Abivax’s Phase I/II ABX196 trial in second-line (2L) hepatocellular carcinoma (HCC) has experts split if the standard of care (SOC) reshuffle in first line (1L) would have a negative impact on ABX196’s immediate- and long-term success potential. The new 1L therapy standard means the 2L efficacy bar could be raised, some noted. However, ABX196, which is under investigation with Bristol-Myers Squibb’s Opdivo (nivolumab), may only have to improve upon Opdivo monotherapy in 2L, which is now a low bar following 1L changes, some said.
Nevertheless, despite ABX196 having a promising mechanism backed by preclinical data, its invariant natural killer T (iNKT) cell agonist approach is yet to prove its worth in oncology, experts agreed. The Phase I/II is recruiting patients who have either progressed from the old 1L SOC Bayer’s Nexavar (sorafenib) or new 1L SOC Roche’s Tecentriq (atezolizumab) plus Avastin (bevacizumab).
The HCC 1L overhaul could mean 2L efficacy expectations are likely to be elevated, experts said. However, ABX196/Opdivo may only have to improve upon Opdivo monotherapy because the latter approach is now precluded for 2L use. Preclusion is due to Opdivo sharing the same immunotherapy approach as Tecentriq. If the Phase I/II ABX196/Opdivo trial is positive, it would keep Opdivo relevant in 2L HCC. Abivax, which declined an interview request, has stated it will seek to outlicense ABX196 once the Phase I/II proof-of-concept trial is concluded.
Due to a more efficacious 1L option, patients may have delayed progression to later-line therapies, meaning this could defer 2L therapy use, experts noted. However, all available approved or under investigation therapies, including ABX196/Opdivo, can make an argument to be considered for 2L SOC as this is still up for debate, they added.
ABX196’s mechanism is logical, as it could make HCC more susceptible to immune system response, experts said, adding iNKT cells are naturally found in the liver. However, there are still many iNKT cell agonist mechanism blanks in oncology, they said. Mouse model data is a nonreliable barometer for success in humans, as iNKT cells are more relevant in mice, they added.
Top-line results for the dose-escalation portion of the 48-patient Phase I/II trial is expected in 2Q, according to the company website. Abivax has a €460.51m ($555.54m) market cap.
Frontline shift has ripple effect in 2L, where SOC is available
The recent change in 1L HCC could mean 2L trial success benchmarks could be raised, due to patients experiencing longer survival, said Phase I/II investigator Dr Ahmed Kaseb, professor, Hepatocellular Carcinoma Program, University of Texas MD Anderson Cancer Centre, Houston. In the Phase III IMbrave150 in 1L HCC, the median overall survival (OS) coprimary endpoint was 19.2 months with Tecentriq/Avastin versus 13.4 months with Nexavar, according to a 12 January Roche media release.
ABX196’s mechanism is designed to circumvent Opdivo monotherapy’s limitations in the new 2L setting, Kaseb said. Because Opdivo is now unlikely to work in the new 2L space, this might lower the efficacy bar for ABX196/Opdivo, said Dr Lorenza Rimassa, deputy director, Medical Oncology Unit, Humanities Cancer Centre, Milan, Italy. ABX196/Opdivo may only have to improve upon Opdivo monotherapy, Rimassa added. If the Phase I/II trial reports of positive results, it would be an upside for Opdivo as it would keep its relevance in 2L HCC, Kaseb noted.
Due to Phase I/II being a proof-of-concept trial, any efficacy signal would be encouraging, said Kaseb. However, superior data versus Opdivo monotherapy, even if current data is in the post-Nexavar setting, would be welcome, he added. The trial has several efficacy secondary endpoints, such as overall response rate and progression-free survival (PFS). In 2L, PFS is a more clinically valuable measure, with Opdivo offering four-month PFS in practice, he said.
SOC change in 1L HCC could defer the use of 2L therapies, said Dr Riad Salem, professor of Radiology, Medicine and Surgery, Northwestern University, Chicago, Illinois. Tecentriq/Avastin as the new 1L SOC is likely to remain unchallenged for an extended period of time due to the magnitude of effect the combination can offer, he added. The combination was FDA approved on 29 May 2020. The Phase I/II ABX196/Opdivo is recruiting patients who progress from Nexavar or at least one prior systemic treatment.
Still, 1L change could offer SOC opportunities for ABX196. Due to the changes in 1L, the new SOC in 2L is up for debate, with all therapies being a potential candidate, including ABX196/Opdivo, added Rimassa. At present, previous 1L therapies like Nexavar could be used off-label in the 2L setting, she noted. However, due to some countries preventing off-label use, current 2L therapies like Exelixis’ Cometriq (cabozantinib) are likely to remain there, despite their 2L data being based on patients progressing from previous 1L SOC Nexavar, she said.
Mechanism logical but yet to prove value in HCC
As for ABX196’s mechanism, the general idea is for the drug to convert a cold HCC tumour into a hot tumour, allowing Opdivo to work, experts said. While there is some early clinical data showing this approach may be relevant in HCC, there could be other more relevant markers yet to be discovered, Rimassa said.
ABX196 is a synthetic agonist of iNKT cells, which is relevant in oncology as they jumpstart the immune system response, explained Paul Savage, professor of Chemistry and Biochemistry, Brigham Young University, Provo, Utah. iNKT cells communicate with the immune system’s dendritic cells, with the latter bolstering antigens to help the immune system find and attack cancer cells, he added. Cancer cells proliferate due to their ability to evade the immune system, he explained. Activating iNKT cells is an attractive mechanism in HCC because they are naturally abundant in the liver, Kaseb added.
However, there are still many caveats to ABX196’s mechanism. The ideal baseline of iNKT cells needed for ABX196 to work is still unknown, noted Mitchell Kronenberg, PhD, chief scientific officer, La Jolla Institute for Immunology, California. The Phase I/II trial’s inclusion/exclusion criteria do not mention baseline iNKT cells required. Blood tests can be conducted to measure patient baselines, but iNKT cell levels vary dramatically among people, Kronenberg added. However, while such variation is pertinent in blood samples, this may not be the case in the liver, which may have a uniform level of iNKT cells, noted Dr Luc Teyton, professor, Department of Immunology and Microbiology, Scripps Research, La Jolla, California.
In a 12 February Abivax presentation, preclinical mouse model data shows ABX196 can convert tumors not responsive to treatment. In a study in retrograde mouse HCC model, ABX196/Opdivo led to 0% macroscopic liver tumor invasion by day 61 or at death, in contrast to anti-programmed cell death protein 1 (anti-PD1) alone (6%), Nexavar (40%) or vehicle only (58%). Mice and humans have comparable iNKT cells, Kronenberg and Teyton said.
The inference of efficacy in humans may not be ideal because iNKT cells are more prevalent in mice, Kronenberg said. In fact, the stimulation of iNKT cells in mice can lead to cytokine storm and liver damage, he added. Such an effect has not yet been seen in humans, but ABX196’s potency might have to be monitored to prevent these issues, he said. The Phase I/II is investigating 0.1µg, 0.2µg and 0.4µg injections of ABX196 administered every eight weeks.
In combination with Opdivo, it is still unclear how much synergy there is between the two treatments in HCC, Kaseb said. Opdivo allows the immune system to detect cancer cells better, but ABX196/Opdivo combination’s mechanisms may not directly overlap, Savage said. However, iNKT cells also have PD1 receptors, and Opdivo can allow iNKT cells to have a longer lifespan, from only a few hours to up to four to six weeks, Teylon noted. ABX196 is injected every eight weeks. While ABX196 is injected about two hours after Opdivo is administered, this wait is not cumbersome in practice as such outpatients are in hospital for an extended period for observation, Kaseb said.
The Phase I/II’s primary endpoint is investigating adverse events. The stimulation of iNKT cells was primarily investigated in the context of vaccine development, with safety benchmarks not applicable in oncology, said Savage and Teyton, who both investigated ABX196 as a vaccine asset. For example, stimulating iNKT cells could lead to mild flu-like symptoms, which may be an issue in vaccine development but would be acceptable in oncology, Savage said. There could also be an alanine transaminase (ALT) increase, which is a marker for liver damage, Teylon added. ALT increase is more concerning in vaccine development for healthy people, since ALT increase is asymptomatic, he noted. While ABX196’s liposome formulation could lead to an allergic effect, this is rare, Kronenberg noted.
Reynald Castaneda is Associate Editor for Clinical Trials Arena parent company GlobalData’s investigative journalism team. A version of this article originally appeared on the Insights module of GlobalData’s Pharmaceutical Intelligence Center. To access more articles like this, visit GlobalData.