Initiation Of Tyrosine Kinase Inhibitors Therapy Research Articles

Digital PCR for BCR‐ABL1 Quantification in CML: Current Applications in Clinical Practice

Molecular monitoring of the BCR-ABL1 transcript for patients with chronic phase chronic myeloid leukemia (CML) has become increasingly demanding. Real-time quantitative PCR (qPCR) is the routinely used method, but has limitations in quantification accuracy due to its inherent technical variation. Treatment recommendations rely on specific BCR-ABL1 values set at timed response milestones, making precise measurement of BCR-ABL1 a requisite. Furthermore, the sensitivity of qPCR may be insufficient to reliably quantify low levels of residual BCR-ABL1 in patients in deep molecular response (DMR) who could qualify for an attempt to discontinue Tyrosine Kinase Inhibitor (TKI) therapy. We reviewed the current use of digital PCR (dPCR) as a promising alternative for response monitoring in CML. dPCR offers an absolute BCR-ABL1 quantification at various disease levels with remarkable precision and a clinical sensitivity reaching down to at least MR5.0. Moreover, dPCR has been validated in multiple studies as prognostic marker for successful TKI treatment discontinuation, while this could not be achieved using classical qPCR. dPCR may thus prospectively be the preferred method to reliably identify patients achieving treatment milestones after initiation of TKI therapy as well as for the selection and timing for TKI discontinuation.

EGFR tyrosine kinase inhibitor therapy continuation with high-dose hypofractionated radiotherapy in EGFR-mutated non-small cell lung cancer (NSCLC) patients with oligoprogressive disease.

e21580 Background: EGFR tyrosine kinase inhibitors (TKIs) represent the standard first-line therapy for advanced non-small cell lung cancer (NSCLC) patients with activating EGFR mutations. However, despite initial marked responses, tumors invariably develop acquired resistance to TKIs. Oligoprogression is commonly observed during treatment with oncogene-directed therapies, including EGFR TKIs, and refers to patients who experience disease progression only in limited sites as a result of heterogeneous mechanisms of resistance. The use of local ablative treatments for these resistant lesions may extend the duration of TKI therapy and potentially improve long-term disease control and survival. We e retrospectively analyzed the efficacy of EGFR TKI therapy continuation with high-dose hypofractionated radiation therapy (RT), in EGFR-mutant NSCLC patients with oligoprogressive disease. Methods: Patients with metastatic EGFR mutant NSCLC who developed oligoprogression during first-line treatment with gefitinib were included in this analysis. We evaluated progression-free survival 1 (PFS 1), defined as the time from initiation of TKI therapy until development of oligoprogression or death, and PFS 2, defined as time of focal progression until further progression of disease or death. Overall survival and safety were also assessed. Results: Thirty-six patients were included in the study. The median PFS 1 was 12.5 (4.0-23.2) months. High-dose hypofractionated RT consisted of intensity-modulated RT in 23 patients (64%) and stereotactic radiotherapy in 13 cases (36%). The median PFS 2 was 6.3 (2-12.5) months. Overall survival was 38.7 months (9.0-46.3). The treatment was well-tolerated and no patient had to discontinue TKI therapy because of adverse events during radiotherapy. Conclusions: Our therapeutic strategy, including high-dose hypofractionated RT in addition to TKI therapy, was feasible in the clinical setting and was associated with significant prolongation of disease control and improvement of survival outcomes, while being associated with manageable side effects. Our study further support the use of definitive therapeutic approaches in oligoprogressive disease, especially in oncogene-driven tumors. Molecular profiling of metastatic sites remains crucial to identify novel biomarkers, involved in the development of acquired resistance and oligoprogression, that may be useful to select patients for local treatments.

High-dose Radiotherapy for Oligo-progressive NSCLC Receiving EGFR Tyrosine Kinase Inhibitors: Real World Data.

Local ablative treatments for oligo-progressive, EGFR mutated non-small cell lung cancer (mut-NCSLC) may improve long-term disease control and survival. We analyzed the efficacy of hypo-fractionated, high-dose radiation therapy (HDRT), in association with prolonged EGFR tyrosine kinase inhibitors (TKI) in oligo-progressive, EGFR mutant-NSCLC. Progression-free survival-1 (PFS-1, date from initiation of TKI therapy until oligo-progression or death), and progression-free survival-2 (PFS-2, date of focal progression until further progression or death) were evaluated. Thirty-six patients were analyzed. The median PFS 1 was 12.5 months. HDHRT consisted of intensity-modulated RT and stereotactic RT in 23 (64%) and 13 (36%) patients respectively. The median PFS 2 was 6.3 months. Overall survival was 38.7 months. Hypo-fractionated HDRT plus TKI therapy, is associated with a significant prolongation of disease control (overall PFS: 18.8 months), with manageable side effects. These real-world data support the use of local ablative approaches in oligo-progressive EGFR mut-NSCLC.

Predictors of delays in initiation of oral tyrosine kinase inhibitors (TKIs) in EGFR and ALK positive advanced non-small cell lung cancer (NSCLC).

134 Background: Molecular testing practices and cost-sharing policies may result in delayed initiation of TKI therapy. We assessed predictors of delayed initiation of TKIs in metastatic EGFR+ or ALK+ NSCLC. Methods: We identified patients with EGFR+ and ALK+ NSCLC diagnosed between 01/01/2010 and 12/31/2016 in the Washington State SEER registry using validated natural language processing methods. We linked registry records to commercial and Medicare (including part D) claims. Eligible patients had stage IV NSCLC, sensitizing EGFR mutations or ALK+ by FISH, ≥ 1 pharmacy claims for EGFR or ALK TKIs, and ≥12 months of insurance enrollment post-diagnosis. Potential predictors included age, sex, race, Census-level median household income, urban status, insurance type, comorbidity, histology, mutation type, and receipt of chemotherapy prior to first TKI claim (pre-TKI chemo). We defined time to TKI initiation as the interval from diagnosis to first pharmacy claim for EGFR or ALK TKIs. We fitted Cox regression models to identify predictors of delays in TKI initiation, defining covariates with a P < 0.05 in a final multivariate model as independently associated with delays. Results: For 122 patients (median age 70; 65% female; 74% White; median income $66,580; 98% metropolitan; 35% Medicare; 80% EGFR+; 12% using pre-TKI chemo), the median time to TKI initiation was 6.7 weeks (IQR = 3.9 to 14.0). Independent predictors of TKI delays included male sex (HR = 0.51; 95%CI = 0.34; 0.76); Medicare insurance (HR = 0.32; 95% CI = 0.20; 0.53) and pre-TKI chemo (HR = 0.37; 95% CI = 0.20; 0.66). Median time to TKI initiation was 9.7 vs. 5.8; 7.8 vs. 4.1; and 16.0 vs. 6.3 weeks in male vs. female, Medicare vs. commercial insurance, and pre-TKI chemo (yes vs no), respectively. Conclusions: Male sex, Medicare insurance, and chemotherapy prior to TKI are associated with delays in TKI initiation for EGFR+ and ALK+ stage IV NSCLC patients. Possible explanations include higher prevalence of smoking in males resulting in lower priority for molecular testing, high cost-sharing policies for TKIs in Medicare patients, and prolonged time to obtain molecular test results leading patients to start chemotherapy first.

Adherence to tyrosine kinase inhibitors among Medicare Part D beneficiaries with chronic myeloid leukemia.

Tyrosine kinase inhibitors (TKIs) improve the survival of patients with chronic myeloid leukemia (CML) dramatically; however, nonadherence to TKI therapy may lead to resistance to the therapy. TKIs are very expensive and are covered under Part D insurance for Medicare patients. To the authors' knowledge, the impact of low-income subsidy status and cost sharing on adherence among this group has not been well studied in the literature. Surveillance, Epidemiology, and End Results (SEER) registry data linked with Medicare Part D data from the years 2007 through 2012 were used in the current study. The authors identified 836 patients with CML with Medicare Part D insurance coverage who were new TKI users. Treatment nonadherence was defined as a binary variable indicating the percentage of days covered was <80% during the 180-day period after the initiation of TKI therapy. Logistic regression was used to examine the relationship between out-of-pocket costs per 30-day drug supply, Medicare Part D plan characteristics, and treatment adherence while controlling for other patient characteristics. Overall, 244 of the 836 patients with CML (29%) were nonadherent to targeted oral therapy during the 180 days after the initiation of treatment with TKIs. The multivariable logistic regression demonstrated that patients with heavily subsidized (odds ratio, 6.7; 95% confidence interval, 2.8-15.9) and moderately subsidized (odds ratio, 3.0; 95% confidence interval, 1.4-6.5) Medicare Part D plans were much more likely to demonstrate nonadherence compared with patients without a subsidy. The current population-based study found a significantly higher rate of nonadherence among heavily subsidized patients with substantially lower out-of-pocket costs, which suggests that future research is needed to help lower the nonadherence rate among these individuals. Cancer 2018;124:364-73. © 2017 American Cancer Society.

Plasma proteomics in CML patients before and after initiation of tyrosine kinase inhibitor therapy reveals induced Th1 immunity and loss of angiogenic stimuli

Background and aimsThe simultaneous measurement of many proteins is now possible using multiplex assays. In this pilot study we investigated a total of 124 proteins in plasma from chronic myeloid leukemia (CML) patients with the purpose of identifying proteins that are differently expressed at diagnosis and after tyrosine kinase inhibitor (TKI) treatment initiation. MethodsSamples were taken from 14 CML patients at diagnosis and after three months of TKI treatment (imatinib or dasatinib). Samples were analyzed by Mesoscale Discovery, Myriad RBM MAP technology and Olink Proseek. ResultsMultiple plasma proteins were differentially expressed before and after initiation of TKI therapy. Protein patterns demonstrated a possible shift towards Th1-immunity and reduced angiogenic stimuli. Further, some plasma proteins were identified that can be of potential interest to study further for biologic, prognostic or therapeutic significance such as E-selectin, uPAR, growth hormone and carbonic anhydrase IX. ConclusionsPlasma proteomics seems feasible and useful in CML patients, both for studying patterns of protein expression and for identifying single proteins differentially expressed before and after treatment. Plasma proteomics may be useful to map disease activity and biological processes. Hence, plasma proteomics can be used to understand drug mechanisms and treatment responses in CML.

Does the Achievement of MR4.5 Improve the Outcome of Patients with Chronic Phase Chronic Myeloid Leukemia (CP-CML) Treated with Front Line Tyrosine Kinase Inhibitors (TKI)?

Background: Aside from the possibility of treatment discontinuation, the prognostic significance of deep molecular responses regarding survival endpoints in pts with CP-CML treated with TKI remains controversial. Achievement of complete cytogenetic response (CCyR) correlates with improved overall survival (OS). Among pts with CCyR, achievement of major molecular response (MMR) correlates with improved event-free survival (EFS). We have previously shown that among pts in sustained CCyR, those who achieve deeper molecular responses at 18 or 24 months may have longer EFS and failure-free survival (FFS) but not transformation-free survival (TFS) or OS. In this analysis, we sought to determine whether the achievement of a MR4.5 might correlate with improved long-term outcome in CP-CML pts who achieve CCyR after frontline TKI therapy.Methods: Pts with CP-CML treated with front line TKI, including imatinib 400 mg daily (IM400), imatinib 800 mg daily (IM800), nilotinib (NILO), or dasatinib (DASA), were included in the analysis. Landmark analyses were conducted at various time points to identify the association between achieving MR4.5 and various survival outcomes. Since the benefit of achieving CCyR is well established, only pts who were in CCyR were considered at each time point. The probabilities of OS, EFS, FFS and TFS were estimated using the Kaplan-Meier method and Cox proportional hazards regression models were fit to assess the association between OS, EFS, FFS, TFS and response. All outcomes were measured from the date treatment was started. OS was measured until death from any cause; TFS until death or transformation to accelerated (AP) or blast phase (BP) during study; EFS until loss of complete hematologic response or major cytogenetic response, transformation to AP or BP, or death from any cause; FFS until any event (as per EFS definition), failure (as defined by the ELN criteria), loss of CCyR, discontinuation or change of therapy for any reason.Results: The study population consisted of 478 pts. 59% of them were males and 9% had high Sokal score at diagnosis. 71 pts received IM400, 204 IM800, 105 NILO, and 98 DASA. Median follow-up is 106 (4-177) months (163 for IM400, 133 for IM800, 61 for NILO and 71 for DASA). The overall cumulative rate of CCyR was 92% (85% for IM400, 90% for IM800, 99% for NILO, and 97% for DASA). The overall cumulative rate of MR4.5 was 73% (56%, 74%, 80% and 78%, respectively for the 4 treatment cohorts). Among pts with CCyR, corresponding rates of MR4.5 were 79% overall and 66%, 81%, 83% and 80%, respectively, for the 4 treatment cohorts. For the entire population, the 5-year OS was 92.7%, TFS 86.0%, EFS 80.7%, and FFS 69.1%. In pts who were in CCyR at 12, 18, 24, 30, 36 or 48 months after initiation of TKI therapy there was no significant difference in terms of EFS, FFS, TFS or OS between pts who achieved a MR4.5 and those who did not (Table).Conclusion: Our analysis suggests that the achievement of MR4.5 does not provide a meaningful improvement in EFS, FFS, TFS, or OS for CP-CML pts who have achieved CCyR after being treated with frontline TKI. While obtaining a MR4.5 may enable the option of TKI discontinuation, our results suggest that failure to do so should not be considered failure or suboptimal response and thus should not prompt a change in TKI in pts who are in CCyR. Change of therapy to achieve MR4.5 with the goal of treatment discontinuation should be considered only within clinical trials.Table 1Cox proportional hazards models for EFS, FFS, TFS, and OS at various time points.Time pointEFSFFSTFSOSHR95% CIp-valueHR95% CIp-valueHR95% CIp-valueHR95% CIp-value12 months0.820.42-1.610.570.940.58-1.530.810.990.46-2.120.981.060.47-2.390.8918 months0.960.51-1.820.90.750.45-1.250.271.340.69-2.810.361.410.68-2.940.3524 months0.850.44-1.650.630.80.49-1.330.390.90.41-2.010.80.990.43-2.250.9730 months0.750.35-1.620.470.640.36-1.150.140.820.34-1.960.650.980.40-2.390.9736 months0.980.46-2.090.960.550.30-1.020.061.110.47-2.650.811.240.52-2.950.6348 months0.860.35-2.100.730.70.35-1.400.310.840.29-2.430.750.860.30-2.480.78 DisclosuresPemmaraju:Stemline: Research Funding; Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; LFB: Consultancy, Honoraria. Cortes:Pfizer: Consultancy, Research Funding; ARIAD Pharmaceuticals Inc.: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Teva: Consultancy, Research Funding.

Abstract 763: Implications of resistance patterns with NSCLC targeted agents

Abstract Introduction: Tyrosine kinase inhibitors (TKIs) can give regression of NSCLCs with mutations of EGFR, HER2 &amp; BRAF and fusion genes for ALK, ROS1 &amp; RET, but resistance develops in most patients. Methods: We reviewed available clinical data for insights on potential approaches to delay resistance. Results: Target absence is a major cause of intrinsic resistance. Most NSCLCs with target undergo at least some regression although the degree varies between patients due to largely unexplored factors. Many mechanisms of acquired resistance have been defined, including outgrowth of subclones with secondary mutations or alternative pathways, and pharmacological effects &amp; sanctuaries. Available data suggest that resistant cells are present in small numbers in the initial tumor but that their growth is suppressed by the more rapidly growing parent tumor cells until this parent population is itself suppressed by TKI initiation. If TKI is stopped due to progression, there can be tumor flare as the initial parent cell population regrows rapidly. Exponential decay nonlinear regression analysis of patient survival curves suggests that TKI discontinuation at time of progression may partially “synchronize” patient deaths. Initial tumor progression may occur in a single site. Available data indicate that focal treatment (eg, radiation) to that site combined with continuation of initial TKI may give optimal control and reduce tumor flare. Of interest, progression may occur in many sites concurrently. Since there are many potential resistance mechanisms one might expect substantial discordance of resistance mechanisms between these sites, but preliminary data with 2nd line agents (eg, anti-T790M agents in EGFR-mutant patients and 2nd generation anti-ALK agents for acquired resistance to crizotinib) indicate response in most sites if any are sensitive, suggesting that all or most sites have a common resistance mechanism. This raises the possibility that an initial resistant site is seeding other distant tumor sites with resistant cells, in keeping with animal data. The probability of a resistant cell being present in an individual tumor deposit is proportional to the total number of tumor cells in that deposit. If 1 area of resistant tumor can seed other tumor areas with resistant cells, then (particularly in oligometastatic disease) we should consider clinical trials exploring: 1) at initiation of TKI therapy treating as many tumor sites as possible (particularly large tumors) with a modality (eg radiation) that is “indifferent” to the factors giving TKI resistance; 2) treating any progressing lesions as early as possible with intensive focal therapy, if feasible, rather than waiting until symptomatic or rather than treating only with low palliative doses. Conclusion: Extrapolation from available data suggests we should explore trials using multifocal radiation at initiation of TKIs for advanced NSCLC and early, intense treatment of areas of isolated progression. Citation Format: David J. Stewart, Paul Wheatley-Price, Rob MacRae, Jason Pantarotto. Implications of resistance patterns with NSCLC targeted agents. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 763. doi:10.1158/1538-7445.AM2015-763

Rapid Evolution to Blast Crisis Associated with a Q252HABL1Kinase Domain Mutation in e19a2BCR-ABL1Chronic Myeloid Leukaemia

A minority of chronic myeloid leukaemia (CML) patients express variant transcripts of which the e19a2 BCR-ABL1 fusion is the most common. Instances of tyrosine kinase inhibitor (TKI) resistance in e19a2 BCR-ABL1 CML patients have rarely been reported. A case of e19a2 BCR-ABL1 CML is described in whom imatinib resistance, associated with a Q252H ABL1 kinase domain mutation, became apparent soon after initiation of TKI therapy. The patient rapidly transformed to myeloid blast crisis (BC) with considerable bone marrow fibrosis and no significant molecular response to a second generation TKI. The clinical course was complicated by comorbidities with the patient rapidly succumbing to advanced disease. This scenario of Q252H-associated TKI resistance with rapid BC transformation has not been previously documented in e19a2 BCR-ABL1 CML. This case highlights the considerable challenges remaining in the management of TKI-resistant BC CML, particularly in the elderly patient.

Response of renal lesions during systemic treatment with sunitinib in patients with metastatic renal cell carcinoma: a single center experience with 14 patients

The tyrosine kinase inhibitor (TKI) sunitinib induces partial remissions (PR) in a substantial proportion of patients with metastatic renal cell carcinoma (mRCC). Only little is known about the activity of sunitinib in renal lesions in patients with metastatic disease, as most patients with synchronous metastases receive palliative nephrectomy. Fourteen patients with clear cell mRCC with renal lesions and sunitinib therapy (50 mg OD, 4/2 scheme) were retrieved retrospectively from clinic records. Tumor assessment consisted of CT scans at least every two cycles, analyzed according to RECIST. In 5 of 14 patients, renal tumors were considered as the primary tumor, while the remaining patients had kidney metastases. In total, 65 target lesions were evaluated. The median progression-free survival (PFS) of sunitinib was 8.7 months (range: 2.7-40.2). Median overall survival (OS) from initiation of TKI therapy was 26 months (range: 3-55). Best response according to RECIST consisted of partial remission (PR) in 4 patients, stable disease (SD) in 7 patients, a complete remission (CR) in 1 patient, and 2 patients with progressive disease (PD). Analyzing the response of renal lesions only, 1 patient had PD, 8 patients had SD, 4 patients had PR, and 1 had a CR. Palliative nephrectomy was performed after two courses of sunitinib in 2 patients. In our cohort, similar responses of renal tumors and peripheral metastases were achieved with sunitinib treatment. Our results support the use of sunitinib to control renal tumor lesions in metastatic patients.