Novel Therapies for Advanced Urologic Cancers

Axel Heidenreich

Disclosures

Curr Opin Urol. 2020;30(4):594-601. 

In This Article

Renal Cell Carcinoma

Until 2019, sunitinib and pazopanib were considered as treatments of choice for the management of metastatic renal clear cell carcinoma.[1] In 2019, three prospective randomized trials had been published that explored the therapeutic efficacy of immuno-oncological therapy (IOT) with both PD-1/PD-L1 inhibitors and CTLA-4 inhibitors or the combination of PD-L1/PD-1 inhibitors with VEGFR-inhibitors.[2–4]

In CheckMate214, a total of 1096 patients with previously untreated mRCC were prospectively randomized to receive nivolumab and ipilimumab or sunitinib.[2] The coprimary endpoints of this trial were overall survival (OS), objective response rate and progression-free survival. The 18-month OS rate was 75 versus 60% and the median OS time was not reached with IOT as compared to 26.0 months for sunitinib (hazard ratio: 0.63, P < 0.001). Also, objective response rates (42 versus 27%, P < 0.001) and median progression-free survival times (11.6 versus 8.4 months, P = 0.03) were superior in the nivo/ipi – arm, respectively. Those data have been substantiated when the follow-up was extended to 32.4 months.[2] Results for the three coprimary efficacy endpoints showed that nivolumab and ipilimumab continued to be superior to sunitinib in terms of OS [median not reached (95% confidence interval, 95% CI 35.6-not estimable) versus 26.6 months (22.1–33.4); hazard ratio 0.66, 95% CI 0.54–0.80, P < 0.0001], progression-free survival [median 8.2 months (95% CI 6.9–10.0) versus 8.3 months (7.0–8.8); hazard ratio 0.77 (95% CI 0.65–0.90), P = 0 0014], and the proportion of patients achieving an objective response [178 (42%) of 425 versus 124 (29%) of 422; P = 0.0001]. Benefits for all primary endpoints were observed in patients with intermediate and poor prognosis but not in those with good prognosis. Grade 3 and 4 treatment-associated toxicities (TAEs) developed in 46 and 63% of patients treated with nivo/ipi and sunitinib, respectively (Table 1).

The KEYNOTE-426 trial randomized 861 patients with untreated mRCC to either the combination of pembroluzimab and axitinib versus sunitinib.[3] The primary end points of the trial were OS and progression-free survival; the secondary endpoint was the objective response rate. The median follow-up was 12.8 months with a significant survival benefit for the pembroluzimab-axitinib group with 89.9 versus 78.3% in the sunitinib arm (hazard ratio for death = 0.53; 95% CI 0.38–0.74, py0.0001). At 18 months, the survival rates were 82.3 and 72.1% in the pembro-axi arm versus sunitinib. The benefit in OS was achieved for all subgroups of patients with good, intermediate and poor risk. The median progression-free survival was significantly superior in the pembro-axi arm with 15.1 months as compared with 11.1 months in the sunitinib group (hazard ratio = 0.69, 95% CI 0.57–0.84, P < 0.001). Also, objective response rate was significantly better in the pembro/axi arm with 59.3 versus 35.7% in the sunitinib arm (P < 0.001). Grade 3 and 4 toxicities were observed in 75.8 and 70.6% of patients who received pembro/axi and sunitinib, respectively (Table 1).

The JAVELIN 101 trial randomized 886 patients with untreated renal cell carcinoma to receive avelumab and axitinib as compared to sunitinib.[4] The two coprimary endpoints were progression-free survival and OS in PD-L1 positive tumours, whereas the secondary endpoint was progression-free survival in the overall cohort. The median progression-free survival for PD-L1 positive tumours was 13.08 and 7.2 months in the avelumab/axitinib and the sunitinib groups, respectively (Table 2). The death rates at a median follow-up were 13.7 and 15.2% in the avelumab/axitinib and sunitinib group (Table 2), respectively The confirmed objective response rates were 55.2 and 25,5% in the avelumab/axitinib and the sunitinib group, respectively. The data for the overall population are given in Table 2. Grade 3 or 4 toxicities occurred in 71.2 and 71.5% of patients in the avelumab and the sunitinib group, respectively (Table 1).

In summary, there are three new first-line therapies available for the management of previously untreated mRCC. Each one of the trials has resulted in a significant OS and PFS benefit. Whereas nivo/ipi is only approved for the management of intermediate and poor risk patients, both avelumab trials have also demonstrated superior treatment outcomes in good risk patients. When choosing one of the three options, one also needs to consider the long median follow-up of more than 32 months in CheckMate214. Comorbidities of the patient and the expected toxicity profile of the different treatment approaches need to be taken into consideration (Table 1). Currently, it is unclear which option should be preferred as first-line treatment and this issue needs to be discussed individually with each patient.

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