Eisai’s Lenvima Should See FDA Approval in Hepatocellular Carcinoma (HCC)

• Valuations unreliable given large timeframe to market

• Likely EU/US pricing pressures to impact revenue forecasting

• Combined Pfizer-AZ pipeline unlikely to create industry leader

Eisai’s (TYO:4523) Lenvima (lenvitanib) for first-line unresectable hepatocellular carcinoma (HCC) has a convincing FDA approval rationale based on positive Phase III results versus Bayer’s (ETR:BAYN) Nexavar (sorafenib), a high efficacy bar, experts agreed. Although some experts raised reservations about the Phase III trial only showing Lenvima as non-inferior to Nexavar in an open-label trial, this shouldn’t be an approval barrier, other experts noted.

Analyst reports have not commented on Lenvima’s approval prospects. But experts noted their confidence in the data, highlighting the outperforming Nexavar which did not prevent Lenvima’s non-inferiority. Lenvima’s potent antiangiogenic mechanism is ideal for HCC since its tumours are highly vascular and dependent on liver vessels to proliferate, further supporting approval justification, they added.

Although one analyst report states Lenvima’s side effect profile is within the known scope, experts noted its hypertension rates are higher than Nexavar. This could potentially be a differentiating factor between the two drugs considering efficacy data puts them neck-and-neck, some noted.

Based on data presented at this month’s American Society of Clinical Oncology (ASCO) in Chicago, Eisai plans to submit regulatory applications for unresectable HCC to the FDA and other territories, a June 2017 media release shows. Data was collected from the randomised Phase III REFLECT trial, which compared Lenvima and Nexavar in 954 subjects (NCT01761266), ClinicalTrials.gov shows.

Some analysts predict Nexavar has potential to reach USD 1bn in all indications. Lenvima was FDA approved for the treatment thyroid cancer in February 2015 and advanced renal cell carcinoma in May 2016.

Eisai did not respond to a request for comment.

Healthy FDA approval prospects

All experts agreed Lenvima’s Phase III results should secure FDA approval, particularly its primary endpoint of Overall Survival (OS) highlighting Lenvima as non-inferior to Nexavar. The median OS in the Lenvima group was 13.6 months compared to 12.3 months for Nexavar (p<0.00001) [Cheng, A. et. al. J Clin Oncol 35, 2017 (suppl; abstr 4001)].

Nexavar’s 12.6 months OS in the Lenvima trial is unusually high in contrast to other Phase III trials featuring Nexavar, which makes Lenvima’s non-inferiority success encouraging for approval

Showing non-inferiority in first-line HCC is a high bar considering many drugs have failed in Phase III when pitted against Nexavar, said Dr Richard Finn, Phase III investigator and assistant professor of medicine, David Geffen School of Medicine, UCLA, and Dr Emmanuel Thomas, assistant professor, Sylvester Comprehensive Cancer Center, Schiff Center for Liver Diseases, Miami, Florida. Bristol-Myers Squibb’s (NYSE:BMY) Phase III trial investigating brivanib (BMS-582664) versus Nexavar failed to demonstrate non-inferiority [Johnson, PJ et. al. J Clin Oncol. 2013 Oct 1;31(28):3517-24]. Pfizer’s (NYSE:PFE) Phase III trial investigating Sutent (sunitinib) versus Nexavar was stopped for futility after first interim analysis [Cheng, A. et. al. J Clin Oncol. 2013 Nov 10;31(32):4067-7].

Finn noted Nexavar’s 12.6 months OS in the Lenvima trial is unusually high in contrast to other Phase III trials featuring Nexavar, which makes Lenvima’s non-inferiority success encouraging for approval. In the Phase III brivanib trial, Nexavar’s OS was 9.9 months. A possible reason to Nexavar’s high OS in the Lenvima trial is that investigators were very experienced with Nexavar and therefore subjects could have been treated earlier than real world patients leading to better outcomes, Finn said.

In the unlikely event Lenvima is not approved it could be due to the trial being a non-inferiority trial which is not very well established design in HCC, said Dr Jorg Trojan, head of gastrointestinal oncology, University Hospital Frankfurt, Goethe University, Frankfurt, Germany. It would have been ideal if the Phase III open-label trial was blinded as allowing investigators to know which drug the subject received may have reduced result subjectivity, added Dr Marcus PeckRadosavljevic, associate professor of medicine, department of gastroenterology and hepatology, Medical University of Vienna, Austria.

But drug approvals based on non-inferiority studies are not unusual and the FDA are unlikely to consider it an approval roadblock, Peck and Finn said. Trojan added Phase III’s head-tohead trial design is welcome as it spells out how Lenvima compares with Nexavar without having to compare two different trials.

Trojan said Lenvima’s mechanism is also logical for HCC, further supporting its approval prospects. Peck said, like Nexavar, Lenvima is a tyrosine-kinase inhibitor (TKI) which seems to be ideal for patients who have failed chemotherapy.

But Lenvima theoretically should be more potent than Nexavar in HCC, since Lenvima has a more specific target, Trojan said. Lenvima is a potent anti-angiogenic drug, meaning it blocks blood vessel growth in cancer, Trojan and Finn said. This is ideal for HCC because its tumours are highly vascular and dependent on liver vessels to spread, Trojan said. In contrast, Nexavar is dubbed as a “dirty TKI” as it targets many pathways, he explained.

Differentiated but reasonable toxicity profile

Trojan said Lenvima’s side effect profile also supports approval, with Finn noting there are no new Lenvima safety signals in the Phase III trial. The most common side effects were hypertension (42%), diarrhea (39%), weight loss (31%) and fatigue (30%), Phase III data shows. Hypertension seems to be more frequent with Lenvima, and it could be due to the drug’s antiVEGF effect, Peck said. This shouldn’t be an approval barrier as it could be an indicator that the drug is reaching the right target, Peck added.

Trojan said this difference in side effects between Lenvima and Nexavar could be a critical differentiation point between the two drugs since Lenvima is only non-inferior. If Lenvima is approved, a likely real-world scenario would be patients who may be susceptible to hypertension would not be given Lenvima, Peck said. In patients who are sensitive to Nexavar’s side effects like diarrhea and hand-foot skin reaction could then be given Lenvima, Trojan said. Finn said there’s a lower frequency of skin reactions with Lenvima due to target profile nuances between the two drugs.

There have been concerns Lenvima could lead to severe bleeding events but this has so far not surfaced, Trojan said. Lenvima has been linked to bleeding events in thyroid cancer and bleeding events can happen with HCC as demonstrated when Roche’s (VTX:ROG) Avastin (bevacizumab) -- a drug which similarly targets VEGF -- was investigated for the indication, Trojan added.

July 3, 2017

Reynald Castaneda

Reporter

London

Reynald Castaneda, prior to moving to London, was a journalist for healthcare newspaper New Zealand Doctor, covering primary care health politics and medical research. He has a BSc in Biological Sciences from the University of Auckland and a postgraduate diploma in journalism from AUT University. Prior to venturing into journalism, Reynald worked as a laboratory technician for Massey University’s Institute of Molecular Biosciences.