Zhu Reviews the Approval of Second-Line Ramucirumab for AFP-Elevated HCC

Andrew X. Zhu, MD, PhD, FACP

Andrew X. Zhu, MD, PhD, FACP

Single-agentramucirumab (Cyramza) was approved by the FDAfor the treatment of patients with hepatocellular carcinoma (HCC) who have high alpha-fetoprotein (AFP) levels of 400 ng/mL or greater and who had previously received sorafenib (Nexavar) in the first-line setting. Prior to this approval, patients within this particular subgroup had limited treatment options and a known poor prognosis after progression on sorafenib.

The approval was based on the findings from the international, double-blind, placebo-controlled, multicenter phase III REACH-2 trial, in which 292 patients were randomized to receive ramucirumab or placebo with best supportive care. Although this was a relatively small sample size, all patients had AFP ≥400 ng/mL and disease progression with frontline sorafenib.

In patients who progressed on or became intolerant to frontline sorafenib, the median overall survival (OS) was 8.5 months in the ramucirumab arm versus 7.3 months with placebo (HR, 0.71; 95% CI, 0.53-0.95,P= .020). The progression-free survival (PFS) was 2.8 months versus 1.6 months (HR, 0.452; 95% CI, 0.339-0.603;P<.0001), also favoring the ramucirumab arm.

Overall, ramucirumab was well tolerated. There were some treatment-related adverse events (AEs); the most common grade &ge;3 AEs noted in the REACH-2 trial included hypertension and hyponatremia. Grade &ge;3 AEs of special interest included liver injury/failure, hypertension, and bleeding/hemorrhage. About 10% of patients discontinued treatment in the ramucirumab arm due to AEs.

&ldquo;The clinician needs to know how to manage the hypertension related to this particular agent,&rdquo; said Andrew X. Zhu, MD, PhD, FACP. &ldquo;With that, we can actually start to experience how to apply this drug very effectively in the practice. I think this clearly represents a very good treatment option for patients who have failed sorafenib, either who progressed on sorafenib or who could not tolerate sorafenib, but also have this high baseline AFP levels defined by at least 400 ng/mL in the blood test.&rdquo;

In an interview withTargeted Oncology,Zhu, professor of medicine at the Harvard Medical School and director of Liver Cancer Research at the Massachusetts General Hospital Cancer Center, discussed the results from the REACH-2 trial and the significance of the approval of ramucirumab monotherapy in patients with advanced HCC and high AFP levels who have previously failed sorafenib.

TARGETED ONCOLOGY:Prior to REACH-2 and the approval of ramucirumab, what did the treatment landscape look like for this patient population?

Zhu:As you know, we have been making some progress in advanced HCC treatments over the past 2 to 3 years. For the first-line setting, we have sorafenib, but also recently, we had the noninferiority trial demonstrating lenvatinib (Lenvima), another tyrosine kinase inhibitor (TKI) with a slightly different target inhibition profile, can also improve the OS and is also not inferior to sorafenib in terms of the OS.

In the second-line setting, we initially had regorafenib (Stivarga) for patients who progressed on sorafenib. We subsequently have cabozantinib (Cabometyx), another TKI with a different target inhibition profile, also being approved for patients who fail sorafenib. Interestingly, the FDA actually gave an accelerated approval of 2 checkpoint inhibitors, nivolumab (Opdivo) and pembrolizumab (Keytruda) based on the durable responses observed in phase II trials.

We already know we have quite a few treatment options, but again, even though we have all these treatment options, the prognosis for this disease remains very poor, particularly for patients with baseline high AFP levels. We can actually define this population= as having AFP levels of at least 400 ng/mL. We have known that this population has a very poor prognosis with limited treatment options, and we also know that this subgroup of patients seems to derive the most benefits from ramucirumab. For that reason, I think the REACH-2 trial certainly has very important messages for this particular disease.

TARGETED ONCOLOGY:What was the rationale for studying ramucirumab in this patient population?

Zhu:In general, angiogenesis is very important for hepatocarcinogenesis; we have known this for quite a while. If you look at the positive phase III trials that actually led to the approval of the prior TKIs, they all universally target the VEGFR2 receptor, which highlights that angiogenesis is a very critical pathway for hepatocarcinogenesis. Ramucirumab is actually a specific monoclonal antibody against VEGFR2. It has a very unique mechanism of action, and we have shown in earlier studies that ramucirumab definitely has anticancer activity in HCC. We even launched a prior phase III study looking at ramucirumab versus placebo in all patients who fail sorafenib.

What&rsquo;s interesting coming out of the initial REACH trial is that even though there was a statistical trend demonstrating improved survival compared with placebo, in the intent-to-treat population the study did not actually meet the statistical significance of improved survival. All the other secondary endpoints including PFS and response rates were also in favor of ramucirumab in comparison with placebo. However, when we look at the prespecified subgroup analysis looking at patients with high AFP at baseline only in the initial REACH trial, we were able to demonstrate that a patient with high baseline AFP definitely has a poor prognosis, and they have shorter median survival. Second, and more importantly, in that subgroup of patients, ramucirumab significantly improved the OS in comparison with placebo.

Patients with high baseline AFP account for 40% to 45% of all the [cases of] advanced HCC. Because of this initial finding, we actually came back to design the subsequent phase III trial, the REACH-2. In this study, only patients with high baseline AFP were enrolled for this particular trial, and as you know, the study was a positive study.

TARGETED ONCOLOGY:Could you discuss the findings from the REACH-2 trial?

Zhu:Granted, this trial had only a very modest sample size because we wanted to get the answer quicker, but even with the sample size of this phase III, we definitively demonstrated that ramucirumab in comparison with placebo clearly improved the median OS and actually reduced the risk of death by 29%; the hazard ratio was 0.71. Likewise, it also reduced the risk of disease progression, and the PFS hazard ratio was 0.45, also in favor of ramucirumab.

This represents the first positive trial in a biomarker-selected population in HCC. We have known for quite a while, based on a lot of extensive molecular genetic testing, that HCC is very heterogenous at the molecular level. We have appreciated the molecular heterogeneity of the disease for quite a while. We have also tried very hard to design a study using the so-called molecular enrichment strategy, meaning we select certain populations based on the molecular signature hoping that we can enrich the efficacy signal of certain targeted agents. On the other hand, so far we have not been able to successfully demonstrate the benefit of any targeted agents in a well-selected population. An example is a phase III effort looking at tivantinib, a c-MET inhibitor, in patients with high c-MET expression in this population and the phase III design failed.

That&rsquo;s why the REACH-2 study highlights that this molecular signature strategy to enrich the population for successful targeted agents in development is still a viable strategy for advanced HCC.

TARGETED ONCOLOGY:Can you speak to the significance of the FDA&rsquo;s approval of ramucirumab based on the REACH-2 trial?

Zhu:Following the recent approval of several agents, I think the addition of ramucirumab in this population is definitely bringing another treatment option for patients suffering from this deadly disease. Our study truly represents the first i biomarker-selected population-based positive phase III trial. We were able to demonstrate that ramucirumab is definitely improving the survival in patients with high baseline AFP levels. This population represents a very poor prognostic subgroup with very limited treatment options; we think that the addition of ramucirumab in this population brings more treatment options to improve the survival in these patients.

TARGETED ONCOLOGY:What are the next steps for incorporating ramucirumab into clinical practice?

Zhu:Obviously, the clinicians need to know the mechanisms of action of this agent and the expected safety profile. This is a typical antiangiogenic agent, and we have known the safety profile very well. The clinician needs to know how to manage the hypertension related to this particular agent. With that, we can actually start to experience how to apply this drug very effectively in practice. I think this clearly represents a very good treatment option for patients who have failed sorafenib, either who progressed on sorafenib or who could not tolerate sorafenib, but also have this high baseline AFP levels defined by at least 400 ng/mL in the blood test.

This is definitely representing a good treatment option for this subgroup population. Also, because of the relatively well-known and distinct tolerated safety profile in comparison to other TKIs, this may actually represent a very good option with relatively good tolerability for this patient population.

TARGETED ONCOLOGY:What types of challenges do you come across in developing new drugs for patients with HCC?

Zhu:It &nbsp;remains to be incredibly challenging how to develop effective targeted therapies or immunotherapy agents in patients with high AFP levels. In general, drug development in HCC remains to be very challenging for several reasons. The first is we still want to identify the molecular driver for HCC so that we can develop effective systemic targeted therapies. Second, the molecular heterogeneity of this disease represents a unique challenge for developing targeted therapies in general in the all-comer patient population. You have to be able to enrich the population based on selected molecular signature so that a certain targeted agent can be enriched for its efficacy. Third, we also know that the majority of patients with HCC occur in the background of underlying liver cirrhosis, and that actually impairs the ability of these patients to tolerate effective systemic therapy.&nbsp;

TARGETED ONCOLOGY:What are some of the ongoing challenges with treating patients with HCC even with the availability of several treatment options?

Zhu:Treating for HCC in the advanced disease setting continues to be a big challenge. We have developed quite a few targeted agents and immunotherapies in this disease; however, we still need to know how to better define the population that is likely to benefit from these drugs. In other words, we need to identify the so-called predictive biomarkers, so we know which population would &nbsp;benefit from a specific agent.

Secondly, with the availability of several agents, we need to know how to sequence these drugs rationally so that patients can derive the maximum benefit of these agents. Third, I think we need to develop additional effective drugs for this disease. We need to identify additional actionable driver signatures so that patients with this disease can have more treatment options.

Lastly, I think we are starting to explore combination strategy already, how to combine agents like ramucirumab with other classes of agents, particularly with checkpoint inhibitors and other immunotherapy, so that we can improve the efficacy signal without compromising the safety profile of these patients. I think that with all these collective approaches, treatment options will continue to be expanded.

Reference:

Zhu AX, Kang YK, Yen CJ, et al; REACH-2 study investigators.Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased &alpha;-fetoprotein concentrations (REACH-2): a randomised, double-blind, placebo-controlled, phase 3 trial.&nbsp;Lancet Oncol.2019 Feb;20(2):282-296. doi: 10.1016/S1470-2045(18)30937-9.