Dose Expansion Part Research Articles

Spartalizumab in combination with platinum-doublet chemotherapy with or without canakinumab in patients with PD-L1-unselected, metastatic NSCLC

BackgroundDespite promising outcomes of treatment with anti-programmed cell death (PD)-1/PD-ligand (L)1 agents in combination with platinum-doublet chemotherapy (PDC) in the first-line setting, a significant unmet medical need remains in patients with PD-L1-unselected non-small cell lung cancer (NSCLC).MethodsThis multicenter, open-label, phase 1b study comprising dose-confirmation and dose-expansion parts investigated the combination of spartalizumab and various PDC regimens, with or without canakinumab, in treatment-naïve patients with PD-L1-unselected, metastatic NSCLC. The primary objectives were to determine maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE) of spartalizumab, with or without canakinumab, in combination with PDC in the dose-confirmation part and antitumor activity of spartalizumab in the dose-expansion part.ResultsThe MTD/RDE of spartalizumab was 300 mg every 3 weeks (Q3W) when administered with either gemcitabine (1250 mg/m2)/cisplatin (75 mg/m2) (group A; no dose-limiting toxicities [DLTs]), pemetrexed (500 mg/m2)/cisplatin (group B; 2 DLTs: grade 2 posterior reversible encephalopathy syndrome and grade 4 hyponatremia), or paclitaxel (200 mg/m2)/carboplatin area under the curve 6 min*mg/mL (group C; 1 DLT: grade 4 neutropenic colitis). The RDE of canakinumab combined with spartalizumab and pemetrexed/cisplatin (group E; no DLTs) was 200 mg Q3W (no dose-expansion part was initiated). No new safety signals were identified. In groups A, B, C, and E, the overall response rates were 57.6%, 55.3%, 51.5%, and 57.1%, respectively. Group B compared with other groups had the longest median progression-free survival (10.4 months vs. 6.2–7.5 months), overall survival (29.7 months vs. 16.1–21.0 months), and duration of response (30.1 months vs. 6.0-8.2 months).ConclusionsThe combination of spartalizumab and PDC, with or without canakinumab, was well tolerated across treatment groups. The antitumor activity across treatment groups was comparable with that of pembrolizumab and pemetrexed combination. Canakinumab did not appear to improve the antitumor activity when combined with spartalizumab, pemetrexed and cisplatin.Trial registrationThe trial was registered in Clinicaltrials.gov with identifier no. NCT03064854. Date of Registration: 06 February 2017.

Valemetostat monotherapy in patients with relapsed or refractory non-Hodgkin lymphoma: a first-in-human, multicentre, open-label, single-arm, phase 1 study.

Few treatment options exist for patients with non-Hodgkin lymphoma, and outcomes remain poor for relapsed or refractory disease. We evaluated the safety and preliminary clinical activity of valemetostat, a novel inhibitor of EZH2 and EZH1, in patients with relapsed or refractory non-Hodgkin lymphomas. This first-in-human, multicentre, open-label, single-arm, phase 1, dose-escalation and dose-expansion trial was done in 19 hospitals across Japan and the USA. Patients were included if they were aged 18 years or older in the USA or 20 years or older in Japan with a primary diagnosis of relapsed or refractory non-Hodgkin lymphoma and an Eastern Cooperative Oncology Group performance status of 0 or 1. In the dose-escalation part, patients received oral valemetostat at doses of 150 mg per day, 200 mg per day, 250 mg per day, and 300 mg per day continuously in 28-day cycles until progressive disease or unacceptable toxicities. All patients received 200 mg per day in the dose-expansion part. The primary endpoints were safety, pharmacokinetics, and the recommended phase 2 dose; the secondary endpoints were the maximum tolerated dose and the antitumour activity of valemetostat. Responses were assessed in patients who received at least one dose, with measurable lesions at baseline according to the International Working Group 2007 revised criteria for malignant lymphoma (peripheral T-cell lymphoma and B-cell non-Hodgkin lymphoma) and the modified 2009 criteria for adult T-cell leukaemia/lymphoma. The trial is registered with ClinicalTrials.gov, NCT02732275, and is currently active, but not recruiting. Between April 7, 2016, and June 10, 2021, 90 patients (53 [59%] males and 37 [41%] females; 49 [54%] Asian, 33 [37%] White, and eight [9%] Black) were enrolled and treated with valemetostat and included in the safety analysis set. 57 (63%) patients had peripheral T-cell lymphoma, 14 (16%) had adult T-cell leukaemia/lymphoma, and 19 (21%) had B-cell non-Hodgkin lymphoma. Seven (8%) patients received valemetostat 150 mg per day, 74 (82%) received 200 mg per day, seven received 250 mg per day, and two received 300 mg per day. Median follow-up was 7·4 months (IQR 3·4-17·6). All patients had at least one treatment-emergent adverse event; the most common treatment-emergent adverse events of any grade were decreased platelet count (52 [58%] of 90 patients), dysgeusia (45 [50%]), and anaemia (38 [42%]). The most common grade 3-4 adverse events were decreased neutrophil count (21 [23%]), decreased platelet count (18 [20%]), and decreased lymphocyte count (17 [19%]). The most common serious adverse event of any grade was Pneumocystis jirovecii pneumonia (four [4%]). No treatment-related deaths occurred. The overall response rate was 54·5% (48 of 88; 95% CI 43·6-65·2) for patients in the efficacy analysis set. The maximum tolerated dose was not reached; the recommended phase 2 dose of 200 mg per day was determined. Valemetostat exposure was variable between patients and was overlapped over the dose range of 150-250 mg per day. The safety profile of valemetostat monotherapy was acceptable in these patients with relapsed or refractory non-Hodgkin lymphoma. Favourable clinical activity was observed. These findings support a new indication for valemetostat in this setting. Daiichi Sankyo.

First-in-human study of DP303c, a HER2-targeted antibody-drug conjugate in patients with HER2 positive solid tumors

DP303c is a HER2-targeted ADC with a cleavable linker-MMAE payload. Previous in vitro studies demonstrated that DP303c showed similar or better antitumor activity than T-DM1 in xenograft models. This was a multicenter, dose escalation and dose expansion phase 1 study in China. Eligible patients were 18-75 years old with HER2-positive advanced solid tumors who were unable to benefit from standard therapy. DP303c was administered intravenously every 3 weeks, with accelerated titration at lower dose of 0.5 mg/kg and 3 + 3 design with dose levels of 1.0, 2.0, 3.0 or 4.0 mg/kg at dose escalation part, followed by the selected dose level at dose expansion part. The primary endpoints were safety and tolerability, as well as identification of recommended phase 2 dose. As of Feb 28, 2023, 94 patients were enrolled and received DP303c (dose escalation: n = 22; dose expansion: n = 72), of whom 68 patients had breast cancer. One dose limiting toxicity (Grade 3 eye pain) was observed at 4.0 mg/kg dose, and the maximum tolerated dose was not reached. The most common treatment-related adverse events at grade 3 or higher were blurred vison (16.0%), dry eye (6.4%), and peripheral neuropathy (5.3%). No treatment-related death occurred. Overall, among 91 efficacy evaluable patients, 39 patients (42.9%) achieved an objective response. Disease control was observed in 62 patients (68.1%). In 66 efficacy evaluable patients with breast cancer, 34 patients achieved an objective response (51.5%). Disease control was achieved in 51 patients (77.3%). Median PFS was 6.4 months. On a molar basis, DP303c Cmax at 3.0 mg/kg doses was 132-folder higher than that for free MMAE. DP303c demonstrated promising anti-tumor activity with acceptable safety in patients with pre-treated advanced HER2 positive solid tumors, especially in breast cancer. Based on safety and efficacy results, 3.0 mg/kg Q3W was determined as recommended phase 2 dose for DP303c. (Trial registration: ClinicalTrials.gov Identifier: NCT04146610).

Safety and clinical activity of BMS-986365 (CC-94676), a dual androgen receptor ligand-directed degrader and antagonist, in heavily pretreated patients with metastatic castration-resistant prostate cancer

Metastatic castration-resistant prostate cancer (mCRPC) that progresses on androgen receptor pathway inhibitors (ARPIs) may continue to be driven by AR signaling. BMS-986365 is an orally administered ligand-directed degrader targeting the AR via a first-in-class dual mechanism of AR degradation and antagonism. CC-94676-PCA-001 (NCT04428788) is a phase I multicenter study of BMS-986365 in patients with progressive mCRPC. Patients who progressed on androgen deprivation therapy, one or more ARPIs, and taxane chemotherapy (unless declined/ineligible) were enrolled. The study included dose escalation (part A) and expansion (part B) of BMS-986365 up to 900 mg twice daily. Primary objectives were safety and tolerability, and to define maximum tolerated dose and/or recommended phase II dose. Key secondary endpoints included decline in prostate-specific antigen ≥50% (PSA50) and radiographic progression-free survival (rPFS). Parts A and B enrolled 27 and 68 patients, respectively. In part B, the median number of prior therapies was 4 (range 2-11). The most common treatment-related adverse events were asymptomatic prolonged corrected QT interval (47%) and bradycardia (34%). Part A maximum tolerated dose was not reached and recommended phase II dose selection is ongoing. Across part B three highest doses (400-900 mg twice daily, n= 60), PSA50 was 32% (n= 19), including 50% (n= 10/20) at 900 mg; median rPFS (95% confidence interval) was 6.3 months (5.3-12.6 months), including 8.3 months (3.8-16.6 months) at 900 mg; and rPFS was longer in patients without versus with prior chemotherapy: 16.5 months (5.5 months-not evaluable) versus 5.5 months (2.7-8.3 months), respectively. Efficacy was observed in patients with mCRPC with AR ligand binding domain (LBD) WT or with AR LBD mutations. BMS-986365 was well tolerated, with a manageable safety profile, and demonstrated activity in heavily pretreated patients with mCRPC with potentially higher benefit in chemotherapy-naive patients. These data show the potential of BMS-986365 to overcome resistance to current ARPIs, regardless of AR LBD mutation status.

An open-label, multicenter, phase 2 study to evaluate the safety and efficacy of BB-1701, a novel antibody drug conjugate (ADC) targeting human epidermal growth factor receptor 2 (HER2), in previously treated patients with HER2-positive (HER2+) or HER2-low unresectable or metastatic breast cancer (BC).

TPS1122 Background: Treatment options for patients (pts) with unresectable or metastatic BC have improved with the development of novel targeted therapies including trastuzumab deruxtecan (T-DXd), an ADC directed against HER2 with a cytotoxic topoisomerase I inhibitor as a payload. Currently, there are limited treatment options for pts with HER2+ or HER2-low metastatic BC that has progressed on T-DXd. BB-1701 is an ADC consisting of a monoclonal antibody targeting HER2 with eribulin (microtubule inhibitor) as a payload that is capable of exerting a bystander effect. A first-in-human dose-finding Study 101 of BB-1701 is ongoing. Here we describe Study 205, an open label, multicenter, phase 2 study of BB-1701 in pts with HER2+ or HER2-low unresectable or metastatic BC who have disease progression after treatment with T-DXd. Methods: Study 205 (NCT06188559) includes dose-optimization and dose-expansion parts for BB-1701. Eligible pts must have histologically confirmed HER2+ or HER2-low, unresectable or metastatic BC, with measurable disease per RECIST v1.1. Prior treatment must include 1–3 prior chemotherapy-based regimens for unresectable or metastatic BC, including T-DXd. The primary objectives of the dose-optimization part include determining the recommended dose (RD) and evaluating safety and tolerability of BB-1701. The RD will be assessed by randomly assigning ~50 pts into 1 of 3 dosing cohorts (1.6 mg/kg on day 1 Q3W, 0.8 mg/kg on days 1 and 8 Q3W, and 1.2 mg/kg on day 1 Q3W; IV) in a 2:2:1 ratio. Randomization will be stratified by HER2 status (HER2+ vs. HER2-low) documented prior to T-DXd treatment. The dose-expansion part will enroll ~85 pts at RD; the primary objective includes evaluating the efficacy of BB-1701 at the RD. In both study parts, secondary objectives include assessment of additional efficacy measures (i.e., duration of response [DOR], progression free survival [PFS], overall survival [OS], disease control rate [DCR], clinical benefit rate [CBR], and time to response [TTR]), and pharmacokinetics. Efficacy endpoints will be assessed per RECIST v1.1 by the investigator during the dose-optimization part or by Blinded Independent Central Review during the dose-expansion part. Safety assessments will consist of recording, monitoring, and grading of adverse events (AEs) based on CTCAE v5.0, AEs of special interest, and serious AEs. In both study parts, exploratory objectives will include evaluation of biomarkers of response to BB-1701 and BB-1701 immunogenicity; other efficacy measures (i.e., PFS on the next line of therapy) and population pharmacokinetics will be analyzed in the dose-expansion part only. Pt enrollment is currently open. Clinical trial information: NCT06188559 .

A phase 1/2 study of REGN7075 in combination with cemiplimab (cemi) in patients (pts) with advanced solid tumors: Efficacy and safety results.

2503 Background: REGN7075, a first-in-class costimulatory bispecific antibody (bsAb), aims to restore immune sensitivity in traditionally non-immunoresponsive tumors by bridging CD28+ T cells with EGFR-expressing tumor cells (unlike other bsAbs that target CD3), facilitating T-cell activation through endogenous tumor antigens. A first-in-human, open-label, Phase 1/2 study (NCT04626635) of REGN7075 (EGFR×CD28) ± cemi (anti–PD-1) in pts with advanced solid tumors was conducted, consisting of a dose escalation (Part 1) and dose expansion (Part 2) phase. This is the first report of efficacy data (Part 1) for this costimulatory bsAb EGFR×CD28 with a novel mechanism of action. Methods: In Part 1, pts with metastatic/locally advanced solid tumors who had exhausted standard treatment options received REGN7075 QW/Q3W + cemi Q3W, including a 3-week REGN7075 monotherapy QW lead-in. Primary objective: assess safety and tolerability of REGN7075 ± cemi; secondary objectives: PK characterization (REGN7075 ± cemi), preliminary efficacy (REGN7075 + cemi), and immunogenicity of REGN7075 and cemi. Biomarkers were also evaluated. Results: At Part 1 data cutoff (Oct 13, 2023), 94 pts (median age, 55.0 years; 48.9% female) were treated with REGN7075 up to the 900 mg IV dose. Most pts (65%) had microsatellite stable colorectal cancer (MSS CRC). Of the 15 pts with MSS CRC without liver metastases treated with active REGN7075 doses (≥100 mg), ORR was 20% and disease control rate was 80% (CR, n=1; PR, n=2; SD, n=9). After data cutoff, 1 additional pt with liver metastases achieved PR. No dose-limiting toxicities (DLTs) were reported; maximum tolerated dose was not reached. Most TRAEs were Grade 1–2; >95% of infusion-related reactions (IRRs) were Grade 1–2. IRRs were manageable with premedication and split/step-up dosing. One pt experienced cytokine release syndrome (CRS; Grade 1 fever). No treatment-related deaths were reported. REGN7075 concentration in serum increased more than dose-proportionally at the dose range studied (0.03–900 mg). T-cell activation-associated IFN-γ was observed with monotherapy lead-in and combination dosing. Conclusions: MSS CRC is historically unresponsive to immunotherapy. REGN7075 is one of the first immune therapies to demonstrate clinical activity in pts with MSS CRC (including a pt with liver metastases), and dose escalation was completed through 900 mg with an acceptable safety profile and no DLTs. One pt experienced Grade 1 CRS, demonstrating differentiation from CD28 superagonists and CD3-targeting bsAbs. IRRs were mitigated with premedication and split/step-up dosing. Efficacy data in non-immunoresponsive tumors, along with encouraging pharmacodynamic evidence, suggest that REGN7075 can enhance immune response and anti-tumor immunity. Initiation of dose expansion (Part 2) in select tumor cohorts with different EGFR levels is planned. Clinical trial information: NCT04626635 .

ADU-1604, a novel CTLA-4 blocking antibody, to modulate pharmacodynamic markers in patients with PD1 relapse/refractory melanoma.

9552 Background: Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) is a negative regulator of T-cell responses, also known as an immune checkpoint. The clinical relevance of CTLA-4 blockade was demonstrated by the approval of ipilimumab for the treatment of melanoma, both in the adjuvant as well as metastatic settings. ADU-1604 is a humanized hIgG1 CTLA-4 antagonist antibody. ADU-1604 binds a unique epitope on CTLA-4 demonstrating, in contrast to ipilimumab full blockade of both CD80 and CD86 interactions. In vitro and in vivo ADU-1604 demonstrates at least as potent efficacy as compared to ipilimumab, was well tolerated in non-human primates and demonstrated enhanced immunogenicity against hepatitis B vaccine in non-human primates. Methods: This is a phase 1, first-in-human (FIH), two-part, open-label clinical trial of intravenous (IV) administration of ADU-1604 given as monotherapy in subjects with advanced-stage, relapsed/refractory melanoma who relapsed or were refractory to a prior anti-PD-1/PD-L1 therapy. Main endpoints are safety of ADU-1604 monotherapy, pharmacokinetics, pharmacodynamics (upregulation of ICOS and Ki-67 on circulation CD4+ T cells and ALC, CD4+ and CD8+ T cells) as well as preliminary clinical efficacy. 20 subjects received escalating doses of ADU-1604 IV (25, 75, 225, 450 mg flat dose) Q3W. In the dose expansion part up to 20 additional patients will be treated with 225 mg dose to confirm recommended Phase 2 dose (RP2D). Safety and preliminary efficacy of ADU-1604 monotherapy in PD1 relapsed/refractory melanoma patients will be evaluated. The study was initiated in June 2022. Results: ADU-1604 was demonstrated to have a typical pharmacokinetic behavior for a human IgG1 antibody and similar exposure was observed as described for ipilimumab. Administration of ADU-1604 in cycle 1 and 2 showed a dose-dependent modulation of ICOS and Ki-67 on circulating CD4+ T cells. Similarly, in cycles 3 and 4 a dose-dependent increase of ALC and CD4+ and CD8+ T cells was detected. Notably, no DLTs across the 25, 75, 225 and 450 mg dose level have occurred. Of the patients treated at 225 and 450 mg dose levels (N=6 at 225 mg and N=6 at 450 mg), two Grade 2 severe adverse events (both immune-related enterocolitis) and two Grade 3 AESIs (ALT elevation and immune-related gastritis) suggesting that ADU-1604 has a relatively mild safety profile. Two patients at 225 mg and one patient at 450 mg demonstrated clinical efficacy. Conclusions: ADU-1604 Phase 1 dose-escalation data indicates clinical activity in line with what has been observed with other CTLA-4 blocking antibodies. Importantly, no DLTs and very limited safety signals were reported during the study. Dose expansion at 225 mg dose is ongoing in subjects with advanced-stage, relapsed/refractory melanoma who relapsed or were refractory to a prior anti-PD-1/PD-L1 therapy. Clinical trial information: 2021-002623-38 .

Phase I/II safety and preliminary efficacy of PM1022, a bispecific antibody targeting PD-L1 and TIGIT, in patients with advanced solid tumors.

e14694 Background: PM1022 is an anti-PD-L1 × TIGIT bispecific antibody that is engineered with a fully human IgG targeting TIGIT in an IgG1 wild type Fc backbone, fused to a VHH at the c-terminus targeting PD-L1. The potential MOA includes releasing T cell inhibition by blocking both the PD-L1/PD-1 and CD155/CD112/TIGIT pathways, as well as depleting Treg cells in the tumor microenvironment and engaging FcγRs to activate myeloid cells. PM1022 showed robust in vitro and in vivo efficacy in preclinical studies, and this is the first in human study. Methods: This phase Ⅰ/Ⅱ study consists of a standard 3+3 dose escalation and dose expansion part. PM1022 was administered intravenously as monotherapy on Day 1 of 21-day cycle. The primary objectives were to assess safety, tolerability and pharmacokinetics in patients with advanced solid tumors. Results: As of January 28, 2024, a total of 15 patients in dose escalation part have received at least 1 dose of PM1022, with 3 patients in each of the 100, 200, 400, 800 and 1200 mg dose levels respectively. No DLT was observed up to 1200 mg. Of the 15 patients, TRAEs occurred in 8 patients (53.3%), ≥ Grade 3 TRAEs occurred in 1 patient with platelet count decreased. No patients were discontinued from PM1022 due to TRAE. The most common TRAEs were rash (20%) and aspartate transaminase increased (20%). 14 patients completed at least one tumor evaluation. The median duration of PM1022 exposure was 6.1 weeks (range, 5.0-48.0 weeks). The ORR per RECIST 1.1 was 7.1% with a DCR of 35.7%. Preliminary antitumor activity has been observed in 1 patient with NSCLC (1200 mg, still on treatment) with previous PD-L1 TPS 100% who was enrolled after previous 3 lines therapy, including chemotherapy and anti-PD-1 treatment, and had a partial response in target lesion with 56.8% reduction. Another patient with esophageal cancer had been on PM1022 for total of 48 weeks until initiation of new anti-cancer therapy. Pharmacokinetics were dose-proportional with a terminal half-life of 7-13 days across the dose range of 100-1200 mg. Conclusions: PM1022 was safe and well-tolerated up to 1200 mg Q3W with preliminary anti-tumor activity. These findings could support further exploration of PM1022 in advanced solid tumors. Clinical trial information: NCT05867771 .

A phase 1 study of HRS-1167 (M9466), a highly selective PARP1 inhibitor, in patients (pts) with advanced solid tumors.

3154 Background: The use of first-generation dual PARP1/2 inhibitors is limited due to their hematological toxicities and inevitable drug resistance. Given that loss of PARP1 is the primary driver of synthetic lethality in homologous recombination repair (HRR) deficient tumors, and PARP2 is largely associated with hematological toxicities, development of next-generation PARPi with selectivity for PARP1 is warranted. Here, we present results of the dose escalation (D-ESC) and dose expansion (D-EXP) parts of a first-in-human study of HRS-1167 (M9466), a highly selective PARP-1 inhibitor, in pts with advanced solid tumors. Methods: Pts were eligible for the D-ESC part if they had advanced solid tumors that had progressed on standard therapies or for which no standard therapies were available. The D-ESC part began with accelerated titration (30 mg; QD) and then switched to the BOIN design (50, 100, 200, and 300 mg; QD). In the D-EXP part, previously treated pts harboring germline or somatic BRCA1/2, PALB2, or RAD51C/D mutations received HRS-1167 at 50, 100, and 200 mg QD. Prior PARPi was allowed. The primary objectives were to assess the safety and tolerability of HRS-1167. Results: As of Nov 20, 2023, 40 pts were enrolled (median lines of prior treatment, 2 [range, 1–5]; prior PARPi, 15.0%). No dose-limiting toxicities occurred, and the maximum tolerated dose was not reached. Grade ≥3 treatment-related adverse events occurred in 12 (30.0%) pts, with the most common being anemia (6 [15.0%]), decreased neutrophil count (5 [12.5%]), and decreased WBC count (5 [12.5%]). Of the 24 pts with HRR mutations who had at least one post-baseline assessment for tumor response, 10 (41.7%) pts had objective responses (8 ovarian cancer, 1 prostate cancer, and 1 pancreatic cancer). PK exposures were approximately dose-proportional. The median Tmax was 1.0–1.5 h, and the mean t1/2 was 10.5–15.0 h following a single dose of HRS-1167 at 30–300 mg. No obvious drug accumulation was observed (Rac, 1.08–1.30 for Cmax; 1.29–1.62 for AUC0-24). Conclusions: HRS-1167 was well-tolerated and exhibited favorable safety and PK profiles in pts with advanced solid tumors, and demonstrated promising anti-tumor activity in pretreated pts with HRR mutations. Clinical trial information: NCT05473624 .

Dose-expansion part of a phase 1b global study of E7386 in combination with lenvatinib (LEN) in patients (pts) with hepatocellular carcinoma (HCC) and other solid tumors including endometrial cancer (EC).

TPS3169 Background: E7386, a first-in-class anticancer agent, inhibits protein-protein interaction between β-catenin and the CREB-binding protein, thus modulating Wnt/β-catenin signaling. E7386 is being tested in combination with LEN in the open-label global phase 1b Study 102. The dose-escalation part of Study 102 determined the recommended dose of E7386 + LEN in pts with HCC and other solid tumors. Here we describe the ongoing dose-expansion part in pts with HCC or EC. Methods: Eligible pts ≥18 years old should have an ECOG PS of 0-1 and a confirmed diagnosis of advanced, unresectable, or recurrent solid tumor. Pts with HCC will have a Child-Pugh score of A and a categorization of BCLC Stage B (not amenable to locoregional therapy or refractory to locoregional therapy, and not amenable to a curative treatment) or Stage C. Pts with HCC should also have received 1 prior immuno-oncology (IO)-based regimen and have progressed on/after prior treatment with IO therapy. If ineligible for IO therapy, pts should not have received prior systemic therapy; pts who previously received LEN are ineligible. In the EC subpart, pts should have disease progression after receiving prior platinum-based chemotherapy (PBT) and an IO-based therapy for EC. Pts may have received 1 additional line of PBT if given in the neoadjuvant/adjuvant setting, but not exceeding 3 lines of therapies. Pts with EC who are ineligible for IO therapy may have received only 1 prior systemic therapy including PBT. Pts who have received prior LEN therapy will be eligible if they meet protocol-specified criteria. Pts with HCC (n≈60) will be randomized in a 2:1 ratio into 1 of 2 treatment arms and will receive either the combination E7386 + LEN or LEN monotherapy in 28-day cycles. E7386 will be administered at 100 mg BID in the combination arm and LEN will be administered QD at 8 mg (if body weight <60 kg) or 12 mg (if body weight ≥60 kg) in both arms. Pts with HCC will be stratified by geographical region (Western Europe and North America vs Japan vs other countries). Pts with EC (n≈30) will receive only the combination E7386 120 mg BID + LEN 14 mg QD. The expansion part of Study 102 aims to assess safety and tolerability (primary endpoints), and pharmacokinetics and preliminary efficacy (secondary endpoints), of E7386 in combination with LEN for pts with HCC and EC. Efficacy of LEN monotherapy will be assessed for HCC (secondary endpoint). Tumors will be assessed by investigator per RECIST v1.1 every 8 weeks from the date of the first dose. Adverse events will be monitored and recorded for up to 30 days after the last dose or until initiation of a new anticancer therapy, whichever occurs first. Study sites will include the United States, France, Republic of Korea, Japan, and Taiwan. As of February 5, 2024, 46 pts with HCC and 16 pts with EC have enrolled. Clinical trial information: NCT04008797 .

A phase 1 study of SHR-A1912, a CD79b targeted antibody-drug conjugate (ADC), in patients (pts) with B-cell non-Hodgkin lymphoma (B-NHL).

7064 Background: CD79b is an attractive therapeutic target for B-NHL. SHR-A1912 is a novel ADC containing an anti-CD79b monoclonal antibody conjugated to the DNA topoisomerase I inhibitor. Here, we present results of the dose-escalation (D-ESC) and dose-expansion (D-EXP) parts of a first-in-human phase 1 study of SHR-A1912 in B-NHL. Methods: Pts with histologically confirmed B-NHL that had failed to respond to or had progressed after ≥1 prior anti-cancer therapy were enrolled. The D-ESC part commenced with accelerated titration at 0.1 and 0.3 mg/kg and then switched to an i3+3 scheme at escalated doses starting from 0.6 mg/kg (Q3W, IV). In the D-EXP part, additional pts were enrolled to selected doses (approximately 10–12 pts in total per dose level). Primary objectives were to assess the safety and tolerability of SHR-A1912 and determine the RP2D. Results: As of Nov 7, 2023, 49 pts were enrolled (n=1, 1, 7, 3, 13, 13, and 11 in the 0.1, 0.3, 0.6, 1.2, 1.8, 2.7, and 3.6 mg/kg dose cohorts), including 33 pts with diffuse large B-cell lymphoma (DLBCL), 12 with follicular lymphoma (FL), and 4 with marginal zone lymphoma (MZL). Pts had received a median of 2 lines of prior treatment (range, 1–9). DLTs occurred in 3 pts during D-ESC (grade 4 decreased neutrophil count lasting ≥3 days in 0.6 and 3.6 mg/kg cohorts, 1 pt for each; grade 3 pneumonia in 2.7 mg/kg cohort, 1 pt). The 1.8, 2.7, and 3.6 mg/kg cohorts were expanded. Overall, grade ≥3 treatment-related adverse events occurred in 20 (40.8%) pts, with the most common (≥20%) being decreased neutrophil count. 41 pts with baseline target lesions had at least one post-baseline assessment; ORR was 56.1% (95% CI, 39.8–71.5), and 6-mo DoR rate was 62.7% (95% CI, 26.7–84.8). As for subtypes, ORR was 51.9% in pts with DLBCL (57.1% and 77.8% in the 2.7 and 3.6 mg/kg cohorts, respectively), 63.6% in pts with FL, and 66.7% in pts with MZL (Table). The mean half-life of conjugated antibody ranged from 4.7 to 5.3 days for pts in the 1.8–3.6 mg/kg cohorts, with volume of distribution close to human plasma volume. The plasma exposure of free toxin was low, with the molar ratio of toxin/conjugated-antibody <1%, and no accumulation was observed. Conclusions: SHR-A1912 was tolerable up to 3.6 mg/kg and had promising anti-tumor activity in pts with previously treated B-NHL, supporting further investigations of SHR-A1912. Clinical trial information: NCT05113069 . [Table: see text]

A first-in-human study of the potent and highly selective BTK degrader ABBV-101 in patients with relapsed/refractory B-cell malignancies.

TPS7091 Background: Bruton tyrosine kinase (BTK) is a clinically validated target with an integral role in the proliferation and survival of neoplastic cells in several B-cell malignancies. Inhibitors of BTK, such as ibrutinib, have revolutionized the treatment landscape for B-cell malignancies. However, long-term use can lead to disease progression and clinical resistance associated with mutations in BTK. ABBV-101 is a reversible BTK degrader. By preclinical kinome profiling, ABBV-101 has demonstrated high selectivity with the potential for best-in-class AE profile. ABBV-101 has also shown potent activity against BTK wildtype and multiple therapy-resistant mutant forms. Degradation eliminates BTK scaffolding and enzymatic functions, which has led to deeper, more durable responses vs covalent and reversible BTKi in animal models (Pan C, et al. ASH 2023). Herein, we describe the first-in-human study of ABBV-101 monotherapy in patients with relapsed/refractory B-cell NHL. Methods: This international phase 1, open-label, multicenter study (NCT05753501) is evaluating the safety, tolerability, pharmacokinetics (PK), and preliminary efficacy of ABBV-101. Eligible patients(≥18 years) have measurable disease, received ≥2 prior systemic therapies, and have no available therapies known to provide clinical benefit.Primary objectives are to characterize safety and tolerability of ABBV-101; secondary objectives are to evaluate PK and preliminary efficacy. The study is conducted in 2 parts: dose escalation (part 1) and dose expansion (part 2). Part 1 aims to establish the maximum administered dose and maximum tolerated dose of ABBV-101 guided by a Bayesian optimal interval design; additional patients may be enrolled to a previous dose level to further explore safety, PK, and efficacy. Patients with WHO-defined chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, follicular lymphoma, marginal zone lymphoma, lymphoplasmacytic lymphoma (including Waldenström macroglobulinemia), and transformed indolent NHL (including Richter’s transformation) are eligible. Part 2 will further characterize the safety and preliminary efficacy of ABBV-101; patients diagnosed with CLL/SLL (up to 3 dose cohorts) and non-germinal center DLBCL (1 cohort) are being enrolled. ABBV-101 is administered orally until disease progression, intolerable toxicity, or other study discontinuation criteria are met. Safety assessments include, but are not limited to, AEs, clinical laboratory parameters, vital signs, and ECG. Response evaluations are performed per disease-specific response criteria at screening and every 8 weeks (1st year), 3 months (2nd year), or 4 months (3rd year onward) until progressive disease. Enrollment is ongoing with active sites in the US and Japan. Clinical trial information: NCT05753501 .

Efficacy and safety of sigvotatug vedotin, an investigational ADC, in NSCLC: Updated phase 1 results (SGNB6A-001).

8521 Background: Integrin beta-6 (IB6), a tumor-associated membrane protein, plays an important role in pathogenesis and invasiveness and its expression correlates with poor outcomes. Sigvotatug vedotin (SV), formerly called SGN-B6A, is an IB6-directed ADC with encouraging activity in NSCLC in the Ph 1 study SGNB6A-001 (NCT04389632) (Hollebecque 2023). Here, we report updated efficacy and safety of SV in NSCLC. Methods: SGNB6A-001 is an open-label, multicenter, Ph 1 study evaluating the safety, pharmacokinetics (PK), and antitumor activity (cORR, DOR, and PFS per RECIST v1.1, and OS) of SV in patients (pts) with advanced solid tumors. Multiple dose regimens were explored during dose escalation (Part A). Dose expansion (Part B) is ongoing with selected regimens in various tumors including NSCLC. Parts C and D will evaluate SV in combination with pembrolizumab in NSCLC and HNSCC. Eligible pts had no therapeutic options (Part A) or had received platinum-based and anti-PD-(L)1 therapy unless contraindicated (Part B) and were dosed with the SV expansion regimens on D1 and D8 in a 21-day cycle (2Q3W; 1.2/1.25 mg/kg total body weight [TBW]) or D1 and D15 in a 28-day cycle (2Q4W; 1.5 mg/kg TBW, 1.8 mg/kg adjusted ideal body weight [AiBW]). Results: As of 01-Dec-2023, 306 pts had received SV; 113 pts with NSCLC received expansion regimens in Parts A and B. Prior lines of therapy and efficacy data for all pts with NSCLC and select subgroups are summarized in the table; cORR was 19.5% (95% CI, 12.6-28.0) in all pts with NSCLC and 32.5% (95% CI, 18.6-49.1) in pts with non-squamous (non-Sq)/taxane-naive NSCLC. Additional time-to-event data will be presented. Rates of TEAEs, ≥G3 TEAEs, SAEs, and TEAEs leading to discontinuation were 98.2%, 46.0%, 33.6%, and 13.3% in pts with NSCLC, and were consistent in all treated pts. The most common ≥G3 TEAEs in pts with NSCLC were dyspnea (9.7%), fatigue (7.1%), and neutropenia (5.3%). One pt with NSCLC had a treatment-related death (pneumonitis). PK variability across weight groups was lowest with 1.8 mg/kg AiBW 2Q4W. Conclusions: SV continues to demonstrate encouraging antitumor activity and a manageable safety profile in pts with NSCLC. Data at 1.8 mg/kg AiBW 2Q4W support initiation of the Ph 3 SGNB6A-002 study in 2/3L NSCLC (NCT06012435) and combination with pembrolizumab in earlier settings. Clinical trial information: NCT04389632 . [Table: see text]

Clinical outcomes from a phase I clinical trial of a novel oncolytic virus VG161 in patients with hepatocellular carcinoma (HCC) refractory after 2 prior lines of therapy including checkpoint inhibitors (CPI).

4105 Background: This study aims to investigate the safety and anti-tumor activity of VG161 expressing IL12, IL15/IL15 receptor α unit, and PD-L1 blocking peptide in patients with HCC refractory to standard therapies. Methods: The study was conducted as a multicenter phase I trial with fast titration and 3+3 dose escalation part (A) and expansion part (B), which enrolled patients with primary liver cancer refractory to standard therapies. Patients in part A were dosed in 5 cohorts on days 1, 2 and 3 by image-guided intratumoral injections with dosing ranges from 1.0×10^8 to 5×10^8 PFU per 28 days treatment cycles. Part B used a single arm Simon's two-stage design at the recommended phase 2 dose (RP2D). The study endpoints were safety, and efficacy assessed by objective response rate (ORR) and Disease Control Rate (DCR) by RECIST1.1 and mRECIST (HCC), PFS and OS. Pretreatment HCC tumor samples were collected and analyzed by RNAseq. Results: 44 patients including 40 HCC (Male/Female: 37/3; median age: 58years) were dosed and no DLTs were reported. The most common Treatment-Related Adverse Events (TRAEs) was fever, which was resolved with symptomatic treatment. RP2D was determined as 1ⅹ10^8 PFU daily on day 1, 2 and 3 of each cycle. Of 40 HCC patients, 35 failed after 2 prior lines of therapy and were eligible for tumor assessment. ORR was 17.14% (6/35), DCR was 60.00% (21/35). The median PFS and OS were 2.90 (95%CI: 1.85-3.95) and 9.40 (95%CI: 0.47-18.33) months respectively. Statistically significant OS prolongation was observed in a subgroup of 22 HCC patients who progressed after receiving at least 3 months of CPI (PreCPI>3 m) as compared to those who received CPI for ≤3 months (PreCPI ≤ 3 m). The median OS was 17.30 months (95%CI: 5.35-29.25) vs. 7.40 months (95%CI: 5.11-9.69), HR: 0.32 (95%CI: 0.10 to 0.98) (p<0.05). Patients who received targeted or CPI therapies after VG161 survived longer than those who did not receive any anticancer treatment although they all previously failed such therapies [20.10 months (95%CI: 13.19-27.01) vs. 8.80 months (95%CI: 6.34-11.26), HR: 0.30 (95%CI: 0.10-0.88), P<0.05]. PreCPI>3 m and anti-cancer treatment after VG161 were the 2 independent factors with significant impact on OS (P<0.05). A gene signature was identified based on RNAseq data which predicted the prolonged OS in the study patients (P<0.01) but not in patients retrieved from TCGA database. Conclusions: VG161 was well tolerated and demonstrated comparable ORR and DCR with other CPIs data in 2L HCC. VG161 also prolonged survival in a subgroup of patients identified by prior treatment or gene signature, supporting further studies with enrichment of patients who may benefit from the treatment. The implications of pre/post VG161 CPI treatment on OS underscore a combination strategy for improving outcomes. Clinical trial information: NCT04806464 .

Phase 1/2 clinical trial of JIN-A02, a 4th generation EGFR-TKI, in patients with 3rd generation EGFR-TKI resistance in EGFR mutated advanced/metastatic non-small cell lung cancer (NSCLC).

TPS8658 Background: Epidermal growth factor receptor (EGFR) mutations are the most common driver mutations in NSCLC. EGFR tyrosine kinase inhibitors (TKIs) are the recommended front-line option for EGFR-mutant advanced NSCLC patients, but patients invariably develop acquired resistance and face disease progression. JIN-A02, a 4th generation EGFR-TKI intended for oral administration, selectively and reversibly binds to EGFR mutations, including the C797S and/or T790M mutation that causes resistance to 3rd generation of EGFR-TKIs. Pre-clinical studies with EGFR C797S and/or T790M mutated cell lines showed that JIN-A02 can inhibit cell growth in a dose dependent manner and has a high degree of selectivity over wild-type EGFR. In vivo studies showed that administration of JIN-A02 dose-dependently inhibited tumor growth in the C797S+ xenograft mice model. Moreover, JIN-A02 shown to penetrate blood-brain barrier and exhibit anti-tumor activity in an intracranial tumor model. The strong potency and high selectivity of JIN-A02 for mutant EGFR may offer improved therapeutic window in the clinical setting vs available EGFR-TKIs. Methods: JIN-A02 is being evaluated in this Phase 1/2, multicenter, an open-label trial (NCT05394831) for subjects with advanced NSCLC harboring C797S and/or T790M mutation as a monotherapy. The primary object of this study is to assess safety, tolerability, pharmacokinetics, and anti-tumor effect for determining the recommended phase 2 dose (RP2D) of JIN-A02. The inclusion criteria are that the subject (≥ 18 years) must have an advanced or metastatic NSCLC showed progress disease (PD) after receiving approved standard EGFR-TKI therapies and/or platinum-based anticancer chemotherapy is allowed up to 1 time after using EGFR-TKI treatment with ECOG status 0 or 1. Before enrollment in the study, the EGFR mutation status is determined using either tumor tissue and/or plasma ctDNA. This study comprises three parts, dose escalation (Part A), dose exploration (Part B), and dose expansion (Part C). In Part A, dose escalation, comprised of 5 cohorts ranged from a starting dose of 12.5 mg P.O, QD to a top dose of 150 mg P.O, QD with every three subjects, is carried out where the maximum tolerated dose (MTD) is evaluated in subjects with 28-day cycles. Dose-limiting toxicities (DLT) are evaluated for 21 days. In Part B, dose exploration is carried out to evaluate the safety of JIN-A02 further and to determine the RP2D using 2 preliminary effective dose levels from Part A in subjects. In Part C dose-expansion study, subjects (n=36 for each cohort) are divided into 5 different cohorts based on the EGFR mutation (both or single positive of C797S and T790M), and the anti-tumor activity of JIN-A02 is evaluated according to RECIST v1.1 at RP2D. Clinical trial information: NCT05394831 .

An open-label phase 1 study to investigate SGNCEACAM5C/SAR445953 in adults with advanced solid tumors (SGNCEA5C-001).

TPS3160 Background: Patients (pts) with recurrent or metastatic solid tumors, including non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), colorectal cancer (CRC), gastric adenocarcinoma (GC), and pancreatic ductal adenocarcinoma (PDAC), have limited treatment options with short PFS and OS despite recent advances (1-3). Carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) is highly expressed across multiple solid tumors, such as CRC, GC, PDAC, and NSCLC. Restricted normal tissue expression and efficient lysosomal trafficking of CEACAM5 highlight its potential as an anticancer target. SGN-CEACAM5C is a novel investigational antibody-drug conjugate (ADC) directed to CEACAM5 composed of the humanized immunoglobulin G (IgG1) anti-CEACAM5 monoclonal antibody tusamitamab chemically conjugated to 8 molecules of the topoisomerase 1 inhibitor 7-aminomethyl-10,11-methylenedioxycamptothecin (AMDCPT). SGN-CEACAM5C selectively binds to CEACAM5 present on the cell surface and is internalized via the endo-lysosomal pathway, with subsequent release of the payload through enzymatic cleavage. Release of the cytotoxic payload induces DNA damage, cell cycle arrest in S phase, and apoptosis in tumor cells. In vitro bystander activity was observed against tumor cells without CEACAM5 surface expression. SGN-CEACAM5C is highly active in multiple patient-derived xenograft models, including CRC, GC, and NSCLC, across various levels of CEACAM5 expression (4,5). These preclinical findings justify evaluation of SGN-CEACAM5C in a clinical trial setting. Methods: SGNCEA5C-001 (NCT06131840) is a phase 1, open-label, multicenter study designed to characterize the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary antitumor activity of SGN-CEACAM5C in adults with select advanced solid tumors. This study consists of dose escalation (Part A), dose and schedule optimization (Part B), and dose expansion (Part C). Eligible pts are adults ≥18 years of age with confirmed metastatic or unresectable solid tumor malignancy, measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, an ECOG PS of 0-1, and 1 of the following tumor types: CRC, GC/gastroesophageal junction adenocarcinoma (GEJ), PDAC, NSCLC (squamous/non-squamous), or SCLC. Primary endpoints include incidence of AEs, laboratory abnormalities, dose modifications due to AEs, dose-limiting toxicities, and cumulative safety. Secondary endpoints include estimates of PK parameters, incidence of antidrug antibodies, objective response rate and best response per RECIST v1.1 by investigator, duration of response, PFS, and OS. Safety and antitumor activity endpoints will be summarized using descriptive statistics. Recruitment is ongoing for Part A in North America. 1. Bordry 2021. 2. Chakrabarti 2022. 3. Merle 2022. 4. Baudat 2023. 5. Baudat 2024. Clinical trial information: NCT06131840 .

ARTEMIS-001: Data from a phase 1a/b study of HS-20093 in patients with relapsed small cell lung cancer (SCLC).

8093 Background: SCLC is characterized by a high rate of proliferation and poor prognosis, and new therapies are urgently needed. B7-H3 is highly expressed in SCLC. HS-20093, a B7-H3-targeted antibody-drug conjugate (ADC), demonstrated antitumor activity in advanced solid tumors in the dose escalation part of ARTEMIS-001 study (Jie Wang et al., JCO, 2023) (NCT05276609). Here, we present results on the efficacy and safety of the expansion doses in patients (pts) with SCLC from phase 1a/b. Methods: ARTEMIS-001 study consisted of dose escalation (1a) and expansion (1b) part. Pts were treated with doses of 1.0 to 16.0 mg/kg HS-20093 every 3 weeks in dose escalation, and were treated with doses at 8.0 mg/kg and 10.0 mg/kg randomly in dose expansion. Pts with SCLC were required to have received prior platinum-based standard therapy. B7-H3 expression was retrospectively evaluated by IHC. Results: As of data cutoff November 30th 2023, a total of 56 pts with extensive stage SCLC (ES-SCLC) were enrolled and received ≥1 dose of HS-20093 with doses at 8.0 mg/kg (n=31) or 10.0 mg/kg (n=25). Median prior lines of therapy was 2.0 (range: 1-6). All pts received platinum plus etoposide and 73.2% (41/56) received immunotherapy. Safety profile was consistent with previous reports. The most common grade≥3 treatment-related adverse events (≧10%) were neutropenia, leukopenia, lymphopenia, thrombocytopenia and anemia. Out of 56 pts, 52 pts were efficacy evaluable (8.0 mg/kg: 31 pts; 10.0 mg/kg: 21 pts). HS-20093 showed encouraging efficacy in relapsed ES-SCLC (Table). Tumor shrinkage in target lesions occurred in 96.2% (50/52) pts with a post-baseline scan. Deep response defined as tumor shrinkage ≥50% was obtained in 44.2% (23/52) pts. Median overall survival has not yet reached. Responses were observed regardless of B7-H3 expression. Pharmacokinetic (PK) showed approximately dose-proportional increase in exposure with a half-life of 3-7 days. PK profiles of total antibody and ADC were similar and exposure to payload was considerably low. Conclusions: HS-20093 demonstrated promising antitumor activity and manageable safety in pts with previously-treated SCLC. Phase 3 study is planned to compare the efficacy and safety of HS-20093 with standard-of-care chemotherapy in relapsed SCLC. Clinical trial information: NCT05276609 . [Table: see text]

4CAST: A phase 1b dose exploration, open-label, single-center study evaluating the safety of INO-464 in combination with chemotherapy in patients with metastatic breast cancer.

e13112 Background: Metastatic triple negative breast cancer (TNBC) has a poor prognosis and the development of new targeted therapies is an area of unmet need. The androgen receptor (AR) antagonist, INO-464, but not abiraterone or enzalutamide, blocks chemotherapy induced cell plasticity to inhibit and primary and metastatic breast cancer (MBC) growth. Single agent INO-464 at a dose of 450mg/d is well tolerated but has low efficacy. Laboratory data demonstrates suppression of metastatic TNBC and an increase in survival with the combination of INO-464 and taxane chemotherapy. Methods: We designed a Phase 1b open-label, single center dose exploration (Part 1) and dose expansion (Part 2) clinical trial of INO-464 450mg/d with docetaxel (IV 75mg/m2 q3wkly) or nab-paclitaxel (IV 100mg/m2 D1/8/15 q4wkly) in any subtype of MBC. The primary objective was to assess the safety and tolerability of INO-464 (450mg/d) and docetaxel or nab-paclitaxel utilizing a rolling 6 design, as well as to determine the maximum tolerated dose (MTD) and the recommended dose of INO-464 to be given with a taxane in the dose expansion study. Secondary objectives included anti-tumor activity and testosterone levels. Results: Recruitment began in August 2022. The cut-off date for this analysis was 19 January 2024. Eight patients have been treated to date and 6 patients were DLT evaluable. All were women with MBC with mean age of 56 (range 48-64) years. Patients had received a median of 5 (range 2 to 7) lines of chemotherapy for MBC. Patient 001 had G3 anaphylaxis due to docetaxel that resolved with adrenaline but came off study and was not DLT evaluable. The protocol was amended to give INO-464 with 1mg of dexamethasone. No DLTs were subsequently observed. Adverse events (AEs) were mostly low grade and chemotherapy related although G2 pneumonitis occurred beyond the DLT period in two patients, one of whom had prior sacituzimab govotecan-related pneumonitis. INO-464-related AEs were G1 fatigue/headache in 4/6 patients. Seven of seven patients had a best response (RECIST1.1) SD, and CA15.3 stability was seen in 4/7 patients. Baseline serum testosterone was detectable in 4/6 patients (range 0.5-1.3 nmol/L, lower limit of detection of <0.5), and remained undetectable or at the lower limit of detection throughout treatment. Conclusions: The MTD of INO-464 is 450mg daily with 0.5mg dexamethasone in combination with docetaxel or nab-paclitaxel chemotherapy. The combination is well tolerated with early efficacy signals. Dose expansion will test the combination in metastatic TNBC with nuclear AR positive breast cancer. Clinical trial information: NCT04947189 .

A phase 1 study of the BET inhibitor ZEN003694 in combination with the MEK1/2 inhibitor binimetinib in solid tumors with RAS pathway alterations and triple-negative breast cancer (NCI number 10449).

TPS3182 Background: Bromodomain and extra-terminal (BET) proteins serve as epigenetic readers and regulate transcription by binding acetylated lysines in histones. BET inhibitors target this epigenetic machinery modifying the expression of oncogenes and have the potential to overcome drug resistance in different settings. Resistance to mitogen-activated extracellular kinase (MEK) inhibition appears to rely upon changes in gene expression, a process that can be potentially inhibited via BET blockade. Preclinical data have demonstrated synergistic efficacy of dual MEK and BET inhibition in MAPK-altered solid tumors. Triple negative breast cancer (TNBC) is a disease frequently found to have gene amplifications in BRAF, NF1 mutations, and upstream regulators of the MAPK pathway and preclinical work has shown efficacy with dual inhibition of MEK and BET. Methods: This phase 1, open-label, multicenter study was designed to evaluate the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of the BET inhibitor ZEN003694 in combination with the MEK inhibitor binimetinib in solid tumors with RAS pathway alterations and TNBC. The study has two parts: dose escalation (part 1) which plans to recruit a maximum of 30 patients and dose expansion (part 2), which will comprise 12 patients. The primary objective of part 1 is to determine the MTD and recommended Phase 2 dose (RP2D), whereas the primary objective of dose expansion is to evaluate safety and toxicity. Secondary objectives include tolerability, pharmacokinetics (PK), and antitumor activity. Additional analyses will explore epigenetic changes such as ChIPseq to determine levels of H3K27ac and ATACseq to determine treatment-induced changes in open chromatin regions. ZEN003694 is given orally daily, and binimetinib is administered orally twice daily in 28-day cycles. Dose escalation is being conducted using a standard 3+3 cohort design to determine the MTD. Part 1 requires evaluable or measurable disease, whereas Part 2 requires measurable disease as per RECIST v1.1. Patients must have an ECOG performance status of ≤2. Included tumors are TNBC (estrogen receptor ≤1%, progesterone receptor ≤1%, human epidermal growth factor receptor 2 (HER2) 0–1+ or non-amplified) or any other solid tumor with actionable MAPK alterations (e.g. KRAS, NRAS, HRAS, or BRAF activating mutations, inactivating NF1 mutations, or BRAF fusions). Patients with any PI3K pathway activating genomic alterations are excluded. Prior therapy with BET, RAF, MEK, or ERK inhibitor is not permitted. This study is currently ongoing in dose escalation. Clinical trial information: NCI number 10449.

First-in-human trial of M9140, an anti-CEACAM5 antibody drug conjugate (ADC) with exatecan payload, in patients (pts) with metastatic colorectal cancer (mCRC).

3000 Background: CEACAM5 is a cell surface protein with limited expression in adult healthy tissues, but high expression in various adenocarcinomas, particularly in CRC (>90% of pts). M9140 is the first anti-CEACAM5 ADC with a topoisomerase 1 inhibitor (Top1i) payload (exatecan). The ß-glucuronide linker connecting the M9140 antibody backbone to the payload is highly stable in circulation (drug-to-antibody ratio=8). In preclinical models, M9140 has demonstrated strong potency, antitumor activity, and a bystander effect. Methods: This Phase 1 trial (NCT05464030) investigated the safety, tolerability, pharmacokinetics (PK), and preliminary clinical activity of M9140 as monotherapy (Q3W [Day 1 of 21-day cycles]; IV) in adults with CRC (ECOG PS ≤1) who had received ≥2 prior lines of treatment. The primary objectives of Part 1A were to determine the maximum tolerated dose (MTD) and/or recommended dose(s) for expansion (RDE). Results: At data cutoff (19 Jan 2024), 40 pts from the US, EU, and Japan were treated across 7 dose levels (DLs): 0.6 mg/kg, 1.2 mg/kg (n=3, each), 2.4 mg/kg (n=7), 2.6 mg/kg (n=4), 2.8 mg/kg (n=12), 3.0 mg/kg (n=4), and 3.2 mg/kg (n=7, including 3 pts with primary G-CSF prophylaxis). Most pts were heavily pretreated (80% had ≥3 lines of prior treatment; 100% received irinotecan). Overall, 6 pts experienced dose-limiting toxicities (DLTs); the majority were hematological adverse events at DLs 3.0 and 3.2 mg/kg; 1 patient (at 2.8 mg/kg) experienced a Grade 5 sepsis. The most frequently reported Grade ≥3 treatment-emergent adverse events (TEAEs) were neutropenia in 16 (40.0%) pts, thrombocytopenia and anemia in 11 (27.5%) pts each, and WBC decreased in 10 (25.0%) pts. No events of ocular toxicity/interstitial lung disease (ILD) were reported. The best objective response per RECIST v1.1 was partial response (PR) in 4 (10.0%) pts (3 confirmed) (all at DLs ≥2.4 mg/kg); stable disease (SD) in 17 (42.5%), including 6 (15.0%) lasting for ≥100 days and progressive disease (PD) in 6 (15.0%) pts. For a total of 13 (32.5%) pts, the best overall response was not evaluable, including 6 (15.0%) who had no on-treatment tumor assessment yet. The preliminary median progression-free survival (PFS) was 6.7 months (95% CI: 4.6, 8.4). As of data cutoff, 15 (37.5%) pts are continuing treatment. Based on the safety, tolerability, preliminary clinical activity, PK, and PK/pharmacodynamics modeling data, 2.8 mg/kg was declared as the MTD, and 2.4 mg/kg and 2.8 mg/kg were chosen as the RDEs and have been taken forward into a randomized expansion study. Conclusions: M9140 demonstrated encouraging activity in heavily pretreated pts with advanced CRC, with a manageable and predictable safety profile. Contrary to approved ADCs with Top1i payloads, no ILD or ocular toxicities were observed. Evaluation of M9140 in mCRC continues in the dose expansion part of this study. Clinical trial information: NCT05464030 .