New Treatments for Renal Cell Carcinoma: Targeted Therapies

Systemic treatment options for advanced renal cell carcinoma (RCC) have expanded considerably with the development of targeted therapies. Clear cell RCC commonly features mutation or inactivation of the von Hippel-Lindau gene and resultant overexpression of vascular endothelial growth factor (VEGF). The first drug to validate VEGF as a target in the treatment of clear cell RCC was the monoclonal antibody bevacizumab. Since then, anti-VEGF receptor therapy with multitargeted kinase inhibitors also has shown substantial efficacy. Sunitinib is now a standard first-line therapy for advanced disease and sorafenib is among the second-line treatment options. Other kinase inhibitors are in development. Mammalian target of rapamycin (mTOR) is a second validated therapeutic target as the mTOR inhibitor temsirolimus has been shown to prolong survival in first-line treatment of poor prognosis RCC of all histologies. Everolimus is an oral mTOR inhibitor and has been shown to prolong progression-free survival when used in second-line treatment. Non-clear cell and sarcomatoid RCC are both underrepresented in completed trials but are the subject of active research. Ongoing and planned studies will also evaluate the use of combinations of targeted agents, a strategy that is not advisable outside of clinical trials. Finally, postnephrectomy adjuvant treatment with targeted agents is not yet standard but is under investigation in phase III trials.

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Adjusted indirect comparison of everolimus and sorafenib in sunitinib-refractory mRCC patients using a robust matching technique.

Journal of Clinical Oncology ◽

10.1200/jco.2011.29.7_suppl.378 ◽

2011 ◽

Vol 29 (7_suppl) ◽

pp. 378-378

Author(s):

G. Di Lorenzo ◽

R. Casciano ◽

E. Malangone ◽

C. Buonerba ◽

S. Sherman ◽

...

Keyword(s):

Kinase Inhibitors ◽

Clear Cell ◽

Treatment Options ◽

Indirect Comparison ◽

Phase Iii ◽

Line Treatment ◽

Second Line ◽

Score Distribution ◽

Random Samples ◽

Comparison Results

378 Background: Vascular endothelial growth factor receptor–tyrosine kinase inhibitors (VEGFr-TKIs) sunitinib (SU) and sorafenib (SO) are approved for first- and second-line (after cytokines) use in metastatic renal cell carcinoma (mRCC). Because most patients progress after first-line VEGFr-TKI, the need for an effective second-line treatment is compelling. Although SO is frequently considered after SU failure, no randomized controlled trials have established clinical benefit in this scenario. Results from the RECORD-1 phase III trial suggest that second-line everolimus (EVE) therapy leads to improved overall survival (OS) vs. placebo. No trial data exist comparing treatment outcomes for EVE vs SO in the second-line setting. Thus, the current analysis provides a robust estimate from an indirect comparison examining the OS benefit of EVE and SO as second-line treatment options after SU failure. Methods: The single-arm SO study was selected as a basis by which to match an EVE SU-refractory subpopulation of the RECORD-1 trial. Patients were limited to those with clear cell histology. An adjusted matching approach was taken in which 1,000 repeated random samples matched to the SO population on risk score distribution were produced. These data were used to generate a distribution of survival outcomes and infer a 95% CI around the mean of all sampled median OS estimates. Results: After adjusted matching, the estimated median OS benefit, based on SO patients with clear cell histology (n = 45) and 1000 random samples of n = 41 from the 127 SU-refractory EVE patients, was 82 weeks (95% CI: 78, 86) and 32 weeks (95% CI: 22, 64) for EVE and SO, respectively. Conclusions: These indirect comparison results suggest that SU-refractory mRCC patients treated with EVE may experience significantly improved OS outcomes compared with patients treated with SO. [Table: see text]

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Second-line treatment of metastatic renal cell carcinoma: The Institut Gustave Roussy experience with targeted therapies in 251 consecutive patients.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.e15049 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. e15049-e15049

Author(s):

Antonin Levy ◽

Jean Menard ◽

Laurence Albiges ◽

Mario Di Palma ◽

Karim Fizazi ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Targeted Therapy ◽

Cell Carcinoma ◽

Targeted Therapies ◽

Predictive Factor ◽

Renal Cell ◽

Line Treatment ◽

Second Line ◽

First Line

e15049 Background: Sequential treatment is currently the standard of care in metastatic renal cell carcinoma (mRCC). However, very little is known on how many patients (pts) can receive second line or further, and on how to predict those pts. Methods: Data from all mRCC patients treated at the IGR from 2005 to 2009 with first-line targeted therapy (sunitinib (SU), sorafenib (SO), bevacizumab (B), temsirolimus or everolimus (pooled together as mTOR)) were analyzed. Only patients with subsequent follow up have been included in this analysis. Patients were defined as “non eligible” for second treatment if: they were (i) still on first line treatment, (ii) not showing progressive (durable stable disease or partial response or complete response), or (iii) if they refused a second line treatment. Results: 251 patients, median age 60 years, median follow-up 20.2 months were treated with targeted therapy with a median OS of 25.8 months. Median OS with SU (127), SO (60) or B (61) were respectively 26.3, 16.4 and 32.5 months respectively. Only 3 patients received an mTOR inhibitor as first line. According to the eligibility criteria, the percentage of patients who received a second line was 59% (n=61/103), 52% (n=30/58) and 79% (n=38/48) for Su, So and B, respectively. MSKCC classification (p = 0.02) and first line agent (p = 0.001) were significant predictive factor for receiving a second line of treatment. Overall, patients receiving B were in better general condition, with 77% of PS = 0 compared to SO (53%) and SU (48%) (p = 0.005). Among the 131 patients who received a second line, the median OS from the start of second line treatment was 20.8 months for a TKI (n=98; 75%) and 16.6 months for an mTOR (n=32; 42%) (p = 0.12). Furthermore, the percentage of patients who received a third line was 56% (27/48), 28% (7/25) and 65% (13/20) for SU, SO and B, respectively. Conclusions: The median OS in patients treated with targeted therapies for mRCC in The Institut Gustave Roussy exceeds 2 years. The use of second line varies from 52% to 79%. Further studies are needed to validate the MSKCC groups and first line therapy as predictive factor for 2nd line treatment.

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Consensus paper: current state of first- and second-line therapy in advanced clear-cell renal cell carcinoma

Future Oncology ◽

10.2217/fon-2020-0403 ◽

2020 ◽

Vol 16 (29) ◽

pp. 2307-2328

Author(s):

Peter J Goebell ◽

Philipp Ivanyi ◽

Jens Bedke ◽

Lothar Bergmann ◽

Dominik Berthold ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

Clear Cell ◽

Treatment Options ◽

Treatment Strategies ◽

Second Line ◽

First Line ◽

Cell Renal Cell Carcinoma ◽

New Treatments

The therapy of advanced (clear-cell) renal cell carcinoma (RCC) has recently experienced tremendous changes. Several new treatments have been developed, with PD-1 immune-checkpoint inhibition being the backbone of therapy. Diverse immunotherapy combinations change current first-line standards. These changes also require new approaches in subsequent lines of therapy. In an expert panel, we discussed the new treatment options and how they change clinical practice. While first-line immunotherapies introduce a new level of response rates, data on second-line therapies remains poor. This scenario poses a challenge for clinicians as guideline recommendations are based on historical patient cohorts and agents may lack the appropriate label for their in guidelines recommended use. Here, we summarize relevant clinical data and consider appropriate treatment strategies.

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Improving Outcomes in Metastatic Clear Cell Renal Cell Carcinoma by Sequencing Therapy

American Society of Clinical Oncology Educational Book ◽

10.14694/edbook_am.2014.34.e228 ◽

2014 ◽

pp. e228-e238 ◽

Cited By ~ 10

Author(s):

Manuela Schmidinger

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

Drug Exposure ◽

Clear Cell ◽

Local Treatment ◽

Line Treatment ◽

Second Line ◽

First Line ◽

Cell Renal Cell Carcinoma

Targeted agents have substantially improved outcomes in metastatic clear cell renal cell carcinoma. However, due to multiple mechanisms of evasive resistance, almost all patients progress at some point and may require subsequent therapies. Various agents have been explored after failure of first-line treatment in randomized clinical trials. However, so far few questions about the optimal sequence have been answered. Both everolimus and axitinib have been considered standard of care after failure of first-line VEGF-TKI; sorafenib has been proposed as an additional option. In clinical practice, several factors may influence the choice of subsequent treatment: these include considerations on appropriate drug exposure in first-line, gained insights on prognostic and predictive factors as well as mechanisms of resistance. Once the decision in second-line has been made and treatment has been initiated, treating physicians may already be challenged by the question of what to offer in third- and later lines. Treatment beyond second-line treatment isn't supported by strong evidence, and at this stage of disease, retrospective reports on rechallenge may help to guide decisions. In addition, local treatment approaches including metastasectomy and stereotactic radiosurgery may help to optimize outcomes in all treatment lines.

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Trends in exposure to multiple lines of treatment and survival of patients with metastatic renal cell carcinoma: A real-world analysis.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.e16064 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. e16064-e16064

Author(s):

Raffaele Ratta ◽

Massimo Di Maio ◽

Elena Verzoni ◽

Paolo Grassi ◽

Rosanna Montone ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Metastatic Renal Cell Carcinoma ◽

Renal Cell ◽

Treatment Options ◽

Line Treatment ◽

Second Line ◽

First Line ◽

Period 2 ◽

First Line Treatment

e16064 Background: In recent years, several new agents have been introduced into clinical practice for patients (pts) with metastatic renal cell carcinoma (mRCC). The aim of this study was to describe the difference in terms of exposure to multiple lines of treatment and overall survival (OS) between two groups of pts who started therapy for mRCC in two different periods of time (period 1: 2005-2010 and period 2: 2011-2016). Methods: Data were retrospectively collected from the database of the Istituto Nazionale Tumori of Milan. The proportion of pts who received subsequent lines of treatment after first disease progression (PD) was compared between the two groups of pts. OS was defined as time from the start of first-line treatment to death or last follow-up. Unadjusted and adjusted analyses for Heng risk groups were done. Results: Overall,457 pts with mRCC were evaluated: 274 pts (60%) started treatment in period 1 and 183 (40%) in period 2. Most pts in both groups had intermediate risk (65.7% and 86.3% respectively). The proportion of poor-risk pts was significantly higher in period 1 (21.2% vs 7.7%). Among pts who stopped first-line treatment due to PD, pts in period 2 had a higher chance of receiving second-line treatment as compared to pts of period 1 (80.8% vs 64.7%, 95% CI 1.31-4.04, p = 0.003). Similarly, among those who stopped second-line treatment due to PD, pts in period 2 had a higher chance of receiving a third-line treatment compared to pts in period 1 (71.2% vs 49.3%, 95% CI 1.32-4.87, p = 0.004). In the whole study population, median OS (mOS) was 24.9 months (95% CI 21.6-31.1): 21.7 months (95% CI 18.8-26.3) in pts of period 1 and 38.2 months (95% CI 27.7-49.0) in pts of period 2 (Hazard Ratio [HR] 0.65,95% CI 0.49-0.84, p = 0.001) respectively. When adjusted for Heng groups, OS remained significantly longer for pts of period 2 (HR 0.76, 95% CI 0.57-1.00, p = 0.05). Conclusions: mRCC pts who started a treatment over the last 5 years have been exposed to a higher number of treatment lines as compared to those treated before 2011. Our data suggest that the increase of treatment options as well as a better clinicians’ expertise is associated with a better outcome.

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Patient profiles as an aim to optimize selection in the second line setting: the role of aflibercept

Clinical & Translational Oncology ◽

10.1007/s12094-021-02568-y ◽

2021 ◽

Author(s):

B. González Astorga ◽

F. Salvà Ballabrera ◽

E. Aranda Aguilar ◽

E. Élez Fernández ◽

P. García-Alfonso ◽

...

Keyword(s):

Colorectal Cancer ◽

Therapeutic Option ◽

Scientific Evidence ◽

Treatment Options ◽

Line Treatment ◽

Second Line ◽

First Line ◽

Effective Therapeutic Option ◽

Line Setting ◽

First Line Treatment

AbstractColorectal cancer is the second leading cause of cancer-related death worldwide. For metastatic colorectal cancer (mCRC) patients, it is recommended, as first-line treatment, chemotherapy (CT) based on doublet cytotoxic combinations of fluorouracil, leucovorin, and irinotecan (FOLFIRI) and fluorouracil, leucovorin, and oxaliplatin (FOLFOX). In addition to CT, biological (targeted agents) are indicated in the first-line treatment, unless contraindicated. In this context, most of mCRC patients are likely to progress and to change from first line to second line treatment when they develop resistance to first-line treatment options. It is in this second line setting where Aflibercept offers an alternative and effective therapeutic option, thought its specific mechanism of action for different patient’s profile: RAS mutant, RAS wild-type (wt), BRAF mutant, potentially resectable and elderly patients. In this paper, a panel of experienced oncologists specialized in the management of mCRC experts have reviewed and selected scientific evidence focused on Aflibercept as an alternative treatment.

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