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.
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 (P= .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;P= .11).
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;P= .05). In the HA-low arm, the median PFS was 5.3 versus 5.6 months, with PEGPH20 and without, respectively (P= .74).
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 ≥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.
Cancer Stem Cell Inhibitors
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.16Fifty-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.17In 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-naïve, 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 ≥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.
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 ≥3.0 cm.
The company developing the vaccine, NewLink Genetics, reported topline results from the phase III IMPRESS trial in November 2015.19In this analysis, median 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 algenpantucel-L failed to improve OS 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.
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 in larger trials, according to Aduro Biotech, the company that manufactures the vaccines.
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.
In a previous phase II study,20treatment 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. 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;P= .011). For patients who received ≥3 doses, the median OS was 9.7 versus 4.6 months, for CRS-207 and GVAX, respectively (HR, 0.44;P= .0074).
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.