Expert Highlights Impact of Lenvatinib in Frontline HCC

Masatoshi Kudo, MD, PhD

Masatoshi Kudo, MD, PhD

With the recent success seen with lenvatinib (Lenvima) as a first-line treatment for patients with hepatocellular carcinoma (HCC), the treatment landscape for this disease is drastically changing, said Masatoshi Kudo, MD, PhD.

After numerous HCC trials over the past decade have failed to show superiority or noninferiority to sorafenib (Nexavar), the REFLECT trial was the first positive trial, which showed lenvatinib was a noninferior first-line treatment option for these patients.

The trial included 954 patients who were randomized to receive lenvatinib or sorafenib. The trial met its primary endpoint of overall survival (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).Lenvatinib also proved to be superior to sorafenib for median progression-free survival and time to progression.

Based on these data, lenvatinib gained FDA approval in August 2018 as a first-line therapy for patients with unresectable HCC.

During the 2019 Gastrointestinal Cancers Symposium, Kudo presented findings from an analysis of survival and objective response in patients in the REFLECT trial, which showed that patients who responded to lenvatinib had better survival outcomes than those who did not respond.

“A multivariate analysis clearly showed lenvatinib was one of the predictive factors of survival. That means lenvatinib objective responses are prognostic factors of OS, and also, lenvatinib is a prognostic factor. This means more patients benefit from lenvatinib than sorafenib,” Kudo said.

In an interview withTargeted Oncology, Kudo, of Kindai University Faculty of Medicine in Osaka, Japan, discussed the results from the REFLECT trial and the analysis presented at the 2019 Gastrointestinal Cancers Symposium, as well as other research currently ongoing for this patient population.

TARGETED ONCOLOGY:Can you provide an overview of the current treatment landscape for HCC?

Kudo:Current treatment strategies for early-stage HCC, which is tumors less than 3 centimeters, is usually [applying] curative therapy, such as resection, ablation, or transplantation. For intermediate-stage HCC, which means multifocal disease, transcatheter hepatic arterial chemoembolization (TACE) is the standard of care. For advanced-stage HCC, like patients with macrovascular invasion and extrahepatic spread, systemic therapy is the standard of care. For final stage, best supportive care is standard.

TARGETED ONCOLOGY:What are some of the unmet needs that still exist within this space?

Kudo:In HCC, the recurrence rate is very high, even after curative treatment. After resection or ablations, the annual recurrence rate is around 15% to 20%, and the 5-year recurrence rate is 80%, so this high recurrence rate after curative treatment is an unmet need for this disease.

Also, TACE is not a curative treatment and recurrence is very high. Currently, there is no adjuvant therapy after curative therapy, and also, in combination with TACE, there is no systemic therapy to suppress recurrence. Another challenge for advanced-stage HCC is that systemic therapy is only applied for patients with good liver function, in other words, Child-Pugh grade A patients. For Child-Pugh grade B or C patients, there is no reduction, so those [patients] are another unmet need.

TARGETED ONCOLOGY:What was the rationale for the REFLECT trial?

Kudo:REFLECT is the first positive trial since the success of the sorafenib trial. We need [more] first-line treatment agents. Eight clinical trials failed to show superiority or even noninferiority to sorafenib. RESOURCE was another trial similar to REFLECT, but it failed to show even noninferiority.

TARGETED ONCOLOGY:What were the results from this trial?

Kudo:After 8 negative trials over 10 years, the REFLECT trial showed noninferiority to sorafenib. It was approved worldwide, so this is a really good alternative to sorafenib, especially not only in noninferiority but also in clinically meaningful antitumor effects, higher levels of response, better progression-free survival, better time to progression, and less hand-foot syndrome.

This trial showed noninferiority, but actually it is superior because first, alpha-fetoprotein (AFP) was not balanced, favoring the sorafenib arm. If it was collected by covariate analysis, the AFP value greater than 200 was more frequently seen in the lenvatinib arm, so after a covariate analysis, the AFP value was adjusted and showed OS in lenvatinib was better than in sorafenib.

That’s one point, but another point is the noninferiority margin was very strict at 1.08. That is very unusually strict as compared with other studies, so achieving this noninferiority is very important. After adjusting the AFP value, REFLECT showed a better survival [with lenvatinib]. More so, objective response rate by independent review using modified RECIST (mRECIST) [criteria] was extremely high, 41% as compared to around 10% in the sorafenib arm. The tumor shrinkage in the necrotic tissue was much better than sorafenib.

At ASCO GI, we presented that the responders in the REFLECT trial showed better survival than non-responders. A multivariate analysis clearly showed lenvatinib was 1 of the predictive factors of survival. That means lenvatinib objective responses are prognostic factors of OS, and also, lenvatinib is a prognostic factor. This means more patients benefit from lenvatinib than sorafenib.

TARGETED ONCOLOGY:How will this treatment impact the field?

Kudo:Currently, in Japan, lenvatinib was approved on March 23, and already 9 months have passed. Over 8000 patients received lenvatinib already, and 9% of the [patients received lenvatinib] first-line. Most of the first-line treatment was replaced by lenvatinib. Also, not only advanced-stage HCC, but also intermediate-stage HCC with extrahepatic spread can be treated by lenvatinib because intermediate-stage HCC is a heterogeneous disease. Patients with a bilobar multifocal disease did not benefit from TACE because TACE induced deeper damage. Also, it did not induce a treatment response. Lenvatinib can provide a good response and does not induce liver deterioration.

Gradually, majority of the intermediate-stage is going to be treated by lenvatinib. The treatment landscape is now drastically changing.

TARGETED ONCOLOGY:Is there other research ongoing in this patient population?

Kudo:There are many ongoing immunotherapy trials, including a combination trial of lenvatinib plus pembrolizumab. That is a phase III trial that is going to start. Another combination in trial combines the PD-L1 antibody atezolizumab plus bevacizumab. That produces a very high response rate with a durable long-lasting response. That will improve the OS further if the result is positive.

Another combination treatment is a PD-L1 antibody plus a CTLA-4 antibody. It’s called the HIMALAYA trial. Those combinations of immunotherapies are very promising. Also, in the adjuvant setting, immunotherapy trials are ongoing now.

TARGETED ONCOLOGY:Where do you see the field heading in the next 5 to 10 years?

Kudo:The treatment landscape will drastically change in a couple of years if combination therapy is applied to the adjuvant setting or these combinations replace TACE treatment. Maybe patient survival will also be drastically improved. Usually, after surgery, the recurrence rate is very high, but maybe, adjuvant therapy by combination is more successful and recurrence will be drastically decreased. HCC may become a curable disease by systemic therapy and also combination of localized therapy plus immunotherapy.