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Johanna Bendell, MD Director, GI Oncology Research Associate Director, Drug Development Unit

Second Line Treatment for Gastroesophageal Cancers: Are We Helping People Feel Better and Live Longer?. Johanna Bendell, MD Director, GI Oncology Research Associate Director, Drug Development Unit Sarah Cannon Research Institute Nashville, TN.

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Johanna Bendell, MD Director, GI Oncology Research Associate Director, Drug Development Unit

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  1. Second Line Treatment for Gastroesophageal Cancers:Are We Helping People Feel Better and Live Longer? Johanna Bendell, MD Director, GI Oncology Research Associate Director, Drug Development Unit Sarah Cannon Research Institute Nashville, TN

  2. Second Line Therapy for Gastroesophageal Cancers – A Difficult Situation • After progression on first line therapy, only roughly 20% of patients receive second-line therapy with a median overall survival of 5.6 months (Chau, GI ASCO 2004) • Patients are sick • Symptomatic – weight loss, anorexia, pain, difficulties eating (with or without prior local intervention), N/V • Do we have data to show second line therapy can help?

  3. Randomized Second Line Trials to Date

  4. Trial Design Arm A (n=84): Docetaxel 75mg/m2 IV every 3 weeks for up to 6 cycles + ASC Assess every 3 weeks for 18 weeks, then every 6 weeks Adenocarcinoma of esophagus, esophagus-gastric junction or stomach refractory to platinum and fluoropyrimide RANDOMISE 1:1 n=168 Arm B (n=84): Active symptom control May include: Radiotherapy, analgesia, anti-emetics, steroids Stratified by: 1.Disease status (Locally advanced vs metastatic); 2. Site of disease (Esophagus vs GEJ vs Stomach); 3. Time to progression after previous chemotherapy ( 0 vs 0-3 vs 3-6 months); 4. ECOG PS ( 0/1 vs 2)

  5. COUGAR-02 • Well-designed with good stratification factors • Screening vs. number enrolled show how difficult these trials are to accrue • Many are ineligible (sick population) • Refusal of study (vs. BSC) • Restaging at 3 and 6 cycles for docetaxel patients, as indicated for BSC patients (no TTP endpoint) • Included QUALITY OF LIFE

  6. This is a difficult population to treat • These patients are sick • Most do not complete treatment plan

  7. Toxicity • Toxicity rates relatively low for q 3 week docetaxel • Only significant differences are neutropenia and febrile neutropenia • Relatively low neuropathy and thrombocytopenia • Due to low amount of chemotherapy given? • Median number of cycles of docetaxel given was 3

  8. Overall survival Median survival: 5.2 months (95% CI 4.1-5.9) for Docetaxel 3.6 months (95% CI 3.3-4.4) for ASC Hazard ratio 0.67 (95% CI 0.49-0.92), p=0.01

  9. Who really received benefit??? • Patients who had disease progression 3-6 months after first line therapy • Longest disease free interval • Selection of patients who respond to therapy better • Patients with ECOG 0

  10. We Help Them Live Longer, But Do We Help Them Feel Better? • QoL forms (EORTC QLQ-C30, STO22, EQ5D) planned in both arms q 3 weeks for 18 weeks, then q 6 weeks • Number of QoL forms expected/returned lower in the control arm – potential source of bias, but common in these types of studies

  11. Quality of life (EORTC QLQ-C30) • Standardised AUC analysis • Comparison using O’Brien global rank procedure • No significant differences in function or global health scale • Symptom score for pain significantly better in chemotherapy arm Global health Pain p=0.53 p=0.0008 CT ASC

  12. COUGAR-2 • Chemotherapy benefits patients in the second line setting • We now see docetaxel and irinotecan work • But overall benefit is still around 1.5 mo • But need to think about who will really benefit • Can we get better at selecting the appropriate patient? • Longer PFI, better PS • Patients who respond better and feel better live longer

  13. Gefitinib in advanced esophageal cancer progressing after chemotherapy Gefitinib 500mg od (n=225) Patients progressing following chemotherapy Simple randomisation Planned: 18 months to recruit 450 patients Primary endpoint: Overall survival - powered to detect an increase in 1 year survival from 10 to 18%, 82.5% power, 5% significance level. Secondary endpoints: PFS, toxicity & PROs Placebo (n=225) • Multi-centre • Double-blind – patients, clinicians and trial office staff blinded to trial treatment • Treated until progression • Regular CT scans

  14. COG • No benefit for overall survival • 3.73 vs. 3.6 mo, HR 0.90 [0.74,1.09] • PFS • 1.60 vs. 1.17 mo, HR 0.795 [0.657,0.962] • Was there a subgroup who had benefit? • Is there a biomarker? Studies ongoing… • Did anyone feel better? • EORTC QLQ-C30 • EORTC QLQ-OG25

  15. Quality of Life • Planned assessments at baseline, 4, 8, and 12 weeks then until progression • Prespecified PRO: global QoL, dysphagia, difficulty eating, odynophagia • Primary evaluation at 4 weeks • Not surprisingly for this patient population, only 70% alive and progression free at 4 weeks (82.5% placebo vs. 74.7% geftinib compliance)

  16. Odynophagia is improved in the gefitinib arm at 4 weeks, and stays consistently better with time out to 12 weeks • This points to a group of patients who appear to benefit from gefitinib • There was a group with tumor shrinkage at 4 weeks • RR 3.1 vs 0.4% • DCR (8 weeks) 26 vs. 16% (p = 0.014) • Can we identify who they are?

  17. It always comes down to the biomarker question… • But what are the biomarkers? • REAL-3 • Mutations/pathway dysregulation not common • EXPAND biomarkers pending • Though we do see EGFR overexpression (50-70%) • Squamous vs. adenocarcinoma • Different responses to EGFR inhibitors? • SCC head and neck respond • Lordick, et al, R ph II SCC esophagus, RR 19 vs. 13%, PFS 5.7 vs. 3.6 mo, OS 9.5 vs. 5.5 mo Chau 2011

  18. Randomized Second Line Trials to Date

  19. Moving forward…

  20. T-DM1 structure Target expression: HER2 Monoclonal antibody: Trastuzumab Cytotoxic agent: DM1 Highly potent cytotoxic agent T-DM1 Linker: MCC Systemically stable T-DM1 is a novel ADC Trastuzumab Average drug:antibody ratio ≅3.5:1

  21. TrastuzumabEmtansine: Phase II Study of 2L treatment for HER2+ Metastatic Gastric Cancer Phase II n=100 2L Her2 positive mGC PS: 0 -1 IHC 3+ or IHC 2+/ISH+ Prior Ctx + prior HER2 N=412 T-DM1 3.6 mg/kg q3 wk 2 T-DM1 2.4 mg/kg/wk 2 Stratified by: region, PS, prior gastrectomy, prior HER2-targeted tx 1 Chemotherapy** • Phase II: 3 arm; 2:2:1 randomization; endpoints: safety, PK, PFS, ORR; n=100 • * Dose selection based on PK/safety/efficacy • ** Investigator’s choice between paclitaxel 80 mg/m2/wk and docetaxel 75 mg/m2 q 3 wk

  22. REGARD: Randomized Phase III Trial 2nd Line Ramicirumab vs. Placebo 22 Ramucirumab IVq 2 weeks Second line metastatic gastric and GEJ adenocarcinoma R 1:1 Placeboq 2 weeks Press release 10/12: met primary endpoint of OS and secondary endpoint of PFS Press release 1/23/13: OS 5.2 vs. 2.6 mo PFS 2.1 vs. 1.3 mo Primary EP: OS N = 355

  23. RAINBOW: Randomized Phase III Trial 2nd Line Paclitaxel +/- Ramicirumab 23 Paclitaxel 80 mg/m2 d1, 8, 15 + Ramucirumab IVq 2 weeks Second line metastatic gastric and GEJ adenocarcinoma R 1:1 Paclitaxel 80 mg/m2 d1, 8, 15 + Placeboq 2 weeks Primary EP: OS N = 665

  24. Second Line Treatment of Gastroesophageal Cancers • Consistent trials showing some benefit to chemotherapy • COUGAR trial shows docetaxel is an appropriate chemotherapy choice • COG trial shows gefitinib overall does not improve survival endpoints • However, both trials show suggestion of subpopulations that may benefit more • COUGAR – longer PFI, better PS • COG – subpopulation with improved QoL factors • Drug development in this setting needs to be more targeted to the right population • We are doing this • TDM1 for HER2 positive patients • Inclusion of biomarker studies and QoL in trials for this population

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