PRODIGE 24/CCTG PA.6: Phase III Trial of Adjuvant mFOLFIRINOX vs Gemcitabine in Patients With Resected Pancreatic Ductal Adenocarcinoma CCO Independent Conference Highlights* of the 2018 ASCO Annual Meeting; June 1-5, 2018; Chicago, Illinois *CCO is an independent medical education company that provides state-of-the-art medical information to healthcare professionals through conference coverage and other educational programs. FOLFIRINOX, leucovorin, 5-fluorouracil, irinotecan, oxaliplatin; m, modified. This activity is supported by educational grants from Amgen; Astellas; AstraZeneca; Celgene Corporation; Eisai; Genentech; Janssen; Merck & Co., Inc.; and Seattle Genetics.

mFOLFIRINOX vs Gemcitabine in Resected Pancreatic Cancer (PRODIGE 24/CCTG PA.6): Background Adjuvant gemcitabine and/or fluoropyrimidine current SoC in resected pancreatic cancer but > 70% of patients relapse within 2 yrs of therapy[1-4] FOLFIRINOX more effective than gemcitabine as first-line treatment of metastatic pancreatic cancer with good performance status but associated toxicity too high for adjuvant use[5] Modified FOLFIRINOX regimen removes bolus fluorouracil, adds hematopoietic growth factor[6] Maintains efficacy with less hematologic toxicity, diarrhea Current phase III Unicancer GI PRODIGE 24/CCTG PA.6 trial evaluated efficacy, safety of adjuvant mFOLFIRINOX vs gemcitabine following resection in patients with metastatic pancreatic ductal adenocarcinoma[7] FOLFIRINOX, leucovorin, 5-fluorouracil, irinotecan, oxaliplatin; m, modified; SoC, standard of care. References 1. Sultana A, et al. Recent Results Cancer Res. 2012;196:65-88. 2. Neoptolemos JP, et al. Lancet. 2017;389:1011-1024. 3. Oettle H, et al. JAMA. 2013;310:1473-1481. 4. Neoptolemos JP, et al. JAMA. 2010;304:1073-1081. 5. Conroy T, et al. N Engl J Med. 2011;364:1817-1825. 6. Mahaseth H, et al. Pancreas. 2013;42:1311-1315. 7. Conroy T, et al. ASCO 2018. Abstract LBA4001. Slide credit: clinicaloptions.com References in slidenotes.

PRODIGE 24/CCTG PA.6: Study Design Randomized, multicenter, phase III trial (data cutoff: April 13, 2018) Median follow-up: 33.6 mos (95% CI: 30.3-36.0) Stratified by center, resection margin (R0 vs R1), post-op CA 19-9 level (≤ 90 U/mL vs 91-179), pN0 vs pN1 mFOLFIRINOX* Q2W x 12 cycles (n = 247†) Patients 18-79 years of age with histologically confirmed R0 or R1 resected pancreatic ductal adenocarcinoma; CA19-9 level < 180 U/mL ≤ 12 wks post surgery; ECOG PS 0/1; no prior chemotherapy or RT (N = 493) CT scans every 3 mos Gemcitabine 1000 mg/m2 Day 1, 8, 15 of 28-day cycle x 6 cycles (n = 246‡) DFS, disease-free survival; ECOG, Eastern Cooperative Oncology Group; FOLFIRINOX, leucovorin, 5-fluorouracil, irinotecan, oxaliplatin; m, modified; post-op, post-operative; PS, performance status; RT, radiation therapy. *On Day 1 of each cycle, oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, and irinotecan 180 mg/m2 (reduced to 150 mg/m2 due to 20% grade 3/4 diarrhea rate in first 30 patients); continuous fluorouracil IV 2.4 g/m2 over 46 hrs. †n = 238 treated. ‡n = 243 treated. Primary endpoint: DFS, defined as no tumor, metastasis, second cancer, or death Secondary endpoints: toxicity, OS, cancer-specific survival, metastasis-free survival Slide credit: clinicaloptions.com Conroy T, et al. ASCO 2018. Abstract LBA4001.

PRODIGE 24/CCTG PA.6: Baseline Patient Characteristics mFOLFIRINOX (n = 247) Gemcitabine (n = 246) Median age, yrs (range) 63 (30-79) 64 (30-81) Male, % 57.5 55.6 ECOG PS 0/1, % 49.8/50.2 52.5/47.5 Diabetes, % 25.3 26.6 Median tumor size, mm (range) 30 (8-90) 30 (6-120) T1-2/T3-4, % 12.5/87.5 9.8/90.2 N0/N1, % 22.3/77.7 24.5/75.5 Stage: I/IIA/IIB/III-IV, % 4.9/17.4/74.1/3.6 5.7/19.1/72.8/2.4 Well/moderately/poorly differentiated tumor grade, % 30.6/54.1/15.3 33.9/53.7/12.5 Whipple resection, % 82.1 76.8 R1 resection 40.1 45.7 Venous resection, % 21.3 28.2 Lymphovascular emboli, % 73.7* 63.1* ECOG, Eastern Cooperative Oncology Group; FOLFIRINOX, leucovorin, 5-fluorouracil, irinotecan, oxaliplatin; m, modified; PS, performance status. *P = .02 Slide credit: clinicaloptions.com Conroy T, et al. ASCO 2018. Abstract LBA4001.

PRODIGE 24/CCTG PA.6: Safety Main nonhematologic adverse events Higher rates with mFOLFIRINOX: diarrhea (especially in cycles 1-2; higher rates related to more lymph nodes examined), sensory peripheral neuropathy, fatigue, vomiting, mucositis, hand–foot syndrome Higher rates with gemcitabine: headache, fever, influenzalike symptoms, ALT increase, AST increase; 1 toxic death Significantly more patients stopped treatment early in mFOLFIRINOX arm (33.6% vs 21.0%, P = .002) Higher rates due to toxicity, patient decision; gemcitabine more often discontinued due to relapse ALT, alanine aminotransferase; AST, aspartate aminotransferase; FOLFIRINOX, leucovorin, 5-fluorouracil, irinotecan, oxaliplatin; m, modified. Slide credit: clinicaloptions.com Conroy T, et al. ASCO 2018. Abstract LBA4001.

PRODIGE 24/CCTG PA.6: Hematologic Adverse Events Grade 3/4 Hematologic Event, % mFOLFIRINOX (n = 238) Gemcitabine (n = 243) Anemia 0.4 Neutropenia 28.4 26.0 G-CSF use 59.9* 3.7* Febrile neutropenia 2.9 3.7 Lymphopenia 1.3 Thrombocytopenia 1.3† 4.5† FOLFIRINOX, leucovorin, 5-fluorouracil, irinotecan, oxaliplatin; G-CSF, granulocyte colony-stimulating factor; m, modified. *P < .001. †P = .03. Slide credit: clinicaloptions.com Conroy T, et al. ASCO 2018. Abstract LBA4001.

PRODIGE 24/CCTG PA.6: Nonhematologic Adverse Events AE, % mFOLFIRINOX (n = 238) Gemcitabine (n = 243) Any Grade Grade 3/4 Diarrhea 84.4 18.6* 49 3.7 Sensory peripheral neuropathy 61.2 9.3 8.7 -- Fatigue 84 11 77.6 4.6 Vomiting 46 5 29 1.2 Mucositis 33.8 2.5 14.9 Alopecia 27 19.5 Hand–foot syndrome 0.4 0.8 AE, % mFOLFIRINOX (n = 238) Gemcitabine (n = 243) Any Grade Grade 3/4 Headache 8.4 -- 19.4 Fever 16.5 0.4 32.4 Flu-like symptoms 1.3 5.0 ALT increase 64 4.2 73.5 AST increase 67 3.8 69 3.3 Toxic death 1 AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; FOLFIRINOX, leucovorin, 5-fluorouracil, irinotecan, oxaliplatin; G-CSF, granulocyte colony-stimulating factor; m, modified. *Cycle 1, 8.6%; cycle 2, 6.3%; cycles 3-5, 3%; cycles 6-12, 1%. All any grade AE comparisons except alopecia incidence were significantly different (P < .05) across treatment arms. Slide credit: clinicaloptions.com Conroy T, et al. ASCO 2018. Abstract LBA4001.

PRODIGE 24/CCTG PA.6: Patient Disposition Parameter mFOLFIRINOX (n = 238) Gemcitabine (n = 243) Completion of all CT cycles, % 66.4* 79.0* Planned administrations, n Median administrations received, n (range) Delayed administrations, % 12 12 (1-12) 14.4† 18 18 (1-18) 3.9† Patients with relative dose intensity > 0.70, % 48.7‡ 91.4‡ Early discontinuation, n (%) Relapse Toxicity Investigator decision Patient decision 80 (33.6)§ 15 (6.3) 21 (8.8) 7 (2.9) 13 (5.4) 51 (21.0)§ 26 (10.7) 11 (4.5) 2 (0.8) CT, chemotherapy; FOLFIRINOX, leucovorin, 5-fluorouracil, irinotecan, oxaliplatin; m, modified. *P = .002. †P < .001. ‡P < .001. §P = .002. Slide credit: clinicaloptions.com Conroy T, et al. ASCO 2018. Abstract LBA4001.

PRODIGE 24/CCTG PA.6: Survival Outcomes mFOLFIRINOX (n = 247) Gemcitabine (n = 246) HR (95% CI) P Value DFS* Median, mos (95% CI) 3-yr, % (95% CI) 21.6 (17.7-27.6) 39.7 (32.8-46.6) 12.8 (11.7-15.2) 21.4 (15.8-27.5) 0.58 (0.46-0.73) < .0001 Median MFS,† mos (95% CI) 30.4 (21.7-NR) 17.7 (14.2-21.5) 0.59 (0.46-0.75) OS 3 yr,‡ % 54.4 (41.8-NR) 63.4 35.0 (28.7-43.9) 48.6 0.64 (0.48-0.86) .003 3-yr disease-specific survival,§ % 66.2 51.2 0.63 (0.47-0.85) DFS, disease-free survival; FOLFIRINOX, leucovorin, 5-fluorouracil, irinotecan, oxaliplatin; m, modified; MFS, metastasis-free survival; NR, not reached; tx, therapy. *314 events. †273 events. ‡192 events. §180 events. DFS benefit favored mFOLFIRINOX across all predefined subgroups Per multivariable analysis, prognostic factors for DFS included mFOLFIRINOX tx (HR: 0.59; P < .001), moderately to poorly differentiated tumor (HR: 1.42; P < .001), portal vein resection (HR: 1.43; P < .001) Slide credit: clinicaloptions.com Conroy T, et al. ASCO 2018. Abstract LBA4001.

PRODIGE 24/CCTG PA.6: Conclusions In patients with resected pancreatic ductal adenocarcinoma, adjuvant mFOLFIRINOX significantly prolonged DFS, MFS, OS, and disease-specific survival vs gemcitabine Median DFS: 21.6 vs 12.8 mos (HR: 0.58; 95% CI: 0.46-0.73; P < .0001) Median MFS: 30.4 vs 17.7 mos (HR: 0.59; 95% CI: 0.46-0.75; P < .0001) Median OS: 54.4 vs 35.0 mos (HR: 0.64; 95% CI: 0.48-0.86; P = .003) DFS benefit favored mFOLFIRINOX across all analyzed subgroups mFOLFIRINOX associated with more toxicity than gemcitabine but AEs generally manageable Investigators conclude that in Western countries mFOLFIRINOX should be considered as new SoC following resection for patients with pancreatic cancer and good performance status AE, adverse event; DFS, disease-free survival; FOLFIRINOX, leucovorin, 5-fluorouracil, irinotecan, oxaliplatin; MFS, metastasis-free survival; m, modified; SoC, standard of care. Slide credit: clinicaloptions.com Conroy T, et al. ASCO 2018. Abstract LBA4001.

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