GI Tumor Board Alan Venook George Fisher 62yo F without significant - PDF document

3/7/2017 17 th Multidisciplinary Management of Cancers: A Case ‐ based Approach Case #1 GI Tumor Board Alan Venook George Fisher • 62yo F without significant PMH presents w/RLQ abdominal pain. Carling Ursem Zach Koontz • CT: asymmetric wall thickening of the cecum with enlarged pericolonic mesenteric LAD. Emily Bergsland Pam Kunz • Colonoscopy: partially obstructing tumor in cecum. Carlos Corvera Brendan Visser Yan Li • Undergoes laparoscopic right hemicolectomy. Mary Feng Ed Kim • Surgical path: high grade adenocarcinoma, 13/19 pericolonic LN Margaret Tempero positive, positive mesenteric LN, and positive mesenteric margin. Case #1 What is the next step in management? • While awaiting medical oncology consultation patient develops 1. Test KRAS exon 2/3, and MSI worsening abdominal pain 2. Test KRAS exon 2/3, NRAS, BRAF and MSI • CT a/p: interval development of markedly bulky retroperitoneal, 3. Start FOLFIRI + cetuximab mesenteric and peritoneal nodal lesions or implants. 4. Start FOLFOXIRI + bevacizumab • CT chest: enlarged para ‐ aortic and retrocrural LAD, suspicious for metastatic disease. 1

3/7/2017 Retrospective analysis of the PRIME study showed that mutations in any of the following conferred a similar lack of benefit from anti ‐ EGFR therapy as KRAS exon 2 mutations: ‐ KRAS exon 3,4 ‐ NRAS exon 2,3,4 In this patient with right sided colon cancer, does KRAS status change your choice of therapy? 1. Yes 2. No Atreya, Corcoran & Kopetz, J Clin Oncol March 2015 Comments & Controversies 2

3/7/2017 HR (95% CI) P Side N (events) Median (95%CI) 732 (550) 33.3 (31.4-35.7) HR (95% CI) P 1.55 Side N (events) Median (95%CI) Left 1.87 <.0001 36.0 (32.6-40.3) Left 376 (270) (1.32-1.82) <.0001 16.7 (13.1-19.4) (1.48-2.32) 19.4 (16.7-23.6) Right 293 (242) Right 143 (121) Office [3]1 Case #1 Continued • Patient continues to experience abdominal pain and weight loss, but otherwise maintains excellent performance status • Molecular profiling shows BRAF V600E mutation and MSI ‐ high by IHC *Approximately 25% of MSI ‐ high tumors are also BRAF mutated. *BRAF mutation is seen only in sporadic MSI ‐ high cases. 3

Slide 12 Office [3]1 discuss how often these two occur at the same time int he same patient Microsoft Office User, 1/31/2017

3/7/2017 BRAF V600E CRC has Distinct Biology What is the next step in management? • BRAF mutation frequency in CRC: ~8% BRAFwt P<0.05 1. Start FOLFIRI compared to BRAF wild type • Associated with microsatellite instability 250% BRAFm P<0.05 Increased incidence P<0.05 • Hyper ‐ methylated 200% 2. Start irinotecan + cetuximab + vemurafenib 150% • Mucinous histology P<0.05 3. Start nivolumab 100% • RAS wild ‐ type 50% 4. Start FOLFOXIRI + bevacizumab • Patients: female, peritoneal & lymph 0% node metastases Tran et al, Cancer 2011 TRIBE • Phase III RCT of FOLFIRI + bevacizumab vs FOLFOXIRI + bevacizumab • At a median of 48 months of follow up, median OS was 25.8mo w/FOLFIRI + bev vs 29.8 w/FOLFOXIRI + bev, HR 0.8 CI 0.65 ‐ 0.98 Loupakis F, et al, J Clin Oncol 33, 2015 4

3/7/2017 Can we do better for BRAF mutant disease? • Kopetz et al. Randomized trial of irinotecan and cetuximab with or without vemurafenib in BRAF ‐ mutant metastatic colorectal cancer (SWOG 1406). GI ASCO 2017. Vemurafenib + cetuximab + irinotecan • Most common grade 3 ‐ 4 AES: • Diarrhea • Neutropenia, anemia • Nausea • Fatigue • Still waiting on OS data • Planned for a sub ‐ group analysis by MSI status 5

3/7/2017 Immunotherapy for MSI ‐ high mCRC Nivolumab in MSI ‐ high mCRC ‐ ORR 31.1% (95% CI 20.8 ‐ 42.9) ‐ table disease in 39.2% ‐ Disease control for ≥ 12 weeks 68.9% Reduction in size of target lesion regardless of: ‐ PDL ‐ 1 expression ‐ Clinical history of Lynch Syndrome ‐ BRAF mutation status • Nivolumab in Patients With DNA Mismatch Repair Deficient/Microsatellite Instability High Metastatic Colorectal Cancer: Update From CheckMate 142. Overman et al. GI ASCO 2017. Case #1 Take Home Points Case #2 • Current actionable mutations: KRAS codon 12, 13, 61, 117, 146; A 72yo M w/no prior NRAS codons 12, 13, 61, 117, 146; BRAF codon 600 medical problems has a CT • Consider FOLFOXIRI +/ ‐ bev induction therapy for fit patients w done for kidney stones unresectable CRC irrespective of RAS/RAF mutation status and is found to have a single lesion in the right • BRAF targeted therapy can be effective, but survival is still poor lobe of the liver. CT guided • If BRAF mutation or MSI present, plan ahead for clinical trial biopsy shows metastatic enrollment colon cancer. Colonoscopy identifies a rectal primary. 6

3/7/2017 Case #2 Next step • CT C/A/P shows no other sites of metastatic disease 1. Start chemotherapy 2. Radiation oncology consultation • MSI stable 3. Surgical oncology consultation • RAS and BRAF wild type 4. Comprehensive geriatric assessment EPOC New EPOC • Phase III RTC of mCRC with liver only metastases, deemed • Phase III RCT of KRASwt mCRC w/liver only mets, resectable or resectable suboptimally resectable • 364 patients assigned to either • Randomized to 12 cycles of peri ‐ operative chemotherapy (68% surgery alone or surgery + 12 peri ‐ FOLFOX) +/ ‐ cetuximab operative cycles of FOLFOX • At 20 months of follow up median PFS was 20.5 months without vs • Non ‐ significant improvement in 14.1 months with cetuximab. (HR 1 ∙ 48, 95% CI 1 ∙ 04–2 ∙ 12, p=0 ∙ 030) 3yr PFS of 7.3 months (HR 0.79, 95% CI 0.62–1.02; p=0.058) • Radiographic complete or partial response in 62% without vs 70% with cetuximab, p=0.59 Nordlinger, Bernard, et al. "Perioperative FOLFOX4 • Non ‐ significant improvement in chemotherapy and surgery versus surgery alone for 5yr OS from 47.8% to 51.2% (HR resectable liver metastases from colorectal cancer 0.88, 95% CI 0.68 ‐ 1.14; p=0.34) (EORTC 40983): long-term results of a randomised, controlled, phase 3 trial." The lancet oncology 14.12 (2013): 1208-1215. 7

3/7/2017 New EPOC Comments • Organizing trials with surgery and chemotherapy is difficult: heterogeneous patients, surgeons and centers • Study was terminated at intermediate analysis: 236/257 randomized WT KRAS exon 2 patients • Quality assurance: • Surgery: margin < 1 cm (40% of patients) • R1 resection (cetuximab: 12%; no cetuximab 8%) • Entry criteria (13% not assessable) • CapeOx: 20%, FOLFIRI 10% • Unresected: cetuximab 27/112 (24%); no cetuximab: 17/110 (15%) 1 Consider Geriatric Assessment • Older adult patients are at higher risk for chemotherapy toxicity than their younger counterparts • Because of this they are less likely to be offered chemotherapy, across disease types • At the same time, a multitude of studies have shown that older adults who can tolerate treatment experience chemotherapy efficacy similar to younger patients 8

3/7/2017 MyCarg.org Case #2 Clinical Course Case #2 Clinical Course • Patient receives 4 cycles of FOLFOX • MRI after 8 cycles of FOLFOX shows significant decrease in size and bulk of rectal mass • Repeat CT shows stability of the initial segment 7 lesion, but question of a possible new segment 6 lesion • Patient then receives chemoradiation with capecitabine to a total of 5000 cGy in 25 daily fractions • Patient is taken for partial hepatectomy, with pathology showing 2 separate lesions, both with negative margins • Currently scheduled for low anterior resection 6 weeks out from his completion of chemoradiation • Post ‐ operatively he resumed FOLFOX for 4 additional cycles, which he tolerated well 9

3/7/2017 Case #3 Case #2 Take Home Points • 64yo previously healthy woman admitted for SBO and noted on imaging to have liver • It is not clear what the role of cetuximab is in oligometastatic, metastases potentially resectable disease • In retrospect, intermittent flushing without • Get surgical and radiation oncology input early for patients who may significant diarrhea be resectable • Working full time, ECOG PS 0 • Consider incorporating geriatric assessment into the evaluation of older adult patients • Labs: Normal LFTs, albumin, CBC, creatinine. 24 hour urine 5 HIAA: 105 mg/24 hours (nl <8) • Lives biopsy: well ‐ differentiated neuroendocrine tumor (NET), Ki67 3% Case #3: Imaging Case #3: Imaging 111 In ‐ octreotide scan: No extrahepatic disease (2 liver lesions, right lobe and segment • 4); no primary tumor identified CT: (+) 2 cm spiculated mass in small bowel mesentery (near TI); (+) several peripherally enhancing hepatic lesions consistent with metastatic disease (at least two in the left and two in the right lobes of the liver); (+) two tiny noncalcified pulmonary nodules; rib and T1 lesions of uncertain significance TI, terminal ilieum 10