Which Treatment Approach is Most Appropriate for Primary Therapy of Gastric Cancer: Neoadjuvant Chemotherapy Joseph Chao, M.D. Assistant Clinical Professor Department of Medical Oncology & Therapeutics Research November 12 th, 2016
Disclosures Description of off-label use of the following agents: bevacizumab, trastuzumab, pertuzumab Research Support: Merck Advisory Boards: Five Prime Therapeutics, Lilly
How Did We Get Here?
Adjuvant Therapy SWOG/INT-0116 Macdonald Regimen Japanese ACTS-GC D0 54% D1 36% D2 9.6% D1 0.1% D2 94% D3 6% Smalley, SR et al. JCO. 2012 Sakuramoto S, et al. NEJM. 2007
Perioperative Chemotherapy MAGIC Epirubicin, Cisplatin, Fluorouracil FFCD 9703 Cisplatin, Fluorouracil 86% of patients assigned to chemotherapy completed all 3 neoadjuvant cycles 42% of all patients assigned to chemotherapy received all 6 cycles 87% of patients assigned to chemotherapy completed at least 2 cycles 48% of patients assigned to chemotherapy received adjuvant cycles Cunningham D, et al. NEJM. 2006 Ychou M, et al. JCO. 2011
More Adjuvant Therapy (After a D2 Surgery) Asian CLASSIC Trial Asian ARTIST Trial Noh SH, et al. Lancet Onc. 2014 Park SH, et al. JCO. 2015
ChemoRadiotherapy after Induction chemotherapy In Cancer of the Stomach Dutch CRITICS Trial What is the role of adjuvant chemoradiation after patients have received neoadjuvant chemotherapy?
Dutch CRITICS Trial Treatment Adherence Verheij M, et al. ASCO 2016 Abstr 4000
Dutch CRITICS Trial Surgical Outcomes Verheij M, et al. ASCO 2016 Abstr 4000
Dutch CRITICS Trial Toxicities with Post-Op Therapy Verheij M, et al. ASCO 2016 Abstr 4000
Dutch CRITICS Trial Overall Survival Results No difference between adjuvant CRT vs. CT 5-yr survival 40.9% vs. 40.8% Median OS 3.3 vs. 3.5 yrs 50% adherence to adjuvant therapy, should efforts focus on neoadjuvant therapy? Verheij M, et al. ASCO 2016 Abstr 4000
UK MRC OE05 Trial Neoadjuvant ECX vs. CF Are 3 drug combinations better than 2 drug combinations for perioperative chemotherapy? Cunningham D, et al. ASCO 2015 Abstr 4002
OE05 Chemotherapy Toxicity Cunningham D, et al. ASCO 2015 Abstr 4002
OE05 Pathologic Responses Cunningham D, et al. ASCO 2015 Abstr 4002
OE05 Progression-Free Survival Median PFS (95% CI) CF 1.53 yrs (1.29, 2.74) ECX 1.78 yrs (1.61, 2.00) HR 0.86 (95% CI, 0.74, 1.01) p = 0.0580 Cunningham D, et al. ASCO 2015 Abstr 4002
OE05 Overall Survival Median OS (95% CI) CF 2.02 yrs (1.80, 2.38) ECX 2.15 yrs (1.93, 2.53) HR 0.92 (95% CI, 0.79, 1.08) p = 0.8582 Cunningham D, et al. ASCO 2015 Abstr 4002
ST-03 Trial (MAGIC-B) Perioperative Bevacizumab Can the addition of biologics improve perioperative chemotherapy? Cunningham D, et al. ESMO/ECC 2015 Abstr 2201
ST-03 Trial (MAGIC-B) Baseline Characteristics Cunningham D, et al. ESMO/ECC 2015 Abstr 2201
ST-03 Trial (MAGIC-B) Chemotherapy Delivery Cunningham D, et al. ESMO/ECC 2015 Abstr 2201
ST-03 Trial (MAGIC-B) Toxicities Cunningham D, et al. ESMO/ECC 2015 Abstr 2201
ST-03 Trial (MAGIC-B) Surgical Outcomes Cunningham D, et al. ESMO/ECC 2015 Abstr 2201
ST-03 Trial (MAGIC-B) Overall Survival Cunningham D, et al. ESMO/ECC 2015 Abstr 2201
ST-03 Trial (MAGIC-B) Overall Survival Cunningham D, et al. ESMO/ECC 2015 Abstr 2201
Ongoing Trials
Australian TOPGEAR Study What is the role of neoadjuvant chemoradiation for patients receiving perioperative chemotherapy? Enrollment: Resectable gastric or GEJ adenocarcinoma ECF x 3 cycles Surgery ECF x 3 cycles ECF x 2 cycles 45 Gy RT/5-FU Surgery ECF x 3 cycles
ARTIST II Trial After D2 resection for patients with lymph node metastases is adjuvant chemoradiation beneficial? Does oxaliplatin provide additional benefit in node positive disease? S-1 (q6 weeks) x 8 cycles Enrollment: D2 Resected Gastric or GEJ adenocarcinoma, N+ S-1 + oxaliplatin (q3 weeks) x 8 cycles S-1 + oxaliplatin x 2 cycles 45 Gy RT/S-1 S-1 + oxaliplatin x 4 cycles
INtegratioN of Trastuzumab Into perioperative chemotherapy of HER2 positive stomach cancer INNOVATION Trial Does the addition of trastuzumab ± pertuzumab increase pathologic complete response rate in HER2-overexpressing gastric cancer? CF or CX Surgery Enrollment: Resectable Gastric or GEJ adenocarcinoma, HER2+ CF or CX + trastuzumab Surgery CF or CX + trastuzumab + pertuzumab Surgery
MAGIC-B (ST03) Trial HER2 Overexpressing Subset Does the addition of lapatinib in HER2-overexpressing tumors provide additional benefit to perioperative chemotherapy? ECX x 3 cycles Surgery ECX x 3 cycles Enrollment: Resectable Gastric or GEJ adenocarcinoma ECX + bevacizumab x 3 cycles Surgery ECX + bevacizumab x 3 cycles bevacizumab x 6 cycles ECX + lapatinib x 3 cycles Surgery ECX + lapatinib x 3 cycles lapatinib x 6 cycles (HER2+)
The Cancer Genome Atlas (TCGA) 295 Primary Gastric Adenocarcinomas TCGA. Nature 2014; 513: 202-209
The Cancer Genome Atlas (TCGA) 295 Primary Gastric Adenocarcinomas TCGA. Nature 2014; 513: 202-209
Precision Medicine Anatomic and Genomic Characterization
Summary Two drug approaches now appear more favorable over three drug approaches for neoadjuvant/perioperative chemotherapy If neoadjuvant chemotherapy is given, continuation of adjuvant chemotherapy after surgery without radiation remains standard of care Targeted therapies/biologic agents have not yet entered standard of practice For all stages of disease continued investigation needs to be performed to discover predictive biomarkers to optimize currently available and future therapies