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Discussion Pancreatic Cancer Abstracts 145, LBA146, 147, & LBA148 Philip Agop Philip, MD, PhD, FRCP Karmanos Cancer Center Wayne State University Detroit,

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Presentation on theme: "Discussion Pancreatic Cancer Abstracts 145, LBA146, 147, & LBA148 Philip Agop Philip, MD, PhD, FRCP Karmanos Cancer Center Wayne State University Detroit,"— Presentation transcript:

1 Discussion Pancreatic Cancer Abstracts 145, LBA146, 147, & LBA148 Philip Agop Philip, MD, PhD, FRCP Karmanos Cancer Center Wayne State University Detroit, Michigan

2 Randomized phase III trial of adjuvant chemotherapy with gemcitabine vs. S-1 for resected pancreatic cancer patients (JASPAC 01 study) K. Uesaka, et al. Japan Adjuvant Study Group of Pancreatic Cancer (JASPAC) Abstract #145

3 #145 2013 ASCO GI JASPAC 01 Randomization GEM 1000 mg/m 2 Q 4 weeks X 6 cycles S-1 40-60mg, BID, PO 4 wks on/2 wks off X 4 cycles Surgery Stratification Center R0/R1 N0/N1

4 #145 2013 ASCO GI JASPAC 01 Randomization GEM 1000 mg/m 2 X 6 cycles S-1 40-60mg, BID, PO 4 wks on/2 wks off X 4 cycles Surgery Stratification Center R0/R1 N0/N1 No Radiotherapy!

5 JASPAC 01 Overall Survival Primary Endpoint S-1 GEM

6 Gemcitabine vs. Fluoropyrimidine (FP): Phase III Adjuvant Studies CONKO-001RTOG 97-04ESPAC-3JASPAC 01 GEM v ObsGEM v inf-FU + C-RT GEM v b-FUGEM v S-1 mDFS mon GEM13.411.414.311.2 FP-10.114.123.2 mOS mon GEM22.820.523.625.5 FP-16.92346.3 Oettle et al, JAMA, 297:267-277, 2007; Regine et al, 299:1019-1026, 2008; Neoptolemus et al, 304:1073-1081, 2010;

7 Gemcitabine vs. Fluoropyrimidine (FP): Phase III Adjuvant Studies CONKO-001RTOG 97-04ESPAC-3JASPAC 01 GEM v ObsGEM v inf-FU + C-RT GEM v b-FUGEM v S-1 mDFS mon GEM13.411.414.311.2 FP-10.114.123.2 mOS mon GEM22.820.523.625.5 FP-16.92346.3 Node positive, %72677263 R0, %81666587

8 JASPAC 01 Superiority of adjuvant S-1 over GEM in Japanese patients with resected panc. ca. “Non-Japanese” studies must be considered to define the role of S-1 in early and late stage disease in conjunction with biomarkers studies (e.g., S-1 metabolism) The role of adjuvant radiation therapy in panc. ca will be determined by the ongoing RTOG/SWOG/EORTC study

9 Randomized Phase III Study of Weekly nab-Paclitaxel plus Gemcitabine vs Gemcitabine Alone in Patients with Metastatic Adenocarcinoma of the Pancreas (MPACT) Daniel D. Von Hoff, et al. Abstract #148

10 Study Design Planned N = 842 Stage IV No prior treatment for metastatic disease Karnofsky PS ≥70 Measurable disease Total bilirubin ≤ULN Planned N = 842 Stage IV No prior treatment for metastatic disease Karnofsky PS ≥70 Measurable disease Total bilirubin ≤ULN nab-Paclitaxel 125 mg/m 2 IV qw 3/4 weeks + Gemcitabine 1000 mg/m 2 IV qw 3/4 weeks nab-Paclitaxel 125 mg/m 2 IV qw 3/4 weeks + Gemcitabine 1000 mg/m 2 IV qw 3/4 weeks Gemcitabine 1000 mg/m 2 IV qw for 7 weeks then qw 3/4 weeks Gemcitabine 1000 mg/m 2 IV qw for 7 weeks then qw 3/4 weeks Von Hoff

11 IMPACT: Efficacy nab-Pacli + GEM GEMHazard ratio p value Med OS, mos8.56.70.72/ 0.000015 Med PFS, mos5.53.70.69/ 0.000024 12-mon alive, %35220.0002 Objective response, % 2371.1x10 -10

12 Major Treatment Options for Metastatic Pancreatic Cancer Gemcitabine +/- erlotinib FOLFIRINOX Nab-paclitaxel plus gemcitabine Others (e.g., GemCape, GTX) Clinical trial

13 Major Treatment Options for Metastatic Pancreatic Cancer Gemcitabine +/- erlotinib FOLFIRINOX Nab-paclitaxel plus gemcitabine Others (e.g., GemCape, GTX) Clinical trials

14 Tolerability: Selected Grade 3+ Toxicities, % nab-pacli + GEM FOLFIRINOX Fatigue1723.6 Diahhrea612.7 Neuropathy179 Neutropenia3845.7 Neutropenic fever35.4 Thrombocytopenia139.1 Conroy et al, NEJM, 364:1817-1825, 2011

15 Efficacy nab-pacli + GEM FOLFIRINOX Median OS, mos8.711.1 Median PFS, mos 5.56.4 ORR (%)23.031.6 Conroy et al, NEJM, 364:1817-1825, 2011

16 Study Populations IMPACTPRODIGE/AC CORD Median age median6361 Liver, %8488 Head of pancreas, %4338 Males, %5861 Good PS, %6038 Median sites of mets32 Number of patients861342 Treatment centersMultiple countries Conroy et al, NEJM, 364:1817-1825, 2011

17 IMPACT Is an example of pre-clinical to pilot testing to Phase III drug stepwise developmental program Nab-paclitaxel plus GEM is a new frontline regimen in patients with metastatic panc. ca. and favorable performance status Nab-paclitaxel +/- GEM (or other drugs) must be investigated in earlier stage disease and in combinations with biologicals The molecular basis of nab-paclitaxel’s activity and its association with a biomarker(s) must be determined (going back to the lab!)

18 Induction GEMCAP Chemotherapy followed by Gemcitabine (Gem) or Capecitabine (Cap)-based Chemoradiation (CRT) for Locally Advanced Pancreatic Cancer (LAPC): the Final Results of the SCALOP Trial S Mukherjee, et al. SCALOP Investigators Abstract LBA146

19 GEMCAP x 3 cycles Gem 1000mg/m 2 D1,8,15 q 4w Cap 830mg/m 2 BD D 1-21 q 4w RANDOMIZATION GEMCAP x 1 cycle Gemcitabine 300mg/m 2 /week + RT 50.4Gy Capecitabine 830mg/m 2 bd + RT 50.4Gy Progressive dx Tumor >6cm diameter PS 2 >10% wt loss Not encompassable in radiation volume SCALOP

20 GEMCAP x 3 cycles Gem 1000mg/m 2 D1,8,15 q 4w Cap 830mg/m 2 BD D 1-21 q 4w RANDOMIZATION GEMCAP x 1 cycle Gemcitabine 300mg/m 2 /week + RT 50.4Gy Capecitabine 830mg/m 2 bd + RT 50.4Gy Progressive ds Tumor >6cm diameter PS 2 >10% wt loss Not encompassable in radiation volume SCALOP 35%

21 GEMCAP x 3 cycles Gem 1000mg/m 2 D1,8,15 q 4w Cap 830mg/m 2 BD D 1-21 q 4w RANDOMIZATION GEMCAP x 1 cycle Gemcitabine 300mg/m 2 /week + RT 50.4Gy Capecitabine 830mg/m 2 bd + RT 50.4Gy Progressive ds Tumor >6cm diameter PS 2 >10% wt loss Not encompassable in radiation volume SCALOP 4 cycles/4 months of systemic therapy

22 Summary of Efficacy Data CAPE-RTGEM-RTp PFS at 9 mos, %62.951.4NS Median PFS, mos12.010.4NS Med OS, mos15.213.40.025 AllRandomizedTaken off N1147440 Med OS, mos12.714.68.1

23 What do we learn from SCALOP? Cape-RT is the current preferred standard and will continue as such Ongoing research questions –The contribution of chemo-RT (GERCOR, Dr P. Hammel; ALLIANCE, Dr A. Ko) –Molecular selection for chemo-RT (RTOG, Dr E. Ben Josef) –More effective systemic therapies Develop study designs and endpoints that are appropriate to each question

24 M. J. Pishvaian, et al. A Phase I/II Study of ABT-888, 5- Fluorouracil and Oxaliplatin in Patients with Metastatic Pancreatic Cancer Abstract #147

25 Phase Ib No patient selection Pre-treatment biopsies for BRCA-1, -2, PALB- B3, FANC gene expression, others

26 PARPi and Pancreatic Cancer A platinum +/- PARPi strategy is worth pursuing in patients with BRCA-2 mutations Explore biologic combinations with PARPi Need to determine relative contributions of platinum vs. PARPi to anti-tumor activity National or “preferably” international collaborative effort is necessary for a timely completion of clinical trials (e.g., ARCAD)

27 Thank you

28 backup

29 Take Home Messages Adjuvant S-1 is a new standard for resected pancreas ca. with a potential for its development outside of Japan nab-Paclitaxel/GEM is a new treatment standard for patients with metastatic pancreas ca. warranting further development in conjunction with a biomarker discovery strategy

30 Take Home Messages (2) Capecitabine 1.66 grams/m 2 /day will continue to be our radisoenstizer of choice in pancreas ca. A treatment strategy of a platinum compound +/- PARPi needs pre-clinical/pilot clinical evaluations in BRCA-2 mutated panc. ca. More tissue-based research and stronger collaborative efforts are necessary for successful studies in pancreatic cancer!

31 Gemcitabine vs. Fluoropyrimidine (FP): Phase III Adjuvant Studies CONKO-001RTOG 97-04ESPAC-3JASPAC 01 GEM v ObsGEM v inf-FU + C-RT GEM v b-FUGEM v S-1 mDFS mon GEM13.411.414.312 FP-10.114.124 mOS mon GEM22.820.523.623 FP-16.92346 Hazard ratio for overall survival0.800.940.56 Oettle et al, JAMA, 297:267-277, 2007; Regine et al, 299:1019-1026, 2008; Neoptolemus et al, 304:1073-1081, 2010;


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