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When considering which frontline option to administer to a patient with renal cell carcinoma, it is important to first understand which risk group they belong to.
When considering which frontline option to administer to a patient with renal cell carcinoma (RCC), it is important to first understand which risk group they belong to, according to Thomas E. Hutson, DO, PharmD, FACP. Upon progression, the question of whether to continue the current therapy or switch to a second-line treatment is raised. Irrespective of the decision made, it is important to ensure that patients are educated on what to expect through all the steps of their treatment journey.
“One of the things that I try to do when I am starting therapy is to set the expectations of the goals of the treatment, and then to give some insight into what I expect the adverse effects [AEs] could be so that patients are not shocked when something develops,” Hutson explained. “The most important thing we found when we use the oral TKIs is that patient education early on really matters, because we want the patient to be able to report AEs to us before the AE presents as a crisis.”
In an interview with OncLive® during a 2021 Institutional Perspectives in Cancer webinar on bladder cancer/RCC, Hutson, the director of the Urologic Oncology Program and co-chair of the Urologic Cancer Research and Treatment Center at Baylor University Medical Center in Dallas, and a professor of medicine at Texas A&M College of Medicine, provided details on a recent RCC case, walked through frontline and second-line treatment decisions, and underscored the importance of patient education throughout the process.
The first case I shared was of a 70-year-old male, who, in May 2018, underwent a left radical nephrectomy for clear cell RCC. He had a history of hypertension, hypercholesterolemia, and rheumatoid arthritis that has been well controlled, and he is off all disease-modifying and anti-rheumatologic drugs. He had a stage IIIA, grade 2 tumor, and he was, as most people are in this setting, followed with serial imaging studies as he is at high risk of recurrence. In the United States, there is an alternative to active surveillance, and that would be 1 year of sunitinib [Sutent]; this was offered to this patient but he did not want it. Unfortunately, in April 2020, on routine CT scans and surveillance, he was found to have pulmonary metastases.
Laboratory studies revealed an elevated lactate dehydrogenase and corrected calcium, and that placed him in that intermediate-risk group, regardless of whether the Memorial Sloan Kettering Cancer Center criteria or the International Metastatic RCC Database Consortium criteria were used. Now, some people do the eyeball check and try to determine whether a patient is in that favorable-, intermediate-, or poor-risk group. Some of us have electronic medical records that mandate us to do this because we must check boxes; that is my particular case. The patient looked healthy, but given the fact that he had these features, he would fall within that intermediate- and poor-risk group.
If we go to our National Comprehensive Cancer Network [NCCN] guidelines, we see that our therapies are broken down based upon what type of risk the patient has, either favorable risk or the poor and intermediate risk, and there are some limitations on therapy.
For instance, if [a patient is] in the poor- or intermediate-risk group, then [we would choose] among nivolumab [Opdivo]/ipilimumab [Yervoy] or cabozantinib [Cabometyx]. Axitinib [Inlyta]/pembrolizumab [Keytruda] is also on that list, and then cabozantinib/nivolumab also has a label that would allow its use in that setting. In the favorable-risk group, you would have single-agent oral drugs, so the VEGF inhibitors like sunitinib, and you would have the combination of immunotherapies plus TKIs like axitinib/pembrolizumab, axitinib/avelumab [Bavencio], and now, cabozantinib/nivolumab. Other options [are available], but these are the preferred ones.
After discussing with the patient, we had a mutual agreement to go with an immunotherapy/TKI [combination] and we chose axitinib/pembrolizumab. He started [axitinib at] 5 mg twice daily, and his infusion of pembrolizumab was every 3 weeks. At the end of his first month of therapy, he reported mild fatigue and was starting to develop hand–foot syndrome at the grade 2/3 level, as well as diarrhea. We instructed him to optimize antidiarrheal usage with loperamide [Imodium], as I find that many patients are shy in using that, and they can use it much more frequently than they tend to. We also discussed giving treatment breaks with axitinib since it has a short half-life; this is a therapy with which you can get improvements in symptoms by just taking a 1 or 2 dose break. The half-life of the drug is measured in just 3 to 5 hours, and the median time to resolution of AEs from the original axitinib trials was 2.3 days. So, he continued on with that type of supportive care, received treatment for 6 months, had a 70% reduction in measurable tumor with necrosis of even the larger lesions, and actually had disappearance of some of the small lung nodules.
Unfortunately, at 12 months on therapy, he ended up having progression. CT scans at that time showed a large heterogenous hepatic mass, as well as some smaller enhancing liver metastases, so there was clear evidence of progression. In that setting, most [of us] would want to consider changing therapy. Certainly, he was along that line at the time of his progression event and his performance status was still excellent. He did have an anemia of 11 g/dL, but other lab studies were within normal limits. At that time of progression, he had been tolerating his axitinib/pembrolizumab well, with only grade 1/2 hand–foot syndrome, fatigue, diarrhea, and hypertension that was treated with antihypertensives.
We have a series of different therapies that we can choose from. However, one [question to ask] is, do you continue the current therapy despite the progression? I mentioned this patient had significant progression, with lesions in new organs. In that setting, I do not feel comfortable doing that, but if I had someone who had met the definition of progression, but the progression was growth in existing lesions, and the patient was tolerating therapy well, then I could entertain continuing on the same therapy a little bit longer. Alternatives would be changing to second-line therapy.
If we go to the NCCN guidelines, we see the preferred regimens in the setting would be changing to cabozantinib as a category 1 option, as well as single-agent nivolumab and nivolumab/ipilimumab as category 1 recommendations. Some phase 2 studies recently presented [examined] continued immunotherapy in the second-line setting. For instance, data for lenvatinib [Lenvima]/pembrolizumab from the phase 3 CLEAR study [NCT02811861] were recently presented. The drugs are not yet approved [for use] in combination, but a phase 2 trial suggests benefit after prior immunotherapy. Additionally, nivolumab/ipilimumab has also phase 2 data showing benefit. Most of us are unclear as to whether there is a real role for continued immunotherapy, so it would not necessarily be considered to be standard of care to do that. Based upon their preferred regimens and knowing that he has already had immunotherapy, I would recommend cabozantinib in this setting; and so, this patient went on cabozantinib.
The patient already had initial therapy, so he has experienced hand–foot syndrome, fatigue, and diarrhea. I would tell him to expect those [toxicities again], and I would also share with him that we start cabozantinib at the full dose, but in the clinical trials [that examined] it, we found that approximately half of patients do require a dose reduction at some point in the treatment [journey], so he should potentially expect that. Then, if he does experience an AE that is really starting to negatively impact his quality of life, he needs to let me know about that and we will consider a lower dose. We find that in giving a lower dose, patients are able to stay on therapy with cabozantinib for a long time and achieve the maximum benefit from treatment. The actual treatment discontinuation rate is quite low, generally 10% or less, as long as we allow those reductions.