Pancreatic Ca Update Caio Max S. Rocha Lima, M.D. M. Robert Cooper Professor in Medical Oncology Co-leader GI Oncology and Co-leader Phase I Program Wake Forest School of Medicine E-mail:crochali@wakehealth.edu
Financial Disclosure I currently have or have had the following relevant financial relations to disclose: -Speaker s Bureau: Celgene, Ypsen Oncology -Honorarium/Fees Paid: Celgene, Ypsen Oncology Wake Forest Baptist Medical Center 2
Off Label Use Disclosure I do not intend to discuss an off label use of a product during this activity. Wake Forest Baptist Medical Center 3
Wake Forest Baptist Medical Center Pancreatic Cancer
Pancreatic Adenocarcinoma Pancreatic ductal adenocarcinoma (PDAC) is now the third leading case of cancer deaths in the USA Although there have been recent advancements in systemic therapy for metastatic disease with the FOLFIRINOX and gemcitabine/nabpaclitaxel regimens, the survival rates for PDAC remain poor The most established risk factor pancreas cancer is cigarette smoking and is associated with about 25% of the cases. A minority of PDAC patients (less than 20%) are diagnosed at an early stage where surgery may be beneficial Ø In these patients, accurate staging is required to define potential resectability In patients with resectable PDAC, the current standard of care is upfront surgery followed by adjuvant therapy 1. American Cancer Society 2016. Cancer Facts and Figures 2. Fuchs CS et al. Arch Intern Med. 1996 Oct;156(19):2255-60.
Adjuvant Therapy Wake Forest Baptist Medical Center 6
CONKO-001 Resected pancreatic cancer 368 patients Stratification: R; T; N Gemcitabine for six months Observation for six months Follow up every eight weeks Oettle H et al. JAMA. 2007;297(3):311-313.
CONKO-001 Survival Results Median DFS13.4 vs. 6.7 months Median OS 22.8 vs. 20.2 months Oettle H et al. JAMA. 2007;297(3):311-313. Abbreviations: DFS, disease free survival; OS, overall survival
ESPAC-3, N=1,088: Gemcitabine Not Better Than 5-FU/FA Median S(t)= 23.0 months (95%CI:21.1, 25.0) Median S(t)= 23.6 months (95%CI:21.4, 26.4) c 2 LR=0.74, p=0.39, HR GEM VS. 5FU/FA =0.94 (95%CI: 0.81, 1.08) Months from Resection No. at Risk 5FU/FA 551 413 249 109 36 15 GEM 537 415 251 103 42 13 Neoptolemos J, et al. J Clin Oncol 34, 2016 (suppl; abstr LBA4006)
ESPAC-4 Trial Stratified log-rank test with 5% 2-sided α, for a 10% difference in 2 year survival, 90% power = 480 events = 722 patients, 361 in @ arm 722 patients Pancreatic ductal adenocarcinoma curative resection < 12 weeks RANDOMIZATION at Liverpool Cancer Trials Unit GEMCITABINE 1000mg/m 2 Days 1, 8, & 15 for 6 cycles GEMCITABINE 1000mg/m2 Days 1, 8, & 15 for 6 cycles CAPECITABINE 1660mg/m2 /day -21-28d i.e. 24 weeks Neoptolemos J. Lancet 389; 1011, 2017 3-monthly follow up from randomization to death
ESPAC-4: Overall Survival Neoptolemos J. Lancet 389; 1011, 2017
ESPAC-4: Reported Toxicity Number of patients in Safety Set with at least one NCI CTC v4 grade 3/4 event CTC 3/4 event * Exploratory analysis: Fisher s exact test GEM Number of patients (% of 366) P-value* GEMCAP Number of patients (% of 359) Anaemia 14 (4%) 0.279 8 (2%) Diarrhoea 6 (2%) 0.008 19 (5%) Fatigue 19 (5%) 0.870 20 (6%) Fever 6 (2%) 1.000 6 (2%) Infection and infestations, Other 24 (7%) 0.012 9 (3%) Lymphocytes 11 (3%) 0.821 9 (3%) Neutrophils 89 (24%) <0.001 137 (38%) Hand-Foot syndrome 0 (0%) <0.001 26 (7%) Platelets 7 (2%) 0.800 8 (2%) Thromboembolic event 9 (2%) 1.000 8 (2%) WBC 28 (8%) 0.242 37 (10%) Neoptolemos J. Lancet 389; 1011, 2017
ESPAC Trials: Summary of Results Trial ESPAC-1 ESPAC-3 ESPAC-4 Treatment Number of patients (N=2,092) 5-Year OS (95% CI) 5FU/FA 149 21 (14.6 28.5) % No chemotherapy 143 8.0 (3.8-14.1) % Chemoradiotherapy (5FU/Rad) 145 10.8 (6.1-17.0) % GEM 539 17.5 (14.0-21.2) % 5FU/FA 551 15.9 (12.7-19.4) % GEM 366 16.3 (10.2-23.7) % GEMCAP 364 28.8 (22.9-35.2) % Stratified Log-Rank x 2 p-value 7.03 0.030* 0.74 0.390* 4.61 0.032 *Stratification factor: resection margin status; stratification factors: resection margin status and country Neoptolemos J. Lancet 389; 1011, 2017
Slide 3 Presented By Thierry Conroy at 2018 ASCO Annual Meeting
Key Inclusion Criteria Presented By Thierry Conroy at 2018 ASCO Annual Meeting
Safety: main nonhematologic AEs Presented By Thierry Conroy at 2018 ASCO Annual Meeting
Disease-Free Survival Presented By Thierry Conroy at 2018 ASCO Annual Meeting
Slide 21 Presented By Thierry Conroy at 2018 ASCO Annual Meeting
Conclusions Presented By Thierry Conroy at 2018 ASCO Annual Meeting
PANCREAS CANCER NEO-ADJUVANT THERAPY PERIOPERATIVE THERAPY
Trial design Presented By Geertjan Van Tienhoven at 2018 ASCO Annual Meeting
Results Presented By Geertjan Van Tienhoven at 2018 ASCO Annual Meeting
Overall survival (ITT) Presented By Geertjan Van Tienhoven at 2018 ASCO Annual Meeting
Disease free survival Presented By Geertjan Van Tienhoven at 2018 ASCO Annual Meeting
Metastases and local recurrence (ITT) Presented By Geertjan Van Tienhoven at 2018 ASCO Annual Meeting
Conclusion Presented By Geertjan Van Tienhoven at 2018 ASCO Annual Meeting
We Have Made Progress in the 1 st -Line Metastatic Setting Trial 1 Date Patients (n) Treatment Burris et al 2 1997 NCIC 3 2007 PRODIGE 4 2011 Ueno, et al 5 2013 MPACT 6 2013 126 (unresectable, LA or metastatic pancreatic cancer) 569 (unresectable, LA or metastatic pancreatic cancer) 342 (metastatic) 834 (LA, or metastatic pancreatic cancer) 861 (metastatic) 5-FU vs. gemcitabine gemcitabine vs. gemcitabine + erlotinib gemcitabine vs. FOLFIRINOX gemcitabine vs. S-1 vs. gemcitabine + S-1 gemcitabine vs. gemcitabine + nab-paclitaxel Median survival (mo) 4.41 5.65* 5.91 6.24 6.8 11.1 8.8 9.7 10.1 6.7 8.5 P value Log-Rank Test 0.0025 0.038 (HR = 0.82 [95% CI, 0.69 0.99]) <0.001 (HR = 0.57 [95% CI, 0.45 0.73]) gemcitabine vs. S-1: <0.001 (non-inferiority; HR = 0.96 [97.5% CI, 0.78 1.18]) gemcitabine vs. gemcitabine + S-1: 0.15 (superiority; HR = 0.88 [97.5% CI, 0.71 1.08]) <0.001 (HR = 0.72 [95% CI, 0.62 0.83]) 1. Ryan DP, et al. N Engl J Med 2014;371:1039; 2. Burris HA, et al. J Clin Oncol 1997;15:2403; 3. Moore MJ, et al. J Clin Oncol 2007;25:1960; 4.Conroy T, et al. N Engl J Med 2011;364:1817; 5. Ueno H, et al. J Clin Oncol 2013;31:1640; 6. Von Hoff DD, et al. N Engl J Med 2013;369:1691.
1 st -line treatment of MPC Nab-paclitaxel + gemcitabine or FOLFIRINOX? Nab-P/Gem (n=431) FOLFIRINOX (n=171) Sites Global France Age >75? Yes? PS 0-2 0-1 Efficacy RR,% PFS, months OS (updated), months 1 year, % Safety, G 3 events, % Febrile neutropenia Growth factors Fatigue Vomiting Diarrhoea Neuropathy 29 5.5 8.7 35 3 26 17 3 6 17 b 31.6 6.4 11.1 48 5 43 24 15 13 9 1. Von Hoff et al. N Engl J Med 2013;369:1691-703; 2. Goldstein et al. JNCI 2015; Jan 31;107. pii: dju413. doi: 10.1093/jnci/dju41; 3. Conroy et al. NEJM 2011;364:1817-25
Design of PRODIGE 35 PANOPTIMOX study Wake Forest Baptist Medical Center Presented By Laetitia Dahan at 2018 ASCO Annual Meeting
PRIMARY ENDPOINT (mitt): <br />6 months Progression Free Survival rate Wake Forest Baptist Medical Center Presented By Laetitia Dahan at 2018 ASCO Annual Meeting
PROGRESSION FREE SURVIVAL (PFS) Wake Forest Baptist Medical Center Presented By Laetitia Dahan at 2018 ASCO Annual Meeting
OVERALL SURVIVAL (OS) Wake Forest Baptist Medical Center Presented By Laetitia Dahan at 2018 ASCO Annual Meeting
CONCLUSIONS Wake Forest Baptist Medical Center Presented By Laetitia Dahan at 2018 ASCO Annual Meeting
Key Eligibility (N=417) NAPOLI-1: PHASE 3 STUDY OVERVIEW 1,2 Confirmed metastatic pancreatic cancer Progression of locally advanced or metastatic disease Prior gemcitabinebased therapy Normal bilirubin Albumin 3.0 g/dl KPS 70 R ONIVYDE (irinotecan liposome injection) 100 mg/m 2, q3w 5-FU/LV 2000/200 mg/m 2 weekly x 4, q6w Initial design n=33 n=30 ONIVYDE + 5-FU/LV 70 mg/m 2 + 2400/400 mg/m 2, q2w After amendment n=118 n=119 Stratification factors: Albumin (<4.0 g/dl vs 4.0 g/dl); KPS (70 and 80 vs 90); and ethnicity (Caucasian vs East Asian vs others) Treatment continued until disease progression or unacceptable toxicity Total n=151 n=149 n=117 n=117 Please see Important Safety Information, including Boxed WARNING, within this presentation and accompanying full Prescribing Information for ONIVYDE. KPS=Karnofsky performance status. References: 1. Wang-Gillam A, et al. Lancet. 2016;387:545 557. Wake Forest Baptist Medical Center 22
EXTENDED OVERALL SURVIVAL 1 ONIVYDE (IRINOTECAN LIPOSOME INJECTION) + 5-FU/LV DEMONSTRATED A STATISTICALLY SIGNIFICANT INCREASE IN MEDIAN OS VS 5-FU/LV Probabilityof Survival 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0 3 6 9 12 15 18 # at risk: Time From Randomization (Months) ONIVYDE + 117 99 51 20 8 0 5-FU/LV 5-FU/LV 119 73 37 12 7 1 Median OS HR=0.68 [95% CI: 0.50, 0.93]; log-rank p=0.014 ONIVYDE + 5-FU/LV (95% CI: 4.8, 8.5) 5-FU/LV (95% CI: 3.3, 5.3) 6.1 MONTHS 4.2 MONTHS ONIVYDE is not indicated as a single agent for the treatment of patients with metastatic adenocarcinoma of the pancreas. There was no improvement in OS for ONIVYDE vs 5-FU/LV (HR=1.00; p=0.97 [two-sided log-rank]) Please see Important Safety Information, including Boxed WARNING, within this presentation and accompanying full Prescribing Information for ONIVYDE. Reference: Wake 1. ONIVYDE Forest Baptist [packaemedical insert]. Ipsen Center Biopharmaceuticals, Inc.; 2017. 31
Current Approach in Treatment Sequencing for mpca 3 rd line 2 nd line 1 st line Gemcitabine-Nabpaclitaxel (PS 0-1): Nal-Irinotecan+ 5FU (PS 2): 5FU, Capecitabine or BSC (PS 0-1): Platinum-based regimen if no prior exposure FOLFIRINOX (PS 0-1): Gemcitabine/nabpaclitaxel? (PS 2): Gemcitabine or BSC?? BSC, best supportive care; PS, performance status.
HALO-202 Randomized Phase 2 Study of PEGPH20 Plus nab-paclitaxel/ Gemcitabine (AG) vs. AG in Patients with Untreated, Metastatic Pancreatic Adenocarcinoma All Patients ( Primary Analysis) High HA ( Exploratory Analysis) Combo PAG AG PAG AG N pts 166 113 49 35 mpfs (mos) 6 5.3 9.2 5.2 HR 0.773 p=0.045 HR 0.51 p=0.048 mos (mos) 11.5 8.5 HR p HR 0.96 p=0.88 RR (%) 40 33 45 31 Main AEs PAG: Fatigue, Hematologic and thromboembolic events AG : Fatigue and Hematologic Hingorani SL. Abs 4008. ASCO 2017, Wake Forest Baptist Medical Center
Which Subsets of Patients Might Benefit From Specific Therapies? MSI-high/mismatch repair-deficient (dmmr) 5/6 patients with dmmr pancreatic cancers showed objective response by RECIST to pembrolizumab BRCA- or PALB2- mutation carriers Rucaparib: 3/19 (16%) with objective response Olaparib: 5/23 pts (22%) with objective response Veliparib: 0/16 pts with objective response Wake Forest Baptist Medical Center 1. Kaufman, et al. J Clin Oncol. 2015;33:244-250. 2. Lowery, et al. ASCO 2015. Abstract 358. 3. Le D, et al. ASCO 2015. Abstract 195.
Slide 64 Presented By Dung Le at 2017 ASCO Annual Meeting
Conclusions 1 FOLFIRINOX is an adjuvant standard in pancreas cancer. PS, organ function, recovery from surgery Perioperative chemotherapy and preoperative hypofractionated radiotherapy is an emerging option for resectable and borderline resectable pancreas cancer Should we incorporate hypofractionated XRT to FOLFIRINOX? Alliance Trial Wake Forest Baptist Medical Center 41
Conclusions 2 Participation in clinical trials is paramount and should be the first line of choice. Folfirinox is an option in good organ function and PS 0-1. Gem/Nab is an option for patients with PS 0-2. Liposomal Irinotecan + 5- FU is the second-line option based on phase III data. Level 1 by NCCN guidelines. The sequence of treatment is dictated by patient characteristics and physician choice rather than efficacy.
Conclusions 3 In metastatic pancreas cancer FOLFIRINOX followed by maintenance 5FU is an option. Activity in MSI-High tumors is stablished Targeted Therapy and immunotherapy combo are emerging. Biomarkers to predict benefit from therapy are desperately needed. Wake Forest Baptist Medical Center
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