scholarly journals ATIM-49 (LTBK-01). AMG 596, A NOVEL ANTI-EGFRVIII BISPECIFIC T CELL ENGAGER (BITE®) MOLECULE FOR THE TREATMENT OF GLIOBLASTOMA (GBM): PLANNED INTERIM ANALYSIS IN RECURRENT GBM (RGBM)

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi283-vi283 ◽  
Author(s):  
Mark A Rosenthal ◽  
Carmen Balana ◽  
Myra E van Linde ◽  
Cyrus Sayehli ◽  
Walter M Fiedler ◽  
...  
Keyword(s):  
T Cell ◽  
Malignant Glioma ◽  
Interim Analysis ◽  
Tumor Antigens ◽  
Phase 1 ◽  
Performance Status ◽  
Objective Response ◽  
Open Label ◽  
Bispecific T Cell Engager ◽  
Group 1

Abstract OBJECTIVES The class III variant of the epidermal growth factor receptor (EGFRvIII) represents the most common EGFR mutation in GBM. AMG 596 is a bispecific T cell engager (BiTE®) molecule designed to engage a patient’s own CD3-positive T cells to EGFRvIII-positive tumor antigens. This is the first clinical data readout for AMG 596. METHODS This phase 1, first-in-human, open-label, sequential dose-escalation/expansion study evaluates continuous intravenous AMG 596 in patients with EGFRvIII-positive GBM or malignant glioma in recurrent (Group 1) or newly diagnosed in maintenance treatment (Group 2) settings. Eligible patients: adults with EGFRvIII-positive GBM or malignant glioma; ≤2 mg/day dexamethasone, ECOG performance status ≤1; life expectancy ≥3 months; and acceptable renal, hematological, and hepatic function. The primary objective evaluates safety and tolerability. Additional assessments include objective response rate per modified Response Assessment in Neuro-Oncology (RANO) Criteria. RESULTS As of June 2019, 15 rGBM patients (Group 1) were enrolled; 14 patients received ≥1 dose AMG 596. 14/15 (93.3%) patients were evaluable at time of analysis (safety analysis set). Median age was 54.5 years (range, 44–68); 50% were male. Seven patients discontinued for progressive disease (PD). AEs occurred in all patients and were serious in 7/14 (50%). None resulted in discontinuation; two (14.3%) fatal AEs were related to PD. Headache and depressed consciousness (both n=2, 14.3%) were the most common grade ≥3 treatment emergent AEs. In patients with sufficient follow-up to assess response (n=8), 1 (12.5%) achieved partial response, 2 (25%) had stable disease, 4 (50%) had PD at initial scan, and 1 (12.5%) discontinued treatment for PD. Semi-quantitative EGFRvIII expression analysis revealed a median H-score of 115 (range, 8–280). CONCLUSION This interim analysis suggests a first indication that AMG 596 may be well-tolerated and offer anti-tumor activity in patients with rGBM. Enrollment is ongoing and additional data will be presented. NCT03296696.

Novel anti-EGFRvIII bispecific T cell engager (BiTE) antibody construct in glioblastoma (GBM): Trial in progress of AMG 596 in patients with recurrent or newly diagnosed disease.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. TPS2071-TPS2071
Author(s):  
Mark Rosenthal ◽  
Carmen Balana ◽  
Myra Ellen Van Linde ◽  
Cyrus Sayehli ◽  
Walter M. Fiedler ◽  
...  
Keyword(s):  
Clinical Trial ◽  
T Cell ◽  
Medical Information ◽  
Group Performance ◽  
Phase 1 ◽  
Performance Status ◽  
Objective Response ◽  
Eastern Cooperative Oncology Group ◽  
Newly Diagnosed ◽  
Bispecific T Cell Engager

TPS2071 Background: GBM is the most aggressive primary brain tumor in adults and is extremely difficult to treat. Patients with GBM tend to progress rapidly within weeks or months. Median overall survival is only 12–15 months despite aggressive treatment, and less than 5% of patients survive 5 years. GBM also severely impacts quality of life and cognitive function. Approximately 50% of GBM tumors test positive for amplification or mutation of the epidermal growth factor receptor (EGFR), the most common of which is the EGFRvIII gain-of-function mutation. AMG 596 is a bispecific T cell engager (BiTE®) antibody construct designed to crosslink and engage CD3-positive T cells to EGFRvIII-positive tumor cells, inducing tumor cell lysis and T cell proliferation. A clinical trial is being conducted for this novel immunotherapy agent in patients with EGFRvIII-positive GBM. Methods: NCT03296696 is a phase 1, first-in-human, open-label, sequential dose-escalation and dose-expansion study evaluating the safety, tolerability, and pharmacokinetics and pharmacodynamics (PK/PD) of AMG 596 in patients with EGFRvIII-positive GBM. AMG 596 is administered via continuous intravenous infusion. The study is expected to enroll approximately 82 patients total and comprises two groups (Group 1: patients with recurrent GBM; Group 2: patients with newly diagnosed GBM in the maintenance treatment phase after standard of care). Key inclusion criteria include: male or female; ≥ 18 years of age; with pathologically documented and diagnosed grade IV GBM; Eastern Cooperative Oncology Group performance status ≤ 1; life expectancy ≥ 3 months per study investigator; and acceptable renal, hematological, and hepatic function. The primary endpoint evaluates the safety and tolerability of AMG 596 via collection of treatment-emergent adverse events. Additional endpoints include objective response rate per modified Response Assessment in Neuro-Oncology Criteria and PK/PD analyses of AMG 596 in serum. The study began enrolling patients in April 2018 and enrollment is ongoing. For more information, please contact Amgen Medical Information: [email protected]. Clinical trial information: NCT03296696.

Plitidepsin Is Active in Peripheral T-Cell Lymphoma (PTCL): A Subset Analysis from An Ongoing Multicenter Phase II Trial.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1566-1566 ◽  
Author(s):  
Christophe Ferme ◽  
Maria Victoria Mateos ◽  
Sergio Szyldergemajn ◽  
Emanuele Zucca ◽  
Jose Espinoza ◽  
...  
Keyword(s):  
T Cell ◽  
Hypersensitivity Reaction ◽  
Phase Ii ◽  
Performance Status ◽  
Objective Response ◽  
Autologous Transplantation ◽  
Large Cell ◽  
Hematologic Toxicity ◽  
Open Label ◽  
Multicenter Phase

Abstract Background: Peripheral T-cell lymphomas (PTCL) represent a small (<10%) yet a particularly aggressive subset of NHL. Up to 75% of those patients (pts) eventually become relapsed/refractory, with no effective options available. Thus, a prospective open-label, multicenter phase II study to evaluate the activity of plitidepsin (Aplidin®) in adult pts with relapsed/refractory aggressive lymphomas was planned and is currently ongoing. We report the preliminary results from a cohort of non-cutaneous PTCL. Patients and methods: As of July 2008, 14 pts were treated with plitidepsin 3.2 mg/m2 i.v. infusion over a 1-h on days 1, 8 and 15 q4wk. Eleven pts are evaluable, one is too early and two were non-evaluable as per protocol criteria: one had a hypersensitivity reaction and one had bone marrow (BM) infiltration only, but achieved a biopsy-documented BM clearance. Pts had a median of 3 (1–6) previous regimens, including 4 pts (33%) with prior autologous transplantation. Lymphoma histology: 8 PTCL-nos, 2 anaplastic large-cell, 2 angioimmunoblastic and 2 NK/T nasal type. Ten pts were male, median age was 56 y (35–74), with performance status 0 in 6 pts, 1 in 5 pts and 2 in 3 pts. Results: One confirmed CR and 3 PR were observed for a 36% objective response rate (95% CI: 11%–70%). Median duration of response was 4 months (range: 1+ – 12+). Median overall survival was 11 months (range 1+ – 24+). Plitidepsin was tolerable in this heavily pre-treated population, particularly with low hematologic toxicity. Of 2 cases of grade (G) 4 neutropenia, 1 was already present at baseline and only 1 pt developed G3 thrombocytopenia during treatment. Transient and reversible G3 ALT/AST elevations occurred in 7 patients and 2 G3 bilirrubin increases. Clinical toxicities mainly consisted of mild to moderate muscular weakness, myalgia and cramps, plus G1-2 fatigue and nausea in 1/3 of the patients. One pt discontinued due to hypersensitivity reaction before being evaluated for response and one pt was diagnosed with Guillain-Barré syndrome while progressing after 2 cycles. Conclusion: Plitidepsin (Aplidin®) shows promising activity and an acceptable safety profile in this difficult-to-treat subset of patients. Remarkably, no significant hematologic toxicity was seen in this heavily pretreated cohort. To confirm these preliminary data an expansion of the cohort is currently ongoing. Updated results will be presented.

ABT-165 plus FOLFIRI versus bevacizumab plus FOLFIRI in patients with metastatic colorectal cancer (mCRC) previously treated with fluoropyrimidine/oxaliplatin and bevacizumab.

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. TPS720-TPS720
Author(s):  
Zev A. Wainberg ◽  
Lan Wang ◽  
Huibin Yue ◽  
Monica Motwani ◽  
Sreeneeranj Kasichayanula ◽  
...  
Keyword(s):  
Tumor Regression ◽  
Phase 1 ◽  
Performance Status ◽  
Objective Response ◽  
Laboratory Data ◽  
Progression Free Survival ◽  
Phase 2 ◽  
Open Label ◽  
Human Colon Cancer

TPS720 Background: Dual variable domain immunoglobulin ABT-165 targets human vascular endothelial growth factor (VEGF) and delta-like ligand 4 (DLL4). Combined VEGF and DLL4 blockade increased inhibition of subcutaneous xenograft growth of human colon cancer-derived cell lines versus blockade of either axis alone. In vivo, ABT-165 plus chemotherapy (CT) induced tumor regression with improved efficacy, vs anti-VEGF monoclonal antibody plus CT. In a phase 1 study, tolerable recommended phase 2 dose was identified for ABT-165 plus FOLFIRI and showed promising efficacy. This phase 2 trial in progress assesses efficacy/safety of ABT-165 plus FOLFIRI vs bevacizumab (bev) plus FOLFIRI in patients with second-line mCRC. Methods: This is an open-label, multicenter, phase 2 randomized (1:1) trial (NCT03368859) in patients (≥ 18 years; Eastern Cooperative performance status: 0–1) with histologically/cytologically confirmed mCRC who progressed after fluoropyrimidine/oxaliplatin and bev. ABT-165 (2.5 mg/kg) plus FOLFIRI (irinotecan: 180 mg/m2; leucovorin: 400 mg/m2; fluorouracil bolus: 400 mg/m2, infusion: 2400 mg/m2) or bev (5 mg/kg) plus FOLFIRI are given intravenously on day 1 of each 14-day cycle, until disease progression/intolerable toxicity. Primary endpoint is progression-free survival (PFS). Secondary endpoints include overall survival (OS), objective response rate (ORR), and safety. Exploratory endpoints include biomarkers predictive for efficacy/safety, correlation of DLL4 levels with PFS, OS, and ORR, pharmacodynamic effects, and efficacy/safety-exposure relationships in ABT-165 arm. Hazard ratios of PFS and OS comparing the 2 groups are estimated using Cox proportional hazard model. Kaplan-Meier methodology is used to estimate PFS and OS curves, median PFS and OS, and their 90% confidence intervals. Safety is assessed by ABT-165 exposure, adverse events (AEs), serious AEs, all deaths, and changes in laboratory data and vital signs. Archival tissue is collected and evaluated for DLL4 expression and angiogenesis signature. Approximately 100 patients are planned to be enrolled, with recruitment initiated January 2018. Clinical trial information: NCT03368859.

SGNTGT-001: A phase 1 study of SEA-TGT, an effector-function enhanced monoclonal antibody (mAb), in advanced malignancies (trial in progress).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS2657-TPS2657
Author(s):  
Elena Garralda ◽  
Rachel E. Sanborn ◽  
Anna Rachel Minchom ◽  
Diwakar Davar ◽  
Giuseppe Curigliano ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Activation ◽  
Immune Cell ◽  
Cell Lymphoma ◽  
Phase 1 ◽  
Objective Response ◽  
B Cell Lymphoma ◽  
Effector Function ◽  
T Regulatory Cell ◽  
Open Label

TPS2657 Background: T-cell immunoreceptor with Ig and ITIM domains (TIGIT) is an inhibitory immune checkpoint receptor expressed on subsets of T cells and NK cells. SEA-TGT is an effector-function enhanced human mAb that targets TIGIT with pico-molar affinity and blocks TIGIT’s interaction with CD155 and CD112. SEA-TGT was developed to have amplified binding to and engagement of Fcγ receptors. Enhanced effector function increases TIGIT+ T-regulatory cell depletion, enhances innate immune cell activation, and augments naïve and memory CD8+ T-cell responses. Preclinically, SEA-TGT elicits superior anti-tumor immune responses compared to other TIGIT mAbs without effector-enhanced backbones, with curative anti-tumor activity as monotherapy and in combination with other immune-modulators. Methods: This phase 1, open-label, multicenter, dose-escalation/expansion study (NCT04254107) is assessing the safety, tolerability and preliminary activity of SEA-TGT monotherapy in up to 205 adults (≥18 years) with histologically or cytologically confirmed relapsed, refractory, or progressive metastatic solid tumors (non-small cell lung, gastric/GE junction carcinomas, cutaneous melanoma, head and neck squamous cell carcinoma, bladder cancer, ovarian cancer or triple-negative breast cancer) or lymphomas (classical Hodgkin lymphoma, diffuse large B-cell lymphoma, or peripheral T-cell lymphoma, not otherwise specified). SEA-TGT will be infused on Day 1 of 21-day cycles. In Part A, the safety and tolerability of SEA-TGT will be assessed in ̃25 subjects to identify the maximum tolerated dose and recommended phase II dose (RP2D). In Part B, the safety and antitumor activity of the RP2D will be assessed in ̃180 subjects in disease-specific expansion cohorts. Primary endpoints are adverse events, laboratory abnormalities, dose-limiting toxicities, and dose-level safety and activity. Secondary endpoints are objective response (OR) rates, duration of OR, complete response, progression-free survival, overall survival, PK, and antidrug antibodies. Exploratory biomarkers of SEA-TGT-mediated pharmacodynamic (PD) effects, PK-PD correlations, and correlative analyses of predictive and PD measurements with response, toxicity, and resistance will be explored. The study was opened April 2020 and is enrolling across sites in North America and Europe. Clinical trial information: NCT04254107.

Atezolizumab in combination with bevacizumab in patients with unresectable locally advanced or metastatic mucosal melanoma: Interim analysis of an open-label phase II trial.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 9511-9511
Author(s):  
Lu Si ◽  
Meiyu Fang ◽  
Yu Chen ◽  
Lili Mao ◽  
Peng Zhang ◽  
...  
Keyword(s):  
Interim Analysis ◽  
Objective Response ◽  
Locally Advanced ◽  
Progression Free Survival ◽  
Mucosal Melanoma ◽  
Stage I ◽  
Efficacy Evaluation ◽  
Open Label ◽  
Full Analysis ◽  
Ecog Ps

9511 Background: Mucosal melanoma is a rare malignant melanoma in Caucasians but ranks the second most common subtype in the Asian population. It is more often diagnosed at an advanced stage and responds poorly to current PD-1/PD-L1 inhibitors. Here we report the interim analysis results of ML41186, an open-label, multicenter, single-arm phase II study, aiming to evaluate the efficacy and safety of atezolizumab in combination with bevacizumab in patients (pts) with advanced mucosal melanoma. Methods: Eligible pts aged 18 to 75 years with histologically confirmed unresectable locally advanced or metastatic mucosal melanoma had at least one measurable lesion per RECIST version 1.1 at baseline, with an ECOG PS 0 or 1 and adequate hematologic and organ function. ML41186 is a Simon two-stage design study, if 22 pts completed ORR evaluation and more than 3 pts respond in stage I, the study then continue to Stage II. Atezolizumab and bevacizumab were administered at a fixed dose of 1200 mg and 7.5 mg/kg Q3W respectively (on day 1 of each 21-day cycle) until unacceptable toxicity or loss of clinical benefit. The primary endpoint is the objective response rate (ORR). The secondary endpoints include progression-free survival (PFS), duration of objective response (DoR), disease control rate (DCR), and safety. Results: By the cut-off date of 9th September 2020, 35 pts has been enrolled, among whom 22 pts in the stage I analysis set has completed two efficacy evaluation, while 28 pts (full analysis set) has completed at least one efficacy evaluation. In ITT populations (n=35), mean age was 58.9 years with 10 (28%) pts had ECOG PS of 1. LDH level elevated in 9 (25.7%) pts. More than half pts (19, 54.3%) had metastatic mucosal melanoma, of whom 3 (15.8%) pts had more than 3 metastasis sites and 4 (21.1%) pts had liver metastasis. In stage I analysis set (n=22), the best confirmed ORR was 36.4% (95% CI, 17.0%-59.3%). Median progression-free survival was 5.32 months (95% CI, 1.58-not reached), and the best confirmed DCR was 59.1% (95%CI, 36.4%-79.3%). The median confirmed DoR was not reached (95% CI, 2.76-NR). In the full analysis set (n=28), the unconfirmed ORR was 42.9% (95%CI, 24.5%-62.8%). In ITT populations (n=35), 28 pts (80%) experienced at least one adverse event (AE) and 5 pts (14.3%) experienced at least one grade 3-4 AEs. Only one patient experienced AE leading to treatment discontinuation. One patient died of autoimmune lung disease. Conclusions: The combination of atezolizumab plus bevacizumab showed promising benefit and was tolerable in pts with advanced mucosal melanoma. At the time of this interim analysis, the primary endpoint did not cross the futility boundary, thus the study will run into Stage II. Clinical trial information: NCT04091217.

A multicenter open-label phase 1 study evaluating the safety and tolerability of HMPL-306 in patients with locally advanced or metastatic solid tumors with IDH mutations.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS3159-TPS3159
Author(s):  
Filip Janku ◽  
John S. Kauh ◽  
Christopher Tucci ◽  
Zhao Yang ◽  
Marek K. Kania ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Tricarboxylic Acid Cycle ◽  
Phase 1 ◽  
Objective Response ◽  
Locally Advanced ◽  
Low Grade Glioma ◽  
Statistical Hypothesis ◽  
Low Grade ◽  
Open Label ◽  
Idh Mutations

TPS3159 Background: Isocitrate dehydrogenase (IDH) is a rate-limiting tricarboxylic acid cycle enzyme with 3 isoforms. Mutations in IDH1 and IDH2 result in gain-of-function activity that can cause tumor formation and/or progression and have been associated with various tumor types. Therefore, selective, single mutant IDH (mIDH) isotype inhibitors (mIDH1 or mIDH2) can lead to insufficient efficacy and the potential for tumor resistance. HMPL-306 is an innovative, small-molecule, orally available, highly selective, potent inhibitor of both mIDH1 and mIDH2. Clinical development of a compound that concurrently targets, inhibits, and suppresses multiple mIDHs could lead to significant and durable clinical benefit for patients (pts) with solid tumors harboring IDH mutations. Methods: This is a phase 1, open-label, dose escalation (Part 1) and dose expansion (Part 2) study to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of HMPL-306 in pts ≥18 years with locally advanced or metastatic solid tumors with any IDH mutations. HMPL-306 will be administered orally, once daily in a 28-day continuous dosing treatment cycle. The HMPL-306 dose will be escalated in Part 1 according to the modified toxicity probability interval-2 (mTPI-2) design in 4 cohorts in approximately 15-20 pts: 50, 100, 150, and 200 mg. Eligible pts must have locally advanced or metastatic solid tumors with IDH1 or IDH2 mutations. The primary objectives are to evaluate safety, dose limiting toxicities (DLTs), tolerability, maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), and PK. Approximately 95 pts will be enrolled at the RP2D in Part 2 to further characterize the safety, tolerability, PK, PD, and preliminary anti-tumor activities of HMPL-306. Part 2 will include 5 dose expansion cohorts: cholangiocarcinoma (n = 20), skeletal chondrosarcoma (n = 20), low-grade glioma (n = 20), perioperative low-grade glioma (n = 15), any other solid tumor harboring an IDH1/2 mutation (n = 20). All pts will continue treatment until disease progression, unacceptable toxicity, withdrawal of consent, or at the investigator’s discretion. Safety will be assessed based on reports of adverse events including clinical laboratory testing, vital signs, physical examinations, and electrocardiograms. All pts who receive any study treatment will be included in safety and efficacy analyses. Antitumor activity based on investigator-assessed overall response will be evaluated using descriptive analyses. Objective response rate will be calculated with 95% confidence interval using the Clopper-Pearson method. The Kaplan-Meier method will be used to summarize the time-to-event data such as progression-free survival and duration of response. No statistical hypothesis testing is planned. Enrollment started February 2021.

BREAKWATER: Randomized phase 3 study of encorafenib (enco) + cetuximab (cetux) ± chemotherapy for first-line (1L) treatment (tx) of BRAF V600E-mutant (BRAFV600E) metastatic colorectal cancer (mCRC).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS3619-TPS3619
Author(s):  
Scott Kopetz ◽  
Axel Grothey ◽  
Rona Yaeger ◽  
Fortunato Ciardiello ◽  
Jayesh Desai ◽  
...  
Keyword(s):  
Checkpoint Inhibitors ◽  
Performance Status ◽  
Objective Response ◽  
Braf Inhibitor ◽  
Braf V600e ◽  
Egfr Inhibitor ◽  
Braf Mutations ◽  
Open Label ◽  
Phase 3 ◽  
Previously Treated

TPS3619 Background: Approximately 10% of patients (pts) with mCRC have BRAF mutations (mostly V600E). 1L tx options for BRAFV600E mCRC are limited to cytotoxic chemotherapy ± anti-VEGF or anti-EGFR, or immune checkpoint inhibitors in pts with MSI-H tumors. In Europe, Japan, and USA, the combination of BRAF inhibitor enco + EGFR inhibitor cetux is approved for tx of BRAFV600E mCRC after prior therapy. In BEACON CRC, enco + cetux resulted in a median overall survival (OS) of 9.3 months (95% confidence interval [CI]: 8.0–11.3) and an objective response rate (ORR) of 19.5% (95% CI: 14.5%–25.4%) in previously treated pts with BRAFV600E mCRC (median follow-up: 12.8 months); 57.4% of pts had grade 3/4 adverse events (AEs); 9% discontinued due to AEs. Given the poor prognosis of pts with BRAFV600E mCRC and based on the efficacy and tolerability of enco + cetux from BEACON CRC, BREAKWATER will evaluate efficacy and safety of enco + cetux ± chemotherapy in tx-naive pts with BRAFV600E mCRC. Methods: BREAKWATER is an open-label, global, multicenter, randomized, phase 3 study with a safety lead-in (SLI). Approximately 60 and 870 pts will be enrolled in the SLI and phase 3 parts of the study, respectively. Pts must have BRAFV600E mCRC (determined using tumor tissue or blood); ECOG performance status 0/1; and adequate bone marrow, hepatic, and renal function. Pts in the SLI must have evaluable disease (RECIST v1.1) and have received ≤ 1 prior tx regimen; those previously treated with a BRAF or EGFR inhibitor, or both oxaliplatin and irinotecan, will be excluded. Pts in the phase 3 study must have measurable disease and be tx naive for metastatic disease. Study tx and endpoints are shown in the table. Enrollment began on 6 January 2021. Clinical trial information: NCT04607421. [Table: see text]

Maintenance durvalumab after first-line platinum-based chemotherapy in advanced oesophago-gastric (OG) adenocarcinoma: Results from the PLATFORM trial.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 4015-4015
Author(s):  
Caroline Fong ◽  
Bijal Patel ◽  
Clare Peckitt ◽  
Elli Bourmpaki ◽  
Katharina von Loga ◽  
...  
Keyword(s):  
Induction Chemotherapy ◽  
Adaptive Design ◽  
Performance Status ◽  
Objective Response ◽  
First Line ◽  
Primary Analysis ◽  
Open Label ◽  
Disease Extent ◽  
Platinum Based Chemotherapy ◽  
Significant Difference

4015 Background: PLATFORM is a prospective, open-label, multicentre, adaptive phase II trial assessing maintenance therapy in patients (pts) with OG adenocarcinoma after platinum-based first-line induction chemotherapy. HER2 negative pts were initially randomised 1:1:1:1:1 to surveillance (A1), capecitabine (A2), durvalumab (A3), with rucaparib (A4) and capecitabine + ramucirumab (A5) added later as per adaptive design. Here we report the primary analysis of durvalumab maintenance vs. surveillance. Methods: Pts were randomised upon achieving response or stable disease following 18 weeks of platinum-based chemotherapy and were stratified by region, disease extent and performance status. A1 pts had 4 weekly surveillance visits and A3 pts received 10mg/kg durvalumab iv Q2W. Target accrual was 154 pts/arm; however, A3 was closed prematurely after cessation of industry support. The primary endpoint was progression-free survival (PFS) from randomisation post induction chemotherapy to disease progression according to RECIST 1.1 criteria, or death. Secondary endpoints were time to treatment failure (TTF), objective response rate (ORR), overall survival (OS) and toxicity. Survival analyses according to PD-L1 using the combined positive score (CPS, Ventana SP263 assay) was conducted. Results: A total of 205 pts were concurrently randomised into A1 (n = 100) and A3 (n = 105). At data cut-off (02 Feb 2021), median follow up was 24.2 months [95% confidence interval (CI) 21.6-36.8]. There was no significant difference in PFS between A1 and A3 [median PFS: 3.2 vs. 4.7 months (hazard ratio (HR) 0.79 (95% CI 0.59-1.06, p = 0.122) respectively]. Median OS was 11.4 vs. 11.3 months (HR 0.92, 95% CI 0.66-1.27, p = 0.60) in A1 and A3 respectively and no significant difference in TTF was detected between both arms (median TTF: 3.2 vs. 3.5 months (HR 0.92, 95% CI 0.69-1.23, p = 0.558)]. ORR was 6% in A3 (n = 2 complete and n = 4 partial responses) whereas no radiological responses were seen in A1. PD-L1 results were available for 76 pts in A1 and 77 pts in A3. PFS was comparable between subgroups using the PD-L1 CPS thresholds of ≥1, ≥5 and ≥10. The safety population consisted of 199 pts (A1: 98 pts and A3: 101 pts). Grade ≥3 treatment-related adverse events were reported in 18% of A3 pts and no new safety signals were identified. Conclusions: Although a survival advantage was not seen with maintenance durvalumab compared to surveillance, a subset of patients who received durvalumab demonstrated incremental radiological responses. Exploratory analysis of PD-L1 expression was not associated with improved survival outcomes. Clinical trial information: NCT02678182.

Antitumor activity of dostarlimab in patients with mismatch repair-deficient/microsatellite instability–high tumors: A combined analysis of two cohorts in the GARNET study.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2564-2564
Author(s):  
Dominique Berton ◽  
Susana N. Banerjee ◽  
Giuseppe Curigliano ◽  
Sara Cresta ◽  
Hendrik-Tobias Arkenau ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Microsatellite Instability ◽  
Mismatch Repair ◽  
Solid Tumors ◽  
Phase 1 ◽  
Objective Response ◽  
Low Grade ◽  
Open Label ◽  
Tumor Types

2564 Background: Dostarlimab is an investigational, humanized programmed death 1 (PD-1) receptor monoclonal antibody that blocks interaction with the PD-1 ligands, PD-L1 and PD-L2. GARNET (NCT02715284) is a phase 1 study assessing the antitumor activity and safety of dostarlimab monotherapy in patients with solid tumors. Methods: This multicenter, open-label, single-arm study is being conducted in 2 parts: dose escalation and expansion. Here we report on the 2 expansion cohorts that enrolled mismatch repair–deficient/microsatellite instability–high (dMMR/MSI-H) patients. Cohort A1 enrolled patients with advanced or recurrent dMMR/MSI-H endometrial cancer (EC), and cohort F enrolled patients with advanced or recurrent dMMR/MSI-H or POLε-hypermutated non-EC solid tumors, mainly gastrointestinal (GI) tumors (99 [93.4%] had GI tumors, including 69 [65.1%] with colorectal cancer). Patients received 500 mg IV of dostarlimab every 3 weeks for 4 cycles, then 1000 mg IV every 6 weeks until disease progression or discontinuation. The primary endpoints were objective response rate (ORR) and duration of response (DOR) by RECIST v1.1. Here we report ORR and DOR, by individual cohort and as an overall population, in patients with dMMR tumors identified by immunohistochemistry testing. Results: For this interim analysis, an efficacy analysis was performed for the patients who had baseline measurable disease and ≥6 months of follow-up in the study (N = 209). The ORR was 41.6% (95% CI, 34.9%–48.6%) for the combined A1+F dMMR cohorts (Table). Responses were durable, and median DOR has not been reached in either cohort (median follow-up: cohort A1, 16.3 months; cohort F, 12.4 months). A total of 267 patients were included in the safety population (all patients who received ≥1 dose; cohort A1, N = 126; cohort F, N = 141). Treatment-related adverse events (TRAEs) were consistent across tumor types. Overall, the most frequently reported any-grade TRAEs were asthenia (13.9%), diarrhea (13.5%), and fatigue (11.2%). The most common grade ≥3 TRAEs were anemia (2.2%), lipase increased (1.9%), alanine aminotransferase increased (1.1%), and diarrhea (1.1%). No deaths were attributed to dostarlimab. Conclusions: Dostarlimab demonstrated durable antitumor activity in patients with dMMR solid tumors, with consistent antitumor activity seen across endometrial and nonendometrial tumor types. The safety profile was manageable, with no new safety signals detected. Most TRAEs were low grade and were similar across cohorts. Clinical trial information: NCT02715284. [Table: see text]

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