Case 1 Metastatic Pancreatic Adenocarcinoma: What Therapy Should I Select First? Marc Peeters, MD, PhD Head of the Oncology Department Antwerp University Hospital Antwerp, Belgium marc.peeters@uza.be
71-year-old man presents with: Clinical Case symptoms of increasing abdominal and back pain anorexia and unitential weight loss of 3 kg in the past two months newly diagnosed diabetes mellitus Comorbidities: ECOG PS: 1 right femoral vein thrombosis and distal pulmonary embolism 10 months ago status post PTCA due to myocardial infarction 2 years ago stage III colon cancer 7 years ago (left hemicolectomy and adjuvant FOLFOX; still feels numbness in his feet) BMI 23 kg/m 2 (weight 70 kg; height 1.75) Patient wants treatment
Clinical Case, Cont. Laboratory: Parameter Value Reference Range Hemoglobin (g/l) 110 120-160 ALT (U/L) 90 <45 AST (U/L) 68 <35 ALP (U/L) 287.5 <115 Bilirubin (μmol/l) 15 <17 Albumin (g/l) 40 35-50 Creatinine (μmol/l) 72 65-115 CA 19-9 (ku/l) 2765 <35 CEA (μg/l) 23 <5
CT Scan CT-guided biopsy of the liver: Poorly differentiated adenocarcinoma
Treatment of Metastatic Pancreatic Cancer is Palliative Benefits Prolong survival Improve clinical symptoms Improve qualiy of life Toxicity
Factors That May Impact Treatment Selection in Metastatic Pancreatic Cancer Efficacy Safety Histopathology Tumor characteristics Patient characteristics Previous treatment Patient preference Goals of therapy Biomarkers
Performance Status Is Important in Treatment Decision Making for Advanced Pancreatic Cancer Meta-analysis of randomized trials confirms that performance status is an important factor in determining who is more likely to benefit from combination chemotherapy Performance Status Benefit From Combination Therapy? ECOG PS 0-1/Karnofsky PS 90% to 100% Yes (HR: 0.76; P<.0001) ECOG PS 2/Karnofsky PS 60% to 80% No (HR: 1.08; P =.40) Heinemann V, et al. BMC Cancer. 2008;8:82.
Which First-Line Therapy? FOLFIRINOX (? modified FOLFIRINOX) Nab-paclitaxel + gemcitabine Gemcitabine alone Clinical trial (eg, Nal-IRI + 5FU-LV, PEGPH20 + nab-paclitaxel + gemcitabine)
Treatment Strategies: ESMO Guideline Ducreux M, et al. Ann Oncol. 2015;26(Supp 5):v56-v68.
Gemcitabine Efficacy Gemcitabine 5-FU Clinical benefit (CB), % Median time to achieve CB, weeks Median duration of CB, weeks 23.8 7 18 4.8 3 13 Median survival, months 5.65 4.41 Median TTP, weeks 9 4 1-year survival, % 18 2 Burris HA 3 rd, et al. J Clin Oncol. 1997;15(6):2403-2413.
Number of Combination Trials With Gemcitabine Did Not Lead to Clinicaly Meaningful Improvements in Overall Survival Overall Survival Overall Survival Gemcitabine vs: # Patients Control Arm (Gemcitabine Alone) Study Arm (Combined) Gemcitabine + cisplatin 192 6.0 months 7.5 months Gemcitabine + oxaliplatin 313 7.1 months 9.0 months Gemcitabine + 5-FU 322 5.4 months 6.7 months Gemcitabine + capecitabine 533 6.2 months 7.1 months Gemcitabine + pemetrexed 565 6.3 months 6.2 months Gemcitabine + irinotecan 360 6.6 months 6.3 months Gemcitabine + tipifarnib 688 6.3 months 6.0 months Gemcitabine + erlotinib 569 6.0 months 6.4 months Gemcitabine + bevacizumab 602 6.1 months 5.8 months Gemcitabine + cetuximab 735 5.9 months 6.4 months Gemcitabine + axitinib 632 8.3 months 8.5 months
FOLFIRINOX: PRODIGE 4 / ACCORD11 Trial Metastatic PCA ECOG PS 0 or 1 <76 years old Overall Survival (Primary Endpoint) R A N D O M I Z E FOLFIRINOX* N = 171 Gemcitabine N = 171 For both arms: CT scans: obtained every 2 months 6 months of chemotherapy recommended FOLFIRINOX Gemcitabine ORR (%) 31.6 9.4 P value <.001 Median PFS (months) 6.4 3.3 HR (95% CI) 0.47 (0.37 0.59) P value <.001 Median OS (months) 11.1 6.8 HR (95% CI) 0.57 (0.45 0.73) P value <.001 Conroy T, et al. N Engl J Med. 2011;364(19):1817-1825. PS, performance status; ORR, objective response rate; PFS, progression free survival
FOLFIRINOX Delays Quality of Life Deterioration Despite Less Favorable Toxicity Profile Time until definitive deterioration >20 points in EORTC Core Quality of Life questionnaire global health status Gourgou Bourgade S, et al. J Clin Oncol. 2013;31(1):23 29.
FOLFIRINOX: Adverse Events (Grade 3/4) Event Hematologic FOLFIRINOX n = 171 Gemcitabine n = 171 P value Neutropenia 45.7% 21.0% <.001 Febrile neutropenia 5.4% 1.2%.03 Thrombocytopenia 9.1% 3.6%.04 Nonhematologic Fatigue 23.6% 17.8% NS Vomiting 14.5% 8.3% NS Diarrhea 12.7% 1.8% <.001 Sensory neuropathy 9.0% 0.0% <.001 Conroy T, et al. N Engl J Med. 2011;364(19):1817-1825.
Nab-Paclitaxel + Gemcitabine: MPACT Trial Stage IV No prior treatment for M1 disease KPS 70 Measurable disease Total bilirubin ULN No age limitation N = 861 Nab-Paclitaxel 125 mg/m 2 IV qw 3/4 + Gemcitabine 1000 mg/m 2 IV qw 3/4 1:1, stratified by KPS, region, liver metastasis Gemcitabine 1000 mg/m 2 IV qw 7/ 8 cycle 1 then qw 3/4 Overall Survival 1 (Primary Endpoint) Independent Review nab-paclitaxel + gemcitabine Gemcitabine ORR 2, % 23 7 P value <.001 Median PFS 2, months 5.5 3.7 HR (95% CI) 0.69 (0.58 0.82) P value <.001 12-month alive 2, % Median OS 2, Months 35 22 <.001 8.5 6.7 HR (95% CI) 0.72 (0.62 0.83) P value <.001 1. Goldstein D, et al. J Natl Cancer Inst. 2015;107(2):dju413. 2. Von Hoff DD, et al. N Engl J Med. 2013;369(18):1691-1703.
Nab-Paclitaxel + Gemcitabine: Adverse Events (Grade 3/4) Grade 3/4 AEs Gemcitabine + nab-paclitaxel (n = 421) Gemcitabine (n = 402) Neutropenia 38% 27% Febrile neutropenia 3% 1% Received growth factors 26% 15% Thrombocytopenia 13% 9% Fatigue 17% 7% Peripheral neuropathy 17% 1% Diarrhea 6% 1% Von Hoff DD, et al. N Engl J Med. 2013;369(18):1691-1703.
Key Differences in Front-Line Regimen Studies FOLFIRINOX Nab-Pac + Gemcitabine Median age, yrs (range) 61 (25-76) 62 (27-86) 65 years old 75 years old 29% - 41% 10% Performance status ECOG 0 1 2 % 37 62 0.6 Karnofsky 100 90 80 70 60 % 16 42 35 7 <1 Growth factors use, % 42 26 Efficacy FOLFIRINOX vs Gem Nab-Pac + Gem vs Gem ORR, % 32 vs 9 23 vs 7 Median PFS, mos 6.4 vs 3.3 5.5 vs 3.7 Median OS, mos 11.1 vs 6.8 8.5 vs 6.7 QOL better for Gem? Yes? Conroy T, et al. N Engl J Med. 2011;364(19):1817-1825. Von Hoff DD, et al. N Engl J Med. 2013;369(18):1691-1703.
ASCO Guideline: Metastatic Pancreatic Cancer First-Line Treatment FOLFIRINOX ECOG PS 0 to 1, favorable comorbidity profile, patient preference and support system for aggressive medical therapy, and access to chemotherapy port and infusion pump management services Nab-paclitaxel + gemcitabine ECOG PS 0 to 1, relatively favorable comorbidity profile, and patient preference and support system for relatively aggressive medical therapy Gemcitabine ECOG PS 2 or a comorbidity profile that precludes more-aggressive regimens and patient wish to pursue cancer-directed therapy The addition of either capecitabine or erlotinib to gemcitabine may be offered in this setting Best supportive care ECOG PS 3 or poorly controlled comorbid conditions Should be offered cancer-directed therapy only on a case-by-case basis Sohal D, et al. J Clin Oncol. 2016;34(23):2784-2796.
Nal-IRI Containing Regimen in Previously Untreated Pancreatic Adenocarcinoma Randomized Phase II Study Part I nal-iri + 5 FU/LV + oxaliplatin 3 + 3 dose escalation Primary endpoint: Safety and tolerability Part 2 nal-iri + 5-FU/LV + oxaliplatin N ~ 156-168 nal-iri + 5-FU/LV Primary endpoint: PFS nab-paclitaxel + gemcitabine Dean A, et al. J Clin Oncol. 2016;34(suppl 4S): Abstract TPS482. National Institutes of Health. www.clinicaltrials.gov/show/nct02551991. Accessed June 29, 2016.
First-Line Treatment Options Gemcitabine Gem + Erlotinib FOLFIRINOX Gem + nab-paclitaxel 1997 PFS 3.55 mos OS 5.65 mos OR 8.0% 2007 PFS 3.75 mos OS 6.24 mos OR 8.6% Skin toxicity 2011 PFS 6.4 mos OS 31.6 mos OR 31.6% Neuropathy Febrile neutropenia 2013 PFS 5.5 mos OS 8.5 mos OR 23.0% Neutropenia