First-line pembrolizumab (pembro) in cisplatin-ineligible patients with advanced urothelial cancer (UC): Response and survival results up to five years from the KEYNOTE-052 phase 2 study.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 4508-4508
Author(s):  
Peter H. O'Donnell ◽  
Arjun Vasant Balar ◽  
Jacqueline Vuky ◽  
Daniel Castellano ◽  
Joaquim Bellmunt ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Nyha Class ◽  
Complete Response ◽  
Phase 2 ◽  
Class Iii ◽  
Open Label ◽  
Kaplan Meier ◽  
Duration Of Response ◽  
Ecog Ps

4508 Background: Pembro was approvedfor cisplatin-ineligible patients with untreated advanced UC based on initial results of the phase 2 KEYNOTE-052 study (NCT02335424), which showed an ORR of 29%. Updated results after up to 5 years of follow-up are presented. Methods: KEYNOTE-052 is a single-arm, multi-site, open-label trial. Patients had advanced or metastatic UC, were cisplatin ineligible (criteria: ECOG PS 2, CrCl ≥30 to ̃60 mL/min, grade ≥2 peripheral neuropathy/hearing loss, NYHA class III heart failure), and had not previously received chemotherapy for advanced/metastatic disease. Patients received pembro 200 mg IV Q3W until progression, unacceptable toxicity, withdrawal, or 24 mo of therapy, whichever occurred first. PD-L1 status was determined by combined positive score (CPS, number of PD-L1–staining cells [tumor cells, lymphocytes, macrophages] divided by the total number of viable tumor cells, multiplied by 100); PD-L1–positive was CPS ≥10. The primary end point was confirmed ORR (RECIST v1.1, independent central review). Key secondary end points were duration of response (DOR), OS, and safety. Results: Among 370 enrolled patients, median age was 74 y, 315 (85.1%) had visceral disease, and 43 (11.6%) completed 24 mo of therapy. Median time from enrollment to data cutoff (Sep 26, 2020) was 56.3 mo (range, 51.2-65.3) for all patients and 56.0 mo (range, 51.4-65.2) for the 110 patients (29.7%) with CPS ≥10. Confirmed ORR for all patients was 28.9% (95% CI, 24.3-33.8); complete response, 9.5% (n=35); partial response, 19.5% (n=72). Median DOR was 33.4 mo (range, 1.4+ to 60.7+); 44.8% and 39.4% of patients had DOR ≥36 and ≥48 mo, (Kaplan-Meier estimates). Median OS was 11.3 mo (95% CI, 9.7-13.1); 24- and 36-mo OS rates were 31.5% and 22.1%. Patients with CPS ≥10 had better outcomes than patients with CPS <10 (Table). Treatment-related adverse events (AEs) occurred in 67.3% of patients; 21.1% of treatment-related AEs were grade ≥3, including 1 death (myositis). Conclusions: After up to 5 y of follow-up, pembro continued to elicit clinically meaningful, durable antitumor activity in cisplatin-ineligible patients with advanced UC. These effects were more pronounced in patients with CPS ≥10. Clinical trial information: NCT02335424. [Table: see text]

KEYNOTE-052: Phase 2 study evaluating first-line pembrolizumab (pembro) in cisplatin-ineligible advanced urothelial cancer (UC)— Updated response and survival results.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 4546-4546 ◽  
Author(s):  
Peter H. O'Donnell ◽  
Arjun Vasant Balar ◽  
Jacqueline Vuky ◽  
Daniel E. Castellano ◽  
Joaquim Bellmunt ◽  
...  
Keyword(s):  
Nyha Class ◽  
Safety Data ◽  
Complete Response ◽  
Phase 2 ◽  
Class Iii ◽  
Duration Of Response ◽  
Combined Positive Score ◽  
Grade 3 ◽  
Ecog Ps

4546 Background: Initial results of the phase 2 KEYNOTE-052 (NCT02335424) study led to approval of pembro for cisplatin-ineligible patients (pts) with advanced UC. Updated results representing follow-up of over 2 y since last pt enrolled are presented. Methods: Pts had confirmed advanced UC, were cisplatin-ineligible (ECOG PS 2, CrCl ≥30 to ˂60 mL/min, grade ≥2 neuropathy/hearing loss, NYHA Class III heart failure), and received no prior chemotherapy for metastatic disease. Pts received pembro 200 mg IV Q3W until progression, unacceptable toxicity, withdrawal, or 24 mo of therapy, whichever occurred first. Primary end point was confirmed ORR (RECIST v1.1, independent central review). Key secondary end points: duration of response (DOR), overall survival (OS), and safety. Data cutoff was September 26, 2018. Results: Among pts assessed (N = 370), median age was 74 y, 85% had visceral disease, and 30% were PD-L1 positive (combined positive score [CPS] ≥10). Median follow-up was 11.4 mo (range, 0.1-41.2) for all pts and 29.3 mo (range 7-41.2) for responders. Confirmed ORR was 29% (95% CI, 24-34): complete response, 9% (n = 33); partial response, 20% (n = 73). Median DOR was 30.1 mo (95% CI, 18.1-not reached [NR]); 67% and 52% of pts had DOR ≥12 and ≥24 mo, respectively. Median OS was 11.3 mo (range 9.7-13.1); 12- and 24-mo OS rates were 47% and 31%, respectively. In pts with CPS ˂10 (n = 251) and ≥10 (n = 110), respectively, confirmed ORR was 20% (95%CI, 16-26) and 47% (95% CI, 38-57). Median DOR for pts with CPS < 10 and ≥10 was 18.2 mo (95% CI, 9.7-NR) and NR (95% CI, 18.1-NR); DOR ≥24 mo was 45% and 57%, respectively. Median OS for pts with CPS < 10 and ≥10 was 9.7 mo (95% CI, 7.6-11.5) and 18.5 mo (95% CI, 12.2-28.5); 24-mo OS rates were 24% and 47% respectively. Treatment-related adverse events (AEs) occurred in 67% of pts. Most common were fatigue and pruritus (18% each); 21% were grade ≥3, including 1 death (myositis). Conclusions: With extended follow-up, pembro continued to elicit clinically meaningful, durable antitumor activity in cisplatin-ineligible pts with advanced UC and was more pronounced in those with PD-L1 expression CPS ≥10. Pembro safety profile was as expected. Clinical trial information: NCT02335424.

Planned survival analysis from KEYNOTE-045: Phase 3, open-label study of pembrolizumab (pembro) versus paclitaxel, docetaxel, or vinflunine in recurrent, advanced urothelial cancer (UC).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 4501-4501 ◽  
Author(s):  
Dean F. Bajorin ◽  
Ronald De Wit ◽  
David J. Vaughn ◽  
Yves Fradet ◽  
Jae-Lyun Lee ◽  
...  
Keyword(s):  
Survival Analysis ◽  
Standard Of Care ◽  
Open Label ◽  
Phase 3 ◽  
Prior Therapy ◽  
Open Label Phase ◽  
Duration Of Response ◽  
Combined Positive Score ◽  
Ecog Ps

4501 Background: Second-line chemotherapies (chemo) for advanced UC have limited clinical benefit (OS, 7-9 mo). Data from the open-label, phase 3 KEYNOTE-045 study (NCT02256436) showed significantly longer OS with pembro v chemo (median, 10.3 v 7.4 mo; hazard ratio [HR], 0.73; P = 0.002) in recurrent, advanced UC. Data from a planned survival analysis are presented. Methods: Pts had histologically or cytologically confirmed UC, progression after platinum, ECOG PS 0-2, measurable disease (RECIST v1.1), and ≤2 lines of systemic therapy. Pts were randomly assigned 1:1 to pembro 200 mg Q3W or investigator’s choice of paclitaxel 175 mg/m2 Q3W, docetaxel 75 mg/m2 Q3W, or vinflunine 320 mg/m2 Q3W. Primary efficacy end points were OS and PFS (RECIST v1.1, blinded central review). ORR (RECIST v1.1, blinded central review) was a secondary end point. Results: 542 pts were enrolled (pembro, 270; chemo, 272). Baseline characteristics were generally similar between arms. As of Jan 18, 2017, median follow-up was 18.5 mo (range, 14.2-26.5). Median OS was significantly longer with pembro v chemo (10.3 v 7.4 mo; HR, 0.70; P < 0.001), and significance was maintained regardless of PD-L1 expression as measured by combined positive score (HR: CPS < 1%, 0.84; CPS ≥1%, 0.59; CPS < 10%, 0.76; CPS ≥10%, 0.57). OS benefit with pembro v chemo was seen regardless of age, ECOG PS, prior therapy, liver metastases, histology, and choice of chemo. The 18-mo OS rate (95% CI) was 36.1% (30.1%-42.0%) with pembro v 20.5% (15.2%-25.8%) with chemo (KM estimate). PFS was not different between arms. ORR was higher with pembro v chemo (21.1% v 11.0%), and median (range) duration of response was longer (not reached [1.6+-20.7+ mo] v 4.4 mo [1.4+-20.3]). 69% (pembro) v 36% (chemo) of responses lasted ≥12 mo. Fewer pts experienced a treatment-related AE with pembro v chemo (any grade, 61.3% v 90.2%; grade ≥3, 16.5% v 49.8%). Conclusions: The OS benefit and superior safety profile of pembro over chemo are maintained with longer follow-up. Combined, these results support the potential of pembro as a new standard of care for patients with UC who previously received platinum. Clinical trial information: NCT02256436.

Keynote 057: Phase II trial of Pembrolizumab (pembro) for patients (pts) with high-risk (HR) nonmuscle invasive bladder cancer (NMIBC) unresponsive to bacillus calmette-guérin (BCG).

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. 350-350 ◽  
Author(s):  
Arjun Vasant Balar ◽  
Girish S. Kulkarni ◽  
Edward M. Uchio ◽  
Joost Boormans ◽  
Loic Mourey ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Complete Response ◽  
Maculopapular Rash ◽  
Median Number ◽  
Kaplan Meier ◽  
Bcg Therapy ◽  
Duration Of Response ◽  
Grade 3 ◽  
Muscle Invasive

350 Background: The PD-1 inhibitor pembro has durable antitumor activity in pts with metastatic urothelial carcinoma. Upregulation of the PD-1 pathway has been observed in BCG-resistant NMIBC, suggesting pembro may benefit. Efficacy and safety of pembro in pts with HR, BCG-unresponsive NMIBC was evaluated in the single-arm phase 2 KEYNOTE-057 study; updated results for pts with carcinoma in situ (CIS) with or without papillary tumor (cohort A) are reported. Methods: Pts with histologically confirmed HR, BCG-unresponsive CIS with or without papillary disease, who received adequate BCG therapy and were unable/unwilling to undergo radical cystectomy received pembro 200 mg Q3W for 24 mo or until recurrence, progression, or unacceptable toxicity. Pts with HR NMIBC or progressive disease during treatment were required to discontinue. Primary end point: complete response rate (CRR); key secondary end points: duration of response and safety. Results: 103 pts (median age 73 years; CIS alone 71.8%; median number of prior BCG instillations 12) have enrolled in cohort A. 3-mo CRR rate was 38.8% (95% CI 29.4%-48.9%) by central assessment. Among 40 pts who achieved CR at 3 mo, 72.5% maintained CR at last follow-up (median 14.0 mo; range 4.0-26.3) and median CR duration has not been reached (range 0+ to 14.1+ mo). 80.2% of pts had a CR duration of ≥6 mo (Kaplan-Meier method). 10 (25.0%) experienced recurrent NMIBC after CR; at the time of analysis, none progressed to muscle invasive or metastatic disease. Treatment-related adverse events (AEs) occurred in 65 (63.1%) pts; most frequent were pruritus (10.7%), fatigue (9.7%), diarrhea (8.7%), hypothyroidism (5.8%), and maculopapular rash (5.8%). Grade 3/4 treatment-related AEs occurred in 13 (12.6%) pts; 1 death was considered treatment-related (colitis in patient inadequately treated with steroids). Immune-mediated AEs occurred in 19 (18.4%) pts. Conclusions: Pembro had encouraging activity in pts with HR, BCG-unresponsive CIS with or without papillary tumors and a safety profile consistent with that of previous experience. Updated data using additional follow-up will be presented. Clinical trial. Clinical trial information: NCT02625961.

scholarly journals 85 Diuretics trajectories in dilated cardiomyopathy

2021 ◽  
Vol 23 (Supplement_G) ◽  
Author(s):  
Vincenzo Nuzzi ◽  
Antonio Cannatà ◽  
Paolo Manca ◽  
Caterina Gregorio ◽  
Giulia Barbati ◽  
...  
Keyword(s):  
Dilated Cardiomyopathy ◽  
Nyha Class ◽  
Diuretic Therapy ◽  
Left Ventricular ◽  
Equivalent Dose ◽  
Left Ventricular Ejection ◽  
Class Iii ◽  
Ventricular Ejection Fraction ◽  
Kaplan Meier

Abstract Aims Diuretics in heart failure (HF) are commended to relieve symptoms at lowest dosage effective. Dilated cardiomyopathy (DCM) is a particular HF setting with several variables that may influence disease trajectory. We aimed to assess the long-term use of diuretics in DCM, the possibility of withdrawal and to explore the prognostic correlations. Methods and results All consecutive DCM patients enrolled from 1990 to 2018 were considered eligible. All the patients had available the information about the furosemide-equivalent dose at baseline and at follow-up evaluation within 24 months. Patients were categorized in stable (diuretic dose variation &lt;50%), increasers (diuretics dose increase ≥50% or initiation of diuretic therapy), and decreasers (diuretics dose decrease ≥50% or never prescribed diuretics in the 24-months observation period). The prognostic role of the diuretics trajectory group was assessed with Kaplan Meier analysis and with a time-dependent multivariable model. The outcome measure was a composite of all-cause death/heart transplantation/HF hospitalization (ACD/HTx/HFH). 908 patients were included [mean age 50 ± 16, 70% male sex, 24% NYHA class III or IV, mean left ventricular ejection fraction (LVEF) 31 ± 9%, 66% treated with diuretics at baseline]. The furosemide-equivalent dose at enrolment had a linear association with the risk of outcome. Compared to other groups, decreaser patients were younger, had less HF symptoms, higher LVEF and more dilated left atrium. Decreasers had a lower prescription rate of diuretics and less frequent indication to renin-angiotensin inhibitors and mineralocorticoid receptors antagonists. Over a median follow-up of 122 (62–195) months decreasers had the lowest incidence of outcome, followed by stable, while increasers had the worst outcome (P &lt; 0.001). After adjustment for other prognosticators, compared to stable patients, decreasers had a reduced risk of ACD/HTx/HFH [HR: 0.497 (95% CI: 0.337–0.731)] while increasers had the highest risk of adverse outcome [HR: 2.027 (95% CI: 1.254–3.276)]. Similarly, amongst patients taking diuretics at baseline, the diuretics withdrawal was in independent outcome predictor. The only multivariable predictors of diuretics withdrawal were younger age and lower furosemide-equivalent dose at enrolment. Conclusions In DCM patients the diuretics dose at baseline is a strong prognosticator. Diuretics dose reduction or its withdrawal provides a prognostic benefit on hard outcome. Diuretics tapering in selected patients should be considered in the short-term follow-up to improve DCM prognosis.

First-line treatment of iNHL or MCL patients with BR or R-CHOP/R-CVP: Results of the BRIGHT 5-year follow-up study.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 7500-7500 ◽  
Author(s):  
Ian Flinn ◽  
Richard van der Jagt ◽  
Julie E. Chang ◽  
Peter Wood ◽  
Tim E. Hawkins ◽  
...  
Keyword(s):  
Progression Free Survival ◽  
Complete Response ◽  
Rank Test ◽  
First Line ◽  
Open Label ◽  
Free Survival ◽  
Non Hodgkin Lymphoma ◽  
Duration Of Response ◽  
Treatment Naïve

7500 Background: BRIGHT, a phase 3, open-label, noninferiority study comparing efficacy and safety of bendamustine plus rituximab (BR) vs rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) or rituximab with cyclophosphamide, vincristine and prednisone (R-CVP) in treatment-naive patients (pts) with indolent non-Hodgkin lymphoma (iNHL) or mantle cell lymphoma (MCL), showed that the complete response rate for first-line BR was statistically noninferior to R-CHOP/R-CVP ( Blood 2014). Pts were monitored for ≥5 years (yr) to assess the overall effect of BR or R-CHOP/R-CVP in a controlled clinical setting. This analysis reports the time-to-event variables of the 5-yr follow-up (FU) study. Methods: Pts with iNHL or MCL randomized to 6-8 cycles of BR or R-CHOP/R-CVP underwent complete assessments at end of treatment, then were monitored regularly. Progression-free survival (PFS), event-free survival (EFS), duration of response (DOR) and overall survival (OS) were compared using a stratified log-rank test. Results: Of 447 randomized pts, 224 received BR, 104 R-CHOP, and 119 R-CVP; 419 entered the FU. The median FU time was 65.0 and 64.1 months for BR and R-CHOP/R-CVP, respectively. The 5-yr PFS rate was 65.5% (95% CI 58.5-71.6) and 55.8% (48.4-62.5), and OS was 81.7% (75.7-86.3) and 85% (79.3-89.3) for BR and R-CHOP/R-CVP, respectively. The hazard ratio (95% CI) for PFS was 0.61 (0.45-0.85; P= .0025), EFS 0.63 (0.46-0.84; P= .0020), DOR 0.66 (0.47-0.92; P= .0134), and OS 1.15 (0.72-1.84; P= .5461) comparing BR vs R-CHOP/R-CVP. Similar results were found in iNHL [PFS 0.70 (0.49-1.01; P= .0582)] and MCL [PFS 0.40 (0.21-0.75; P= .0035)], with the strongest effect in MCL. Use of R maintenance was similar, 43% in BR and 45% in R-CHOP/R-CVP. B was included as second-line in 27 (36%) of the 75 pts requiring therapy who originally received R-CHOP/R-CVP. Comparable safety profiles with expected adverse events were observed in the FU study in BR vs R-CHOP/R-CVP. Conclusions: The long-term FU of the BRIGHT study has confirmed that PFS, EFS, and DOR were significantly better for BR, and OS was not statistically different between BR and R-CHOP/R-CVP. The safety profile was as previously reported. Clinical trial information: NCT00877006.

Subcutaneous daratumumab in patients with multiple myeloma who have been previously treated with intravenous daratumumab: A multicenter, randomized, phase II study (LYNX).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS8553-TPS8553
Author(s):  
Nizar J. Bahlis ◽  
Jeffrey A. Zonder ◽  
Susan Wroblewski ◽  
Ming Qi ◽  
Thomas Renaud ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Partial Response ◽  
Residual Disease ◽  
Progression Free Survival ◽  
Standard Of Care ◽  
Complete Response ◽  
Similar Efficacy ◽  
Phase 2 ◽  
Open Label ◽  
Duration Of Response

TPS8553 Background: The intravenous (IV) formulation of daratumumab (DARA), a human CD38-targeted monoclonal antibody, is approved in many countries for use as monotherapy in relapsed/refractory multiple myeloma (RRMM) and in combination with standard-of-care regimens in RRMM or newly diagnosed MM. A subcutaneous (SC) formulation of DARA is under investigation in several ongoing studies. In the phase 3 COLUMBA study, DARA SC was shown to be non-inferior to DARA IV, demonstrating similar efficacy and pharmacokinetics, with a significantly decreased rate of infusion-related reactions and reduced administration time. The phase 2 LYNX (MMY2065) study will evaluate the efficacy and safety of retreatment with DARA. Methods: In this ongoing, multicenter, open-label, randomized phase 2 study, ~230 patients (pts) with prior exposure to DARA will be randomized 1:1 to receive carfilzomib and dexamethasone (Kd) ± DARA. Pts must have received 1 to 2 prior lines of therapy (at least one of which included DARA IV), with DARA-based therapy completed ≥3 months prior to randomization. Eligible pts have achieved a partial response or better (IMWG criteria) to DARA-based therapy, with a duration of response of ≥4 months. Pts must not have discontinued DARA due to a related adverse event or received prior treatment with carfilzomib. Pts will receive 20 mg/m2 carfilzomib IV on Day 1 of Cycle 1, escalated to 70 mg/m2 on Days 8 and 15; carfilzomib 70 mg/m2 will be administered on Days 1, 8, and 15 of each 28-day cycle thereafter. Dexamethasone 40 mg will be administered (IV or PO) QW for Cycles 1-9 and then on Days 1, 8 and 15 from Cycle 10 onwards. Pts in the D-Kd group will also receive DARA SC (1,800 mg co-formulated with recombinant human hyaluronidase PH20 [rHuPH20; Halozyme]) QW in Cycles 1-2, Q2W in Cycles 3-6, and Q4W thereafter. The primary endpoint is the rate of pts achieving a very good partial response or better. Secondary endpoints include overall response rate, rate of pts achieving complete response or better, progression-free survival, overall survival, overall minimal residual disease-negativity rate, time to next treatment, pharmacokinetics, and safety. Clinical trial information: NCT03871829 .

scholarly journals Ruxolitinib for the treatment of steroid-refractory acute GVHD (REACH1): a multicenter, open-label phase 2 trial

Blood ◽  
2020 ◽  
Vol 135 (20) ◽  
pp. 1739-1749 ◽  
Author(s):  
Madan Jagasia ◽  
Miguel-Angel Perales ◽  
Mark A. Schroeder ◽  
Haris Ali ◽  
Nirav N. Shah ◽  
...  
Keyword(s):  
Hematopoietic Cell Transplantation ◽  
Complete Response ◽  
Phase 2 ◽  
Open Label ◽  
Overall Response ◽  
End Point ◽  
Phase 2 Trial ◽  
Open Label Phase ◽  
Duration Of Response ◽  
Steroid Refractory

Abstract Patients who develop steroid-refractory acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic cell transplantation have poor prognosis, highlighting an unmet therapeutic need. In this open-label phase 2 study (ClinicalTrials.gov identifier: NCT02953678), patients aged at least 12 years with grades II to IV steroid-refractory aGVHD were eligible to receive ruxolitinib orally, starting at 5 mg twice daily plus corticosteroids, until treatment failure, unacceptable toxicity, or death. The primary end point was overall response rate (ORR) at day 28; the key secondary end point was duration of response (DOR) at 6 months. As of 2 July 2018, 71 patients received at least 1 dose of ruxolitinib. Forty-eight of those patients (67.6%) had grade III/IV aGVHD at enrollment. At day 28, 39 patients (54.9%; 95% confidence interval, 42.7%-66.8%) had an overall response, including 19 (26.8%) with complete responses. Best ORR at any time was 73.2% (complete response, 56.3%). Responses were observed across skin (61.1%), upper (45.5%) and lower (46.0%) gastrointestinal tract, and liver (26.7%). Median DOR was 345 days. Overall survival estimate at 6 months was 51.0%. At day 28, 24 (55.8%) of 43 patients receiving ruxolitinib and corticosteroids had a 50% or greater corticosteroid dose reduction from baseline. The most common treatment-emergent adverse events were anemia (64.8%), thrombocytopenia (62.0%), hypokalemia (49.3%), neutropenia (47.9%), and peripheral edema (45.1%). Ruxolitinib produced durable responses and encouraging survival compared with historical data in patients with steroid-refractory aGVHD who otherwise have dismal outcomes. The safety profile was consistent with expectations for ruxolitinib and this patient population.

Pembrolizumab (pembro) versus investigator’s choice of paclitaxel, docetaxel, or vinflunine in recurrent, advanced urothelial cancer (UC): 5-year follow-up from the phase 3 KEYNOTE-045 trial.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 4532-4532
Author(s):  
Joaquim Bellmunt ◽  
Andrea Necchi ◽  
Ronald De Wit ◽  
Jae-Lyun Lee ◽  
Lawrence Fong ◽  
...  
Keyword(s):  
Locally Advanced ◽  
Open Label ◽  
Phase 3 ◽  
Durable Response ◽  
End Points ◽  
Prior Therapy ◽  
Open Label Phase ◽  
Duration Of Response ◽  
Ecog Ps

4532 Background: Pembro was approved for the treatment of locally advanced or metastatic UC that progressed during or after a platinum-containing regimen, based on the phase 3 KEYNOTE-045 (NCT02256436) trial that showed significantly improved OS with use of pembro. Updated results are presented from KEYNOTE-045 after >5 y of follow-up since the last patient (pt) was randomized. Methods: KEYNOTE-045 is a randomized, multisite, open-label, phase 3 trial. Pts with histologically or cytologically confirmed UC, progression after platinum-containing chemo, ECOG PS 0-2, measurable disease per RECIST v1.1, and ≤2 prior lines of systemic therapy were eligible. Pts were randomly assigned 1:1 to receive pembro 200 mg Q3W or investigator’s choice of paclitaxel 175 mg/m2 Q3W, docetaxel 75 mg/m2 Q3W, or vinflunine 320 mg/m2 Q3W. Primary end points are PFS (RECIST v1.1, blinded central review) and OS. ORR and duration of response (DOR) were key secondary end points. Results: As of Oct 1, 2020, among 542 enrolled pts, median time from randomization to data cutoff was 62.9 mo (range 58.6-70.9). 9.4% and 0% of pts in the pembro and chemo arms, respectively, completed 2 years of therapy. Median OS was longer for pembro vs chemo (10.1 vs 7.2 mo; HR, 0.71 [95% CI, 0.59-0.86]) overall and in pts with CPS ≥10 (8.0 vs 4.9 mo; HR, 0.59 [95% CI, 0.40-0.86]). For pts with CR or PR, median OS was not reached and 16.4 (95% CI, 11.3-25.1) mo in the pembro and chemo arms, respectively (Table). OS rates at 48 mo were 16.7% for pembro and 10.1% for chemo; 60-mo OS rates were 14.9% and 8.7%, respectively. OS benefit with pembro vs chemo continued regardless of age, ECOG PS, prior therapy, liver metastases, baseline hemoglobin, time from last chemo, histology, risk factors, and chemo choice. Median DOR for responders was longer for pembro vs chemo (29.7 mo [1.6+ to 60.5+] vs 4.4 mo [1.4+ to 63.1+]), and a greater proportion of responses lasted ≥48 mo (40.9% vs 28.3%, Kaplan-Meier) and ≥60 mo (32.8% vs 28.3%). ORR was higher for pembro vs chemo (21.9% vs 11.0%; difference 10.8% [95% CI, 4.6-17.0]). Fewer pts given pembro vs chemo experienced a treatment-related AE of any grade (62.0% vs 90.6%) or grade ≥3 (16.9% vs 50.2%). Conclusions: After 5 y, pembro maintained clinically meaningful OS benefit vs chemo in pts with locally advanced or metastatic UC that progressed during or after platinum-based chemo. Pts who responded to pembro experienced a durable response (median >2 y). Clinical trial information: NCT02256436 .[Table: see text]

ALPINE: Phase III zanubrutinib (BGB-3111) versus ibrutinib in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. TPS7572-TPS7572 ◽  
Author(s):  
Peter Hillmen ◽  
Jennifer R. Brown ◽  
John C. Byrd ◽  
Barbara Eichhorst ◽  
Nicole Lamanna ◽  
...  
Keyword(s):  
Progression Free Survival ◽  
Complete Response ◽  
Geographic Region ◽  
Lymphocytic Leukemia ◽  
Phase Iii ◽  
Open Label ◽  
Duration Of Response ◽  
Treatment Naïve ◽  
Independent Review ◽  
Ecog Ps

TPS7572 Background: Inhibition of Bruton tyrosine kinase (BTK) has emerged as a strategy for targeting B-cell malignancies including CLL/SLL. Zanubrutinib, an investigational inhibitor of BTK, was specifically engineered to optimize selectivity, half-life and solubility in an effort to decrease toxicities and better penetrate tumor tissue. Early clinical data suggested that zanubrutinib treatment in patients with treatment-naïve (TN; n = 16) or R/R (n = 50) CLL/SLL induced deep responses: 94% overall response rate (ORR), including 6% and 2% complete response rates in TN and R/R CLL/SLL, respectively (ICML 2017). This study is designed to evaluate whether zanubrutinib monotherapy exhibits non-inferior and potentially superior efficacy based on the ORR vs ibrutinib monotherapy in patients with R/R CLL/SLL. Methods: This ongoing phase 3, randomized, open-label, global study (NCT03734016, BGB-3111-305) is comparing the efficacy and safety of zanubrutinib vs ibrutinib in adult patients with R/R CLL/SLL. Approximately 400 patients will be randomized, 1:1 to each arm and stratified by age (< 65 vs ≥ 65 years), refractory status (yes vs no), geographic region, and del(17p)/ TP53 mutation status (present vs absent). Key inclusion criteria include R/R CLL/SLL requiring treatment per iwCLL criteria, ECOG PS 0-2, and adequate hematologic function. The primary endpoint is ORR as determined by an independent review committee according to iwCLL guidelines, with modification for treatment-related lymphocytosis for patients with CLL and per 2014 Lugano Classification for patients with SLL. The study is powered to test the non-inferiority and superiority of the ORR for zanubrutinib vs ibrutinib. Secondary endpoints include progression-free survival, safety, duration of response, and overall survival. Recruitment is ongoing. Clinical trial information: NCT03734016.

FRACTION-RCC: Innovative, high-throughput assessment of nivolumab + ipilimumab for treatment-refractory advanced renal cell carcinoma (aRCC).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 5007-5007 ◽  
Author(s):  
Toni K. Choueiri ◽  
Harriet M. Kluger ◽  
Saby George ◽  
Scott S. Tykodi ◽  
Timothy M. Kuzel ◽  
...  
Keyword(s):  
Partial Response ◽  
Adaptive Design ◽  
Checkpoint Inhibitor ◽  
Checkpoint Inhibitors ◽  
Objective Response ◽  
Progression Free Survival ◽  
Complete Response ◽  
Open Label ◽  
Duration Of Response

5007 Background: The immuno-oncology (I-O) combination nivolumab + ipilimumab (NIVO+IPI) is approved for first-line (1L) and NIVO is approved for second-line treatment post TKI therapy in aRCC. The open-label, randomized, phase 2 Fast Real-Time Assessment of Combination Therapies in Immuno-Oncology (FRACTION-RCC; NCT02996110) platform study has an adaptive design allowing rapid evaluation of I-O therapies, including NIVO+IPI or other investigational combinations. This FRACTION analysis reports preliminary outcomes with NIVO+IPI in aRCC pts after progression on checkpoint inhibitor therapy. Methods: All pts, except 1, had previously received and progressed on checkpoint inhibitor treatment. Pts received NIVO+IPI (NIVO 3 mg/kg + IPI 1 mg/kg Q3W ×4, then after 6 weeks, NIVO 480 mg Q4W), up to 2 years or until progression, toxicity, or protocol-specified discontinuation. Primary endpoints were confirmed objective response rate (ORR; per investigator using RECIST v1.1), duration of response (DOR), and progression-free survival probability at week 24. Safety outcomes were reported. Results: 46 pts were randomized to NIVO+IPI. Pts had 0 (n = 1), 1 (n = 10), 2 (n = 12), 3 (n = 10), or ≥4 (n = 13) prior lines of therapy. All pretreated pts had prior anti-PD-(L)1-, none had prior anti-CTLA-4- therapy, and 37 had prior TKI-based therapy; 45 pts progressed on anti-PD-(L)1 as the most recent therapy. Most pts had clear cell aRCC (n = 44). After a median study follow-up of 8.9 months, ORR was 15.2%; no pts achieved complete response and 7 achieved partial response. DOR ranged from 2–19+ months (n = 7); 5 pts had ongoing response. Six of 7 responders had received ≥2 prior lines of therapy. Any-grade treatment-related adverse events (AEs) were reported in 36 pts (78.3%; fatigue, rash [both 19.6%], and diarrhea [17.4%] were most common). Grade 3–4 treatment-related AEs were reported in 13 pts (28.3%; diarrhea [8.7%], ↑amylase and ↑lipase [both 6.5%] were most common). Treatment-related immune-mediated AEs of any grade were reported in 22 pts (47.8%; rash [19.6%], diarrhea [17.4%], and ↑alanine aminotransferase [8.7%]). No treatment-related deaths were reported. Updated and expanded results with an additional 3 months of follow-up will be presented. Conclusions: These results suggest that NIVO+IPI may provide durable partial response in some pts with prior progression on checkpoint inhibitors, including some heavily pretreated pts. The safety profile of NIVO+IPI in FRACTION pts was similar to historic data in aRCC with this combination. Clinical trial information: NCT02996110 .

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