octubre 2020

Addition of Primary Metastatic Site on Bone, Brain, and Liver to IMDC Criteria in Patients With Metastatic Renal Cell Carcinoma: A Validation Study

Massari F, Nunno V, Guida A, et al.
Clin Genitourin Cancer. 2020 Jun 27
DOI: 10.1016/j.clgc.2020.06.003.

Abstract

Background

The International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) criteria have been largely adopted in clinical practice. In a recent retrospective study, we assessed that the addition of the first site of metastatic disease to brain, bone, and liver improves prognostic stratification of patients with metastatic renal cell carcinoma (mRCC). Here, we performed an external validation in patients with mRCC. Our aim was to evaluate if the addition of a new independent variable could improve IMDC prognosis prediction and reduce heterogeneity within risk categories.

Patients and methods

We selected all 1073 patients treated at a single institution for mRCC and included in the Institute Gustave Roussy Renal Cell Carcinoma database. All patients included received at least 1 line of targeted therapy or immune checkpoint inhibitors. Univariate and multivariate analyses (Cox regression model) were performed. Bootstrap validation of the final model was also carried out for internal validation. The IMDC modified classification was defined by the addition of the seventh variable, and we defined the modified IMDC good-risk criteria as 0 risks, intermediate-risk as 1 to 2 risks, and poor-risk as 3 or more risks.

Results

The presence of brain, bone, and/or liver as the first site of metastatic disease plus the other variables included in the IMDC score were statistically significant variables associated with overall survival (OS) after univariate and multivariate analysis and bootstrap validation. Finally, 122 (15%) patients had a modification of their initial risk category. The median OS in the poor-, intermediate-, and favorable-risk groups was 10, 26, and 52 months, respectively (P < .001). The bias-corrected concordance index in patients receiving immune checkpoint inhibitors (n = 241) was 0.71.

Conclusion

The addition of brain, bone, and/or liver metastases as an additional variable to the other IMDC variables improves the prognostic predictive power of the model.

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Exposure-response modeling of cabozantinib in patients with renal cell carcinoma: Implications for patient care

Castellano D, Maroto JP, Benzaghou F, et al.
Cancer Treat Rev. 2020 Sep;89:102062
DOI: 10.1016/j.ctrv.2020.102062
Free article

Abstract

Cabozantinib is an oral tyrosine kinase inhibitor (TKI) approved for the treatment of patients with advanced renal cell carcinoma (RCC) at a dose of 60 mg/day. As with other TKIs, cabozantinib is associated with high interpatient variability in drug clearance and exposure that can significantly impact safety and tolerability across a patient population. To optimize cabozantinib exposure (maintaining efficacy and tolerability) for the individual, patients may require treatment interruption with dose reduction (40 mg/day and then 20 mg/day). In the pivotal Phase 3 METEOR trial, cabozantinib significantly improved overall survival, progression-free survival and the objective response rate compared with everolimus in patients with advanced RCC who had received previous treatment with a VEGFR TKI. Dose reductions were common for patients receiving cabozantinib (60%) but effective as only 9% discontinued treatment due to adverse events (AEs). In this review, we discuss pharmacometric analyses that evaluated the impact of cabozantinib dose on efficacy and safety outcomes during the METEOR study. Exposure-response models demonstrate that the risk of experiencing adverse events and dose reduction is increased in patients with low cabozantinib clearance versus typical clearance and decreased in patients with high clearance. Dose reduction of cabozantinib to manage AEs is predicted to have minimal impact on efficacy as AEs are more likely to occur in patients with low clearance and higher exposure to cabozantinib. These analyses further support a dose modification strategy to optimize cabozantinib exposure for individual patients.

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Survival outcomes and independent response assessment with nivolumab plus ipilimumab versus sunitinib in patients with advanced renal cell carcinoma: 42-month follow-up of a randomized phase 3 clinical trial

Motzer RJ, Escudier B, McDermott D, et al.
J Immunother Cancer. 2020 Jul;8(2):e000891.
DOI: 10.1136/jitc-2020-000891.

Abstract

Background

The extent to which response and survival benefits with immunotherapy-based regimens persist informs optimal first-line treatment options. We provide long-term follow-up in patients with advanced renal cell carcinoma (aRCC) receiving first-line nivolumab plus ipilimumab (NIVO+IPI) versus sunitinib (SUN) in the phase 3 CheckMate 214 trial. Survival, response, and safety outcomes with NIVO+IPI versus SUN were assessed after a minimum of 42 months of follow-up.

Methods

Patients with aRCC were enrolled from October 16, 2014, through February 23, 2016. Patients stratified by International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk and region were randomized to nivolumab (3 mg/kg) plus ipilimumab (1 mg/kg) every 3 weeks for four doses, followed by nivolumab (3 mg/kg) every 2 weeks; or SUN (50 mg) once per day for 4 weeks (6-week cycle). Primary endpoints: overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) per independent radiology review committee in IMDC intermediate-risk/poor-risk patients. Secondary endpoints: OS, PFS, and ORR in the intention-to-treat (ITT) population and safety. Favorable-risk patient outcomes were exploratory.

Results

Among ITT patients, 550 were randomized to NIVO+IPI (425 intermediate/poor risk; 125 favorable risk) and 546 to SUN (422 intermediate/poor risk; 124 favorable risk). Among intermediate-risk/poor-risk patients, OS (HR, 0.66; 95% CI, 0.55–0.80) and PFS (HR, 0.75; 95% CI, 0.62–0.90) benefits were observed, and ORR was higher (42.1% vs 26.3%) with NIVO+IPI versus SUN. In ITT patients, both OS benefits (HR, 0.72; 95% CI, 0.61–0.86) and higher ORR (39.1% vs 32.6%) were observed with NIVO+IPI versus SUN. In favorable-risk patients, HR for death was 1.19 (95% CI, 0.77–1.85) and ORR was 28.8% with NIVO+IPI versus 54.0% with SUN. Duration of response was longer (HR, 0.46–0.54), and more patients achieved complete response (10.1%–12.8% vs 1.4%–5.6%) with NIVO+IPI versus SUN regardless of risk group. The incidence of treatment-related adverse events was consistent with previous reports.

Conclusion

NIVO+IPI led to improved efficacy outcomes versus SUN in both intermediate-risk/poor-risk and ITT patients that were maintained through 42 months’ minimum follow-up. A complete response rate >10% was achieved with NIVO+IPI regardless of risk category, with no new safety signals detected in either arm. These results support NIVO+IPI as a first-line treatment option with the potential for durable response.

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Are immune checkpoint inhibitors a valid option for papillary renal cell carcinoma? A multicentre retrospective study

Manon de Vries-Brilland, Marine Gross-Goupil, Valérie Seegers
Eur J Cancer. 2020 Sep;136:76-83.
DOI 10.1016/j.ejca.2020.02.019.

Abstract

Background

Papillary renal cell carcinoma (pRCC) is the most common non-clear cell RCC (nccRCC). Pivotal studies evaluating immune checkpoint inhibitors mostly excluded nccRCC. The aim of this retrospective and multicentre study was to evaluate the activity of programmed death-1 (PD-1)/ programmed death-ligand 1 (PD-L1) inhibitors specifically in metastatic pRCC.

Methods

The primary end-point was time to treatment failure (TTF). Secondary endpoints included objective response rate (ORR), overall survival (OS) and treatment-related adverse events (TRAEs).

Results

From 02/2016 to 01/2019, 57 patients with pRCC were included. Histology included 16 (28%) type 1 pRCC, 34 (60%) type 2 pRCC and 7 (12%) unclassified pRCC. Treatment with immune checkpoint inhibitors was used in the first-line setting in 4 patients (7%), in the second-line setting in 32 patients (56%) and in the third-line setting or more in 21 patients (37%). With a median follow-up of 12 months (95% confidence interval [CI]: 9.9-21.0), the median TTF was 3.1 months (95% CI: 2.7-5.0). Among the 55 patients evaluable for ORR, best response was complete response/partial response in 6 patients (11%), stable disease in 18 patients (33%) and progressive disease in 31 patients (56%). The median OS was 14.6 months (95% CI: 9.0- not reached). TRAEs of grade III-IV were noted in 6 patients (10%) leading to treatment discontinuation, and no grade V TRAEs were observed.

Conclusion

PD-1/PD-L1 inhibitors exhibit limited activity as monotherapy in this pRCC population, which remains an unmet need. Our findings underline the need for further prospective clinical trials evaluating immune checkpoint inhibitor combinations in patients with pRCC.

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