scholarly journals 417 Phase 3 study of pembrolizumab + belzutifan + lenvatinib or pembrolizumab/quavonlimab + lenvatinib versus pembrolizumab + lenvatinib as first-line treatment for advanced renal cell carcinoma

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A447-A447
Author(s):  
Toni Choueiri ◽  
Elizabeth Plimack ◽  
Thomas Powles ◽  
Martin Voss ◽  
Howard Gurney ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Antitumor Activity ◽  
Line Treatment ◽  
First Line ◽  
Phase 3 ◽  
End Points ◽  
Once Daily ◽  
Link Type ◽  
The World ◽  
First Line Treatment

BackgroundPembrolizumab + vascular endothelial growth factor (VEGF) inhibitor lenvatinib demonstrated antitumor activity as first-line treatment for advanced clear cell renal cell carcinoma (ccRCC) in phase 3 trial KEYNOTE-581/CLEAR (NCT02811861). Hypoxia-inducible factor 2α (HIF-2α) inhibitor belzutifan (MK-6482) showed antitumor activity in ccRCC, and a coformulation of pembrolizumab and CTLA-4 inhibitor quavonlimab (MK-1308A) showed antitumor activity in non–small cell lung cancer. HIF-2α or CTLA-4 inhibition with PD-1 and VEGF inhibition backbone combination may provide additional benefit as first-line treatment in ccRCC. This open-label, randomized, phase 3 study (NCT04736706) will be conducted to compare novel combination therapies pembrolizumab + belzutifan + lenvatinib (arm A) and MK-1308A + lenvatinib (arm B) with pembrolizumab + lenvatinib (arm C).MethodsApproximately 1431 adults with metastatic ccRCC, measurable disease per RECIST v1.1, and Karnofsky Performance Status Scale score ≥70% who had not previously undergone systemic therapy for advanced ccRCC will be enrolled. Patients will be randomly assigned 1:1:1 to arm A (belzutifan 120 mg + lenvatinib 20 mg oral once daily + pembrolizumab 400 mg IV every 6 weeks), arm B (MK-1308A [quavonlimab 25 mg + pembrolizumab 400 mg] IV every 6 weeks and lenvatinib 20 mg oral once daily), or arm C (pembrolizumab 400 mg IV every 6 weeks + lenvatinib 20 mg oral once daily). Treatment will continue until documented disease progression, withdrawal of consent, or other discontinuation event; patients will receive pembrolizumab and MK-1308A for up to 18 cycles (approximately 2 years). Patients will be stratified by International mRCC Database Consortium (IMDC) score (favorable vs intermediate vs poor), region of the world (North America vs Western Europe vs rest of the world), and sarcomatoid features (yes vs no). Response will be assessed by CT or MRI per RECIST v1.1 by blinded independent central review (BICR) at week 12 from randomization, every 6 weeks through week 78, and every 12 weeks thereafter. Adverse events and serious adverse events will be monitored throughout the study and for 90 days after treatment. Dual primary end points are progression-free survival per RECIST v1.1 by BICR and overall survival. Primary end points will be assessed in arm A compared with arm C and in arm B compared with arm C for patients with IMDC intermediate/poor status and in all patients regardless of IMDC status. Secondary end points are objective response rate and duration of response per RECIST v1.1 by BICR, patient-reported outcomes, and safety.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, and Eisai Inc., Woodcliff Lake, NJ, USA. Funding for this research was provided by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA,Eisai Inc., Woodcliff Lake, NJ, USA.Trial RegistrationClinicaltrials.gov, NCT04736706Ethics ApprovalThe study and the protocol were approved by the Institutional Review Board or ethics committee at each site.

Relative risk of hematological toxicities in patients with advanced renal cell carcinoma treated with upfront immune checkpoint inhibitors.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 675-675
Author(s):  
Nusrat Jahan ◽  
Somedeb Ball ◽  
Miguel Quirch ◽  
Shabnam Rehman ◽  
Kyaw Zin Thein ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Relative Risk ◽  
Immune Checkpoint ◽  
Renal Cell ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Line Treatment ◽  
First Line ◽  
Phase 3 ◽  
First Line Treatment

675 Background: Sunitinib was the standard first-line treatment of advanced renal cell carcinoma (aRCC) for the past decade, but it has been associated with significant hematological toxicities. Immune checkpoint inhibitors (ICI) based regimens have become the new preferred treatment for aRCC in the first-line setting. We conducted a meta-analysis of phase 3 randomized controlled trials (RCTs) to determine the relative risk of hematological toxicities associated with upfront use of ICI-based regimens for aRCC. Methods: We conducted a systematic search at PUBMED, MEDLINE, EMBASE, and meeting abstracts as per PRISMA guidelines from inception until May 2019. Phase 3 RCTs using ICIs in the intervention arm for the first-line treatment of aRCC were included. We used the Mantel-Haenszel (MH) method utilizing random effects model to calculate pooled risk ratio (RR) with 95% confidence interval (CI). Heterogeneity was tested with I2 value. Results: Four phase 3 RCTs, CheckMate 214, IMmotion151, JAVELIN Renal 101 and KEYNOTE-426, randomizing 3706 patients were included in the analysis of anemia and thrombocytopenia. CheckMate 214 did not report the number of neutropenia. Hence, other 3 RCTs that included 2624 patients were analyzed for neutropenia. Following regimens were used in the study arms — CheckMate 214: nivolumab+ipilimumab, IMmotion151: atezolizumab+bevacizumab, JAVELIN Renal 101: axitinib+avelumab; and KEYNOTE-426: axitinib+ pembrolizumab. Sunitinib was used in the control arms for all the studies. The pooled RR of any-grade hematological toxicities are as follows — anemia: 0.31 (95% CI:0.24-0.41, P< 0.00001, I2=39%); thrombocytopenia: 0.11 (95% CI: 0.06-0.19, P<0.00001, I2=63%); neutropenia: 0.08 (95% CI: 0.05-0.13, P<0.00001, I2=0%). The pooled RR of grade 3 and higher hematological toxicities are as follows — anemia: 0.14 (95% CI:0.08-0.25, P< 0.00001, I2=0); thrombocytopenia: 0.06 (95% CI:0.02-0.16, P<0.00001, I2=4%); neutropenia: 0.06 (95% CI: 0.02-0.16, P<0.00001, I2=0%). Conclusions: ICI-based regimens have significantly reduced risk of any-grade as well as high-grade hematological toxicities compared to sunitinib in patients with aRCC.

A phase 3 trial to compare efficacy and safety of lenvatinib in combination with everolimus or pembrolizumab versus sunitinib alone in first-line treatment of patients with metastatic renal cell carcinoma.

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. TPS706-TPS706 ◽  
Author(s):  
Robert J. Motzer ◽  
Viktor Grünwald ◽  
Thomas E. Hutson ◽  
Camillo Porta ◽  
Thomas Powles ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Growth Factor ◽  
Cell Carcinoma ◽  
Metastatic Renal Cell Carcinoma ◽  
Renal Cell ◽  
Growth Factor Receptor ◽  
Line Treatment ◽  
First Line ◽  
Phase 3 ◽  
First Line Treatment

TPS706 Background: Lenvatinib (LEN) is a multikinase inhibitor of vascular endothelial growth factor (VEGF) receptor 1–3, fibroblast growth factor receptor 1–4, platelet-derived growth factor receptor alpha, and RET and KIT. Based on a phase 2 study (Motzer et al. Lancet Oncol. 2015), LEN was approved in combination with everolimus (EVE) for the treatment of metastatic renal cell carcinoma (RCC) following 1 prior VEGF-targeted therapy. A phase 1b/2 study of LEN in combination with pembrolizumab (PEM) in patients (pts) with RCC LEN is also underway. We report the design of a multicenter, open-label, phase 3 trial of LEN plus EVE or PEM vs sunitinib (SUN; a standard therapy for RCC) as first-line treatment for advanced RCC. Methods: Pts aged ≥ 18 years with confirmed advanced RCC diagnosis, ≥ 1 measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, Karnofsky Performance Status ≥ 70, controlled blood pressure, and adequate blood coagulation, renal, hepatic, and bone marrow function are eligible. Pts will be randomized 1:1:1 to receive LEN 18 mg/d + EVE 5 mg/d, LEN 20 mg/d + PEM 200 mg every 3 wks, or SUN 50 mg/d (on a schedule of 4 wks on treatment followed by 2 wks off) until disease progression, unacceptable toxicity, withdrawal of consent, or study end. The primary endpoint is to show superiority of LEN+EVE or LEN+PEM over single-agent SUN as first-line treatment for advanced RCC in improving progression-free survival (PFS). Secondary endpoints include comparison of objective response rate, overall survival, PFS on next-line therapy, health-related quality of life, and safety and tolerability in pts receiving LEN+EVE or LEN+PEM vs SUN. Exploratory endpoints include PFS in the LEN+PEM arm using immune-related RECIST, comparison of duration of response, disease control rate, and clinical benefit rate in pts treated with LEN+EVE or LEN+PEM vs SUN, and analysis of the relationship between blood biomarkers and outcome. No interim analysis is planned for efficacy or futility. Enrollment of 735 pts is planned to achieve 90% power at 2-sided α = 0.05 to detect a difference in ≥ 1 of the primary comparisons. Clinical trial information: NCT02811861.

scholarly journals Phase II trial of continuous once-daily dosing of sunitinib as first-line treatment in patients with metastatic renal cell carcinoma

Cancer ◽  
2011 ◽  
Vol 118 (5) ◽  
pp. 1252-1259 ◽  
Author(s):  
Carlos H. Barrios ◽  
David Hernandez-Barajas ◽  
Michael P. Brown ◽  
Se-Hoon Lee ◽  
Luis Fein ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Phase Ii ◽  
Metastatic Renal Cell Carcinoma ◽  
Renal Cell ◽  
Phase Ii Trial ◽  
Line Treatment ◽  
First Line ◽  
Once Daily ◽  
First Line Treatment

Lenvatinib (len) plus pembrolizumab (pembro) for the first-line treatment of patients (pts) with advanced hepatocellular carcinoma (HCC): Phase 3 LEAP-002 study.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. TPS4152-TPS4152 ◽  
Author(s):  
Josep M Llovet ◽  
Masatoshi Kudo ◽  
Ann-Lii Cheng ◽  
Richard S. Finn ◽  
Peter R. Galle ◽  
...  
Keyword(s):  
Objective Response ◽  
Locoregional Therapy ◽  
Advanced Hepatocellular Carcinoma ◽  
Line Treatment ◽  
First Line ◽  
Phase 3 ◽  
End Points ◽  
Advanced Hcc ◽  
Ecog Ps ◽  
First Line Treatment

TPS4152 Background: Len, an inhibitor of VEGF receptors 1-3, FGF receptors 1-4, PDGF receptor α, RET, and KIT, is approved for first-line treatment of unresectable HCC (uHCC) based on the open-label phase 3 REFLECT study in which len showed noninferior overall survival (OS) and significantly improved objective response rate (ORR), progression-free survival (PFS), and time-to-progression (TTP) vs sorafenib. In the phase 2 KEYNOTE-224 study of pembro (a PD-1 inhibitor) as second-line treatment of advanced HCC, pembro showed meaningful clinical efficacy in pts previously treated with sorafenib, with median PFS 4.9 mo, median OS 12.9 mo, and a manageable safety profile. In results from the phase 1b KEYNOTE-524 trial, len+pembro was well-tolerated, with promising antitumor activity in pts with uHCC. LEAP-002 is a phase 3 study to evaluate the safety and efficacy of len+pembro vs len+placebo as first-line therapy for advanced HCC. Methods: Eligible pts are ≥18 y and have HCC confirmed by radiology, histology, or cytology; ECOG PS 0/1; BCLC stage C or stage B disease not amenable to locoregional therapy or curative treatment approach; CP class A liver score within 7 days before study; and ≥1 measurable lesion by RECIST v1.1. Pts with past or ongoing HCV infection and those with controlled HBV are eligible. 750 pts will be randomized 1:1 to receive len 12 mg (body weight [BW] ≥60 kg) or 8 mg (BW <60 kg) orally once daily plus pembro 200 mg or placebo IV Q3W. Pembro and len will be administered until disease progression or unacceptable toxicity, with a maximum 35 cycles for pembro. Stratification will be by geographic region (Asia vs Japan and Western regions); macroscopic portal vein invasion or extrahepatic spread or both (yes or no); alpha fetoprotein ≤400 ng/mL vs >400 ng/mL; and ECOG PS 0/1. Primary end points are PFS per RECIST v1.1 by blinded independent central review (BICR) and OS. Secondary end points are ORR, duration of response, disease control rate, and TTP per RECIST v1.1 by BICR, efficacy per modified RECIST, pharmacokinetics, and safety. Imaging assessments will be performed Q9W on study. AEs will be graded per CTCAE v4.0 and monitored up to 90 days after last dose. Clinical trial information: NCT03713593.

Relative risk of pneumonitis associated with first-line use of immune checkpoint inhibitors in advanced renal cell carcinoma.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 676-676
Author(s):  
Nusrat Jahan ◽  
Francis Mogollon-Duffo ◽  
Srikala Meda ◽  
Fred L. Hardwicke ◽  
Lukman Aderoju Tijani
Keyword(s):  
Renal Cell Carcinoma ◽  
Relative Risk ◽  
Immune Checkpoint ◽  
Renal Cell ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Line Treatment ◽  
First Line ◽  
Phase 3 ◽  
First Line Treatment

676 Background: After approval in 2006, sunitinib remained the standard for the first line treatment of advanced renal cell carcinoma (aRCC) for a decade. Immune checkpoint inhibitors (ICI) have changed the landscape of aRCC management in recent years. Pneumonitis is a significant immune related adverse event (iRAE) associated with ICIs causing morbidity, mortality and treatment interruption. We conducted a meta-analysis of phase 3 randomized controlled trials (RCTs) to determine the relative risk of pneumonitis associated with first line use of ICIs for aRCCs. Methods: We conducted a systematic search using PUBMED, MEDLINE, EMBASE, and meeting abstracts as per PRISMA guidelines from inception until May 2019. Phase 3 RCTs using ICIs in the intervention arm for the first line treatment of aRCC and reporting the number of pneumonitis for both intervention and control arms were included in the analysis. We used the Mantel-Haenszel (MH) method utilizing random effects model to calculate pooled risk ratio (RR) with 95% confidence interval (CI). Heterogeneity was tested with I2 value. Results: Three phase 3 RCTs, CheckMate 214, IMmotion151 and KEYNOTE-426, randomizing 2833 patients (1427 in the ICI arms and 1406 in the control arms) were included in the analysis. ICI regimens used in the study arms were as follows — CheckMate 214: nivolumab and ipilimumab, IMmotion151: atezolizumab and bevacizumab, and KEYNOTE-426: pembrolizumab and axitinib. Sunitinib was used for all the control arms. Randomization was 1:1 in all three studies. Pneumonitis of any-grade was reported in 56 (3.92%) patients in the ICI arms versus 1 (0.07%) patient in the control arms. The pooled RR of any grade pneumonitis was 22.11 (95% CI: 5.34-91.55, P<0.0001, I2=0%). Grade 3 and above pneumonitis was reported in 12 (0.84%) patients in the ICI arms versus 0 (0%) patient in the control arms with pooled RR of 8.39 (95% CI: 1.54-45.80, P=0.01, I2=0%). Conclusions: The relative risk of any-grade as well as high-grade pneumonitis are significantly higher with ICI based regimens compared to sunitinib for aRCC. Early detection and prompt intervention are vital to reduce morbidy and mortality associated with this iRAE.

346 KEYNOTE-991: phase 3 study of pembrolizumab plus enzalutamide and androgen deprivation therapy (ADT) for patients with metastatic hormone-sensitive prostate cancer (mHSPC)

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A371-A371
Author(s):  
Christian Gratzke ◽  
Christian Gratzke ◽  
Christian Gratzke ◽  
Cuizhen Niu ◽  
Christian Poehlein ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Antitumor Activity ◽  
The United States ◽  
Phase 3 ◽  
End Points ◽  
Once Daily ◽  
Link Type ◽  
Patient Reported ◽  
Biomarker Analysis ◽  
Modified Recist

BackgroundCombination of pembrolizumab, an anti–PD-1 antibody, added to enzalutamide, a nonsteroidal antiandrogen agent, has shown antitumor activity in abiraterone-resistant mCRPC (KEYNOTE-365, NCT02861573) and in patients with mCRPC for whom enzalutamide was ineffective (KEYNOTE-199, NCT02787005). These data indicate that the combination of pembrolizumab + enzalutamide with ADT warrants phase 3 evaluation. Also, efficacy in enzalutamide may be proimmunogenic, suggesting that it may be additive or synergistic in antitumor activity when combined with pembrolizumab.MethodsThe KEYNOTE-991 (NCT04191096) phase 3 trial will evaluate the efficacy and safety of enzalutamide + ADT (LHRH agonist/antagonist during study treatment or bilateral orchiectomy) + pembrolizumab or placebo in patients with mHSPC. Eligibility criteria include age ≥18 years, mHSPC, ≥2 bone lesions or visceral disease, no prior treatment with next-generation hormone agents, adequate organ function, and ECOG PS 0 or 1. Patients must provide tissue for biomarker analysis. Approximately 1232 patients will be randomized in a 1:1 ratio to receive enzalutamide 160 mg orally once daily + ADT + pembrolizumab 200 mg IV every 3 weeks (Q3W) or enzalutamide 160 mg orally once daily + ADT + placebo IV Q3W. Treatment will continue with pembrolizumab up to 35 cycles and treatment with enzalutamide will proceed continuously from day 1 of cycle 1 until disease progression, unacceptable toxicity, or withdrawal of consent. The stratification factors are prior docetaxel therapy (yes or no) and presence of high-volume disease (yes or no). CT or MRI and radionuclide bone imaging will be used to assess response according to Prostate Cancer Working Group 3 (PCWG3)–modified RECIST v1.1 by blinded independent central review (BICR) Q12W from the date of randomization. Imaging will continue until the end of treatment and will resume Q12W during the posttreatment period. The co-primary end points are BICR-assessed radiographic PFS (according to PCWG3-modified RECIST v1.1) and OS. Key secondary end points are time to first subsequent anticancer therapy and time to symptomatic skeletal-related event. Other end points are PFS2 (progression after next line of therapy or death), PSA response rate, time to PSA progression, PSA undetectable rate, ORR, duration of response, time to soft tissue and radiographic bone progression per PCWG3-modified RECIST v1.1, safety, and patient-reported outcomes (eg, time to pain progression). Safety and tolerability will be evaluated using a tiered approach. KEYNOTE-991 is enrolling at 40 sites in Australia, Chile, Colombia, Israel, Japan, Poland, South Korea, Spain, Switzerland, Taiwan, and the United States.ResultsN/AConclusionsN/ATrial RegistrationClinicalTrials. gov: NCT04191096Ethics ApprovalThe study and the protocol were approved by the Institutional Review Board or ethics committee at each site.

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