In the ongoing study, patients with metastatic pancreatic cancer were randomized to nab-paclitaxel plus gemcitabine with or without PEGPH20, a pegylated version of recombinant human hyaluronidase. After enrolling 146 patients the study was placed on hold to address concerns regarding thromboembolic events in the investigational arm. At this point, the protocol was amended to exclude those at high risk for a thromboembolic event. Additionally, prophylaxis with enoxaparin was required in the ongoing study.

In the study, 74 patients in the PEGPH20 arm and 61 in the control arm received treatment prior to the hold placed on the study (Stage 1). Additionally, following the protocol adjustment, the study enrolled an additional 114 patients (Stage 2). Efficacy data presented at ASCO were from Stage 1, while safety data included limited data from Stage 2 and all of Stage 1.

For patients treated in the overall population, the ORR was 41% with PEGPH20 versus 34% in the control arm (

= .48). The median duration of response (DoR) was 7.4 versus 4.2 months, in the investigational and control arms, respectively. The PFS in the full population was 5.7 months with PEGPH20 versus 5.2 months with nab-paclitaxel/gemcitabine (HR, 0.69;

The median PFS in the HA-high group was 9.2 months with PEGPH20 versus 4.3 months in the control arm (HR, 0.39;

= .05). In the HA-low arm, the median PFS was 5.3 versus 5.6 months, with PEGPH20 and without, respectively (

For those with HA-high tumors, the ORR was 52% with a DOR of 8.1 months compared with 24% and a DoR of 3.7 months, for PEGPH20 and the control, respectively. There was 1 complete response in the PEGPH20 arm, with a median DoR of 7.4 months. In the low group, the ORRs were similar between the two arms (37% vs 38%).

There was a trend toward improvement in OS with the triplet therapy; however, this was not deemed statistically significant. At the analysis, the median OS was 12 months with PEGPH20 versus 9 months without (HR, 0.62; CI, 0.26-1.46).

At a median follow-up of 7 months, all but 4 patients had discontinued Stage 1 of the study, primary as a result of progression (44.3% in the PEGPH20 arm versus 52.5% in the comparator). AEs were the cause of discontinuation for 18.6% of patients in the PEGPH20 arm versus 16.4% in the control arm.

The most significantly increased AEs of all grades with PEGPH20 versus without were peripheral edema (58.1% vs 31.1%), muscle spasms (55.4% vs 1.6%), and neutropenia (32.4% vs 18%). The most frequently observed grade &ge;3 adverse event with PEGPH20 was neutropenia (24.3%).

A phase III study will assess PEGPH20 in combination with nab-paclitaxel and gemcitabine for patients with metastatic pancreatic cancer with high HA levels. The primary endpoint of the study is PFS, with secondary outcomes measures focused on toxicity and OS. Halozyme hopes to use PFS data from the study for a potential new drug application.

A group of cancer stem cell inhibitors are currently in development for patients with pancreatic cancer. These agents target different pathways and both are being combined with nab-paclitaxel and gemcitabine.

A phase Ib study explored demcizumab plus gemcitabine with or without nab-paclitaxel in 56 patients with pancreatic cancer.

Fifty-six patients at a median age of 65 years were treated across doses of demcizumab. Overall, 32 patients received the triplet and 24 received the doublet.

Of evaluable patients in the triplet arm (n = 28), the ORR was 50% by RECIST criteria. Additionally, 11 patients had stable disease for a clinical benefit rate of 89%. The median PFS was 7.1 months and the median OS was 12.7 months.

The most common AEs with demcizumab plus gemcitabine were fatigue, vomiting, hypertension, nausea, and decreased appetite. The most common AEs with the triplet were fatigue, nausea, diarrhea, and BNP increase, which appears to be an early indicator of cardiotoxicity that can be prevented with proper management.

The stemness inhibitor napabucasin (BBI-608) has demonstrated promising clinical activity when used in combination with weekly paclitaxel in heavily pretreated patients with metastatic pancreatic cancer, according to phase Ib/II data.

In the extension phase, 41 patients received oral napabucasin continuously at a starting dose of 480 mg or 500 mg twice daily along with paclitaxel at 80 mg/m2 intravenously on days 3, 10, and 17 of each 28-day cycle.

Median PFS in the overall population of 41 patients was 2.2 months and median OS was 6.0 months. In 23 patients who were taxane-na&iuml;ve, median PFS was 3.9 months and median OS was 7.4 months. The durable disease control and the prolonged OS in this pretreated population were notable.

Treatment-related grade 3 AEs included diarrhea (4.9%), abdominal pain (4.9%), and nausea (2.4%), and were rapidly reversible. Diarrhea was the most common event of any grade. Overall, 65.9% of patients experienced grade 1 diarrhea and 29.3% had a grade 2 event. Grade 1 fatigue occurred in 26.8% of patients and grade 2 events were experienced by 17.1%.

A second study also exploring napabucasin also showed promising results. In this phase Ib study,18 31 patients at a median age of 64 years with pancreatic cancer received treatment with napabucasin plus nab-paclitaxel/gemcitabine. Overall, 55% of patients had an ECOG PS of 1. Efficacy data were evaluable for 7 patients at the data cutoff.

Overall, 7 of 7 patients responded to the triplet, with a partial response or stable disease. A prolonged response of &ge;24 weeks was experienced by 86% of patients. Of these responses, 3 were partial responses and 3 were stable disease.

The combination of napabucasin, nab-paclitaxel, and gemcitabine was well tolerated. The majority of AEs were grade 1/2 gastrointestinal-related events that were manageable with antidiarrheal and antiemetic therapies.

Immunotherapy Under Exploration for PancreaticCancer

The therapeutic vaccine algenpantucel-L, which is genetically engineered from human cell lines, showed initial signs of activity; however, these results were not duplicated in the phase III IMPRESS trial. At this point, thee PILLAR trial is still under way.&nbsp;

In the IMPRESS trial, 722 patients were randomized between algenpantucel-L plus gemcitabine and radiation with or without 5-FU or gemcitabine with or without 5-FU chemoradiation. The median age of patients was 65 years and 52% of patients are male, with 80% of tumors resected from the head of the pancreas. Nodal status (N+) is 70% and 55% of patients had tumor size &ge;3.0 cm.

The company developing the vaccine, NewLink Genetics, reported topline results from the phase III IMPRESS trial in November 2015.

In this analysis, median&nbsp;OS was 28.5 months from time of randomization for both cohorts blended together. However, despite these early signs of success, a recent analysis showed that&nbsp;algenpantucel-L failed to improve OS&nbsp;versus standard of care. The median OS was 27.3 months when combining algenpantucel-L with standard of care (chemotherapy with or without radiation) versus 30.4 months with standard of care alone. For both groups combined, the OS from the time of randomization was 29.3 months.&nbsp;

The second study, PILLAR (NCT01836432), launched in October 2012. The trial is a two-arm, open-label, randomized study that has accrued 280 patients. Patients with borderline resectable or locally advanced unresectable pancreatic cancer receive either a regimen of FOLFIRINOX or gemcitabine/nab-paclitaxel with or without algenpantucel-L.

The primary endpoint for PILLAR is OS and secondary endpoints include PFS, safety (frequency and grade of AEs) of administration of algenpantucel-L, and immune response to the immunotherapy agent. NewLink Genetics reports that enrollment was completed in December 2015.

Adding to this setback, the combination of the immunotherapy CRS-207 and the vaccine GVAX Pancreas, which had received a breakthrough therapy designation for its potential as a treatment for patients with metastatic pancreatic cancer, failed to improve outcomes&nbsp;in larger trials, according to Aduro Biotech, the company that manufactures the vaccines.&nbsp;

In the open-label phase IIb ECLIPSE trial, 303 previously treated patients with metastatic pancreatic cancer were randomized to the dual vaccine regimen along with low-dose cyclophosphamide, CRS-207 alone, or chemotherapy. Individuals on the chemotherapy arm received gemcitabine, capecitabine, 5-FU, irinotecan, or erlotinib in accordance with the defined treatment regimen. The primary endpoint was OS, with secondary outcome measures including safety and evaluation of clinical and immune response.

The median OS was 3.8 months for patients receiving CRS-207/GVAX compared with 5.4 and 4.6 months for patients receiving CRS-207 alone and chemotherapy, respectively. The vaccines were well tolerated overall, and there were no unexpected toxicities with the immunotherapy combination.

treatment with low-dose cyclophosphamide plus GVAX followed by CRS-207 improved OS by 46% compared with cyclophosphamide plus GVAX alone for patients with pancreatic ductal adenocarcinoma.&nbsp;After a median follow-up of 7.8 months, the median OS was 6.1 months with CRS-207 versus 3.9 months with GVAX alone HR, 0.54;

= .011). For patients who received &ge;3 doses, the median OS was 9.7 versus 4.6 months, for CRS-207 and GVAX, respectively (HR, 0.44;

Although results have yet to be presented specifically for patients with pancreatic cancer, a number of studies are exploring the immune checkpoint inhibitors as part of combination strategies. In other solid tumors, the PD-1/PD-L1 inhibitors have dramatically impacted the standard of care, a paradigm that researchers hope to duplicate in pancreatic cancer.

The PD-1 inhibitor pembrolizumab (Keytruda) is being explored with nab-paclitaxel and gemcitabine for patients with metastatic pancreatic cancer, in the PembroPlus trial. This phase I/II study is assessing dosing, safety, and efficacy, with an estimated primary completion date of December 2016 (NCT02331251).

In another study, the PD-1 inhibitor nivolumab (Opdivo) is being explored with nab-paclitaxel alone or with gemcitabine for patients with pancreatic cancer. The primary endpoint of the phase I open-label study is dose-limiting toxicity with secondary endpoints focused on efficacy. The study hopes to report initial results in July 2017 (NCT02309177).

In addition to the PD-1 inhibitors, the CTLA-4 inhibitor ipilimumab (Yervoy) is being explored following FOLFIRINOX in combination with GVAX/CRS-207 vaccine as maintenance therapy. The primary endpoint of this phase II study is OS. The primary completion date is November 2018 (NCT01896869). Another study is also assessing GVAX/CRS-207 with or without nivolumab. OS is also the primary endpoint of this phase II study (NCT02243371).

PD-1 inhibitors are also being explored along with the reovirus vaccine Reolysin. However, phase II data of Reolysin given in the first-line treatment of metastatic adenocarcinoma of the pancreas found that the virus did not improve outcomes in the overall population of the 73 patients in the study. Researchers are still looking at blood and tissue samples for a potential biomarker to better determine which patients could benefit from this therapy.

Articles

Clinical Articles

The tolerability of nab-paclitaxel and gemcitabine has opened the door to a host of novel combination strategies that use the two agents as a backbone.

New Agents Under Exploration in Pancreatic Cancer

In a small retrospective case study exploring nab-paclitaxel plus gemcitabine as neoadjuvant therapy for borderline resectable or unresectable locally advanced pancreatic adenocarcinoma,

both the R0 resection rate and the response rate were 20%. Findings from the study were presented at the 2016 Gastrointestinal Cancers Symposium.

The study looked at 20 patients at a median age of 69 years. The most common ECOG PS was 1 (55%). A majority of the patients had borderline resectable disease (n = 14; 70%).

Out of 6 patients who went on to receive surgery, 83% also had preoperative radiation and 67% had R0 resections. All patients with an R0 resection (n = 4) were initially defined as borderline resectable. Two patients with unresectable disease by imaging at presentation were able to undergo potentially curative surgery, although an R0 resection was not achieved. Median progression-free survival was 9.1 months (95% CI, 6.2-12.0).

The majority of patients in the study received 6 to 9 doses of nab-paclitaxel and gemcitabine. The partial response rate was 20% and the stable disease rate was 70%. In total, dose reductions were required for 64% of patients, a finding that will be applied to future studies.

Larger studies with longer follow-up are planned to determine whether low-dose neoadjuvant nab-paclitaxel and gemcitabine followed by radiation can lead to long-term disease control for patients with borderline resectable or unresectable locally-advanced pancreatic adenocarcinoma. University of Pennsylvania researchers are also doing a small dose escalation study involving 25 patients, in which the dose of both nab-paclitaxel and radiation are increased, with data available in about a year.

Additionally, researchers are now exploring the same strategy in a prospective fashion in a study with 280 patients accrued across the United States, according to the senior author of the poster Peter Hosein, MD, assistant professor of medicine at the University of Kentucky.

Another trial, known as NEONAX, is examining the use of nab-paclitaxel prior to surgery. In this trial, one arm will receive nab-paclitaxel plus gemcitabine both before and after surgery, while the other arm will receive the combination only after surgery. The trial is investigating the treatment in patients with non-metastatic pancreatic cancer.

As part of the trial, researchers will also investigate potential biomarkers such as hENT1, CDA, DCK, 5&acute;-nucleotidase, CA19-9, SPARC, and neutrophil-lymphocyte ratio. The NEONAX researchers intend to enroll 166 participants, with a primary completion date of March 2019 (NCT02047513).

Following surgery, the phase III APACT trial is comparing nab-paclitaxel plus gemcitabine with gemcitabine alone in patients with resectable cancer who have already undergone surgery. Investigators intend to enroll 800 patients, with a primary completion date of April 2019. An R0 or R1 resection is required prior to entry into this trial.

In APACT, biomarkers will also be assessed as exploratory endpoints. The primary outcome will measure disease-free survival, with secondary endpoints focused on OS and safety. At this time, gemcitabine alone is the standard adjuvant therapy for patients with pancreatic cancer.

In the study, nab-paclitaxel will be administered at 125 mg/m2 along with gemcitabine at 1000 mg/m2 on days 1, 8, and 15 for 6 cycles. Gemcitabine will be administered alone at 1000 mg/m2 on days 1, 8, and 15. The trial is currently recruiting (NCT01964430).

With the wealth of data demonstrating efficacy in the metastatic setting, researchers are now assessing nab-paclitaxel/gemcitabine as both an adjuvant and neoadjuvant treatment for patients with pancreatic cancer. 

Earlier Use on Horizon for Novel Agents in Pancreatic Cancer

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.

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.

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;

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;

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.

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;

= .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;

= .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;

= .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.

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

Abbreviations: ESA, erythropoiesis-stimulating agents; G-CSF, granulocyte-colony stimulating factor

Adverse events were higher with the combination versus the control arm (

). 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.

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,

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.

Among patients who received second-line therapy, 59% and 74% discontinued first-line therapy because of progression in the nab-paclitaxel/gemcitabine and gemcitabine monotherapy arms, respectively. Adverse events led to discontinuation for 26% of those in the combination arm versus 14% with single-agent gemcitabine.

Initial treatment with nab-paclitaxel was associated with significantly longer total survival among patients who received second-line therapy (

= .015). Additionally, in those who did not receive second-line treatment, OS was still significantly improved with the addition of nab-paclitaxel (6.2 vs 4.7 months;

OS-2 was similar in the nab-paclitaxel combination and gemcitabine groups among patients who received second-line therapy (6.7 vs 6.4 months;

= .273), suggesting that second-line therapies were not the cause for the extension in OS in the MPACT trial. In those who did not receive second-line treatment, the OS-2 was significantly longer with nab-paclitaxel versus gemcitabine alone (2.5 vs 1.6 months;

TABLE 2. Overall Survival With Second-Line Therapy

First-line therapies with improved efficacy might encourage use of second-line treatment in a larger proportion of patients with advanced pancreatic cancer. 

Second-Line Options Allow for Treatment Sequencing in Pancreatic Cancer

To explore the multiple factors, a study looked at the effectiveness and supportive care utilization associated with first-line treatment with nab-paclitaxel/gemcitabine or FOLFIRINOX for patients with metastatic pancreatic cancer.

In this retrospective cohort study, data were selected from an electronic medical record platform involving patients throughout the United States. This analysis provided real-world data to support decision-making, including sequencing, in an era of expanding second-line options.

The main 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.

Data were assessed for 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;

<.001) but, otherwise, the groups were similar.

The median TTD was 3.4 months with nab-paclitaxel/gemcitabine and 3.8 months with FOLFIRINOX. Database persistence also did not differ between the two groups, at 8.6 months for both arms.

FOLFIRINOX was associated with a higher incidence of all-grade adverse events (95% vs 84%) and significantly greater prophylactic use of G-CSF and other supportive care medications (

). In the FOLFIRINOX arm, 39% of patients utilized an average of 4.41 doses of G-CSF per patient per 100 days. With nab-paclitaxel/gemcitabine, just 8% utilized G-CSF an average of 2.02 doses per patient per 100 days (

<.01). Additionally, a significantly greater number of patients required erythropoiesis-stimulating agents in the FOLFIRINOX arm (0.9 vs 0.13 doses per 100 patient days;

TABLE. Number of Doses Per Patient Per 100 Days

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 (

When considering the overall cost of care, supportive care and other considerations should be taken into account. With this in mind, nab-paclitaxel and gemcitabine could be the most cost-effective option for the first-line treatment of patients with metastatic pancreatic cancer, according to a recent health resources management study.

In the study, the costs and clinical outcomes of nab-paclitaxel/gemcitabine versus erlotinib plus gemcitabine were assessed using drug cost per cycle multiplied by the median cycles delivered from clinical trials. The comparison included the cost of the drugs and expenses related to administering the therapy and managing adverse events of grade 3/4 severity. These costs were based on 4 months of therapy for nab-paclitaxel/gemcitabine versus 3.9 months for erlotinib/gemcitabine.

In this comparison, the costs associated with the nab-paclitaxel regimen were $24,984 versus $23,044 with erlotinib. When considering the respective survival advantages, the nab-paclitaxel arm showed a $15,522 per life year benefit versus the erlotinib group.

FOLFIRINOX was considerably cheaper in upfront costs compared with nab-paclitaxel/gemcitabine, since gemcitabine, 5-fluorouracil, irinotecan, and oxaliplatin are available in generic form. However, when considering the need for G-CSF, infusion costs, hydration, and the management of additional AEs, the cost associated with FOLFIRINOX was similar to nab-paclitaxel/gemcitabine. When taking these factors into account, the total cost for gemcitabine alone was $8,567 versus $31,761 with nab-paclitaxel/gemcitabine and $67,299 for FOLFIRNOX. In addition to dose modification strategies, a panel of experts also explored factors that influence frontline treatment decisions. This conversation included input from Thomas A. Abrams, MD, Dana-Farber Cancer Institute, George P. Kim, MD, Mayo Clinic, and Caio Rocha Lima, MD, Gibbs Cancer Center & Research Institute.

What factors influence your frontline treatment selection?

: The FOLFIRINOX trial, or the PRODIGE 4 trial, differed from the MPACT trial in patient selection. Patients in the FOLFIRINOX trial really all came from France. They had, for the most part, a better performance status than the folks in the MPACT trial. They were ECOG 0 and 1, whereas the folks in MPACT were KPS 70% and above, which really doesn&rsquo;t necessarily translate evenly, but may in fact show that there were a little bit poorer performance status patients getting the gemcitabine and the nab-paclitaxel. But, on the other hand, both control arms were gemcitabine, and the overall survivals were essentially identical. So, it does make one question whether they were really truly meaningful differences in the trials with respect to the patients.

That said, clearly, the FOLFIRINOX patients had more in the way of toxicity, slightly more in the way of neutropenia and diarrhea than those in the MPACT trial randomized to the experimental arm. And they had a much higher overall survival: 11 months versus 8.5 months. I think based on those data, most people feel that FOLFIRINOX might be a little bit more effective, might have a better response rate, but it&rsquo;s again with the proviso that cross-trial comparison is very, very difficult and fraught with landmines.

It depends on the patient. What does the patient want to do? Does the patient want to wear a pump and have potential toxicities, be hospitalized, need Neupogen, Neulasta? Or do they want to get treated weekly, maybe come in every week and go home, stay at work and still be able to support their family and get their insurance?

I think it depends on what the patient wants and what best fits them. I&rsquo;m going to stir the pot a little bit. There are good survival data. There&rsquo;s this kind of urban legend that we&rsquo;re supposed to use FOLFIRINOX in the really good performance status patients, but there are data out there in the ECOG 0 patient that survival can be as high as 12.6 months with nab-paclitaxel/gemcitabine, and that data is out there in the public domain.

You can use gemcitabine/nab-paclitaxel, especially out in the community. I think there is some fear that if you don&rsquo;t have the support for FOLFIRINOX, you run into side effects. Gemcitabine or nab-paclitaxel is a very reasonable option in that population, that good performance status population. I think the other end of it is, the poor performance status patients we always think, well, let&rsquo;s just give them gemcitabine. But you can give them gemcitabine and nab-paclitaxel, and there does appear to be a benefit to that group of patients as well.

We are moving to a new paradigm now. We&rsquo;re thinking about sequence. We actually have the option in pancreatic cancer, believe it or not, so it&rsquo;s going to be a discussion further along among us.

Now we have irinotecan in a new formulation that showed a benefit in survival combined to 5-FU in second-line gemcitabine-pretreated patients. It threw us off a little bit in how to choose the first-line because if you pick FOLFIRINOX, you don&rsquo;t have randomized phase III data with gemcitabine/nab-paclitaxel in second-line. But you now have randomized phase III data with 5-FU and the MM-398.

I tend to go for sequence, because I think I would also diminish the risk for toxicities for the patient, and I&rsquo;ll be basing phase III trial in my first-line and second-line treatment.

A multitude of factors contribute to the selection of frontline treatment for patients with advanced pancreatic cancer, specifically in regard to selecting first- and second-line therapies.

Factors Determining Frontline Therapy Selection for Pancreatic Cancer

Despite the varying tactics that exist, phase III data are not available to verify which strategy is optimal. A panel discussion was formed to explore the various strategies available for dose modifications. This discussion included insight from Thomas A. Abrams, MD, Dana-Farber Cancer Institute, George P. Kim, MD, Mayo Clinic, Caio Rocha Lima, MD, Gibbs Cancer Center & Research Institute, and Philip A. Philip, MD, PhD, Wayne State University.

What are your dose reduction strategies for FOLFIRINOX?

Most of the time when we combine agents, we tend to drop the doses, predominantly in cytotoxic drugs. Now, we have in pancreatic cancer, two regimens that use full doses of all drugs: FOLFIRINOX and gemcitabine plus nab-paclitaxel. You have two regimens at full doses, so it&rsquo;s very tempting to do a modificationboth in the FOLFIRINOX regimen as well as in the nab-paclitaxel/gemcitabine. But, we are not basing modifications on phase III trials or on experience. So I try to shy away from it. I try to modify the doses after starting rather than start low and escalate. Whenever I use them, I start them at full doses.

I&rsquo;m not so brave. I definitely drop the bolus for FOLFIRINOX, and even take a dose-level reduction of the irinotecan to 150 mg/m2. It&rsquo;s the institutional practice. I think most of my colleagues are doing the same thing and we&rsquo;ve written protocols that have piggy backed on that dose regimen. And I think it is more tolerable.

Obviously, you&rsquo;re right, we don&rsquo;t have the phase III data to decide whether it&rsquo;s really as effective, but just as clinical trials tend not to have the same real-world toxicities as we see in the clinic, I think we have to account for that and try to dose reduce them just a tad, so that we can at least get them through a few cycles and assess the response. But, I agree with your rationale. I understand it.

I found it very difficult to give full-dose FOLFIRINOX, and full-dose gemcitabine/nab-paclitaxel for that matter. I do start them off on full dose, but I tend to have modifications very quickly. It is not that easy a regimen to get through either.

The reality is we don&rsquo;t know how these drugs interact. We know there&rsquo;s an interaction between oxaliplatin and irinotecan. We know there&rsquo;s an interaction between 5-FU and oxaliplatin. Remember oxaliplatin almost got kicked out because by itself it didn&rsquo;t do anything. So we don&rsquo;t know what the real interactions are.

I was with de Gramont on a bus and I asked him, what is it, is it the bolus, is it the continuous infusion? He says to me, &ldquo;I don&rsquo;t know.&rdquo; And he&rsquo;s the father of that regimen. So, I take the irinotecan down by about 20%, and I take the bolus down by about 20%, but I don&rsquo;t throw it out. And you&rsquo;re right. With gemcitabine/nab-paclitaxel you do have to make dose modifications. Remember, it&rsquo;s a higher dose, 125 mg/m2, not the lung dose. But I might push that dose and try to lower my gemcitabine like we did in the old days.

What strategies do you use for nab-paclitaxel/gemcitabine?

We don&rsquo;t have any good evidence to support either how to modify or to see the results of the modification in terms of efficacy. And that type of data will never come. I personally do dose modifications for the nab-paclitaxel and gemcitabine combination, and I do that mostly in the older patients and also in patients who are younger who are going on treatment for months and months. Because then they start to have side effects that, even if you use G-CSF, you&rsquo;re not going to overcomefatigue, neuropathy, the malaise&mdash;which goes with the treatment.

But sometimes, in older patients with performance status that is borderline, I would start with every other week. In fact, I can tell you my personal experience has shown that every other week really makes patients feel better after experiencing a lot of the side effects with the fatigue. Starting off right away with every other week, I would not do it in an average patient. And in the minority of patients who I think that are not going to tolerate it, I do it every other week. But in patients who are continuing for a while, that&rsquo;s something I will do.

Yeah, I agree. I think it&rsquo;s nice to have gemcitabine/nab-paclitaxel, at least some data supporting an every two-week dose regimen, because it is so much easier on patients, and it is a really nice way to dose it. And the fact that, even in a single arm sort of setting, that it seems safe and reasonably effective, that&rsquo;s nice because it is a very nice way to dose modify that regimen.

I still give it weekly. I shorten the cycle day 1, day 8, every 21 if I&rsquo;m worried about that. But every two weeks? We talk about modifying FOLFIRINOX. We don&rsquo;t know the outcome when we do it every two weeks. It&rsquo;s a single institution study, so I think you&rsquo;ve got to stay close to how that protocol was.

Given the benefits of nab-paclitaxel plus gemcitabine and FOLFIRINOX, efforts have been made to improve the toxicity profiles through dose modifications.

Minimizing Adverse Events With Dose Modification in Pancreatic Cancer

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.

between 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 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.

In the 126-patient trial that established gemcitabine,

the 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 (

= .003). Median OS was 5.7 months with gemcitabine versus 4.4 months with 5-FU (

= .0025). The clinical benefit rate with gemcitabine was 23.8% versus 4.8% with 5-FU (

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.

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,

patients 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;

= .038). The 1-year OS rate was 23% with erlotinib versus 17% with gemcitabine alone (

= .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;

= .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 demonstrated superiority versus gemcitabine monotherapy in the phase III PRODIGE 4/ACCORD 11 trial,

which was conducted only at French academic centers in a selective patient population (ECOG 0-1; age &le;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 (

= .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 &ge;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;

<.001). Median PFS with FOLFIRINOX was 6.4 months versus 3.3 months with gemcitabine (HR, 0.47; 95% CI, 0.37-0.59;

<.001). The investigator-assessed ORR was 31.6% in the FOLFIRINOX arm versus 9.4% with gemcitabine arm (

There were significantly more AEs in the FOLFIRINOX group versus gemcitabine, including febrile neutropenia in 5.4% of patients (

). 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;

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

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

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.

The 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;

<.001). The combination also demonstrated a superior overall response rate of 23% compared with 7% for gemcitabine alone (

TABLE 2. Median OS in Prespecified Subgroups

Frontline therapies for patients with metastatic pancreatic cancer have advanced in the past 5 years, with the FDA approval of nab-paclitaxel plus gemcitabine.

Evolving Paradigms in Pancreatic Cancer: Frontline Treatment Regimens

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Pelzer U, Schwaner I, Stieler J, et al. Best supportive care (BSC) versus oxaliplatin, folinic acid and 5-fluorouracil (OFF) plus BSC in patients for second-line advanced pancreatic cancer: a phase III-study from the German CONKO-study group.

Chen L-T, Von Hoff DD, Li C-P, et al. Expanded analyses of NAPOLI-1: Phase 3 study of MM-398 (nal-IRI), with or without 5-fluorouracil and leucovorin, versus 5-fluorouracil and leucovorin, in metastatic pancreatic cancer (mPAC) previously treated with gemcitabine-based therapy.

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Bekaii-Saab T, Mikhail S, Langleben A, et al. A phase Ib/II study of BBI608 combined with weekly paclitaxel in advanced pancreatic cancer.

Shahda S, El-Rayes BF, O&rsquo;Neil BH, et al. A phase Ib study of cancer stem cell (CSC) pathway inhibitor BBI-608 in combination with gemcitabine and nab-paclitaxel (nab-PTX) in patients (pts) with metastatic pancreatic ductal adenocarcinoma (mPDAC).

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Evolving Paradigms in Pancreatic Cancer: References