Upfront Tyrosine Kinase Inhibitors Research Articles

Mutations in myeloid transcription factors and activated signaling genes predict chronic myeloid leukemia outcomes

AbstractAdvancements in genomics are transforming the clinical management of chronic myeloid leukemia (CML) toward precision medicine. The impact of somatic mutations on treatment outcomes is still under debate. We studied the association of somatic mutations in epigenetic modifier genes and activated signaling/myeloid transcription factors (AS/MTFs) with disease progression and treatment failure in patients with CML after tyrosine kinase inhibitor (TKI) therapy. A total of 394 CML samples were sequenced, including 254 samples collected at initial diagnosis and 140 samples taken during follow-up. Single-molecule molecular inversion probe (smMIP)–based next-generation sequencing (NGS) was conducted targeting recurrently mutated loci in 40 genes, with a limit of detection of 0.2%. Seventy mutations were detected in 57 diagnostic samples (22.4%), whereas 64 mutations were detected in 39 of the follow-up samples (27.9%). Carrying any mutation at initial diagnosis was associated with worse outcomes after TKI therapy, particularly in AS/MTF genes. Patients having these mutations at initial diagnosis and treated with imatinib showed higher risks of treatment failure (hazard ratio, 2.53; 95% confidence interval, 1.13-5.66; P = .0239). The adverse prognostic impact of the mutations was not clear for patients treated with second-generation TKIs. The multivariate analysis affirmed that mutations in AS/MTF genes independently serve as adverse prognostic factors for molecular response, failure-free survival, and progression risk. Additionally, there was an observable nonsignificant trend indicating a heightened risk of progression to advanced disease and worse overall survival. In conclusion, mutations in the AS/MTF genes using smMIP-based NGS can help identify patients with a potential risk of both treatment failure and progression and may help upfront TKI selection.

Effect of Different Timing of Local Brain Radiotherapy on Survival of EGFR-Mutated NSCLC Patients with Limited Brain Metastases.

(1) Background: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have been the first line therapy for EGFR-mutant lung adenocarcinoma (LAC) patients with brain metastases (BMs). However, the role and the optimal time of brain radiotherapy remains controversial. We aimed to investigate the role of upfront brain stereotactic radiotherapy (SRS) and the impact of deferral radiotherapy on patients' clinical outcomes. (2) Methods: We retrospectively studied 53 EGFR-mutant LAC patients with limited synchronous BMs between 2014 and 2020 at our institute. The limited BMs was defined with one to four BM lesions, with a maximal size of ≤4 cm. Patients were categorized into two groups: upfront brain SRS (upfront RT) and upfront TKIs. The intracranial progression-free survival (iPFS), progression-free survival (PFS), and overall survival (OS) between groups were analyzed. (3) Results: The median iPFS (21.0 vs. 12.0 months, p = 0.002) and PFS (20.0 vs. 11.0 months, p = 0.004) of the upfront RT group was longer than that of the upfront TKI group. There were no significant differences in median OS (30.0 vs. 26.0 months, p = 0.552) between the two groups. The upfront RT group is less likely to suffer from intracranial progression of the original sites than that of upfront TKIs during the disease course (36.1% vs. 0.0%, p = 0.025). Multivariate analysis showed that the Karnofsky Performance Scale and the presence of synchronous meningeal metastases were associated with overall survival. (4) Conclusions: Compared with upfront TKI, the combination of upfront SRS with TKIs can improve the iPFS and PFS in EGFR-mutant LAC with synchronous BMs. The addition of upfront brain SRS was useful for the original intracranial metastatic lesions.

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

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

CNS Downstaging: An Emerging Treatment Paradigm for Extensive Brain Metastases in Oncogene-Addicted Lung Cancer

IntroductionFor extensive brain metastases (BrM) presentations arising from oncogene-addicted lung cancer, tyrosine kinase inhibitors (TKIs) with high response rates in the central nervous system (CNS) could potentially downstage the CNS disease burden, allowing for the avoidance of upfront whole-brain radiotherapy (WBRT) and the conversion of some patients into candidates for focal stereotactic radiosurgery (SRS). MethodsWe describe the outcomes of patients with ALK, EGFR, and ROS1-driven NSCLC with extensive BrM presentations (defined as > 10 BrMs or leptomeningeal disease) treated with upfront newer generation CNS-active TKIs alone, including osimertinib, alectinib, brigatinib, lorlatinib, and entrectinib, from 2012 to 2021 at our institution. All BrMs were contoured at study entry, best CNS response (nadir), and first CNS progression. ResultsTwelve patients met criteria including 6 with ALK, 3 with EGFR, and 3 with ROS1-driven NSCLC. The median number and volume of BrMs at presentation were 49 and 19.6 cm3, respectively. Eleven patients (91.7 %) achieved a CNS response by modified-RECIST criteria to upfront TKI (10 partial responses, 1 complete response, 1 stable disease) with nadir observed at a median of 5.1 months. At nadir, the median number and volume of BrMs were 5 (median 91.7 % reduction per-patient) and 0.3 cm3(median 96.5 % reduction per-patient), respectively. Eleven patients (91.6 %) developed subsequent CNS progression (7 local failures, 3 local + distant, 1 distant) at a median of 17.9 months. At CNS progression, the median number and volume of BrMs were 7 and 0.7 cm3, respectively. Seven patients (58.3 %) received salvage SRS and no patients received salvage WBRT. The median overall survival from initiation of TKI for the extensive BrM presentation was 43.2 months. ConclusionIn this initial case series, we describe CNS downstaging as a promising multidisciplinary treatment paradigm involving the upfront administration CNS-active systemic therapy and close MRI surveillance for extensive BrMs as a strategy to avoid upfront WBRT and to convert some patients into SRS candidates.

Somatic Mutations in Myeloid Transcription Factors and in Activated Signaling Pathway, but Not in Epigenetic Modifier Pathway, Predict the Risk of Treatment Failure and Progression to Advanced Phase in Chronic Myeloid Leukemia

Background Next-generation sequencing (NGS) is currently reforming contemporary clinical practice into precision medicine incorporating genomics-based knowledge into the clinic. Recently, multiple studies showed that mutations in epigenetic modifier genes are associated with poor treatment outcomes following tyrosine kinase inhibitor (TKI) therapy in chronic myeloid leukemia (CML), particularly after Imatinib treatment. However, it is uncertain whether they either originated from clonal hematopoiesis or the CML clone. For example, ASXL1 mutation is the most recurrent mutation at CML diagnosis, and its presence is correlated with adverse prognosis in CML. Finding of rapid reduction in ASXL1 allele frequency following TKI therapy (Kim et al, Blood 2017) raises the question of whether it is a real driver of treatment failure in CML or not. In addition, it is of interest whether 2nd generation TKI (2G-TKI) therapies can abrogate the adverse impact of somatic mutations in CML. Accordingly, the present study attempted to evaluate the prognostic impact of mutation profiles on clinical outcomes in CML patients treated either with Imatinib or 2G-TKIs. Patients and Methods Our cohort includes a total of 394 samples including 254 samples collected at initial diagnosis and 140 samples taken during follow-up from 309 CML patients in two CML treating centers. Disease characteristics and treatment outcomes were evaluated and compared according to mutation profiles at initial diagnosis and during follow-up after TKI therapy. Treatment outcomes include any response with respect to major molecular response (MMR), molecular response (MR) with 2-log/deeper (MR2) or 4-log/deeper (MR4) with any lines of TKI therapy, failure-free survival (FFS), progression and overall survival (OS). Instead of conventional NGS, we applied smMIP-based NGS (limit of detection up to 0.2%) using our in-house CML-specific panel targeting 40 genes including epigenetic modifiers, myeloid transcription factors (TFs), tumour suppressors, genes in activated signaling, spliceosome and, cohesin complex. ResultsPatient group and treatment summary Summary of patient characteristics are as follows: median age of 54 years; male:female n=143/111 (56.3:43.7); disease status at presentation includes chronic- (n=233; 91.7%), accelerated- (n=15; 5.9%), blastic phase (n=4; 1.6%), or N/A (n=2; 0.8%); Sokal score, low (n=61, 24.0%), intermediate (n=84, 33.1%), high (n=74, 29.1%), or N/A (n=35, 13.8%). Frontline therapy includes Imatinib (n=190; 74.8%), or 2G-TKI (n=62) including Dasatinib (n=15; 6.0%), Nilotinib (n=37; 14.7%), Bosutinib (n=10; 4.0%), or other (n=2; 0.8%). Mutation profiles and their correlation with clinical outcomes following TKI therapy70 mutations were detected in 57 (22.4%) out of 254 diagnostic samples, while 64 mutations were detected in 39 (27.9%) out of 140 follow-up samples.Any mutation detected at initial diagnosis is associated with worse outcomes following TKI therapy. The adverse impact of somatic mutation was mainly from myeloid TF or activated signaling pathway mutations. Patients having those mutations at initial diagnosis showed higher risks of treatment failure (HR 2.8 95% CI [1.4-5.4], p = 0.003) and progression (HR 3.1 95% CI [1.1-9.1], p = 0.04), mainly when treated with Imatinib. On the other hand, the adverse impact of epigenetic modifiers was not apparent although a trend was observed toward a lower response rate for MR2 and MMR in patients carrying mutations in epigenetic modifiers.The adverse prognostic impact from these mutations seems to be abrogated by the use of 2G-TKI therapy, supporting the use of smMIP-based NGS for upfront TKI selection in newly diagnosed CML patients.In the cross-sectional analysis of follow-up samples, overall mutation frequency was significantly higher in the treatment failure or progression group compared to the optimal responders (p=0.012), suggesting longitudinal tracking of mutation profiles may help identify cases of impending treatment failure or progression early. Conclusion Our study shows that mutation profiling utilizing smMIP-based NGS can help identify patients with a potential adverse prognosis from initial diagnosis and may help upfront TKI selection. Further follow-up analysis is ongoing to evaluate the effect of TKI therapy on longitudinal kinetics of mutations in serially collected samples. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Management of Patients with Newly Diagnosed Desmoid Tumors in a First-Line Setting.

Simple SummaryDesmoid tumors are benign neoplasms that invade locally, causing significant disability and morbidity. Historically, patients with desmoid tumors have been treated with surgery despite the significant morbidity associated with this modality. Less invasive treatments have emerged, including active surveillance, systemic therapy, radiotherapy, and local ablation. However, it remains unclear which patients would benefit most from an initial conservative rather than interventional approach. To answer this question, we retrospectively analyzed 262 patients with desmoid tumors treated at our institution over a period of 30 years. Our results suggest that initial active surveillance is a good option for patients with small and minimally symptomatic desmoid tumors, while tyrosine kinase inhibitors, local ablation, and surgery seem to be equally effective in those with more aggressive disease. The initial management of desmoid tumors (DTs) is shifting from surgery towards active surveillance, with systemic and locally ablative treatments reserved for enlarging and/or symptomatic disease. However, it remains unclear which patients would benefit most from an initial conservative rather than interventional approach. To answer this question, we retrospectively analyzed adult and pediatric patients with DTs treated at a tertiary academic cancer center between 1992 and 2022. Outcomes measured were progression-free survival (PFS) and time to next treatment (TTNT) after first-line therapy. A total of 262 treatment-naïve patients were eligible for analysis with a median age of 36.5 years (range, 0–87 years). The 5-year PFS and the median TTNT (months) after first-line treatment were, respectively: 50.6% and 69.1 mo for surgery; 64.9% and 149.5 mo for surgery plus adjuvant radiotherapy; 57.1% and 44.7 mo for surgery plus adjuvant systemic therapy; 24.9% and 4.4 mo for chemotherapy; 26.7% and 5.3 mo for hormonal therapy; 41.3% and 29.6 mo for tyrosine kinase inhibitors (TKIs); 44.4% and 8.9 mo for cryoablation and high intensity focused ultrasound; and 43.1% and 32.7 mo for active surveillance. Age 40 years (p < 0.001), DTs involving the extremities (p < 0.001), a maximum tumor diameter 60 mm (p = 0.04), and hormonal therapy (p = 0.03) predicted a higher risk of progression. Overall, our results suggest that active surveillance should be considered initially for patients with smaller asymptomatic DTs, while upfront TKIs, local ablation, and surgery achieve similar outcomes in those with more aggressive disease.

Outcome prediction of chronic myeloid leukemia (CML) in children.

We evaluated the feasibility of existing risk assessment tools for chronic myeloid leukemia (CML) in children. Fifty-five patients with newly diagnosed CML between 1996 and 2019 were included. Forty-nine patients presented in chronic phase, thirty-six of whom were treated with upfront tyrosine kinase inhibitor (CP-TKI group); one presented in accelerated phase and four in blastic phase. Treatment, survival, responses, and tolerance were evaluated. All patients in the CP-TKI group received imatinib as their first TKI treatment. The 10-year overall survival (OS), progression-free survival (PFS), and event-free survival (EFS) of TKI-treated group was 97%, 91.4%, and 72.3%, respectively. At 60 months, the rates of major molecular response were 81.2% and deep molecular response was 67.5%. The EUTOS long-term survival (ELTS) risk grouping did not predict OS, PFS, or EFS. The IMAFAIL risk groups were correlated with the risk of imatinib failure. Further studies are required to modify the existing risk assessment tools for children.

The Optimal Sequence of Intracranial Radiotherapy Compared to Systematic TKI for Brain Metastases in Targeted Treatment Era

The high intracranial efficacy of target therapy agents challenges the sequence of local radiation therapy (RT) and systematic tyrosine kinase inhibitors (TKI) in brain metastases (BM) patients. Therefore, we conducted a single institutional retrospective cohort study to demonstrate the appropriate treatment strategy of upfront RT or upfront TKI in these patients, including an assessment of its feasibility and toxicity.Patients with brain metastases who received hypofractionated stereotactic radiotherapy (HFSRT) with/without whole brain radiotherapy (WBRT) at our institution from October 2010 to October 2020 were included in this study. The primary endpoint was intracranial progression-free survival (IPFS). The secondary endpoints were overall survival (OS), brain metastases specific survival (BMSS) and toxicity. Intracranial progression was estimated using the Fine-Gray competing risks model. Kaplan-Meier analysis and Log-rank tests were used to evaluate and compare OS and BMSS. Multivariate analysis was performed using Cox logistic regression analysis.Among 885 patients, 570 patients enrolled in the study. 130 patients received upfront TKI with RT, 193 patients received upfront RT with TKI, and 247 patients received RT alone. The median follow-up time was 56.4 months. Upfront RT group showed lower intracranial progression risk with adjusted SHR 0.51 (95% CI, 0. 40- 0.667) than upfront TKI group (median IPFS, 17.2 months vs. 8.5 months; P<0.001), but no longer median time to OS (35.6 vs. 41.5 months, P = 0.383) and BMSS (66.2 vs. 58.0 months, P = 0.746) after the salvage therapy. RT alone group showed similar IPFS (18.0 months; 95% CI 14.1-22.0 months; P = 0.686) and a trend of lower OS (19.9 months; 95% CI, 17.6 - 22.3 months; P = 0.010), BMSS (44.8 months; 95% CI 30.7 - 58.9 months; P = 0.002) than upfront RT group. Treatment-related grade 3-4 adverse events were rare, and similar hematological toxicities, liver and renal dysfunctions were observed among different groups.Compared to upfront TKI group, upfront RT group got longer median IPFS time in BM patients but no significant OS or BMSS benefit with similar well-tolerated toxicities. TKI group had better OS and BMSS than RT alone group. The best timing of intracranial RT remains to be further verified.S. Yang: None. J. Xiao: None. H. Zhang: None. Q. Liu: None. Y. Zhang: None. X. Chen: None. K. Wang: None. X. Huang: None. Y. Ma: None. R. Zhao: None. N. Bi: None. J. YI: None. S. Wang: None. Y. LI: None.

Value and significance of brain radiation therapy during first-line EGFR-TKI treatment in lung adenocarcinoma with EGFR sensitive mutation and synchronous brain metastasis: Appropriate timing and technique.

BackgroundFor lung adenocarcinoma patients with epidermal growth factor receptor (EGFR) sensitive mutation and synchronous brain metastasis (syn‐BM), when and how to apply radiotherapy (RT) during first‐line tyrosine kinase inhibitor (TKI) treatment remains debatable.MethodsFrom a real‐world multicenter database, EGFR‐mutant patients with syn‐BM diagnosed between 2010–2020 and treated with first‐line TKIs were enrolled and divided into upfront TKI + RT and upfront TKI groups. Median intracranial progression‐free survival (mIC‐PFS), median overall survival (mOS), and their risk factors were estimated.ResultsThere were 60 and 186 patients in the upfront TKI + RT group and upfront TKI group, respectively. Their mIC‐PFS were 28.9 months (m) and 17.5 m (p = 0.023), and mOS were 42.7 m and 40.1 m (p = 0.51). Upfront brain RT improved mIC‐PFS in patients ≤60‐year‐old (p = 0.035), with symptomatic BM (p = 0.002), and treated with first‐generation TKIs (p = 0.012). There was no significant difference in mOS in any subgroup. Upfront brain stereotactic radiosurgery (SRS) showed a trend of better mIC‐PFS and mOS. mIC‐PFS was independently correlated with symptomatic BM (HR = 1.54, p = 0.030), EGFR L858R mutation (HR = 1.57, p = 0.019), and upfront brain RT (HR = 0.47, p = 0.001). mOS was independently correlated with being female (HR = 0.54, p = 0.007), ECOG 3–4 (HR = 10.47, p < 0.001), BM number>3 (HR = 2.19, p = 0.002), and third‐generation TKI (HR = 0.54, p = 0.044) or antiangiogenic drugs (HR = 0.11, p = 0.005) as first/second‐line therapy.ConclusionsUpfront brain RT based on first‐line EGFR‐TKI might improve IC‐PFS but not OS in EGFR‐mutant lung adenocarcinoma patients, indicating potential survival benefit from brain SRS and early application of drugs with higher intracranial activity.

Outcomes Based On Brain Metastases Characteristics And Treatment Modality For Patients With EGFR-Mutated And ALK-Rearranged Non-Small Cell Lung Cancer (NSCLC)

Lung cancer patients with driver mutations and brain metastases can be managed with various modalities given intracranial penetrance of available tyrosine kinase inhibitors (TKIs). We sought to determine these patient’s outcomes based on brain metastases characteristics and the upfront treatment modalities utilized, including stereotactic radiosurgery (SRS) and whole brain radiation therapy (WBRT). Cases of EGFR-mutant or ALK-rearranged NSCLC with brain metastases treated at our institution were retrospectively identified. Eligible patients had brain metastases at any time point during their cancer course. Brain metastases were contoured in the treatment planning system to calculate maximal tumor diameter and total volume of disease. Intracranial progression free survival (IC-PFS), with an event representing intracranial progression or death, was estimated using the Kaplan-Meier method. Cox regression analyses were performed to identify prognostic clinical or treatment characteristics. Neurological toxicities observed in follow-up were scored according to the CTCAE v5.0. From 2010-2019, 49 eligible patients were identified, 41 EGFR, 8 ALK. Median follow-up from initial brain metastases diagnosis was 15 months. Forty-one patients were initially managed with TKIs, 26 of those also with radiation (13 SRS, 13 WBRT +/- SRS). Most (67%) had brain metastases at diagnosis, whereas the remaining were diagnosed at a median time of 29 months (range 1.1-61.7 months) following original lung cancer diagnosis. Patients with brain metastases at time of cancer diagnosis experienced improved IC-PFS compared to those who initially were diagnosed with only extra-cranial disease (median 15.9 vs. 5.1 months, hazard ratio 0.27, p < 0.03). Metastatic burden in the brain and presence of neurological symptoms were not predictive for IC-PFS (p > 0.05). There was no difference in IC-PFS between TKI alone and TKI + radiotherapy (median 15.7 months vs 18.3 months, p > 0.05). TKI alone, without radiation, was more frequently used when brain metastases maximum diameter was less than 1.5 cm (p = 0.041). There was no increase in neurologic death with upfront TKI alone compared to any radiotherapy (14% vs 22%, p = 0.585). Median time to intracranial progression after any initial brain treatment was 11.2 months. Median overall survival for the entire cohort was 30 months. Grade 3+ treatment related neurotoxicity occurred in 1 patient (2%), following WBRT and SRS. For patients with EGFR-mutated or ALK-rearranged NSCLC and brain metastases, there was no difference in IC-PFS based on number or volume of brain metastases. Those treated with TKI alone experienced similar IC-PFS and risk of neurologic death as those also treated with radiotherapy. Further studies are needed to evaluate optimal treatment strategies for these patients, particularly for those with larger or symptomatic brain metastases when radiation is typically recommended.

Optimal Timing And Technique Of Local Therapy For Brain Metastases From Non-Small Cell Lung Cancer With Driver Mutations

Brain metastases (BM) are frequent in non-small cell lung cancer patients with driver mutations (dm-NSCLC). Since the availability of brain-penetrating tyrosine kinase inhibitors (TKI), the role of local therapy (LT) for BM from dm-NSCLC is frequently discussed. This analysis examines prognostic factors, particularly the effect of LT timing and technique, in patients with BM from dm-NSCLC. Between 2009 and 2019, 179 patients from one institution were diagnosed with BM from dm-NSCLC and subsequently received TKI-therapy. 78.8% (n = 141) were TKI-naive and selected for analysis. 108 patients (76.6%) had Epidermal Growth Factor Receptor (EGFR) mutations with exon19 deletion most prevalent (n = 61, 56.5%); 33 (23.4%) showed translocation of the Anaplastic Lymphoma Kinase (ALK) gene. 75 patients (41.9%) presented with ≥5 BM. 87 patients (61.7%) received early LT, whereas 54 (38.3%) received delayed LT upon progression (n = 34; 24.1%) or none (n = 20; 14.2%). LT consisted of stereotactic radiosurgery (SRS) (n = 40; 34.2%) or whole brain radiotherapy (WBRT) (n = 77; 65.8%); neurosurgical resection was performed with (n = 15; 10.6%) or without (n = 4; 2.8%) post-operative radiotherapy (RT) in 19 cases. TKI treatment comprised first (n = 93; 66.0%), second (n = 31; 22.0%) or third generation substances (n = 17; 12.1%). A univariate and multivariate Cox proportional hazards model was fitted for overall survival (OS) and intracranial progression-free survival (icPFS). Median OS was 23.0 [IQR 14.6-54.5] months for all patients, 49.1 [IQR 22.7-NA] months for the ALK subgroup and 19.5 [IQR 12.8-46.3] months for the EGFR subgroup (HR 2.6, 95%CI: [1.5-4.7], p = 0.001). Median icPFS was 15.7 [8.9-26.2] months for all patients, 15.7 [10.3-26.2] months and 14.0 [7.9-22.0] months for the subgroups, respectively (HR 1.1, 95%CI: [0.6-1.8], p = 0.814). On multivariate analysis, early LT improved icPFS (HR 0.5, 95%CI: [0.3-0.9], p = 0.009) but not OS (HR 1.4, 95%CI: [0.9-2.3], p = 0.140). This effect was reproduced in independent analysis of the ALK subgroup, but not in the EGFR subgroup. Here, exon 19 deletion (HR 0.4, 95%CI: [0.2-0.8], p = 0.009) and singular BM (HR 0.4, 95%CI: [0.2-0.7], p = 0.002) were independently prognostic of longer icPFS. In the combined cohort, RT technique (SRS vs. WBRT) and number of BM did not influence icPFS or OS. In this analysis, early LT improved icPFS but not OS in TKI-naive patients with BM from dm-NSCLC, compared to upfront TKI treatment. No benefit was shown for WBRT over SRS regarding either icPFS or OS. In light of the toxicities of WBRT, the choice of RT technique should be considered carefully in the context of overall prognosis and quality of life. Especially patients presenting initially with multiple BM may benefit from delaying RT or from individualized approaches like the SRS of multiple or only selected BM instead of WBRT.

Oncogene-Addicted Non-Small-Cell Lung Cancer: Treatment Opportunities and Future Perspectives.

Before the introduction of tyrosine kinase inhibitors (TKIs) for a particular subgroup of patients, despite platinum-based combination chemotherapy, the majority of patients affected by non-small-cell lung cancer (NSCLC) did not live longer than one year. With deeper understanding of tumor molecular biology, treatment of NSCLC has progressively entered the era of treatment customization according to tumor molecular characteristics, as well as histology. All this information allowed the development of personalized molecular targeted therapies. A series of studies have shown that, in some cases, cancer cells can grow and survive as result of the presence of a single driver genomic abnormality. This phenomenon, called oncogene-addiction, more often occurs in adenocarcinoma histology, in non-smokers (except BRAF mutations, also frequent in smoking patients), young, and female patients. Several different driver mutations have been identified and many studies have clearly shown that upfront TKI monotherapy may improve the overall outcome of these patients. The greater efficacy of these drugs is also associated with a better tolerability and safety than chemotherapy, with fewer side effects and an extremely good compliance to treatment. The most frequent oncogene-addicted disease is represented by those tumors carrying a mutation of the epidermal growth factor receptor (EGFR). The development of first, second and third generation TKIs against EGFR mutations have dramatically changed the prognosis of these patients. Currently, osimertinib (which demonstrated to improve efficacy with a better tolerability in comparison with first-generation TKIs) is considered the best treatment option for patients affected by NSCLC harboring a common EGFR mutation. EML4-ALK-driven disease (which gene re-arrangement occurs in 3–7% of NSCLC), has demonstrated to be significantly targeted by specific TKIs, which have improved outcome in comparison with chemotherapy. To date, alectinib is considered the best treatment option for these patients, with other newer agents upcoming. Other additional driver abnormalities, such as ROS1, BRAF, MET, RET and NTRK, have been identified as a target mirroring peculiar vulnerability to specific agents. Oncogene-addicted disease typically has a low early resistance rate, but late acquired resistance always develops and therefore therapy needs to be changed when progression occurs. In this narrative review, the state of art of scientific literature about targeted therapy options in oncogene-addicted disease is summarized and critically discussed. We also aim to analyze future perspectives to maximize benefits for this subgroup of patients.

Dasatinib and Nilotinib As Upfront Therapy for Chronic-Phase Chronic Myeloid Leukemia (CML-CP) in Qatar: A Cost Effectiveness Analysis (CEA)

Objectives: Many tyrosine kinase inhibitors (TKIs) are approved for treating the chronic phase of chronic myeloid leukemia (CML-CP). This study aims at identifying the optimal upfront TKI treatment strategy; considering cost-effectiveness for CML patients from Qatar healthcare system perspective. Evaluated strategies included the newer generation TKIs; dasatinib 100 mg once daily and nilotinib 300mg twice daily. We evaluated both treatments considering their molecular and cytogenetic response outcomes at 12 months follow up as well their respective acquisition costs. Methods: A decision tree model was developed linking clinical effectiveness (defined as major molecular response MMR and/or complete cytogenetic response CCyR), utility, and cost data over a 12-months period. The choice of 12 months period is due to the evidence that the degree of short-term molecular and cytogenetic responses at certain follow- up times is correlated with CML prognosis. Patients who achieve a CCyR are shown to have high remission rates as well overall survival (OS) rates. Patients with newly diagnosed CML are adopted from Qatar Cancer Registry.The probability of primary clinical outcome is calculated from DASISON (dasatinib) and ENESTnd (nilotinib) trials. Direct healthcare costs were derived from the national healthcare payer system, whereas ADR data were derived from local incident reporting system. Results: In the first-line treatments of CML patients, with greater MMR (39% nilotinib vs 12% dasatinib) and CCyR (24% nilotinib vs 16% dastinib) response outcomes, and more adverse drug reactions (ADR) than dasatinib (13.3% vs 4%), nilotinib use is more cost effective with annual costs (QAR 232,102) and after 12 months follow up. Despite the lower acquisition annual cost of dasatinib (QAR 217,125), the incremental cost effectiveness ratio (ICER) of nilotinib versus dasatinib per MMR/CCyR achieved was 56,506 QAR per year. There were no cases in both arms that progressed to accelerated or blast phase. At a threshold of 3 times GDP per capita of Qatar and according to WHO recommendation, the nilotinib use is still cost-effective. Limitations: For the surrogate outcome, we only consider the percentage of patients with or without MMR / CCyR response at 12 months. Nevertheless, we do not consider the depth and the duration of the MMR or CCyR. Conclusions: Upfront therapy of CML-CP patients by nilotinib plan appears to be more cost-effective than dasatinib. Although local real-life data for the effectiveness of these drugs are still warranted. The results of this study implying that nilotinib would be advantageous as first-line treatment for CML-CP patients from Qatar healthcare system perspective. Disclosures No relevant conflicts of interest to declare.

A Fast and Accurate Diagnostic Method for Ph-like ALL Using the Ncounter System

Ph-like acute lymphoblastic leukemia (also known as BCR-ABL1-like ALL) is a new disease entity of B-cell ALL (B-ALL) that exhibits a mRNA expression profile similar to that of Philadelphia chromosome-positive ALL (Ph+ ALL). Ph-like signature is presumably driven by kinase-activating gene alterations. Thus, both gene expression pattern and DNA mutational status should be assessed to make a definitive diagnosis for Ph-like ALL. A variety of approaches combining multiple methods, including RNA sequencing (RNA-seq), Taqman low-density array (LDA), fluorescence in situ hybridization (FISH) and targeted DNA sequencing, are being tested; however, such multi-omics approaches are available only in limited institutions. Since Ph-like ALL patients generally exhibit poor response to standard chemotherapy, and tyrosine kinase inhibitors (TKIs) may benefit them when used in a timely manner, a fast, accurate and generalizable diagnostic method is critically needed. In the present study, we have developed a nCounter-based diagnostic method for Ph-like ALL and validated it using a cohort of Japanese adult B-ALL cases. To identify genes that are uniquely expressed (or not expressed) in Ph+ B-ALL, we first obtained publicly-available gene expression datasets comprising 1146 B-ALL cases and identified 82 differentially-expressed genes in Ph+ ALL cases. We then assessed expression levels of those genes in an independent cohort using the nCounter, which enables fast, sensitive and accurate RNA detection. We also tested whether nCounter-based methods can detect fusion transcripts relevant for Ph-like ALL pathogenesis using probes targeting ABL1, ABL2, CSF1R, PDGFRB, and JAK2. We analyzed 123 samples (Ph+ = 42, Ph- = 81, age 16 to 67) obtained from newly-diagnosed adult B-ALL patients enrolled in two clinical trials conducted by the Fukuoka Blood and Marrow Transplantation Group (FBMTG) (Nagafuji et al. Eur J Haematol 2019). Unsupervised hierarchical clustering successfully stratified 123 cases into two disease clusters: Ph+ and Ph- subgroups. As expected, Ph+ subgroup included almost all Ph+ ALL cases (40 out of 42 cases), while 18 out of 81 Ph- ALL cases (22%) were categorized into the Ph+ subgroup. We defined these cases as Ph-like ALL. To validate the nCounter-based Ph-like ALL classification, we performed RNA-seq and target-capture DNA sequencing of all Ph- ALL cases. As expected, we detected kinase-activating fusions/rearrangements, including CRLF2 rearrangements (7 cases), PDGFRB fusions (3 cases), JAK2 fusions (2 cases), EPOR rearrangements (2 cases), ABL1 fusion (1 case), and FLT3 internal tandem duplication (1 case) in 16 Ph-like ALL cases, while no genetic alterations were detected in 2 cases. Fusion genes involving PDGFRB were consistently detected by nCounter (3/3); however, detection of those involving JAK2 (1/2) and ABL1 (0/1) were inconsistent. JAK2 and/or RAS mutations were detected in 5 of 7 Ph-like ALL cases harboring CRLF2 rearrangements. Of note, CRLF2 protein expression was detected by FACS in all CRLF2-rearranged cases. We next assessed significance of the Ph-like signature on clinical outcomes using a cohort of 40 Ph- ALL cases, in which minimal/measurable residual disease (MRD) status, assessed by IgH and/or TCR rearrangements, as well as clinical data were available (Nagafuji et al. Eur J Haematol 2019). Ph-like ALL cases exclusively exhibited MRD positivity after induction therapy as compared to non-Ph-like cases (p=0.04), indicative of the chemo-resistant nature of Ph-like ALL as previously reported (Roberts et al. N Engl J Med, 2014 and Roberts et al. J Clin Oncol, 2017). As expected, Ph-like ALL cases exhibited significantly poor disease-free survival compared with non-Ph-like ALL cases (p=0.04); however, no significant difference was evident in overall survival (p=0.62) presumably due to the fact that all MRD-positive cases were subjected to allo-HSCT after induction therapy. These data indicate that MRD-based therapy stratification could overcome chemo-resistant nature of Ph-like ALL. Our data suggest that nCounter-based diagnostic method is fast and accurate to identify Ph-like ALL. Since Ph-like signature generally dictates poor clinical outcomes, and upfront TKI therapy may improve them, our method could facilitate precision medicine in the treatment of Ph- B-ALL. Disclosures Akashi: Sumitomo Dainippon, Kyowa Kirin: Consultancy; Celgene, Kyowa Kirin, Astellas, Shionogi, Asahi Kasei, Chugai, Bristol-Myers Squibb: Research Funding.

1541P - PTEN loss as predictor of tumour heterogeneity (TH) and poor prognosis in EGFR-mutant advanced non-small cell lung cancer (ANSCLC) patients (pts) receiving tyrosine-kinase inhibitors (TKIs)

BackgroundAlthough the dramatic activity of EGFR TKIs for EGFR-mutant ANSCLC, nearly 20% of pts do progress rapidly. Poor prognosis was demonstrated to be associated with TH, which may be mirrored by the co-existance of concomitant mutant drivers, such as PTEN. The aim of this analysis was to investigate the correlation between the loss of function of PTEN (as a mirror of TH), and the activity/efficacy of EGFR-TKIs for advanced EGFR mutant ANSCLC pts. MethodsFFPE-tumor blocks of EGFR-mutant ANSCLC pts undergone upfront TKIs from 2015 to 2017 were retrospectively collected (follow-up >18mo. was required for maturity). The status of 4 genes (PTEN, TP53, c-MET, IGFR) was evaluated by immunohistochemistry (IHC) and it was correlated with objective response rate (ORR), overall- and progression-free-survival (OS/PFS). Kaplan-Maier (KM) analysis was performed for independent factors at multivariate analysis. ResultsForty-two EGFR-mutant ANSCLC pts were included [median age 65 yrs (42-86); M/F: 45/55%; current/former/never smoker: 13.5/35/51.5%; PS (ECOG) 0/1/2/3: 30/55/12.5/2.5%; GEF/AFA/ERL: 72.5/25/2.5%; del19/L858R/rare: 60/35/5%]. At multivariate analysis, PTEN loss (HR 6.02, 95% CI 2.48-14.5, p<0.0001) and metastatic sites >2 (HR 2.38, 95% CI 1.01-5.62, p=0.048) were significantly associated with shorter PFS. At KM analysis, pts with PTEN loss (13) had a median PFS of 2.0mo. (95% CI 0-5.4) and a 1-year PFS of 7.7%, in comparison with pts without (27), median PFS 18.3mo. (95% CI 16.5-20.1), 1-year PFS 69.6% (log-rank p<0.0001). Coherently, at the multivariate analysis, PTEN loss (HR 5.11, 95% CI 2.06-12.6, p<0.0001) and PS of 2-3 (HR 6.57, 95% CI 2.01-21.5, p<0.002) were significantly associated with shorter OS. Pts with PTEN loss had a median OS of 4.5mo. (95% CI 0.2-8.9) and a 1-year PFS of 15.4%, in comparison with pts without, median OS 26.9mo. (95% CI 16.7-37.1), 1-year OS 81.5% (log-rank p<0.0001). ConclusionsA low-cost and reproducible IHC assay for PTEN-loss analysis represents a potential tool for identifying TH of EGFR-mutant ANSCLC pts. A powered clinical validation is currently ongoing. Legal entity responsible for the studyEmilio Bria. FundingComprehensive Cancer Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Università Cattolica del Sacro Cuore, Rome, Italy. DisclosureE. Bria: Advisory / Consultancy: Roche; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: MSD; Research grant / Funding (institution): AstraZeneca. All other authors have declared no conflicts of interest.

The Changing Paradigm of Treatment for Non-Small Cell Lung Cancer Intracranial Metastases

Evaluate safety and efficacy of newer systemic therapies for intracranial metastases (IM) from non-small cell lung cancer (NSCLC) when given alone and with concurrent radiation therapy (RT) and determine which patients with IM may benefit from upfront systemic therapy while withholding RT. In NSCLC, chemotherapy regimens are associated with approximately 20% intracranial overall response rates (ORRs) and immunotherapies 30–50% intracranial ORRs. However, tyrosine kinase inhibitor (TKI) therapies for EGFR-mutated patients provide ORRs ranging from 50 to 90%. Prospective data suggest erlotinib, when combined with stereotactic radiosurgery (SRS) and whole-brain radiation therapy (WBRT), substantially increases grade 3–5 toxicities. For immunotherapy, retrospective studies suggest increased intracranial control rates with concurrent RT, though possibly with increased radiation necrosis rates. Upfront TKIs may allow appropriately selected patients to avoid or delay RT and possible resultant RT side effects. However, delayed RT is counterbalanced by retrospective data that suggests upfront RT prolongs overall survival (OS) when performed before starting TKI therapy.

Efficacy of brain radiotherapy plus EGFR-TKI for EGFR-mutated non-small cell lung cancer patients who develop brain metastasis.

IntroductionTo analyze the appropriate treatment methods or timing to use epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) and brain radiation treatment (RT) for symptomatic and asymptomatic brain metastases (BM) in patients with EGFR mutation non-small cell lung cancer (NSCLC).Material and methodsWe retrospectively studied patients diagnosed with EGFR gene mutated NSCLC who developed brain metastasis between June 2006 and December 2015 at Zhejiang Cancer Hospital. Treatment data were assessed in 181 patients with 49 symptomatic BM and 132 asymptomatic BM retrospectively.ResultsIn 49 symptomatic BM patients, the median OS of the stereotactic radiosurgery (SRS)-treated group was longer than in the whole brain radiotherapy (WBRT) group (37.7 vs. 21.1 months) (p = 0.194). In the group of 132 asymptomatic brain metastasis patients, the median overall survival (mOS) was longer in upfront brain radiotherapy compared with the upfront TKI group (24.9 vs. 17.4 months) (p = 0.035). In further analysis regarding the timing of using radiotherapy, out of all 74 patients, 33 underwent concurrent TKI and brain radiation, 13 received TKI after first-line RT treatment and 28 patients received radiotherapy after TKI failure. The intracranial progression free survival (iPFS) of the three groups was 11.1 months, 11.3 months and 8.1 months (p = 0.032), respectively. The mOS of the three groups was 21.9 months, 26.2 months and 17.1 months, respectively (p = 0.085).ConclusionsOur research indicated that delayed brain RT may result in inferior iPFS in EGFR mutated NSCLC patients with asymptomatic brain metastases, but no OS benefit was obtained. In addition, our study revealed that patients treated with SRS had a significantly longer OS for symptomatic BM. Future prospective study of the optimal management strategy with WBRT or SRS and TKI for this patient cohort is urgently needed.

TARIBO trial: Cytoreductive nephrectomy in metastatic renal cell carcinoma patients treated with targeted agents.

TPS4601 Background: In the cytokine era cytoreductive nephrectomy (CN) has been shown to increase survival in patients (pts) with metastatic renal cell carcinoma (mRCC). Efficacy of tyrosine kinase inhibitors (TKIs), including first-line sunitinib and pazopanib has been demonstrated. It is unclear if similar survival benefit could be achieved without CN with TKIs since most of pts enrolled into phase III trials had undergone CN. Methods: A total of 270 mRCC pts will be randomized to receiveCN followed by TKIs vs upfront TKIs without CN. Patients will receive pazopanib 800 mg orally daily or sunitinib 50 mg daily, 4 weeks on/ 2 weeks off. The choice of TKI will be done according to investigator’s clinical practice. Primary objective: to compare clinical benefit, as measured by overall survival (OS), provided by CN followed by TKIs vs upfront TKIs in pts with mRCC. Secondary objectives: i) to compare clinical benefit, as measured by progression-free survival (PFS) and response rate (RR) provided by CN followed by TKIs vs upfront TKIs; ii) Safety; iii) Exploratory analyses: evaluation of the predictive role of circulating tumor cells count and circulating tumor DNA at baseline, before and after surgery (in pts undergoing CN), 24 weeks after randomization and at the time of disease progression. Key inclusion criteria: Favorable or intermediate MSKCC or Heng prognostic risk group; histological diagnosis of RCC with a clear-cell component; resectable asymptomatic mRCC with primary tumor in place; up to three different metastatic sites; ≥ 3 metastatic lesions. Key exclusion criteria: Widespread disease ( &gt; or = 4 metastatic organ sites); disease suitable of metastasectomy ( &lt; 3 lesions confined at one organ site). Statistical plan: The sample size was calculated in order to compare 5-year OS between subjects randomized to receive CN followed by TKIs and those randomized to receive upfront TKIs. A total of 191 deaths will yield 80% power to detect a hazard ratio of 1.5 of upfront TKIs vs CN followed by TKIs with an overall type 1 error of 0.05 (two-sided log-rank test). Such a HR corresponds to an increase in the 5-year OS, from an anticipated value of 10% for TKIs to 21.5% for CN followed by TKIs. To date 10/270 pts have been enrolled. Clinical trial information: NCT02535351.

P3.02b-074 Brain Radiotherapy with EGFR-TKI Plays an Important Role in 181 EGFR Mutant Non-Small Cell Lung Cancer Patients with Brain Metastasis: Topic: EGFR Clinical

To perform a retrospective analysis of patients with epidermal growth factor receptor (EGFR)-mutant NSCLC patients who developed brain metastases (BM) to assess the appropriate use of EGFR tyrosine kinase inhibitors (TKIs), and radiation therapy (RT) for symptomatic and asymptomatic BM. There were 482 patients diagnosed with EGFR mutant NSCLC between June 2006 and December 2015 at Zhejiang Cancer Hospital. Treatment outcomes had been retrospectively evaluated in 181 patients with 132 asymptomatic BM and 49 symptomatic BM. 39 patients received first-line brain RT, 23 patients received delayed brain RT, and 34 patients did not receive brain RT. In all 49 symptomatic BM patients received radiotherapy, except 4 patients were refusal of treatment. There were 45 patients had brain radiotherapy, 39 received WBRT and 6 were SRS. Among 132 asymptomatic brain metastasis patients, 74 received radiotherapy (63 WBRT and 11 SRS). The BM of 26 patients had still stable by the follow-up time. 22 patients did not get information about brain RT after intracranial progression and until the last follow-up. 10 patients were refusal of brain RT treatment. In 49 symptomatic BM patients, 45 received RT including 40 WBRT and 5 SRS. Among 6 SRS. The iPFS for patients treated with SRS and WBRT was 12.4 months and 9.5 months (P=0.895). Median OS in the SRS group was also greater than in those treated with WBRT (37.7 vs 21.1 months)(P=0.194). In the group of 132 asymptomatic BM patients, There were 86 patients who had not received brain radiotherapy before TKI and 46 received RT whether upfront or concurrent TKI. The median OS in the upfront RT group was also longer than in the upfront TKI (24.9 vs 17.4 months)(P=0.035). Further analysis with subgroup to the timing of using radiotherapy, among the 74 patients, 33 underwent concurrent TKI and radiation therapy, 13 were given TKI after failure of first-line radiotherapy plus chemotherapy and 28 patients received radiotherapy after TKI. The iPFS of three groups was 11.1 months, 11.3 months and 8.1 months (P=0.032). The mOS of three groups was 21.9 months, 26.2 months and 17.1 months (P=0.085). The study suggests that the deferral of brain RT may result in inferior OS in NSCLC patients harboring EGFR mutations and asymptomatic BM. For now, the standard-of-care treatment for newly diagnosed BM whether symptomatic or asymptomatic brain metastases should remain upfront RT followed by EGFR-TKI therapy. First-line brain RT may improve long-term survival in EGFR mutation patients.

PUB034 Profile of Lung Cancer in Developing Country: Single Centre Experience? Changing Paradigm

Adenocarcinoma is the commonest histological subtype of non-small cell lung cancer (NSCLC) in most of the Western countries. However, in India squamous cell carcinoma has been reported as the commonest histological type in most of the series. The aim of the study is to analyze the clinico-pathological profile , treatment outcome and survival of NSCLC treated at our center. We analyzed 364 NSCLC registered at our centre over a period of three years. They were evaluated for their clinical and pathological profiles, treatment received and outcome. We also analyzed epidermal growth factor receptor (EGFR) in 250 patients for which formalin-fixed paraffin-embedded tissues was available. EGFR sequencing was performed with ABI PRISM 310 genetic analyzer. Median age was 55 years with a male:female ratio of 5:1. 70% of patients were smokers. Adenocarcinoma was the commonest histological subtype after the pathology review. Among NSCLC, 75% cases were of stage IV. 40% of patients had mutation in one of the four exons characterized. Patients whose EGFR mutational status was not available at presentation before the start of treatment were started on chemotherapy. If EGFR mutational analysis was available and mutations were present, the patients were started on either upfront tyrosine kinase inhibitor (TKI), 30% or if on chemotherapy arm were allowed to finish six cycles and then start with maintenance TKIs, 40%. The median progression free survival for patients with and without mutations was 12 months and 8 months. A median PFS of 16 months was seen in the mutation-positive group that received both chemotherapy followed by switch maintenance with TKIs versus 9 months in the group that received only TKI. This analysis suggests that adenocarcinoma , the commonest histological subtype in India, Most of the patients present at advanced stage and outcome remains poor. The prevalence of EGFR mutations in this population of NSCLC patients was 42% with exon 19 mutation being the most common.