Advances in esophageal cancer: Current and future strategies Yelena Y. Janjigian, MD Assistant Attending Physician Gastrointestinal Oncology Service Memorial Sloan-Kettering Cancer Center 18th Annual Perspectives in Thoracic Oncology November 15, 2013

Esophageal and GEJ US Incidence in 2013 Esophagus and GEJ: 17,900 cases 7th leading cause of cancer death in men Decline in Gastric Cancer Incidence Increase in Esophageal , GE JX, cardia adenocarcinoma (not squamous) Increases in obesity  GERD, smoking OS improvement, 1975-77, 1984-86, 1999-2006 Esophageal: 5%  10%  19% Siegel et al, CA 63: 11-30; 2013

New AJCC Staging: Survival in over 4600 pts with esophageal and GEJ cancer T3 or N+ T3N+, N2-3 Rice Cancer 2010

Gastroesophageal Junction Tumors: Classification and Treatment Siewart Classification1 Type I: lesions with center 1-5 cm proximal to the GE junction Type II: lesions with center 1 cm proximal to and 2 cm distal to the GE junction Type III: lesions with center 2-5 cm distal to the GE junction AJCC Staging Siewert I-III considered esophageal cancers 1. Siewert et al. Ann Surg. 2000.232:353. 2. Stahl. Onkologie. 2004.27:33.

Preop therapy for T2-3 or N+ EMR for T1a Surgery for T1b

PET SCAN: 1) Staging: 15% occult mets 2) Determine Response to Preop Chemo Supraclavicular LN = Stage IV Response to Preop Chemo SUV = 10.6 SUV = 2.2

Esophageal GEJ Cancer: Neoadjuvant Therapy Poor survival with Surgery Alone Staging should include EUS and PET scan Preoperative Therapy Chemo (U.K., Magic) Chemoradiotherapy (U.S.) Increasingly validated by randomized trials Carboplatin + Paclitaxel + RT a new standard option Chemoradiotherapy Alone nonoperative management PET scan to direct preop chemo under study Targeted Agents

Esophageal Adenocarcinoma: Consensus on Adjuvant Therapy T2-3 or N+: Something more than surgery alone should be done Preoperative chemo ECF, CF improves overall survival in some but not all trials MAGIC (ECF): 13% ↑ OS at 5 yr (esophagus and GEJ: 120 pts) No pathologic CR No improvement in RO resection FFCD / FNLC (CF): 14% ↑ OS at 5 yr (esophagus and GEJ: 180 pts)  same as MAGIC, no epirubicin Improved R0 resection rate by 11% Cunningham NEJM 355: 11; 2006, Ychou J Clin Oncol 29: 1715; 2011

Esophageal Adenocarcinoma: Consensus on Adjuvant Therapy Trials focusing purely on esophageal and GE junction cancers Preop chemo CF failed: U.S. INT 113 (CF): 450 pts No impact on OS or any endpoint, including R0 rate MRC 0E0-2 (CF): 800 pts 5 year update: 6% OS increase No impact on distant recurrence Impact due to increase in R0 resection EORTC 40954 (CF): 70 pts No impact on OS, improved R0 resection Alllum J Clin Oncol 2009, Kelsen NEJM 1988, Schuhmacher J Clin Oncol 278: 5210; 2010

Preop Chemo vs Surgery Alone: 2062 patients, 10 Trials HR favoring Chemo 0.87 (p = 0.005) Squamous: HR 0.92 (p = 0.18) Adeno: HR 0.83 (p = 0.01) Sjoquist Lancet Oncol 12: 681; 2011

Paclitaxel 50mg/m2 + Carboplatin AUC=2 on days 1, 8, 15, 22 and 29 Concurrent radiotherapy of 41.4 Gy in 23 fractions of 1.8 Gy Surgery within 6 weeks after completion of chemoradiotherapy (THE/TTE) Van Hagen et al NEJM 366: 2074; 2012

CROSS: Major Results EUS staged patients T3N0-1 75%, median age 60 74% Adenocarcinoma 93% received all courses chemotherapy 23% had > = grade 3 toxicity from pre-op therapy Post-operative morbidity and mortality almost identical (mortality 3.7-3.8%)

Resection rate and resection margins Resection rate of all randomized patients Surgery alone CRT + surgery 186/188 (99%) 168/178 (95%) Resection margins R0 111/161 (69%) 148/161 (92%) p<0.002 R0 = no tumor within 1 mm of the resection margins CROSS study

CROSS: Overall Survival HR 0.67 95% CI (0.49 - 0.91) 5-year survival 47% vs 34% Median survival 49 vs 24 months, HR 0.66, p = 0.003) Squamous HR 0.453, Adeno HR 0.732 Squamous path CR 49%, Adeno 23% (p = 0.008) 18

Subgroups: Impact on OS with Chemo RT

Preop Chemo vs ChemoRT Stahl J Clin Oncol: 27: 836; 2009

Preop Chemo vs Chemo RT: Stahl EUS, laparoscopy staged pts Siewert I-III, T3-4 adenocarcinoma Arm N R0 pCR N0 Median Survival 3 yr OS Local Control Chemo 59 70% 2% 37% 21 mos 28% 59% Chemo RT 60 72% 16% 64% 33 mos 47% P = 0.07 77% P = 0.06 Stahl J Clin Oncol: 27: 836; 2009

Sjoquist Lancet Oncol 12: 681; 2011 Preop Chemo RT vs Surgery Alone: 1932 patients, 13 trials –All cause mortality HR favoring Chemo RT: 0.78 (p < 0.0001) Squamous HR 0.8 (p = 0.004) Adeno HR 0.75 ( p = 0.02) Sjoquist Lancet Oncol 12: 681; 2011

Esophageal and GEJ Cancer: Preop Chemo, RT, or Both? Conclusions Something more than surgery alone should be done for T2-T3 or N+ disease Preop Chemo, Cisplatin + 5-FU based improves survival and is feasible Toxicity of chemo backbone may limit the addition of targeted agents RT + Chemo, Carbo + Paclitaxel: potentially superior OS, more path CR’s Low toxicity of therapy makes this regimen an ideal backbone for targeted therapy

Esophageal and GEJ Cancer and the Role of Surgery? Low rate of pathologic complete response after chemo RT (23% CROSS trial) Surgery considered for most patients Chemo RT alone: Elderly, co morbidities Delay surgery in responders, use as a salvage procedure

Esophageal Cancer: Predictive Accuracy of post ChemoRT Endoscopy 137 pts: Cisplatin based chemo RT  surgery  EGD and biopsy  Surgery 104 pts (76%) negative biopsy post therapy Poor Predictor: Only 35% had pathologic CR at surgery A negative biopsy better predictor for squamous cell carcinoma (p <0.001) More accurate assessment to predict Path CR Sarkaria JCO 24: Abs 4024, 182, 2006

PET Scan and Path CR: Esophageal Cancer 493 pts preop chemoRT, 87% cisplatin based chemort PET scan prior, after chemort 80% Adeno Path CR 27% PET response not associated with pCR In squamous cancer patients: SUV response correlated with pCR SUV reduction < 50%, 50-75%: : pCR 29-44% SUV reduction > 75%: pCR 85% Rizk J Clin Oncol 27: Abstr 4552; 2009

Esophageal Cancer: PET scan response to Induction / Preop Chemo Weber: Preop chemo in esophageal and GEJ cancers 5-FU, cisplatin based for 3 months PET scan performed at day 14 PET responders: SUV decline > = 35% PET responders 2 yr survival 60% vs 37% for non responders Weber J Clin Oncol 19:3058;2001

Treatment Plan: MUNICON-1 trial Lordick Non-Responder Resection CTx AEG type I-II PET d14 PET d0 CTx: 3 months Responder Resection Response definition: Decrease of the SUVmean PETd14 / PETbaseline > 35% Weber et al. J Clin Oncol 2001;19:3058-65 Ott et al. J Clin Oncol 2006;24:4692-8

Comparison with historic cohort Ott et al. J Clin Oncol 2006;24:4692-8 CTx for 12 weeks in all patients MUNICON-1 study; 2007 CTx stopped after 2wks in Non-Responders PET-Responder Survival PET-Non-Responder Survival time [months] Survival (median) Responders: not reached Non-Responders: 18 months Survival (median) Responders: not reached Non-Responders: 26 months

Esophageal Cancer: PET scan trials It is unlikely that nonresponding pts will gain from continuing the same chemo Discontinuing inactive chemo did not adversely affect outcome Will changing chemo improve outcome?

PET Scan Directed Therapy Trial Design: CALGB 80803 PET-responders: ≥ 35% SUV decrease: continue same chemo + concurrent RT (5040cGy in 180cGy fx) T3/4 or N1 Esophageal Adenoca PET/CT: Induction Chemo: modified FOLFOX6 days 1,15, 22 or Carbo/Taxol days 1,8,22,29 Surgical resection 6 weeks post-RT PET Scan day 29-35 PET- nonresponders: < 35% SUV decrease: Cross over to alternate chemo + RT (5040cGy in 180cGy fx) Hypothesis: changing chemo in PET non responding patients will improve pCR during chemo + RT

Adding a Targeted Agent to Chemo, Chemo RT Neoadjuvant Therapy Validation of agent in advanced disease trials Specific targeting of an over expressed or activated target Biomarker enrich selection of treatment population Potential for agent to have systemic activity and reduce or suppress systemic micrometasases Potential for agent to enhance radiotherapy or overcome radiotherapy resistance Non overlapping toxicity with chemotherapy Less of an issue with 5-FU, capecitabine, oxaliplatin Clearly an issue with ECF and variants

Molecular Targets: Esophageal and Gastric Cancer KRAS mutation: < 5% BRAF mutation: < 5% EGFr over expression: 50-80% Over expression may be prognostic EGFr mutation: < 5% , amplification in 15% VEGF over expression Correlates with advanced stage, worse prognosis HER2 over expression: 10-25%, not prognostic in local disease CMET amplification: IHC over expression 40%, poorer prognosis in metastatic disease Amplification in 10% Galizia W J Surg 31: 1458; 2007 Mammano Anticancer Res 26: 3547; 2006 Lee Oncogene 22: 6942; 2003 Yano Oncol Rep 15: 65; 2006 Gold GI CA Symp 2008 Abs 96

Targeted Agents: Neoadjuvant Therapy Only validated Biomarker Selected Targeted Agent is Trastuzumab, HER2+ pts Ongoing RTOG Trial 1010 of Trastuzumab + ChemoRT in HER2+ Esophageal and GEJ Cancers Negative phase II, phase III trials for Bevacizumab and Cetuximab + chemo RT Ongoing trial of Bevacizumab + EOX in Gastric Cancer CMET and other pathways under active investigation in early phase trials Biomarker for selection for over expression or activation of a target remains a key component of trial design

Management of Residual Disease After chemo RT and surgery, observation alone is standard therapy. Any preop therapy has a modest benefit: 60-80% of pts still die Survival improvements 6-14% Pts with no treatment effect, N + residual disease post surgery: poor outcome

After preop therapy and surgery, should chemo be continued post op? Does continuing same chemo even benefit responding patients? Timing of therapy 4-5 + months after diagnosis Similar survival outcomes with short duration vs protracted chemo OS increases in trials of chemo only during RT, CROSS Trial = to MAGIC, FFCD trials (3 pre 3 post op cycles) Unlikely that non responding patients will gain from more of the same treatment

Targeted Therapy Post Op? Maintenance therapy with a novel targeted agent , high risk residual disease pts Suppress rather than eradicate micro metastatic disease CALGB/Alliance, GEJ cancer High risk N+ pts post chemort and surgery 1 year Regorafenib (Anti VEGF TKI) vs Placebo Based on phase II activity for Sorafenib (MSKCC)