Genomic Testing Offers New Therapy Options for Hepatobiliary Cancers

Gareth Hughes’ life has always been a fast-paced adventure. As a producer for CBS Sports, the 41-year-old father of two frequently flew from his home in Brooklyn, New York, to various U.S. cities to cover the Super Bowl, the national semifinals for the NCAA Tournament known as the Final Four and other huge sports events.

But he wasn’t ready for the news he received shortly after working 2019’s regional semifinals for the NCAA Tournament known as the Sweet 16.

If the University of North Carolina (UNC) had won, he would have worked all weekend. When they lost to Auburn on Friday, Hughes headed home from the New York City studio and played with his kids. But he felt awful, and it had nothing to do with basketball. He recalls meeting with his psychiatrist the day before (on Thursday in NYC). “I curled up in a ball and cried, and I’d never done that before,” he says. Because Hughes continued having severe pain in his side on Saturday morning, his wife encouraged him to go to the hospital and get it taken care of before he flew to Minneapolis for the Final Four.

Given his youth and health — he’d quit drinking three years earlier — the doctors jumped to the obvious conclusion: time to take out his gallbladder. But after an ultra- sound, X-ray and additional imaging at the emergency department, the doctors changed their tune. “You could tell by the look on their faces that this was not going to be as easy as classic gallbladder problems,” Hughes says. The doctor sat on his bed and explained that there were spots on his liver, either from an infection or cancer. And infection didn’t seem likely.

After a CT scan and biopsy, Hughes knew he wouldn’t be covering the Final Four that year. Instead, he and his wife wrangled with news that changed their lives.

“You go from that Friday night, sitting on the stoop, listening to the music and playing buddy ball, a game we made up, with my 4-year-old son, and by Saturday evening, I’ve been admitted to the hospital and (I don’t know it yet), but my life is never going to be the same,” he says.

By the time he was discharged, it was clear that it was cancer. At an appointment with an NYU Langone Health oncologist, while fielding text messages from work about the Final Four set he’d worked a month to build, Hughes received an official diagnosis of intrahepatic cholangiocarcinoma — cancer of the bile ducts inside his liver. “It was a very strange moment where work and life collided,” he says.

After the appointment, he and his wife just rode the Second Avenue bus for a while, crying, talking and texting the news to friends. “In that initial moment you’re so lost. You don’t know anything,” he says.

The cancer hadn’t metastasized beyond Hughes’ liver, but it had gone too far for resection surgery. He had a grapefruit-sized tumor with satellites on the right side and two dots on the left — dots that essentially ruled out surgery because the risk of recurrence would be too high. He would begin chemotherapy treatment, the first-line standard of care for cholangiocarcinoma. Instead of receiving gemcitabine and cisplatin, however, Hughes sought a second opinion at Memorial Sloan Kettering Cancer Center in New York City, which prompted him to choose a pump that delivered floxuridine directly to an artery in his liver while he received gemcitabine and oxaliplatin. He also underwent testing to see if his tumors contained any mutations.

Hughes, like most Americans, had never heard of cholangiocarcinoma. He had also never heard of the FGFR2 fusion mutation, a gene alteration present in his tumor that broadened treatment options beyond standard chemotherapy — and an example of why doctors are increasingly encouraging people with hepatobiliary cancers to get genomic testing.

Hepatobiliary Cancers Vary Greatly

Hepatobiliary cancers include those in the liver, bile ducts and gallbladder. According to the National Cancer Institute, more than 42,000 people in the U.S. receive a diagnosis of liver or intrahepatic cholangiocarcinoma each year — a rate that has tripled since 1980 and continues to increase due to rising rates of hepatitis B and C infections, cirrhosis from alcohol consumption, and obesity and type 2 diabetes, which contribute to fatty liver disease. In addition, nearly 12,000 others, according to the American Cancer Society, are diagnosed with gallbladder cancer or extrahepatic cholangiocarcinoma, which occurs in the bile ducts outside the liver. The two extrahepatic types are perihilar, occurring in the bile ducts just outside the liver, and distal, occurring in the portion of the bile duct nearest the small intestine. Cholangiocarcinoma is rare — a couple of cases per 100,000 Americans each year — but intrahepatic cholangiocarcinoma is increasing, possibly due to increased detection as scans are done more readily and often.

Only surgery can cure hepatobiliary cancers when they’re caught early enough, but most patients don’t experience symptoms until the cancer has spread far enough to rule out curative surgery. Recurrence is common even after completely resecting a tumor that has spread, and post-surgery treatments vary greatly depending on where the cancer is.

For unresectable liver cancer, on the other hand, first-line treatment usually includes either the combination of the immunotherapy drug Tecentriq (atezolizumab) and the targeted drug Avastin (bevacizumab), or Nexavar (sorafenib) or Lenvima (lenvatinib), both targeted drugs. Second-line treatments include a range of immunotherapy and targeted drugs, including oral tyrosine kinase inhibitors, that have become available.

“With hepatocellular cancers, there has really been a sea change,” says Dr. Milind Javle, a professor of gastrointestinal oncology at The University of Texas MD Anderson Cancer Center in Houston. “Several agents (have been) approved in the last five years, whereas for a decade we had nothing other than sorafenib.” Those approvals include the immunotherapy drugs Keytruda (pembrolizumab), Opdivo (nivolumab) and Yervoy (ipilimumab) as well as the targeted drugs Stivarga (regorafenib), Cabometyx (cabozantinib) and Cyramza (ramucirumab).

For unresectable gallbladder and biliary cancers, however, not many options exist after first-line treatment with chemotherapy, nearly always gemcitabine and cisplatin. Without formal guidelines, most doctors use FOLFOX — folinic acid plus the chemo combo of fluorouracil and oxaliplatin — for second-line treatment of gallbladder cancer and cholangiocarcinoma.

Yet much of that is changing by the day. An increased understanding of tumor mutations across all hepatobiliary cancers is rapidly transforming patients’ treatment options, and doctors are increasingly encouraging patients to undergo genomic testing as the landscape of therapies expands to include more targeted drugs for these cancers.

Genomic and Genetic Testing

Two types of testing that look at the genes are informative, says Dr. Kenan Onel, director of the Center for Cancer Prevention and Wellness at the Tisch Cancer Institute at Mount Sinai in New York City. Genetic testing looks at a person’s innate genetic code to see if they have any germ- line, or inherited, mutations that increase the risk of cancer developing. These mutations include ones familiar in other cancers, such as in the BRCA1 and BRCA2 genes.

Genomic testing, also called molecular profiling, on the other hand, looks only at the genes in the tumor itself that are not inherited, with the goal of finding mutations that can be targeted with specific drugs. No germline mutations have yet been linked to all gall bladder or bile duct cancers, Onel says, so genetic testing offers little insight for people with these cancers. But genomic testing, particularly with a method called next-generation sequencing, is already standard of care for biliary cancer and rapidly becoming so for liver cancer, Javle says.

“For both cancers, increasingly we are understanding that there are subgroups of the patients that have specific genomic alterations that render them more likely to respond to a specific treatment or more likely to be resistant to other treatments,” explains Dr. Lewis Roberts, a professor of medicine at Mayo Clinic who specializes in liver, biliary and gallbladder cancers. “That is perhaps more the case with bile duct cancer than with liver or gallbladder cancer.”

Only one targeted drug has been approved by the Food and Drug Administration (FDA) for cholangiocarcinoma — Pemazyre (pemigatinib). It was approved in April 2020 for advanced intrahepatic cholangiocarcinoma containing FGFR2 fusion or rearrangement mutations, the one Hughes had, after first-line standard chemotherapy. But additional targeted drugs may be coming soon as scientists learn more about genomic targets in biliary tumors, and more are avail- able in clinical trials — the direction Hughes ultimately took.

When his genetic and genomic testing results came back, Hughes learned he didn’t have any germline mutations that predisposed him to cancer, which also meant this cancer was unrelated to the testicular cancer he had at 11 months old that was cured by removal of one testicle. He also learned he hadn’t brought this cancer on himself with drinking, a fear he’d harbored since hearing the news. His doctor told him to “accept that this is random.”

The most important news from the testing was his having an FGFR2 fusion mutation, found in 15% of people with intrahepatic cholangiocarcinoma. That left open a door for oral therapies if chemotherapy failed. “From the get-go, they’re mentioning surgery, and that’s what I had in my head,” Hughes says. “What I should have had in my head were these pills.”

Hughes remained on the triplet chemotherapy regimen from May 2019 until Thanksgiving 2019, when scans showed the tumors were shrinking but his liver function had plummeted. While trying to kill the malignant cells, the chemotherapy had also killed too many healthy cells. Hughes had also developed a common allergy to oxaliplatin. While Hughes was on a long break from chemotherapy, his pain worsened, his pain medications increased, and he frequently visited the emergency department with pain and tumor fevers. By January 2020, his tumor markers had skyrocketed. He restarted chemotherapy, but because it continued to injure his liver, he stopped it in March 2020. It was time to try FGFR inhibitors.

Gene Targets in Cholangiocarcinoma and Gallbladder Cancer

An estimated 40% of patients with cholangiocarcinoma have tumor mutations that could potentially be treated with targeted therapies, but low enrollment in clinical trials has slowed progress in learning about effectiveness of these treatments.

Trials are currently investigating the FGFR inhibitors Balversa (erdafitinib), derazantinib, ponatinib, pazopanib, and Debio 1347, and researchers are testing Pemazyre or infigratinib against chemotherapy for first-line treatment. Another potential target in intrahepatic cholangiocarcinoma is the IDH1 mutation, occurring in approximately 10% to 20% of these tumors. IHD1 encodes an enzyme that can “turn off” the expression of certain cancer protection genes. Recent clinical trials showed improvements in progression- free survival with the IDH1 inhibitor Tibsovo (ivosidenib) in patients whose tumors harbor this mutation. Even the less common BRAF V600E mutation, which occurs in 5% of patients with cholangiocarcinoma, has shown some response in a trial testing the combination of the BRAF inhibitor Tafinlar (dabrafenib) with the MEK inhibitor Mekinist (trametinib). And tumors with HER2 mutations responded to the drug Nerlynx (neratinib) in a 2019 clinical trial.

Genomic testing can also benefit patients by offering insight into whether they’ll respond better — or more poorly — to different therapies. For example, some research suggests tumors with the IDH1 mutation respond to the TKI inhibitor Sprycel (dasatinib) even though it’s not specifically an IDH1 inhibitor. Meanwhile, tumors with FGFR2 mutations did not respond to Pemazyre if they also had TP53 mutations. Three mutations that occur in 15% to 20% of both intrahepatic and extrahepatic cholangiocarcinoma — KRAS, TP53 and ARID1A — lack approved drugs that target them, but emerging research still offers some hope. The ARID1A mutation may be susceptible to a group of drugs called poly (ADP-ribose) polymerase, or PARP, inhibitors, and recent results from a lung cancer trial heralded the first drug to successfully target KRAS, called sotorasib. Scientists have long sought drugs targeting KRAS mutations, which occur in several cancers, so sotorasib may offer benefit for other cancers with these mutations, too.

Though no targeted therapies for gallbladder cancer have been FDA approved yet, a number of mutations could soon have targeted drugs. One recent study by Javle found that 87% of 760 people with gallbladder cancer had a mutation that a drug may potentially target. The most common mutation was CDKN2A, followed by ERBB2, PIK3CA, MDM2, CCNE1, STK11, ERBB3, ATM and PTEN. Similarly, a recent study by Dr. Chirag Nepal and colleagues analyzed sequences from 92 tumors and found nearly a third (29%) had mutations in the TP53 gene, another gene that has attracted researchers’ attention because it’s so commonly mutated across many cancers. The researchers also found ELF3, ERBB2, CDC27, TGFBR2, PIK3CA, KIR2DL4, KIR2DL3 and ARID2 gene mutations, any of which might eventually help determine the most optimal therapies for tumors with these mutations.

With all these targets to investigate and all the experimental therapies out there, it takes additional research to discover what therapies might work against tumors with different mutations. Hughes started first with Balversa, the only other FGFR inhibitor approved by the FDA. However, because it’s approved only for advanced urothelial cancers with FGFR2/3 mutations, Hughes took it off-label. The most common side effect of FGFR inhibitor drugs is high phosphate levels in the blood, followed by fatigue, hair loss, diarrhea, constipation, losing nails, inflammation of the mouth and dry eye. Hughes vomited for a week after starting Balversa, took a brief break and started it again. It worked.

His tumors shrank by half until June, when treatment-related hand-foot syndrome (HFS) caused such painful sores on his feet that he couldn’t walk, and he had to stop the drug. “I became comfortable with the idea that taking breaks was going to be an important part of treatment,” Hughes says. “You have to build in breaks to give your body time to recover.” Hughes continued Balversa until October, when it was no longer working and the tumors began to grow again. He then enrolled in a trial for another FGFR inhibitor that didn’t even have a name yet. But he stopped that drug after just three weeks because his tumor marker doubled.

Fortunately, he qualified for a phase 1 trial with RLY-4008, a drug that targets FGFR2 mutations. Hughes began in December, and after one dose reduction so he could better tolerate it, his main tumor had shrunk 27% by the day after the Super Bowl. “Other drugs you feel drugged and stupid, but this one has kept me feeling normal,” he says, adding that he’s optimistic about his response so far. This drug still causes HFS and requires him to take breaks, but it isn’t as rough on his liver function.

Hughes wouldn’t have had access to this drug without genomic testing revealing the FGFR2 mutation and his choosing to enroll in a clinical trial.

“We should consider every patient as potentially someone who should be participating in a clinical trial,” Roberts says. “At every stage of cancer, there are trials that people can participate in that could potentially help them (and) increase the knowledge that we have and allow us to be offering better treatments over time.” The many trials investigating genomic targets also make Roberts optimistic about future treatments for hepatobiliary cancers.

“These biliary tract cancers are some of the most lethal cancers we have,” says Roberts, but FGFR inhibitors are already showing success in slowing them down — and that’s only one target. “Just knowing you have certain mutations gives us some idea about your likely outcomes because patients with different mutations seem to respond differently, and patients who respond to these treatments have substantially improved outcomes,” he says. “I think many of us are quite hopeful that with time, we’ll be able to continue to make progress and develop better and better treatments and cover a larger proportion of tumors with personalized treatment.”

That’s certainly Hughes’ hope as he’s come to accept the ups and downs of trying different therapies.

“My treatment has moved into a chronic phase, and that’s the most likely way I’ll be living with it for the rest of my life,” he says. “There’s a small possibility that things could break right and things could shrink. I don’t think the odds of that are that great.”

He prefers his odds with the new targeted drugs in development, such as RLY-4008. “I have this dream,” he says, “of this drug acting as my chronic answer.”

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