTE-177)
NCT02563002 Phase 3 dMMR Refractory PembroSOC
Study of Pembrolizumab (MK-3475) as Monotherapy in Participants With Previously-Treated Locally Advanced Unresectable or Metastatic Colorectal Cancer (KEYNOTE-164)
NCT02460198 Phase 2 dMMR Refractory PembroSOC
Phase II Study to Evaluate the Efficacy of MEDI4736 (Durvalumab) in Immunological Subsets of Advanced Colorectal Cancer
NCT02227667 Phase 2 dMMR Refractory Durvalumab
Avelumab Plus 5-FU Based Chemotherapy as Adjuvant Treatment for Stage 3 MSI-High or POLE Mutant Colon Cancer (POLEM)
NCT03827044 Phase 3 dMMR First Line/ Adjuvant setting
Adjuvant AvelumabNo intervention
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5-FU, Fluorouracil; dMMR, Mismatch Repair Deficient; MSI-H, Microsatellite Instability-High; PD-1, Programmed cell death protein 1; PD-L1, Programmed death-ligand 1; Pembro, Pembrolizumab; SOC, standard of care
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RESISTANCE MECHANISMS TO IMMUNE CHECKPOINT INHIBITORS
APC, antigen presenting cell; β2M, β2 microglobulin; dMMR, Mismatch Repair Deficient; MHC, Major histocompatibility complex; SoC, standard of care; TCR; T cell receptor; TNFSF, Tumor necrosis factor superfamily
Adapted Illustration from Jenkins RW et al. British journal of cancer. 2018;118(1):9.
FORMATION OF TUMOR REACTIVE CELLS (1/2)
• Resistance 1. Lack of suitable neoantigen2. Impaired intra-tumoural immune
infiltration
• Promising solutions• promote immunogenic cell death
- Chemotherapy and Radiotherapy- Targeted therapy- Ablative therapies- TRAIL-R agonists and TNFSF
NCT03414983
NCT01633970
NCT02997228
NCT02713373
NCT02992912
NCT02060188
NCT03802747
NCT02437136
NCT02860546
NCT02484404
NCT02997228 Phase 3 dMMR First Line mFOLFOX+ BevacizumabAtezolizumabmFOLFOX+Bevacizumab+Atezolizumab
NCT03414983 Phase 2/3 – First Line FOLFOX + Bevacizumab (SoC)FOLFOX + Bevacizumab + Nivolumab
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REGORAFENIB + NIVOLUMAB – (PHASE IB):DESIGN AND ENDPOINTS
• Background: TAMs may contribute to resistance to anti-PD-1/PD-L1 inhibitors. Regorafenib, a broad spectrum tyrosine kinase inhibitor, reduced TAMs in tumormodels1
• REGONIVO: Open-label, dose-finding and dose-expansion Phase 1b trial
• 50 previously treated patients enrolled with advanced gastric cancer (n=25) or advanced CRC (n=25)
• Regorafenib (80 to 160 mg) was administered once daily for 3 weeks on/1 weekoff, with nivolumab (3 mg/kg) given every 2 weeks
• Primary endpoint: dose-limiting toxicity during cycle one (4 weeks) to estimate the maximum tolerated dose and the recommended dose
CRC, colorectal cancer; PD-1, Programmed cell death protein 1; PD-L1, Programmed death-ligand 1; TAMs, tumor-associated macrophages 1Abou-Elkacem L, et al. Mol Cancer Ther. 2013 Jul;12(7):1322-31; Fukuoka S, et al. J Clin Oncol 2019; 37(Suppl): Abstract 2522; ClinicalTrials.govregistration number: NCT03406871
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REGORAFENIB + NIVOLUMAB – (PHASE IB): RESULTS
• Manageable safety and encouraging anti-tumor activity
• These results warrant further investigation of this combination in a larger cohort
CRC, colorectal cancer; GC, gastric cancer; MSI-H, microsatellite instability-high; MSS; microsatellite stable; ORR, objective response rate; PD, progressive disease; PD-L1, Programmed death-ligand 1; PR; partial response; SD, stable disease; WT, wild-typeFukuoka S, et al. J Clin Oncol 2019; 37(Suppl): Abstract 2522; ClinicalTrials.gov registration number: NCT03406871
Progression-free survival in all patients (A) and in patients with CRC and GC (B)
A B
Waterfall plot of best tumorshrinkage in patients with CRC
• 77-year-old mal with RAS WT metastatic rectum cancer• Disease progression after FOLFIRI+Bevacizumab, FOLFOX,
Irinotecan+cetuximab, trifluridine/tipiracil• MSS, PD-L-1 CPS 0
Anti-tumor activity
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RESISTANCE MECHANISMS TO IMMUNE CHECKPOINT INHIBITORS
APC, antigen presenting cell; β2M, β2 microglobulin; CD-40, Cluster of differentiation 40; GM-CSF, Granulocyte-macrophage colony-stimulating factor; MHC, Major histocompatibility complex; TCR; T cell receptor
Illustration from Jenkins RW et al. British journal of cancer. 2018;118(1):9.
• Resistance• Impaired processing and/or
presentation of tumor antigens
• Promising solutions • Enhance APC/APC function
and adjuvanticity- Vaccine therapy- Immune adjuvants- Toll like receptors- Interferon- GM-CSF- CD-40
NCT02834052
NCT02886897
FORMATION OF TUMOR REACTIVE CELLS (2/2)
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RESISTANCE MECHANISMS TO IMMUNE CHECKPOINT INHIBITORS
Arg1, arginase 1; β2M, β2 microglobulin; CTLA4, Cytotoxic T lymphocyte antigen 4; IDO, indolamine dioxygenase; INF, interferon; JAK1, janus kinase 1; LAG-3, Lymphocyte-activation gene 3; M2 M⌽, M2 macrophage; MHC, Major histocompatibility complex; MDSC, myeloid derived suppressor cell; PD-1, Programmed cell death protein 1; PD-L1, Programmeddeath-ligand 1; PI3K, Phosphoinositide 3-kinases; PGE2, ; TCR; T cell receptor; TIM3, T-cell immunoglobulin and mucin-domain containing-3; Tregs, regulatory T cells
Illustration from Jenkins RW et al. British journal of cancer. 2018;118(1):9.
• Resistance4. Impaired IFNɣ signaling5. Metabolic/ Inflammatory mediators6. Immune suppressive cells7. Alternate Immune Checkpoints
• Promising solutions– IDO1 Inhibitors (indoximod, epacadostat)– Anti- LAG 3 antibodies– TIM3 inhibitors– PI3K inhibitors
NCT02327078
NCT02060188ACTIVATION OF EFFECTOR T-CELL FUNCTION
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RESISTANCE MECHANISMS TO IMMUNE CHECKPOINT INHIBITORS
CD4+, cluster of differentiation 4 positive cell; CD8+, cluster of differentiation 8 positive T cell; HDAC, Histone deacetylases; MHC, Major histocompatibilitycomplex; PD-1, Programmed cell death protein 1; TCR; T cell receptor;
Illustration from Jenkins RW et al. British journal of cancer. 2018;118(1):9.
FORMATION OF EFFECTOR OF MEMORY T-CELLS
• Resistance
8. Severe T Cell exhaustion9. T- Cell epigenetic changes
• Promising solutions
- Hypomethylating agents- HDAC inhibitors
NCT02260440
NCT02437136
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THE CLINICAL TRIAL LANDSCAPE FOR PD1/PD-L1 IMMUNE CHECKPOINT INHIBITORS
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PD-1, Programmed cell death protein 1; PD-L1, Programmed death-ligand 1
Illustration from: Tang J et al. Nat Rev Drug Discov. 2018;17(12):854-855
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CD134, ; MGN1703, ; OS, overall survival; PFS, progression-free survival; TLR-9, Toll-like receptor 9 1Aspeslagh A, et al. European Journal of cancer, 2016; 52:50-66; 2Schmoll HJ, et al. J Cancer Res Clin Oncol. 2014 Sep;140(9):1615-24; 3Press release MOLOGEN AG, Berlin; August 5, 2019. https://otp.tools.investis.com/clients/de/mologen_ag/dgap/dgap_1/dgap-story.aspx?cid=2294&culture=en-US&newsid=13540 AccessedAugust 9, 2019.
• OX40 (CD134), a co-stimulatory molecule that can be expressed by activated immune cells1
– Several anti-OX40 agonistic monoclonal antibodies are currently tested in early phase cancer clinical trials
• TLR 9 agonist (MGN1703) was evaluated in IMPACT2 (Phase II) and IMPALA3 (Phase III).
• Phase II data showed improvement in PFS and OS2 but did not translate into a successful outcome in the Phase III study3
IMMUNE STIMULATORY (ANTI-OX40 AGONISTS, TOLL LIKE RECEPTOR-9 AGONISTS)
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CEA, Carcinoembryonic antigen; DC, dendritic cell; mCRC, metastatic colorectal cancer; VEGF, Vascular endothelial growth factor 1Hazama S, et al. Journal of translational medicine. 2014;12:108; 2Caballero-Baños M, et al. Eur J Cancer. 2016;64:167-74; 3Kaufman HL, et al. Clin Cancer Res. 2008;14(15):4843-9; Inoda S, et al. Experimental and molecular pathology. 2011;90(1):55-60; Morse MA Clinical Cancer Research. 1999 Jun 1;5(6):1331-8
• Activates a host’s immune response against cancer
• Autologous, DC, peptide, and viral vectors
• Phase II clinical trials evaluating five human leukocyte antigen (HLA)-A*2402-restricted peptides (three from onco-antigens and two from VEGF receptors)1, an autologous tumor lysate dendritic cell vaccine2 and non-replicating canary pox virus (ALVAC) expressing CEA and B lymphocyte antigen B7 (B7-1; CD80) (ALVAC-CEA/B7-1)3 vaccine showed no-limited benefit
• Currently, no approved vaccines are available for patients with mCRC
VACCINES
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16mCRC, metastatic colorectal cancer1Geevarghese SK, et al Human gene therapy. 2010;21(9):1119-28; Wrobel P & Ahmed S. 2019;34(1):13-25.
• Selectively infect and damage malignant cells without affecting the normal tissue
• A phase I/II - genetically engineered oncolytic herpes simplex virus, NV1020, in patients with previously treated mCRC. Approximately two thirds of patients had disease control with a 1-year survival rate of 47.2%1
• Currently, no approved oncolytic therapies are available for patients with mCRC
ONCOLYTIC VIRUSES
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• Immunotherapy has the potential to become the new standard of care in the management of mCRC
• Checkpoint inhibitors have clearly shown benefit in MSI- H tumors and are FDA approved in MSI-H mCRC
• Overcoming the resistance of ICI’s is the most exciting avenue of research in mCRC
• Better biomarkers are needed to predict response with ICIs
• Other immunotherapy agents are in early research. None approved in mCRC
CONCLUSIONS
FDA; Food and Drug Administration; ICI, immune checkpoint inhibitor; mCRC, metastatic colorectal cancer; MSI-H, Microsatellite Instability-High
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• Dr. Heloisa Soares MD PhD, UNM Comprehensive Cancer Center
• GI CONNECT Scientific Committee https://giconnect.info/masterclass/the-scientific-commitee/
ACKNOWLEDGMENTS
GI; gastrointestinal; UNM; University of New Mexico
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APPENDIX- COMBINATION STRATEGIES WITH PD-1/PD-L1 INHIBITORS: LIST OF CLINICAL TRIALS (1/2)
Title Identifier Phase MMR/MSI Status
Therapy Line
Treatment Arms
Nivolumab, or Nivolumab Combinations in Recurrent and Metastatic Microsatellite High (MSI-H) and Non-MSI-H Colon Cancer
NCT02060188 Phase 2 All mCRC Refractory Nivo+ IpiNivo+Ipi + cobimetinibNivo+ anti- LAG 3 antibodyNivo+ daratumumab
An Investigational Immunotherapy Study of Nivolumab With Standard of Care Therapy vs Standard of Care Therapy for First-Line Treatment of Colorectal Cancer That Has Spread (CheckMate 9X8)
NCT03414983 Phase 2/3 – First Line First lineFOLFOX + bevacizumabFOLFOX + bevacizumab+ nivolumab
Combination Chemotherapy, Bevacizumab, and/or Atezolizumab in Treating Patients With Deficient DNA Mismatch Repair Metastatic Colorectal Cancer
NCT02997228 Phase 3 dMMR First Line mFOLFOX+ bevacizumabAtezolizumabmFOLFOX+bevacizumab
A Study of Atezolizumab Administered in Combination with Bevacizumab and/or With Chemotherapy in Participants With Locally Advanced or Metastatic Solid Tumors
NCT01633970 Phase 1 – Refractory Atezolizumab + bevacizumabAtezolizumab + bevacizumab + FOLFOXAtezolizumab + carboplatin + paclitaxelAtezolizumab + carboplatin + pemetrexedAtezolizumab + carboplatin + nab-paclitaxelAtezolizumab + nab-paclitaxel
Cetuximab and Pembrolizumab in Treating Patients With Colorectal Cancer That is Metastatic or Cannot Be Removed by Surgery
NCT02713373 Phase Ib/II – Second Line
Cetuximab+ pembrolizumab
Efficacy of the Anti-PD-L1 Antibody Atezolizumab (MPDL3280A) Administered With Stereotactic Ablative Radiotherapy (SABR) in Patients With Metastatic Tumours
NCT02992912 Phase 2 – Refractory Atezolizumab+ hypofractionated SABR will be delivered at a dose of45 Gy in 3 fractions of 15 Gy
MEDI4736 in Combination With Olaparib and/or Cediranib for Advanced Solid Tumors and Advanced or Recurrent Ovarian, Triple Negative Breast, Lung, Prostate and Colorectal Cancers
NCT02484404 Phase I/ II pMMR/MSS Refractory Durvalumab + olaparib + cediranib
Pembrolizumab (MK-3475) and Poly-ICLC in Patients With Metastatic Mismatch Repair-proficient (MRP) Colon Cancer
NCT02834052 Phase I/II pMMR/MSS Refractory Pembrolizumab + poly-ICLC
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dMMR, deficient expression of DNA mismatch repair gene; Ipi, Ipilimumab; FOLFOX, folinic acid, fluorouracil and oxaliplatin; Gy, gray; LAG-3, Lymphocyte-activation gene 3; MSI-H, microsatellite instability-high; MSS, microsatellite stable; Nivo, Nivolumab; PD-1, Programmed cell death protein 1; PD-L1, Programmed death-ligand 1;pMMR, Proficient expression of DNA mismatch repair gene; SABR, Stereotactic ablative radiotherapy
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Title Identifier Phase MMR/MSI Status
Therapy Line
Treatment Arms
A Study of Combinations of D-CIK Immunotherapy And Anti-PD-1 In Refractory Solid Tumors
NCT02886897 Phase 1/2 – Refractory D-CIK and anti-PD-1 antibody
Immunotherapy Combined With Y-90 and Stereotactic Body Radiation Therapy (SBRT) for Colorectal Liver Metastases
NCT03802747 Phase 1 – Durvalumab + Y-90 + SBRTDurvalumab and tremelimumab + Y-90 + SBRT
Ph1b/2 Dose-Escalation Study of Entinostat With Pembrolizumab in NSCLC With Expansion Cohorts in NSCLC, Melanoma, and Colorectal Cancer
NCT02437136 Phase 1 – Refractory Pembrolizumab + entinostat
Regorafenib and Nivolumab Simultaneous Combination Therapy for Advanced and Metastatic Solid Tumors (REGONIVO)
NCT03406871 Phase 1/2 dMMR/MSS Refractory Nivolumab + regorafenib
A Study of the Safety, Tolerability, and Efficacy of Epacadostat Administered inCombination With Nivolumab in Select Advanced Cancers
NCT02327078 Phase 1/2 – Refractory Nivolumab + epacadostatNivolumab + epacadostat + Chemo
A Dose Escalation and Cohort Expansion Study of Anti-CD27 (Varlilumab) and Anti-PD-1 (Nivolumab) in Advanced Refractory Solid Tumors
NCT02335918 Phase 1 – Refractory varlilumab + nivolumab
Pembrolizumab (MK-3475) in Combination With Azacitidine in Subjects With Chemo-refractory Metastatic Colorectal Cancer
NCT02260440 Phase 2 – Refractory Pembrolizumab + azacitidine
A Phase 2 Study With Safety Lead-in, Evaluating TAS-102 Plus Nivolumab in Patients With Microsatellite Stable Refractory Metastatic Colorectal Cancer
NCT02860546 Phase 2 pMMR/MSS Refractory TAS-102 (Lonsurf) + nivolumab
Dual Immune Checkpoint Blockade With Durvalumab Plus TremelimumabFollowing Palliative Hypofractionated Radiation in Patients With Metastatic Colorectal Cancer Progressing on Chemotherapy
NCT03007407 Phase 2 pMMR/MSS Refractory Radiation + durvalumab (MEDI4736) +tremelimumab
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Chemo, chemotherapy; D-CIK, dendritic and cytokine-induced killer cell; dMMR, deficient expression of DNA mismatch repair gene; MSS, microsatellite stable; NSCLC, Non-Small Cell Lung Cancer; PD-1, Programmed cell death protein 1; PD-L1, Programmed death-ligand 1; SRBT, Stereotactic Body Radiation Therapy; Y-90, yttrium-90
APPENDIX- COMBINATION STRATEGIES WITH PD-1/PD-L1 INHIBITORS: LIST OF CLINICAL TRIALS (2/2)
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IMMUNOTHERAPY IN THE TREATMENTOF METASTATIC COLORECTAL CANCER
Sakti Chakrabarti, MDMayo Clinic, Rochester, MN
October 18 th, 2019
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DISCLOSURE
Dr. Sakti Chakrabarti does not have any relevant financial relationship to disclose.
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October, 2016:
• 40 year old Caucasian man presented with abdominal pain and anemia
• Colonoscopy- Partially obstructing ascending colon mass
• Biopsy (colon mass): Adenocarcinoma, loss of MSH6
• Family history of colon/endometrial cancer (subsequent work up confirmed Lynch syndrome)
• Staging scans: Solitary liver metastasis (5.2 cm) in segment 5/6
• CEA at baseline 3.2 ug/L
Early November, 2016
• Loop ileostomy to relieve obstructive symptoms
CASE PRESENTATION
CEA, carcinoembryonic antigen; MHS6, MutS homolog 6
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BASELINE POST NEO-ADJUVANT CTX
5.2 CM4.8 CM
AFTER 3 MONTHS (NOVEMBER, 2016–JANUARY, 2017) OF NEO-ADJUVANT FOLFOX
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CTX, chemotherapy; FOLFOX, folinic acid, fluorouracil and oxaliplatin
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March 16, 2017FOLFOX resumed – stoppedafter 1 cycle because of
hepatic abscess
March–June, 2017Hepatic abscess required catheter drainage and prolonged antibiotic therapy.
** Chemotherapy was on hold
February 14, 2017• Rt. Hemicolectomy• Liver segment 5/6 resection• Ileostomy reversal
Pathology: pT3pN1c(0/18),M1
CLINICAL COURSE
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FOLFOX, folinic acid, fluorouracil and oxaliplatin
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June 14, 2017Disease progression in the form of a new liver lesion near the dome
No other site of metastatic disease
July 2017• Biopsy of the new
liver lesionconfirmedadenocarcinoma
• FOLFIRI initiated but poorly tolerated, stopped after 2 cycles
October 10, 2017(after 3 doses of pembrolizumab)
CT scan: stable disease, possible recurrent liver
abscess
August 8, 2017
Pembrolizumabinitiated
CLINICAL COURSE
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CT, computerized tomography; FOLFIRI: folinic acid, fluorouracil and irinotecan; FOLFOX, folinic acid, fluorouracil and oxaliplatin; PD-1, Programmed celldeath protein 1
After FOLFOX and FOLFIRI chemotherapy options, immunotherapy was initiated in August 8, 2017:
• Pembrolizumab: Immune Checkpoint Inhibitor (PD-1 inhibitor)
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2.6 cm 2.7 cm
JULY, 2017 OCTOBER, 2017
abscess?
AFTER 3 CYCLES OF PEMBROLIZUMAB
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October 16, 2017
• Abdominal exploration and subsegmental resection of liver segments V, VI, and VII
• Pathology: NO VIABLE TUMOR (pCR)
December, 2017–February, 2018
• “Adjuvant” pembrolizumab- tolerated well
• Post-therapy scan: no evidence of disease
CLINICAL COURSE (LAST STATUS)
Subsequent course
• Observation with periodic scans.
• In complete remission to date (May, 2019)
pCR, pathologic complete response
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29dMMR, deficient mismatched repair; PD-1, programmed cell death protein 1
• Radiological studies can be misleading in assessing tumor response to immunotherapy with PD-1 blockade
• PD-1 blockade should be considered early in the treatment of dMMRmetastatic colorectal cancer
TAKE HOME MESSAGES