First-line pembrolizumab (pembro) monotherapy for advanced non-clear cell renal cell carcinoma (nccRCC): Results from KEYNOTE-427 cohort B.

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. 546-546 ◽  
Author(s):  
David F. McDermott ◽  
Jae-Lyun Lee ◽  
Marek Ziobro ◽  
Rustem Airatovich Gafanov ◽  
Vsevolod Borisovich Matveev ◽  
...  
Keyword(s):  
Clear Cell ◽  
Single Agent ◽  
Objective Response ◽  
Open Label ◽  
Cell Renal Cell Carcinoma ◽  
End Points ◽  
Open Label Phase ◽  
Duration Of Response ◽  
Prior Systemic Therapy ◽  
Combined Positive Score

546 Background: PD-1/L1 pathway inhibitors are effective in clear cell (cc)RCC, but efficacy of PD-1 inhibitors (or any therapy) in nccRCC has not been established. KEYNOTE-427 is a single-arm, open-label, phase 2 study of pembro monotherapy in patients (pts) with advanced ccRCC (cohort A) and nccRCC (cohort B). Cohort B results are presented. Methods: 165 pts with histologically confirmed nccRCC, no prior systemic therapy, measurable disease (RECIST v1.1), and KPS ≥70% enrolled. Pts received pembro 200 mg IV Q3W for 35 cycles (~2 y) or until progressive disease (PD), unacceptable toxicity, or withdrawal. Pts were followed after PD for overall survival. Primary end point: objective response rate (ORR) per RECIST v1.1 by blinded independent central review. Secondary end points included duration of response (DOR) and population description by International Metastatic RCC Database Consortium (IMDC) risk. Exploratory end points: ORR by histology and PD-L1 expression (combined positive score [CPS] ≥1 for PD-L1+). Results: Histology was confirmed by a central pathologist: papillary 72% (n=118), chromophobe 13% (n=21), unclassified 16% (n=26). 68% of patients were at intermediate/poor IMDC risk, and 62% were PD-L1+. At analysis, 49 pts had died and 3 had withdrawn. At a median follow-up duration of 11.1 mo (range, 0.9-21.3), 56% of pts discontinued pembro due to PD or clinical progression. Overall ORR was 24.8% (95% CI, 18.5-32.2; 8 [4.8%] CRs, 33 [20%] PRs); median DOR was not reached. ORR (95% CI) was 25.4% (17.9-34.3) with papillary, 9.5% (1.2-30.4) with chromophobe, and 34.6% (17.2-55.7) with unclassified nccRCC. ORR (95% CI) was 28.3% (16.8-42.3) with favorable and 23.2% (15.8-32.1) with intermediate/poor IMDC risk and 33.3% (24.3-43.4) and 10.3% (3.9-21.2) with CPS≥1 and CPS<1, respectively. Grade 3-5 treatment-related adverse events (TRAEs) occurred in 11% of pts; 6% discontinued due to TRAEs. 6 pts died due to AEs, 2 of which were TRAEs (pneumonia and cardiac arrest). Conclusions: Single-agent pembro showed encouraging antitumor activity in nccRCC, especially with papillary or unclassified histology. Safety profile of pembro was generally as expected. Clinical trial information: NCT02853344.

KEYNOTE-427 cohort B: First-line pembrolizumab (pembro) monotherapy for advanced non‒clear cell renal cell carcinoma (NCC-RCC).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 4569-4569 ◽  
Author(s):  
Jae-Lyun Lee ◽  
Marek Ziobro ◽  
Rustem Gafanov ◽  
Vsevolod Borisovich Matveev ◽  
Cristina Suarez ◽  
...  
Keyword(s):  
Clear Cell ◽  
Single Agent ◽  
Objective Response ◽  
Open Label ◽  
Cell Renal Cell Carcinoma ◽  
Open Label Phase ◽  
Duration Of Response ◽  
Prior Systemic Therapy ◽  
Sarcomatoid Differentiation

4569 Background: Efficacy of PD-1 inhibitors (or any therapy) in NCC-RCC has not been established. KEYNOTE-427 (NCT02853344) is a single-arm, open-label, phase 2 study of pembro monotherapy in patients (pts) with advanced clear cell RCC (cohort A) and NCC-RCC (cohort B). Cohort B results are presented. Methods: 165 pts with histologically confirmed NCC-RCC, no prior systemic therapy, measurable disease (RECIST v1.1), and KPS ≥70% enrolled. Pts received pembro 200 mg IV Q3W for 35 cycles (~2 y) or until progressive disease (PD), unacceptable toxicity, or withdrawal. Primary end point: objective response rate (ORR) per RECIST v1.1 by blinded independent central review. Additional end points: duration of response (DOR), population description by sarcomatoid differentiation, histology and PD-L1 expression (combined positive score [CPS] ≥1 for PD-L1+). Results: Histology was confirmed by a central pathologist: papillary 72% (n = 118), chromophobe 13% (n = 21), unclassified 16% (n = 26); 62% were PD-L1+. At analysis, 49 pts had died and 3 had withdrawn. At median follow-up of 11.1 mo (range, 0.9-21.3), 56% of pts discontinued pembro due to PD or clinical progression. Overall ORR was 24.8% (95% CI, 18.5-32.2; 8 [4.8%] CR, 33 [20.0%] PR). Median DOR was not reached. For responding pts, 81.5% had a response ≥6 mo. 12-mo PFS and OS rates were 22.8% and 72.0%, respectively. ORR (95% CI) was 25.4% (17.9-34.3) with papillary, 9.5% (1.2-30.4) with chromophobe, and 34.6% (17.2-55.7) with unclassified NCC-RCC; for responding pts, 82.1%, 50.0%, and 87.5% had a response ≥6 mo, respectively. Median DOR was not reached in any group. ORR (95% CI) was 44.7% (28.6-61.7) for pts with sarcomatoid differentiation (n = 38). ORR (95% CI) was 33.3% (24.3-43.4) and 10.3% (3.9-21.2) with CPS≥1 and CPS < 1, respectively. Grade 3-5 treatment-related adverse events (TRAEs) occurred in 11% of pts. 6 pts died of AEs, 2 of TRAEs (pneumonia and cardiac arrest). Conclusions: Single-agent pembro showed encouraging antitumor activity in NCC-RCC, especially with papillary or unclassified histology. Safety profile of pembro was as expected. Updated data with additional follow-up will be presented. Clinical trial information: NCT02853344.

First-line pembrolizumab (pembro) monotherapy in advanced clear cell renal cell carcinoma (ccRCC): Updated results for KEYNOTE-427 cohort A.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 4570-4570 ◽  
Author(s):  
Scott S. Tykodi ◽  
Frede Donskov ◽  
Jae-Lyun Lee ◽  
Cezary Szczylik ◽  
Jahangeer Malik ◽  
...  
Keyword(s):  
Clear Cell ◽  
Single Agent ◽  
Objective Response ◽  
Progression Free Survival ◽  
First Line ◽  
Open Label ◽  
Cell Renal Cell Carcinoma ◽  
Duration Of Response ◽  
Prior Systemic Therapy

4570 Background: KEYNOTE-427 (NCT02853344) is an open-label, single-arm, phase 2 study to evaluate efficacy and safety of first-line single-agent pembro, a programmed death 1 (PD-1) inhibitor, in patients (pts) with ccRCC (cohort A) and non–clear cell RCC (cohort B). Updated follow up from cohort A are presented. Methods: Pts with histologically confirmed ccRCC, measurable per RECIST v1.1, and no prior systemic therapy were eligible. Pts received pembro 200 mg IV Q3W for 2 y or until confirmed progressive disease, unacceptable toxicity, or pt decision to withdraw. Primary end point was objective response rate (ORR; per RECIST v1.1 blinded independent central review). Additional end points included duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. Results: 110 pts enrolled; median (range) follow-up was 18.0 (2.5-22.7) mo. Median age (range) was 64 (29-87); 38.2%, 47.3%, and 14.5% had favorable, intermediate, and poor IMDC risk, respectively; 47.3% were PD-L1 positive. Confirmed ORR was 36.4% with 3 (2.7%) CRs and 37 (33.6%) PRs. Median DOR was not reached. Median PFS was 7.1 mo (95% CI, 5.6-11.0) and median OS was not reached. Results by IMDC category are outlined in the table. By PD-L1 status, confirmed ORR was 44.2% and 29.3% for positive and negative, respectively. By sarcomatoid differentiation (n=11), confirmed ORR was 63.6%. Treatment-related AEs occurred in 80.9%, with pruritus (28.2%) and fatigue (28.2%) most commonly reported. One pt died of treatment-related pneumonitis. Conclusions: With a median 18-months’ follow up, first-line pembro monotherapy continued to show antitumor activity in pts with ccRCC. Meaningful responses were observed in pts with intermediate/poor IMDC risk, PD-L1 positive and sarcomatoid differentiated tumors. Safety profile was comparable to previously reported. Clinical trial information: NCT02853344. [Table: see text]

scholarly journals Open-Label, Single-Arm Phase II Study of Pembrolizumab Monotherapy as First-Line Therapy in Patients With Advanced Clear Cell Renal Cell Carcinoma

2021 ◽  
Vol 39 (9) ◽  
pp. 1020-1028
Author(s):  
David F. McDermott ◽  
Jae-Lyun Lee ◽  
Georg A. Bjarnason ◽  
James M. G. Larkin ◽  
Rustem A. Gafanov ◽  
...  
Keyword(s):  
Phase Ii ◽  
Response Rate ◽  
Clear Cell ◽  
Phase Ii Study ◽  
Single Agent ◽  
Objective Response ◽  
First Line ◽  
Open Label ◽  
Cell Renal Cell Carcinoma ◽  
Metastatic Rcc

PURPOSE Pembrolizumab, a programmed death 1 inhibitor, demonstrated promising single-agent activity in untreated patients with various cancer types. The phase II KEYNOTE-427 study evaluated efficacy and safety of single-agent pembrolizumab in treatment-naive patients with advanced clear cell renal cell carcinoma (ccRCC; cohort A) and advanced non-ccRCC (cohort B). Results of cohort A are reported. METHODS In this open-label, single-arm phase II study, patients with advanced ccRCC received pembrolizumab 200 mg every 3 weeks for ≤ 24 months. The primary end point was objective response rate by RECIST, version 1.1. RESULTS In the total population (N = 110), median time from enrollment to data cutoff was 35.9 (range, 29.5-40.3) months. Objective response rate was 36.4% with four (3.6%) complete responses and 36 (32.7%) partial responses; disease control rate was 58.2% (95% CI, 48.4 to 67.5). Most patients (68.2%) had a decrease in target lesions, including 30.9% with a reduction ≥ 60%. Median duration of response was 18.9 (range, 2.3-37.6+) months; 64.1% of responders had a response ≥ 12 months (Kaplan-Meier). Median progression-free survival was 7.1 months (95% CI, 5.6 to 11.0). Median overall survival was not reached; 12-month and 24-month overall survival rates were 88.2% and 70.8%, respectively. Durable responses were observed across all International Metastatic RCC Database Consortium categories. Grade 3-5 treatment-related adverse events were reported in 30.0% of patients, of which colitis and diarrhea were most frequent. CONCLUSION Single-agent pembrolizumab showed promising antitumor activity as a first-line treatment in patients with advanced ccRCC, with durable responses across International Metastatic RCC Database Consortium categories. Safety and tolerability profile of pembrolizumab monotherapy was comparable to what has been previously described in other tumor types.

scholarly journals Apatinib plus camrelizumab (anti-PD1 therapy, SHR-1210) for advanced osteosarcoma (APFAO) progressing after chemotherapy: a single-arm, open-label, phase 2 trial

2020 ◽  
Vol 8 (1) ◽  
pp. e000798
Author(s):  
Lu Xie ◽  
Jie Xu ◽  
Xin Sun ◽  
Wei Guo ◽  
Jin Gu ◽  
...  
Keyword(s):  
Pulmonary Metastases ◽  
Single Agent ◽  
Objective Response ◽  
Progression Free Survival ◽  
Phase 2 ◽  
Open Label ◽  
Phase 2 Trial ◽  
Open Label Phase ◽  
High Grade Osteosarcoma

BackgroundResults of our previous study showed high objective response but short-term activity of apatinib in advanced osteosarcoma. We aimed to investigate the activity of apatinib in combination with camrelizumab in patients with inoperable high-grade osteosarcoma progressing after chemotherapy.MethodsThis open-label, phase 2 trial was conducted at Peking University People’s Hospital. We enrolled patients with advanced osteosarcoma progressed after chemotherapy. Patients received 500 mg apatinib orally once daily plus 200 mg camrelizumab by intravenous infusion every 2 weeks until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS) and clinical benefit rate at 6 months, which were based on RECIST V.1.1.Results43 patients were enrolled between January 25 and September 4, 2018. With median follow-up time of 48.3 (Q1, Q3, 30.6, 66.6) weeks, 13 (30.23%, 95% CI 17.2%, 40.1%) of 43 patients were progression free at 6 months and the 6-month PFS rate was 50.9% (95% CI 34.6%, 65.0%). Until final follow-up, the objective response rate was 20.9% (9/43) and two patients with durable disease control were observed. Patients with programmed cell death 1 ligand-1 (PD-L1) tumor proportion score ≥5% and pulmonary metastases tended to have a longer PFS in comparison to the others (p=0.004 and 0.017, respectively). Toxic effects led to dose reductions, or interruptions, or both in 24 (55.8%) of 43 patients and permanent discontinuation in 4 (9.3%) patients. There were no treatment-related deaths.ConclusionsAlthough the combination of apatinib and camrelizumab seemed to prolong PFS in comparison to single agent apatinib in treating advanced osteosarcoma, it did not reach the prespecified target of 6-month PFS of 60% or greater. Overexpression of PD-L1 and the presence of pulmonary metastases only were associated with longer PFS.Trial registration numberNCT03359018.

scholarly journals Single-agent belantamab mafodotin for relapsed/refractory multiple myeloma: analysis of the lyophilised presentation cohort from the pivotal DREAMM-2 study

2020 ◽  
Vol 10 (10) ◽  
Author(s):  
Paul G. Richardson ◽  
Hans C. Lee ◽  
Al-Ola Abdallah ◽  
Adam D. Cohen ◽  
Prashant Kapoor ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Single Agent ◽  
Pathological Finding ◽  
Progression Free Survival ◽  
Antibody Drug Conjugate ◽  
Open Label ◽  
Blurred Vision ◽  
Refractory Multiple Myeloma ◽  
Open Label Phase ◽  
Duration Of Response

Abstract DREAMM-2 (NCT03525678) is an ongoing global, open-label, phase 2 study of single-agent belantamab mafodotin (belamaf; GSK2857916), a B-cell maturation antigen-targeting antibody-drug conjugate, in a frozen-liquid presentation in patients with relapsed/refractory multiple myeloma (RRMM). Alongside the main study, following identical inclusion/exclusion criteria, a separate patient cohort was enrolled to receive belamaf in a lyophilised presentation (3.4 mg/kg, every 3 weeks) until disease progression/unacceptable toxicity. Primary outcome was independent review committee-assessed overall response rate (ORR). Twenty-five patients were enrolled; 24 received ≥1 dose of belamaf. As of 31 January 2020, ORR was 52% (95% CI: 31.3–72.2); 24% of patients achieved very good partial response. Median duration of response was 9.0 months (2.8–not reached [NR]); median progression-free survival was 5.7 months (2.2–9.7); median overall survival was not reached (8.7 months–NR). Most common grade 3/4 adverse events were keratopathy (microcyst-like corneal epithelial changes, a pathological finding seen on eye examination [75%]), thrombocytopenia (21%), anaemia (17%), hypercalcaemia and hypophosphatemia (both 13%), neutropenia and blurred vision (both 8%). Pharmacokinetics supported comparability of frozen-liquid and lyophilised presentations. Single-agent belamaf in a lyophilised presentation (intended for future use) showed a deep and durable clinical response and acceptable safety profile in patients with heavily pre-treated RRMM.

scholarly journals OS4.1 MEVITEM: A European, randomized, open-label, Phase I/II study of vismodegib in combination with temozolomide versus temozolomide alone in adult patients with recurrent or refractory medulloblastoma presenting an activation of the Sonic Hedgehog (SHH) pathway

2019 ◽  
Vol 21 (Supplement_3) ◽  
pp. iii10-iii10
Author(s):  
D Frappaz ◽  
M Barritault ◽  
L Montané ◽  
F Laigle-Donadey ◽  
O Chinot ◽  
...  
Keyword(s):  
Sonic Hedgehog ◽  
Type I Error ◽  
Single Agent ◽  
Objective Response ◽  
Progression Rate ◽  
Type I ◽  
Filamin A ◽  
Open Label ◽  
Shh Pathway ◽  
Open Label Phase

Abstract BACKGROUND Vismodegib (V) suppresses sonic hedgehog (SHH) signaling. We postulated that vismodegib together with chemotherapy may be more efficient than chemotherapy alone in patients (pts) relapsing of a SHH-activated medulloblastoma (MB). MATERIAL AND METHODS Adult pts with recurrent SHH-MB not previously exposed to temozolomide (T) were randomly assigned (2:1 ratio) to Arm A (V daily 150mg/d, po) + T (D1-5: 150 mg/m2 for cycle 1 and 200 mg/m2 thereafter; n=up to 25pts) or Am B (T alone; n=up to 13pts). Identification of SHH activation was performed centrally by IHC (GAB1, β-catenin, filamin A, and YAP1). NGS analyses were performed to identify the mutations responsible for SHH activation. Primary objectives were to assess the incidence of severe toxicities (safety run-in based on a 3 + 3 design) and the 6-month non-progression rate (NPR-6m) according to WHO criteria and based on central read tumor assessment (Phase II). A Minimax Simon’s two-stage design was used to detect NPR-6m of 55% (p0: 30%, type I error rate of 5%, power of 80%). At first stage, ≥ 3/9 pts without progression at 6m were required for the accrual of 16 additional pts in Arm A. A 3rd independent and parallel arm with V as single agent (Arm C, n= up to15pts) was added for pts previously treated by T. RESULTS 24 SHH-MB pts were enrolled (Arm A: 10, Arm B: 5 and Arm C: 9; median age: 37 y [21–55]). At the end of the safety run-in; no major safety concerns were reported. At the end of Stage I: no objective response were reported and 2 pts among 10 were free of progression at 6m among in Arm A. According to statistical rules, the study was definitively closed to enrolment. NGS analyses showed a PTCH1 inactivating mutation in 6 pts (n=4 in arm A; n= 2 in arm B); a SMO activating mutation in 4 pts (n= 3 in Arm A; n=1 in Arm B). For 1 pt in each arm, no tumor sample was available for analysis, for 1 pt in Arm A DNA quality was insufficient, and for 1 patient in each arm no mutations of SMO, PTCH1, SUFU or SHH were found. Out of the 4 pts in Arm A with an inactivating PTCH1 mutation, only 1 was progression free at 6m. PFS and OS data will be presented at the meeting. CONCLUSION The combination of vismodegib with monthly T failed to demonstrate superior activity as compared with T alone. Further studies are warranted to refine therapeutic indication for vismodegib

ELOQUENT-2: A phase III, randomized, open-label trial of lenalidomide/dexamethasone (Len/Dex) with or without elotuzumab (Elo) in relapsed or refractory multiple myeloma (RR MM) (CA204-004).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. TPS8112-TPS8112
Author(s):  
Sagar Lonial ◽  
Paul Gerard Guy Richardson ◽  
Philippe Moreau ◽  
Robert Z. Orlowski ◽  
Jesùs F. San-Miguel ◽  
...  
Keyword(s):  
Objective Response ◽  
Progression Free Survival ◽  
Response Duration ◽  
Surface Glycoprotein ◽  
Phase Iii ◽  
Open Label ◽  
Cell Surface Glycoprotein ◽  
Open Label Phase ◽  
Related Quality ◽  
Duration Of Response

TPS8112 Background: MM remains incurable and patients (pts) typically relapse or become refractory to current treatments. Novel regimens are needed to improve pt outcomes. Elo is a humanized monoclonal IgG1 antibody targeting the cell surface glycoprotein CS1, which is highly expressed on >95% of MM cells. Len/Dex is approved for treatment of relapsed MM and an objective response rate (ORR) of ~60% was reported in phase III trials of this combination in RR MM. In a phase II study (N=73) of Elo (10 or 20 mg/kg) in combination with Len/Dex in pts with RR MM, the 10 mg/kg group (n=36) demonstrated an ORR of 92% and median progression-free survival (PFS) that was not reached after a median follow-up of 14.1 months. Encouraging activity was seen in patients with high-risk cytogenetics and/or stage 2-3 disease. Based on these data, a randomized, open-label phase III trial has been initiated to determine if the addition of Elo to Len/Dex will improve PFS in patients with RR MM compared with Len/Dex alone. Methods: Pts (N=640) with RR MM and 1-3 prior therapies are eligible, including pts with mild or moderate renal impairment. Pts are randomized in a 1:1 ratio to receive 28-day cycles of Len 25 mg PO (days 1-21) and Dex 40 mg PO (days 1, 8, 15 and 22) with or without Elo. Elo dose and schedule is 10 mg/kg IV on days 1, 8, 15, 22 in the first 2 cycles and on days 1 and 15 in subsequent cycles. Dex 8 mg IV + 28 mg PO is used during the weeks with Elo. Treatment will continue until disease progression, death, or withdrawal of consent. Patients will be followed for tumor response every 4 weeks until progressive disease and then survival every 12 weeks. The primary endpoint is PFS (90% power for a hazard ratio [experimental to control arm] of 0.74) and the secondary endpoints are ORR and overall survival. Exploratory endpoints are safety, time to response, duration of response, time to subsequent therapy, health-related quality of life, and pharmacokinetics and immunogenicity of Elo. Potential biomarkers will also be assessed. As of January 10th, 2012, 107 pts were enrolled and 68 pts were treated. NCT01239797.

Efficacy of vemurafenib in patients (pts) with non-small cell lung cancer (NSCLC) with BRAFV600 mutation.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 9074-9074 ◽  
Author(s):  
Vivek Subbiah ◽  
Radj Gervais ◽  
Gregory J. Riely ◽  
Antoine Hollebecque ◽  
Jean-Yves Blay ◽  
...  
Keyword(s):  
Response Rate ◽  
Objective Response ◽  
Progression Free Survival ◽  
Braf Mutations ◽  
Open Label ◽  
Braf Inhibition ◽  
Duration Of Response ◽  
Secondary Endpoints ◽  
Prior Systemic Therapy ◽  
Grade 3

9074 Background: BRAFV600 mutations occur in 1–2% of pts with NSCLC. We previously reported the efficacy of vemurafenib, a selective BRAFV600 inhibitor, in BRAF mutation-positive non-melanoma tumors (VE-BASKET study). We now present final data for the expanded NSCLC cohort. Methods: This open-label, histology-independent, phase 2 study included 6 prespecified cohorts (including NSCLC) plus one ‘all-others’ cohort. Pts received vemurafenib (960 mg bid) until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (RECIST v1.1). Secondary endpoints included best overall response rate, duration of response (DoR), progression-free survival (PFS), and overall survival (OS). Because the pre-specified clinical benefit endpoint was met in the initial NSCLC cohort, the cohort was expanded. ClinicalTrials.gov identifier NCT01524978. Results: Database lock was 12 Jan 2017. Of 208 pts enrolled at 25 centers worldwide, 62 pts had NSCLC: median age 65 years; 56% male; 13% had no prior systemic therapy; 50% had ≥2 prior therapies. Responses were seen in previously treated and untreated pts (Table). The most common all-grade adverse event (AE) was nausea (40%); grade 3–5 AEs included keratoacanthoma (15%) and squamous cell carcinoma of the skin (15%). Six pts discontinued vemurafenib due to AEs; two had non-treatment-related fatal AEs. Conclusions: Vemurafenib showed evidence of encouraging efficacy in pts with NSCLC with BRAFV600 mutation, with prolonged PFS in previously untreated pts; median OS was not estimable due to ongoing responses. The safety profile of vemurafenib was similar to that seen in melanoma studies. Our results suggest a role for BRAF inhibition in NSCLC with BRAF mutations. Clinical trial information: NCT01524978. [Table: see text]

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.

Durable clinical benefit from combination ipilimumab (IPI) and nivolumab (NIVO) in anti-PD-1 therapy resistant, platinum resistant metastatic urothelial carcinoma (mUC).

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. 481-481 ◽  
Author(s):  
Niamh M. Keegan ◽  
Samuel Aaron Funt ◽  
Brooke Elizabeth Kania ◽  
Gopa Iyer ◽  
Jessica Mary Clement ◽  
...  
Keyword(s):  
Disease Control ◽  
Single Agent ◽  
Objective Response ◽  
Gene Mutations ◽  
Open Label ◽  
Clinical Endpoints ◽  
Platinum Resistant ◽  
Mutation Burden ◽  
Major Interest ◽  
Duration Of Response

481 Background: Overcoming resistance to anti-PD-1 therapy in UC patients (pts) is of major interest given the modest single agent response rates for pts with mUC. Herein we report the outcome of combined NIVO and IPI in pts who progressed on single agent NIVO. Methods: This prospective, open label, adaptive study treated platinum resistant mUC pts with NIVO monotherapy with the designated intent to add IPI at disease progression. RECIST 1.1 assessments were performed every 6 wks for 24 wks then every 12 wks. Primary endpoint was objective response rate (ORR). Secondary endpoints included overall survival (OS) and possible associations between clinical endpoints and tumor genomic characteristics. Next generation sequencing (NGS) was performed to assess DNA Damage Response (DDR) gene mutations and Tumor Mutation Burden (TMB). Results: To date, 21 pts who progressed after NIVO monotherapy have received IPI plus NIVO. ORRs to prior NIVO monotherapy were variable; partial response (PR = 4/21, 19%), stable disease (SD = 6/21, 29%) and progressive disease (PD = 11/21,52%). 57% (12/21) had visceral metastases. For IPI + NIVO the ORR was 19% (PR: n=4, CR: n=0) and duration of response >12 mo in a subset; 2 pts with PR remain on treatment (3+, 5+ mo), 1 pt has an ongoing PR (13+ months) after stopping treatment due to toxicity. Responding disease sites include node, liver and lung. Immune-related toxicity ≥ G3 seen in 9 pts (43%), of whom 4 (44%) had disease control (PR+SD≥3mo). No correlation detected between clinical outcome and TMB or DDR mutations. Conclusions: IPI plus NIVO responses can be seen in pts with NIVO resistance and the benefit from combined checkpoint blockade can be prolonged. Immune related toxicity frequently accompanied disease control. TMB and DDR were not associated with benefit in this small cohort; immune correlative analyses are ongoing. Clinical trial information: NCT02553642. [Table: see text]

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