Sequencing Strategies Necessary After Expansion of Therapy Options in HCC


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According to a presentation during the 2018 International Liver Cancer Association Annual Conference, the rapid development of novel therapies for patients with unresectable hepatocellular carcinoma has dramatically expanded systemic treatment options over the last 2 years. This has created a need for new sequencing strategies in HCC. 

Tim Meyer, MD, PhD

Tim Meyer, MD, PhD

According to a presentation during the 2018 International Liver Cancer Association (ILCA) Annual Conference, the rapid development of novel therapies for patients with unresectable hepatocellular carcinoma (HCC) has dramatically expanded systemic treatment options over the last 2 years. This has created a need for new sequencing strategies in HCC.

This welcome change comes after a decade in which sorafenib (Nexavar) was the only available therapy for this patient population, but Tim Meyer, MD, PhD, a professor and director of the University College of London Experimental Cancer Medicine Centre in the United Kingdom, said treating patients has become more complex.

Frontline lenvatinib (Lenvima) appears to have more benefit compared to sorafenib, but there are no data on outcomes for second-line options after progression, Meyer said.

According to Meyer, study findings have established benefits with regorafenib (Stivarga), cabozantinib (Cabometyx), and ramucirumab (Cyramza) in the second-line; subgroup analyses identify patient populations that help inform therapy selection. Meanwhile, the PD-1/PD-L1 checkpoint inhibitors nivolumab (Opdivo), pembrolizumab (Keytruda), and atezolizumab (Tecentriq) are demonstrating promising outcomes in phase II trials that could eventually change the paradigm.

Meyer mapped out several sequencing strategies based on median overall survival (OS) outcomes from pivotal studies.

At the same time, he noted that, from a clinician’s viewpoint, his top concerns are more immediate. “If you have a patient in front of you, then you have to decide what’s the best treatment to give that patient at that moment rather than decide, ‘If I give this treatment then I have the option to give him that subsequent treatment.’ We know that a lot of patients will never get on to a second-line treatment.”

Lenvatinib Versus Sorafenib

In August 2018, the FDA approved lenvatinib as a first-line therapy for patients with unresectable HCC based on data from the phase III REFLECT trial, which randomized 954 patients to lenvatinib (n = 478) or sorafenib (n = 476). The trial met its primary endpoint of OS noninferiority; the median OS by investigator review with lenvatinib was 13.6 months compared with 12.3 months for sorafenib (HR, 0.92; 95% CI, 0.79-1.06).1

Notably, however, the secondary endpoint of objective response rate (ORR) shows &ldquo;quite remarkably high response rates for lenvatinib,&rdquo; Meyer said. The ORRs by modified RECIST (mRECIST) criteria were 40.6% for lenvatinib versus 12.4% for sorafenib (HR, 0.60;P<.0001). By RECIST 1.1 criteria, the ORRs were 18.8% versus 6.5%, respectively.

In terms of toxicities, the incidence rates of hypertension were higher for patients treated lenvatinib than with sorafenib (all grade, 42% vs 30%; grade &ge;3, 23% vs 14%, respectively) as were the rates for weight loss (all grade, 31% vs 22%; grade &ge;3, 8% vs 3%). Among patients who received sorafenib, the incidence of palmar-plantar erythrodysesthesia was greater compared with lenvatinib (all grade, 52% vs 27%; grade &ge;3, 11% vs 3%) as were the rates for diarrhea (all grade, 45% vs 39%; grade &ge;3, 4% each).

&ldquo;When you&rsquo;re looking at toxicities it&rsquo;s important to find out what&rsquo;s the implication for the patient,&rdquo; Meyer said. &ldquo;Patients generally don&rsquo;t care about hypertension as long as it can be treated. They do care about diarrhea and hand—foot skin reaction.&rdquo;

In analyzing patient subgroups, lenvatinib held an advantage over sorafenib for those with greater tumor burden, defined as macroscopic portal vein invasion, extrahepatic spread (EHS) or both. The median OS for these patients was 11.5 months with lenvatinib compared with 9.8 months with sorafenib (HR, 0.87; 95% CI, 0.73-1.04). Additionally, patients with hepatitis B virus (HBV) who received lenvatinib had a higher median OS of 13.4 months verses 10.2 months for those who took sorafenib (HR, 0.83; 95% CI, 0.68-1.02).

However, the REFLECT trial excluded patients with main portal vein invasion. As a result, the European Association for the Study of the Liver (EASL) did not recommend lenvatinib as a first-line option for these patients in its recently updated guidelines.2Nevertheless, Meyer said, it is not clear from prior studies that sorafenib offers a greater benefit for these patients.

Otherwise, EASL recommended both lenvatinib and sorafenib as first-line options for patients who are classified as Child-Pugh A and Barcelona Clinic Liver Cancer (BCLC) C status or have earlier stage tumors that progress with or are unsuitable for locoregional therapies.

In the National Comprehensive Cancer Network guidelines, which are under discussion for possible revisions, lenvatinib was added as a first-line option for patients with Child-Pugh class A as a category 2A recommendation for inoperable disease by performance status or comorbidity, local disease including with minimal extrahepatic involvement, and metastatic disease or extensive liver tumor burden.3

Second-Line Options Abound

For second-line therapy, EASL recommends regorafenib for patients who have tolerated but are progressing on sorafenib and have well-preserved liver function (Child-Pugh A status) and good performance scores.2 The guidelines also make note of recent positive findings for cabozantinib. Meyer noted that the guidelines were developed prior to the release of data for several additional agents.

In April 2017, the FDA approved regorafenib as a second-line treatment for patients who have previously received sorafenib based on the phase III RESORCE trial, in which the median OS was 10.6 months with regorafenib plus best supportive care compared with 7.8 months for placebo plus best supportive care, representing a 38% reduction in the risk of death (HR, 0.62; 95% CI, 0.50-0.78;P<.001).4

Regarding cabozantinib, the FDA accepted a supplemental new drug application (sNDA) for the multikinase inhibitor as a treatment for patients with previously treated advanced HCC. The FDA is scheduled to decide on the application by January 14, 2019. The sNDA is based on findings from the phase III CELESTIAL trial, in which OS was improved by 2.2 months with cabozantinib versus placebo. 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).5

Findings from the 2 studies show similar outcomes for survival, tolerability, response rates, and key subgroups such as EHS, HBV and hepatitis C status, Meyer said. All patients in both trials received prior sorafenib; however, Meyer noted that the RESORCE trial excluded patients who could not tolerate sorafenib, which he said represents about 20% of patients. That would be a distinguishing factor for choosing between the 2 drugs as second-line therapy.

Ramucirumab is another potential second-line option with a mechanism of action that differs from the small molecule inhibitors that make up the first- and second-line choices. Whereas the other HCC drugs are multikinase inhibitors, ramucirumab is a monoclonal antibody directed against VEGFR2.

Treatment with ramucirumab improved median OS by 3.1 months compared with placebo in patients with alpha-fetoprotein (AFP) levels &ge;400 ng/mL, according to combined results from the phase III REACH and REACH-2 trials.6In the prespecified pooled analysis of the studies (N = 542), the median OS was 8.1 months with ramucirumab compared with 5.0 months for placebo, representing a 30.6% reduction in the risk of death with the VEGFR2 inhibitor (HR, 0.694; 95% CI, 0.571-0.842;P= .0002).

Both phase III trials enrolled patients treated with prior sorafenib with a BCLC stage of B or C and Child-Pugh A HCC. The REACH-2 study only enrolled those with elevated AFP levels (&ge;400 ng/mL), based on observed superiority in subgroup analyses of the REACH investigation. The median baseline AFP across all patients in the pooled analysis was 408 ng/mL, and levels were similar between the placebo and ramucirumab arms, according to a presentation at the 2018 World Gastrointestinal Cancer Congress.6

The pooled analysis results showed a greater benefit than the findings for the entire population in the REACH trial in which the median OS for the ramucirumab group was 9.2 months versus 7.6 months for the placebo group (HR, 0.87; 95% CI, 0.72-1.05;P= .14).7

As a result, AFP levels would be important in deciding whether to use ramucirumab in the second-line setting, said Meyer.

PD-1/PD-L1 Inhibitor Therapy

Immune checkpoint inhibitors that target the PD-1/PD-L1 pathway are emerging as another option for second-line therapy in patients with advanced HCC in phase II clinical trials.

In September 2017, the FDA granted an accelerated approval for the use of nivolumab in patients with HCC following prior sorafenib, regardless of PD-L1 status. The approval is based on outcomes among 154 patients enrolled in the phase I/II CheckMate-040 trial, in which the ORR by blinded independent central review was 18.2% per mRECIST criteria. Additionally, 3.2% of patients experienced a complete response. The ORR by RECIST 1.1 was 14.3% with nivolumab and the response duration ranged from 3.2 to more than 38.2 months.8

&ldquo;If you look at the patients who responded, the survival is outstanding,&rdquo; said Meyer. &ldquo;We are beginning to see in [patients with] HCC what was seen in melanoma and lung cancer that if you respond to immunotherapy, then that response can be very, very durable.&rdquo;

He noted similar durability has been observed with pembrolizumab, which the FDA also is evaluating for previously treated patients with advanced HCC based on findings from the phase II KEYNOTE-224 trial. In the study, single-agent pembrolizumab induced an ORR of 17% (95% CI, 11%-26%) among 104 patients previously treated with sorafenib. Among the 18 patients who responded, there was 1 complete response and 17 partial responses. Forty-six patients had stable disease, 34 patients had progressive disease, and 6 patients were not evaluable.9The application has a priority review designation and a decision is expected by November 9, 2018.

Additionally, the FDA has granted a breakthrough designation to the combination of atezolizumab and bevacizumab (Avastin) as a first-line treatment for patients with advanced or metastatic HCC. The regimen demonstrated ORRs of a 61% and 65%, respectively, by investigator and independent review, among 23 patients treated during the phase Ib GO30140 study.10After a median follow-up of 10.3 months, 10 responses were ongoing for &ge;6 months, including 3 for &ge;1 year.

Meyer said the field is anticipating results of the first-line CheckMate-459 study of nivolumab versus sorafenib and the second-line KEYNOTE-240 study of pembrolizumab versus best supportive care. &ldquo;These may have a big impact on practice,&rdquo; he said.


  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. European Association for the Study of the Liver.J Hepatol. 2018;69(1):182-236. doi: 10.1016/j.jhep.2018.03.019.
  3. Hepatobiliary cancers version 3.2018. NCCN website. Published August 29, 2018. Accessed September 14, 2018.
  4. Bruix J, Qin S, 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 [erratum in 2017;389(10064):36. doi: 10.1016/S0140-6736(16)32615-0].Lancet. 2017;389;10064):56-66. doi: 10.1016/S0140-6736(16)32453-9.
  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 4S; abstr 208).
  6. Zhu A, et al. Ramucirumab as second-line treatment in patients with advanced hepatocellular carcinoma (HCC) and elevated alpha-fetoprotein (AFP) following first-line sorafenib: pooled efficacy and safety across two global randomized Phase 3 studies (REACH-2 and REACH).Ann Oncol. 2018;29(suppl 5; abstr LBA-001).
  7. Zhu AX, Park JO, Ryoo BY, et al; REACH Trial Investigators. Ramucirumab versus placebo as second-line treatment in patients with advanced hepatocellular carcinoma following first-line therapy with sorafenib (REACH): a randomised, double-blind, multicentre, phase 3 trial.Lancet Oncol. 2015;16(7):859-70. doi: 10.1016/S1470-2045(15)00050-9.
  8. Crocenzi TS, El-Khoueiry AB, Yau T, et al. Nivolumab (nivo) in sorafenib (sor)-naive and -experienced pts with advanced hepatocellular carcinoma (HCC): CheckMate 040 study.J Clin Oncol. 2017;35(suppl; abstr 4013).
  9. Zhu AX, Finn RS, Edeline J, et al. Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial [published online June 1, 2018].Lancet Oncol.doi: 10.1016/S1470-2045(18)30351-6.
  10. He AR, Baek-Yeol Ryoo BY, Lee KH, et al. Preliminary safety and clinical activity results from a phase Ib study of atezolizumab plus bevacizumab in hepatocellular carcinoma. Presented at: 2018 International Liver Cancer Association Annual Meeting; September 14-16; London, England. Abstract O-011.
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