Ramesh K. Ramanathan, MD, director, Gastrointestinal Medical Oncology Program, Mayo Clinic, discusses the treatment of patients with pancreatic cancer.

In the first-line, the 2 regimens used to treat patients with pancreatic cancer are gemcitabine plus nab-paclitaxel (Abraxane), and FOLFIRINOX. In practice, the regimen is chosen based on the individual patient, Ramanathan says. Generally, patients will be on 1 regimen for 4 to 6 months, develop side effects, and then switch to a second regimen.

In the second-line, there is MM-398 (irinotecan liposome injection; Onivyde) in combination with 5-fluorouracil (5-FU), which is used after gemcitabine plus nab-paclitaxel or single-agent gemcitabine.

There are a number of new agents in clinical trials, and Ramanathan says that molecular profiling is becoming more common in pancreatic cancer. It is important to know if a patient has a genetic alteration such as microsatellite instability, as pembrolizumab (Keytruda) can be given, Ramanathan explains. There is also a lot of interest in identifying patients with a BRCA2 mutation, as these patients often respond better to platinum-based regimens or PARP inhibitors and may have a better survival.

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Ramesh K. Ramanathan, MD, director, Gastrointestinal Medical Oncology Program, Mayo Clinic, discusses the treatment of patients with pancreatic cancer.
 

Dr. Ramanathan Discusses the Treatment of Pancreatic Cancer

Ramesh K. Ramanathan, MD, director, Gastrointestinal Medical Oncology Program, Mayo Clinic, discusses emerging therapeutic targets in patients with pancreatic cancer.

There has been a lot of attention on the pancreatic stroma, says Ramanathan. There has been a lot of research focusing on agents that affect the stroma in combination with chemotherapy. Pegylated hyaluronidase (PEGPH20) has been examined in clinical trials in combination with FOLFIRINOX. That study yielded negative results, says Ramanathan.

There is a pilot study with gemcitabine and nab-paclitaxel (Abraxane) which has not shown a detrimental effect on patients. Patients who have high levels of hyaluronan seem to benefit from PEGPH20 with gemcitabine and nab-paclitaxel. The combination has shown promising efficacy, says Ramanathan. This has led to a phase III study with a biomarker component.

A number of other drugs targeting the stroma are being examined. Napabucasin (BBI608) is currently in a randomized phase III study with gemcitabine and nab-paclitaxel.

Dr. Ramanathan on Emerging Therapeutic Targets in Patients With Pancreatic Cancer

Ramesh K. Ramanathan, MD, vice chair of research in the Department of Hematology/Oncology at Mayo Clinic, discusses why pancreatic cancer is resistant to several therapies, as well as the early, preclinical promise observed with immunotherapy.

Pancreatic cancer is very resistant to systemic chemotherapy, Ramanathan explains. Additionally, there are only a handful of drugs with some clinical activity, and response rates that are usually between 20% and 30%. This is possibly due to the fact that there are no commonly detected mutations across patients. Pancreatic cancers are centered by a very dense stroma, which is unlike other tumor types. This can prevent chemotherapy drugs and immune cells from entering tumor cells, leading to a barrier for effective agents, he adds.

Checkpoint inhibitors are being combined with IDO inhibitors and other agents in preclinical studies, which have shown promising results but need longer follow-up in patients. Furthermore, chimeric antigen receptor T cells look promising but the data are very early, Ramanathan says.

Dr. Ramanathan on Treatment Resistance in Pancreatic Cancer

Ramesh K. Ramanathan, MD, medical director, Clinical Trials Program, Virginia G. Piper Cancer Center, describes a phase II study that analyzed gemcitabine and nab-paclitaxel followed by consolidation with mFOLFIRINOX in patients with metastatic pancreatic cancer.

This study, presented at the 2014 Gastrointestinal Cancers Symposium, set out to evaluate the feasibility of gemcitabine and nab-paclitaxel followed by FOLFIRINOX in this space. Thirty patients were treated with gemcitabine and nab-paclitaxel for up to 6 months. At the end of 6 months, or if progression occured earlier, patients went on to receive FOLFIRINOX.

About 50% of patients treated with gemcitabine and nab-paclitaxel were able to receive FOLFIRINOX while others received FOLFIRI or FOLFOX. Ramanathan says it was encouraging to see that 1-year survival was about 60% and median survival was about 14.5 months. Though this was just a small pilot phase II study, this sequence is worth pursuing, Ramanathan says, as well as the alternate sequence: FOLFIRINOX followed by gemcitabine and nab-paclitaxel.

Ramesh K. Ramanathan, MD, describes a phase II study that analyzed gemcitabine and nab-paclitaxel followed by consolidation with mFOLFIRINOX in patients with metastatic pancreatic cancer.

Dr. Ramanathan on Gemcitabine and Nab-Paclitaxel in Pancreatic Cancer

Ramesh K. Ramanathan, MD, medical director, Clinical Trials Program, Virginia G. Piper Cancer Center, describes the results from an analysis of metabolic response by positron emission tomography (PET) compared with tumor response by computed tomography (CT) from the phase III MPACT trial.

Ramanathan says the study, which was presented at the 2014 Gastrointestinal Cancers Symposium in San Francisco, analyzed a subset of patients from the MPCAT study, which compared nab-paclitaxel plus gemcitabine versus gemcitabine alone for patients with metastatic adenocarcinoma of the pancreas.

A subset analysis of about 250 patients from the MPACT study had PET and CT scans done at baseline, 8 weeks, and 16 weeks, Ramanathan says. The analysis showed that the PET response was doubled regardless if the patients received gemcitabine alone or with nab-paclitaxel. The patients who had a PET response had a higher median survival rate compared to those who had a CT response alone.

Ramanathan says the results indicate that PET may be a better indicator of response. However, there was a group of patients who had PET response but no CT response that showed progression. These patients need to be looked at further, Ramanathan says.

Dr. Ramanathan on an Analysis of the MPACT Trial

Ramesh K. Ramanathan, MD, medical director, Clinical Trials Program, Virginia G. Piper Cancer Center, discusses the potential of identifying actionable targets in appendiceal cancers.

Ramanathan says this study, which was presented at the 2014 Gastrointestinal Cancer Symposium, looked at the molecular profiling data from the KRAS target database of about 250 appendiceal tumors and found a number of molecular markers which might help in formulating a treatment regimen.

The majority of the tumors tested showed that the incidence of thymidylate synthases was low, suggesting that 5-FU-based chemotherapy may be a treatment option, Ramanathan says. The incidence of KRAS mutation was around 50%, similar to colon cancer. There were also a number of other molecular biomarkers, such as PI3K, TOPO I, TOPO II mutations, which can lead to potential treatment options for patients.

This approach, especially in tumors that do not have any standard treatment, may be useful for patients and oncologists, Ramanathan says.

View more from the 2014 GI Cancers Symposium

Ramesh K. Ramanathan, MD, discusses the potential of identifying actionable targets in appendiceal cancers.

Dr. Ramanathan on Biomarkers in Appendix Cancer

Ramesh K. Ramanathan, MD, Medical Director of the Virginia G. Piper Cancer Center Clinical Trials Program at Scottsdale Healthcare, discusses the phase III MPACT study that examined gemcitabine plus nab-paclitaxel (Abraxane) in patients with metastatic adenocarcinoma of the pancreas.

Ramanathan notes that the MPACT trial is the largest trial to be conducted in patients with pancreatic cancer. He adds that the trial was a large international, multi-institution, trial that provided very promising results for the combination, which has been a long sought after goal in pancreatic cancer.

In the trial, 842 patients were enrolled and randomized to receive the combination of nab-paclitaxel at 125 mg/m

 or gemcitabine alone. The median overall survival was 8.5 months for the combination compared to 6.7 for gemcitabine alone (HR = 0.72; 

 = .000015). Moreover, the time to treatment failure was significantly prolonged with the combination from 3.5 months to 5.1 (HR = 0.70; 

Ramanathan notes that, as expected, there was more toxicity with the combination of nab-paclitaxel and gemcitabine than gemcitabine alone. The most common grade 3 adverse events were neutropenia, fatigue, and neuropathy. The rate of febrile neutropenia was 3% for the combination compared to 1% for the single agent.

View coverage from the 2013 GI Cancers Symposium

Ramesh K. Ramanathan, MD, from the Virginia G. Piper Cancer Center, discusses the phase III MPACT study that examined gemcitabine plus nab-paclitaxel in patients with metastatic adenocarcinoma of the pancreas.

Ramesh K. Ramanathan, MD

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