CALGB 90601 (Alliance): Randomized, double-blind, placebo-controlled phase III trial comparing gemcitabine and cisplatin with bevacizumab or placebo in patients with metastatic urothelial carcinoma.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 4503-4503 ◽  
Author(s):  
Jonathan E. Rosenberg ◽  
Karla V. Ballman ◽  
Susan Halabi ◽  
Colleen Watt ◽  
Olwen Mary Hahn ◽  
...  
Keyword(s):  
Urothelial Carcinoma ◽  
Primary Endpoint ◽  
Objective Response ◽  
Phase Iii ◽  
Adverse Event Rate ◽  
Rank Test ◽  
Prior Chemotherapy ◽  
Log Rank Test ◽  
Metastatic Urothelial Carcinoma ◽  
Grade 3

4503 Background: The combination of gemcitabine (G) and cisplatin (C) is a standard therapy for metastatic urothelial carcinoma (mUC). Based on data that angiogenesis plays a role in UC growth and progression, a randomized placebo-controlled trial was performed. Methods: Patients mUC, no prior chemotherapy for metastatic disease and >12 months from prior (neo)adjuvant chemotherapy and ECOG PS 0-1 were randomized 1:1 to G 1000 mg/m2 IV days 1 and 8 and C IV 70 mg/m2 day 1 with bevacizumab (GCB) 15 mg/kg IV or placebo (GCP) day 1 every 21 days. Randomization was stratified by the presence of visceral metastases and prior chemotherapy. The primary endpoint was overall survival (OS) defined as the time from randomization to death or last follow-up (FU). Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and ≥ grade 3 toxicity. With 445 deaths, the log-rank test had an 87% power to detect a hazard ratio (HR) of 0.74 with a 2-sided α=0.05. The primary analysis was based on the stratified log-rank test adjusting on stratification factors. Alliance Data Safety and Monitoring Board approved the final OS analysis be performed at 420 events due to lower than expected event rates. Results: 506 patients were randomly assigned (252 GCB, 254 GCP) stratified by the presence of visceral disease and prior chemotherapy for UC. The median FU for patients still alive was 46.2 months. Median OS was 14.5 months for patients treated with GCB and 14.3 months for patients treated with GCP with a HR of 0.87 (95%CI 0.72-1.06; 2-sided Wald p=0.17). The HR for PFS was 0.77 (95%CI 0.63-0.93) in favor of GCB (p=0.0074). Grade 3 or greater adverse event rate was 83.5% with GCB compared to 80.7% with GCP. Conclusions: The addition of bevacizumab to GC chemotherapy did not result in improved OS (primary endpoint) in patients with mUC but there was a PFS improvement. The observed median OS of about 14 months is consistent with prior phase III trials of cisplatin-based chemotherapy. Support: U10CA180821, U10CA180882, U10CA180820, U10CA180853, U10CA180888, Genentech https://acknowledgments.alliancefound.org. Clinical trial information: NCT00942331.

Final results from ClarIDHy, a global, phase III, randomized, double-blind study of ivosidenib (IVO) versus placebo (PBO) in patients (pts) with previously treated cholangiocarcinoma (CCA) and an isocitrate dehydrogenase 1 (IDH1) mutation.

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. 266-266
Author(s):  
Andrew X. Zhu ◽  
Teresa Macarulla ◽  
Milind M. Javle ◽  
Robin Kate Kelley ◽  
Sam Joseph Lubner ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Primary Endpoint ◽  
Failure Time ◽  
Objective Response ◽  
Idh1 Mutation ◽  
High Rate ◽  
Phase Iii ◽  
Double Blind Study ◽  
Grade 3

266 Background: CCA is a rare cancer for which there are limited effective therapies. IDH1 mutations occur in ~20% of intrahepatic CCAs, resulting in production of the oncometabolite D-2-hydroxyglutarate, which promotes oncogenesis. IVO (AG-120) is a first-in-class, oral, small-molecule inhibitor of mutant IDH1 (m IDH1). ClarIDHy aimed to demonstrate the efficacy of IVO vs PBO in pts with unresectable or metastatic m IDH1 CCA. The primary endpoint was met with significant improvement in progression-free survival (PFS) by independent radiology center (IRC) with IVO vs PBO (hazard ratio [HR] = 0.37, p < 0.0001). Objective response rate (ORR) and stable disease for IVO were 2.4% (3 partial responses) and 50.8% (n = 63) vs 0% and 27.9% (n = 17) for PBO. IVO pts experienced significantly less decline in physical and emotional functioning domains of quality of life at cycle 2 day 1 vs PBO pts (nominal p < 0.05). Methods: Pts with m IDH1 CCA were randomized 2:1 to IVO (500 mg PO QD) or matched PBO and stratified by prior systemic therapies (1 or 2). Key eligibility: unresectable or metastatic m IDH1 CCA based on central testing; ECOG PS 0–1; measurable disease (RECIST v1.1). Crossover from PBO to IVO was permitted at radiographic progression. Primary endpoint: PFS by IRC. Secondary endpoints included overall survival (OS; by intent-to-treat), ORR, PFS (by investigator), safety, and quality of life. The planned crossover-adjusted OS was derived using the rank-preserving structural failure time (RPSFT) model. Results: As of 31 May 2020, ~780 pts were prescreened for an IDH1 mutation and 187 were randomized to IVO (n = 126) or PBO (n = 61); 13 remain on IVO. Median age 62 y; M/F 68/119; 91% intrahepatic CCA; 93% metastatic disease; 47% had 2 prior therapies. 70% of PBO pts crossed over to IVO. OS data were mature, with 79% OS events in IVO arm and 82% in PBO. Median OS (mOS) was 10.3 months for IVO and 7.5 months for PBO (HR = 0.79; 95% CI 0.56–1.12; one-sided p = 0.093). The RPSFT-adjusted mOS was 5.1 months for PBO (HR = 0.49; 95% CI 0.34–0.70; p < 0.0001). Common all-grade treatment emergent adverse events (TEAEs, ≥ 15%) in the IVO arm: nausea 41%, diarrhea 35%, fatigue 31%, cough 25%, abdominal pain 24%, decreased appetite 24%, ascites 23%, vomiting 23%, anemia 18%, and constipation 15%. Grade ≥ 3 TEAEs were reported in 50% of IVO pts vs 37% of PBO pts, with grade ≥ 3 treatment-related AEs in 7% of IVO pts vs 0% in PBO. 7% of IVO pts experienced an AE leading to treatment discontinuation vs 9% of PBO pts. There were no treatment-related deaths. Conclusions: IVO was well tolerated and resulted in a favorable OS trend vs PBO despite a high rate of crossover. These data – coupled with statistical improvement in PFS, supportive quality of life data, and favorable safety profile – demonstrate the clinical benefit of IVO in advanced m IDH1 CCA. Clinical trial information: NCT02989857.

scholarly journals ACTR-32. NRG ONCOLOGY RTOG 1205: RANDOMIZED PHASE II TRIAL OF CONCURRENT BEVACIZUMAB AND RE-IRRADIATION VS. BEVACIZUMAB ALONE AS TREATMENT FOR RECURRENT GLIOBLASTOMA

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi20-vi20 ◽  
Author(s):  
Christina Tsien ◽  
Stephanie Pugh ◽  
adam Dicker ◽  
Jeffrey Raizer ◽  
Martha Matuszak ◽  
...  
Keyword(s):  
Objective Response ◽  
Patient Characteristics ◽  
Recurrent Glioblastoma ◽  
Rank Test ◽  
Significance Level ◽  
Log Rank Test ◽  
Kaplan Meier ◽  
Randomized Phase Ii ◽  
Grade 3 ◽  
Recurrent Gbm

Abstract This study sought to determine whether re-irradiation (ReRT) and concurrent bevacizumab (BEV) improves overall survival (OS) compared to BEV alone in recurrent glioblastoma (GBM). Patients (pts) were randomized 1:1 to ReRT (35 Gy/10 fractions) plus BEV (IV 10 mg/kg q2 wks) vs. BEV alone. With 160 pts, there was 80% power to detect a 31% reduction in death hazard for BEV+RT at a one-sided significance level of 0.10 using a log rank test. OS and PFS were estimated by Kaplan-Meier and HRs estimated by exact binomial distribution. Objective response was assessed using MacDonald and RANO criteria. From 11/2012 to 4/2016, 182 pts were randomized, with 170 eligible, analyzable pts. 11 pts did not receive protocol treatment. Patient characteristics (age, KPS, re-resection rates) were balanced between arms. Median f/u for censored pts was 12.8 months (mos; min-max, 0.03–52.8). BEV+ReRT did not improve OS vs BEV alone, with median OS of 10.1 vs 9.7 mos, (HR=0.98, 95% CI=0.70–1.38, p=0.46). Median PFS for BEV+RT and BEV was 7.1 vs. 3.8 mos, respectively (HR=0.73, 95% CI=0.53–1.0, p=0.051). BEV+ReRT improved 6-mo PFS rate (PFS6): 54 vs. 29%, (HR=0.42, 95% CI=0.34–0.5, p=0.001). Overall, treatment was well tolerated: 5% acute and 0% delayed grade 3+ treatment-related AE. Most patients died from recurrent GBM. CONCLUSION: RTOG 1205 is the first, prospective, randomized multi-institutional study to evaluate the safety and efficacy of ReRT in recurrent GBM using modern RT techniques. Overall, ReRT was shown to be safe and well tolerated. BEV+ReRT did not demonstrate a benefit in OS but an improved PFS6, and clinically meaningful PFS improvement. Molecular correlates of response analyses are ongoing. Funded by U10CA180868, U10CA180822 from the National Cancer Institute.

scholarly journals Sequencing of Androgen-Deprivation Therapy With External-Beam Radiotherapy in Localized Prostate Cancer: A Phase III Randomized Controlled Trial

2020 ◽  
Vol 38 (6) ◽  
pp. 593-601 ◽  
Author(s):  
Shawn Malone ◽  
Soumyajit Roy ◽  
Libni Eapen ◽  
Choan E ◽  
Robert MacRae ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Deprivation Therapy ◽  
Androgen Deprivation ◽  
Phase Iii ◽  
Localized Prostate Cancer ◽  
Definitive Treatment ◽  
Rank Test ◽  
Log Rank Test ◽  
Significant Difference ◽  
Grade 3

PURPOSE Dose-escalated radiotherapy (RT) with androgen-deprivation therapy (ADT) is a standard definitive treatment of localized prostate cancer (LPCa). The optimal sequencing of these therapies is unclear. Our phase III trial compared neoadjuvant versus concurrent initiation of ADT in combination with dose-escalated prostate RT (PRT). PATIENTS AND METHODS Patients with newly diagnosed LPCa with Gleason score ≤ 7, clinical stage T1b to T3a, and prostate-specific antigen < 30 ng/mL were randomly allocated to neoadjuvant and concurrent ADT for 6 months starting 4 months before RT (neoadjuvant group) or concurrent and adjuvant ADT for 6 months starting simultaneously with RT (concurrent group). The primary end point was biochemical relapse-free survival (bRFS). Stratified log-rank test was used to compare bRFS and overall survival (OS). Incidence of grade ≥ 3 late RT-related toxicities was compared by log-rank test. RESULTS Overall, 432 patients were randomly assigned to the neoadjuvant (n = 215) or concurrent group (n = 217). At 10 years, bRFS rates for the two groups were 80.5% and 87.4%, respectively. Ten-year OS rates were 76.4% and 73.7%, respectively. There was no significant difference in bRFS ( P = .10) or OS ( P = .70) between the two groups. Relative to the neoadjuvant group, the hazard ratio for the concurrent group was 0.66 (95% CI, 0.41 to 1.07) for bRFS and 0.94 (95% CI, 0.68 to 1.30) for OS. No significant difference was observed in the 3-year incidence of late RT-related grade ≥ 3 GI (2.5% v 3.9%) or genitourinary toxicity (2.9% v 2.9%). CONCLUSION In our study, there was no statistically significant difference in bRFS between the two treatment groups. Similarly, no difference was seen in OS or late RT-related toxicities. On the basis of these results, both neoadjuvant and concurrent initiations of short-term ADT with dose-escalated PRT are reasonable standards of care for LPCa.

An international, randomized, placebo-controlled, double-blind phase III study (MONET1) of motesanib plus carboplatin/paclitaxel (C/P) in patients with advanced nonsquamous non-small cell lung cancer (NSCLC).

2011 ◽  
Vol 29 (18_suppl) ◽  
pp. LBA7512-LBA7512 ◽  
Author(s):  
G. Scagliotti ◽  
I. Vynnychenko ◽  
Y. Ichinose ◽  
K. Park ◽  
K. Kubota ◽  
...  
Keyword(s):  
Cox Model ◽  
Objective Response ◽  
Stage Iv ◽  
Progression Free Survival ◽  
High Rate ◽  
Phase Iii ◽  
Rank Test ◽  
Double Blind ◽  
Grade 3 ◽  
Nonsquamous Nsclc

LBA7512 Background: This study evaluated whether motesanib (a selective oral inhibitor of VEGFR 1, 2 and 3; PDGFR and Kit) plus C/P improved overall survival (OS) compared with placebo + C/P in patients (pts) with nonsquamous NSCLC and in a subset of pts with adenocarcinoma. Methods: Pts had stage IIIB/IV or recurrent nonsquamous NSCLC and no prior systemic therapy for advanced NSCLC. The study initially enrolled all histologies but was amended to exclude pts with squamous NSCLC owing to a high rate of hemoptysis. Pts were randomized 1:1 to receive up to six 3-wk cycles of C (AUC 6 mg/mL·min) and P (200 mg/m2) with either motesanib 125 mg QD (Arm A) or placebo QD (Arm B) orally continuously. The primary endpoint was OS; secondary endpoints included progression-free survival (PFS), adverse events (AEs), objective response rate (ORR) and association between placental growth factor (PLGF) change and OS. OS was evaluated using a stratified Cox model and 2-sided log-rank test (α=0.03 for nonsquamous pts and α=0.02 for adenocarcinoma pts). Results: 1090 pts with nonsquamous NSCLC were randomized (Arm A/B, n=541/549); 890 had adenocarcinoma (n=448/442). 61% were men; median age was 60 years (range 21–87); 83% had stage IV disease. At the time of analysis, 753 pts had died (608 pts with adenocarcinoma). Median follow-up was 10.6 mo. OS was not significantly improved in Arm A compared with Arm B (Table). In Arm A, PLGF analysis did not show an association with OS. The incidence of grade ≥3 AEs in Arms A/B was 73/59%. Grade ≥3 AEs occurring more frequently in Arm A than B included neutropenia (22/15%), diarrhea (9/1%), hypertension (7/1%) and cholecystitis (3/0%). The incidence of grade 5 AEs was 14/9% in Arms A/B. Conclusions: In pts with advanced nonsquamous NSCLC, treatment with motesanib + C/P did not significantly improve OS compared with C/P alone. [Table: see text]

Randomized phase III study of panitumumab (pmab) vs. cetuximab (cmab) in chemorefractory wild-type (WT) KRAS exon 2 metastatic colorectal cancer (mCRC): Outcomes by hypomagnesemia (hypomag) in ASPECCT.

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. 705-705
Author(s):  
Timothy Jay Price ◽  
Marc Peeters ◽  
Tae Won Kim ◽  
Jin Li ◽  
Stefano Cascinu ◽  
...  
Keyword(s):  
Primary Endpoint ◽  
Objective Response ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Exon 2 ◽  
Secondary Endpoints ◽  
Phase Iii Study ◽  
Grade 3 ◽  
Dose Modifications ◽  
Kras Exon

705 Background: ASPECCT met its primary endpoint of non-inferiority of overall survival (OS) of pmab vs. cmab. We evaluate outcomes by hypomag, an on-treatment, anti-EGFR related adverse event that develops due to the inhibition of EGFR function. Conflicting reports have suggested hypomag is associated with survival. Methods: Patients with previously treated WT KRAS exon 2 mCRC were randomized 1:1 to receive pmab or cmab. The primary endpoint was non-inferiority of OS. Progression-free survival (PFS) and objective response rate (ORR) were secondary endpoints. Patients were categorized ± any grade hypomag during the study and data analyzed by treatment arm. Analysis of Mg supplementation during hypomag was not conducted. Results: 999 patients were randomized and treated: 499 pmab, 500 cmab. Any grade hypomag was 28.8% and grade ≥3 was 7.3% in the pmab arm vs. 18.9% and 2.6% in the cmab arm, respectively. Median time to first hypomag onset was 82 days in the pmab arm and 57 days in the cmab arm. In the pmab arm, 1.0% of patients discontinued treatment and 5% of patients had dose modifications due to hypomag vs. <0.5% and 3% in the cmab arm, respectively. Results are shown (Table). Conclusions: In ASPECCT, rates of hypomag were higher in the pmab vs. the cmab arm. Patients who developed any grade hypomag with pmab or cmab had higher ORR, PFS, and OS compared with those patients who did not. Clinical trial information: NCT00788957. [Table: see text]

Prognostic Impact of APOBEC3B Expression for Tumor-infiltrating Cytotoxic T cells in Metastatic Urothelial Carcinoma

2020 ◽  
Author(s):  
Hyunho Kim ◽  
Okran Kim ◽  
Myung Ah Lee ◽  
Ji Youl Lee ◽  
Sung-Hoo Hong ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Confidence Interval ◽  
Urothelial Carcinoma ◽  
Cytotoxic T Cells ◽  
Tumor Infiltrating Lymphocytes ◽  
Rank Test ◽  
Log Rank Test ◽  
Metastatic Urothelial Carcinoma ◽  
Infiltrating Lymphocytes

Abstract Background: The APOBEC3B enzymes are endogenous carcinogenic mutagens. Metastatic urothelial carcinomas often harbor APOBEC3B-mediated mutations in which tCw to T or G substitution occurs. A high mutation burden in urothelial carcinoma can increase T-cell immunity against cancer cells, affecting prognosis. In this study, we aimed to evaluate patient survival and CD8+ T-cell density according to APOBEC3B expression in patients with metastatic urothelial carcinoma who underwent cytotoxic chemotherapy.Methods: We performed a retrospective study in 94 patients with urothelial carcinoma who were treated with the first line palliative chemotherapy. Immunohistochemistry staining was performed to evaluate APOBEC3B expression and CD8+/CD3 ratio of tumor-infiltrating lymphocytes. Survival curves according to APOBEC3B expression were generated using the Kaplan–Meier method and compared using the log-rank test. The correlation between APOBEC3B expression and tumor-infiltrating lymphocytes was analyzed using Pearson’s chi-squared test. Results: A high APOBEC3B expression was detected in 71 of the 94 patients (75.5%). The median overall survival of patients with high APOBEC3B expression (15 months) was longer than that of patients with low APOBEC3B expression (p = 0.045 by log-rank test). The hazard ratio based on the Cox regression analysis was 0.252 (95% confidence interval 0.082–0.781, p = 0.017). APOBEC3B expression was associated with the CD8+/CD3+ ratio of tumor-infiltrating lymphocytes (odds ratio 2.914, 95% confidence interval 1.030–8.249, p = 0.039).Conclusions: APOBEC3B expression was an independent prognostic factor in patients with metastatic urothelial carcinoma treated with platinum-based chemotherapy. Tumor-infiltrating cytotoxic T cells correlated with APOBEC3B expression.

scholarly journals Immune Checkpoints Inhibitors and Chemotherapy as First-Line Treatment for Metastatic Urothelial Carcinoma: A Network Meta-Analysis of Randomized Phase III Clinical Trials

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1484
Author(s):  
Hsiao-Ling Chen ◽  
Vinson Wai-Shun Chan ◽  
Yu-Kang Tu ◽  
Erica On-Ting Chan ◽  
Hsiu-Mei Chang ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Adverse Events ◽  
Urothelial Carcinoma ◽  
Safety Profile ◽  
Survival Benefit ◽  
Meta Analysis ◽  
Phase Iii ◽  
Immune Checkpoints ◽  
Metastatic Urothelial Carcinoma ◽  
Grade 3

Immune checkpoints inhibitors (ICIs) were considered as second-line treatments in metastatic urothelial carcinoma (mUC) based on better survival benefit and safety profile than chemotherapy (CTX). We aimed to assess different ICIs regimens in the efficacy and safety for front-line treatments in mUC patients. A comprehensive literature search was performed and Phase II-III randomized controlled trials (RCTs) on ICIs for patients with mUC were included. The outcome was evaluated by overall survival (OS), progression of free survival (PFS), objective response rate (ORR), and grade 3–5 adverse events. Network meta-analysis was used to estimate the effect size. Surface under cumulative ranking curves (SUCRAs) were applied to rank the included treatments for each outcome. Results: The survival benefit of a single ICI was non-inferiority to chemotherapy (CTX). Although no superior effects were indicated, combination therapy (either ICIs plus CTX or ICIs plus ICIs) presented better OS compared with CTX alone. In terms of PFS, combination therapy produced a noticeable benefit over CTX. Regarding the SUCRA ranking, atezolizumab plus CTX was associated with the best ranking for OS and pembrolizumab plus CTX was the best in PFS. In terms of safety, a single ICI had better safety profile than CTX and combination therapy had a similar risk of grade 3–5 adverse events with CTX. Conclusions: Our NMA results revealed that combination therapy has better ranking compared with monotherapy in OS and acceptable AEs. ICIs alone present non-inferior OS but a lower incidence of AEs compared with CTX.

A phase III study (APROMISS) of AL3818 (Catequentinib, Anlotinib) hydrochloride monotherapy in subjects with metastatic or advanced synovial sarcoma.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 11505-11505
Author(s):  
Brian Andrew Van Tine ◽  
Sant P. Chawla ◽  
Jonathan C. Trent ◽  
Breelyn A. Wilky ◽  
Rashmi Chugh ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Synovial Sarcoma ◽  
Primary Endpoint ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Rank Test ◽  
Phase 3 ◽  
Free Survival ◽  
Grade 3 ◽  
Clinical Trial Information

11505 Background: AL3818 (Catequentinib, Anlotinib) is a novel, orally administered, small molecule tyrosine kinase inhibitor. The primary objective of this Phase 3 study is to evaluate the efficacy of AL3818 monotherapy in patients (pts) with synovial sarcoma (SS) comparing with dacarbazine in randomization setting. Methods: Patients with a diagnosis of synovial sarcoma requiring second line or further line treatment were eligible for enrollment. The regimen was a 21-day cycle with oral AL3818 administered on 14 days on and 7 days off. This phase 3 trial is randomized in 2:1 ratio of AL3818 comparing to dacarbazine with option of crossover after PD of dacarbazine treatment. Progression free survival (PFS) with Log Rank test is the primary endpoint and this trial for SS is currently completed enrolled in US and Italy. Results: Total 79 pts initiated treatment and are evaluable, 52 received AL3818 as treatment arm (T), and 27 received dacarbazine (D) as control arm (C). Arms T/C median ages were 40.5/42.0 years (range: 18-70+) and 20/16 (38.5%/59.3%) were male. Overall, PFS was 2.89 months (95% CI: 2.73 – 6.87) for AL3818 and 1.64 (95% CI: 1.45 – 2.70) for D. The PFS of study met the primary endpoint with a p-value of 0.0015 and a HR of 0.449 (95% CI: 0.270– 0.744). At the month 4, 6, and 12, the percentages of progression free patients for AL3818 were 48.1%, 42.3% and 26.9%; and for D were 14.85%, 11.1% and 3.7%. For grade 3 treatment-related adverse events, 12(23.1%) of pts experienced for AL3818 and 7(25.9%) of pts experienced for D. The most common AL3818 related grade 3 AEs were diarrhea (5.8%) and hypertension (3.8%). Conclusions: This phase III trial demonstrates improved disease control and superior progression free survival for AL3818 vs dacarbazine in advanced SS. In addition, the study further confirms the acceptable benefit-risk profile of AL3818 from the prior randomized Phase 2b soft tissue sarcoma study (NCT02449343). AL3818 is a meaningful treatment option for pts with advanced SS. Clinical trial information: NCT 03016819 Clinical trial information: NCT03016819.

Primary results of EV-301: A phase III trial of enfortumab vedotin versus chemotherapy in patients with previously treated locally advanced or metastatic urothelial carcinoma.

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 393-393
Author(s):  
Thomas Powles ◽  
Jonathan E. Rosenberg ◽  
Guru Sonpavde ◽  
Yohann Loriot ◽  
Ignacio Duran ◽  
...  
Keyword(s):  
Urothelial Carcinoma ◽  
Interim Analysis ◽  
Objective Response ◽  
Locally Advanced ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Antibody Drug Conjugate ◽  
Free Survival ◽  
Phase Iii Study ◽  
Metastatic Urothelial Carcinoma

393 Background: Patients with locally advanced or metastatic urothelial carcinoma (la/mUC) have poor survival following progression after platinum-containing chemotherapy and PD-1/L1 inhibitor regimens. Enfortumab vedotin (EV) is an antibody-drug conjugate directed to Nectin-4, a cell adhesion molecule highly expressed in urothelial carcinoma, with remarkable efficacy observed in a single-arm trial in this setting. This randomized phase III study (EV-301) was performed to confirm these findings. Methods: EV-301 (NCT03474107) is a global, open-label phase III study of EV vs chemotherapy conducted in patients with la/mUC who had received a prior platinum-containing chemotherapy and had disease progression during or after PD-1/L1 inhibitor treatment. Patients were randomized 1:1 to receive EV (1.25 mg/kg) on Days 1, 8, and 15 of each 28-day cycle or investigator choice of standard docetaxel, paclitaxel, or vinflunine chemotherapy. The primary endpoint was overall survival (OS); secondary endpoints included investigator-assessed progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR) per RECIST v1.1, as well as safety/tolerability. A prespecified interim analysis, which tested OS at an adjusted 1-sided significance level of P = 0.00679, was performed when ≥285 deaths had occurred. The results of this interim analysis are presented here. Results: Overall, 608 patients with la/mUC were randomly assigned to EV (n=301) or chemotherapy (n=307). As of July 15, 2020, 301 deaths had occurred (EV, n=134; chemotherapy, n=167). After an 11.1 mo follow-up, median OS was significantly prolonged by 3.9 mo with EV compared with chemotherapy (median OS: 12.9 vs 9.0 mo, respectively; HR=0.70 [95% CI: 0.56-0.89], 1-sided P =0.001). Additionally, the OS benefit of EV was retained in the majority of prespecified subgroups. Progression-free survival also was improved with EV (5.6 mo) vs chemotherapy (3.7 mo) (HR=0.61 [95% CI: 0.50-0.75]; 1-sided P <0.00001). Both ORR and DCR were significantly higher with EV vs chemotherapy (40.6% vs 17.9% and 71.9% vs 53.4%, respectively; 1-sided P <0.001 each). Rates of treatment-related adverse events (TRAEs; 93.9% vs 91.8%), including serious TRAEs (22.6% vs 23.4%), were comparable between the EV and chemotherapy groups. Rates of grade ≥3 TRAEs were ~50% in both groups; decreased neutrophil count (13.4%) and white blood cell count (6.9%) were more common in the chemotherapy group, and maculo-papular rash (7.4%) was more common in the EV group. Conclusions: EV is the first therapy to show significant survival advantage over standard chemotherapy in patients with treatment-experienced la/mUC. With robust clinical benefit and a tolerable safety profile, EV is a new standard of care for this aggressive disease. Clinical trial information: NCT03474107.

ARCHER: Dacomitinib (D; PF-00299804) versus erlotinib (E) for advanced (adv) non-small cell lung cancer (NSCLC)—A randomized double-blind phase III study.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. TPS7615-TPS7615 ◽  
Author(s):  
Michael J. Boyer ◽  
Pasi A. Janne ◽  
Tony Mok ◽  
Kenneth John O'Byrne ◽  
Luis G. Paz-Ares ◽  
...  
Keyword(s):  
Phase Ii ◽  
Kras Mutation ◽  
Objective Response ◽  
Phase Iii ◽  
Rank Test ◽  
Double Blind ◽  
Mutation Status ◽  
Log Rank Test ◽  
Ecog Ps ◽  
Kras Mutation Status

TPS7615 Background: D is a highly selective irreversible small molecule inhibitor of all catalytically active members of the HER (human epidermal growth factor receptor) family of tyrosine kinases. In a randomized phase II trial in patients (pts) who had received 1–2 prior systemic therapy regimens for adv NSCLC, D demonstrated significantly longer progression-free survival (PFS) vs. E in the overall population (12.4 vs. 8.3 weeks; HR=0.66, P=0.012), with benefit consistent across several clinical and molecular subgroups. Median PFS in the KRAS wild-type (WT) subgroup was 16.1 vs. 8.3 weeks for D and E, respectively (HR=0.55, P=0.006). Methods: Based on phase II data, a randomized, double-blinded phase III clinical trial (ARCHER; NCT01360554) was designed to compare the efficacy of D with E in two co-primary populations of pts with adv NSCLC: (a) all enrolled pts with adv NSCLC, and (b) pts with KRAS WT NSCLC. Pts with locally adv/metastatic pathologically confirmed NSCLC, radiologically measurable disease, 1 or 2 prior chemotherapy regimens, ECOG PS 0–2, and tissue available for molecular analysis will be randomized to receive D 45 mg or E 150 mg orally once daily. As of Jan 31, 2012, 117 of a planned 800 pts have been enrolled. The primary endpoint is PFS. Secondary endpoints include overall survival, objective response rate, duration of response, safety and tolerability, and pt-reported outcomes of health-related quality of life and disease-/treatment-related symptoms. Study design provides 90% and 80% power to detect ≥33% and ≥45% improvement in PFS in all pts receiving D vs. E, and in pts with KRAS W T NSCLC, respectively, and HR ≤0.75 and ≤0.69 using a 1-sided stratified log-rank test at a significance level of 0.015 and 0.01, respectively. The final primary analysis stratified log-rank test will include ECOG PS, KRAS mutation status and EGFR mutation status as stratification factors. The sample sizes above will also allow the assessment of OS in the co‑primary populations with adequate power. Post-hoc analyses will be performed to explore EGFR, HER family, and KRAS mutation status, as well as other tumor-derived biomarkers collected from all pts in this trial.

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