Recent developments in second and third line therapy of metastatic renal cell carcinoma

KEYWORDS:

• Cabozantinib
• nivolumab
• renal cell cancer
• government funding
• metastatic
• second line
• third line
• therapy

Renal cell carcinoma (RCC) represents 2–3% of all adult malignancies. Over the last few years, many agents such as VEGF- and mTOR-inhibitor have been developed for the treatment of metastatic RCC. Patients treated with a sequential use of these drugs have improved survival but the prognosis remains poor and oncologists need new treatment options. For patients treated with one or more previous tyrosine kinase inhibitor, the current available drugs are axitinib and everolimus [1–5]. Two randomized, controlled, Phase III trials in which cabozantinib [6] and nivolumab [7] proved to be superior as compared to everolimus are recently published. This article is focused on the recent developments of the treatment of metastatic renal cell cancer patients after failure of VEGF-inhibitor.

Nivolumab is a (PD-1) immune checkpoint inhibitor antibody that selectively blocks the interaction between PD-1, which is expressed on activated T cells, and PD-1 ligand 1 (PD-L1) and 2 (PD-L2), which are expressed on immune cells and tumor cells. Interaction between PD-1 and PD-L1 or PD-L2 normally results in inhibition of the cellular immune response [8–10]. Phase I and II trials demonstrated encouraging activities of Nivolumab in metastatic renal cell cancer patients: durable responses, improved overall survival (OS), and a good profile of toxicity [11].

In CheckMate 025 trial, 821 patients with metastatic RCC, previously treated with one or two anti-angiogenic therapy, were randomized 1:1 to receive Nivolumab 3 mg/kg intravenous every 2 weeks or Everolimus 10 mg/die orally. Treatment beyond progression was permitted if clinical benefit was observed and drug tolerated. The primary endpoint was OS while secondary endpoints were objective response rate (ORR), progression-free survival (PFS), safety and quality of life (QoL). The study met its primary endpoint: Nivolumab was associated to a medium OS of 25 months and Everolimus to 19.6 months (Hazard ratio, 0.73 (98.5% CI, 0.57–0.93) p = 0.002). The benefit in OS was observed regardless of PD-L1 expression. Nivolumab also led an improved response rate (25% Nivolumab and 5% Everolimus; odds ratio 5.98; 95% CI, 3.68–9.72; p < 0.001). There was no difference in PFS between the two arms. The median PFS was 4.6 months (95% CI, 3.7–5.4) in the nivolumab group and 4.4 months (95% CI, 3.7–5.5) in the everolimus group (hazard ratio, 0.88; 95% CI, 0.75–1.03; p = 0.11). However, post analysis of those who had not progressed at 6 months favored nivolumab. About safety, nivolumab was well tolerated with a better quality of life (QoL). Most common toxicities with nivolumab were fatigue, nausea, pruritus, diarrhea, and decreased appetite [7]. Nivolumab received US FDA approval in November 2015 for metastatic renal cell cancer after progression with VEGF-targeted therapy.

At Genitourinary Cancers Symposium (American Society of Clinical Oncology (ASCO)) 2016, an analysis of OS and response in key subgroups (based on risk groups, number of sites of metastasis, sites of metastasis, months of previous therapy, and type and number of prior therapy) was presented. About risk groups (Motzer and IDMC), there was an improved OS in all groups and a high benefit with nivolumab in poor risk group. The benefit was revealed in patients with both liver and bone metastasis and in patients with one or two/more sites of metastasis.

Median follow-up was 17–18 mo. A total of 77% and 23% of patients received 1 or 2 prior anti-angiogenic therapies, respectively, for advanced RCC, mainly sunitinib (63%) or pazopanib (32%). In patients who had prior sunitinib, median OS was 23.6 mo for nivolumab (NIVO) vs. 19.8 mo for everolimus (EVE); in those who had prior pazopanib, median OS was not estimable (NE) for NIVO vs. 17.6 mo for EVE. For those who had prior IL-2 (10%), median OS was NE for NIVO vs. 17.2 mo for EVE. Outcomes by subsequent anticancer therapy are planned [12].

Therefore, nivolumab is a new treatment option for patients with metastatic renal cell cancer after failure of VEGF-inhibitor.

Cabozantinib is an oral, small-molecule kinase inhibitor that targets the MET receptor and VEGFR-2 and other potentially relevant receptor tyrosine kinases including RET, KIT, AXL, and FLT3. AXL and MET are implicated in acquired resistance to VEGF-targeted therapy [6].

In the METEOR trial, 650 patients with metastatic RCC, who have received prior treatment with at least one VEGFR-targeting tyrosine kinase inhibitor and must have had radiographic progression during treatment or within 6 months after the most recent dose of the VEGFR inhibitor, were randomized to receive cabozantinib at a dose of 60 mg daily or everolimus at a dose of 10 mg daily. The primary end point was PFS. Secondary efficacy endpoints were OS and objective response rate. The trial has reached its primary endpoint and median PFS was 7.4 months with cabozantinib and 3.8 months with everolimus. The rate of progression or death was 42% lower with cabozantinib than with everolimus (hazard ratio, 0.58; 95% confidence interval [CI] 0.45–0.75; p < 0.001). Cabozantinib was associated with an improved response: the objective response rate was 21% with cabozantinib and 5% with everolimus (p < 0.001). In terms of safety, cabozantinib is associated with toxiticity: 68% of patients had a G3-4 toxicity and 60% had a reduction of dose. OS data are not yet available but there was a trend in favor of cabozantinib.

At genitourinary ASCO 2016, an analyses of subgroups revealed that clinical benefit with cabozantinib was independent of MSKCC group, ECOG status, organ involvement including bone and overall tumor burden, extent and type of prior therapy, and prior PD-1/PD-L1 therapy. In particular, Cabozantinib was better than everolimus in patients with ECOG 0, favorable/intermediate risk group, high tumor burden, 2 or more involved organs, visceral and bone metastasis, previous therapy with sunitinib, and the duration of prior TKI therapy more than 6 months [13].

Lenvatinib is an oral multitarget tyrosine kinase inhibitor of VEGFR1, VEGFR2, and VEGFR3, which inhibits fibroblast growth factor receptors (FGFR1, FGFR2, FGFR3, and FGFR4), PDGFRα, RET, and KIT. In a Phase II trial, 153 patients were randomized in a 1:1:1 ratio to lenvatinib (24 mg/day), everolimus (10 mg/day), or lenvatinib plus everolimus (18 mg/day and 5 mg/day, respectively) administered orally in continuous 28-day cycles until disease progression or unacceptable toxic effects. The primary objective was PFS in the intention-to-treat population.

At primary analyses assessed by investigators, lenvatinib plus everolimus significantly prolonged PFS compared with everolimus alone (median 14.6 months [95% CI 5.9–20.1] vs. 5.5 months [3.5–7.1]; hazard ratio [HR] 0.40, 95% CI 0.24–0.68; p = 0.0005), but not compared with lenvatinib alone (7.4 months [95% CI 5.6–10.2]; HR 0.66, 95% CI 0.30–1.10; p = 0.12). Single-agent lenvatinib significantly prolonged PFS compared with everolimus alone (HR 0.61, 95% CI 0.38–0.98; p = 0.048).

About Grade 3/4 toxicity, single agent everolimus was well tollerated (25 [50%]) than lenvatinib alone (41 [79%]) or lenvatinib plus everolimus (36 [71%]). The most common Grade 3 or 4 adverse event was diarrhea (ten [20%]) in patients who received lenvatinib plus everolimus, proteinuria (ten [19%]) for single-agent lenvatinib, and anemia for single-agent everolimus (six [12%])[14].

The PFS updated analysis assessed by independent radiologic review (IRR) was: 12.8 months (95% CI 7.4–17.5) in the lenvatinib plus everolimus group, 9 months (5.6–10.2) in the lenvatinib group, and 5.6 months (3.6–9.3) in the everolimus group. PFS was significantly longer in patients in the lenvatinib plus everolimus group than in those in the everolimus alone group (HR 0.45 [95% CI 0.27–0.79]; p = 0.0029). However, no significant difference in PFS was noted between patients who received lenvatinib alone and those who received everolimus alone (HR 0.62 [95% CI 0.37–1.04]; p = 0.12), which contrasts with the result for this comparison in the investigator-assessed responses [15]. Both lenvatinib/everolimus and levantinib alone were statistically significant superior than everolimus alone in response results of primary and updated analyses.

In Phase II, the combination of everolimus and lenvatinib can prolong PFS at the cost of greater toxicity. Therefore, after progression with first-line therapy with VEGF-targeted therapy, both axitinib and everolimus are valid treatment options. They have shown significantly improved PFS over placebo (everolimus) or sorafenib (axitinib), but not OS [4,5].

The RECORD-1 trial showed that PFS in untreated patients was 1.9 months and 4.9 months in those receiving everolimus. In the AXIS trial, PFS was 4.8 months with axitinib and 3.4 months with sorafenib.

For the first time, in CheckMate025 trial, nivolumab is able to prolong OS of 6 months in the second line while in the METEOR trial, patients receiving cabozantinib had a PFS of 7.4 months. In both studies, everolimus and cabozantinib were compared with a standard therapy such as everolimus. Nivolumab had no benefit in terms of PFS. It remains to be determined what to do in case of pseudoprogression. Lenvatinib plus Everolimus is an active combination but new trials are needed. New trials will compare these new agents with axitinib. Everolimus is an option for some patients but a new treatment algorithm should be defined.

Financial and 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.