Updated Apr 2017 by Dr. Ko (Medical Oncologist, Abbotsford Cancer Centre)

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1 Metastatic Esophagogastric Cancer Summary Updated Apr 2017 by Dr. Ko (Medical Oncologist, Abbotsford Cancer Centre) Reviewed by Dr. Yoo-Joung Ko (Medical Oncologist, Sunnybrook Odette Cancer Centre, University of Toronto), Dr. Vincent Tam (Medical Oncologist, Tom Baker Cancer Centre, University of Calgary) DISCLAIMER: The following are study notes compiled by the above PGY-5 medical oncology residents and reviewed by a staff medical oncologist. They reflect what we feel is relevant knowledge for graduating medical oncology residents preparing for their final examination. The information has not been surveyed or ratified by the Royal College. Initial therapy - Many trials include both SCC and adenocarcinomas, making it difficult to determine benefit in each subtype. - No consensus but chemotherapy definitely prolongs survival Ø Meta-analysis (2010 Cochrane): 35 trials, 5726 patients, comparison consistently showed significant benefit in OS in favor of group receiving chemo (HR 0.37). Comparison of combination vs single agent chemo provides evidence for a survival benefit in for of combo chemo (HR 0.82) - Combination chemo give higher RRs than single agents, but translates only into modestly longer durations of disease control and survival that are measured in few weeks to months - In RCTs, CF/ECF/DCF combos have emerged a standard regimen. - Based on REAL2 trial (below), EOX is a reasonable 1 st line regimen for pts who are able to tolerate combo chemo if oxaliplatin funded. - In addition, ongoing phiii trials using FOLFOX as a chemo backbone. - For older pts or with poor PS: leucovorin-modulated 5FU alone or single agent cape o Other possibilities: irinotecan or low dose weekly taxanes o Single agent irinotecan or lower dose weekly taxanes o If gastric or GEJ cancer and Her2 +, add trastuzumab Single agents - Taxanes, irinotecan, and vinorelbine - In multiple studies, monotherapy w either single agent paclitaxel or docetaxel produced RR in range of 15 to 25% - In 2 reports involving 83 previously untreated pts, irinotecan RR was 14-20% - Oral fluoropyrimidines as single agents associated w RR as high as 41% but mos have not exceeded 9 months - Phase III studies have shown equivalence between infusional 5FU, capecitabine, and S-1 Combination chemo - Higher RR s (up to 65%) reported in phase II trials in advanced esophageal and gastric cancer, but consistently lower in the setting of RCTs. - Combination vs single agent therapy o o Cis plus 5FU One of the most commonly use regimens in both metastatic and localized esophageal cancer due to its activity and well established toxicity profile Cis plus newer fluoropyrimidines Capecitabine Capecitabine and oxaliplatin for advanced esophagogastric cancer (REAL-2)

2 (Cunningham NEJM 2008) ECF vs ECX vs EOF vs EOX OS non-inferiority trial Unresectable and metastatic esophageal and gastric cancer. Although both SCC and adeno were included, the great majority of patients had adenocarcinoma. Size (N) 1002 Results - Noninferiority in OS for the triplet therapies containing capecitabine as compared w FU and for those containing oxaliplatin as compared w Cisplatin - For capecitabine-fu comparison, HR for death in cape group was For oxaliplatin-cis comparison, HR for oxaliplatin group The upper limit of CI sf for both HR s excluded the predefined non-inferiority margin of mos in ECF, ECX, EOF, and EOX groups were 9.9, 9.9, 9.3, and 11.2 months. - Survival rates at 1 year were 37.7, 40.8, 40.4, and 46.8% - In SECONDARY analysis, OS was longer w EOX than with ECF, with a HR for death of 0.80 in EOX group (p=0.02) - PFS and RR did NOT differ significantly among the regimens Toxic effects of cape and FU were similar As compared w cis, oxaliplatin associated w lower gd 3 or 4 neutropenia, alopecia, renal toxicity, and thromboembolism, but w slightly higher incidences of grade 3 or 4 diarrhea and neuropathy Capecitabine and oxaliplatin are as effective as FU and cisplatin in pts w previously untreated esophagogastric cancer Prospective, Randomized, Multicenter, Phase III Study of Fluorouracil, Leucovorin, and Irinotecan Versus Epirubicin, Cisplatin, and Capecitabine in Advanced Gastric Adenocarcinoma: A French Intergroup (Fédération Francophone de Cancérologie Digestive, FédérationNationale des Centres de LutteContre le Cancer, and GroupeCoopérateurMultidisciplinaire en Oncologie) Study (Guimbaud JCO 2014) FOLFIRI Q2w vs ECX Q3w (dosing of cape 1000mg/m2 BID x 14/21d different from REAL2 625mg/m2 BID x 21/21d) Crossover mandated in the trial design (48% of ECX vs 39% of FOLFIRI patients crossed over) TTF Locally advanced or metastatic gastric cancer, ECOG <=2, no previous palliative chemotherapy Adjuvant chemotherapy (>=6 mo from study entry) allowed Patients with brain mets excluded Size (N) 416 Results - TTF 5.08 vs 4.24, (significant) - PFS 5.75 vs 5.29m (NS) - OS 9.72 vs 9.49 m (NS) - RR 37.8 vs 39.2% Median number of cycles 3 vs 2 cycles Stopped due to toxicity 3.9 vs 14.5% ECX: greater hematologic toxicities, non-hematologic toxicity approximately equal 53%

3 FOLFIRI as first-line treatment for advanced gastric and EGJ cancer demonstrated significantly better TTF than did ECX. Other outcome results indicate that FOLFIRI is an acceptable first-line regimen in this setting and should be explored as a backbone regimen for targeted agents. - Meta-analysis of these trials concludes that, compared with 5FU combinations, capecitabine combinations were associated with a higher RR (OR 1.38) and better OS (HR for death 0.87) Phase III study of docetaxel and cisplatin plus fluorouracil compared with cisplatin and fluorouracil as first-line therapy for advanced gastric cancer: a report of the V325 Study Group (TAX 325) (Van Cutsem JCO 2006) Untreated advanced gastric cancer patients TTP Docetaxel 75mg/m2 and cisplatin 75mg/m2 d1 plus FU 75 mg/m2/d (d1-5) every 3 weeks Vs Cisplatin 100mg/m2 d1 plus FU 1000mg/m2/d (d1-5) every 4 weeks Size (N) 445 Results - TTP longer w DCF vs CF (32% risk reduction, log rank p<0.001) - ORR higher w DCF (chi2 p=0.01) - OS longer w DCF vs CF (23% risk reduction, log rank p=0.02) - Two year survival rate 18% w DCF vs 9% w CF Gd ¾ toxicities for DCF vs CF: neutropenia, stomatitis, diarrhea, lethargy Adding docetaxel to CF sig improved TTP, survival, and RR in gastric cancer pts but resulted in some increased toxicity Incorporation of docetaxel, as in DCF or with other active drugs, is a new therapy option for pts w untreated advanced gastric cancer Phase III study of docetaxel and cisplatin plus fluorouracil compared with cisplatin and fluorouracil as first-line therapy for advanced gastric cancer: a report of the V325 Study Group (TAX 325) (Van Cutsem JCO 2006) Untreated advanced gastric cancer patients TTP Docetaxel 75mg/m2 and cisplatin 75mg/m2 d1 plus FU 75 mg/m2/d (d1-5) every 3 weeks Vs Cisplatin 100mg/m2 d1 plus FU 1000mg/m2/d (d1-5) every 4 weeks Size (N) 445 Results - TTP longer w DCF vs CF (32% risk reduction, log rank p<0.001) - ORR higher w DCF (chi2 p=0.01) - OS longer w DCF vs CF (23% risk reduction, log rank p=0.02) - Two year survival rate 18% w DCF vs 9% w CF Gd ¾ toxicities for DCF vs CF: neutropenia, stomatitis, diarrhea, lethargy Adding docetaxel to CF sig improved TTP, survival, and RR in gastric cancer pts but resulted in some increased toxicity Incorporation of docetaxel, as in DCF or with other active drugs, is a new therapy option for pts w untreated advanced gastric cancer - No benefit with addition of ramucirumab in front line setting at this time. RAINFALL study currently ongoing. Ø Benefit for frontline therapy in conjunction w 1 st line FOLFOX could not be shown in a RCTIII in which 168 pts w previously untreated esophagogastricadenoca were randomly assigned to FOLFOX with Ramucirumab (8 mg/kg iv) or iv placebo every 14 days

4 Ø In a preliminary report presented at 2014 ASCO annual meeting, there was no significant difference in mos(11.7 vs 11.5 mo) or PFS (6.4 vs 6.7 mo) HER2 overexpressing adenoca - ~7-22% of esophagogastricadenoca s overexpress the type II EGFR HER2, a similar percentage to that seen in breast cancer - HER2 positivity is more common w intestinal type than with diffuse type gastric cancer (32 vs 6% in one analysis) - Assessment of HER2 status in upper GI cancers o HER2 status can be assess using same FDA approved Her2 assays as for breast tumors o This includes an assessment of HER2 protein expression by IHC and HER2 gene amplification by FISH o However, interpretive criteria for determining the IHC score in esophagogastric cancers are distinct in 2 ways from breast tumors, underscoring the importance of utilizing tumor-specific criteria in clinical practice HER2 protein expression in esophagogastric tends to spare the digestive luminal membrane and results in membrane staining that is not completely circumferential As a result, an esophagogastric cancer with only partially circumferential (ie basolateral or lateral ) membrane staining can still be categorized as 2+ or 3+. By contrast, a breast tumor must show complete circumferential membrane staining to be designated as 2+ or 3+ A greater degree of intratumoral HER2 heterogeneity in esophagogastric tumors, in that HER2 positive clones comprised only a minority of the tumor in esophagogastric tissue samples This heterogeneity may increase the likelihood that esophagogastric tissue samples, esp biopsies, will miss a HER2 positive region of the tumor As a result, the cut point in the percentage of cancer cells that must show HER2 expression is fairly low in esophagogastric biopsy specimens Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. (Bang Lancet 2010) Untreated advanced gastric or gastro-oesophageal junction cancer patients Inclusion: Tumor overexpression of HER2 by IHC or gene amplification by FISH 1:1 cape plus cis or FU plus Cis Every 3 weeks for 6 cycles Vs Chemo in combination with IV trastuzumab Size (N) 594 Results - mos 13.8 w trastuzumab plus chemo vs 11.1 mo in those assigned to chemo alone (HR 0.74, p=0.0046) Most common AE s in both groups: nausea, vomiting, and neutropenia Rates of overall grade 3 or 4 AE s and cardiac AE s did not differ between groups Trastuzumab in combination w chemo is considered as a new standard option for pts w HER2 positive advanced gastric or gastro-esophageal

5 junction cancer - Lapatinib (orally active small molecule inhibitor of both EGFR type I and II (HER2) o Benefit for adding lapatinib to weekly paclitaxel vs paclitaxel alone could not be seen in pts w previously treated advanced gastric cancer on the TyTAN trial o Benefit from adding lapatinib to 1 st line chemo was also not shown in the TRIO 013/LOGiC trial of capecitabine/oxaliplatin with or without lapatinib for 1 st line treatment in 545 pts w advanced GE cancer. o In a prelim report presented at the 2013 ASCO annual meeting, the primary endpoint (OS of pts who were centrally confirmed to be FISH positive for HER2) was not met (mos 12.2 vs 10.5 mo, HR 0.91) o There was no correlation between intensity of staining for HER2 by IHC and outcomes o However, certain subgroups seemed to benefit from adding lapatinib In prespecified subgroup analysis: Asian pts (mos 16.5 vs 10.9 mo, HR 0.68), and those under age 60 (mos 12.9 vs 9 mo, HR 0.69) seemed to benefit from lapatinib. Second-line and third-line therapy Cougar-02: A randomized phase III study of docetaxel versus active symptom control in patients with relapsed esophago-gastric adenocarcinoma. (Cook ASCO 2013) Docetaxel 75mg/m2 every 3 weeks for up to 6 cycles Vs Active symptom control Advanced esophagogastric (EGC) adenocarcinoma Size (N) 168 Results - ORR 7% - mos 5.2 vs 3.6m (HR 0.67, p=0.01) QoL 7% feb neutropenia On QLQ-C30, pts on docetaxel arm reported significantly les pain and trend for less nausea and vomiting and constipation than those on ASC arm sifor QLQ-ST022, trend seen for less dysphagia, and pain symptoms for pts on docetaxel arm Docetaxel provided a significant OS benefit over ASC w improvement in symptoms scores and no loss in overall HRQL Docetaxel can be considered a standard of care in this setting. Randomized, Open-Label, Phase III Study Comparing IrinotecanWith Paclitaxel in Patients With Advanced Gastric Cancer Without Severe Peritoneal Metastasis After Failure of Prior Combination Chemotherapy Using Fluoropyrimidine Plus Platinum: WJOG 4007 Trial (Hironaka JCO 2013) Paclitaxel (80 mg/m2 on days 1, 8, and 15, every 4 weeks) or irinotecan (150 mg/m2 on days 1 and 15, every 4 weeks) Advanced gastric cancer refractory to treatment with fluoropyrimidine plus platinum. Size (N) 219 Results - Median OS was 9.5 months in 108 patients allocated to the paclitaxel group and 8.4 months in 111 patients allocated to the irinotecan group (hazard ratio [HR], 1.13; 95% CI, 0.86 to 1.49; P =.38).

6 - Median PFS was 3.6 months in the paclitaxel group and 2.3 months in the irinotecan group (HR, 1.14; 95% CI, 0.88 to 1.49; P =.33). - Response rate was 20.9% in the paclitaxel group and 13.6% in the irinotecan group (P =.24). - Third-line chemotherapy was administered in 97 patients (89.8%) after paclitaxel treatment and in 80 patients (72.1%) after irinotecan treatment (P =.001). Common grade 3 to 4 adverse events were neutropenia (paclitaxel group, 28.7%; irinotecan group, 39.1%), anemia (21.3%; 30.0%), and anorexia (7.4%; 17.3%). Treatment-related deaths occurred in two patients (1.8%) in the irinotecan group. No statistically significant difference was observed between paclitaxel and irinotecan for OS. Both are reasonable second-line treatment options for advanced gastric cancer. Salvage Chemotherapy for Pretreated Gastric Cancer: A Randomized Phase III Trial Comparing Chemotherapy Plus Best Supportive Care With Best Supportive Care Alone (Kang JCO 2012) Docetaxel 60mg/m2 Q3w or IRI 150mg/m2 Q2w VS BSC Advanced gastric cancer, previously treated with 1-2 lines of chemotherapy containing platinum and 5-FU, ECOG 0-1 Size (N) 202 Results - RR 17, SD 43%, duration 4.4m, OS 5.2m - IRI RR 10%, SD 42%, duration 4.2m, OS 6.5m - mos 5.3 vs 3.8m (significant) cannot compare D and I (not powered) Salvage chemotherapy (SLC) was generally well tolerated, and adverse events were similar in the SLC and BSC arms. In pretreated patients, SLC is tolerated and significantly improves OS when added to BSC. Ramucirumab monotherapy for previously treated advanced gastric or gastrooesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial. (Fuchs Lancet 2014) Ramucirumab 8 mg/kg Vs Placebo Iv q2weely OS Advanced gastric or gastroesophageal junction adenoca with disease progression after 1st line platinum containing or fluoropyrimidine containing chemo Size (N) 355 Results - OS 5.2 vs 3.8 mo, HR 0.776, p= Survival benefit remained unchanged w Ramucirumab after multivariable adjustment HTN higher in Ramucirumab group whereas rates of other adverse events were mostly similar between the two groups 2% death in both group were related to study drug. Ramucirumab is the first biological treatment given as a single drug that has survival benefits in pts w advanced gastric or gastroesophageal junction adenoca progressingafter 1st line chemo.

7 Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial (Wilke Lancet Oncol 2014) 1:1 Ramucirumab 8 mg/kg Vs Placebo iv d1,15 + paclitaxel 80mg/m2 iv d1,8,15 of a 28 day cycle Previously treated advanced gastric or GE JnadenoCa Size (N) 665 Results - OS sig longer in Ramucirumab plus paclitaxel group than placebo plus paclitaxel (9.6 vs 7.4 mo, HR 0.807) Grade 3 or higher AE s in more than 5% on Ramucirumab/PAC group vvs placebo/pacli Included neutropenia, leucopenia, ht, fatigue, anemia, and abdo pain Gd 3 or higher FN low in both groups (3 vs 2%) The combination of Ramucirumab with paclitaxel sig increases OS compared w placebo plus paclitaxe. Phase III study of apatinib in advanced gastric cancer: A randomized, double-blind, placebo-controlled trial. (Shukui Qin ASCO 2014) Apatinib 850 mg po daily for 28 day cycle Vs Placebo daily 28 days as one cycle Advanced gastric cancer with prior failure to 2nd line chemo Size (N) 270 Results - mpfs prolonged in apatinib group (78 vs 53 days, HR 0.44, p<0.0001) - ORR 2.84% vs 0.00% - mos sig prolonged in apatinib group compared with the placebo 195 vs 140d, HR 0.71, p<0.016 Apatinib generally well tolerated Gd ¾ AE s in more than 2% of pts were htn, HFS, proteinuria, fatigue, anorexia, elevated aminotransferase This study further confirmed the efficacy and safety of apatinib in the pts w advanced gastric cancer. 850 mg daily is the recommended dose for clinical use. Nivolumab treatment for oesophageal squamous-cell carcinoma: an open-label, multicentre, phase 2 trial (Kudo Lancet Oncol 2017) Patients were treated with 3 mg/kg nivolumab given intravenously once every 2 weeks in 6-week cycles. ORR advanced squamous-cell carcinoma, adenosquamous-cell carcinoma, or adenocarcinoma of the oesophagus refractory or intolerant to fluoropyrimidine-based, platinum-based, and taxane-based chemotherapy Size (N) 64 Results 11 (17%, 95% CI 10 28) of 64 patients had a centrally assessed objective response FAST: An international, multicenter, randomized, phase II trial of epirubicin, oxaliplatin,

8 and capecitabine (EOX) with or without IMAB362, a first-in-class anti-cldn18.2 antibody, as first-line therapy in patients with advanced CLDN18.2+ gastric and gastroesophageal junction (GEJ) adenocarcinoma. (Al-Batran ASCO 2016) Arm 1: first-line EOX (epirubicin 50 mg/m2 and oxaliplatin 130 mg/m2 d1, and capecitabine 625 mg/m2 bid, d1 21; qd22) Arm 2: Arm 1 + IMAB362 (loading dose 800 mg/m2, then 600 mg/m2 d1, qd21). The study was extended by an exploratory Arm3 (N = 85) to investigate a high dose IMAB362 (1000 mg/m2) plus EOX PFS advanced squamous-cell carcinoma, adenosquamous-cell carcinoma, or adenocarcinoma of the oesophagus refractory or intolerant to fluoropyrimidine-based, platinum-based, and taxane-based chemotherapy Size (N) 730 Results PFS 5.7 vs 7.9m (significant) HR 0.5 OS 8.7 vs 12.5m (significant) HR 0.5 Toxicities Note In the subpopulation with very high CLDN18.2 expression ( 2+ intensity in 70% tumor cells), efficacy was more pronounced (PFS, 6.1 vs 9.1 mon; HR 0.46; OS, 9.3 v 16.6 mon; HR 0.44) vomiting, neutropenia, and anemia, which were mostly of NCI-CTC grade 1/2. Grade 3/4 events were not significantly increased by IMAB362. IMAB362 combined with first-line chemotherapy exhibited a clinically relevant benefit in PFS and OS and a favorable risk/benefit profile IMAB362 is a chimeric monoclonal antibody that mediates specific killing of CLDN18.2-positive cancer cells by activation of immune effector mechanisms. IMAB362 has demonstrated single-agent activity and was safe and tolerable in patients (pts) with pretreated gastric cancer. CLDN18.2 is expressed in more than 50% of gastric tumors