Michael B. Atkins, MD, recently shared treatment considerations he would make when treating patients with metastatic renal cell carcinoma (RCC), based on 2 case scenarios.
Michael B. Atkins, MD
Michael B. Atkins, MD
Michael B. Atkins, MD, recently shared treatment considerations he would make when treating patients with metastatic renal cell carcinoma (RCC), based on 2 case scenarios. Atkins, deputy director, Georgetown-Lombardi Comprehensive Cancer Center, and professor of oncology and medicine, Georgetown University School of Medicine, discussed these cases during aTargeted Oncologylive case-based peer perspectives dinner.
In the first case, a 48-year-old Caucasian man presented to his physician complaining of right upper quadrant discomfort and back pain. A CT scan of the abdomen and pelvis showed a large right renal mass with retroperitoneal adenopathy, with the largest node measuring 2.5 cm on the right axis. A metastatic lytic lesion to T8 was also found. The patient underwent cytoreductive nephrectomy and a retroperitoneal node biopsy. He was diagnosed with stage IV renal cell carcinoma with clear-cell histology, and metastases to the bone and contralateral adrenal gland.
After radiation therapy to T8, he was started on pazopanib (Votrient) at 800 mg. The first follow-up scan showed a decrease in the size of the adrenal lymph node. The patient reported moderate diarrhea and mild fatigue, which was controlled with antidiarrheal medication and rest. He continues to do well with improved tolerance after a dose adjustment to 600 mg.
The patient complained of increasing back pain and pain in multiple other bony sites. He reports nausea and rapid weight loss during the last 3 weeks. Imaging showed slow but steady progression in the adrenal lesion and new bone lesions in the thoracic lumbar spine. Pazopanib was discontinued and the patient was started on cabozantinib (Cabometyx) at 60 mg.
TARGETED ONCOLOGY:How do you define progression in patients with mRCC?
I define progression as either a growth in target lesionsbased
on RECIST criterianew lesions developing, or symptomatic progression in metastatic disease. In this case, it sounds like there is at least symptomatic progression of metastatic disease and, based on the description, probably the new bone metastases, and likely, growth of the adrenal gland that was significant. So, this is clinical and radiographic progression.
TARGETED ONCOLOGY:What factors would weigh into the decision to switch therapy versus treating beyond progression?
It used to be that the only treatments we had available for patients with metastatic kidney cancer were high-dose interleukin-2, which had a defined treatment schedule of two 5-day courses separated by a week. We would continue treatment if there was clear evidence of tumor shrinkage at 12-week intervals, or [give] a VEGF receptor tyrosine kinase inhibitor [TKI]. With the VEGF receptor TKIs, because we didn't have something good to give afterwards, we would sometimes continue treatment even after radiographic progression in the absence of symptomatic progression.
In the past 1.5 years, we've had 3 new FDA-approved second-line treatment approaches that appear to be at least as good as, if not better, than the frontline treatment of sunitinib [Sutent] and pazopanib, for patients with metastatic kidney cancer who have progressed on a VEGF inhibitor. Therefore, we have a lower threshold for defining when we should switch to those therapies.
TARGETED ONCOLOGY:Which patients do you consider treating beyond progression?
The only patients I would potentially consider treating beyond progression nowadays would be patients who are receiving checkpoint inhibitor immune therapy in the frontline, where we know that disease can sometimes get worse before it gets better. In an asymptomatic patient with radiographic progression, we usually would continue treatment for another 6 weeks, get another scan, and confirm that this is true progression, rather than just pseudoprogression, before stopping and changing to a different therapy. For patients who are on sunitinib, or, like this patient, on pazopanib, if there is evidence of radiographic progression, that is usually real progression. Even in the absence of symptomatic progression, we would switch to a different second-line therapy.
TARGETED ONCOLOGY:What are the choices for second-line therapy in this patient?
The choices for second-line therapy in this patient include nivolumab [Opdivo], cabozantinib, axitinib [Inlyta], and lenvatinib [Lenvima] plus everolimus [Afinitor]. We no longer consider everolimus a viable treatment option in the second-line setting, because randomized trials have shown that nivolumab, cabozantinib, and lenvatinib/everolimus are superior to everolimus monotherapy.
Axitinib is potentially still an option for patients, as it's the most selective of the VEGF inhibitors. Someone who is otherwise asymptomatic, who has had progression on sunitinib, or had [tolerability issues] and had to reduce or stop the treatment and that led to disease progression, might be someone where you would choose the least toxic of the VEGF receptor inhibitor approaches, which is axitinib. But more and more, we're choosing between cabozantinib and nivolumab, because those are the 2 second-line agents that have the best efficacy profile that has been confirmed by phase III trials.
For the majority of patients, I would choose nivolumab as the second-line treatment, because it uses a different mechanism of activity than sunitinib or pazopanib, being a checkpoint inhibitor rather than a VEGF inhibitor, and because it offers the potential for durable response and even potentially stopping therapy, and therefore treatment-free survival. You can often tell early whether or not the treatment is working.
Treatment with a checkpoint inhibitor does not appear to negatively impact subsequent treatment with another VEGF pathway inhibitor. However, in this patient, because there is symptomatic bony progression, and since principle activity of cabozantinib [has been shown] in patients who have bone metastases, compared with everolimus and also compared with sunitinib, this might be one of the few cases where I would consider switching to cabozantinib as the next treatment approach.
TARGETED ONCOLOGY:Which factors influence your decision-making for second-line therapy?
The type of factors that might influence my decision would be response or tolerance to upfront VEGF TKI therapy. In someone who is responding well to frontline VEGF receptor TKI therapy but can't tolerate it, I might consider switching them to axitinib, which is a better tolerated and more selective VEGF inhibitor.
The aggressiveness of the recurrence and the symptoms and tempo of the disease progression might also factor in. Although, I think if someone had symptomatic bony disease, I would lean more toward cabozantinib. But if there's time to see whether the patient can respond to a checkpoint inhibitor, I would lean towards nivolumab.
Disease burden and sites and number of metastases don’t matter, except for the potential issue of bone metastases, which leads one to favor cabozantinib in those patients. The toxicity of TKIs vs immunotherapies certainly plays in because, in general, immunotherapies are going to be less toxic than VEGF receptor TKIs, with most patients having very little side effects.
In patients with a history of autoimmune conditions, such as colitis or inflammatory arthritis, the toxicity may not be worth it. The checkpoint inhibitor might make those toxicities worse. Or, in patients who are on immunosuppressive drugs, these may interfere with the efficacy of the checkpoint inhibitor, and those drugs can't be weaned because they are necessary for controlling symptoms.
TARGETED ONCOLOGY:What is the rationale for choosing cabozantinib in this patient?
My principal reason for choosing cabozantinib in this patient is based on data from the METEOR trial, which showed that cabozantinib produced tumor responses in about 20% of patients, had a significant prolongation in median progression-free survival [PFS] compared to everolimus, and produced a survival advantage compared to everolimus.1When one looks at the forest plot, the group of patients that achieved the most benefit relative to everolimus were patients who had more aggressive disease. Particularly due to the symptomatic bone metastases, I would lean towards cabozantinib in this particular patient.
I don't think the choice between IV and oral is a major consideration. The root of administration doesn't seem to play a role in this decision.
My choice in general is to go toward a checkpoint inhibitor and that would certainly be the case if a patient were frailer and I was worried about their potential ability to tolerate the side effects of cabozantinib.
Finally, if the patient’s [disease had been] controlled with radiation and was just progressing in the adrenal glands, lungs, or lymph nodes, that would be a situation where I would lean toward nivolumab in the second-line setting rather than cabozantinib.
TARGETED ONCOLOGY:Can you discuss toxicity management for cabozantinib?
As with many VEGF inhibitors, it does cause hypertension, mucositis, hand-foot syndrome, and gastrointestinal toxicities, particularly diarrhea. When I start someone on cabozantinib, if I'm starting them on the full dose of 60 mg, I plan to see them in 2 weeks’ time to see how they're tolerating it, check their labs, and make sure there aren't any liver function test abnormalities. I want to make sure before I let them go a long time without a clinic visit that I get a sense of how they're going to tolerate it.
If a patient is having problems already at the 2-week visit with tolerating the medicine, I use it as a reason to reduce the dose to 40 mg. I do instruct patients before they start taking cabozantinib that they should have comfortable fitting shoes and avoid repetitive motions with their hands for the first couple of weeks, and avoid agents that might have concomitant liver toxicities, such as alcohol. I also encourage them to not eat spicy foods to minimize the risk of trauma to the mouth that may have trouble healing while on a VEGF inhibitor.
TARGETED ONCOLOGY:How will the first-line cabozantinib data from the CABOSUN trial impact sequencing in patients with mRCC?
I think the CABOSUN trial, which compared cabozantinib to sunitinib in treatment-naive patients, was interesting in that it showed an improvement in median PFS for the patients getting cabozantinib, compared to sunitinib, and that was particularly true in patients with aggressive disease and in patients with bone metastases.2In many patients, particularly those with the most aggressive disease or bone metastases, one might, in the future, consider cabozantinib as opposed to sunitinib or pazopanib as frontline therapy. But at the moment, the drug is not approved in that setting, and I think our general practice is to either put someone on sunitinib or pazopanib with a low threshold for stopping and switching to an alternative agent, or on a frontline protocol that might involve a checkpoint inhibitor.
In the second case, a 70-year-old female presented to her physician with symptoms of nausea, fatigue, and weight loss. An abdominal CT scan showed a 9-cm left renal tumor and a small solitary spot on the liver. She was referred to urology and underwent left radical nephrectomy with removal of the liver lesion. Post-surgical imaging showed multiple liver lesions. She was then referred to medical oncology and was started on sunitinib 50 mg daily on a 4/2 schedule. Stable disease was achieved after 6 weeks. Moderate fatigue, diarrhea, and increasing severity of hand-foot syndrome were managed with treatment interruption and then dose reduction to 37.5 mg daily.
Four months later, the patient reported increasing fatigue, nausea, and weight loss. An abdominal CT showed progression of her liver metastasis. She was then switched from sunitinib to nivolumab 3 mg/kg every 2 weeks. The patient reported that her symptoms had improved. Imaging at 8 weeks showed a response in the liver. She was maintained on nivolumab without any toxicity.
Eleven months later, the patient complained of fatigue, abdominal discomfort, and weight loss; she subsequently developed back pain. A CT scan of the abdomen and chest showed new liver lesions and progression of previously identified lesions. MRI of the spine showed multiple metastatic lesions of the thoracic and lumbar vertebrae, with no evidence of cord compression. She sought a second opinion at an academic center.
The patient was subsequently switched to cabozantinib at a dose of 60 mg. Her symptoms subsided within 4 weeks. CT and MRI imaging at 8 weeks showed response with improvement of both liver and spine metastases. She was maintained on cabozantinib for approximately 4 months and developed diarrhea and hand-foot skin reaction. Her dose was reduced to 40 mg daily which was maintained for 13 months until she developed disease progression. At that time, the patient was being considered for enrollment into a clinical trial.
TARGETED ONCOLOGY:How do you define progression in a patient receiving immunotherapy?
I would use the RECIST criteria as an initial definition of progression, and I do not usually do repeat scans of patients on nivolumab until 12 weeks into treatment to minimize confusion when you could potentially see disease growth or new lesions develop before you see a response. In patients who are on immune therapy and are tolerating it well and their scans show either a new lesion or a growth of existing lesions, we would often continue them on therapy for another 6 weeks and then have a confirmatory scan to determine whether that progression was real or pseudoprogression. About 90% of the time, that next scan will show continued progression, but occasionally you'll see some of the new lesions beginning to shrink.
In that case, one would potentially be able to continue patients on nivolumab and some of those patients have done very well. In patients with confirmed progression, they're not going to respond to continued nivolumab, and at that point, I’d stop the treatment and consider alternative approaches. I don't think there's a risk of waiting to change therapy in a patient who is asymptomatic but has evidence of disease progression to confirm that progression. However, in patients with symptomatic progression, that is almost certainly real progression and I would not delay in switching to a different therapy.
TARGETED ONCOLOGY:What are the available choices for third-line treatment for this patient?
This patient received sunitinib upfront, nivolumab in the second line, and available third-line options would include axitinib, cabozantinib, everolimus, or levatinib/everolimus, and of those 3 options, the one that has shown the most solid efficacy beyond the second-line, based on a phase III trial, is cabozantinib, and so I would choose that in this case.
TARGETED ONCOLOGY:How do the following factors affect your decision when switching from immunotherapy to a third-line agent: age, performance status, aggressiveness of relapse, and sites and number of metastases?
I'm going to choose cabozantinib as the third-line treatment in a patient like this. It’s the agent with the best track record in patients with advanced kidney cancer, based on the phase III METEOR trial.1But if a patient is older, frailer, or didn't tolerate their first-line sunitinib, then I might consider starting the cabozantinib at 40 mg rather than 60 mg.
TARGETED ONCOLOGY:How well does cabozantinib work in a patient who received nivolumab as a second-line therapy?
We don't have a lot of data on that because in the METEOR trial, very few patients had received checkpoint inhibitors previously.1But there's no reason to think cabozantinib is not going to be as effective after nivolumab as it would have been after sunitinib. In some ways, having a break from VEGF inhibition allows the tumor to reset and become dependent on VEGF again, and so maybe that treatment break enables the efficacy to be restored.
The one thing one has to watch for, though, is that nivolumab has a very long effect on the body's immune system. It's possible that having nivolumab still in the body or the immune system still being active when you start cabozantinib might predispose patients to enhanced cabozantinib toxicity. If you see side effects that could be enhanced cabozantinib toxicity in a treatment that was started soon after someone stopped nivolumab, one might consider treating that with steroids to decrease the immune enhancement of the toxicity, rather than lowering the dose.
In general, if someone has good organ function and can tolerate sunitinib reasonably well, I would start out with cabozantinib at 60 mg and watch the patient carefully. However, in older patients or someone who had side effects from sunitinib, I might start with a reduced dose of 40 mg. I think it's a judgement call. She did have some trouble tolerating sunitinib and had to have her dose reduced and she is somewhat on the older side. I think this would be a discussion with the patient as to which dose to start with. One would particularly be careful to watch this patient have a low threshold for holding the dose and restarting at a lower dose if the patient developed toxicities.
TARGETED ONCOLOGY:What are practical suggestions for getting in the maximum number of lines of therapy for each patient?
My overall approach to treating patients with kidney cancer, and for that matter, other cancers, is to try to treat it as a potentially curative disease. My goal is to get immunotherapy into a patient as soon as possible. If we're dealing with palliative treatments that are non-curative, such as the VEGF receptor TKIs, my approach is to delay starting those treatments as long as possible to have a low threshold for stopping sunitinib or pazopanib as frontline treatments, because I think their therapeutic index is not as good as some of the options we have for later lines of treatment.
If I haven't been able to give immunotherapy in the frontline setting, I prefer to go to nivolumab in the second-line setting, unless there is a symptomatic patient with bone metastases who absolutely needs a response. Then I reserve cabozantinib as my third-line treatment for most patients and delay starting that after nivolumab until there is clear evidence that the disease is progressing and the patient is potentially at risk of having symptoms from that.
Sometimes, if it's a patient who did not tolerate sunitinib or pazopanib in the frontline, and had to have it stopped, I might use axitinib as a third-line treatment because it potentially has a nice therapeutic index in someone who hasn't already developed resistance to a VEGF inhibitor.
In a patient who has clearly progressed while taking a VEGF inhibitor, my preference would clearly by cabozantinib over axitinib in that setting. Finally, I use lenvatinib and everolimus as my last treatment choice and I would give it for patients who progressed on nivolumab and cabozantinib, and the only place where I might use it earlier is in patients with non-clear cell histology, patients who are refractory to sunitinib and didn't respond to nivolumab, where next-generation sequencing shows a mutation in the PI3K/MTOR-related pathway.