scholarly journals Selumetinib in Combination With Dacarbazine in Patients With Metastatic Uveal Melanoma: A Phase III, Multicenter, Randomized Trial (SUMIT)

2018 ◽  
Vol 36 (12) ◽  
pp. 1232-1239 ◽  
Author(s):  
Richard D. Carvajal ◽  
Sophie Piperno-Neumann ◽  
Ellen Kapiteijn ◽  
Paul B. Chapman ◽  
Stephen Frank ◽  
...  
Keyword(s):  
Overall Survival ◽  
Uveal Melanoma ◽  
Objective Response Rate ◽  
Response Rate ◽  
Single Agent ◽  
Objective Response ◽  
Hazard Ratio ◽  
Phase Iii ◽  
Double Blind ◽  
Metastatic Setting

Purpose Uveal melanoma is the most common primary intraocular malignancy in adults with no effective systemic treatment option in the metastatic setting. Selumetinib (AZD6244, ARRY-142886) is an oral, potent, and selective MEK1/2 inhibitor with a short half-life, which demonstrated single-agent activity in patients with metastatic uveal melanoma in a randomized phase II trial. Methods The Selumetinib (AZD6244: ARRY-142886) (Hyd-Sulfate) in Metastatic Uveal Melanoma (SUMIT) study was a phase III, double-blind trial ( ClinicalTrial.gov identifier: NCT01974752) in which patients with metastatic uveal melanoma and no prior systemic therapy were randomly assigned (3:1) to selumetinib (75 mg twice daily) plus dacarbazine (1,000 mg/m2 intravenously on day 1 of every 21-day cycle) or placebo plus dacarbazine. The primary end point was progression-free survival (PFS) by blinded independent central radiologic review. Secondary end points included overall survival and objective response rate. Results A total of 129 patients were randomly assigned to receive selumetinib plus dacarbazine (n = 97) or placebo plus dacarbazine (n = 32). In the selumetinib plus dacarbazine group, 82 patients (85%) experienced a PFS event, compared with 24 (75%) in the placebo plus dacarbazine group (median, 2.8 v 1.8 months); the hazard ratio for PFS was 0.78 (95% CI, 0.48 to 1.27; two-sided P = .32). The objective response rate was 3% with selumetinib plus dacarbazine and 0% with placebo plus dacarbazine (two-sided P = .36). At 37% maturity (n = 48 deaths), analysis of overall survival gave a hazard ratio of 0.75 (95% CI, 0.39 to 1.46; two-sided P = .40). The most frequently reported adverse events (selumetinib plus dacarbazine v placebo plus dacarbazine) were nausea (62% v 19%), rash (57% v 6%), fatigue (44% v 47%), diarrhea (44% v 22%), and peripheral edema (43% v 6%). Conclusion In patients with metastatic uveal melanoma, the combination of selumetinib plus dacarbazine had a tolerable safety profile but did not significantly improve PFS compared with placebo plus dacarbazine.

Results of a phase II study of capecitabine-based doublets in the treatment of metastatic triple-negative breast cancer (mTNBC).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e11538-e11538
Author(s):  
Ying Fan ◽  
Binghe Xu ◽  
Yuqian Liao ◽  
Fei Ma ◽  
Peng Yuan ◽  
...  
Keyword(s):  
Overall Survival ◽  
Objective Response Rate ◽  
Response Rate ◽  
Objective Response ◽  
Progression Free Survival ◽  
Cytotoxic Agents ◽  
Free Survival ◽  
Metastatic Setting ◽  
Secondary Endpoints

e11538 Background: It is extremely important to identify proper cytotoxic agents for TNBC which had limited choices except chemotherapy. Capecitabine are well established as a major chemotherapeutic agent in metastatic setting. The efficacy of capecitabine-based chemotherapy has not been prospectively studied in TNBC and data remains scant. This study was designed to investigate the efficacy of capecitabine-based doublets in the treatment of metastatic TNBC. Methods: Eligible metastatic TNBC women with measurable diseases were recruited to receive either TX regimen (docetaxel 75mg/m2 iv d1 plus capecitabine 1000mg/m2 bid, d1-14,q3w) or NX regimen (vinorelbine 25mg/m2 iv d1, 8 plus capecitabine 1000mg/m2 bid, d1-14, q3w) at the discretion of physicians for up to 6 cycles, until disease progression or unacceptable toxicity. The primary endpoint was objective response rate and secondary endpoints included progression free survival (PFS), overall survival (OS). Results: 45 mTNBC patients, 27 in TX and 18 in NX were recruited, mostly (73.3%) as 1st line and the remaining as the 2nd line. The total objective response rate was 20.0% and clinical benefit rate was 62.2%. After a median follow-up of 28 months, PFS was 5.2 months (95%CI, 4.1-6.3mons) and OS was 18.2months (95%CI, 8.7-27.7mons). Almost half of the patients (22/45) progressed during treatment or within one month of the treatment discontinuation. PFS was significantly longer if patients got CR/PR (9.6 vs 4.3mons, P=0.015). When comparing two doublets, the response rate was numerically but not statistically lower in TX group than in NX group (14.8% vs 27.8%, P=0.449). Similarly, no difference was found in either PFS (4.9 vs 5.2 mons, P=0.483) or OS (21.5 vs 18.3 mons, P=0.964) between two regimens. Conclusions: Although the overall survival seems to be reasonable, efficacy of capecitabine-contained TX or NX regimen was relatively poor in terms of tumor remission and progression free survival in mTNBC patients, suggesting capecitabine may have limited potency in this subtype. These two combinations may be considered to be acceptable but may not be recommended as prior choice for mTNBC patients.

KEYNOTE-811 pembrolizumab plus trastuzumab and chemotherapy for HER2+ metastatic gastric or gastroesophageal junction cancer (mG/GEJc): A double-blind, randomized, placebo-controlled phase III study.

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. TPS463-TPS463
Author(s):  
Hyun Cheol Chung ◽  
Yung-Jue Bang ◽  
Charles S. Fuchs ◽  
Shukui Qin ◽  
Taroh Satoh ◽  
...  
Keyword(s):  
T Cell Activation ◽  
Objective Response Rate ◽  
Cell Activation ◽  
Response Rate ◽  
Performance Status ◽  
Gastroesophageal Junction ◽  
Objective Response ◽  
Phase Iii ◽  
Double Blind ◽  
End Points

TPS463 Background: Combination therapy with the anti-HER2 antibody trastuzumab plus fluoropyrimidine and platinum is the current standard of care for patients with HER2+ mG/GEJc. We hypothesize that combination anti–PD-1 and anti-HER2 therapy will result in T-cell activation, augment antibody-dependent, cell-mediated cytotoxicity, and potentiate antitumor immune response in HER2+ patients. A phase 2 study in HER2+ mG/GEJc demonstrated the safety and preliminary efficacy of trastuzumab/pembrolizumab/chemotherapy; the objective response rate was 87%, and the disease control rate was 100% (Janjigian YY, ASCO GI 2019). KEYNOTE-811 (ClinicalTrials.gov, NCT03615326), a global, multicenter, randomized, placebo-controlled, phase 3 study, is underway. Methods: Key eligibility criteria are age ≥18 years; previously untreated unresectable or metastatic HER2+ (centrally confirmed IHC 3+ or IHC 2+/ISH > 2.0) G/GEJ cancer; life expectancy > 6 months with RECIST v1.1 measurable disease; and adequate organ function and performance status (ECOG PS of 0 or 1). Patients will be randomly assigned 1:1 to receive chemotherapy with pembrolizumab 200 mg intravenously (IV) or placebo with trastuzumab 6 mg/kg (after 8 mg/kg load) every 3 weeks (Q3W) up to 2 years or until intolerable toxicity or disease progression. Investigator-choice chemotherapy will include day 1 cisplatin 80 mg/m2 IV and 5-fluorouracil 800 mg/m2/day IV (days 1-5) or oxaliplatin 130 mg/m2 IV and capecitabine 1000 mg/m2 BID days 1-14 (Q3W). Primary end points are progression-free survival and overall survival. Secondary end points are objective response rate, duration of response, and safety and tolerability. Adverse events are graded per CTCAE v4.0 and will be monitored for 30 or 90 days after treatment. Patients will be followed up for survival. Planned enrollment is approximately 692 patients. Clinical trial information: NCT03615326.

Phase III Study to Evaluate Temsirolimus Compared With Investigator's Choice Therapy for the Treatment of Relapsed or Refractory Mantle Cell Lymphoma

2009 ◽  
Vol 27 (23) ◽  
pp. 3822-3829 ◽  
Author(s):  
Georg Hess ◽  
Raoul Herbrecht ◽  
Jorge Romaguera ◽  
Gregor Verhoef ◽  
Michael Crump ◽  
...  
Keyword(s):  
Mantle Cell Lymphoma ◽  
Objective Response Rate ◽  
Response Rate ◽  
Cell Lymphoma ◽  
Objective Response ◽  
Hazard Ratio ◽  
Phase Iii ◽  
Choice Group ◽  
Mantle Cell ◽  
Phase Iii Study

PurposeTemsirolimus, a specific inhibitor of the mammalian target of rapamycin kinase, has shown clinical activity in mantle cell lymphoma (MCL). We evaluated two dose regimens of temsirolimus in comparison with investigator's choice single-agent therapy in relapsed or refractory disease.Patients and MethodsIn this multicenter, open-label, phase III study, 162 patients with relapsed or refractory MCL were randomly assigned (1:1:1) to receive one of two temsirolimus regimens: 175 mg weekly for 3 weeks followed by either 75 mg (175/75-mg) or 25 mg (175/25-mg) weekly, or investigator's choice therapy from prospectively approved options. The primary end point was progression-free survival (PFS) by independent assessment.ResultsMedian PFS was 4.8, 3.4, and 1.9 months for the temsirolimus 175/75-mg, 175/25-mg, and investigator's choice groups, respectively. Patients treated with temsirolimus 175/75-mg had significantly longer PFS than those treated with investigator's choice therapy (P = .0009; hazard ratio = 0.44); those treated with temsirolimus 175/25-mg showed a trend toward longer PFS (P = .0618; hazard ratio = 0.65). Objective response rate was significantly higher in the 175/75-mg group (22%) compared with the investigator's choice group (2%; P = .0019). Median overall survival for the temsirolimus 175/75-mg group and the investigator's choice group was 12.8 months and 9.7 months, respectively (P = .3519). The most frequent grade 3 or 4 adverse events in the temsirolimus groups were thrombocytopenia, anemia, neutropenia, and asthenia.ConclusionTemsirolimus 175 mg weekly for 3 weeks followed by 75 mg weekly significantly improved PFS and objective response rate compared with investigator's choice therapy in patients with relapsed or refractory MCL.

BEYOND: A Randomized, Double-Blind, Placebo-Controlled, Multicenter, Phase III Study of First-Line Carboplatin/Paclitaxel Plus Bevacizumab or Placebo in Chinese Patients With Advanced or Recurrent Nonsquamous Non–Small-Cell Lung Cancer

2015 ◽  
Vol 33 (19) ◽  
pp. 2197-2204 ◽  
Author(s):  
Caicun Zhou ◽  
Yi-Long Wu ◽  
Gongyan Chen ◽  
Xiaoqing Liu ◽  
Yunzhong Zhu ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Overall Survival ◽  
Objective Response Rate ◽  
Response Rate ◽  
Objective Response ◽  
Small Cell ◽  
Phase Iii ◽  
Chinese Patients ◽  
Small Cell Lung ◽  
First Line

Purpose The phase III BEYOND trial was undertaken to confirm in a Chinese patient population the efficacy seen with first-line bevacizumab plus platinum doublet chemotherapy in globally conducted studies. Patients and Methods Patients age ≥ 18 years with locally advanced, metastatic, or recurrent advanced nonsquamous non–small-cell lung cancer (NSCLC) were randomly assigned to receive carboplatin (area under the curve, 6) intravenously and paclitaxel (175 mg/m2) intravenously (CP) on day 1 of each 3-week cycle, for ≤ six cycles, plus placebo (Pl+CP) or bevacizumab (B+CP) 15 mg/kg intravenously, on day 1 of each cycle, until progression, unacceptable toxicity, or death. The primary end point was progression-free survival (PFS); secondary end points were objective response rate, overall survival, exploratory biomarkers, safety. Results A total of 276 patients were randomly assigned, 138 to each arm. PFS was prolonged with B+CP versus Pl+CP (median, 9.2 v 6.5 months, respectively; hazard ratio [HR], 0.40; 95% CI, 0.29 to 0.54; P < .001). Objective response rate was improved with B+CP compared with Pl+CP (54% v 26%, respectively). Overall survival was also prolonged with B+CP compared with Pl+CP (median, 24.3 v 17.7 months, respectively; HR, 0.68; 95% CI, 0.50 to 0.93; P = .0154). Median PFS was 12.4 months with B+CP and 7.9 months with Pl+CP (HR, 0.27; 95% CI, 0.12 to 0.63) in EGFR mutation–positive tumors and 8.3 and 5.6 months, respectively (HR, 0.33; 95% CI, 0.21 to 0.53), in wild-type tumors. Safety was similar to previous studies of B+CP in NSCLC; no new safety signals were observed. Conclusion The addition to bevacizumab to carboplatin/paclitaxel was well tolerated and resulted in a clinically meaningful treatment benefit in Chinese patients with advanced nonsquamous NSCLC.

scholarly journals OCEANS: A Randomized, Double-Blind, Placebo-Controlled Phase III Trial of Chemotherapy With or Without Bevacizumab in Patients With Platinum-Sensitive Recurrent Epithelial Ovarian, Primary Peritoneal, or Fallopian Tube Cancer

2012 ◽  
Vol 30 (17) ◽  
pp. 2039-2045 ◽  
Author(s):  
Carol Aghajanian ◽  
Stephanie V. Blank ◽  
Barbara A. Goff ◽  
Patricia L. Judson ◽  
Michael G. Teneriello ◽  
...  
Keyword(s):  
Fallopian Tube ◽  
Objective Response Rate ◽  
Response Rate ◽  
Objective Response ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Fallopian Tube Cancer ◽  
Double Blind ◽  
Phase Iii Trial ◽  
Platinum Sensitive

Purpose This randomized, multicenter, blinded, placebo-controlled phase III trial tested the efficacy and safety of bevacizumab (BV) with gemcitabine and carboplatin (GC) compared with GC in platinum-sensitive recurrent ovarian, primary peritoneal, or fallopian tube cancer (ROC). Patients and Methods Patients with platinum-sensitive ROC (recurrence ≥ 6 months after front-line platinum-based therapy) and measurable disease were randomly assigned to GC plus either BV or placebo (PL) for six to 10 cycles. BV or PL, respectively, was then continued until disease progression. The primary end point was progression-free survival (PFS) by RECIST; secondary end points were objective response rate, duration of response (DOR), overall survival, and safety. Results Overall, 484 patients were randomly assigned. PFS for the BV arm was superior to that for the PL arm (hazard ratio [HR], 0.484; 95% CI, 0.388 to 0.605; log-rank P < .0001); median PFS was 12.4 v 8.4 months, respectively. The objective response rate (78.5% v 57.4%; P < .0001) and DOR (10.4 v 7.4 months; HR, 0.534; 95% CI, 0.408 to 0.698) were significantly improved with the addition of BV. No new safety concerns were noted. Grade 3 or higher hypertension (17.4% v < 1%) and proteinuria (8.5% v < 1%) occurred more frequently in the BV arm. The rates of neutropenia and febrile neutropenia were similar in both arms. Two patients in the BV arm experienced GI perforation after study treatment discontinuation. Conclusion GC plus BV followed by BV until progression resulted in a statistically significant improvement in PFS compared with GC plus PL in platinum-sensitive ROC.

scholarly journals Network meta-analysis of nivolumab plus ipilimumab in the second-line setting for advanced hepatocellular carcinoma

2021 ◽  
Author(s):  
Neehar D Parikh ◽  
Alexander Marshall ◽  
Keith A Betts ◽  
Jinlin Song ◽  
Jing Zhao ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Overall Survival ◽  
Objective Response Rate ◽  
Response Rate ◽  
Meta Analysis ◽  
Objective Response ◽  
Credible Interval ◽  
Hazard Ratio ◽  
Advanced Hepatocellular Carcinoma ◽  
Second Line

Aims: To compare the efficacy of nivolumab 1 mg/kg + ipilimumab 3 mg/kg with regorafenib 160 mg, cabozantinib 60 mg and nivolumab 3 mg/kg monotherapy for second-line treatment of advanced hepatocellular carcinoma. Materials & methods: Indirect comparison using network meta-analysis and propensity score weighting. Results: Nivolumab 1 mg/kg + ipilimumab 3 mg/kg had significantly higher objective response rate (median 31.2% [95% credible interval: 19.6–44.5%]) than cabozantinib (4.2% [2.0–6.5%]) and regorafenib (4.8% [1.1–8.3%]), and significantly longer overall survival (cabozantinib: hazard ratio: 0.46 [95% credible interval: 0.27–0.79]; regorafenib: 0.56 [0.32–0.97]). Nivolumab 1 mg/kg + ipilimumab 3 mg/kg had significantly better objective response rate (difference 21.0% [4.5–37.5%]) and overall survival (hazard ratio: 0.58 [0.35–0.96]) than nivolumab monotherapy. Conclusion: Nivolumab 1 mg/kg + ipilimumab 3 mg/kg had a superior efficacy versus cabozantinib 60 mg, regorafenib 160 mg and nivolumab 3 mg/kg monotherapy as second-line therapy for advanced hepatocellular carcinoma.

Vandetanib Plus Pemetrexed for the Second-Line Treatment of Advanced Non–Small-Cell Lung Cancer: A Randomized, Double-Blind Phase III Trial

2011 ◽  
Vol 29 (8) ◽  
pp. 1067-1074 ◽  
Author(s):  
Richard H. de Boer ◽  
Óscar Arrieta ◽  
Chih-Hsin Yang ◽  
Maya Gottfried ◽  
Valorie Chan ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Overall Survival ◽  
Objective Response Rate ◽  
Response Rate ◽  
Objective Response ◽  
Growth Factor Receptor ◽  
Small Cell ◽  
Phase Iii ◽  
Second Line ◽  
Small Cell Lung

Purpose Vandetanib is a once-daily oral inhibitor of vascular endothelial growth factor receptor and epidermal growth factor receptor signaling. This randomized, placebo-controlled phase III study assessed the efficacy of vandetanib plus pemetrexed as second-line therapy in advanced non–small-cell lung cancer. Patients and Methods Patients (N = 534) were randomly assigned to receive vandetanib 100 mg/d plus pemetrexed 500 mg/m2 every 21 days (n = 256) or placebo plus pemetrexed (n = 278). Progression-free survival (PFS) was the primary end point; overall survival, objective response rate, disease control rate, time to deterioration of symptoms, and safety were secondary assessments. Results There was no significant difference in PFS between treatment arms (hazard ratio [HR], 0.86; 97.58% CI, 0.69 to 1.06; P = .108). Overall survival was also not significantly different (HR, 0.86; 97.54% CI, 0.65 to 1.13; P = .219). Statistically significant improvements in objective response rate (19% v 8%; P < .001) and time to deterioration of symptoms (HR, 0.71; P = .0052; median, 18.1 weeks for vandetanib and 12.1 weeks for placebo) were observed in patients receiving vandetanib. Adding vandetanib to pemetrexed increased the incidence of some adverse events, including rash, diarrhea, and hypertension, while showing a reduced incidence of nausea, vomiting, anemia, fatigue, and asthenia with no reduction in the dose intensity of pemetrexed. Conclusion This study did not meet the primary end point of statistically significant PFS prolongation with vandetanib plus pemetrexed versus placebo plus pemetrexed. The vandetanib combination showed a significantly higher objective response rate and a significant delay in the time to worsening of lung cancer symptoms versus the placebo arm as well as an acceptable safety profile in this patient population.

scholarly journals A Phase II Study of Glembatumumab Vedotin for Metastatic Uveal Melanoma

Cancers ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 2270
Author(s):  
Merve Hasanov ◽  
Matthew J. Rioth ◽  
Kari Kendra ◽  
Leonel Hernandez-Aya ◽  
Richard W. Joseph ◽  
...  
Keyword(s):  
Overall Survival ◽  
Uveal Melanoma ◽  
Phase Ii ◽  
Stable Disease ◽  
Objective Response Rate ◽  
Response Rate ◽  
Phase Ii Study ◽  
Objective Response ◽  
Progression Free Survival ◽  
Free Survival

Glembatumumab vedotin (CDX-011, GV) is a fully human Immunoglobulin G2 monoclonal antibody directed against glycoprotein NMB coupled via a peptide linker to monomethyl auristatin E (MMAE), a potent cytotoxic microtubule inhibitor. This phase II study evaluated the overall response rate and safety of GV, glycoprotein NMB (GPNMB) expression, and survival in patients with metastatic uveal melanoma. Eligible patients with metastatic uveal melanoma who had not previously been treated with chemotherapy received GV 1.9 mg/kg every three weeks. The primary endpoint was the objective response rate (ORR). Secondary endpoints included GPNMB expression, progression-free survival (PFS), overall survival (OS), and toxicity analysis. GPNMB expression was assessed pre- and post-treatment via immunohistochemistry for patients with available tumor tissue. Out of 35 patients who received treatment, two patients had confirmed partial responses (PRs; 6%), and 18 patients had a stable disease (SD; 51%) as the best objective response. 38% of the patients had stable disease >100 days. The grade 3 or 4 toxicities that occurred in two or more patients were neutropenia, rash, hyponatremia, and vomiting. The median progression-free survival was 3.1 months (95% CI: 1.5–5.6), and the median overall survival was 11.9 months (95% CI 9.0–16.9) in the evaluable study population. GV is well-tolerated in metastatic uveal melanoma. The disease control rate was 57% despite a low objective response rate. Exploratory immune correlation studies are underway to provide insight into target saturation, combination strategies, and antigen release.

Bevacizumab plus interferon-alpha versus interferon-alpha monotherapy in patients with metastatic renal cell carcinoma: Results of overall survival for CALGB 90206

2009 ◽  
Vol 27 (18_suppl) ◽  
pp. LBA5019-LBA5019 ◽  
Author(s):  
B. I. Rini ◽  
S. Halabi ◽  
J. Rosenberg ◽  
W. M. Stadler ◽  
D. A. Vaena ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Overall Survival ◽  
Cell Carcinoma ◽  
Interferon Alpha ◽  
Renal Cell ◽  
Objective Response Rate ◽  
Response Rate ◽  
Objective Response ◽  
Phase Iii ◽  
Type I

LBA5019 Background: Bevacizumab (BEV) plus interferon alpha (IFN) demonstrated a superior objective response rate and progression-free survival (PFS) versus IFN monotherapy in renal cell carcinoma (RCC) patients in 2 phase III trials. The primary objective of CALGB 90206 was to compare overall survival (OS) for advanced RCC patients receiving BEV plus IFN or IFN alone. Methods: Patients with previously-untreated, metastatic RCC with a clear cell component and Karnofsky performance status of ≥ 70% were eligible. Patients were prospectively randomized to receive BEV (10 mg/kg intravenously every 2 weeks) plus IFN (9 million units subcutaneously three times weekly) or the same dose and schedule of IFN as monotherapy. Randomization was stratified by nephrectomy status and number of MSKCC adverse features. The primary endpoint was OS, defined as the time from randomization to death due to any cause. The trial was designed with 86% power to detect a hazard ratio (HR) of 0.76, assuming a two-sided type I error of 0.05. The primary analysis was an intent-to-treat approach using the stratified log-rank statistic, and the present analysis was based on the target number of 588 deaths. Results: Between October 2003 and July 2005, 732 patients were enrolled; 369 pts to BEV plus IFN and 363 pts to IFN monotherapy. The median duration of follow up among censored patients was 46.2 months (IQR=45.2–48.2). The median OS was 18.3 months (95% CI; 16.5–22.5) for BEV plus IFN and 17.4 months (95% CI; 14.4–20.0, unstratified log rank p = 0.097) for IFN monotherapy. The stratified HR was 0.86 (95% CI; 0.73–1.01) for BEV plus IFN compared to IFN (stratified log-rank p = 0.069). The median OS for BEV plus IFN versus IFN was 32.5 vs. 33.5 months (p = 0.524) for MSKCC good risk, 17.7 vs. 16.1 months (p = 0.174) for intermediate risk and 6.6 vs. 5.7 months (p = 0.245) for poor risk patients. The median PFS was 8.4 months vs. 4.9 months (p<0.0001). Fifty-three percent of patients received subsequent systemic therapy. Conclusions: The addition of BEV to IFN significantly improves the objective response rate and PFS versus IFN monotherapy. Overall survival favored the BEV plus IFN arm, not meeting pre-defined criteria for significance. [Table: see text]

E2112: Randomized Phase III Trial of Endocrine Therapy Plus Entinostat or Placebo in Hormone Receptor–Positive Advanced Breast Cancer. A Trial of the ECOG-ACRIN Cancer Research Group

2021 ◽  
pp. JCO.21.00944
Author(s):  
Roisin M. Connolly ◽  
Fengmin Zhao ◽  
Kathy D. Miller ◽  
Min-Jung Lee ◽  
Richard L. Piekarz ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Advanced Breast Cancer ◽  
Endocrine Therapy ◽  
Hormone Receptor ◽  
Objective Response Rate ◽  
Response Rate ◽  
Objective Response ◽  
Hazard Ratio ◽  
Phase Iii ◽  
End Points

PURPOSE Endocrine therapy resistance in advanced breast cancer remains a significant clinical problem that may be overcome with the use of histone deacetylase inhibitors such as entinostat. The ENCORE301 phase II study reported improvement in progression-free survival (PFS) and overall survival (OS) with the addition of entinostat to the steroidal aromatase inhibitor (AI) exemestane in advanced hormone receptor (HR)–positive, human epidermal growth factor receptor 2 (HER2)–negative breast cancer. PATIENTS AND METHODS E2112 is a multicenter, randomized, double-blind, placebo-controlled phase III study that enrolled men or women with advanced HR-positive, HER2-negative breast cancer whose disease progressed after nonsteroidal AI. Participants were randomly assigned to exemestane 25 mg by mouth once daily and entinostat (EE) or placebo (EP) 5 mg by mouth once weekly. Primary end points were PFS by central review and OS. Secondary end points included safety, objective response rate, and lysine acetylation change in peripheral blood mononuclear cells between baseline and cycle 1 day 15. RESULTS Six hundred eight patients were randomly assigned during March 2014-October 2018. Median age was 63 years (range 29-91), 60% had visceral disease, and 84% had progressed after nonsteroidal AI in metastatic setting. Previous treatments included chemotherapy (60%), fulvestrant (30%), and cyclin-dependent kinase inhibitor (35%). Most common grade 3 and 4 adverse events in the EE arm included neutropenia (20%), hypophosphatemia (14%), anemia (8%), leukopenia (6%), fatigue (4%), diarrhea (4%), and thrombocytopenia (3%). Median PFS was 3.3 months (EE) versus 3.1 months (EP; hazard ratio = 0.87; 95% CI, 0.67 to 1.13; P = .30). Median OS was 23.4 months (EE) versus 21.7 months (EP; hazard ratio = 0.99; 95% CI, 0.82 to 1.21; P = .94). Objective response rate was 5.8% (EE) and 5.6% (EP). Pharmacodynamic analysis confirmed target inhibition in entinostat-treated patients. CONCLUSION The combination of exemestane and entinostat did not improve survival in AI-resistant advanced HR-positive, HER2-negative breast cancer.

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