Pharmacy director Kirollos Hanna, PharmD, BCPS, BCOP, FACC, discusses how to navigate shared toxicities between combination immunotherapy and VEGF inhibitors for patients with renal cell carcinoma.
When considering treatment with combination immunotherapy and VEGF inhibition for renal cell carcinoma (RCC), consideration for adverse effects (AEs), especially shared AEs, is important and needs to be navigated with care, according to Kirollos Hanna, PharmD, BCPS, BCOP, FACC.
In conjunction with Kidney Cancer Awareness Month, CancerNetwork® spoke with Hanna, director of Pharmacy at Minnesota Oncology and assistant professor of Pharmacy at the Mayo Clinic School of Medicine, to discuss challenges related to care in the RCC space, from financial toxicities to adverse effects to patients frailty impacting clinical trial enrollment.
When we look at kidney cancer or RCC, the past several years have brought to light a lot of exciting treatment modalities and opportunities for our patients. Several years back where we were utilizing even just monotherapy VEGF inhibition, the outcomes for patients who had advanced or metastatic disease and those with a poor prognosis were suboptimal.
What we have learned over time is that the combination with VEGF inhibition, immunotherapy, or even the combination of certain immunotherapies like ipilimumab [Yervoy]/nivolumab [Opdivo], have expanded upon the treatment options for patients with RCC, as well as expanding upon the various therapeutic sequencing strategies that we have for this disease state.
That has posed [many] challenges to some extent, as well. Obviously, the cost of care for RCC has increased over time with these specific modalities. We also have barriers and some logistics around which therapeutic options should be utilized up front. How do we sequence the optimal set of therapeutics to try and expand upon the efficacy for patients? We also have some barriers around the tolerability of some of these agents, as well.
Based on that, it’s a very exciting time, but a lot of work and clinical trials are ongoing to expand upon this specific disease state. We’re even starting to see therapeutics in the adjuvant setting for patients with stage III disease. Immunotherapy in the adjuvant setting is one of the most recent things that we have started to see.
The common [AEs] with immunotherapy you can expect is any type of inflammatory process that can manifest. Generally, it’s very well tolerated. You may see some endocrinopathies, AST/ALT [aspartate aminotransferase/alanine aminotransferase] changes, some skin toxicities or GI [gastrointestinal] toxicities, but for the most part, the immunotherapeutic options are well tolerated.
There are areas in RCC, where we do have [combination treatments] like ipilimumab plus nivolumab [Opdivo]. When you look at the safety profile of a pembrolizumab [Keytruda]–based regimen in RCC, such as pembrolizumab with axitinib [Inlyta] vs something like an ipilimumab plus nivolumab–based regimen because of the CTLA-4 mechanism on top of the PD-1 mechanism, we sometimes do see higher rates of immune-mediated AEs when you have that combination IO [immunotherapy]/IO therapy.
With VEGF inhibition, that’s a completely different set of [AEs], although there are some AEs that are shared between the 2 therapeutic classes. When you look at VEGF inhibition, we see things like hypertension and protein urea. Some of these patients may have GI AEs. Some of them may have hematologic AEs, but as I mentioned, the shared AE profile with immunotherapy sometimes does make it challenging when we are combining these therapeutics.
Cabozantinib plus nivolumab, pembrolizumab plus axitinib, and avelumab [Bavencio] plus axitinib is a potential other combination. All these are combinations of VEGF with immunotherapy. Some of those AEs that are shared are endocrinopathies. Both therapeutic classes can lead to hypothyroidism or various types of endocrinopathies.
How you address that is generally the same. You’re going to put patients on some type of hormone replacement, but then we start to see things like AST/ALT elevation. It’s very hard to know [whether] it is due to the VEGF inhibitor or if it is primarily due to the immunotherapy? Our approach there is going to be a little bit different. If it's an immunotherapy-related transaminase elevation, it may require steroids, whereas with the VEGF inhibitors, the steroids are not going to do too much—things like skin toxicities or diarrhea. If you have a patient who has diarrhea, it could be induced due to VEGF, or it could be induced resulting from maybe colitis that occurred with the immunotherapy.
Although some supportive care may help manage that diarrhea, your immune-mediated version of diarrhea may require steroids to suppress T-cell activity. We have to understand the half-life and the mechanisms of these different therapeutics when you are trying to intervene around an AE, especially those AEs that are shared.
[If a patient does] have diarrhea, look at the immunotherapies that are dosed every 3 weeks, every 4 weeks, every 6 weeks. There’s not much that you’re going to do from the immunotherapy perspective if you’re trying to assess whether it due to the VEGF or the immunotherapy. The VEGF inhibitors generally have a short half-life; the majority of our VEGF inhibitors are dosed once a day or twice a day. You can sometimes intervene by simply holding the VEGF inhibitor for just a few days and seeing if that AE has improved. If it hasn’t, that could steer you to think this could be immune-related because those immune-mediated AEs are going to linger for a long time unless we suppress that T-cell activity.
Things like hypertension—that is a VEGF-specific toxicity— speak to the need for either pharmacists, nurses, or someone to be involved in an oral chemotherapy program where they all are calling patients to assess what their blood pressure looks like. I have seen patients who may start on therapy and their blood pressure shoots up within a week or 2 of starting VEGF inhibitors. In other patients, hypertension is never a problem and they do just fine. Early assessments are important to just ensure we are controlling hypertension if it does occur and we address it, whether it’s through optimization of their current antihypertensives or it’s initiating new antihypertensives. For the most part, the majority of the therapeutic combinations do tend to be well tolerated.
We don’t run into too many barriers within the RCC space as anything else within [other disease types]. RCC doesn’t stand out over everything else. Financial toxicity is always a topic of interest in the grand scheme of things. The VEGF inhibitors are branded products; we have those go through pharmacy benefits, so patients will oftentimes have copays and we have to ensure we’ve gotten all that coverage for them. On the infusion side, the immunotherapies are going through medical benefits.
Sometimes coordination tends to be a barrier. There is the medical side that is getting squared away for the infusion therapies. On the pharmacy side, there’s always a conversation about whether the oral VEGF inhibitor can be dispensed from my institution because I have a specialty pharmacy, or do I not have a specialty pharmacy or am I restricted or mandated by a payer for that to go outside of my institution, which sets operational barriers; [this includes] how long it takes to get to the patient or if there are dose adjustments that are required, it becomes a little bit fragmented.
Sometimes we may square away everything and get that infusion all teed up and ready to go, but then we don’t know yet where the oral [agent] is sitting. In RCC, some of the mechanisms shared with VEGF inhibition as well as immunotherapy are synergistic. That’s a disease state where we try our best to start both therapeutics within a close timeframe of one another. It could be one of the barriers that we observe in RCC.
For most of our patients, access to care is readily available in terms of transportation and [other factors]. One thing that we do see in RCC, though, is that the patient population in general tends to be a little bit sicker than your average patient. An area in RCC that also poses a barrier is that beyond first-line treatment, and second-line treatment, even though we have third-line options and clinical studies, the patients end up just simply being too frail. They’ve had too many toxicities or AEs potentially from the therapies that they end up transitioning to maybe palliative care or a hospice type of modality at that point in time. Enrollment on clinical trial with therapies that are better tolerated could help address some of these barriers and challenges.
One big area that’s a barrier or a challenge within RCC, if you look at the IMDC [International Metastatic RCC Database Consortium] criteria, the survival trends for someone with favorable-risk disease vs someone with poor-risk disease is significantly different. You have maybe 4 of 5 people with favorable-risk disease alive at about 5 years. Whereas poor-risk disease, you have 1 of 10 people generally alive at 1 year or 2 years. That prognosis is significant. We need to improve upon those people with poor-risk disease or even intermediate-risk disease in terms of therapeutic options because we still have not made a significant improvement in the trend for outcomes for those patients.
As I highlighted, there are a lot of novel therapeutic targets that are being looked at within the RCC space with a lot of varying combinations. Some of the combinations are being looked at in clinical trials right now, are combining VEGF inhibition with maybe dual [immunotherapy] IO/IO; this is something like an ipilimumab/nivolumab combination with a VEGF inhibitor. It is going to be exciting to see what comes of all of that. Cost containment is going to be something that we will need to focus more and more on as we start to see different combinations come to light. I do think that even if we start to find combinations of things like a triplet regimen, we do have to be cognizant of how that is going to impact subsequent line treatments because you’re going to [run] through therapeutics that would potentially be sequenced, but instead they would ultimately be combined based on the efficacy data.
Another exciting thing is the role of adjuvant therapy for RCC. We do need to make an improvement in that area. There are some studies focusing on this to try and see if we can minimize or delay the progression of disease into that metastatic setting. You have to keep in mind that up until stage III kidney cancer, you could technically excise these tumors and patients could have a long healthy life cancer-free. But it’s what’s needed to maintain that because, still, a good portion of those patients are progressing. One exciting therapeutic approach is pembrolizumab in the adjuvant setting. The data are better than just watching these patients, but we certainly need to make more strides on that but is an exciting pipeline in the disease.