Reducing Adverse Events Through Dose Optimization

EP: 1.Overview of Toxicity Associated With TKIs in Solid Tumors

EP: 2.Understanding and Detecting TKI-Specific Hepatotoxicity

EP: 3.Vigilance Is Key in Mitigating TKI-Associated Hepatotoxicity

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EP: 4.Reducing Adverse Events Through Dose Optimization

EP: 5.Novel Investigational Combination Strategies

EP: 6.Future Directions: Optimizing Care Through Combinations

Transcript:

Tanios S. Bekaii-Saab, MD: We have a number of targeted strategies in oncology in solid tumors and the same in GI [gastrointestinal] malignancies. Some other agents that are in use, such as immune checkpoint inhibitors, can be associated with hepatotoxicity, but the liver toxicity is typically different. It’s autoimmune hepatitis, different in nature. That brings us to the point: using more of these tyrosine kinase inhibitors in combination with immune checkpoint inhibitors, how do we ensure that we clearly differentiate between the 2? The answer is that we don’t. When there is a level of toxicity, you assume that both agents are instigators. You stop both of them, you treat for the immune component, and you observe. The mechanisms of actions are a little different, right? It’s mostly idiosyncratic with the tyrosine kinase inhibitors, likely from the formation of reactive metabolites. But with I/O [immuno-oncology] agents, it’s mostly autoimmune hepatitis.

With most tyrosine kinase inhibitors, the toxicities reflect the dose. Understanding that liver injury can occur at lower doses vs higher doses is idiosyncratic. But one can assume only that a lower dose, or the optimal dose of the agent, is preferable in terms of bringing down the toxicity level overall. Hypothetically, this also brings the risk of liver toxicity to a more acceptable level. In that sense, I’ll mention how we work through most of our tyrosine kinase inhibitors, based on some of the data we’ve presented and published. With regorafenib dose optimizations in the ReDOS study, we’ve shown, essentially, that if you go sequentially from 80 mg to 120 mg to 160 mg—160mg was the approved dose—then they find and optimize, in some ways, the individual dose for each patient, which ends up being the 1 associated with the least toxicities. It becomes even more important as we combine these agents with immune checkpoint inhibitors. We’ve seen for most of these agents that the dosages have to be diluted down significantly to improve the level of tolerance, yet see significant synergistic activity.

It’s very important to keep in mind the key aspect of keeping a close eye on the toxicities while working with the tyrosine kinase inhibitor dosing in an optimized manner. It’s the same with cabozantinib. For example, in HCC [hepatocellular carcinoma], I never start with 60 mg. I start with 40 mg and then escalate to 60 mg. Sunitinib is the same. Those are agents that I use in clinic. Some agents are “more specific to the target,” such as HER2 [human epidermal growth factor receptor 2]– and VEGF-targeted agents. They’re highly specific to the target, with hitting less of the other targets. One example would be tucatinib. That hits primarily HER2 and very little of EGFR, unlike the other oral tyrosine kinase inhibitors. Perhaps some of the VEGFR2 inhibitors are way more specific and hit less of the other targets. The higher dose of these agents may be relatively more acceptable to start with than other agents that are multikinase inhibitors hitting multiple targets with variable potency.

Transcript edited for clarity.