HCC Armamentarium Expands, With Promising Agents on the Horizon

Partner | Cancer Centers | <b>Georgetown Lombardi Comprehensive Cancer Center</b>

Aiwu Ruth He, MD, PhD, discusses the newly crowded treatment landscape of hepatocellular carcinoma and highlights next steps for research.

Aiwu Ruth He, MD, PhD

Several positive trials in advanced hepatocellular carcinoma (HCC) have led to an influx of available treatment options in a field that had become relatively stagnant, said Aiwu Ruth He, MD, PhD, and more promising agents are coming down the pike.

For more than a decade, sorafenib (Nexavar) was the only FDA-approved drug available for use in the advanced setting, but in the last 2 years, 5 additional agents have been added to the treatment armamentarium: lenvatinib (Lenvima), regorafenib (Stivarga), cabozantinib (Cabometyx), nivolumab (Opdivo), and pembrolizumab (Keytruda).

An agent of particular interest, pembrolizumab, was granted an accelerated approval by the FDA as a treatment for patients with HCC who were previously treated with sorafenib, based on positive data from the KEYNOTE-224 trial. However, in February 2019, Merck, the manufacturer of the drug, announced that the coprimary endpoints in its confirmatory trial, KEYNOTE-240, had not been met. Although single-agent pembrolizumab was found to improve overall survival (OS) compared with placebo, the difference in benefit was not considered to be statistically significant per the prespecified statistical plan (HR, 0.78; 95% CI, 0.611-0.998; P = .0238).1

Despite this, He said that the patients who respond to pembrolizumab do appear to experience clinical benefit from the therapy, though they account for a smaller subset of the overall population of patients with HCC. Therefore, investigators will need to identify a biomarker to determine which patients will benefit most from checkpoint inhibition.

Beyond pembrolizumab, there are other emerging agents in the space that He said possess ample potential. Data with ramucirumab (Cyramza) from the phase III REACH-2 trial, for example, have shown improved OS with the agent compared with placebo in patients with HCC who had previously received sorafenib and have alpha-fetoprotein concentrations of at least 400 ng/mL.2 Further, the combination of atezolizumab (Tecentriq) plus bevacizumab (Avastin) has shown promising antitumor activity in patients with advanced disease in early-phase trials.3

OncLive: What agents have entered the HCC treatment paradigm in recent years?

In an interview during the 2019 OncLive® State of the Science Summit™ on Gastrointestinal Cancers, He, an associate professor of medicine at Georgetown-Lombardi Comprehensive Cancer Center, discussed the newly crowded treatment landscape of HCC and highlighted next steps for research.He: In the frontline setting, we have 2 TKIs: sorafenib and lenvatinib. Sorafenib was FDA approved in 2007. Lenvatinib was just approved last year, supported by data from the pivotal REFLECT trial. In the second-line setting, we now have 2 TKIs and 2 immune checkpoint inhibitors available. Regorafenib, a TKI, was approved by the FDA in 2017 for use in patients who have tolerated sorafenib and progressed on the drug. This [regulatory decision] was supported by positive data from the RESORCE trial. Cabozantinib was FDA approved in January 2019, based on results from the CELESTIAL trial.

How do you select patients for lenvatinib or sorafenib?

How have you seen the FDA approval of second-line cabozantinib incorporated into practice?

What are your thoughts on the KEYNOTE-240 trial failing to meet its primary endpoint?

For community oncologists, how might these data affect their practice?

Could you speak to the RESORCE study? What were the key findings?

What are some investigational agents that have potential?

In terms of immunotherapy, we have 2 FDA-approved agents. Nivolumab was granted an accelerated approval pending confirmation of the clinical benefit described in a confirmatory study. That agent received approval in 2017. The use of pembrolizumab was supported by data from KEYNOTE-224; it was also approved [pending] supporting data from a confirmatory study.Lenvatinib was compared with sorafenib in the REFLECT study, which had a noninferiority design. The study showed that lenvatinib was comparable with sorafenib in terms of OS benefit. In terms of other efficacy data, lenvatinib showed a higher response rate compared with sorafenib; it also doubled PFS. If we have a patient for whom we are looking for a response and tumor shrinkage, those would be important factors to consider. Based on toxicity profile, I would choose either one. Both agents show very similar side effect profiles. Lenvatinib, in the REFLECT study, showed a little bit more grade 3/4 hypertension, while sorafenib showed a little bit more grade 3/4 hand-foot reaction.This approval adds another second-line choice. The CELESTIAL trial was very inclusive, incorporating patients with very advanced-stage disease. About 20% of the patients in the study had received at least 2 prior lines of therapy. There was a significant survival benefit for the patients who received cabozantinib. I have some experience with this drug, and it is well tolerated. This gives us an additional option after the frontline setting.If you look at the initial FDA approval, pembrolizumab received an accelerated approval based on durable responses, pending confirmation of benefit in a larger study. In the KEYNOTE-240 trial, the hazard ratio was 0.78 and the P value was a little over .023. It was slightly worse compared with the prespecified hazard ratio. Therefore, [that raises the question of], “What is considered clinical benefit?" I believe that in patients who respond to pembrolizumab, they do benefit from the therapy. However, this is a smaller portion of the general population of patients with HCC. We need a biomarker that will help us select these patients.If the approval of pembrolizumab is not withdrawn, it will still be used. The median onset of response is a little over 2 months. Physicians probably still want to use it for a couple of months to see if patients will have a response or not. If patients have stable disease or progressive disease, they should be switched to a TKI, which have been shown to have significant survival benefit. We can make sure that we select the right patients who may benefit from this treatment.In the RESORCE study, patients who were enrolled to receive second-line regorafenib treatment had to be able to tolerate sorafenib for at least 28 days. The majority of those patients actually progressed on sorafenib and went on to receive regorafenib. If you count the 2 lines of therapy, median OS is past 2 years, which are amazing data. This is the first sequential pair of treatments to show a survival benefit for more than 2 years.The benefit of ramucirumab in patients with elevated alpha-fetoprotein levels over 400 ng/mL and prior sorafenib treatment was tested in comparison with placebo in a study called REACH-2. The data have met the primary endpoint and have shown a survival benefit with this agent. This was the first study that actually selected patients based on a biomarker. The data are currently under review by the FDA. We are watching for, hopefully, an FDA approval.

Even more exciting is that we have seen early promising data with combination immunotherapy. The data on bevacizumab plus atezolizumab has shown a durable response rate of 32%. The phase III trial will evaluate the combination versus sorafenib, and it has completed enrollment.

Another combination, lenvatinib plus pembrolizumab, has been tested in a phase I/II study, and showed a durable response rate of over 40%. There is a phase III trial looking at the use of this combination against lenvatinib alone. Another combination, durvalumab (Imfinzi) plus tremelimumab, is being evaluated in a randomized international trial and enrollment is halfway completed. All of those are very promising combinations.


  1. Merck Provides Update on KEYNOTE-240, a Phase 3 Study Of KEYTRUDA® (Pembrolizumab) in Previously Treated Patients With Advanced Hepatocellular Carcinoma. Merck. Published February 20, 2019. https://bit.ly/2SQ6J45. Accessed February 20, 2019.
  2. Zhu AX, Kang Y-K, Yen C-J, et al. Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased α-fetoprotein concentrations (REACH-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2019;20(2):282-296. doi: 10.1016/S1470-2045(18)30937-9.
  3. Pishvaian MJ, Lee MS, Ryoo B-Y, et al. Updated safety and clinical activity results from a phase 1b study of atezolizumab + bevacizumab in hepatocellular carcinoma (HCC). Ann Oncol. 2018;29 (suppl 8; abstr LBA26). doi: 10.1093/annonc/mdy424.028.