Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Treatment of HER2-Positive Gastroesophageal Carcinoma Manish A. Shah, MD Director, Gastrointestinal Oncology Weill Cornell Medical College NewYork-Presbyterian Hospital New York, New York This program is supported by an educational donation from Gastroesophageal Carcinoma: New Directions in Mechanistically Targeted Therapy clinicaloptions.com/oncology About These Slides Our thanks to the presenters who gave permission to include their original data Users are encouraged to use these slides in their own noncommercial presentations, but we ask that content and attribution not be changed. Users are asked to honor this intent These slides may not be published or posted online without permission from Clinical Care Options Disclaimer The materials published on the Clinical Care Options Web site reflect the views of the authors of the CCO material, not those of Clinical Care Options, LLC, the CME providers, or the companies providing educational grants. The materials may discuss uses and dosages for therapeutic products that have not been approved by the United States Food and Drug Administration. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or using any therapies described in these materials. Gastroesophageal Carcinoma: New Directions in Mechanistically Targeted Therapy clinicaloptions.com/oncology Program Faculty Program Director: Manish A. Shah, MD Director, Gastrointestinal Oncology Weill Cornell Medical College NewYork-Presbyterian Hospital New York, New York Gastroesophageal Carcinoma: New Directions in Mechanistically Targeted Therapy clinicaloptions.com/oncology Faculty Disclosure Manish A. Shah, MD, has disclosed that he has received consulting fees and contracted research support from Genentech and sanofi-aventis. Gastroesophageal Carcinoma: New Directions in Mechanistically Targeted Therapy clinicaloptions.com/oncology Gastroesophageal Cancer: Treatment Overview Surgery is primary treatment for medically fit, resectable cases[1] For advanced disease, treatment may include perioperative chemotherapy or preoperative chemoradiation Postoperative treatment options – Chemoradiation (fluoropyrimidine-based or capecitabine) – Palliative chemotherapy or best supportive care Recurrent or metastatic disease – Chemotherapy – Palliative chemotherapy, clinical trial, or best supportive care Significant need exists for deeper understanding of tumor subtypes, biomarkers for treatment response[2] 1. NCCN. Clinical practice guidelines in oncology: gastric cancer, v2. 2011. 2. Power DG, et al. Cancer Treat Rev. 2010;36:384-392. Gastroesophageal Carcinoma: New Directions in Mechanistically Targeted Therapy clinicaloptions.com/oncology Gastroesophageal Cancer: Systemic Therapy for Metastatic Disease First-line options[1] – DCF/modified DCF – ECF/modified DCF – Single agent or combination regimens (fluoropyrimidine or taxane based) – Trastuzumab + standard chemotherapy for HER2positive tumors Second-line options[1] – Trastuzumab + standard chemotherapy for HER2positive tumors if no first-line trastuzumab – Paclitaxel or docetaxel – Single agent irinotecan or irinotecan-based combination – Phase III trials under way with other targeted agents[2] 1. NCCN. Clinical practice guidelines in oncology: gastric cancer, v2. 2011. 2. Power DG, et al. Cancer Treat Rev. 2010;36:384-392. Gastroesophageal Carcinoma: New Directions in Mechanistically Targeted Therapy clinicaloptions.com/oncology Targeted Therapies Conventional, cytotoxic chemotherapy has limited benefit Targeted agents: attempt to block specific tumor growth pathways – Monoclonal antibodies – Tyrosine kinase inhibitors – Soluble receptors to growth factors – Inhibition of pathways involved in protein synthesis and degradation Gastroesophageal Carcinoma: New Directions in Mechanistically Targeted Therapy clinicaloptions.com/oncology Molecular Targets: Esophagogastric Cancer KRAS mutation: < 5% to 10%[1,2] BRAF mutation: < 5%[1,2] EGFR overexpression: ~ 50% to 80%[3,4] – TKIs inactive[4] – Cetuximab monotherapy inactive[5] EGFR mutation: very low[4,6] HER2 overexpression: 10% to 25%[7] HGF/c-Met: over/aberrant expression reported in various human cancers, including gastric cancer[8] 1. Lee SH, et al. Oncogene. 2003;22:6942-6945. 2. Kim IJ, et al. Hum Genet. 2003;114:118-120. 3. Galizia G, et al. World J Surg. 2007;31:1458-1468. 4. Dragovich T, et al. J Clin Oncol. 2006;24:4922-4927. 5. Chan JA, et al. Ann Oncol. 2011;22:1367-1373. 6. Mammano E, et al. Anticancer Res. 2006;26:3547-3550. 7. Yano T, et al. Oncol Rep. 2006;15:65-71. 8. Birchmeier C, et al. Nat Rev Mol Cell Biol. 2003;4:915-925. Gastroesophageal Carcinoma: New Directions in Mechanistically Targeted Therapy clinicaloptions.com/oncology ToGA: Trastuzumab + Chemotherapy in Advanced HER2+ Gastric Cancer Rationale: a subpopulation of gastric cancers overexpress HER2 Stratified by ECOG PS, advanced vs metastatic, gastric vs GEJ, measurable disease, capecitabine vs 5-FU Patients with advanced gastric cancer screened for HER2 status (N = 3803) Patients with HER2-positive advanced gastric cancer (n = 810; 22% of successful screenings) R (n = 584) 5-FU or Capecitabine* + Cisplatin 80 mg/m2 q3w x 6 + Trastuzumab 6 mg/kg q3w until PD (8 mg/kg loading dose) (n = 294) 5-FU or Capecitabine* + Cisplatin 80 mg/m2 q3w x 6 (n = 290) Primary endpoint: OS *Selected at investigator’s discretion: 5-FU 800 mg/m2/day infusional on Days 1-5 q3w x 6; capecitabine 1000 mg/m2 BID on Days 1-14 q3w x 6. Bang YJ, et al. Lancet. 2010;376:687-697. Gastroesophageal Carcinoma: New Directions in Mechanistically Targeted Therapy clinicaloptions.com/oncology ToGA: Efficacy Outcome Outcome Chemotherapy + Trastuzumab (n = 294) Chemotherapy Alone (n = 290) HR (95% CI) P Value Median OS, mos 13.8 11.1 0.74 (0.60-0.91) .0046 Median PFS, mos 6.7 5.5 0.71 (0.59-0.85) .0002 ORR, % 47 35 -- .0017 CR 5 2 -- .0599 PR 42 32 -- .0145 Preplanned subgroup analysis indicated improved OS benefit with increasing HER2 expression by IHC Exploratory analysis of IHC 2+/FISH+ and IHC 3+ cohort demonstrated a 4-mo increase in OS with trastuzumab – HR: 0.65 (95% CI: 0.51-0.83) Bang YJ, et al. Lancet. 2010;376:687-697. Gastroesophageal Carcinoma: New Directions in Mechanistically Targeted Therapy clinicaloptions.com/oncology ToGA: OS by HER2 Status HER2 Status Subgroup Median OS, Mos (CT + T vs CT Alone) HR* (95% CI) 13.8 vs 11.1 0.74 (0.60-0.91) IHC 0/FISH+ (n = 61) 10.6 vs 7.2 0.92 (0.48-1.76) IHC 1+/FISH+ (n = 70) 8.7 vs 10.2 1.24 (0.70-2.20) IHC 2+/FISH+ (n = 159) 12.3 vs 10.8 0.75 (0.51-1.11) IHC 3+/FISH+ (n = 256) 17.9 vs 12.3 0.58 (0.41-0.81) IHC3+/FISH- (n = 15) 17.5 vs 17.7 0.83 (0.20-3.38) IHC 0 or 1+/FISH+ (n = 131) 10.0 vs 8.7 1.07 (0.70-1.62) IHC 2+/FISH+ or IHC 3+ (n = 446) 16.0 vs 11.8 0.65 (0.51-0.83) All patients (N = 584) Preplanned analysis Exploratory analysis *HR < 1 favors chemotherapy + trastuzumab; HR > 1 favors chemotherapy alone. Bang YJ, et al. Lancet. 2010;376:687-697. Gastroesophageal Carcinoma: New Directions in Mechanistically Targeted Therapy clinicaloptions.com/oncology Survival Probability ToGA: OS in IHC 2+/FISH+ or IHC 3+ (Exploratory Analysis) 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 Events, Median n OS, Mos HR FC + T 120 136 FC 11.8 0 2 4 6 95% CI 0.65 0.51-0.83 16.0 11.8 16.0 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 Mos Pts at Risk, n FC + T 228 218 196 170 142 122 100 84 65 51 39 28 20 12 11 FC 218 198 170 141 112 96 75 53 39 28 20 13 11 4 3 Bang YJ, et al. Lancet. 2010;376:687-697. 5 3 4 0 1 0 0 0 Gastroesophageal Carcinoma: New Directions in Mechanistically Targeted Therapy clinicaloptions.com/oncology ToGA: Select Toxicities Adverse Event, % Chemotherapy + Trastuzumab (n = 294) Chemotherapy Alone (n = 290) Neutropenia 27 30 Anemia 12 10 Diarrhea 9 4 Nausea 7 7 Cardiac events 6 6 Grade 3/4 1 3 5 1 Grade 3/4 hematologic events Grade 3/4 nonhematologic events LVEF reduction of ≥ 10% to absolute value < 50%* *Chemotherapy plus trastuzumab: n = 237; chemotherapy alone: n = 187. Bang YJ, et al. Lancet. 2010;376:687-697. Gastroesophageal Carcinoma: New Directions in Mechanistically Targeted Therapy clinicaloptions.com/oncology ToGA: HER2 Positivity by IHC Score Surgical Specimen Staining Pattern Biopsy Specimen Staining Pattern HER2 Overexpr. Assessment 0 No reactivity or membranous reactivity in < 10% of tumor cells No reactivity or no membranous reactivity in any tumor cell Negative 1+ Faint or barely perceptible membranous reactivity in ≥ 10% of tumor cells; cells are reactive only in part of their membrane Tumor cell cluster with faint or barely perceptible membranous reactivity regardless of % of tumor cells stained Negative 2+ Weak to moderate complete, basolateral or lateral membranous reactivity in ≥ 10% of tumor cells Tumor cell cluster with weak to moderate complete, basolateral or lateral membranous reactivity regardless of % of tumor cells stained Equivocal* 3+ Strong complete, basolateral or lateral membranous reactivity in ≥ 10% of tumor cells Tumor cell cluster with strong complete, basolateral or lateral membranous reactivity regardless of % of tumor cells stained Positive *FISH or other in situ hybridization method recommended by NCCN guidelines panel. Bang YJ, et al. Lancet. 2010;376:687-697. NCCN. Clinical practice guidelines in oncology: gastric cancer, v2. 2011. Gastroesophageal Carcinoma: New Directions in Mechanistically Targeted Therapy clinicaloptions.com/oncology HER2 Testing in Gastroesophageal Cancer HER2 more heterogeneous in gastric vs breast cancer Objectives – Evaluate IHC-FISH concordance in processed samples – Determine applicability of ASCO/CAP HER2 breast cancer scoring system to gastroesophageal carcinomas FISH IHC 0 IHC 1+ IHC 2+ IHC 3+ Total, n (%) Positive (HER2/CEP17 > 2.2) 0 1 3 16 (100) 20 (15) Negative (HER2/CEP17 < 1.8) 60 (97) 39 (93) 4 0 103 (77) 2 (1.9; 2.0)* 2 (2.1; 1.8)* 1 (2.1)* 0 5 (4) 2 2 0 1 5 (4) 64 (48) 44 (33) 8 (6) 17 (13) 133 Equivocal (HER2/CEP17 1.8-2.2) Failure Total, n (%) *Data in parentheses show individual values, not percentages. Tafe LJ, et al. Arch Pathol Lab Med. 2011;135:1460-1465. Gastroesophageal Carcinoma: New Directions in Mechanistically Targeted Therapy clinicaloptions.com/oncology Median OS Increased to > 1 Yr With Trastuzumab-Based Therapy 12 mos BSC[1] FAMTX[2] C + S1[3] CF[4] IF[5] EOF[6] DCF[4] ECF[6] ECX[6] XP[7] EOX[6] Trastuzumab + XP/FP[8] HER2 IHC 2+/FISH+ or IHC 3+ 15 10 5 0 Median OS in Patients With Advanced Gastric Cancer (Mos) 1. Murad AM, et al. Cancer. 1993;72:37-41. 2. Vanhoefer U, et al. J Clin Oncol. 2000;18:2648-2657. 3. Ajani JA, et al. J Clin Oncol. 2010;28:1547-1553. 4. Van Cutsem E, et al. J Clin Oncol. 2006;24:4991-4997. 5. Dank M, et al. Ann Oncol. 2008;19:1450-1457. 6. Cunningham D, et al. N Engl J Med. 2008;358:36-46. 7. Kang YK, et al. Ann Oncol. 2009;20:666-673. 8. Bang YJ, et al. Lancet. 2010;376:687-697. Gastroesophageal Carcinoma: New Directions in Mechanistically Targeted Therapy clinicaloptions.com/oncology Definition of HER2 Positivity for Gastroesophageal Carcinoma HER2-Positivity Requirements for Approved Trastuzumab Use US European Union IHC 3+ or IHC 3+ or FISH+ (ratio > 2.0) IHC 2+ and FISH+ (ratio > 2.0) Gastroesophageal Carcinoma: New Directions in Mechanistically Targeted Therapy clinicaloptions.com/oncology Prognostic Role of HER2 in Gastric Cancer Prognostic value of HER2 controversial with > 20 yrs of conflicting data Systematic literature analysis involving 12,749 patients in 42 studies[1] – 71% of studies demonstrated association between HER2 positivity and poor survival (40%) or clinicopathologic features (31%; eg, serosal invasion, LN metastases, disease stage, or distant metastases) – However, multivariate analyses performed in only ~ 50% of studies Systematic literature review involving 11,337 patients in 49 studies included 35 studies evaluating effect of HER2 overexpression on survival[2] – 57%: no effect on OS – 6%: significantly longer OS with HER2 overexpression – 37%: significantly poorer OS with HER2 overexpression 1. Jørgensen JT, et al. J Cancer. 2012;3:137-144. 2. Chua TC, et al. Int J Cancer. 2012;130:2845-2856. Gastroesophageal Carcinoma: New Directions in Mechanistically Targeted Therapy clinicaloptions.com/oncology Gastric Cancer Surgical cure rates are high with lesions limited to the mucosa or submucosa (ie, T1) However, for patients with stage II or higher, 5-yr survival remains poor Patients increasingly presenting with T1 N0 disease, but proportion remains low 40% to 50% of patients will present with unresectable disease Overall 5-yr survival remains low This is a bad disease – After surgery, chances of long-term survival for most patients remains < 50%. Can we do better?? Gastroesophageal Carcinoma: New Directions in Mechanistically Targeted Therapy clinicaloptions.com/oncology Gastric INT 116: Postoperative Chemoradiotherapy vs Surgery Alone 20% were GEJ tumors 100 – Similar survival benefit in this subset OS Patients (%) 80 60 Chemoradiotherapy 40 20 Surgery only 0 0 24 48 72 Mos After Registration Macdonald JS, et al. N Engl J Med. 2001;345:725-730. 96 120 Gastroesophageal Carcinoma: New Directions in Mechanistically Targeted Therapy clinicaloptions.com/oncology Meta-analysis: Surgery vs Surgery + Any Adj CT in Resectable GC Survival (%) Survival benefit for addition of chemotherapy 100 90 80 70 60 50 40 30 20 10 0 Any chemotherapy Surgery alone HR: 0.82 (95% CI: 0.76-0.90; P < .001) 0 1 2 3 4 5 6 7 8 Yrs From Randomization Pts at Risk, n Any chemotherapy 1924 1688 1385 1217 1080 929 Surgery along 1857 1568 1300 1092 952 782 GASTRIC Group, et al. JAMA. 2010;303:1729-1737. 9 10 709 526 390 297 243 583 407 267 172 138 Gastroesophageal Carcinoma: New Directions in Mechanistically Targeted Therapy clinicaloptions.com/oncology Chemotherapy in Resectable Gastric Cancer Addition of pre/peri/postsurgery chemotherapy consistently demonstrates benefit vs surgery alone Study Primary Endpoint Primary Endpoint Results P Value Surgery vs surgery + adjuvant capecitabine/oxaliplatin 3-yr DFS 59% vs 74% < .0001 MAGIC[2] Surgery vs surgery + periop ECF 5-yr OS 23% vs 36% .009 Sakuramoto et al[3] Surgery vs surgery + adjuvant S-1 3-yr OS 70% vs 80% .003 CLASSIC[1] Regimens 1. Bang YJ, et al. Lancet. 2012;379:315-321. 2. Cunningham D, et al. N Engl J Med. 2006;355:11-20. 3. Sakuramoto S, et al. N Engl J Med. 2007;357:1810-1820. Gastroesophageal Carcinoma: New Directions in Mechanistically Targeted Therapy clinicaloptions.com/oncology Chemotherapy in Resectable Gastric Cancer However, resounding lack of progress in improving patient outcomes with any specific CT/CRT regimen vs any other chemotherapy regimen Study CALGB 80101[1] ARTIST[2] Regimens Primary Endpoint Primary Endpoint Results P Value Postop 5-FU/LV CRT vs ECF CRT OS 37 vs 38 mos .80 Postop CT vs CRT (capecitabine/cisplatin) 3-yr DFS 74% vs 78% .086 1. Fuchs CS, et al. ASCO 2011. Abstract 4003. 2. Lee J, et al. J Clin Oncol. 2012;30:268-273. Gastroesophageal Carcinoma: New Directions in Mechanistically Targeted Therapy clinicaloptions.com/oncology RTOG 1010: Neoadjuvant Phase III Trial in Esophageal/GEJ Adenocarcinoma Stratified by presence of adenopathy and involved celiac nodes Patients with confirmed HER2overexpressing esophageal or GEJ adenocarcinoma (Planned N = 160) Radiation (50.4 Gy) + Paclitaxel + Carboplatin + Trastuzumab Surgery 5-8 wks after radiation completion Radiation (50.4 Gy) + Paclitaxel + Carboplatin Surgery 5-8 wks after radiation completion Primary endpoint: DFS (15 → 27 mos; HR: 0.56) Principal investigator: H. Safran, Providence, RI. ClinicalTrials.gov. NCT01196390. Maintenance Trastuzumab q3w x 13 Gastroesophageal Carcinoma: New Directions in Mechanistically Targeted Therapy clinicaloptions.com/oncology LOGiC: Phase III Trial of Lapatinib + CapeOx in HER2+ Gastric Cancer Patients with HER2-amplified locally advanced, unresectable, or metastatic gastric, esophageal, or GEJ cancer (Planned N = 535) Primary endpoint: OS (was PFS) Data expected mid-2012 ClinicalTrials.gov. NCT00680901. CapeOx + Lapatinib CapeOx + Placebo Gastroesophageal Carcinoma: New Directions in Mechanistically Targeted Therapy clinicaloptions.com/oncology Pertuzumab & Trastuzumab Bind Distinct Epitopes on HER2 Extracellular Domain Pertuzumab Trastuzumab Activates ADCC Activates ADCC Prevents HER2 domain cleavage Has a major effect on role of HER2 as a coreceptor with HER3 or EGFR Inhibits HER2-mediated signaling pathways Hubbard SR. Cancer Cell 2005;7:287-288. Inhibits multiple HERmediated signaling pathways Gastroesophageal Carcinoma: New Directions in Mechanistically Targeted Therapy clinicaloptions.com/oncology Second-line Paclitaxel + Lapatinib vs Paclitaxel for Advanced Gastric Cancer Patients with HER2-amplified gastric cancer and PD after 1 previous 5-FU and/or cisplatin regimen (N = 273) Paclitaxel + Lapatinib Paclitaxel Primary endpoint – Initial pilot analysis: tolerability to determine optimal dosing – Randomized part: OS ClinicalTrials.gov. NCT00486954. Gastroesophageal Carcinoma: New Directions in Mechanistically Targeted Therapy clinicaloptions.com/oncology Phase II Studies of Targeted Agents in HER2-Positive Disease PF-00299804, pan-EGFR inhibitor (NCT01152853) AUY922, Hsp90 inhibitor (NCT01402401) Pertuzumab + trastuzumab + chemotherapy (NCT01461057) Bevacizumab + trastuzumab + docetaxel, oxaliplatin and capecitabine chemotherapy (NCT01359397) Bevacizumab + trastuzumab + capecitabine and oxaliplatin (NCT01191697) Afatinib (NCT01522768) ClinicalTrials.gov. Gastroesophageal Carcinoma: New Directions in Mechanistically Targeted Therapy clinicaloptions.com/oncology Summary HER2 represents the first validated target in gastric and gastroesophageal junction adenocarcinoma All patients with metastatic gastric/GEJ adenocarcinoma who are HER2 positive should be considered for trastuzumab-based therapy There are few data on the use of trastuzumab in the preoperative or adjuvant setting, or on its continued use after progression on trastuzumab-based therapy Drug development targeting HER2 in gastric cancer is active and ongoing Go Online for More CCO Coverage of Chicago 2012! Capsule Summaries of all the key data, plus CME-certified Slidesets exploring the clinical implications of these findings Downloadable slides: for use as a study resource or in your noncommericial presentations clinicaloptions.com/oncology