Experts Anticipate a Growing Menu of Frontline Options in Liver Cancer Christin Melton, ELS Published: Wednesday, Jul 04, 2018
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.
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.Emerging First-Line ApproachesLenvatinib
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.
“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.Novel Second-Line TherapiesCabozantinib
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.
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.New Treatments and Challenges“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.”
Lenvatinib是一种多激酶抑制剂,靶向血管内皮生长因子和成纤维细胞生长因子(FGF)受体,血小板衍生生长因子受体α,RET和KIT癌基因.1在随机多中心III期REFLECT试验中,将Lenvatinib与索拉非尼进行比较。入组患者未经治疗,无法切除的HCC(N = 954).1“使用lenvatinib治疗效果良好;超过20%的患者--4例患者中有1例 - 有部分反应[PR],“Catherine Frenette医师表示。相比之下,索拉非尼与9%PR率相关.1与索拉非尼组相比,lenvatinib组显示出显着更长的进展时间(9 vs 4 mo; P <.0001)和更长的无进展生存期(PFS; 7对于4 mo; P <.0001).1 Frenette说有趣的是,与索拉非尼相比,lenvatinib组的这些优势结果“并未转化为使用lenvatinib的统计学上显着的长期总体生存[OS]。”研究发现lenvatinib不劣于索拉非尼.1基于REFLECT研究结果的lenvatinib新药申请尚待批准,FDA计划于2018年8月24日作出决定。
何博士说,如果缺乏基于证据的策略,在第一线选择索拉非尼和lenvatinib,临床医生将不得不考虑每种药物的毒性特征。主持该项目的医学博士Ghassan K. Abou-Alfa表示,尽管他同意AEs会成为治疗选择的一个因素,“还有其他事情可以发挥作用。”他指出了两种药物'不同的分子靶点和使用lenvatinib的OS和PFS在甲胎蛋白(AFP)水平≥200ng/ mL(HR,分别为0.78和0.59)患者亚组中的显着改善.1