Era Of Targeted Therapy Research Articles

Carboplatin desensitization in the era of target therapies: still worthwhile?

Unresectable pediatric low-grade gliomas (LGG) usually need adjuvant therapy, and carboplatin hypersensitivity reaction (HR) commonly leads to premature treatment cessation of a standard chemotherapy regimen. In the molecular era, advances in understanding tumor genetic characteristics allowed the development of targeted therapies for this group of tumors; however, cost-effectiveness assessment of treatments, especially in low-income countries, is crucial. The aim is to describe the results of carboplatin desensitization protocol in a single center in a middle-income country. Prospective analysis of children with LGG submitted to carboplatin desensitization from December 2017 to June 2020 with follow-up until April 2024. Nine patients were included. The mean age was 11years. Five patients were male. Seven had optic pathway and two cervicomedullary location. Six had histologic diagnosis and four molecular analyses. The incidence of carboplatin reactions during the study period was 39.1%. Six patients underwent skin prick test, three with positive results. The first HR occurred, on average, around the 9th cycle of treatment. All patients had cutaneous symptoms, and five out of nine had anaphylaxis as the first reaction. 77.7% of the patients completed the protocol, and the clinical benefit rate (stable disease and partial response) was 88.8%. Six patients further required other lines of therapy. Monthly, the total cost for carboplatin was $409.09, and for target therapies (dabrafenib plus trametinib), $4929.28 to $5548.57. Our study presented an interesting and cost-effective option where desensitization allowed children with HR to be treated with first-line therapy, avoiding the discontinuation of an effective treatment.

Predictive Factors and the Role of Conventionally Fractionated Radiation Therapy for Bone Metastasis from Renal Cell Carcinoma in the Era of Targeted Therapy.

Background and Objectives: Despite rapid advances in targeted therapies for renal cell carcinoma (RCC), bone metastases remain a major problem that significantly increases morbidity and reduces patients' quality of life. Conventional fractionated radiotherapy (CF-RT) is known to be an important local treatment option for bone metastases; however, bone metastases from RCC have traditionally been considered resistant to CF-RT. We aimed to investigate the effectiveness of CF-RT for symptomatic bone metastasis from RCC and identify the predictive factors associated with treatment outcomes in the targeted therapy era. Materials and Methods: Between January 2011 and December 2023, a total of 73 lesions in 50 patients treated with a palliative course of CF-RT for symptomatic bone metastasis from RCC were evaluated, and 62 lesions in 41 patients were included in this study. Forty-five lesions (72.6%) were treated using targeted therapy during CF-RT. The most common radiation dose fractionations were 30 gray (Gy) in 10 fractions (50%) and 39 Gy in 13 fractions (16.1%). Results: Pain relief was experienced in 51 of 62 lesions (82.3%), and the 12-month local control (LC) rate was 61.2%. Notably, 72.6% of the treatment course in this study was combined with targeted therapy. The 12-month LC rate was 74.8% in patients who received targeted therapy and only 10.9% in patients without targeted therapy (p < 0.001). Favorable Eastern Cooperative Oncology Group performance status (p = 0.026) and pain response (p < 0.001) were independent predictors of improved LC. Radiation dose escalation improved the LC in radiosensitive patients. A consistent treatment response was confirmed in patients with multiple treatment courses. Conclusions: CF-RT enhances pain relief and LC when combined with targeted therapy. Patients who responded well to initial treatment generally showed consistent responses to subsequent CF-RT for additional painful bone lesions. CF-RT could therefore be an excellent complementary local treatment modality for targeted therapy.

A Single Center Experience of Pulmonary Arterial Hypertension Management in Korea: A 25-Year Comparative Analysis Following the Introduction of Targeted Therapy.

The transformation of pulmonary arterial hypertension (PAH) treatment in Korea, ushered by targeted therapy's advent, prompted our analysis of baseline attributes, treatment trends, and survival shifts within our single-center registry. We examined 230 patients (72.6% female, mean age 40.6±17.4 years) diagnosed and/or treated between 1980 and 2021 in our PAH clinic. Given targeted therapy's introduction and active use since 2007, we compared diagnostic classification, demographics, and treatment patterns at that juncture. Survival analysis encompassed PAH types and the overall population. For historical survival comparison, 50 non-registry patients were retrospectively added, and age-sex matching enabled pooled analysis. Congenital heart disease-associated pulmonary arterial hypertension (CHD-PAH) constituted the largest subset (43.0%), trailed by connective tissue disease-associated PAH (CTD-PAH, 29.6%) and idiopathic PAH (IPAH, 19.1%). Post-2007, CTD-PAH proportions surged, notably with an elevated initiation rate of targeted therapy (95.4%). Overall survival rates at 1, 5, and 10 years stood at 91.3%, 77.4%, and 65.8%, respectively, with CHD-PAH exhibiting superior survival to idiopathic or CTD-PAH. Age-sex matching analysis indicated survival disparities between those starting immediate targeted therapy vs. conservative treatment upon diagnosis, especially driven by IPAH. In the post-introduction of the targeted therapy era, patients with PAH promptly started treatment right away, and higher survival rates of patients who started initial PAH-targeted therapy were demonstrated. The transition towards early treatment initiation might have likely contributed to the elevated survival rates observed in Korea's PAH patient cohort.

Improved Survival of Patients With Chronic Lymphocytic Leukemia Between 1998-2022, Including the Era of Target Therapies With BCL2 and BTK Inhibitors.

The treatment for chronic lymphocytic leukemia (CLL) has changed dramatically over the last two decades. The current study aimed to investigate the impact on overall survival (OS) and time to next treatment (TTT) among CLL patients from 1998 to 2022. The cohort was based on data obtained from electronic medical records of Maccabi, the second largest healthcare organization in Israel. All included patients were diagnosed with CLL based on the IWCLL criteria and complete clinical, laboratory, and treatment data were available. The study encompassed 3,964 patients diagnosed with CLL during the specified study period. Patients with CLL who required therapy were divided into three eras based on the dominant treatment approach: chemotherapy alone before 2010, therapy with chemotherapy and anti-CD20 between 2010 and 2017, and therapy with targeted agents between 2017 and 2022. Median OS was 4.1 years, 7.5 years, and not reached, respectively. The six-year OS rates were 40%, 55%, and 69%, respectively, (p=0.0001). The median time to the next treatment improved from 5.5 years before 2010, to 8.3 between 2010-2017, to not reached after 2017 (p=0.0021). Marked improvements in survival subsequent to fundamental changes in first-line therapy were found in patients with CLL from before 2010 to after 2017.

The role of cytoreductive nephrectomy (CN) in the immune checkpoint inhibitor (ICI) era of metastatic renal cell carcinoma (mRCC): A systematic review and individual patient data (IPD) meta-analysis of 2319 patients.

425 Background: The combination of CN and systemic therapy has been established as one of the mainstay treatments for mRCC during the targeted therapy era. However, the role of CN in the ICI era remains unclear. Methods: We performed a systematic search of the MEDLINE, EMBASE, and Web of Science databases until August 26th, 2023, for studies comparing the combination of CN + ICI vs. ICI alone in mRCC. Using published Kaplan-Meier overall survival (OS) curves, we reconstructed IPD and then performed one-stage and two-stage meta-analyses with both parametric and non-parametric effect estimates. To account for immortal time bias, we performed 6-month and 12-month landmark analyses. We also performed a subgroup analysis according to ICI line of treatment. The risk of bias was assessed using the ROBINS-I tool. Results: We identified eight retrospective cohort studies fulfilling our inclusion criteria. Only two out of eight studies adjusted for immortal time bias and none of them adequately adjusted for all predetermined confounding factors. A total of 2319 (1264 CN + ICI and 1055 ICI only) patients were included in our analysis. Patients in CN + ICI group were younger (median age 58.2 vs. 62.8), had lower proportions of non-clear cell histology (8.8% vs. 15.2%), ≥2 metastatic sites (60.0% vs. 68.5%), liver metastases (9.0% vs. 21.9%), and poor IMDC risk score (21.7% vs. 43.9%), but had higher proportions of sarcomatoid histology (15.6% vs. 10.6%) and ≥2nd line treatment (38.1% vs. 17.1%). The combination of CN + ICI was associated with superior OS in the one stage (HR: 0.45, 95% CI 0.38–0.52), 6-month landmark (HR: 0.45, 95% CI 0.37–0.54), 12-month landmark (HR: 0.50, 95% CI 0.31–0.50) and two-stage (HR: 0.38, 95% CI 0.29–0.49) meta-analyses. Similarly, the combination of CN + ICI was associated with superior OS in the subgroup of patients receiving first-line ICI (HR 0.39, 95% CI: 0.30–0.48). Conclusions: The combination of CN + ICI for mRCC may be associated with superior OS compared to ICI alone, but currently available data are subject to selection bias. More studies, including well-designed randomized controlled trials, are needed to determine the role of CN in the ICI era. [Table: see text]

Antibody-Drug Conjugates: The Dynamic Evolution from Conventional to Next-Generation Constructs.

Introduced almost two decades ago, ADCs have marked a breakthrough in the targeted therapy era, providing clinical benefits to many cancer patients. While the inherent complexity of this class of drugs has challenged their development and broad application, the experience gained from years of trials and errors and recent advances in construct design and delivery have led to an increased number of ADCs approved or in late clinical development in only five years. Target and payload diversification, along with novel conjugation and linker technologies, are at the forefront of next-generation ADC development, renewing hopes to broaden the scope of these targeted drugs to difficult-to-treat cancers and beyond. This review highlights recent trends in the ADC field, focusing on construct design and mechanism of action and their implications on ADCs' therapeutic profile. The evolution from conventional to innovative ADC formats will be illustrated, along with some of the current hurdles, including toxicity and drug resistance. Future directions to improve the design of next-generation ADCs will also be presented.

Life-threatening Pneumocystis jiroveci Pneumonia with Cytomegalovirus Coinfection in a Follicular Lymphoma Patient During Rituximab-based Chemotherapy

Abstract In the era of target therapy, we face the challenge of the risk of opportunistic infection in patients with B-cell lymphoma who receiving rituximab-based chemotherapy. Opportunistic infections such as Pneumocystis jiroveci pneumonia (PJP) and Cytomegalovirus (CMV) pneumonia are life-threatening diseases. However, PJP with CMV coinfection is rare. Here, we report a follicular lymphoma patient who suffered from PJP with CMV coinfection after receiving three cycles of rituximab, cyclophosphamide, vincristine, and prednisone regimen and was successfully rescured after timely identification and treatment. We emphasize that physicians should be alert for the coinfection of PJP and CMV in lymphoma patients receiving rituximab-based chemotherapy and the timely recognition, and treatment that may avoid a deadly outcome.

Paris saponin VII reverses resistance to PARP inhibitors by regulating ovarian cancer tumor angiogenesis and glycolysis through the RORα/ECM1/VEGFR2 signaling axis.

The emergence of Poly (ADP-ribose) polymerase inhibitors (PARPi) has marked the beginning of a precise targeted therapy era for ovarian cancer. However, an increasing number of patients are experiencing primary or acquired resistance to PARPi, severely limiting its clinical application. Deciphering the underlying mechanisms of PARPi resistance and discovering new therapeutic targets is an urgent and critical issue to address. In this study, we observed a close correlation between glycolysis, tumor angiogenesis, and PARPi resistance in ovarian cancer. Furthermore, we discovered that the natural compound Paris saponin VII (PS VII) partially reversed PARPi resistance in ovarian cancer and demonstrated synergistic therapeutic effects when combined with PARPi. Additionally, we found that PS VII potentially hindered glycolysis and angiogenesis in PARPi-resistant ovarian cancer cells by binding and stabilizing the expression of RORα, thus further inhibiting ECM1 and interfering with the VEGFR2/FAK/AKT/GSK3β signaling pathway. Our research provides new targeted treatment for clinical ovarian cancer therapy and brings new hope to patients with PARPi-resistant ovarian cancer, effectively expanding the application of PARPi in clinical treatment.

Abstract B010: Spatially-resolved prediction of gene expression signatures in H&amp;E whole slide images using additive multiple instance learning models

Abstract Background: Newly developed molecular technologies, such as spatial multiplexed assays and single-cell sequencing, have provided increased resolution and output for tumor analysis. However, these assays are often cost-prohibitive, making them inadequate ways to detect clinical biomarkers. In contrast, hematoxylin and eosin (H&amp;E) staining is routine for cancer diagnostics but does not provide molecular information, potentially limiting its utility in the targeted therapy era. Machine learning models could augment the information revealed by H&amp;E, potentially allowing molecular information to be inferred. Here, we describe a novel approach to predict gene expression signatures (GES) in H&amp;E-stained whole slide images (WSI) using an additive multiple instance learning (aMIL) end-to-end model (1). We present results in breast cancer predicting spatially resolved levels of a TGFb GES, a proposed biomarker for TGFb antagonists and immunotherapy. Methods: H&amp;E-stained WSI from the TCGA BRCA cohort (N=1090) were split into training (60%), validation (20%), and test (20%) sets. TGFb-CAF GES (2) were computed, and median expression cut-off on training data was used to define “high” and “low” TGFb-CAF levels. aMIL models were optimized in training data for the binary classification of TGFb-CAF levels. Top-performing model iterations were compared on the validation set, and the optimal model was deployed on the held-out test set. aMIL heatmaps were merged with PathExplore tumor microenvironment (TME) model heatmaps to characterize cell, tissue, and nuclear spatial distributions and morphology in terms of human interpretable features (HIFs). HIFs were extracted from high-importance patches (top 25% of aMIL scores) for both TGFb-CAF-high and -low. Results: Our model accurately predicted TGFb-CAF-high vs. -low BRCA samples (test AUROC=0.80). Also, model deployment on WSI provided interpretable heatmaps depicting TGFb-CAF predictions in tissue, providing spatial resolution to TGFb-CAF expression. Patches contributing most to TGFb-CAF-high prediction were enriched for cancer stroma, as well as cancer-infiltrating and stromal fibroblasts. Furthermore, significant differences in HIFs relating to fibroblast nucleus size and lymphocyte nucleus shape were observed between patches contributing most to TGFb-CAF-high and -low predictions. Conclusions: We have developed a method to predict GES with spatial resolution in H&amp;E-stained WSI. aMIL models provide exact marginal contributions of each patch towards every class prediction, allowing downstream analysis of tissue, cell, and nuclear features and providing biological interpretability not found in typical black-box models. The ability of our method to detect GES in H&amp;E-stained WSI allows complex molecular information to be detected in routine clinical specimens with spatial specificity, providing a means for GES to potentially be realized as clinical biomarkers.

The Incidence, Clinical Application and Prognostic Significance of MYD88 and CXCR4 Mutation in Chinese Patients with Lymphoplasmacytic Lymphoma/ Waldenström Macroglobulinemia

Introduction Waldenström macroglobulinemia (WM)/lymphoplasmacytic lymphoma (LPL) is a rare B-cell lymphoma with prevalent somatic mutations, including MYD88 and CXCR4. However, their mutation rates in Chinese LPL/WM and the comparison of different detection methods remain unclear. Moreover, the clinical implications of MYD88 and CXCR4 mutations in the immunochemotherapy and targeted therapy eras need exploration. Methods This study included 458 LPL/WM patients (418 WM, 40 non-IgM LPL) from December 2014 to June 2023. Four methods, such as Sanger sequencing, next-generation sequencing (NGS), allele-specific quantitative polymerase chain reaction (AS-PCR), and droplet digital polymerase chain reaction (ddPCR), were used to detect MYD88L265P and CXCR4 mutations. Demographic data, clinical characteristics, tumor burden, cytogenetic abnormalities, treatment regimens, and survival data were collected. Results A total of 458 patients were assessed for MYD88 L265P mutation, of whom 266 were tested by Sanger sequencing, 300 by NGS, 370 for AS-PCR, 251 for ddPCR. The MYD88 L265P mutation was found in 398/458 (86.9%) of the patients. AS-PCR and ddPCR showed the highest sensitivity (97.2% and 96.5%, respectively), outperforming Sanger sequencing and NGS, which had higher false-negative rates in low tumor load patients. A high false-negative rate for MYD88 by Sanger sequencing and NGS was observed in patients with tumor burden less than 10% (40.0% and 21.9% respectively). There was no significant difference in the MYD88 mutation rate detected by ddPCR and ASPCR among patients with different tumor burden groups (P=0.402, P=0.252). MYD88 mutation was detected in a high incidence of 86.7% and 85.5% in less than 1% infiltrated WM tumor cells specimens by ddPCR and ASPCR. Thus, ddPCR and ASPCR assay were effective and accurate enough for un-sorted low infiltrated WM specimens. CXCR4 mutation testing was performed in 428 patients of LPL/WM, comprising 311 with Sanger sequencing, 300 with NGS, and 371 with AS-PCR. Overall, 31.8% (136/428) patients were identified as having the CXCR4 mutation. NGS exhibited the highest sensitivity (79.2%) among the three detection means. Among the 458 patients of LPL/WM, 60 (13.1%) were classified as MYD88 wild-type patients. MYD88 wild-type patients had a significantly lower hemoglobin levels (median 83g/L vs. 92g/L, P=0.044), lower proportion of males (56.7% vs. 72.5%, P=0.012) and a significantly higher proportion elevated β2-macroglobulin (81.5% vs. 68.5%, P=0.027), and lactic dehydrogenase (32.2% vs. 11.1%, P&amp;lt;0.001). However, there were no significant differences in either PFS or OS between MYD88 L265P wild-type and MYD88 L265P mutation group (PFS: median 35.7 months vs. 52.9 months, P=0.40; OS: 5-year rate 72.0% vs. 81.8%, P=0.62). MYD88 wild-type patients had worse PFS and post-BTKi failure-free survival under immunochemotherapy (median 34.3 months vs. 58.4 months, P=0.03), and BTKi regimens (median: 26.2 months vs. 45.2 months, P=0.02), respectively. Patients with CXCR4 mutation tended to be older (median 64 vs. 60, P=0.001), had lower hemoglobin levels (median 83g/L vs. 94g/L, P=0.008), and higher baseline BM involvement (by FCM, median 12.6% vs. 6.2%, P&amp;lt;0.001) compared with CXCR4 wild-type patients. The proportion of patients with thrombocytopenia (43.7% vs. 20.6%, P&amp;lt;0.001), serum IgM level more than 40g/L (47.4% vs. 34.6%, P=0.019) was significantly higher, the proportion of patients with low risk profile of IPSSWM (17.2% vs. 30.5%, P=0.007) was significantly lower in mutation group. Notably, CXCR4 mutation group had significantly worse survival compared with the wild-type group (PFS: median 40.5 months vs. 62.5 months, P=0.024; OS: median 103.8 months vs. not reached, P=0.022). Meanwhile, patients with CXCR4 mutation experienced inferior post-BTKi failure-free survival (median 30.4 months vs. 57.6 months, P=.04) and post-BTKi overall survival (3-year rate 71.9% vs. 84.9%, P=0.03) in BTKi therapy groups. Conclusions This study sheds light on MYD88 and CXCR4 mutations in Chinese WM/LPL based on a large cohort. AS-PCR and ddPCR were highly sensitive for MYD88 mutation detection, especially in low infiltrated WM. NGS was the most sensitive method for detecting CXCR4 mutation. MYD88 mutation had prognostic significance in BTKi-based therapy, while CXCR4 mutation indicated higher tumor burden and inferior survival in BTKi-based therapy.

Prevention and management of hepatitis B virus reactivation in patients with hematological malignancies in the targeted therapy era.

Hepatitis due to hepatitis B virus (HBV) reactivation can be serious and potentially fatal, but is preventable. HBV reactivation is most commonly reported in patients receiving chemotherapy, especially rituximab-containing therapy for hematological malignancies and those receiving stem cell transplantation. Patients with inactive and even resolved HBV infection still have persistence of HBV genomes in the liver. The expression of these silent genomes is controlled by the immune system. Suppression or ablation of immune cells, most importantly B cells, may lead to reactivation of seemingly resolved HBV infection. Thus, all patients with hematological malignancies receiving anticancer therapy should be screened for active or resolved HBV infection by blood tests for hepatitis B surface antigen (HBsAg) and antibody to hepatitis B core antigen. Patients found to be positive for HBsAg should be given prophylactic antiviral therapy. For patients with resolved HBV infection, there are two approaches. The first is pre-emptive therapy guided by serial HBV DNA monitoring, and treatment with antiviral therapy as soon as HBV DNA becomes detectable. The second approach is prophylactic antiviral therapy, particularly for patients receiving high-risk therapy, especially anti-CD20 monoclonal antibody or hematopoietic stem cell transplantation. Entecavir and tenofovir are the preferred antiviral choices. Many new effective therapies for hematological malignancies have been introduced in the past decade, for example, chimeric antigen receptor (CAR)-T cell therapy, novel monoclonal antibodies, bispecific antibody drug conjugates, and small molecule inhibitors, which may be associated with HBV reactivation. Although there is limited evidence to guide the optimal preventive measures, we recommend antiviral prophylaxis in HBsAg-positive patients receiving novel treatments, including Bruton's tyrosine kinase inhibitors, B-cell lymphoma 2 inhibitors, and CAR-T cell therapy. Further studies are needed to determine the risk of HBV reactivation with these agents and the best prophylactic strategy.

Impact of surgical resection for gastrointestinal stromal tumor (GIST) patients with initially diagnosed synchronous hepatic metastases on long-term survival outcomes.

The effect of surgical resection on the long-term outcome of GIST patients with initially diagnosed synchronous hepatic metastases in the targeted therapy era is still uncertain. The main aims of this study were to investigate the role of surgery in the treatment of these patients and establish clinical predictive models for assessing prognosis. We identified these patients from the Surveillance, Epidemiology and End Results (SEER) database between 2010 and 2018. The selection bias in comparisons was minimized by performing propensity score matching (PSM). The risk factors associated with long-term survival outcomes were identified by a Cox proportional hazards model and thus used to establish the nomograms. Nomograms were validated by concordance indexes (C-indexes), time-dependent receiver operator characteristic (ROC) curves, calibration plots, and decision curve analyses (DCA). Of these 523 eligible patients, there were 187 (35.8%) and 336 (64.2%) patients in the surgical and nonsurgical groups, respectively. Multivariate analysis revealed that surgical resection was an independent prognostic factor for OS (hazard ratio [HR] 0.62; 95% confidence interval [CI] 0.44-0.88, p=0.0068) and CSS (HR 0.51; 95% CI 0.33 - 0.77, p=0.0016). After PSM, it was found that surgical resection still showed significantly improved OS (5-year 54.9% vs 38.8%, p=0.028) and CSS (5-year 65.8% vs 50.3%, p=0.077). In addition, the C-indexes of the nomograms for OS and CSS prediction were 0.692 and 0.705, respectively, and the nomograms showed good consistency. This study revealed that surgical resection has a favorable impact on the long-term outcome of patients with synchronous GIST liver metastases, and the nomograms showed remarkable prediction performance for OS and CSS.

Clinical resistance predictors to first-line VEGFR-TKI monotherapy for metastatic renal cell carcinoma: a retrospective multicenter real-life case series

Aim: For many years, systemic treatment of metastatic Renal Cell Carcinoma (mRCC) was based on sequential targeted agent monotherapies. In this real-life case series, we evaluated easily accessible clinical factors useful for disease course prediction. Methods: We exploited patients' clinical pathological characteristics and systemic treatment outcomes in a real-world population of 365 mRCC patients who received sequential monotherapies in the targeted therapy era, and we identified an early progressors subpopulation, resistant to first-line VEGFR-TKI monotherapy in less than 6 months. Results: Early progressors (n = 124) show a far worse OS compared with patients progressing beyond the sixthmonth of therapy (13.5 vs. 44.8 months, P-value &lt; 0.0001, HR = 0.41, 95%CI: 0.29-0.53). However, these patients did not show far worse performance in second and third-line settings compared to first-line responders. In the univariate analysis, IMDC risk class, sarcomatoid features, and Systemic Inflammation Index (SII) were correlated with first-line therapy Progression-Free Survival (PFS1). In multivariate analysis, variables correlated with first-line outcome were IMDC risk class, histotype, and number of metastatic sites at the diagnosis. Conclusion: Real-world data can contribute to developing easy-to-use prognostic factors associated with refractory disease that could support clinicians in identifying the most appropriate treatment strategy for each patient.

Clinical Outcomes of Patients with Epidermal Growth Factor Receptor–Mutated Non-Small-Cell Lung Cancer with Leptomeningeal Metastasis in the Modern Target Therapy Era

Leptomeningeal metastasis (LM) is a severe complication in patients with non-small-cell lung cancer (NSCLC) and the optimal treatment strategy remains a challenge. This study aimed to investigate the treatment strategies and clinical outcomes in these patients. We retrospectively reviewed the data of 44 patients with epidermal growth factor receptor (EGFR)-mutated NSCLC with LM between 2014 and 2020 at our institute. The patient characteristics, treatment approaches, LM progression-free survival (LMPFS) and overall survival (OS) after the diagnosis of LM (OSLM) were analyzed. The median OSLM was 16.0 months and the 3-year OS rate was 22.5%. The PFSLM in EGFR T790M-positive NSCLC patients with leptomeingeal disease was significantly improved by initiation of third-generation tyrosine kinase inhibitors (TKIs) compared with that of patients who were T790M negative (14.0 vs. 7.0 months; P= 0.030). A significantly higher LM disease control rate was shown in patients who received third-generation TKIs compared with previous generations of TKIs (90.1% vs. 60.0%; P= 0.024). Better Eastern Cooperative Oncology Group performance status, EGFR exon 19del, and clinical improvement of LM after therapy were independently associated with better OS. The survival of patients with NSCLC with LM has improved in the target therapy era. Our study provided real-world clinical evidence that patients with EGFR-mutated NSCLC who developed LM from previous TKIs can be benefit from third-generation EGFR-TKIs, especially for patients with EGFR T790M-positive.

1056P KRAS and LKB1 mutation conferring prognostic and predictive role on liquid biopsy in advanced NSCLC

Liquid biopsy (LB) is a feasible tool able to detect genomic alterations in cancer at baseline and also as a longitudinal monitoring to identify resistance mutations. In patients (pts) with mNSCLC, when tissue biopsy remains a difficult procedure, LB might be crucial for therapeutical options, especially in the immunotherapy (IO) and target therapy era. The aim of this bicentric study is to assess the prognostic value of LB in mNSCLC. Data from mNSCLC with any gene alteration/PD-L1 expression were collected at Istituto Nazionale Tumori of Milan and Policlinico Universitario of Naples. Liquid biopsy was performed by 73-gene Guardant360® CDx / 29-gene Archer® LiquidPlex™panels. Effects of circulating genomic alterations on Overall Survival (OS) (from 4-stage diagnosis to death/last FUP) were assessed using Cox proportional hazard model cell free. Kaplan-Meier curves were performed to assess OS between IO and non-IO treatments arms. Of 488 pts underwent LB, most were male (56.9%), former smoker (46.3%), with adenocarcinoma (73.6%) and PD-L1 > 1% (55.6%). 301/488 patients (62.6%) were treated with IO alone or in combination with chemotherapy, in first (47.0%) or second line (102 – 29.2%). In 133 (32.1%) cases, LB was performed at IO baseline, while in 101 (24.5%) cases at IO progression. Among the most relevant genes, STK11+/LKB1+ confers the worst OS (HR for OS 2.12 months, CI 95% 1.26 – 3.56; p = 0.005), regardless treatments. LKB1+/KRAS+ have a poorer OS than LKB1-/KRAS- (OS: 13 vs 24 m, HR 2.34 95% IC 1.19 – 4.61) and LKB1-/KRAS+ (OS: 13 vs 34 m HR 2.99 95% IC 1.36-6.54). When analyzing the effect of KRAS on IO and non-IO arms, KRAS-/IO have the best prognosis compared to KRAS+/non-IO which have the worst prognosis, while KRAS+/IO seems to have a similar prognosis to KRAS-/non-IO pts (HR 0.82 95% IC 0.43 – 1.58). Results reported on LB confirmed previous reports on tissue: STK11+ pts, have the worst prognosis regardless treatments. KRAS+ compare to STK11+/KRAS+ pts and STK11-/KRAS- pts seems to have the best prognosis. IO seems to play a relevant role on survival regardless KRAS status, in fact when using IO the negative prognostic effect of KRAS+ pts decreases and becomes similar to KRAS-/non-IO pts.

What We Have Learnt from CARMENA and SURTIME and What Should Be Done Differently in Future Trials on Cytoreductive Nephrectomy

Upfront cytoreductive nephrectomy (CN) was the standard treatment for selected patients with metastatic Renal Cell Carcinoma (RCC) in the cytokine era for many years. In the recent ‘targeted therapy era’ it has been re-challenged by both the CARMENA and SURTIME trials. As first-line therapy for treatment-naive metastatic clear-cell RCC has now changed to immune checkpoint inhibitor combination therapy (ICI), and previous studies concerning CN were built in the targeted therapy era, the role and sequence of CN needs to be revisited. Here we address what we have learnt from both trials and how future trials should be designed to investigate CN.

Brain Metastases Management in Oncogene-Addicted Non-Small Cell Lung Cancer in the Targeted Therapies Era.

The therapeutic landscape in patients with advanced non-small-cell lung cancer harboring oncogenic biomarkers has radically changed with the development of targeted therapies. Although lung cancers are known to frequently metastasize to the brain, oncogene-driven non-small-cell lung cancer patients show a higher incidence of both brain metastases at baseline and a further risk of central nervous system progression/relapse. Recently, a new generation of targeted agents, highly active in the central nervous system, has improved the control of intracranial disease. The intracranial activity of these drugs poses a crucial issue in determining the optimal management sequence in oncogene-addicted non-small-cell lung cancer patients with brain metastases, with a potential change of paradigm from primary brain irradiation to central nervous system penetrating targeted inhibitors.

P-278 Impact of surgical resection for gastrointestinal stromal tumors (GISTs) patients with initially diagnosed synchronous hepatic metastases on long-term survival outcomes

The impact of surgical resection on the long-term outcome of GIST patients with initially diagnosed synchronous hepatic metastases in the targeted therapy era is still uncertain. This study aimed to investigate the role of hepatectomy in the treatment of the aforementioned patients and establish the clinical predictive models for assessing the prognosis of these patients.

Characterization of avoidable hospital admissions in patients with lung cancer in the immunotherapy and targeted therapy era.

e21133 Background: Hospitalization is the second largest contributor of cancer care spending, and over 50% of lung cancer patients are admitted to the hospital while receiving treatment. Patients who avoid hospital admission have reduced health care costs with a higher quality of life. This is the first study that characterizes the risk factors and outcomes for avoidable hospital admissions of lung cancer patients. It is the first to examine the extent to which hospitalizations from immunotherapy and targeted therapy could be avoided. Methods: A retrospective chart review of lung cancer patients admitted January 2018 through December 2018 was conducted. Demographics, disease and treatment history, admission characteristics, outcomes, and end-of-life care utilization were recorded. Following a multidisciplinary consensus review, hospitalizations were determined “avoidable” or “unavoidable.” Generalized estimating equation logistic regression models analyzed risks and outcomes associated with avoidable admissions. Kaplan-Meier estimators examined the median overall survival (mOS) between patients with and without avoidable admissions. Results: We evaluated 319 admissions from 188 patients with a median age of 66 and 16%/84% SCLC/NSCLC. Cancer-related symptoms accounted for 66% of hospitalizations; pneumonia and other infections comprised 34%, and 32% were due to cancer-related pain, vomiting, or failure to thrive (FTT). Common causes of unavoidable hospitalizations were unexpected disease progression causing symptoms, COPD exacerbation, and infection. Of the 47 hospitalizations identified as avoidable (15%), the mOS was 1.6 months; the mOS of unavoidable hospitalizations was 9.7 months (HR 2.07; 95% CI 1.34-3.19; p &lt; 0.001). Significant reasons for avoidable admissions included cancer-related pain (p = 0.021), hypervolemia (p = 0.033), patient desire to initiate hospice services (p = 0.011), and errors in medication reconciliation or distribution (p &lt; 0.001). Errors in medication management caused 26% of the avoidable hospitalizations. Of admissions in patients on immunotherapy (n = 102) or targeted therapy (n = 44), 9% were due to adverse effects of treatment. Patients on immunotherapy and targeted therapy were not more likely to have avoidable hospitalizations compared to patients not on the treatments (p = 0.323 and 0.133, respectively). Patients with avoidable admissions were 3.02 times more likely to enroll in hospice within 30 days of hospitalization compared to unavoidable admissions (95% CI 1.54-5.92; p = 0.001). Conclusions: Patients on immunotherapy or targeted therapy were only rarely admitted due to side effects of treatment. Hospitalizations may be avoided with more aggressive outpatient symptom management, earlier hospice discussion with at-risk patients, and outpatient pharmacist review of medications following hospital discharge.

The Role of Cytoreductive Nephrectomy and Targeted Therapy on Outcomes of Patients With Metastatic Sarcomatoid Renal Cell Carcinoma: A Population-Based Analysis.

Sarcomatoid renal cell carcinoma (sRCC) is a rare but aggressive form of kidney cancer with a poor prognosis. Despite recent advances in therapies for kidney cancers, an effective management strategy for sRCC is uncertain. We evaluated the impact of targeted therapy and cytoreductive nephrectomy (CN) on survival outcomes of patients with metastatic sRCC. We identified patients diagnosed with sRCC between January 1, 1973, and December 31, 2014, within the Surveillance, Epidemiology and End Results (SEER) database. Patients with metastatic sRCC were stratified based on the era of diagnosis (before or after the introduction of targeted systemic therapy in 2006) and the status of CN. Cancer-specific survival (CSS) and overall survival (OS) were analyzed. Data of 993 patients with metastatic sRCC were available for analysis. The median age was 62 years. Most patients were male (69%), Caucasian (71%), and were diagnosed in the targeted therapy era (83%); 53% of patients underwent CN. CSS and OS of the whole cohort were 5.0 months and 4.0 months, respectively. While the introduction of targeted therapy did not improve outcomes, CN improved CSS and OS in both pre-targeted therapy and targeted therapy era. On multivariable analysis, CN was a predictor of an improved CSS (hazard ratio [HR] 0.54, p < 0.0001) and OS (HR 0.51, p < 0.0001). Among other factors, older age at diagnosis, higher T stages, and node positivity were associated with worse outcomes. Our results showed that the introduction of targeted therapy did not improve outcomes in patients with metastatic sRCC. CN improved survival in both pre-targeted and targeted therapy eras.