‘Tip of the Iceberg’: More Targeted Therapies for Pancreatic Cancer to Come

For the longest time, there were no active therapy options for patients with pancreatic cancer and survival was “horrifyingly” short, according to Dr. Kim A. Reiss Binder.

However, that all changed in 2001 and has been steadily improving over the past two decades.

Binder, an assistant professor of medical oncology at the Abramson Cancer Center at the University of Pennsylvania, recently highlighted what’s new in the treatment of pancreatic cancer during the 12th Annual Joining FORCES Against Hereditary Cancer Conference. But before she discussed the newer developments in the treatment of the disease, Binder reviewed the history of platinum-based chemotherapies and how they have improved outcomes. Moreover, she discussed how the development of targeted therapies for the disease is just getting started.

Expansion of Active Therapies

As Binder explained, the first single-agent treatment option — gemcitabine — didn’t come into the picture for pancreatic cancer until 2001. The drug was developed and, Binder said, showed a benefit in patients. But it would take another 10 years for more treatments to be developed. In fact, developments occurred in 2011, 2013, 2016, 2017 and 2020, according to Binder.

The three most recent developments — which all target genetic mutations — include Keytruda (pembrolizumab), Lynparza (olaparib) and the combination of gemcitabine and cisplatin. Of note, Keytruda targets tumors that are MSI or MMR deficient and Lynparza as well as the gemcitabine and cisplatin combination target BRCA and PALB2 mutations.

“As we move forward with this disease, we are kind of starting at the tip of the iceberg to start to get some targeted therapies for patients,” she said.

Chemo and BRCA-Related Disease

During the presentation, Binder reviewed multiple clinical trials that demonstrated overwhelming support for the use of platinum-based chemotherapies in individuals with BRCA- or PALB2-related pancreatic cancer.

In fact, one study she referenced showed that platinum-based chemotherapy resulted in a treatment response among approximately 70% of patients with those two mutations.

“Just for reference, our best chemotherapy has about a 30% response rate,” she mentioned. “This was a really important study … because the investigators showed that people with (pancreatic) cancer responded prospectively in a trial so well to platinum-based therapy.”

The takeaway from the trial, according to Binder, was that platinum-based therapy should be the standard of care as a first-line treatment option for patients with BRCA-related disease.

Addressing a New Problem

Although research has shown platinum-based chemotherapy to be effective as a first-line treatment option, there are problems that still need to be addressed, Binder mentioned.

To discuss this point further, she cited a personal experience with a patient in her clinic. The patient, according to Binder, was diagnosed with operable pancreatic cancer in 2012. He underwent surgery in June 2012 and then proceeded to receive six months of gemcitabine. Unfortunately, she noted, his disease returned near the end of that treatment. He was then started on FOLFIRINOX — which is a combination of leucovorin calcium (Folinic Acid), fluorouracil, irinotecan hydrochloride and oxaliplatin, and is still commonly used today, she said.

Binder continued and explained that he remained on that treatment for a little more than a year with no evidence of disease. However, over that time he experienced a multitude of side effects including worsening nerve damage and diarrhea. Luckily, Binder noted, the patient was tested for genetic mutations while receiving chemotherapy and the results indicated he had a BRCA2 mutation. That result allowed him to be a candidate for a clinical trial that was newly recruiting patients in 2014 to assess a novel targeted therapy.

And although many patients do well with platinum-based chemotherapy, Binder acknowledged that people, including her patient, can’t remain on the treatment long-term.

“People with incurable (pancreatic) cancer and BRCA (mutations) often do exceptionally well with platinum-based chemotherapy,” she said. “That is fabulous in a disease that we have trouble controlling in general, but it means that there's progressive toxicity that we then have to deal with. We need a better option for those patients; you can't keep a human on chemotherapy for years, it just isn't attainable for most patients.”

Introducing Maintenance Therapy

To combat the serve toxicity of long-term platinum-based chemotherapy, Binder noted that there was a push for introducing maintenance therapy. The goal, she explained, was to give a patient chemotherapy for several months to shrink the tumor and then switch to a less toxic maintenance option that may keep the disease at bay.

That’s where Lynparza comes into the fold. In 2019, the Food and Drug Administration (FDA) approved this drug as a first-line maintenance treatment option for patients with metastatic pancreatic cancer.

The FDA approved the drug based on results of a phase 3 trial that showed that Lynparza following a minimum of four months of platinum-based chemotherapy extended progression-free survival (the time a patient lives without their disease getting worse) more than placebo.

“This is now an option for patients who need a chemotherapy break after four to six months of chemo,” Binder noted.

She highlighted, however, that the results of that trial were quite variable. Meaning that there was a portion of patients whose tumors did not respond to treatment during their first six months on the trial, but there was also a portion of patients who were able to remain on the study for one to two years and even more so a group of individuals who stayed on the trial well over two years without disease progression.

Future Directions

For incurable patients, Binder said, there’s a tremendous amount of interest looking into the continued role of immunotherapy and how it relates to patients with BRCA-related pancreatic cancer. She noted that several studies are looking further into PARP inhibitors, or PARP plus immunotherapy and PARP plus other drugs.

Moreover, she explained that patients with curable disease should continue to receive platinum-based therapy in the front-line setting.

She wrapped up her presentation by returning to the patient she had introduced to the audience earlier. She noted that he first enrolled in a clinical trial assessing Rubraca (rucaparib) in 2014. Now seven years later, she said, he remains on treatment with his metastatic disease.

“These are the people we need to figure out,” she concluded. “Why does he have this response? How can we get other people to that level?”

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