Systemic Treatments for Esophagogastric and Pancreas Cancer in the Adjuvant and Metastatic Settings

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1 Systemic Treatments for Esophagogastric and Pancreas Cancer in the Adjuvant and Metastatic Settings Peter C. Enzinger, MD Dana-Farber Cancer Institute & Harvard Medical School 2017 Master Class Course

2 Localized Esophageal Cancer What Can Surgery Accomplish?

3 Localized Esophageal Cancer Treated With Surgery Rice, Blackstone, Rusch. Ann Surg Oncol 2010

4 Localized Esophageal Cancer Does (Neo)Adjuvant Chemotherapy Improve Surgical Outcomes?

5 Neoadjuvant Chemotherapy Compared with Surgery Alone for Localized Esophageal Cancer Sjoquist et al. Lancet Oncol 2011;12(7):681-92

6 Localized Esophageal Cancer Does Neoadjuvant Chemoradiation Therapy Improve Surgery Outcomes?

7 All-Cause Mortality Estimates for Neoadjuvant C/RT Compared with Surgery Alone Sjoquist et al. Lancet Oncol 2011; 12(7):681-92

8 CROSS Study: Schema Chemoradiotherapy regimen: Paclitaxel 50mg/m 2 + Carboplatin AUC=2 on days 1, 8, 15, 22 and 29 Concurrent radiotherapy of 41.4 Gy in 23 fractions of 1.8 Gy Surgery within 6 weeks after completion of chemoradiotherapy (THE/TTE) Van Hagen et al. N Engl J Med 2012;366:

9 CROSS Study: Overall survival HR, 0.657; 95% CI mo 49.4 mo Van Hagen et al. N Engl J Med 2012;366:

10 POET: Schema Arm A PLF I PLF II PLF III (3 weeks) Surgery Week PLF I PLF II 15 x 2 Gy in 3 weeks Surgery Arm B PE (1 week) PLF: Cisplatin 50mg/m 2, 1h, d 1,15,29. Leukovorin/5-FU 500mg/m 2 2h / 2g/m2 24h, d1,8,15,22,29,36 PE: Cisplatin 50 mg/m 2, 1h, d 2+8. Etoposide 80 mg/m 2, 1h, d 3-5 Stahl M, et al. J Clin Oncol.2009;27:

11 POET: Overall Survival Arm A Arm B 47.4% 27.7% Log rank P = 0.07 HR Arm B vs A 0.67; 95% CI, ) Arm A Arm B Median survival 21.1 mo 33.1 mo Median follow-up 45.2 mo 46.2 mo Stahl M, et al. J Clin Oncol.2009;27:

12 Localized Esophageal Cancer Can Surgery Improve the Outcome of Chemoradiation?

13 Prospective Randomized Intergroup Study: Radiation Therapy vs Chemotherapy + Radiation Therapy for Localized SCC or ADC of the Esophagus Schema tumor size histology weight loss R A N D O M I Z E 2 x Cisplatin (75 mg/m 2 ) + 5-fluorouracil (1000 mg/m 2 /d CI x 4d) + radiation therapy (5000 cgy) radiation therapy (6400 cgy) Herskovic A, et al. N Engl J Med. 1992;326: al-sarraf M, et al. J Clin Oncol. 1997;15:

14 Intergroup Study Herskovic A, et al. N Engl J Med. 1992;326: al-sarraf M, et al. J Clin Oncol. 1997;15:

15 Prodige 5 - ACCORD 17 - Schema Inoperable esophageal cancer R A N D O M I Z E 50 Gy/5 weeks + Folfox, 3 cycles 50 Gy/5 weeks + 5FU/cisplatin, 2 cy. Folfox, 3 cycles 5FU/cisplatin, 2 cycles Stratification : adenocarcinoma vs squamous cell vs adenosquamous pretreatment weight loss < 10% vs 10% performance status: 0 vs 1 vs 2 center Conroy et al. Lancet Oncol Mar;15(3):

16 Prodige 5 - ACCORD 17 - Survival FOLFOX: more gr. 1-2 PN, fewer toxic & sudden deaths, less mucositis, less alopecia, decreased renal toxicity, shorter chemotherapy (12 days vs days) in an outpatient setting. Conroy et al. Lancet Oncol Mar;15(3):

17 Chemoradiation Therapy With or Without Surgery: French Phase III Trial A total of 455 patients with localized esophageal cancer were given 2 courses of 5-FU/cisplatin plus radiation therapy. 259/455 patients experienced a partial response, were considered operative candidates, and entered the randomized component of the trial. Bedenne. J Clin Oncol. 2007;25:

18 Chemoradiation Therapy With or Without Surgery: French Phase III Trial 3-month Survival mortality median 2-year Partial Response (259 pts) R A N D O M I Z E 5-FU/CDDP x 3 + 1% Radiation therapy 19.3 months Surgery 9% 17.7 months 40% P= % Bedenne. J Clin Oncol. 2007;25:

19 Chemoradiation Therapy With or Without Surgery: German Phase III Trial - Schema Patients: (N = 177) ut3-4,n0-1, M0 with SCC 3 cycles: 5-FU/LV + Cisplatin + Etoposide R A N D O M I Z E Chemoradiation: Cisplatin + Etoposide + 40 Gy RT Surgery Chemoradiation: Cisplatin + Etoposide + > 60 Gy RT Stahl. J Clin Oncol. 2005;23:

20 Chemoradiation Therapy With or Without Surgery: German Phase III Trial - Results Arm Completed Treatment 3-yr Local Median 3-Year Survival Treatment Mortality Recurrence Survival Induction Chemo All Responder Arm A: C/RT S 62% 12.8% 41% 16 mo. 31% 54% Arm B: C/RT 85% 3.5% 64% 15 mo. 24% 54% (P = 0.03) (P = 0.004) (P = 0.02) Stahl. J Clin Oncol. 2005;23:

21 Chemoradiation Therapy With or Without Surgery: German Phase III Trial - Survival Median survival (N = 172): Arm A (C/RT S) months Arm B (C/RT only)-14.9 months 31.3% (P = 0.02) 24.4% Stahl. J Clin Oncol. 2005;23:

22 Conclusions from these Studies Localized Esophageal Pre-operative cisplatin/5-fu chemotherapy offers a small survival advantage in distal esophageal and GE junction cancer. Neoadjuvant platinum-based chemoradiation (esp. w. carbo/tax) offers a greater survival advantage with better local control but increased surgical morbidity. Surgery may not be needed in patients who have a clinical response to chemoradiation. FOLFOX may be the best choice for these patients.

23 Localized Gastric Cancer What Can Surgery Accomplish?

24 Survival for Resected Localized Gastric Cancer Survival for 10,601 patients with resected gastric cancer using SEER data and AJCC 7 th ed. Washington. Ann Surg Oncol 2010

25 Localized Gastric Cancer What are Proven Strategies to Enhance Outcomes for Surgical Resection?

26 Intergroup Protocol 0116 Adjuvant Therapy for Gastric Cancer Stratify R depth of tumor penetration number involved nodes A N D O M 5-FU/leucovorin x 1 5-FU/leucovorin cgy radiation 5-FU/leucovorin x 2 location of tumor I Z observation extent of surgery E Macdonald JS, et al. N Engl J Med. 2001;345(10):

27 Intergroup Protocol years 41% 50% Chemoradiotherapy Surgery Only Macdonald JS, et al. N Engl J Med. 2001;345: Smalley SR, et al. J Clin Oncol. 2012; 30:

28 MAGIC Trial: Schema Cunningham D, et al. N Engl J Med. 2006;355: Patients: 15% Lower Third 12% GE Junction ECF x 3 q3/ weeks CSC S Within 6 weeks Resection Resection 6-12 weeks ECF x 3 q3/52 Follow-up

29 MAGIC: Survival

30 CALGB 80101: Study Schema R A N D 5-FU/LV X1 5-FU IVCI RT 5-FU/LV X2 O M I ECF 5-FU IVCI ECF Z E X1 RT X2 All pts treated with: RT: 45 Gy (1.8 Gy X 25 fractions) with 5-FU 200 mg/m2/d CI Mayo 5-FU/LV: 5-FU 425 mg/m2 d1-5, LV 20 mg/m2 d1-5 ECF (pre-rt): Epirubicin 50mg/m2 d1, Cisplatin 60mg/m2 d1, & 5-FU 200mg/m2/d1-21 ECF (post-rt): Epirubicin 40mg/m2 d1, Cisplatin 50mg/m2 d1, & 5-FU 200mg/m2/d1-21 Fuchs. ASCO 2011

31 CALGB 80101: Overall Survival by Treatment Arm Overall Survival by Arm Proportion Surviving Years from Study Entry ECF 5-FU P, log rank = 0.80 Fuchs. ASCO 2011

32 ITACA-S: Intensive Adjuvant Chemo vs. 5FU/LV

33 ITACA-S: Intensive Adjuvant Chemo vs. 5FU/LV Despite significantly increased toxicity: Bajetta et al. Ann Oncol 2014; 25:

34 What s going on in SouthEast Asia? CLASSIC TRIAL - Schema Stage II-IIIB Gastric D2 R0 Resection Stratified: Country (S. Korea vs. China vs. Japan) Stage (II vs. IIIa vs. IIIb) N = 520 R N = 515 CAPOX x 8 (6 months): Capecitabine: 1000/m 2 twice daily d1-14; q3 wks Oxaliplatin 130/m 2 d1; q3 weeks Observation Primary endpoint: 3yr Disease-Free Survival Bang et al. Lancet 2012; 379:

35 CLASSIC TRIAL (SE Asia): Survival Disease-Free Survival Overall Survival 5-yr DFS: HR 0.58; p<0.0001) Surgery: 53% (47-58) S+CAPOX: 68% (63-73) 5-yr OS: HR 0.66; p=0.0015) Surgery: 69% (64-73) S+CAPOX: 78% (74-82) Noh et al. Lancet Oncol 2014; 15:

36 ARTIST TRIAL (S. Korea): Schema Stage IB-IV(M0) Gastric D2 R0 Resection Stratified: Not stated N = 228 R N = 230 XP x 6 cycles (18 weeks): Capecitabine 2000mg/2; d1-14 (q3weeks) Cisplatin 60mg/m2; d1 (q3weeks) XP/XRT/XP (17+ weeks): XP x 2 cycles XRT 45Gy / Cape 1650mg/m2 x 5 weeks XP x 2 cycles Primary endpoint: Disease-Free Survival Lee et al. J Clin Oncol 2012: 30(3);

37 ARTIST Trial (S. Korea) : Efficacy Disease-Free Survival Overall Survival DFS: 0.74; p= yr DFS: 74% vs. 78% OS: 1.13; p= yr OS:73% vs. 75% How applicable is this in the West? Lee et al. J Clin Oncol 2012: 30(3);

38 Conclusions from these Results Localized Gastric: Post-operative 5-FU-based chemoradiation therapy remains the standard of care for muscle-invasive or LN positive disease. The MAGIC trial demonstrates that pre- and post-operative ECF improves survival. It may be particularly beneficial for downstaging extensive local disease. More aggressive chemotherapy is not better. Unclear how applicable data from SE Asia is for Western patients.

39 Metastatic Esophagogastric Cancer What are the Active Agents and Combinations for this Disease?

40 Evolution of Therapy in Advanced Esophagogastric Cancer Randomized Phase III Randomized Phase II Multi-center Phase II 5-FU < FAM FAM < FAMTX CF = ELF = FAMTX > EAP FOLFOX DC < DCF IP < FOLFIRI PELF = FAMTX < ECF FOL = CF FOX DCF > CF CF = FOLFIRI ECF > MCF FOL =ECF FOX mdcf FOLFIRI = EOX ECF = ECX = EOF = EOX

41 CALGB / ECOG E1206: Schema ARM A: (ECF + cetuximab); 1 cycle = 21 days Cetuximab mg/m2 IV, weekly Epirubicin 50 mg/m2 IV, day 1 Cisplatin 60mg/m2 IV, day 1 Fluorouracil 200mg/m2/day, days 1-21 Stratification: ECOG 0-1 vs 2 ADC vs. SCC ARM B: (IC + cetuximab); 1 cycle = 21 days Cetuximab mg/m2 IV, weekly Cisplatin 30 mg/m2 IV, days 1 and 8 Irinotecan 65 mg/m2 IV, days 1 and 8 ARM C: (FOLFOX + cetuximab); 1 cycle = 14 days Cetuximab mg/m2 IV, weekly Oxaliplatin 85 mg/m2 IV, day 1 Leucovorin 400 mg/m2, day 1 Fluorouracil 400 mg/m2 IV bolus, day 1 Fluorouracil 2400 mg/m2 IV over 46hrs (days 1-2) Enzinger. J Clin Oncol 2016

42 CALGB / E1206: Survival FOLFOX-C has similar efficacy to ECF-C in Esophageal and GEJ Cancer Progression-Free Survival Overall Survival Probability Progression-free Survival Events Median 95% CI n/n (%) months ECF-C 65/67 (97.0%) IC-C 72/73 (98.6%) FOLFOX-C 70/73 (95.9%) Log-rank test p= Months from Study Entry Probability Overall Survival Events n/n (%) Median 95% CI months ECF-C 63/67 (94.0%) IC-C 68/73 (93.2%) FOLFOX-C 65/73 (89.0%) Log-rank test p= Months from Study Entry Number of Patients at Risk ECF-C IC-C FOLFOX-C Number of Patients at Risk ECF-C IC-C FOLFOX-C Treatment modifications: FOLFOX-C (73%) vs IC-C (85%) vs ECF-C (91%) (χ 2, p=0.013). Discontinued treatment for adverse event or treatment-related death: FOLFOX-C (11%) vs. ECF-C (19%) vs IC-C (26%) (χ 2, p=0.17). Enzinger. J Clin Oncol 2016

43 Phase III: DCF vs CF for Esophagogastric Cancer Time to Progression Overall Survival Grade 3-4 Toxicity DCF CF Neutropenia 82% 57% Febrile Neutropenia 29% 12% Stomatitis 21% 27% Diarrhea 19% 8% Vomiting 14% 17% Van Cutsem et al. J Clin Oncol 2006

44 Randomized PII: Modified DCF vs. DCF for Met Gastric Grade 3-4 Toxicity mdcf DCF Neutropenia w GCSF 56% 45% Febrile Neutropenia 9% 16% Stomatitis 0 13% Diarrhea 6% 3% Vomiting 2% 19% Shah et al. JCO 2015;33:

45 Phase 3: FOLFIRI vs ECX for Met Gastric/GEJ Guimbaud. J Clin Oncol 2014

46 REAL-2: Schema Previously untreated patients with locally advanced or metastatic oesophagogastric cancer Stratified for: R A N D O M I S A T I O N - Center (63 centers, mainly UK, 2 Aus) - Locally advanced vs metastatic - PS 0/1 vs 2 2 x 2 design Epirubicin Cisplatin Fluorouracil Epirubicin Cisplatin Xeloda (capecitabine) Epirubicin Oxaliplatin Fluorouracil Epirubicin Oxaliplatin Xeloda (capecitabine) Cunningham D, et al. N Engl J Med. 2008;358:36-46.

47 REAL-2: Survival (ITT) 100 Arm OS (m) 1-year survival (95% CI) P-value HR (95% CI) Probability of survival (%) ECF EOF ECX EOX ( ) 40.4 ( ) 40.8 ( ) 46.8 ( ) EOX ( ) 0.92 ( ) 0.80 ( ) 20 ECF Time since randomisation (years) Cunningham D, et al. N Engl J Med. 2008;358: ECF EOF ECX EOX

48 ToGA - Schema Phase III, randomized, open-label, international, multicenter study 3807 patients screened HER2-positive (22.1%) Stratification factors Advanced vs metastatic GC vs GEJ Measurable vs non-measurable ECOG PS 0-1 vs 2 Capecitabine vs 5-FU HER2-positive advanced GC (n = 584) R 5-FU or capecitabine + cisplatin (n = 290) 5-FU or capecitabine a + cisplatin + trastuzumab (n = 294) a Chosen at investigator s discretion GEJ, gastroesophageal junction Bang, Y-J et al. Lancet 2010; 376:687

49 ToGA: Overall Survival 2.7 mo. (HER2 3+ or 2+/FISH+)

50 Metastatic Esophagogastric Cancer Is 2 nd line therapy of benefit?

51 Cougar-02: Randomized Trial of Docetaxel vs. BSC in Relapsed Esophagogastric Adenocarcinoma 168 patients : R A N D O M I Z E Docetaxel 75 mg/m 2 q 3 weeks Best supportive care Primary Endpoint: Overall Survival Ford et al. Lancet Oncol Jan;15(1):78-86.

52 Cougar 02: 2 nd line Docetaxel vs. BSC: Overall Survival 3.6 mo 5.2mo HR: 0.67, 95% CI ; p=0.01 Ford et al. Lancet Oncol Jan;15(1):78-86.

53 REGARD Study Design S C R E E N R A N D O M I Z E N = 355 2:1 Ramucirumab 8 mg/kg q2wk + BSC (n = 238) Placebo q2wk + BSC (n = 117) Treatment until disease progression or intolerable toxicity Tumor assessment, survival, and safety followup Multicenter, randomized, double-blind, placebo-controlled, phase 3 trial Gastric or GEJ adenocarcinoma Stratification factors: region, weight loss ( 10% vs. <10% over 3 months), location of primary tumor (gastric vs. GEJ) Global: 6 continents, 30 countries, 120 study centers Abbreviations: BSC=best supportive care; GEJ= gastroesophageal junction Fuchs et al. Lancet Jan 4;383(9911):31-9.

54 REGARD: Overall Survival 1.0 HR (95% CI) = (0.603, 0.998) Log rank P-value (stratified) = Overall Survival Ramucirumab Placebo Patients / Events 238 / / 99 Median (mos) (95% CI) 5.2 (4.4, 5.7) 3.8 (2.8, 4.7) 6-month OS 42% 32% 12-month OS 18% 11% Δ mos = 1.4 months Ramucirumab Placebo Censored Censored Months No. at Risk Ram Plcb Fuchs et al. Lancet Jan 4;383(9911):31-9.

55 Wilke et al. Lancet 2014; 15: RAINBOW: Study Design S C R E E N 1:1 R A N D O M I Z E Ramucirumab 8 mg/kg day 1&15 + Paclitaxel 80 mg/m 2 day 1,8 &15 of a 28-day cycle N = 330 Placebo day 1&15 + Paclitaxel 80 mg/m 2 day 1,8 &15 N = 335 Treat until disease progression or intolerable toxicity Survival and safety followup Important inclusion criteria: - Metastatic or loc. adv. unresectable gastric or GEJ* adenocarcinoma - Progression after 1 st line platinum/fluoropyrimidine based chemotherapy Stratification factors: - Geographic region, - Measurable vs non-measurable disease, - Time to progression on 1 st line therapy (< 6 mos vs. 6 mos) * GEJ= gastroesophageal junction; gastric and GEJ will be summarized under the term GC

56 RAINBOW: Overall Survival HR (95% CI) = (0.678, 0.962) Stratified log rank p-value = RAM + PTX PBO + PTX Patients / Events 330 / / 260 Median(mos) (95% CI) 9.63 (8.48, 10.81) 7.36 (6.31, 8.38) 6-month OS 72% 57% 12-month OS 40% 30% Δ mos = 2.3 months Censored No. at risk RAM + PTX PBO + PTX Wilke et al. Lancet 2014; 15:

57 Presented by:

58 Keynote -012: Pembrolizumab for GEJ and Gastric Muro et al. Lancet Oncol 2016; 17:717-26

59 Keynote -012: Pembrolizumab for GEJ and Gastric Progression-Free Survival Overall Survival Muro et al. Lancet Oncol 2016; 17:717-26

60 ONO-4538: Phase 3 Study of Nivolumab vs Placebo in Patients With Refractory GC Key eligibility criteria: Age 20 years Unresectable advanced or recurrent GC or GJC Histologically confirmed adenocarcinoma Prior treatment with 2 regimens and refractory to/intolerant of standard therapy ECOG PS of 0 or 1 Study Design and Endpoints R 2:1 Nivolumab 3 mg/kg IV Q2W Placebo Primary endpoint OS Secondary endpoints Efficacy Safety Exploratory endpoint Biomarkers Stratification based on: Country (Japan vs Korea vs Taiwan) ECOG PS (0 vs 1) Number of organs with metastases (<2 vs 2) Patients were permitted to continue treatment beyond initial RECIST v1.1-defined disease progression as assessed by the investigator if receiving clinical benefit and tolerating study drug. Adapted from presentation by Yoon-Koo Kang, Gastrointestinal Cancers Symposium, Kang Y-K et al. J Clin Oncol. 2017;35(suppl 4):abstract 2.

61 ONO-4538: Overall Survival Patients n Events n Median OS Mos. 95% CI) 12-Month OS % (95% CI) Probability of survival (%) Patients at risk: Nivolumab 330 Placebo Nivolumab ( ) Placebo ( ) Placebo Time (months) HR = 0.63 (95% CI, ) P< Nivolumab ( ) 10.9 ( ) Adapted from presentation by Yoon-Koo Kang, Gastrointestinal Cancers Symposium, Kang Y-K et al. J Clin Oncol. 2017;35(suppl 4):abstract 2.

62 ONO-4538: Progression-Free Survival Probability of PFS (%) Patients at risk: Nivolumab 330 Placebo 163 Placebo Patients n Events n 10 Time (months) Median PFS Mos. (95% CI) Nivolumab ( ) Placebo ( ) HR = 0.60 (95% CI, ) P< Nivolumab Month PFS % (95% CI) ( ) 1.5 ( ) Adapted from presentation by Yoon-Koo Kang, Gastrointestinal Cancers Symposium, Kang Y-K et al. J Clin Oncol. 2017;35(suppl 4):abstract 2.

63 Conclusions from these Results Metastatic Esophagogastric: The most active single agents are the fluoropyrimidines, platinum analogues, taxanes, and irinotecan. 1 st Line: Fluoropyrimidine & platinum combos are standard. Trastuzumab should be added for HER2/neu 3+ or FISH+ tumors. Pts should receive at least 2 lines of therapy for their dz. 2 nd Line: Paclitaxel + Ramucirumab is probably the best choice for most patients. Checkpoint inhibitors are effective in esophagogastric cancer.

64 Pancreatic Cancer: Staging and Prognosis Stage classification % at diagnosis 5-year survival Localized 8 20% Locally advanced/ unresectable 31 8% Metastatic 61 2%

65 GITSG: Addressing the Role of Adjuvant 5-FU Based Chemoradiation in Pancreatic Cancer Median survival: 20 vs 11 months (P = 0.03) 2 yr survival 43 vs. 18% (4000 cgy XRT in splitcourse with concurrent 5-FU, followed by weekly 5-FU x 2 years) Note: based on 43 patients only, accrued over 8 years. Study terminated prematurely before reaching original accrual goal. Kalser MH, et al. Arch Surg. 1985;120:

66 ESPAC: European Study Group for Pancreatic Cancer N = x 2 factorial design pooled analysis Median survival, chemo vs no chemo: 20.1 vs 15.5 months Median survival, chemoxrt vs no chemoxrt: 15.9 vs 17.9 months Authors conclusions: chemotherapy produces survival benefit s/p pancreatic ca resection; whereas chemoradiation has deleterious effect Observation (69) Chemotherapy (75) ChemoXRT (73) ChemoXRT chemotherapy (72) - Chemotherapy regimen: 5FU/LV monthly x 6 - Chemoradiation regimen: 4000 cgy XRT (split course) with concurrent 5-FU Neoptolemos JP, et al. N Engl J Med. 2004;350(12):

67 CONKO-001 TRIAL 71% node (+) 81% R0 resection Resected pancreatic cancer (N = 368) Stratified by age, tumor status, nodal status, resection margin Gemcitabine x 6 months (n = 186) Observation (n = 182) Oettle.JAMA. 2007;297: Oettle.JAMA Oct 9;310(14): % node (+) 85% R0 resection 5yr DFS: 16.6% vs. 7.0% 5yr OS: 20.7% vs. 12.2%

68 ESPAC-4: Schema R0/R1 Resected Panc Adenoca WHO <2; <12 wks N= 730 R A N D O M IZ Stratify: R0 vs R1, Country (UK vs rest) Primary Endpoint: Overall survival E Gemcitabine 1,000 mg/m 2 d 1,8,15 q4 wks x6 (N= 366) Gemcitabine + Capecitabine 1,660mg/m 2 d1-21 q4 wks x6 (N= 364) Stratified log-rank 5% 2-sided alpha for 10% diff 2 year survival (47.5% 57.5%, 90% power with 480 deaths, planned N= 722) Neoptolemos. Annu Mtg Proc Am Soc Clin Oncol 2016

69 ESPAC-4: Overall Survival Neoptolemos. Annu Mtg Proc Am Soc Clin Oncol 2016

70 Should Neoadjuvant Therapy be Considered for Operable Disease? THEORETICAL ADVANTAGES OVER POSTOPERATIVE TREATMENT Improved rate of negative surgical margins No prolonged postoperative recovery before administering treatment In older postop studies, ~20-25% of patients intended for adjuvant therapy do not end up receiving it Patients with distant metastases on restaging are spared the morbidity of surgery Allows testing of novel agents for on-target tumor effects MD Anderson experience: approx 66% of patients make it to surgery with a 2-4 months course of preop chemoxrt; of these, median OS = months (Evans DB. J Clin Oncol. 2008;26: Varadhachary GR. J Clin Oncol. 2008;26: ) MAJOR CONCERN: delay of only potentially curative option (surgery)

71 Locally Advanced Pancreas Cancer Distant metastasis (including non-regional lymph node metastasis) Head/uncinate process: Solid tumor contact with SMA or celiac axis >180 o Solid tumor contact with the first jejunal SMA branch Thrombosis of SMV or portal vein Contact with most proximal jejunal branch of SMV Body and tail: Solid tumor contact of >180 o with the SMA or celiac axis Solid tumor contact with the celiac axis and aortic involvement Thrombosis of SMV or portal vein NCCN Guidelines Version

72 LAP 07 - SCHEMA Random 1 EVALUATION : non progressive EVALUATION : non progressive Random 2 Cape RT Cape EVALUATION EVALUATION EVALUATION Until Progression RT 1 month = Gemcitabine 1000 mg/m 2 /wk x 3 Erlotinib with gem : 100 mg/d Cape RT Capecitabine 1600 mg/m 2 /d plus radiation therapy 54 Gy (5 x 1.8 Gy/d) 150 mg/d as single agent (maintenance) Secondary surgery allowed at any time Hammel. JAMA 2016 May 3;315(17):

73 LAP 07 Survival Overall Survival Progression-Free Survival Hammel. JAMA 2016 May 3;315(17):

74 Should FOLFIRINOX Therapy be Considered for Inoperable Disease? MGH experience: 22 patients with LAPC treated with FOLFIRINOX between July 2010 and February ORR was 27.3%, and median PFS was 11.7 months. R0 resection: 5 of 22 patients (23%) Recurrence: 3 of 5patients with distant recurrence within 5 months. Hospitalization: 32% on FOLFIRINOX. Faris et al. Oncologist. 2013;18(5):543-8.

75 Conclusions from these Results: Localized Pancreatic: Adjuvant gemcitabine therapy is most important in the postoperative treatment of resected pancreas cancer. The addition of capecitabine appears to improve survival. C/RT presently plays a lesser role and is given at most centers now at the end of an adjuvant treatment course. Neoadjuvant C/RT remains experimental. Unresectable dz is rarely converted with this approach. Pts with LAPC can be treated with chemo alone or chemo C/RT. FOLFIRINOX may improve resectability but long-term survival is?

76 Treatment of Metastatic Disease: Can We move beyond Gemcitabine? Gemcitabine approved in 1997 for first-line therapy of advanced PADC Median survival (vs bolus 5-FU): 5.65 vs 4.41 mos. (P = ) 1-yr survival: 18% vs 2% Clinical benefit: 23.8% vs 4.8% RR: 5.4% vs 0% Burris HA. J Clin Oncol. 1997;15:

77 What About Combination Therapy?: Gemcitabine/Platinum Doublets for Advanced Pancreatic Cancer (Phase III Trials) Gruppo Oncologia dell Italia Meridionale Study (n = 107) German Multicentre Study (n = 190) GERCOR/GISCAD Intergroup Study (n=313) ECOG 6201 (n=833) * Third arm = FDR gem Treatment Progression-free survival Gemcitabine 8 wks 5 mos Median survival Gemcitabine/cisplatin 20 wks (p=0.048) 7.5 mos (P = 0.48) Combined analysis: gemcitabine/platinum results in significant improvement in overall survival (HR 0.85, P = 0.01) Gemcitabine 3.1 mos 6.0 mos Gemcitabine/cisplatin 5.3 mos (p=0.053) 7.5 mos (P = 0.15) Gemcitabine 3.7 mos 7.1 mos Gemcitabine/oxaliplatin 5.8 mos (p=0.04) 9.0 mos (P = 0.13) Gemcitabine N/A 4.9 mos Heinemann et al, BMC Cancer 2008 Gemcitabine/oxaliplatin N/A 5.9 mos Viret et al (n=83) Gemcitabine 2.5 mos 6.7 mos Gemcitabine/cisplatin 2.2 mos (p=ns) 8.0 mos (P = 0.73)

78 Other Gemcitabine-Based Doublets: Phase III Trials of GEM-CAP VS Gemcitabine GEM-CAP Gemcitabine Statistically significant? Cunningham D, et al. J Clin Oncol. 2009; 27: N Combined analysis: gemcitabine/capecitabine results in significant improvement in overall survival (HR, 0.86; P = 0.02) Cunningham, J Clin Oncol 2009 Med survival 7.1 months 6.2 months P = 0.08 Herrmann R, et al. J Clin Oncol. 2007;25: (SAKK study) N Med survival 8.4 months 7.2 months P = (SAKK study, post hoc analysis on pts with KPS ) N Med survival P = 0.014

79 Phase III Study of Gemcitabine + Erlotinib in Advanced Pancreatic Cancer (NCIC PA.3) Moore MJ, et al. J Clin Oncol. 2007;25:

80 NCIC PA.3: SURVIVAL RESULTS Moore MJ, et al. J Clin Oncol. 2007;25: PFS: 3.75 vs 3.55 months (P = 0.004) RR: 8.6 vs 8.0% (P = NS)

81 Prodige 4 -ACCORD 11/0402: Gemcitabine vs. FOLFIRINOX R Gemcitabine 1000 mg/m2 qwk x 7/8, then qwk x 3/4 30 min 2 h Bolus 5-FU 400 mg/m 2 Oxaliplatin Leucovorin Continuous 5-FU 85 mg/m mg/m mg/m 2 Irinotecan 2 h 180 mg/m 2 46 h q2wks 1 h 30 Conroy. N Engl J Med. 2011;364(19):

82 PRODIGE 4: Objective Response Rate Folfirinox N=171 Gemcitabine N=171 p Complete response 0.6% 0% Partial response 31% 9.4% CR/PR 95% CI [ ] [ ] Stable disease 38.6% 41.5% Disease control CR+PR+SD 70.2% 50.9% Progression 15.2% 34.5% Not assessed 14.6% 14.6% Median duration of response 5.9 mo. 4 mo. ns Conroy. N Engl J Med. 2011;364(19):

83 PRODIGE 4: Overall Survival 3.3 vs. 6.4 mos 6.8 vs mos Conroy. N Engl J Med. 2011;364(19):

84 MPACT: Study Design Planned N = 842 Stage IV No prior treatment for metastatic disease KPS 70 Measurable disease Total bilirubin ULN Primary Endpoint: OS Secondary Endpoints: PFS and ORR by Independent Review (RECIST) Safety and Tolerability by NCI CTCAE v3.0 nab-paclitaxel 125 mg/m 2 IV qw 3/4 weeks + Gemcitabine 1000 mg/m 2 IV qw 3/4 weeks 1:1, stratified by KPS, region, liver metastasis Gemcitabine 1000 mg/m 2 IV qw for 7/8 weeks then qw 3/4 weeks With 608 events, 90% power to detect OS HR = (2 sided α = 0.049) 1 interim analysis for futility Treat until progression CT scans every 8 weeks Von Hoff et al., N Engl J Med Oct 31;369(18):

85 MPACT: Response Rates Variable nab-p + Gem (n = 431) Gem (n = 430) P-value Overall Response Rate Independent Review, % (95% CI) Investigator Assessment, % (95% CI) 23 ( ) 29 ( ) 7 ( ) 8 ( ) 1.1x x10-16 Disease Control Rate by Independent Review, a % (95% CI) 48 ( ) 33 ( ) 7.2x10-6 a Includes CR + PR + SD 16 weeks PRODIGE 4 Folfirinox N=171 Gemcitabine N=171 p Complete response 0.6% 0% Partial response 31% 9.4% CR/PR 95% CI [ ] [ ] Disease control CR+PR+SD 70.2% 50.9% Von Hoff et al., N Engl J Med Oct 31;369(18):

86 MPACT: Overall Survival Proportion of Survival Pts at Risk nab-p + Gem: Gem: nab-p + Gem Gem Events/N (%) Months OS, months Median (95% CI) th Percentile 333/431 (77) ( ) /430 (83) ( ) 11.4 FOLFIRINOX vs. Gem 0.57 HR = % CI ( ) P = Von Hoff et al., N Engl J Med Oct 31;369(18):

87 Safety: FOLFIRINOX vs. Gemcitabine vs. G+Nab-Paclitaxel Prodige 4 G3-4 Toxicity FOFIRINOX Gemcitabine ANC 45.7% 18.7% Febrile ANC 5.4% 0.6% Received GCSF 42.5% 5.3% Anemia 7.8% 5.4% Plts 9.1% 2.4% Fatigue 23.2% 14.2% Peripheral Neuro 9% 0.6% Diarrhea 12.7% 1.2% Death 0.6% 0.6% MPACT Gemcitabine G+Nab-Paclitaxel 27% 38% 1% 3% 15% 26% 12% 13% 9% 13% 7% 17% <1% 17%* 1% 6% 4% 4% *Median time to improvement to Grade <1 = 29 days

88 Wang-Gillam et al. Lancet 2016 Feb 6;387(10018):545-57

89 Response Rate: MM-398+5FU/LV: 16% 5FU/LV: 1% Wang-Gillam et al. Lancet 2016 Feb 6;387(10018):545-57

90 Wang-Gillam et al. Lancet 2016 Feb 6;387(10018):545-57

91 Conclusions from these Results Metastatic Pancreatic: Gemcitabine monotherapy remains an acceptable treatment option for older or asymptomatic pts. Addition of platinum or capecitabine boosts response and PFS but compromises 2 nd line CAPOX or FOLFOX*. Addition of Nab-paclitaxel improves OS but is more toxic. Unclear how would compare to FOLFIRINOX. FOLFIRINOX has best response and survival but is most toxic. It should be considered for stronger, symptomatic pts or potentially resectable disease. MM398+5FU is an option after Gem+Nab-paclitaxel. Unclear if any benefit after FOLFIRINOX. *Pelzer et al. Eur J Cancer Jul;47(11):