Moving The Bar in Upper GI Malignancies: A Review of Recent Upper Gastrointestinal Phase III Studies – Clinically Meaningful or Just Statistically Positive? Eileen M. O’Reilly, M.D. Associate Member, Associate Attending Memorial Sloan-Kettering Cancer Center Associate Professor Weill Medical College of Cornell University
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Moving The Bar in Upper GI Malignancies: A Review of Recent Upper Gastrointestinal Phase III Studies – Clinically Meaningful or Just Statistically Positive?
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Moving The Bar in Upper GI Malignancies: A Review of Recent Upper Gastrointestinal Phase III Studies – Clinically Meaningful or
Just Statistically Positive?
Eileen M. O’Reilly, M.D.Associate Member, Associate AttendingMemorial Sloan-Kettering Cancer Center
Associate ProfessorWeill Medical College of Cornell University
Three Perspectives
• Review of Recent Phase III Studies in Upper Gastrointestinal Malignancies– Eileen M. O’Reilly, M.D.
• Health Care Economics in Relation to Upper Gastrointestinal Cancers– Neal J. Meropol, M.D.
• Statistical Review of the benefit: Is it Meaningful?– Donna Niedzwicki, Ph.D.
• Trastuzumab has benefit in Her-2 overexpressing GC cell lines and Her-2+ tumors in mice xenografts
Fujimoto, 2007. Gravolos, 2008. Kim, Int J Oncol, 2008. Kasprzyk, PG, Cancer Res, 1992
Bang, Y., et al. Lancet, 2010
ToGA Trial: Gastric CancerRandomized Phase III
Stratification₋ Location: Stomach vs GE junction₋ Measurable vs non-measurable₋ ECOG 0-1 vs 2₋ Fluropyrimidine: 5-FU (800mg/m2 IV d 1-5) vs capecitabine (1000mg/m2 PO BID d 1-14)
N= 3807 screened↓
N= 810 (22%)Her-2 Positive GC
↓N= 594 eligible
N= 294 FU + Cisplatin 80 mg/m2
x 6 cycles + Trastuzumab q 3wks
N= 290 FU + Cisplatin 80 mg/m2
x 6 cycles
RANDOMIZE
Bang, Y., et al. Lancet, 2010
ToGA Design & Endpoints
• Randomized, double-blind, placebo-controlled• Her-2 testing – central lab (Germany)
– Positive: IHC 3+ or FISH+ (> 2) in IHC 0, 1+ or 2+
• 65% risk reduction in POD/(death)• Mostly grade 1-2 side effects• Mature survival data pending• Benefit in subpopulations (further data poster
discussion session 6/6)• Long-term use question• Combination therapy?
PNETs and Sunitinib
• PNET’s– Angiogenesis key role in development PNET’s– High VEGF expression correlated with poorer prognosis– Express PDGFR, c-KIT, VEGFR2, VEGFR3, EGF
• EMEA approved 12/10; FDA approved 05/11 • Concerns about study design
– Small trial, N= 171– Only 28% of 260 planned PFS events – inflated
effect?– Several unplanned analyses– High cross-over rate – Side effects of sunitinib
Integration of Therapy in PNET
• Everolimus, sunitinib – new options in rare malignancy• What’s the best time to start therapy?• Which therapy first?• Toxicity profile• How to sequence with other systemic/regional
treatment approaches?• Combination of targeted medications?• Role of systemic chemotherapy, e.g., temozolomide +
capecitabine
Pancreas Adenocarcinoma
Example of statistically significant phase III trial but clinically limited therapeutic impact
Moore, M. J Clin Oncol, 2007
NCI PA.3 Phase IIIGemcitabine/Erlotinib vs Gemcitabine/Placebo
Randomization 1: 1Stratification Locally advanced vs M1 Center PS 0-1 vs 2
N= 569 LA or M1 Untreated Pancreas Adenoca
N= 284 Gemcitabine + Placebo
N= 285 Gemcitabine + Erlotinib
(100mg, 150mg)
RANDOMIZE
PA.3 Study Design & Endpoints
• Randomized phase III, double-blind, placebo-controlled
Overall response rate 32% 9.4%Stable disease 39% 42%Rate of disease control 70% 51%
FOLFIRINOX vs Gemcitabine
Conroy, T. NEJM, 2011
Phase III Trials in Upper GI Malignancies:Clinically Meaningful or Statistically Significant?
• Practice changing results in some cases– Trastuzumab, FOLFIRINOX
• Statistically significant: Erlotinib• We don’t fully now yet: Everolimus, sunitinib • Drug approvals in rare diseases – PNET• New FDA precedent: PFS in diseases with long hx• Era of cost constraints: all agents palliative, all
expensive and all have added toxicity• Future – strength of rationale for agent, robustness