Liver Cancer Treatment Paradigm Undergoing Major Overhaul

Targeted Therapies in OncologyOctober 2018
Volume 7
Issue 10

Until recently, few systemic therapies had been approved for the treatment of patients with liver cancer, as few agents could demonstrate significant benefit over placebo. Sorafenib was the first systemic therapy that extended median overall survival over placebo by nearly 3 months,<sup>1</sup> and, in December 2007, it became the first systemic therapy approved by the FDA for patients with unresectable hepatocellular carcinoma.

Richard Finn, MD

Until recently, few systemic therapies had been approved for the treatment of patients with liver cancer, as few agents could demonstrate significant benefit over placebo. Sorafenib (Nexavar) was the first systemic therapy that extended median overall survival (OS) over placebo by nearly 3 months (10.7 versus 7.9 months),1and, in December 2007, it became the first systemic therapy approved by the FDA for patients with unresectable hepatocellular carcinoma (HCC).

&ldquo;Sorafenib was a significant development in the field. It showed that a drug could improve survival in advanced liver cancer, and it changed how we think about treating liver cancer,&rdquo; said Richard Finn, MD, in an interview withTargeted Therapies in Oncology. Finn is an assistant professor of medicine, Department of Medicine, Division of Hematology/ Oncology, at the David Geffen School of Medicine at the University of California, Los Angeles.

&ldquo;Previously, we thought that injecting drugs in tumors to make them shrink would improve survival regardless of the size or stage of the tumor, although there weren&rsquo;t strong data to support that,&rdquo; he noted. &ldquo;But, with the SHARP study [of sorafenib versus placebo in patients with advanced HCC], we realized that medical therapy had a role in treating advanced HCC that was invading the vasculature or had spread outside the liver.&rdquo;

For the next decade, researchers conducted several phase III clinical trials with other tyrosine kinase inhibitors (TKIs) in first-line settings, including brivanib, sunitinib (Sutent), erlotinib (Tarceva), and linifanib alone or in combination with sorafenib.2

However, &ldquo;sorafenib has held that [leading] position for more than a decade because these [other] drugs have failed to show a greater survival benefit or noninferiority to sorafenib,&rdquo; said Finn.

Researchers were also interested in &ldquo;moving sorafenib to an earlier-line setting, such as an adjuvant therapy to surgery or transarterial chemoembolization,&rdquo; said Finn. However, numerous studies with transarterial chemoembolization were negative, including the phase III STORM trial, which found that sorafenib is not an effective adjuvant treatment for patients with HCC following resection or ablation.3

Therapies including brivanib, everolimus (Afinitor), and ramucirumab (Cyramza) in an unselected population also showed negative results when they were tested in second-line settings after patients progressed on sorafenib.

Researchers who have analyzed why so many TKIs have failed in trials of first- or second-line treatment mention the &ldquo;lack of understanding of critical drivers of tumor progression/dissemination, liver toxicity, flaws in trial design, or marginal antitumoral potency. These trials are also challenging time to progression as a surrogate endpoint of survival.&rdquo;4

Targeted Therapies

However, in the past year and a half, the FDA has approved new drugs for advanced HCC based on the results of positive studies with targeted therapies and immunotherapies (FIGURE).

Regorafenib (Stivarga), an oral multikinase inhibitor, was approved in April 2017 for the treatment of patients with HCC who have progressed following treatment with sorafenib. In findings from the phase III RESORCE trial (see cover, page 31 for coverage), regorafenib plus best supportive care induced a median OS of 10.6 months compared with 7.8 months with placebo plus best supportive care (HR, 0.63; 95% CI, 0.50-0.78;P<.0001). The objective response rate (ORR) was 10.6% with regorafenib versus 4.1% with placebo (P= .005).5

Lenvatinib (Lenvima), a TKI, was approved in August 2018 as a first-line treatment for patients with unresectable HCC.

Finn, a co-investigator of the phase III REFLECT study, commented, &ldquo;Lenvatinib was noninferior to sorafenib in terms of survival, but it had a higher ORR, confirmed by a blinded independent review, and prolonged progression-free survival [PFS] and time to progression [TTP] as well.&rdquo;

Findings from the trial, which were published in February 2018 in The Lancet,6showed the median OS with lenvatinib was 13.6 months compared with 12.3 months for sorafenib (HR, 0.92; 95% CI, 0.79-1.06). Lenvatinib was also superior to sorafenib for PFS and TTP. The median PFS for lenvatinib was 7.4 months versus 3.7 months for sorafenib (HR, 0.66; 95% CI, 0.57-0.77;P<.0001). TTP was 8.9 months for lenvatinib compared with 3.7 months for sorafenib (HR, 0.63; 95% CI, 0.53-0.73;P<.0001).

The ORR by investigator review was 24.1% with lenvatinib versus 9.2% with sorafenib (odds ratio, 3.13; 95% CI, 2.15-4.56;P<.0001). The median duration of treatment was 5.7 months with lenvatinib and 3.7 months for sorafenib. However, a larger number of serious treatment-related adverse effects occurred in the lenvatinib arm (18%) compared with sorafenib (10%).

In May 2018, the FDA accepted a supplemental new drug application for cabozantinib (Cabometyx), a multikinase inhibitor, for the treatment of patients with previously treated advanced HCC. The application was based on findings from the phase III CELESTIAL trial, in which OS was improved by 2.2 months with cabozantinib versus placebo. The median OS with cabozantinib was 10.2 versus 8.0 months for placebo, representing a 24% reduction in the risk of death (HR, 0.76; 95% CI, 0.63-0.92;P= .0049).7

The median PFS was 5.2 months compared with 1.9 months for placebo, which was a 56% reduction in the risk of progression or death with the targeted therapy (HR, 0.44; 95% CI, 0.36-0.52;P<.001). The ORR was 4% with cabozantinib compared with less than 1% with placebo (P= .009). When including those patients with stable disease, the disease control rate with the multikinase inhibitor was 64% compared with 33% for placebo.

Under the Prescription Drug User Fee Act, the FDA will render a decision on cabozantinib by January 14, 2019.

In addition, an analysis of subgroups from the CELESTIAL trial that was released in September at the 2018 International Liver Cancer Association Conference (see pages 31-35 for coverage) showed that second-line cabozantinib was also effective in treating patients with a history of hepatitis B virus (HBV) infection, a highly prevalent cause of the malignancy. In the subgroup analysis, cabozantinib showed an OS benefit in patients with an HBV etiology (9.7 vs 6.1 months; HR, 0.69; 95% CI, 0.51-0.94).8

Ramucirumab (Cyramza), an immunoglobulin G1 monoclonal antibody and VEGF receptor-2 antagonist, was shown recently to be effective in improving survival for patients with advanced HCC. The phase III REACH-2 study presented at the 2018 ASCO Annual Meeting showed that this agent was active in the second-line setting after sorafenib in patients with elevated alpha-fetoprotein (&ge;400 ng/mL) levels.

The results showed a significant survival benefit by reducing the risk of death by 29% in patients who had progressed on or were intolerant to sorafenib. Ramucirumab improved OS compared with placebo, with a median OS of 8.5 versus 7.3 months, respectively (HR, 0.710; 95% CI, 0.531-0.949;P= .0199). At 18 months, the OS rate was 24.5% with ramucirumab compared with 11.3% for placebo.9

The median PFS with ramucirumab was 2.8 months compared with 1.6 months with placebo (HR, 0.452; 95% CI, 0.339-0.603;P<.0001). The ORR was 4.6% with ramucirumab versus 1.1% with placebo (P = .1697) and the disease control rate (ORR + stable disease) was 59.9% with ramucirumab versus 38.9% with placebo (P = .0006). Treatment was well tolerated, with a safety profile that was consistent with the established profile for single-agent ramucirumab.

&ldquo;This is the first biomarker-selected positive study we have seen in HCC,&rdquo; Finn said. Eli Lilly, Inc, which manufactures ramucirumab, will be seeking FDA approval for the drug this year.10


While targeted therapies offer a modest OS benefit, &ldquo;immunotherapy drugs and immunotherapy combinations offer more potential benefits,&rdquo; said Stacey Stein, MD, an assistant professor of medicine (medical oncology) at the Yale Cancer Center, Yale School of Medicine, in an interview with Targeted Therapies in Oncology. &ldquo;Although overall survival is still the gold standard, we can think about other endpoints such as progression-free survival and symptom control.&rdquo;

The FDA granted nivolumab (Opdivo) an accelerated approval in September 2017 to treat patients with HCC following treatment with sorafenib. The approval was granted for patients regardless of their PD-L1 status.

Approval was based on a subgroup of 154 patients enrolled in the phase I/II CheckMate 040 trial, conducted in patients with HCC and Child- Pugh A cirrhosis who had progressed on or were intolerant to sorafenib. In addition to including patients without active hepatitis viral infection, the trial enrolled patients with either active HBV (31%) or hepatitis C virus (HCV; 21%) but not those with active co-infection with HBV and HCV or with hepatitis D virus infection.

The confirmed overall response rate by blinded independent central review for treatment with nivolumab was 14.3% (95% CI, 9.2%-20.8%), with 3 complete responses and 19 partial responses. Response duration ranged from 3.2 to 38.2+ months, with 91% having responses that lasted &ge;6 months and 55% with responses lasting &ge;12 months.11

Atezolizumab (Tecentriq) was granted a breakthrough therapy designation by the FDA in July 2018 for use in combination with bevacizumab (Avastin) as a first-line treatment regimen for patients with advanced or metastatic HCC. This designation will expedite the development and review of the combination in this setting.

In a phase Ib study, after a median follow-up of 10.3 months, atezolizumab plus bevacizumab induced an overall response rate of 65% (n = 15) among 23 evaluable patients, according to the independent review facility, leading to the breakthrough designation. Responses were also observed across patient subgroups. The ORR was 60% in HBV-positive patients, 78% in HCV-positive patients, and 50% in nonviral patients.12

&ldquo;This is a very significant response rate if confirmed. This is obviously a very small sample size, but it is exciting to see these numbers,&rdquo; Finn said.

The ongoing phase III IMbrave150 study (NCT03434379) is investigating the combination of atezolizumab and bevacizumab in comparison with sorafenib in the frontline setting for patients with locally advanced or metastatic HCC.

Finn commented, &ldquo;IMbrave150 is an important study. Based on what we have seen in other diseases, including renal cell and lung cancer, there seems to be some synergy between PD-1 inhibitors and VEGF/ VEGFR targeting with TKIs or with antibodies.&rdquo;

Drugs in the Pipeline

&ldquo;Another big opportunity for immunotherapy drugs is in frontline treatment settings where, so far, only single-agent TKIs have been approved,&rdquo; said Finn. &ldquo;We are anxiously awaiting the results of the CheckMate 459 study [NCT02576509], comparing nivolumab with sorafenib powered for superiority. If it&rsquo;s a positive study, it will change the way we practice.&rdquo;

In addition, the PD-1 inhibitor pembrolizumab (Keytruda) has been granted a priority review designation by the FDA for use in previously treated patients with HCC. The FDA is scheduled to make a decision on the supplemental biologics license application by November 9, 2018.

In findings from the phase II KEYNOTE-224 trial, on which the application is based, single-agent pembrolizumab induced an overall response rate of 17% (95% CI, 11%-26%) among 104 patients with advanced HCC who were previously treated with sorafenib, consisting of 1 complete response and 17 partial responses.13The median OS with pembrolizumab was 12.9 months (95% CI, 9.7-15.5) and at 12 months, the OS rate was 54% (95% CI, 44%-63%).

Finn and his coinvestigators have also completed accrual of the phase III KEYNOTE-240 trial comparing pembrolizumab plus best supportive care versus placebo plus best supportive care in patents with previously treated advanced HCC (NCT02702401).14

&ldquo;We are awaiting the results. This is also a very important study as we have no randomized data with PD-1 inhibitors in the second-line setting,&rdquo; Finn commented. &ldquo;This is likely the last placebo-controlled study in second-line given the progress we have made to date.&rdquo;

Researchers are also awaiting the results of an open-label phase Ib study designed to evaluate the tolerability and safety of lenvatinib in combination with pembrolizumab in participants with HCC (NCT03006926).

Stein commented, &ldquo;Things are moving at a fast pace. The challenge for clinicians will be to think about how to incorporate these new drugs into clinical practice and determine what the optimal treatment sequence is. Instead of having 1 drug on the market, it&rsquo;s exciting to have positive data where there could be a debate about the best way to sequence treatment.&rdquo;

Finn added, &ldquo;These positive studies are generating a lot of interest in getting new drugs to patients. We now have more drugs in liver cancer with high-level evidence that they improve survival. As more drugs become approved, we expect patient survival to increase.&rdquo;


  1. Llovet JM, Ricci S, Mazzaferro V, et al; SHARP Investigators Study Group. Sorafenib in advanced hepatocellular carcinoma.N Engl J Med.2008;359(4):378-390. doi: 10.1056/NEJMoa0708857.
  2. Sun W, Cabrera R. Systemic treatment of patients with advanced, unresectable hepatocellular carcinoma: emergence of therapies.J Gastrointest Cancer.2018;49(2):107-115. doi: 10.1007/s12029-018-0065-8.
  3. Bruix J, Takayama T, Mazzaferro V, et al; STORM Investigators. 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. doi: 10.1016/S1470-2045(15)00198-9.
  4. Llovet JM, Hernandez-Gea V. Hepatocellular carcinoma: reasons for phase III failure and novel perspectives on trial design.Clin Cancer Res.2014;20(8):2072-2079. doi: 10.1158/1078-0432.CCR-13-0547.
  5. Bruix J, Shukui Q, Merle P, et al; RESORCE Investigators. 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.
  6. 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.
  7. Abou-Alfa GK, Meyer T, Cheng AL, et al. Cabozantinib in patients with advanced and progressing hepatocellular carcinoma.N Engl J Med.2018;379(1):54-63. doi: 10.1056/NEJMoa1717002.
  8. Meyer T, Baron A, Gordan J, et al. Outcomes in patients (pts) with hepatitis B virus (HBV) in the phase 3 CELESTIAL trial of cabozantinib (C) versus placebo (P) in advanced hepatocellular carcinoma (HCC). Presented at: 2018 International Liver Cancer Association Annual Meeting; September 14-16, 2018; London, England. Abstract O-012. ILCA-2018-Final-Programme-and-Book-of-Abstracts_LR_compressed-2.pdf.
  9. Zhu A, Yoon-Koo K, Chia-Jui Y, et al. REACH-2: a randomized, double-blind, placebo-controlled phase 3 study of ramucirumab versus placebo as second- line treatment in patients with advanced hepatocellular carcinoma (HCC) and elevated baseline alpha-fetoprotein (AFP) following first-line sorafenib.J Clin Oncol.2018;36(suppl; abstr 4003). meetinglibrary.asco. org/record/159169/abstract.
  10. Lilly announces CYRAMZA&reg; (ramucirumab) phase 3 REACH-2 study in second-line hepatocellular carcinoma patients met overall survival endpoint [news release]. Indianapolis, IN; Eli Lilly and Company; April 4, 2018. lilly-announces-cyramza-ramucirumab-phase-3-reach-2-study-in-second-line-hepatocellular- carcinoma-patients-met-overall-survival-endpoint-300624113.html. Accessed September 19, 2018.
  11. FDA grants accelerated approval to nivolumab for HCC previously treated with sorafenib. US Food & Drug Administration website. Posted September 22, 2017. Accessed September 19, 2018.
  12. Stein S, Pishvaian MJ, Lee MS, et al. Safety and clinical activity of 1L atezolizumab + bevacizumab in a phase Ib study in hepatocellular carcinoma (HCC).J Clin Oncol.2018;36(suppl; abstr 4074). record/160179/abstract.
  13. 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.Lancet Oncol.2018;19(7):940-952. doi: 10.1016/S1470- 2045(18)30351-6.
  14. Finn RS, Chan SL, Zhu AX, et al. KEYNOTE-240: Phase 3, randomized study of pembrolizumab (pembro) vs best supportive care (BSC) for second-line advanced hepatocellular carcinoma (HCC).Ann Oncol.2017;28(suppl 5; abstr 775TiP):v209-v268. doi: 10.1093/annonc/mdx369.
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