Standard Tyrosine Kinase Inhibitors Research Articles

A phase 2, open-label, single-arm study evaluating the combination of pembrolizumab (pembro), lenvatinib, and chemotherapy in patients (pts) with metastatic non-small cell lung cancer (NSCLC) harbouring a targetable mutation who experienced disease progression on standard tyrosine kinase inhibitors (TKIs).

198 Background: Pts with metastatic NSCLC harbouring a targetable mutation who progressed on standard TKIs often receive chemotherapy as the next line of treatment. We report efficacy and safety of a novel combination of pembro, lenvatinib and chemotherapy for these pts. Methods: This was a phase 2, open-label, single-centre, single-arm study enrolling pts with metastatic NSCLC with sensitizing EGFR, ALK or ROS1 mutation who progressed on standard TKIs. Eligible pts had measurable disease, no untreated brain metastasis and ECOG PS ≤1. Pts received pembro 200 mg, pemetrexed 500 mg/m2 and carboplatin AUC 5 every 3 weeks for 4 cycles plus lenvatinib 8 mg QD. The maintenance regimen without carboplatin was continued as tolerated for up to 2 years. The primary endpoint was objective response rate (ORR) by independent radiology review (IRR) as per RECIST 1.1. The secondary endpoints were PFS, overall survival (OS) and safety. Results: At the data cutoff date (2nd February 2024), 24 pts were screened and 19 were enrolled: median age 64 years (range 29–77); 10 (53%) female. Four pts were excluded at screening due to untreated brain metastasis. All enrolled pts were evaluated for safety while 15 pts were evaluable for response. All pts had adenocarcinoma with targetable mutation: EGFR mutation in 18 (95%) pts and ALK fusion in 1 (5%) pt. The median follow-up time was 11.3 months. Treatment was ongoing in 8 pts on the date of analysis, while 6 pts permanently discontinued due to disease progression and 1 pt permanently discontinued due to a treatment-related adverse event (TRAE). The ORR was 40% (6/15, 95% CI 19.8%–64.3%). All responses were partial responses. The median PFS was 11.9 months (range 3.5–20.3). The OS was not reached. TRAEs of any grade (Gr) occurred in 74% (14/19) of the pts. Most of the TRAEs were Gr 1–2, which occurred in 63% (12/19) of the pts. The most common TRAEs were hypothyroidism (31.6%), nausea (26.3%), neutropenia (26.3%), thrombocytopenia (26.3%), anorexia (21.1%), hypertension (15.8%), anaemia (10.5%), pruritus (10.5%) and rash (10.5%). G1 diarrhoea was reported in 1 pt (5.3%) and G1 adrenal insufficiency in 1 pt (5.3%). Gr 3 TRAEs were neutropenia in 2 pts, anaemia in 1 pt and thrombocytopenia in 1 pt. The only Gr 4 TRAE was thrombocytopenia. No treatment related death was observed. Conclusions: The combination of pembro, lenvatinib and chemotherapy demonstrated a favourable ORR and safety in treating metastatic NSCLC pts with a targetable mutation who progressed on standard TKIs. Clinical trial information: NCT04989322 .

Camrelizumab plus rivoceranib vs sorafenib as first-line therapy for unresectable hepatocellular carcinoma (uHCC): Final overall survival analysis of the phase 3 CARES-310 study.

4110 Background: The phase 3 CARES-310 trial is the first to demonstrate significant progression-free survival (PFS) and overall survival (OS) benefits with immunotherapy plus an anti-angiogenic tyrosine kinase inhibitor (TKI) over standard TKI as first-line treatment for uHCC. In the primary analysis of PFS (data cut-off [DCO], May. 10, 2021) and interim analysis of OS (DCO, Feb. 8, 2022), significant improvements were observed with camrelizumab (C; anti-PD-1 antibody) + rivoceranib (R; VEGFR2-TKI) vs. sorafenib (S). Here, we report updated data at the final analysis (FA), after an additional follow-up of ~16 mo. Methods: In this international, randomized, open-label, phase 3 trial, 543 patients with uHCC who had not previously received systemic treatment were randomized 1:1 to receive either C (200 mg, iv, q2w) + R (250 mg, po, qd) or S (400 mg, po, bid). As of Jun.14, 2023, 351 (65%) deaths occurred, and a protocol-specified FA was performed. Results: 272 patients were allocated to C+R and 271 to S. At DCO of FA, median follow-up was 22.1 mo in C+R group and 14.9 mo in S group. After end of study treatment, 36% of patients in C+R group and 42% in S group received subsequent targeted therapy; 17% and 36% received immunotherapy, respectively. Median OS was significantly prolonged with C+R vs . S (23.8 mo [95% CI 20.6-27.2] vs. 15.2 mo [95% CI 13.2-18.5]; hazard ratio (HR) 0.64 [95% CI 0.52-0.79]; 1-sided p <0.0001). OS rate with C+R vs.S was 49.0% vs. 36.2% at 24 mo, and 37.7% vs. 24.8% at 36 mo. OS benefits with C+R was generally consistent across subgroups, regardless of geographical region, race, and aetiology. Benefits in PFS, objective response rate (ORR) and duration of response (DoR) with C+R were also sustained after prolonged follow-up (Table). Safety data aligned with the interim OS analysis, with no new signals noted. Conclusions: At the protocol-specified FA, C+R continued to show clinically meaningful survival improvement compared with S, with manageable safety. The extended follow-up further confirmed the favorable benefit-to-risk profile of C+R, supporting it as a new first-line treatment option for uHCC. Clinical trial information: NCT03764293 . [Table: see text]

Synthesis, Docking Study, and Cytotoxicity Evaluation of New Hydroxy benzoic Acid Derivatives

Hydroxy benzoic acid derivatives are an important scaffold in medicinal chemistry. A review of the literature revealed that they have a wide range of biological activities, including anti-inflammatory, antibacterial, and anti-tumor properties. The current study aimed to synthesize three new hydroxy benzoic acid derivatives (compounds 8, 9, and 10) and test them as epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in silico and in vitro. Traditional organic synthesis methods were applied to produce these compounds. Docking studies revealed that compound 8 had nearly equal binding energy (DG) to erlotinib, the standard EGFR tyrosine kinase inhibitor. -8.56 and -8.75 kcal/mol, respectively. Using the MTT (3-(4, 5-dimethylthiazolyl-2)-2, 5-diphenyltetrazolium bromide) viability assay, the cytotoxicity of the new hydroxy benzoic acid derivatives was tested against DLD-1 colorectal adenocarcinoma cells, HeLa cervical cancer cells, and MCF-7 breast cancer cells. Compound 8 showed cytotoxicity against the three cancer cell lines tested (25.05, 23.88, and 48.36 µM, respectively), while compound 9 showed cytotoxicity against HeLa cells only (37.67 µM), and compound 10 was cytotoxic to DLD-1 and HeLa cells (27.26 and 19.19 µM, respectively. The half maximal inhibitory concentrations (IC50) of compound 8 were comparable to those of the standard tyrosine kinase inhibitor drug erlotinib (13.86, 36.41, and 87.34 µM, respectively). In conclusion, the findings of the present study indicate that compound 8, through its EGFR inhibitory activity, is a promising cytotoxic agent.

Abstract 3808: Spatially resolved transcriptomics of cellular architecture in EGFR-mutated lung cancer

Abstract Introduction: Single-cell RNA sequencing of dissociated tumors enables the profiling of cellular states in fine detail, but erases the cellular organization of the analyzed tissue. Spatially resolved transcriptomics (SRT) using 10X Genomics’ Visium platform combines histological staining and RNA sequencing by capturing each transcript across spatially barcoded microarrays. SRT yields gene-expression matrices resolved within 55-micron array spots, and creates opportunities to explore how lung biology is affected by lung adenocarcinoma and how tumor cells and the proximal microenvironment are modulated by targeted therapy. Methods: SRT reactions (n=8) were performed on surgical specimens from human lung adenocarcinomas driven by kinase domain mutations of EGFR (exon 19 deletion, L858R point mutation, exon 20 insertion). SRT reactions analyzed primary lung cancer (n=5) or paired tumor-adjacent lung tissues (n=3). Results: 28458 array spots were recorded across all samples, and array spots captured a median of 5800 total transcripts and a median of 2416 unique transcripts. Single marker gene expression and unsupervised clustering across array spots corresponded with histological annotations of lung structures and adenocarcinoma. Integration of single-cell RNA sequencing data from lung adenocarcinoma specimens permitted mapping and quantification of 15 major cell types, including cancer cells, T- and B- lymphocytes, macrophages, dendritic cells, fibroblasts, and endothelial cells. Compared with paired tumor-adjacent lung tissues, adenocarcinoma tissues contained fibroblast-enriched desmoplasia and B-cell enriched tertiary lymphoid structures. In a clinical case with resistance to Osimertinib, the standard tyrosine kinase inhibitor, gene signature analysis of cancer-containing array spots revealed enrichment of gap-junction, fatty acid metabolism, and kynurenine pathway signatures compared to treatment naïve array spots. Conclusion: This pilot study demonstrates the feasibility of using SRT in lung adenocarcinoma. Paired with a single-cell atlas of lung adenocarcinoma during targeted therapy, this approach enables hypothesis-generation to investigate the alterations of tumor and tumor microenvironmental architecture in relation to targeted therapy. Citation Format: Daniel L. Kerr, Wei Wu, Whitney Tamaki, Anatoly Urisman, Yu-Ting Chou, Philippe Gui, David M. Jablons, Trever G. Bivona, Collin M. Blakely. Spatially resolved transcriptomics of cellular architecture in EGFR-mutated lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3808.

Predicting patient treatment response and resistance via single-cell transcriptomics of their tumors.

e20540 Background: Tailoring the best treatments to cancer patients is an important open challenge. Here, we build a precision oncology data science and software framework for PERsonalized single-Cell Expression-based Planning for Treatments In Oncology (PERCEPTION). Methods: Our approach capitalizes on recently published matched bulk and single-cell transcriptome profiles of large-scale cell-line drug screens to build treatment response models from patients’ single-cell (SC) tumor transcriptomics. Our approach is a two-step process: first, the prediction models are trained on large-scale bulk-expression profiles of cancer cell lines and then, in a second step, the models’ performance is further optimized by training on SC-expression profiles of cancer cell lines. Results: First, we show that PERCEPTION successfully predicts the response to monotherapy and combination treatments in screens performed in cancer and patient-tumor-derived primary cells based on SC-expression profiles. Second, it successfully stratifies responders to combination therapy based on the patients’ tumor’s SC-expression in two very recent multiple myeloma and breast cancer clinical trials. Thirdly, it captures the development of clinical resistance to five standard tyrosine kinase inhibitors using tumor SC-expression profiles obtained during treatment in a lung cancer patients’ cohort. Notably, PERCEPTION outperforms state-of-the-art bulk expression-based predictors in all three clinical cohorts. Conclusions: In sum, this study provides a first-of-its-kind conceptual and computational method that is predictive of response to therapy in patients, based on the clonal SC gene expression of their tumors.

Osimertinib as Neoadjuvant Therapy for Resectable Non-Small Cell Lung Cancer: A Case Series

Background: Evidence of osimertinib as neoadjuvant therapy for resectable non-small cell lung cancer (NSCLC) are currently lacking. This case series study aimed to assess the safety and feasibility of neoadjuvant osimertinib therapy followed by surgery for resectable NSCLC. Materials and methods: Patients with resectable NSCLC with epidermal growth factor receptor (EGFR) mutation who received osimertinib as neoadjuvant therapy followed by surgery at our center were included. Demographic features, radiologic and pathological assessment of response, surgery-related details and complications, toxicity profiles, and prognostic outcomes were extracted. Results: A total of 13 patients were included in this study. The median age at the time of surgical resection was 57 years (interquartile range: 52–64 years), and eight (61.5%) patients were female. The objective response rate (ORR) was 69.2% (9/13), and the complete resection rate was 100%. The rates of pathologic downstaging and lymph node downstaging were 100% (13/13) and 66.7% (6/9), respectively. There were no perioperative deaths and only three (23.1%) patients had postoperative complications. Seven (53.8%) and 13 (100%) patients experienced grade 1 treatment-related adverse reactions and laboratory abnormalities, respectively. No patients experienced drug withdrawal or surgical delays due to the adverse events. No patients showed grade 2 or worse toxicity profiles. One patient was lost to follow-up. The other 12 patients were alive and free of disease recurrence with a median follow-up time of 9.5 months. Conclusion: Neoadjuvant osimertinib therapy seemed to be safe and feasible for resectable EGFR-mutated NSCLC. Future large prospective studies are warranted to confirm whether osimertinib as neoadjuvant therapy outperforms standard tyrosine kinase inhibitors (TKIs) or chemotherapy for resectable EGFR-mutated NSCLC.

Initial or salvage treatment with apatinib shows promise against radioiodine-refractory differentiated thyroid carcinoma.

ObjectiveSorafenib and lenvatinib have been recommended as standard tyrosine kinase inhibitors (TKIs) for progressive radioiodine-refractory differentiated thyroid carcinoma (RR-DTC). However, their efficacy remains limited with unresolved drug resistance. Therefore, we conceived this open-label study based on real-world evidence to investigate the efficacy and safety of apatinib in patients with progressive RR-DTC.MethodsOff-label use of apatinib as either initial treatment or salvage treatment for sorafenib resistance was investigated. The primary endpoint was progression-free survival (PFS) and the secondary endpoints included objective response rate (ORR), overall survival (OS), and safety.ResultsFor all 28 enrolled patients, the median PFS was 15.1 months, with an ORR of 69.6%. The median OS was not reached at the data cut-off. In detail, the median PFS of 17.3 months and the ORR of 75% were determined in patients with TKI-naive RR-DTC (initial treatment group, n = 14). And, in patients with first-line sorafenib-resistant RR-DTC (salvage treatment group, n = 14), a median PFS of 12.0 months was reached, with an ORR of 45.5%. In the salvage treatment group, the median OS from the start of apatinib administration was 20.6 months, reaching 89.1 months from sorafenib treatment initiation. Adverse events at grade 3 or higher occurred in 64.3% of all subjects treated with apatinib.ConclusionsThis study demonstrated that apatinib shows promise against RR-DTC with tolerable toxicity, representing a novel initial treatment for progressive RR-DTC and effective salvage treatment for RR-DTC resistant to sorafenib.

Russian Prospective Non-Randomized Clinical Study on Dose Reduction of Tyrosine Kinase Inhibitors with Subsequent Complete Therapy Discontinuation in Chronic Myeloid Leukemia Patients with Stable Deep Molecular Response (READIT-2020): Background, Aim, Main Objectives, Design, and Expected Results

Background. A withdrawal of tyrosine kinase inhibitor (TKI) therapy in chronic myeloid leukemia (CML) patients with optimal response, especially in patients with drug toxicity, is a matter of current interest. According to the results of numerous clinical studies, the probability of sustaining treatment-free remission (TFR) in CML patients with deep molecular response (DMR) is about 40-60 %. Great attention has recently been paid to personalized therapy consisting in TKI dose modification aimed at reducing or preventing therapy adverse events. Many large retrospective studies showed that reduced TKI doses in CML patients with major molecular response (MMR) and DMR is a safe therapy option. The follow-up of patients receiving reduced TKI doses is also carried out under prospective clinical studies as a stage prior to therapy discontinuation. This approach shows that the probability of sustaining TFR after the stage of TKI dose reduction is about 70 % which is higher than that after the withdrawal of standard TKI doses. Aim. To present the background, aim, and mai n objectives of the study as well as the design and expected results. Materials & Methods. READIT-2020 (Russian prospective study of REduction And DIscontinuation Treatment of TKI) is a Russian prospective non-randomized clinical study with the main aim of developing a safe management regimen for CML patients with MMR and DMR, who receive reduced TKI doses, with subsequent follow-up in the period of TFR under the control of minimal residual disease. The study is going to enroll 100 patients. Each stage of the clinical study will include a regular molecular genetic monitoring at the central laboratory (National Research Center for Hematology, Moscow). The primary objective is to assess survival without MMR loss (BCR-ABL > 0.1 %) both on reduced TKI doses and during TFR. The primary endpoint is the follow-up period of 12 months after TKI discontinuation. Trial Registration No.: NCT04578847 (Clinicaltrial.gov).

Can we identify a preferred first-line strategy for sarcomatoid renal cell carcinoma? A network meta-analysis.

Background: Combinations based on immune checkpoint inhibitors are the new first-line standard treatment for metastatic renal cell carcinoma. Sarcomatoid renal cell carcinoma (sRCC) has a dismal prognosis but good immunogenicity. Methods: The authors performed a network meta-analysis of Phase III randomized trials of immune checkpoint inhibitor-based combinations versus standard tyrosine kinase inhibitor monotherapy reporting data for sRCC. The end points were overall survival, progression-free survival and objective response rate. Results: Five trials comprising 569 sRCC patients (out of a total of 4409 metastatic renal cell carcinoma patients) were included. Nivolumab-cabozantinib was the highest ranking treatment for overall survival (p-score = 88%) and progression-free survival (p-score = 81%). Atezolizumab-bevacizumab had the highest rank for objective response rate (p-score = 80%). Conclusion: Despite some limitations, nivolumab-cabozantinib might be the preferred first-line option for sRCC in terms of efficacy.

GMP-compliant production of [68Ga]Ga-NeoB for positron emission tomography imaging of patients with gastrointestinal stromal tumor

Background[68Ga]Ga-NeoB is a novel DOTA-coupled Gastrin Releasing Peptide Receptor (GRPR) antagonist with high affinity for GRPR and good in vivo stability. This study aimed at (1) the translation of preclinical results to the clinics and establish the preparation of [68Ga]Ga-NeoB using a GMP conform kit approach and a licensed 68Ge/68Ga generator and (2) to explore the application of [68Ga]Ga-NeoB in patients with gastrointestinal stromal tumors (GIST) before and/or after interventional treatment (selective internal radiotherapy, irreversible electroporation, microwave ablation).ResultsValidation of the production and quality control of [68Ga]Ga-NeoB for patient use had to be performed before starting the GMP production. Six independent batches of [68Ga]Ga-NeoB were produced, all met the quality and sterility criteria and yielded 712 ± 73 MBq of the radiotracer in a radiochemical purity of > 95% and a molar activity of 14.2 ± 1.5 GBq/μmol within 20 min synthesis time and additional 20 min quality control. Three patients (2 females, 1 male, 51–77 yrs. of age) with progressive gastrointestinal stromal tumor metastases in the liver or peritoneum not responsive to standard tyrosine kinase inhibitor therapy underwent both [68Ga]Ga-NeoB scans prior and after interventional therapy. Radiosynthesis of 68Ga-NeoB was performed using a kit approach under GMP conditions. No specific patient preparation such as fasting or hydration was required for [68Ga]Ga-NeoB PET/CT imaging. Contrast-enhanced PET/CT studies were performed. A delayed, second abdominal image after the administration of the of [68Ga]Ga-NeoB was acquired at 120 min post injection.ConclusionsA fully GMP compliant kit preparation of [68Ga]Ga-NeoB enabling the routine production of the tracer under GMP conditions was established for clinical routine PET/CT imaging of patients with metastatic GIST and proved to adequately visualize tumor deposits in the abdomen expressing GRPR. Patients could benefit from additional information derived from [68Ga]Ga-NeoB diagnosis to assess the presence of GRPR in the tumor tissue and monitor antitumor treatment.

Gastrointestinal stromal tumours.

Gastrointestinal stromal tumours (GIST) have an incidence of ~1.2 per 105 individuals per year in most countries. Around 80% of GIST have varying molecular changes, predominantly mutually exclusive activating KIT or PDGFRA mutations, but other, rare subtypes also exist. Localized GIST are curable, and surgery is their standard treatment. Risk factors for relapse are tumour size, mitotic index, non-gastric site and tumour rupture. Patients with GIST with KIT or PDGFRA mutations sensitive to the tyrosine kinase inhibitor (TKI) imatinib that are at high risk of relapse have improved survival with adjuvant imatinib treatment. In advanced disease, median overall survival has improved from 18 months to >70 months since the introduction of TKIs. The role of surgery in the advanced setting remains unclear. Resistance to TKIs arise mainly from subclonal selection of cells with resistance mutations in KIT or PDGFRA when they are the primary drivers. Advanced resistant GIST respond to second-line sunitinib and third-line regorafenib, as well as to the new broad-spectrum TKI ripretinib. Rare molecular forms of GIST with alterations involving NF1, SDH genes, BRAF or NTRK genes generally show primary resistance to standard TKIs, but some respond to specific inhibitors of the activated genes. Despite major advances, many questions in both advanced and localized disease remain unanswered.

Opportunities of Chronic Myeloid Leukemia Treatment with Reduced Doses of Tyrosine Kinase Inhibitors

Tyrosine kinase inhibitor (TKI) therapy results in deep molecular response (MR) in 60-70 % of chronic myeloid leukemia (CML) patients. However, despite high efficacy of TKIs, many patients experience drug toxicity during the treatment. According to clinical studies, the probability of sustaining off-treatment remission in CML patients with deep MR is about 40-60 %. Great attention has recently been paid to personalized therapy of chronic phase CML. It consists in TKI dose modification to reduce or prevent adverse events. Major retrospective studies proved that in patients with optimal response TKI reduced doses can be considered safe from the point of view of sustaining major and deep MRs achieved with standard TKI doses. Also, prospective clinical trials deal with the follow-up using TKI reduced doses as pre-withdrawal period. But up to now, the results of only 4 of such studies have been available. To take a closer look at long-term follow-up of CML patients receiving reduced doses of TKIs, prospective clinical trials need to be carried out. The present article reviews the results of main studies dealing with management of CML patients treated with TKI reduced doses.

Association of Tuberculosis in Patients with Chronic Myeloid Leukemia, a Treatment Proposal Based on Literature Review

Introduction: Chronic Myeloid leukemia (CML) is a chronic myeloproliferative neoplasm with an increased undifferentiated proliferation of granulocytic lineage of the white blood cells. It is an acquired disorder of the hematopoietic stem cells due to a cytogenetic aberration known as the Philadelphia chromosome. It occurs due to a phenomenon of a reciprocal translocation between chromosomes t(9,22) and results in BCR/ABL fusion gene. The product of this gene has tyrosine kinase property, which predominantly causes the disease. Tyrosine kinase inhibitors (TKI) are the mainstay of the treatment to achieve remission, while bone marrow transplant is the only proven cure. Tuberculosis (TB), both active and reactivation of latent TB, remains the most common infectious disease worldwide and leads to high mortality. Currently, one-fourth of the global population has been infected by Mycobacterium tuberculosis. The incidence of TB has been reportedly increasing in patients with cancer. It has been mostly found in association with non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL). Recently, the incidence increased in patients with CML during treatment with Imatinib (IM) has also been reported in a retrospective cohort study in Taiwan by Lui C-J et. al. and few other published cases in literature. This might be due to impairment of the T lymphocytes signal transduction leading to increased host susceptibility to TB, hepatitis B, and varicella-zoster infection. TB treatment is mainly based on the susceptibility of the Mycobacterium Tuberculosis to the anti-TB medications. First-line therapy includes of four drugs, Isoniazid (INH), Rifampicin (RIF), Pyrazinamide (PZA), and Ethambutol (EMB). Anti TB drugs administration also needs close monitoring because of potential side effects. These include, but not limited to hepatoxicity, optic neuritis, impaired color vision, peripheral neuropathy, and gastrointestinal disturbances. Their occurrence necessitate discontinuation of the culprit drug from the regimen. Certain anti TB drugs are also known to disrupt bioavailability of other drugs metabolized in the liver when concomitantly administered by influencing the hepatic cytochrome P450 enzyme. This happens while using anti-TB medication to treat concomitant TB infection in CML patients on tyrosine kinase inhibitors therapy. Methods and critical analysis of the reviewed study articles: The authors reviewed the current literature focusing on all articles addressing TB infections and their diagnosis and management in patients with CML (PubMed and Google Scholar between 2000 and 2020). Our review aimed to provide the necessary data to improve clinical diagnosis and clarify the management strategy of this condition. Conclusion and treatment proposal: Throughout our review of multiple research articles, it has been realized that patients with CML and other hematological malignancies and solid tumors (e.g., non-Hodgkin lymphoma, chronic lymphocytic leukemia, metastatic gastric tumors), have a higher risk of having TB infection. TB infection (pulmonary and extra-pulmonary) occurs 2-9 times more than the general population in patients with hematological malignancies. In CML patients, treatment therapy with Imatinib posed a higher risk of development of TB due to defective cellular immunity. Co-administration of 1st line anti Tb medications mainly rifampicin with standard TKIs therapy Imatinib and Dasatinib has resulted in sub-therapeutic levels of these drugs due to induction of CYP4503A enzyme. Either by changing the TB treatment regimen to a non-rifampicin based therapy line with a combination of a fluoroquinolone, increasing the dose, or switching to a different TKI class may result in clinical improvement. To the best of our knowledge, there are no randomized control trials, or FDA approved guidelines to treat concomitant TB infection in CML patients. Therefore, a clear strategy to deal with such a clinical condition is lacking. The immediate treatment for the concomitant disease has been suggested based on clinical experience and clinical response of some patients published in few case reports, case series, and retrospective cohort studies. After careful literature review, we put forth our management proposals, However it need further research studies and clinical trials to bring recommendations and guidelines. Disclosures No relevant conflicts of interest to declare.

Comment on low‐dose tyrosine kinase inhibitors before treatment discontinuation do not impair treatment‐free remission in chronic myeloid leukemia patients: Results of a retrospective study

We read with interest the study by Cayssials et al1 describing how in chronic myeloid leukemia, a reduced dosage of tyrosine kinase inhibitors (TKIs) does not seem to reduce the possibility of a prolonged treatment-free remission in comparison with the standard TKI dosage. We observed that the reduction of TKI therapy was in most cases related to nonhematological toxicity, with dose reductions being due to hematological toxicity in only 2 cases; we should point out that generally hematological toxicities are more frequent among patients with advanced disease. The appearance of toxicity during TKI treatment is related to patient-specific features that influence pharmacodynamics; as such, plasma drug monitoring could be a correct approach to maximizing the efficacy of therapy and minimizing adverse events.2, 3 We are aware that plasma drug monitoring is not a diffused and standardized technology, but we feel that knowing whether patients experiencing toxicity have higher plasma concentrations could be valuable, especially with respect to the assessment of responses and the possibility of discontinuing TKIs in such patients. Some previous studies4-6 have reported a nondetrimental effect of de-escalation of TKI therapy before treatment discontinuation in patients with a deep molecular response, but they have not been able to explain this phenomenon. We agree with the authors that patients treated with TKIs at a low dose on account of treatment-related toxicity could achieve the same treatment-free remission as patients treated with the standard dosage, but in our opinion, the plasma drug dosage could be helpful for understanding this phenomenon and designing tailored therapy. No specific funding was disclosed. The authors made no disclosures.

Therapeutic inhibition of Fc\u03b3RIIb signaling targets leukemic stem cells in chronic myeloid leukemia

Despite the successes achieved with molecular targeted inhibition of the oncogenic driver Bcr-Abl in chronic myeloid leukemia (CML), the majority of patients still require lifelong tyrosine kinase inhibitor (TKI) therapy. This is primarily caused by resisting leukemic stem cells (LSCs), which prevent achievement of treatment-free remission in all patients. Here we describe the ITIM (immunoreceptor tyrosine-based inhibition motif)-containing Fc gamma receptor IIb (FcγRIIb, CD32b) for being critical in LSC resistance and show that targeting FcγRIIb downstream signaling, by using a Food and Drug Administration-approved BTK inhibitor, provides a successful therapeutic approach. First, we identified FcγRIIb upregulation in primary CML stem cells. FcγRIIb depletion caused reduced serial re-plaiting efficiency and cell proliferation in malignant cells. FcγRIIb targeting in both a transgenic and retroviral CML mouse model provided in vivo evidence for successful LSC reduction. Subsequently, we identified BTK as a main downstream mediator and targeting the Bcr-Abl-FcγRIIb-BTK axis in primary CML CD34+ cells using ibrutinib, in combination with standard TKI therapy, significantly increased apoptosis in quiescent CML stem cells thereby contributing to the eradication of LSCs.. As a potential curative therapeutic approach, we therefore suggest combining Bcr-Abl TKI therapy along with BTK inhibition.

A Phase I Study of Asciminib (ABL001) in Combination with Dasatinib and Prednisone for Untreated BCR-ABL1-Positive ALL in Older Adults

Introduction The BCR-ABL1 gene fusion is the most common molecular aberration in adult ALL and confers an adverse prognosis. The incorporation of ABL1 tyrosine kinase inhibitors (TKIs) into ALL chemotherapy regimens has dramatically improved outcomes for BCR-ABL1+ ALL. Subsequently, reduced-intensity TKI-based regimens have been shown to be as effective and less toxic than intensive TKI-based regimens (Foa et al. Blood 2011; Chalandon et al. Blood 2015). Asciminib (ABL001) is a potent, specific allosteric inhibitor of ABL1 that binds to a site spatially distinct from the catalytic domain. Asciminib was developed for efficacy against BCR-ABL1 mutations conferring resistance to standard TKIs. Preclinical studies demonstrated that the combination of asciminib and TKI leads to sustained disease control in a cell line xenograft model of BCR-ABL1+ CML (Wylie et al. Nature 2017). We also observed that the addition of asciminib to TKI significantly prolongs survival in patient-derived xenograft models of BCR-AB1L+ ALL, even in the context of a pre-existing subclonal T315I mutation (unpublished). An ongoing phase I Novartis study (NCT02081378) has shown safety and efficacy of asciminib alone and in combination with TKIs in relapsed/refractory (R/R) BCR-ABL1+ ALL and CML. We hypothesized that dual ABL blockade with catalytic domain and allosteric inhibitors would be tolerable and effective in older adults with BCR-ABL1+ ALL. Methods This is an investigator initiated, phase I study (NCT03595917) of asciminib in combination with dasatinib plus prednisone in BCR-ABL1+ ALL. The study uses a 3+3 dose escalation design with an expansion cohort with the primary objective to determine the MTD or RP2D. Secondary objectives include defining the depth of molecular remissions at early time points and durability of responses. Patients (pts) ≥ 50 years (yrs) with newly diagnosed BCR-ABL+ ALL or CML in blast phase with p190 or p210 transcripts are eligible. Younger pts (18-49 yrs) unfit for intensive chemotherapy, or pts ≥ 18 yrs with ALL R/R to intensive chemotherapy are also eligible (excluded if prior dasatinib or asciminib exposure). Pts are treated with dasatinib 140 mg daily and prednisone 60 mg/m2 days 1-24 (max 120 mg daily, tapered days 25-32) following Foa et al with escalating doses of asciminib once daily administered fasting (DL1: 40 mg; DL2: 80 mg; DL3: 160 mg; DL: 320 mg). Pts receive CNS prophylaxis with intra-thecal chemotherapy. Transplant-eligible pts are recommended to be consolidated with allogeneic transplant as medically appropriate at or after day 85; transplant-ineligible pts may remain on therapy if deriving clinical benefit. Correlative science efforts aim to identify biomarkers of response to combined BCR-ABL1 blockade and molecular signatures enriched in minimal residual disease, based on targeted tumor sequencing and serial single-cell RNA sequencing of leukemia and stromal populations from blood and marrow. Results As of July 31, 2019, 6 adults (3 male/3 female) have enrolled and 3 have completed DL1. All 6 had newly diagnosed, untreated BCR-ABL1+ ALL. The median age at registration was 67 (range 53 - 83) yrs. Three pts treated on DL1 have been evaluated for DLT and discontinued therapy (1 per pt decision after 4 cycles; 2 pts bridged to transplant after 4 cycles). At the time of this report, there has been no induction mortality, no DLTs, and no grade 3 or higher AEs at DL1. At DL1, 1 pt was treated entirely outpatient, the other 2 pts required short hospital stays (4 and 5 days) after treatment initiation. Responses for the 3 pts treated at DL1 are summarized in the table. Pre-treatment tumor genotyping and serial on-treatment, single-cell profiling of tumor and microenvironment fractions from marrow and blood have been performed in all pts to date and have revealed biophysical, transcriptional, and genetic inter-tumor heterogeneity. These data will be used to illuminate disease biology and define predictive biomarkers, pending further maturation of clinical endpoints. Conclusion Dual ABL1 kinase inhibition with asciminib and dasatinib plus prednisone in newly diagnosed BCR-ABL1+ ALL is feasible in older adults with no increase in toxicity. The last pt at DL2 is completing treatment and being evaluated for DLT before planned escalation to DL3. An expansion cohort of 10 pts at the MTD or RP2D is planned to further characterize safety and clinical activity of the combination. Disclosures Stevenson: Celgene: Research Funding. Weinstock:Celgene: Research Funding. DeAngelo:Incyte: Consultancy; Pfizer: Consultancy; Jazz Pharmaceuticals Inc: Consultancy; Novartis: Consultancy, Research Funding; GlycoMimetics: Research Funding; Abbvie: Research Funding; Shire: Consultancy; Celgene: Consultancy; Takeda Pharmaceuticals: Consultancy; Amgen: Consultancy; Blueprint: Consultancy, Research Funding.

1702P - Efficacy and safety of apatinib for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib: An open-label, multicenter, single-arm, phase II trial

BackgroundGastrointestinal stromal tumors (GISTs) patients (pts) who develop resistance to imatinib and sunitinib have few therapeutic options. Apatinib is a multiple tyrosine kinase inhibitor and targetsVEGFR2, PDGFRβ and c-Kit, which is effective in several solid tumors. We aimed to assess the efficacy and safety of apatinib in pts with advanced GISTs who failed previous standard tyrosine kinase inhibitors. MethodsIn this single-arm, open-label, phase II study, we enrolled pts (aged ≥18 years) with advanced GISTs resistant to imatinib and sunitinib from 3 comprehensive cancer centers or university hospitals in China and assigned them to 500mg oral apatinib once daily in 4-week cycles. Pts were assessed for response by RECIST 1.1 every 2 cycles. The primary endpoint was investigator-assessed progression-free survival. The secondary endpoints included response rate, overall survival and advent events. ResultsBetween September 2017 and February 2019, 10 pts were enrolled (7 evaluable for response), and pts are still being accrued to the trial. Here we present the preplanned early analysis of clinical outcomes. The median follow-up was 16.6 months. Four pts reached stable disease. The median PFS was 5.4 months (95% CI 2.0–9.8), and the 4-month PFS rate was 57.1%. Drug-related adverse events were reported in 9 (90%) pts and the most common apatinib-related adverse events of grade 3 or higher were hypertension (3 of 10, 30%), hand-foot skin reaction (4 of 10, 40%), fatigue (5 of 10, 50%) and proteinuria (2 of 10, 20%). There was no treatment-related death. ConclusionsApatinib appears to have promising anti-tumor activity and an acceptable toxicity profile in pts with advanced GISTs previously treated with imatinib and sunitinib. Apatinib warrants further investigation in GISTs. Clinical trial identificationChiCTR1800020407. Legal entity responsible for the studyThe authors. FundingChinese Society of Clinical Oncology. DisclosureAll authors have declared no conflicts of interest.

Abstract 1269: P-glycoprotein expression in refractory gastrointestinal stromal tumors and its implication in the efficacy of paclitaxel as a salvage treatment

Abstract BACKGROUND: KIT-targeting tyrosine kinase inhibitors (TKIs) such as imatinib, sunitinib and regorafenib are the standard treatment for patients with gastrointestinal stromal tumor (GIST). However, most patients eventually develop treatment resistance to these standard therapies, and new agents must be introduced upon disease progression. Before TKIs were available, most of the conventional cytotoxic agents did not show sufficient clinical activity in GIST patients. However, a recent preclinical study demonstrated that 37 of the 89 FDA-approved anti-tumor drugs including paclitaxel (PTX) possess antitumor effect in at least one GIST cell line. Therefore, in this study, we aimed to evaluate the efficacy of PTX as a salvage treatment for GIST patients who exhibited treatment failure after standard TKI therapy using in-vitro/vivo models. MATERIALS and METHODS: The effect of PTX in GIST was examined by cell viability assay and rhodamine 123 (Rho123) efflux assay using GIST cells including established patient-derived GIST cell lines, and in animal models with patient-derived xenografts (PDXs) established from patients with GIST tumors refractory to TKIs. Multidrug resistance 1 (MDR1) mRNA expression by reverse transcription-PCR (RT-PCR) and P-glycoprotein (Pgp) expression by Western blotting or immunohistochemistry were evaluated in 20 patients’ tumor tissues, 9 GIST cell lines and 21 PDXs. To investigate the role of Pgp on PTX treatment, a stable MDR1-expressing GIST T1 cell line (GIST-T1-ABCB1#17) was prepared and compared with parent GIST T1 cell line. Verapamil was used as a Pgp inhibitor. RESULTS: Compared to imatinib-sensitive GIST-T1 harboring KIT exon 11 mutation and imatinib-resistant GIST-T1/816 harboring KIT exon 11 and 17 mutations, the patient-derived imatinib- and sunitinib-resistant GIST-R3 cell line harboring KIT exon 11 and 17 mutations was more resistant to PTX. Higher Rho123 efflux was observed in GIST-R3 which had high Pgp expression than in GIST-T1 and GIST-T1/816 which had low Pgp expression. The tumor growth inhibition of PTX was greater in xenografts with low Pgp expression (GIST-T1/816 xenografts and GIST-RX10 PDXs) than in xenografts with high Pgp expression (GIST-R3 xenografts and GIST-RX4 PDX). The GIST-T1-ABCB1#17, a stable MDR1-expressing GIST T1 cell line, exhibited a higher Pgp activity and a less sensitivity to PTX than the parent GIST-T1 cell line. The resistance of GIST-T1-ABCB1#17 to PTX was overcome by verapamil. CONCLUSION: Pgp expression was an important mechanism of resistance to PTX in preclinical GIST models. PTX is worth being tried clinically as a salvage treatment in patients with refractory GISTs with low Pgp expression. Citation Format: Young-Soon Na, Min-Hee Ryu, Young Soo Park, Chae-Won Lee, Ju-Kyung Lee, Jung Min Park, Yangsoon Park, Yoon-Koo Kang. P-glycoprotein expression in refractory gastrointestinal stromal tumors and its implication in the efficacy of paclitaxel as a salvage treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1269.

Implementation of functional precision medicine for anaplastic lymphoma kinase-rearranged non-small lung cancer

Anaplastic lymphoma kinase (ALK)-rearranged kinase drives non-small cell lung cancer (NSCLC) in 3–7% of patients and treatment consists of a broad range of approved inhibitors which are administered sequentially in case of resistance developing invariably after approximately 1 year of therapy. Besides the former standard tyrosine kinase inhibitor (TKI) crizotinib, the second-line ALK inhibitors alectinib, ceritinib, brigatinib, as well as the third-line lorlatinib are approved for the treatment of ALK-positive NSCLC patients. The main challenge is to find individual schemes of ALK inhibitors therapy which provide the best benefit for the patients. A host of ALK fusion partners, rearrangement variants and ALK mutations prevent a direct correlation of ALK alterations and sensitivity to specific TKIs within the framework of genomic precision medicine. However, recurrent ALK-positive NSCLC is an aggressive disease resulting in accumulation of tumor cells in pleural effusions which may be collected for in vitro sensitivity testing in a manner designated as functional precision medicine. Provided that these cells are present in sufficient numbers, they can be exposed to all possible drug candidates and their chemosensitivity tested in short-term proliferation assays. In addition to ALK-directed TKIs, cytotoxic drugs and inhibitors of non-target bypassing pathways may be included in the tests. In contrast to other trials in genome-guided precision medicine, a range of suitable therapeutics is available for modified ALK proteins. In summary, ALK-positive NSCLC with pleural effusions offer a unique model to develop, test and validate concepts of functional precision medicine.

A phase I trial of palbociclib in combination with dexamethasone in relapsed or refractory adult B-cell acute lymphoblastic leukemia (ALL).

TPS7065 Background: c-Myb is a DNA-binding transcription factor that is highly expressed in immature hematopoietic cells. c-Myb and its products are essential in regulating normal hematopoiesis and influencing leukemogenesis. Knockdown of c-Myb causes cell cycle arrest and apoptosis in pre-B-ALL cells. The effects of c-Myb depend on transcriptional regulation of CDK6 and Bcl-2. c-Myb-silenced Ph+ ALL cells exhibit Rb-dependent cell cycle arrest and apoptosis, both of which are rescued by ectopic expression of cyclin D3, CDK6, and Bcl-2 expression. Preclinical studies suggest that the cytotoxic activity of dexamethasone in ALL cells may be due to decreased c-Myb expression and reduced Bcl-2 levels. Thus, the novel combination of palbociclib, a small molecule CDK4/6 inhibitor, and dexamethasone is a logical approach for the treatment of B-cell ALL. Methods: This is a single arm, phase I, dose escalation study with a traditional 3+3 design. Adult patients with relapsed or refractory B-cell ALL are eligible. Patients with Ph+ ALL must be refractory to or intolerant of standard tyrosine kinase inhibitor therapy. Patients receive a 1-week lead-in of palbociclib alone followed by induction with 4 weeks of palbociclib and dexamethasone. If an adequate response is seen, patients move to maintenance therapy, which consists of 1 week of palbociclib plus dexamethasone followed by 3 weeks of palbociclib alone. Treatment continues until disease progression, dose limiting toxicity, or availability of an alternative therapy. The primary endpoints are dose limiting toxicity and maximum tolerated dose of palbociclib and dexamethasone. Correlative studies, which are performed on pretreatment, day +1 and day +8 samples, include RB phosphorylation and FOXM1 expression as measures of palbociclib activity; CD19+ cell gene expression profiling of (1) p21 expression as an indicator of cell cycle activity, (2) S-Phase, Annexin V/Caspase 3 activation as indicators of proliferation and apoptosis and (3) Myb and Bcl-2 expression as indicators of dexamethasone sensitivity. Cohort 1 is currently enrolling. Once a maximum tolerated dose is established, an expansion cohort is planned. Clinical trial information: NCT03472573.