Evolving treatment landscape in metastatic renal cell carcinoma: where are we now?

Two randomized phase 3 studies have been recently published, focusing on patients with advanced renal cell carcinoma who had received one or two previous antiangiogenic targeted therapies and have everolimus as comparator arm.

The CheckMate 025 study was designed to demonstrate a superiority in overall survival (OS) of nivolumab versus everolimus as primary end point, while progression-free survival (PFS), response rate (RR) and quality of life were secondary end points.[1]

Overall, 821 patients were randomized and 803 patients were treated according to the study design.

The two arms of treatment were well balanced according to both patients (including age, race and Karnofsky performance status) and disease characteristics (such as sites of metastases, Memorial Sloan Kettering Cancer Center (MSKCC) prognostic score and previous nephrectomy).

Overall, 72% of patients had received one prior tirosin kinase inhibitor (TKI) including sunitinib or pazopanib), while the remaining 28% of patients had received two TKIs.

This study has met its primary end point: nivolumab has shown an improvement in OS versus everolimus (25 months vs. 19.6 months, hazard ratio 0.75, p = 0.002).

The subgroup analysis has confirmed the advantage of nivolumab irrespective of MSKCC risk, previous antiangiogenic therapies, sex, and region, with the exception of very elderly cases (75 years old and over).

Nivolumab has also shown an increase in RR (25 vs. 5%, p = 0.001) without differences in terms of PFS (4.6 vs. 4.4 months, p = 0.11) over everolimus. Nivolumab was associated with less grade 3–4 adverse events (19% vs. 35%).

The PD-L1 expression measured in 92% of patients enrolled was not predictive of response to nivolumab, but if expressed in more than 1% it was associated with a worse prognosis.

The METEOR (Cabozantinib versus everolimus in patients with advanced renal cell carcinoma) study was designed to test the superiority of cabozantinib over everolimus in terms of PFS; secondary end points were OS and RR.[2]

Overall, 658 cases were randomized. The two arms of treatment were well balanced for age, sex, race, geographic area, Karnofsky performance status, MSKCC criteria, and previous nephrectomy. The number of previous antiangiogenic therapies were superimposable and the same as those reported in the CheckMate 025 study.

A few patients received sorafenib, bevacizumab, axitinib, or cytokines before entering the study.

The METEOR study has met its primary end point: cabozantinib is superior to everolimus in median Progression Free Survival (7.4 vs. 3.8 months, p < 0.001) with a reduction of disease progression or relapse of 42%.

A subgroup analysis confirmed the PFS benefit irrespective of MSKCC group and number of previous antiangiogenic therapies.

A post-hoc analysis undertaken in the 153 cases that received cabozantinib after sunitinib as first line showed an impressive PFS of 9.1 months versus 3.7 months in everolimus arm, with an overall reduction of disease progression or death of 41%.

The objective RR was 21% and 5% in cabozantinib and everolimus arm, respectively, (p < 0.001) and only 14% of patients developed disease progression as best response during cabozantinib treatment compared to 27% of patients treated in the everolimus arm.

A planned interim analysis reported an increase in OS (p = 0.005) in favor of cabozantinib, which did not cross the significant boundary.

Cabozantinib needed more dose reduction due to toxicity compared to everolimus (60% vs. 25% respectively).

So, how should we look at these trials in order to define a sequential treatment strategy?

Some points may be confounding and merit further discussion:

• (1) The benefit in OS reported with nivolumab was impressive and is the best reported after antiangiogenic therapies. Until we have definitive data of OS in the METEOR study, physicians may consider nivolumab as reference treatment in this setting. Moreover, if we get future confirmation that OS of cabozantinib is better than everolimus, physicians may empirically perform an indirect comparison between the absolute value of OS in both studies to define the treatment choice in clinical practice. This may be wrong from a methodological point of view and of course it appears arbitrary from a clinical point of view.

• (2) The overall PFS and that reported in patients receiving cabozantinib after sunitinib showed the best outcome for a single agent used for metastatic renal cell carcinoma (mRCC) treatment. Besides, the PFS reported in the same study with everolimus was similar to that reported in the RECORD 1 (Phase 3 trial of everolimus for metastatic renal cell carcinoma) study.[3] This supports the METEOR study that suggests that the characteristics of this study population may not be more favorable in comparison to previous studies.

  The CheckMate-025 study did not demonstrate any PFS differences between nivolumab and everolimus. The mechanism of action of nivolumab could explain these results; nevertheless, the role of PFS and the choice of the right surrogate end point for OS for future clinical trial design still remains unclear.

• (3) In the METEOR study, only few cases developed progressive disease as best response with cabozantinib, while 35% of patients treated with nivolumab showed disease progression as best response. The definition of progressive disease by RECIST criteria may be confounding when applied to immunotherapies. Moreover, a standardized methodology to assess radiological treatment-related pseudoprogression as well as the potential impact of nivolumab treatment beyond progression still represent major issues. These considerations may indirectly support the concept that cabozantinib may potentially be able to better overcome antiangiogenic resistance.

• (4) Both studies enrolled patients receiving one or two prior antiangiogenic treatments and they both pushed everolimus over second line. On the other hand, these studies have not clarified which role should be given to second-line TKI, such as axitinib, following upfront TKI. Should nivolumab be considered second line for all patients or physicians may still consider axitinib as second line for select cases? Clinical data now available do not seem to be conclusive.

• (5) The safety profile and tolerability of nivolumab and cabozantinib were very different. In general, nivolumab was associated with less all grades adverse events and showed a good patients compliance. In contrast, 60% of patients receiving cabozantinib received a dose reduction due to toxicity. As a result, the management of the toxicity of patients receiving cabozantinib may be a potential key driver for treatment choice.

• (6) A randomized phase 3 trial comparing the association between nivolumab plus ipilimumab versus sunitinib in first-line mRCC has recently completed the accrual.[4] The results of this study, whose coprimary efficacy end points are PFS and OS, are awaited to define the potential role of first line immunotherapy.

In conclusion, the armamentarium of agents against kidney cancer will be improved with the next availability of nivolumab and cabozantinib in clinical practice.

We are not sure on where to place nivolumab and cabozantinib into treatment algorithm.

A sequential strategy including cabozantinib after nivolumab may be suitable for some patients who had previously received sunitinib or pazopanib. Moreover, a second TKI, such as axitinib or cabozantinib could be an optional treatment to defer nivolumab in third line.

The duration of response to first TKI, the aggressive behavior of the disease and the different toxicity profile of available agents may be considered to define a sequential treatment strategy.

We hope to identify predictive factors able to drive the treatment choice alternatively the choices will be based on well-known clinical factors.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.