Antitumor Activity In Patients Research Articles

Effect of a novel anti-PD-1-proIL-2 bifunctional fusion protein on potent anti-tumor activity via PD-1 checkpoint inhibition and conditional IL-2R agonism.

e14697 Background: HD IL-2 was approved by FDA for metastatic melanoma (mM) and renal cell carcinoma (mRCC) but the treatment is associated with severe toxicities. PD-1 blockade has improved the overall survival, but only in 20-30% of cancer patients and many of them experience frequent relapses. Interestingly, HD IL-2 therapy displayed durable anti-tumor activity in mM and mRCC patients who progressed on anti-PD-1. Furthermore, combination therapy of IL-2 and pembrolizumab in mRCC has shown durable 70% response rate, while the ORR of monotherapy is 20% and 33% for IL-2 and pembrolizumab, respectively. Thus, combining IL-2 receptor activation and PD-1 blockade may represent a promising strategy in the post PD-1 era to overcome the resistance and improve the clinical efficacy. PTX-912 is a novel bifunctional PD-1-proIL-2v fusion protein designed to simultaneously harness PD-1 blockade and PD-1-cis directed IL-2R agonism conditionally in TME without the peripheral toxicities associated with IL-2. Methods: The biological functions were demonstrated in human PBMC assays. Anti-tumor efficacy and biomarker studies were evaluated in mouse / human PBMC xenograft models. Tox studies were performed in NHP. Results: PTX-912 shows dose-dependent inhibition of PD-1 pathway measured by GM-CSF and IFNgamma production in an MLR assay. Protease activated PTX-912, but not the intact drug, stimulates the phosphorylation of STAT5 of NK and T cells, the proliferation of CD8 T cells as well as the cytokine production in human whole blood. The potency of pSTAT5 by protease activated product is enhanced by > 10 folds on PD-1+ T cells than T cells without PD-1. When tested in mouse tumor models resistant to PD-1 blockade, PTX-912 demonstrated high potency of tumor inhibition at as low as 0.1 mg/kg dose. In contrast, non-targeted proIL-2v at molar equivalent or higher dose showed minimal antitumor effect in either monotherapy or combination with anti-PD-1. Analysis of PTX-912 treated mice showed increased tumor infiltrating CD4+ and CD8+ T cells, including PD-1+Tcf-1+ and PD-1+ IL-18Ra+TIM3- CD8+ T cells, referred to “stem-like” progenitor effector cells and “better” effector cells, respectively. Activation of the IL-2v in PTX-912 was observed in mouse tumor tissues but not in the plasma. In monkey GLP-compliant 4-week repeat-dose toxicity study, PTX-912 demonstrated excellent safety profiles without overt irAEs that are characteristic of IL-2. Conclusions: Our preclinical data demonstrated that PTX-912 effectively stimulated the expansion and reinvigoration of antigen specific T cells in the tumor tissue resulting in strong anti-tumor efficacy while it did not cause significant peripheral toxicity. Phase 1 clinical trial of PD-1-proIL-2v is planned to start in early 2024 to evaluate the safety, pharmacokinetics and anti-tumor activity in patients with advanced solid tumors.

Senaparib as first-line maintenance therapy in advanced ovarian cancer: a randomized phase 3 trial.

Poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors as maintenance therapy after first-line chemotherapy have improved progression-free survival in women with advanced ovarian cancer; however, not all PARP inhibitors can provide benefit for a biomarker-unselected population. Senaparib is a PARP inhibitor that demonstrated antitumor activity in patients with solid tumors, including ovarian cancer, in phase 1 studies. The multicenter, double-blind, phase 3 trial FLAMES randomized (2:1) 404 females with advanced ovarian cancer (International Federation of Gynecology and Obstetrics stage III-IV) and response to first-line platinum-based chemotherapy to senaparib 100 mg (n = 271) or placebo (n = 133) orally once daily for up to 2 years. The primary endpoint was progression-free survival assessed by blinded independent central review. At the prespecified interim analysis, the median progression-free survival was not reached with senaparib and was 13.6 months with placebo (hazard ratio 0.43, 95% confidence interval 0.32-0.58; P < 0.0001). The benefit with senaparib over placebo was consistent in the subgroups defined by BRCA1 and BRCA2 mutation or homologous recombination status. Grade ≥3 treatment-emergent adverse events occurred in 179 (66%) and 27 (20%) patients, respectively. Senaparib significantly improved progression-free survival versus placebo in patients with advanced ovarian cancer after response to first-line platinum-based chemotherapy, irrespective of BRCA1 and BRCA2 mutation status and with consistent benefits observed between homologous recombination subgroups, and was well tolerated. These results support senaparib as a maintenance treatment for patients with advanced ovarian cancer after a response to first-line chemotherapy. ClinicalTrials.gov identifier: NCT04169997 .

Abstract RF01-04: Final results from the phase 2, open-label FOENIX-MBC2 study: efficacy and safety of futibatinib in adult patients with locally advanced/metastatic HR+/HER2− breast cancer harboring high-level FGFR1 gene amplification

Abstract Background: Fibroblast growth factor receptor 1 (FGFR1) gene amplification and overexpression is associated with an adverse prognosis in hormone receptor–positive (HR+)/human epidermal growth factor receptor 2–negative (HER2−) breast cancer and is observed in ~10% of all invasive breast cancers. The phase 2 FOENIX-MBC2 study (NCT04024436) was designed to evaluate the effect of futibatinib, a highly selective and potent irreversible covalent inhibitor of FGFR1–4 (FDA-approved for intrahepatic cholangiocarcinoma), used either alone or in combination with fulvestrant in patients with metastatic breast cancer. Here, we report final efficacy and safety data for the cohort of patients receiving futibatinib plus fulvestrant for HR+/HER2− breast cancer harboring high-level FGFR1 gene amplification. Methods: Patients were eligible if they had disease progression after prior therapy for advanced/metastatic disease, had measurable disease per RECIST v1.1, had an ECOG performance status of 0 or 1, were fulvestrant-naïve, and had previously received 1–2 endocrine-containing therapies, ≤1 chemotherapy regimen, and a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor for advanced cancer (unless ineligible). High-level FGFR1 gene amplification, determined in tumor tissue using next-generation sequencing, fluorescence in situ hybridization (FISH), or similar assays, was defined as FGFR1/centromere 8 ratio ≥5 or FGFR1 copy number ≥10 signals per cell. Local FGFR1 determination results were confirmed in tumor tissue by a central laboratory using FISH. Patients received oral futibatinib 20 mg once daily and standard fulvestrant dosing until disease progression, unacceptable toxicity, or other discontinuation criteria were met. The primary endpoint was the 6-month progression-free survival (PFS) rate. Key secondary endpoints included objective response rate (ORR), PFS, and overall safety. Results: Overall, 22 female patients were enrolled in this cohort. Patients were a median age of 58 years, had received a median of 3 lines of any prior systemic anticancer therapy, and had all received CDK4/6 inhibitor pretreatment. PFS at 6 months was observed in 10 (45.5%) patients (95% CI: 24.4, 67.8) and the median PFS was 7.2 (95% confidence interval [CI]: 2.1, 7.6) months. Four patients had a confirmed partial response (ORR: 18.2%; 95% CI: 5.2, 40.3). The median duration of response was 6.3 (range: 3.3–12.8) months. All patients had ≥1 treatment-related adverse event (TRAE), the most common being hyperphosphatemia (95.5%), alopecia (54.5%), constipation (45.5%), and dry mouth (40.9%). There were 5 (22.7%) patients with a Grade 3 TRAE (no Grade 4 or 5). TRAEs leading to study treatment interruption or reduction were seen in 9 (40.9%) and 15 (68.2%) patients, respectively. There were 2 (9.1%) patients who had TRAEs leading to study treatment discontinuation. No treatment-related serious adverse events were reported. Conclusions: Futibatinib plus fulvestrant showed antitumor activity in patients with advanced HR+/HER2− breast cancer with FGFR1 amplification progressing on prior CDK4/6 inhibitors, with a numerically higher ORR and doubling in PFS relative to historical fulvestrant results in post-CDK4/6 patients. The safety profile was consistent with those of the individual study drugs. Further biomarker work is ongoing. Citation Format: Senthil Damodaran, Fabrice André, Nisha Unni, Marta Ferreira, Karthik Giridhar, Brooke Daniel, Marco Colleoni, Luis Costa, Thomas Bachelot, Ciara O’Brien, Gail Wright, Masashi Shimura, Gareth Tomlinson, Maciej Gil, Nicholas Turner. Final results from the phase 2, open-label FOENIX-MBC2 study: efficacy and safety of futibatinib in adult patients with locally advanced/metastatic HR+/HER2− breast cancer harboring high-level FGFR1 gene amplification [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr RF01-04.

Abstract PO4-04-01: Antitumor activity and safety of sacibertinib (Hemay022) in combination with endocrine therapy in patients with ER and HER2 both positive metastatic breast cancer: A phase Ib study

Abstract Abstract PURPOSE Sacibertinib (Hemay022) is a novel irreversible tyrosine kinase inhibitor (TKI) blocking epidermal growth factor receptor and human epidermal growth factor receptor 2 (HER2). This study aimed to explore the safety and efficacy of sacibertinib plus endocrine therapy in patients with estrogen receptor-positive ( PATIENTS AND METHODS Using a phase 1b 3+3 dose escalation and expansion study design, patients with ER+/HER2+ MBC were treated with sacibertinib (200mg-500mg daily) plus endocrine therapy including exemestane, letrozole, fulvestrant. The safety, pharmacokinetic and clinical efficacy, including objective response rate (ORR), clinical benefit rate (CBR), disease control rate (DCR) and progression-free survival (PFS) were assessed. RESULTS A total of 55 ER+/HER2+ MBC patients pretreated with chemotherapy and anti-HER2 therapy were enrolled in the study between March, 2018 and July, 2021. The incidence of ORR ranged from 17.6% to 42.9%, DCR ranged from 63.0% to 86.8%, CBR ranged from 42.3% to 69.7%, and the overall median PFS was 9.0 (95% CI, 5.5 ~ 11.00) months. In the 400 mg Sacibertinib plus exemestane cohort (N = 18), ORR was 38.9% (7/18), DCR was 72.2%(13/18), CBR was 66.7%(12/18), and median PFS was 8.9 months; In the 500 mg Sacibertinib plus exemestane cohort (N = 12), ORR was 25.0%(3/12), DCR was 100.0%(12/12), CBR was 50.0%(6/12), and median PFS was 9.0 months. The ORR, CBR, and DCR were better in the 400 mg and above dose cohorts than in the 200 mg and 300 mg cohorts. The DCR of the 500 mg combined with exemestane cohort was better than that of the other dose cohorts. Sacibertinib plus endocrine therapy was well-tolerated without dose-limiting toxicities. The most frequent grade 3 adverse events included diarrhoea (9.1%), leucopenia(5.5%), neutropenia (3.6%). One (1.8%) had grade 4 hydropericardium. CONCLUSION Sacibertinib plus endocrine therapy had a favorable safety profile and antitumor activity in patients with ER+/HER2+ MBC, 400-500mg daily showed more efficacy, supporting further assessment in randomized studies. This figure showed response of Sacibertinib plus endocrine therapy in ER+/HER2+ metastatic breast cancer. Citation Format: Hui-Ping Li, Qingyuan Zhang, Ruyan Zhang, Yaxin Liu, Xianjun Hu. Antitumor activity and safety of sacibertinib (Hemay022) in combination with endocrine therapy in patients with ER and HER2 both positive metastatic breast cancer: A phase Ib study [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-04-01.

Abstract PO3-06-11: Undated analyses from a Phase Ib open-label study of Pucotenlimab (HX008) in combination with gemcitabine and cisplatin as first-line treatment of metastatic triple-negative breast cancer

Abstract Background: Gemcitabine plus cisplatin (GP) therapy war preferred in China as the first-line therapy for metastatic triple-negative breast cancer (mTNBC), with a median progression-free survival (PFS) of 7.73 months, and a median overall survival (OS) of 19.37 months [1]. Pucotenlimab (HX008) is a novel humanized IgG4 anti-PD-1 monoclonal antibody with an engineered Fc domain. Preliminary results from the phase 1b trial [2] have shown that HX008 combined with GP has a manageable safety profile and demonstrates promising antitumor activity in patients (pts) with mTNBC. Here, we present the updated results from the long-term survival analysis. Methods: Eligible subjects were those who were treatment-naïve mTNBC patients and had measurable lesion. Participants received HX008 at a dose of 3 mg/kg every 3 weeks in combination with chemotherapy (gemcitabine + cisplatin) for 6 cycles and maintained with HX008 until disease progression or unacceptable toxicity occurred. The primary endpoints included overall response rate (ORR) and safety, and the secondary endpoints included duration of response (DoR), PFS, and OS. Results: Between July 2019 and March 2020, a total of 31 pts were enrolled in this study. The median age of patients was 50 years (range 29–69). By the cut-off date (April 24th, 2023), the median follow-up period was 20.7 m (IQR: 12.2, 25.6). The confirmed ORR was consistent with the previously reported data and remains at 74.2% (95% CI: 55.4%, 88.1%). The median PFS was 9.0 months (95% CI, 7.3, 9.3). The median DoR was 7.3 months (95% CI, 5.0, 9.8). The OS was immature, with the result of 23.1 months (95% CI, 13.4, NE), while the 12-m, 24-m and 36-m OS rate was 77.4% (95%CI: 64.0%, 93.6%), 42.7% (95%CI: 28.0%, 65.3%), and 24.4% (95%CI: 11.3%, 52.7%), respectively. The most common grade 3 or 4 treatment-related adverse events included neutropenia (71.0%), leukopenia (45.2%), anemia (38.7%), and thrombocytopenia (32.3%). There was no treatment-related death and no new safety signals were identified. Conclusion: The combination therapy of HX008 plus GP demonstrates favorable clinical efficacy with a manageable safety profile in pts with mTNBC. The combination therapy led to a longer PFS and OS than GP therapy reported previously, regardless of PD-L1 status. The safety profile was consistent with the known toxic effects of each agent. In this updated analysis, no new safety signals were identified. Clinical trial information: NCT04750382

Abstract PO1-17-09: Real-world clinical outcomes in US patients with brain metastases secondary to HR+/HER2- metastatic breast cancer treated with abemaciclib

Abstract Background: Abemaciclib has demonstrated pharmacologically relevant intracranial concentrations and antitumor activity in patients with brain metastases secondary to HR+/HER2- metastatic breast cancer (MBC). However, clinical data is limited, and further assessments are warranted. This retrospective study describes real-world outcomes following abemaciclib initiation in patients with brain metastases secondary to HR+/HER2- MBC. Methods: Data were accessed from the US nationwide Flatiron Health electronic health records-derived de-identified database from 01/01/2011 to 12/31/2021. This real-world study included adult patients with a diagnosis of HR+/HER2- MBC with brain metastases prior to abemaciclib initiation. Patient and treatment characteristics were summarized using descriptive statistics. Kaplan-Meier methods were used to assess clinical outcomes from abemaciclib initiation: time to treatment discontinuation (TTD), progression-free survival (rwPFS), overall survival (rwOS). Intracranial rw best responses were also reported. Results: This study included 82 patients (one male) diagnosed with MBC and brain metastases prior to abemaciclib initiation and the median follow-up was 12.8 months. At data cut-off, 17 (20.7%) patients remained on abemaciclib therapy. Twenty-three (28%) patients received abemaciclib as the first line of therapy for MBC. Of the 82 patients in the study, 68 (82.9%) patients used concomitant endocrine therapy. Prior to abemaciclib initiation, 25 (30.5%) patients received chemotherapy and 33 (40.2%) patients received a CDK4 and 6 inhibitor. Most patients (67.1%) initiated abemaciclib at a dose of 150 mg twice daily. The median time from diagnosis of brain metastasis to abemaciclib initiation was 2.1 months (interquartile range:1.0, 8.0); 16 (19.5%) did not undergo surgical resection or receive radiation to the brain during this time. Sixty-six (80.5%) patients received brain radiation of which 56.1% received stereotactic radiosurgery (SRS) and 47.0% received whole-brain radiation (WBRT) either alone or in combination with craniotomy/metastasectomy, intrathecal chemotherapy, or surgery. The median TTD for abemaciclib was 7.1 months (95% confidence interval [95% CI]: 4.6, 11.3); most common reasons for discontinuation were disease progression (39.0%) or adverse events (29.3%). The median rwPFS was 9.2 months (95% CI: 6.0, 11.6) and median rwOS was 20.8 months (95% CI: 13.9, 26.0). Of the patients where response data were available (n = 51), rw intracranial clinical benefit rate (CBR; complete response [CR]/partial response [PR]/stable disease [SD] ≥24 weeks of abemaciclib initiation) was 62.7% (Table 1). Conclusion: In this real-world study, most patients with brain metastases secondary to HR+/HER2- MBC who initiated abemaciclib treatment received SRS or WBRT prior to or concurrent with abemaciclib initiation. While the clinical outcomes, rwPFS and intracranial CBR were encouraging, these findings should be interpreted with caution due to the nature of the real-world study design. Table 1. Intracranial Real-World Best Responses Citation Format: Wambui Gathirua-Mwangi, Holly Martin, Dan He, Shen Zheng, Kristin Sheffield, Jincy John, Sarah Rybowski, Priscilla Brastianos. Real-world clinical outcomes in US patients with brain metastases secondary to HR+/HER2- metastatic breast cancer treated with abemaciclib [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-17-09.

Abstract PO2-27-11: Antitumor efficacy and safety of sacibertinib (Hemay022) in combination with endocrine therapy in patients with ER+ and HER2+ metastatic breast cancer: A phase Ib study

Abstract PURPOSE Sacibertinib (Hemay022) is a novel irreversible tyrosine kinase inhibitor (TKI) blocking epidermal growth factor receptor and human epidermal growth factor receptor 2 (HER2). This study aimed to explore the safety and efficacy of sacibertinib plus endocrine therapy in patients with estrogen receptor-positive (ER+) and HER2-positive (HER2+) &amp;gt;metastatic breast cancer (MBC). PATIENTS AND METHODS Using a phase 1b 3+3 dose escalation and expansion study design, patients with ER+/HER2+ MBC were treated with sacibertinib (200mg-500mg daily) plus endocrine therapy including exemestane, letrozole, fulvestrant . The safety, pharmacokinetic (PK) and clinical efficacy, including objective response rate (ORR), clinical benefit rate (CBR), disease control rate (DCR) and progression-free survival (PFS) were assessed. (Clinical Trials.gov identifier: NCT03308201). RESULTS A total of 55 ER+/HER2+ MBC patients pretreated with chemotherapy and anti-HER2 therapy were enrolled in the study between March, 2018 and July, 2021. Fifty-five patients were included in safety analysis and 51 patients were assessed for efficacy analysis. Sacibertinib plus endocrine therapy was well-tolerated without dose-limiting toxicities. The overall median PFS was 9.0 months [95% confidence interval (95% CI), 5.5 ~ 11.0]. The ORR, CBR, and DCR were better in the 400 mg and 500mg dose cohorts than in the 200 mg and 300 mg cohorts. The DCR of the 500 mg combined with the exemestane cohort was better than that of cohorts of other doses. In the 400 mg sacibertinib plus exemestane cohort (N = 18), ORR was 38.9% (7/18) , DCR was 72.2%(13/18), CBR was 66.7%(12/18), and median PFS was 8.9 months (95%CI, 2.7 ~ 16.4 ) ; In the 500 mg sacibertinib plus exemestane cohort (N = 12), ORR was 25.0% (3/12), DCR was 100%(12/12), CBR was 50.0%(6/12), and median PFS was 9.0 months (95%CI, 2.1~NA. Treatment-emergent AEs (TEAEs) were mostly within grades 1–2. The most frequent grade 3 TEAE was diarrhea (9.1%). One (1.8%) had grade 4 abnormal liver function. CONCLUSIONS Sacibertinib plus endocrine therapy had a favorable safety profile and antitumor activity in patients with ER+/HER2+ MBC, 400 -500mg sacibertinib daily showed more efficacy, supporting further assessment in randomized studies. Summary of efficacy data(EAS) NOTE. NA, not available (because cannot be calculated) Treatment-Emergent Adverse Events Occurring in ≥ 10% of Patients in the Safety Population Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; Waterfall plot of best change rate in target-lesion size from baseline Citation Format: Hui-Ping Li, Qingyuan Zhang, Ruyan Zhang, Yaxin Liu, Chang Liu, Xianjun Hu. Antitumor efficacy and safety of sacibertinib (Hemay022) in combination with endocrine therapy in patients with ER+ and HER2+ metastatic breast cancer: A phase Ib study [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-27-11.

Safety and Efficacy of Vicriviroc (MK-7690) in Combination With Pembrolizumab in Patients With Advanced or Metastatic Microsatellite Stable Colorectal Cancer

BackgroundPembrolizumab, a monoclonal antibody against PD-1, has shown limited efficacy in patients with microsatellite stable or mismatch repair proficient (MSS/pMMR) metastatic colorectal cancer (CRC). We evaluated vicriviroc (small-molecule C-C motif chemokine ligand 5 antagonist) plus pembrolizumab in patients with advanced or metastatic MSS/pMMR CRC. Patients and methodsThis open-label, phase 2 trial (NCT03631407) enrolled adults with histologically confirmed, locally advanced, unresectable or metastatic CRC that was MSS per local assessment. All patients had received previous treatment with standard therapies. Patients were randomized 1:1 to vicriviroc 150 mg orally once daily plus pembrolizumab 200 mg intravenously every 3 weeks or vicriviroc 250 mg orally once daily plus pembrolizumab 200 mg intravenously every 3 weeks for up to 35 cycles (2 years). Primary endpoints were the objective response rate (ORR) as assessed by the investigator per RECIST v1.1, dose-limiting toxicities (DLTs), adverse events (AEs), and discontinuations due to AEs. ResultsForty patients were enrolled and treated. ORR was 5% (95% CI, 0.1%-24.9%) in both treatment groups. There were no complete responses; 1 patient in each treatment group experienced a partial response. No patient in the vicriviroc 150 mg plus pembrolizumab group experienced a DLT. Two patients in the vicriviroc 250 mg plus pembrolizumab group experienced DLTs (1 grade 4 encephalopathy and 1 grade 4 pneumonitis). ConclusionThe combination of vicriviroc at doses of 150 or 250 mg plus pembrolizumab 200 mg showed limited antitumor activity in patients with advanced or metastatic MSS/pMMR CRC. Toxicity with the combination was manageable.

Varlitinib and Paclitaxel for EGFR/HER2 Co-Expressing Advanced Gastric Cancer: a Multicenter Phase Ib/II Study (K-MASTER-13).

Varlitinib is a pan-human epidermal growth (HER) inhibitor targeting epidermal growth factor receptor (EGFR), HER2, and HER4. We present a phase Ib/II study of a combination of varlitinib and weekly paclitaxel as a second-line treatment for patients with EGFR/HER2 co-expressing advanced gastric cancer (AGC). Patients whose tumors with EGFR and HER2 overexpression by immunohistochemistry (IHC) (≥1+) were enrolled. Varlitinib and paclitaxel were investigated every 4 weeks. After determining the recommended phase II dose (RP2D) in phase Ib, a phase II study was conducted to evaluate the antitumor activity. RP2D was treated with a combination of varlitinib (300 mg twice daily) and paclitaxel. Among 27 patients treated with RP2D, the median PFS and overall survival (OS) were 3.3 months and 7.9 months, respectively, with a median follow-up of 15.7 months. Among 16 patients with measurable disease, the objective response rate (ORR) and disease control rate were 31% and 88%, respectively. Patients with strong HER2 expression (n=8) had a higher ORR and longer OS, whereas those with strong EGFR expression (n=3) had poorer outcomes. The most common adverse events (AEs) of any grade were neutropenia (52%), diarrhea (27%), AST/ALT elevation (22%), and nausea (19%). No treatment-related deaths or unexpected AEs resulting from treatment cessation were observed in patients with RP2D. A combination of varlitinib and paclitaxel displayed manageable toxicity and modest antitumor activity in patients with EGFR/HER2 co-expressing AGC who progressed after first-line chemotherapy.

Anti-EGFR Rechallenge in Patients With Refractory ctDNA RAS/BRAF wt Metastatic Colorectal Cancer

The available evidence regarding anti-epidermal growth factor receptor (EGFR) inhibitor rechallenge in patients with refractory circulating tumor DNA (ctDNA) RAS/BRAF wild-type (wt) metastatic colorectal cancer (mCRC) is derived from small retrospective and prospective studies. To evaluate the efficacy of anti-EGFR rechallenge in patients with refractory ctDNA RAS/BRAF wt mCRC. This nonrandomized controlled trial used a pooled analysis of individual patient data from patients with RAS/BRAF wt ctDNA mCRC enrolled in 4 Italian trials (CAVE, VELO, CRICKET, and CHRONOS) and treated with anti-EGFR rechallenge between 2015 and 2022 (median [IQR] follow-up, 28.1 [25.8-35.0] months). Patients received anti-EGFR rechallenge therapy, including cetuximab plus avelumab, trifluridine-tipiracil plus panitumumab, irinotecan plus cetuximab, or panitumumab monotherapy. Overall survival (OS), progression-free survival (PFS), overall response rate (ORR), and disease control rate (DCR) were calculated. Exploratory subgroup analysis evaluating several clinical variables was performed. Safety was reported. Overall, 114 patients with RAS/BRAF wt ctDNA mCRC (median [IQR] age, 61 [29-88] years; 66 men [57.9%]) who received anti-EGFR rechallenge as experimental therapy (48 received cetuximab plus avelumab, 26 received trifluridine-tipiracil plus panitumumab, 13 received irinotecan plus cetuximab, and 27 received panitumumab monotherapy) were included in the current analysis. Eighty-three patients (72.8%) had received 2 previous lines of therapy, and 31 patients (27.2%) had received 3 or more previous lines of therapy. The ORR was 17.5% (20 patients), and the DCR was 72.3% (82 patients). The median PFS was 4.0 months (95% CI, 3.2-4.7 months), and the median OS was 13.1 months (95% CI, 9.5-16.7 months). The subgroup of patients without liver involvement had better clinical outcomes. The median PFS was 5.7 months (95% CI, 4.8-6.7 months) in patients without liver metastasis compared with 3.6 months (95% CI, 3.3-3.9 months) in patients with liver metastasis (hazard ratio, 0.56; 95% CI, 0.37-0.83; P = .004). The median OS was 17.7 months (95% CI, 13-22.4 months) in patients without liver metastasis compared with 11.5 months (95% CI, 9.3-13.9 months) in patients with liver metastasis (hazard ratio, 0.63; 95% CI, 0.41-0.97; P = .04). Treatments showed manageable toxic effects. These findings suggest that anti-EGFR rechallenge therapy has promising antitumor activity in patients with refractory ctDNA RAS/BRAF wt mCRC. Within the limitation of a subgroup analysis, the absence of liver metastases was associated with significant improved survival. ClinicalTrials.gov Identifiers: NCT02296203; NCT04561336; NCT03227926; NCT05468892.

Abstract CT097: IMM27M, a humanized Fc-engineered anti CTLA-4 antibody, in patients with advanced solid tumors: A phase I dose-escalation study

Abstract Background: IMM27M is a humanized Fc-engineered IgG1 CTLA-4 monoclonal antibody with enhanced ADCC. In pre-clinical models, IMM27M could enhance immune responses and promote Treg depletion. The pre-clinical results showed IMM27M induced a significantly stronger anti-tumor activity than ipilimumab and resulted in complete tumor remission even at a low dose. Methods: This study is an open-label, multi-center, phase I dose-escalation study to evaluate the safety, tolerability, maximum tolerated dose/recommended dose for expansion, PK and anti-tumor activity in patients with advanced solid tumors. The study was designed with an accelerated titration followed by a standard 3+3 design. IMM27M (0.1, 0.3, 1.0, 2.0, 3.0, 5.0, 7.5, 10.0 mg/kg) was administered as monotherapy Q3W. Results: As of 3 Nov 2023, the dose has been escalated to 7.5 mg/kg. 25 patients (20 females, 5 males) were enrolled and treated (1 at 0.1 mg/kg, 3 at 0.3 mg/kg, 3 at 1.0 mg/kg, 4 at 2.0 mg/kg, 4 at 3.0 mg/kg, 7 at 5.0 mg/kg, 3 at 7.5 mg/kg), including 13 patients with breast cancer (10 HR+ mBC), 4 patients with melanoma, 3 patients with RCC, each 1 patient with HCC, NSCLC and ovarian cancer, respectively. Median age was 51 years (range 31-72). 92.0% of the patients previously received ≥ 2 lines of systemic therapies and 52.0% received anti PD-1/PD-L1 treatment. Treatment-related adverse events (TRAEs) occurred in 24 patients (96.0%) by the data cutoff. Most TRAEs were grade 1 or 2. The most common TRAEs (≥ 30%) of all grades were anaemia (56.0%), lymphocyte count decreased (48.0%), aspartate aminotransferase increased (40.0%), hypoalbuminaemia (40.0%), decreased appetite (40.0%). Grade ≥3 TRAEs occurred in 11 patients (44.0%). Grade ≥3 TRAEs (≥10%) were lymphocyte count decreased (16.0%) and anaemia (12.0%). Treatment related SAE occurred in 8 patients (32.0%). No DLT was observed. One TRAE (Grade 3 immune related enteritis) led to treatment discontinuation. No TEAE leading to death was reported. Recommended Phase 2 Dose (RP2D) was 5 mg/kg. In 25 response evaluable patients, 2 patients had confirmed PR: 1 patient with mBC (HR+/HER2+, IO naïve, 6L previous treatments) at 3.0 mg/kg and response durable for 7 months; 1 patient with mBC (HR+/HER-, IO naïve, 4L previous treatments) at 5.0 mg/kg and response durable for 3 months by data cut-off. In addition, 9 patients had BOR SD and 4 out of 9 were previously treated with IO. Another 2 out of 8 patients with HR+ mBC had BOR SD with over 10% decreased tumor burden. IMM27M in vivo exposure increased with dose. The T1/2 mean value range in the 3-7.5mg/kg dose group was 8.2-11.5 days. Conclusions: IMM27M monotherapy in general was well-tolerated at the dose levels evaluated and preliminarily single agent activity was seen in patients with heavily pretreated advanced solid tumors. The dose escalation study of IMM27M in advanced solid tumors is ongoing.Clinical trial information: NCT05235438. Citation Format: Shusen Wang, Qiufan Zheng, Quanli Gao, Qingyuan Zhang, Shikai Wu, Zhihua Li, Enxiao Li, Qiying Lu, Frank Gan, Wenzhi Tian. IMM27M, a humanized Fc-engineered anti CTLA-4 antibody, in patients with advanced solid tumors: A phase I dose-escalation study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT097.

Abstract CT133: A phase 1b multicenter study of anti-TIM3 (S095018/Sym023) in combination with anti-PD1 (Sym021) in patients with advanced/metastatic recurrent biliary tract cancer

Abstract Background: TIM3 is an inhibitory immunoreceptor linked to decreased activity of immune cells in the tumor microenvironment. S095018 is a human anti-TIM3 IgG2 antibody which blocks binding of phosphatidyl serine to TIM3 promoting the stimulation of T-cells, dendritic cells (DCs) and macrophages. Sym021 is a humanized IgG1 antibody that inhibits binding of PD-1 with its ligands PD-L1 and PD-L2. Preclinical data demonstrated that Sym021 combined with S095018 results in enhanced immunostimulatory antitumor activity. Methods: S095018 in combination with Sym021 was tested in patients with advanced/metastatic biliary tract cancer whose disease progressed under treatment with at least one line of systemic therapy and who had not received prior treatment with PD-1/-L1 inhibitors (NCT04641871). The dose/schedule of Sym021 and S095018 was 3mg/kg IV Q2W and 10mg/kg IV Q2W, respectively. Primary endpoints included overall response rate (ORR) using RECIST v1.1 and incidence/severity of adverse events. Key secondary endpoints included PK parameters, disease control rate (DCR), progression free survival (PFS) and overall survival (OS). Results As of 31-Oct-2023, 35 patients with stage IV biliary tract cancer (34 cholangiocarcinoma, 1 gallbladder adenocarcinoma) received S095018 in combination with Sym021. All patients were naïve to prior immune checkpoint inhibitor treatment. Twenty-two patients (62.9%) had received 1 prior antineoplastic systemic treatment for advanced/metastatic disease, 34.3% had received ≥2 prior treatments for advanced/metastatic disease. Overall, 34 patients (97.1%) discontinued treatment, 85.7% due to disease progression. Best overall response was 2 PR (5.7%), 11 SD (31.4%), 18 PD (51.4%) and 4 not evaluable. Median PFS and OS were 1.9 months (90% CI 1.8-3.7) and 13.4 months (90% CI 8.2-27.1) respectively. Disease control rate (CR+PR+SD) with SD≥16 weeks, ≥24 weeks and ≥12 months was 28.6%, 22.9% and 8.6% respectively. Treatment emergent adverse events of any grade occurring in &amp;gt;5% of patients included fatigue, pruritus, alkaline phosphatase increase, amylase increase, IRR (each 8.6%) and hypothyroidism, hyperthyroidism, AST increase, lipase increase and myalgia (each 5.7%). Exploratory biomarker analyses in paired tumor biopsies (N=18) showed an intratumoral increase in CD8 T-cell density, as well as upregulation of gene signatures related to IFNg signaling, antigen presentation, T-cell activation and cytotoxicity upon treatment. Baseline tumor biopsies from the two patients who achieved confirmed PR showed high PD-L1 expression. Conclusions: S095018 in combination with Sym021 exhibited antitumor activity in patients with advanced/metastatic recurrent biliary tract cancer who had not received prior treatment with PD-1/-L1 inhibitors. The combination was well tolerated without new safety signals. Further biomarker analysis is ongoing. Citation Format: Francois Ghiringhelli, Richard Kim, Teresa Macarulla, Irene Moreno, Albiruni Razak, Jordi Rodon, Chih-Yi Liao, Thomas Marron, Judith Raimbourg, Helene Kaplon, Julia Geromini, Najah Harouki, Christelle Rodrigues, Pauline Darcel, Niels Jorgen Skartved, Rikke Hald, Daleen Lopez-Ravnborg, Peng He, Xenophon Ianopoulos, Vasileios Askoxylakis, Nehal J. Lakhani, Sarah Davis, Amit Mahipal. A phase 1b multicenter study of anti-TIM3 (S095018/Sym023) in combination with anti-PD1 (Sym021) in patients with advanced/metastatic recurrent biliary tract cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT133.

Abstract CT104: Results from a phase 1 study of the anti-immunoglobulin-like transcript 4 (ILT4) monoclonal antibody MK-4830 plus pembrolizumab in patients with previously treated advanced solid tumors

Abstract Background: In the dose escalation phase of a first-in-human phase 1 study (NCT03564691), the anti-ILT4 IgG4 monoclonal antibody MK-4830 + pembrolizumab (pembro) had a manageable safety profile and demonstrated promising antitumor activity in patients (pts) with previously treated advanced solid tumors, including those with PD on immunotherapy. Here, we present safety, efficacy, and biomarker analyses for MK-4830 + pembro for the previously treated pancreatic adenocarcinoma, glioblastoma, head and neck squamous cell carcinoma (HNSCC), and gastric cancer cohorts of the expansion phase. Methods: Eligible pts were aged ≥18 y with metastatic pancreatic adenocarcinoma and 1-3 lines of prior therapy (cohort A), unresectable glioblastoma and 1 prior line of therapy (cohort B), recurrent or metastatic HNSCC that progressed on a platinum-based chemotherapy and PD-(L)1 inhibitor (cohort C), or recurrent or metastatic gastric or gastroesophageal junction adenocarcinoma that progressed on ≥2 prior chemotherapy regimens (cohort I). Pts in cohorts A, B, and I had not previously received a PD-(L)1 inhibitor. All pts received MK-4830 800 mg + pembro 200 mg Q3W for 35 cycles or until PD, unacceptable toxicity, or study withdrawal. Primary objectives were to evaluate safety and ORR per RECIST v1.1 (cohorts A, C, and I) or Response Assessment in Neuro-Oncology (RANO) criteria (cohort B) by investigator assessment. Exploratory objectives included evaluating DOR and PFS per RECIST v1.1 (cohorts A, C, and I) or RANO criteria (cohort B) by investigator assessment. Results: At data cut-off (September 27, 2023), 33 pts were enrolled and received treatment in cohort A, 20 pts in cohort B, 35 pts in cohort C, and 35 pts in cohort I. Median follow-up duration was 38.4 mo (range, 35.5-39.9) in cohort A, 34.1 mo (32.3-36.2) in cohort B, 37.5 mo (33.4-42.1) in cohort C, and 29.5 mo (22.3-36.4) in cohort I. Treatment-related adverse events (TRAEs) occurred in 15 pts (45%) in cohort A, 13 pts (65%) in cohort B, 19 pts (54%) in cohort C, and 16 pts (46%) in cohort I; grade 3 or 4 TRAEs occurred in 3 pts (9%), 0 pts, 2 pts (6%), and 4 pts (11%), respectively. No deaths due to TRAEs occurred. ORR was 6% (95% CI, 1-20) in cohort A, 5% (0-25) in cohort B, 0% (0-10) in cohort C, and 20% (8-37) in cohort I. Median DOR was 14.3 mo (range, 14.0-14.7) in cohort A, 7.4 mo (7.4-7.4) in cohort B, and 9.6 mo (3.0-27.6+) in cohort I. Median PFS was 1.9 mo (95% CI, 1.6-2.0) in cohort A, 1.2 mo (1.1-1.4) in cohort B, 2.2 mo (1.9-4.1) in cohort C, and 1.4 mo (1.3-3.0) in cohort I. Conclusions: In pts with select previously treated advanced or metastatic solid tumors, MK-4830 + pembro had a manageable AE profile but no significant antitumor activity beyond that historically observed with pembro monotherapy. Other treatment options must be explored for these difficult-to-treat tumors. Citation Format: Lillian L. Siu, Marta Gil-Martin, Byoung Chul Cho, Ruth Perets, John Hilton, Ravit Geva, Iwona Lugowska, Martin Gutierrez, Marcelo Bonomi, Rafal Dziadziuszko, Drew Rasco, Eytan Ben-Ami, Cristina P. Rodriguez, Shabana Siddiqi, Nicole Myer, Leah Suttner, Douglas Wilson, Ombololaji O. Akala, Maria de Miguel. Results from a phase 1 study of the anti-immunoglobulin-like transcript 4 (ILT4) monoclonal antibody MK-4830 plus pembrolizumab in patients with previously treated advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT104.

SEAMARK: phase II study of first-line encorafenib and cetuximab plus pembrolizumab for MSI-H/dMMR BRAFV600E-mutant mCRC.

Patients with both BRAF V600E mutations and microsatellite instability-high (MSI-H)/mismatch repair-deficient (dMMR) metastatic colorectal cancer (mCRC) have poor prognosis. Currently, there are no specifically targeted first-line treatment options indicated for patients with mCRC whose tumors harbor both molecular aberrations. Pembrolizumab is a checkpoint inhibitor approved for the treatment of MSI-H/dMMR mCRC, and the BRAF inhibitor encorafenib, in combination with cetuximab, is approved for previously treated BRAF V600E-mutant mCRC. Combination of pembrolizumab with encorafenib and cetuximab may synergistically enhance antitumor activity in patients with BRAF V600E-mutant, MSI-H/dMMR mCRC. SEAMARK is a randomized phase II study comparing the efficacy of the combination of pembrolizumab with encorafenib and cetuximab versus pembrolizumab alone in patients with previously untreated BRAF V600E-mutant, MSI-H/dMMR mCRC.

Updated Efficacy and Safety of Lorlatinib in a Phase 2 Study in Chinese Patients With Previously Treated Advanced ALK‐Positive Non‐small Cell Lung Cancer

ObjectivesLorlatinib, a brain-penetrant, third-generation anaplastic lymphoma kinase (ALK) inhibitor, demonstrated robust overall and intracranial antitumor activity in patients with advanced ALK-positive non-small cell lung cancer (NSCLC) previously treated with an ALK inhibitor in a global phase 1/2 study (NCT01970865) and a multicenter phase 2 study conducted in China (NCT03909971). We report updated 3-year follow-up data from the phase 2 study. Materials and MethodsChinese patients with locally advanced or metastatic ALK-positive NSCLC that progressed after crizotinib as the only prior ALK inhibitor (cohort 1) or after 1 non-crizotinib ALK inhibitor (cohort 2), were enrolled in the study. All patients received lorlatinib 100 mg once daily. ResultsAt data cutoff, of 109 enrolled patients, the median duration of follow-up for progression-free survival (PFS) was 35.8 months in cohort 1 (n = 67) and 33.1 months in cohort 2 (n = 42). Median PFS (95% CI) per independent central review was 26.3 months (16.6-35.9) and 5.6 months (2.9-12.4), respectively. The median duration of follow-up for overall survival (OS) was 36.4 months and 37.5 months, respectively. Median OS (95% CI) was not reached (NR; NR-NR) and 21.9 months (11.9-NR), respectively. Median intracranial time to progression (95% CI) was NR (NR-NR) and NR (9.7 months-NR), respectively. No new safety signals emerged with long-term treatment. ConclusionThe long-term data confirm robust overall and intracranial clinical activity of lorlatinib, with no new safety signals emerging. These results support using lorlatinib in Chinese patients with previously treated ALK-positive NSCLC with or without brain metastases.ClinicalTrials.gov NCT03909971.

Abstract 49: LYL119, an investigational ROR1-targeted CAR T-cell product incorporating four novel reprogramming technologies designed for effective cell therapy for solid tumors

Abstract Effective solid tumor cell therapy requires new strategies to improve T-cell activation, persistence, and durable function. We developed four complementary T-cell reprogramming technologies to enhance chimeric antigen receptor (CAR) T-cell therapy in solid tumors: 1) overexpression of the activator protein 1 (AP-1) family transcription factor c-Jun to delay T-cell exhaustion and improve antitumor activity; 2) nuclear receptor subfamily 4A member 3 (NR4A3) gene knockout (KO) to further delay exhaustion and enhance functionality; 3) Epi-RTM manufacturing protocols to preserve stem-like characteristics; and 4) Stim-RTM technology, a novel activating reagent to improve product potency compared with standard reagents. LYL119 is an investigational ROR1-targeted CAR T-cell product that combines these technologies to create potent and durable CAR T cells. Healthy or NSCLC patient donor T cells were manufactured with the Epi-R protocols, activated with Stim-R or a standard reagent, and transduced with a vector encoding a ROR1 CAR and c-Jun. The NR4A3 gene or a control gene was edited using SpyFiTM Cas9 nuclease (Aldevron®). Cytotoxicity, cytokine production, phenotype, and single-cell transcriptomic and epigenetic profiles were evaluated in vitro after antigen restimulation assays designed to promote exhaustion. CAR T cell activity was evaluated in vivo using a ROR1+ NSCLC xenograft mouse model. Research and clinical scale LYL119 products achieved ~90% genome editing efficiency at the NR4A3 target gene resulting in a 13-fold protein reduction compared to non-edited CAR T cells. LYL119 exhibited superior cytotoxicity and cytokine production upon antigen restimulation across 7 different ROR1+ solid tumor cell lines compared to CAR T cells that lacked one or more reprogramming technologies. After repeated rounds of tumor cell killing, LYL119 displayed reduced surface expression of exhaustion-related receptors (e.g. TIM-3) and higher expression of stemness-related markers (e.g. CD127) compared to non-edited CAR T cells. Furthermore, transcriptomic analysis revealed global downregulation of exhaustion-related gene signatures and retention of unique cell subsets characterized by upregulation of memory and effector-associated gene signatures. LYL119 exhibited robust antitumor efficacy in vivo across a 10-fold dose range, including a very low dose of 1 × 105 CAR T cells. Lastly, LYL119 derived from NSCLC patient donor T cells also demonstrated enhanced cytotoxicity in vitro compared to control CAR T cells. These nonclinical data suggest LYL119, which combines c-Jun overexpression, NR4A3 KO, Epi-R protocols, and Stim-R technology, can limit exhaustion, maintain stem-like features, and has the potential to provide effective and durable CAR T-cell antitumor activity in patients with ROR1+ solid tumors. Citation Format: Viola C. Lam, Aileen Li, Meritxell Galindo Casas, Jessica Barragan, Christina Cheung, Jessica Briones, Esha Afreen, Grant Vavra, Jia Lu, Purnima Sundar, Rowena Martinez, Candace Sims, Shobha Potluri, Omar Ali, Alexander S. Cheung, Rachel C. Lynn. LYL119, an investigational ROR1-targeted CAR T-cell product incorporating four novel reprogramming technologies designed for effective cell therapy for solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 49.

First-in-human phase I study of BEBT-109 in previously treated EGFR exon 20 insertion-mutated advanced non-small cell lung cancer

BEBT-109 is an oral pan-mutant-selective inhibitor of epidermal growth factor receptor (EGFR) that demonstrated promising antitumor potency in preclinical models. This first-in-human study was a single-arm, open-label, two-stage study. Phase Ia dose-escalation study evaluated the safety and pharmacokinetics of BEBT-109 in 11 patients with EGFR T790M-mutated advanced non-small cell lung cancer (aNSCLC). Phase Ib dose-expansion study evaluated the safety and efficacy of BEBT-109 in 18 patients with EGFR exon 20 insertion (ex20ins)-mutated treatment-refractory aNSCLC. The primary outcomes were adverse events and antitumor activity. Clinical trial registration number CTR20192575. The phase Ia study demonstrated no dose-limiting toxicity, no observation of the maximum tolerated dose, and no new safety signals with BEBT-109 in the dose range of 20-180mg/d, suggesting that BEBT-109 had an acceptable safety profile among patients with EGFR T790M-mutated aNSCLC. Plasma pharmacokinetics of BEBT-109 showed a dose-proportional increase in the area under the curve and maximal concentration, with no significant drug accumulation. The dose-expansion study demonstrated that BEBT-109 treatment was tolerable across the three dose levels. The three most common treatment-related adverse events were diarrhea (100%; 22.2% ≥Grade 3), rash (66.7%; 5.6% ≥Grade 3), and anemia (61.1%; 0% ≥Grade 3). The objective response rate was 44.4% (8 of 18). Median progression-free survival was 8.0months (95% confidence intervals, 1.33-14.67). Preliminary findings showed that BEBT-109 had an acceptable safety profile and favorable antitumor activity in patients with refractory EGFR ex20ins-mutated aNSCLC. National Natural Science Foundation of China.

Abstract 6069: Discovery and preclinical development of orally bioavailable potent BTK degrader, and its early clinical development for the treatment of relapsed and refractory B-cell malignancies

Abstract Background : Bruton tyrosine kinase (BTK) is an important signaling hub that activates the B-cell receptor (BCR) signaling cascade, which is critical for growth and survival of B-cell lymphoma or leukemia. BTK inhibitors have shown anti-tumor activity in patients with B-NHL. However, nearly half of the patients on current BTK inhibitors discontinue the treatment due to adverse effects and/or mutation-induced drug resistance. A degrader is a heterobifunctional chemical compound aimed at eliminating disease-causing proteins, rather than simply inhibiting proteins’ enzymatic function, through the ubiquitin-proteasome system (UPS)-mediated protein degradation. This approach offers a unique solution for addressing relapse or refractory disease by removing overexpressed and mutated proteins, unlike traditional inhibitors. We thus designed UBX-382, a degrader targeting BTK. Results : UBX-382 showed superior degradation activity for both wild-type (WT) and mutant BTK proteins in a single-digit nanomolar range of half-maximal degradation concentration when compared to the competing degrader programs in diffuse large B-cell lymphoma cell line. UBX-382 effectively addressed 7 out of 8 previously reported resistant BTK mutants in in vitro experiments and outperformed ibrutinib, ARQ-531, and MT-802 in inhibiting tumor growth in murine xenograft models harboring WT or C481S mutant BTK-expressing TMD-8 cells. Remarkably, oral dosing of UBX-382 for &amp;lt;2 weeks led to complete tumor regression in 3 and 10 mg/kg groups in murine xenograft models. Following this, further optimization was carried out for potency and PK profile. We nominated the candidate for IND filing and are planning a phase 1 clinical trial. For the first-in-human, open-label, multicenter, phase 1 study, patients in part 1 (dose escalation with BOIN design) had R/R B-cell malignancies and had received at least 2 prior therapies. The candidate will be administered orally at 5 mg once daily followed by 2 days, for a 7-day schedule over 28-day cycles. Part 2 (dose expansion) consisted of disease-specific cohorts, including CLL/SLL, DLBCL, MCL, FL, MZL, and WM. The primary endpoints were safety and tolerability, along with the definition of the maximum tolerated dose. Secondary endpoints included pharmacokinetics/pharmacodynamics and preliminary efficacy. Conclusions : We have discovered potent BTK degrader exhibiting excellent anti-tumor activity in vitro and in vivo. In pre-clinical safety studies, the candidate of UBX demonstrated an acceptable safety profile. The candidate of UBX is currently preparing phase 1 clinical trials for hematological malignancies. Citation Format: Song Hee Lee, Sun-Mi Yoo, Ye Seul Lim, Han Wool Kim, Je Ho Ryu, Jong Hwan Lim. Discovery and preclinical development of orally bioavailable potent BTK degrader, and its early clinical development for the treatment of relapsed and refractory B-cell malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6069.

Abstract 7632: Final survival outcomes and post-hoc tumor gene expression pathway analyses of complete responders from a phase Ib clinical trial of HSP90 inhibitor onalespib and paclitaxel in patients with advanced triple-negative breast cancer

Abstract Background: Heat shock protein 90 (HSP90) is a molecular chaperone required for stabilization of client proteins over-activated in triple-negative breast cancer (TNBC). Over-expression of HSP90 client proteins has been implicated in paclitaxel resistance, therefore, it was hypothesized that the potent HSP90 inhibitor onalespib could improve paclitaxel efficacy. As TNBCs are a heterogenous population of tumors, it is important to establish biomarkers of response to this treatment combination. Methods: Patients with TNBC were treated with intravenous (IV) paclitaxel and IV onalespib at doses ranging from 120 mg/m2 to 260 mg/m2 on days 1, 8, and 15 of a 28-day cycle utilizing a standard 3+3 design. The primary objectives were to determine dose-limiting toxicities and maximum tolerated dose. Secondary objectives included determination of overall response rate (ORR), duration of response (DOR), and progression-free survival (PFS). Retrospectively, archival tumor tissue was obtained from study patients and processed for RNA expression analysis by NanoString nCounter platform with the Breast Cancer 360 panel. Post-hoc gene expression analysis was performed through Qiagen Ingenuity Pathway Analysis (IPA). Linear models were employed to detect differential expression between conditions while considering cartridge effect. Results: 31 patients were enrolled in this study, of which 90% received prior taxane therapy. The established recommended phase II dose was 260 mg/m2 onalespib when given with 80 mg/m2 paclitaxel. ORR was 20%, median DOR was 5.6 months. Three patients achieved complete responses (CR), all of whom had received prior taxane therapy. Nanostring profiling analysis revealed that patients who had a CR to treatment expressed higher levels of several breast cancer-associated genes also known to be dependent upon HSP90 activity compared to patients with progressive disease (PD) as their best treatment response. These genes include FGFR4, JAK2, PIK3R1, TGFB3, and TGFBR2 (all p&amp;lt;0.05). Tumor genes overexpressed in patients with PD versus CR included IRF6, MMP7, and KRT17 (all p&amp;lt;0.01). Additionally, IPA showed patients with CR to have substantial upregulation of PD-1, PD-L1, CTLA-4, p53, HER2, and cyclin/cell cycle regulatory signaling pathways compared to patients with PD (all p&amp;lt;0.01). Conclusions: Combination treatment with onalespib and paclitaxel had an acceptable toxicity profile and showed anti-tumor activity in patients with advanced TNBC. Gene expression analysis of patient tumor samples suggest that TNBCs with greater activation of immune checkpoint pathways and those with proteins dependent on HSP90 activity, including p53 and HER2, may be more susceptible to HSP90 inhibition. ClinicalTrials.gov study identification: NCT02474173 Citation Format: Dionisia Marie Quiroga, Himanshu Savardekar, Emily Schwarz, Nicole O. Williams, Courtney Johnson, Adam Brufsky, Mara Chambers, Saveri Bhattacharya, Maria Patterson, Sagar D. Sardesai, Daniel Stover, Maryam Lustberg, Anne Noonan, Mathew Cherian, Darlene M. Bystry, Kasey Hill, Min Chen, Mitch A. Phelps, Julie Stephens, Lianbo Yu, Bhuvaneswari Ramaswamy, Robert Wesolowski, William E. Carson. Final survival outcomes and post-hoc tumor gene expression pathway analyses of complete responders from a phase Ib clinical trial of HSP90 inhibitor onalespib and paclitaxel in patients with advanced triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7632.

Abstract 2673: Copper chelation overcomes the immunosuppressive neuroblastoma microenvironment to potentiate anti-GD2 antibody therapy

Abstract Neuroblastoma is the most frequent extra-cranial pediatric cancer with high-risk disease possessing a dismal five-year survival rate &amp;lt;50%. Antibody-based therapies targeting the surface disialoganglioside GD2 have shown promising anti-tumor activity in patients however efficacy is strongly hampered by immunosuppressive mechanisms present in the tumor microenvironment. Neuroblastomas typically feature low mutational burdens, limited major histocompatibility complex class I expression, increased immune checkpoint markers, sparse immune infiltration, and soluble mediators which drastically limit anti-tumor immunity. Given the emerging link between elevated copper levels and tumoral immune evasion, we explored copper chelation as a therapeutic strategy using the agents tetraethylenepentamine (TEPA) and the clinically approved analogue triethylenetetramine (TETA). Using the immunocompetent TH-MYCN model, we performed single-cell RNA sequencing supported by OPAL multiplex immunohistochemistry and cytokine profiling of resected tumors to assess cellular and molecular changes occurring after one week of TEPA treatment. Therapy was observed to successfully deplete intratumoral copper and reinvigorate anti-tumor immunity with increased infiltration and activity of pro-inflammatory immune cells, and was specifically found to induce egress and N1-polarisation of neutrophils. Further mechanistic studies in vitro revealed the sequestration of copper by neuroblastoma cells attenuated neutrophil function, which could be successfully reversed upon TEPA treatment. Findings propose a novel mechanism of immune evasion, highlighting copper chelation as a therapeutic strategy to counteract immunosuppression. Using the TH-MYCN model, TEPA was employed as a priming agent to effectively potentiate anti-GD2 antibody therapy and achieve durable tumor control. Importantly, this was associated with increased Fc-receptor-bearing natural killer and myeloid cells, which elicit tumor clearance via antibody-dependent cellular cytotoxicity. Currently indicated for the treatment of copper overload disorder Wilson’s disease, TETA was evaluated for potential repurposing as a novel immunomodulatory agent. Using the syngeneic NXS2 model, TETA exhibited an exceptional safety profile and combination therapy achieved durable tumor control with no relapses occurring after treatment cessation. This result was similarly associated with the infiltration of pro-inflammatory immune cells, including N1 neutrophils. Collectively, this study credentials copper chelation as a non-toxic strategy to disrupt the immunosuppressive tumor microenvironment and reinvigorate anti-tumour immunity. Findings provide crucial translational evidence for repurposing TETA to potentiate anti-GD2 antibody therapy and improve neuroblastoma patient responses. Citation Format: Jourdin R. Rouaen, Antonella Salerno, Fabio Luciani, Jayne Murray, Tyler Shai-Hee, Nicodemus Tedla, Michelle Haber, Toby N. Trahair, Orazio Vittorio. Copper chelation overcomes the immunosuppressive neuroblastoma microenvironment to potentiate anti-GD2 antibody therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2673.