Line Tyrosine Kinase Inhibitors Research Articles

Response to lorlatinib rechallenge in a case of ALK-rearranged metastatic NSCLC with a resistance mutation to second generation TKIs.

Several anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) have been developed for the treatment of echinoderm microtubule-associated protein-like 4 (EML4)-ALK-rearranged non-small cell lung cancer (NSCLC), with the newer generation agents brigatinib, alectinib and lorlatinib showing prolonged responses. With the increasing number of target therapies available, the optimal sequence is yet to be defined, as resistance profiles may evolve over time and in response to sequential ALK inhibitors. Therefore, ALK-targeted strategies may be personalized based upon the presence of specific ALK resistance mutations. Here, we report on the case of a patient who has been treated with a sequence of three ALK TKIs after receiving diagnosis of ALK-rearranged metastatic NSCLC in 2015 and gained further benefit upon lorlatinib rechallenge after the acquisition of the G1202R resistance mutation to second generation TKIs. In this case, the first ALK resistance mutation detected after progression on first line TKI, the I1171N, is a common resistance mutation after alectinib and confers sensitivity to brigatinib, that the patient received afterwards with a long-term disease stability. The second ALK resistance mutation detected after a chemotherapy interval, the G1202R, is the most common resistance mutation after second generation ALK TKIs and has been associated with sensitivity to third generation TKIs, such as lorlatinib. This case of a patient with EML4-ALK-rearranged NSCLC shows that sequential treatment with next-generation ALK TKIs, including rechallenge, can induce profound remissions, even in heavily pretreated patients, and that ALK-targeted strategies may be personalized by considering the presence of distinct ALK resistance mutations.

Abstract 4548: Discovering novel ALK-lung carcinoma therapeutic strategies by identifying combinations with Alectinib from ALK-positive lung carcinoma cell lines

Abstract Background: The therapeutic landscape for chromosomally rearranged anaplastic lymphoma kinase (ALK) has focused on the development of Tyrosine-kinase inhibitors (TKI) that specifically target ALK activity. However, as patients progress on first- and second line TKIs, over 50% of resistance is due to non-mutational resistance via compensatory pathways, also known as ALK-non dominant resistance. Alterations in other drivers such as EGFR, KRAS, MET account for some of the resistance mechanisms. Thus, here we explore the therapeutic activity of drug combinations that pair an ALK inhibitor with a drug that targets a "second driver". We describe our high-throughput drug screening platform that combines Alectinib, a selective blocker of ALK, with a panel of hundreds of chemical compounds curated to be active against a diverse array of pathways involved in cellular functions dysregulated in cancer. In this work, we identified several synergistic combinations that further increased the sensitivity of five ALK-positive lung cancer cell lines (DFCI 032, NCI-H3122, NCI-H2228, SNU2535, SNU324) to Alectinib in comparison to single treatment with the final goal of targeting resistance, before it emerges. Methods: ALK-positive cancer cell sensitivity to different compounds was assessed by generating the IC50 curves in the presence and absence of Alectinib. Cells were characterized by bulk-RNAseq, bulk-DNA seq, Reverse-phase protein array, and Mass spectrometry to identify perturbed RNA pathways, DNA mutations, and proteome alterations. Results: In this study, we present for the first time, a group of compounds, such as Gilteritinib, Trametinib, Dinaciclib, WYE-125132, Cenisertib, SN-38 which exhibit the capacity to induce cytotoxic effects in ALK-positive lung cancer cells, when combined with Alectinib. Our findings demonstrate a novel sensitivity of ALK driven by non-conventional parallel signaling, apart from conventional targets previously described, such as phosphoinositol-3kinase (PI3K)/Akt, signal transducer and activator of transcription 3 (STAT3), and extracellular signal-regulated kinases (ERK). Conclusions: Through the integration of different multiomic approaches on five ALK-positive lung cancer cell lines, we have pinpointed a novel role of MAPK, CDK, and mTOR, pathways and their regulators, as a promising avenue for advancing treatment strategies for ALK-positive lung cancer. These findings, along with the identification of several other significant targetable elements illustrate a new approach towards the discovery of new drug combinations and targetable pathways to tackle ALK TKI resistance in ALK-positive patients before it emerges. We have previously generated Alectinib-resistant models and are in the process of screening to identify any resistant pathways that may align with those identified in the sensitive lines. Citation Format: Hamadi Madhi, Habib Serhan, Nathalie M. Vandecan, Zhaoping Qin, Albert Liu, Aaron Udager, Sofia D. Merajver, Matthew B. Soellner, Nathan Merrill. Discovering novel ALK-lung carcinoma therapeutic strategies by identifying combinations with Alectinib from ALK-positive lung carcinoma cell lines [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 4548.

Асциминиб у больных хроническим миелолейкозом, не имеющих альтернативных методов лечения: результаты исследования в рамках программы расширенного доступа МАР (Managed Access Program, NCT04360005) в России

Aim. To assess the efficacy and tolerability of asciminib in chronic myeloid leukemia (CML) patients after failure of ≥ 2 lines of tyrosine kinase inhibitors (TKIs) therapy under the МАР (Managed Access Program, NCT04360005) in Russia. Materials & Methods. The study enrolled 68 patients with Ph-positive CML chronic phase (CF), over 18 years of age, after failure of ≥ 2 lines of TKI therapy. The analysis was conducted on data from 50 patients who were followed-up for at least 3 months and did not undergo allo-HSCT. Dosing regimens were prescribed depending on T315I mutation. Asciminib 200 mg per os was administered twice a day to 20 patients with this mutation, and asciminib 40 mg per os was administered twice a day to 30 patients without this mutation. By the time of admission into the MAP, there were 42 (82 %) CF CML patients as well as 8 patients with second CF after accelerated phase (AF, n = 7) and myeloid blast crisis (BC, n = 1). None of them could be treated with any therapeutic alternative. 92 % of patients had received ≥ 3 lines of prior TKI therapy. Overall survival (OS) and discontinuation-free survival were estimated by the Kaplan-Meier method. A cumulative incidence function (CIF) was used to calculate the probability of achieving response. Multivariate analysis was based on Cox regression model. Results. The median asciminib treatment duration was 11 months (range 4–30 months). The probable 2-year OS was 96 %. After 12 and 24 months, discontinuation-free survival was 92 % and 70 %, respectively. On asciminib therapy, complete cytogenetic (CCyR/МR2), major molecular (MMR), and deep molecular (MR4) responses were achieved in 17 (42 %), 14 (30 %), and 9 (19 %) patients who had not responded to prior treatment at the point of enrollment. After completing the 12- and 24-month therapy, the probability of CCyR/МR2 achievement was 44 % and 62 %, that of MMR achievement was 32 % and 40 %, and that of MR4 achievement was 26 % and 37 %, respectively. The patients treated with different doses did not significantly differ in achieving either CCyR/МR2 or MMR. By multivariate analysis, the independently significant factor impacting the probability of achieving MMR on asciminib treatment was the best MR (BCR::ABL1 < 1 % vs. 1–10 % vs. ≥ 10 %) after prior TKI therapy (hazard ratio 7.5873; p = 0.0072). In 22 (44 %) patients, adverse events (AEs) of all grades were observed, and 8 (16 %) patients showed AEs grade 3/4 (predominantly thrombocythemia and neutropenia). None of the patients discontinued asciminib treatment due to AEs. Conclusion. Asciminib demonstrated highly promising efficacy in previously TKI-treated patients with T315I mutation (200 mg BID) and without it (40 mg BID). Asciminib can be regarded as therapeutic option after failure of other TKIs. Different doses of asciminib were equally well tolerated, which makes it applicable for patients with intolerance to other TKIs and also provides ground for considering dose increases in non-responders. Good prospects are also expected for studying asciminib efficacy at earlier treatment stages (in first or second lines) as well as in combination with ATP-binding TKIs in CML patients with insufficient response to TKI treatment.

Chimeric antigen-receptor (CAR) engineered natural killer cells in a chronic myeloid leukemia (CML) blast crisis model.

During the last two decades, the introduction of tyrosine kinase inhibitors (TKIs) to the therapy has changed the natural history of CML but progression into accelerated and blast phase (AP/BP) occurs in 3-5% of cases, especially in patients resistant to several lines of TKIs. In TKI-refractory patients in advanced phases, the only curative option is hematopoietic stem cell transplantation. We and others have shown the relevance of the expression of the Interleukin-2-Receptor α subunit (IL2RA/CD25) as a biomarker of CML progression, suggesting its potential use as a therapeutic target for CAR-based therapies. Here we show the development of a CAR-NK therapy model able to target efficiently a blast crisis cell line (K562). The design of the CAR was based on the scFv of the clinically approved anti-CD25 monoclonal antibody (Basiliximab). The CAR construct was integrated into NK92 cells resulting in the generation of CD25 CAR-NK92 cells. Target K562 cells were engineered by lentiviral gene transfer of CD25. In vitro functionality experiments and in vivo leukemogenicity experiments in NSG mice transplanted by K562-CD25 cells showed the efficacy and specificity of this strategy. These proof-of-concept studies could represent a first step for further development of this technology in refractory/relapsed (R/R) CML patients in BP as well as in R/R acute myeloblastic leukemias (AML).

BCR-ABL Kinase Domain Mutations in CML patients, Experience from a tertiary care center in North India.

Background: Chronic Myeloid Leukemia is characterized by the presence of the Philadelphia Chromosome (Ph) which contains the BCR::ABL1 fusion gene that occurs due to a reciprocal translocation between chromosomes 9 and 22. This accounts for up to 15% of all adult leukemias [1]. Most patients treated with first line tyrosine kinase inhibitor (TKI) imatinib achieve durable response but may undergo relapse at some stage [2]. The most important mechanism that may confer imatinib resistance is point mutation within BCR::ABL kinase domain. Other generation ABL tyrosine kinase inhibitors such as dasatinib, nilotinib, bosutinib and ponatinib help to overcome imatinib resistance [3]. Sensitivity of the patient to each of the above TKIs depends upon the individual candidate mutation present. Thus, it is important to perform mutation analysis for effective therapeutic management of CML patients once they show imatinib resistance. We used direct sequencing to identify the different types of mutations responsible for resistance of imatinib treatment from north India. Methods: In this study, the patient resistance for the imatinib were analyzed for BCR::ABL kinase domain mutation by direct sequencing and the detected mutations along with their percentage prevalence were reported. Results: 329 patients with CML-CP were analyzed for BCR::ABL kinase domain mutation. Total 66 (20.06%) patients out of 329 had mutation in at least one of the domains of BCR::ABL conferring resistance to different generations of TKI. Mutations in BCR::ABL kinase domain was observed in different domain of BCR::ABL. ATP binding P-Loop (42.42%), Direct binding site (36.36%), C-Loop (10.60%), A-Loop (6.06%), SH2 contact (3.03%), SH3 contact (1.51%). Conclusion: Total 20.06% patients (66/329) show mutation in at least one of the structural motifs of BCR-ABL kinase domain, which further confer the resistance to a particular generation of TKI.

Spectrum of BCR-ABL mutations in Azerbaijanian imatinib-resistant patients with chronic myeloid leukemia.

Objective: BCR-ABL1 kinase domain (KD) mutations can lead to resistance to first- and second-generation tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML). Here, we present the first report of the spectrum of mutations in the BCR-ABL1 KD of CML patients from Azerbaijan. Materials and methods: Samples for mutation screening were obtained from patients experiencing resistance to first line TKIs or from patients in acceleration phase (AP) or blast crisis (BC) at the time of diagnosis. The cDNA region corresponding to BCR-ABL1 KD was sequenced by pyrosequencing method. The χ2 test was used to assess the association of categorical variables between mutation-positive and -negative groups. In addition, the Kaplan-Meier method was applied to generate survival curves. Results: Eight different point mutations were identified in 22 (13.4%) out of 163 CML patients experiencing resistance to TKIs. The types of mutations detected were as follows: Contact binding site mutations 50% (11), SH2 domain mutations 27.4% (six), P-loop mutations 18.1% (four), and SH3 domain mutations accounting for 4.5% (one). The most common mutation was T315I, accounting for 5% (n = 8) of all patients. Significant association was identified between BCR-ABL1 mutations and additional chromosomal aberrations as well as between the mutations and disease phases (p < 0.05). Twelve out of 22 patients with BCR-ABL1 mutations and seven out of eight with T315I were in BC. Overall survival (OS) of the patients with BCR-ABL1 mutations was significantly lower comparing to the patients with no mutation (p < 0.05) and 8 patients with T315I mutation presented OS of 0%. Conclusion: T315I was the most commonly identified BCR-ABL1 mutation in TKI-resistant CML patients of Azerbaijani origin, being associated with disease progression and poor OS.

Tyrosine Kinase Inhibitors in pediatric chronic myeloid leukemia: a focused review of clinical trials.

Tyrosine Kinase Inhibitors (TKIs) is revolutionizing the management of pediatric Chronic Myeloid Leukemia (CML), offering alternatives to Allogeneic Hematopoietic Stem Cell Transplantation (AHSCT). We conducted a comprehensive review of 16 Randomized Controlled Trials (RCTs) encompassing 887 pediatric CML patients treated with TKIs including Imatinib, Dasatinib, and Nilotinib. The median patient age ranged from 6.5 to 14 years, with a median white blood cell count of 234 x 10^9/uL, median hemoglobin level of 9.05 g/dL, and median platelet count of 431.5 x 10^9/µL. Imatinib seems to be predominant first line TKI, with the most extensive safety and efficacy data. BCR::ABL response rates below 10% ranged from 60% to 78%, CCyR at 24 months ranged from 62% to 94%, and PFS showed variability from 56.8% to 100%, albeit with differing analysis timepoints. The Safety profile of TKIs was consistent with the known safety profile in adults. With the availability of three TKIs as first line options, multiple factors should be considered when selecting first line TKI, including drug formulation, administration, comorbidities, and financial issues. Careful monitoring of adverse events, especially in growing children, should be considered in long term follow-up clinical trials.

Individualized Dosing Patterns in the Treatment of Older Patients with Gastrointestinal Stromal Tumors: Results of a Registry-Based Observational National Cohort Study Including 871 Patients.

While the effectiveness of tyrosine kinase inhibitors (TKIs) seems similar in older patients with gastrointestinal stromal tumors (GIST) compared with younger patients, toxicities in older patients treated with TKIs more often lead to discontinuation of treatment. To better understand the age-related pharmacology and pharmacodynamic differences in patients with GIST treated with TKIs, the primary aim of this study was to evaluate TKI dosing patterns in older patients with GIST, while the secondary aims were to evaluate differences in imatinib trough plasma concentrations between age groups and to compare the overall survival (OS) in patients with and without dose reductions in all treatment lines in a palliative setting. Patients (18 years of age or older) with histologically proven GIST diagnosed between January 2009 and June 2021 and treated with one or more lines of TKIs were selected from the Dutch GIST Registry (DGR) database. Age groups were divided into younger patients (age <70 years) and older patients (age ≥70 years). All imatinib trough plasma concentrations of blood withdrawals taken from initiation of imatinib until a maximum of 1 year of treatment with imatinib were collected. Reasons for first adjustment of treatment were classified as adverse event, dose modification, progressive disease and other reasons. The next treatment steps after first adjustment of treatment were defined as dose escalation, dose reduction, dose interruption, or end of treatment. The association of dose reduction and OS was analyzed using the landmark approach. Overall, 871 patients were included in this study, including 577 younger patients and 294 older patients. Older patients more often had an adverse event as the reason for first adjustment of treatment with both imatinib (45.6%; p<0.001) and sunitinib (58.6%; p=0.224) compared with younger patients (19.5% and 42.7%, respectively). Adjustment of imatinib and sunitinib after starting on a standard dose because of an adverse event most often resulted in dose reduction in both age groups. Median trough plasma concentrations of all samples taken within the first year after initiation of imatinib were higher in older patients (1228ng/mL, interquartile range [IQR] 959-1687) compared with younger patients (1035ng/mL [IQR 773-1377]; p<0.001). No significant differences were seen between OS in patients with or without dose reduction in all treatment lines (imatinib: p=0.270; sunitinib: p=0.547; and regorafenib: p=0.784). Older patients showed higher imatinib trough plasma concentrations compared with younger patients and also had earlier and more often adverse events as the reason for first adjustment of treatment with imatinib followed by dose reduction. However, in a landmark analysis, patients with imatinib dose reductions had no poorer outcomes compared with patients not requiring a dose reduction.

Incidence, Interpretation and Management of Liver Function Abnormalities in Patients with Chronic Myeloid Leukemia (CML) Treated with Tyrosine Kinase Inhibitors (TKI)

Background: Hepatotoxicity is a well-recognised side effect of tyrosine kinase inhibitors (TKI) and in some patients it can be a challenge to find a well-tolerated and effective drug. Isolated hyperbilirubinemia is common but, particularly in the case of nilotinib, is generally attributed to concomitant Gilbert's syndrome, characterized by the reduced expression of uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1). We have previously reported hyperbilirubinemia in association with the homozygous Gilbert genotype in patients treated with imatinib, dasatinib and nilotinib and have now extended our studies to more recent TKI. In addition we have analysed the incidence of TKI-associated transaminitis and attempted to identify safer alternative TKI. Methods: From our database of &amp;gt;900 patients presenting with CML CP1 from 2000-2022 and treated with a TKI, we identified 467 individuals who had received only TKI (prior interferon, combination experimental therapy, auto- and allografted patients all excluded), had normal liver function tests (LFT) at TKI start and for whom serial consecutive LFT were available. Variations in dinucleotide repeats in the UGT1A1 promoter region were analyzed by PCR with genotypes: 6/6 (homozygous for (TA) 6 allele; wild-type), 7/7 (homozygous for (TA) 7 allele) and 6/7 (heterozygous). Because individual patients could receive more than one TKI, we defined the period on treatment with each TKI as an ‘episode’ so as to attribute abnormal LFT to a specific drug. Abnormal LFT were graded according to the CTCAE version 4.0 and any occurrence of abnormalities was cross-checked to exclude a confounding reason (e.g. antibiotics, cholecystitis). Patients were censored at last LFT. Results: 229 females and 238 males (median age at diagnosis 47 yrs (range 11-90) had 955 separate TKI episodes: imatinib 406, dasatinib 222, nilotinib 189, bosutinib 87, ponatinib 28 and asciminib 23. The median number of LFT per patient was 47 (range 3-264). 7 UGT1A1 genotypes were identified, of which 45%, 41% and 13% were wild type 6/6, heterozygous 6/7 and homozygous 7/7 respectively (6 patients with other genotypes excluded). With the exception of asciminib, hyperbilirubinemia was more frequent in homozygous patients for all TKI. It was also common in all patients treated with nilotinib but in wild type and heterozygous patients, was frequently associated with concomitant transaminitis. A close temporal relationship between start of TKI and raised bilirubin suggests causality (Fig 1a-d). The incidences of transaminitis of any grade were 44%, 47%, 65%, 66%, 43% and 39%, and of &amp;gt;grade 1 were 7%, 8%, 17%, 32%, 18% and 13% for imatinib, dasatinib, nilotinib, bosutinib, ponatinib and asciminib respectively. Of 202 patients with a transaminitis on first line TKI, 94 were subsequently switched to a 2 nd line TKI, and 27 of those to a 3 rd line TKI. Irrespective of the TKI used, recurrent transaminitis of any grade was common occurring in 60/94 (64%) on 2 nd line and 19/27 (71%) on 3 rd line, although abnormalities &amp;gt;grade 2 were unusual (&amp;lt;1% on 2 nd line, &amp;lt;5% on 3 rd line). 179 patients developed transaminitis on imatinib, 46 and 29 switched (rarely for transaminitis) to dasatinib and nilotinib respectively. 28 (61%) on dasatinib and 23 (79%) on nilotinib had a second transaminitis (dasatinib - 14% &amp;gt;grade 1, nilotinib - 22% &amp;gt;grade 1)). Of 227 patients without transaminitis on imatinib, 63 and 67 switched to dasatinib or nilotinib. 28 (44%) on dasatinib and 38 (57%) on nilotinib developed further transaminitis (dasatinib - 0% &amp;gt;grade 1, nilotinib 19% &amp;gt;grade1). With respect to identifying a ‘safer’ drug we studied in detail 15 patients with grades 3-4 transaminitis on 1 st line therapy; imatininb-10, dasatinib-1, nilotinib-3, bosutinib -1. Four settled on dose reduction, and of the remaining 11, 7 returned to normal or maximum grade 1 on dasatinib. Conclusion: With the exception of asciminib the previous association of TKI, homozygous Gilbert and hyperbilirubinemia was confirmed. Grade 1 transaminitis is common on all TKIs, with higher grades of severity most frequent on bosutinib. Patients experiencing abnormal transaminases on 1 st line TKI are likely to have similar problems on 2 nd and 3 rd line agents, with a trend to higher incidence/severity on nilotinib compared to dasatinib.

The Updated Results of Asciminib Managed-Access Program (MAP) in Patients with Chronic Myeloid Leukemia in Russia

Background: Therapy choice in chronic myeloid leukemia (CML) patients (pts) with ≥2 lines of tyrosine kinase inhibitors (TKIs) failure or in pts with T315I mutationis a relevant problem. Efficacy and good tolerability of a first-in-class BCR::ABL1 allosteric inhibitor Asciminib (ASC) in chronic phase (CP) CML pts were confirmed in clinical trials. The out-study world data of ASC use in Managed Access Program (MAP) is of particular interest. Aim: to report the updated results of the ASC use within MAP in 3 clinical centers of Russia. Methods : Adult (≥18 years) CML pts with the lack of efficacy or intolerance to ≥2 lines of TKIs or T315I-positive pts after ≥1 prior TKI were included into a MAP. Inclusion criteria for our analysis were: CML-CP, ASC therapy for &amp;gt;3 months (mo). Two dosing regimen were used: 40 mg BID in BCR::ABL1 T315I-negative pts (40BID group) and 200 mg BID in BCR::ABL1 T315I-positive pts (200BID group). Complete cytogenetic response (CCyR, equivalent of MR2 or BCR::ABL1≤1%), major molecular response (MMR) and deep molecular response (MR4) achievement was assessed by cumulative incidence function (CIF) with Gray's test for comparison. Survival analysis was performed by Kaplan-Meier method according to “intention-to-treat” principle. Results: A total 82 pts received ASC in the MAP, 68 of them met the criteria for analysis (baseline characteristics are in table 1), while 14 were excluded. The median follow-up was 26 mo (range 4-49). The 2-year overall survival was 93% and 83%, the progression free survival was 90% and 70% in 40BID and 200BID groups, respectively. In 40BID group 17/43 pts discontinued ASC: 2 progressed to AP/BP, 2 - for bone marrow transplantation (BMT), 13 - failure (3 pts died due to CML after ASC discontinuation). In 200BID group 12/25 pts discontinued ASC: 2 developed AP, 3 -BMT, 7 - failure (one pt died). CIF of CCyR/MMR/MR4 by 24 mo was 58%/68%/19% in 40BID group and 65%/56%/32% in 200BID group. The achieved CCyR was preserved in 93% (14/15) and 77% (10/13) pts in 40BID and 200BID group, respectively. CIF of MMR in ponatinib-naïve pts was higher in both groups than in ponatinib-pretreated pts (picture). Dose escalation to 80-100 mg BID in 8/43 pts of 40BID group (due to lack of efficacy) resulted in achieving MMR for 2/8 pts with no MMR before escalation. Dose reduction in two groups was done both for adverse events (AEs) grade 3-4 (n=8) and stable MR4,5. In 4 pts (200BID) with no AEs and having a stable MR4,5 for &amp;gt;1 year, no MR4,5 loss was observed after ASC dose reduction to 100 mg BID. Subclone with emerging a new mutation was detected in 3 pts of 40BID group (A337T, G250A, T315I) while no new mutations were found in 200 mg BID group. AEs associated with ASC have been identified in 27/43 pts and 13/25 pts in 40BID and 200BID group, respectively, with no significant difference in AE spectrum and frequency. Most common (≥5%) AEs in two groups were: thrombocytopenia (29%), neutropenia (18%), cholesterol high (13%), anemia (6%), skin rash (5%). AEs grade 3-4 were detected in 13 (30%) and 4 (16%) pts in 40BID and 200BID group, respectively, and mostly presented by hematologic/cytopenic AEs (24%). No pt discontinued ASC due to toxicity, no arterial occlusive AEs were observed. Conclusion: ASC shows effectiveness and good safety profile in pts after prior failure to TKIs and those with T315I mutation. The CIF of any response was higher in ponatinib-naive pts at any dose. Different mutational subclones evolution was observed, including emergence of myristoyl-site mutation in 1 pt. ASC half dose reduction was safe in pts with previous MR4,5 stable response.

The Applicability of Tyrosine Kinase Inhibitors in Pediatric Chronic Myeloid Leukemia

INTRODUCTION The advent of tyrosine kinase inhibitors (TKIs) has shifted the treatment paradigm of adult CML, limiting SCT to a last-resort option for TKI-ineligible or resistant cases. However, determination of the optimal dosing and duration, potential long-term side effects, and the viability of therapy discontinuation remain under-explored aspects of TKIs in pediatric CML. Emerging data supports administering novel TKIs as initial or second-line treatments in pediatric CML amid variable results. This review discusses the RCTs conducted on pediatric patients with CML who received TKIs, aiding in better understanding of the effectiveness and safety of TKIs in the pediatric CML population. METHODS We searched Medline, OVID, and Web of Science for all RCTs reporting the efficacy and safety of TKI in pediatric CML (&amp;lt; 18 years). We compiled the individual efficacy and safety data into distinct tables, emphasizing demographics, treatment modalities, and outcomes pertaining to both the safety and efficacy of TKI. RESULTS This review analyzed 17 Randomized Controlled Trials (RCTs) with 887 pediatric CML patients. Median age was 11.3 years (range 6.5-14 years). Efficacy studies had 718 patients, safety studies had 851.. The median white blood cell count was 234 x10 9/uL [range 19 to 378; reported in 9 RCTs], median hemoglobin level was 9 g/dL [range 5.6 to 10.8; from 7 RCTs], and the median platelet count was 431.5 x10 9/µL, [range 31 to 594; from 6 RCTs]. TKIs were first-line treatment in 65% of the studies, Imatinib being the commonest (61% of studies). Dasatinib and Nilotinib were used in 17% and 11% of studies, respectively, while 6% received a combination of imatinib and chemotherapy. Efficacy reporting in the RCTs was a major concern that challenged the accumulation of results (Table 1). BCR-ABL response of &amp;lt;10% ranged from 60 % to 78%, and the complete cytogenetic response (CCYR) at 24 months ranged from 62% to 94%. Progression free survival (PFS) ranged from 56.8% to 100%; however, the timepoint for PFS analysis was not standardized among studies (36 to 48 months). Safety data from 16 studies (851 patients) included anemia (n=228), thrombocytopenia (n=161), neutropenia (n=257), hepatotoxicity (n=98), and cutaneous side-effects (n=156). Cardiovascular complications with second generation TKIs included QTc prolongation with Nilotinib (n= 11) and heart failure with Dasatinib (n=4). Nausea/vomiting were reported in 119 patients on imatinib, vs. 64 and 37 patients on Dasatinib and Nilotinib, respectively. Diarrhea occurred in 40 patients on Imatinib ,and 20 and 2 patients in Dasatinib and Nilotinib cohorts, respectively. Other AEs included impaired bone growth (70 on Imatinib and 10 on Dasatinib), headache (44 on Imatinib, 38 on Nilotinib and 13 in Dasatinib), musculoskeletal pain (161 on Imatinib, 31 on Dasatinib and 8 on Nilotinib). Treatment AEs leading to drug discontinuation were reported in 22 patients (6 studies), however the exact AE leading to drug discontinuation were not reported. CONCLUSION There remains a limited experience in treating pediatric CML with TKIs. Hence, evidence from prospective clinical trials and real-life clinical practice are required to establish appropriate guidelines for the standard therapeutic management in this population. Imatinib has the most extensice efficacy and toxicity data in pediatric patients. The Safety profile of TKIs was consistent with the known safety profile in adults. With the availability of three TKIs as first line options, multiple factors should be considered when selecting first line TKI, including drug formulation, administration, comorbidities, and financial issues. Careful monitoring of adverse events, especially in growing children should be considered in long term follow-up clinical trials.

Successful Treatment-Free Remission in Low- and Middle-Income Countries

Introduction Discontinuation of tyrosine kinase inhibitors (TKIs) is feasible in a subset of chronic myeloid leukemia (CML) patients who have maintained a deep molecular response (MR) for ≥2 years. Numerous TKI discontinuation trials from high-income settings show that ~50% of patients relapse after discontinuing TKIs and need to restart treatment. However, most patients with CML worldwide are from low- and middle-income countries LMIC where TKI access and molecular testing make routine care and attempts of treatment-free remission (TFR) problematic. The successful implementation of TFR in LMICs would benefit both CML patients as well as the health economics of each country. This analysis describes the experience of attempting TKI discontinuation in the LMIC setting. Methods The Max Foundation's TFR Support Program provides financial and wrap-around support for patients attempting TFR in LMICs. The program operates in countries where The Max Foundation has existing partner institutions and physicians, imatinib and second line TKIs are available, and there is ≥1 reliable method of quantitative RT-PCR testing for BCR::ABL1. Eligible patients were &amp;gt;18 years old, diagnosed with chronic phase CML and treated with imatinib for ≥10 years with no history of resistance, and had a BCR-ABL level MR 4.5 or better (≤0.0032%) for ≥12 months (m) as demonstrated by 2 RT-PCR tests. Patients who consented were enrolled in the program and monitored by their treating physician. Upon starting TFR, patients' BCR::ABL1 levels were tested monthly for the first 6 m, then every 3 m for the following 6 m, then every 6 m. Patients who relapsed (BCR::ABL1 loss of MR 3 or &amp;gt;0.1%) after beginning TFR restarted imatinib and were tested approximately every 1-3 m until they achieved MR 3. We conducted a retrospective analysis on the outcomes of patients enrolled in The Max Foundation's TFR Support Program to better understand TFR outcomes in an LMIC setting. Results The molecular results pre- and post-TKI discontinuation are shown in Figure 1. In total, 39 patients from sites in 5 countries (Armenia, Honduras, India, Kenya, and Paraguay) were followed by 8 program physicians. The mean age of the patients was 51 years (range, 22-77), with 22 females and 17 males. Patients had been on imatinib for an average of 15 years (range, 10-20). At time of discontinuation, all but 1 patient was on 400 mg/day of imatinib (1 treated at 300 mg/day). Thirty-two patients had undetectable BCR::ABL1 for both pre-discontinuation tests, 6 had one test with a value of &amp;lt;0.01%, and 1 had both tests detectable at &amp;lt;0.01%. Of the 39 patients, 32 remain actively followed, with 14 patients completing &amp;gt;12 m of follow-up. Nine patients had a molecular relapse (23%) with a BCR::ABL1 &amp;gt;0.1% IS after a median of 2 m of discontinuation (range, 1-18 m). Of these, 2 patients have not had repeat testing to confirm molecular relapse, and 1 patient became undetectable on follow-up 1 m later. None of these 3 patients have restarted TKI therapy. Seven of 39 patients (18%) have restarted TKI treatment. Of these 7 patients, 3 were restarted on TKI, but have not had a follow-up BCR::ABL1 evaluation. Of the remaining 4 patients who restarted TKI, 2 had no detectable BCR::ABL1 at the 9 m and 12 m follow-up, and 2 remain with evidence of BCR::ABL1 at 12 m and 17 m follow-up. Conclusions The data suggest that under conditions that allow frequent follow-up examination and testing, patients attempting TFR in LMIC have similar outcomes to those patients described in controlled clinical trials from academic settings in high-income countries. Additional confirmation of these findings will likely impact both the health of CML patients and the health economics in these LMICs. Figure 1. BCR:ABL1 and outcomes following TKI discontinuation.

Preliminary Results of Phase 2 Open Label Study of Lorlatinib Monotherapy in Relapsed/Refractory ALK + Lymphomas Previously Treated with Other Tyrosine Kinase Inhibitors

Introduction: Both aggressive T and B cell lymphoma may harbour Anaplastic Lymphoma Kinase (ALK) translocations: ALK+ Anaplastic Large Cell lymphoma (ALCL) offer a good outcome with first line therapy with 5-year survival of 79%, but relapses occur in half of the patients (pts) and salvage therapy still represents a challenge for clinicians; ALK+ large B cell lymphoma (LBCL) are very rare cases but with dismal prognosis. In addition other hematologic neoplasms can be caused by ALK fusions. Crizotinib, an ALK/MET tyrosine kinase inhibitor (TKI), provides long-term response in up to 70% relapsed/refractory (R/R) ALK+ ALCL and can obtain a similar but less durable response rates in ALK+ LBCL. In both cases the loss of response to crizotinib is frequently a fatal event. Lorlatinib, a selective ALK and ROS1 TKI, demonstrated preclinical inhibition of all reported ALK kinase domain mutations responsible for resistance to Crizotinib. Methods: From 2019 to 2022 six relapsed/refractory ALK + neoplasm pts previously treated with at least one ALK-inhibitor were enrolled in a phase 2 open label monocentric study with lorlatinib monotherapy (EudraCT2016-003970-41): Three patients had diagnosis of ALK+ LBCL (# 1, 2, 3) and 2 (#5 and #6) had ALK+ ALCL. One patient (#4) with an ALK+ histiocytosis was also included. Median age was 22 years (range 19-57), Ratio M/F was 1, all pts were in stage IV. Median prior therapy lines was 3 (range 2-5); all pts previously received Crizotinib, two pts received also Alectinib and 1 Ceritinib as TKI treatment. Lorlatinib was administered daily at dose of 100 mg. Clinical, laboratory, radiological and molecular data were collected at screening and during scheduled follow-up. Response was evaluated with 18F-FDG PET/CT (and with contrast enhanced (ce) CT scan) according Lugano Classification, and with ALK RT-PCR on peripheral blood and bone marrow. Side effects were classified according to CTCAEv4.03. PFS and OS were determined from Lorlatinib start to relapse and/or death. The primary endpoint was the evaluation of ORR considering 18F-FDG PET/CT scan and ALK- RT-PCR. Secondary endpoints were: PFS, OS, toxicity, QoL. Results: ALK rearrangement fusion pattern was detected in 6/6 pts: 3 pts with LBCL harboured Clathrin-ALK (CTCL::ALK) rearrangement and 2 ALCL pts the ATIC::ALK fusion; the ALK+ histiocytosis patient harbored an EML4::ALK rearrangement. Median follow-up was 13.7 months (IQR 22-55). At month +1 (M1) 3/6 patients had complete response (CR) defined as complete metabolic and complete radiologic response (CMR/CR) according to PET/CT scans and ALK RT-PCR negativity. The remaining 3 pts had a partial response (PR), for an Overall Response Rate (ORR) of 100% (95%CI: 0.6-1.0). One pt is still on treatment and in CR at 45 months, receiving Lorlatinib 100 mg daily with neither toxicities nor need for Allogenic Stem Cell Transplantation (ASCT); 2 CR pts underwent ASCT after 1 month, resumed lorlatinib after ASCT and are still in CR. 2 pts with PR relapsed within month +3: one pt received salvage therapy without benefit, the other one underwent ASCT but progressed 3 months later. Both pts had ALK+ BCL with CTCL-ALK rearrangement. 1 pts in PR AT M1 (ALK+ istiocytosis) obtain CR at M3 after surgical resection of a residual lung mass and is still receiving Lorlatinib at month 36. Median PFS and OS were not reached: PFS at 6 and 12 months is 83% and 62% respectively; OS at 6 and 12 months is 83% and 55%. Safety: 2/6 pts had thrombocytopenia grade 1, whereas 3/6 pts showed grade I-II hypertriglyceridemia/hypercholesterolemia and muscle cramps. Conclusions: Lorlatinib represents a safe and effective salvage therapy for ALK+ Lymphoma patients failing first line TKI treatment. The obtainment of CR at M1 seems to represent a pivotal prognostic factor. Lorlatinib also offers a promising bridging regimen to salvage ASCT especially for ALK+ BCL patients, with high response rates and no additional toxicities, .

HJKC3-0006: Outcome of Patients with CML Treated on Second Line or Later Therapy in Routine Clinical Practice

Background: First-line therapies for chronic-phase (CP) CML include the tyrosine kinase inhibitors(TKIs) dasatinib, nilotinib, bosutinib or imatinib, while ponatinib and asciminib are indicated only in later lines. There are typically high response rates to first-line therapy in CP-CML, with responses to second- and third-line therapy lower and highly dependent on the specific TKI. Our goal in this study is to evaluate the role of ponatinib in the treatment of patients with CML using data from routine clinical practice. Study design and methods: Data will come from the H. Jean Khoury Cure CML Consortium (HJKC3) CML registry, a North American multi-site research database. Participating sites include the HJKC3 members (curecml.org). Patient inclusion criteria include a diagnosis CML in chronic phase, receiving second line therapy after initial therapy with a second generation TKI (dasatinib, nilotinib, or bosutinib) or receiving third or later line TKI therapy for CML. Participating patients provide consent to collect their data both retrospectively and prospectively for 1 year. Clinical data, including toxicities and complications of TKI therapy, are abstracted from the electronic health record. Participating patients are invited to complete a questionnaire to assess health-related quality of life. Data are managed using REDCap, a secure web application. Study Objectives: The primary objective is to compare the outcome of patients treated with ponatinib vs. other TKIs as second or later line therapy. Secondary objectives are to evaluate patient-reported outcomes (PRO) for CML treated with second or later line therapy and to determine if there are any patient or disease characteristics that can predict outcomes. Statistical plan for clinical outcomes: Descriptive statistics will be used to compare baseline demographic characteristics. Categorical variables will be compared using the Chi-square test. Continuous variables will be compared using ANOVA. Overall survival will be calculated from the time of diagnosis to death from any cause and patients will be censored if they were alive at the last follow-up. Survival probabilities will be computed using the Kaplan-Meier method and compared with the log-ranktest. Cox regression analyses will be used to determine significant factors that influence survival, and hazard ratios with 95% confidence intervals will be presented. Event free survival (EFS) and transformation free survival (TFS) will be calculated for patients. For EFS, loss of complete hematologic remission, loss of major cytogenetic response, progression to accelerated or blast phase, or death from any cause at any time will be considered an event. For TFS, transformation to accelerated or blast phase while on therapy or death on study will be considered an event. Statistical plan for PRO: Different PRO domains will be analyzed separately (for example, depression separate from fatigue, etc.). Descriptive statistics for each PRO measure will be reported and compared to previously published studies. Differences by treatment type will be evaluated.

Tyrosine Kinase Inhibitor (TKI) Treatment Patterns in 5,261 Chronic Phase (CP) Chronic Myeloid Leukemia (CML) Patients in “Real-Life” Settings: A Population-Based Study Using a Nationwide Claim Database

Introduction The introduction of TKI in CP-CML enabled responders to reach a similar survival to that of the general population. However, recent small-sized real-life studies showed that 1 in 5 CP-CML patients (pts) received at least 3 lines of TKI, mainly due to resistance or the onset of adverse events (AE). The objective of this study is to document real-life TKI treatment patterns nationwide in CML pts with a long-term follow-up, with a focus on pts who initiated at least a 3 rd line and associated disease burden. Methods This real-life non-interventional study was conducted using the French nationwide claim database (SNDS, Système National des Données de Santé), covering over 99% of French beneficiaries. Pts who initiated their first TKI with an indication for CML (imatinib, dasatinib, nilotinib, bosutinib, ponatinib) between January 2010 and December 2018, aged 18 years old or older at TKI initiation (index date T 0), and with healthcare resource use (HCRU) markers of CML - i.e., reasons for hospitalization and reported Long-Term Disease - without markers of confounding disease for the use of TKIs, were included. Treatment patterns were assessed from T 0 to December 2020 or death, through the description of TKI treatment sequences (TKI lines), adherence - discontinuations (≥ 3 months) during a TKI line and Medication Possession Ratio (MPR) -, and line duration (Time to Next Treatment (TTNT) estimates). TTNT was calculated as cumulative incidence of TKI switches, with death as competing risk; switches were defined as discontinuation of a TKI followed by the start of a different TKI. Results A total of 5,261 CML pts initiated their 1 st line TKI, with a median age at T 0 of 59.5 years (IQR: 23.2) and a M/F ratio of 1.2. The median follow-up from T 0 was 5.6 years (IQR: 4.6). Respectively 2,299, 1,017 and 426 pts initiated 2 nd, 3 rd and 4 th TKI line. Most frequent TKIs used as 1 st and 2 nd lines were imatinib (73.1%), and dasatinib (60.4%; Figure 1), respectively. From the 3 rd line, TKI patterns changed following the reimbursement of bosutinib in 2015 and ponatinib in 2016, and subsequently stabilized; shares in pts treated in 3 rd line and more at the beginning of 2020 were roughly equally distributed between marketed TKIs. TKI discontinuations rates during a line varied from 76.2% for 1 st line to 56.2% for 4 th lines. The median cumulative duration of discontinuations tended to decrease across lines (2.9, 2.5, 2.3 and 2.1 months for 1 st, 2 nd, 3 rd, and 4 th line, respectively); IQRs across lines were similar. The proportion of pts with a good medication adherence (MPR ≥ 80%) was around 80% for all TKI lines. TTNT was similar across all TKIs and all lines; 10-year TTNT rates were 48% (95CI: [47%; 50%]), 56% [53%; 59%], 56% [51%; 61%], 48% [42%; 54%] for 1 st, 2 nd, 3 rd, and 4 th lines. For pts who switched, most of switches occurred during the first year following line initiation (51% of switches observed in the first year for both 1 st, 2 nd, 3 rd, and 4 th lines), 24% occurred during the second year, and 10% during the third year. The 10-year cumulative incidences of death were 12% (95CI: [11%; 14%]), 9% [8%; 11%], 12% [9%; 16%], 14% [6%; 25%] for 1 st, 2 nd, 3 rd, and 4 th lines, respectively. The proportion of CML pts who initiated at least 3 lines of TKIs was 19.3% from raw estimates (n=1,017/5,261) and would be 27% based on TTNT estimates. Their characteristics were similar to pts who initiated 1 st line TKI (sociodemographic, comorbidities). Regarding HCRU, respectively 37.2% and 29.8% of pts had at least one hospitalization during 1 st and 6 th semesters following 3 rd line initiation; 7.9% to 5.8% visited emergency room, and around 10% had at least one sick leave per semester. Conclusion Using one of the largest cohorts of CML pts ever studied, with a follow-up period up to 10 years (median 5.6 years), this real-life study confirmed that multiple TKI switches are now common. We confirmed that at least 1 out of 5 CML patient fails at least two TKI lines. From TTNT estimates, surrogate marker for the duration of clinical benefit, lines of TKI would be effective over the long-term for around half of pts, and half of the switches occur within the first two years, regardless of line position. Finally, this real-world study illustrates the need for permanent care of these pts and alternative treatment options to avoid resistance or intolerance and induce a similar survival as the general population of the same age.

HJKC3-007: Outcomes of Patients with Chronic Myeloid Leukemia in Chronic Phase Treated with Asciminib and Other Tyrosine Kinase Inhibitors in Routine Clinical Practice

Background and significance: There are typically high response rates to first line TKI therapies in chronic phase chronic myeloid leukemia (CP-CML). However, responses in later lines (second line and beyond) are diminished and highly dependent on the specific tyrosine kinase inhibitors (TKIs) used. Asciminib received FDA approval in October 2021 for the treatment of adult patients with Philadelphia chromosome-positive (Ph+) CML-CP who were previously treated with two or more TKIs, and in patients with Ph+ CML-CP with the T315I mutation. Our goal in this study is to evaluate the role of asciminib therapy for patients with CML beyond clinical studies, in routine clinical practice. Study Design and methods: Data for this study will be abstracted from the HJKC3 (H. Jean Khoury Cure CML Consortium) CML registry project (HJKC3-0005); the HJKC3 CML Registry is a collaborative academic multi-site registry. Patients will be consented to allow collection of both retrospective and prospective data for the HJKC3 CML Registry. The data forms and surveys will be built and managed through the Research Electronic Data Capture (REDCap), a secure web application managed by the Clinical &amp; Translational Science Institute. Participating sites include members of the HJKC3 (curecml.org). This study will be an opportunity to evaluate asciminib usage in ‘real-world’ academic practices across the United States. This observational study will include cohorts of patients diagnosed with CP-CML previously treated with two or more tyrosine kinase inhibitors and/or receiving asciminib and/or those with a T315I mutation, not currently enrolled in a randomized controlled trial. The HJKC3 CML Registry intends to collect clinical and patient reported outcome (PRO) data. After obtaining patient consent, patients will be invited to complete PRO assessments. The study will attempt to collect PRO data regardless of disease or treatment status. PRO assessments will be primarily administered online, though study staff will offer alternatives (e.g., phone) for participants without internet access. Study subjects will be emailed a link to access a secure platform hosted by one of the study sites, Medical College of Wisconsin (MCW), using the REDCap platform. Study Objectives: The primary objective of the study is to describe characteristics of patients who were previously treated with two or more TKIs and treated with asciminib or with any other TKIs. The secondary objectives are to describe the clinical outcomes and PRO of those patients. Exploratory objectives include description of characteristics, treatment outcome and PRO for patients with T315I mutation. Statistical plan: The sample size of approximately 225 participants during the 5-year recruitment period is based on the available clinical expertise and ongoing recruitment data in the HJKC3 CML registry in lieu of statistical power analysis. We estimate that 150 patients in the HJKC3 CML registry will be treated with other TKI and 75 treated with asciminib. Among a total of 225 patients, we estimate that 75 patients with the T315I mutation will be enrolled in the registry. No formal statistical inference will be drawn to compare the outcomes between these two groups. Bayesian predictive probability (PP) will be utilized for the exploratory analysis of Major Molecular Response (MMR). Survival probabilities will be computed using the Kaplan-Meier method, and the p-values from the log-rank test will be provided. Different PRO domains of the patient's symptoms and functioning will be analyzed separately (e.g., depression separate from fatigue, separate from GI symptoms, etc.) since combining them into a summary score may dilute the effects of the individual (and not necessarily related) components and mask actual change. The main objective for the analyses of PRO data from the registry is to describe any differences by treatment type in patients treated with asciminib and other TKIs.

Siglec 15 as a biomarker or a druggable molecule for non-small cell lung cancer.

Lung cancer has been the main cause of cancer mortality worldwide. Furthermore, lung cancer rates of new cases per year evidenced a large incidence of this neoplasm in both men and women. Because there is no biomarker for early detection, it is frequently detected late, at an advanced state. The introduction of multiple lines of tyrosine kinase inhibitors in patients with EGFR, ALK, ROS1, and NTRK mutations has modified the therapy of lung cancer. Immunotherapy advances have resulted in substantial improvements in overall survival and disease-free survival, making immune checkpoint inhibitors (ICIs) a potential option for lung cancer treatment. Current PD-1/PD-L1/CTLA-4 immunotherapies have resulted in important response and survival rates. However, existing medicines only function in around 20% of unselected, advanced NSCLC patients, and primary and acquired resistance remain unsolved obstacles. Therefore, precise predictive indicators must be identified to choose the best patients for ICI treatment. Thus, Sialic acid-binding immunoglobulin-like lectin 15 (Siglec-15) stands out as a potential tumor biomarker, with distinctive expression in normal tissues, in tumor immune involvement, and a high structural similarity to PD-L1. Understanding the tumor immune response and the search for new therapeutic targets leads to the improvement of therapeutic pathways directed at the tumor microenvironment. The present review aims to analyze Siglec-15 potential as a diagnostic, prognostic, and response biomarker in lung cancer, considering its results evidenced in the current literature.

Tackling Imatinib Resistance via Au‐nanoconjugates using A Cml Resistant Cell Line

AbstractChronic myeloid leukemia (CML) is a rare malignant proliferative hematopoietic disease due to overexpression of a tyrosine kinase (TK) derived from the breakpoint cluster region (BCR)‐abelson tyrosine‐protein kinase 1 (ABL1) gene fusion. Imatinib (IM), blocks this tyrosine kinase, and is the first line TK inhibitor (TKI) used in CML treatment. In a high percentage of CML patients, a poor response with relapse and disease progression is associated to acquisition of resistance through different mechanisms, including dysregulation of c‐MYC proto‐oncogene. Gold nanoparticles (AuNPs) are shown to allow improved efficacy in gene silencing approaches toward cancer therapy. Herein, the silencing potential of AuNPs functionalized with antisense oligonucleotides selectively targeting the e14a2 BCR‐ABL1 or the c‐MYC, alone and combination is evaluated. It is demonstrated efficient silencing of gene expression that translated to a downregulation of protein levels in IM resistant CML cells (K562‐IM). This combination allowed for increased death of the malignant cells. These Au‐nanoconjugates may be useful to tackle IM‐resistance mechanisms, providing an additional tool for future combinatory schemes to fight CML with imatinib resistance.

A phase II study of cabozantinib and temozolomide in patients with unresectable or metastatic leiomyosarcoma and other soft tissue sarcomas.

11505 Background: Potentiation of chemotherapy, without increased toxicity, to improve outcome is an area of interest. Preclinical and clinical evidence shows simultaneous utilization of antiangiogenic agents and chemotherapy have a synergistic effect. We hypothesized that the dual targeting of VEGF and c-MET pathways with cabozantinib (CAB) would result in clinical benefit for patients with soft tissue sarcoma (STS) when combined with temozolomide (TMZ), an alkylating agent. Utilization of CAB/TMZ is anticipated to produce a synergistic antitumor effect worthwhile to explore in STS. Methods: A multicenter phase II study of CAB/TMZ in patients with unresectable/metastatic leiomyosarcoma (LMS) and other STS was conducted by the Midwest Sarcoma Trials Partnership. Age ≥ 18, adequate performance status, organ function, measurable disease (RECIST 1.1), and 0-5 prior chemotherapy regimens were required. CAB 40 mg PO daily plus TMZ 150-200 mg/m2 PO 1-5 days were given in 28-day cycles until disease progression or unacceptable toxicity. Patients enrolled in 2 cohorts: 1. Uterine and non-uterine LMS 2. Other STS. The first 14 subjects to be enrolled in the study in either cohort served as a safety lead in. The primary endpoint was progression-free rate (PFR) at 12 weeks for cohort 1. Secondary endpoints include overall response rate (ORR), clinical benefit rate, median progression-free survival (PFS), overall survival, and safety and tolerability. The exploratory endpoint was to estimate the correlation of PFR and OS to expression levels of VEGF, amongst others. A Simon 2-stage design was used. Results: A total of 42 patients were enrolled in Cohort 1, and 30 in Cohort 2, across 5 sites. For Cohort 1, median age was 59 years (range 35-86), 85.7% were non-Hispanic, 73.8% were female, 61.9% had ECOG of 0. The PFR at 12 weeks was 45.9% (for 37 evaluable patient) with a median PFS of 6.4 months (95% CI 4.6-6.7). Five PR were observed for an ORR of 13.5%. For Cohort 2, median age was 63 (20-86), 83.3% were non-Hispanic, 36.7% were female, 53.3% had ECOG of 0. The PFR at 12 weeks was 50% (for 28 evaluable patients) with a median PFS of 3.2 months (95% CI 1.4-4.6). One PR was observed. Reported grade 3-4 adverse events attributed to one or both intervention drugs affecting ≥10% of patients (n = 70) included hypertension (10%), decreased neutrophils (18.7%), decreased platelets (31%). Conclusions: The combination therapy of CAB/TMZ in patients with unresectable or metastatic LMS exceeded its primary endpoint with a PFR at 12 weeks &gt; 39%. The PFS of 6.4 months in Cohort 1 exceeds rates achieved with second line tyrosine kinase inhibitors (TKIs) and alkylators in LMS patients. Treatment was feasible and did not reveal any previously unreported toxicities. The combination with CAB with TMZ demonstrated meaningful clinical benefit and is worth further exploration in LMS. Clinical trial information: NCT04200443 .

Real-world treatment patterns and survival of patients with ROS1 rearranged stage IV non-squamous NSCLC in the Netherlands

IntroductionRearrangement of c-ros oncogene 1 (ROS1) is a rare gene alteration in patients with stage IV non-squamous non-small cell lung cancer (NSCLC). Molecular testing for ROS1 is recommended to enable primary treatment with tyrosine kinase inhibitors (TKI). Aim of this study was to describe real-world treatment patterns and survival for patients with ROS1 in the Netherlands. MethodsAll non-squamous NSCLC stage IV patients, diagnosed 2015–2019, were identified from the population-based Netherlands Cancer Registry (N = 19,871). For patients with ROS1 rearrangements (ROS1+ ) who received first line TKI, additional information about progression and second-line treatment was retrieved by active follow-up. Overall survival (OS) and progression-free survival (PFS) were calculated using Kaplan-Meier estimators. ResultsA total of 67 patients (0.43%) were diagnosed with a ROS1+ NSCLC. Systemic treatment was administered in 75% which was most often TKI (n = 34) followed by chemotherapy (n = 14). Two-year OS for patients receiving upfront TKI versus other systemic treatment was 53% (95% CI 35–68) and 50% (95% CI 25–71), respectively. For patients receiving TKI, median OS was 24.3 months. Survival was inferior in case of brain metastasis (BM) at diagnosis (5.2 months). One in five patients receiving TKI as a first line treatment had BM at diagnosis, of the remaining 22 another 9 developed BM during follow up. PFS was also inferior for patients with BM at diagnosis with a median PFS of 4.3 months versus 9.0 without BM. ConclusionIn this real-world population of ROS1+ NSCLC patients, only half received primary treatment with TKI. Overall survival and PFS during TKI were disappointing, mainly related to brain metastasis. TKI treatment with agents that have intra-cranial activity may be beneficial in this patient population and our results confirm the importance of performing an MRI of the brain as part of the standard diagnostic work up in patients with ROS1+ NSCLC.