Introduction: ATR kinase is a critical component of DDR machinery and is activated by DNA damage or replication stress. Elimusertib is a selective ATR inhibitor with promising antitumor activity in pts with advanced solid tumors with ataxia telangiectasia mutated (ATM) protein loss and/or ATM putative deleterious alterations (Yap et al. Cancer Discov 2021). We report here the safety and efficacy of elimusertib in expansion cohorts of pts with a range of cancer types and DDR deficiencies and/or ATM loss. We also explored an alternative dose schedule in pts with ATM aberrations. Methods: Pts with advanced solid tumors resistant or refractory to standard treatment were screened for pathogenic DDR defects by next-generation sequencing or ATM protein loss by immunohistochemistry (IHC) analysis of baseline tumor tissue. Pts were assigned to cohorts: colorectal cancer (CRC); castration-resistant prostate cancer (CRPC); HER2− breast cancer (BC); gynecologic (GYN, mainly ovarian and endometrial); and advanced cancers with ATM IHC loss. Pts were treated with elimusertib 40 mg twice daily (BID) 3 days on/4 days off (3 on/4 off). A schedule of 3 on/11 off was also explored by dose escalation in pts with ATM loss or inactivating mutation. Results: 143 pts received ≥1 dose of elimusertib 40 mg BID 3 on/4 off, including 24 CRC, 19 CRPC, 19 BC, 45 GYN, and 36 ATM loss. 56% of pts had ≥4 prior therapy lines. Drug-related grade 3 and 4 treatment-emergent adverse events (TEAEs) were observed in 69% and 15% of pts, respectively, mainly anemia, leukopenia/neutropenia, and thrombocytopenia leading to dose modification but not withdrawal. 32 pts were treated 3 on/11 off with doses from 60 to 120 mg BID. Compared with 3 on/4 off, drug-related grade ≥3 hematologic TEAEs and dose modifications improved at lower doses, with 80 mg 3 on/11 off determined as the recommended dose. In pts receiving elimusertib 3 on/4 off, 5 RECIST partial responses were observed: 1 in ovarian (BRCA1 heterozygous mutation), 1 in BC (BRCA2 mutation), and 3 in ATM IHC loss: 2 CRPC pts both with ATM mutations (1 heterozygous, 1 homozygous), including 1 with FANCA mutation; 1 esophageal with ATM mutation. In pts with ATM IHC loss, objective response rate (ORR) was 9% and disease control rate (DCR) was 65%. A similar ORR was seen on 3 on/11 off in pts with ATM aberrations. In GYN pts, ORR was 2.3% and DCR was 73%. Conclusions: Elimusertib monotherapy demonstrated clinical activity in pts with DDR defects. Overall safety was manageable and hematologic toxicity improved on the 3 on/11 off schedule. Further biomarker analysis is underway to identify potential gene signatures associated with response. Clinical development of elimusertib in combination with checkpoint inhibitors and chemotherapy is ongoing (NCT04095273, NCT04514497). Citation Format: Timothy A. Yap, David S. Tan, Anastasios Stathis, Geoffrey I. Shapiro, Satoru Iwasa, Markus Joerger, Jingsong Zhang, Ruth Plummer, Michael Sawyer, Aaron C. Tan, Vincent Castonguay, Nashat Gabrail, Nobuaki Matsubara, Gary Wilkinson, Matthias Ludwig, Yinghui Zhou, Claudia Merz, Joseph Hreiki, Neelesh Sharma, Johan deBono. Phase Ib expansion trial of the safety and efficacy of the oral ataxia telangiectasia and Rad3-related (ATR) inhibitor elimusertib in advanced solid tumors with DNA damage response (DDR) defects [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT006.
242 Background: T-DXd is an antibody-drug conjugate comprising an anti-HER2 antibody, a cleavable tetrapeptide-based linker, and a topoisomerase I inhibitor. DESTINY-Gastric01 (DS8201-A-J202; ClinicalTrials.gov, NCT03329690) is an open-label, multicenter, randomized, phase 2 trial of T-DXd in patients with HER2–positive advanced gastric cancer (GC) or GEJ adenocarcinoma. In the primary analysis (101 OS events; median survival follow-up, 12.3 mo), T-DXd showed statistically significant benefit vs standard chemotherapy in objective response rate (ORR) and OS (Shitara K, et al. N Engl J Med. 2020;382:2419-2430); here, we present the final OS analysis as well as updated efficacy and safety. Methods: Patients (pts) with locally advanced or metastatic, centrally confirmed HER2–positive (IHC3+ or IHC2+/ISH+ on archival tissue) GC or GEJ cancer that had progressed after ≥2 previous lines of therapy including trastuzumab were randomly assigned 2:1 (T-DXd 6.4 mg/kg Q3W or physician’s choice [PC] of irinotecan [I] or paclitaxel [P]). Pts were stratified by country, ECOG performance status (0, 1), and HER2 status. Primary endpoint was ORR by independent central review. Key secondary endpoints were OS, duration of response (DOR), progression-free survival (PFS), disease control rate (DCR), confirmed ORR, and safety. Final OS analysis was performed at 133 OS events. Results: 187 pts received T-DXd (n = 125) or PC (n = 62 [55 I; 7 P]); 79.7% of pts were Japanese and 20.3% were Korean. Pts had a median of 2 prior lines of therapy, and 44.4% had ≥3. At data cutoff (June 3, 2020), 8% of T-DXd and 0% of PC pts remained on treatment (median survival follow-up, 18.5 mo). OS was improved with T-DXd vs PC (median OS, 12.5 vs 8.9 mo; hazard ratio [HR], 0.60 [95% CI, 0.42-0.86]); 12-month OS, 52.2% vs 29.7%. ORR was 51.3% (61/119; 11 CR; 50 PR) with T-DXd vs 14.3% (8/56; all PR) with PC ( P< 0.0001); confirmed ORR, 42.0% (50/119; 10 CR; 40 PR) vs 12.5% (7/56; all PR) ( P= 0.0001); DCR, 85.7% vs 62.5% ( P= 0.0005); confirmed median DOR, 12.5 vs 3.9 mo; median PFS, 5.6 vs 3.5 mo (HR, 0.47 [95% CI, 0.31-0.71]; P= 0.0003). Grade ≥3 AEs occurred in 85.6% of T-DXd pts vs 56.5% with PC; the most common were neutrophil count decreased (51.2%, 24.2%), anemia (38.4%, 22.6%), and white blood cell count decreased (20.8%, 11.3%). 16 pts (12.8%) had T-DXd–related interstitial lung disease (ILD; 13 grade 1/2, 2 grade 3, 1 grade 4, no grade 5) vs 0 with PC. As reported in the primary analysis, there was 1 T-DXd–related death from pneumonia (non-ILD). Conclusions: With additional follow-up after the primary analysis, T-DXd continued to demonstrate OS benefit and clinically relevant improvement in ORR compared with standard chemotherapy, and a manageable safety profile, in HER2–positive advanced GC or GEJ adenocarcinoma. Clinical trial information: NCT03329690.
106 Background: E7386 is a novel oral anticancer agent that inhibits the binding of β-catenin to its transcriptional co-activator, CBP, thereby modulating Wnt/β-catenin signaling. In preclinical studies, E7386 showed promising activity (eg, modulation of tumor angiogenesis, alteration of the immune microenvironment, and inhibition of tumor growth). At a prior cutoff point for the dose-escalation part of a phase 1 study of E7386 in pts with advanced solid tumors, we reported 2 dose-limiting toxicities (DLTs; both grade 3 decreased appetite) with E7386 160 mg twice daily (BID). Here we describe an update of the dose-escalation part of this phase 1 study—we mainly report updated safety, tolerability, and preliminary efficacy and biomarker results, which led to the inclusion of an additional dose level for investigation in the expansion part of this study. Methods: E7386 was administered orally in escalating doses on a BID continuous schedule in 28-day cycles. Adverse events (AEs) were graded using CTCAE v5.0. Tolerability was judged by DLTs during cycle 1 (C1). Tumor response was assessed every 8 weeks from C1 day (D) 1, or sooner if clinically indicated, and at the end of treatment by investigators using RECIST v1.1. Samples for pharmacokinetic analyses were collected on C1D1 and C1D8; samples for biomarker analyses were collected at protocol-defined time points. To determine the appropriate dose(s) for the expansion part of this study, additional investigation of the dose-escalation part was conducted. Results: As of the data cutoff (DCO) date (30 June 2022), 36 pts (24 men, 12 women; median age, 61.5 y) were enrolled in E7386 dose cohorts (10 to 160 mg BID). Doses were tolerable up to 120 mg BID. The most common treatment-related AEs (all grades; > 10%) were nausea (80.6%), vomiting (58.3%), aspartate aminotransferase increased (16.7%), and alanine aminotransferase increased, decreased appetite, and diarrhea (13.9% each). Nausea and vomiting were well-controlled with antiemetics such as 5HT3 antagonists, except in the 160 mg BID cohort. Two pts with a Wnt-related adenomatous polyposis coli (APC)- mutation (small bowel adenocarcinoma and desmoid tumor) showed a partial response. As of the DCO date, 2 pts (who continued on-treatment as of that date) had received over 1.5 y of E7386 treatment. The preliminary PK analysis showed plasma exposure of E7386 generally increased with an increasing dose over the assessed dose range. FGF21 levels in plasma increased following E7386 administration. Conclusions: E7386 120 mg BID was tolerated and determined as the recommended dose for the expansion part. Based on additional analyses of the dose-escalation part of this study, further investigation of safety, preliminary efficacy, PK, and biomarker analyses of E7386 is ongoing using 2 dose levels (100 and 120 mg BID) in the expansion part. Clinical trial information: NCT03833700 .
Background: Development of primary or secondary resistance to anticancer treatments has been a critical challenge since implementation of immune checkpoint inhibitor (ICI) treatments across multiple cancer subtypes. Preclinical studies have indicated that a mechanism of resistance to ICIs, including PD-1/PD-L1 inhibitors, is activation of the Wnt/β-catenin signaling pathway. E7386 is a novel compound that has been shown to modulate this pathway in vivo, by inhibiting the interactions between CREB-binding protein and β-catenin. Preclinical models have also shown that E7386 may be able to eliminate drug-resistant cancer stem cells and resensitize resistant tumors to conventional treatment or therapy with an ICI, such as the PD-1 inhibitor pembrolizumab. There are no expected overlapping clearance, metabolic pathways, nor any known overlapping toxicities between E7386 and pembrolizumab monotherapies. Therefore, this combination may provide a novel anticancer treatment in patients with ICI-resistant tumors. This study aims to determine tolerability and efficacy of E7386 in combination with pembrolizumab in previously treated patients with selected solid tumors. Methods: This open-label, multicenter, phase 1b/2 study (NCT05091346) will assess E7386 + pembrolizumab in patients with certain pretreated advanced solid tumors. Patients with melanoma, colorectal cancer (CRC), or hepatocellular carcinoma (HCC) are eligible. Patients should be ≥ 18 years of age with measurable lesions as assessed by an investigator by RECIST v1.1. In the phase 1b dose escalation, patients (n=6 per dose level; up to n=18 in total) are treated with E7386 orally + pembrolizumab 200 mg IV Q3W (fixed dose). If the initial starting dose of E7386 100 mg BID is considered tolerable (≤1 patient with a dose-limiting toxicity), E7386 may be escalated to 120 mg BID; if not tolerable, E7386 may be reduced to 80 mg BID. Primary objectives for phase 1b are to assess safety and tolerability, as well as to determine the recommended phase 2 dose (RP2D), of E7386 + pembrolizumab. Upon determination of the RP2D, additional patients will be enrolled (approximately 30 patients in each tumor cohort) at this dose to assess safety, tolerability, and efficacy. The primary objective of phase 2 is to assess objective response rate according to RECIST v1.1. Secondary objectives for phases 1b and 2 include efficacy assessments (duration of response, disease control rate, clinical benefit rate) in each tumor cohort, and pharmacokinetics of E7386 when administered in combination with pembrolizumab. Exploratory objectives include assessment of biomarkers, PFS, and OS. Tumors will be assessed by an investigator based on RECIST v1.1, every 6 weeks, and all adverse events (as graded by CTCAE v5.0) will be monitored and recorded. As of January 6, 2022, 2 patients have been enrolled in phase 1b. Citation Format: Takayuki Yoshino, Masafumi Ikeda, Richard S. Finn, Thomas R. Jeffry Evans, Lidong Weng, Kenichi Saito, Kalgi Mody, Toshiyuki Tamai, Costanza Paoletti, Satoru Iwasa. An open-label, multicenter, phase 1b/2 Study of E7386 (Wnt/β-catenin pathway inhibitor) + pembrolizumab in patients with pretreated advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT523.
337 Background: E7389-LF is a liposomal formulation of the microtubule dynamics inhibitor, eribulin. Treatment with E7389-LF plus the programmed cell death 1 inhibitor nivolumab may result in an increased antitumor effect through vascular remodeling. The phase 1b part of the open-label Study 120 assessed dosing and safety of E7389-LF combined with nivolumab in patients (pts) with solid tumors; the phase 2 part assessed efficacy and safety in expansion cohorts, including an esophageal cancer (EGC) cohort. Methods: For the EGC cohort in the phase 2 part of Study 120, pts were required to have unresectable, measurable (by RECIST v1.1) EGC lesion(s) that showed progression during or after first-line chemotherapy with no other systemic chemotherapy. The primary objective of the phase 2 part was to assess objective response rate (ORR), with success defined as Bayesian posterior probability over 85% beyond threshold (20%) for best overall response (ie, 9 responders of planned 32 pts enrolled). Secondary objectives included assessment of safety and progression-free survival (PFS). The recommended phase 2 dosing regimen was previously determined to be E7389-LF 2.1 mg/m2 every 3 weeks (Q3W) plus nivolumab 360 mg Q3W. Tumor assessments were performed by RECIST v1.1 every 6 weeks. All adverse events (AEs) were monitored and recorded. Results: In the EGC cohort, 35 pts were included. Most pts (88.6%) were male, and the median age was 69.0 years (range 47–85). At data cutoff (May 31, 2022), 5 pts (14.3%) were still undergoing treatment. Discontinuations occurred in 30 pts (85.7%)—25 (71.4%) due to disease progression, 4 (11.4%) due to an adverse event, and 1 (2.9%) due to patient preference. ORR with E7389-LF + nivolumab was 22.9% (95% CI 10.4–40.1) and the disease control rate (DCR) was 62.9% (95% CI 44.9–78.5). Median PFS was 2.81 months (95% CI 1.31–4.17) and the 6-month PFS rate was 20.2% (95% CI 8.7–35.0). Median OS was not reached (95% CI 6.54–not estimable), and the 6-month OS rate was 71.4% (95% CI 53.4–83.5). Treatment-related treatment-emergent (TE) AEs of any grade and of grade ≥3 occurred in 94.3% and 80.0% of pts, respectively. The most common treatment-related TEAEs of any grade were neutropenia (65.7%), leukopenia (57.1%), and decreased appetite (45.7%). The most common treatment-related TEAEs of grade ≥3 were neutropenia (54.3%), leukopenia (34.3%), and febrile neutropenia (22.9%). TEAEs led to dose reduction of E7389-LF in 17 pts (48.6%). TEAEs led to withdrawal of either E7389-LF or nivolumab in 5 pts (14.3%): pneumonia (n=2), traumatic hemothorax (n=1), acute kidney injury (n=1), and pneumonitis (n=1). Conclusions: E7389-LF combined with nivolumab showed an ORR of 22.9% in pts with EGC. Despite this modest ORR, the DCR of 62.9% was notable. No new safety signals were observed compared to the known profiles of each monotherapy. Clinical trial information: NCT04078295 .
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