Experts Anticipate a Growing Menu of Frontline Options in Liver Cancer

Aiwu Ruth He, MD, PhD

The recent introduction of novel therapies for patients with hepatocellular carcinoma (HCC) ended a 10-year drought in new drugs for the tumor type and may represent the leading edge of a wave of change in how the malignancy is managed, according to experts who participated in an OncLive Peer Exchange^® program.

In 2017, the FDA approved regorafenib (Stivarga) and nivolumab (Opdivo) for patients with HCC previously treated with sorafenib (Nexavar). Sorafenib, a multikinase inhibitor, was approved for unresectable HCC in 2007, making it the first systemic therapy for advanced liver cancer. For a decade, it was the only available targeted therapy for HCC, and patients whose disease stopped responding to the drug had few options other than enrolling on a clinical trial.

Now, researchers say several promising new agents are poised to join the growing armamentarium. “The landscape for hepatocellular carcinoma is shifting. I suspect we will have more frontline therapy options to choose from,” A. Ruth He, MD, PhD, said during the Peer Exchange panel discussion.

Emerging First-Line Approaches

The panelists reviewed data for lenvatinib (Lenvima), which is under priority review by the FDA as a firstline treatment for HCC, and for novel drugs under investigation in the second line, such as cabozantinib (Cabometyx/Cometriq) and pembrolizumab (Keytruda). The panelists agreed that although novel treatments offer benefits, they introduce new challenges for clinicians, including sequencing and management of adverse events (AEs), especially for patients with comorbid liver diseases. Lenvatinib

Lenvatinib is a multikinase inhibitor that targets vascular endothelial growth factor and fibroblast growth factor (FGF) receptors, platelet-derived growth factor receptor α, and the RET and KIT oncogenes.¹ Lenvatinib was compared with sorafenib in the randomized multicenter phase III REFLECT trial that enrolled patients with untreated, unresectable HCC (N = 954).1 “There was a fair response rate with lenvatinib; over 20% of patients—1 in 4 patients—had a partial response [PR],” Catherine Frenette, MD, said. In comparison, sorafenib was associated with a 9% PR rate.1 Compared with the sorafenib arm, the lenvatinib arm demonstrated significantly longer time to progression (9 vs 4 mo; P <.0001) and longer progression-free survival (PFS; 7 vs 4 mo; P <.0001).¹ Frenette said it was interesting that these superior outcomes in the lenvatinib arm “didn’t translate to a statistically significant prolonged overall survival [OS] with lenvatinib compared with sorafenib.” The study found lenvatinib noninferior to sorafenib.¹ A new drug application for lenvatinib based on the REFLECT findings is pending, with the FDA scheduled to make a decision by August 24, 2018.

Dr He said that, absent an evidence-based strategy for choosing between sorafenib and lenvatinib in the first line, clinicians will have to consider each agent’s toxicity profile. Ghassan K. Abou- Alfa, MD, who moderated the program, said that although he agreed that AEs would be a factor in treatment selection, “There are other things that can play a role as well.” He pointed to the 2 drugs’ different molecular targets and the significant improvements in OS and PFS with lenvatinib in the subgroup of patients with an α-fetoprotein (AFP) level ≥200 ng/mL (HR, 0.78 and 0.59, respectively).¹

Riccardo Lencioni, MD, said a patient’s hepatitis status might be another consideration. “There are data that suggest that patients with hepatitis B—related cirrhosis and HCC will have less benefit from sorafenib than patients with hepatitis C–related cirrhosis and HCC,” he said. A 2017 meta-analysis of 3 trials involving 1643 patients found that sorafenib improved OS in patients negative for hepatitis B virus (HBV) and positive for hepatitis C virus (HCV) but not for patients positive for HBV.² Lencioni said the data suggest “one could prioritize sorafenib for HCV HCC patients and lenvatinib for HBV HCC patients.”

Checkpoint Immunotherapy

The checkpoint inhibitor nivolumab is also being compared with sorafenib as frontline therapy in the randomized phase III CheckMate-459 trial, which has a primary endpoint of OS. “These are previously untreated patients with advanced HCC, Child-Pugh A, who will be randomized to nivolumab versus the current standard of care, sorafenib,” said Anthony B. El-Khoueiry, MD. He said he believed the trial has completed accrual and results are pending.

Abou-Alfa is one of the lead researchers for HIMALAYA, an ongoing randomized phase III study comparing sorafenib versus durvalumab (Imfinzi) versus a combination of durvalumab and tremelimumab for untreated unresectable HCC.³ Durvalumab and tremelimumab are checkpoint inhibitors with different targets: Durvalumab targets PD-L1 and tremelimumab targets CTLA-4. No data from HIMALAYA have been reported, but El-Khoueiry said a phase I study in the same population reported an objective response rate of about 18%.⁴ “Patients with no viral infection— no hepatitis B or C—had a response rate of 30%. We don’t know if this is a factor or just numbers or that it’s truly a difference between etiologies,” he said. El-Khoueiry said that 4 or 5 years ago, no one imagined there would be a role for checkpoint inhibitors in HCC because the liver was thought to induce an immune tolerant state instead of an immune response. “We’ve learned over time that liver cancer, like other cancers, has many mechanisms by which to shut down the immune system and prevent it from recognizing the cancer and acting against it,” he said.

Novel Second-Line Therapies

“I was not surprised to see the immune checkpoint inhibitors have activity in HCC,” Frenette said. In her work with patients undergoing liver transplant for HCC, she said the immune suppressive drugs make the cancer progress much faster than it does in patients without immune suppression. “In the transplant population, we do not want to have anything to do with immune checkpoint inhibitors,” she cautioned, noting that they increase the risk of organ rejection.Cabozantinib

At the 2018 Gastrointestinal Cancers Symposium, Abou-Alfa presented data from the phase III CELESTIAL trial, which randomly assigned patients 2:1 to cabozantinib or placebo.⁵ He said cabozantinib showed a significant benefit in OS, which was the study’s primary endpoint. “The cabozantinib arm showed a median OS of 10.2 months, and the placebo arm had a median OS of more than 8 months,” Abou-Alfa said. Although cabozantinib is a c-MET inhibitor, he said trial investigators “specifically avoided that selectivity of the patient with c-MET expression” because evidence for using c-MET expression as a biomarker of treatment response is lacking.

The panel discussed findings from an earlier phase III trial of the c-MET inhibitor tivantinib in previously treated patients with HCC and high c-MET expression that failed to improve OS compared with placebo.⁶ Frenette said that several studies in HCC have tried to identify biomarkers that predict response, including PD-L1, c-MET, endothelial growth factor receptor, and FGF. “Really, none of these biomarkers have panned out yet, and I think that part of the reason is because HCC is a really heterogeneous cancer, even within 1 tumor or within 1 patient,” she said.

The FDA has accepted a supplemental new drug application for cabozantinib as a therapy for patients with previously treated advanced HCC, based on the CELESTIAL findings. The deadline for a decision is January 14, 2019.

Pembrolizumab

Data from the phase II KEYNOTE-224 study of pembrolizumab were also presented at the symposium and recently published in Lancet Oncology.^7,8 The study enrolled 104 patients with previously treated HCC. “We see a response rate of 16%, which is certainly consistent with what we’ve seen with nivolumab,” El-Khoueiry said. He added that the toxicity profile was also consistent with what investigators have observed in clinical trials of pembrolizumab and other checkpoint inhibitors in other tumor types. “It provides more confidence in the whole activity of checkpoint inhibitors in this disease,” he said.

New Treatments and Challenges

Lencioni said the duration of response in KEYNOTE-224 was especially impressive. “More than 90% of responders had a response in place for more than 6 months. Clearly with these immune-oncology drugs, responses are dramatic and sustained,” he said.“This is a very exciting time in HCC research,” Lencioni said, adding that, “We now have 5 drugs that have been shown to have significant and meaningful effects on patients with advanced-stage HCC.” He expressed a wish for more studies to investigate possible synergism between novel systemic agents and locoregional interventional therapies, such as transarterial chemoembolization (TACE) or Yttrium-90.

El-Khoueiry agreed there was “a strong rationale for combining locoregional therapy with immunotherapy” and said several trials were in development or underway. He mentioned a National Cancer Institute study that showed combining tremelimumab with ablation was feasible in patients with advanced HCC.⁹ “Certainly, this will be something that we will see a lot of over the next few years,” he said. Abou-Alfa said an ongoing trial is evaluating TACE plus nivolumab (NCT03143270).

Dr He said the goals of any strategy should be to “cause tumor shrinkage and long-term disease control without hurting the liver.” She emphasized the need to start thinking of liver cancer as 2 diseases: HCC and cirrhosis liver failure. “Attention should be put on how to preserve the liver function and look at the real liver toxicities of each treatment modality,” she said.

Everyone agreed preserving liver function was an important concern with the emerging treatments and that doing so would require a multidisciplinary approach. “We really need to talk about a treatment plan, and that needs to involve all the different specialists so that we can have the best outcomes for our patients,” Frenette said.

Abou-Alfa recommended moving away from the all-in-one-basket approach to managing HCC. He described a current collaborative effort to collect and test tissue from cohorts across the globe with different demographics and disease pathologies and analyze the data to determine which patients stand to benefit most from which therapy. El-Khoueiry predicted molecular biomarkers would become an increasingly important focal point in HCC research.

The introduction of new treatments and the enhanced efforts to learn more about HCC come none too soon for the United States, where HCC is a growing problem. As Frenette noted early during the discussion, “In the last 30 years, HCC has more than tripled in incidence and prevalence, and it is now among the top 10 reasons for death.”

References

1. Kudo M, Finn RS, Qin S, et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet. 2018;391(10126):1163-1173. doi: 10.1016/S0140-6736(18)30207-1.
2. Jackson R, Psarelli E-E, Berhane S, Khan H, Johnson P. Impact of viral status on survival in patients receiving sorafenib for advanced hepatocellular cancer: a meta-analysis of randomized phase III trials. J Clin Oncol. 2017;35(6):622-628. doi: 10.1200/JCO.2016.69.5197.
3. Abou-Alfa GK, Chan SL, Furuse J, et al. A randomized, multicenter phase 3 study of durvalumab (D) and tremelimumab (T) as first-line treatment in patients with unresectable hepatocellular carcinoma (HCC): HIMALAYA study. J Clin Oncol. 2018;36(suppl 15, abstr TPS4144). ascopubs.org/doi/abs/10.1200/JCO.2018.36.15_suppl.TPS4144.
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5. Abou-Alfa GK, Meyer T, Cheng A-L, et al. Cabozantinib (C) versus placebo (P) in patients (pts) with advanced hepatocellular carcinoma (HCC) who have received prior sorafenib: Results from the randomized phase III CELESTIAL trial. J Clin Oncol. 2018;36(suppl 4, abstr 207). ascopubs.org/doi/abs/10.1200/JCO.2018.36.4_suppl.207.
6. Rimassa L, Assenat E, Peck-Radosavljevic M, et al. Tivantinib for second-line treatment of MET-high, advanced hepatocellular carcinoma (METIV-HCC): a final analysis of a phase 3, randomised, placebo-controlled study. Lancet Oncol. 2018;19(5):682-693. doi: 10.1016/S1470-2045(18)30146-3.
7. Zhu AX, Finn RS, Cattan S, et al. KEYNOTE-224: pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib. J Clin Oncol. 2018;36(suppl 4, abstr 209). ascopubs.org/doi/abs/10.1200/JCO.2018.36.4_suppl.209.
8. Zhu AX, Finn RS, Edeline J, et al; KEYNOTE-224 Investigators. Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial [published online June 3, 2018]. Lancet Oncol. doi: 10.1016/S1470-2045(18)30351-6.
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