Second-Line Treatment Feasible, Beneficial After Upfront Nab-Paclitaxel in Pancreatic Cancer

David Goldstein, MD

Second-line treatment of metastatic pancreatic cancer proved to be feasible and beneficial, particularly for patients who received nab-paclitaxel in addition to gemcitabine in the first-line setting, according to extension data from a phase III trial.

Patients who received any second-line therapy after progression had a median total overall survival (OS) of 12.8 months if their initial treatment was nab-paclitaxel and gemcitabine compared with 9.9 months if they received gemcitabine alone in first-line.1 Second-line treatment containing 5-FU or capecitabine was associated with a median total survival of 13.5 months after first-line nab-paclitaxel and gemcitabine versus 9.5 months with gemcitabine monotherapy.

Patients who received second-line FOLFIRINOX after first-line nab-paclitaxel and gemcitabine had the longest total survival, a median of 15.7 months, as reported at the 2016 Gastrointestinal Cancers Symposium.

“The take-home message from this analysis is that second-line therapy for metastatic pancreatic cancer is feasible, and patients benefit from it,” said David Goldstein, MD, a medical oncologist at Prince of Wales Hospital in Sydney, Australia. “Until now, second-line therapy for metastatic pancreatic cancer has received little consideration.”

“The keys to successful second-line treatment are patient selection—patients who are otherwise in good condition—and selection of appropriate regimens for second-line,” he added.

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, Goldstein noted.

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. Analysis of nab-paclitaxel’s performance in first-line treatment can inform treatment planning, including consideration of second-line therapy.

Goldstein and colleagues performed a posthoc analysis of the randomized phase III MPACT trial, which evaluated first-line treatment of metastatic pancreatic cancer with gemcitabine alone or in combination with nab-paclitaxel. 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 primary objectives of the analysis of data from the extension phase 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 patients who received FOLFIRINOX in second-line had better performance status at the end of first-line treatment.

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

Among patients who received second-line therapy, 59% and 74% of those from the nab-paclitaxel and gemcitabine monotherapy arms, respectively, discontinued first-line therapy because of progression, and 26% and 14% discontinued because of adverse events.

Initial treatment with nab-paclitaxel was associated with significantly longer total survival among patients who received second-line therapy (P = .015) and those who did not (6.2 vs 4.7 months; P <.001). OS-2 was similar in the nab-paclitaxel and gemcitabine groups among patients who received second-line therapy (6.7 vs 6.4 months; P = .273) but was significantly longer with nab-paclitaxel among patients who did not receive second-line therapy (2.5 vs 1.6 months; P <.001).

A second study focused on the effectiveness and resource utilization associated with first-line treatment of metastatic pancreatic cancer with the combination of nab-paclitaxel and gemcitabine or FOLFIRINOX, which demonstrated superiority versus gemcitabine monotherapy in the phase III ACCORD trial.2 Investigators performed a retrospective cohort study, using data from an electronic medical record platform involving patients throughout the United States.

Such an analysis would provide real-world data to support decision making, including sequencing, in an era of expanding second-line options, Fadi S. Braiteh, MD, a medical oncologist at the University of Nevada-Las Vegas, and colleagues noted in a poster presentation during the meeting.

The principal objectives of the analysis were to determine time to treatment discontinuation (TTD), database persistence (a proxy for survival), adverse events, supportive care before and during chemotherapy, proportion of patients receiving second-line therapy, time to next treatment, and duration of first- and second-line treatment.

The analysis included 122 patients treated with first-line nab-paclitaxel and gemcitabine and 80 treated with FOLFIRINOX. Patients treated with nab-paclitaxel/gemcitabine were significantly older (67.0 vs 61.4 years; P <.001) but, otherwise, the 2 groups were similar.

Braiteh and colleagues found that TTD did not differ between the groups: 3.4 months with nab-paclitaxel/gemcitabine and 3.8 months with FOLFIRINOX. Database persistence also did not differ (8.6 months for both groups). By way of comparison, median OS with nab-paclitaxel/gemcitabine was 8.7 months in the MPACT trial and 11.1 months for FOLFIRINOX in the ACCORD trial, which was conducted only at academic centers.

FOLFIRINOX was associated with a higher incidence of all-grade adverse events (95% vs 84%), significantly greater prophylactic use of growth factor support (G-CSF, 39% of patients, 4.41 doses per patient per 100 days vs 8% and 2.02; P <.01), and significantly greater use of erythropoiesis-stimulating agents (0.9 vs 0.13 doses per 100 patient days; P <0.01).

Approximately one-third of patients initially treated with nab-paclitaxel/gemcitabine received 5-FU—based second-line treatment, and about half of the FOLFIRINOX group received second-line gemcitabine-based regimens. Duration of treatment in second-line was similar between the groups (about 8.5 months). Database persistence was 12.7 months for the nab-paclitaxel/gemcitabine group and 9.3 months with the FOLFIRINOX group, a difference that did not achieve statistical significance (P = .48).

1. Goldstein D, Chiorean EG, Tabernero J, et al. Outcome of second-line treatment (2L Tx) following nab-paclitaxel (nab-P) + gemcitabine (G) or G alone for metastatic pancreatic cancer (MPC). J Clin Oncol. 2016;34 (suppl 4S; abstract 333).
2. Braiteh FS, Patel M, Parisi M, et al. Comparative effectiveness and resource utilization of nab-paclitaxel plus gemcitabine (nab-P + G) versus FOLFIRINOX (FFX) in first-line treatment of advanced pancreatic adenocarcinoma in a US community oncology setting. J Clin Oncol. 2016;34 (suppl 4S; abstract 433).