Preliminary Antitumor Activity Research Articles

Results of a Phase Ib Study Investigating Durvalumab in Combination with Eribulin in Patients with HER2-Negative Metastatic Breast Cancer and Recurrent Ovarian Cancer

Introduction: The release of tumor-associated antigens with cytotoxic chemotherapy treatment may enhance the response to immune checkpoint blockade. Eribulin is a microtubule inhibitor with proven overall survival (OS) benefit in metastatic breast cancer (MBC), which may also enhance intratumoral vascular remodeling. Durvalumab, a humanized monoclonal antibody, targets the programmed cell death ligand-1 (PD-L1) receptor. This study sought to determine the maximum tolerated dose and recommended phase II dose (RP2D) of eribulin in combination with durvalumab, as well as the safety and preliminary antitumor activity of the combination in patients with previously treated HER2-negative (HER2−) MBC and recurrent ovarian cancer (ROC). Methods: Cohorts of 3–6 patients with HER2− MBC and ROC were treated in a modified 3+3 design. Eligible patients received escalating doses of eribulin (1.1 mg/m2 or 1.4 mg/m2 IV on day 1 and day 8) with durvalumab (1.12 g IV on day 1) in 21-day cycles until dose-limiting toxicity (DLT), intolerable adverse events (AEs), disease progression, or other reasons for withdrawal. Primary endpoint: the rate of DLTs during cycles 1 and 2 of therapy. Secondary endpoints: AE rate, objective response rate (ORR), progression-free survival (PFS), and OS. Results: Nine patients with a median of 4 prior therapies for advanced disease were treated: 5 patients with HER2− MBC (1 with triple-negative disease and 4 with hormone-positive disease) and 4 patients with ROC. The RP2D of eribulin was 1.4 mg/m2 in combination with durvalumab. There were no DLTs experienced during the first two cycles of therapy. The most common treatment-related AEs (>50%) were fatigue, neutropenia, decreased white blood cell count, anemia, AST and alkaline phosphatase elevation, hyperglycemia, and nausea; most were grade 1 or 2. There was one immune-related AE of grade 3 (hepatitis) after 5 cycles of treatment, for which patient came off study. Two other patients discontinued study drug related to toxicity (neutropenia [n = 1], hepatic toxicity [n = 1]). ORR was 55%, and 4 additional patients experienced stable disease. All MBC patients exhibited a response to therapy. Median PFS was 6.2 months. Median OS was 15.0 months. Conclusion: The combination of eribulin at a dose of 1.4 mg/m2 with standard dose durvalumab had a favorable AE profile in patients with previously treated HER2− MBC and ROC. The early antitumor activity observed in all MBC patients enrolled in the study suggests that further investigation of this combination is warranted.

AdvanTIG-105: Phase 1b dose-expansion study of ociperlimab (OCI) + tislelizumab (TIS) with chemotherapy (chemo) in patients (pts) with stage IV gastric/gastroesophageal adenocarcinoma (GC/GEJC).

31 Background: T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains (TIGIT) inhibitor in combination with an anti-programmed cell death protein 1 (PD-1) antibody has shown antitumor activity in solid tumors. AdvanTIG-105 (NCT04047862) is a phase 1/1b open-label study designed to assess the safety and preliminary antitumor activity of OCI, an anti-TIGIT monoclonal antibody (mAb), + TIS, an anti-PD-1 mAb, in pts with unresectable, locally advanced or metastatic solid tumors. In the dose-escalation part, OCI + TIS was well tolerated with preliminary antitumor activity observed, and the recommended phase 2 dose (RP2D) of OCI 900 mg intravenously (IV) every three weeks (Q3W) + TIS 200 mg IV Q3W was established. We report results from the dose-expansion part (GC/GEJC Cohort 9) of the AdvanTIG-105 study. Methods: Eligible pts had histologically/cytologically confirmed stage IV GC/GEJC. Pts were excluded if they had squamous cell, undifferentiated or other histological types of GC, had GC/GEJC with positive HER2 expression, or if they had received any prior therapy for metastatic disease. Pts received either the RP2D of OCI + TIS with oxaliplatin + capecitabine Q3W for 6 cycles (C), followed by maintenance therapy with the RP2D of OCI + TIS, + capecitabine Q3W, or the RP2D of OCI + TIS with cisplatin + 5-fluorouracil Q3W for 6 C. Treatment continued until disease progression, intolerable toxicity, or withdrawal of consent. The primary endpoint was investigator-assessed overall response rate (ORR) per RECIST v1.1. Secondary endpoints included progression-free survival (PFS), duration of response (DoR), disease control rate (DCR) per RECIST v1.1, and safety. Results: As of September 29, 2022, 60 pts with a median age of 61.5 years (range 35-82) were enrolled; 59 were efficacy evaluable. Median study follow-up was 31.1 weeks (range 1.4-78.4). ORR was 50.8% (95% CI: 37.5, 64.1); DCR was 84.7% (95% CI: 73.0, 92.8) with a median DoR of 8.1 months (95% CI: 4.5, not evaluable [NE]). Median PFS was 8.2 months (95% CI: 5.8, NE). In a subgroup analysis, ORR in pts with PD-L1 tumor area positivity (TAP) score ≥5% (n=27) was 59.3% (95% CI: 38.8, 77.6), and 50.0% (95% CI: 30.7, 69.4) in pts with PD-L1 TAP <5% (n=28). All 60 pts reported ≥1 treatment-emergent adverse event (TEAE), the most common being anemia (43.3%) and platelet count decreased (41.7%). In total, 43 pts (71.7%) had ≥grade 3 TEAEs and 28 (46.7%) had serious adverse events. TEAEs leading to discontinuation of TIS and OCI occurred in 5 (8.3%) pts. TEAEs led to death in 2 (3.3%) pts; one event (neutropenic sepsis) was related to chemo, while the other (pulmonary embolism) was not treatment related. Conclusions: OCI 900 mg + TIS 200 mg + chemo was generally well tolerated and showed encouraging antitumor activity in pts with stage IV GC/GEJC. Clinical trial information: NCT04047862 .

Sintilimab plus bevacizumab, oxaliplatin and capecitabine as first-line therapy in RAS-mutant, microsatellite stable, unresectable metastatic colorectal cancer: an open-label, single-arm, phase II trial

Microsatellite stable (MSS) and RAS-mutant metastatic colorectal cancer (mCRC) patients are characterized by an immunosuppressive microenvironment and a low response rate to immunotherapy. Chemotherapy and anti-angiogenesis therapy have been reported to potentially promote immunotherapy response. This study aims to assess the preliminary anti-tumor activity and safety of sintilimab plus bevacizumab, oxaliplatin and capecitabine as a treatment option for patients with RAS-mutant MSS mCRC. This study was an open-label, single-arm, phase II trial in China. Patients with unresectable, RAS-mutant and MSS metastatic colorectal adenocarcinoma received treatment by intravenous sintilimab (200mg, day 1) plus bevacizumab (7.5mg/kg, day 1), oxaliplatin (135mg/m2, day 1) and oral capecitabine (1g/m2, day 1-14) in each 21-day cycle. The primary endpoints included objective response rate (ORR) and adverse events. Biomarker analysis was performed to identify potential predictors of good response to treatment. This study is registered with ClinicalTrials.gov, number NCT04194359. Between April 2021 and December 2021, 25 patients were enrolled. Two (8%) patients showed complete response (CR), 19 (76%) had partial response (PR) and 4 (16%) presented with stable disease. ORR reached 84% (95% CI, 63.9-95.5) and the disease control rate was 100% (95% CI, 86.3-100). The median progression-free survival (PFS) was 18.2 months for the full analysis set. The most common treatment-related adverse events (TRAEs) in all grades were anemia (21/25, 84%), neutropenia (20/25, 80%), and hand-foot syndrome (14/25, 56%). The most frequent grade 3 or 4 TRAEs were neutropenia (3/25, 12%) and increased alanine transaminase (2/25, 8%). No grade 5 adverse events occurred. In the exploration of biomarkers, 5 patients could be characterized as TTN/OBSCN "double-hit" after treatment, and the copy number variants burden was significantly decreased in tumor tissues after treatment compared with the baseline. Nanostring panel RNA sequencing analysis indicated a better tumor immune microenvironment cell infiltration in CR/PR patients compared with non-CR/PR patients as well as the PFS-long (≥12.5 months) group compared with the PFS-short group. Combination treatment with sintilimab plus bevacizumab, oxaliplatin and capecitabine as first-line treatment demonstrated a promising antitumor activity and a manageable safety profile in RAS-mutant, MSS and unresectable mCRC. Exploratory biomarker assessment analysis showed that some RAS-mutant and MSS patients changed into "immune-hot" subtype after the treatment. This study was supported by the Key R&D Program of Zhejiang Province (2021C03125 to Ying Yuan), the National Natural Science Foundation of China (81872481 to Ying Yuan, 82072624 to Kefeng Ding), the Fundamental Research Funds for the Central Universities (No. 226-2022-00009 to Kefeng Ding), and the Zhejiang Provincial Natural Science Foundation of China (No. LY22H160024 to Hanguang Hu).

JSKN003, A NOVEL BIPARATOPIC ANTI-HER2 ANTIBODY-DRUG CONJUGATE, EXHIBITS POTENT ANTITUMOR EFFICACY

Abstract In human advanced solid tumors, expression of HER2 protein has been reported in various tumor tissues and a variety of cultured tumor cell lines including breast cancer, gastric cancer, pancreatic cancer, lung cancer, colorectal cancer, and ovarian cancer. Due to the critical roles of HER2 in carcinogenesis, two main targeted therapies have been developed in the past two decades to block the HER2-driven pathways, which include small molecule compounds that inhibit the tyrosine kinase activity of the intracellular domain, and mono-antibodies (mAbs) that target the extracellular domain (ECD) of the receptors. JSKN003 is an antibody-drug conjugate (ADC) comprised of a recombinant, humanized anti-human epidermal growth factor receptor 2 (HER2) bispecific antibody conjugated to a topoisomerase I inhibitor via a dibenzocyclooctyne tetrapeptide linker. The anti-HER2 component, KN026, is a recombinant, humanized bispecific antibody that targets both extra-cellular domains II (pertuzumab binding site) and IV (trastuzumab binding site) of HER2. JSKN003 showed high affinity binding to human HER2 with KDs of 2.209 E-10M, which is comparable to its parental antibody KN026 and bound to NCI-N87 and BxPC-3 cells in a concentration-dependent manner. At the same time JSKN003 showed more extensive and faster internalization than DS8201 on NCI-N87 cells. As expected, JSKN003 showed directly inhibits growth by targeting HER2 positive tumor model (NCI-N87 and BT474 cell models). The single dose and multiple dose pharmacokinetics study in cynomolgus monkey indicated that JSKN003, total antibody and DXd had general linear dynamic characteristics, and pharmacokinetics parameters showed no significant differences between males and females in the range 0.3-30 mg/kg. The HNSTD (highest non-severely toxic dose) of JSKN003 was determined as 30mg/kg in cynomolgus monkeys. These preclinical data suggest that JSKN003 could potentially benefit patients with tumors co-expressing HER2 through improved drug selectivity and efficacy. JSKN003’s safety, tolerability and preliminary anti-tumor activity are currently being evaluated in a first-in-human phase I study in advanced stage solid tumors in Australia (NCT05494918) using a BOIN design. This ADC is targeted on the subjects who has HER2 expression and/or HER2-gene mutation and may address an unmet medical need for these patients.

Preclinical and clinical activity of DZD1516, a full blood–brain barrier-penetrant, highly selective HER2 inhibitor

BackgroundPatients with HER2-positive metastatic breast cancer (MBC) are at high risk of developing central nervous system (CNS) metastases. A potent and selective HER2 inhibitor with good blood–brain barrier (BBB) penetration is highly desirable.MethodsThe design and structure–activity relationship of DZD1516 was described. The potency and selectivity of DZD1516 were determined by enzymatic and cellular assays. The antitumor activity of DZD1516 monotherapy or in combination with HER2 antibody–drug conjugate was assessed in CNS and subcutaneous xenograft mouse models. A phase 1 first-in-human study evaluated the safety, tolerability, pharmacokinetics, and preliminary antitumor activity of DZD1516 in patients with HER2+ MBC who relapsed from standard of care.ResultsDZD1516 showed good selectivity against HER2 over wild-type EGFR in vitro and potent antitumor activity in vivo. Twenty-three patients were enrolled and received DZD1516 monotherapy treatment across six dose levels (25–300 mg, twice daily). Dose-limiting toxicities were reported at 300 mg, and thus 250 mg was defined as the maximum tolerated dose. The most common adverse events included headache, vomiting, and hemoglobin decreased. No diarrhea or skin rash was observed at ≤ 250 mg. The mean Kp,uu,CSF was 2.1 for DZD1516 and 0.76 for its active metabolite DZ2678. With median seven lines of prior systemic therapy, the best antitumor efficacy in intracranial, extracranial and overall lesions was stable disease.ConclusionsDZD1516 provides positive proof of concept for an optimal HER2 inhibitor with high BBB penetration and HER2 selectivity. Further clinical evaluation of DZD1516 is warranted, with the RP2D being 250 mg BID.Clinicaltrials.gov identifier NCT04509596. Registered on August 12, 2020; Chinadrugtrial: CTR20202424 Registered on December 18, 2020.

Safety, Tolerability, and Antitumor Activity of Zipalertinib Among Patients With Non-Small-Cell Lung Cancer Harboring Epidermal Growth Factor Receptor Exon 20 Insertions.

Although several agents targeting epidermal growth factor receptor (EGFR) exon 20 insertions (ex20ins) have recently been approved by the US Food and Drug Administration, toxicities related to the inhibition of wild-type (WT) EGFR are common with these agents and affect overall tolerability. Zipalertinib (CLN-081, TAS6417) is an oral EGFR tyrosine kinase inhibitor (TKI) with a novel pyrrolopyrimidine scaffold leading to enhanced selectivity for EGFR ex20ins-mutant versus WT EGFR with potent inhibition of cell growth in EGFR ex20ins-positive cell lines. This phase 1/2a study of zipalertinib enrolled patients with recurrent or metastatic EGFR ex20ins-mutant non-small-cell lung cancer (NSCLC) previously treated with platinum-based chemotherapy. Seventy-three patients were treated with zipalertinib at dose levels including 30, 45, 65, 100, and 150 mg orally twice a day. Patients were predominantly female (56%), had a median age of 64 years, and were heavily pretreated (median previous systemic therapies 2, range 1-9). Thirty six percent of patients had received previous non-ex20ins EGFR TKIs and 3/73 (4.1%) patients received previous EGFR ex20ins TKIs. The most frequently reported treatment-related adverse events of any grade included rash (80%), paronychia (32%), diarrhea (30%), and fatigue (21%). No cases of grade 3 or higher drug-related rash or diarrhea were observed at 100 mg twice a day or below. Objective responses occurred across all zipalertinib dose levels tested, with confirmed partial response (PR) observed in 28/73 (38.4%) response-evaluable patients. Confirmed PRs were seen in 16/39 (41%) response-evaluable patients at the dose of 100 mg twice a day. Zipalertinib has encouraging preliminary antitumor activity in heavily pretreated patients with EGFR ex20ins-mutant NSCLC, with an acceptable safety profile, including low frequency of high-grade diarrhea and rash.

Connexin43 is associated with the progression of clear cell renal carcinoma and is regulated by tangeretin to sygergize with tyrosine kinase inhibitors

BackgroundThe roles of Connexin43 (Cx43) in clear cell renal cell carcinoma (ccRCC) microenviroment remains to be poorly defined. MethodsThe expression profile, prognosis and immune analysis of Cx43 in various cancers, particularly in ccRCC were performed using TCGA database, and various biological function assays were applied to explore the physiological role of Cx43 and tangeretin in ccRCC. Western blot were applied to examine the protein expression and Kunming mice were used to evaluate preliminary safety or anti-tumor activity of tangeretin and sunitinib. ResultsCompared with the normal group, higher expression levels of Cx43 in ccRCC, and distinct associations between Cx43 expression and ccRCC prognosis or immune infiltration, were found. Notably, the expression of Cx43 was found to be highly correlated with that of receptor tyrosine kinases (RTKs), particularly with VEGFR1, VEGFR2 and VEGFR3. The expression of Cx43 and EGFR was also found to be higher in ccRCC than that in the para-cancerous specimens. Knocking down Cx43 expression decreased RCC cell viability, cell migration, p-EGFR, MMP-9 and survivin expression. Using 14 Chinese medicine monomers, tangeretin was screened and found to inhibit tumor cell viability and Cx43 expression. Tangeretin also enhanced the sensitivity of RCC cells to tyrosine kinase inhibitors (TKIs) sunitinib and sorafenib. However, the same concentration of tangeretin exerted a less prominent effect on normal renal cell viability. ConclusionsCx43 is strongly associated with RTK expression and ccRCC progression, while tangeretin can inhibit RCC cell malignancy by inhibiting Cx43 expression and enhance the sensitivity of RCC cells to TKIs.

Preliminary antitumor activity of the combination of COM701 + BMS-986207 + nivolumab in patients with recurrent, metastatic MSS endometrial cancer.

5595 Background: There is a high unmet medical need for the treatment of patients [pts] with microsatellite stable [MSS], recurrent, metastatic, endometrial cancer [EC]. We reported encouraging preliminary antitumor activity with the triple combination of COM701 + BMS-986207 + nivolumab in patients with platinum resistant epithelial ovarian cancer [1]. COM701 is a novel, 1st-in-class immune checkpoint inhibitor [ICI] that binds to PVRIG, a DNAM-1 axis member, leading to activation of T-and NK-cells; BMS-986207 is an ICI of TIGIT. Nivolumab is an ICI of PD-1. We hypothesized that in pts with EC, the triple combination would demonstrate antitumor activity with a favorable safety and tolerability profile. We present encouraging preliminary results. Methods: As part of an expansion cohort, we enrolled 9 patients [pts] with EC. All pts received COM701 20 mg/kg + BMS-986207 480 mg + nivolumab 480 mg all IV Q4W. Primary objectives were safety/tolerability, with secondary objective of antitumor activity in pts with EC. Key inclusion criteria: Age ≥ 18 yrs, measurable disease, MSS by IHC or genomic testing, ≤2 prior systemic cytotoxic therapies, prior PD-1/PD-L1 permissible. Key exclusion criteria: prior receipt of anti-PVRIG, anti-TIGIT. Investigator assessed responses were per RECIST v1.1, safety per CTCAE v5.0. Results: Median age 71yrs, median of 2 prior lines of therapy, prior PD-1/PD-L1 3/9 [33%]. All pts received prior cytotoxic therapy. Objective response rate (ORR) 2/9 [22%] pts; 2 pts with SD. Disease control rate [CR + PR + SD] 4/9 [44%]. There were 2 pts with confirmed PR; 1 of these pts was refractory to prior receipt of lenvatinib + pembrolizumab [best response assessment of progressive disease]. Treatment related AEs were reported in 6/9 [67%] pts, the majority 4/6 [67%] were Grade 1 [1 pt each with chills, pyrexia, back pain and pruritus, lipase increased]. No new safety signals are reported. Conclusions: The combination of COM701 + BMS-986207 + nivolumab demonstrates encouraging preliminary signal of antitumor activity in pts with EC including in a pt refractory to prior exposure to lenvatinib + pembrolizumab. The triplet combination has a favorable safety/tolerability profile. Additional data analyses and pt follow up are ongoing and will be presented at the conference. Data extract 01/24/2023. 1. Moroney JW, Yeku O et al. Triple blockade of the DNAM-axis with COM701 + BMS-986207 + nivolumab demonstrates preliminary antitumor activity in patients with platinum resistant OVCA. Annals of Oncology (2022) 16 (suppl_1): 100104-100104. 10.1016/iotech/iotech100104. Clinical trial information: NCT04570839 .

Phase 1 study of LB1410, a bivalent TIM-3/PD-1 bispecific antibody, in patients with advanced solid tumors or lymphoma.

TPS2663 Background: Cancer immunotherapies targeting PD-1 or PD-L1 have been proven effective in causing durable antitumor immune responses with less toxicity in many types of tumors. However, the response rate of anti-PD-1/PD-L1 treatments is far from satisfactory and most patients show primary or acquired resistance to the treatments. Tim-3, one of the next generation of immune checkpoint targets, co-expressed on exhausted T cells with PD-1. It is also expressed by innate immune populations, including NK and DC. Dual blocking PD-1 and Tim-3 not only on T cells but also on DC, NK cells may achieve better clinical benefit. LB1410 is a recombinant humanized anti-PD-1/TIM-3 bispecific antibody (BsAb) developed by L&L Biopharma Co., Ltd. for the patients who are resistant to or refractory from PD-1/PD-L1 treatments. It blocked the immune checkpoint PD-1 and TIM-3-mediated immunosuppressive signal pathways simultaneously, showed better T/DC cell activity and in vivo anti-tumor efficacy compared to Tim-3 and PD-1 antibody combination in preclinical studies. Methods: This is a FIH, multicenter, non-randomized, open label, phase 1 study of LB1410 in Participants With Advanced Solid Tumor or Lymphoma（Keyplus-001）. The planned sample size is approximately 100 patients in two parts: part 1 dose escalation will evaluate safety, tolerability, pharmacokinetics (PK), pharmacodynamics, and determine the maximum tolerated dose (MTD) and/or the recommended phase 2 dose (RP2D), and Part 2 dose expansion will further characterize the safety profile and preliminary tumor response in several cohorts including NSCLC, CRC, EC etc. Enrollment criteria include adults with life expectancy of > 3 months, ECOG performance status 0-1，histologically or cytologically confirmed advanced and/or metastatic solid tumor malignancies or lymphoma for which standard treatment fails, or no standard treatment is available, or standard treatment is not applicable at this stage. Exclusion criteria include pregnancy, lactation, or breastfeeding, ongoing or recent evidence of significant autoimmune disease that required treatment with systemic immunosuppressive treatments. The primary endpoints are incidence of dose limiting toxicities and adverse events, MTD, and recommended phase 2 dose. Secondary objectives will evaluate PK parameters, preliminary antitumor activity, and immunogenicity of LB1410. Besides, the pharmacodynamics (PD) biomarkers related to LB1410 treatment, clinical activity will be explored. This clinical trial is in progress; cohorts 1 to 5 in dose escalation part have been completed. Clinical trial information: NCT05357651 .

17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023.

Introduction: CD19 is an established target of multiple B-cell lymphoma therapies. Blockade of CD47, a macrophage immune checkpoint inhibitory ligand, induces tumor-cell phagocytosis. TG-1801 is a CD19/CD47 bispecific antibody designed to selectively block CD47 on CD19+ cells, while retaining a functional IgG1 Fc domain. Herein we report updated results from the FIH study. Methods: The primary objectives of this phase I 3+3 study were to characterize the safety profile and determine the recommended phase 2 dose (RP2D) as monotherapy and in combination with ublituximab. Pharmacokinetics, pharmacodynamics, and preliminary antitumor activity were also assessed. Eligible patients (pts) had relapsed/refractory (R/R) B-cell lymphoma after ≥1 prior standard therapy. TG-1801 doses evaluated included: 20 mg, 60 mg, 180 mg, 360 mg, & 500 mg. In the monotherapy arm, treatment consisted of weekly fixed dosing 1h-infusions of TG-1801 in a 4-week cycle: day (D)1, D8, D15, and D22 of cycle (C) 1 and C2. Pts who had at least stable disease after 2 cycles continued with TG-1801 once every 4 weeks for 4 further infusions. Intra-pt dose escalations were permitted. A second arm explored the combination of TG-1801 with ublituximab; an anti-CD20 mAb. Pts received TG-1801 and ublituximab, IV every 4 weeks: D1, D8, and D15 of C1; D1 of C2-C6; and D1 of C9 and every 3 cycles thereafter, up to 24 cycles. 2 dose levels of TG-1801 (300 mg and 400 mg) with 900 mg of ublituximab were tested. Responses were assessed by Lugano 2014 criteria. Results: As of October 2022, 14 pts (MZL = 5, DLBCL including Richter’s transformation = 5, FL = 4) received monotherapy and 16 pts received combination therapy (DLBCL = 9, FL = 4, MZL = 2, MCL = 1). Pts had a median of 3 prior therapies (range, 1–8) with 16 pts (53%) refractory to their last therapy. One DLT of grade (G) 4 thrombocytopenia occurred at 500 mg monotherapy. Most frequent (>20%) treatment emergent adverse events (TEAEs) at monotherapy doses of 20 mg to 360 mg (n = 10) included fatigue, thrombocytopenia, and infusion-related reaction (3 pts each), with no G3/4 TEAEs occurring in >20% of pts. Combination therapy was also well tolerated (TG-1801 at 300 mg N = 3, 400 mg N = 13) without DLT. Most common TEAEs (≥20%) for combination therapy were anemia, headache, and fatigue (5 pts each), with no G3/4 TEAEs occurring in >20% of pts. 2 pts permanently discontinued therapy due to TEAEs (1 infusion reaction [500 mg monotherapy], 1 rash [360 mg monotherapy]). Among 13 evaluable monotherapy pts, there were 3 (ORR = 23%) partial responses (PR). In combination (n = 16), a 44% ORR was observed with 1 complete response (CR) in a pt with FL and 6 PR (5 pts with DLBCL and 1 pt with FL) for a 56% ORR in DLBCL and 50% ORR in FL. The research was funded by: TG Therapeutics Inc. Keywords: Combination Therapies, Immunotherapy, Targeting the Tumor Microenvironment Conflicts of interests pertinent to the abstract. E. A. Hawkes Consultant or advisory role: Advisory board and speaker fees (institutional or personal) from Roche, Merck Sharpe & Dohme, Astra Zeneca, Gilead, Antigene, Novartis, Regeneron, Janssen, Specialised Therapeutics, outside the submitted work Research funding: Roche, Bristol Myers Squibb, Merck KgA, Astra Zeneca and Merck K. L. Lewis Consultant or advisory role: Astrazeneca, Roche, Loxo/Lilly, IQVIA, MSD Honoraria: Astrazeneca, Janssen, Roche H. P. Miskin Employment or leadership position: TG Therapeutics Inc. Stock ownership: TG Therapeutics Inc. P. Sportelli Employment or leadership position: TG Therapeutics Inc. Stock ownership: TG Therapeutics Inc. K. S. Kolibaba Employment or leadership position: TG Therapeutics Inc. Stock ownership: TG Therapeutics Inc. E. Normant Employment or leadership position: TG Therapeutics Inc. Stock ownership: TG Therapeutics Inc. T. Turpuseema Employment or leadership position: TG Therapeutics Inc. Stock ownership: TG Therapeutics Inc. C. Y. Cheah Consultant or advisory role: Roche, Janssen, Gilead, AstraZenecca, Lilly, TG therapeutics, Beigene, Novartis, Menarini, Daizai, Abbvie, Genmab. BMS Honoraria: Roche, Janssen, Gilead, AstraZenecca, Lilly, TG therapeutics, Beigene, Novartis, Menarini, Daizai, Abbvie, Genmab. BMS Research funding: BMS, Roche, Abbvie; MSD, Lilly

Phase 1 multicenter dose escalation and dose expansion study of antibody-drug conjugate (ADC) MYTX-011 in subjects with non-small cell lung cancer.

TPS9147 Background: cMET is a receptor tyrosine kinase and proto-oncogene whose activity is upregulated across a wide range of cancers. In NSCLC, expression of cMET is upregulated by DNA amplification (2% to 5%), exon 14 skipping mutations (2% to 4%), and overexpression (30% to 60%). In NSCLC, cMET upregulation has also been demonstrated to be a resistance mechanism for several approved EGFR-targeted kinase inhibitors, and this may limit their effectiveness. Despite the approval of MET tyrosine kinase inhibitors, almost half of patients do not respond to these inhibitors and resistance is inevitable. MYTX-011 is an ADC incorporating the clinically validated vcMMAE linker-payload conjugated to a novel, pH-dependent anti-cMET antibody. In preclinical studies, MYTX-011, compared to a surrogate of an advanced clinical stage cMET ADC, showed markedly higher ( > 3 fold) internalization and increased cytotoxicity in cMET+ tumor cells in vitro, which translates to greater (≥3 fold) efficacy in high or moderate c-Met+ xenograft models in vivo. PK and toxicity studies revealed that MYTX-011 exhibited favorable PK characteristics, and a toxicity profile similar to previously described MMAE-based ADCs. Methods: MYTX-011-01 (ClinicalTrials.gov Identifier: NCT05652868) is a first-in-human Phase 1 dose escalation and dose expansion study. MYTX-011 will be administered intravenously every 21 days for a maximum of 2 years. Part 1 (dose escalation) will assess the safety and tolerability of MYTX-011 in patients with advanced NSCLC and identify the recommended Phase 2 dose (RP2D). Part 2 (dose expansion) will include subjects with NSCLC with cMET overexpression or MET amplification/exon 14 skipping mutations. In Part 1, subjects will be enrolled to evaluate the safety of escalating doses of MYTX-011 as a single-agent and to establish the RP2D and/or MTD. The dose escalation scheme is based on a 3-subject cohort minimum Bayesian Optimal Interval (BOIN) design. The RP2D will be selected as a biologically active dose at or below the MTD (or the highest dose tested if an MTD is not identified during the study) and will be informed by safety, tolerability, pharmacokinetic data, and preliminary anti-tumor activity of MYTX-011 based on RECIST 1.1. Part 2 of the study will be initiated once the RP2D has been determined and will enroll subjects into different cohorts based on cMET IHC positivity cutoff and/or presence of MET genetic alterations ( MET amplification or exon 14 skipping). All cohorts are defined to explore preliminary antitumor activity in populations with different thresholds of cMET positivity that were selected based on data for cMET expression and efficacy observed with MYTX-011 in preclinical models, published data for responses to cMET targeting agents, and on the prevalence of subject tumors with different expression levels. Enrollment in the MYTX-011-01 study is ongoing. Clinical trial information: NCT05652868 .

A first-in-human trial of intravesical enfortumab vedotin (EV), an antibody-drug conjugate (ADC), in patients with non-muscle invasive bladder cancer (NMIBC): Interim results of a phase 1 study (EV-104).

4596 Background: A majority of patients (pts) with bladder cancer present with non-muscle invasive disease; for pts with high-risk tumors, standard of care (SOC) is resection of tumor followed by intravesical Bacillus Calmette-Guerin (BCG). Once pts experience recurrence and develop BCG-unresponsive disease, SOC is radical cystectomy (RC), which many pts are unfit for or refuse. EV is an ADC directed to Nectin-4, which is highly expressed in bladder tumors. Intravenous EV has demonstrated survival benefit in pts with previously treated la/mUC. In preclinical models with intravesical administration, EV was well tolerated and showed antitumor activity. Here we present the first clinical data for intravesical administration of EV in pts with NMIBC. Methods: EV-104 (NCT05014139) is an ongoing phase 1, open-label, multicenter, dose-escalation and expansion study of intravesical EV evaluating the safety, tolerability, PK, and antitumor activity of intravesical EV in pts with high-risk BCG-unresponsive NMIBC with carcinoma in situ (CIS) with or without papillary disease who are ineligible for or refuse RC. Dose escalation phase aims to identify the MTD or recommended dose of intravesical EV at the following dose levels: 125mg, 250mg, 500mg, and 750mg. Pts receive intravesical EV weekly for 6 weeks in the induction phase, followed by 9 monthly maintenance doses. Preliminary safety, PK, and efficacy data for 125mg and 250mg doses are presented in this abstract. Results: As of data cutoff (1 Dec 2022), 6 pts received intravesical EV across 2 dose levels: 4 pts at 125mg completed 6 induction cycles and proceeded to maintenance; 2 pts at 250mg had received at least 3 doses of intravesical EV. Of 6 pts across doses, there were no Grade ≥3 TRAEs, treatment-related SAEs, TRAEs leading to dose reduction or discontinuation. 4 of 6 pts (3 at 125mg and 1 at 250mg) experienced ≥1 treatment-related adverse event (TRAE) of Grade 1 or 2. Most common TRAEs were fatigue (3 of 6) and micturition urgency (2 of 6). As of data cutoff, no DLTs were observed for 125mg; the DLT evaluation period for 250mg was not complete. All blood PK analyses (ADC and unconjugated MMAE) for pts at 125mg were undetectable; no PK data was available for 250mg. Of 4 pts receiving 125mg of intravesical EV, 3 achieved CR and continue in response. The fourth pt discontinued tx due to persistent disease but remains on study. Pts at 250mg had not been evaluated for response at data cutoff. Detailed safety and additional efficacy data will be presented. Conclusions: Preliminary data from EV-104 show intravesical EV is well tolerated with no evidence of systemic exposure at 125mg. Preliminary antitumor activity was observed at 125mg with 3 of 4 pts achieving a CR. Dose escalation is ongoing to identify the MTD or recommended dose for dose expansion. Clinical trial information: NCT05014139 .

GFH018, a small molecular inhibitor targeting TGF-βRI kinase, in patients with advanced solid tumors: Final results of the phase I study.

e15117 Background: TGF-β signaling pathway activation inhibits anti-tumor response, promoting tumor progression and metastasis. GFH018, a small molecule inhibiting TGF-βRI kinase, blocks TGF-β signaling transduction thus downregulates its pathway. GFH018 had significant growth inhibitory effects on several in vivo tumor models as monotherapy and demonstrated synergistic effects combined with anti-PD-1 antibody. This phase I study assessed safety, PK, and preliminary efficacy of GFH018 in pts with advanced solid tumors. Here we report the final results from the completed study. Methods: The study includes a modified 3 + 3 dose escalation and an expansion part. Adult pts with advanced solid tumors failed to standard treatments were enrolled. The starting dose was 5 mg and up to 8 cohorts were planned. In the escalation part, pts were administrated with GFH018 BID (14d-on/14d-off) two days after receiving single dose orally on C1D1. The subsequent cycle was 28 days. The safety of 85 mg BID 7d-on/7d-off was also explored. AEs were graded per NCI-CTCAE v5.0. PK was analyzed using a non-compartmental method. Efficacy was evaluated per RECIST 1.1. Blood samples were collected for biomarker analysis. Results: From Aug 1, 2019 to Aug 11, 2022, fifty pts (14d-on/14d-off: 5 mg [n = 4], 10 mg [n = 3], 20mg [n = 4], 30 mg [n = 7], 40 mg [n = 4], 50 mg [n = 4], 65 mg [n = 6] and 85 mg [n = 12]; 7d-on/7d-off: 85 mg [n = 6]) were enrolled. Thirty-seven pts (74.0%) had ≥3 prior systemic treatment lines. No DLT was observed, and the MTD was not reached. No significant cardiotoxicities or bleeding events were reported. Forty-three pts (86.0%) had at least one treatment related AE (TRAE), and 3 (6.0%) experienced ≥ G3 TRAEs. The most common TRAEs (all G/≥G3) were proteinuria (26.0%/2.0%), AST increased (18.0%/0), anemia (14.0%/2.0%), ALT increased (12.0%/0), GGT increased, ALP increased, and LDH increased (all 10.0%/0). Common TRAEs (≥2 pts) for 7d-on/7d-off was lymphocyte decreased (2/6) with no ≥ G3 reported. No significant differences were observed between the two regimens in safety. GFH018 was absorbed rapidly with median Tmax of 0.50 ~0.96h and displayed a linear pharmacokinetic behavior with T1/2 of 4.08~10.92 h (5~85 mg). Nine pts achieved stable disease (SD), among whom a pt with thymic carcinoma receiving 65 mg achieved tumor shrinkage (maximum target lesion decreased by 18.4%). Results for 85 mg BID, 14d-on/14d-off showed a DCR of 25.0%. The RP2D was 85 mg BID, 14d-on/14d-off. Serum TGF-β1 level was not associated with clinical responses. Available pharmacodynamic data of SMAD2 phosphorylation levels in peripheral blood mononuclear cells (PBMCs) were not reliable due to assay issues. Conclusions: GFH018 shows a favorable safety profile and preliminary anti-tumor activity. The clinical studies of GFH018 in combination with Toripalimab and with Toripalimab + concurrent chemoradiotherapy are ongoing. Clinical trial information: NCT05051241 .

A phase 1 study of the OX40 agonist, BGB-A445, with or without tislelizumab, an anti-PD-1 monoclonal antibody, in patients with advanced solid tumors.

2574 Background: OX40 is an immune costimulatory receptor, expressed on activated CD4+ and CD8+ T cells, which promotes T cell proliferation and survival in the tumor microenvironment. BGB-A445 is a novel monoclonal antibody (mAb) OX40 agonist that does not compete with endogenous OX40 ligand binding. BGB-A445 has demonstrated antitumor activity as a single agent and in combination with an anti-PD-1 mAb in preclinical studies. Here, we report data from the ongoing dose-escalation part of a multicenter, phase 1 dose escalation/expansion study (NCT04215978) of BGB-A445 alone or in combination with tislelizumab (TIS) in patients (pts) with advanced solid tumors. Methods: Eligible pts were enrolled into seven sequential dose escalation cohorts of BGB-A445 IV as monotherapy (Part A) or five increasing dose levels of BGB-A445 IV in combination with TIS 200 mg IV (Part B) on day 1 of 21-day cycles. Dose escalation was guided by a Bayesian (mTPI-2) approach. This study assessed safety, tolerability, pharmacokinetics (PK) profile, and preliminary antitumor activity (RECIST v1.1). Results: As of August 31, 2022, 59 pts were enrolled in Part A and 32 pts in Part B. Median (range) age was 59 years (28-80) and 61 years (37-75) in Parts A and B, respectively; 26 (44%) and 13 (41%) pts were male, respectively. ≥Grade 3 treatment-emergent AEs (TEAEs) were reported in 24 (41%) and 17 (53%) pts in Parts A and B, respectively; the most commonly reported (≥3 reported) ≥grade 3 TEAEs were gastrointestinal disorders (diarrhea, nausea, and abdominal pain). Serious TEAEs were reported in 23 (39%) pts in Part A and 16 (50%) in Part B. Treatment-related AEs leading to treatment discontinuation were reported in 1 (2%) pt in Part A and 0 (0%) pts in Part B. In Part A, all grade immune-mediated AEs (imAEs) were reported in 11 (19%) pts; no pts reported ≥grade 3 imAEs. In Part B, all grade imAEs were reported in 14 (44%) pts; ≥grade 3 imAEs were reported in 1 (3%) pt (one event each of rash maculopapular and diarrhea). There were no dose-limiting toxicities or concerning patterns of safety/tolerability observed. BGB-A445 PK (maximum concentration [Cmax] and area under the curve from day 0 to 21 [AUC0-21]) were linear and dose proportional in all tested dose ranges. In the efficacy-evaluable population of Parts A (n=50) and B (n=30), respectively, partial response was observed in 2 (4%) pts (unconfirmed) and 7 (23%) pts (confirmed); stable disease in 18 (36%) and 13 (43%) pts (confirmed), and progressive disease in 26 (52%) and 8 (27%) pts. Conclusions: In the dose escalation part of this study, BGB-A445 alone or in combination with TIS was generally well tolerated across all doses in pts with advanced solid tumors, and demonstrated preliminary antitumor activity as both a single and combination agent. The dose expansion part of the study is ongoing in pts with non-small cell lung cancer and head and neck squamous cell carcinoma. Clinical trial information: NCT04215978 .

SI-B003 (PD-1/CTLA-4) in patients with advanced solid tumors: A phase I study.

e14668 Background: Although marketed antibodies against PD-1/L1 or CTLA-4 have been shown to be efficacious in a variety of tumors, the overall response rate (ORR) remains low. SI-B003 is a PD-1/CTLA-4 bispecific antibody. We hypothesized that co-targeting PD-1 and CTLA-4 simultaneously could achieve a better anti-tumor activity due to cooperative binding to exhausted T-cell subsets. Methods: Patients with recurrent or metastatic solid tumors who had failed standard therapy were eligible to participate. SI-B003 was administered intravenously every other week (Q2W) in a four-week cycle. The phase Ia dose escalation consisted of an accelerated titration phase (the first 2 dose levels) and a mTPI-2 with a total of five dose levels: 0.1, 0.3→1.0, 3, 5 and 10 mg/kg. The phase Ib consisted of a dose expansion and indication expansion cohorts with 5, 10 mg/kg Q2W and 7.5mg/kg Q3W. The primary objectives of phase Ia were to assess dose-limiting toxicity (DLT), maximum tolerated dose (MTD) or maximum administration dose (MAD), and treatment emergent adverse events (TEAEs). The primary objectives of phase Ib included safety, tolerability, and identification of the recommended phase 2 dose (RP2D). Results: As of December 31, 2022, 60 patients with solid tumors received SI-B003 at six different dose levels (14 in Ia, 46 in Ib). Median age was 55.5 years. The median PFS (95%CI) was 3.7 (1.6~5.7) months. Among 56 evaluable patients, the objective response rate (ORR) (n/N, 95%CI) was 16.1% (9/56, 7.6~28.3%) and disease control rate (DCR) was 50.0% (28/56). Confirmed ORR, DCR, median duration of response (DoR) and median progression free survival (PFS) were 9.5% (2/21, 1.2~30.4%), 42.9% (9/21), NR and 2.1 (95%CI, 1.4~NA) months in the 5mg/kg Q2W group and 8.3% (2/24, 1.0~27.0%), 62.5% (15/24), 7.1 (95%CI, 1.9~NA) and 5.7 (95%CI, 1.9~8.7) months in 10mg/kg Q2W group respectively. One patient received 7.5mg/kg Q3W had a confirmed response and was still under treatment. Among 21 evaluable patients who had received prior PD-1/L1 treatment, the ORR and DCR were 14.3% (3/21, 3.1~36.3%) and 52.4% (11/21). The mDoR (95%CI) and mPFS (95%CI) were 4.2 (NA) months and 4.1 (1.4, 5.7) months. The most common TRAEs were rash (35%), AST increased (28%), ALT increased (28%). The most common grade ≥3 TRAEs were AST increased (3%). One patient died from an immune-mediated pneumonia. Conclusions: SI-B003 demonstrated a tolerable safety profile and preliminary anti-tumor activity in patients with recurrent or metastatic solid tumors. Anti-tumor effects of SI-B003 were observed in patients who had progressed on prior PD-1/L1 immunotherapy suggesting that SI-B003 may be beneficial for patients who have developed resistance to PD-1/L1 drugs. Clinical trial information: NCT04606472 .

Safety, pharmacokinetics (PK), pharmacodynamics (PD) and preliminary efficacy of AZD2936, a bispecific antibody targeting PD-1 and TIGIT, in checkpoint inhibitor (CPI)-experienced advanced/metastatic non-small-cell lung cancer (NSCLC): First report of ARTEMIDE-01.

9050 Background: PD-1 and TIGIT are implicated in cancer-related T cell immunosuppression. AZD2936 is a bispecific, humanized IgG1 (triple-mutated to minimize Fc effector function) targeting PD-1 and TIGIT. It has demonstrated encouraging activity compared to both anti-PD-1 and anti-PD-1/-TIGIT combinations in murine models. We report data from dose escalation (Part A) and an expansion cohort (Part B) of the first-in-human study ARTEMIDE-01 (NCT04995523). Methods: This open-label, multicenter study enrolled pts with advanced NSCLC who had prior CPI treatment and a PD-L1 tumor proportion score ≥1%. Part A evaluated doses of 70–1500 mg IV Q3W; Part B evaluated the recommended phase 2 dose (RP2D). Primary endpoints included safety, tolerability, dose-limiting toxicities (DLTs) and preliminary efficacy. Secondary endpoints included PK and PD, defined as percentage PD-1 and TIGIT receptor occupancy (RO). Results: As of Dec 5, 2022, 80 pts were enrolled (Part A, n=48; Part B, n=32). Pts were 62.5% male, median age 63.5 years; 72.5% had adenocarcinoma, 23.8% had squamous cell carcinoma; 96.3% had metastatic disease; and 22.5% had brain metastases. They had a median of 2 prior regimens. Median duration of therapy was 11 wks. AZD2936 was well tolerated with no DLTs. In total, 46.3% of pts had treatment-related adverse events (TRAEs), all grade 1–3; the most common were pruritus, rash and lipase increased (6.3% each). Serious TRAEs occurred in 3 pts (3.8%): immune system disorder, acute hepatitis and fatigue (n=1 each). AZD2936 systemic exposure increased in a near dose-proportional manner. Doses of ≥210 mg achieved ~90% PD-1 and TIGIT RO in peripheral T cells. The RP2D was determined to be 750 mg Q3W based on safety, preliminary efficacy, PK/PD and modeling analysis predicting intratumoral RO. Among 76 evaluable pts, 3 had a partial response and 30 had stable disease (Table). Time to response was 1.9–4.0 mos and duration of response was 2.1–6.4 mos. Conclusions: In this interim analysis, AZD2936 showed an acceptable safety profile and preliminary antitumor activity in pts with advanced/metastatic NSCLC previously treated with standard therapy including CPIs. Further exploration of AZD2936 in CPI-naïve NSCLC pts, including a randomized dose optimization cohort is ongoing. Clinical trial information: NCT04995523 . [Table: see text]

A first-in-human, open label, multiple dose, dose escalation, and cohort expansion phase I study to investigate the safety, tolerability, pharmacokinetics and antitumor activity of BB-1701 in patients with locally advanced/metastatic HER2-expressing solid tumors.

3029 Background: BB-1701 is an antibody-drug conjugate consisting of a humanized IgG1κ monoclonal antibody and eribulin. When BB-1701 targets HER2-expressing cancer cells and is internalized, free eribulin is cleaved from the ADC by cathepsin b and causes cytotoxicity to cancer cells. The neighboring cells were affected with bystander effects, like cytotoxicity on tumor cells and non-cytotoxic effects on microenvironment by free eribulin. Here, we report preliminary results from this phase 1 study (NCT04257110). Methods: This dose escalation study followed an accelerated titration and traditional "3 + 3" design with 6 dose levels from 0.4 to 2.6 mg/kg Q3W. Patients with confirmed advanced/metastatic HER2 overexpressing solid tumors, who had progressed on, or were intolerant to prior standard therapies, aged ≥ 18 years, with ECOG PS ≤ 2, and measurable disease, were enrolled. HER2 expressions were determined by IHC or next generation sequencing. Tumor imaging was conducted every 9 weeks. The primary objective is the assessment of safety and tolerability, and the secondary objective is the assessment of PK and preliminary anti-tumor activity. Results: A total of 29 patients were enrolled in this study. Tumor types were breast cancer, gastric/gastroesophageal junction cancer, colorectal cancer, gallbladder cancer, ovarian cancer and urothelial cancer. The medium prior lines of systemic therapy were 3 (range 1 – 6). During this study, no DLT was observed and the MTD was not reached. The most commonly reported (≥20%) treatment-related adverse events (TRAEs) were peripheral neuropathy, aspartate aminotransferase increased, neutrophil count decreased, white blood cell count decreased, alanine aminotransferase increased, hypertriglyceridemia, anemia, platelet count decreased. The most commonly reported ≥ grade 3 TRAEs (≥10 %) was peripheral neuropathy. There were two grade 4 adverse events: neurological symptom and sepsis. There was no interstitial lung disease observed during the study. Nine patients discontinued the study treatment due to peripheral neuropathy. Thirteen patients out of 26 patients evaluable for antitumor activity achieved partial response (PR), and 11 patients had stable diseases (SD). The best overall response rate (BOR) was 50.0% (13/26) and the disease control rate (DCR) was 92.3% (24/26). For 17 breast cancer patients in the study, 12 patients achieved PR, and 5 patients had SD. The BOR was 70.5% (12/17) and the DCR was 100% (17/17). For 5 gastric cancer patients in the study, all patients had SD. The duration of treatment ranged from 2 weeks to 66 weeks. Conclusions: BB-1701 was generally well tolerated up to 2.6 mg/kg dose levels and has shown promising antitumor activity in patients with HER2-overexpression solid tumors. Clinical trial information: NCT04257110 .

Trial START-001: A phase 1/2 study of STAR0602, a first-in-class, selective T cell receptor (TCR)-targeting, bifunctional antibody-fusion molecule, as monotherapy in patients with antigen-rich tumors post checkpoint inhibitor (CPI) treatment.

TPS2671 Background: Many patients do not respond to CPI-based therapies and most responders eventually develop resistance. Thus, the development of more effective therapies for CPI treatment resistance is a significant unmet medical need. STAR0602, a first-in-class, TCR β chain-targeting bifunctional antibody fused to a costimulatory molecule, binds the germline Vβ6/Vβ10 TCRs of human alpha/beta (aβ) T cells, and promotes the selective activation and expansion of CD8+ and CD4+ Vβ6/Vβ10 effector memory T cells by simultaneously engaging direct TCR activation with IL-2 receptor binding and activation in cis. Preclinical studies with STAR0602 and its murine surrogate showed potent single-agent anti-tumor activity in multiple CPI-refractory human organoid and murine syngeneic tumor models, and acceptable tolerability and limited cytokine release in monkeys and mice. Durable anti-tumor responses, with long-term protection from tumor re-challenge, was associated with de novo expansion and tumor infiltration of targeted Vβ T cell subsets with a novel effector memory gene signature and striking increase in TCR repertoire diversity. These data provide strong scientific rationale to investigate the safety and efficacy of STAR0602 in patients with CPI-resistant cancers. Methods: Using a 3+3 trial design, Phase 1 of START-001 is a dose escalation through eight provisional dose levels of STAR0602, administered via an intravenous infusion once every two weeks, to determine a recommended Phase 2 dose (RP2D), based on safety and tolerability, pharmacokinetics, pharmacodynamics, and preliminary anti-tumor activity. Subjects must have one of the following, histologically confirmed solid tumors that are unresectable, locally advanced or metastatic and for which standard curative therapies do not exist or are no longer effective: 1) high mutational burden solid tumors (TMB-H); 2) MSI-H/mismatch repair-deficient (dMMR) cancers; 3) Virally associated tumors including Merkel cell carcinoma, cervical, oropharyngeal, anal, penile, vaginal, and vulval cancers. After an RP2D is selected, Phase 2 (dose expansion at this RP2D) will begin to further investigate the safety and preliminary anti-tumor activity of STAR0602 in 10 provisional cohorts of patients who have the following solid tumors: TMB-H, CPI experienced; TMB-H, no prior CPI experience; MSI-H/dMMR; virally associated tumors; K-RAS wild-type and MSI-L/MMR proficient colorectal cancer (CRC); K-Ras mutant CRC; metastatic triple-negative breast cancer; relapsed and refractory epithelial ovarian cancer; metastatic castration-resistant prostate cancer; primary stage IV or recurrent non-small cell lung cancer. Phase 1 enrollment has begun since January 2023. Clinical trial information: NCT05592626 .

A phase 1 study to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics and immunogenicity of LB4330, a peptide fused to CLDN18.2 antibody targeting the tumor antigen associated CD8+t CELLS in patients with advanced solid tumors.

TPS4196 Background: PD-1/PD-L1-targeted immunotherapies have become critical roles in the treatment for many tumors. However, there is limited progress in pancreatic ductal adenocarcinoma (PDAC). PDAC is low immunogenicity. PDAC microenvironment is immunosuppressive. More than 70% PDACs have few or no CD8+ T cells around the tumor cell or in the tumor microenvironment (TME). Therefore, immunotherapy like PD-1/PD-L1 antibody alone is rarely effective for PDACs. Some cytokine or analogs may activate CD8+ T cells. An analog specifically activating tumor antigen associated (TAA) CD8+ T cells was designed and fused to anti-CLDN18.2 antibody. This specific bi-functional molecule LB4330 has high affinity to human anti-CLDN18.2 (14pM) and CD8+T cells. LB4330, as a novel, first-in-class molecule, may activate TAA CD8+ T cells in TME and has potential in alone or in combination with PD-1/PD-L1 mAb, for the treatment of advanced solid tumors, especially for Claudin 18.2 positive PDAC. Methods: This is a FIH, phase 1 study to evaluate the safety, tolerability, pharmacokinetics and immunogenicity of LB4330 in patients with advanced solid tumors (MEETCD8-001). The planned sample size is approximately 66 patients in two parts: part 1 dose escalation, will evaluate safety, tolerability, pharmacokinetics (PK), pharmacodynamics, and determine the maximum tolerated dose (MTD) and/or the recommended phase 2 dose (RP2D). Part 2 dose expansion will further characterize the safety profile and preliminary tumor response in advanced gastric and gastroesophageal junction adenocarcinoma and PDAC with Claudin 18.2 expression. In dose escalation stage, patients will be recruited with advanced solid tumors who have failed standard treatment, or for whom standard treatment is not available or applicable at this stage. Exclusion criteria include a greater risk for gastric bleeding, irritable bowel syndrome with symptoms, active virus infections. The primary endpoints are incidence of dose limiting toxicities and adverse events, MTD, and recommended phase 2 dose. Secondary objectives will evaluate PK parameters, preliminary antitumor activity, and immunogenicity of LB4330. Tumor response will be assessed per RECIST and iRECIST every 2 cycles. The Phase I study in advanced solid tumors is ongoing. Enrollment in cohort 1 began in Nov 2022. Clinical trial information: NCT05707676 .

A first-in-human phase I, dose-escalation and dose-expansion study of SY-5007, a highly potent and selective RET inhibitor, in Chinese patients with advanced RET positive solid tumors.

9111 Background: RET gene fusions have been identified as oncogenic drivers in 1-2% of non-small-cell lung cancer (NSCLC) and 10-20% of papillary thyroid carcinomas. Activating RET mutations occur in 50-60% of medullary thyroid cancer (MTC). Recently, selective RET TKIs, selpercatinib and pralsetinib, were approved for RET positive solid tumors by FDA. SY-5007 is a highly potent RET inhibitor that selectively targets RET fusions and mutations. This study is to investigate the safety, PK characteristics and preliminary efficacy of SY-5007 in Chinese patients with advanced RET-altered solid tumors. Methods: In this first-in-human phase I study, eligible patients previously treated and with positive RET were enrolled. In the dose escalation phase, following 3+3 design, the patients were administered orally with SY-5007 20 mg once daily, or 20, 40, 80, 120, 160, 200 mg twice daily in a 28-day cycle. The expansion doses (160 and 200 mg twice daily) were executed in a dose expansion phase to determine a recommended phase II dose (RP2D). Then three cohorts ( RET fusion-positive NSCLC or thyroid cancers and RET mutant MTC) at RP2D were expanded in eligible patients. Primary endpoints included safety, tolerability, MTD, DLTs. Secondary endpoints included PK and preliminary antitumor activity of SY-5007 per RECIST v1.1. Results: As of Feb.06, 2023, a total of 60 patients including 55 RET fusion NSCLC and 5 RET mutant solid tumors were enrolled into dose escalation cohorts (n = 17) and dose expansion cohorts (n = 43).Totally, 55 (91.7%) patients experienced treatment-related adverse events (TRAEs) including increased aspartate aminotransferase (50.0%), increased alanine aminotransferase (41.7%), diarrhea (41.7%), etc. Grade ≥3 TRAEs were observed in 22 (36.7%) patients including hypertension (15%), diarrhea (5%), increased alanine aminotransferase (3.3%), etc. PK study showed SY-5007 was absorbed rapidly, exposure of SY-5007 increased in a dose-dependent manner at doses between 20 and 160 mg twice daily, and it was saturated at 160 mg twice daily. In 50 evaluable patients, the overall ORR and DCR was 62.0% (95% CI, 47.2-75.4) and 94.0 % (95% CI, 83.5-98.8), respectively. 29 patients (24 NSCLC, 4 MTC) received SY-5007 at 160 mg twice daily, 27 of 28 (96.4%) evaluable patients showed tumor regression, ORR and DCR was 72.4% (95% CI, 52.8-87.3) and 89.7% (95% CI, 72.7-97.8), respectively. For NSCLC patients, the ORR and DCR was 75.0% (95% CI, 53.3-90.2) and 91.7% (95% CI, 73.0-99.0), respectively. Conclusions: SY-5007 was well tolerated in patients. Preliminary antitumor activity was also observed in patients with advanced RET-fusion positive NSCLS and RET mutant MTC. The pivotal Phase II clinical study of SY-5007 in NSCLC patients is ongoing. Research Sponsor: Shouyao Holdings (Beijing) Co., Ltd. Clinical trial information: NCT05278364 .