Role Of Tyrosine Kinase Inhibitors Research Articles

#752 Ponatinib exacerbates renal damage in MRL/lpr lupus model mice through the lipid metabolism pathway

Abstract Background and Aims The role of tyrosine kinase inhibitors (TKIs) in lupus nephritis is controversial. Ponatinib is a third-generation tyrosine kinase inhibitor that targets multiple receptors. This study aims to explore the effect of ponatinib in lupus nephritis, with the hope of providing insights for the clinical application of ponatinib. Method At 8 weeks of age, mice were randomly divided into four groups. One group received no treatment, while the other three groups were respectively administered Ponatinib, prednisolone acetate, and a combination of Ponatinib and prednisolone acetate. The treatment was concluded when the mice reached 16 weeks of age. ELISA was employed to measure the levels of anti-dsDNA IgG, ANA, and C3 in mouse serum. DEGs and DELs were identified using the DESeq2 package in R. Pathway and gene ontology enrichment analyses were performed using the MetaCore database. Results Compared to the negative control, those mice receiving ponatinib showed a significant increase in the urinary protein/creatinine ratio (P < 0.01), along with notable elevations in blood creatinine and blood urea nitrogen. Pathological examination of kidney tissue suggested predominant acute lesions, including transparent thrombi, cellulose-like necrosis, cellular/fibrous crescents, and interstitial inflammation. Interestingly, serum testing in MRL/lpr mice revealed no significant differences in lupus activity-related indicators, including autoantibodies ANA, double-stranded DNA, and complement C3, between the negative control group and the ponatinib group. Furthermore, it was discovered that the kidney damage caused by ponatinib in MRL/lpr mice could be reversed by prednisone. RNA-Seq of kidney tissue from MRL/lpr mice showed a total of 44 differentially expressed genes when comparing the negative control with mice receiving ponatinib, including 23 upregulated and 21 downregulated genes. Pathway analysis revealed that the top four pathways were all related to lipid metabolism. Conclusion Ponatinib significantly exacerbated kidney damage in MRL/lpr mice and did not induce changes in lupus activity.

The ASCENT Trial: a phase 2 study of induction and consolidation afatinib and chemoradiation with or without surgery in stage III EGFR-mutant NSCLC.

The role of tyrosine kinase inhibitors (TKIs) in early-stage and metastatic oncogene-driven non-small cell lung cancer (NSCLC) is established, but it remains unknown how best to integrate TKIs with concurrent chemoradiotherapy (cCRT) in locally advanced disease. The phase 2 ASCENT trial assessed the efficacy and safety of afatinib and cCRT with or without surgery in locally advanced epidermal growth factor receptor (EGFR)-mutant NSCLC. Adults ≥18 years with histologically confirmed stage III (AJCC 7th edition) NSCLC with activating EGFR mutations were enrolled at Mass General and Dana-Farber/Brigham Cancer Centers, Boston, Massachusetts. Patients received induction afatinib 40mg daily for 2 months, then cisplatin 75mg/m2 and pemetrexed 500mg/m2 IV every 3 weeks during RT (definitive or neoadjuvant dosing). Patients with resectable disease underwent surgery. All patients were offered consolidation afatinib for 2 years. The primary endpoint was the objective response rate (ORR) to induction TKI. Secondary endpoints were safety, conversion to operability, progression-free survival (PFS), and overall survival (OS). Analyses were performed on the intention-to-treat population. Nineteen patients (median age 56 years; 74% female) were enrolled. ORR to induction afatinib was 63%. Seventeen patients received cCRT; 2/9 previously unresectable became resectable. Ten underwent surgery; 6 had a major or complete pathological response. Thirteen received consolidation afatinib. With a median follow-up of 5.0 years, median PFS and OS were 2.6 (95% CI, 1.4-3.1) and 5.8 years (2.9-NR), respectively. Sixteen recurred or died; 6 recurrences were isolated to CNS. The median time to progression after stopping consolidation TKI was 2.9 months (95% CI, 1.1-7.2). Four developed grade 2 pneumonitis. There were no treatment-related deaths. We explored the efficacy of combining TKI with cCRT in oncogene-driven NSCLC. Induction TKI did not compromise subsequent receipt of multimodality therapy. PFS was promising, but the prevalence of CNS-only recurrences and rapid progression after TKI discontinuation speak to unmet needs in measuring and eradicating micrometastatic disease.

Biomarker Testing and Role of Tyrosine Kinase Inhibitors and Immunotherapy for Esophageal Squamous Cell Carcinoma

Esophageal squamous cell carcinoma (ESCC) constitutes an aggressive subset of esophageal cancers that portends a poor prognosis. Management of ESCC has been historically challenging due to the limited effective therapeutic options. Broadening our understanding of the molecular landscape and identifying reliable biomarkers are essential in early detection, monitoring disease response and advancing treatment strategies. Recently, immunotherapy and tyrosine kinase inhibitors have changed the treatment algorithm of ESCC. In this review, we explore the molecular landscape and biomarkers that can aid in the management of ESCC and discuss the role of immunotherapy and tyrosine kinase inhibitors in the treatment of ESCC.

Novel strategies to prevent and overcome relapse after allogeneic hematopoietic cell transplantation in acute lymphoblastic leukemia.

The outcome of B-cell acute lymphoblastic leukemia (B-ALL) has improved over time with the incorporation of multi-agent chemotherapy in the treatment landscape as well as the recent approval of immunotherapeutic agents allowing a larger proportion of patients to undergo allogeneic hematopoietic cell transplantation (allo-HCT) which is still considered a potential curative approach. However, relapse post-transplant is still occurring and constitutes a common cause of treatment failure in B-ALL. The present review aims to discuss the novel strategies and therapies used to prevent and overcome relapse post allo-HCT in patients with ALL, focusing on the role of tyrosine kinase inhibitors in Philadelphia chromosome positive B-ALL, the role of innovative agents such as blinatumomab and inotuzumab ozogamicin, and finally the role of cellular therapy.

The Role of Tyrosine Kinase Inhibitors in Reduction of Mortality from Non-small Cell Lung Cancer: A Meta-analysis.

Tyrosine kinase inhibitors are widely used in the treatment of non-small cell lung cancer. However, the exact role of these inhibitors, particularly in the reduction of mortality of non-small cell lung cancer, is unclear so far. As a result, we used RevMan 5 to conduct a meta- analysis of accessible data from randomised clinical trials. The studies were categorised based on the inclusion and exclusion criteria after being collected from PubMed using appropriate MeSH terms. The fixed or random effect model was used based on heterogeneity among studies. The overall estimate was estimated as an odd ratio with a confidence interval of 95%. The heterogeneity among studies was calculated by I2 and Cochrane Q test. The qualitative analysis of publication bias was done using a funnel plot. The overall estimate measures [OR 1.02 (0.83, 1.25)] have shown non-significant role of tyrosine kinase inhibitors in reduction of deaths of non-small cell lung cancer patients as compared to non-tyrosine kinase inhibitors group. The subgroup analysis of individual tyrosine kinase inhibitors (erlotinib, gefitinib, afatinib, osimertinib and vandetanib) has also shown similar findings. Based on available data, there is no significant role played by tyrosine kinase inhibitors in the reduction of deaths of non-small cell lung cancer patients.

Sudden Vision Loss Secondary to Optic Nerve Infiltration as a Presenting Symptom of Metastatic Lung Adenocarcinoma

To report a rare case of left-sided metastatic optic nerve infiltration and right-sided choroidal mass with exudative retinal detachment caused by EGFR exon 19 deletion positive non-small-cell lung adenocarcinoma that responded to targeted therapy with osimertinib (EGFR-TKI). Our patient demonstrated an excellent response with reduced size of the metastatic choroidal mass of the right orbit and improved visual acuity, in addition to systemic disease control. A 66-year-old male patient with a history of diabetes mellitus, hypertension, and tobacco use presented with sudden vision loss in the left eye secondary to optic nerve infiltration and subacute vision loss in the right eye secondary to exudative retinal detachment from a choroidal metastasis. He was found to have a right lung mass, multiple metastatic pulmonary nodules, and liver and bone metastases. Biopsy from a mediastinal lymph node confirmed the diagnosis of metastatic lung adenocarcinoma. He was found to have exon 19 deletion on next-generation sequencing. We treated him with local radiation therapy to the left eye and systemic osimertinib (EGFR-TKI). To our knowledge, our case is the first report of a patient who initially presented with acute vision loss and was found to have metastatic retrobulbar optic nerve infiltration in one eye and metastatic choroidal lesion with exudative retinal detachment in the fellow eye secondary to lung adenocarcinoma. Due to the rarity of this condition, literature regarding effective treatment is scarce. Our patient demonstrated significant improvement in visual acuity and resolution of exudative retinal detachment in the right eye following osimertinib treatment and radiation therapy to the left eye. Further investigation into the role of tyrosine kinase inhibitors and radiation therapy in treating intraocular metastasis involving the optic nerve is needed.

EP08.02-017 Time on Treatment for Patients Treated With Anti-EGFR Tyrosine Kinase Therapy for Metastatic NSCLC: Real-World Experience Data

Clinical trials have established the role of tyrosine kinase inhibitor (TKI) targeted therapy for metastatic non-small cell lung cancer (mNSCLC) patients with driver mutation, but real-world data are limited. We describe time on treatment (rwTOT) for first-line (1L) mNSCLC patients with EGFR mutation in a 2.5-million-member state-mandated health provider in Israel.

Tyrosine Kinase Inhibitors in the Treatment of Metastasised Renal Cell Carcinoma-Future or the Past?

Simple SummaryRenal cell carcinoma (RCC) is the sixth most frequently diagnosed cancer in men and the tenth in women with a rising incidence. The treatment of metastasized RCC has dramatically changed in the last decade, improving the overall survival of patients significantly. In this context, cornerstones of the treatment have been tyrosine kinase inhibitors (TKI), with Sunitinib being the preferred first-line treatment for most cases. With the introduction of immunotherapy and combination therapy, this changed recently. The current article summarizes the available literature on TKI treatment of metastasized RCC and shows the current part of TKIs in the treatment algorithm as well as its potential future role.Background: To review and discuss the literature on applying tyrosine kinase inhibitors (TKIs) in the treatment of metastasised renal cell carcinoma (mRCC). Materials and Methods: Medline, PubMed, the Cochrane database, and Embase were screened for randomised controlled trials, clinical trials, and reviews on treating renal cell carcinoma, and the role of TKI. Each substance’s results were summarised descriptively. Results: While TKI monotherapy is not currently recommended as a first-line treatment for metastasized renal cell carcinoma, TKIs are regularly applied to treat treatment-naïve patients in combination with immunotherapy. TKIs depict the first-choice alternative therapy if immunotherapy is not tolerated or inapplicable. Currently, seven different TKIs are available to treat mRCC. Conclusions: The importance of TKIs in a monotherapeutic approach has declined in the past few years. The current trend toward combination therapy for mRCC, however, includes TKIs as one significant component of treatment regimens. We found that to remain applicable to ongoing studies, both when including new substances and when testing novel combinations of established drugs. TKIs are of major importance for the treatment of renal cancer now, as well as for the foreseeable future.

Role of tyrosine kinase inhibitor in chronic myeloid leukemia patients with SARS-CoV-2 infection: A narrative Review.

Severe acute respiratory syndrome (SARS) caused by a novel coronavirus-2 (CoV-2), also known as COVID-19, has spread rapidly worldwide since it is recognized as a public health emergency and has now been declared a pandemic on March 11, 2020, by the World Health Organization.The genome of SARS-CoV-2 comprises a single-stranded positive-sense RNA approximately 27 to 30 kb in size. The virus is transmitted through droplets from humans to humans. Infection with the SARS virus varies from asymptomatic to lethal, such as fever, cough, sore throat, and headache, but in severe cases, pneumonia and acute respiratory distress syndrome.Recently, no specific and effective treatment has been recommended for patients infected with the SARS virus. However, several options can be investigated to control SARS-CoV-2 infection, including monoclonal antibodies, interferons, therapeutic vaccines, and molecular-based targeted drugs.In the current review, we focus on tyrosine kinase inhibitor management and their protective role in SARS-CoV-2 patients with chronic myelogenous leukemia.

Real-world experience of tyrosine kinase inhibitors in patients (pt) with recurrent bone tumours (BT): A CanSaRCC study.

11530 Background: Survival after relapse in osteosarcoma (OST), Ewing Sarcoma (ES) and chondrosarcoma (CS) remains dismal. Recent reports suggest a role of tyrosine kinase inhibitors (TKI) including regorafenib (R) and cabozantinib (C). We conducted a retrospective multi-centre pan-Canadian study to assess real-word outcomes with these novel treatments in recurrent BT. Methods: After ethics approval, data from pts treated in 7 different institutions was extracted from the CanSaRCC (Canadian Sarcoma Research and Clinical Collaboration) Database. Pt characteristics, treatment and outcomes were analyzed. Response was assessed per RECIST 1.1. PFS, OS were estimated using Kaplan-Meier. TTP was defined as time from TKI start to progression. Results: From June 2018-Dec 2021, 44 pts received R or C and best response by histology are listed in Table, with an overall clinical benefit rate of 63.6%. Median time to best response was 2.3 mo (range 1 – 17). 15 pts (34.1%) required dose reduction; most common reasons were hand-foot syndrome (13.6%), mucositis (9.1%) and hypertension (9.1%). At median FU of 6.4 mo (range 1.6 – 29), 25 pts (56.8%) died, 19 (43.2%) were alive with disease (AWD). Median PFS was 4.1 mo (95%CI 2.9 – 5.7), for OST was 5.0 (N = 25, 95%CI 2.6 – 10.6), for ES was 4.1 (N = 10, 95%CI 2-5.9), and for CS 4.0 (N = 9, 1 Progressed). Median OS was 10.5 mo (95%CI 7 – 14). By univariate analysis, age, line of therapy, gender, location of primary, or R vs. C did not correlate with PFS. Conclusions: Consistent with previous published studies, our pan-country real-world analysis shows that TKI have meaningful activity in the setting of recurrent BT with acceptable toxicities. Inclusion in earlier lines of treatment and/or maintenance therapy could be questions for future research. [Table: see text]

Tyrosine kinase inhibitors in sarcoma treatment (Review)

Sarcomas are a group of rare mesenchymal malignant tumors that arise from transformed cells of the mesenchymal connective tissue, which are challenging to treat. The majority of sarcomas are soft tissue sarcomas (STSs; 75%) and this heterogeneous group of tumors is further comprised of gastrointestinal stromal tumors (~15%) and bone sarcomas (10%). Although surgery remains the current primary therapeutic approach for localized disease, recurrent, metastatic and refractory sarcomas require cytotoxic chemotherapy, which usually yields poor results. Therefore the efficiency of sarcoma treatment imposes a difficult problem. Furthermore, even though progress has been made towards understanding the underlying molecular signaling pathways of sarcoma, there are limited treatment options. The aim of the present study was therefore to perform a systematic literature review of the available clinical evidence regarding the role of tyrosine kinase inhibitors (TKIs) in patients with recurrent or refractory STSs and bone sarcomas over the last two decades. Tyrosine kinases are principal elements of several intracellular molecular signaling pathways. Deregulation of these proteins has been implicated in driving oncogenesis via the crosstalk of pivotal cellular signaling pathways and cascades, including cell proliferation, migration, angiogenesis and apoptosis. Subsequently, small molecule TKIs that target these proteins provide a novel potential therapeutic approach for several types of tumor by offering significant clinical benefits. Among the eligible articles, there were 45 prospective clinical trials, primarily multicentric, single arm, phase II and non-randomized. Numerous studies have reported promising results regarding the use of TKIs, mainly resulting in disease control in patients with STSs. The lack of randomized clinical trials demonstrates the ambiguous efficiency of various studied treatment options, which therefore currently limits the approved drugs used in clinical practice. Research both in clinical and preclinical settings is needed to shed light on the underlying molecular drivers of sarcomagenesis and will identify novel therapeutic approaches for pretreated patients.

What Do We Currently Know About Chronic Myeloid Leukemia (CML) and COVID-19?

Purpose of Review COVID-19 is highly contagious; since it was first identified, the virus has rapidly spread to more than 100 countries and was declared a pandemic on March 11, 2020, by the World Health Organization (WHO). This disease presents several challenges when managing patients with leukemia. We review the information about chronic myeloid leukemia (CML) and COVID-19: risk factors, prognosis, and the role of tyrosine kinase inhibitors (TKIs).Recent FindingsAt present, we find no data suggesting that patients with CML-chronic phase (CML-CP) are at higher risk of infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) than the general healthy population. TKIs had been proposed to fight the SARS-CoV-2-related disease (COVID-19).SummaryCML patients should continue receiving their TKIs if they have COVID-19 disease. The role of TKIs as protective factors against SARS-CoV-2 infection in patients with CML should be confirmed by large-scale epidemiologic studies.

Targeted therapies for unresectable stage III non-small cell lung cancer.

Until recently, the standard treatment in unresectable stage III non-small cell lung cancer was concurrent chemoradiotherapy, but often with dismal outcome. The introduction of consolidation treatment with immune checkpoint inhibitors has shifted the treatment landscape and prognosis of these patients. However, patients whose tumors harbors an epidermal growth factor receptor (EGFR) mutation derived less benefit, with an increased risk of immune-related adverse events. Moreover, current data suggested that patients with oncogenic addicted tumors, mainly EGFR-positive tumors, and also anaplastic lymphoma kinase (ALK)-positive have poorer progression free survival after chemoradiotherapy. Indeed, these tumors have also inferior distant control compared with those who have wild-type disease, especially in the central nervous system, highlighting the need for assessing the role of targeted therapies in this patient population. It is speculated that outcome could probably increase with a consolidation treatment strategy including an EGFR tyrosine kinase inhibitor. However, a personalized treatment approach is not considered standard of care in this setting due to lack of robust evidence, as the majority of trials were performed in unselected patients, number of patients is limited and the majority of these studies were underpowered. In this review we summarize the role of tyrosine kinase inhibitors in unresectable stage III NSCLC, specifically focusing on EGFR-mutant tumors.

P-194 Study of efficacy and safety of combination of octreotide acetate LAR with lenvatinib as second-line therapy in patients with advanced G1-G2 NETs of non-pancreatic origin

There is a documented role of tyrosine kinase inhibitors e.g. sunitinib, axitinib, etc. in grade 2 NET. Lenvatinib is a multikinase inhibitor which includes inhibition of VEGFR-1,2,3, platelet-derived growth factor receptor α (PDGFRα), KIT and RET, as well as FGFR1-4. The aim of this study was to assess the efficacy and toxicity of lenvatinib and octreotide acetate LAR combination in patients with advanced G1-2 extra-pancreatic NETs.

Current Approaches to Philadelphia Chromosome-Positive B-Cell Lineage Acute Lymphoblastic Leukemia: Role of Tyrosine Kinase Inhibitor and Stem Cell Transplant.

Over the past two decades, tyrosine kinase inhibitors (TKIs) have changed the management of patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL), and this has led to significant improvement in their outcome. In this review, we will provide an overview of the current understanding of treatment of Ph+ ALL focusing on TKIs, alloHSCT, and novel therapies. The advent of more potent TKIs and the novel therapeutic options including blinatumomab, inotuzumab ozogamicin, and CD19 CAR-T therapy has changed the role of allogeneic hematopoietic stem cell transplant (alloHSCT) and intensive chemotherapy. To avoid toxicity from the historical treatment strategies, a more individualized, targeted approach to therapy including detection and monitoring of measurable residual disease (MRD) has become of interest. The treatment of patients with Ph+ ALL has been rapidly evolving with a more individualized, targeted treatment and use of TKIs and novel therapy.

Tyrosine kinase Inhibitors in Dermatology: A Systemic Review

The inhibition of enzyme subgroups of tyrosine kinases can block the ability of various cytokines at the same time. Tyrosine kinase inhibitors are a class of drugs that can be used either primarily as oral medicines or in dermatological definitions locally. In several skin problems, restraint of tyrosine kinases has been demonstrated to be advantageous. Aim of this article is to explore the role of tyrosine kinase inhibitors in various skin diseases. Tyrosine inhibitors have demonstrated a guaranteed response in psoriasis, alopecia areata, Vitiligo, while the variable response in other skin disorders, including atopic dermatitis, chronic actinic dermatitis, dermatomyositis, erythema multiforme, graft-versus-host disease, hypereosinophillic syndrome, STING vasculopathy, palmoplantar pustulosis and lupus. The approach of Tyrosine inhibitors in dermatology has been met with incredible interest. This class of prescriptions can generously propel the treatment of inflammatory and immune mediated dermatoses. It is still too early to make a strong inference regarding these medicines' place in dermatological treatment, even though the evidence provides promising results.

P033 Scleroderma-like fibrotic disorder associated with a gastro-intestinal stromal tumour which responded only to imatinib

Abstract Background/Aims Gastro-intestinal stromal tumour (GIST) is recognised as the most prevalent mesenchymal tumour of the gastro-intestinal (GI) tract. The vast majority of GIST display activating mutations in receptor tyrosine kinases, such as platelet-derived growth factor receptor alpha (PDGFRA) and c-kit. This characteristic has lead to the development and approval of targeted therapies such as Imatinib for metastatic GIST. Scleroderma is an idiopathic fibrotic syndrome which involves excess collagen deposition in multiple tissues and organs. There is emerging evidence that dysfunctional fibroblasts are central to the underlying pathogenesis of this disease. An increasing awareness of the complex interplay of these fibroblasts with other cells and inflammatory mediators, such as platelet-derived growth factor (PDGF), is being recognised. This novel case serves to further develop our understanding of these pathological interactions, and to highlight a prospective role for Imatinib in disrupting them. Methods We present a case report below. Results A 54-year-old Caucasian male was referred to our rheumatology clinic due to worsening Raynaud's syndrome, arthralgia, and dry cough. He subsequently developed weight loss, pyrosis and skin thickening. This clinical picture was suggestive of a new diagnosis of systemic sclerosis. However, fibrotic skin changes did not extend to the distal finger, and anti-nuclear antibody (ANA) was negative. Symptoms were also refractory to various vasodilator and immunosuppressive therapies, including nifedipine, repeated iloprost infusions, azathioprine, mycophenolic acid, prednisolone, and sildenafil. Computed tomography (CT) imaging revealed interstitial pulmonary fibrosis and a mass within the gastric fundus. Histopathologic features and immunological staining of this mass were consistent with a GIST. Resection of the tumour did not improve fibrotic symptoms. Surveillance imaging one-year later was highly concerning for metastatic recurrence, which was later confirmed with tissue biopsy. He was subsequently initiated on Imatinib therapy, which led to a rapid improvement in fibrotic changes within weeks. Conclusion While there have been previous descriptions of para-neoplastic fibrotic syndromes, this is the first reported case of a scleroderma-mimicking disorder associated with GIST. It hints at an important potential overlap in the pathogenesis of these disease processes, and a potential role for tyrosine-kinase inhibitors in the treatment of scleroderma-like fibrotic disorders. Disclosure Z.A. Butt: None. W. Ng: None. D. Howard: None. K. Osman: None.

Metastatic Renal Cell Carcinoma Management: From Molecular Mechanism to Clinical Practice.

The therapeutic sc"enario of metastatic renal cell cancer (mRCC) has noticeably increased, ranging from the most studied molecular target therapies to those most recently introduced, up to immune checkpoint inhibitors (ICIs). The most recent clinical trials with an ICI-based combination of molecular targeted agents and ICI show how, by restoring an efficient immune response against cancer cells and by establishing an immunological memory, it is possible to obtain not only a better radiological response but also a longer progression-free and overall survival. However, the role of tyrosine kinase inhibitors (TKIs) remains of fundamental importance, especially in patients who, for clinical characteristics, tumor burden and comorbidity, could have greater benefit from the use of TKIs in monotherapy rather than in combination with other therapies. However, to use these novel options in the best possible way, knowledge is required not only of the data from the large clinical trials but also of the biological mechanisms, molecular pathways, immunological mechanisms, and methodological issues related to both new response criteria and endpoints. In this complex scenario, we review the latest results of the latest clinical trials and provide guidance for overcoming the barriers to decision-making to offer a practical approach to the management of mRCC in daily clinical practice. Moreover, based on recent literature, we discuss the most innovative combination strategies that would allow us to achieve the best clinical therapeutic results.

OA05.03 Real-World Global Data on Targeting Epidermal Growth Factor Receptor in Stage III Non-Small Cell Lung Cancer: The Results of the KINDLE Study

Tyrosine kinase inhibitors (TKIs) are the standard of care for patients with metastatic non-small cell lung cancers (NSCLC) harbouring epidermal growth factor receptor mutations (EGFRm). However, the role of TKIs is not established in the management of stage III EGFRm disease. We describe the real-world practice of EGFRm testing and use of TKIs in stage III NSCLC in the KINDLE study, a multicentre, multi-country observational non-interventional study.

Neoadjuvant tyrosine kinase inhibitors in rectal gastrointestinal stromal tumours: a provision for enhanced oncological and functional outcomes

BackgroundThe role of tyrosine kinase inhibitors (TKI) in the neoadjuvant setting and the optimal duration of therapy remains poorly defined. As such, we aim to evaluate the impact of neoadjuvant TKI on oncological and functional outcomes in our cohort of patients with rectal GISTs.MethodsA retrospective analysis of 36 consecutive patients who underwent treatment for rectal GIST at the National Cancer Centre Singapore from February 1996 to October 2017 was analysed. Surgical, recurrence and survival outcomes between the groups who underwent neoadjuvant therapy and those who underwent upfront surgery were compared.ResultsPatients who received neoadjuvant treatment had significantly larger tumours (median size 7.1 vs. 6.0 cm, p = 0.04) and lower mitotic count (> 10 per 50 HPF, 14 vs. 70%, p = 0.03) when compared with the non-neoadjuvant group. With TKI pre-treatment (median duration 8.8 months), majority of patients (82%) achieved at least partial response to the therapy coupled with a significant downsizing effect of up to 39% (median size of 7.1–3.6 cm), resulting in similar rates of sphincter-sparing surgery (75 vs. 76%, p = 0.94) when compared with the non-neoadjuvant group. In general, neoadjuvant group had lower rates of local recurrence (0 vs. 69%, p = 0.04) and higher overall survival (7.4 vs. 5.7 years, p = 0.03) as compared to the non-neoadjuvant group.ConclusionsNeoadjuvant TKI has the benefit of downsizing unresectable rectal GIST to benefit from sphincter-sparing procedure and also confers protection against local recurrence and improves overall survival.