How can FGFR2 inhibitors like RLY-4008 help with patients suffering with cholangiocarcinoma and what makes it a clinical significance? The ReFocus study is a trial, it's a phase 1/2B study including all solid tumors, mainly focused on cholangiocarcinoma, and some other separate subsets including breast cancer, some of the GYN malignancies as well.
Looking at a novel FGFR2 inhibitor RLY-4008. So there are several existing FGFR2 (tyrosine kinase) inhibitors in cholangiocarcinoma and bladder cancer. And all of them look to be quite effective and really great treatment options, but many of them we develop resistance over time, they're not effective against FGFR2 mutations, amplifications, they typically work for fusions or rearrangements in the gene.
And so we've always been looking for ways to augment our activity against the target FGFR2. And also trying to limit some of the toxicities that we see sometimes with off-target effects. So high phosphorus hypercalcemia can be big problems with the existing pan-FGFR inhibitors.
So the hope is that RLY-4008, by being a more selective FGFR2 inhibitor, would avoid some of those toxicities and then also increase the activity of it. And the early data have looked very promising in cholangiocarcinoma. So there was data presented at ESMO this year in September. They looked at the first 17 patients with FGFR2 fusions with Calandra carcinoma, and it showed a 88% response rate in that population, which is dramatically higher really than everything seen with the existing pan-FGFR2 inhibitors.
And also showed, a relatively well tolerated side effect profile, hand-foot syndrome typically is the most difficult thing to treat with this class. But those toxicities were manageable. So we're excited to see this particular abstract was basically presenting this trial to the breast cancer world because it does seem that this is, this mutation is present in about 3 to 5% of patients with advanced breast cancer.
And we're excited to see what that activity might look like in this disease because the data in cholangiocarcinoma has looked really exciting.
Cancer of the bile ducts is an uncommon condition in which malignant cells grow in the bile ducts. Cancer of the bile duct is also known as cholangiocarcinoma.
The liver, gallbladder, and small intestine are connected by a network of tubes called ducts. This network begins in the liver, where bile is collected by several tiny ducts (a fluid made by the liver to break down fats during digestion). Together, the tiny ducts constitute the right and left hepatic ducts, which exit the liver. Outside of the liver, the two channels unite to form the common hepatic duct. Connecting the gallbladder to the common hepatic duct is the cystic duct. Bile from the liver is stored in the gallbladder after traveling through the hepatic ducts, common hepatic duct, and cystic duct.
Bile stored in the gallbladder is released after digestion and travels through the cystic duct, common bile duct, and small intestine.
I think the most common question I get about this study is within the alterations of FGFR2, which would this drug likely work for? So typically, we separate these into fusions and rearrangements as one group, amplification is another, and then mutations as another. And our, we know for sure that it's likely to work in the fusions rearrangements group.
We're hoping to see, good signal with the patients who have amplifications and mutations as well. Because of the design of the drug being much more selective and higher activity for FGFR2, our hope is that it would work for those but time will really tell.
I'm hoping it will. Maybe not exactly today, the data for cholangiocarcinoma really is very exciting. And so I hope that with continued accrual and as we get the numbers up into the trial, that we can get this to an FDA indication sometime very soon. Because, it does seem like it is extremely active (site) and hopefully more than the existing FGFR inhibitors.
The FGFR2 gene codes for the fibroblast growth factor receptor 2 protein (FGFR2). Fibroblast growth factor receptors are related proteins that play crucial roles in cell growth and division (cell proliferation), cell maturation (differentiation), bone (formation) development, blood vessels formation (angiogenesis), wound healing, and embryonic development.
The FGFR2 protein spans the cell's outer membrane (protein), so that one end of the protein remains within the cell while the other end protrudes from the cell's surface. This location enables the FGFR2 protein to interact with certain growth factors outside the cell and to receive signals that assist the cell in responding to its surroundings. When growth factors bind to the FGFR2 protein, the receptor initiates a cascade of chemical processes within the cell that instruct the cell to mature and acquire specialized activities.
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So the next step really is to, I think one is to increase the number of patients with cland or carcinoma that we've treated with this disease to confirm that. That response rate. We all expect that 88% is a very high number. We all anticipate it will come down to some degree, but we're hoping that will land somewhere, more in the 50 to 60% territory as we get more numbers there.
I think the other bigger, big thing that we're hoping to see with this drug is to see activity globally across solid tumors. FGFR2 inhibition really could be the next tumor agnostic approval in oncology. This mutation while rare, it's present in probably 15, 20, 30 different solid tumors and we can see activity in all of them.
So our hope is that, we'll see that this drug works not just in cholangiocarcinoma, but across many solid tumors.
Context: Previous, nonselective FGFRi have validated FGFR2 f/r as a target in CCA by attaining an ORR of 20-40% and DOR of 5-9 months. Off-target toxicity and polyclonal FGFR2 resistance restrict efficacy. RLY-4008, the first highly selective, powerful FGFR2 inhibitor, targets driver changes and FGFR resistant mutations. In FGFR2 f/r, FGFRi-naïve CCA patients, RLY-4008 showed initial effectiveness.
Methodology: In ReFocus (RLY-4008-101), Phase 1/2 patients with advanced solid malignancies received RLY-4008 orally (20-200 mg QD or BID). Local testing determined FGFR2 f/r. Investigator-assessed ORR per RECIST v1.1, DOR, and safety were goals. Safety and efficacy were assessed in all dosed patients with FGFR2 f/r, FGFRi-naïve CCA with detectable disease and less than two tumor evaluations to confirm response.
Implications: There were 38 FGFR2 f/r, FGFRi naïve CCA patients were efficacy-evaluable as of 01AUG22. Most patients (68%) received the recommended phase 2 dose (RP2D) and stayed on treatment for 6 months (<0.1 - 18.5 months). All doses were effective, especially the RP2D with an ORR of 88%. (Table). One RP2D patient achieved a near-complete response and curative tumor excision. Most DOR answers are still underway. Low-grade stomatitis (48%), PPE (46%), and dry mouth (31%). No grade 4/5 TRAEs occurred.
I think the key takeaway from this is that FGFR2 inhibition really is an important target across solid tumors. It's been known in cholangiocarcinoma, it's been known in bladder cancer and a few other types, but it really is present across many solid tumors and we can't see activity with this drug regardless of what the primary tumor was.
This drug is an oral agent, and again, besides sort of the hand-foot issues, some mucositis, it's generally a very well tolerated agent compared to many of the chemotherapies we would often use in these diseases. So really I think it's an exciting drug. I think there's a lot more research to be done, but I hope this pans out for our patients.
Suneel Kamath, MD - About The Author, Credentials, and Affiliations
Medical oncology, hematology, and internal medicine board-certified Dr. Kamath is an Assistant Professor of Medicine at the Cleveland Clinic Lerner College of Medicine at Case Western Reserve University.
Dr. Kamath earned his medical degree from Columbia University College of Physicians & Surgeons after studying biology at Case Western Reserve University. His post-doctoral training comprised internal medicine residency and hematology/oncology fellowship at Northwestern University Feinberg School of Medicine.
JAMA, JCO, JNCCN, and Cancer Research have published Dr. Kamath's research. He also writes medical editorials for U.S. News & World Report, Chicago Tribune, Abcnews.go.com, and Stat News.
Dr. Kamath develops innovative immunotherapy and precision medicine techniques for gastrointestinal malignancies. His research on oncology health and financing disparities raises awareness and funds for underfunded diseases such gastrointestinal cancers. He lobbied Congress for cancer research funding equity.
NIH - What Is Bile Duct Cancer (Cholangiocarcinoma)? NIH, 2022
Medline Plus - FGFR2 gene. Medline Plus, June 1, 2020
OncologyPro - LBA12 - Efficacy of RLY-4008, a highly selective FGFR2 inhibitor in patients (pts) with an FGFR2-fusion or rearrangement (f/r), FGFR inhibitor (FGFRi)-naïve cholangiocarcinoma (CCA): ReFocus trial. OncologyPro, September 11, 2022