2nd TKI Research Articles

A Real World Analysis of Safety and Efficacy of Nilotinib when Used as First Line and Beyond: Retrospective Single Centre Study Representing Largest Cohort of Indian Patients Treated with Nilotinib

Background: Efficacy and toxicity of TKIs may vary depending on the ethnic background or genetic factors; hence it is important to gather data from individual populations pertaining to each drug. The pivotal registration trial had not enrolled any patient from India and there are very limited published studies on its efficacy as well as safety from Indian patients with CML. Methods: Hospital Electronic Medical Record was screened for adult (age > 18 years) CML patients registered (n = 1290) at our hospital from 1st May 2018 to 31st December 2022. CML-CP or CML-AP patients, those who have received Nilotinib as 1st line (n = 40) or 2nd line (n = 66) or 3rd line TKI (n = 20) for at least 90 days (3 months) and have at least one RQ PCR BCR: ABL value post Nilotinib initiation, were enrolled in this study (n = 126). Results: Eighty (74.1%) patients achieved BCR/ABL of ≤ 1% at 12 months. MMR and MR4 at 12 months was seen in 44 (40.7%) and 19 (17.6%) patients respectively. The most common haematological toxicity was thrombocytopenia of any grade seen in 54 (42.8%) patients. Conclusion: Our study demonstrates that treatment with Nilotinib was well-tolerated in Indian patients and was effective in achieving molecular remission rates in 1st, 2nd or 3rd line therapy in the real-world setting. Safety and efficacy were in line with published western or Asian studies.

24P Efficacy and safety of 1st generation EGFR TKI retreatment in EGFR mutation-positive, T790M-negative patients previously treated with 1st or 2nd generation EGFR TKI and cytotoxic chemotherapy

24P Efficacy and safety of 1st generation EGFR TKI retreatment in EGFR mutation-positive, T790M-negative patients previously treated with 1st or 2nd generation EGFR TKI and cytotoxic chemotherapy

EP08.02-051 High-dose Aumolertinib as First-line Treatment in Patients With Brain Metastases Associated With EGFR Mutated NSCLC

Brain metastases are associated with significant morbidity and poor survival outcomes. They are found in 10-20% of patients with non-small cell lung cancer (NSCLC) at presentation, and in up to 50% of patients during the course of their illness. Brain metastases occur most frequently in patients with adenocarcinoma and tumor harbouring epidermal growth factor receptor (EGFR) mutations or ALK rearrangements, especially after treating with 1st or 2nd generation EGFR TKI. Aumolertinib, the third generation irreversible EGFR TKI, has been developed to target T790M mutation.

P47.08 A Phase II, Single-arm, Multicenter, Efficacy of 80 mg Osimertinib in Patients With Leptomeningeal Metastases Associated With EGFR Mutated NSCLC

Leptomeningeal metastases (LM) are severe, an aggressive complication of cancer, characterized by tumor cell spread to the cerebrospinal fluid (CSF) and leptomeninges. The higher incidence of LM in EGFR mutated non-small cell lung cancer (NSCLC) has been observed, especially after treated with 1st or 2nd generation EGFR TKI. The Osimertinib, the third generation irreversible EGFR TKI, has been developed to target T790M mutation. Unlike other EGFR TKIs, Osimertinib showed homogenous distribution to the brain suggesting high penetration of blood-brain barrier, and clinical efficacy in intracranial lesions has been demonstrated from the retrospective analyses.

1214P High dose osimertinib in patients with advanced stage EGFR exon 20 mutation-positive NSCLC: Results from a phase II multicenter study, POSITION20

Clinical benefit to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKI’s) is lacking for non-small cell lung cancer (NSCLC) patients with an EGFR exon 20 mutation (EGFRex20+), with known response rate (RR) from 0-28%, and median progression free survival (PFS) of ∼3 months to 1st and 2nd generation EGFR TKI’s (Remon, Cancer Treatment Reviews 2020). A high dose of the 3rd generation TKI osimertinib shows promising antitumor activity to EGFRex20+ in vitro. The safety and efficacy results from a multicenter single arm phase II study investigating osimertinib in EGFRex20+ NSCLC patients are reported here.

FP14.07 Combination Osimertinib plus Selpercatinib for EGFR-mutant Non-Small Cell Lung Cancer (NSCLC) with Acquired RET fusions

Selpercatinib is a highly selective and potent FDA-approved RET inhibitor that has demonstrated marked and durable efficacy in RET fusion-positive NSCLC. While RET fusions are the primary oncogenic driver in ∼2% of NSCLC, RET fusions have also been identified as acquired resistance alterations following treatment with EGFR inhibitors, including osimertinib, in EGFR-mutant NSCLC. We sought to evaluate the safety and preliminary efficacy of the combination of osimertinib and selpercatinib in patients progressing on osimertinib. Patients received selpercatinib in combination with osimertinib across three selpercatinib compassionate access programs: single patient protocols (SPP), named patient programs (NPPs), and an expanded access program (EAP). All patients had advanced EGFR-mutated NSCLC with a RET fusion detected from tissue or plasma following osimertinib therapy. Clinicopathologic and outcomes data were collected retrospectively. Across 12 patients identified, 11 had an EGFR exon 19 deletion (92%) and one had an EGFR L858R mutation (8%). The most common emergent RET fusion was CCDC6-RET (five patients, 42%), followed by NCOA4-RET (four patients, 33%), KIF5B-RET (two patients, 17%), and RUFY2-RET (one patient, 8%). All patients had received prior osimertinib and seven (58%) had also received a 1st or 2nd generation EGFR TKI. Most patients received selpercatinib at 80 mg BID (92%, range 100 mg QD - 120 mg BID) and osimertinib at 80 mg daily (75%, range 40 mg QD - 80 mg BID). Of twelve identified patients, 10 were evaluable for response per RECIST 1.1. Among RECIST evaluable patients five had a response (50%, four confirmed partial responses, one unconfirmed partial response). One patient, unevaluable per RECIST for non-measurable disease at baseline, demonstrated sustained clinical radiographic improvement ongoing at 8.2 months. The second unevaluable patient discontinued treatment prior to reassessment for unrelated clinical events preventing oral medication administration. The median duration of combination treatment across all 12 identified patients was 7.4 months (range 0.6 – 16.7+ months). For patients who achieved a RECIST response, the median treatment duration was 11 months (range 7.4 – 16.7+ months). Treatment was discontinued due to disease progression in seven patients, one patient discontinued for toxicity (grade 2 pneumonitis), one patient for intolerance to oral medication administration, and three patients remained on therapy at data cut-off. In one patient with a response lasting 10 months, plasma sequencing at resistance revealed persistence of EGFR 19del (22% AF) and RET fusion (0.4% AF) plus newly detected second-site resistance mutations in both EGFR (C797S, 0.1%) and RET (G810S, 0.8%), providing additional confirmation of the biologic relevance of the acquired RET fusion. For patients with EGFR-mutant NSCLC with an acquired RET fusion as a mechanism of EGFR inhibitor resistance, the addition of selpercatinib to osimertinib was feasible, with evidence of radiographic responses and durable benefit. These findings support future investigation of this combination, which will be evaluated prospectively as an arm of the phase 2 ORCHARD platform study (NCT03944772). The availability of active combination targeted therapy strategies highlights the need for assessment for genomic mechanisms of resistance following initial EGFR targeted therapy in NSCLC.

COVID-19 in Patients (pts) with Chronic Myeloid Leukemia (CML): Results from the International CML Foundation (iCMLf) CML and COVID-19 (CANDID) Study

COVID-19 in Patients (pts) with Chronic Myeloid Leukemia (CML): Results from the International CML Foundation (iCMLf) CML and COVID-19 (CANDID) Study

Abstract 5198: JNJ-61186372, a novel EGFR/c-Met bispecific antibody, exhibits potent antitumor activity in broad-spectrum of acquired resistance to EGFR-TKIs

Abstract Background: 1st generation (erlotinib & gefitinib), 2nd generation (afatinib), and 3rd generation (osimertinib) EGFR TKIs have marked efficacy in patient with EGFR-mutant NSCLC. Unfortunately, patients who show T790M (-) mutation after treated with 1st and 2nd generation EGFR TKI or have C797S (+) mutation or other mechanisms of acquired resistance to 3rd generation EGFR TKI have no therapeutic options for curing cancer in clinic. We introduce a potent therapeutics for overcoming acquired resistance to EGFR-TKIs in several EGFR mutant NSCLC models using JNJ-61186372 (JNJ-372), a bispecific antibody that targets the EGFR and c-Met receptors. Methods: We classified PDC and PDX models into two groups: i) 1st and 2nd generation EGFR TKI acquired resistance models with T790M (-) mutation (YU-1093, YU-1152), ii) 3rd generation EGFR TKI acquired resistance models with C797S (+) mutation (YU-1097), and C797S (-) mutation with unknown resistance mechanisms (YU-1095, YU-1089, YU-1096, YUX-1024_YH1R, YHIM-1035, YHIM-1045, and YHIM-1053). We established 7 patient-derived cells (PDC) and 3 patient-derived xenografts (PDX) model from patients with broad-spectrum acquired resistance to EGFR-TKIs. We performed cell viability test and western blot to investigate antitumor activity of JNJ-372. We evaluated then in vivo antitumor activity of JNJ-372 in PDX and PDC-xenograft models. JNJ-372 was administrated i.p. twice a week at 30 mg/kg. Results: We assessed the ability of JNJ-372 to overcome broad-spectrum of EGFR-TKI acquired resistances. JNJ-372 significantly inhibited cancer cell growth in vitro and in vivo in PDC model harboring T790M (-) mutation. JNJ-372 significantly decreased cell proliferation rate and EGFR downstream signaling in BaF3 cell harboring Del19 (L858R)/T790M/C797S mutant and PDC model harboring Del19/T790M/C797S mutant with amplified KRAS and loss of Rb. C797S (-) cases of four PDCs and three PDX models had i) loss of T790M with c-Met amplification or other acquired resistance mutation and ii) T790M (+) with amplified c-Met. In these models we identified dramatic tumor regression and reduction of EGFR and c-Met expression in vitro and in vivo PDX and PDC-xenograft models. Interestingly, we observed combination treatment of JNJ-372 and c-Met inhibitor showed synergistic immune cell mediated cellular cytotoxicity in EGFR-TKI acquired resistance models harboring c-Met amplification. JNJ-372 exhibited potent inhibition of tumor growth in preclinical models through targeting EGFR and c-Met receptor, decreasing EGFR and c-Met receptor level, inhibiting EGFR downstream signaling cascade and activating ADCC effect in vivo. Conclusion: Our results suggest that JNJ-372 will provide potential and effective therapeutic options for patients with no therapeutic option to overcome broad-spectrum of acquired resistance to EGFR-TKIs. Citation Format: SooHwan Lee, Jiyeon Yun, Seo-Yoon Jeong, Chae Won Park, Seok-Young Kim, Min Hee Hong, Hye Ryun Kim, Byoung Chul Cho. JNJ-61186372, a novel EGFR/c-Met bispecific antibody, exhibits potent antitumor activity in broad-spectrum of acquired resistance to EGFR-TKIs [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5198.

Updated overall survival (OS) and safety data from the randomized, phase III ALEX study of alectinib (ALC) versus crizotinib (CRZ) in untreated advanced ALK+ NSCLC.

9518 Background: Final, mature PFS from the global phase III ALEX study (NCT02075840) of ALC vs CRZ in untreated, advanced/metastatic ALK+ NSCLC have been previously published: ALC 34.8 months (m) (95% CI 17.7–NR) vs CRZ 10.9 m (95% CI 9.1–12.9), (HR 0.43, 95% CI 0.32–0.58). We report 5-year OS and updated safety data from ALEX with a further 12 m follow-up (FU) (cutoff date: Nov 29, 2019). Methods: Patients (pts) with stage IIIB/IV ALK+ NSCLC (by central IHC), ECOG PS 0–2 and no prior systemic therapy for advanced NSCLC were randomized 1:1 to ALC 600 mg BID (n = 152) or CRZ 250 mg BID (n = 151). Asymptomatic CNS metastases (mets) at baseline (BL) were allowed. OS was a secondary endpoint, and no formal statistical testing was planned. Results: Median duration of FU: 48.2 m with ALC vs 23.3 m with CRZ. OS data remain immature (events: 37%; stratified HR 0.67 [95% CI 0.46–0.98]); median OS with CRZ was 57.4 m (95% CI 34.6–not estimable [NE]) vs NE with ALC. The 5-year survival rate was 62.5% (95% CI 54.3–70.8) with ALC vs 45.5% (95% CI 33.6–57.4) with CRZ (Table). In pts with CNS mets at BL the OS HR was 0.58 (95% CI 0.34–1.00) and 0.76 (95% CI 0.45–1.26) in pts without CNS mets at BL. The OS benefit of ALC vs CRZ was generally consistent across all subgroups. Considering the longer treatment duration for ALC (28.1 m) vs the previous analysis (27.7 m), the safety profile of ALC remains consistent; no new safety signals were observed. With ALC, 35% of pts remain on study treatment vs 9% of pts remaining on CRZ. In pts with ≥1 known post-progression treatment (ALC: 32.2%; CRZ: 45.7%), lorlatinib was the most common ALK TKI received after first-line ALC (7.2%), compared with ceritinib after first-line CRZ (15.2%). Conclusions: This is the first global randomized study of a 2nd generation ALK TKI to demonstrate a clinically meaningful improvement in OS vs CRZ in ALK+ NSCLC (5-year survival rate: 62.5%, ALC vs 45.5%, CRZ); longer FU is required as OS data remain immature. Clinical trial information: NCT02075840 . [Table: see text]

Inotuzumab ozogamicin (INO) plus bosutinib (BOS) in R/R PH+ ALL or CML in lymphoid blast phase (CML LBP).

7512 Background: Pts with R/R Ph+ ALL and CML LBP have poor outcomes. INO is an anti-CD22 antibody drug conjugate approved for R/R ALL. BOS is a 2nd generation BCR-ABL TKI approved for CML. Methods: This was a phase I/II study of INO + BOS for R/R Ph+ ALL and CML LBP. Primary objective was to determine safety and the maximum tolerated dose (MTD) of the combination. Secondary objective was to assess efficacy. Pts with T315I mutation were excluded. Pts needed to have adequate organ function (Cr ≤2 gm/dL, total bilirubin ≤2 mg/dL, ALT & AST ≤3xULN). BOS was dosed once daily starting on cycle 1 day 1, and 3 dose levels were evaluated (300, 400, 500 mg) in a standard 3+3 design. INO was given IV weekly during cycle 1 (0.8 mg/m2 day 1; 0.5 mg/m2 day 8; 0.5 mg/m2 day 15). In responding pts, INO was subsequently administered at 1 mg/m2 once every 4 weeks for a total of 6 cycles. Results: Between June 2015 and December 2019 we enrolled 18 R/R pts (16 Ph+ ALL, 2 CML LBP). The median age was 62 yrs (range 19-74), median no. of prior therapies was 1 (range 1-5) and 9 pts had ABL kinase domain mutations at screening. There were no early deaths (<30 days). 3 pts were treated at BOS dose level 1; 6 pts at dose level 2; 9 pts at dose level 3. 1 pt had a DLT at dose level 2 - G3 skin rash, and 2 pts had a DLT at dose level 3 - both G3 skin rash. First 3 pts at dose level 3 did not receive ≥80% BOS doses during cycle 1 due to issues unrelated to adverse events (AE). As 2/6 DLT evaluable pts at dose level 3 had DLTs thus exceeding the MTD, the dose level 2 was identified as the MTD. Most frequent AE were diarrhea in 50%, rash in 50%, and nausea in 39%. Grade 3 AEs were rash (3), reversible ALT elevation (1) and hyponatremia (1). No pts had veno-occlusive disease. Pts have received a median of 3 cycles (range 1-8) with a median of 1 cycle to response (range 1-2). Responses are shown in Table. Median time to response was 1 months (mo, range 0.8-2.1), median time to negative MRD by flow cytometry (FCM) was 6.9 mo (range 3.4-18) and median time to complete molecular response (CMR) was 9.1 mo (range 3.4-18). After a median follow-up of 32 mo, the median overall survival was 15.4 mo and median event-free survival censored at stem-cell transplantation (SCT) was 6.1 mo. 6 pts underwent SCT, 8 pts relapsed, 10 pts are alive and 2 pts continue therapy. Conclusions: INO + BOS was well tolerated and showed promising activity in R/R Ph+ ALL and CML LBP. Clinical trial information: NCT02311998 . [Table: see text]

Dasatinib overcomes stroma-based resistance to the FLT3 inhibitor quizartinib using multiple mechanisms.

FLT3-ITD mutations occur in 20–30% of AML patients and are associated with aggressive disease. Patients with relapsed FLT3-mutated disease respond well to 2nd generation FLT3 TKIs but inevitably relapse within a short timeframe. In this setting, until overt relapse occurs, the bone marrow microenvironment facilitates leukemia cell survival despite continued on-target inhibition. We demonstrate that human bone marrow derived conditioned medium (CM) protects FLT3-ITD+ AML cells from the 2nd generation FLT3 TKI quizartinib and activates STAT3 and STAT5 in leukemia cells. Extrinsic activation of STAT5 by CM is the primary mediator of leukemia cell resistance to FLT3 inhibition. Combination treatment with quizartinib and dasatinib abolishes STAT5 activation and significantly reduces the IC50 of quizartinib in FLT3-ITD+ AML cells cultured in CM. We demonstrate that CM protects FLT3-ITD+ AML cells from the inhibitory effects of quizartinib on glycolysis and that this is partially reversed by treating cells with the combination of quizartinib and dasatinib. Using a doxycycline-inducible STAT5 knockdown in the FLT3-ITD+ MOLM-13 cell line, we show that dasatinib-mediated suppression of leukemia cell glycolytic activity is STAT5-independent and provide a preclinical rationale for combination treatment with quizartinib and dasatinib in FLT3-ITD+ AML.

BCR-ABL1 p190 in CML: A Minor Breakpoint with a Major Impact

Introduction: The oncoprotein Bcr-Abl has two major isoforms, depending on the breakpoint in BCR gene, p190 and p210. While p210 is the hallmark of chronic myeloid leukemia (CML), p190 occurs in the majority of Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL) patients. p190 occurs as a sole transcript in 1-2% CML patients, associated with distinct features like monocytosis and frequent additional cytogenetic abnormalities (ACA) at diagnosis. It also confers a risk of treatment failure and progression in chronic phase (CP) CML patients. However, the underlying mechanisms are largely unknown. Here we explore the characteristics of p190 and p210 in CML and ALL patients using next generation sequencing, phospho-flowcytometry and high throughput drug testing. Patients and methods: Peripheral blood mononuclear cells (PMNC) were collected at diagnosis from four CP-CML patients harboring p190 isoform from Helsinki University Hospital. Genetic alterations were identified by whole exome sequencing. RNA sequencing was employed to analyze transcriptional profiles of p190 CML (n=3) in contrast to p210 CML patients (n=4). A thorough transcriptional, phosphorylation and drug sensitivity profiling were applied to five p190- and three p210-expressing Ph+ALL patients. Expression alterations were further characterized in two cell line models mimicking BCR-ABL positive leukemia (Ba/F3 and HPCLSK). Phosphorylation profiles were analyzed by flowcytometry and phospho-array (Tyrosine Phosphorylation ProArray, Full Moon Biosystems). For drug sensitivity and resistance testing (DSRT), a custom plate set comprising 75 approved and investigational oncology drugs was used for patient samples and more extensive 528-drugs plates were used for the cell lines. Results: CML patients with p190 had a median age of 72.5 years at the diagnosis (range: 50-80) and all received imatinib as a frontline treatment. Only one patient achieved a fluctuating major molecular response (MMR) by 12 months while the rest of the patients showed primary resistance to treatment and were shifted to a 2nd line TKI, nilotinib (n=2) or proceeded to HSCT (n=1). By exome sequencing we identified 26 variants in p190-CML samples (median per patient=7, range: 2-10), including variants in ASXL1, DNMT3A and KDM4D genes. RNA-sequencing analysis identified 19 and 97 dysregulated genes (Q <0.05) between p190- and p210 in CML and Ph+ ALL cells respectively. In CML, enrichment analysis revealed upregulation of TNF, interferon (IFN), IL1-R and Toll-like receptor (TLR) signaling, TP53-related, cell cycle and apoptosis pathways. Among Ph+ ALL samples, many CML-related genes were upregulated in samples encompassing p210 while IFN-, TP53- and cell cycle-related molecules were upregulated in p190 samples. p190 samples exhibited hyper-phosphorylation of Src kinase compared to p210 samples. DSRT results also revealed increased sensitivity of primary Ph+ ALL-p190 cells to Src-inhibitors (dasatinib and saracatinib), glucocorticoids and MDM2 inhibitors/TP53 activators (SAR405838 and idasanutlin). Regarding cell lines, Ba/F3-p190 showed the upregulation of interferon signaling pathways compared to p210. Src was also hyperphosphorylated in both Ba/F3 and HPCLSK p190 models. In addition to glucocorticoids and Src-inhibitors, compounds blocking the activity of the inhibitors of apoptosis protein (IAP) family were highly effective at reducing the viability of p190 compared to p210 cells in both cell lines. Conclusions: In CML, p190 isoform of BCR-ABL1 is associated with distinct features and should be considered as a high-risk group. Combining clinical, genomic, phosphorylation and drug sensitivity data, we demonstrated that p190 activates specific cancer pathways, notably Src signaling and interferon pathways. Data also suggests that CML patients with p190 could benefit from broad spectrum TKI with Src inhibiting activity or combination of TKI with MDM2- or IAP-inhibitors. Disclosures Heckman: Orion Pharma: Research Funding; Celgene: Research Funding; Novartis: Research Funding; Oncopeptides: Research Funding. Porkka:Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding. Mustjoki:Novartis: Research Funding; Pfizer: Research Funding; BMS: Honoraria, Research Funding.

1533P - Treatment patterns of EGFR mt+ NSCLC IV pts: Real-world data of the NOWEL network

BackgroundThe percentage of pts switching from 1st gen TKI in 1st line to 3rd gen TKI in 2nd line seems to be low with 30% and it is questionable whether these data represent real world treatments. Therefore, we investigated the treatment pattern and especially the attrition rate between 1st and 2nd line therapy in EGFR mt+ pts from the NOWEL network. MethodsA retrospective study of 1539 pts with non-squamous NSCLC IV was accomplished. 965/1536 (63%) pts were tested for EGFR mt+ between 2009-2018. 148/965 (15%) pts with an EGFR mt+ were identified. To calculate PFS and OS we used Kaplan Meier methods and the log rang test for p-values. ResultsBaseline characteristics of 148 EGFR mt+ pts: median age 65 yrs; 64% female (n=95/148); 64% never/light smoker (n=94/148). 135/148 pts (91%) carried an EGFR mt+ either del19 (n=81) or L858R (n=55). 144/148 pts were treated with TKI on 1st or 2nd line (after chemotherapy) and 4 pts received no therapy at all. 14/144 pts are still on 1st line, 9 pts were lost to follow-up and 3 pts died while on 1st line therapy. We identified 118/144 candidates for 2nd line therapy (because of progression on 1st line TKI) and only 84/118 (70%) pts received a 2nd line therapy. 30% (36/118) of pts did not receive a 2nd line therapy because of bad PS (n=26), pts refusal (n=2), fast progression (n=6) and death (n=2). After accessibility of 3rd gen TKI 72 pts were candidates for 2nd line treatment and 51/71 pts (71%) received a 2nd line therapy. MOS of pts receiving 2nd line therapy after access to 3rd gen TKI was 35mo for pts with 2nd line therapy vs. 10mo without 2nd line (p<0.000). 32/51 pts (63%) were tested for T790M and 20/32 (62%) were T790M+. Highest T790M testrate in one center was 22/28 (79%). 16/20 (80%) T790M+ pts received 3rd gen TKI for 2nd line therapy. MOS of pts receiving 3rd gen TKI (n=31) was 51mo vs. 25mo for pts without 3rd gen TKI (p<0.002). ConclusionsIn real world, a significant number of pts treated with 1st or 2nd gen TKI do not reach 2nd line therapy even with broad accessibility of 3rd gen TKI. Reasons for not receiving 2nd line therapy are in most cases deterioration of PS, death and no testing for T790M in a minority of cases. These data are important for the interpretation of the OS data of the FLAURA study as they reflect real world treatment algorithms in dedicated German lung cancer centers. Legal entity responsible for the studyCarl v. Ossietzky University of Oldenburg, Prof. Dr. Griesinger. FundingHas not received any funding. DisclosureJ. Roeper: Honoraria (self): Boehringer Ingelheim; Honoraria (self): Roche; Honoraria (self): AstraZeneca. M. Falk: Advisory / Consultancy: Pfizer; Honoraria (self), Advisory / Consultancy: Boehriger Ingelheim; Honoraria (self): Roche; Honoraria (self): AstraZeneca. M. Tiemann: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Novartis; Honoraria (self), Advisory / Consultancy: Boehriger Ingelheim; Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self), Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy: Roche ; Honoraria (self): AstraZeneca. F. Griesinger: Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Research grant / Funding (institution): AstraZeneca; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Research grant / Funding (institution): Boehriger Ingelheim; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Research grant / Funding (institution): Novartis; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Research grant / Funding (institution): Pfizer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Research grant / Funding (institution): Roche; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Research grant / Funding (institution): BMS; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Research grant / Funding (institution): MSD; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Research grant / Funding (institution): Celegene; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Research grant / Funding (institution): Lilly; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Research grant / Funding (institution): Takeda; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Research grant / Funding (institution): Siemens; Honoraria (self), Advisory / Consultancy: AbbVie; Honoraria (self), Advisory / Consultancy: Bayer. All other authors have declared no conflicts of interest.

Abstract 3999: Advanced lung adenocarcinoma cell bank (ALACB) : A comprehensive preclinical platform

Abstract Purpose: Patients with advanced lung adenocarcinoma often lack large clinical specimens required for molecular testing which limits next therapeutic options. Patient-derived cells (PDC) from malignant effusions can predict patient drug responses and provide a valuable tool for studying drug resistance mechanisms. In this study, we created an Advanced Lung Adenocarcinoma Cell Bank (ALACB) consisting of 28 unique PDCs established from patients who progressed on various tyrosine kinase inhibitor TKIs including 3rd generation EGFR TKI osimertinib. Experimental design: Patient malignant effusion samples were tested for malignancy, processed, observed by light microscopy, and cultured with appropriate media and supplements. The criteria for established PDCs include the following: sharing the same driver mutation as the patient; free of stromal fibroblasts confirmed by FACS staining; recapitulating patient’s drug response; and can be cryopreserved and re-grown. Established PDCs were further authenticated by STR profiling and microplasma testing to maintain cell quality. We were able to perform various in vitro assays and next generation sequencing for detailed analysis of individual PDC. Results: We were able to successfully establish 28 PDCs incorporating unique patient characteristics. Among the total 146 samples, we observed a success rate of 30% only accounting 95 malignancy positive samples. Established PDCs consists of 20 EGFR mutation positive cell lines, 3 with ALK rearrangements, 6 with ROS1 rearrangements, 1 with BRAF K601E mutation and 1 with KRAS G12D mutation. Seven PDCs were established from patients who progressed on osimertinib, two from olmutinib (HM61713), and others from 1st and 2nd generation EGFR TKI such as gefitininb and erlotinib. We were able to newly generate 3 PDCs harboring a T790M mutation with an activating EGFR mutation. Moreover, we are one of the few labs to successfully establish an EGFR del19/T790M/C797S triple mutant PDC showing resistance to osimertinib treatment in vitro. Other established PDCs harbored rare EGFR mutations including exon 20 insertion, L861Q and G719X/S768I. PDC with EGFR G719X/S768I compound mutation showed high sensitivity to afatinib but was resistant to gefitininb and osimertinib treatment. Three ALK-positive PDCs were derived from crizotinib-resistant, alectinib-resistant and ceritinib-resistant tumors. Furthermore, of 6 ROS1 fusion positive PDCs, 3 were derived from TKI-naïve tumors, and 3 from crizotinib-resistant tumors. Conclusions: Successfully established PDCs reflecting patient genomic profiles and drug response is a valuable resource for biological assays, generating in vitro drug-resistant models, and evaluating novel drugs and therapeutic targets. Further advances in drug development combined with a library of cell bank will facilitate lung cancer translational research. Citation Format: Hyeong-Seok Joo, Dong Hwi Kim, Seok-Young Kim, Ji-Yeon Lee, Mi-Ran Yun, Han-Na Kang, Byoung Chul Cho, Hye Ryun Kim. Advanced lung adenocarcinoma cell bank (ALACB) : A comprehensive preclinical platform [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3999.

PB1925 COMPARATIVE STUDY OF GLIVEC VERSUS STATE SPONSORED GENERIC IMATINIB MESYLATE AS FIRST LINE THERAPY IN CHRONIC MYELOID LEUKEMIA‐ CHRONIC PHASE

Background:In a developing economy like India, Imatinib usage has increased manifold after generic formulations were introduced. 25 brands of generic Imatinib are approved by the Drug Controller General of India. The efficacy and safety of these brands have been repeatedly questioned by different studies. In most of these studies, generic Imatinib were used as a switch from the innovator. Institute of Hematology and Transfusion Medicine (IHTM) in Medical College, Kolkata is state run institute where two generic brands of Imatinib (Veenat; Natco, and Imatinate; KLabs) are available free of cost to the patients. Also there are patients who were on Glivec from the GiPAP and Max foundation at either free of cost or reduced cost. We took this opportunity to initiate a study to compare the efficacy and safety of these generic brands with the innovator brand (GIG vs IIG).Aims:1. To study the response rates, hematologic and non‐hematologic toxicities, tolerance, compliance and drop out rates of patients on generic Imatinib (GIG)2. To compare the above parameters in patients on innovator Imatinib (IIG)Methods:68 treatment naive CML‐CP patients who were started on generic Imatinib 400 mg/d from July 2015 to April 2016 were enrolled in the study. They were followed up for a median period of 30 months. The results were compared with 70 patients treated in our institute since Jan, 2014 on GiPAP program. Cytogenetic responses were assessed by FISH on bone marrow aspirates on 6 and 12months, and molecular responses were assessed by standardised qT‐ PCR on 3, 6, 12, and 18months of therapy to a resolution of 1 in 10‐4. Patients who were non‐compliant to therapy, response assessment and who failed hematologic response at 3 months were excluded from the analysisResults:Among the 60 patients of GIG included in the analysis, 43 were on Imatinate @KLabs and 17 were on Veenat @Natco. In GIG, 41.6% and 66.6% achieved complete cytogenetic response (CCyR) at 6 and 12 months as compared to 46.2% and 72.1% in IIG (p &gt; 0.05). The rates of optimum molecular responses (ELN 2013) in GIG at 3 and 6 months were 90% and 80% as compared to 92% and 86% in the IIG (p &gt; 0.05). However, the rates of MMR at 12 months in GIG and IIG were 63.3% and 71.4% respectively (p &lt; 0.05). The rates of failure of response by 18 months in GIG and IIG were 33.3% and 17.4% (p &lt; 0.05). In a median follow up of 30 months, 9 patients in GIG progressed to accelerated or blast phase and 20 patients were switched to 2nd line agents. In the IIG, 4 patients progressed and 12 patients were switched to 2nd line TKIs (p &lt; 0.05). There were 3 deaths in GIG and 2 in IIG. Grade 1/2 hematologic toxicities occurred in 100% patients in IIG as compared to 94% in GIG. Grade 3/4 hematologic toxicities occurred in 30% of IIG and 26% in GIG (p &gt; 0.05). Among the non‐hematologic toxicities, skin hypo‐pigmentation, gastritis, muscle cramps and arthritis were most common occurring in 58%, 50%, 30% and 24% in IIG and 50%, 44%, 32% and 30% in GIG. The rates of intolerance and therapy withdrawal are 10% in GIG as compared to 15% in IIG (p &gt; 0.05).Summary/Conclusion:When compared to the innovator brand (Glivec @Novartis), early cytogenetic and molecular responses in patients on generic Imatinib were similar. However, responses at 12 months, rates of failure of Imatinib, and progression of disease are significantly inferior in the GIG and more patients in GIG were switched to 2nd line TKI. Assessment of Deep molecular response rates might yield more significant results. The groups were similar in toxicity profile and therapy discontinuation

PB1955 REAL LIFE DATA OF NILOTINIB IN PATIENTS WITH CHRONIC MYELOID LEUKEMIA RESISTANT OR INTOLERANT TO IMATINIB

Background:Nilotinib is an effective treatment option for patient's refractory or intolerant to imatinib and can be given as 2nd or 3rd line treatment in Turkey.Aims:In this retrospective study, we aim to demonstrate the frequency of side effects in patients on Nilotinib.Methods:We analyzed 253 patients with chronic myeloid leukemia (CML) followed by Marmara University Hematology Department. 53 of these patients (%20.9) were on Nilotinib in a period of their treatment. Clinical characteristics of the patients are given in table 1.Results:Median duration of patients on imatinib before switching to 2ndline TKI were 19 months (1‐96). Reasons for changing therapy were primary imatinib resistance in 13 patients (%24.5), loss of response in 31 patients (%58.4), drug intolerance in 8 patients (%15.1). In one patient cause of treatment change could not be found.Nilotinib was used as 2nd line TKI in 37 of patients (%69.8) and was used after Dasatinib as 3rd line TKI in 16 of patients (%30.2). Median dasatinib treatment duration before switching to nilotinib was 14 months. Reasons for switching to nilotinib therapy were primary resistance in 3 patients (%18.7), loss of response in 4 patients (%25) and drug intolerance in 8 patients (%50).Nilotinib dosage were 800 mg, median duration of treatment on Nilotinib was 28 months (1‐120). 31 patients (%58.5) are still on Nilotinib. Reasons for discontinuation were primary Nilotinib resistance in 3 patients (%5.6), loss of response in 6 patients (%11.3) and drug intolerance in 8 patients (%15.1). Five patients were lost to follow up.Adverse events were seen on 21 patients (%39.6) and 9 of these (%17) were serious adverse events (SAE). SAE were ischemic cerebrovascular disease in 1 patient, myocardial infarct (MI) in 3 patients, acute pancreatitis in 2 patients, treatment‐resistant nausea‐vomiting in 1 patient, treatment‐resistant rash in 1 patient and grade IV thrombocytopenia in 1 patient. Treatment duration of Nilotinib in patients with MI were 24, 45 and 50 months. Cardiovascular risk factors were not observed in 2 of 3 patients who had MI; other patient had diabetes and hypertension. Treatment duration of Nilotinib in patients with pancreatitis were 1 and 25 months.Summary/Conclusion:In conclusion, Nilotinib is a highly effective treatment for patients who are refractory or intolerant to imatinib or dasatinib. Patients should be followed carefully in terms of side effects such as MI, arterial occlusive diseases and pancreatitis.image

Early circulating tumor (ct)DNA dynamics and efficacy of lorlatinib in patients (pts) with advanced ALK-positive non-small cell lung cancer (NSCLC).

9019 Background: Lorlatinib is a selective, potent, brain-penetrant, 3rd generation (gen) ALK/ROS1 TKI approved for pts with advanced ALK+ NSCLC previously treated with a 2nd gen ALK TKI. We recently showed that ALK mutation tumor genotyping after failure of a 2nd gen ALK TKI may identify pts more likely to respond to lorlatinib.1 To identify other molecular response correlates, we evaluated if early ctDNA dynamics predict clinical outcome on lorlatinib. Methods: In pts enrolled on the ongoing ph 2 study (NCT01970865), plasma samples were prospectively collected for ctDNA analysis at baseline (BL), cycle 3 day 1 (C3D1, or 6 weeks) and end of treatment. Plasma DNA was analyzed using Guardant360. Change in variant allele fraction (dVAF)2 of ALK alterations (fusions and/or mutations) was calculated as (mean VAFC3D1) – (mean VAFBL); dVAF &lt; 0 indicated decreased ctDNA at C3D1. BOR, PFS and OS were evaluated according to dVAF. Results: Of 121 paired BL/C3D1 samples collected from 158 ALK+ pts previously treated with one or more 2nd gen ALK TKIs, 57 (47%) harbored a detectable ALK alteration at BL. At C3D1, mean VAF of ALK fusions and/or mutations was significantly decreased compared to BL (-1.07, p = 0.0014). Mean tumor volume was reduced by 26% in pts with dVAF &lt; 0 (n = 40), but only by 12% in pts with dVAF ≥0 (n = 13) (p = 0.049). Mean dVAF at C3D1 was significantly decreased compared to BL for pts with CR/PR, while there was no significant difference with SD or PD/IND; mean dVAF -1.84, -0.74, and +0.35 in pts with CR/PR, SD, or PD/IND, respectively (p = 0.0011, 0.1444 and 0.3383). Median PFS was 6.6 months (mo) in pts with dVAF &lt; 0 (n = 44) and 2.6 mo in pts with dVAF ≥0 (n = 13) (HR = 2.6, 95% CI: 1.2, 5.8). Median OS was 18.0 mo in pts with dVAF &lt; 0 (n = 34) and 8.6 mo in pts with dVAF ≥0 (n = 13) (HR 2.0, 95% CI, HR 0.9–4.6). Conclusions: Early ctDNA dynamics may predict lorlatinib efficacy in ALK+ NSCLC, with decreased ctDNA at 6 wks associated with better response and longer PFS. Further studies are needed to validate these findings and to determine whether early intervention based on dynamic ctDNA monitoring may improve outcome.

Dacomitinib versus gefitinib for the first-line treatment of advanced EGFR mutation positive non-small cell lung cancer (ARCHER 1050): A randomized, open-label phase III trial.

LBA9007 Background: Dacomitinib is a 2nd generation EGFR TKI with encouraging clinical activity as 1st-line therapy in patients with EGFR-activating mutation positive advanced NSCLC (Jänne, Lancet Oncol 2014). We performed the first randomized phase III trial, currently ongoing, comparing dacomitinib (D) with gefitinib (G) as 1st-line therapy (1L) (NCT01774721). Methods: Patients (pts) with newly diagnosed stage IIIB/IV/ recurrent NSCLC harboring an EGFR- activating mutation (exon 19 del or exon 21 L858R mu +/- exon 20 T790M mu) were randomized 1:1 to D 45 mg PO QD or G 250mg PO QD; stratification was by race and EGFR mutation subtype. The primary endpoint was PFS per blinded independent review (IRC) analyzed by Kaplan-Meier method with log-rank test and Cox model. Secondary endpoints included: overall survival, objective response rate (ORR), duration of response (DR), PFS per Investigator (INV), time to treatment failure (TTF), restricted mean survival time (RMST) for PFS, safety and patient-reported outcomes (PROs). Results: The ITT population included 452 pts with baseline characteristics fairly well balanced between the arms. ORR per IRC was similar between arms (75% [95% CI: 69, 80] for D and 72% [95% CI: 65, 77]; 2-sided p-value = 0.39; OS is not mature. The most commonly reported grade 3 adverse events with dacomitinib were dermatitis acneiform (13.7%) and diarrhea (8.4%) and with gefitinib ALT (8.5%); no new safety signals were identified. Conclusions: ARCHER 1050 was the first phase III head-to-head study of EGFR TKIs and demonstrated statistically significant and clinically meaningful improvement in efficacy of D vs. G in 1L NSCLC pts with EGFR-activating mutations with a manageable safety profile, to offer a new 1L treatment option. Clinical trial information: NCT01774721. [Table: see text]

Physicians' Attitude Towards Selection of Second Line Therapy with Nilotinib and Dasatinib in Chronic Myeloid Leukemia Patients

Background:One of the main challenges in the treatment of chronic myeloid leukemia (CML) is the selection of second line therapy. While Nilotinib (NILO) and dasatinib (DASA) are available for use as second line treatment for several years, few evidence-based data is available on how physicians make decisions on the use of one drug over another.Aim:We performed a pilot study to describe which factors physicians consider most relevant when deciding therapy with either NILO or DASA in patients who previously failed or were intolerant to Imatinib (IMA) therapy.Patients and methods:Analyses are based on a sample 67 CML patients, recruited as part of a larger international study, who switched from IMA therapy to either NILO (N=36; 53.7%) or DASA (N=31; 46.3%). Patients had to be in second line treatment for at least three months to be eligible for this analysis. Also, in all participating centers, NILO and DASA should have been equally available for use. There were 15 physicians involved in the management of these patients and they were asked to complete an ad-hoc questionnaire investigating reasons based on which they made the decision to either use one drug over another. All questions were phrased as follows: "To what extent have the following issues been determinant to make a decision on which agent (NILO or DASA) to use for this patient?" All answers were rated on a four point likert-scale (ie, not at all, a little, quite a bit and very much). Items investigated were: 1) accessibility of the drug in the hospital; 2) cost of drug; 3) patients' comorbidities; 4) patients' age; 5) patients' personality profile; 6) discussion with patients about Pro and Cons; 7) different treatment schedule of drugs; 8) type of mutation during IMA therapy. Physician characteristics were also collected and analyzed. Other treatment-related variables were investigated such as main reason for changing of TKI (IMA intolerance or resistance), high grade adverse events (AEs) experienced during IMA treatment, or previous duration of IMA therapy.Results:Physicians' experience in treating CML patients was on average 14 years (range 4-32). Patient median age at the time of treatment switch was 47 and 55 years in the NILO and DASA group, respectively. Median time of duration of IMA therapy, before receiving second line therapy, was 1.4 years and 3.3 years for those who switched respectively to NILO or DASA. No differences existed between groups with regard to reasons for switching from IMA therapy (intolerance or resistance) or AEs reported with previous IMA therapy. The top issue considered as most relevant when making the decision was previous discussion with patients on advantages and disadvantages of drugs, being reported as "quite a bit" and "very much" important in 73% of evaluations. Cost of the drug was not considered relevant at all, in the selection of which drug to use, in 97% of the 69 evaluations considered. Also, type of mutation during IMA therapy was considered as of negligible relevance for the decision, but it should not be overlooked that mutations were detected in few patients. Patient's comorbidity or personality profile was quoted as a 'quite a bit' or 'very much' relevant reason for the selection of 2nd line TKI, respectively in 43% or 48% of all questionnaires. Low relevance was assigned to patient age and different treatment schedule: 'not at all' or 'a little' relevance was reported respectively in 64% and 70% of all questionnaires. The analysis of physician-reported grading distribution according to the type of second line treatment did not show any significant difference (no reason lead to a preferential selection of one drug), see table 1.Conclusions:No differences were detectablein selected factors, driving the decision to switch either to NILO or DASA when physicians consider switching from first line IMA therapy. Also, type of TKI selection does not seems to be guided by only one factor. Further research is needed to elucidate on potential reasons underlying clinical decision making in 2nd TKI selection. [Display omitted] DisclosuresEfficace:Seattle Genetics: Consultancy; TEVA: Consultancy, Research Funding; Lundbeck: Research Funding; Bristol Myers Squibb: Consultancy. Rosti:Pfizer: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Ariad: Consultancy, Honoraria, Speakers Bureau. Breccia:Celgene: Honoraria; Pfizer: Honoraria; Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Honoraria; Ariad: Honoraria. Baccarani:Novartis: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Ariad: Consultancy, Honoraria, Speakers Bureau.

MP69-07 IMPACT OF TARGETED AGENTS ON RENAL FUNCTION IN PATIENTS WITH METASTATIC RCC

You have accessJournal of UrologyKidney Cancer: Advanced II1 Apr 2015MP69-07 IMPACT OF TARGETED AGENTS ON RENAL FUNCTION IN PATIENTS WITH METASTATIC RCC Yuta Kojima, Jotaro Mikami, Shingo Hatakeyama, Hayato Yamamoto, Atsushi Imai, Takahiro Yoneyama, Yashuhiro Hashimoto, Takuya Koie, and Chikara Ohyama Yuta KojimaYuta Kojima More articles by this author , Jotaro MikamiJotaro Mikami More articles by this author , Shingo HatakeyamaShingo Hatakeyama More articles by this author , Hayato YamamotoHayato Yamamoto More articles by this author , Atsushi ImaiAtsushi Imai More articles by this author , Takahiro YoneyamaTakahiro Yoneyama More articles by this author , Yashuhiro HashimotoYashuhiro Hashimoto More articles by this author , Takuya KoieTakuya Koie More articles by this author , and Chikara OhyamaChikara Ohyama More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2015.02.2511AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Targeted therapy is now considered to be a standard therapy for metastatic renal cell cancer (mRCC). However, there are few studies about renal function after sequential targeted therapy. The aim of this study was to assess the decrease of renal function after targeted therapy for mRCC. METHODS We retrospectively evaluated the change of estimated glomerular filtration rate (eGFR) levels in RCC patients before and after treatment with sequential targeted therapy. Changes of eGFR were compared base line to 1 month after targeted therapy. The eGFR was calculated using age, gender, and serum creatinine by a modified version of the abbreviated Modification of Diet in Renal Disease Study formula for Japanese patients. Risk factors for eGFR decline more than 10% during targeted therapy were determined by multivariate logistic regression analysis. RESULTS Between May 2008 and Sep 2014, we treated 64 patients with mRCC. Median follow up time was 14.9 months (range 1 to 55 months). Major sequence therapy in our hospital is 1st TKI, 2nd TKI, 3rd mTOR, 4th TKI and 5th TKI. The eGFR differences during sequential therapy were not observed, and type of targeted therapy had no impact on renal function decline. However, 42 patients (66%) experienced eGFR decline, and multivariate logistic regression analysis showed body mass index (< 25 kg/m2, HR: 5.1, P=0.017) and number of targeted argent (> 1 argent, HR: 3.5, P=0.032) were selected as independent risk factor for 10% decline of eGFR. CONCLUSIONS Sequential targeted therapy has a limited impact on renal function in patients with mRCC. However, 66% of patients experienced eGFR decline, and increased sequences of targeted therapy might have negative impact on renal function decline. Further studies are required to clarify this consideration. © 2015 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 193Issue 4SApril 2015Page: e869 Advertisement Copyright & Permissions© 2015 by American Urological Association Education and Research, Inc.MetricsAuthor Information Yuta Kojima More articles by this author Jotaro Mikami More articles by this author Shingo Hatakeyama More articles by this author Hayato Yamamoto More articles by this author Atsushi Imai More articles by this author Takahiro Yoneyama More articles by this author Yashuhiro Hashimoto More articles by this author Takuya Koie More articles by this author Chikara Ohyama More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...