CLO19-035: Safety Profile and Adverse Events of Sunitinib as a First-Line Treatment for Advanced/Metastatic Clear-Cell Renal Cell Carcinoma: Pooled Analysis of Randomized Controlled Trials

Background: Metastatic clear-cell renal cell carcinoma (RCC) is largely incurable, and its treatment remains challenging. Sunitinib, a tyrosine kinase inhibitor, is one of the current standard-of-care options for treatment-naïve patients with metastatic RCC. Despite the proven efficacy of sunitinib, prolonged treatment with some tyrosine kinase inhibitors (TKIs) has been associated with significant adverse events (AEs). Therefore, we aimed to calculate the exact prevalence of all sunitinib-related AEs in a pooled analysis from all available randomized controlled trials (RCTs). Methods: A comprehensive electronic database search was conducted for all RCTs comparing the clinical outcomes and adverse events of sunitinib versus all other available treatments for treatment-naïve advanced/metastatic clear-cell renal cell carcinoma. We then calculated the pooled prevalence of the most common reported side effects of sunitinib. All statistical analyses were performed using R Statistical Software v3.4.0 (R Foundation, Vienna, Austria). Results: We included 8 RCTs, with a total of 4,106 patients. The mean age was 62, with 66.44% males. Any grade AEs were reported in 72% of patients with the following frequencies: fatigue, 44%; diarrhea, 38%; nausea, 31%; hand-foot syndrome, 30%; hypertension, 27%; dysgeusia, 25%; hypothyroidism, 25%; cconstipation, 20%; stomatitis, 20%; inflammation of the mucosa, 18%; dyspepsia, 16%; vomiting, 14%; rash, 12%; asthenia, 11%; and epistaxis, 10%. Grade 3 (severe) AEs were reported in 52% of patients with the following frequencies: hypertension, 9%; fatigue, 8%; hand-foot syndrome, 5%; asthenia, 5%; diarrhea, 4%; and inflammation of the mucosa, 2%. Laboratory abnormalities were also reported as follows: increased AST, 7%; increased lipase, 6%; neutropenia, 6%; thrombocytopenia, 6%; hypophosphatemia, 5%; lymphocytopenia, 5%; anemia, 4%; and leukopenia, 3%. Conclusion: Despite sunitinib being one of the current standard treatments for patients with metastatic/advanced clear-cell RCC, its safety profile is concerning, with a high prevalence of reported dangerous side effects. These findings underscore the importance of the emergence of newer drugs and treatment plans for patients with metastatic RCC, not only to achieve similar or better clinical outcomes but also to decrease the burden of adverse events.

Download Full-text

Efficacy and safety profile of sunitinib as a first line treatment for advanced/metastatic clear-cell renal cell carcinoma: Pooled analysis of randomized controlled trials.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.e16067 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. e16067-e16067

Author(s):

Tarek Haykal ◽

Varun Samji ◽

Yazan Zayed ◽

Ragheed Al-Dulaimi ◽

Inderdeep Gakhal ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

Clear Cell ◽

Pooled Analysis ◽

Current Standard ◽

Cell Renal Cell Carcinoma ◽

Hand Foot Syndrome ◽

Treatment Naïve ◽

Grade 3

e16067 Background: Metastatic clear-cell renal cell carcinoma (RCC) is largely incurable, and its treatment remains challenging. Sunitinib, a tyrosine kinase inhibitor, is one of the current standard-of-care options for treatment-naïve patients with metastatic RCC. Despite the proven efficacy of Sunitinib, prolonged treatment with some tyrosine kinase inhibitors (TKIs) has been associated with significant adverse events (AEs). Therefore, we aimed to calculate the exact efficacy in addition to the prevalence of all AEs of Sunitinib in a pooled analysis from all available randomized controlled trials (RCTs). Methods: A comprehensive electronic database search was conducted for all RCTs comparing the clinical outcomes and adverse events of Sunitinib versus all other available treatments for treatment-naïve advanced/metastatic clear-cell renal cell carcinoma. We then calculated the pooled outcomes and prevalence of the most common reported side effects of Sunitinib. All statistical analyses were performed using R Statistical Software v3.4.0 (R Foundation, Vienna, Austria). Results: We included 8 RCTs, with a total of 4106 patients. The mean age was62, with 66.44% males.The efficacy of Sunitinib was reported as 3 main outcomes: Median progression free survival at 10.73 [7.76, 13.7] months, median overall survival at 23.28 [16.74, 29.81] months and the estimated objective response rate at 25[13, 37] %. Any grade AEs were reported in 72% of patients with the following frequencies: fatigue 44%, diarrhea 38%, nausea 31%, hand-foot syndrome 30%, hypertension 27%, dysgeusia 25%, hypothyroidism25%, constipation 20%, stomatitis 20%, inflammation of the mucosa 18%, dyspepsia 16%, vomiting 14%, rash 12%, asthenia 11%, and epistaxis10%.Grade 3&4 (severe) AEs were reported in 52% of patients with the following frequencies: hypertension 9%, fatigue 8%, hand-foot syndrome 5%, asthenia 5%, diarrhea 4%, and inflammation of the mucosa 2%. Conclusions: Despite Sunitinib being one of the current standard treatments for patients with metastatic/advanced clear-cell RCC, with well-described efficacy, its safety profile is still concerning with a significant prevalence of reported grade 3-4 AEs of 52% of the treated patients in the included RCTs. These findings underscore the importance of the emergence of newer drugs and treatment plans for patients with metastatic RCC, not only to achieve similar or better clinical outcomes but also to decrease the percentage of grade 3-4 AEs.

Download Full-text

Clinical activity of PD1/PDL1 inhibitors in metastatic non-clear cell renal cell carcinoma (nccRCC).

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.6_suppl.482 ◽

2017 ◽

Vol 35 (6_suppl) ◽

pp. 482-482 ◽

Cited By ~ 7

Author(s):

Raphael Brandao Moreira ◽

Rana R. McKay ◽

Wanling Xie ◽

Daniel Yick Chin Heng ◽

Guillermo de Velasco ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

Clear Cell ◽

Clinical Activity ◽

Significant Activity ◽

Cell Renal Cell Carcinoma ◽

Treatment Naïve ◽

Retrospective Multicenter Study

482 Background: PD1/PDL1 inhibitors have shown significant activity in the treatment of patients (pts) with metastatic clear cell renal cell carcinoma (ccRCC), but their activity in nccRCC is poorly characterized. Methods: We conducted a retrospective multicenter study of pts with metastatic nccRCC treated with PD1/PDL1 inhibitors. Baseline clinical parameters, overall response rate (ORR) by RECIST, time-to-treatment failure (TTF), and overall survival (OS) were summarized. Results: We identified 40 pts across 8 academic institutions. Fourteen (35%) had papillary histology, 10 (25%) chromophobe, 3 (8%) translocation, and 7 (18%) unclassified. Six (16%) had ccRCC with a sarcomatoid component > 30%. 20% had International Metastatic RCC Database Consortium (IMDC) favorable-risk disease, 60% intermediate, and 20% poor-risk. Ten (25%) were treatment-naïve and the majority received PD1/PDL1 monotherapy (n=30, 75%), while the remaining received a combination of PD1/PDL1 with anti-VEGF(R) or anti-CTLA4 therapy. ORR for the total cohort was 18% and 10% for PD1/PDL1 monotherapy pts (Table). With a median follow-up of 5.6 months, the overall median TTF was 4.7 months (2.9-15.9) and six-month OS was 81% (60-91%). Conclusions: PD1/PDL1 blockade resulted in some activity in pts with various nccRCC histologies. In the absence of available clinical trials, this data may support the use of PD1/PDL1 blocking agents in pts with nccRCC. [Table: see text]

Download Full-text

Results of a phase II study of atezolizumab and bevacizumab in non-clear cell renal cell carcinoma (nccRCC) and clear cell renal cell carcinoma with sarcomatoid differentiation (sccRCC).

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.7_suppl.548 ◽

2019 ◽

Vol 37 (7_suppl) ◽

pp. 548-548 ◽

Cited By ~ 15

Author(s):

Rana R. McKay ◽

Bradley Alexander McGregor ◽

Kathryn Gray ◽

John A. Steinharter ◽

Meghara K. Walsh ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Adverse Events ◽

Cell Carcinoma ◽

Phase Ii ◽

Renal Cell ◽

Clear Cell ◽

Collecting Duct ◽

Cell Renal Cell Carcinoma ◽

Histologic Subtype ◽

Sarcomatoid Differentiation

548 Background: NccRCC and sccRCC have historically been underrepresented in clinical trials. Even with targeted therapy, most patients have inferior survival compared to clear cell renal cell carcinoma. The combination of atezolizumab and bevacizumab has demonstrated safety and efficacy in ccRCC. In this multicenter, phase II, open-label, single arm trial we evaluate the efficacy of atezolizumab and bevacizumab in patients with nccRCC and sccRCC with >20% sarcomatoid differentiation. Methods: Eligible patients had an ECOG performance status of 0-2 and may have received prior therapy. Prior PD-1/PD-L1 therapy was not allowed. Patients underwent a mandatory baseline biopsy and subsequently received atezolizumab 120 mg and bevacizumab 15 mg/kg intravenously every 3 weeks. Patients remained on therapy until radiographic progression, unacceptable adverse events, or withdrawal. The primary end point was overall response rate (ORR) as determined by RECIST version 1.1. Results: 65 patients were enrolled of whom 52 had ≥1 response assessment and were included in this analysis. 36 patients had nccRCC (papillary n=14, chromophobe n=8, unclassified RCC n=3, collecting duct n=3, translocation n=3, other n=5), and 16 patients had sccRCC. 17 patients received prior systemic therapy, 16 of whom had nccRCC. The ORR was 31% in the overall cohort (Table 1). 10 patients (19%) developed grade 3 treatment-related adverse events (AEs), half of which were immune-related. There were no grade 4-5 AEs. Conclusions: In this study, we show that therapy with atezolizumab and bevacizumab was safe and demonstrated anti-tumor activity in nccRCC and sccRCC. Further analyses will report ORR by histologic subtype and PD-L1 expression status. Analysis of tissue and blood-based biomarkers of response are ongoing. Clinical trial information: NCT02724878. [Table: see text]

Download Full-text

Obesity induces limited changes to systemic and local immune profiles in treatment-naive human clear cell renal cell carcinoma

PLoS ONE ◽

10.1371/journal.pone.0233795 ◽

2020 ◽

Vol 15 (5) ◽

pp. e0233795 ◽

Cited By ~ 1

Author(s):

Justin T. Gibson ◽

Katlyn E. Norris ◽

Gal Wald ◽

Claire M. Buchta Rosean ◽

Lewis J. Thomas ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

Clear Cell ◽

Cell Renal Cell Carcinoma ◽

Treatment Naïve

Download Full-text

UNISON - nivolumab then ipilimumab + nivolumab in advanced non-clear cell renal cell carcinoma (ANZUP 1602): Part 1—Nivolumab monotherapy.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.6_suppl.325 ◽

2021 ◽

Vol 39 (6_suppl) ◽

pp. 325-325

Author(s):

Craig Gedye ◽

David William Pook ◽

Laurence Eliot Miles Krieger ◽

Carole A. Harris ◽

Jeffrey C. Goh ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Adverse Events ◽

Disease Control ◽

Cell Carcinoma ◽

Renal Cell ◽

Clear Cell ◽

Checkpoint Inhibitors ◽

Single Agent ◽

Cell Renal Cell Carcinoma ◽

Papillary Type

325 Background: Immune checkpoint inhibitors (ICI) are active in many cancers, but people with rare variant, non clear-cell renal cell carcinoma (nccRCC) have been excluded from most clinical trials in RCC. UNISON (NCT03177239) aimed to test 2 hypotheses; the activity of nivolumab in nccRCC (Part 1), and the benefit of adding ipilimumab to nivolumab, in people whose cancers progress on nivolumab (Part 2). Methods: 83 participants (pts) with advanced nccRCC with good (ECOG0/1) performance status, were enrolled including papillary type 1 (17%), papillary type 2 (28%), chromophobe (18%), Xp11 translocation (6%), hereditary leiomyomatosis renal cell carcinoma syndrome-associated renal cell carcinoma (6%), RCC unclassified (10%) and other (15%) histological subtypes. Participants took nivolumab (N) 240mg every two weeks in Part 1 in total. If they experienced progression and remained eligible they could take N (3mg/kg) plus ipilimumab (I; 1mg/kg) every 3 weeks for up to 4 doses (Part 2). Pts with disease control after N or N + I could continue N for up to 1 year. UNISON was powered to distinguish a clinically-relevant improvement in objective tumor response rate (OTRR) from 15% to 30% in people taking N+I in Part 2 in pts whose cancers were refractory to single-agent first-line N. Here we report results of Part 1. Results: Pts experience of N appeared similar to previous reports, with most experiencing mild adverse events. 12 treatment related SAE occurred in 11 patients (13%). 14 pts (17%) experienced treatment delays, or permanent treatment discontinuation (10%). The median time on treatment was 5.1 months. The OTRR was 17% with 3 complete responses and 11 partial responses. The median duration of response was 21 months. Stable disease occurred in 49% of pts and disease progression in 34%. The disease control rate at 6 months was 45% (95% CI: 34%, 56%). The median PFS was 4.0 months (95% CI: 3.6, 7.4). The 6 month progression-free survival (PFS) was 45% (95% CI: 34-55) and the 12 months PFS was 30% (95% CI: 21%, 40%). Conclusions: Pts with nccRCC treated with N experience similar adverse events compared to pts with other cancers. A substantial minority of people with nccRCC derive benefit, but many pts have cancers refractory to anti-PD1, similar to other reports. The activity of I and N in this PD1-refractory population is of considerable interest and will be reported at a later date. Clinical trial information: NCT03177239 .

Download Full-text

The 2021 Updated European Association of Urology Guidelines on Renal Cell Carcinoma: Immune Checkpoint Inhibitor–based Combination Therapies for Treatment-naive Metastatic Clear-cell Renal Cell Carcinoma Are Standard of Care

European Urology ◽

10.1016/j.eururo.2021.04.042 ◽

2021 ◽

Author(s):

Jens Bedke ◽

Laurence Albiges ◽

Umberto Capitanio ◽

Rachel H. Giles ◽

Milan Hora ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

Immune Checkpoint Inhibitor ◽

Clear Cell ◽

Checkpoint Inhibitor ◽

Standard Of Care ◽

Combination Therapies ◽

Cell Renal Cell Carcinoma ◽

Treatment Naïve

Download Full-text

416 An open-label phase 2 study of 2 doses of the hypoxia-inducible factor (HIF)–2α inhibitor belzutifan for the treatment of advanced clear cell renal cell carcinoma after progression on systemic therapy

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2021-sitc2021.416 ◽

2021 ◽

Vol 9 (Suppl 3) ◽

pp. A446-A446

Author(s):

Michael Atkins ◽

Yanfang Liu ◽

Rodolfo Perini ◽

Ananya Roy ◽

John Haanen

Keyword(s):

Renal Cell Carcinoma ◽

Adverse Events ◽

Cell Carcinoma ◽

Systemic Therapy ◽

Renal Cell ◽

Clear Cell ◽

Phase 2 ◽

Open Label ◽

Cell Renal Cell Carcinoma ◽

Once Daily

BackgroundAccumulation and aberrant stabilization of transcription factor HIF-2α drives the expression of genes associated with progression of clear cell renal cell carcinoma (ccRCC). Belzutifan, a first-in-class HIF-2α inhibitor, has demonstrated promising antitumor activity with a favorable safety profile in patients with heavily pretreated ccRCC. The efficacy and safety of 2 doses of belzutifan in patients with advanced ccRCC who experienced progression after systemic therapy will be evaluated in this randomized, open-label, multicenter, phase 2 trial (NCT04489771).MethodsApproximately 150 adults will be randomly assigned 1:1 to receive oral belzutifan 120 mg once daily or 200 mg once daily. Patients with locally advanced or metastatic ccRCC (per RECIST v1.1) who experienced progression on or after 1 line of anti–PD-1/PD-L1 therapy as monotherapy or combined with other agents, with the immediately preceding line of treatment an anti–PD-1/PD-L1 therapy, will be enrolled. Progression is defined as received ≥2 doses of an anti–PD-1/PD-L1 agent and having demonstrated radiographic disease progression (per investigator). Other key eligibility criteria: ≤3 prior systemic regimens and a Karnofsky Performance Status Scale score ≥70%. Patients who previously received belzutifan or another HIF-2α inhibitor; require supplemental oxygen; have a baseline hemoglobin level <10 g/dL; have a history of HIV, hepatitis B, or hepatitis C infection; or have active central nervous system metastases are excluded. Patients will be stratified by International mRCC Database Consortium prognostic scores (0, 1 or 2, or 3–6) and by number of prior tyrosine kinase inhibitor–containing therapies (0, 1, or 2 or 3). Treatment will continue until progression, unacceptable toxicity, or withdrawal of consent. Computed tomography or magnetic resonance imaging will be performed at baseline, every 8 weeks through week 49, and every 12 weeks thereafter. Adverse events will be monitored throughout the study and for 30 days after treatment (90 days for serious adverse events). The primary end point is objective response rate per RECIST v1.1 by blinded independent central review (BICR). Secondary end points are progression-free survival, duration of response, and clinical benefit rate per RECIST v1.1 by BICR, overall survival, pharmacokinetics, and safety. The study will enroll patients in at least 9 countries (Australia, Belgium, Greece, Ireland, Israel, Netherlands, Russia, the United Kingdom, and the United States) and is recruiting.AcknowledgementsMedical writing and/or editorial assistance was provided by Matthew Grzywacz, PhD of ApotheCom (Yardley, PA, USA). This assistance was funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Funding for this research was provided by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.Trial RegistrationClinicaltrials.gov, NCT04489771Ethics ApprovalThe study and the protocol were approved by the Institutional Review Board or ethics committee at each site.

Download Full-text