Novel Investigational Combination Strategies

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

EP: 4.Reducing Adverse Events Through Dose Optimization

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EP: 5.Novel Investigational Combination Strategies

EP: 6.Future Directions: Optimizing Care Through Combinations

Transcript:

Tanios S. Bekaii-Saab, MD: What we’re seeing more of is taking these tyrosine kinase inhibitors [TKIs] and combining them with agents such as PD-1 inhibitors or other targeted agents. For example, in colon cancer, we presented some data at ESMO [European Society for Medical Oncology Congress] with tucatinib and trastuzumab, based on the fact that with tucatinib alone and trastuzumab alone, if given singly in colorectal cancer with HER2 [human epidermal growth factor receptor 2]–positive disease, you get less than 10% response rates. When you put them together, our response rate went up to about 40% with durable responses. Many times, we’re finding ourselves in situations where we have to combine the 2. Combining the 2 agents means you also combine some of the toxicities, or you’re bringing the toxicities to each of the other elements. It’s the same with a lot of these agents and I/O [immuno-oncology]: a lot of these multikinase inhibitors and VEGF inhibitors have been combined with immune checkpoint inhibitors with interesting results, although it’s a mixed bag.

For some, we’re seeing some good results. With others, we’re not, but the toxicities have been prominent in a lot of these I/O–TKI combinations. That hasn’t stopped the development of these combinations in GI [gastrointestinal] malignancies, but we see in renal cell cancer and other malignancies that these combinations have become dominant in the treatment of patients. It’s my understanding that it’s the same with some gynecology cancers.

The tyrosine kinase inhibitor is going to hit the target intracellularly, and then the antibody hits the target extracellularly, so you’re hitting the 2: the extracellular and intracellular domains. We’re shutting down, with more complexity, the specific pathways. Predominantly, with VEGF inhibitors, TKIs, and I/O, you’re mostly working on the microenvironment and enhancing the immune response, which is thought to enhance the activity of these immune agents. That comes with some additional toxicities, but this is where we weigh the risk-benefit ratio as we move forward with some of these.

There are instances where we have to think about patients who may be more eligible for TKIs vs the monoclonal antibodies. The perfect example is HCC [hepatocellular carcinoma]. For the longest time, we had tyrosine kinase inhibitors as the standard of care in the first line. Then we had some immune checkpoint inhibitor studies that were extremely disappointing vs these tyrosine kinase inhibitors. Ultimately, a combination of an I/O agent, atezolizumab, which is a PD-L1 inhibitor, and bevacizumab, which is a VEGF ligand inhibitor, showed superiority to a tyrosine kinase inhibitor.

In these instances, how do we select patients who may be eligible for a tyrosine kinase inhibitor vs an antibody? It relies on a lot of things. One is the performance status of the patient—in this instance, the Child-Pugh score. Also, if the patient had a transplant and they’re not eligible for immune checkpoint inhibitors, they would be better off with a tyrosine kinase inhibitor such as lenvatinib or sorafenib. If the patient has severe autoimmune disease, they’re not eligible for immune checkpoint inhibitors. Those are the patients for whom lenvatinib or sorafenib would make sense. We have other antibodies, dual checkpoint inhibitors—tremelimumab and durvalumab—which also appear to have some promise.

One thing that was interesting in HCC is that, like our experience with other malignancies, combining lenvatinib with pembrolizumab did not improve outcome vs lenvatinib. In this instance, if the interest is to consider lenvatinib, that study has suggested that lenvatinib remains a very potent, important asset against HCC. But adding I/O to that agent did not seem to improve outcomes vs the agent alone. In my practice, the way I think about combination antibody therapy vs TKIs is for most patients, atezolizumab-bevacizumab is considered the standard of care. For very few patients, it could be durvalumab plus or minus tremelimumab. We are very heavy on transplant at the Mayo Clinic. For some patients who recur in the setting of transplant, lenvatinib has become our standard. Even for some patients who need a bridge to transplant, we’ve adopted more lenvatinib as a bridge to transplant. In this setting, we’re juggling a lot of these agents—TKIs, antibodies—and selecting patients depending on the setting. That also applies to a lot of the other diseases we treat.

Transcript edited for clarity.