Entrectinib Effective in Pancreatic Cancer Subgroup

Michael J. Pishvaian, MD, PhD

In a study of patients with metastatic pancreatic cancer who harbor NTRK and ROS1 fusions, investigators evaluated the selective TRK and ROS1 inhibitor entrectinib, which is both potent and active in patients with CNS metastases, where results showed early signs of antitumor activity.

This study, which was presented during the 2018 Gastrointestinal Cancers Symposium, included 3 patients with pancreatic cancer—2 with TPR-NTRK gene fusion and 1 with an SCL-ROS1 gene fusion. These patients were given entrectinib at 600 mg daily, which has shown substantial clinical activity in patients with advanced or metastatic solid tumors that harbor these fusions.

Entrectinib was found to be well tolerated in this trial, and treatment was associated with response and prolonged disease control. The activity seen with entrectinib suggests that there is a need for more molecular testing in patients with pancreatic cancer, as they may derive benefit from these types of targeted agents, said lead author Michael J. Pishvaian, MD, PhD.

Chemotherapy is the mainstay of treatment for pancreatic cancer, as it is one of the only therapies that has shown improvement in survival in a disease with such a poor prognosis. Response rates with chemotherapy remain less than 50%, though, and there may be benefit in using targeted therapies for distinct molecular subgroups, suggested Pishvaian.

OncLive: Can you provide some background on this study?

In an interview with OncLive, Pishvaian, director of the Phase I Clinical Program, co-director of the Ruesch Center Pancreatic Cancer Program Medical Oncology, Otto J. Ruesch Center for the Cure of Gastrointestinal Cancer, Georgetown-Lombardi Comprehensive Cancer Center, discussed the findings with entrectinib in this population, as well as the potential implications of widespread molecular testing in pancreatic cancer.Pishvaian: Patients with pancreatic cancer obviously have limited therapeutic options. We know that chemotherapy can be of benefit—we all use chemotherapy regularly, but we are certainly looking for something better. There is a relatively small population of patients who have defined molecular actionable alterations, although that list is growing. There are no approved therapies that are targeted to metastatic pancreatic cancer, except for the small subgroup of patients who are known to have microsatellite instability-high pancreatic cancer, for which pembrolizumab (Keytruda) may be of benefit.

What were the findings of this early study?

This study was done for a very small population of patients who have an NTRK fusion, which accounts for less than 1% of all patients with cancer across the board. However, it so happens that we found some patients with pancreatic cancer who have this fusion. In this disease type, and other disease types, when a NTRK fusion was identified, there is potential for significant benefit from single-agent therapy. It suggests that this was a sort of a driving mutation of the cancer.We found 3 patients, 2 of whom had NTRK fusions, and 1 with a ROS1 rearrangement; entrectinib is also active against ALK and ROS rearrangements. Given that this drug targets those specific rearrangements or fusions and their downstream pathways, this drug was used in these 3 patients. It was very well tolerated, in fact, in at least 1 patient who was very sick going into this study, they had a significant improvement in their quality of life. For all of the patients in general, there was at least a maintenance of a high level of quality of life.

For 2 of the 3 patients, there was a response in their disease, and in 1 patient there was long-term stabilization of disease. While this wasn't compared with chemotherapy, the response in this small subgroup of patients was certainly a better outcome than what we typically see in patients who receive chemotherapy. What are the implication of these findings for the future treatment of pancreatic cancer? It means that we are actually finding new things to treat patients with—we just have to go looking for them. This was a very small subgroup of patients, it would only be found with these extensive molecular profiling efforts. In fact, some of the standard molecular profiling next-generation sequencing DNA tests don't even identify these fusions. It is really an RNA-based test that is the best way to go about looking for these fusions.

Therefore, it means that you have to go looking for it. However, it also means that when you find these driver mutations, even in a small subgroup of patients, [they can] benefit from [targeted agents]. It dramatically improves their quality of life and probably expand their quantity of life, although we can't say that definitively. We can offer great benefit to these patients.

Are there any next steps following this study?

The other thing to not be dismissed is that while entrectinib is a great drug and this trial looks promising, it also opens the door to what we now know are second- and perhaps third-generation drugs targeted at NTRK fusions or ALK or ROS1 rearrangements. My particular patient with the ROS1 rearrangement, who did have progression on entrectinib, is now on a second-generation ROS1-targeting agent and still benefitting.There are efforts, and the first effort is findings these patients. There is a lot of controversy about whether we should be doing molecular profiling on patients in pancreatic cancer, which is such a devastating disease. If we screened or profiled the 50,000 patients a year diagnosed with pancreatic cancer, if we only helped 1% of those patients dramatically, that is still 500 patients a year where we are significantly improving their outcomes. There are other diseases where these fusions or rearrangements are identified, in which entrectinib or drugs similar to it could definitely be of benefit.

What do you hope that practitioners take away from this study?

Both this trial and other trials with similar agents are actively looking at the mechanisms of resistance to these NTRK inhibitors, and hopefully are identifying ways to overcome, or even circumvent, resistance pathways to get more benefit from frontline therapy or identify second- and third-line therapies.This is a poster of 3 patients who have benefit, but there are other patients out there who have had NTRK fusions identified on molecular sequencing efforts and they are benefiting as well. The takeaway message is to go and start looking for these patients.

Pishvaian MJ, Rolfo CD, Lie SV, et al. Clinical benefit of entrectinib for patients with metastatic pancreatic cancer who harbor NTRK and ROS1 fusions. J Clin Oncol. 2018;36 (suppl 4S;abstr 521).