Second-Line Options for Poor-Risk Advanced RCC


Earle Burgess, MD:Returning to our case in the context of the recent update of the CheckMate 214 study, we know that this patient had poor-risk disease using the IMDC [International Metastatic Renal Cell Carcinoma Consortium] criteria. He received induction IPI/NIVO [ipilimumab, nivolumab] and achieved a partial response. He then went on to receive 6 months of maintenance nivolumab followed by progression, at which time he was transitioned to cabozantinib.

An update from the CheckMate 214 study was recently published inThe Lancet Oncologyin the past few months. This included a median follow-up of over 30 months. The CheckMate 214 study, recall, compared the combination of ipilimumab, nivolumab to sunitinib primarily in intermediate and poor-risk patients.

With this longer follow-up it was confirmed that the overall survival in the ipilimumab, nivolumab arm was superior to the sunitinib arm in the intermediate and poor-risk patients, as in our case. The median overall survival in the ipilimumab, nivolumab] arm was not reached compared to over 26 months in the sunitinib arm with a hazard ratio of 0.66. The response rates also favor the ipilimumab, nivolumab arm. The overall response rate was 42% in the ipilimumab, nivolumab arm with an 11% complete response [CR] rate compared to 29% overall response rate in the sunitinib arm with a 1% CR rate. The median duration of response in the ipilimumab, nivolumab arm has not yet been reached compared to 18 months in the sunitinib arm.

Putting our patients’ experience in the context of these updated results from CheckMate 214, we know that our patient initially achieved a partial response, as 40% of the patients in CheckMate 214 did.

However, because our patient progressed at the 9-month mark, his progression event was earlier than the median that’s been shown thus far in CheckMate 214.

After patients progress on frontline therapy, most of whom are now receiving an immune checkpoint inhibitor regimen, the key decision I think that influences what to use in the second-line setting is really based on their frontline therapy. If a patient has received an immune checkpoint inhibitor in the frontline setting, as most are doing now, I think that the preferred regimen in the second-line setting should be TKI [tyrosine kinase inhibitor]-based. Prior to the availability of immune checkpoint inhibitors in the frontline setting, we had the option of nivolumab versus changing to an alternate TKI in the second-line setting. I think that decision is less relevant today given the fact most patients are receiving immune checkpoint inhibitors up front.

When considering TKIs in the second-line setting, the 2 most utilized regimens now that are supported by category 1 recommendations with NCCN [National Comprehensive Cancer Network] include cabozantinib monotherapy or the combination of everolimus and lenvatinib.

I think today the primary consideration is between those 2 regimens for patients who have failed immune checkpoint inhibitors. For that matter, however, for the select patient who still receives TKI monotherapy in the frontline setting, could be considered for an alternate TKI or perhaps an immune checkpoint inhibitor.

The real decision today commonly is what to use following immune checkpoint inhibitor, and how best to select between either cabozantinib or the combination of lenvatinib and everolimus.

The factors that I consider when trying to choose between cabozantinib and lenvatinib and everolimus are as follows. Those regimens haven’t been directly compared. The strength of the evidence is different. The underlying trial that led to the approval of cabozantinib in the post-frontline setting is the METEOR trial. This was a large randomized phase III study that established the superiority of cabozantinib over everolimus.

When considering between cabozantinib and lenvatinib, everolimus, there are 2 key points that influence my decision, and I tend to use cabozantinib primarily in the second-line setting. Those 2 points are the strength of the evidence. The trial that led to the approval of cabozantinib is a large phase III, so level 1 evidence, compared to a smaller phase II trial for lenvatinib and everolimus. Anecdotally and based on the adverse event profiles that were reported in both of the respective trials, I find that cabozantinib monotherapy is generally better tolerated than lenvatinib and everolimus combination at the approved dose. The strength of the evidence and the underlying tolerability lean me to use cabozantinib most often in the second-line setting.

Transcript edited for clarity.

Case: A 68-Year-Old Man With Poor-Risk RCC

A 68-year-old man presented with a 6-week history of painless intermittent hematuria, fatigue and a 7-lb weight loss.

H & P:

  • History of medically controlled hypertension and hypercholesterolemia
  • 30 pack/year smoking history, social alcohol use  
  • Thin, ill-appearing; able to meet activities of daily living but unable to work due to fatigue. He spends more than half the day active on his feet


  • CBC: Hb 11.4 g/dL, corrected Calcium,11.2 mg/dL, WBC, PLT, LFT all WNL
  • BP: 134/92
  • Lipid panel: WNL
  • U/A: gross hematuria


  • CT scan of the chest/abdomen/pelvis showed a left-sided 8.7 (I believe he said 8cm) cm renal mass, para-aortic lymph nodes, and pulmonary metastases


  • Underwent radical left nephrectomy; found to have Fuhrman grade 4 clear cell carcinoma without sarcomatoid features
  • IMDC risk-score: poor


  • Initiated treatment with ipilimumab 1mg/kg IV + nivolumab 3mg/kg IV q3w for 4 doses; achieved partial response; received maintenance nivolumab for 6 doses (q4w) followed by disease progression
  • Patient was switched to cabozantinib 60mg PO qDay
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