Issue: June 10, 2021
Source: Llovet JM, et al. Nat Rev Dis Primers. 2021;10.1038/s41572-020-00240-3.
Disclosures: Finn reports consultant roles with AstraZeneca, Bayer, Bristol Myers Squibb, CStone Pharmaceuticals, Eisai, Eli Lilly, Exelixis, Genentech/Roche, Merck and Pfizer. Hwang reports a speakers bureau and consultant role with Bristol Myers Squibb. Kelley reports compensated advisory board roles or independent data monitoring committee membership with Exact Sciences, Genentech/Roche and Gilead; research funding or compensation for scientific advisory board and/or steering committee roles paid to her institution from Agios, AstraZeneca, Bayer, Bristol Myers Squibb, Eli Lilly, EMD Serono, Exelixis, Merck, Novartis, Partner Therapeutics, QED, Relay Therapeutics and Taiho; and travel support from Ipsen. Llovet reports research support from Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Eisai and Ipsen; and consultant fees from AstraZeneca, Bayer, Bristol Myers Squibb, Celsion, Eisai, Eli Lilly, Exelixis, Genentech/Roche, Glycotest, Ipsen, Merck, Mina Alpha Ltd., Nucleix and Sirtex Medical.
June 10, 2021
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New approvals for liver cancer mark ‘golden age’ of treatment

Issue: June 10, 2021
Source: Llovet JM, et al. Nat Rev Dis Primers. 2021;10.1038/s41572-020-00240-3.
Disclosures: Finn reports consultant roles with AstraZeneca, Bayer, Bristol Myers Squibb, CStone Pharmaceuticals, Eisai, Eli Lilly, Exelixis, Genentech/Roche, Merck and Pfizer. Hwang reports a speakers bureau and consultant role with Bristol Myers Squibb. Kelley reports compensated advisory board roles or independent data monitoring committee membership with Exact Sciences, Genentech/Roche and Gilead; research funding or compensation for scientific advisory board and/or steering committee roles paid to her institution from Agios, AstraZeneca, Bayer, Bristol Myers Squibb, Eli Lilly, EMD Serono, Exelixis, Merck, Novartis, Partner Therapeutics, QED, Relay Therapeutics and Taiho; and travel support from Ipsen. Llovet reports research support from Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Eisai and Ipsen; and consultant fees from AstraZeneca, Bayer, Bristol Myers Squibb, Celsion, Eisai, Eli Lilly, Exelixis, Genentech/Roche, Glycotest, Ipsen, Merck, Mina Alpha Ltd., Nucleix and Sirtex Medical.
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Liver cancer — the fastest-growing cause of cancer death in the U.S. — has been notoriously difficult to treat.

Based on an estimated 41,000 deaths, liver and intrahepatic bile duct cancer is poised to become the third most common cause of cancer-related death by 2040, surpassing colorectal cancer, according to results of a cross-sectional study published in April in JAMA Network Open.

Liver cancer fundamentally represents two diseases in one, according to Robin K. (Katie) Kelley, MD. “The vast majority of patients have underlying liver disease, as well as the cancer,” she said. “Choice of therapy and management of toxicity really requires that we address both aspects of their disease.”
Liver cancer fundamentally represents two diseases in one, according to Robin K. (Katie) Kelley, MD. “The vast majority of patients have underlying liver disease, as well as the cancer,” she said. “Choice of therapy and management of toxicity really requires that we address both aspects of their disease.”

Source: UC Regents.

“It’s really a striking, sobering figure,” Robin K. (Katie) Kelley, MD, professor of clinical medicine and chair of the data and safety monitoring committee in the division of hematology and oncology at UCSF Helen Diller Family Comprehensive Cancer Center, told HemOnc Today. “Year upon year we have increasing referrals for patients with hepatobiliary cancers, specifically hepatocellular carcinoma, but also intrahepatic cholangiocarcinoma. We are seeing more patients coming to us from community practices, as well as internal referrals.”

Although this trend is troubling, progress in research over the last 15 years has increased optimism in the liver cancer community. Advancements in immunotherapy have paved the way for care-defining treatments, led by the introduction of sorafenib (Nexavar, Bayer) in 2007.

“I think we’re really on a roll,” Richard S. Finn, MD, professor of medicine in the division of hematology/oncology at David Geffen School of Medicine at University of California, Los Angeles and Jonsson Comprehensive Cancer Center, told HemOnc Today. “It’s very gratifying to work in the clinic and see patients who benefit. Had we had these drugs 5 years ago, there may be patients who would be alive who missed this golden age.”

HemOnc Today spoke with oncologists on the front lines of hepatobiliary cancer care and research about the expanding treatment landscape within the field, evolving studies of drug combinations and biomarkers, and the push to answer remaining questions that may drive the next breakthrough for the treatment of HCC.

Global burden

With an estimated 30,200 deaths in 2018, liver cancer is the most rapidly growing cause of cancer death in the U.S., according to data from American Cancer Society.

In a study published in Cancer, Ma and colleagues showed that the overall liver cancer death rate per 100,000 people increased between 2000 and 2015 from 7.5 to 11.2 among men and from 2.8 to 3.8 among women.

A steady increase in global liver cancer incidence represents another worrisome trend.

In another Cancer study, Liu and colleagues reported a growing number of primary liver cancer cases in most developed countries, especially among older age groups. From 1990 to 2017, the number of cases worldwide increased from 216,561 to 359,770 among those aged 30 years to 59 years and from 241,189 to 578,344 among those aged 60 years and older.

Despite the availability of hepatitis B vaccination and effective treatments for hepatitis C virus — two liver diseases that are the leading causes of liver cancer — Liu and colleagues found that the rise in cases appears to be driven in part by growing incidence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Those two obesity-associated diseases are likely to drive continued increases in liver cancer cases over the next 3 to 5 decades without greater preventive efforts, according to the researchers.

Jimmy J. Hwang, MD
Jimmy J. Hwang

“As Western countries have a greater degree of obesity, in theory you will see more fatty liver disease as a result,” Jimmy J. Hwang, MD, chief of gastrointestinal medical oncology at Levine Cancer Institute at Atrium Health and a HemOnc Today Editorial Board Member, said in an interview. “We are at the point where liver cancer related to hepatitis B is starting to drop off, and hepatitis C is being detected when blood is screened prior to transfusion. The fact that the numbers have still gone up is a reflection of alcohol use — and we’ll see if the pandemic will affect that in the future — and nonalcoholic fatty liver disease.”

Liver cancer fundamentally represents two diseases in one, Kelley said.

“The vast majority of patients have underlying liver disease, as well as the cancer,” she said. “Choice of therapy and management of toxicity really requires that we address both aspects of their disease and their comorbidity may be due, even differentially, more to the liver disease than the cancer in some cases.”

Breakthroughs

As recently as 15 years ago, there was no treatment for liver cancer that prolonged OS.

Richard S. Finn, MD
Richard S. Finn

“We gave chemotherapy to patients with advanced disease, really for no reason other than we wanted to do something for them,” Finn said.

The breakthrough clinicians needed arrived in 2007, when Josep M. Llovet, MD, founder and director of the liver cancer program and professor of medicine at Mount Sinai School of Medicine, presented results of the SHARP trial at ASCO Annual Meeting.

In the phase 3, double-blind, randomized trial that included 602 patients with advanced disease, those who received sorafenib had a 44% increase in OS compared with those assigned placebo (median OS, 10.7 months vs. 7.9 months; HR = 0.69; 95% CI, 0.55-0.87).

“It was the first time we had a systemic therapy for HCC,” Llovet told HemOnc Today. “People were standing up and clapping. It was very, very nice.”

These data ushered in a period of intense clinical development in liver cancer research, according to Finn.

“[The SHARP trial] showed that sorafenib improved survival by a median of about 3 months,” he said. “Tumors didn’t necessarily shrink, but it improved survival, which is ultimately the most important thing. It set the stage for progress. The results showed you can develop a drug for liver cancer, that you can be successful in a well-designed study.”

Still, the progress that followed moved slowly at first.

Josep M. Llovet, MD
Josep M. Llovet

“We had 10 years of additional drugs being tested and all trials were negative. We were shocked,” Llovet said. “Some were negative because the drug was powerful but toxic, like sunitinib [Sutent, Pfizer], and others were not powerful enough.”

The next breakthrough occurred in April 2017.

Regorafenib (Stivarga, Bayer) — a kinase inhibitor that works by blocking several enzymes that promote cancer growth — became the first FDA-approved treatment for advanced liver cancer since sorafenib. Sixteen months later, based on data from the phase 3 REFLECT trial, lenvatinib (Lenvima, Eisai) received FDA approval, becoming the first front-line therapy approved for unresectable HCC in a decade. Within a year, FDA approved two more multi-kinase inhibitors, cabozantinib (Cabometyx, Exelixis) and ramucirumab (Cyramza, Eli Lilly).

Three additional treatments received accelerated approval — the anti-PD-1 antibodies nivolumab (Opdivo, Bristol Myers Squibb) and pembrolizumab (Keytruda, Merck), and nivolumab plus the anti-CTLA-4 antibody ipilimumab (Yervoy, Bristol Myers Squibb) — although these approvals have been the subject of an FDA review.

After a decade-long drought, the tidal wave of drugs approved for HCC from 2017 to 2020 opened the window to a myriad of opportunities for advancing research and improving outcomes.

“We’ve learned some things from what we did during those negative studies, in regard to trial design and the natural history of liver cancer,” Finn said. “It took time and trial and error to develop these more active drugs.”

Finn led the phase 3 IMbrave150 trial, which compared the PD-L1 inhibitor atezolizumab (Tecentriq, Genentech/Roche) plus the VEGF inhibitor bevacizumab (Avastin, Genentech/Roche) with sorafenib among patients with unresectable HCC. Results of the trial, published last May in The New England Journal of Medicine, are considered the next milepost in research and led to FDA approval of the combination for this patient population.

An updated analysis presented in January after median follow-up of 15.6 months showed the combination reduced the risk for death by 34% (median OS, 19.2 months vs. 13.4 months; HR = 0.66; 95% CI, 0.52-0.85).

“It’s the dawn of a new era of combinations, a true breakthrough,” Llovet said. “The first HR reported [from IMbrave150] was 0.58, which is outstanding. With longer follow-up there was some regression to the HR, to 0.66, which is still outstanding. The objective response rate of approximately 30% is very, very good.”

The next steps

Although these new FDA-approved therapies have changed the treatment landscape for advanced HCC, the most common form of liver cancer, the understanding of disease biology that led to their success also has paved the way for testing new treatments and combinations.

Trials currently underway are exploring combinations of checkpoint inhibitors and tyrosine kinase inhibitors or anti-VEGF therapies, or combinations of two immunotherapy regimens, with results “expected to change the landscape of HCC management at all evolutionary stages,” Llovet, Kelley, Finn and others wrote in an article published in January in Nature Reviews Disease Primers.

The rationale behind such combinations is that VEGFR inhibitors can switch “cold” tumors into “hot” tumors, enabling the immune checkpoint inhibitor to have greater effect.

“The beauty of the combinations is, depending on the partner, a higher percentage of the cells will lose the capacity to hide from the immune system,” Llovet said. “That’s because these drugs are immune modulators. The hot tumors are recognized by the immune system, but the cold tumors are not. If the cold tumors are switched to hot, the immune system will react. Once the immune system is engaged, then the paradigm changes, because we’re talking long-lasting responses, beyond 12 months and sometimes beyond 20 months, which leads to outstanding survival.”

One such combination that has been investigated in a phase 1b trial is lenvatinib — a multi-kinase inhibitor that targets the VEGFR1, VEGFR2 and VEGFR3 kinases — and pembrolizumab.

Finn and colleagues evaluated the combination as first-line treatment among 104 patients with unresectable HCC. The results, published last year in Journal of Clinical Oncology, showed an objective response rate of 36% per RECIST and 46% by modified RECIST, with median PFS of 9.3 months, median OS of 22 months and no dose-limiting toxicities. These results prompted the initiation of a phase 3 trial comparing lenvatinib-pembrolizumab with lenvatinib alone.

The combination of a multi-kinase inhibitor and an immune checkpoint inhibitor also is being evaluated in a phase 3 trial of cabozantinib plus atezolizumab vs. sorafenib in the advanced setting.

In their primer, Llovet and colleagues also highlighted the potential to combine complementary, nonredundant immune checkpoint inhibitors to augment the proportion of patients achieving antitumor immune responses.

For instance, a phase 3 trial testing the combination of nivolumab and ipilimumab as front-line therapy is ongoing, and that combination already has been approved for treatment of HCC after sorafenib.

In addition, Kelley and colleagues presented data at last year’s ASCO20 Virtual Scientific Program from a trial testing different doses of the combination of durvalumab (Imfinzi, AstraZeneca), which blocks PD-L1, with tremelimumab (MedImmune, AstraZeneca), a fully human monoclonal antibody against CTLA-4, among patients with advanced HCC who failed on prior sorafenib. Results showed median OS of 18.7 months and a 22.7% ORR among 75 patients at one of the dose levels, with a tolerable safety profile.

Data are expected soon from a confirmatory phase 3 trial of the durvalumab-tremelimumab regimen compared with durvalumab or sorafenib alone for first-line treatment of unresectable HCC.

Kelley said that combinations with immune checkpoints inhibitors have “enormous potential.”

“Looking at the combination of durvalumab with tremelimumab, the dual targeting of the immune system to augment the chances of immune response is quite intriguing as a way to achieve these deep and durable responses we know are possible with immune therapy,” she said. “In the next 12 to 24 months, we’re going to have an overwhelming amount of data to look at, and I’m excited about it.”

Challenges remain

The latest approvals for HCC have presented oncologists with many treatment options for their patients. Choosing the right treatments from this ever-changing landscape has been challenging, especially in later treatment settings.

“We don’t yet have level-one evidence or clinical trial data to guide our decisions after first-line therapy,” Kelley said. “Most of us right now are very much eagerly awaiting meta-analyses and future clinical trials to give us the kind of prospective evidence we need. In the meantime, we’re treating patients on a patient-to-patient basis and looking at a variety of factors, including risk factors and comorbidity profile.”

Therapy selection is particularly challenging due to the lack of established biomarkers in HCC. Only one treatment, ramucirumab, has a biomarker known to predict treatment outcomes — that treatment is indicated only for patients with a serum alpha-fetoprotein level of 400 ng/mL or greater. The other multi-kinase inhibitors available have been shown to benefit patients across serum alpha-fetoprotein levels, but active research is exploring the possibility of using circulating tumor DNA or PD-L1 levels as biomarkers.

“Alpha-fetoprotein is a biomarker in this sense, but it’s not an ideal biomarker, such as when there is a driver mutation that a drug blocks,” Llovet said. “Right now, there is a huge effort to define biomarkers for predicting response to checkpoint inhibitors.”

It also is important to differentiate whether treatment benefits differ according to disease etiology, Hwang said.

“Is there a difference for patients with nonalcoholic fatty liver disease vs. patients who have hepatitis C vs. patients who have alcoholic liver disease?” he said. “My feeling is there certainly may be. If we can do better in predicting who is going to benefit from a treatment, we can spare those who won’t from both side effects and cost.”

The fact that clinical trial data doesn’t necessarily reflect a large segment of the patient population also clouds treatment decisions, according to Hwang. He said one-third of all patients with HCC do not have optimal liver function and, thus, aren’t accounted for in recent and ongoing studies.

“Clinical trials will give you a hint of what will happen in patients who fit clinical trial criteria,” Hwang said. “When you look at most clinical trials for liver cancer, patients must have pretty normal liver function to enroll. How safe and effective is it in those patients who don’t qualify for the study? We don’t really know.”

Patients on these clinical trials also underwent upper endoscopy within 6 months of starting treatment to check for esophageal varices, Hwang added.

“That’s not something we would normally do in the real-world treatment setting,” he said. “It becomes a limiting factor for patients, as there are additional costs involved with that, and the insurance company may hassle about the procedure.”

In a subanalysis of IMbrave150 presented in April during American Association for Cancer Research Annual Meeting, Finn and colleagues focused on patients with high-risk features, defined as tumor invasion of the main trunk of the portal vein or its branch contralateral to the primarily involved lobe, bile duct invasion or tumor occupancy of at least 50% of the liver.

This analysis included 64 patients assigned atezolizumab-bevacizumab and 37 assigned sorafenib, with median OS of 7.6 months vs. 5.5 months (HR = 0.62; 95% CI, 0.39-1), median PFS of 5.4 months vs. 2.8 months (HR = 0.74; 95% CI, 0.47-1.17), and ORRs of 25% vs. 14%.

“Even in this high-risk group, there’s a very consistent benefit with atezolizumab-bevacizumab in regard to survival benefit, PFS and response rate,” Finn said. “And, OS in the nonhigh-risk group — the rest of the patients — reached 22.8 months. So, certainly, baseline characteristics of patients and their tumors are associated with outcome, but even the patients who are high risk benefit from the regimen.”

Also concerning to researchers and clinicians is liver cancer’s link to historically underrepresented groups and patients facing socioeconomic disparities, which has led to a stigma surrounding HCC.

“[HCC] afflicts people with poverty. It is a disease that discriminates by race and ethnicity. It seeks those with substance abuse,” Kelley said. “One of the challenges in treating patients is not just the tumor and underlying liver disease, but often patients don’t have adequate insurance to get their treatments. That’s something that we need to face head-on — as oncologists, as medical professionals, as a society — to try to decouple our health care and disease with some of these underlying structural disparities.”

To better serve these patients and give them the best chance at achieving optimal outcomes will take a team effort, Finn said.

“We need to be very supportive of the interactions between industry and academia, because that is really what’s helping drive a lot of this progress,” Finn said. “At the end of the day, the goal for everybody is to help patients live longer. That is not a one-person effort. There has to be collaboration among all the players — including government, insurance companies, academia, clinicians and industry — to get new drugs out, make them available and to help keep moving things forward.”

The next big break

The explosion in research and drug approvals in HCC has set new expectations, goals and benchmarks for trials moving forward.

“We have to continue to move the bar higher,” Finn said. “We have a median OS with atezolizumab-bevacizumab of 19 months, so our next challenge is getting to 24 months.”

Although pending phase 3 trials may be positive because they used sorafenib or lenvatinib as the control therapy, the results seen with atezolizumab-bevacizumab are now the reference for improvement, Finn said.

“Will the magnitude of benefit [of these new combinations] be similar to what we saw with IMbrave150?” he said. “It’s possible that will be the case, and then we’ll be choosing between various front-line regimens based on efficacy, safety and tolerability.”

Fine-tuning these combinations to boost the immune system is the next step toward achieving cure, Llovet said.

“We need one out-of-the-box approach to cure liver cancer at advanced stages,” he said. “There’s still a lot to do in achieving a cure. There’s an additional layer of complexity there.”

Another potential breakthrough in terms of disease management would be the use of liquid biopsy to detect liver cancer tumors at earlier stages, Llovet said.

“If we detect tumors at their earliest, at less than 2 cm, the likelihood of complete response, meaning cure, is 90%,” he said. “It would be outstanding if we could discover key blood biomarkers to define tumors, even when they’re that tiny.”

Despite all the progress over the last 14 years in the treatment of liver cancer, when discussing the next big breakthrough, many of the experts with whom HemOnc Today spoke returned to the fact that, for 80% of patients, liver cancer starts with liver disease.

“We need to raise awareness of chronic liver disease,” Finn said. “There is great underappreciation for the importance of screening for patients who have chronic liver disease and cirrhosis specifically; although subspecialty societies recommend it, the U.S. Preventive Services Task Force has no recommendation on screening for liver cancer.

“When patients are found at advanced stages, we now have better treatments, and they can be treated,” he added. “But, finding disease early is the difference between treatment and cure.”

Click here to read the Point/Counter to this Cover Story.