Pancreatic Adenocarcinoma: Management of Advanced Unresectable and Metastatic Disease
Second-Line Systemic Treatment
Case Continued
The patient and oncologist opt to begin treatment with modified FOLFIRINOX therapy, and after the patient completes 10 cycles CT scan shows progression of disease. His oncologist decides to refer the patient to a comprehensive cancer center for evaluation for participation in clinical trials, as his performance status remains very good (ECOG 1) and he would like to seek a novel therapy. His liver mass biopsy and blood liquid biopsy are sent for tumor mutational profile evaluation; results show a high tumor mutational burden and microsatellite instability.
- What are second-line treatment options for metastatic pancreatic cancer?
Second-line regimen recommendations for metastatic pancreatic cancer depend on which agents were used in first-line therapy and the patient’s performance status and comorbidities. Patients who progressed on first-line FOLFIRINOX and continue to have a good performance status (ECOG 0 or 1) may be considered for gemcitabine/nab-paclitaxel therapy; otherwise, they may be candidates for gemcitabine plus capecitabine or gemcitabine monotherapy based on performance status and goals of care. Patients who progressed on front-line gemcitabine/nab-paclitaxel may opt for FOLFIRINOX (or an oxaliplatin-based regimen [FOLFOX] or irinotecan-based regimen [FOLFIRI] if FOLFIRINOX is not tolerable), nanoliposomal irinotecan/fluorouracil/leucovorin, or a short-term infusional fluorouracil and leucovorin regimen. The preferences for second-line treatment are not well established, and patients should be encouraged to participate in clinical trials. Chemotherapy should be offered only to those patients who maintain good performance status after progression on first-line therapy. For patients with poor performance status (ECOG 3 or 4) or multiple comorbidities, a discussion about goals of care and palliative therapy is warranted.
Gemcitabine-Based Therapy
An AGEO prospective multicenter cohort assigned 57 patients with metastatic pancreatic adenocarcinoma who had disease progression on FOLFIRINOX therapy to receive gemcitabine/nab-paclitaxel (dose as per MPACT trial).21 The median OS was 8.8 months and median PFS was 5.1 months after FOLFIRINOX. There were reported manageable grade 3/4 toxicities in 40% of patients, which included neutropenia (12.5%), neurotoxicity (12.5%), asthenia (9%), and thrombocytopenia (6.5%). A phase 2 clinical trial that evaluated gemcitabine monotherapy in 74 patients with metastatic pancreatic cancer who had progressed on fluorouracil showed a 3.85-month survival benefit.22
Irinotecan-Based Regimens
The NAPOLI-1 (NAnoliPOsomaL Irinotecan) trial evaluated nanoliposomal irinotecan (MM-398, nal-IRI) and fluorouracil/leucovorin in patients with metastatic pancreatic cancer refractory to gemcitabine-based therapy.23 This global, open-label phase 3 trial initially randomly assigned and stratified 417 patients in a 1:1 fashion to receive either nanoliposomal irinotecan monotherapy (120 mg/m2 every 3 weeks, equivalent to 100 mg/m2 of irinotecan base) or fluorouracil/leucovorin combination. A third treatment arm consisting of nanoliposomal irinotecan (80 mg/m2, equivalent to 70 mg/m2 of irinotecan base) with fluorouracil and leucovorin every 2 weeks was added later in a 1:1:1 fashion. Patients assigned to nanoliposomal irinotecan plus fluorouracil/leucovorin had a significantly improved OS of 6.1 months compared to 4.2 months with fluorouracil/leucovorin (HR 0.67 [95% CI 0.49 to 0.92], P = 0.012). The results of an intention-to-treat analysis favored the nanoliposomal irinotecan regimen, with a median OS of 8.9 months compared with 5.1 months (HR 0.57, P = 0.011). In addition, median PFS was improved in the nanoliposomal irinotecan arm (3.1 months versus 1.5 months; HR 0.56, P < 0.001), and median OS did not differ between patients treated with nanoliposomal irinotecan monotherapy and those treated with fluorouracil/leucovorin (4.9 months versus 4.2 months; HR 0.99 [95% CI 0.77 to 1.28], P = 0.94). The grade 3/4 adverse events that occurred most frequently in the 117 patients assigned to nanoliposomal irinotecan plus fluorouracil/leucovorin were neutropenia (27%), diarrhea (13%), vomiting (11%), and fatigue (14%). Nanoliposomal irinotecan combination provides another second-line treatment option for patients with metastatic pancreatic adenocarcinoma who have progressed on gemcitabine-based therapy but are not candidates for FOLFIRINOX.
Oxaliplatin-Based Regimens
Regimens that combine oxaliplatin with fluorouracil and leucovorin or capecitabine have shown superiority to fluorouracil/leucovorin or best supportive care (BSC). The CONKO study group compared oxaliplatin plus fluorouracil/leucovorin to BSC as second-line therapy in patients with advanced pancreatic cancer who progressed while on gemcitabine therapy (CONKO-003).24 In this phase 3 trial, patients were randomly assigned (1:1) and stratified based on duration of first-line therapy, performance status, and tumor stage to receive BSC alone or the OFF regimen, which consisted of oxaliplatin (85 mg/m2 on days 8 and 22) plus short-term infusional fluorouracil (2000 mg/m2 over 24 hours) and leucovorin (200 mg/m2 over 30 minutes), both given on days 1, 8, 15, and 22 of a 6-week cycle. This trial was terminated early according to predefined protocol regulations because of insufficient accrual (lack of acceptance of BSC by patients and physicians). Median second-line survival was 4.82 months for patients who received OFF treatment and 2.30 months for those who received BSC (HR 0.45 [95% CI 0.24 to 0.83], P = 0.008). Neurotoxicity (grade 1/2) and nausea, emesis, and diarrhea (grade 2/3) were worse in the chemotherapy arm; otherwise, the regimen was well tolerated.
A later modification of the CONKO-003 trial changed the comparison arm from BSC to fluorouracil/leucovorin.25 The median OS in the OFF group was 5.9 months versus 3.3 months in the fluorouracil/leucovorin group (HR 0.66 [95% CI 0.48 to 0.91], log-rank P = 0.010). Time to progression was significantly extended with OFF (2.9 months) as compared with fluorouracil/leucovorin (2.0 months; HR 0.68 [95% CI 0.50 to 0.94], log-rank P = 0.019). Rates of adverse events were similar between the treatment arms, with the exception of grades 1/2 neurotoxicity, which were reported in 38.2% and 7.1% of patients in the OFF and fluorouracil/leucovorin groups, respectively (P < 0.001).
The phase 3 PANCREOX trial failed to show superiority of modified FOLFOX6 (mFOLFOX6; infusional fluorouracil, leucovorin, and oxaliplatin) over fluorouracil/leucovorin.26 A phase 2 trial of oxaliplatin plus capecitabine for second-line therapy in gemcitabine-treated advanced pancreatic cancer patients with dose adjustments for performance status (ECOG 2) and age (> 65 years) showed a median OS of 5.7 months without a comparison.27 A modified oxaliplatin regimen may be a reasonable second-line therapy option for gemcitabine-treated patients who are not candidates for an irinotecan-based regimen (eg, elevated bilirubin) and continue to have an acceptable performance status.
