NEW YORK – Researchers from Cedars-Sinai Samuel Oschin Cancer Center are exploring the efficacy of RAF-targeted therapy for patients with pancreatic cancer driven by RAF alterations.
Last month, the researchers published a retrospective real-world data study in JCO Precision Oncology analyzing the prevalence of RAF alterations in pancreatic cancer and the treatment implications for this subset of tumors. Based on those findings, the same research team has begun a Phase II trial exploring the activity of a combination of Pfizer drugs — the MEK inhibitor binimetinib (Mektovi) and the BRAF inhibitor encorafenib (Braftovi) — in metastatic pancreatic cancer patients who have BRAF V600E mutations in their tumors.
In the retrospective study, researchers led by Andrew Hendifar, medical director for pancreatic cancer at Cedars-Sinai, found that RAF alterations occurred in 2.2 percent of pancreatic cancer patients. The most common RAF alterations they identified were BRAF V600E exon 15 mutations, BRAF ΔNVTAP exon 11 mutations, and SND1-BRAF fusions.
The findings are based on real-world data from more than 3,700 patients collected from several databases, including the Perthera Platform, the Know Your Tumor program run by the Pancreatic Cancer Action Network, and the American Association for Cancer Research's Project GENIE, short for Genomics Evidence Neoplasia Information Exchange.
"When precision medicine started to be adopted as a standard approach for patients in the clinic, it was a little bit frustrating for our pancreas cancer patients because we would test them and they'd mostly have KRAS alterations that were really not targetable," Hendifar said.
Researchers continued to drill down into mutations in pancreatic cancer looking for actionable hits, he added, and this study is the first to identify a subgroup of patients who were KRAS wild type but also harbored other targetable RAF alterations.
Of the 3,781 patients included in the study, 81 had RAF-mutated pancreatic cancer. The researchers considered how this subset of patients fared on standard-of-care chemotherapy or targeted therapy.
Eighteen patients received targeted therapy — either BRAF inhibitors, pan-RAF inhibitors, MEK inhibitors, or ERK inhibitors. Those with the BRAF exon 15 mutations (three patients) saw the greatest benefit from treatment with BRAF and MEK inhibitors, with a 100 percent clinical benefit rate. Four of five patients in the BRAF/RAF1 fusions subgroup saw clinical benefit from treatment with MEK inhibitors. Around 40 percent of patients with BRAF exon 11 mutations derived clinical benefit from targeted treatment.
"If you have a RAF alteration and you have a KRAS wild-type tumor, that is a significant alteration," Hendifar said. "It's driving the tumor and RAF-targeted agents have benefit." In contrast, researchers didn't observe the clinical benefit on targeted therapy among pancreatic cancer patients who had other driver mutations alongside a RAF alteration, such as a KRAS mutation.
The researchers also found that patients with RAF mutations appeared to benefit more from a certain chemotherapy regimen. Patients who received combination regimen FOLFIRINOX as a first-line therapy had a median progression-free survival of 6.5 months, while those who received gemcitabine plus nab-paclitaxel had a median progression-free survival of 4.7 months. Both types of chemo are currently standard treatments for pancreatic cancer.
In later lines of therapy, Hendifar's group similarly saw that RAF-altered pancreatic cancer patients, particularly those with a RAF fusion, fared better on a 5-fluorouracil-based treatment, like FOLFIRINOX, compared to gemcitabine plus nab-paclitaxel. In the RAF fusion subgroup, patients who received FOLFIRINOX had a median progression-free survival of 8.9 months compared to 2.8 months on gemcitabine plus nab-paclitaxel.
"We don't have predictive and prognostic markers that can really help stratify our patients, other than maybe BRCA1/2 mutations," Hendifar said. "We had a very comprehensive database, which included [data on] how long patients were receiving their therapies. We took advantage of that to see if these alterations in fact predicted responses to different chemotherapies in pancreas cancer."
The only established predictive biomarkers for pancreatic cancer are BRCA1 and BRCA2 gene mutations, but even if patients have these mutations, it doesn't help them get on targeted therapy as a frontline option, Hendifar said.
In 2019, the US Food and Drug Administration approved AstraZeneca's PARP inhibitor olaparib (Lynparza) as a maintenance treatment for metastatic pancreatic cancer patients who have germline BRCA1/2 mutations and have responded to first-line platinum-based chemo without progression for at least four months.
As such, in the first-line setting, if a patient has BRCA1/2-positive advanced pancreatic cancer, the consensus is to first try a platinum-based treatment, Hendifar said.
Given the lack of targeted treatment options in this setting, Hendifar and his team decided to follow up on their retrospective real-world data study with a Phase II clinical trial, in which they will look at the activity of binimetinib and encorafenib in metastatic pancreatic cancer patients with a somatic BRAF V600E mutation. This drug combination is currently approved in the US to treat unresectable or metastatic melanoma with a BRAF V600E or V600K mutation.
Other companies are similarly exploring targeted treatment approaches in pancreatic cancer. Deciphera Pharmaceuticals, for example, is investigating a combination of its ULK kinase inhibitor DCC-3116 and Novartis' MEK inhibitor trametinib (Mekinist) in solid tumors including BRAF-mutated pancreatic cancer.
Outside of RAF alterations, Cardiff Oncology is studying its PLK1 inhibitor onvansertib plus chemo in KRAS-mutated pancreatic cancer, and Clovis Oncology is exploring the PARP inhibitor rucaparib (Rubraca) as a maintenance treatment for pancreatic cancer patients with BRCA1/2 and PALB2 mutations.
Meanwhile, Cedars-Sinai's Phase II investigator-sponsored trial is recruiting at several sites in the US, including Cedars-Sinai, Mayo Clinic, Dana-Farber Cancer Institute, and Johns Hopkins University. The trial will enroll up to 29 participants. The primary endpoint is objective response rate, and the researchers will also evaluate other measures of response to the binimetinib-encorafenib combination.
While RAF alterations are rare in pancreatic cancer, Hendifar hopes Cedars-Sinai's Phase II trial will be the "proof of principle" that encourages other researchers and drugmakers to investigate targeted treatment strategies for this subgroup of patients. Hendifar also hopes to begin another trial exploring targeted therapy against Class II RAF mutations, which include non-V600 BRAF mutations.
Because there are limited biomarker-informed targeted treatment opportunities for pancreatic cancer patients, oncologists may not consider performing genomic testing to look for actionable biomarkers. For this reason, Hendifar said genomic profiling is often not part of the workflow for doctors seeing pancreatic cancer patients, whose tumors are difficult to biopsy for samples for genomic sequencing.
"If we could get all the physicians in the country to sequence their pancreas cancer patients, it would add up," Hendifar said, noting that there are around 60,000 new patients a year, of which about 75 percent have advanced disease. "If you start to do the math, it's definitely worthwhile to sequence them for developing targeted treatment approaches."