Phase III study of first-line pembrolizumab (pembro) plus lenvatinib (len) in patients (pts) with advanced urothelial carcinoma (UC) ineligible for platinum-based chemotherapy: LEAP-011.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. TPS597-TPS597
Author(s):  
Yohann Loriot ◽  
Arjun Vasant Balar ◽  
Ronald De Wit ◽  
Jorge A. Garcia ◽  
Petros Grivas ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Objective Response ◽  
Locally Advanced ◽  
Previous Treatment ◽  
Phase Iii ◽  
End Points ◽  
Platinum Based Chemotherapy ◽  
Patient Reported ◽  
Ecog Ps ◽  
To Receive

TPS597 Background: KEYNOTE-052 (NCT02335424) results led to pembro, a PD-1 inhibitor, to become the standard of care for cisplatin-ineligible pts with locally advanced or metastatic UC with tumors expressing PD-L1 and for pts unable to receive platinum-based chemotherapy regardless of PD-L1 status. Len, a potent, multiple-receptor, tyrosine kinase inhibitor has activity in multiple solid tumors. KEYNOTE-146 (NCT02501096) results showed promising efficacy and manageable safety with pembro+len in previously treated pts with advanced UC, regardless of PD-L1 status. Methods: LEAP-011 (NCT03898180) is a randomized phase 3 study to assess efficacy and safety of pembro+len, compared with pembro+placebo, in pts with advanced UC. An estimated 694 pts will be enrolled. Adults (≥18 years) with histologically confirmed locally advanced unresectable or metastatic UC who are either cisplatin-ineligible with tumors expressing PD-L1 (combined positive score [CPS] ≥10) or ineligible to receive any platinum-based chemotherapy are eligible. Pts are required to have an ECOG PS of 0-2 and provide tumor tissue for PD-L1 analysis. Previous treatment with systemic chemotherapy for advanced UC is not permitted, except in cases of recurrence after 1 year of platinum-based chemotherapy for either muscle-invasive bladder cancer (neoadjuvant) or after radical cystectomy (adjuvant). Pts will be randomly assigned 1:1 to receive pembro 200 mg IV every 3 weeks for up to 35 cycles (~2 y) plus either len 20 mg or placebo orally once daily. Pts will be stratified as follows: ineligible for any platinum containing chemotherapy and ECOG PS 2 (CPS ≥10 vs <10); cisplatin ineligibility and CPS ≥10 (ECOG 0-1 vs 2). Radiologic assessment will include CT/MRI of the chest, abdomen, and pelvis, and bone imaging. Responses will be assessed per RECIST v1.1 by blinded independent central review (BICR). Coprimary end points are PFS and OS. Secondary end points are objective response rate, duration of response, and disease control rate per RECIST v1.1 by BICR; patient-reported outcomes; and safety. Tissue-and blood-based biomarkers will be explored. Accrual began May 6, 2019. Clinical trial information: NCT03898180.

CONTACT-01: A phase III, randomized study of atezolizumab plus cabozantinib versus docetaxel in patients with metastatic non-small cell lung cancer (mNSCLC) previously treated with PD-L1/PD-1 inhibitors and platinum-containing chemotherapy.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS9134-TPS9134
Author(s):  
Joel W. Neal ◽  
Palak Kundu ◽  
Tomohiro Tanaka ◽  
Ida Enquist ◽  
Sid Patel ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Randomized Study ◽  
Phase Iii ◽  
Clinical Activity ◽  
Open Label ◽  
Eligibility Criteria ◽  
Recist 1.1 ◽  
Platinum Based Chemotherapy ◽  
Patient Reported ◽  
Previously Treated

TPS9134 Background: Patients with mNSCLC who progress on anti–PD-L1/PD-1 therapy administered in combination with or after platinum-based chemotherapy (PBC) are mainly treated with docetaxel or pemetrexed monotherapy. These therapies only have modest clinical activity, leaving a high unmet medical need. Cabozantinib, a tyrosine kinase inhibitor (TKI), promotes an immune-permissive environment and may enhance the efficacy of PD-L1/PD-1 inhibitors, offering a promising second/third-line therapeutic opportunity for patients with mNSCLC. In a Phase Ib multi-cohort study (COSMIC-021; NCT03170960), cabozantinib plus atezolizumab (anti–PD-L1) showed an acceptable safety profile and promising efficacy (ORR: 27%; mDOR: 5.7 mo [range: 2.6-6.9]; disease control rate [CR + PR + SD]: 83%) in 30 patients with mNSCLC who had progressed after prior anti–PD-L1/PD-1 therapy plus chemotherapy (Neal et al. J Clin Oncol 2020). The Phase III CONTACT-01 study will further evaluate the efficacy and safety of atezolizumab plus cabozantinib versus docetaxel monotherapy in patients with mNSCLC who have progressed during or after prior treatment with anti–PD-L1/PD-1 therapy and PBC. Methods: CONTACT-01 (NCT04471428) is a Phase III, multi-center, randomized, open-label study that will enroll ≈350 patients from 150 to 200 sites internationally. Key eligibility criteria include histologically or cytologically confirmed mNSCLC, disease progression with concurrent or sequential anti–PD-L1/PD-1 treatment and PBC, measurable disease (RECIST 1.1), ECOG PS of 0-1 and the availability of tissue specimens for centralized PD-L1 testing or known PD-L1 status using a health authority–approved PD-L1 assay. Patients with NSCLC previously treated with cabozantinib, docetaxel or anti–PD-L1/PD-1 + VEGFR TKIs are excluded. Patients with known sensitizing EGFR/ALK mutations and active or untreated CNS metastases are also excluded. Patients will be randomized 1:1 to receive either atezolizumab (1200 mg IV every 3 weeks) + cabozantinib (40 mg orally once daily) or docetaxel (75 mg/m2 IV every 3 weeks). The primary endpoint is OS. Secondary endpoints include investigator-assessed PFS, ORR and DOR per RECIST 1.1; TTD in patient-reported physical function and global health status (EORTC QLQ-C30); investigator-assessed PFS rates at 6 months and 1 year; OS rates at 1 and 2 years; safety and PK. Clinical trial information: NCT04471428.

CS1001-304: A phase III study of fluorouracil and cisplatin (FP) with CS1001, an anti-PD-L1 antibody, or placebo in unresectable locally advanced, recurrent or metastatic esophageal squamous cell carcinoma (ESCC).

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. TPS255-TPS255
Author(s):  
Jin Li ◽  
Yuxian Bai ◽  
Qingshan Li ◽  
YouEn Lin ◽  
Hao Jiang ◽  
...  
Keyword(s):  
Safety Profile ◽  
Tumor Therapy ◽  
Locally Advanced ◽  
Phase Iii ◽  
Transgenic Rat ◽  
First Line ◽  
Multiple Tumor ◽  
Platinum Based Chemotherapy ◽  
Phase Iii Study ◽  
Ecog Ps

TPS255 Background: ESCC is the predominant histological subtype of esophageal cancer, particularly in Asian countries. Platinum-based chemotherapy is the first-line standard therapy for patients with unresectable, locally advanced, recurrent or metastatic ESCC. The FP regimen is recommended as the preferred treatment by guidelines. However, the survival benefit conferred by this therapy leaves considerable space for improvement, with median OS being less than 1 year. Blockade of the immune checkpoint receptors has shown clinical benefits in multiple tumor types. Recent studies combining standard treatments with checkpoint inhibitors have shown encouraging efficacy and favorable safety profile in patients with unresectable, locally advanced, recurrent or metastatic ESCC. CS1001 (sugemalimab) is the first full-length, fully human immunoglobin G4 (IgG4, s228p) anti-programmed death-ligand 1 (PD-L1) monoclonal antibody developed by the OMT transgenic rat platform. In an ongoing Phase Ib trial, CS1001 in combination with FP regimen demonstrated an ORR of 67.6% (25/37) and an mPFS of 9.0 months with a manageable safety profile in unresectable, locally advanced or distantly metastatic ESCC (19 Feb 2020 data cutoff; Shen, L., et al, ESMO 2020). Methods: CS1001-304 is a randomized, double-blind Phase III study to compare the efficacy and safety of FP regimen with CS1001 or placebo as first-line treatment in ESCC. The study enrolls patients with histologically or cytologically confirmed unresectable locally advanced, recurrent or metastatic ESCC who have ECOG PS of 0-1, patients are not eligible for curative therapy (curative surgery or definitive chemoradiotherapy), and have not received any prior systemic anti-tumor therapy for locally advanced or metastatic disease. Approximately 540 patients will be randomized at 2:1 into CS1001 + FP and placebo + FP arms respectively, stratified by PD-L1 expression status (PD-L1 expression < 1% vs ≥ 1% and < 10% vs ≥10%), ECOG PS (0 vs 1) and distant metastasis (no vs yes). Patients randomized to either arm will receive FP regimen (fluorouracil: 800 mg/m2/day, continuous intravenous infusion [IV], D1-4 of each cycle; cisplatin: 80 mg/m2, IV, D1 of each cycle), Q3W for up to 6 cycles in combination with CS1001 1200 mg or placebo (IV, D1 of each cycle), Q3W for up to 24 months. AEs will be monitored throughout the study and graded per NCI CTCAE v5.0. Tumor response will be assessed by RECIST v1.1 every 6 weeks in the first 12 months, and every 12 weeks thereafter. The primary endpoints are blinded independent central review (BICR)-assessed PFS and OS. Secondary endpoints include investigator-assessed PFS, BICR and investigator-assessed ORR and DoR, safety, PK profile, and immunogenicity. The study is actively enrolling patients in over 60 sites in China. Clinical trial information: NCT04187352.

scholarly journals Neratinib Plus Capecitabine Versus Lapatinib Plus Capecitabine in HER2-Positive Metastatic Breast Cancer Previously Treated With ≥ 2 HER2-Directed Regimens: Phase III NALA Trial

2020 ◽  
Vol 38 (27) ◽  
pp. 3138-3149 ◽  
Author(s):  
Cristina Saura ◽  
Mafalda Oliveira ◽  
Yin-Hsun Feng ◽  
Ming-Shen Dai ◽  
Shang-Wen Chen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Kinase Inhibitor ◽  
Objective Response ◽  
Metastatic Breast ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Her2 Positive ◽  
End Points ◽  
Cns Disease

PURPOSE NALA (ClinicalTrials.gov identifier: NCT01808573 ) is a randomized, active-controlled, phase III trial comparing neratinib, an irreversible pan-HER tyrosine kinase inhibitor (TKI), plus capecitabine (N+C) against lapatinib, a reversible dual TKI, plus capecitabine (L+C) in patients with centrally confirmed HER2-positive, metastatic breast cancer (MBC) with ≥ 2 previous HER2-directed MBC regimens. METHODS Patients, including those with stable, asymptomatic CNS disease, were randomly assigned 1:1 to neratinib (240 mg once every day) plus capecitabine (750 mg/m2 twice a day 14 d/21 d) with loperamide prophylaxis, or to lapatinib (1,250 mg once every day) plus capecitabine (1,000 mg/m2 twice a day 14 d/21 d). Coprimary end points were centrally confirmed progression-free survival (PFS) and overall survival (OS). NALA was considered positive if either primary end point was met (α split between end points). Secondary end points were time to CNS disease intervention, investigator-assessed PFS, objective response rate (ORR), duration of response (DoR), clinical benefit rate, safety, and health-related quality of life (HRQoL). RESULTS A total of 621 patients from 28 countries were randomly assigned (N+C, n = 307; L+C, n = 314). Centrally reviewed PFS was improved with N+C (hazard ratio [HR], 0.76; 95% CI, 0.63 to 0.93; stratified log-rank P = .0059). The OS HR was 0.88 (95% CI, 0.72 to 1.07; P = .2098). Fewer interventions for CNS disease occurred with N+C versus L+C (cumulative incidence, 22.8% v 29.2%; P = .043). ORRs were N+C 32.8% (95% CI, 27.1 to 38.9) and L+C 26.7% (95% CI, 21.5 to 32.4; P = .1201); median DoR was 8.5 versus 5.6 months, respectively (HR, 0.50; 95% CI, 0.33 to 0.74; P = .0004). The most common all-grade adverse events were diarrhea (N+C 83% v L+C 66%) and nausea (53% v 42%). Discontinuation rates and HRQoL were similar between groups. CONCLUSION N+C significantly improved PFS and time to intervention for CNS disease versus L+C. No new N+C safety signals were observed.

Efficacy, tolerability, and biomarker analyses from a phase III, randomized, placebo-controlled, parallel group study of gefitinib as maintenance therapy in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC; INFORM; C-TONG 0804).

2011 ◽  
Vol 29 (18_suppl) ◽  
pp. LBA7511-LBA7511
Author(s):  
L. Zhang ◽  
M. Shenglin ◽  
X. Song ◽  
B. Han ◽  
Y. Cheng ◽  
...  
Keyword(s):  
Maintenance Therapy ◽  
Objective Response ◽  
Locally Advanced ◽  
Phase Iii ◽  
Chinese Patients ◽  
Symptom Improvement ◽  
First Line ◽  
Parallel Group Study ◽  
Parallel Group ◽  
Platinum Based Chemotherapy

LBA7511 Background: INFORM (a phase III, randomized, multicenter, parallel group study; NCT00770588 ) investigated the efficacy, safety and tolerability of gefitinib (G) vs. placebo (P) as maintenance therapy in pts with locally advanced/metastatic NSCLC following standard first-line platinum based chemotherapy. Methods: Pts (≥18 years, with stage IIIB/IV NSCLC and WHO performance status 0-2) had completed 4 cycles of first-line platinum based doublet chemotherapy without progression/unacceptable toxicity. Pts were randomized 1:1 to G 250mg/day or P on discontinuation of first-line therapy. Progression-free survival (PFS; primary endpoint) was assessed in the intent to treat population (Cox proportional hazards adjusted for histology [adenocarcinoma vs. non-adenocarcinoma], smoking status [never-smoker vs. smoker], EGFR mutation status [positive vs. negative vs. unknown] and best response to first-line chemotherapy [complete response/partial response vs. stable disease]). PFS was considered superior with gefitinib if the G:P hazard ratio (HR) upper confidence interval (CI) was <1.00. Secondary endpoints included overall survival (OS), objective response rate, disease control rate, symptom improvement and tolerability. Results: 296 pts (n=148 G, n=148 P) were randomized (27 centers in china; 26 September 2008-10 August 2009). PFS data cutoff on 24 January 2011. Median duration of follow-up was 16.8 months: 91% pts progressed; 59% deaths. Demography was balanced between treatments; overall, 54.1% pts were never-smokers, 70.6% had adenocarcinoma, and 40.9% were female. For G vs. P, PFS HR=0.42; 95% CI 0.32-0.54; p<0.0001; median PFS 4.8 vs. 2.6 months. Most common AEs (any grade) with G were rash (49.7%), diarrhea (25.2%), and ALT increase (21.1%) which were generally mild/moderate. Overall incidence of serious AEs: G (6.8%); P (3.4%). Other secondary endpoint data (including OS and biomarkers) will be presented. Conclusions: PFS was significantly longer with G compared with P as maintenance therapy in Chinese patients with locally advanced NSCLC.

A phase III trial of virulizin plus gemcitabine vs. gemcitabine alone in advanced pancreatic cancer: Results of subgroup analysis

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 4116-4116 ◽  
Author(s):  
J. A. Wright ◽  
J. Osterlee ◽  
S. Fekete ◽  
Y. Lee ◽  
A. H. Young
Keyword(s):  
Pancreatic Cancer ◽  
Metastatic Cancer ◽  
Performance Status ◽  
Locally Advanced ◽  
Advanced Pancreatic Cancer ◽  
Phase Iii ◽  
Double Blind ◽  
Significant Difference ◽  
Ecog Ps ◽  
To Receive

4116 Background: Virulizin (V) is a novel antitumor immune modulator that improves survival in pancreatic cancer patients (pts) as monotherapy. A double-blind, multicenter, randomized, phase III study was conducted to evaluate the survival benefits and safety of V in combination with gemcitabine (G) in pts with advanced pancreatic cancer. Methods: Chemo-naive pts with locally advanced or metastatic pancreatic cancer with ECOG Performance Status (PS) of 0, 1 or 2 were enrolled. Pts were randomized to receive intramuscular injections of either V or placebo (P) 3 times weekly + G (1,000 mg/m2 weekly ×7 with 1 week rest, then weekly ×3 q4w). Randomization was stratified according to ECOG PS (0 or 1, and 2) and extent of disease (locally advanced and metastatic). Pts who showed no clinical benefit or were intolerant to G entered 2nd-line therapy (stage 3), in which pts continued to receive either V or P alone or with 5-FU, or best supportive care. The primary endpoint was survival, defined as time from baseline/treatment day 1 to time of death from any cause. Results: The intent to treat (ITT) population comprised 434 pts, of which 377 were efficacy evaluable (EE). Median overall survival for V + G was 6.3 months for the ITT population (6.8 months for EE pts) and 6 months for P + G for both ITT and EE pts. While differences in survival times were not statistically significant, exploratory analysis showed encouraging results in specific subgroups treated with V + G ( table ). Importantly, a significant difference was found in stage 3 pts who received V in a salvage setting compared to pts who received P. Conclusions: Pancreatic cancer pts with either low ECOG PS or metastatic cancer showed a survival benefit when treated with V + G, which was significant in pts who continued to receive V as a salvage therapy. Further studies in these targeted patient populations are being considered. [Table: see text] No significant financial relationships to disclose.

A phase III, randomized, double-blind, multicenter trial comparing the investigational agent orteronel (TAK-700) plus prednisone (P) with placebo plus P in patients with metastatic castration-resistant prostate cancer (mCRPC) that has progressed during or following docetaxel-based therapy.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. TPS4693-TPS4693 ◽  
Author(s):  
Robert Dreicer ◽  
David B. Agus ◽  
Joaquim Bellmunt ◽  
Johann Sebastian De Bono ◽  
Daniel Peter Petrylak ◽  
...  
Keyword(s):  
Disease Progression ◽  
Fusion Gene ◽  
Phase 1 ◽  
Objective Response ◽  
Specific Antigen ◽  
Phase Iii ◽  
Double Blind ◽  
Investigational Agent ◽  
Patient Reported ◽  
To Receive

TPS4693 Background: The investigational agent orteronel is a selective inhibitor of 17,20-lyase, a key enzyme in the testosterone synthesis pathway. In a phase 1/2 study in men with mCRPC, orteronel reduced prostate-specific antigen (PSA) levels, and inhibited testosterone and DHEA-S consistent with potent 17,20-lyase inhibition (Agus D, et al. J Clin Oncol 2012;30:s5 abst 98). Docetaxel-based chemotherapy is an effective but noncurative therapy for mCRPC that has progressed on hormonal therapy; new therapeutic options are needed. Methods: This double-blind, multicenter study is assessing orteronel + P vs placebo + P in men with mCRPC (NCT01193257; C21005). Patients must have evidence of disease progression during or after receiving a total of ≥360 mg/m2 docetaxel within a 6-mo period. Patients who are clearly intolerant to docetaxel or have progressive disease before receiving ≥360 mg/m2 are also eligible if they have received at least 225 mg/m2 of docetaxel within a 6-mo period and meet the other inclusion criteria. Other eligibility criteria include radiographically documented metastatic disease and baseline testosterone <50 ng/dL following surgical or medical castration. Prior adrenal-targeted therapies are not permitted. Men may have opioid-requiring bone pain. The planned sample size is 1083; men will be randomized 2:1 to receive orteronel 400 mg twice daily (BID) plus P 5 mg BID or placebo plus P. The primary endpoint is overall survival; other endpoints are radiographic progression-free survival, PSA decrease of ≥50% at 12 wks, pain response at 12 wks, safety, time to PSA progression, objective response by RECIST, circulating tumor cell and endocrine marker changes, and patient-reported outcomes. After disease progression, men may continue to receive study drug. Tumor specimens will be analyzed for biomarkers that may predict orteronel antitumor activity, including the TMPRSS2:ERG fusion gene. The same regimens are being evaluated in a concurrent phase 3 study in chemotherapy-naïve men with mCRPC (NCT01193244).

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.

Neratinib + capecitabine versus lapatinib + capecitabine in patients with HER2+ metastatic breast cancer previously treated with ≥ 2 HER2-directed regimens: Findings from the multinational, randomized, phase III NALA trial.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 1002-1002 ◽  
Author(s):  
Cristina Saura ◽  
Mafalda Oliveira ◽  
Yin-Hsun Feng ◽  
Ming-Shen Dai ◽  
Sara A. Hurvitz ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Kinase Inhibitor ◽  
Objective Response ◽  
Metastatic Breast ◽  
Stage Iv ◽  
Phase Iii ◽  
Open Label ◽  
Cns Disease ◽  
Patient Reported

1002 Background: NALA (ClinicalTrials.gov NCT01808573) is a multinational, randomized, open-label, phase III trial of neratinib (an irreversible pan-HER tyrosine kinase inhibitor [TKI]) + capecitabine (N+C) vs lapatinib (a reversible dual TKI) + capecitabine (L+C) in patients with stage IV HER2+ metastatic breast cancer (MBC) who had received ≥2 prior HER2-directed regimens for MBC. Methods: Patients were randomized 1:1 to N (240 mg qd po) + C (750 mg/m2 bid po) or L (1250 mg qd po) + C (1000 mg/m2 bid po). Co-primary endpoints were centrally assessed progression-free survival (PFS) and overall survival (OS). Secondary endpoints were investigator-assessed PFS; objective response rate (ORR); duration of response (DoR); clinical benefit rate (CBR); time to intervention for symptomatic metastatic central nervous system (CNS) disease; safety; and patient-reported health outcomes. Results: 621 patients were randomized (307 to N+C; 314 to L+C). The risk of disease progression or death was reduced by 24% with N+C vs L+C (HR = 0.76; 95% CI 0.63–0.93; p = 0.006); 6- and 12-month PFS rates were 47.2% vs 37.8% and 28.8% vs 14.8% for N+C vs L+C, respectively. OS rates at 6 and 12 months were 90.2% vs 87.5% and 72.5% vs 66.7% for N+C vs L+C, respectively (HR = 0.88; 95% CI 0.72–1.07; p = 0.2086). ORR in patients with measurable disease at screening was improved with N+C vs L+C (32.8% vs 26.7%; p = 0.1201), as was CBR (44.5% vs 35.6%; p = 0.0328) and DoR (HR = 0.50; 95% CI 0.33–0.74; p = 0.0004). Time to intervention for symptomatic CNS disease (overall cumulative incidence 22.8% vs 29.2%; p = 0.043) was delayed with N+C vs L+C. Treatment-emergent adverse events (TEAEs) were similar between arms, but there was a higher rate of grade 3 diarrhea with N+C vs L+C (24.4% vs 12.5%). TEAEs leading to neratinib/lapatinib discontinuation were lower with neratinib (10.9%) than with lapatinib (14.5%). Conclusions: N+C significantly improved PFS with a trend towards improved OS vs L+C. N+C also resulted in a delayed time to intervention for symptomatic CNS disease. Tolerability was similar between the two arms, with no new safety signals observed. Clinical trial information: NCT01808573.

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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