First-line Tyrosine Kinase Inhibitor Treatment Research Articles

Genomic profiling of non-small cell lung cancer with rare aberrations in EGFR codon L858 and the survival outcome under real-world first-line EGFR tyrosine kinase inhibitor treatment compared to classic EGFRL858R.

8596 Background: Rare genomic aberrations in EGFR codon L858 causing L858R (rare EGFRL858R) or non-L858R mutations have been reported, besides the predominant c.2573T>G genomic mutation leading to classic EGFRL858R. However, molecular features, survival benefit under EGFR tyrosine kinase inhibitors (TKIs), and resistance mechanisms of these rare mutations lack comprehensive investigation in non-small cell lung cancer (NSCLC). Methods: We retrospectively included 489 NSCLCs with treatment-naive tumor tissues/plasma biopsies harboring rare EGFRL858R (N=124), EGFRL858Q/M (N=17), or classic EGFRL858R mutations (N=348). Mutational landscapes, tumor mutation burden (TMB), and chromosome instability (CIN) scores, were investigated using tissue samples subject to a targeted next-generation sequencing panel covering 437 cancer-related genes. Advanced NSCLCs receiving EGFR TKIs as first-line therapy were sub-grouped to study survival benefit and resistance mechanisms. Results: NSCLCs with rare EGFRL858R had less-frequently mutated TP53 (59% vs. 72%, P=0.04) and lower CIN scores (0.29 vs. 0.23, P=0.02) than those with classic EGFRL858R, while age, sex, stage at diagnosis, histology subtype, and TMB were comparable. We also detected the cooccurrence of EGFRL858Q/M with EGFRL861Q ( P<0.01), particularly in patients carrying EGFRL858M (100%). Compared to 233 advanced NSCLCs harboring classic EGFRL858R, 58 patients with rare EGFRL858R exhibited superior first-line progression-free survival (PFS) [median: 13.0 vs. 10.0 months, hazard ratio (HR): 0. 57, 95% confidence interval (CI): 0.41–0.80], with a similar association observed in approximately 80% of included patients who received first-generation EGFR TKIs (median: 12.0 vs. 10.0 months, HR: 0.64, 95% CI: 0.45–0.92). After controlling for age, sex, histological subtype, EGFR TKI category, and anti-vascular therapy, rare EGFRL858R remained associated with improved PFS (adjusted HR: 0.55, 95% CI: 0.39–0.77). Patients with EGFRL858Q/M also had better PFS than those with classic EGFRL858R (adjusted HR: 0.26, 95% CI: 0.10–0.67). Of note, NSCLCs with combined EGFRL858M and EGFRL861Q appeared to have lower progression risks when receiving afatinib than using gefitinib/icotinib as first-line therapy. Furthermore, matched samples at baseline and progression revealed similar resistance mechanisms between NSCLCs with rare and classic EGFRL858R. Conclusions: NSCLCs carrying rare genomic aberrations in EGFR codon L858 were likely to get more survival benefits from first-line EGFR TKI treatment than those with classic EGFRL858R, giving scientific evidence supporting the clinical application of EGFR TKIs in these patients.

Comorbidities and outcomes of patients with chronic myeloid leukemia treated with tyrosine kinase inhibitors: a real-world, nationwide, retrospective study from Hungary.

Purpose: This study aimed to provide real-world evidence on the characteristics, treatment patterns, and outcomes of patients with chronic myeloid leukemia (CML) receiving tyrosine kinase inhibitor (TKI) treatment in Hungary between 2011 and 2019. Patients and methods: This nationwide, retrospective study included patients who were newly diagnosed with CML in Hungarian clinical practice between January 2011 and December 2019. The analysis was based on the reimbursed prescription claims for imatinib, bosutinib, dasatinib, nilotinib, or ponatinib with the ICD-10 code C9210 in a public pharmacy between January 2009 and December 2019 using data from the National Health Insurance Fund (NHIF) of Hungary. CML incidence and prevalence, TKI treatment patterns, comorbidities, and overall survival (OS) were examined. Results: Between 2011 and 2019, altogether 1,407 patients were diagnosed with CML, with an annual average of 156 patients. The number of patients newly initiating first-line TKI therapy for CML significantly increased between 2011 and 2019 (2011: n = 136 vs. 2019: n = 191; p = 0.0043). Nilotinib was typically prescribed for younger patients (≤64years), while older patients (≥65years) mostly received imatinib. The most common comorbidity of CML patients was hypertension, and the proportion of patients with other malignancies was relatively high in all treatment groups. 5-year OS was 77.1% during the whole study period. Patients initiating first-line TKI treatment for CML in 2015 had significantly better 4-year OS compared to those starting treatment in 2011 (82.4% vs. 73.5%, respectively, (HR 0.53 (95%CI 0.32-0.87) p = 0.0118). Conclusion: This study is the first to provide insights into the characteristics, treatment patterns, and outcomes of CML patients treated with TKIs in Hungarian clinical practice between 2011 and 2019. We found slightly lower OS rates compared to other European countries, however, there was a statistically significant improvement in 4-year OS during the study period. The management of CML was in line with international guidelines and recommendations.

Unusual presentation of extramedullary blast crisis in chronic myeloid leukemia: A case report

BACKGROUND Extramedullary blast crisis in chronic myeloid leukemia (CML) is an uncommon occurrence of leukemic blast infiltration in regions other than the bone marrow. Malignant infiltration of the serosal membranes should be considered in cases where CML presents with ascites or pleural effusion. CASE SUMMARY A 23-year-old female with CML presented with progressively worsening ascites and pleural effusion despite first-line tyrosine kinase inhibitor treatment. Her blood work indicated leukocytosis with myelocyte bulge and 2% blasts. Analysis of the patient’s bone marrow confirmed the chronic phase of CML. Abdominal ultrasound revealed hepatosplenomegaly with ascites. The fluid investigation of both ascites and pleural effusion revealed a predominance of neutrophils with exudate. However, no acid-fast bacilli or growth was observed after culturing. Although hydroxyurea reduced cell counts, there was no observed effect on ascites or pleural effusion. Repeat investigation of the ascitic and pleural fluid revealed a polymorphous myeloid cell population consisting of myelocytes, metamyelocytes, band forms, neutrophils and a few myeloblasts. Extramedullary blast crisis was suspected, and mutation analysis was performed. We switched the patient to dasatinib. The patient’s symptoms were relieved, and ascites and pleural effusion diminished. CONCLUSION Serosal membrane involvement in CML is extremely rare. In this case, the patient responded well to dasatinib treatment.

Evaluation of the effectiveness of a nationwide precision medicine program for patients with advanced non-small cell lung cancer in Germany: a historical cohort analysis

The national Network Genomic Medicine (nNGM) Lung Cancer provides comprehensive and high-quality multiplex molecular diagnostics and standardized personalized treatment recommendation for patients with advanced non-small cell lung cancer (aNSCLC) in Germany. The primary aim of this study was to investigate the effectiveness of the nNGM precision medicine program in terms of overall survival (OS) using real-world data (RWD). A historical nationwide cohort analysis of patients with aNSCLC and initial diagnosis between 04/2019 and 06/2020 was conducted to compare treatment and OS of patients with and without nNGM-participation. Patients participating within the nNGM (nNGM group) were selected based on a prospective nNGM database. The electronic health records (EHR) of the prospective nNGM database were case-specifically linked to claims data (AOK, German health insurance). The control group was selected from claims data of patients receiving usual care without nNGM-participation (non-nNGM group). The minimum follow-up period was six months. Overall, n=509 patients in the nNGM group and n=7213 patients in the non-nNGM group met the inclusion criteria. Patients participating in the nNGM had a significantly improved OS compared to the non-nNGM group (median OS: 10.5 months vs. 8.7 months, p=0.008, HR=0.84, 95% CI: 0.74-0.95). The 1-year survival rates were 46.8% (nNGM) and 41.3% (non-nNGM). The use of approved tyrosine kinase inhibitors (TKI) in the first-line setting was significantly higher in the nNGM group than in the non-nNGM group (nNGM: 8.4% (43/509) vs. non-nNGM: 5.1% (366/7213), p=0.001). Overall, patients receiving first-line TKI treatment had significantly higher 1-year OS rates than patients treated with PD-1/PD-L1 inhibitors and/or chemotherapy (67.2% vs. 40.2%, p<0.001). This is the first study to demonstrate a significant survival benefit and higher utilization of targeted therapies for aNSCLC patients participating within nNGM. Our data indicate that precision medicine programs can enhance collaborative personalized lung cancer care and promote the implementation of treatment innovations and the latest scientific knowledge into clinical routine care. The study was funded by the AOK Federal Association Germany.

Therapy in Patients with Chronic Myeloid Leukemia Outside of Clinical Trials: Results of the German CML-Registry (CML-VI)

Introduction: Tyrosine kinase inhibitors (TKI) have significantly improved treatment outcomes for patients with newly diagnosed chronic myelogenous leukemia (CML) in chronic phase (CP). With the introduction of 2nd and 3rd generation TKI, the options in the management of CML have increased. In clinical trials, 25%-50% of patients do not remain on initial treatment due to intolerance or inefficacy. Information outside of clinical trials is limited. Aim: The aim of this study is to analyze the use of different TKI in first-line treatment and the frequency of TKI switches in CML in real world. Methods: Patients with newly diagnosed CML between 1.1.2013 and 31.12.2019 were registered and followed annually up to 31.12.2021. Primary endpoint was the time to and reason for switching of any first-line treatment including treatment free remission (TFR)attempt. Further endpoints were progression-free survival (PFS), overall survival (OS), cytogenetic and molecular response. Analyses were performed using Kaplan-Meier estimates with SPSS. Results: 540 adult patients have been registered from 91 centers, 512 were evaluable. 281 patients (55%), were treated by resident oncologists, 231 patients (45%) in hospitals including 82 patients (16%) in university hospitals. 271 patients (53%) were male. At diagnosis, median age was 59 (range 16-100) years. The median follow-up was 67 (3-108) months. Information on first-line TKI treatment was available for 480 patients: 203 patients (42%) were treated with imatinib, 137 (29%) with nilotinib and 140 (29%) with dasatinib. TKI switch was reported in 155 cases (31%) after a median of 11 (0-68) months. Reasons for switching was failure in 49 patients (32%), intolerance in 88 patients (57%), and 18 patients (11%) switched TKI because of other reasons (study inclusion, desire to have children, patient request, unknown). 33 patients (7%) switched TKI more than once. 13 (8,4%) of the 155 patients with TKI-switch died during follow-up, whereas only 16 of 325 (4,9%) patients without TKI-switch. OS of patients with TKI-switch was 90%, of patients without TKI-switch 94% after 6 years. TKI stop for more than one month has been reported in 118 patients (24%) due to different reasons (attempt for TFR, intolerance, patient wish, pregnancy). 61 patients (12%) started a TFR attempt after a median of 46 (10-96) months of TKI treatment. Discontinuation criteria were not always met. Only 10 patients (6,5%) with TKI-switch started a TFR attempt compared to 51 patients (16%) who had only been treated with one TKI. 501 patients were in CP at diagnosis, 11 patients in accelerated phase (AP) and 2 patients in blast crisis (BC). Progression occurred in 9 patients (BC n=6, AP n=3) after a median time of 12 (9-22) months. Overall, AP and BC were diagnosed in 22 patients (2,3%). Of the total cohort, 29 patients died, OS was 93% after 6 years. An evaluable cytogenetic examination was carried out in 291 patients (57%) at diagnosis or in the course of disease. No statements can be made about achieving of complete cytogenetic remission as follow up results were only available in 15% and monitoring was carried out using RQ-PCR in most patients. A major molecular response (MMR, BCR::ABL1 <0.1%) was reached by 422 patients (85%), a deep molecular response (defined as BCR::ABL1 ≤0.01) by 365 patients (74%) within the follow-up period. Cumulative incidence calculation and study of patients who lost their MMR are ongoing. There is no information about the molecular status of 18 patients. Conclusion: Results of the CML VI-registry provided information on treatment but also on baseline characteristics and diagnostic parameters of CML patients in real world. The median age of the patients at diagnosis was higher than in other clinical trials. In routine care, data demonstrated high switching rates of first-line treatment and frequent TFR attempts without meeting the guideline criteria. OS rates were as high as in clinical trials and confirm normal life expectation of CML patients. MMR was reached in 85% and DMR in 74% in this population. Progression is rare. In conclusion, the CML-registry offers importing data confirming a good outcome of response and survival for CML patients outside of clinical trials. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Long-Term Response to Tyrosine Kinase Inhibitors for Metastatic Renal Cell Carcinoma.

Background: Tyrosine kinase inhibitors (TKIs) prolong progression-free survival (PFS) in patients with metastatic renal cell carcinoma (mRCC), some of which may achieve long-term responses. Herein, we report clinical and pathological characteristics of patients who achieved long-term responses during first-line TKI treatment. Methods: Patients receiving TKI as first-line therapy from January 2010 to December 2017 in seven Italian Oncology Centers were reviewed. Sixty-six patients were considered as long-term responders, as they remained progression-free for 36 months or more during TKI treatment. A logistic regression model was performed to evaluate the effect of each clinical-pathological variable on the probability of responding long-term. Results: A total of 335 patients with a median age of 66 years were included in the analysis. The median PFS and overall survival among the long-term responders was 70 and 106 months, respectively. At a landmark PFS analysis performed 36 months after the start of treatment, the median PFS was 34 months. Multivariate analysis from all patients identified previous nephrectomy, Eastern Cooperative Oncology Group Performance Status (ECOG PS) < 1, and lack of liver metastasis as favorable prognostic factors for long-term response. Female gender and lack of liver metastasis positively correlated with long-term responses in favorable-risk-score population, as well as ECOG PS < 1 in intermediate-poor risk score population. Patients Summary: Previous surgery, clinical condition, and lack of liver metastasis may predict long-term responses to tyrosine kinase inhibitors. Conclusions: TKIs can lead to a long-term response in a subset of patients with metastatic RCC. Previous nephrectomy, optimal performance status (ECOG PS = 0), and lack of liver metastasis may predict long-term responses.

Prognostic Values of Inflammatory Indexes and Clinical Factors in Patients with Epidermal Growth Factor Receptor Mutations in Lung Adenocarcinoma and Treated with Tyrosine Kinase Inhibitors.

This study aimed to access the predictive value of inflammatory indices and clinical factors in toxicity and survival in patients with epidermal growth factor receptor (EGFR)-mutated lung adenocarcinoma receiving first-line tyrosine kinase inhibitor (TKI)-treatment. A total of 259 patients with stage IIIB–IV lung adenocarcinoma and actionable EGFR mutation who received first-line TKI treatment between 2008 and 2020 were retrospectively enrolled and analyzed. The prognostic factors of TKI-related toxicity, overall survival (OS), and progression-free survival (PFS) were identified by using logistic regression analysis and Cox proportional hazards models. Pre-TKI high platelet-to-lymphocyte ratio (PLR) was associated with post-TKI anemia. Hypoalbuminemia was associated with acneiform rash. Elderly age (≥70 years) and lower body mass index (<18.5 kg/m2) were also associated with hypoalbuminemia. Elderly age, stage IV, EGFR-mutated with L858R and uncommon mutations, and neutrophil-to-lymphocyte ratio were found to be independent prognostic factors for PFS, while elderly age, uncommon EGFR-related mutations, and lymphocyte-to-monocyte ratio were found to be independent prognostic factors for OS. A useful prognostic scoring tool for improving the survival risk stratification of patients was established by incorporating the above essential factors. Baseline hypoalbuminemia and PLR could be crucial clinical assessment factors when initiating TKI therapy. In addition, the optimization of individualized treatment strategies for these patients may be assisted by using the risk-scoring model.

Treatment Characteristics and Deep Molecular Response in Chronic Phase - Chronic Myeloid Leukemia Patients Treated with Second-Line Nilotinib or Dasatinib: A Multi-Country Retrospective Chart Review Study

BackgroundAchievement of deep molecular response (i.e., MR4.5, BCR-ABL1 ≤0.0032% on international scale, or 4.5-log reduction) is an important goal of tyrosine kinase inhibitor (TKI) treatment for patients (pts) with chronic myeloid leukemia (CML). Pts achieving a sustained MR4.5 are potential candidates for treatment-free remission. However, data on MR4.5 after TKI therapy outside of clinical trial setting are limited, especially in second-line TKI treatment setting.ObjectiveThis study aims to describe pt and treatment characteristics by regions and investigate frequency and time to achieving MR4.5 in pts with chronic phase (CP)-CML treated with second-line nilotinib or dasatinib in 10 countries, categorized into two regions, Europe [France, Germany, Italy, Netherlands]/Australia and Latin America - LATAM [Argentina, Brazil, Chile, Colombia, and Mexico]).MethodsOnline physician panel approach was used to recruit oncologists (N=172) globally to conduct physician-based chart reviews. To increase the representativeness of physician sample, each physician was allowed to review up to four patients, and was instructed to select these pts via randomization scheme. Eligible pts were diagnosed with CP-CML at age ≥18 years, initiated second-line nilotinib or dasatinib between 1/1/11 and 7/1/15, and had ≥12 months of follow-up since initiating the first-line or second-line TKI. A multivariate Fine and Gray's extension of Cox proportional hazards model was used to assess time to first recorded MR4.5 for nilotinib vs dasatinib as second-line therapy. The model accounted for competing-risk event of TKI resistance and random effect of country clustering of data, and was adjusted for age, gender, Sokal risk score at CML diagnosis, prior hydroxyurea use, first-line TKI agent (1st vs 2nd generation TKI), first-line TKI treatment duration, and reasons for first-line TKI discontinuation. Adjusted hazard ratios (HR) and 95% confidence intervals (CI) were reported.ResultsThe study included 285 pts treated with nilotinib (N=138[48%]) or dasatinib (N=147[52%]) as second-line TKI, including 111 nilotinib and 117 dasatinib pts from Europe/Australia (80%), and 27 nilotinib and 30 dasatinib pts from LATAM (20%). Median follow-up time was 19.5 and 18.9 months for nilotinib and dasatinib in both regions, respectively. In Europe/Australia, 85% of pts had received imatinib as first-line TKI, and in LATAM, 96% (Table 1). In Europe/Australia, 85% of pts discontinued first-line TKI due to ineffectiveness (per treating physician) and 16% due to toxicity; corresponding percentages were 79% and 23% in LATAM. Median (range) age at second-line TKI initiation was 58 (18-88) years in Europe/Australia vs 49 (22-77) in LATAM. In Europe/Australia, more second-line nilotinib (21%) than dasatinib (10%) pts had high-risk Sokal score at CML diagnosis. Compared to Europe/Australia, more pts in LATAM had a high-risk Sokal score in both the nilotinib (30%) and dasatinib (27%) cohorts.The raw proportion of pts achieving first recorded MR4.5 by 24 months of second-line TKI therapy was 34% for nilotinib and 31% for dasatinib. After controlling for country clustering effects and baseline covariates, adjusted multivariate Cox model showed that nilotinib was associated with a significantly higher rate of achieving MR4.5 (HR=1.37, 95% CI [1.12, 1.67], p<0.01) than dasatinib. Additionally, high-risk Sokal score was significantly inversely associated with achieving MR4.5 (HR=0.34, 95% CI [0.14, 0.81], p=0.01) while discontinuing first-line TKI due to resistance (HR=0.57, 95% CI [0.30, 1.08], p=0.08) reached borderline statistical significance at the two-sided α-level of <0.10 (Figure 1). MR4.5 outcome will be reported by regions in the presentation.ConclusionThis retrospective chart review study shows some variations in pt and treatment characteristics across regions. A significant percentage of second-line TKI pts can reach MR4.5 after failure to first-line TKI. In addition, this study suggests that second-line nilotinib may be associated with a higher rate of MR4.5 than dasatinib in this setting. Given its retrospective and observational nature, our results should be taken with caution as this study is susceptible to unmeasured confounding and biases. Rigorous clinical assessment in a prospective setting is needed to conclusively compare rates of achieving MR4.5 in ptstreated with nilotinib versus dasatinib. [Display omitted] DisclosuresCortes:ARIAD: Consultancy, Research Funding; Teva: Research Funding; Novartis Pharmaceuticals Corporation: Consultancy, Research Funding; Sun Pharma: Research Funding; BMS: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Huynh:Novartis Pharmaceuticals Corporation: Research Funding. Mendelson:Novartis Pharmaceuticals Corporation: Employment. Brandt:Novartis Pharmaceuticals Corporation: Employment. Dalal:Novartis Pharmaceuticals Corporation: Employment. Dersarkissian:Novartis Pharmaceuticals Corporation: Research Funding; Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Research Funding. Cortina:Novartis Pharmaceuticals Corporation: Employment. Narkhede:Novartis Pharmaceuticals Corporation: Research Funding. Duh:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Research Funding; Novartis Pharmaceuticals Corporation: Research Funding.

Routine Molecular Screening of Patients with Advanced Non-SmallCell Lung Cancer in Circulating Cell-Free DNA at Diagnosis and During Progression Using OncoBEAMTM EGFR V2 and NGS Technologies

Background and ObjectivesThe use of ultra-sensitive diagnostic tests to detect clinically actionable somatic alterations within the gene encoding the epidermal growth factor receptor (EGFR) within circulating cell-free DNA is an important first step in determining the eligibility of patients with non-small cell lung cancer to receive tyrosine kinase inhibitors.MethodsWe present the clinical validation (accuracy, sensitivity, and specificity) of a highly sensitive OncoBEAMTM EGFR V2 test, which we compare to a custom next-generation sequencing assay, for the treatment of patients with non-small cell lung cancer with EGFR tyrosine kinase inhibitor therapies. The OncoBEAMTM digital-polymerase chain reaction method detects 36 different EGFR alterations in circulating cell-free DNA, whereas the next-generation sequencing assay covers major solid tumor oncodrivers. Of the 540 samples analyzed with the OncoBEAMTM EGFR V2 test, 42.4% of patients had undergone molecular testing at diagnosis (N = 229/540) and 57.7% of patients during disease progression (N = 311/540).ResultsThe sensitivity and specificity were measured for this BEAMing assay. The number of mutant beads and mutant allelic fraction were measured for each EGFR alteration and the level of detection was established at 0.1% for a median of 2861 genome equivalent (GE) in each reaction using HD780 horizon control DNA, as well as by an internal quality reference standard. Approximately 10%, 27%, and 63% of the 540 samples contained < 1500 GE, a range of 1500–3000 GE, and > 3000 GE, which corresponded to a maximal assay sensitivity of 2.0%, 0.5–0.1%, and 0.1–0.05% mutant allelic fraction, respectively. In a routine hospital setting, 11.4% of non-small cell lung cancer tumors were positive at diagnosis for EGFR alterations, while 43.7% samples harbored EGFR mutations at progression, among which 40.3% expressed EGFR resistance mutations after first-line tyrosine kinase inhibitor treatment with first- and second-generation drugs.ConclusionsThe OncoBEAMTM EGFR V2 is a sensitive, robust, and accurate assay that delivers reproducible results. Next-generation sequencing and BEAMing technologies act complementarily in the routine molecular screening. We show that using a next-generation sequencing assay, despite its lower sensitivity, enables the identification of rare EGFR alterations or resistance mechanisms (mutation, deletion, insertion, and copy number variation) to orient first- and second-line treatments.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40291-021-00515-9.

Clinical Value of EGFR Copy Number Gain Determined by Amplicon-Based Targeted Next Generation Sequencing in Patients with EGFR-Mutated NSCLC.

BackgroundThe clinical relevance of epidermal growth factor receptor (EGFR) copy number gain in patients with EGFR mutated advanced non-small cell lung cancer on first-line tyrosine kinase inhibitor treatment has not been fully elucidated.ObjectiveWe aimed to estimate EGFR copy number gain using amplicon-based next generation sequencing data and explored its prognostic value.Patients and MethodsNext generation sequencing data were obtained for 1566 patients with non-small cell lung cancer. EGFR copy number gain was defined based on an increase in EGFR read counts relative to internal reference amplicons and normal controls in combination with a modified z-score ≥ 3.5. Clinical follow-up data were available for 60 patients treated with first-line EGFR-tyrosine kinase inhibitors.ResultsSpecificity and sensitivity of next generation sequencing-based EGFR copy number estimations were above 90%. EGFR copy number gain was observed in 27.9% of EGFR mutant cases and in 7.4% of EGFR wild-type cases. EGFR gain was not associated with progression-free survival but showed a significant effect on overall survival with an adjusted hazard ratio of 3.14 (95% confidence interval 1.46–6.78, p = 0.003). Besides EGFR copy number gain, osimertinib in second or subsequent lines of treatment and the presence of T790M at relapse revealed significant effects in a multivariate analysis with adjusted hazard ratio of 0.43 (95% confidence interval 0.20–0.91, p = 0.028) and 0.24 (95% confidence interval 0.1–0.59, p = 0.001), respectively.ConclusionsPre-treatment EGFR copy number gain determined by amplicon-based next generation sequencing data predicts worse overall survival in EGFR-mutated patients treated with first-line EGFR-tyrosine kinase inhibitors. T790M at relapse and subsequent treatment with osimertinib predict longer overall survival.Supplementary InformationThe online version contains supplementary material available at 10.1007/s11523-021-00798-2.

Abstract PS7-87: Incidence, treatment and survival of patients with brain metastases at initial metastatic breast cancer diagnosis: A real-world experience in national cancer center, China

Abstract Background: To characterize the incidence, treatment and survival of patients with brain metastases at initial diagnosis of metastatic breast cancer (MBC) in China. Methods: The China National Cancer Center database was used to identify 2087 MBC patients diagnosed between 2003 to 2015. Clinicopathological features, treatment and survival information were extracted. Multivariable logistic and Cox regression were performed to determine factors predictive of brain metastases at MBC diagnosis and survival, respectively. Results: Brain metastases occurred in ninety patients (4.3%) at MBC diagnosis, and in 27 patients (2.5%), 42 patients (7.2%) and 21 patients (5.2%) with hormone receptor positive, human epidermal growth factor receptor 2 negative (HR+HER2-), HER2-positive and triple negative breast cancer (TNBC), respectively. HER2-positive subtype (OR = 2.38; 95% CI 1.40 -4.04; p &amp;lt;0.0001), TNBC subtype (OR = 1.89; 95% CI 1.02-3.51; p =0.005), and metastases to all three sites of bone, liver and lungs (OR = 3.23; 95% CI 1.52-6.87; p =0.002) were shown to increase the risk of BM at MBC diagnosis. Median survival after BM was 23.7 months. First-line tyrosine kinase inhibitors (TKI) improved survival compared to trastuzumab-based regimen (44.9 vs 35.4 months, p=0.09). Factors that independently decreased BM death risk were ECOG&amp;lt;2, brain metastases only and multidisciplinary treatment. Conclusion: HER2-positive and TNBC subtypes have a higher incidence of BM at initial MBC diagnosis. Brain screening might be considered in patients with HER2-positive or triple-negative diseases or with extensive extracranial metastases. First-line TKI and multidisciplinary treatment helped to extend survival. Citation Format: Yiqun Li, Qiao Li, Hongnan Mo, Xiuwen Guan, Shaoyan Lin, Zijing Wang, Yimeng Chen, Ye Zhang, Dainan Zhang, Shanshan Chen, Ruigang Cai, Jiayu Wang, Yang Luo, Ying Fan, Peng Yuan, Pin Zhang, Qing Li, Fei Ma, Binghe Xu. Incidence, treatment and survival of patients with brain metastases at initial metastatic breast cancer diagnosis: A real-world experience in national cancer center, China [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS7-87.

Real world data of efficacy and safety of erlotinib as first-line TKI treatment in EGFR mutation-positive advanced non-small cell lung cancer: Results from the EGFR-2013-CPHG study

BackgroundPhase III clinical trials have demonstrated the merits of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKI) in the treatment of non-small cell lung cancer (NSCLC) patients with EGFR-activating mutations. Using a cohort of unselected patients treated with erlotinib, we sought to further describe patient and tumour characteristics, and to evaluate their progression-free survival (PFS) and overall survival (OS). MethodsOverall, 44 pulmonologists included patients with the required characteristics as follows: Stage IIIB-IV NSCLC, EGFR-activating mutation, age≥18 years, and having to start erlotinib therapy or receiving erlotinib therapy as the first-line TKI, regardless of treatment-line. The analyses were performed using R software, with survival rates calculated according to the Kaplan–Meier method. ResultsA total of 177 patients, aged 72 years on average, were enrolled over a 2-year period. The cohort included 123 women (69.5%), 158 Caucasians (89.3%), 112 non-smokers (63.2%), and 167 adenocarcinomas (94.3%), at either stage IIIB (21) or IV (156), with a good performance status (PS 0–1, 127). Overall, 40 exhibited brain metastases at baseline (22.6%), while 75 had undergone earlier treatment (42.4%). Median PFS was 11.7 months and OS 25.8 months, with respectively a 1-year rate of 48.6% and 74%. The risk of death correlated with ECOG status (PS=2, HR=4.48, P<0.001) but not with brain metastasis (HR=1.67, P=0.278). ConclusionsThis study has confirmed erlotinib's efficacy and safety for unselected patients, with PFS and OS comparable to those obtained in phase III trials.

Trends in Hepatic Functional Reserve of Patients with Hepatocellular Carcinoma Treated with Tyrosine Kinase Inhibitors

Objective: Functional hepatic reserve is important when considering sequential tyrosine kinase inhibitor (TKI) therapy for patients with advanced hepatocellular carcinoma (HCC). We assessed albumin-bilirubin (ALBI) score and Child-Pugh class as indices of liver function during sorafenib and lenvatinib treatment. Methods: A total of 212 patients with advanced HCC and Child-Pugh class A status who initiated TKI treatment at our hospital were enrolled in this retrospective cohort study. A total of 74 of the 212 patients underwent blood testing before starting sorafenib treatment and every 2 months after treatment initiation. Results: In 74 patients, the median ALBI score before TKI treatment was –2.53, and after 2, 4, and 6 months it was –2.45, –2.44, and –2.36, respectively. ALBI scores tended to increase during TKI therapy. Among patients who experienced a time to progression ≤3.8 months, ALBI scores had increased 2 months after treatment initiation, and at 4 and 6 months, significant differences were observed (p < 0.01). In all 212 patients, during first-line TKI treatment, the Child-Pugh class deteriorated to B or C in 72.2% of the patients, and the median time to deterioration was 3.9 months. The factors in hepatic reserve deterioration were serum albumin ≤3.8 g/dL and the presence of macroscopic vascular invasion. The hepatic reserve of 68.0% of the patients with deterioration of liver function recovered to Child-Pugh class A following dose reduction, drug withdrawal, or treatment intended for recovery of liver function. Conclusion: ALBI scores deteriorate in patients treated with TKIs, suggesting that tumor progression induces these changes.

Nationwide Real-world Cohort Study of First-line Tyrosine Kinase Inhibitor Treatment in Epidermal Growth Factor Receptor-mutated Non–small-cell Lung Cancer

BackgroundOnly a few randomized trials directly compared the relative efficacy of tyrosine kinase inhibitors (TKIs) in patients with advanced epidermal growth factor receptor (EGFR)-mutated non–small-cell lung cancer (NSCLC), and most trials comprised selected series from Asian populations. Therefore, the aim of this study was to assess the overall survival (OS) of advanced EGFR-mutated NSCLC in a large white population and to evaluate variation between different TKIs and identify predictors of survival. Patients and MethodsInformation about clinical characteristics, treatment, and survival for 873 patients with stage IV EGFR + NSCLC, diagnosed from 2015 through 2017, was derived from the Netherlands Cancer Registry. OS was evaluated by actuarial analysis and multivariable Cox regression. Prognostic factors are reported as hazard ratios and 95% confidence intervals. ResultsA total of 596 (68%) patients received first-line treatment with regular TKIs, providing a median survival of 20.2 months. Forty-five percent of patients were 70 years and older, and 54% of patients had distant metastasis in multiple organs. In the multivariate analysis, survival was significantly worse for men, and patients with higher age, poorer performance, and ≥ 3 organs with metastasis. Compared with erlotinib, OS was worse for gefitinib users (adjusted hazard ratio, 1.30; 95% confidence interval, 1.02-1.64), predominantly in patients with brain metastasis. ConclusionDutch patients with EGFR-mutated NSCLC who received first-line treatment with regular TKIs have a median OS of 20.2 months in a nationwide real-world cohort. In patients with brain metastasis, erlotinib showed superior results compared with gefitinib and was similar to afatinib.

Analysis of Progression Patterns and Failure Sites of Patients With Metastatic Lung Adenocarcinoma With EGFR Mutations Receiving First-line Treatment of Tyrosine Kinase Inhibitors

BackgroundReliable prediction of progression patterns and failure sites for patients with stage IV lung adenocarcinoma is valuable for physicians to deliver personalized tyrosine kinase inhibitor (TKI) treatment. Patients and MethodsWe retrospectively enrolled 266 patients who had stage IV lung adenocarcinoma and received first-line TKI treatment from 2013 to 2017 in Shanghai Chest Hospital. The clinical characteristics at initial diagnosis, progression patterns, and failure sites were analyzed with the attempt to identify some predictive factors for progression patterns and failure sites. ResultsAmong all patients, 62.4% developed systemic progression, and 37.6% developed oligoprogression. Both cohorts had a median progression-free survival (PFS) of 9 months. The percentage of patients who developed original and distant failure was 39.1% and 60.9%, respectively. Patients with oligometastasis at initial diagnosis were more prone to develop oligoprogression (odds ratio [OR], 4.370; 95% confidence interval [CI], 1.881-10.151; P = .001), whereas pulmonary metastasis was negatively correlated with oligoprogression (OR, 0.567; 95% CI, 0.330-0.974; P = .04). Both oligometastasis diagnosis (OR, 2.959; 95% CI, 1.347-6.500; P = .007) and the maximum diameter of the primary lung lesion (threshold 3.25 cm: OR, 3.646; 95% CI, 2.041-6.515; P = .0001) were strong predictive factors for original failures. Osseous metastasis at initial diagnosis might be an indication for distant failure (OR, 0.536; 95% CI, 0.316-0.909; P = .021). ConclusionOver one-half of patients with stage IV lung adenocarcinoma receiving first-line TKI treatment developed systemic progression and distant failure. Metastasis patterns at initial diagnosis was the most important predictive factor for progression patterns and failure sites. The maximum diameter of the primary lung lesion and evidence of osseous metastasis were also found to be significant indicative factors for failure sites.

Treatment outcomes of chronic-phase chronic myeloid leukemia with resistance and/or intolerance to a 1st-line tyrosine kinase inhibitor in Japan: the results of the New TARGET study 2nd-line.

We herein report the results of the New TARGET study 2nd-line, which collected data on patients with chronic-phase (CP) chronic myeloid leukemia (CML) who received a 2nd-line tyrosine kinase inhibitor (TKI) because of resistance and/or to a 1st-line TKI. A total of 98 patients were enrolled intolerance between April 2010 and March 2013, and 82 patients were analyzed. The median age was 54years (range 22-88years). Seventy-six patients (93%) received imatinib as the 1st-line TKI. Forty-five (55%) and 37 (45%) patients began nilotinib and dasatinib treatments at entry, respectively. First-line TKI treatment achieved complete hematological response in 79 patients (96%) and complete cytogenetic response (CCyR) in 49 patients (60%), respectively. Nine patients (11%) had BCR-ABL1 kinase domain point mutations at enrollment. The estimated 3-year progression-free-survival rate after enrollment was 98.7% (95% CI 91.1-99.8%). Overall, the probabilities of achieving CCyR and a major molecular response were 89.3% (95% CI 81.4-94.8%) and 87.2% (95% CI 78.1-93.8%), respectively. There were no new safety issues. This study demonstrated that CML-CP patients in Japan who are resistant and/or intolerant to a 1st-line TKI can achieve an extremely good outcome by 2nd-line TKI treatment.

Prognostic factors of EGFR-mutated metastatic adenocarcinoma of lung

PurposeThe first-line treatment of metastatic lung adenocarcinoma with epidermal growth factor receptor (EGFR) mutation is tyrosine kinase inhibitor (TKI). This study aimed to evaluate potential factors affecting the progression-free survival under TKI treatment. MethodsForty one patients with EGFR-mutated metastatic lung adenocarcinoma under first-line TKI treatment were retrospectively evaluated. Ten factors potentially influencing the progression-free survival were studied: patients’ age, gender, smoking history, number of comorbidities, performance status, tumor mutation site, maximum of standardized uptake value (SUVmax) of primary tumor in FDG PET/CT, serum CEA level, number of metastatic organs and presence of pleural/pericardial effusion. Mantel-Cox tests and waterfall plots were performed for statistical analyses. ResultsStatistical evaluation demonstrated that primary SUVmax, serum CEA level, gender and smoking history were important prognostic factors, with corresponding p values of 0.001, 0.023, 0.034 and 0.041 respectively in Mantel-Cox analyses. ConclusionLow primary SUVmax, low serum CEA level, female and never smoker were four prognostic factors suggestive of good response to TKI in mutated EGFR metastatic lung adenocarcinoma. SUVmax is probably the most important among the four factors.

Augmenting the randomized controlled trial with real-world data to aid clinical decision making in metastatic renal cell carcinoma: a systematic review and meta-analysis.

Aim: To evaluate how efficacy outcomes from real-world data (RWD) can support those from randomized controlled trials (RCTs), in the context of first-line tyrosine kinase inhibitor treatment of metastatic renal cell carcinoma. Patients & methods: PubMed, Ovid, MEDLINE and EMBASE were searched for RCTs and RWD studies with ≥50 adult patients per arm published in 2000-2017. Outcome measures were median progression-free survival, median overall survival and objective response rate. Results: A total of 13 RCTs and 22 RWD studies met eligibility criteria; 31, 28 and 25 studies, respectively, reported median progression-free survival, median overall survival and objective response rate. Summary outcome measures were similar in RWD and RCTs. Conclusion: RWD validates efficacy-based outcomes from RCTs and may provide supportive evidence to inform clinical decisions.

1530P - Different stories for different EGFR exon 19 deletion variants

BackgroundEpidermal growth factor receptor (EGFR) exon 19 deletion (19del) and L858R mutation respond differently to first generation tyrosine kinase inhibitors (TKIs), however, the clinical outcomes of different 19del variants to TKIs and the resistance patterns are not well studied. MethodsFrom April 2016 to August 2017, 194 treatment-naive NSCLC patients detected as EGFR exon 19 deletions using amplification-refractory mutation system were included. DNA sequencing was used to detect the subtypes. Clinicopathological features as well as patients’ outcomes to first-line EGFR TKIs were analyzed. ResultsTwelve EGFR 19del variants were confirmed in 169 of the 194 samples. Among these, p.E746_A750del was the most frequent variant (147/169, 87.0%). p.E746_A750del was more frequently found in females (p=0.008) and never smokers (p=0.004) than other deletions. And deletions starting with E746 was also more frequently found in these patients than L747 (p=0.014 and p=0.018, respectively). Interestingly, T790M occurred more frequently in p.E746_A750del than other deletions (64.3% vs 18.2%, p=0.017) or deletions started with E746 than L747 (63.6% vs 11.1%, p=0.012). Patients harboringdeletions starting with L747 plus insertions had significantly shorter progression-free survival (PFS) than no insertions (8.3m vs 15.0m, p=0.008), as well as other subtypes (8.3m vs 12.8m, p=0.016). Multivariate analysis showed that only L747 deletion plus insertions and age were independent factors influencing PFS (p=0.015 and 0.046, respectively). Conclusionsp.E746_A750del was the most frequent variant of EGFR exon 19del in NSCLC patients. It was more frequently found in female and never smoking patients. T790M mutation had a higher ratio in these patients when they were resistant to first-line TKI treatment. Deletions starting with L747 plus insertions had shorter PFS than other variants. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

Prognostic value of EGFR 19-del and 21-L858R mutations in patients with non-small cell lung cancer.

Previous studies have demonstrated a significant difference in clinical characteristics between patients with non-small cell lung cancer (NSCLC) harboring exon 19 deletion (19-del) and an exon point mutation (21-L858R) in EGFR. The present retrospective study aimed to investigate the differential prognosis in patients with NSCLC harboring exon 19-del and 21-L858R mutations. The clinical and follow-up data of 137 patients treated at the Zhongnan Hospital of Wuhan University (Wuhan, Hubei, China) between August 2012 and August 2016, who were diagnosed with stage IIIB-IV NSCLC harboring either exon 19-del or 21-L858R mutations, were analyzed. The patients were divided into the first-line tyrosine kinase inhibitor (TKI), first-line chemotherapy and second-line TKI treatment groups. The median progression-free survival (PFS) time of patients harboring the exon 19-del mutation was significantly improved compared with that in patients harboring the 21-L858R mutation (11.3 vs. 8.8 months, respectively; P=0.017) following first-line TKI treatments. However, no significant difference in the median PFS time was observed between the exon 19-del and 21-L858R groups following the first-line chemotherapy or second-line TKI treatment. In patients with the exon 19-del, first-line TKI treatment achieved an increased objective response rate (ORR; 51.9 vs. 18.5%; P=0.004) and disease control rate (96.2 vs. 77.8%; P=0.030), and a longer PFS time (11.3 vs. 8.0 months; P=0.034) compared with that in the patients following first-line chemotherapy. First- and second-line TKI treatment achieved a similar PFS time (11.3 vs. 11.0 months, respectively; P=0.140). However, in patients with the 21-L858R mutation, the first-line TKI therapy and first-line chemotherapy groups exhibited a similar PFS time (8.8 vs. 3.5 months, respectively; P=0.063), while the second-line TKI treatment group exhibited a significantly longer PFS time compared with the first-line TKI treatment group (13.6 vs. 8.8 months, respectively; P=0.030). There was a differential sensitivity to treatment between patients harboring the exon 19-del and 21-L858R mutations. Therefore, chemotherapy may increase the sensitivity to TKIs in patients harboring the 21-L858R mutation.