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Biomarker-driven cancer therapy has revolutionized precision oncology. With a better understanding of tumor biology, tissue-agnostic targets have been characterized and explored, which ultimately led to therapeutics with pan-cancer efficacy. To date, five molecular biomarkers have obtained FDA tissue-agnostic approval for targeted therapies and immunotherapies. Those include BRAFV600E mutations, RET fusions, NTRK fusions, high tumor mutation burden (TMB), and deficient mismatch repair/high microsatellite instability (dMMR/MSI-High). Herein, we have used data from AACR project GENIE to explore the clinico-genomic landscape of these alterations. AACR GENIE is a publicly accessible registry of genomic data from multiple collaborating cancer centers. Current database (version 13.0) includes sequencing data of 168,423 samples collected from patients with different cancers. We were able to identify BRAFV600E, RET fusions, NTRK fusions, and high TMB in 2.9%, 1.6%, 1.5%, and 15.2% of pan-cancer samples, respectively. In this article, we describe the distribution of those tissue-agnostic targets among different cancer types. In addition, we summarize the current prospect on the biology of these alterations and evidence on approved drugs, including pembrolizumab, dostarilmab, larotrectinib, entrectinib, selpercatinib, and dabrafenib/trametinib combination.

Summary: The current approaches for cancer drug development lag behind an accelerated need in the field for a fast and efficient method for evaluating drugs in the personalized medicine era. In that regard, N-of-1 studies emerge as a potential addition to the drug development arsenal, although there are several considerations before its broad application becomes feasible. In essence, N-of-1 trials are a departure from the traditional “drug-centric” model to a “patient-centric” model. Herein, we review the concept of N-of-1 trials and provide real-world examples of their use in the developmental therapeutics field. N-of-1 trials offer an exceptional opportunity for fast-tracking of cancer drug development in the precision oncology era.

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Frequency of tissue-agnostic targets in other additional different tumors (alphabetically arranged) in AACR GENIE v.13

Genes most frequently mutated in cases with tissue-agnostic targets in the overall altered population and top 5 cancers with highest number of profiled samples in each alteration

Biomarker-driven cancer therapy has revolutionized precision oncology. With a better understanding of tumor biology, tissue-agnostic targets have been characterized and explored, which ultimately led to therapeutics with pan-cancer efficacy. To date, five molecular biomarkers have obtained FDA tissue-agnostic approval for targeted therapies and immunotherapies. Those include BRAFV600E mutations, RET fusions, NTRK fusions, high tumor mutation burden (TMB), and deficient mismatch repair/high microsatellite instability (dMMR/MSI-High). Herein, we have used data from AACR project GENIE to explore the clinico-genomic landscape of these alterations. AACR GENIE is a publicly accessible registry of genomic data from multiple collaborating cancer centers. Current database (version 13.0) includes sequencing data of 168,423 samples collected from patients with different cancers. We were able to identify BRAFV600E, RET fusions, NTRK fusions, and high TMB in 2.9%, 1.6%, 1.5%, and 15.2% of pan-cancer samples, respectively. In this article, we describe the distribution of those tissue-agnostic targets among different cancer types. In addition, we summarize the current prospect on the biology of these alterations and evidence on approved drugs, including pembrolizumab, dostarilmab, larotrectinib, entrectinib, selpercatinib, and dabrafenib/trametinib combination.

PurposeHypereosinophilia represents a heterogenous group of severe medical conditions characterized by elevated numbers of eosinophil granulocytes in peripheral blood, bone marrow or tissue. Treatment options for hypereosinophilia remain limited despite recent approaches including IL-5-targeted monoclonal antibodies and tyrosine kinase inhibitors.MethodsTo understand aberrant survival patterns and options for pharmacologic intervention, we characterized BCL-2-regulated apoptosis signaling by testing for BCL-2 family expression levels as well as pharmacologic inhibition using primary patient samples from diverse subtypes of hypereosinophilia (hypereosinophilic syndromen = 18, chronic eosinophilic leukemia not otherwise specifiedn = 9, lymphocyte-variant hypereosinophilian = 2, myeloproliferative neoplasm with eosinophilian = 2, eosinophilic granulomatosis with polyangiitisn = 11, reactive eosinophilian = 3).ResultsContrary to published literature, we found no difference in the levels of the lncRNAMorrbidand its targetBIM. Yet, we identified a near complete loss of expression of pro-apoptoticPUMAas well as a reduction in anti-apoptoticBCL-2. Accordingly,BCL-2inhibition using venetoclax failed to achieve cell death induction in eosinophil granulocytes and bone marrow mononuclear cells from patients with hypereosinophilia. In contrast,MCL1inhibition using S63845 specifically decreased the viability of bone marrow progenitor cells in patients with hypereosinophilia. In patients diagnosed with Chronic Eosinophilic Leukemia (CEL-NOS) or Myeloid and Lymphatic Neoplasia with hypereosinophilia (MLN-Eo) repression of survival was specifically powerful.ConclusionOur study shows thatMCL1inhibition might be a promising therapeutic option for hypereosinophilia patients specifically for CEL-NOS and MLN-Eo.

Background: Biomarker-driven trials have led to multiple FDA tissue-agnostic approvals. We aimed to explore the clinic-genomic landscape of alterations currently actionable by tissue-agnostic targeted therapies. Methods: We mined AACR Project GENIE to extract data about three molecular targets currently on the list of FDA tissue-agnostic approvals (RET fusions, NTRK fusions, and BRAFV600E mutations). Results: Among 137401 patients in GENIE database (153,834 samples), 4506 samples harbored BRAFV600E mutations (3%), 390 had NTRK fusions (0.3%), and 375 had RET fusions (0.2%) (Table 1). Cancers with BRAFV600E mutations included melanoma (n=1278; 28%), CRC (n=1120; 25%), thyroid cancer (n=845; 19%), glioma (n=359; 8%), NSCLC (n=300; 7%); and multiple other tumor types (n=1882; 42%). The most frequent co-occurring alterations were TERT and TP53. NTRK fusions were observed in breast cancer (n=42; 11%), glioma (n=37; 10%), thyroid cancer (n=37; 10%), soft tissue sarcomas (n=34; 9%), and NSCLC (n=32; 8%); among others (n=208; 53%). The most common fusion partners were ETV6, TPM3, and LMNA and most frequent co-occurring mutations were TP53 and TERT. RET fusions were seen in NSCLC (n=208; 56%), thyroid cancer (n=88; 24%), CRC (n=15; 4%), breast cancer (n=11; 3%), and gastroesophageal cancer (n=8; 2%); among others (n=45; 12%). Common fusion partners were were KIF5B, CCDC6, and NCOA4 and most frequent co-occurring alterations were TP53 and SETD2. Conclusions: BRAF, RET and NTRK alterations are prevalent across multiple tumors. Although rare, together they are found in around 3.4% of all human cancers. Further analysis of co-occurring TP53, TERT and SETD2 alterations and their impact on response to targeted therapies is warranted, in order to tailor personalized treatments for patients harboring these alterations. Table 1: Tissue spectrum of activity for anticancer drugs with tissue-agnostic approvals Approved Alteration Most Common Diagnoses Prevalence in Literature Prevalence in Disease Specific Analysis Approved Drug(s) Tissue Agnostic FDA Approval Year Tissue Agnostic ORR from Clinical Trials NTRK Fusions Breast Cancer 0.08-0.13% 0.3% Larotrectinib; Entrectinib 2018 (Larotrectinib); 2019 (Entrectinib) ORR: 75% and DOR: NR (Larotrectinib); ORR: 57% and 12mDOR: 45% (Entrectinib) Glioma 0.55% 0.4% Thyroid Cancer 2.22-2.28% 1.7% Soft Tissue Sarcoma 0.68-1.17% 0.8% NSCLC 0.16-0.23% 0.1% Salivary Gland Cancer 79.6-84.9% 3% CRC 0.26-0.35% 0.2% Gastroesophageal Cancer N/A 0.4% Pancreatic Cancer 0.30-0.34% 0.3% Melanoma 0.36-0.54 0.2% RET Fusions NSCLC 2% 0.9% Selpercatinib 2022 ORR: 44% and DOR: 24.5m Thyroid Cancer 5-10% 4.1% CRC Citation Format: Mohamed A. Gouda, Blessie E. Nelson, Lars Buschhorn, Adam Wahida, Vivek Subbiah. Landscape of 4,506 pan-cancer samples harboring BRAFV600E mutations, and NTRK/RET Fusions from 137,401 adult patients with cancer: Clinical implications for tissue agnostic therapies [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 1173.

Introduction Targeting the cell cycle machinery represents a rational therapeutic approach in myelodysplastic syndromes (MDS) and secondary acute myeloid leukemia (sAML). Despite substantial response rates, clinical use of the PLK inhibitor volasertib has been hampered by elevated side effects such as neutropenia and infections. Objectives The primary objective was to analyse whether a reduced dose of volasertib was able to limit toxic effects on the healthy haematopoiesis while retaining its therapeutic effect. Methods Bone marrow mononuclear cells (BMMNCs) of patients with MDS/sAML (n = 73) and healthy controls (n = 28) were treated with volasertib (1 μM to 1 nM) or vehicle control. Short-term viability analysis was performed by flow cytometry after 72 hours. For long-term viability analysis, colony-forming capacity was assessed after 14 days. Protein expression of RIPK3 and MCL-1 was quantified via flow cytometry. Results Reduced dose levels of volasertib retained high cell death-inducing efficacy in primary human stem and progenitor cells of MDS/sAML patients without affecting healthy haematopoiesis in vitro. Interestingly, volasertib reduced colony-forming capacity and cell survival independent of clinical stage or mutational status. Conclusions Volasertib offers a promising therapeutic approach in patients with adverse prognostic profile. RIPK3 and MCL-1 might be potential biomarkers for sensitivity to volasertib treatment.

Patients with Myelodysplastic Syndromes (MDS) and secondary Acute Myeloid Leukemia (sAML) have a very poor prognosis after failure of hypomethylating agents (HMA). Stem cell transplantation is the only effective salvage therapy, for which only a limited number of patients are eligible due to age and comorbidity. Combination therapy of venetoclax and azacitidine (5-AZA) seems to be a promising approach in myeloid malignancies, but data from patients with HMA failure are lacking. Furthermore, a considerable concern of combination regimens in elderly AML and MDS patients is the toxicity on the remaining healthy hematopoiesis. Here, we report in vitro data showing the impact of venetoclax and 5-AZA, alone or in combination, in a larger cohort of MDS/sAML patients (n = 21), even after HMA failure (n = 13). We especially focused on the effects on healthy hematopoiesis and the impact on colony forming capacity as a parameter for long-term effects. To the best of our knowledge, we show for the first time that venetoclax in combination with capped dose of 5-AZA targets cell malignancies, while sparing healthy hematopoiesis. Electronic supplementary material The online version of this article (10.1186/s40164-019-0133-1) contains supplementary material, which is available to authorized users.