Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer. The majority of newly diagnosed patients are at an advanced stage and dependent on systemic treatment. Unfortunately, only 1 in 3 patients respond to first-line treatment (Tecentriq/Avastin). Medivir develops fostrox with the goal of becoming the first regulatory approved option for patients where current first-line treatment is ineffective or not tolerated.
Fostrox is currently being evaluated in a fully recruited phase Ib/IIa study in combination with the cancer drug Lenvima, to evaluate safety and efficacy.
The study is ongoing and no new unexpected safety events have occurred. Late last year, Medivir reported high and sustained disease control at 12 weeks and that more than 75 percent of patients showed reduced tumor size.
New encouraging data
New data, announced on January 17, show that the combination therapy remains tolerable. Only 5 percent of patients have discontinued the study due to adverse events and there has been a lower need for dose reduction than expected. Equally important, clinical benefit continues to improve as the data matures. The Overall Response Rate (ORR) has increased to 25 percent and the median time to progression has improved to 5,1 months, with more than 40 percent of patients still on study treatment.
Data from this phase Ib/IIa study will be presented at ASCO GI Congress in San Francisco on January 19 by Dr. Maria Reig. She is the head of Barcelona Clinic Liver Cancer (BCLC) and Liver Oncology Unit at Hospital Clinic of Barcelona in Spain, and one of the investigators in the study.
CMO comments
BioStock contacted Medivir's CMO Pia Baumann to learn more about the new results and the implications for the future of the HCC project.
Pia, the Overall Response Rate (ORR) has increased to 25 percent. Can you elaborate on the importance of this?
– Our new clinical data are very encouraging. Historically, only 5-10 percent of patients treated in second-line HCC have responded to treatment after progressing in first-line therapy. Achieving a response rate of 25 percent clearly indicates that fostrox adds clinical benefit in combination with Lenvima and has the potential to transform second-line HCC treatment as the first approved treatment, following the current standard of care for first-line therapy.
– Given the dismal prognosis of advanced HCC, not only objective responses but also stable disease are recognized as treatment benefits, which is why disease control rate (DCR) has become an important efficacy measure in clinical trials. In this study, we could see that DCR was 80 percent at first assessment and >60 percent at 18 weeks, which also indicates long-lasting clinical benefit.
The median time to progression has improved to over five months, and more than 40 percent of patients are still on treatment. How does this extended time to progression contribute to the overall clinical benefit of fostrox + Lenvima?
“Patients are being helped and staying on treatment longer than we had anticipated when we started the study. A median time to progression of over 5 months is higher than historical controls in second-line HCC, and is actually more in line with what is seen in first-line HCC treatment. It is exciting that, with more than 40 percent of patients still on treatment in the study, there is a reasonable expectation that the median time to progression will continue to improve further in this difficult-to-treat second-line population.”
The safety profile remains good, with a tolerability level that allows patients to continue treatment long-term. How does the combination treatment differ from current therapies?
– The consistent tolerability profile of fostrox + Lenvima is particularly important for three reasons. First, HCC patients are more sensitive to side effects due to their underlying liver disease and to obtain long-term clinical benefit, the combination must be safe over time, as we have seen in this study.
– Second, the addition of fostrox to Lenvima has no negative impact on the ability to tolerate and obtain optimal benefit from Lenvima itself, as can be seen in the lower expected need for dose adjustment.
– Third, cancer treatment itself can cause damage to vital liver function, which has not been seen with the fostrox + Lenvima combination. All of this is very encouraging as patients are helped by both drugs in combination and can tolerate and continue treatment as long as they have clinical benefit, without affecting the ability to tolerate a potential third-line treatment.
The patient who has been on treatment the longest shows a partial response after approximately 17 months. What does this say about the duration and effectiveness of fostrox + Lenvima in an acute patient scenario?
"It shows that the combination can provide the important balance between clinical efficacy and side effects, enabling a durable response with long-term treatment. It also highlights that with promising tolerability, the chances of continued tumor shrinkage over time increase."
Data from the ongoing Phase Ib/Iia study supports an acceleration of the fostrox development program. What important milestones do you see ahead in 2024?
– This is the first clinical data from this study to be presented at a scientific conference and we expect additional data to be released in 2024 as the data matures. Additionally, we are accelerating our regulatory interactions in the first half of the year to confirm the upcoming design of the Phase IIb study, including opening an IND in the US. We are also prioritizing our collaboration based on the data presented at ASCO GI as we seek to establish a development and commercialization partnership with a focus on Asia.
How do you plan to further explore this potential in a randomized, controlled trial, and what are the key considerations in designing such a trial?
– There are currently no approved second-line HCC treatments beyond current standard first-line therapy (Tezentriq/Avastin)With the encouraging results for fostrox + Lenvima and the high medical need in second-line HCC, we plan to accelerate the development of fostrox.
– We are therefore planning a randomized phase IIb study evaluating fostrox + Lenvima compared to Lenvima alone, with the intention of applying for conditional approval after completion of the study, estimated to be in 2027.
“We are designing the study to meet the criteria communicated by the FDA regarding accelerated approval requirements, including ensuring a sufficient patient safety database and selecting a regulatory-approved primary endpoint. With this accelerated approach, fostrox has the potential to become the first approved treatment in a market worth $2,5 billion annually by 2028.”
Finally, Karin Tunblad, PhD and project manager for fostrox at Medivir, will be presenting clinical data at the EASL Liver Cancer Summit in February. Can you comment on the pharmacokinetic data she will present?
– The data is still under embargo so the details will have to wait until February, but what I can say is that this is another important component that further supports our accelerated regulatory interactions and strengthens the continued development of fostrox. It is also another example of how we are moving forward as quickly as we can, to maximize the chance of fostrox becoming the first approved treatment in second-line HCC.