NEW YORK – After seeing encouraging results in a case study, a group of researchers at Ohio State University are gearing up to more formally investigate the activity of therapies designed to target FGFR2 fusion-positive pancreatic cancer.
Based on responses observed in four metastatic pancreatic cancer patients, as well as a retrospective analysis of 30,299 pancreatic cancer tumor samples, the researchers are planning to launch a decentralized study of FGFR inhibitors in pancreatic cancer.
Sameek Roychowdhury, a medical oncologist at Ohio State University Medical Center and senior author on the NPJ Precision Oncology case study, said that the planned clinical trial will likely be deployed in the next six to eight weeks in a decentralized fashion with the help of telemedicine in this biomarker-selected group of pancreatic cancer patients.
The decentralized design is key for this type of study given the ultrarare prevalence of FGFR alterations, Roychowdhury and coauthors noted in the paper. Gain-of-function FGFR genomic alterations occur in 1 percent to 1.5 percent of pancreatic ductal adenocarcinoma patients in the US, making it difficult to identify and enroll eligible study participants.
"With the increasing use of telemedicine, there is an emerging push to adapt towards decentralized clinical trials monitored virtually regardless of location," they wrote. Already, the researchers managed one of the patients in their case study via telemedicine, which they say highlights the feasibility of this design.
Three of the four FGFR2 fusion-positive metastatic pancreatic cancer patients in the case study received FGFR inhibitors through participation in other basket trials. The fourth patient received off-label treatment outside of the clinical trial setting. All four of these patients responded to FGFR inhibitors.
The patients underwent serial monitoring for changes in their FGFR2 variant allele fractions using an FGFR-focused cell-free DNA assay dubbed FGFR-Dx. The three patients who received treatment through basket trials underwent serial cell-free DNA analysis with liquid biopsies according to the study protocols.
One patient, a 60-year-old man, received multiple cycles of chemotherapy before biomarker testing revealed he had an FGFR2-INA fusion. At that point, he enrolled in a basket trial for Takeda's multi-tyrosine kinase inhibitor (TKI) Iclusig (ponatinib). After experiencing side effects, the investigators switched this patient to off-label treatment with Novartis' multi-TKI Votrient (pazopanib). With Votrient, this patient experienced stable disease for 10 months.
A second patient, a 44-year-old woman, received multiple lines of chemotherapy after surgical resection. When, after disease progression, she underwent biomarker testing, the investigators learned she had an FGFR2-USP33 fusion. This patient then enrolled in a basket trial for Incyte's FGFR inhibitor Pemazyre (pemigatinib). She had a partial response to the treatment — with a 43 percent reduction in tumor size — and remained on treatment for 28 months.
Pemazyre, of note, is US Food and Drug Administration-approved for FGFR2 fusion-positive cholangiocarcinoma and for patients with myeloid or lymphoid neoplasms harboring FGFR1 rearrangements. None of the FGFR inhibitors on the market are FDA-approved for pancreatic cancers.
Due to lymph node involvement, investigators then switched this patient to QED Therapeutics' FGFR inhibitor Truseltiq (infigratinib), and her cancer remained stable for nine weeks. Truseltiq, of note, received accelerated approval from the FDA and was commercially available for a time as a treatment for FGFR-mutated bile duct cancer, but was pulled off the market this past spring due to issues enrolling and conducting a confirmatory clinical trial required under the accelerated approval pathway.
A third patient, a 69-year-old man, also received both surgery and chemotherapy before undergoing biomarker testing that revealed an FGFR2-CEP55 fusion. At this point, he enrolled in an Iclusig basket trial, and his pancreatic cancer target lesion shrank 21.2 percent. He experienced stable disease for 15 months before being switched to a Truseltiq basket trial. On this drug, he experienced a 40 percent reduction in target lesions, which lasted 10 months.
Finally, a fourth patient in the case report, a 78-year-old man, underwent chemotherapy before testing revealed an FGFR2-INA fusion. He then received Pemazyre off-label, and he has been responding for 20 months.
For the patients treated in the clinical trial setting, Roychowdhury and colleagues took a closer look at the correlation between blood-based biomarkers and FGFR inhibitor treatment response. They considered both CA19-9, a blood biomarker typically elevated in pancreatic cancer patients, as well as FGFR2 fusion variant allele fractions in plasma cell-free DNA. While the results varied from patient to patient, the researchers ultimately observed a clinical correlation between FGFR2 fusions in cell-free DNA and patients' outcomes.
These patient cases, to be sure, are anecdotal and don't amount to broad evidence of FGFR targeted therapy's benefit in this setting. That said, the fact that each of these patients' metastatic pancreatic cancer, a notoriously difficult-to-treat tumor with a poor prognosis, responded to some extent to the TKIs was enough for the investigators to look more closely at this possible application.
Each of the four patients displayed improved survival, living between two and seven years, as well as durable responses or disease control, Roychowdhury noted, adding that the outcomes should be viewed in the broader context: The five-year survival rate for pancreatic ductal adenocarcinoma hovers around 12 percent. Accordingly, these patients experienced improved outcomes and quality of life.
To this end, Roychowdhury and colleagues wanted to take a broader look at the landscape of FGFR alterations in pancreatic cancer. To do so, they analyzed the genomic results from 30,229 tumors tested with Foundation Medicine's next-generation sequencing assay FoundationOne CDx.
Here, they found a 0.81 percent incidence of FGFR fusions in pancreatic cancer and noted that the FGFR2 fusions generally occurred in isolation, suggesting that they were indeed the genomic drivers of the cancers.
Though their study involved only four patients, Roychowdhury and colleagues noted in the NPJ Precision Oncology paper that their investigation was the largest of its kind to look at the prevalence of FGFR2 fusions while also studying the role of these biomarkers in guiding targeted treatment.
"[The patients'] clinical data provides strong support that FGFR alterations are clinically actionable in pancreatic ductal adenocarcinoma," they wrote. Going forward, if more patients are treated with FGFR inhibitors in this disease setting, the investigators noted that they will have a chance to study the mechanisms of acquired resistance.
This further study will begin with Roychowdhury and colleagues' plan to conduct a decentralized clinical trial, for which they will partner with local oncologists, commercial labs, and the Pancreatic Cancer Action Network.
With genomic profiling through labs including Foundation Medicine, Caris Life Sciences, and Tempus, advanced pancreatic cancer patients whose tumors harbor FGFR2 fusions or other exploratory FGFR biomarkers will have the chance to go through the informed consent process via telemedicine, then receive treatment with Pemazyre monotherapy along with telemedicine-based follow-up visits.
Patients enrolled in the trial will undergo serial cell-free DNA testing using the custom FGFR-Dx assay used for the patients detailed in the case report.
"This will enable us to study the dynamics of cfDNA and how to apply this for clinical decision making," Roychowdhury said. Even though there are commercially available liquid biopsy tests that can, in theory, pick up FGFR alterations in plasma DNA, Roychowdhury noted that, at least among the patients detailed in the case reports, there were several instances where commercial assays missed the FGFR alterations that FGFR-Dx picked up.
"Liquid biopsy is still a new tool [so] particular gene fusions may be missed by commercial assays unless they've done a detailed validation for that particular fusion," he said.
Importantly, Roychowdhury also highlighted the need, going forward, to test pancreatic cancer patients for actionable genomic alterations at the onset. All four of the patients in the case report received, and then progressed on, chemotherapy before biomarker testing revealed actionable FGFR biomarkers.
"We recommend early genomic testing at the time of diagnosis for any advanced solid tumor," he said. "We do not recommend waiting until after disease progression."