Options for mRCC After Nivolumab

Nizar M. Tannir, MD:The question is, how do we define progressive disease in a patient who is receiving nivolumab or immune checkpoint inhibitors? This is a very important question that medical oncologists have to face and address. I think there has been literature with immune checkpoint inhibitors that suggest patients may initially have progression radiographically. However, they may be responding to therapy and that’s called “pseudoprogression.” The caveat of this is that patients should not prematurely discontinue therapy if they are feeling better and they have other parameters that suggest response to immune therapy. For example, if they had pain, weight loss, night sweats, fever, or chills that are related to the tumor and these have resolved or have improved—if their laboratory parameters initially showed elevated, let’s say, white blood cell count, platelets, anemia, hypercalcemia, or elevated serum LDH—these are markers of progressive disease, markers of poor response or poor risk. Those patients, if they had response in these parameters, then that is a sign that the patient is responding to immune therapy. One should not prematurely discontinue therapy, but should continue.

However, this can be a slippery slope. My cautionary note here is patients who develop new symptoms or they develop obvious new metastatic disease, by imaging studies, those patients should not be continued with therapy that is already failing, like in this case, for example, where the patient developed back pain while on nivolumab after initial response and the MRI of the spine showed metastatic disease in the spine, which she did not have before. She did not have that pain, and she did not have those lesions in the spine. So, this is not pseudoprogression; this is real progression. I think one should be cautious not to continue with therapy that is already failing. And this is my message to medical oncologists: If you are facing a scenario like this, this is a time to change therapy and not continue and assume that this is pseudoprogression. Let me mention that pseudoprogression occurs in about 5% to 6% of the cases; it is not a high occurrence. So, for the majority of the patients, if they have progressive disease, they have progressive disease, and therapy, therefore, needs to be changed.

There are many treatment options available for patients in the salvage setting after they receive standard-of-care first-line therapy, such as this lady here received sunitinib or pazopanib, which would be the other VEGFR TKI. For this lady, her local medical oncologist elected to give her nivolumab. So, now there are 3 options available for salvage that are FDA-approved. Let’s examine these options one-by-one. One option is cabozantinib. Cabozantinib is a VEGFR TKI, but it also blocks important pathways that are relevant in disease progression, especially after prior exposure to VEGF blockade. Those pathways are c-MET and AXL. There is a phase III trial published, the METEOR trial, where patients with clear cell RCC, who received prior VEGFR TKI therapy, were randomized to cabozantinib versus everolimus. The primary endpoint was progression-free survival, and this was in favor of cabozantinib. It was 7.4 months’ median progression-free survival compared to 3.9 months’ median progression-free survival with everolimus, but the response rate was 17% versus 3% with everolimus. And very importantly, median overall survival was in favor of cabozantinib-treated patients.

So, this trial produced 3 endpoints that were in favor of cabozantinib: progression-free survival, overall survival, and response rate. And this was a phase III trial, which has the highest level of evidence, so the NCCN guidelines chose, or have listed, cabozantinib as level 1 evidence for salvage therapy after first-line therapy with VEGFR TKI. They give it a preferred selection for salvage therapy. They also gave preferred selection for nivolumab as second-line therapy. So, both nivolumab, based on the CheckMate-025 study, and cabozantinib, based on the METEOR phase III trial, have received a level 1 indication, or listing, plus preferred selection.

Now, there are other options for salvage as third-line therapy after what this lady received. One is axitinib, which was one of the 2 main salvage therapies after first-line VEGFR TKI—and those were pre-2015, before we had the 3 trials that brought 3 novel therapies in the salvage setting. Axitinib—based on the AXIS trial that was comparing axitinib versus sorafenib—had its progression-free survival endpoint met, but there was no survival advantage for patients treated with axitinib versus sorafenib. So, pre-2015, axitinib was 1 of 2 options. The other one was everolimus; however, based on the METEOR and CheckMate-025 studies, there is no, in my opinion, justification to use everolimus as monotherapy anymore in the salvage setting. And, therefore, in my opinion, cabozantinib would be the preferred agent in the salvage setting, along with nivolumab after VEGFR TKI in the first-line, rather than axitinib or everolimus.

Now, lenvatinib—a novel VEGFR and BFGFR inhibitor in combination with everolimus, the mTOR inhibitor—was shown in a randomized phase II trial of 153 patients versus everolimus as the comparator. It showed impressive results with prolongation of median progression-free survival, which was 14.6 months by investigators’ assessment and 12.8 months by an independent radiology committee review. However, the limitation of this trial is that it is a randomized phase II, not randomized phase III, so it does not have the highest or the strongest evidence to support its use, in my opinion, compared to nivolumab or cabozantinib. The other issue with choosing a second-line therapy or third-line therapy is tolerability. And in my opinion, in a society that now is aware of the fiscal and financial constraints, we need to be cost-effective. So, lenvatinib/everolimus is a combination of 2 drugs that, in that randomized phase II study I alluded to, was associated with a high rate of dose reductions because of adverse events. That was 71% and a 25% discontinuation because of adverse events. So, that was the fact that it is a randomized phase II trial, plus the cost is double the cost of single-agent cabozantinib, for example. It put it, in my opinion, in a lower rank down below nivolumab and cabozantinib.

Case Presentation

February 2016

• 70-year old female, presented to her physician with symptoms of nausea, fatigue, and weight loss
• Abdominal CT 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 within 6 weeks
• Moderate fatigue, diarrhea, and increasing severity of hand—foot syndrome were managed with treatment interruption and then dose reduction to

June 2016

• Four months later the patient reported increasing fatigue, nausea, and weight loss
• Abdominal CT showed progression of her liver metastasis
• She was then switched from sunitinib to nivolumab
• 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

February 2017

• Eight months later, the patient complained of fatigue, abdominal discomfort, and weight loss; she subsequently developed back pain
• CT scan of 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
• She was subsequently switched to cabozantinib 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 of cabozantinib was reduced to 40 mg daily on which she was maintained for 13 months until she developed disease progression
• At this time the patient is being considered for enrollment into a clinical trial