Evolving Paradigms in Pancreatic Cancer: Frontline Treatment Regimens

In the advanced stage, pancreatic cancer primarily metastasizes to the peritoneal cavity and liver, with other sites including the lungs, bone, brain, and other organs. For patients with stage IV disease, treatment may consist of surgery, radiation, chemotherapy, biological therapy, or a combination of these strategies.

According to the SEER database,¹between 2006 and 2012 the 5-year survival rate for patients with pancreatic cancer was 7.7%. For those with localized pancreatic cancer, which is more amenable to surgery and comprises 29% of patients, the 5-year survival rate is 29.3%. In those with metastatic disease, which is 52% of new diagnoses, the 5-year survival rate is just 2.6%.

In this issue, we will focus on pivotal data from randomized controlled trials, which are starting to make progress toward improving long-term outcomes. Additionally, the review will provide expert opinion, subgroup analyses from large prospective studies, real-world evidence supporting optimal sequencing approaches, new therapies for advanced pancreatic cancer, and novel options on the horizon, including immunotherapies and cancer stem cell inhibitors.

Frontline Treatment Regimens

Frontline therapies for patients with metastatic pancreatic cancer have advanced in the past 5 years, with the FDA approval of nab-paclitaxel (Abraxane) plus gemcitabine (Gemzar). These advancements branch off the established treatment paradigm of gemcitabine monotherapy, which showed a significant extension in overall survival (OS) compared with 5-FU alone in a phase III study.²

In the 126-patient trial that established gemcitabine,²the agent was administered at 1,000 mg/m2 weekly for 7 weeks followed by 1 week of rest then weekly for 3 weeks with 1 week of rest (n = 63). 5-FU was administered at 600 mg/m2 once weekly (n = 63). The Karnofsky performance status (KPS) was 50 to 70 for approximately 69% of patients enrolled in the study.

In data from the trial, which were published in 1997, gemcitabine demonstrated a 1-year OS rate of 18% versus 2% with 5-FU (P= .003). Median OS was 5.7 months with gemcitabine versus 4.4 months with 5-FU (P= .0025). The clinical benefit rate with gemcitabine was 23.8% versus 4.8% with 5-FU (P= .0022).

After a significant lull in new approvals for patients with advanced pancreatic cancer, several new regimens have become available including the chemotherapy combination FOLFIRINOX (oxaliplatin, irinotecan, fluorouracil, and leucovorin), the combination of nab-paclitaxel and gemcitabine, and the second-line combination of irinotecan liposome injection, 5-FU, and leucovorin.

Erlotinib Plus Gemcitabine

EGFR is often expressed by pancreatic tumors, leading to the investigation of the EGFR-targeted TKI erlotinib (Tarceva) in combination with gemcitabine. In a phase III study reported in 2007,³patients at a median age of 64 years were randomized to receive erlotinib plus gemcitabine (n = 285) or gemcitabine plus placebo (n = 284). Gemcitabine was administered at the dose and scheduled approved for single-agent use and erlotinib was given at 100 or 150 mg per day. Patient characteristics were well balanced between the two arms, except for gender.

Median OS was 6.2 months with erlotinib and gemcitabine versus 5.9 months for placebo and gemcitabine (HR, 0.82; 95% CI, 0.69-0.99;P= .038). The 1-year OS rate was 23% with erlotinib versus 17% with gemcitabine alone (P= .023). Median progression-free survival (PFS) was 3.8 months with erlotinib versus 3.6 months with gemcitabine (HR, 0.77; 95% CI, 0.64-0.92;P= .004). The addition of erlotinib led to significantly more adverse events (AEs).

This trial was the first demonstration of improved OS with the addition of a second agent to gemcitabine. Although this regimen is rarely used in 2016, this work set the stage for other novel combination approaches with gemcitabine.

FOLFIRINOX

FOLFIRINOX demonstrated superiority versus gemcitabine monotherapy in the phase III PRODIGE 4/ACCORD 11 trial,⁴which was conducted only at French academic centers in a selective patient population (ECOG 0-1; age ≤75 years). Based on this data, the regimen became commonly used, although it is not FDA approved. Each of the individual agents in the FOLIRINOX regimen are generic and approved to treat cancer.

In the trial, 342 patients from French centers were randomized to receive FOLFIRINOX (n = 171) or gemcitabine (n = 171). FOLFIRINOX consisted of oxaliplatin at 85 mg/m2, irinotecan at 180 mg/m2, leucovorin at 400 mg/m2, and fluorouracil at 400 mg/m2 bolus followed by 2400 mg/m2 infusion. Gemcitabine was administered at 1000 mg/m2. The primary endpoint was OS.

Overall, 19.5% of patients in the FOLFIRINOX arm had lung metastases versus 28.7% in the control arm (P= .05). The median age of patients was 61 years, and nearly all had an ECOG PS of 0 or 1 (99.3%). The median number of metastatic sites was 2. CA19-9 levels were elevated ≥59xULN for 41.5% to 46.7% of patients, in the FOLIRINOX and gemcitabine arms, respectively.

In the study, the median OS was 11.1 months with FOLFIRINOX compared with 6.8 months for gemcitabine alone (HR, 0.57; 95% CI, 0.45-0.73;P<.001). Median PFS with FOLFIRINOX was 6.4 months versus 3.3 months with gemcitabine (HR, 0.47; 95% CI, 0.37-0.59;P<.001). The investigator-assessed ORR was 31.6% in the FOLFIRINOX arm versus 9.4% with gemcitabine arm (P<.001).

There were significantly more AEs in the FOLFIRINOX group versus gemcitabine, including febrile neutropenia in 5.4% of patients (TABLE 1). However, at 6 months, 31% of patients treated with FOLFIRINOX had a definitive degradation in quality of life versus 66% in the gemcitabine (HR, 0.47; 95% CI, 0.30-0.70;P<.001).

TABLE 1. Grade 3/4 AEs in PRODIGE 4/ACCORD 11

FOLFIRINOX

Gemcitabine

Neutropenia

45.7%

21%

Fatigue

23.6%

17.8%

Vomiting

14.5%

8.3%

Diarrhea

12.7%

1.8%

Thrombocytopenia

9.1%

3.6%

Sensoryneuropathy

9.0%

NA

ALT increase

7.3%

20.8%

Anemia

7.8%

6.0%

Thromboembolism

6.6%

4.1%

Abbreviations: AEs, adverse events; ALT, alanine aminotransferase; NA, not applicable

Nab-Paclitaxel/Gemcitabine

In 2013, the FDA approved nab-paclitaxel plus gemcitabine as a first-line treatment for patients with metastatic adenocarcinoma of the pancreas, based on the phase III MPACT trial.⁵The approval of this combination displaced single-agent gemcitabine, which had been the standard of care for more than 15 years.

The phase III MPACT trial enrolled 861 patients who had not received prior chemotherapy for metastatic pancreatic cancer with adenocarcinoma histology. Patients were randomized in a 1:1 ratio to receive weekly intravenous nab-paclitaxel at 125 mg/m2 plus 1000 mg/m2 of gemcitabine for 3 weeks followed by 1 week of rest (n = 431) or 1000 mg/m2 of weekly gemcitabine for 7 weeks with 1 week of rest followed by the same schedule as the investigational arm (n = 430). The primary endpoint of the trial was OS.

Patients were primarily enrolled in North America (63%) at community and academic centers. All patient characteristics were well balanced between the arms. There was no upper age limit for enrollment in the study, and 42% of patients were &ge;65 years in age. The trial included those with a KPS of 70 to 100. Thirty-nine percent of patients had lung metastases, and 14% of patients had &ge;3 metastatic sites. CA19-9 levels were &ge;59x ULN for 52% of patients.

The trial found a PFS advantage favoring the nab-paclitaxel combination of 5.5 months compared to 3.7 months (HR, 0.69; 95% CI, 0.58—0.82;P<.001). The combination also demonstrated a superior overall response rate of 23% compared with 7% for gemcitabine alone (P<.001).

TABLE 2. Median OS in Prespecified Subgroups

Nab-paclitaxelPlus Gemcitabine(months)

Median OS

Hazard Ratio

Age <65

9.2

6.8

0.65 (95% CI, 0.53-0.79)

Age &ge;65

7.8

6.6

0.81 (95% CI, 0.63-1.03)

KPS, 70-80

7.6

4.3

0.61 (95% CI, 0.48-0.78)

KPS, 90-100

9.7

7.9

0.75 (95% CI, 0.62-0.92)

Australia

9.2

6.7

0.67 (95% CI, 0.45-1.01)

Eastern Europe

7.7

5.9

0.84 (95% CI, 0.58-1.23)

North America

8.7

6.8

0.68 (95% CI, 0.56-0.82)

Liver metastases

8.3

5.9

0.69 (95% CI, 0.59-0.81)

No liver metastases

11

10.7

0.86 (95% CI, 0.56-1.33)

Abbreviations: KPS, Karnofsky performance status; OS, overall survival

In a long-term assessment, the nab-paclitaxel arm demonstrated a significantly higher OS than gemcitabine monotherapy (8.7 vs 6.6 months; HR, 0.72; 95% CI, 0.62—0.83;P<.001).⁶Four percent of patients in the nab-paclitaxel arm lived beyond 3 years versus none with gemcitabine alone. OS was consistent across stratification factors (TABLE 2).

The most common grade &ge;3 AEs with nab-paclitaxel/gemcitabine versus gemcitabine alone were neutropenia (38% vs 27%), fatigue (17% vs 7%), and neuropathy (17% vs 1%). Febrile neutropenia occurred in 3% versus 1% of the patients in the nab-paclitaxel and control arm, respectively. At a median of 29 days, grade &ge;3 neuropathy improved to grade 1 or lower.

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