1 / 32

Targeted therapies in Gastroesophageal Malignancies Dawn of a new era

Targeted therapies in Gastroesophageal Malignancies Dawn of a new era. Manish A. Shah, MD Associate Professor of Medicine Weill Cornell Medical College of Cornell University New York-Presbyterian Hospital Director, Gastrointestinal Oncology Center for Advanced Digestive Care.

talen
Télécharger la présentation

Targeted therapies in Gastroesophageal Malignancies Dawn of a new era

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Targeted therapies in Gastroesophageal MalignanciesDawn of a new era Manish A. Shah, MD Associate Professor of Medicine Weill Cornell Medical College of Cornell University New York-Presbyterian Hospital Director, Gastrointestinal Oncology Center for Advanced Digestive Care

  2. Discussion of abstracts: LBA6 – Suntharalingam and colleagues RTOG 0436 – phase III study of chemo/RT (cisplatin and paclitaxel) with and without cetuximab for esophageal cancer treated without surgery LBA7 – Wilke and colleauges: RAINBOW – phase III study of paclitaxel with or without ramucirumab in 2nd line gastric/GEJ adenocarcinoma Objectives

  3. The Initial Report of RTOG 0436: A Phase III Trial evaluating the addition of Cetuximab to Paclitaxel, Cisplatin, and Radiation for Patients with Esophageal Cancer Treated without Surgery Suntharalingam M, Winter K, Ilson D, Dicker A, Kachnic L, Konski A, Chakravarthy B, Anker C, Thakrar H, Horiba N, Kavadi V, Deutsch M, Raben A, Roof K,Videdic G, Pollock J, Crane C

  4. Abstract LBA6 - BackgroundRTOG 0436 – Cetuximab in Esophageal CA • Why paclitaxel / Cisplatin? Cisplatin + Paclitaxel with radiation was equivalent to cisplatin/FU + radiation, but with less toxicity. (enrollment 2001-2005) Ajani J A et al. RTOG 0113: Phase II randomized trial of two nonoperative regimens of chemoradiation in localized esophageal CA. JCO 2008;26:4551-4556

  5. Abstract LBA6 - BackgroundRTOG 0436 – Cetuximab in Esophageal CA • Context in the CROSS preoperative study Eligibility: T1N1 – T2-3Nx (stage 1-3) Treatment: Radiation 4140 cGy + weekly taxol (50 mg/m2) and Carboplatin (AUC 2) van Hagen P et al. Preoperative chemoradiotheapy for esophageal or junctional cancer. NEJM 2012;366:2074-84.

  6. Abstract LBA6 - BackgroundRTOG 0436 – Cetuximab in Esophageal CA • Why cetuximab? • Cetuximab: a chimeric (mouse/human) monoclonal antibody against epidermal growth factor receptor (EGFR) • EGFR expression in ~80% (30-90%) esophageal cancer, ~40% gastric cancer • EGFR expression correlates with prognosis in esophagogastric ACA and SCC • KRAS mutations occur in ~2% (0-9%) of esophageal cancers Mukaida. Cancer 1991; Itakura. Cancer 1994; Yacoub. Mod Pathol 1997; Torzewski. Anticancer Res 1997; Koyama. J Cancer Res ClinOncol 1999; Lea. Carcinogenesis 2006

  7. RTOG 0436: Overall Survival 2-Year Rates: • Well designed and performed study, • Reasonable stratification • No survival difference (n=328) 44.0% 41.7% Median follow-up for alive patients = 24.3 months (0.1-60.7)

  8. Comment • Cetuximab does not improve survival or response when combined with chemotherapy for localized unresectable esophageal cancer. • Consistent with previous results in metastatic disease.

  9. Phase III studies EGFR Ab inhibitors are metastatic disease

  10. Comment • Cetuximab does not improve survival or response when combined with chemotherapy for localized unresectable esophageal cancer. • Consistent with previous results in metastatic disease. • These data are definitive. • Would the results be different in a pre-operative setting. Likely not!

  11. Comment • Why didn’t this work? (now or previously) Are esophageal cancers driven by EGFR signaling? TP53 CDKN2A EYS ARID1A SMAD4 PIC3CA EGFR mutations did not occur as top mutations. But it is more complicated – EGFR amplification did occur frequently. Dulak AM et al. Whole-exome and whole-genome sequencing of esophageal adenocarcinoma identifies recurrent driver events and mutational complexity. Nat Genet. 2013;45(5):478-=86.

  12. Comment • What have we learned? • Clinical response to chemo/RT is prognostic.

  13. Implications: Our best approach to improving survival in this disease is to improve response to therapy. • PET directed therapy CALGB 80803: PET directed chemo + chemo/RT • Targeted therapy RTOG 1010: Trastuzumabwith chemo/RT • Improve our understanding of tumor biology RTOG 0436: 85% tissue collected

  14. LBA7 RAINBOW: A Global, Phase 3, Randomized, Double-Blind Trial of Ramucirumab and Paclitaxel (PAC) Versus Placebo and PAC in the Treatment of Metastatic Gastric or Gastroesophageal Junction (GEJ) Adenocarcinoma Following Disease Progression on First-Line Platinum- and Fluoropyrimidine-Containing Combination Therapy H. Wilke* Eric Van Cutsem, Sang Cheul Oh, György Bodoky, Yasuhiro Shimada, Shuichi Hironaka, Naotoshi Sugimoto, Oleg Lipatov, Tae You Kim, David Cunningham, Atsushi Ohtsu, Philippe Rougier, Michael Emig, Roberto Carlesi, Kumari Chandrawansa, Kei Muro *On behalf of the RAINBOW Investigators

  15. RAINBOW: Study Design 1:1 Ramucirumab 8 mg/kg day 1&15 + Paclitaxel 80 mg/m2day 1,8 &15 of a 28-day cycle N = 330 R A N D O M I Z E Treat until disease progression or intolerable toxicity Survival and safety follow-up S C R E EN Placebo day 1&15 + Paclitaxel 80 mg/m2 day 1,8 &15 N = 335 • Important inclusion criteria: • - Metastatic or loc. adv. unresectable gastric or GEJ* adenocarcinoma • - Progression after 1st line platinum/fluoropyrimidine based chemotherapy • Stratification factors: • - Geographic region, • - Measurable vs non-measurable disease, • - Time to progression on 1st line therapy (< 6 mos vs. ≥ 6 mos) * GEJ=gastroesophageal junction; gastric and GEJ will be summarized under the term GC

  16. RAINBOW: Overall Survival Δ mOS = 2.3 months Censored No. at risk

  17. Comment • Well performed international study – kudos to the investigators and to Lilly. • Why did it work?

  18. AvagastOverall Survival : Cis/Cape +/- Bevacizumab Survival rate XP + Placebo XP + Bev 1.0 0.9 0.8 HR = 0.87 95% CI 0.73–1.03 p = 0.1002 0.7 0.6 12.1 0.5 0.4 10.1 0.3 0.2 0.1 0.0 12 0 15 18 21 24 3 9 6 Study month

  19. Bevacizumab plus CT for Advanced GastroesophagealAdenocarcinoma (GC): Combined U.S. experience* *Data from 4 investigator initiated U.S. phase II studies of chemotherapy plus bevacizumab for the treatment of metastatic/unresectable gastric cancer were pooled. Sites involved were: 1) Memorial Sloan-Kettering Cancer Center, 2) Dana-Farber/Harvard Cancer Center, 3)Yale Cancer Center, and 4) Stanford Comprehensive Cancer Center. Smyth, et al. ASCO 2011 (Abstract 4056)

  20. Patient characteristics by region AVAGAST Study *1 additional patient had an ECOG PS of 4 • There was an imbalance of >10% between the regions

  21. Avagast vs. Ramicirumab

  22. Avagast vs. Ramicirumab

  23. Avagast vs. Ramicirumab

  24. Biomarkers- pVEGFA and NRPCandidate Biomarkers for Bevacizumab Efficacy in Gastric Cancer Van Cutsem E [Shah MA]. JCO 2012;30:2119-2127

  25. Implications • Targeting the angiogenesis pathway in gastric/ GEJ adenocarcinoma is now validated • Ramicirumab + paclitaxel is a viable, safe, effective treatment option following 1st line therapy. • Is VEGFR2 specific inhibition any different than blocking VEGF-A?

  26. What have we learned • Disease biology is important, as shown by gastric cancer heterogeneity. Immune SNPs IL1, IL4, etc. Distal non diffuse Gastric CA Family History: CDH1 MMR APC TP53 Genetic Risk Environment H. Pylori cag A strain Behavior Proximal non diffuse Gastric Cancer Diffuse Gastric CA Tobacco use/ diet (salt) (fruits/vegetables)

  27. Are we at theDawn of a new era? Shah MA. Nat Rev ClinOncol 2014;11:10-11.

  28. Are we at theDawn of a new era?

  29. Targeted Successes

  30. Dawn of …. more of the same?

  31. We are in a New Era ! • Greater emphasis on obtaining tissue and biospecimens • Greater tools at our disposal • [put your – omic here] Focus our efforts on • understanding how therapy works • understanding why therapy doesn’t work • why therapy stops working

  32. That is our next move….

More Related