Medivir presents the first clinical data with fostrox + Lenvima at the ASCO GI scientific congress, showing further improved clinical benefit vs previous interim updates from the ongoing phase Ib/IIa study in advanced hepatocellular carcinoma. According to the company, the data supports the planning for a pivotal phase IIb study in 2024. BioStock reached out to Pia Baumann, Medivir’s CMO, to learn more about the new data.

Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer. The majority of newly diagnosed patients are in an advanced stage and dependent on systemic treatment. Unfortunately, only 1 in 3 patients respond to the preferred first-line treatment (Tecentriq/Avastin). Medivir is developing fostrox with the aim to become the first regulatory approved alternative in patients where e current first-line treatment is ineffective or intolerable.

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 communicated high and durable disease control at 12 weeks and that more than 75 per cent of patients showed tumour shrinkage.

New encouraging data

New data, announced on 17 January, show that the combination therapy remains tolerable. Only 5 per cent of the patients have discontinued the study due to adverse events and a lower need for dose reductions than expected is seen. Equally important, as data matures, clinical benefit continues to improve. Overall Response Rate (ORR) has increased to 25 per cent and median time to progression has improved to 5.1 months, with more than 40 per cent of patients still on treatment in the study.

The data from this phase Ib/IIa study will be presented at the ASCO GI Congress in San Francisco on January 19^th by Dr Maria Reig. She is the Director of the Barcelona Clinic Liver Cancer (BCLC) and the Liver Oncology Unit at the Hospital Clinic of Barcelona in Spain, and an investigator in the study.

Comments from the CMO

BioStock reached out to Medivir’s CMO Pia Baumann to learn more about the new data and the implications for the future of the HCC project.

Pia, the Overall Response Rate (ORR) has increased to 25 per cent. Can you elaborate on the importance of this?

– Our new clinical data are very encouraging. Historically, only 5 – 10 per cent of patients treated in second-line HCC have responded to treatment after progressing on first-line treatment. Achieving a 25 per cent response rate clearly indicates that fostrox is adding clinical benefit in combination with Lenvima and has the potential to transform second-line treatment in HCC as the first approved treatment after current standard of care in first-line.

– Considering the dismal prognosis in advanced HCC, not only objective responses but also stable disease is recognised as treatment benefit, why disease control rate (DCR) has become an important endpoint in clinical studies. In this study we could see that the DCR was 80 per cent at first assessment and >60 per cent at 18 weeks, indicating also long duration of clinical benefit.

The median time to progression has improved to over five months, with more than 40 per cent of patients still on treatment. How does this prolonged progression time contribute to the overall clinical benefit of fostrox + Lenvima?

– Patients are benefitting from and staying on treatment longer than we had anticipated when starting 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 you see in first-line treatment of HCC. Exciting is that with more than 40% 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 rate that allows patients to stay on treatment long-term. How does this differentiate the combination treatment from current therapies?

– The consistent tolerability profile for fostrox + Lenvima is particularly important for three reasons. Firstly, HCC patients are more sensitive to adverse events due their underlying liver disease and to gain longer term clinical benefit the combination need to be safe over time which we have seen in this study.

– Secondly, the addition of fostrox to Lenvima does not negatively impact the ability to tolerate and gain optimal benefit from Lenvima itself, as seen in the lower-than-expected need for dose modification.

– Thirdly, the anti-cancer treatment itself can cause damage and detrimental effect on the vital liver function, which has not been seen with the combination of fostrox + Lenvima. All this is highly encouraging as patients can benefit in full from both drugs in combination and that they are able to tolerate and stay on treatment as long as they have clinical benefits without impacting the ability to tolerate a potential third-line treatment.

With the longest-running patient still on treatment after approximately 17 months, sustaining a partial response, what does this case reveal about the durability and effectiveness of fostrox + Lenvima in real-world scenarios?

– It shows that the combination can provide the important balance between clinical efficacy and side effects, enabling durable response with long-term treatment. It also highlights that with promising tolerability, the possibility of continuous tumour shrinkage with time is increased.

The data from the ongoing phase Ib/IIa study supports accelerating the fostrox development programme. What key milestones do you anticipate in 2024?

– This is the first clinical data from this study presented at a scientific congress and we anticipate additional data to be released throughout 2024 as data matures. In addition, we are accelerating our regulatory interactions in the first half of the year to confirm the upcoming phase 2b study design, including opening an IND in the USA. We are also prioritising our partnering outreach on the back of the data presented at ASCO GI as we aim to establish a development and commercialisation partnership with focus on Asia.

How do you plan to further explore this potential in a randomised, controlled trial, and what are the key considerations in designing such a trial?

– There are currently no approved treatments in second-line HCC after current standard of care in first-line (Tezentriq/Avastin). With the encouraging results presented for fostrox + Lenvima and the high unmet need in second-line HCC, we plan to accelerate the development of fostrox. We are therefore planning a randomised phase 2b study evaluating fostrox + Lenvima vs Lenvima alone with the intention to apply for accelerated approval after completion of the study, estimated in 2027.

– We are designing the study to meet the criteria FDA has communicated with regard to accelerated approval requirements, including ensuring a sufficient patient safety database and choosing 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 bn annually by 2028.

Finally, Karin Tunblad PhD, Project Director for fostrox at Medivir, will present clinical data at EASL Liver Cancer Summit in February. Can you comment on the pharmacokinetic data that she will present?

– The data is still under embargo so 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 an additional example of how we are moving forward with as much speed as we can, to maximise the chance of fostrox becoming the first approved treatment in second-line HCC.

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