New Combination Treatment Approach Studied in Pancreatic Cancer

For patients with pancreatic cancer, treatment decisions often come with difficult conversations about current treatment options and the quality of life that will follow the onset of therapy. However, emerging research is beginning to challenge long-standing expectations in this disease.

Dr. Meredith Pelster, associate director of gastrointestinal cancer research at Sarah Cannon Research Institute and a medical oncologist at SCRI Oncology Partners, sat down for an interview with CURE to discuss new data surrounding atebimetinib, a targeted therapy being studied in combination with chemotherapy for metastatic pancreatic cancer. During the conversation, she explains how this investigational approach differs from traditional chemotherapy and what these data may mean for survival and daily living.

In a separate CURE article, Dr. Pelster also reflected on the importance of World Cancer Day and the need for continued progress in cancer research and patient care, which readers can explore here!

CURE: How does atebimetinib work differently from traditional chemotherapy for pancreatic cancer, and what does that mean for patients’ daily lives?

Atebimetinib is a targeted therapy that targets a pathway in pancreas cancer cells that is dysregulated. Focusing on it as a targeted therapy is what makes it very different from traditional chemotherapy. For decades, the only type of treatment option we have had to offer pancreas cancer patients is traditional chemotherapy, which works by trying to kill cells that rapidly divide. However, as a targeted therapy, atebimetinib really focuses on pathways specifically in pancreas cancer that are not working as they should. Atebimetinib is given with a modified version of the standard aggressive chemotherapy that patients think about when they hear about chemotherapy for pancreas cancer.

One of our standard pancreas cancer therapies is a chemo regimen called gemcitabine with nab-paclitaxel, and it is typically given as a weekly treatment for three weeks followed by one week off. When we give the chemotherapy in combination with the targeted therapy atebimetinib, we give the chemotherapy every other week, which really helps with chemo side effects. This means a lot for patients' daily lives in that they have fewer visits to the infusion center since it is every other week; additionally, the recovery time between infusions is longer, and overall, those chemo side effects are less severe than we would anticipate with traditional chemotherapy.

What was the trial aiming to investigate, and who was being evaluated throughout the study?

Atebimetinib has been investigated in phase 1 and 2 studies thus far, and we have most recently been talking about results from the phase two study in which atebimetinib was investigated in combination with the modified gemcitabine and nab-paclitaxel that we discussed. It is that trial that has generated a lot of the data and excitement that we are going to talk about, and it also serves as the foundation for an upcoming phase 3 trial in which the combination of atebimetinib and modified gemcitabine and nab-paclitaxel will be compared against standard gemcitabine and nab-paclitaxel chemotherapy.

The trial showed 64% overall survival at 12 months. What makes these results so significant for patients with newly diagnosed pancreatic cancer?

These are very significant results for patients with pancreatic cancer. Based on the prior trials that justified the use of our current chemotherapy regimens, when I meet a new pancreas cancer patient with metastatic disease, I have to have the difficult conversation that the median overall survival is less than a year. This is a difficult thing for patients and families to hear, which makes this diagnosis one of the most devastating for many patients.

The fact that the phase 2 trial showed that 64% of patients were alive at a year changes that conversation compared to the historical outcomes we have. This is a very significant finding, which is why this combination is going to be investigated in a phase 2 trial to show, in a comparative fashion, whether this combination is better than what we have had in the past.

How does combining atebimetinib with chemotherapy affect side effects compared with standard aggressive treatments?

The data from the phase 2 study, as well as my own personal experience, show that this regimen is well tolerated compared to historical data. With other aggressive chemotherapy regimens, such as gemcitabine and nab-paclitaxel, FOLFIRINOX, or NALIRIFOX, we see lower rates of neuropathy (numbness and tingling in the hands and feet), which can be a major side effect from chemotherapies that impacts patients' daily lives. We also see that there is no worsening of other chemotherapy side effects, such as low blood counts, and in general, the treatment is well tolerated.

I would like to share a story of one of my own patients who was treated as part of the phase two trial, which I think highlights how tolerable this regimen is. This patient was newly diagnosed with pancreas cancer and, as many patients with a new diagnosis are, she was highly symptomatic from the disease itself. She had pain, fatigue, and a low appetite. She was started on treatment and tolerated it very well. She has been on it for over six months now, and we have actually seen her symptom burden and her functional status improve over this time as the treatment has gained control over her cancer. When I first met her, she was relying on family members to help her out considerably.

She felt like she had lost a lot of her independence with this diagnosis, but when I most recently saw her, she was driving herself to her appointments. She had rejoined her neighborhood walking group; she was feeling so much better to be able to do that and was really just living her life while on treatment for pancreas cancer, which I think is truly significant.

How could this approach change the way oncologists think about long-term treatment, resistance, and maintaining quality of life during therapy?

Because this is a very tolerable treatment, it shows that we can continue to treat patients. When a regimen is tolerable, we can use it for longer, and we can potentially see greater durability of benefit when patients can tolerate the therapy for a longer period of time.

Do these findings have implications for treating other cancers beyond pancreatic, and what might that mean for future patient options?

Pancreas cancer, specifically, is highly driven by abnormal functions in a particular pathway called the MAP kinase pathway. Atebimetinib, which is a MEK inhibitor, specifically acts on this pathway, making it a great option for patients with pancreas cancer because we know there is such a tremendously high prevalence of alterations in this pathway in this disease. However, there are many other cancers that have alterations in the MAP kinase pathway due to RAS and other mutations, which are very prevalent across cancer types.

There are certainly other cancers for which this therapy could be explored, but I'm very glad that we are exploring it in pancreas cancer. Clearly, the phase 2 results are very exciting. Pancreas cancer is a disease for which we desperately need new and better treatment options, and because of what we know about the molecular landscape of pancreas cancer biologically, I'm so glad that we have this option being investigated.

What should patients know about how atebimetinib is taken, and what may be ahead for patients in future trials?

Atebimetinib is a pill-based therapy. it's a daily pill that they use in addition to the every-other-week chemotherapy that we discussed. For folks who are really interested in the specific mechanism of the drug, it is different from other MEK inhibitors that are out there for the treatment of other diseases. It achieves what is called deep, cyclic inhibition.

The drug has a short plasma half-life, but it is very potent, meaning we get very deep inhibition of MEK. However, that inhibition is then released because the half-life is short, allowing for normal cells to utilize the pathway. We think this is what impacts the side effect profile. For folks who are interested in that part, that is what is really unique about this drug, and I think it drives many of the results we have seen thus far.

Additionally, this phase 3 trial is coming, and it's going to be a really wonderful option for our patients.

Transcript has been edited for clarity and conciseness.

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