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Second-Line Options Allow for Treatment Sequencing in Pancreatic Cancer

Published Online: May 17,2016
The ability to consider second-line therapies is a relatively new concept for patients with pancreatic cancer; however, use of second-line therapy in metastatic pancreatic cancer has remained limited for unclear reasons. The aggressive nature of the disease is a possible contributing factor, but first-line therapies that have improved efficacy might encourage use of second-line treatment in a larger proportion of patients.

Gemcitabine has an established role in first-line treatment of patients with metastatic pancreatic cancer. More recently, nab-paclitaxel has been integrated as an addition to gemcitabine in the first-line setting along with FOLFIRINOX. These agents can effectively be sequenced along with newer options. 

5-FU, Leucovorin, and Oxaliplatin

The combination of 5-FU, leucovorin, and oxaliplatin (OFF regimen) demonstrated efficacy as a second-line option for patients with advanced pancreatic cancer following a gemcitabine-based regimen.11 In an open-label phase III study, the OFF regimen was compared with best support care; however, the study was stopped early due to poor accrual. 

The OFF regimen consisted of leucovorin at 200 mg/m2 followed by 5-FU at 2,000 mg/m2 on days 1, 8, 15, and 22 plus oxaliplatin at 85 mg/m2 on days 8 and 22. After a rest of 3 weeks, the next cycle was started on day 43. Overall, 46 patients were enrolled in the trial. 

Median OS with the OFF regimen was 4.8 months compared with 2.3 months with best supportive care (HR, 0.45; 95% CI, 0.24-0.83; P = .008); however, this P value was misleading because the study was stopped early. Those who received gemcitabine in the frontline setting followed by the OFF regimen had a total median OS of 9.1 versus 7.9 months for those who took gemcitabine followed by best supportive care (HR, 0.50; 95% CI, 0.27-0.95; P = .031).

Irinotecan Liposome Injection 

In October 2015, the FDA approved irinotecan liposome injection (MM-398; Onivyde) in combination with 5-FU and leucovorin as a treatment for patients with metastatic pancreatic cancer following prior administration of a gemcitabine-based regimen. The approval was based on data from the phase III NAPOLI-1 trial, which enrolled 417 patients with gemcitabine-refractory metastatic pancreatic cancer.12 

In the trial, patients were randomized to irinotecan liposome injection monotherapy, 5-FU with leucovorin (control), or irinotecan liposome injection plus 5-FU and leucovorin. Per standard irinotecan protocols, dexamethasone and a 5-HT3 antagonist could be administered in the combination arms. 

In the irinotecan liposome injection combination arm, the median OS was 6.1 months compared with 4.2 months with 5-FU and leucovorin alone (HR, 0.57; 95% CI, 0.41-0.80; P = .0009). The median PFS was 3.1 months for the combination compared with 1.5 months with the control (HR, 0.56; 95% CI, 0.41-0.75; P = .0001). At 12 weeks, 57% of patients treated with the combination were alive and progression-free compared with 26% with 5-FU and leucovorin alone.

Irinotecan liposome injection monotherapy did not demonstrate superior efficacy compared with 5-FU and leucovorin. The median OS with monotherapy was 4.9 months versus 4.2 months with 5-FU and leucovorin (HR, 0.93; P = .5545). Moreover, irinotecan liposome injection alone was associated with more AEs compared with the combination, suggesting that the drug should only be used in combination.

Adverse events were higher with the combination versus the control arm (TABLE 1). For the combination versus single-agent irinotecan liposome injection, grade 3/4 diarrhea occurred in 12.8% versus 21.1% and the rates of vomiting were 11.1% versus 13.6%, respectively. Additionally, febrile neutropenia occurred in 1.7% of patients in the combination arm compared with 4.1% with irinotecan liposome injection monotherapy and not at all with 5-FU/leucovorin alone. Given the differences in efficacy and AEs, irinotecan liposome injection was specifically not approved for use as a single agent, the FDA emphasized in a statement. 

TABLE 1. Grade 3/4 Adverse Events in NAPOLI-1

  MM-398 Plus
5-FU Plus LV
Neutropenia 20% 2%
Fatigue 14% 4%
Diarrhea 13% 5%
Vomiting 11% 3%
Nausea 8% 3%
Asthenia 8% 7%
Abdominal Pain 7% 6%
Anemia 6% 5%
Abbreviations: ESA, erythropoiesis-stimulating agents; G-CSF, granulocyte-colony stimulating factor

Clinical Trial Data Provides Sequencing Clues

With second-line options now available, optimal treatment sequences have become a focus of research. According to findings presented at the 2016 GI Cancers Symposium,13 second-line therapy is feasible, particularly following frontline nab-paclitaxel plus gemcitabine, yet it is often underutilized.

Patients who received any second-line therapy after progression on nab-paclitaxel/gemcitabine had a median OS of 12.8 months compared with 9.9 months for those who received gemcitabine alone in the first-line setting. Patients who received second-line FOLFIRINOX after frontline nab-paclitaxel and gemcitabine had the longest total survival (median OS of 15.7 months). 

The analysis of second-line therapy was conducted on data from the MPACT trial. When the randomized treatment ended in 2013, an extension study was initiated to accumulate additional information about survival and clinical management, including second-line treatment for metastatic pancreatic cancer.

The dual primary objectives of the extension phase analysis were total OS from initial randomization and OS-2, defined as survival from the end of first-line therapy. About 40% of patients in the MPACT trial received second-line therapy, which included 5-FU or capecitabine in more than 75% of cases.

Patients who received second-line therapy had better baseline performance status, and those who received FOLFIRINOX in the second-line setting had better performance status at the end of first-line treatment.

During the randomized phase of the trial, 431 patients received nab-paclitaxel plus gemcitabine and 430 received gemcitabine alone. In the extension study, 170 patients in the nab-paclitaxel arm received second-line therapy, as did 177 patients randomized to the gemcitabine alone arm.

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Second-Line Options Allow for Treatment Sequencing in Pancreatic Cancer
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