After a 10-Year Lull, Trials in Liver Cancer Show Promise

Ghassan K. Abou-Alfa, MD

The incidence of liver cancer in the United States has risen sharply since 1980, with the American Cancer Association reporting an approximate annual increase of 3% in women and 4% in men from 2004 to 2013.¹ Liver cancer remains difficult to cure, and the mortality rate from liver cancer has increased an estimated 3% each year between 2010 and 2014. The 5-year survival rate for early-stage liver cancer is only 31%, which decreases to 3% for liver cancer with distant metastases.²

Early-Stage Liver Cancer

Limited options are available to treat advanced disease. A panel of experts discussed standard treatments for early-stage and advanced liver cancer during a recent OncLive Peer Exchange^® program moderated by Ghassan K. Abou-Alfa, MD. They also reviewed investigational second-line therapies and expressed optimism that some of these therapies may one day improve outcomes for patients.The treatment of liver cancer requires a multidisciplinary approach. “More so than many other cancers, we really rely on our colleagues across disciplines in hepatology, radiation, [and] surgery,” R. Kate Kelley, MD, said. Standard treatment for early-stage liver cancer is typically surgical resection or liver transplantation.³

Richard S. Finn, MD, said that resection should be considered before transplant, which he described as a last resort, adding that the presence of underlying liver disease may be a deciding factor when choosing between resection or transplant.

“Practicing in the United States, we see a lot of patients who have hepatitis C. Unfortunately, by the time they develop liver cancer, many of them have less compensated cirrhosis, in which case transplant is a better option,” Finn said. In contrast, patients with hepatitis B typically have better liver function at diagnosis and may not need a transplant.

Laura M. Kulik, MD, noted that for many patients, “[transplantation] is the only potentially curative option.” She said when the patient’s tumor is too large (>5 cm) or the patient has too many tumors for transplant, she attempts to downstage the disease. Kulik explained down-staging involves using arterial-directed therapies, such as transarterial chemoembolization or transarterial radioembolization with yttrium-90 (Y-90) microspheres, to shrink the tumor to <5 cm. Arterial-directed therapies are generally contraindicated for patients with main portal vein thrombosis and Child-Pugh Class C liver function.³ Kulik said 5 cm is the cutoff for transplant because “once you start reaching a tumor burden of 5 cm, there’s about a 50% chance that you’re going to have vascular invasion present and explant, which has the highest chance of recurrence,” Kulik said.

“Transplant is really aimed at the sick liver...a sick liver means that you can’t resect it,” Abou-Alfa said. He highlighted the controversy over whether to pursue resection or transplant for resectable patients with Child-Pugh Class A liver function.³ “Some people will argue that transplant should be a first indication, as well,” he noted.

Riad Salem, MD, the panel’s only radiologist, noted that radiofrequency ablation (RFA) is increasingly being recognized as a potentially curative option. Radiofrequency ablation is a low-risk, minimally invasive treatment that used to be reserved for patients whose liver cancer was unresectable or who were unable to receive a transplant.⁴ However, Salem said that because RFA allows for ablation of a small area of the liver without the risks associated with surgical resection, “ablation has now been moved way ahead of resection for small lesions in the guidelines.”

Advanced Liver Cancer

The risk of recurrence remains high after resec-tion or ablation,³ however. Kelley said there are really no adjuvant options available to reduce the risk. The phase III STORM trial evaluated whether adjuvant sorafenib (Nexavar), a multikinase inhibitor approved to treat unresectable hepatocellular carcinoma (HCC), could improve outcomes after resection or ablation. Kelley said, “[Sorafenib] showed really no benefit in reducing recurrence or improving survival after curative surgery or curative ablation in high-risk patients.”⁵Many patients will present with metastatic disease or, sadly, many patients...will progress or recur,” Abou-Alfa said. Options for those patients are extremely limited. In 2007, sorafenib became the rst drug approved by the FDA for patients with advanced unresectable HCC and it remains the only FDA-approved systemic treatment for this cohort. Approval was based on results from the phase III SHARP trial, which randomly assigned 600 treatment-naïve patients with HCC to sorafenib or placebo.⁶ Median overall survival (OS) was 10.7 months with sorafenib versus 7.9 months with placebo,⁶ which Kelley said was “highly statistically significant” and made sorafenib the first systemic therapy to show a true survival benefit. Abou-Alfa said that despite some of the doubts expressed about the value of sorafenib for HCC, its adoption as a standard of care for HCC was important.

Finn agreed. “Sorafenib has been around for a decade, and it’s held its place as the frontline treatment despite numerous attempts to unseat it,” he said. Although the full dose is 400 mg twice daily, Finn said clinicians often must adjust the dose if patients have tolerance issues, which is true for most drugs. “The toxicities are very predictable, [with] the most common being hand-foot skin reactions and gastrointestinal toxicities—specifically diarrhea,” Finn said. Because early intervention can reduce the risk of toxicities and help patients remain on the drug longer, Finn said that he has all patients return for a follow-up visit 10 to 14 days after starting sorafenib.

Abou-Alfa said clinicians are sometimes quick to consider other therapies when a patient has tolerance issues but that with sorafenib, “you clearly have to take the time to kind of let the dose that really is appropriate for the patient settle into place.” He and the other panelists discussed the challenges of convincing patients that sorafenib is working even if their tumors are not shrinking.

Kelley said it is helpful to remind patients that although less than 2% of them have a measurable response to sorafenib in clinical trials, many patients achieve stable disease for months, even years. “The benefits of sorafenib are not well captured by just response rate or the size of the tumor...Even though tumors aren’t shrinking, sometimes we’ll see some necrosis or decrease in the blood ow to the tumor that can indicate less activity of the tumor,” she said.

After Sorafenib

Kulik emphasized the importance of reminding patients that “they do not have a curative option” and that “sorafenib is the only drug that is currently available, at this point in time, that has shown survival.” Sorafenib can also decrease symptoms, like pain, and improve patients’ quality of life, Kulik said.Patients with liver cancer eventually experience progression during treatment with sorafenib; investigational agents for second-line therapy are in development. One of the most promising is regorafenib (Stivarga), which the FDA is evaluating for second-line HCC under its priority review program, with a decision due by June.

“Regorafenib, like sorafenib, is a multitargeted therapy. It hits several kinases,” Finn said. Regorafenib inhibits angiogenic activity plus tumor growth, metastasis, and immunity through inhibition of multiple protein kinases,⁷ which Finn said include VEGFR2 and the TIE2 receptor. Regorafenib is already approved for metastatic colorectal cancer and gastrointestinal stromal tumors.

The phase III RESORCE trial randomly assigned 573 patients with HCC who progressed during sorafenib therapy to regorafenib or placebo. Finn called the RESORCE trial a light at the end of a 10-year tunnel that has seen no new treatments for liver cancer. Median OS in the RESORCE trial was approximately 11 months compared with 8 months for placebo (HR, 0.63).⁷ In the regorafenib group, the complete response rate was 1% and the partial response rate was 10% per modi ed RECIST criteria compared with 0 and 4%, respectively, in the placebo group.⁷ “This was a well-conducted, randomized, phase III, double-blind, placebo-controlled study...I think we can confodently say that this is establishing, potentially, a new standard of care in second-line once [regorafenib] receives regulatory approval,” Finn said.

Kelley said based on her experience with regorafenib in other cancers, it has a toxicity profile similar to sorafenib’s. “We see a sizable proportion of patients with palmar-plantar or erythrodysesthesia...the hand-foot syndrome that we see with this class of drugs,” Kelley said. She also cautioned about the risk of hypertension, which is also common with sorafenib. Hypertension, hand-foot skin reaction, fatigue, and diarrhea were among the most common treatment-related adverse events observed in the RESORCE study.⁷

Finn pointed out that patients enrolled in RESORCE had been taking sorafenib for a median of 7.8 months and were required to have tolerated sorafenib well, which he said might explain the lower discontinuation rate with regorafenib in RESORCE compared with trials of the drug in other cancers. “With that being said, the clinical activity of the compound was very similar to actually the frontline data: 3 months’ improvement in overall survival. I think it’s important for us to recognize what the phase III data represent and then incorporate that into our practice,” Finn said.

“The balance and the art of this will be learning when to transition from first-line therapy to regorafenib and identifying progression at a time when patients are able to capitalize on a second-line agent,” Kelley said. She said patients’ tolerance of regorafenib will depend on how healthy they are, their liver function, and their visceral function after they progress on sorafenib.

Several other novel drugs are being studied for advanced HCC. Tivantinib, a selective MET inhibitor under study for patients with HCC with high c-MET expression, raised hopes that the field would gain its first biomarker-driven treatment. However, tivantinib failed to meet its primary endpoint in 2 phase III trials, according to the companies developing the drug.

Cabozantinib, which is approved for thyroid cancer and renal cell carcinoma (Cometriq/Cabometyx), targets VEGFR2/3, c-MET, RET, and AXL. Kelley said a phase II study of cabozantinib “showed pretty encouraging overall survival greater than 11 months in largely a second-line population.” A phase III trial comparing cabozantinib versus placebo in patients who have received prior sorafenib is ongoing (NCT01908426).

Finn said interesting data have also been reported from studies of lenvatinib (Lenvima), a multitargeted kinase inhibitor, and ramucirumab (Cyramza), a monoclonal antibody to the VEGF receptor. The ramucirumab study was negative except in a subgroup of patients with an alpha-fetoprotein serum level >400 who showed a meaningful survival benefit.⁸ Finn expressed optimism that studies would identify biomarkers that might lead to a “smarter way, maybe, of developing drugs in liver cancer.”

Immune checkpoint inhibitors are also being explored for liver cancer. Some ongoing trials are evaluating monotherapy with PD-1 inhibitors nivolumab (Opdivo) or pembrolizumab (Keytruda). Others are combining or comparing PD-1 inhibitors with CTLA-4 inhibitors. Salem said several clinical trials are assessing immune checkpoint inhibitors with localized therapies, such as RFA. “We’re very excited to see how the results will play out,” Kelley said.

One of the concerns with immune checkpoint inhibitors is how they might affect underlying hepatitis C or B. “This is really an unleashing of the immune system and not necessarily with control,” Abou-Alfa said. “In HCC specifically, this is not necessarily as simple as we might think it is.”

“Finally, we’re seeing momentum following along in drug development and a huge amount of interest in finding new therapies and promise for many of these therapies to make a difference,” Kelley said. Salem agreed, and emphasized the importance of keeping up with the literature to optimize treatment outcomes.

References

1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2017. CA Cancer J Clin. 2017;67(1):7-30. doi: 10.3322/caac.21387.
2. Liver Cancer: Statistics. Cancer.net website. http://www.cancer.net/cancer-types/liver-cancer/statistics. Accessed March 31, 2017.
3. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology (NCCN Guidelines): hepatobiliary cancers. Version 1.2017. https://www.nccn.org/professionals/physician_gls/pdf/hepatobiliary.pdf. Updated March 15, 2017. Accessed March 28, 2017.
4. McDermott S, Gervais DA. Radiofrequency ablation of liver tumors. Semin Intervent Radiol. 2013;30(1):49-55. doi: 10.1055/s-0033-1333653.
5. Bruix J, Takayama T, Mazzaferro V, et al. Adjuvant sorafenib for hepatocellular carcinoma after resection or ablation (STORM): a phase 3, randomised, double-blind, placebo-controlled trial. Lancet Oncol. 2015;16(13):1344-1354.
6. Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359:378-390. doi: 10.1016/S1470-2045(15)00198-9.
7. Bruix J, Qin S, Merle P, et al. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017;389(10064):56-66. doi: 10.1016/S0140-6736(16)32453-9.
8. Zhu AX, Baron AD, Malfertheiner P, et al. Ramucirumab as second-line treatment in patients with advanced hepatocellular carcinoma: analysis of REACH trial results by Child-Pugh score published online September 22, 2016]. JAMA Oncol. doi: 10.1001/jamaoncol.2016.4115.