Platform trial of ezabenlimab (BI 754091), an anti-PD-1 antibody, in patients (pts) with previously treated advanced solid tumors: Combination with BI 836880, a VEGF/Ang2-blocking nanobody.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2582-2582
Author(s):  
Maen A. Hussein ◽  
Ivor John Percent ◽  
Johanna C. Bendell ◽  
Edward Arrowsmith ◽  
Hendrik-Tobias Arkenau ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Preliminary Data ◽  
Synergistic Effects ◽  
Objective Response ◽  
Locally Advanced ◽  
Complete Response ◽  
Prior Treatment ◽  
Tumor Cell Death ◽  
Open Label ◽  
Angiopoietin 2

2582 Background: The combination of anti-PD-1 antibodies with other immunomodulatory or targeted therapies has the potential for synergistic effects. This open-label, Phase II platform trial is assessing ezabenlimab, an anti-PD-1 antibody, in combination with other agents. Here, we report preliminary data from Module C, which assesses ezabenlimab in combination with BI 836880, a humanized bispecific nanobody that targets vascular endothelial growth factor (VEGF) and angiopoietin-2 (Ang2). VEGF and Ang2 play key roles in tumor angiogenesis and have an immunosuppressive effect in the tumor microenvironment. Combining anti-VEGF/Ang2 with an anti-PD-1 therapy promotes an immunopermissive state supportive of T-cell-mediated tumor cell death. Methods: Pts are being enrolled into 5 cohorts: locally advanced/metastatic gastric or gastroesophageal adenocarcinoma with ≥1 prior treatment (anti-PD-[L]1 naïve; Cohort 1); any advanced/metastatic solid tumor (excluding non-squamous NSCLC or melanoma) with prior anti-PD-(L)1 treatment, which progressed after achieving at least stable disease (SD) for ≥4 months (Cohort 2); advanced/metastatic solid tumors with no benefit from prior anti-PD-(L)1 treatment (SD or progressive disease [PD] in < 4 months; Cohort 3); locally advanced/metastatic microsatellite stable (MSS) colorectal cancer with ≥1 prior treatment (anti-PD-[L]1 naïve; Cohort 4); advanced MSS and mismatch repair-proficient endometrial carcinoma, which progressed after 1 line of chemotherapy (anti-PD-[L]1 naïve; Cohort 5). Pts will receive BI 836880 720 mg and ezabenlimab 240 mg IV every 3 weeks. The primary endpoint is investigator-assessed objective response (complete response [CR] or partial response per RECIST v1.1). Safety is also being assessed. Results: As of Jan 2021, 29 pts have received ezabenlimab plus BI 836880; 26 pts remain on treatment. Cohorts 1/2/3/4/5 included 0/6/3/19/1 pts; median age 63 yrs; 20 (69%) pts were male . Overall, 22 (76%) pts experienced an adverse event (AE; any-cause), most commonly (all%/G3%) nausea (31/3), hypertension (28/7) and fatigue (21/0). No G4/5 AEs were reported; 5 (17%) pts experienced serious AEs. One pt had an immune-related AE (G1 rash). Eighteen (62%) pts had a drug-related AE, most commonly nausea (24%), vomiting, fatigue, and hypertension (all 14%). Three pts had infusion-related reactions (G1, n = 2; G2, n = 1) and 1 pt had an AE that led to treatment discontinuation (non-related G3 bile duct stone). Of 7 pts evaluable for response prior to cycle 3, 5 have SD (Cohort 2, n = 2; Cohort 4, n = 3), and 2 have PD (Cohorts 3 and 4, n = 1 each). Updated data will be presented. Conclusions: These preliminary data suggest that ezabenlimab in combination with BI 836880 has a manageable safety profile. Cohorts are continuing to recruit (approximately 30 pts per cohort). Clinical trial information: NCT03697304.

Platform trial of BI 754091, an anti-PD-1 antibody, in patients with previously treated advanced solid tumors: Combination with BI 836880, a VEGF/Ang2-blocking nanobody.

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. TPS152-TPS152
Author(s):  
Maen A. Hussein ◽  
Johanna C. Bendell ◽  
Hendrik-Tobias Arkenau ◽  
Quincy S. Chu ◽  
Aaron Richard Hansen ◽  
...  
Keyword(s):  
Cell Death ◽  
Solid Tumors ◽  
Objective Response ◽  
Locally Advanced ◽  
Progression Free Survival ◽  
Prior Treatment ◽  
Tumor Cell Death ◽  
Open Label ◽  
Open Label Phase ◽  
Metastatic Solid Tumor

TPS152 Background: Combining anti-programmed cell death protein 1 (PD-1) antibodies with other immuno-modulatory or targeted therapies may improve outcomes. NCT03697304 is an open-label, Phase II, platform trial assessing BI 754091, an anti-PD-1 antibody, combined with other agents. Here, we describe Module C in which BI 754091 will be combined with BI 836880, a humanized bispecific nanobody, that targets vascular endothelial growth factor (VEGF) and angiopoietin2 (Ang2). VEGF and Ang2 play key roles in tumor angiogenesis and have an immunosuppressive effect in the tumor microenvironment. Combining anti-VEGF/Ang2 with an anti-PD-1 therapy promotes an immunopermissive state supportive of T-cell-mediated tumor cell death. Methods: Patients are being enrolled in 5 cohorts: 1) locally advanced/metastatic gastric or gastroesophageal adenocarcinoma with ≥1 prior treatment (anti-PD-[L]1 naïve); 2) any advanced/metastatic solid tumor (excluding NSCLC and melanoma) with prior anti-PD-(L)1 treatment, which progressed after achieving at least stable disease (SD) for 4 months; 3) advanced/metastatic solid tumors with no benefit from prior anti-PD-(L)1 treatment (SD <4 months); 4) locally advanced/metastatic microsatellite stable (MSS) colorectal cancer with ≥1 prior treatment (anti-PD-[L]1 naïve); 5) advanced MSS and mismatch-repair proficient endometrial carcinoma which progressed following 1 line of chemotherapy (anti-PD-[L]1 naïve). Patients will receive BI 836880 (720 mg every 3 weeks [Q3W] intravenously [IV]) and BI 754091 (240 mg Q3W IV). Treatment will continue until progressive disease, unacceptable toxicity, consent withdrawal, or for a maximum of 1 year (treatment may be extended in case of clinical benefit). The primary endpoint is objective response (OR; complete or partial response per RECIST v1.1 as assessed by the investigator). Secondary endpoints are duration of OR, disease control and progression-free survival. Safety will also be assessed. Approximately 30 patients will be enrolled per cohort at sites in North America and the United Kingdom. Clinical trial information: NCT03697304.

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.

A phase II basket study of MCLA-128, a bispecific antibody targeting the HER3 pathway, in NRG1 fusion-positive advanced solid tumors.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS3654-TPS3654
Author(s):  
Alison M. Schram ◽  
Alexander E. Drilon ◽  
Teresa Macarulla ◽  
Eileen Mary O'Reilly ◽  
Jordi Rodon ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Kinase Inhibitors ◽  
Bispecific Antibody ◽  
Objective Response ◽  
Locally Advanced ◽  
Disease Stage ◽  
Tumor Type ◽  
Open Label ◽  
Eligibility Criteria ◽  
Downstream Signaling

TPS3654 Background: NRG1 fusions are oncogenic drivers across various cancers. NRG1 fusion proteins bind to HER3, leading to HER2/HER3 heterodimerization, increased downstream signaling, and tumor growth. Clinical responses to anti-HER3 antibodies or HER2 tyrosine kinase inhibitors have been reported. In contrast to these agents, MCLA-128 is a HER2/HER3 bispecific antibody that blocks both NRG1 binding and HER2/3 dimerization. Two patients with chemotherapy-resistant ATP1B1-NRG1-positive pancreatic KRAS-wild-type adenocarcinomas who received MCLA-128 through FDA-approved single-patient Investigational New Drug (IND) applications showed significant tumor shrinkage and durable tumor marker (CA-19-9) response. These data support the evaluation of MCLA-128 in NRG1 fusion-positive tumors using a basket approach. Methods: This is a global, open-label, multicenter phase 2 basket trial of MCLA-128 in patients with solid tumors harboring NRG1 gene fusions. Main eligibility criteria are locally advanced unresectable or metastatic cancers harboring an NRG1 fusion, and failure under prior standard therapy appropriate for the tumor type and disease stage. Genomic screening of tumor tissue is done at a local laboratory (with post-hoc central confirmation) or central laboratory (RNA sequencing). Three NRG1 fusion-positive tumor cohorts are being evaluated: pancreatic cancer, NSCLC, and other solid tumors. The sample size for the first two cohorts is up to 25 patients; the basket group may enroll up to 40 patients. The primary endpoint for all cohorts is investigator-assessed objective response rate (RECIST v1.1). The key secondary endpoint is duration of response. Other secondary endpoints include progression-free and overall survival. Eligible patients receive a bi-weekly dosing regimen of 750 mg of MCLA-128 (2-hour infusion), every 2 weeks, in 4-week cycles. The study is actively accruing patients in North America, Europe, and Asia. Previously presented at ESMO 2019, 685TiP, Schram et al.-Reused with permission. Clinical trial information: NCT02912949 .

CRESTONE: Clinical study of response to seribantumab in tumors with neuregulin-1 (NRG1) fusions—A phase II study of the anti-HER3 mAb for advanced or metastatic solid tumors (NCT04383210).

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. TPS449-TPS449
Author(s):  
Johanna C. Bendell ◽  
Kian-Huat Lim ◽  
Mark E. Burkard ◽  
Samuel J Klempner ◽  
Mark A. Socinski ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Solid Tumors ◽  
Checkpoint Inhibitors ◽  
Locally Advanced ◽  
Disease Free Survival ◽  
The United States ◽  
Prior Treatment ◽  
Response To Treatment ◽  
Open Label ◽  
Neuregulin 1

TPS449 Background: NRG1 (Neuregulin-1) gene fusions are rare oncogenic drivers found in 0.2% of solid tumors, including lung, pancreatic, gallbladder, breast, ovarian, colorectal, neuroendocrine, and sarcomas. NRG1 is the predominant ligand of HER3 and to a lesser extent HER4. NRG1 fusion proteins retaining an active EGF-like domain drive tumorigenesis and proliferation through aberrant HER3 activation. Importantly, NRG1 fusions are often mutually exclusive with other known driver alterations. NRG1 fusions have been correlated with worse overall and disease-free survival and poor response to treatment with standard therapies including chemotherapy, PD-(L)1 checkpoint inhibitors and combinations of these agents. Inhibition of HER3 and its dimerization partners represents a rational and novel therapeutic approach for tumors harboring an NRG1 fusion supported by case studies of clinical responses to anti-HER3 antibodies or pan-ERBB (tyrosine kinase inhibitors) TKIs like afatinib. Seribantumab is a fully human IgG2 mAb against HER3 uniquely able to inhibit NRG1-dependent activation of HER3, HER3-HER2 dimerization, and downstream signaling through the PI3K/AKT and MAPK pathways. The clinical safety profile of seribantumab has been well characterized through prior monotherapy and combination studies in over 800 patients. Methods: CRESTONE is an open label, multicenter phase 2 basket trial of seribantumab in adult patients with NRG1 fusion-positive locally advanced or metastatic solid tumors who have progressed on or are nonresponsive to available therapies. The trial will enroll at least 75 previously treated patients across three cohorts. Cohort 1 (N=55) will include patients who have not received prior treatment with any ERBB targeted therapy. Cohort 2 (up to N=10) will include patients who have progressed after prior treatment which includes ERBB targeted therapy. Cohort 3 (up to N=10) will include patients harboring NRG1 fusions without an EGF-like binding domain. NRG1 fusion status for enrollment will be determined through a local CLIA or similarly accredited molecular assay. NRG1 fusion status for patients in Cohort 1 will be centrally confirmed using an RNA-based NGS assay. This study will evaluate a novel dosing regimen of weekly induction, biweekly consolidation, and Q3W maintenance designed to rapidly achieve steady state levels, optimize exposure, and deliver maximal NRG1 inhibition. The primary endpoint is ORR per RECIST v1.1 by independent radiologic review. Secondary endpoints include duration of response (DoR), safety, PFS, OS, and overall clinical benefit rate. An interim analysis is planned following enrollment of 20 patients in Cohort 1. CRESTONE is open and accruing patients in the United States. Clinical trial information: NCT04383210.

Mobocertinib (TAK-788) in EGFR exon 20 insertion (ex20ins)+ metastatic NSCLC (mNSCLC): Additional results from platinum-pretreated patients (pts) and EXCLAIM cohort of phase 1/2 study.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 9014-9014
Author(s):  
Suresh S. Ramalingam ◽  
Caicun Zhou ◽  
Tae Min Kim ◽  
Sang-We Kim ◽  
James Chih-Hsin Yang ◽  
...  
Keyword(s):  
Brain Metastases ◽  
Safety Profile ◽  
Phase 1 ◽  
Objective Response ◽  
Locally Advanced ◽  
Safety Data ◽  
Complete Response ◽  
Open Label ◽  
Platinum Based Chemotherapy ◽  
Exon 20

9014 Background: No approved targeted therapies are available for EGFR ex20ins+ mNSCLC. Mobocertinib, a first-in-class, potent, oral TKI targeting EGFR ex20ins mutations, has Breakthrough Therapy Designation in the US and China for post-platinum-based chemotherapy pts with EGFR ex20ins+ mNSCLC. Methods: This 3-part, open-label, multicenter study (NCT02716116) has dose-escalation/expansion and extension (EXCLAIM) cohorts. Pts with EGFR ex20ins+ mNSCLC, ECOG status 0–1, and ≥1 prior line of therapy for locally advanced/metastatic disease received mobocertinib 160 mg QD. Primary endpoint was confirmed objective response rate (ORR; RECIST v1.1) assessed by independent review committee (IRC). We present additional efficacy and safety data for 114 platinum-pretreated pts (PPP) and 96 pts from EXCLAIM safety cohort. Results: Results are from Nov 1, 2020, data cutoff. Among PPP pts (n=114; median age 60 y [27–84 y]), 66% were female, 60% were Asian, and 59% had ≥2 prior systemic anticancer lines. Confirmed ORR per IRC was 28%, including 1 complete response (CR); disease control rate (DCR) was 78% [95% CI: 69–85]; median duration of response (DOR) was 17.5 mo (Table). In EXCLAIM (n=96; median age 59 y [27–80 y]), 65% were female, 69% were Asian, and 49% had ≥2 prior lines. Confirmed ORR per IRC was 25%, with 1 CR; DCR was 76% [95% CI: 66–84]; median DOR was not reached (Table). In EXCLAIM, baseline brain metastases were present in 33/96 pts (34%); the first site of disease progression by IRC was the brain in 40% of all pts and 73% of pts with baseline brain metastases. Confirmed responses were seen in all prespecified subgroups in PPP and EXCLAIM. Efficacy by EGFR ex20ins mutation variant will be presented. Treatment-related adverse events (TRAEs; >20%) in PPP were diarrhea (91%), rash (45%), paronychia (38%), decreased appetite (35%), nausea (34%), dry skin (31%), vomiting (30%), increased blood creatinine (25%), stomatitis (24%), and pruritus (21%); the only grade ≥3 TRAE in ≥5% was diarrhea (22%). AEs leading to discontinuation in >2% were diarrhea (4%) and nausea (4%). A similar safety profile was observed in EXCLAIM. Conclusions: Mobocertinib demonstrated clinically meaningful benefit for pts with EGFR ex20ins+ mNSCLC in PPP and EXCLAIM cohorts, with a manageable safety profile. Clinical trial information: NCT02716116. [Table: see text]

Trial in progress: A phase 1b study of sotorasib, a specific and irreversible KRASG12C inhibitor, as monotherapy in non-small cell lung cancer (NSCLC) with brain metastasis and in combination with other anticancer therapies in advanced solid tumors (CodeBreaK 101).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS2669-TPS2669
Author(s):  
David S. Hong ◽  
John H. Strickler ◽  
Marwan Fakih ◽  
Gerald Steven Falchook ◽  
Bob T. Li ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Objective Response ◽  
Locally Advanced ◽  
Antitumor Efficacy ◽  
Tolerability Profile ◽  
Molecular Testing ◽  
Open Label ◽  
Eligibility Criteria ◽  
Phase 1B ◽  
Combination Regimens

TPS2669 Background: Kirsten rat sarcoma viral oncogene homolog ( KRAS) p.G12C mutation is an oncogenic driver mutation in several solid tumors. Sotorasib is a specific, irreversible, small molecule inhibitor of KRASG12C that has demonstrated durable clinical benefit in NSCLC, with mild and manageable toxicities. The combination of sotorasib with other anticancer therapies may enhance antitumor efficacy. This master protocol is designed to evaluate safety, tolerability, pharmacokinetics (PK), and efficacy of multiple sotorasib combinations in patients (pts) with KRASp.G12C mutated solid tumors. Herein, we overview 1 monotherapy and 11 combination cohorts. Methods: This is a phase 1b, open-label study evaluating sotorasib alone and in combination regimens (Table) in pts with advanced KRAS p.G12C mutated solid tumors. Dose exploration will evaluate the safety and tolerability of sotorasib alone and in combination regimens; dose expansion will then verify the safety and tolerability profile of sotorasib regimens and assess antitumor efficacy. Key eligibility criteria include locally-advanced or metastatic solid tumor with KRAS p.G12C mutation identified through molecular testing in pts who have received ≥1 lines of prior systemic therapy. Primary endpoints include dose-limiting toxicities and treatment-emergent or treatment-related adverse events. Secondary endpoints include PK profile of combination regimens and efficacy (eg, objective response, disease control, duration of response, progression-free survival, and duration of stable disease assessed per RECIST 1.1). Enrollment began in December 2019 and is ongoing. Clinical trial information: NCT04185883. [Table: see text]

A phase Ia/Ib, open label, multicenter, dose-escalation study of BI 907828 (MDM2-p53 antagonist) in adult patients with advanced or metastatic solid tumors.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. TPS3166-TPS3166 ◽  
Author(s):  
Curtis Robert Chong ◽  
Todd Michael Bauer ◽  
Scott Andrew Laurie ◽  
Manish R. Patel ◽  
Noboru Yamamoto ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Escalation ◽  
Treatment Cycle ◽  
Objective Response ◽  
Locally Advanced ◽  
Negative Regulator ◽  
Recommended Dose ◽  
Open Label ◽  
Number Of Patients ◽  
Phase 1B

TPS3166 Background: Inactivation of tumor protein 53 (TP53) is a central mechanism of tumors to promote survival and proliferation. The murine double minute 2 ( MDM2) oncogene is the primary cellular negative regulator of TP53. Small molecule inhibitors of the MDM2-p53 interaction are currently being evaluated in clinical trials as new anti-cancer drugs, and clinical data published to date support the rationale to target MDM2-amplified tumors. BI 907828 is a potent MDM2-p53 antagonist that has shown efficacy in mouse models of human cancer. Methods: NCT03449381 is a Phase 1a/1b, open-label, multicenter, dose-escalation trial of BI 907828 in patients aged ≥18 years with advanced/metastatic solid tumors. Primary objectives of the Phase 1a (dose-escalation) part are to determine: the maximum tolerated dose (MTD) of BI 907828 based on dose-limiting toxicities (DLTs) during the first treatment cycle; the recommended dose for expansion (RDE); safety and tolerability. Patients in Arm A will receive one dose of BI 907828 every 21 days, and patients in Arm B one dose on Days 1 and 8, every 28 days. Secondary objectives include pharmacokinetics (PK), pharmacodynamics (PD) [GDF-15 induction in plasma], and preliminary anti-tumor activity. Primary endpoints are the number of patients with DLTs during the first treatment cycle, and the MTD. Phase 1a will include ≈50 evaluable patients with locally advanced or metastatic solid tumors with either a known TP53 wild type (wt) status or unknown TP53 status, regardless of MDM2 amplification status at the time of study entry. The main objectives of Phase 1b (expansion cohorts) are to assess efficacy, safety, and PK profiles at the RDE, and to determine the recommended dose for Phase 2. The primary endpoint is objective response, where best response is determined according to RECIST v1.1, or RANO criteria for patients with glioblastoma. Phase 1b will include up to 150 evaluable patients with TP53 wt tumors, assigned to four different cohorts, including non-squamous NSCLC, soft tissue sarcoma, glioblastoma, urothelial carcinoma, and solid tumors with brain metastases. As of 8th February 2019, 11 patients have been enrolled. Clinical trial information: NCT03449381.

A phase Ib study of abemaciclib in combination with pembrolizumab for patients with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) locally advanced or metastatic breast cancer (MBC) (NCT02779751): Interim results.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 1051-1051 ◽  
Author(s):  
Hope S. Rugo ◽  
Peter Kabos ◽  
Joseph Thaddeus Beck ◽  
Michael Jon Chisamore ◽  
Anwar Hossain ◽  
...  
Keyword(s):  
Partial Response ◽  
Objective Response ◽  
Locally Advanced ◽  
Metastatic Breast ◽  
Progression Free Survival ◽  
Complete Response ◽  
Primary Objective ◽  
Open Label ◽  
Phase Ib ◽  
Metastatic Setting

1051 Background: Abemaciclib is an orally administered, selective small molecule cyclin-dependent kinase (CDK)4 and 6 inhibitor, approved to treat HR+, HER2- MBC patients (pts) on a continuous twice daily dosing schedule as monotherapy or in combination with an aromatase inhibitor as initial endocrine based therapy or in combination with fulvestrant. Abemaciclib monotherapy increased tumor immunogenicity and synergized with anti-PD-1 to boost antitumor efficacy in murine models. Here we report safety and antitumor activity of abemaciclib plus pembrolizumab in HR+, HER2- MBC pts. Methods: This multicenter, nonrandomized, open-label, multi-cohort phase Ib study of abemaciclib plus pembrolizumab enrolled a cohort of endocrine resistant HR+, HER2- MBC pts who had received 1 or 2 prior chemotherapy regimens for MBC. No prior CDK4/6 inhibitor was allowed. Patients received 150mg abemaciclib orally every 12 hours plus pembrolizumab 200mg IV on day 1 every 21 days. Primary objective was to characterize safety of the abemaciclib plus pembrolizumab combination. Secondary objectives included objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Results: Of 28 pts enrolled, 15 (54%) received 1 line and 10 (36%) 2 lines of prior systemic chemotherapy in the locally advanced/metastatic setting. Safety of the combination was generally consistent with known side effects of abemaciclib and pembrolizumab and was generally manageable. Grade 3/4 adverse events in >2 pts included neutropenia (8 pts/29%), AST increase (5 pts/18%), diarrhea, and ALT increase (3 pts/11% each). Eight pts had confirmed partial response (29% ORR), and disease control rate (complete response [CR]+partial response [PR]+stable disease [SD]) was 82%. Clinical benefit rate (CR+PR+SD persisting for ≥6 months) was 46%. Median PFS and OS were 8.9 months (95% CI 3.9, 11.1) and 26.3 months (95% CI 20.0, 31.0), respectively. Conclusions: Combination of abemaciclib plus pembrolizumab demonstrated a generally tolerable safety profile with numerically higher rate of transaminase elevations than reported for the individual treatments. Compared to historical data for abemaciclib monotherapy in a similar pt population, a numerically higher but not obviously different ORR, PFS, and OS was observed. Clinical trial information: NCT02779751 .

EV-202: A phase II study of enfortumab vedotin in patients with select previously treated locally advanced or metastatic solid tumors.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS3647-TPS3647
Author(s):  
Justine Yang Bruce ◽  
Lajos Pusztai ◽  
Fadi S. Braiteh ◽  
Seema Rao Gorla ◽  
Chunzhang Wu ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Human Monoclonal Antibody ◽  
Objective Response ◽  
Locally Advanced ◽  
High Dose ◽  
Motor Neuropathy ◽  
Antibody Drug Conjugate ◽  
Open Label ◽  
Metastatic Setting ◽  
Previously Treated

TPS3647 Background: Nectin-4, a transmembrane cell adhesion protein, is highly expressed in urothelial carcinoma (UC), breast cancer (BC), non-small cell lung cancer (NSCLC), and gastroesophageal cancers (GEC); targeting Nectin-4 on these tumors may provide a novel treatment approach. Enfortumab vedotin (EV), an investigational human monoclonal antibody-drug conjugate, binds to Nectin-4 and upon internalization releases MMAE resulting in cell cycle arrest and cell death. Recently, EV received accelerated approval by the FDA for the treatment of adults with locally advanced/metastatic UC who previously received a PD-1 or PD-L1 inhibitor, and a platinum-containing chemotherapy in the neoadjuvant/adjuvant, locally advanced or metastatic setting. Use of EV in this study is investigational. Methods: This open-label phase 2 study (NCT04225117) will assess the efficacy and safety/tolerability of EV in patients (pts) with previously treated locally advanced/metastatic malignant solid tumors. Adult pts (~240) with histologically or cytologically confirmed disease and an ECOG ≤1 will be enrolled into 1 of 6 tumor-specific cohorts (Table), with ~40 pts each. While Nectin-4 expression is not required for enrollment, it is being tested retrospectively. Patients with active CNS metastases, grade ≥2 preexisting sensory or motor neuropathy, grade ≥3 immunotherapy-related hypothyroidism or panhypopituitarism, ongoing grade >3 immunotherapy-related AEs requiring high-dose steroids, or a history of uncontrolled diabetes mellitus within 3 months of the study will be excluded. All pts will receive EV 1.25 mg/kg IV on Days 1, 8, and 15 of each 28-day cycle until treatment discontinuation criteria are met; dose reductions/interruptions will be permitted. For all cohorts, the primary endpoint is investigator-assessed confirmed objective response rate (RECIST v1.1); secondary endpoints include duration of response, disease control rate, progression-free and overall survival, and safety/tolerability of EV. This study is recruiting as of February 2020. Clinical trial information: NCT04225117 . [Table: see text]

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