SANDPIPER: Phase III study of the PI3-kinase (PI3K) inhibitor taselisib (GDC-0032) plus fulvestrant in patients (pts) with estrogen receptor (ER)-positive, HER2-negative locally advanced or metastatic breast cancer (BC) enriched for pts with PIK3CA-mutant tumors.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. TPS1119-TPS1119 ◽  
Author(s):  
Jose Baselga ◽  
Javier Cortés ◽  
Michelino DeLaurentiis ◽  
Susan Dent ◽  
Véronique Diéras ◽  
...  
Keyword(s):  
Single Agent ◽  
Objective Response ◽  
Locally Advanced ◽  
Pik3ca Mutation ◽  
Pi3k Inhibitor ◽  
Phase Iii ◽  
Pik3ca Mutations ◽  
Patient Reported ◽  
Er Positive ◽  
Phase Iii Study

TPS1119 Background: As one of the most frequent genomic alterations in BC, PIK3CA mutations occur in ~40% of ER-positive, HER2-negative breast tumors. PIK3CA mutations may mediate resistance to endocrine therapies and promote growth and proliferation of tumors in BC. Taselisib is a potent and selective PI3K inhibitor that preferentially degrades mutant versus wild-type PI3Kα via a unique mechanism not seen with alpelisib and pictilisib. In PIK3CA-mutant BC cell lines, taselisib had enhanced activity. Confirmed partial responses were reported in pts with PIK3CA-mutant BC treated with taselisib either as a single agent or in combination with fulvestrant. Methods: SANDPIPER is a double-blind, placebo-controlled, randomized, phase III study, designed to evaluate the efficacy and safety of taselisib plus fulvestrant in pts with ER-positive, HER2-negative, PIK3CA-mutant locally advanced or metastatic BC. Postmenopausal pts will be randomized 2:1 to receive either taselisib (4 mg qd) or placebo in combination with fulvestrant (500 mg intramuscular on Days 1 and 15 of Cycle 1, and on Day 1 of each subsequent 28-day cycle). Pts must have had disease recurrence or progression during or after aromatase inhibitor treatment. Randomization will be stratified by visceral disease, endocrine sensitivity, and geographic region. SANDPIPER enriches for pts with PIK3CA-mutant tumors and a centrally assessed, valid cobas PIK3CA Mutation Test result in tumor tissue is required prior to enrollment; pts with PIK3CA-mutant tumors are randomized separately from those with non-mutant tumors. The primary efficacy endpoint is investigator-assessed progression-free survival in pts with PIK3CA-mutant tumors (estimated by Kaplan–Meier methodology). Other endpoints include overall survival, objective response rate, clinical benefit rate, duration of objective response, safety, pharmacokinetics, and patient-reported outcomes. Enrollment is open for pts with PIK3CA-mutant tumors. Target enrollment is 600 pts and > 300 patients have been enrolled. Clinical trial information: NCT02340221.

Phase III study of taselisib (GDC-0032) + fulvestrant (FULV) v FULV in patients (pts) with estrogen receptor (ER)-positive, PIK3CA-mutant (MUT), locally advanced or metastatic breast cancer (MBC): Primary analysis from SANDPIPER.

2018 ◽  
Vol 36 (18_suppl) ◽  
pp. LBA1006-LBA1006 ◽  
Author(s):  
Jose Baselga ◽  
Susan Faye Dent ◽  
Javier Cortés ◽  
Young-Hyuck Im ◽  
Véronique Diéras ◽  
...  
Keyword(s):  
Single Agent ◽  
Objective Response ◽  
Locally Advanced ◽  
Pik3ca Mutation ◽  
Metastatic Breast ◽  
Phase Iii ◽  
Primary Analysis ◽  
Double Blind ◽  
Er Positive ◽  
Phase Iii Study

LBA1006 Background: Taselisib, a potent, selective PI3K inhibitor, has enhanced activity in PIK3CA-MUT BC cell lines and confirmed partial responses in PIK3CA-MUT BC as a single-agent or with FULV. We assessed taselisib + FULV in pts with ER-positive, HER2-negative, PIK3CA-MUT locally advanced or MBC. Methods: SANDPIPER (NCT02340221) is a double-blind, placebo (PBO)-controlled, randomized, phase III study. Postmenopausal pts with disease recurrence or progression during or after an aromatase inhibitor were randomized 2:1 to receive taselisib (4 mg oral, qd) or PBO + FULV (500 mg). Stratification factors were: visceral disease, endocrine sensitivity, and geographic region. Pts with PIK3CA-MUT tumors, assessed by central cobas PIK3CA Mutation Test, were randomized separately from non-MUT tumors. The primary endpoint was investigator-assessed progression-free survival (INV-PFS) in pts with PIK3CA-MUT tumors. Secondary endpoints included objective response rate (ORR), overall survival (OS), clinical benefit rate (CBR), duration of objective response (DoR), PFS by blinded independent central review (BICR-PFS), and safety. Results: 516 pts were randomized in the PIK3CA-MUT intention-to-treat (ITT) population. Efficacy is shown in the Table. Taselisib + FULV significantly improved INV-PFS (hazard ratio [HR] 0.70) as confirmed by BICR-PFS (HR 0.66). OS is immature. The most common grade ≥3 adverse events (AEs; preferred terms) in the taselisib + FULV arm in safety-evaluable pts who received ≥ 1 dose of treatment were diarrhea (12%), hyperglycemia (10%), colitis (3%), and stomatitis (2%). AEs led to more taselisib discontinuations (17% v 2%) and dose reductions (37% v 2%), v PBO. Conclusions: Taselisib + FULV significantly improved INV-PFS, v PBO + FULV, in pts with ER-positive, HER2-negative, PIK3CA-MUT locally advanced or MBC. The safety profile is largely consistent with previous studies. Clinical trial information: NCT02340221. [Table: see text]

TROPiCS-04: Study of sacituzumab govitecan in metastatic or locally advanced unresectable urothelial cancer that has progressed after platinum and checkpoint inhibitor therapy.

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. TPS498-TPS498
Author(s):  
Petros Grivas ◽  
Scott T. Tagawa ◽  
Joaquim Bellmunt ◽  
Maria De Santis ◽  
Ignacio Duran ◽  
...  
Keyword(s):  
Clinical Benefit ◽  
Topoisomerase I ◽  
Progressive Disease ◽  
Group Performance ◽  
Checkpoint Inhibitor ◽  
Single Agent ◽  
Objective Response ◽  
Locally Advanced ◽  
Eastern Cooperative Oncology Group ◽  
Phase Iii

TPS498 Background: Treatment options are limited for patients with locally advanced unresectable or metastatic urothelial carcinoma (mUC) who progress following prior platinum-based and checkpoint inhibitor (CPI) therapy. Sacituzumab govitecan (SG) is an antibody-drug conjugate consisting of an anti–Trop-2 monoclonal antibody coupled to SN-38 (an active metabolite of irinotecan, a topoisomerase-I inhibitor) via a unique hydrolyzable linker. A phase II registrational study, TROPHY-U-01 study, confirmed the initial positive efficacy signal in mUC. SG demonstrated an objective response rate (ORR) of 27% and median overall survival (OS) of 10.5 months in patients with mUC (median 3 prior lines of therapy and 87% with ≥1 Bellmunt risk factors) who progressed after prior platinum-based and CPI therapies (n=113; Loriot ESMO 2020). The results compared favorably with historic single-agent chemotherapy (ORR ~10%; OS ≤7 months). A phase III trial has been initiated to confirm these findings. Methods: TROPiCS-04 (NCT04527991) is a global, multicenter, open-label, randomized, controlled trial in patients with locally advanced unresectable or mUC who progressed after prior platinum-based and CPI therapies (with Eastern Cooperative Oncology Group performance status 0–1 and adequate hematologic, hepatic, and renal function). Patients will be randomized 1:1 to receive SG 10 mg/kg intravenously (IV) on day 1 and 8 of 21-day cycles or single-agent treatment of physician’s choice (paclitaxel 175 mg/m2, docetaxel 75 mg/m2, or vinflunine 320 mg/m2 IV on day 1 of 21-day cycles) until progressive disease, unacceptable toxicity, or withdrawal of consent. Treatment beyond progressive disease may be permitted in patients deemed to be receiving clinical benefit per investigator assessment. Approximately 482 patients will be enrolled to provide 90% power on the primary endpoint of OS. Secondary endpoints include progression-free survival, ORR, clinical benefit rate, duration of response (all per Response Evaluation Criteria in Solid Tumors v1.1), safety, and quality of life. Study initiation is ongoing and enrollment begins in Q4 2020 across ~90 sites. Clinical trial information: NCT04527991.

Gemcitabine plus docetaxel versus docetaxel in patients (pts) with HER2-negative locally advanced or metastatic breast cancer (MBC): A randomized phase III study

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 1015-1015
Author(s):  
D. L. Nielsen ◽  
S. T. Langkjer ◽  
K. Bjerre ◽  
S. Cold ◽  
L. Stenbygaard ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Single Agent ◽  
Locally Advanced ◽  
Metastatic Breast ◽  
Phase Iii ◽  
Rank Test ◽  
Hematologic Toxicity ◽  
Phase Iii Study ◽  
Her 2 ◽  
Grade 3

1015 Background: Gemcitabine (G), either as a single agent or in combination with taxanes, has demonstrated efficacy in MBC in phase II and III studies. We conducted a phase III study to compare time to progression (TTP) of G plus docetaxel (T) versus (vs.) T alone. The secondary endpoints included overall survival (OS), overall response rate (ORR), and toxicity. Methods: Females with HER-2-negative locally advanced or MBC and a WHO performance status ≤ 2 were randomized to GT (G 1,000mg/m2 day 1 + 8; T 75mg/m2 day 1) or T (100mg/m2 day 1) every 21 days. Pts were previously untreated, had prior anthracycline-based (neo)adjuvant chemotherapy or had received a single prior anthracycline-bsed chemotherapy regimen for MBC. Time-to-event endpoints were estimated using the Kaplan-Meier method, and the log-rank test was applied for comparisons between regimens. The planned sample size was 254 evaluable pts with α I and β of 0.05 and 0.90, respectively. Results: A total of 336 pts were randomized (170 GT; 166 T), data from one centre are yet missing and the present evaluation is based on data from 306 pts (155 GT; 151 T). The pts had a median age of 58 years in both regimens; range 36–73 years and 30–74 years, respectively. The median TTP was 7.5 months for the GT regimen vs. 6.5 months for the T regimen. The GT arm demonstrated an ORR of 44% vs. 38% in the T arm with 4 and 3 % complete responses, respectively. The OS was 13.4 vs. 13.2 months in the GT and T arm, respectively. Hematologic toxicity was common, especially grade 3–4 neutropenia (GT = 69%; T = 61%); infection was reported in 22 and 20% of the pts, respectively (none of the pts received G-CSF). The most commonly reported non-hematologic toxicities of grade 3–4 included mucositis (GT = 2%; T = 5%), diarrhea (GT = 4%; T = 7 %), fatigue (GT = 6%; T = 11%), oedema (GT = 10%; T = 3%), and peripheral neuropathy (GT = 9%; T = 28%). Conclusions: Preliminary data of GT as first- or second-line chemotherapy demonstrates a TTP advantage among HER-2-negative pts with advanced breast cancer. Updated results and proper statistical analyses will be presented. No significant financial relationships to disclose.

A randomized trial of gemcitabine (G) versus G plus cisplatin in chemotherapy-naive advanced pancreatic adenocarcinoma: The GIP-1 (Gruppo Italiano Pancreas— GOIM/GISCAD/GOIRC) study

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 4504-4504
Author(s):  
G. Colucci ◽  
R. Labianca ◽  
F. Di Costanzo ◽  
V. Gebbia ◽  
G. Cartenì ◽  
...  
Keyword(s):  
Pancreatic Adenocarcinoma ◽  
Clinical Benefit ◽  
Karnofsky Performance Status ◽  
Single Agent ◽  
Objective Response ◽  
Locally Advanced ◽  
Haematological Toxicity ◽  
Phase Iii ◽  
Line Treatment ◽  
Advanced Pancreatic Adenocarcinoma

4504 Background: Single-agent gemcitabine (G) remains standard treatment for advanced pancreatic adenocarcinoma (APC). The GIP-1 randomized phase III trial (clinicaltrials.gov ID NCT00813696 ) was performed to compare the combination of cisplatin (P) and G vs. G alone as 1st-line treatment. Methods: Patients (pts) with locally advanced and/or metastatic pancreatic adenocarcinoma, age 18–75, Karnofsky Performance Status (KPS) ≥50, were randomized to receive G (arm A) or G+P (arm B). In arm A, G was administered at 1000 mg/m2 weekly for 7 consecutive wks, and, after a 2-week rest, on day 1, 8, 15 every 4 wks. In Arm B, P 25 mg/m2 weekly (with the exception of day 22) was added to G, same dose used in Arm A (Colucci et al, Cancer 2002; 94:902–10). No maximum number of cycles was planned. Primary endpoint was overall survival (OS). Clinical benefit (CB), objective response rate (ORR), progression-free survival (PFS), toxicity and quality of life were secondary endpoints. To have 80% power of detecting a 0.74 Hazard Ratio (HR) of death (corresponding to increase in median OS from 4.8 to 6.5 months, with bilateral alpha=0.05, 400 pts were planned and 355 deaths were required for final analysis. Results: From April 2002 to April 2007, 400 pts were enrolled (A:199, B; 201) in 46 Italian Institutions. Median age was 63 yrs (range 35–75), 59% were males, 84% stage IV, 83% KPS≥80. After a median follow-up of 38.2 months and 357 deaths, median OS was 8.3 vs 7.2 months in arm A and B, respectively (HR 1.10, 95% CI 0.89–1.35, p=0.38). Median PFS was 3.9 vs 3.8 months in arm A and B, respectively (HR 0.97, 95% CI 0.80–1.19, p=0.80). ORR was 10.1% in arm A and 12.9% in B (p=0.37). CB response was experienced by 23.0% and 15.1% (Arm A vs B, p=0.057). Patients assigned to combination arm experienced more anaemia (all grades: 50% vs 39%, G3: 5% vs 1%), more neutropenia (all grades: 44% vs 36%, G3&4: 25% vs 14%) and more thrombocytopenia (all grades: 57% vs 29%, G3&4: 16% vs 5%). No relevant differences were seen in non-haematological toxicity. Conclusions: Weekly combination of P and G, compared to single-agent G as 1st-line treatment of APC, failed to demonstrate any improvement in OS, PFS, ORR and clinical benefit. No significant financial relationships to disclose.

MIRASOL (GOG 3045/ENGOT OV-55): A randomized, open-label, phase III study of mirvetuximab soravtansine versus investigator’s choice of chemotherapy in advanced high-grade epithelial ovarian, primary peritoneal, or fallopian tube cancers with high folate-alpha (FRα) expression.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS6103-TPS6103
Author(s):  
Kathleen N. Moore ◽  
Toon Van Gorp ◽  
Jiuzhou Wang ◽  
Brooke Esteves ◽  
Patrick A Zweidler-McKay
Keyword(s):  
Fallopian Tube ◽  
Single Agent ◽  
Objective Response ◽  
Pegylated Liposomal Doxorubicin ◽  
Phase Iii ◽  
Clinical Activity ◽  
Antibody Drug Conjugate ◽  
Open Label ◽  
Fallopian Tube Cancer ◽  
Phase Iii Study

TPS6103 Background: Elevated FRα expression is a characteristic of several solid tumors, including epithelial ovarian cancer (EOC), thereby providing an attractive candidate for targeted therapeutic approaches. Mirvetuximab soravtansine is an antibody-drug conjugate (ADC) comprising a FRα-binding antibody, cleavable linker, and the maytansinoid DM4, a potent tubulin-targeting agent that has shown consistent and meaningful single agent clinical activity, along with favorable tolerability, in patients with high FRα expressing tumors. Methods: MIRASOL is a randomized phase III study designed to evaluate the efficacy of mirvetuximab soravtansine compared with that of standard-of-care chemotherapy in adult patients with platinum-resistant EOC, primary peritoneal cancer, or fallopian tube cancer. Confirmation of high FRα positivity by immunohistochemistry (high expression; ≥ 75% of cells with PS2+ staining intensity) and ≤ 3 prior lines of therapy are required for inclusion. MIRASOL is designed to randomize 430 patients, 1:1 to Arm 1 (intravenous mirvetuximab soravtansine at a dose of 6 mg/kg, calculated using adjusted ideal body weight, on Day 1 of a 21-day cycle) or Arm 2 (investigators’ choice chemotherapy: paclitaxel, pegylated liposomal doxorubicin, or topotecan). The primary efficacy endpoint is progression-free survival (PFS; by investigator) and secondary endpoints include objective response rate, quality of life, overall survival, and safety and tolerability. MIRASOL opened for enrollment in December 2019. Clinical trial information: NCT04209855.

Phase II, two-stage, two-arm, PIK3CA mutation stratified trial of MK-2206 in recurrent endometrial cancer (EC).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 5524-5524 ◽  
Author(s):  
Andrea P. Myers ◽  
Russell Broaddus ◽  
Vicky Makker ◽  
Panagiotis A. Konstantinopoulos ◽  
Ronny Drapkin ◽  
...  
Keyword(s):  
Mutation Analysis ◽  
Single Agent ◽  
Objective Response ◽  
Pik3ca Mutation ◽  
Mtor Inhibitors ◽  
Skin Toxicity ◽  
Pi3k Pathway ◽  
Pik3ca Mutations ◽  
Primary Endpoints ◽  
Grade 3

5524 Background: EC has high rates of PI3K pathway alteration including PTEN mutation (50%) or IHC loss (>50%), PIK3CA mutation (25-40%) and PIK3R1 (20%) mutation. MK-2206 is an allosteric inhibitor of AKT, an effector kinase of PI3K signals. We hypothesized that pts whose tumors harbored PIK3CA mutations would be more likely to benefit from MK-2206 than those without PIK3CA mutation. Methods: Pts had recurrent or advanced EC; all histologies except MMMT were eligible. Up to 2 prior chemo lines were permitted; excluding prior treatment with PI3K/MTOR inhibitors. The first 19 pts were treated with MK-2206 200mg QW; due to initial skin toxicity rates, the starting dose was amended to 135mg QW. Co-primary endpoints were objective response and 6 mo PFS. The first 37 pts were stratified retrospectively. PIK3CA MT included R88Q, K111N, E110K, E418K, C420R, E453K, E542K/V,E545K, Q546R, H701P, M1043V, H1047R/L/Y changes. Independent Simon 2-stage tests were planned within PIK3CA MT and WT stratum: for MT, n1=15 and n2=10 pts would allow discrimination of RR<5% and 6moPFS<10% versus RR>25% or 6moPFS>35%; for WT, n1=31 and n2=24 pts would discriminate RR<5% and 6moPFS<10% versus RR>20% or 6moPFS>25%. Results: 37 pts were enrolled (1 ineligible) before accrual was stopped as timely CLIA-compliant prospective mutation analysis was not feasible. By PIK3CA mutation analysis, 9 pts were MT: 1 pt had both PR and 6moPFS. 27 pts were WT: 1 pt had PR and 3 pts had 6moPFS. 2 pts with 6moPFS were treated at 200mg; 2 pts with 6moPFS were treated at 135mg. Each group had 1 PR. The most common toxicity was grade 3 rash (19%). Grade 3 and 4 toxicities occurred in 50% and 8% of pts. Exploratory analysis of histology found all pts with 6moPFS were classified as serous (4 of 8) as compared to all other histologies (0 of 28, p=.001). Targeted exome sequencing and copy number analysis of the PI3K pathway and PTEN IHC are underway. Associative studies will be reported. Conclusions: There is limited single agent activity of MK-2206 in both PIK3CA MT and PIK3CA WT EC populations. Activity was detected in pts with serous histology tumors and warrants further study. Clinical trial information: NCT01307631. [Table: see text]

EV-301: Phase III study to evaluate enfortumab vedotin (EV) versus chemotherapy in patients with previously treated locally advanced or metastatic urothelial cancer (la/mUC).

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. TPS497-TPS497 ◽  
Author(s):  
Daniel Peter Petrylak ◽  
Jonathan E. Rosenberg ◽  
Ignacio Duran ◽  
Yohann Loriot ◽  
Guru Sonpavde ◽  
...  
Keyword(s):  
Disease Progression ◽  
Response Rate ◽  
Checkpoint Inhibitors ◽  
Single Agent ◽  
Objective Response ◽  
Locally Advanced ◽  
Phase Iii ◽  
Survival Duration ◽  
Metastatic Urothelial Cancer ◽  
Platinum Based Chemotherapy

TPS497 Background: Standard first-line treatment for patients (pts) with la/mUC is cisplatin-based chemotherapy or carboplatin-based chemotherapy for pts unfit for cisplatin. Immune checkpoint inhibitors (CPIs) are standard treatment options for pts who progressed during or after platinum-based chemotherapy. While some pts with la/mUC achieve durable responses with CPIs, less than 25% of pts respond. Following failure of a CPI, no therapies are approved. Enfortumab vedotin is a fully humanized monoclonal antibody that delivers the microtubule-disrupting agent monomethyl auristatin E to tumors expressing Nectin-4, which is expressed in 97% of mUC pt samples (Petrylak et al. ASCO, 2017). In a phase 1 study (EV-101; NCT02091999), single-agent EV 1.25 mg/kg was generally well tolerated and demonstrated a confirmed objective response rate (ORR) of 42% across the overall population of pts with mUC; in pts with prior CPI therapy or liver metastasis at baseline confirmed ORRs of 42% and 36% were observed. A pivotal phase 2 study of EV in la/mUC pts with prior CPI treatment (EV-201; NCT03219333) is ongoing. Methods: EV-301 is a global, multicenter, open-label phase 3 trial (NCT03474107) enrolling adult pts with la/mUC and an ECOG performance status score ≤1, who have received a prior platinum-containing chemotherapy, and have experienced disease progression during or following treatment with a CPI. Approximately 550 pts will be randomized (1:1) to receive EV (1.25 mg/kg) administered by IV infusion over approximately 30 minutes on Days 1, 8, and 15 of each 28-day cycle ( Arm A), or investigator choice of IV docetaxel, paclitaxel, or vinflunine (EU only) on Day 1 of each 21-day cycle ( Arm B). Treatment with the study drug will continue until radiological disease progression, intolerance, or other discontinuation criterion is met. Radiological assessments of tumor response status will be performed at baseline and every 8 weeks. The primary endpoint is overall survival; secondary endpoints include progression-free survival, duration of response, and overall response rate, as well as assessment of safety/tolerability, and quality-of-life parameters. Clinical trial information: NCT02091999.

Phase III study of the hypoxia-inducible factor 2α (HIF-2α) inhibitor MK-6482 versus everolimus in previously treated patients with advanced clear cell renal cell carcinoma (ccRCC).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS5094-TPS5094 ◽  
Author(s):  
Toni K. Choueiri ◽  
Laurence Albiges ◽  
Li Fan ◽  
Rodolfo F. Perini ◽  
Naseem J. Zojwalla ◽  
...  
Keyword(s):  
Controlled Trial ◽  
Phase 1 ◽  
Objective Response ◽  
Locally Advanced ◽  
Prognostic Scores ◽  
Phase Iii ◽  
Once Daily ◽  
Patient Reported ◽  
Previously Treated ◽  
Metastatic Rcc

TPS5094 Background: In RCC, the Von Hippel-Lindau ( VHL) tumor suppressor gene is inactivated in most cases, resulting in the accumulation and overactivation of HIF-2α. HIF-2α is a key oncogenic driver in RCC and is involved in the activation of genes associated with angiogenesis, tumor progression, and metastasis, such as vascular endothelial growth factor A ( VEGFA), cyclin D1, and CXCR4. MK-6482 is a potent and selective small molecule inhibitor of HIF-2α, and it has shown antitumor activity in a phase 1/2 study in patients with previously treated advanced ccRCC. Methods: The current study (NCT04195750) is a phase 3, open-label, multicenter, randomized, active-controlled trial to compare the efficacy and safety of MK-6482 with everolimus in patients with previously treated advanced ccRCC. Adults aged ≥18 years will be eligible if they have unresectable, locally advanced, or metastatic ccRCC; have measurable disease per RECIST v1.1; and received ≤3 prior systemic regimens, which must include a PD-1/PD-L1 inhibitor (≥2 doses) and a VEGF-targeted therapy, for locally advanced or metastatic RCC. Approximately 736 patients will be randomly assigned 1:1 to receive MK-6482 120 mg orally once daily or everolimus 10 mg orally once daily. At randomization, patients will be stratified by International Metastatic RCC Database prognostic scores (0 vs 1-2 vs 3-6) and by the number of prior anti-VEGF–targeted therapies received for advanced RCC (1 vs 2-3). Responses will be assessed by CT or MRI per RECIST v1.1 by blinded independent central review at week 9 from the date of randomization, then every 8 weeks through week 49, and then every 12 weeks thereafter. Treatment will continue until documented disease progression, withdrawal of consent, or other discontinuation event. Dual primary endpoints are progression-free survival per RECIST v1.1 and overall survival. Key secondary endpoints include objective response rate, duration of response, patient-reported outcomes, and safety. Clinical trial information: NCT04195750 .

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