Selected Tumor Types Research Articles

BGB-A317-212: A multicenter, open-label, phase II study to evaluate the efficacy and safety of tislelizumab in combination with lenvatinib in patients with selected solid tumors.

2610 Background: Tislelizumab, an anti-programmed cell death protein 1 (PD-1) monoclonal antibody, has demonstrated promising efficacy in several advanced solid tumors. However, some patients (pts) do not respond or develop resistance to tislelizumab monotherapy. Lenvatinib, a receptor tyrosine kinase inhibitor targeting VEGFR 1-3, FGFR 1-4, PDGFR alpha, KIT, and RET, has shown a potential synergistic effect with anti-PD-1 therapy. Here, we report the primary results of a phase II study evaluating the combination of tislelizumab plus lenvatinib in pts with solid tumors (NCT05014828). Methods: Pts with histologically/cytologically confirmed selected solid tumors, naïve to lenvatinib and anti-programmed death-ligand 1 (PD-L1)/PD-1 therapies were enrolled. Part 1 (safety run-in) determined the recommended phase II dose (RP2D) of lenvatinib in combination with tislelizumab 400 mg IV every 6 weeks. In Part 2 (expansion), pts received lenvatinib at the RP2D from Part 1 (20 mg orally/day) plus tislelizumab per the Part 1 regimen until disease progression, withdrawal, or death. The primary endpoints were safety and RP2D determination (Part 1) and overall response rate (ORR; Part 2). Results: At data cutoff (Oct 20, 2023; median follow-up 12.1 months [mo; renal cell carcinoma, RCC]; 10.8 mo [head and neck squamous cell carcinoma, HNSCC]; 14.8 mo [gastric cancer, GC], and 22.0 mo [non-small cell lung cancer, NSCLC]), 58 pts were treated in Part 2 (RCC, n=23; HNSCC, n=27; GC, n=3; NSCLC, n=5), 6 of whom were also included in Part 1. The ORR was 66.7% in pts with RCC, 33.3% (HNSCC), 33.3% (GC), and 20.0% (NSCLC). Median duration of response (mDoR) was 18.5 mo and 9.6 mo in pts with NSCLC and HNSCC, respectively; not estimable (NE) for RCC and GC (Table). No new safety signals were identified; grade ≥3 treatment-related adverse events were reported in 78.3%, 59.3%, 33.3% and 60.0%, of pts with RCC, HNSCC, GC, and NSCLC, respectively (Table). Conclusions: Tislelizumab plus lenvatinib had a manageable safety profile and showed preliminary antitumor activity in pts with selected tumor types. Longer follow-up is needed to further investigate the potential of this combination to benefit pts with advanced solid tumors. Clinical trial information: NCT05014828 .[Table: see text]

A phase I open-label study of a novel IL-2Rβ/γ cytokine agonist, LTC004, in patients with advanced or metastatic solid tumors.

2652 Background: LTC004, a novel IL-2Rβ/γ cytokine agonist, designed to minimize toxicity with improved potency. It has selective affinity for the receptor IL-2Rβγ subunits, preferentially stimulates CD8+ effector T cells and natural killer cells which are associated with tumor killing, while minimizing the activation of immunosuppressive regulatory T cells. LTC004 has shown significant in vitro and in vivo anti-tumor activity in multiple cell lines and murine models respectively. Methods: This is a first-in-human, multicenter, open-label, dose-escalation and dose-expansion phase I study of LTC004 in advanced solid tumors. Dose escalation part assessed safety and tolerability of intravenous LTC004 with doses ranging from 3.0 to 360 µg/kg. The dose escalation schedule utilized an accelerated titration and Bayesian Optimal Interval (BOIN) design. Eligible pts with advanced solid tumor were required to have received prior standard therapy. LTC004 is administrated intravenously once every 3 weeks. Results: The study completed dose-escalation part (3.0 to 360 µg/kg) as of cutoff date (Jan 10, 2024). 17 pts of multiple tumor types (including non-small cell lung, cervical, colorectal, sarcoma, melanoma, parotid adenocarcinoma, thymic adenocarcinoma, gastric and ovarian cancers) were enrolled and received ≥1 dose of LTC004. At baseline, 12 pts (70.6%) had received ≥2 prior lines therapy, 11 pts (64.7%) had received prior targeted therapy, 10 pts (58.8%) had received prior immune checkpoint inhibitor (ICI) therapy. LTC004 generally well tolerated and no dose-limiting toxicities (DLTs) up to and including 360 µg/kg was observed. The most common TEAEs overall in ≥30% of pts were fever, white blood cell decreased, anemia, AST/ALT increased, neutrophil count decreased, GGT increased, nausea and hypotension. Most of the reported AEs were G1 and G2, all drug related events reversible and responsive to supportive care therapy. Fever can be resolved with standard anti-pyretic treatment or steroids, transient hypotension can be preventable with prophylactic fluid infusion. Of 17 pts enrolled evaluable for efficacy per RECIST v1.1, the ORR were 5.9% (1/17), DCR were 58.8% (10/17). A confirmed PR was achieved in a pMMR/MSS CRC patient with prior therapies including fluoropyrimidines, irinotecan, oxaliplatin, targeted therapy and TKI. The starting dose was 45µg/kg, titration to 90µg/kg after 4 consecutive doses at 45µg/kg Q3W. As of cutoff date, the patient sustained PR for 4.8 months with follow-up ongoing. Conclusions: LTC004 demonstrated encouraging anti-tumor efficacy including cold tumor, and well tolerated in patients with advanced or metastatic solid tumors. The further dose expansion in selected tumor types is ongoing, and evaluations in combination with other agents are being planned. Clinical trial information: NCT05666635 .

A phase I/II, first-in-human study of VLS-1488, an oral KIF18A inhibitor, in patients with advanced cancer.

TPS3181 Background: Chromosomal instability (CIN) is a hallmark of cancer characterized by high rates of chromosomal segregation errors during mitosis. This creates structural and numerical changes to chromosomes, driving genetic heterogeneity and cancer evolution. KIF18A is a mitotic kinesin protein shown to be important for successful division of cancer cells with CIN but not required for mitosis in normal diploid cells. Pre-clinical studies demonstrated that treatment of chromosomally unstable cancer cells in vitro and in xenograft models (HCC15 and OVCAR-3) with a KIF18A inhibitor resulted in failure of chromosomal congression, mitotic arrest, cell death and dose-dependent inhibition of tumor growth. VLS-1488 is an oral small molecule inhibitor of KIF18A that is being examined in an open-label, phase I/II, first-in-human study evaluating the safety, tolerability, pharmacokinetics (PK) and preliminary anti-tumor activity in advanced solid tumors with high prevalence of CIN. Methods: Key eligibility criteria include specific histologically confirmed metastatic or advanced tumor types with at least one site of measurable disease per RECIST 1.1, adequate organ function, and mismatch repair proficient/microsatellite stable.Eligible tumor types include high grade serous ovarian/fallopian tube/primary peritoneal cancer, squamous non-small cell lung cancer, triple negative breast cancer, gastric adenocarcinoma, gastroesophageal cancer, esophageal cancer, colorectal adenocarcinoma, transitional cell carcinoma of bladder, head and neck squamous cell carcinoma, ovarian or uterine carcinosarcoma, and uterine serous carcinoma. Subjects will receive VLS-1488 monotherapy continuously for 28-day cycles once daily. The study consists of two parts, Dose Escalation and Dose Expansion. Utilizing a Bayesian Optimal Interval (BOIN) design, Dose Escalation will examine the safety and tolerability of VLS-1488 at various dose levels (DLs) to identify the Maximum Tolerated Dose (MTD) and to select DLs for Dose Expansion. Dose Expansion may commence after the MTD or DLs of interest are identified. Dose Expansion will examine the safety, tolerability, preliminary efficacy and preliminary drug-drug interaction (DDI) and food effect risk of VLS-1488 in selected tumor types. Subjects enrolled to specific tumor type cohorts may be randomized to DLs of interest. Enrollment to Dose Escalation began in September 2023 and is ongoing. Clinical trial information: NCT05902988 .

Heterogeneous Profile of ROR1 Protein Expression across Tumor Types.

The Wnt receptor ROR1 has generated increased interest as a cancer therapeutic target. Research on several therapeutic approaches involving this receptor is ongoing; however, ROR1 tissue expression remains understudied. We performed an immunohistochemistry analysis of ROR1 protein expression in a large cohort of multiple tumor and histologic types. We analyzed 12 anonymized multi-tumor tissue microarrays (TMAs), including mesothelioma, esophageal and upper gastrointestinal carcinomas, and uterine endometrioid carcinoma, among other tumor types. Additionally, we studied 5 different sarcoma types of TMAs and 6 patient-derived xenografts (PDX) TMAs developed from 19 different anatomic sites and tumor histologic types. A total of 1142 patient cases from different histologic types and 140 PDXs placed in TMAs were evaluated. Pathologists assessed the percentage of tumor cells in each case that were positive for ROR1 and the intensity of staining. For determining the prevalence of staining for each tumor type, a case was considered positive if >1% of its tumor cells showed ROR1 staining. Our immunohistochemistry assays revealed a heterogeneous ROR1 expression profile. A high prevalence of ROR1 expression was found in mesothelioma (84.6%), liposarcoma (36.1%), gastrointestinal stromal tumors (33.3%), and uterine endometrioid carcinoma (28.9%). Other histologic types such as breast, lung, renal cell, hepatocellular, urothelial carcinoma, and colon carcinomas; glioblastoma; cholangiocarcinoma; and leiomyosarcoma showed less ROR1 overall expression, ranging between 0.9 and 13%. No ROR1 expression was seen in mesenchymal chondrosarcoma, rhabdomyosarcoma, or gastric adenocarcinoma cases. Overall, ROR1 expression was relatively infrequent and low in most tumor types investigated; however, ROR1 expression was infrequent but high in selected tumor types, such as gastroesophageal GIST, suggesting that ROR1 prescreening may be preferable for those indications. Further, mesothelioma exhibited frequent and high levels of ROR1 expression, which represents a previously unrecognized therapeutic opportunity. These findings can contribute to the development of ROR1-targeted therapies.

Group 3 medulloblastoma transcriptional networks collapse under domain specific EP300/CBP inhibition

Chemical discovery efforts commonly target individual protein domains. Many proteins, including the EP300/CBP histone acetyltransferases (HATs), contain several targetable domains. EP300/CBP are critical gene-regulatory targets in cancer, with existing high potency inhibitors of either the catalytic HAT domain or protein-binding bromodomain (BRD). A domain-specific inhibitory approach to multidomain-containing proteins may identify exceptional-responding tumor types, thereby expanding a therapeutic index. Here, we discover that targeting EP300/CBP using the domain-specific inhibitors, A485 (HAT) or CCS1477 (BRD) have different effects in select tumor types. Group 3 medulloblastoma (G3MB) cells are especially sensitive to BRD, compared with HAT inhibition. Structurally, these effects are mediated by the difluorophenyl group in the catalytic core of CCS1477. Mechanistically, bromodomain inhibition causes rapid disruption of genetic dependency networks that are required for G3MB growth. These studies provide a domain-specific structural foundation for drug discovery efforts targeting EP300/CBP and identify a selective role for the EP300/CBP bromodomain in maintaining genetic dependency networks in G3MB.

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 CT084: A phase 1 study of LY4101174 (ETx-22), an antibody-drug conjugate targeting nectin-4, in patients with advanced or metastatic urothelial cancer and other solid tumors (trial in progress)

Abstract Background: Nectin-4 is a cell adhesion molecule expressed in multiple tumor types.1 Enfortumab vedotin (EV), an antibody-drug conjugate (ADC) comprising a fully humanized nectin-4 antibody conjugated to the microtubule inhibitor, monomethyl auristatin E (MMAE), is approved for the treatment of advanced urothelial cancer (UC). However, skin toxicity, peripheral neuropathy, and hyperglycemia are clinically significant toxicities with EV. LY4101174 (ETx-22) is a next-generation nectin-4 targeting ADC comprising a humanized IgG1 Fc-silent monoclonal antibody linked to the topoisomerase I inhibitor, exatecan, via a maleimide-ß-glucuronide poly-sarcosine linker with improved stability and a homogeneous drug-antibody ratio (DAR) of 8. Preclinically, LY4101174 has demonstrated robust in vivo efficacy in tumor models across a range of nectin-4 expression levels and in the nectin-4-MMAE ADC treated resistant tumor model.2 Methods: LOXO-ENC-23001 is a global, open-label, multi-center, first-in-human phase 1 study of LY4101174 in patients (pts) with advanced or metastatic solid tumors known to express nectin-4. LY4101174 will be administered intravenously and evaluated initially on either every 2 weeks or 3 weeks schedule. Eligible pts (≥18 years) must have good performance status (ECOG PS 0-1) with metastatic UC, head and neck squamous cell carcinoma, esophageal, pancreatic, prostate, non-small cell lung, cervical, ovarian, or triple-negative breast cancer, and must have received or not be a candidate for available standard therapies. The study will be conducted in 2 phases: phase 1a dose escalation/dose optimization and phase 1b dose expansion. Dose escalation will utilize a Bayesian optimal interval design. Additional pts will be allowed to backfill to previously cleared dose levels that demonstrate therapeutically relevant exposures or direct evidence of clinical activity. The dose-limiting toxicity evaluation period will be 21 or 28 days based on dosing schedules. Phase 1b dose expansion cohorts will enroll pts with selected tumor types: mUC with no prior EV treatment (cohort B1), mUC with prior EV treatment (cohort B2), and other selected non-UC tumors (cohort C). Primary objectives are to determine the recommended phase 2 dose (RP2D) and assess the safety of LY4101174. Key secondary objectives are to evaluate the pharmacokinetic profile, immunogenicity, and antitumor activity of LY4101174 per RECIST v1.1. Nectin-4 expression and other biomarker data will be generated and correlated with clinical activity. 1Challita-Eid PM et al. 2016 Cancer Res 76(10):3003-13. 2Azim H et al. 2023 Mol Cancer Ther 22(12_Suppl):B128. Citation Format: Jonathan Rosenberg, Renaud Sabatier, Armelle Viceneux, Thibault de La Motte Rouge, Stephane Champiat, Loic Lebellec, Philippe Barthélémy, Guru Sonpavde, Xin Gao, Scot Niglio, Tian Zhang, Craig Gedye, Matthew Galsky, Matthew Milowsky, Melissa Reimers, Andrew Weickhardt, Enrique Grande, Daniel E. Castellano, Mehmet Bilen, Amita Patnaik, Robert Zerbib, Minna Balbas, Xiaojian Xu, Kaitlyn Aptaker, Arjun V. Balar, Ahmad H. Awada. A phase 1 study of LY4101174 (ETx-22), an antibody-drug conjugate targeting nectin-4, in patients with advanced or metastatic urothelial cancer and other solid tumors (trial in progress) [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 CT084.

Improving the pharmacokinetics, biodistribution and plasma stability of monobodies.

Cancer is a leading cause of death worldwide. Several targeted anticancer drugs entered clinical practice and improved survival of cancer patients with selected tumor types, but therapy resistance and metastatic disease remains a challenge. A major class of targeted anticancer drugs are therapeutic antibodies, but their use is limited to extracellular targets. Hence, alternative binding scaffolds have been investigated for intracellular use and better tumor tissue penetration. Among those, monobodies are small synthetic protein binders that were engineered to bind with high affinity and selectivity to central intracellular oncoproteins and inhibit their signaling. Despite their use as basic research tools, the potential of monobodies as protein therapeutics remains to be explored. In particular, the pharmacological properties of monobodies, including plasma stability, toxicity and pharmacokinetics have not been investigated. Here, we show that monobodies have high plasma stability, are well-tolerated in mice, but have a short half-life in vivo due to rapid renal clearance. Therefore, we engineered monobody fusions with an albumin-binding domain (ABD), which showed enhanced pharmacological properties without affecting their target binding: We found that ABD-monobody fusions display increased stability in mouse plasma. Most importantly, ABD-monobodies have a dramatically prolonged in vivo half-life and are not rapidly excreted by renal clearance, remaining in the blood significantly longer, while not accumulating in specific internal organs. Our results demonstrate the promise and versatility of monobodies to be developed into future therapeutics for cancer treatment. We anticipate that monobodies may be able to extend the spectrum of intracellular targets, resulting in a significant benefit to patient outcome.

Phase 1a dose escalation study of ivonescimab (AK112/SMT112), an anti-PD-1/VEGF-A bispecific antibody, in patients with advanced solid tumors

BackgroundStudies showed that vascular endothelial growth factor (VEGF) inhibitors could improve therapeutic efficacy of PD-1/PD-L1 antibodies by transforming the immunosuppressive tumor microenvironment (TME) into an immunoresponsive TME. Ivonescimab is a...

Abstract 1743: Pan-cancer review of TP53 somatic alterations as a function of tumor type: Sometimes lost, sometimes gained, frequently altered

Abstract Background: TP53 is the gene most frequently disrupted by somatic alterations in cancer. Mutations include single nucleotide variants resulting in functional alterations, as well as premature stop codons, splice variants, and cryptic alterations. TP53 gene dosage is disrupted by heterozygous and homozygous deletions, copy-neutral loss of heterozygosity, and other structural changes such as intragenic deletions and fusions. TP53 is altered by epigenetic events and viral oncogenes, such as E6 expressed by the human papillomavirus. The readout of altered TP53 includes decreased gene expression of either variant or wild-type alleles. Epistatic alteration of TP53 pathway components have also been described, with the E3 ubiquitin ligase MDM2 being the canonical example. Depending on the type of TP53 alteration, there may be differential signaling consequences, ranging from loss of function and dominant negative to oncogenic signaling. Hypothesis: Patterns of TP53 mutations will vary based on tumor type. Differential alterations of TP53 will suggest differential pathway dependence and downstream pathophysiology that may be relevant to signaling and therapeutic potential. Methods: We analyzed extensive cancer genomics repositories, such as the Pan-Cancer Atlas (10,000+ tumors, >30 cancer types) from The Cancer Genome Atlas project and the International Cancer Genome Consortium. Assessing genes in the TP53 pathway, we examined somatic mutations, copy number alterations, structural changes, and gene expression. Epigenetic data was considered when available. Results: A significant pattern amongst sarcomas, prostate cancers, and urothelial carcinomas emerged, revealing that certain tumors exhibited a predominant classic tumor suppressor gene genotype. This genotype featured frequent homozygous deletions, inactivating mutations, and relatively low TP53 gene expression, often accompanied by epistatic MDM2 amplification. By contrast, other tumors demonstrate an atypical pattern in which TP53 mutations were rarely if ever associated with loss of TP53 gene expression with low levels of homozygous TP53 gene deletion. Likewise, atypical TP53 mutant tumor types rarely demonstrated MDM2 amplifications, and in opposition to typical TP53 cases, MDM2 amplification was positively associated with TP53 mutation rather than anti-correlated. Head and neck squamous cell carcinoma, uterine carcinoma, and pancreatic adenocarcinoma followed this pattern. Investigation within selected tumor types such as lung squamous cell carcinoma suggested that both typical and atypical TP53 mutation patterns could be observed. Conclusions: TP53 mutation patterns were strongly associated with tumor type and may suggest differential pathway activation according to the somatic alteration status. Citation Format: Ubaid A. Tanveer, David N. Hayes, Julie George, Jeremiah R. Holt, Martin Peifer, Roman Thomas. Pan-cancer review of TP53 somatic alterations as a function of tumor type: Sometimes lost, sometimes gained, frequently altered [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 1743.

Abstract 3365: Reliable detection of potentially therapeutically actionable ecDNA using clinical-grade NGS in a large pan-cancer cohort

Abstract Background Focal high-level oncogene amplifications (FH-amp) (e.g., MYC, EGFR) frequently occur on extrachromosomal DNA (ecDNA), highly transcribed units of circular non-chromosomal DNA. FH-amp on ecDNA promote intra-tumoral heterogeneity, resistance to therapies, and poor prognosis. Recently, a Phase 1 clinical trial exploring ecDNA-directed treatments has begun. However, to date, bioinformatic detection of ecDNA has relied on whole-genome sequencing data, and no standard method exists to detect ecDNA on targeted NGS. We thus sought to explore the feasibility of detecting ecDNA in a large cohort of patients with solid tumors sequenced with the targeted NGS panel, MSK-IMPACT, and describe the pan-cancer prevalence of oncogenes amplified on ecDNA. Methods We utilized a novel bioinformatic ecDNA-diagnostic algorithm, ECHO, to determine the presence of oncogene FH-amp on ecDNA (including HSR) vs. chromosomal in clinical-grade NGS data. 72,651 tumor samples profiled by MSK-IMPACT were queried for high level oncogene FH-amp (AR, CCNE1, CDK4/6, EGFR, FGFR1-4, KRAS, MDM2, MDM4, MET, MYC, MYCL, and MYCN) above a fold-change of three, and subsequently annotated with ECHO. Patients with concomitant oncogenic driver mutations or fusions (e.g., EGFR L858R, EML4-ALK) were excluded based on the hypothesis that they might be mutually exclusive with oncogene FH-amp. Results FH-amp of any above listed oncogene were found in 3065 (4.2%) samples. Cancer types with frequent FH-amp without concomitant driver alterations were liposarcoma (LPS) (61% FH-amp; 43% were ecDNA+), glioblastoma (GBM) (22%; 72%), gastroesophageal adenocarcinoma (GE AD) (10%; 57%) squamous cell lung cancer (7%; 18%), and breast cancer (BRCA) (7%; 23%). Among tumors with oncogene FH-amp, GBM and GE AD had high frequencies of ecDNA+ FH-amp of EGFR (39% and 15% of all EGFR ecDNA+). LPS had the highest frequency of ecDNA+ FH-amp of CDK4 (64%), followed by GBM (15%). The majority of ecDNA+ FGFR1 and FGFR2 FH-amp were in BRCA (75% and 47%). EGFR in GBM and EGFR or FGFR2 in GE AD were ecDNA+ in more than 90% of patients, while CDK4 in LPS and FGFR1 in BRCA were ecDNA+ in 45% and 39% respectively.Evaluation the relationship between ecDNA+ by ECHO and amp FC range showed higher ecDNA+ in samples with higher level amp (FC > 5; 58% ecDNA+) compared to lower level amp (FC 4~5; 12%, FC 3~4; 6% ecDNA+). Conclusions A novel ecDNA clinical diagnostic tool, ECHO, was successfully applied to a large clinical cohort of patients enriched for actionable oncogene amplifications sequenced with MSK-IMPACT. The results demonstrate that detection of ecDNA using clinical-grade NGS assays is feasible and that key oncogene FH-amp on ecDNA (e.g., EGFR, FGFR2) are common in select tumor types. ECHO may be developed as a clinical trial device to prospectively identify patients with oncogene ecDNA+ FH-amp for clinical testing of ecDNA-directed therapies. Citation Format: Matteo Repetto, Klaus Wagner, Shalabh Suman, Peter Krein, Pavitra Rao, Maria Arcila, Christian Hassig, Mark Donoghue, Alexander Drilon, Michael Berger. Reliable detection of potentially therapeutically actionable ecDNA using clinical-grade NGS in a large pan-cancer cohort [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 3365.

Abstract 1918: LX-101, a novel, clinical stage, payload-bearing targeted therapy directed to the insulin-like growth factor receptor (IGF-1R), demonstrates potent preclinical anti-tumor activity against multiple cancer types with well-established ties to the IGF-1/IGF-1R pathway

Abstract Objective: LX-101 is a next-generation, targeted therapy directed to the insulin-like growth factor 1 receptor (IGF-1R). LX-101 consists of a proprietary IGF-1 variant coupled to a cytotoxic methotrexate payload. LX-101 was previously evaluated in Phase 1 trials of adult patients with advanced, pretreated cancers, where it was well-tolerated and demonstrated single agent activity. Neither a dose limiting toxicity, nor a maximum tolerated dose was reached, leaving potential room for additional dose escalation and schedule optimization. Multiple aggressive cancers of unmet need have genetic alterations affecting the IGF-1R pathway and/or high IGF-1R expression that correlates with poor outcomes, including certain cancers of the breast, head and neck, Ewing’s sarcoma, osteosarcoma, and others. Prior attempts at inhibiting IGF-1R with non-payload bearing naked monoclonal antibodies or small molecules produced a range of clinical outcomes including some partial and complete responses. None of these agents, however, were ultimately approved, potentially due to suboptimal potency that allowed for escape mechanisms, including redundant signaling pathways, and the lack of enrichment for select tumor types with strong ties to the IGF-1/IGF-1R pathway. Herein, we investigated the anti-tumor activity of the payload-bearing agent LX-101 against IGF-1R-involved cancer cell lines. Methods: Cell lines were incubated with LX-101 (~1.6 - 2500nM). Cell viability was assessed by CellTiter-Glo after 4 days. IC50s were calculated using GraphPad PRISM software. Results: LX-101 displayed potency against head and neck cancer (FaDu, IC50 = 9 nM), triple negative breast cancer (BT-20, IC50 = 17 nM), Ewing’s sarcoma, including EWSR1-FLI1 gene fusion-positive cell lines RD-ES (IC50 = 10 nM), A-673 (IC50 = 14 nM), and SK-ES-1 (IC50 = 29 nM) and EWSR1-ERG gene fusion-positive cell line CADO-ES1 (IC50 = 14 nM). LX-101 was also potent against PAX3-FOXO1 gene fusion positive alveolar rhabdomyosarcoma (SJCRH30, IC50 = 23 nM), osteosarcoma (143B, IC50 = 6 nM; HOS, IC50 = 7 nM; U2OS, IC50 = 32 nM), and neuroblastoma (SK-N-AS, IC50 = 16 nM; IMR-32, IC50 = 20 nM; SH-SY5Y, IC50 = 30 nM). Conclusion: These results demonstrate that LX-101 has potent preclinical anti-tumor activity against multiple cancer cell lines with well-established ties to the IGF-1/IGF-1R pathway, including with different genetic and epigenetic alterations. These data support further clinical development of LX-101 in IGF-1R-involved cancers. New clinical trials are planned. Citation Format: Matt Hoberman, Arkadiusz Z. Dudek. LX-101, a novel, clinical stage, payload-bearing targeted therapy directed to the insulin-like growth factor receptor (IGF-1R), demonstrates potent preclinical anti-tumor activity against multiple cancer types with well-established ties to the IGF-1/IGF-1R pathway [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 1918.

The Role of Carbon Ion Therapy in the Changing Oncology Landscape-A Narrative Review of the Literature and the Decade of Carbon Ion Experience at the Italian National Center for Oncological Hadrontherapy.

Currently, 13 Asian and European facilities deliver carbon ion radiotherapy (CIRT) for preclinical and clinical activity, and, to date, 55 clinical studies including CIRT for adult and paediatric solid neoplasms have been registered. The National Center for Oncological Hadrontherapy (CNAO) is the only Italian facility able to accelerate both protons and carbon ions for oncological treatment and research. To summarise and critically evaluate state-of-the-art knowledge on the application of carbon ion radiotherapy in oncological settings, the authors conducted a literature search till December 2022 in the following electronic databases: PubMed, Web of Science, MEDLINE, Google Scholar, and Cochrane. The results of 68 studies are reported using a narrative approach, highlighting CNAO's clinical activity over the last 10 years of CIRT. The ballistic and radiobiological hallmarks of CIRT make it an effective option in several rare, radioresistant, and difficult-to-treat tumours. CNAO has made a significant contribution to the advancement of knowledge on CIRT delivery in selected tumour types. After an initial ramp-up period, CNAO has progressively honed its clinical, technical, and dosimetric skills. Growing engagement with national and international networks and research groups for complex cancers has led to increasingly targeted patient selection for CIRT and lowered barriers to facility access.

First in human phase Ⅰ study of BMS-986299 as monotherapy and combined with nivolumab and ipilimumab in advanced solid tumors.

e14584 Background: Immune checkpoint inhibitors (ICIs) face hurdles in overcoming the immunosuppressive tumor microenvironment. BMS-986299 is first-in-class, NOD-, LRR-, and pyrin domain containing 3 (NLRP3) inflammasome agonist enhancing adaptive immune and T cell memory responses. In-vivo studies demonstrated BMS-986299 synergy with ICIs and induction of durable immunological memory. Methods: This multicenter, open-label, phase I [NCT03444753] study assessed safety and tolerability of intra-tumoral (IT) BMS-986299 monotherapy (Part 1A) and in combination (Part 1B) with the programmed death 1 receptor antibody nivolumab (N), and the anti-cytotoxic T lymphocyte associated protein 4 antibody ipilimumab (I) in advanced solid tumors. Eligible patients (pts) regardless of prior ICI with accessible solid tumors (≥ 2 lesions) received IT BMS-986299 administered on day 1, 8, 15, 22, 29 for Cycle 1 (C1) and on days 1, 29 until C2, 8 weeks apart across 7 dose escalation cohorts in Part 1A (75μg-4000μg; Bayesian Logistic Regression Model (BLRM). In Part 1B, BMS-986299 was given across 3 dose escalation cohorts (75μg-2000μg; BLRM Copula) with nivolumab 480 mg q4weeks and ipilimumab 1 mg/kg q8weeks (fixed dosing) from day 1 up to 24 months (m). Cross-over (CS) was allowed from Part 1A to Part 1B. Results: The study was terminated early, unrelated to safety, due to the COVID-19 pandemic and did not complete enrollment. From April 2018 to February 2022, 50 pts were treated (33; Part 1A and 17; Part 1B). Eleven pts crossed over to Part 1B. Median age of pts enrolled was 59 years and with preponderance in female gender (58.0%) and white (80.0%) pt. participation. Forty-two pts (70%) had treatment related adverse events (TRAEs). Grade (G)3/G4 TRAEs included tubulointerstitial nephritis (1; Part 1A), hepatitis (1; CS), colitis, diabetic ketoacidosis, elevated liver enzymes (1 each; Part 1B). No G5 TRAEs or dose limiting toxicities were seen. In Part 1A, 3 pts (melanoma; bladder; anal) achieved stable disease (SD). In CS cohort, 1 triple negative breast cancer (BC) pt had partial response (PR; -60%) for 27.4 m and 3 had SD (breast; cSCC, squamous oropharynx). In Part 1B, 3 pts had PR including 2 pts with hormone positive BC (1 pt with -86%; 3.2m and 1 pt with -39%; 2m) and 1 pt with cutaneous squamous cell cancer (cSCC) (-43%; 1m). Four pts in part 1B had SD (2 breast, 1 lung, 1 chondrosarcoma). All 4 responders received the combination of BMS-986299 with N + I with 3 responders receiving BMS-986299 at 2000μg and one at 300μg. 3 responders (2 breast; 1 cSCC) had prior ICI therapy. Conclusions: BMS-986299 in combination with ICI resulted in modest clinical activity in select tumor types and carried a manageable toxicity profile. However, definitive conclusions could not be drawn as the study was not powered for inference testing. Further exploration is warranted to define the role of this novel agent in the ICI refractory population. Clinical trial information: NCT03444753 .

ARTEMIS-001: Phase 1 study of HS-20093, a B7-H3–targeting antibody-drug conjugate, in patients with advanced solid tumor.

3017 Background: B7-H3, a member of the B7 superfamily, is highly expressed in various solid tumors, but has limited expression at low level in normal tissues. HS-20093 is a B7-H3-targeted antibody-drug conjugate. It could be an attractive therapeutic option for advanced solid tumors, especially the patients (pts) who have failed in multi-line therapy requiring novel and more effective treatment. Methods: This is a first-in-human, multicenter, open-label phase 1 study of HS-20093 in advanced solid tumors (NCT05276609). Dose escalation part assessed safety and tolerability of intravenous HS-20093 with doses ranging from 1.0 to 16.0 mg/kg. The dose escalation schedule utilized an accelerated titration and interval 3+3 design. Pts with advanced solid tumor were required to have received prior standard therapy. HS-20093 is administrated intravenously every 3 weeks. Results: The study completed all planned dose cohorts (1.0 to 16.0 mg/kg) as of cutoff date (20 December 2022). In dose escalation study, 53 pts of multiple tumor types were enrolled and received ≥1 dose of HS-20093, which included 29 pts with non-small cell lung cancer, 11 pts with small cell lung cancer (SCLC), 9 pts with sarcoma and 4 pts with other advanced solid tumors. At baseline, 25 pts (47.2%) had received ≥3 prior lines therapy with a mean of 3.2 (range, 1-12) prior lines of therapy. Three pts experienced dose-limiting toxicities (1 pt at 12.0 mg/kg; 2 pts at 16.0 mg/kg). The maximum tolerated dose was determined to be 12.0 mg/kg. Treatment-emerged adverse events (TEAEs) occurred in 53 pts (100%). The most common TEAEs overall in ≥30% of pts were leukopenia, neutropenia, anemia, pyrexia, nausea, thrombocytopenia, hypoalbuminemia, vomiting, lymphopenia, infusion-related reaction and fatigue. No interstitial lung disease was reported. Of 40 response-evaluable pts, regardless of baseline B7-H3 expression level, 14 partial responses (PRs) were observed in pts treated with HS-20093 from 4.0 mg/kg to 12.0 mg/kg doses (response rate: 35.0%), including 9 confirmed PRs and 5 PRs awaiting confirmation. The disease control rate was 85.0% (34/40, 95% CI: 70.2-94.3). The patient with the longest treatment duration (349 days) remains on treatment. In the subset of 9 SCLC pts, 7 PRs were observed (response rate: 77.8%) with the median depth of response of 50.5%, including 3 confirmed PRs and 4 PRs awaiting confirmation. All responses of SCLC pts occurred at the first disease assessment; the median time to first response was 6 weeks. HS-20093 displayed anti-tumor activity in SCLC pts who have progressed on prior derivative of camptothecin treatment. Conclusions: The safety profile of HS-20093 was acceptable. HS-20093 demonstrated promising antitumor activity in several tumor types, especially in SCLC. The further dose expansion study on efficacy and safety of HS-20093 in selected tumor types is ongoing. Clinical trial information: NCT05276609 .

First-in-human phase 1 study of pimicotinib (ABSK021), a CSF-1R inhibitor, in patients with advanced solid tumors.

3100 Background: Colony-stimulating factor 1 (CSF-1) pathway is involved in the development of various types of cancer. Pimicotinib is an orally available, selective, potent small molecule CSF-1R inhibitor with significant pre-clinical anti-tumor activity. Here we present the results of the phase 1 trial. Methods: The escalation part employed a 3+3 design with a starting dose of 25 mg QD (28-day/ cycle) to determine the maximum tolerated dose (MTD) and the recommended dose for expansion (RDE). Additional pts with selected tumor types including pancreatic carcinoma, triple-negative breast cancer, lung cancer, and sarcoma were treated at RDE in the expansion part for further evaluation. Tenosynovial giant cell tumor (TGCT) cohorts were analyzed and reported separately. Results: As of December 31, 2022, 74 pts received at least one dose of pimicotinib at 25 mg (n=6), 50 mg (n=58), 75 mg (n=8), or 100 mg (n=2) QD. respectively. Median age was 59 y; 68.9% were female; 47.3% were white, 33.8% were Asian and 18.9% were African American. 74.3% were ECOG PS 1; 85.1% had metastasis; 67.6% had ≥3 lines of prior systemic anti-tumor therapies. Median duration of treatment was 49.5 days (range 4-377). Treatment-related adverse events (TRAEs), Grade ≥3 TRAEs, and serious TRAEs occurred in 74.3%, 21.6%, and 4.1% of pts, respectively. The most common TRAEs (≥20%) were serum enzyme elevations, including CPK, AST and LDH, which were all believed to be pimicotinib MOA related, with CPK increase (14.9%) being the only Grade ≥3 TRAE reported in ≥10% of pts. 3 pts (4.1%) reported serious TRAEs of ascites, blood bilirubin increase, and vaginal hemorrhage. After single and multiple dosing, pimicotinib plasma exposure increased slightly less than dose proportion. The rapid oral absorption (median tmax of 0.87 - 1.52 hrs) with moderate terminal t1/2 (mean t1/2 ranges: 43.6 - 63.5 hrs) suggested sustained drug exposure was achieved with a once daily dosing schedule. No dose adjustment was needed based on tested covariates including weight, age and race. Pimicotinib treatment led to a more than 85% reduction of non-classical monocytes (NCM) across all dose levels. Plasma CSF-1 levels were significantly increased from 25mg QD to 50mg QD and reached a plateau at 50mg QD, with ~40-fold maximal induction. Reduced CD163+ macrophages in skin and tumor tissues were seen at 50mg QD. All tested doses showed adequate inhibition of NCM, and CSF-1 change showed a positive correlation with plasma pimicotinib concentration. The MTD and RDE were determined as 75 mg QD and 50 mg QD. Conclusions: Tolerable safety profile and favorable PK/PD properties supported pimicotinib to be further evaluated in advanced solid tumors, including combinations. Clinical trial information: NCT04192344 .

Abstract CT056: A multicenter, open-label phase 1/2 trial evaluating the safety, tolerability, and efficacy of MORAb-202, a folate-receptor-alpha-targeting antibody-drug conjugate in patients with selected tumor types

Abstract Background: MORAb-202 (farletuzumab ecteribulin) is an antibody-drug conjugate (ADC) comprised of the humanized antifolate receptor-alpha (FRα) monoclonal antibody, farletuzumab, and the cytotoxic microtubule inhibitor, eribulin, conjugated by a cathepsin B-cleavable linker. MORAb-202 targets the eribulin payload to tumor cells expressing FRα, where internalization leads to lysosomal cleavage of the ADC and intracellular release of eribulin, causing apoptosis, cell-cycle arrest, and bystander effects in adjacent cells. A previous phase 1 study in Japan of MORAb-202 (NCT03386942) demonstrated antitumor activity across multiple tumor types and identified interstitial lung disease (ILD) as an adverse event of interest (Shimizu CCR 2021). An expansion cohort (doses: 0.9, 1.2 mg/kg) in patients with platinum-resistant ovarian cancer (OC) found meaningful efficacy across FRα-expression levels and ILD/pneumonitis (mainly low grade) was the most common adverse event (Nishio ASCO 2022). Methods: This multicenter phase 1/2 study (NCT04300556) consists of Dose-Escalation and Dose-Confirmation cohorts. In the Dose-Escalation phase, the primary objectives were to evaluate safety/tolerability and determine the recommended phase 2 dose of MORAb-202 in patients with OC, endometrial cancer (EC), non-small cell lung cancer (NSCLC), or triple-negative breast cancer (TNBC). In the ongoing Dose-Confirmation phase, the primary objectives are (1) to further evaluate safety/tolerability and (2) to evaluate preliminary efficacy (Objective Response Rate) in patients with OC or EC. Based on a population pharmacokinetics model (Hayato ASCO 2022), body-surface-area-based dosing is utilized. The initial cohort has enrolled 7 patients at a MORAb-202 25 mg/m2 IV Q3W dose and is ongoing; further enrollment of patients at 25 mg/m2 and 33 mg/m2 will occur following ILD safety evaluation. Tumor assessments will be conducted by investigators using RECIST v1.1 at screening, every 6 weeks for 24 weeks, then every 12 weeks or as needed. Assessments of computed tomography scans for ILD will be conducted by a central expert review board. Citation Format: Robert Wenham, Sharad Ghamande, Vicky Makker, June Hou, Linda Duska, Daniela Matei, Manali Bhave, Rachael Scott, Natalyn Hawk, Tingting Song, Deborah K. Armstrong. A multicenter, open-label phase 1/2 trial evaluating the safety, tolerability, and efficacy of MORAb-202, a folate-receptor-alpha-targeting antibody-drug conjugate in patients with selected tumor types [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT056.

Abstract CT257: First-in-human phase 1 studies of PTPN2/1 inhibitors ABBV-CLS-484 and ABBV-CLS-579 in locally advanced or metastatic tumors

Abstract Background: Protein tyrosine phosphatase non-receptor type 2 and type 1 (PTPN2/1) antagonists inhibit PTPN2/1-mediated negative regulation of immune response pathways. They may promote antitumor activity by increasing function of immune cells such as T cells and dendritic cells, inducing cytokine production, increasing antigen presentation, and amplifying interferon gamma-mediated tumor growth arrest. ABBV-CLS-484 and ABBV-CLS-579 are potent, orally bioavailable, first-in-class PTPN2/1 inhibitors that showed promising antitumor activity and were well tolerated in preclinical models. Preclinical data also indicated that PTPN2/1 inhibitors have improved efficacy when combined with PD-1-targeting agents (eg, pembrolizumab) or vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs) in multiple tumor models. Here, we describe 2 first-in-human trials of ABBV-CLS-484 or ABBV-CLS-579 as monotherapy and in combination with pembrolizumab or VEGFR TKI in patients with locally advanced/metastatic tumors. Methods: These phase 1, open-label, multicenter, non-randomized trials (ABBV-CLS-484: NCT04777994; ABBV-CLS-579: NCT04417465) comprise dose-escalation (ESC) and dose-expansion (EXP) phases. ESC is guided by a Bayesian optimal interval design based on dose-limiting toxicities. ESC data are used to inform evaluation of EXP cohorts in select tumor types including relapsed/refractory (R/R) head and neck squamous cell carcinoma, R/R non-small cell lung cancer, advanced renal cell carcinoma, and microsatellite instability-high tumors. In both ESC and EXP phases, the study drug (ABBV-CLS-484 or ABBV-CLS-579) is administered orally either alone or in combination with pembrolizumab (200 mg intravenously once every 3 weeks) and is slated to also be administered in combination with a VEGFR TKI. Eligible patients have locally advanced/metastatic tumors for which no effective standard therapy exists (or has failed), and Eastern Cooperative Oncology Group performance status ≤2. Patients (≥18 years) must have received ≥1 prior systemic anticancer therapy for the indication being considered, have relapsed or be refractory to ≥1 prior anti-PD-1/PD-L1 therapy (EXP monotherapy and pembrolizumab combination), or have relapsed after ≤1 (ABBV-CLS-484) or ≥1 (ABBV-CLS-579) prior VEGFR TKI therapy (EXP VEGFR TKI combination). Primary objectives are to assess safety, tolerability, pharmacokinetics, and to determine the recommended expansion dose and/or maximum tolerated dose of ABBV-CLS-484 or ABBV-CLS-579, both as monotherapy and in combination. Evaluation of objective response rate (RECIST v1.1) is a primary objective in EXP phase and a secondary objective in ESC phase. Both studies are active, and as of 30 Nov 2022, 30 (ABBV-CLS-484) and 45 (ABBV-CLS-579) patients had been enrolled in ESC phase. Citation Format: Patricia M. LoRusso, Emiliano Calvo Aller, Noboru Yamamoto, Chia-Chi Lin, Thaddeus Beck, David Sommerhalder, Do-Youn Oh, John D. Powderly, Talia Golan, Linu Sara Abraham, Joel S. Hayflick, Tamar Uziel, Priya Brunsdon, Wijith Munasinghe, Marcia Paddock, Cathleen Brdlik Hartman, Jonathan Powell, Bruno Medeiros, Martha R. Neagu, Benedito A. Carneiro. First-in-human phase 1 studies of PTPN2/1 inhibitors ABBV-CLS-484 and ABBV-CLS-579 in locally advanced or metastatic tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT257.

Abstract 3432: Ataxia-telangiectasia mutated loss of function displays variant and tissue specific differences across tumor types

Abstract Introduction: ATM loss of function (LOF) in cancer may serve as a predictive biomarker of response for antitumor therapies. However, clinical studies of targeted treatments in ATM-aberrant patients have yielded mixed results; thus, identifying the optimal strategy for selecting patients with ATM LOF tumors remains a critical area of unmet need. Methods: In order to investigate the heterogeneity observed in ATM aberrant tumors, we conducted a pan-cancer genomic and proteomic profiling of ATM LOF, and also performed retrospective review of clinical outcomes for a subset of patients with ATM LOF treated with platinum or ATR inhibition. Results: We identified 10,609 ATM variants in 8,587 patients with cancer. The prevalence of deleterious (Tier 1) versus variants of unknown significance (VUS)/benign (Tier 2) variants differed by cancer tissue type, as did selective pressure for loss of heterozygosity (LOH). Analysis of ATM protein staining in 471 patient tumors showed tumors with null, inactivating variants were significantly (p<0.005) more likely to display ATM loss of protein (LOP) than tumors with missense or wildtype, but 19% (N=27/140) and 9% (N=13/149) of tumors with ATM-VUS and wildtype showed loss of protein. In addition, concordance between inactivating mutations and loss of protein also differed based on tumor tissue context, with ovarian and breast cancer showing stronger concordance (greater than 80%) than melanoma and lung cancer ( less than 20%). Patients treated with platinum chemotherapy with select tumor types with deleterious variants in ATM and ATM LOP display improved progression free survival (PFS) (HR 0.50, P=0.03). Lastly, patients with tumor types that have stronger ATM variant-to-protein loss concordance display increased benefit from ATR inhibition (HR 0.40, P=0.04). Conclusions: Our data highlight that there is heterogeneity in ATM LOF in patients due to multiple variables, including notable tissue-specific differences in the type of variants seen and the relationship between ATM variant status and ATM protein. This genomic heterogeneity and tissue-specificity has implications for predictive biomarker development and clinical trial designs. Citation Format: Patrick G. Pilie, Daniel Mcgrail, Wei-Lien Wang, Natalie Ngoi, Keith Kyewalabye, Khalida Wani, Hung Le, Erick Campbell, Vijaykumar Holla, Kenna R. Shaw, Funda Meric-Bernstam, Alexander J. Lazar, Virginia Giuliani, Timothy Heffernan, Timothy A. Yap. Ataxia-telangiectasia mutated loss of function displays variant and tissue specific differences across tumor types [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3432.

Abstract 925: NTRK gene fusion in adults and pediatrics with solid tumors: a record linkage study of expression frequency and patient characteristics using the Auria Biobank in Finland

Abstract Introduction: Selective tropomyosin receptor kinase (TRK) inhibitors are targeted therapies for patients with solid tumors harboring a neurotrophic-receptor tyrosine kinase (NTRK) gene fusion. Estimates of the frequency of NTRK gene fusions and knowledge about characteristics of affected patients from population-based settings are limited. Methods: This was a retrospective cohort study using archival tissue samples from patients with histologically-confirmed solid tumors identified from the Auria Biobank in the Turku region of Finland (January 2005-December 2019). We evaluated all solid tumor types in pediatrics, and selected tumor types in adults (colorectal cancer [CRC], non-small cell-lung cancer [NSCLC], sarcoma, and salivary/parotid cancer). Expression of TRK protein was determined by pan-TRK immunohistochemistry (IHC) staining of tumor samples scored by a certified pathologist. NTRK gene fusion including fusion partners was then confirmed by next generation sequencing (NGS). Patients’ demographics, clinical characteristics, and survival status were determined through linkage to hospital electronic health records and the national vital statistics database; patients were followed from 1 year before cancer diagnosis until the end of follow-up/death. Results: NTRK gene fusion frequency and descriptions of patient and tumor characteristics are shown in the Table. The number of patients confirmed as NTRK positive after NGS as a proportion of those deemed NTRK positive after IHC staining was 80% (8/10) for CRC, 5% (1/21) for NSCLC, 6% (1/18) for salivary/parotid cancer, 0% (0/21) for sarcoma, and 25% (4/16) for pediatric solid tumors. Conclusions: This study shows that NTRK gene fusions are rare in adult CRC, NSCLC, parotid/salivary tumors, sarcoma, and pediatric solid tumors. Frequency of NTRK gene fusion in pediatric and select adult solid tumors, and characteristics of NTR NTRK gene fusion-positive NTRK gene fusion subtypes Fusion partners Median age (category) at diagnosis (years) Sex Tumor details Treatment/follow-up status Adults CRC (N=1151) 8 (0.7%) NTRK1 (n=6) NTRK2 (n=1) NTRK3 (n=1) NTRK1: TPM3 (n=3), LMNA (n=1), TPR (n=1), IRF2BP2 (n=1) NTRK2*: FXN (n=1), LPPR1 (n=1) NTRK3: GABRG1 (n=1) *In a single patient with two tumor samples NTRK2 was identified in both samples, but the fusion partner (and other genomic co-alterations) were different between the two samples. 60-69 3 male, 5 female All were grade 2-3 ECOG score 1 (n=4)† MSI: abnormal (n=4), normal (n=1), missing (n=1) †ECOG score was missing for the remaining patients. Chemotherapy: n=3 Radiotherapy: n=1 All alive at end of follow-up (range, 0.3-11.5 years) Sarcoma (N=379) 0 (0.0%) - - - - - - NSCLC (N=288) 1 (0.3%) NTRK3 (n=1) SGCZ (n=1) 60-69 Female Stage IVA, grade II, ECOG score 1 Chemotherapy but not radiotherapy Alive at 0.6 years‘ follow-up Salivary/parotid (N=114) 1 (0.9%) NTRK3 (n=1) ETV6 (n=1) 60-69 Male Salivary cancer, stage 1, T2N0M0 ECOG score was missing No chemotherapy/radiotherapy Alive after 13.9 years‘ follow-up Fibrosarcoma (n=1) Primitive neuroectodermal cancer (n=1) Ewing’s sarcoma (n=1) Papillary thyroid cancer (n=1) Pediatric solid tumors (N=127) 4 (3.1%) NTRK1 (n=1) NTRK2 (n=2) NTRK3 (n=1) NTRK1: TPM3 (n=1) NTRK2: DAB2IP (n=1), LPPR1 (n=1) NTRK3: RAD51B (n=1) NTRK1-TPM3; male, age category‡ 2-11 years, tumor stage unknown, no chemotherapy/radiotherapy. Alive at 15.1 years‘ follow-up. ‡According to US FDA age categories for pediatrics. NTRK2-DAB2IP; male, age category‡ 2-11 years, Grade III tumor, received both chemo- and radiotherapy. Died - survival time 0.9 years. ‡According to US FDA age categories for pediatrics. NTRK2-LPPR1; male, age category‡ 12-18 years, stage IV tumor, received both chemo- and radiotherapy. Died - survival time 1.1 years. ‡According to US FDA age categories for pediatrics. NTRK3-RAD51B; female, age category‡ 12-18 years, tumor stage unknown, no chemotherapy/radiotherapy. Alive at 7.4 years‘ follow-up. ‡According to US FDA age categories for pediatrics. Citation Format: Wei Zhang, Merja Perälä, Roosa E. Kallionpää, Niina Pitkänen, Korinna Jöhrens, Renate Schulze-Rath, Arndt A Schmitz, Helen Guo, Jihong Zong. NTRK gene fusion in adults and pediatrics with solid tumors: a record linkage study of expression frequency and patient characteristics using the Auria Biobank in Finland [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 925.