In the future we will have to think about the complexities of the cancer cell and its microenvironment. Targeting a cancer with very specific agents that home in on 1 target is not cutting it for most patients. The reason for this is that there are very few cancers where we know the specific driver, and there’s only 1 driver taking us into the path. Blocking 1 target may induce a response, but these responses tend to be fleeting and not necessarily durable. In that sense, it’s important to continue these considerations about monoclonal antibodies—inhibiting VEGF or others—and how to optimize their activities and combine them with multikinase inhibitors that work on the cells and the microenvironment. A number of multikinase inhibitors are being developed that appear to have more favorable pharmacokinetic profiles. They will likely have less hepatotoxicity, at least theoretically, based on their improved pharmacokinetic profile.

These will offer improved outcomes for patients and safer administration to patients, but they’ll be easier and safer to combine with a lot of the agents we have on hand, whether immune checkpoint inhibitors, VEGF inhibitors, or others. We’re learning quite a bit. Meanwhile, it’s very important to understand that with these multikinase inhibitors on hand, the risk of hepatotoxicity is there. It’s not overwhelming, but it’s there, and close monitoring is our best tool to prevent complications and the rare event of liver failure. Acting early, switching, reducing the dose, starting low and going slowly higher, as we do with regorafenib and others—these are mitigating factors to improve outcomes and ensure that our patients are able to navigate a very treacherous terrain with safety and optimize their outcomes. This means prolonging their survivals, improving their responses, and finding our way toward a cure, even in the more advanced settings.

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Tanios S. Bekaii-Saab, MD, describes the future direct of clinical research into immune check point inhibitors for solid tumors, which he believes will be to explore additional combinations with targeted therapies.

Future Directions: Optimizing Care Through Combinations

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.

Tanios S. Bekaii-Saab, MD, provides insight into ongoing research exploring novel combinations of tyrosine kinase inhibitors and immune checkpoint inhibitors across solid tumors.

Novel Investigational Combination Strategies

When does liver injury develop? It usually develops as early as 2 weeks, and possibly as late as 2 to 3 months, after initiating therapy. In these instances, features of hypersensitivity are typically absent. Essentially, you don’t see this as an allergic reaction or a hypersensitivity reaction, but direct cell injury. The incidence of these adverse events, if unmitigated—meaning stopping the drug or readjusting the dose—depending on what literature you look at, can progress to severe liver injury in 5% to 25% of patients. It’s more likely to be 5% or less because most of us keep a close eye on this hepatotoxicity. But this brings up the importance of raising the awareness of hepatotoxicity among health care professionals. Most practicing physicians and health care professionals understand this concept, but I want to make sure it’s also made clear that this has to be a constant point of raising awareness among colleagues. The good news is that most of the time, this is reversible if we do all the right things. But if we don’t, there’s the risk of not just permanent liver injury but even liver failure.

It’s key to keep a close eye on tyrosine kinase–induced hepatotoxicity within the first 2 to 3 months of initiating treatment. There are some rare instances where this toxicity can happen later rather than earlier. In terms of follow-up, the first 2 to 3 months should allow us very close follow-up. We already do that with a lot of these tyrosine kinase [inhibitors] because of the other toxicities, not just liver toxicity. With regorafenib, for example, given the hand-foot syndrome reaction and the fatigue, we tend to keep a close eye on patients in the first month, even on a weekly basis. We check labs every couple of weeks. You can slow it down to once a month, but I would continue to keep a close eye on the liver numbers. Patients should be closely and carefully monitored for tyrosine kinase inhibitor–induced hepatotoxicities more intensely at the beginning and then routinely after a couple of months. I’ll emphasize that the risk is manageable by dose adjustment or stopping the drug altogether. The good news is that oftentimes, the question that comes up is, “If you have liver toxicity or hepatotoxicity from 1 tyrosine kinase inhibitor, does that typically translate into the same level of toxicity with a different tyrosine kinase inhibitor?” The answer is no.

We don’t have those data. Oftentimes, if the liver function tests have improved, and if they’re indicated for that particular disease, it’s reasonable to switch to a suitable alternative tyrosine kinase inhibitor. Although this is a class effect, that doesn’t mean that if it happens with 1, it’s going to happen with all of them. In all these discussions, the risk-benefit ratio has to be assessed in a good discussion with the patient. It’s very important, primarily in the setting of palliation in the more advanced settings, to ensure that the concept of “Do no harm” precedes all else in terms of optimizing care for patients.

Liver injury can occur within 2 weeks of starting therapy with a tyrosine kinase inhibitor, although it can also be seen as late as 2 months, describes Tanios S. Bekaii-Saab, MD, making vigilance key for proper mitigation of this adverse event.

Vigilance Is Key in Mitigating TKI-Associated Hepatotoxicity 

The majority of these tyrosine kinase inhibitors that are approved and are available to us in clinic will induce some level of hepatic injury. Essentially, that’s where they get metabolized and ultimately cleansed out of the system. A lot of these agents end up causing some level of hepatocellular injury—liver cell injury. A lot of these multitargeted VEGF receptor tyrosine kinase inhibitors, like the ones we use in GI [gastrointestinal] oncology: regorafenib, cabozantinib, lenvatinib, sunitinib, sorafenib. There are quite a few. Several of those have been reported to cause hepatoxicity. Some are more significant than others. For example, in our practice, we use regorafenib and sunitinib. The concern was high enough that they ended up with a box-label warning by the FDA. That certainly raises the level of awareness that these agents can significantly increase the risk of hepatotoxicity and, in few cases, liver failure. The concern is not just reversible hepatotoxicity but also, if it becomes irreversible and severe, liver failure.

Thankfully, these are rare events. But when they happen—I’ve seen them happen on incredibly rare occasions, thankfully—they can be quite catastrophic. The best way to prevent those, although they’re not 100% preventable, is close monitoring. Once we see a level of rise that’s concerning, we should make sure to do the appropriate measures. We’ll talk about those in a bit. Hepatotoxicity also has been reported for other tyrosine kinase inhibitors that are in use in practice. All of them can induce it. On a very strict basis, few have box-label warnings thought to cause more severe hepatotoxicity. But all of them have that risk. As an example, if you look at gefitinib vs pazopanib, and you look at the frequency of liver injury, it can range from 11% for gefitinib to 50% with pazopanib. When we look at the risk of liver failure in patients receiving these agents, it could be between 0.5% and 1% of patients treated with regorafenib, cabozantinib, sorafenib, and sunitinib in our practices. The good news is that even in those most severe cases, fatalities are rare.

I want to go back to an understanding of what hepatotoxicity is. As I said, the most common reason for hepatotoxicity is that these agents cause direct cell injury. When you injure the cell, the 2 lab parameters that show up first as elevated would be AST and ALT, so SGOT and SGPT. We routinely measure those in patients who are being treated with these tyrosine kinase inhibitors. Bilirubin, alkaline phosphatase, and others, if they aren’t already elevated because of the risk of from the cancer, come later when there’s significant destruction of liver cells. Ultimately, liver injury can get worse, and then you can start seeing the other parameters show up. The 2 most important lab parameters that would give you the first hint are elevations of AST and ALT following treatment with these tyrosine kinase inhibitors. The cholestasis, which is measured by bilirubin, has been reported. But these do occur following elevation of AST and ALT, not proceeding it, more often than not. Is it possible that we see elevations in bilirubin before AST and ALT? Possibly, in some cases. Any elevation in liver function tests that would not be attributable to the cancer itself should raise a red flag. It’s important to keep an eye on this.

Tanios S. Bekaii-Saab, MD, describes the hepatotoxicity commonly seen with tyrosine kinase inhibitors (TKIs) and how to monitor and detect it with aspartate aminotransferase (AST) and alanine transaminase (ALT). 

Understanding and Detecting TKI-Specific Hepatotoxicity

In our world, we’re moving more toward these oral medications, these tyrosine kinase inhibitors, which have multiple targets. These targets can be different among the different agents. When we look at the agents available to us in solid tumors overall, not just in GI [gastrointestinal] cancers, you have multiple classes of agents; many share targets. Others are more specific to a target, although it can hit other targets as well. For example, oral EGFR inhibitors are more commonly used in lung cancer, but for a little while, we used erlotinib as 1 agent in pancreatic cancer. I can see significant rash, diarrhea, mucositis, and occasionally even pneumonitis. The most common agents we use in GI malignancies are those that target VEGF and those with a point of entry for HER2 [human epidermal growth factor receptor 2] tyrosine kinase inhibitors.

Across the board, when you look at all the tyrosine kinase inhibitors, they’ve all induced some level of fatigue. For example, those that hit VEGF have wound-healing complications but also hand-foot syndrome reactions. It’s interesting to see varying degrees of that. For example, let’s take HCC [hepatocellular carcinoma], where we use lenvatinib, sorafenib, regorafenib, and cabozantinib. You can see that regorafenib would have the highest risk of hand-foot syndrome reaction. Lenvatinib has a lower risk, but you see a higher risk of hypertension because the VEGF is targeted at a higher level. For HER2 disease, we just presented data with tucatinib, a HER2-specific tyrosine kinase inhibitor.

This is an interesting agent compared with a lot of the others like lapatinib, lorlatinib, and others. This 1 is very specific to HER2. There’s very little targeting of EGFR, so you don’t have the rash. Or if you have it, it’s very faint and not as problematic. You have less diarrhea. These agents, although they can share similar pathways, some of them are more dominant on 1 target than others. That can also affect the levels of toxicities with tucatinib. You can see some left ventricular dysfunction in very rare cases, although I can most see the transient drops in ejection fraction that normalize. Across the board, we see some level of hepatotoxicity across all these tyrosine kinase inhibitors.

Tanios S. Bekaii-Saab, MD, describes the common adverse events associated with each type of tyrosine kinase inhibitor (TKI), which are specific to the targets hit by that TKI and commonly include fatigue and hepatotoxicity.

Overview of Toxicity Associated With TKIs in Solid Tumors

 Dr El-Khoueiry, please present patient profile No. 2.

 Our second case is a 63-year-old woman who has chronic active hepatitis C infection. She was recently started on antiviral therapy and presented with elevated liver function tests. That triggered a CT scan of the abdomen, which showed multifocal infiltrative liver lesions in the right lobe. There was an enhancing as well, tumor thrombus in the right posterior portal vein. This is evidence of vascular invasion by the tumor and a separate bland thrombus at the splenic confluence and SMV [superior mesenteric vein] and a nodular surface of the liver consistent with cirrhosis.

The platelet count was low, consistent with portal hypertension at 68,000 per mm3. AFP [alpha-fetoprotein] was 5000 ng/mL, bilirubin 1.3 was mg/dL, albumin was 3.7 g/dL, AST [aspartate aminotransferase] was 76 U/L, ALT [alanine aminotransferase] was 112 IU/L, and hepatitis C RNAs were detectable at 1 million [units transferred]. The patient was diagnosed based on imaging criteria with hepatocellular carcinoma. The patient must have shown arterial phase enhancement on the scans with venous phase washout to meet the standard imaging criteria for diagnosis. The patient has Child-Pugh A disease and an excellent performance status: with ECOG 0.

 It’s a straightforward case. Pierre, how would you treat this patient?

 This patient has Child-Pugh A cirrhosis. She is a prototypical BCLC-C [Barcelona Clinic Liver Cancer stage C] patient, with a tumor invading a large blood vessel. She doesn’t appear to have any significant contraindications to the combination of atezolizumab and bevacizumab, so based on the evidence, that would be our go-to first-line model.

 What would make you reluctant to consider atezolizumab-bevacizumab in such a patient?

 There’s a concern when combining these agents for risk of bleeding, primarily related to portal hypertension. One would be well advised to assess portal hypertension risk in this Child-Pugh A patient. We can do this to some extent noninvasively, although the broader hepatology and medical oncology community has relied on endoscopy to assess for the presence of esophageal or gastric varices. The fact that cross-sectional imaging doesn’t show splenomegaly, abdominal varices, or esophageal varices is reassuring.

Depending on where the tumor is located, a FibroScan may or may not be a good test because if you have a tumor, this could alter the stiffness of the liver and give you erroneous information. That’s a possibility. There are other tests for assessment of fibrosis we could do, but nothing points to limitations in our ability to initiate atezolizumab-bevacizumab. There’s no uncontrolled hypertension, and there doesn’t appear to be any underlying autoimmune disease that would be adversely affected by that combo.

 That’s your choice. Mark, what are the data telling us about atezolizumab-bevacizumab, with IMbrave150?

 This is the preferred first-line systemic regimen for anybody who’s eligible for it. It was studied in the randomized study of IMbrave150 vs sorafenib, and this was a positive study regarding every end point that we care most about: OS [overall survival], PFS [progression-free survival], ORR [overall response rate], and quality of life. You need a reason not to use it in first line. Pierre listed several of them, and in this case it’s the appropriate choice.

Centering discussion on a patient with advanced-stage HCC, expert panelists discuss the frontline use of atezolizumab + bevacizumab as a standard of care.

Patient Profile 2: Frontline Therapy for Advanced HCC

Tanios S. Bekaii-Saab, MD, FACP, medical oncologist, medical director, Cancer Clinical Research Office, vice chair and section chief, Medical Oncology, Department of Internal Medicine, Mayo Clinic, discusses the safety profile of the combination of tucatinib and trastuzumab (Herceptin) in patients with 

-amplified metastatic colorectal cancer (mCRC). 

According to results of the phase II MOUNTAINEER trial, the combination appeared to be very well tolerated in this patient population, says Bekaii-Saab. Tucatinib has a relatively low rate of off-target toxicities apart from fatigue and diarrhea, which are manageable. 

Initial results from the trial showed that the median duration of response was not reached. Moreover, patients who responded to treatment have tolerated it very well and have, for the most part, been able to return to their daily lives, says Bekaii-Saab. The trial is expected to have a large impact on the field and increase access to HER2-targeted therapy in mCRC.

Tanios S. Bekaii-Saab, MD, discusses the safety profile of the combination of tucatinib and trastuzumab in patients with HER2-amplified metastatic colorectal cancer. 
 

Tanios S. Bekaii-Saab, MD

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