Advanced Solid Tumor Malignancies Research Articles

An open-label study to assess the safety and efficacy of naporafenib (ERAS-254) administered with trametinib in previously treated patients with locally advanced unresectable or metastatic solid tumor malignancies with RAS Q61X mutations (SEACRAFT-1).

TPS3178 Background: The rat sarcoma viral oncogene (RAS)/mitogen-activated protein kinase (MAPK) pathway is a key signaling cascade that drives cell proliferation, differentiation, and survival. Inappropriate activation of this pathway drives tumorigenesis in a subset of solid tumors. There are 3 isoforms of RAS (KRAS, NRAS, and HRAS) with the most commonly mutated codons being 12, 13, and 61. While these codon mutations map to the active site of RAS, they appear to have differential impacts on pathway activation. Mutations at codon 61 (RAS Q61X) are generally thought to be the most MAPK pathway-activating relative to mutations at codons 12 and 13 and are therefore thought to be the most oncogenic. Naporafenib is a pan-RAF inhibitor that is being evaluated in combination with trametinib, which inhibits MEK, a downstream node of the RAS/MAPK pathway. Clinical proof of concept (PoC) in patients with NRASm melanoma (of which 80 to 90% have Q61X mutations) and preliminary PoC for patients with RAS Q61X NSCLC have been established for the combination. Preclinical data across tumor types suggest that RAS Q61X is a potential predictive biomarker for the combination of naporafenib with trametinib, a hypothesis being tested in this trial. Methods: SEACRAFT-1 (NCT05907304) is a Phase 1b, open-label study evaluating the clinical activity and safety of the combination of naporafenib and trametinib in pts with locally advanced, unresectable, or metastatic solid tumor malignancies that are not responsive to standard therapies or for which there are no standard therapies. Eligible pts must be ≥18 years (or ≥12 and <18 years in an adolescent substudy) with documented RAS Q61X mutation by an analytically validated assay. Pts must also have ≥1 measurable lesion per RECIST (Response Evaluation Criteria in Solid Tumors, v1.1) and Eastern Cooperative Oncology Group (ECOG) Performance Status ≤2 (or Karnofsky/Lansky Performance Status ≥70 for adolescent pts). Exclusion criteria include prior therapy with an ERK, MEK, RAF, or RAS inhibitor, QTcF >450 ms at baseline, and left ventricular ejection fraction (LVEF) <50% at baseline. A total of up to 115 pts will be enrolled to receive naporafenib 200 mg BID and trametinib 1 mg QD continuous in 28-day cycles until disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint is ORR; secondary endpoints include assessment of PFS, DOR, safety, and tolerability. Clinical trial information: NCT05907304 .

Safety and preliminary efficacy of different doses of fecal microbiota capsule transplantation combined with anti-PD-1 inhibitor for patients with advanced malignant solid tumors.

e14622 Background: Chemotherapy combined with anti-PD-1 inhibitors has now become the standard first-line(1L) treatment for most malignant solid tumors. However, most Phase III studies have found that overall progression-free survival (PFS) with 1L combined subsequent immuno-maintenance therapy (IMT) is still less than 1 year. Fecal microbiota transplantation (FMT) has been shown to synergize with PD-1 antibodies to enhance efficacy. In this study, we administered oral microbiota capsule transplantation to patients(pts) during 1L IMT to evaluate its safety, preliminary efficacy, optimal dosage, and explore the changes in gut microbiota composition and serum metabolism (ChiCTR2100054928). Methods: This is a dose-escalation, exploratory clinical trial. The donor capsules were derived from the feces of a healthy 10-year-old child from a rural area. Twelve late-stage pan-cancer pts who had received standard 1L chemotherapy + PD-1 antibodies and achieved stable or responsive disease were enrolled. The first 3 patients were in the i group (5 capsules po tid d1-3). If no dose-limiting toxicities (DLTs) were observed, another 3 patients were escalated to the i+1 group (10 capsules po bid d1-3). If no DLTs were observed again, another 3 patients were escalated to the i+2 group (10capsules po tid d1-3), and so forth, until the i+3 dose group (20 capsules po bid d1-3). Simultaneously, patients continued receiving the original PD-1 IMT. Fecal samples were collected at baseline (S0), after 10 days (S1), 25days (S2), and 50days (S3) of FMT. Results: From March 2023 to December 2023, 12 pts were successfully enrolled. As of the data cutoff date (December 31, 2023), the median follow-up time was 9.05 months (6.5-9.5 months), and the median PFS has not been reached, with 3 patients experiencing disease progression. Four patients (33.3%) experienced Grade 1-2 FMT-related toxicities, including diarrhea, bloating, and abdominal pain, with no Grade 3 or higher adverse events observed. Fecal metagenomic sequencing analysis showed that the relative abundance levels of Blautia and Faecalibacterium significantly increased after FMT, peaking at day 25 and remaining higher than pre-transplant levels at day 50. We also found that patients in the i+1 group exhibited the greatest changes in microbial composition before and after transplantation, with high absolute and relative transplantation indices. Further analysis of host serum metabolism revealed an increase in molecules related to fatty acid metabolism, such as L-carnitine, stearic acid, and arachidic acid, especially a more pronounced increase in the i+1 group. Conclusions: This preliminary study demonstrates that the combination of oral microbiota capsule and immunotherapy can open up a more economical, safe, and effective avenue for 1L maintenance immunotherapy in tumors. Clinical trial information: ChiCTR2100054928.

Safety and preliminary efficacy of different doses of fecal microbiota capsule transplantation combined with anti-PD-1 inhibitor for patients with advanced malignant solid tumors.

e14622 Background: Chemotherapy combined with anti-PD-1 inhibitors has now become the standard first-line(1L) treatment for most malignant solid tumors. However, most Phase III studies have found that overall progression-free survival (PFS) with 1L combined subsequent immuno-maintenance therapy (IMT) is still less than 1 year. Fecal microbiota transplantation (FMT) has been shown to synergize with PD-1 antibodies to enhance efficacy. In this study, we administered oral microbiota capsule transplantation to patients(pts) during 1L IMT to evaluate its safety, preliminary efficacy, optimal dosage, and explore the changes in gut microbiota composition and serum metabolism (ChiCTR2100054928). Methods: This is a dose-escalation, exploratory clinical trial. The donor capsules were derived from the feces of a healthy 10-year-old child from a rural area. Twelve late-stage pan-cancer pts who had received standard 1L chemotherapy + PD-1 antibodies and achieved stable or responsive disease were enrolled. The first 3 patients were in the i group (5 capsules po tid d1-3). If no dose-limiting toxicities (DLTs) were observed, another 3 patients were escalated to the i+1 group (10 capsules po bid d1-3). If no DLTs were observed again, another 3 patients were escalated to the i+2 group (10capsules po tid d1-3), and so forth, until the i+3 dose group (20 capsules po bid d1-3). Simultaneously, patients continued receiving the original PD-1 IMT. Fecal samples were collected at baseline (S0), after 10 days (S1), 25days (S2), and 50days (S3) of FMT. Results: From March 2023 to December 2023, 12 pts were successfully enrolled. As of the data cutoff date (December 31, 2023), the median follow-up time was 9.05 months (6.5-9.5 months), and the median PFS has not been reached, with 3 patients experiencing disease progression. Four patients (33.3%) experienced Grade 1-2 FMT-related toxicities, including diarrhea, bloating, and abdominal pain, with no Grade 3 or higher adverse events observed. Fecal metagenomic sequencing analysis showed that the relative abundance levels of Blautia and Faecalibacterium significantly increased after FMT, peaking at day 25 and remaining higher than pre-transplant levels at day 50. We also found that patients in the i+1 group exhibited the greatest changes in microbial composition before and after transplantation, with high absolute and relative transplantation indices. Further analysis of host serum metabolism revealed an increase in molecules related to fatty acid metabolism, such as L-carnitine, stearic acid, and arachidic acid, especially a more pronounced increase in the i+1 group. Conclusions: This preliminary study demonstrates that the combination of oral microbiota capsule and immunotherapy can open up a more economical, safe, and effective avenue for 1L maintenance immunotherapy in tumors. Clinical trial information: ChiCTR2100054928.

A phase 2 clinical trial of first-in-class fascin inhibitor NP-G2-044 as monotherapy and in combination therapy with anti-PD-1 immunotherapy in patients with advanced solid tumor malignancies.

A phase 2 clinical trial of first-in-class fascin inhibitor NP-G2-044 as monotherapy and in combination therapy with anti-PD-1 immunotherapy in patients with advanced solid tumor malignancies.

Oncolytic virus V937 in combination with PD-1 blockade therapy to target immunologically quiescent liver and colorectal cancer

V937 is an investigational, genetically unmodified Kuykendall strain of coxsackievirus A21, which has been evaluated in the clinic for advanced solid tumor malignancies. V937 specifically infects and lyses tumor cells that overexpress intercellular adhesion molecule-1 (ICAM-1). Intratumoral V937 as a monotherapy and in combination with anti-PD-1 antibody pembrolizumab has shown clinical response in patients with metastatic melanoma, which overexpresses ICAM-1. Here, we investigate in pre-clinical studies the potential bidirectional cross-talk between hepatocellular carcinomas (HCC) or colorectal carcinomas (CRC) and immune cells when treated with V937 alone or in combination with pembrolizumab. We show that while V937 treatment of tumor cell lines or organoids or peripheral blood mononuclear cells (PBMCs) alone induced a minimal immunological response, V937 treatment of non-contact co-cultures of tumor cell lines or CRC organoids with PBMCs led to robust production of pro-inflammatory cytokines and immune cell activation. In addition, both recombinant interferon-gamma (IFN-γ) and pembrolizumab increased ICAM-1 on tumor cell lines or organoids and, in turn, amplified V937-mediated oncolysis and immunogenicity. These findings provide critical mechanistic insights on the cross-talk between V937-mediated oncolysis and immune responses, demonstrating the therapeutic potential of V937 in combination with PD-1 blockade to treat immunologically quiescent cancers.

Abstract CT162: Trial in progress: A phase I, open-label, multicenter study of ZL-1218, an anti-CCR8 IgG1, as a single agent and as combination therapy with anti-PD-1 antibody to evaluate the safety, tolerability, and pharmacokinetics in subjects with advanced solid tumor

Abstract Background ZL-1218 is an anti-chemokine receptor 8 (CCR8) humanized IgG1 antibody with enhanced antibody-dependent cellular cytotoxicity (ADCC) activity. CCR8 demonstrates a preferential expression in tumor-associated Tregs over peripheral Tregs. Thus, targeting CCR8 may allow for specific depletion of intratumoral Tregs without impacting peripheral Tregs/other immune cells. ZL-1218 is intended to decrease the intratumoral Tregs by binding to both high- and low-expressing CCR8+ cells and eliciting potent ADCC activity. ZL-1218 blocked CCR8 ligand CCL1 from binding to CCR8, and reduced Treg recruitment by blocking chemotaxis of CCR8+ cells (unpublished data). Additionally, ZL-1218 demonstrated enhanced antitumor activity in preclinical models in combination with anti-PD-1. Methods This is a Phase I study of ZL-1218 as a single agent and in combination with pembrolizumab (P) to evaluate the safety, tolerability, pharmacokinetics/pharmacodynamics, and preliminary antitumor activity in subjects with advanced solid tumor malignancies. The study consists of Part 1 Dose Escalation and Part 2 Cohort Expansion. In Part 1, subjects will be treated with escalating doses of ZL-1218 alone and in combination with a fixed dose of P to identify the maximum tolerated dose (MTD) and/or the recommended expansion dose (RD). The Bayesian optimal interval (BOIN) design is used and adopted with overdose control. Upon progression in the single agent group, a subject may enroll into combination therapy of ZL-1218 with P. Subjects will start at their respective single agent dose or the cleared combination dose level, whichever is lower. Part 2 will explore the combination with pembrolizumab in subjects with selected tumor types, with or without prior CPI therapy. Major inclusion criteria include: (1) Subjects must have histologically confirmed and documented diagnosis of locally advanced unresectable/metastatic advanced solid tumor that is refractory/intolerant to standard treatment, or for which no standard treatment exists, and no greater than 3 prior lines of therapy in the relapse/refractory setting (2). Subjects must have at least one target lesion as defined by RECIST v1.1 on CT, PET/CT, or MRI scan. (3) Subjects must have a site of disease which is not previously irradiated and is safe and amenable to biopsy. Major exclusion criteria include: (1) Prior exposure to CCR8 inhibitor, or severe hypersensitivity (≥ Grade 3) to P and/or any of its excipients. (2) Subjects with symptomatic or uncontrolled brain metastasis requiring concurrent treatment, impaired major organ functions, active autoimmune disease, or active infections. Part 1 Dose Escalation is ongoing in the US and EU. Citation Format: Elena Garralda, Valentina Boni, David Vincente Baz, Arvind Chaudhry, Ignacio Gil Bazo, Martin Gutierrez, Jyoti Malhotra, Casal Guzman Alonso, Valentina Gambardella, Michael Chisamore, Renke Zhou, Maria Tea, Deborah Doroshow. Trial in progress: A phase I, open-label, multicenter study of ZL-1218, an anti-CCR8 IgG1, as a single agent and as combination therapy with anti-PD-1 antibody to evaluate the safety, tolerability, and pharmacokinetics in subjects with advanced solid tumor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT162.

Abstract 5707: Preclinical evaluation of KRLS-017, a potent, highly selective and reversible CDK7 inhibitor with broad antitumor effect in preclinical models, in preparation for a Phase 1 clinical trial in advanced solid tumor malignancies

Abstract KRLS-017 is a potent, selective, and reversible inhibitor of Cyclin Dependent Kinase 7 (CDK7). Its molecular formula is C24H35N5O2Si and its molecular weight is 453.65 Daltons. KRLS-017 is being developed for the treatment of patients with advanced solid tumor malignancies. To differentiate KRLS-017 from other CDK7 inhibitors, we created a reversible inhibitor to allow for treatment schedule optimization and maximization of therapeutic index in clinic. High selectivity of KRLS-017 for CDK7 was confirmed using a panel of 313 recombinant human kinases. The IC50 of KRLS-017 against recombinant human CDK7 was determined to be 16 nM, and no other kinases in the panel showed IC50 values less than 300 nM. Antiproliferative activity of KRLS-017 was investigated in vitro using a broad panel of human tumor cell lines. KRLS-017 showed potent antiproliferative effect across a wide variety of both solid and hematologic tumor types, producing GI50 values <200 nM in 258/302 human tumorcell lines tested. Antitumor activity of KRLS-017 was investigated in vivo using multiple mouse xenograft tumormodels at dose levels ranging from 25 mg/kg to 200 mg/kg using both continuous (daily) andintermittent dosing schedules. Statistically significant tumor growth inhibition was seen at doselevels of 50 mg/kg and higher, with tumor regression observed at 100 mg/kg and 200 mg/kg. Better in vivo tolerability at efficacious doses was observed using intermittent dosing schedules in mouse xenograft models, which led to adoption of an intermittent schedule in the proposed first-in-human phase 1 trial. KRLS-017 is orally bioavailable in mice, rats, and dogs and plasma drug exposure increased in a proportional manner with dose. Comparing first dose and 28th dose in the dog, minimal plasma accumulation was observed, suggesting once daily dosing in humans would be initially tested. Repeat dose 28 day GLP toxicology studies in rat and dog showed adverse effects in highly proliferative bone marrow and gastrointestinal tissues which is consistent with the known mechanism of action for CDK7 and is considered to be monitorable and manageable in the setting of oncology. The clinical development plan for KRLS-017 includes an initial Phase 1 dose escalation study (KRLS-017-101) in patients with refractory solid tumor malignancies to assess pharmacokinetics/pharmacodynamics and to determine an optimal dose level and treatment schedule to test in expansion cohorts. Given the potential of CDK7 inhibitors in the treatment of hormone receptor positive breast cancer, combination work with other agents (such as selective estrogen receptor degraders) is on-going. Citation Format: Alison L. Hannah, Steve Ritland, Thomas Steele, Steven Smith, Ashwin Ram, BT Slingsby, Kapil Dhingra, James Chrisman, Rajesh Dua, Yasunori Tokunaga, Shigeyuki Kono, Yasuhiro Aga. Preclinical evaluation of KRLS-017, a potent, highly selective and reversible CDK7 inhibitor with broad antitumor effect in preclinical models, in preparation for a Phase 1 clinical trial in advanced solid tumor malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5707.

Abstract 12: TCR-gated control of costimulatory switch protein (CSP) activation in rTCR-T cells expressing PD1-41BB

Abstract Chimeric antigen receptor (CAR-)/T cell receptor (TCR-)T-based immunotherapies have shown promising results in the treatment of patients suffering from hematological malignancies. However, targeting solid cancer patients with CAR-T/TCR-T cells represents a more challenging approach, due to various factors present within the hostile tumor micro-environment (TME), inhibiting T cell functionality and leading to T cell exhaustion. Programmed cell death ligand-1 (PD-L1) is expressed on tumor cells as well as various cell types within the TME and binds to programmed cell death protein 1 (PD-1) expressed on the surface of activated T cells, thereby inducing T cell exhaustion and mediating tumor immune escape. To impair this inhibitory mechanism and improve TCR-T cell efficacy for the treatment of solid tumors, we use the chimeric costimulatory switch protein (CSP) PD1-41BB that turns the inhibitory signal mediated via the PD-1-PD-L1 axis into a costimulatory one. The CSP-mediated costimulatory signal is TCR-gated, whereby costimulation can only occur if a specific peptide-HLA complex present on a target cell interacts with a recombinant TCR expressed in T cells. In vitro co-cultures of rTCR-T cells expressing the CSP (CSP rTCR-T cells) and antigen-negative or -positive cell lines carrying or lacking PD-L1 demonstrated that CSP rTCR-T cells display functionality only if the respective target antigen is expressed in target cells, but not in the absence of target antigen. PD-L1-positive, antigen-negative tumor cells are not lysed by CSP rTCR-T cells, not even in the presence of antigen-positive tumor cells, showing gated functionality and a favorable safety profile of CSP-armored TCR-T cells. CSP rTCR-T cells displayed enhanced cytokine release and killing after encounter of PD-L1-positive tumor cell lines, compared to tumor cells lacking PD-L1, and showed the capacity to recognize and lyse a large panel of tumor cell lines expressing various levels of HLA-A*02, target antigen and PD-L1 in vitro. 3D spheroids derived from PD-L1-positive, target antigen-positive tumor cell lines mimicking cell-cell interactions within a solid tumor mass efficiently triggered CSP rTCR-T cells, leading to specific IFN-γ release and lysis of tumor spheroids. Furthermore, CSP rTCR-T cells showed enhanced proliferative capacity and expansion in co-cultures with PD-L1-positive tumor cells, compared to tumor cells lacking PD-L1 expression. Importantly, various target antigen-negative healthy cell types expressing or lacking PD-L1 and representing different vital organs were not cross-recognized by CSP rTCR-T cells in vitro. Our preclinical in vitro assessments of CSP rTCR-T cell functionality and safety proved their superior and gated functionality as well as favorable safety profile, showing the great potential for the treatment of cancer patients suffering from advanced solid tumor malignancies. Citation Format: Maja Buerdek, Petra U. Prinz, Kathrin Mutze, Andrea Coluccio, Stefanie Tippmer, Miriam Bosch, Giulia Longinotti, Mario Catarinella, Kathrin Davari, Christiane Geiger, Barbara Loesch, Kirsty Crame, Dolores J. Schendel. TCR-gated control of costimulatory switch protein (CSP) activation in rTCR-T cells expressing PD1-41BB [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 12.

Abstract 3195: SHR-4602, next generation of HER2-targeting ADC with potent anti-tumor efficacy overcoming the resistance of HER2 ADC with Topo I inhibitor payload in xenograft models

Abstract Background: Current clinical HER2-targeting ADCs (i.e. DS-8201) have shown promising clinical efficacy in HER2 expressing or mutant cancer patients. However, most of them will ultimately experience disease progression due to different mechanisms. Herein, we presented a novel HER2 ADC, SHR-4602, which demonstrated good in vitro and in vivo anti-tumor activities and could overcome the resistance caused by HER2 ADC including DS-8201 analogue (synthesized using DS-8201 structure) and SHR-A1811 (composed of trastuzumab, a cleavable linker, and a Topo I inhibitor payload, in phase III clinical trials) in xenograft models. Method: We used a stable enzyme-cleavable linker technology to conjugate the HER2 ADC using the amino acid sequence of pertuzumab and ER300 (eribulin derivative). The in vitro biological and anti-tumor activities were assessed by a series of assays. The in vivo anti-tumor efficacies were evaluated in the JIMT-1 (HER2 low expressing) as well as the SHR-A1811 and DS-8201 analogue induced JIMT-1 resistance (caused by treating with SHR-A1811 followed by DS-8201 analogue for a long-term) xenograft models in BALB/c nude mice. Results: Through the SPR assay, SHR-4602 exerted single nanomolar binding affinity to human and rhesus monkey HER2, but no binding activity against rat HER2. It demonstrated varying inhibitory activity on the proliferation of cancer cell lines with various HER2 expression levels, with the IC50 at the range of 0.007 nM to 8.21 nM. SHR-4602 showed highly efficient internalization in NCI-N87 HER2 expressing cells and could be translocated to the lysosome followed by releasing ER300. The cytotoxic activity of SHR-4602 was predominantly mediated by released ER300 through microtubule dynamics inhibition, G2/M arrest and apoptosis induction. Furthermore, SHR-4602 showed a strong in vitro bystander effect in the co-culture of HER2 positive/negative cells. SHR-4602 showed significant anti-tumor efficacy in JIMT-1, SHR-A1811 and DS-8201 analogue both-resistant JIMT-1 xenograft models. In SHR-A1811 and DS-8201 analogue both-resistant xenograft models, treatment with 10 mg/kg SHR-A1811 or DS-8201 analogue exerted negligible anti-tumor activity (TGI% < 17%), whereas SHR-4602 at 2.5, 5 and 10 mg/kg significantly inhibited the tumor growth (p < 0.001, vs. vehicle), with TGI% of 84.96%, 101.64% and 113.11% on Day 42, respectively, which indicated a superior anti-tumor efficacy against SHR-A1811 and DS-8201 analogue both-resistant xenograft models. Conclusion: SHR-4602 represents a new generation HER2-targeting ADC to deliver a potent cytotoxin to HER2 expressing tumor cells and may be more efficacious to the tumors in which current anti-HER2 therapies are ineffective. SHR-4602 is now in the phase I clinical development stage for advanced malignant solid tumors (NCT05819684). Citation Format: Yunan Tian, Xing Sun, Changyong Yang, Cheng Liao. SHR-4602, next generation of HER2-targeting ADC with potent anti-tumor efficacy overcoming the resistance of HER2 ADC with Topo I inhibitor payload in xenograft models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3195.

Abstract B011: Phase 2, multicenter, open-label basket trial of nab-sirolimus for malignant solid tumors harboring pathogenic inactivating alterations in TSC1 and TSC2 (PRECISION I)

Abstract Introduction/objective: PRECISION I (NCT05103358) is an ongoing trial of nab-sirolimus in advanced cancers harboring pathogenic inactivating alterations in TSC1 or TSC2. TSC1 and TSC2 alterations have been observed in patients with various cancers, including the most common cancer of the female reproductive organs, endometrial cancer, where ~3% contain TSC1 and/or TSC2 alterations. nab-Sirolimus, approved in the USA for patients with advanced malignant perivascular epithelioid cell tumor (PEComa), is an albumin-bound mTOR inhibitor (mTORi) that inhibits the mTOR pathway via suppression of the mTORC1 complex. When TSC1 or TSC2 is inactivated via mutation or loss, the mTOR pathway may be aberrantly activated. In an exploratory analysis of AMPECT (NCT02494570), a pivotal trial of nab-sirolimus in advanced malignant PEComa, 64.3% (9/14) of patients with pathogenic inactivating TSC2 or TSC1 alterations had a confirmed response. Most treatment-related adverse events in AMPECT were grade 1/2 (none were grade ≥4) and were consistent with mTORi-class adverse events. Based on the clinical observations from AMPECT and the underlying mechanism of action of nab-sirolimus, the PRECISION I trial was designed to assess the safety and efficacy of nab-sirolimus in a tumor-agnostic study of patients with advanced cancers with TSC1 or TSC2 inactivating alterations. Patients with endometrial cancer are expected to be enrolled based on the frequency of TSC1 and TSC2 inactivating alterations. Methods: Eligible patients are ≥12 years old and mTORi-naïve, possess advanced or metastatic malignant solid tumors with TSC1 or TSC2 inactivating alterations identified using next-generation sequencing (NGS) in tumor tissue or liquid biopsy (confirmed by central review of NGS reports), and have received appropriate standard treatments, per investigator. nab-Sirolimus 100 mg/m2 is given intravenously over 30 min on days 1 and 8 of each 21-day cycle. The primary endpoint is overall response rate per independent radiographic review (IRR) using Response Evaluation Criteria in Solid Tumors v1.1. Other endpoints include duration of response, time to response, progression-free survival by IRR, overall survival, patient-reported quality of life, and safety. Trial Status: Enrollment began in March 2022 and is expedited through collaboration with leading NGS providers; ongoing study access is facilitated through a just-in-time approach to trial location activation. Citation Format: Debra L. Richardson, Gopa Iyer, Li Ding, Anita N. Schmid, Willis Navarro, David Kwiatkowski, Jordi Rodon Ahnert. Phase 2, multicenter, open-label basket trial of nab-sirolimus for malignant solid tumors harboring pathogenic inactivating alterations in TSC1 and TSC2 (PRECISION I) [abstract]. In: Proceedings of the AACR Special Conference on Endometrial Cancer: Transforming Care through Science; 2023 Nov 16-18; Boston, Massachusetts. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(5_Suppl):Abstract nr B011.

A retrospective study on the efficacy and safety of Envafolimab, a PD-L1 inhibitor, in the treatment of advanced malignant solid tumors.

Envafolimab, a PD-L1 inhibitor, has demonstrated potential in treating advanced malignant solid tumors (AMST). To study its' efficacy and safety in AMST, our retrospective study recruited 64 patients with various AMST, and treated with Envafolimab (400mg every 3weeks). We divided the patients into two cohorts: Cohort 1 (25 patients) receiving Envafolimab as first-line therapy, and Cohort 2 (39 patients) receiving it as second-line or subsequent therapy. Our analysis focused on Envafolimab's efficacy and safety. Over a median follow-up of 7.1 months, Cohort I reported a Disease Control Rate (DCR) of 72.0% and an Objective response rate (ORR) of 12.0%, while Cohort II had a DCR of 51.3% and an ORR of 5.1%. Notably, patients with more than four treatment cycles showed higher DCR and longer Progression-Free Survival (PFS) than those with fewer cycles. Adverse events were observed in 68.8% of patients, with severe events (CTCAE grade 3/4) in 14.1%. Most adverse events were mild, leading to treatment discontinuation in only 3.1% of patients, with no life-threatening events reported. In summary, Envafolimab is a safe and effective treatment for AMST, in both initial and later therapy stages, particularly with extended treatment duration, meriting further clinical trials.

PRECISION 1: A phase 2, multicenter, open-label basket trial of nab-sirolimus for malignant solid tumors harboring pathogenic inactivating alterations in TSC1 and TSC2.

TPS585 Background: SEER data report that US patients with advanced gastrointestinal (GI) cancers have a poor prognosis as indicated by low 5-year survival rates in patients with colorectal (15.6%), liver (3.5%), and other GI cancers, highlighting the need for more efficacious treatments. Dysregulation of the mTOR pathway contributes to tumor growth and disease progression in many cancers, including GI cancers. The tumor suppressor genes TSC1 and TSC2 are critical negative regulators of mTOR activity whose inactivation can lead to tumor cell growth. Inactivating TSC1 and TSC2 alterations have been observed in GI cancers with a combined frequency of up to 6.5% in hepatocellular carcinoma, 1.7% in colorectal adenocarcinoma and gastrointestinal stromal tumors, and 1.6% in cholangiocarcinoma. nab-Sirolimus, approved in the US for patients with advanced malignant perivascular epithelioid cell tumor (PEComa), is an albumin-bound mTOR inhibitor (mTORi) that inhibits the mTOR pathway via suppression of the mTORC1 complex. In an exploratory analysis of the pivotal AMPECT trial of nab-sirolimus in advanced malignant PEComa (NCT02494570), 8/9 (89%) and 1/5 (20%) patients with inactivating alterations in TSC2 and TSC1, respectively, had a confirmed response. Most treatment-related adverse events were grade 1/2 (none were grade ≥4) and were consistent with mTORi-class adverse events. Based on the clinical observations from AMPECT and the underlying mechanism of action of nab-sirolimus, the PRECISION 1 trial was designed to assess the safety and efficacy of nab-sirolimus in a tumor-agnostic study of patients with advanced cancers harboring TSC1 or TSC2 inactivating alterations. The trial is open to patients with GI cancers with inactivating alterations in TSC1 or TSC2. Methods: In PRECISION 1 (NCT05103358), eligible patients are ≥12 years old and mTORi-naïve, have advanced malignant solid tumors harboring TSC1 or TSC2 inactivating alterations identified using next-generation sequencing (NGS) of tumor tissue or liquid biopsy (confirmed by central review of NGS reports), and have received appropriate standard treatments, per investigator. nab-Sirolimus 100 mg/m2 is given intravenously over 30 min on days 1 and 8 of each 21-day cycle. The primary endpoint is overall response rate per independent radiographic review (IRR) using Response Evaluation Criteria in Solid Tumors v1.1. Other endpoints include duration of response, time to response, progression-free survival by IRR, overall survival, patient-reported quality of life, and safety. Enrollment began in March 2022. Collaboration with leading NGS vendors is expediting the identification of patients with qualifying TSC1 and TSC2 alterations; ongoing study access is facilitated through a just-in-time approach to trial location activation. Clinical trial information: NCT05103358 .

Proof-of-concept study of the caninized anti-canine programmed death 1 antibody in dogs with advanced non-oral malignant melanoma solid tumors.

The anti-programmed death 1 (PD-1) antibody has led to durable clinical responses in a wide variety of human tumors. We have previously developed the caninized anti-canine PD-1 antibody (ca-4F12-E6) and evaluated its therapeutic properties in dogs with advance-staged oral malignant melanoma (OMM), however, their therapeutic effects on other types of canine tumors remain unclear. The present clinical study was carried out to evaluate the safety profile and clinical efficacy of ca-4F12-E6 in dogs with advanced solid tumors except for OMM. Thirty-eight dogs with non-OMM solid tumors were enrolled prospectively and treated with ca-4F12-E6 at 3 mg/kg every 2 weeks of each 10-week treatment cycle. Adverse events (AEs) and treatment efficacy were graded based on the criteria established by the Veterinary Cooperative Oncology Group. One dog was withdrawn, and thirty-seven dogs were evaluated for the safety and efficacy of ca-4F12-E6. Treatment-related AEs of any grade occurred in 13 out of 37 cases (35.1%). Two dogs with sterile nodular panniculitis and one with myasthenia gravis and hypothyroidism were suspected of immune-related AEs. In 30 out of 37 dogs that had target tumor lesions, the overall response and clinical benefit rates were 6.9% and 27.6%, respectively. The median progression-free survival and overall survival time were 70 days and 215 days, respectively. The present study demonstrated that ca-4F12-E6 was well-tolerated in non-OMM dogs, with a small number of cases showing objective responses. This provides evidence supporting large-scale clinical trials of anti-PD-1 antibody therapy in dogs.

The co-crystal structure of Cbl-b and a small-molecule inhibitor reveals the mechanism of Cbl-b inhibition

Cbl-b is a RING-type E3 ubiquitin ligase that is expressed in several immune cell lineages, where it negatively regulates the activity of immune cells. Cbl-b has specifically been identified as an attractive target for cancer immunotherapy due to its role in promoting an immunosuppressive tumor environment. A Cbl-b inhibitor, Nx-1607, is currently in phase I clinical trials for advanced solid tumor malignancies. Using a suite of biophysical and cellular assays, we confirm potent binding of C7683 (an analogue of Nx-1607) to the full-length Cbl-b and its N-terminal fragment containing the TKBD-LHR-RING domains. To further elucidate its mechanism of inhibition, we determined the co-crystal structure of Cbl-b with C7683, revealing the compound’s interaction with both the TKBD and LHR, but not the RING domain. Here, we provide structural insights into a novel mechanism of Cbl-b inhibition by a small-molecule inhibitor that locks the protein in an inactive conformation by acting as an intramolecular glue.

Phase I dose escalation study and pilot efficacy analysis of LXI-15029, a novel mTOR dual inhibitor, in Chinese subjects with advanced malignant solid tumors

BackgroundThe mammalian target of rapamycin (mTOR) kinase, a central component of the PI3K/AKT/mTOR pathway, plays a critical role in tumor biology as an attractive therapeutic target. We conducted this first-in-human study to investigate the safety, pharmacokinetics (PK), and pilot efficacy of LXI-15029, an mTORC1/2 dual inhibitor, in Chinese patients with advanced malignant solid tumors.MethodsEligible patients with advanced, unresectable malignant solid tumors after failure of routine therapy or with no standard treatment were enrolled to receive ascending doses (10, 20, 40, 60, 80, 110, and 150 mg) of oral LXI-15029 twice daily (BID) (3 + 3 dose-escalation pattern) until disease progression or intolerable adverse events (AEs). The primary endpoints were safety and tolerability.ResultsBetween June 2017 and July 2021, a total of 24 patients were enrolled. LXI-15029 was well tolerated at all doses. Only one dose-limiting toxicity (grade 3 increased alanine aminotransferase) occurred in the 150 mg group, and the maximum tolerated dose was 110 mg BID. The most common treatment-related AEs were leukocytopenia (41.7%), increased alanine aminotransferase (20.8%), increased aspartate aminotransferase (20.8%), prolonged electrocardiogram QT interval (20.8%), and hypertriglyceridemia (20.8%). No other serious treatment-related AEs were reported. LXI-15029 was absorbed rapidly after oral administration. The increases in the peak concentration and the area under the curve were greater than dose proportionality over the dose range. Eight patients had stable disease. The disease control rate was 40.0% (8/20; 95% CI 21.7–60.6). In evaluable patients, the median progression-free survival was 29 days (range 29–141).ConclusionsLXI-15029 demonstrated reasonable safety and tolerability profiles and encouraging preliminary antitumor activity in Chinese patients with advanced malignant solid tumors, which warranted further validation in phase II trials.Trial registrationNCT03125746(24/04/2017),http://ClinicalTrials.gov/show/NCT03125746

Abstract LB_B12: Phase 2, multicenter, open-label basket trial of nab-Sirolimus for malignant solid tumors harboring pathogenic inactivating alterations in TSC1 and TSC2 (PRECISION I)

Abstract BACKGROUND. nab-Sirolimus, approved in the US for patients with advanced malignant PEComa, is a novel albumin-bound mTOR inhibitor (mTORi) that inhibits the mTOR pathway via suppression of the mTORC1 complex. When TSC1 or TSC2 is inactivated via mutation or loss, the mTOR pathway may be aberrantly activated. Clinically, in an exploratory analysis of the pivotal AMPECT trial of nab-sirolimus in advanced malignant PEComa (NCT02494570), 8/9 (89%) and 1/5 (20%) patients with inactivating alterations in TSC2 and TSC1, respectively, had confirmed response (Wagner, J Clin Oncol, 2021). TSC1 and TSC2 alterations have been observed in patients with various cancers. Most treatment-related adverse events in AMPECT were grade 1/2 (none were grade ≥4) and were consistent with mTORi-class adverse events. Based on the clinical observations from AMPECT and the underlying mechanism of action of nab-sirolimus, the PRECISION I trial (NCT05103358) was designed to assess the safety and efficacy of nab-sirolimus in a tumor-agnostic study of advanced cancers with TSC1 or TSC2 inactivating alterations. METHODS. Eligible patients are ≥12 years old and mTORi-naïve, possess advanced malignant solid tumors with TSC1 or TSC2 inactivating alterations identified using next-generation sequencing (NGS) in tumor tissue or liquid biopsy (confirmed by central review of NGS reports), and have received appropriate standard treatments, per investigator. nab-Sirolimus 100 mg/m2 will be given intravenously over 30 min on Days 1 and 8 of each 21-day cycle. The primary endpoint is overall response rate per independent radiographic review (IRR) using RECIST v1.1. Other endpoints include duration of response, time to response, progression-free survival by IRR, overall survival, patient-reported quality of life, and safety. Enrollment began March 2022. Collaboration with leading NGS vendors will expedite the identification of patients with qualifying TSC1 and TSC2 mutations; ongoing study access is facilitated through a just-in-time approach to trial location activation. Based on the prevalence of TSC1 and TSC2 inactivating alterations, the most frequent tumor types expected are bladder, hepatobiliary, endometrial, soft tissue sarcoma, ovarian, and esophagogastric. Citation Format: Candace Haddox, Gopa Iyer, Michael J. Demeure, Li Ding, Anita N. Schmid, Willis H. Navarro, David J. Kwiatkowski, Jordi Rodon Ahnert. Phase 2, multicenter, open-label basket trial of nab-Sirolimus for malignant solid tumors harboring pathogenic inactivating alterations in TSC1 and TSC2 (PRECISION I) [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr LB_B12.

Meaning-centered pain coping skills training for patients with metastatic cancer: Protocol for a randomized controlled efficacy trial

BackgroundMany patients with advanced cancer describe pain as a debilitating symptom that greatly interferes with daily activities and enjoyment of life. Psychosocial interventions can improve cancer-related pain but rarely address spiritual concerns (e.g., loss of meaning, peace), which can influence the pain experience for those facing life-threatening illness. To address these needs, we systematically developed and pilot tested a novel psychosocial intervention called Meaning-Centered Pain Coping Skills Training (MCPC). In this randomized controlled trial, we aim to determine MCPC's efficacy for reducing pain interference (primary outcome) and improving secondary outcomes. We will also estimate MCPC's cost-effectiveness. Method/DesignPatients (target N = 210) with advanced solid tumor malignancies (Stage IV) and clinically-elevated pain interference will be enrolled and block randomized with equal allocation to MCPC + enhanced usual care or enhanced usual care alone. MCPC's four, videoconferenced, 45–60 min weekly sessions will be individually delivered by trained study therapists. Primary (pain interference) and secondary (pain severity, anxiety and depressive symptoms, pain self-efficacy, social support, spiritual well-being) patient-reported outcomes will be assessed at baseline, and 8-weeks (primary endpoint) and 12-weeks after baseline. ConclusionOur MCPC intervention is the first to systematically address the biopsychosocial-spiritual aspects of pain in patients with advanced cancer. If MCPC demonstrates efficacy, next steps will involve hybrid efficacy-effectiveness and implementation work to broaden access to this brief, manualized, remotely-delivered intervention, with the goal of reducing suffering in patients with life-threatening illness.

Phase 1 Study of JNJ-64619178, a Protein Arginine Methyltransferase 5 Inhibitor, in Advanced Solid Tumors.

In this first-in-human, Phase 1, open-label, multicenter study, we evaluated JNJ-64619178, a selective and potent PRMT5 inhibitor, in patients with advanced malignant solid tumors or non-Hodgkin lymphomas (NHL). The primary objective was to evaluate the safety and to identify a recommended Phase 2 dose (RP2D) of JNJ-64619178. Adult patients with treatment-refractory advanced solid tumors or NHL and measurable disease received escalating doses of JNJ-64619178 following two schedules (Schedule A: 14 days on/7 days off; Schedule B: every day on a 21-day cycle). Safety, pharmacokinetics (PK), pharmacodynamics (PD), and clinical activity were evaluated. Ninety patients received JNJ-64619178. Thrombocytopenia was identified as the only dose-limiting toxicity. JNJ-64619178 showed dose-proportional PK and robust target engagement, as measured by plasma symmetric dimethylarginine, across all dose levels. The objective response rate was 5.6% (5 of 90). Patients with adenoid cystic carcinoma (ACC) had an ORR of 11.5% (3 of 26) and a median progression-free survival of 19.1 months. JNJ-64619178 demonstrated manageable dose-dependent toxicity and preliminary evidence of antitumor activity in ACC and other tumor types. Plasma exposure was dose dependent, and target inhibition was maintained with intermittent and continuous dosing. On the basis of safety, clinical activity, PK, and PD findings, two provisional RP2Ds were selected: 1.5 mg intermittently and 1.0 mg once daily. Aside from ACC, clinical benefit was limited, and biomarkers to enrich for responsiveness to PRMT5 inhibition will be needed for further development.

Efficacy and safety of penpulimab-containing regimens for advanced malignant solid tumors that have failed immunotherapy: A real-world study.

e14700 Background: Immuno-checkpoint inhibitors (ICI) have shown good anti-tumor efficacy and survival benefits in a variety of solid tumors, such lung cancer, gastric cancer, esophageal cancer, head and neck squamous cell carcinoma (HNSCC). ICI have rewritten the guidelines for multiple tumor types. However, there are still a large number of patients who are ineffective or initially effective after use ICI, and subsequently develop ICI resistance. For these patients, how we choose further treatment is currently uncertain clinically. Some studies suggest that even if the treatment of PD - (L) 1 is ineffective or progresses, it can still bring a certain degree of benefit to re-challenge with other target ICI. This study was to evaluate the efficacy and safety of the patients with advanced malignant solid tumors with the regimen of penpulimab. Methods: This is a non-interventive registration study. Eligible participants must be ≥ 18 years old and have proven malignant tumors that are ineffective, fail for immunotherapy and have no other standard treatment. Patients were treated with penpulimab alone or in combination with chemotherapy or anti-angiogenic agents until progression or unacceptable toxicity. The primary endpoint is objective response rate (ORR). Secondary endpoints were disease control rate (DCR), progression free survival (PFS), overall survival (OS) and safety. Results: Form Sep 2021 to Feb 2023, 28 patients (median age 59.5 years, male 71.4%）were recruited, including 9 pts with NSCLC, 5 pts with HNSCC, 4 pts with Nasopharyngeal carcinoma (NPC), 3 pts with esophageal cancer and 7 with other tumor types. Among all, 1 achieved confirmed PR, 21 achieved SD, the ORR was 3.6% (1/28) and the DCR was 78.6% (22/28). The median treatment duration was 9 months. Among the 9 pts with NSCLC, the median treatment duration was 5.6 months and the DCR was 77.8%. Treatment-related adverse events (TRAEs) of grade 3 were observed in 5 (17.9%) of the 28 patients. The most common TRAEs were decreased lymphocyte count (50%, 14/28), anemia (50%, 14/28), hypoalbuminemia (39.3%, 11/28), hyponatremia (25%, 7/28) and hypercholesterolemia (25%, 7/28). Conclusions: Penpulimab-containing regimens for advanced malignant solid tumors that have failed ICI have shown significant efficacy and a favorable safety profile.

A novel anti-HER2 monoclonal antibody IAH0968 in HER2-positive, heavily pretreated solid tumors: Results from a phase Ⅰa/Ⅰb, first-in-human, open-label, single-center study.

e15098 Background: IAH0968 is an afucosylated anti-epidermal growth factor receptor 2 (HER2) monoclonal antibody which possessing the same binding properties to HER2 as trastuzumab and improving antibody-dependent cellular cytotoxicity (ADCC) activity and superior anti-tumor efficacy. We present results from patients with advanced HER2 positive malignant solid tumors including trastuzumab resistant and ineffective patients to establish the recommended dose of IAH0968 for phase II trials, as well as to investigate the safety, tolerability, pharmacokinetics (PK) and preliminary clinical activity of the drug. Methods: This was a single institution investigator-initiated phaseⅠa/Ⅰb study, using 3+3 design. The primary endpoint was safety, tolerability and preliminary clinical activity. Secondary endpoints included PK, recommended phase II dose, and anti-drug antibody (ADA). PK detection used ELISA to quantitatively determine blood drug concentration of IAH0968. Results: Eighteen pts were evaluable for safety and fifteen pts were suitable for efficacy analysis. The primary cancer sites included breast (8/18), colon (3/18), stomach (2/18), rectum (2/18), biliary tract (2/18), and pancreas (1/18). Median age was 54.2±9.7, ECOG 1/2 = 17/1, and 72.2% received anti-HER2 therapy in prior lines. Doses escalation were 6mg/kg (N = 3), 10mg/kg (N = 6), 15mg/kg (N = 5), and tolerable up to 20mg/kg (N = 4). Only one DLT was found at dosage 10mg/kg, and no MTD was reached. No ADA against IAH0968 was detected. The main PK parameters included mean T1/2 for doses 6~20 mg/kg ranging from 105 to 118 hours. The volume of distribution (Vz-obs) ranged from 4110.16 mL to 5395.64 mL. EC50 of ADCC activity of IAH0968 was 17.75~63.25 ×10-3 µg/mL. All grade treatment-related adverse events (TRAEs) occurred in 100% of pts, including grade 3 in 16.7%, and grade 4 in 5.6% of pts. The most common grade 3 TRAEs were hypokalemia (5.6%), arrhythmia (5.6%), QTC interval extension (5.6%), and infusion reaction (5.6%). The grade 4 TRAE was arrhythmia (5.6%). No serious TRAE or G5 were reported. 22.2% of pts had a TRAE leading to dose adjustment and 16.7% leading to discontinuation of IAH0968. After a median follow-up of 56.5 days (range, 0-479), objective response rate (ORR) was 13.3% (2/15), disease control rate (DCR) was 53.3% (8/15), and median progression-free survival (PFS) was 57.5 days (range, 42-236), with 4/15 responses ongoing. Conclusions: In heavily pretreated metastatic pts with HER2 positive, IAH0968 demonstrated promising clinical activity and tolerable safety profiles. IAH0968 will be further assessed in Phase Ⅱ study in combination treatment. Clinical trial information: NCT04934514 .