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The Evolving Management of Advanced Renal Cell Carcinoma

Dr-Rana-R-McKayA review from the American website of Dr. Rana R. McKay State-of-the-Art lecture providing a comprehensive presentation of the evolving management of advanced renal cell carcinoma (RCC) at the SUO2017 (Society of Urologic Oncology) Conference.

You may find our GLOSSARY OF TERMS useful when reading this article.

First-Line Therapies

Since 2007, there have been several large randomized control trials (RCTs) in the first line setting. The phase III COMPARZ trial randomized advanced RCC patients (n=890) with no prior therapy and clear cell histology to pazopanib vs sunitinib [1]. Pazopanib progression-free survival (PFS) was non-inferior to sunitinib (median PFS 8.4 months for pazopanib vs 9.5 months for sunitinib) HR 1.05, 95%CI 0.90-1.22. The objective response rate (ORR) was 31% for pazopanib and 24% for sunitinib; median overall survival (OS) was 28.4 months for pazopanib and 29.3 months for sunitinib.

The phase III CheckMate 214 trial randomized advanced RCC patients (n=1082) with no prior therapy and clear cell histology to nivolumab + ipilimumab vs sunitinib [2]. Over a median follow-up of 25.2 months, nivolumab + ipilimumab demonstrated an improvement in OS (HR 0.63, 99.8%CI 0.44-0.89) compared to sunitinib, although there was no difference in PFS (HR 0.82, 99.1%CI 0.64-1.05). In the intention to treat (ITT) population the ORR for nivolumab + ipilimumab was 39% compared to 32% for sunitinib (p=0.0191), while in favorable risk patients the ORR was 29% for nivolumab + ipilimumab compared to 52% for sunitinib (p=0.002). Importantly, 60% of patients treated with nivolumab + ipilimumab required systemic corticosteroids for an adverse event.

There are several questions that Dr. McKay raises regarding the CheckMate 214 trial:

Does timing matter? No crossover was allowed as patients in the sunitinib arm never received access to nivolumab + ipilimumab
Which patient population? Are there patients with intermediate-risk disease who may benefit more from sunitinib?
The phase II CABOSUN trial randomized advanced RCC patients (n=157) with no prior therapy and clear cell histology to cabozantinib vs sunitinib [3]. Median PFS was 8.2 months for cabozantinib and 5.6 months for sunitinib (aHR 0.66, 95%CI 0.46-0.95). The ORR was 46% for cabozantinib and 18% for sunitinib. The phase II IMmotion 150 trial randomized advanced RCC patients (n=305) with no prior therapy to atezolizumab + bevacizumab vs atezolizumab vs sunitinib [4]. First-line PFS for patients with ≥1% of IC expressing PD-L1 was 14.7 months for atezolizumab + bevacizumab compared to 7.8 months (HR 0.64, 95%CI 0.38-1.08).

According to Dr. McKay, the optimal first-line therapy for patients with clear cell histology and no prior therapy should be either (i) VEGF targeted therapy, (ii) nivolumab + ipilimumab, specifically for patients with intermediate or poor risk disease by IMDC criteria, (iii) high-dose interleukin 2, specifically for select patients with good performance status and organ function, or (iv) a clinical trial.

Second-Line or Beyond Therapies

Similar to the first-line, since 2007 there have been several impactful RCTs in the second line setting. The phase III Axis trial randomized advanced RCC patients (n=723) with one prior therapy and clear cell histology to axitinib vs sorafenib [5]. Median PFS was 6.7 months for axitinib and 4.7 months for sorafenib (HR 0.665, 95%CI 0.544-0.812), whereas there was no difference in OS. Furthermore, axitinib also had an improved ORR (19%) compared to sorafenib (9%, p<0.0001).

The phase III CheckMate-25 trial randomized advanced RCC patients (n=443) with 1-2 prior anti-angiogenic therapies and clear cell histology to nivolumab vs everolimus [6]. Patients receiving nivolumab had an improved OS (25 months) compared to everolimus (19.6 months; HR 0.73, 95%CI 0.57-0.93), whereas there was no difference in PFS. ORR was 25% for nivolumab and 5% with everolimus (OR 5.98, 95%CI 3.68-9.72). Furthermore, there was a benefit observed with nivolumab irrespective of PD-L1 expression.

The phase III METEOR trial randomized advanced RCC patients (n=658) with at least one prior VEGFR TKI and clear cell histology to cabozantinib vs everolimus [7]. Patients receiving cabozantinib had significantly improved PFS compared to patients receiving everolimus (HR 0.58, 95%CI 0.45-0.75), improved OS (HR 0.66, 95%CI 0.53-0.83), and an improved ORR (21% vs 5%, p<0.001).

The phase II lenvatinib + everolimus trial randomized advanced RCC patients (n=153) with one prior VEGF targeted therapy and clear cell histology to lenvatinib + everolimus vs lenvatinib vs everolimus [8]. Median PFS was 14.6 months for patients receiving combination therapy compared 5.5 months for those receiving everolimus (HR 0.40, 95%CI 0.24-0.68). Similarly, median OS for combination therapy was 25.5 months vs 15.4 months for everolimus (HR 0.51, 95%CI 0.30-0.88). The ORR was 43% for lenvatinib + everolimus compared to 5% for everolimus (RR 7.2, 95%CI 2.3-22.5).

When comparing second-line therapies, Dr. McKay notes the significance of much fewer grade 3-4 adverse events associated with nivolumab (18%) compared to other second line agents (50-63%). According to Dr. McKay, the optimal second-line therapy for patients with clear cell histology and previous treatment should be either (i) nivolumab or cabozantinib, or lenvatinib + everolimus or axitinib or sorafenib, (ii) a clinical trial, or (iii) treating based on genomic testing.

Novel Combinations and Upcoming Trials

Certainly, there are many phase Ib/2 trials testing many combinations of therapies. For example, these combinations include axitinib + pembrolizumab, axitinib + avelumab, lenvatinib + pembrolizumab, and cabozantinib + nivolumab (+ ipilimumab). As Dr. McKay notes, these trials have ORRs >50%, except for cabozantinib + nivolumab (38%) and cabozantinib + ipilimumab (22%). One specific combination trial that Dr. McKay further highlighted was the phase I/II ECHO-202/KeyNote-037 trial, with a dose escalation/safety expansion design for epacadostat + pembrolizumab, followed by an open label cohort expansion. Early results demonstrated an ORR of 33%. There are several exciting phase III studies that will be reporting in the next 5 years, continuing to provide further clarity to the optimal combination of therapies.

Non-Clear Cell RCC Therapies

Traditionally, phase II/III studies are exclusive to clear cell RCC, however recently there have been trials specific to non-clear cell RCC histologies. For example, the ESPN trial was a phase II study randomizing patients (n=68) with non-clear cell RCC to sunitinib vs everolimus [9]. The mPFS in first-line therapy was 6.1 months with sunitinib and 4.1 months with everolimus (p=0.6), while median (OS) was not reached with sunitinib and was 10.5 months with everolimus, respectively (p=0.014). As Dr. McKay notes from the NCCN guidelines, the current preferred options for non-clear cell histologies are a clinical trial or sunitinib. At this point in time there are six phase II trials ongoing and one phase III trial (savolitinib vs sunitinib for papillary histology) scheduled to be completed in 2021.

Dr. McKay concluded with several take-home messages from this state-of-the-art lecture:

The standard of care for advanced RCC has dramatically changed in era of targeted therapy and no immunotherapy
New advances have improved response rates, overall survival, and treatment-related toxicities
Despite the approval of multiple agents, clinical trials of novel agents and combinations are underway to continue to improve outcomes for patients


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