Outcomes Of Tyrosine Kinase Inhibitors Research Articles

Somatic Mutations in Cancer-Related Genes Were Observed More Frequently in AYA CML Patients Compared to Elderly at Diagnosis, Whereas the Frequency Was Markedly Higher in Elderly Patients during TKI Treatment

CONCLUSIONS Several works showed that patients with chronic myeloid leukemia (CML) diagnosed at the age of 18 to 39 years (adolescent and young adults, AYAs), had a worse outcome of tyrosine kinase inhibitors (TKI) therapy compared to elderly patients. Only limited data on the molecular background differing AYA from the other age groups are available. To characterize the somatic mutation landscape of AYA CML patients in chronic phase at the time of diagnosis and follow-up in comparison to pediatric and elderly patients, and to follow their clonal evolution. Ph-positive acute lymphoblastic leukemia (Ph+ ALL) patients were included for comparison. Samples from the time of diagnosis (CML children N=18; AYA N=69; elderly N=70; Ph+ ALL children N=32, AYA N=13, elderly N=39) and TKI treatment follow-up (CML AYA N=69, elderly N=70) were analyzed with custom panel (22 whole genes, 40 selected exons). To follow the clonal evolution vital cells available from 10 CML patients were FACS sorted into populations of neutrophils, monocytes, T- and B-lymphocytes. Genomic BCR::ABL1 (g BCR::ABL1) and mutations were quantified using ddPCR in the sorted cells. At the time of diagnosis, a slightly higher frequency of somatic mutations was detected in AYA CML patients (28%, 19/69) compared to elderly (20%, 14/70) and children (11%, 2/18). The similar trend with markedly higher differences was observed in Ph+ ALL patients (62% 8/13 of AYA, 31% 12/39 of elderly, 22% 7/32 of pediatric). The most frequently mutated genes in AYA and elderly CML patients were identically ASXL1, DNMT3A, and TET2. Other mutated genes in AYA were FBXW7, IDH2, IKZF1 PHF6 and KDM6A, SETD2, SF3B1 in elderly. Considering the treatment response, a higher number of mutations at diagnosis were found in the AYA patients that responded optimally in follow-up (21%, 7/33) than in elderly 4% (1/26) and a slightly higher frequency of mutations in AYA patients who later failed on TKI (35%, 8/23) than in elderly 30% (13/43). In contrary, the frequency of acquired mutations or persisted mutations from diagnosis detected during TKI therapy was higher in elderly that failed on TKI therapy (67%, 29/43) than in AYA (52%, 12/23). The treatment failure was associated with de novo mutations in ABL1, RUNX1, TET2, ASXL1 in AYA and elderly CML patients, and in addition in IKZF1, and in DNMT3A, WT1, JAK2, respectively. Sorted cells were analyzed from the time of optimal response in 7 CML patients (+ diagnostic sample of 2 patients) with mutated ASXL1 in 6 patients, FBXW7 in 1 patient, DNMT3A in 1 patient and IDH2 in 1 patient. Samples from the time of therapy failure were available for sorting of 3 patients (+ diagnostic sample of 1 patient). All mutations were detected in g BCR::ABL1 positive neutrophiles and monocytes. The g BCR::ABL1 levels matched exactly with the levels of mutations except for 1 patient with ASXL1-mutated subclone (VAF 5%), which was found in g BCR::ABL1 positive cells. Similar data were found in patients with therapy failure. However, in one patient with secondary failure, the ASXL1 mutation detected at diagnosis disappeared. In all 10 CML patients, g BCR::ABL1 and mutations were not detected in T- and B- lymphocytes under the therapy. In diagnostic samples some g BCR::ABL1 and mutations positive T- and B- lymphocytes were found, but the levels were 3-4 log lower compared to levels in neutrophils and monocytes, which likely correspond to the contamination (purity check was done after sorting) than to the presence of a very small subset of physiological lymphoid cells. Of all age groups, AYAs had the highest number of mutations detected at the time of diagnosis with differences in the spectrum between CML and Ph+ ALL. A markedly higher de novo acquisition of mutations was observed in elderly CML patients during TKI treatment. Moreover, therapy failures were observed more frequently in elderly than in AYA CML patients. Clonal analysis of 10 CML patients outlined that myeloid, but not lymphoid stem/progenitor cells were mutated. Supported by MZCR NU21-07-00225

Tyrosine kinase inhibitors and reduced-dose chemotherapy for adult Philadelphia chromosome-positive acute lymphoblastic leukemia

ABSTRACT Objectives: To compare the outcomes of tyrosine kinase inhibitors (TKIs) in combination with reduced-dose chemotherapy with those of standard induction chemotherapy, as well as the outcomes between chemotherapy and transplantation, in adults with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). Methods: We retrospectively reviewed cases of Ph+ ALL treated with TKIs and combination chemotherapy. The patients were allocated to either the TKIs with reduced-dose chemotherapy group or the TKIs with standard chemotherapy group. In additions, patients were further stratified into either the transplant group or the non-transplant group. Results: The complete remission rate (88.7% vs. 83.9%, p = 0.372), major molecular response (58.9% vs. 56.0%, p = 0.750), molecular complete response (20.5% vs. 22.0%, p = 0.891), and early mortality rate (3.2% vs. 3.5%, p = 0.922) were similar between the TKIs with reduced-dose chemotherapy group and the TKIs with standard chemotherapy group. The proportions of lung infections, bloodstream infections, patients with >21 days of hospitalization, the total costs, transfusion costs, and antimicrobial costs were higher in the standard chemotherapy group than in the TKIs with reduced-dose chemotherapy group. The 3-year overall survival rates (59.0% [95% CI, 46.6–74.7%] vs. 38.4% [95% CI, 29.9–49.4%]) and disease-free survival rates (48.6% [95% CI, 34.2–69.1%] vs. 32.0% [95% CI, 23.5–43.7%]) were significantly better in the transplant group than in the non-transplant group. Conclusion: An induction regimen combining TKIs with reduced-dose chemotherapy and transplantation during the first complete remission remains a suitable and effective option for patients with Ph+ ALL.

MO24-2 Clinical outcomes of tyrosine kinase inhibitors immediately after immune checkpoint inhibitors in renal cell carcinoma

Immune checkpoint inhibitors (ICIs) demonstrated a survival benefit in first-line or second-line settings for patients with metastatic renal cell carcinoma (mRCC). However, there have been few reports about the efficacy and safety of subsequent tyrosine kinase inhibitors (TKIs) immediately after ICIs failure in mRCC patients.

Real-world Outcomes of Tyrosine Kinase Inhibitors Immediately After Immune Checkpoint Inhibitors in Renal Cell Carcinoma.

Immune checkpoint inhibitors (ICIs) have demonstrated a survival benefit for patients with cancer. However, the clinical outcomes of subsequent tyrosine kinase inhibitors (TKIs) after ICI failure in patients with metastatic renal cell carcinoma (mRCC) remain unclear. We retrospectively examined 38 patients with mRCC who started TKIs immediately after nivolumab with (combination group) or without ipilimumab (nivolumab group) between September 2016 and July 2019. Of the 38 patients, 16 and 11 achieved partial response and stable disease, respectively, resulting in a 42.1% objective response rate and 71.1% disease control rate. The median progression-free survival (PFS) from TKI initiation was 8.8 and 12.9 months in the nivolumab and combination groups, respectively. PFS and overall survival were significantly longer in patients with long-term responses to previous ICI treatment (p=0.0152 and p=0.0155, respectively). TKIs demonstrate adequate anti-tumour activity after treatment with ICIs in real-world settings.

Improving Outcomes of Tyrosine Kinase Inhibitors in Hepatocellular Carcinoma: New Data and Ongoing Trials.

Targeted therapies such as oral tyrosine kinase inhibitors (TKIs) are the main therapeutic strategy effective for advanced hepatocellular carcinoma (HCC). Currently six tyrosine kinase inhibitors for HCC therapy have been approved. The newly approved first-line drug donafenib represent the major milestones in HCC therapeutics in recent years. However, drug resistance in HCC remains challenging due to random mutations in target receptors as well as downstream pathways. TKIs-based combinatorial therapies with immune checkpoint inhibitors such as PD-1/PD-L1 antibodies afford a promising strategy to further clinical application. Recent developments of nanoparticle-based TKI delivery techniques improve drug absorption and bioavailability, enhance efficient targeting delivery, prolonged circulation time, and reduce harmful side effects on normal tissues, which may improve the therapeutic efficacy of the TKIs. In this review, we summarize the milestones and recent progress in clinical trials of TKIs for HCC therapy. We also provide an overview of the novel nanoparticle-based TKI delivery techniques that enable efficient therapy.

Outcomes of tyrosine kinase inhibitors after immunotherapy in advanced hepatocellular carcinoma: A multi-center study.

e16181 Background: Immune checkpoint inhibitors (ICIs) and tyrosine kinase inhibitors (TKIs) are widely adopted in contemporary advanced HCC (aHCC) treatment algorithms. Nevertheless, the optimal strategy for treatment after ICI exposure is unknown. We evaluated the pattern of use, response, survival and safety of TKIs in aHCC patients who previously received ICIs. Methods: We performed an international, multi-centre study of aHCC patients who received TKIs after prior treatment with ICIs. Objective response rate (ORR), disease control rate (DCR), time-to-progression (TTP), overall survival (OS) and adverse events (AE) were assessed. Results: Between January 2015 and December 2020, one-hundred and forty-eight patients were included. The median age was 63 (range 29-84) and 78.4% were of Child-Pugh Grade A. 75.7% had hepatitis-B related HCC. 64.9% received TKI as single agent and 35.1% received TKI in combination with other agents. 75% who received TKI combinations had concomitant ICIs. 48.6% had prior TKIs. The median follow-up was 23.3 months. For single agent TKI patients, the ORR was 14.6%, DCR was 38.5%, median TTP was 3.9 months (95% C.I. 3.3-4.5) and median OS was 8.6 months (95% C.I. 5.8-11.4). For patients receiving TKI combinations, the ORR was 25%, DCR was 38.5%, median TTP was 3.5 months (95% C.I. 1.7-5.2) and median OS was 15.1 months (95% C.I. 5.7-24.5). There were no significant differences in ORR, DCR and median OS between patients who had primary resistance to prior ICI compared to those with acquired ICI resistance and between those who were TKI-naive compared to those who were TKI-exposed. Notably, patients who received TKI-ICI combinations had significantly superior survival compared to single agent TKI patients (median OS 15.1 months (95% C.I. 6.7-23.5) vs. 8.6 months (95% C.I. 5.6-11.7), p = 0.011) but not significantly superior ORR, DCR or TTP. Amongst patients who received single agent TKI and were naive to both sorafenib and lenvatinib, those who received lenvatinib had significantly superior DCR, TTP and OS compared to those who received sorafenib (DCR 51.5% vs 25.8%, p = 0.035; median TTP 6.3 months (95% C.I. 3.0-9.7) vs. 1.8 months (95% C.I. 0-3.6), p = 0.003; median OS 12.0 months (95% C.I. 7.0-17.0) vs. 5.9 months (95% C.I. 1.9-10.0), p = 0.008). 70.3% and 15.5% of all patients, and 77.1% and 15.6% of patients who received single agent TKI experienced all grade and grade ≥3 AEs respectively. The most common AEs were hand foot syndrome, skin rash and diarrhea. Conclusions: TKIs can achieve encouraging anti-tumour response and survival outcomes with acceptable safety in prior ICI-treated aHCC patients. Moreover, TKI-ICI combinations were associated with better survival than single agent TKIs. Notably, among patients who received single agent TKIs, lenvatinib had significantly better responses and survival results than sorafenib.

Treatment patterns and clinical outcomes of tyrosine kinase inhibitors in chronic‐phase CML in clinical practice: 3‐year European SIMPLICITY data

ObjectivesSIMPLICITY (NCT01244750) is an observational study of patients with chronic‐phase chronic myeloid leukemia (CP‐CML) in routine clinical practice receiving first‐line tyrosine kinase inhibitors (TKIs). We evaluated TKI treatment changes and how switching affects clinical response in patients recruited in Europe with ≥3 years of follow‐up.MethodsThe SIMPLICITY European cohort (France, Germany, Italy, the Netherlands, Russia, and Spain) included 431 patients. 370 (86%) were followed for ≥3 years.ResultsProportions of patients experiencing treatment interruptions, TKI switching, and discontinuations decreased over 3 years’ follow‐up. Intolerance was a key driver for treatment changes. Complete cytogenetic response (CCyR) was achieved in 87.5% of patients switching TKI within 3 years of initiation vs 91.7% of non‐switchers. Major molecular response (MMR) was achieved in 82.4% of switchers vs 92.9% of non‐switchers. Over 3 years, not switching TKI was a strong predictor for achieving CCyR or MMR (both P < .05). Three‐year survival remained high, irrespective of treatment changes (95.3% switchers, 96.4% non‐switchers).ConclusionsEuropean patients with CP‐CML who do not switch TKI are more likely to achieve clinical response, while intolerance is a key driver for switching. Successful CML management may require careful selection of initial TKI, with early monitoring of response and intolerance.

Establishment and validation of a novel droplet digital PCR assay for ultrasensitive detection and dynamic monitoring of EGFR mutations in peripheral blood samples of non-small-cell lung cancer patients

BackgroundDroplet digital PCR (ddPCR)-based blood detection of EGFR mutations plays significant roles in the individualized therapy of non-small-cell lung cancer (NSCLC) patients. However, a standard assay that is approved by health authorities is still lacking. Additionally, the proper application of this method in clinical settings also needs further investigation. MethodsThe performance of a newly established ddPCR assay was first evaluated using reference samples and then validated by comparing this method with the amplification refractory mutation system (ARMS) using cell-free DNA (cfDNA) in patients’ peripheral blood. Further, the correlation between dynamic quantification of EGFR mutation in the patients and their clinical outcome of tyrosine kinase inhibitors (TKIs) therapy was investigated. ResultsA total of 77 patients were included, with 50 in the test group and 27 in the validation group. According to the results of the reference samples and the blood samples in the test group, the cut-off value for patient detection was proposed as mutation rate ≥ 0.1% (total copy number of cfDNA ≥ 1000) or at least one copy of mutation DNA was detected (total copy number of cfDNA < 1000). With this criterion, superior sensitivity of our assay to that of ARMS was observed (P = 0.002 for Ex19Del & L858R and P < 0.001 for T790M). The dynamic quantification of EGFR mutations during TKI therapy indicated that an increase in mutation abundance was correlated with resistance, while a decline was associated with response. Notably, a rebound in mutation abundance during chemotherapy may indicate a desirable chance for TKI re-treatment. ConclusionThe novel ddPCR assay showed superior sensitivity in the detection of EGFR mutation in blood. The dynamic quantification of EGFR mutations by this assay would greatly facilitate the administration of TKI therapy, including the monitoring of resistance and response, as well as cohort screening for retreatment.

Impact of Use of Gastric-Acid Suppressants and Oral Anti-Cancer Agents on Survival Outcomes: A Systematic Review and Meta-Analysis.

We performed a systematic review and meta-analysis to evaluate the role of gastric acid suppressant use on outcomes of tyrosine kinase inhibitors (TKIs) and oral chemotherapy. We identified all research evaluating the effect of GAS (gastric acid suppressants) use on patients receiving oral chemotherapy or TKIs for solid tumors. The pooled hazard ratios (HRs) and 95% confidence interval (95%CI) for overall survival (OS) and progression-free survival (PFS) were calculated with a fixed-effects or a random effects model. The study population included n = 16 retrospective studies and 372,418 patients. The series concerned gastrointestinal tract tumors (n = 5 studies), renal cell carcinomas (RCC, n = 3 studies), non-small cell lung cancers (NSCLC, n = 5 studies), and soft tissue sarcomas or mixed histologies solid tumors in n = 3 studies. The pooled HRs for OS and PFS were 1.31 (95%CI: 1.20–1.43; p < 0.01) and 1.3 (95%CI 1.07–1.57; p < 0.01) for GAS and no GAS users, respectively. Only studies of EGFR (epidermal growth factor receptor) mutated NSCLC patients receiving TKIs and those with colorectal cancer receiving oral chemotherapy showed a significant correlation between GAS and poor survival. Our study supports the evidence of a possible negative impact of concomitant GAS therapy on survival outcomes of patients receiving oral anti-cancer drugs.

Sarcopenia is a prognostic factor for TKIs in metastatic thyroid carcinomas.

Among patients with various cancers receiving anticancer drugs, sarcopenia is associated with poor survival and treatment outcomes. We conducted an observational study using skeletal muscle index (SMI) evaluation to investigate the association between sarcopenia and treatment outcomes of tyrosine kinase inhibitors (TKIs) in metastatic thyroid cancer patients. We included 54 patients (19 men, 35 women; age, 66.5 ± 10.9 years) with differentiated thyroid carcinoma (DTC) or medullary thyroid carcinoma (MTC). The records of patients with metastatic DTC and MTC treated with TKIs were retrospectively reviewed. Patients were divided into sarcopenia and non-sarcopenia groups based on SMI. The SMI cutoff values for sarcopenia were 42 and 38 (cm2/m2) for males and females, respectively. Thirty-three patients had sarcopenia before TKI treatment. The sarcopenia group had more females and a lower body mass index. The median progression-free survival (PFS) durations were 13.6 (95% confidence interval (CI): 6.1-29.9) and 41.9 (95% CI: 25.2-not estimable) months in the sarcopenia and non-sarcopenia groups (p= 0.017), respectively. Univariate analysis showed that sarcopenia was significantly associated with PFS (p= 0.037). Sex, age, and performance status did not affect PFS. Multivariate analysis showed that sarcopenia was the only independent prognostic factor for PFS (hazard ratio: 2.488, 95% CI: 1.058-5.846, p= 0.037). Sarcopenia could be a predictive factor of TKI treatment outcomes in patients with metastatic thyroid cancer as well as intervention target to improve prognosis. Further prospective investigations are needed to confirm these preliminary data.

Survival outcome of tyrosine kinase inhibitors beyond progression in association to radiotherapy in oligoprogressive EGFR-mutant non-small-cell lung cancer.

Aim: The association of tyrosine kinase inhibitors (TKIs) and local radiotherapy in EGFR-mutated non-small-cell lung cancer patients experiencing disease progression under TKIs could be a valid an option. Patients & methods: We included 131 patients experiencing disease progression during first-line TKI. In group A, patients received TKI beyond progression and site(s) of progression were irradiated; in group B, patients remained on TKI alone beyond progression; and group C stopped TKI at first disease progression. Results: Median overall survival resulted longer in group A versus B and C (p<0.0001). Group A had a trend toward a longer second progression-free survival (measured from the time of first progression until second progression) versus group B (p=0.06). Conclusion: TKI beyond progression in association with local ablative treatment is a valid treatment option in oligoprogressive patients.

JCSE01.03 Any Difference on Efficacy and Toxicity Between East and West?

Lung cancer is now the most commonly diagnosed cancer and the leading cause of cancer related mortality, taking about 1.6 million lives each year. There has been long evidenced that different population display differential sensitivity and safety profiles on different treatment. in addition, many other factors can also influence therapeutic response of patients, such as lifestyle, metabolism, dietary etc. Here we try to explore the impact and underlying mechanism of ethnic difference on response and tolerance of various therapeutic regimens such as cytotoxic chemotherapy, TKIs, antiangiogenic drugs and ICIs. Treatment patterns of lung cancer has been transformed over the years, leading to the better outcomes of patients. The 5-year overall survival (OS) rate of advanced NSCLC is less than 5% in the standard chemotherapy era. Although widely used of tyrosine kinase inhibitors (TKIs) prolonged progression-free survival (PFS) and OS in patients harboring driver gene mutations, the long-time survival rate was still low due to acquired drug resistance. Over the last five years, emergence of immune checkpoint inhibitors (ICIs) has greatly improved outcomes of NSCLC with objective response rate (ORR) about 20% and 5-year OS rate nearly 16% in previous treated patients based on multiple clinical trials data. A retrospective review of the SEER database found that Asian population presented with higher percentage of metastatic lung cancer but significantly greater overall survival rate among nine different ethnic groups. Furthermore, among the total Asian population, Chinese has the highest percentage of adenocarcinomas (69.4%). The latest data show mutation rate of epidermal growth factor receptor (EGFR) in Adenocarcinoma is 40.3∼64.5% and 75% in certain clinically enriched population such as non-smoking adenocarcinoma. These data can fully explain the better outcomes of TKIs in Asia population. There has evidence that different population has different sensitivity and toxicity to different anti-tumor regiments. Studies showed that hematological toxicities of docetaxel were more frequently observed in Japanese compared to US/European patients. In addition, it is reported that docetaxel-induced grade 3/4 neutropenia is higher in Asian clinical trials than non-Asian trials. On the other hand, the discrepancy of dosage regimen between Japanese (60 mg/m2) and western population implies ethnic difference in PK. Similar data of carbo-platin/paclitaxel and irinotecan-based regimens have been reported in many phase 3 or phase 2 trials. Meanwhile, there are many studies compared the adverse events of TKIs in different ethnics and data suggested that incidence of ILD caused by gefitinib and erlotinib is higher in Japan (1.2∼5.4%) than in the rest of the world. Despite promising outcomes of ICIs, the clinical trials for Asia population is still rare now. Checkmate 078 was the first trial to predominantly recruit Chinese NSCLC patients, the ORR of Chinese population was 17%, which is in accordance with Caucasian population. However, according to PMS study of Japan and several published meta-analysis results, Asian patients were more likely to develop pneumonitis with the incidence rate 5.7∼9.6% in ICIs mono-therapy and these rates would be increased significantly when combined with other drugs. Many genetic studies have revealed the prevalence of genetic polymorphisms (i.e. mutation of SFTPC, ABCA3; telomere-associated genes like TERT, TERC, RTELI, PARN; SNP of MUC5B etc.) was associated with susceptibility to ILD in Japanese. Understanding characteristics of genomic profile will be of no doubt to facilitate the selection of targeted population of ICIs. Except for the toxicity of ICIs, we should pay attention to the drug response of particular groups of population, which were excluded from clinical trials according to the entry criteria of RCT. Among these HBV-infected NSCLC patients seemed to be more emergency as HBV infected population of Asia is accounted for 62% of global HBV burden, therefore, efficacy and toxicity of ICIs on HBV infected NSCLC patients will be discussed based on many clinical trials or real world data. In a word, ethnic difference can influence efficacy and toxicity of different treatment options. More genomic mapping and preclinical research should be implemented to explore the relationship between ethnic diversity and varying degrees of response. ethnic, efficacy, toxicity, TKIs, ICIs

Outcomes of tyrosine kinase inhibitors (TKI) after immunotherapy in unresectable or advanced hepatocellular carcinoma (HCC) patients.

361 Background: The outcomes of tyrosine kinase inhibitor(TKI) treatment after immune checkpoint inhibitors (PD-1i, PD-L1i, CTLA-4i) in unresectable/advanced HCC population is largely unknown. Methods: Retrospective analysis of advanced HCC patients treated with immune checkpoint inhibitors followed by TKI therapy at Queen Mary Hospital, Hong Kong were reviewed for the outcomes. Patients received locoregional therapy immediately after immunotherapy were excluded. Results: From January 2016 to July 2018, 30 HCC patients (83% of HBV, 80% of Child Pugh A, 83% of EHS/ MVI, median AFP=1,353ng/mL) who received TKI (11 lenvatinib, 10 sorafenib, 6 regorafenib, 3 axitinib) after immunotherapy were identified. TKI post-immunotherapy ("index TKI") was administered as third-line or beyond in 70% of patients. At the time of analysis (September 2018), median duration of index TKI was 72 days (IQR 36- 119∗) (∗3 patients were still receiving TKI). AFP declined in 53% of patients and the median change from baseline to nadir was -25% (IQR -65% to +6%). 40% of patients received subsequent systemic therapy. Median OS from index TKI was 602 days (95%CI 124-not reached; death event rate: 47%). 3 patients achieved partial response to TKI and they had at least stable disease with the previous immunotherapy. No unexpected safety issues of TKI and death related to adverse events were noted (table). Conclusions: TKI is active with good tolerabilty following immunotherapy in advanced HCC patients.[Table: see text]

Clinical outcome of tyrosine kinase inhibitors alone or combined with radiotherapy for brain metastases from epidermal growth factor receptor (EGFR) mutant non small cell lung cancer (NSCLC).

This study compared treatment outcomes between TKI monotherapy and TKI administration combined with brain radiotherapy (TKI + RT) in 133 non-small cell lung cancer (NSCLC) patients with brain metastasis (BM). We also evaluated the association of different epidermal growth factor receptor (EGFR) mutation subtypes with treatment outcome. To screen for potential variables affecting cranial progression free survival (PFS) and overall survival (OS), we performed univariate and multivariate analysis based on Cox proportional-hazards models. Median cranial PFS and OS were longer for the TKI + RT group (n = 67) than TKI alone group (n = 66). Intracranial metastasis correlated with a better median OS than extracranial metastasis. For patients with exon 21 mutations, TKI + RT yielded a better median OS and cranial PFS than TKI alone. However, there were no significant differences in median OS and cranial PFS between the two treatment groups for patients with exon 19 deletions. Thus EGFR-mutant NSCLC patients with BM could benefit more from TKI + RT than from TKI monotherapy, especially when they suffer from exon 21 mutations. However, TKI + RT confers no advantage over TKI treatment alone for patients with exon 19 deletions. These results underscore the urgent need to develop individualized disease management strategies in clinical practice.

A retrospective study of the prescribing and outcomes of tyrosine kinase inhibitors in chronic myeloid leukaemia over a period of more than 10 years.

Since their introduction, tyrosine kinase inhibitors (TKIs) have been increasingly used in clinical practice. We describe the prescribing and the clinical and biological consequences of two such inhibitors, imatinib and erlotinib, in patients with chronic myeloid leukaemia (CML) in a practice setting over a period of more than 10 years. All patients who received at least one TKI for chronic phase CML between 2001 and 2012 in our university hospital were included in the study. Of the 139 patients, with a median age of 57 years, who were surveyed, imatinib and nilotinib were prescribed as the first TKI in 131 (94%) and 8 (6%) patients, respectively. With a median follow-up of 6 years, 342 treatment modifications were observed: 113 (33%) increased doses, 109 (32%) decreased doses, 89 (26%) TKI changes, 14 (4%) definitive discontinuations, 13 (4%) temporary discontinuations and 4 (1%) additions of IFN-α. The main reasons for the 342 treatment modifications were adverse events (n = 112, 33%), long-term optimal response (n = 58, 17%) and failure (n = 57, 17%). Eighty-five (61%), 31 (22%), 18 (13%) and 5 (4%) patients had no, 1, 2 and 3 TKI changes, respectively. Imatinib was the most prescribed TKI (75%). Adverse events resulting in treatment modifications occurred in 18% of patients for imatinib, 49% for nilotinib and 41% for dasatinib (P < 0·001). Median time to TKI change whatever the reason was >50 months (not achieved) for imatinib, 22 months for nilotinib and 27 months for dasatinib (log-rank test, P < 0·001). Imatinib was the most prescribed TKI both in the first and in subsequent therapeutic lines for chronic phase CML. Our study showed a very good efficacy-safety profile for imatinib at a median follow-up of 6 years in an unselected French population.

Single-nucleotide polymorphisms of ABCG2 increase the efficacy of tyrosine kinase inhibitors in the K562 chronic myeloid leukemia cell line

The tyrosine kinase inhibitors (TKIs) used in the treatment of chronic myeloid leukemia are substrates for the efflux transport protein ATP-binding cassette subfamily G member 2 (ABCG2). Variations in ABCG2 activity might influence pharmacokinetics and therapeutic outcome of TKIs. The role of ABCG2 single-nucleotide polymorphisms (SNPs) in TKI treatment is not clear and functional in-vitro studies are lacking. The aim of this study was to investigate the consequences of ABCG2 SNPs for transport and efficacy of TKIs [imatinib, N-desmethyl imatinib (CGP74588), dasatinib, nilotinib, and bosutinib]. ABCG2 SNPs 34G>A, 421C>A, 623T>C, 886G>C, 1574T>G, and 1582G>A were constructed from ABCG2 wild-type cDNA and transduced to K562 cells by retroviral gene transfer. Variant ABCG2 expression in cell membranes was evaluated and the effects of ABCG2 SNPs on transport and efficacy of TKIs were measured as the ability of ABCG2 variants to protect against TKI cytotoxicity. Wild-type ABCG2 had a protective effect against the cytotoxicity of all investigated compounds except bosutinib. It was found that ABCG2 expression provided better protection against CGP74588 than its parent compound, imatinib. ABCG2 421C>A, 623T>C, 886G>C, and 1574T>G reduced cell membrane expression of ABCG2 and the protective effect of ABCG2 against imatinib, CGP74588, dasatinib, and nilotinib cytotoxicity. These findings show that the ABCG2 SNPs 421C>A, 623T>C, 886G>C, and 1574T>G increase the efficacy of investigated TKIs, indicating a reduced transport function that might influence TKI pharmacokinetics in vivo. Furthermore, the active imatinib metabolite CGP74588 is influenced by ABCG2 expression to a greater extent than the parent compound.

Outcomes Of Tyrosine Kinase Inhibitors In Combination With Various Treatments Regimens In Adult Patients With Philadelphia Chromosome Positive Acute Lymphocytic Leukemia

BackgroundPhiladelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL) is characterized by t(9;22) and is associated with poorer outcomes. Ph+ ALL responds initially to conventional chemotherapy but overall survival (OS) is low at < 20% with no curative form of post-remission chemotherapy. Allogeneic hematopoietic stem cell transplantation (HSCT) in first remission has historically been the only curative treatment modality, yet only cures approximately 30% of patients, typically in younger patients (less than 60 years of age). The introduction of tyrosine kinase inhibitors (TKIs) that target the fusion protein Bcr-ABL have altered the management of Ph+ ALL, with durable remission of 40-50%. Debate remains over the optimal chemotherapy “backbone” to combine with TKIs in the treatment of Ph+ ALL, given outcomes reported using nonmyeloablative approaches (Foà R, et al. Blood 2011; 118:6521). MethodsWe conducted a single-center, retrospective analysis of patients with newly diagnosed Ph+ ALL treated with various induction regimens in combination with TKIs. Patients aged 18 or older were included and comparisons were made between regimens considered to be intensely myelosuppressive (IMS) (i.e. hyperCVAD or ALL-2) and regimens considered less myelosuppressive (LMS) (i.e. ECOG 2993, L-20, or vincristine ± corticosteroids). The primary endpoint was a comparison of overall survival between treatment groups. Secondary endpoints included assessment of complete remission (CR) rates, disease free survival (DFS), likelihood to proceed to allogeneic HSCT, the effect of HSCT on overall survival, and hematologic and non-hematologic toxicities. ResultsTwenty-seven patients were included in this analysis. In combination with imatinib or dasatinib, eighteen patients were treated with IMS regimens while nine patients received LMS regimens. The groups were well-matched in baseline characteristics other than age (median: IMS - 49.6 years old vs. LMS -70.6 years old, p = 0.022). CR rates were high in both treatment groups (IMS - 94.4% vs. LMS -88.9%). No difference was observed in overall survival between the groups (3-year OS rate: IMS - 43.2% vs. LMS - 44.4%, Log-rank p = 0.921). There was a nonsignificant difference in DFS for patients favoring with IMS regimens (3-year DFS rate: IMS -43.2% vs. LMS - 33.3%, Log-rank p = 0.606). Patients treated with IMS regimens were more likely to proceed to transplant in CR1 [IMS - 88.2% (n = 15/17) vs. LMS - 22.2% (n = 2/ 9), p = 0.002). When evaluating the impact of HSCT on 3-year OS using a landmark analysis of 6 months post-induction therapy there was no difference between 13 patients who proceeded to HSCT compared to the 9 who did not (3-year OS rate post landmark: Yes HSCT - 33.7% vs. No HSCT - 55.6%, Log-rank p = 0.4). Overall, the toxicity during induction was similar in both treatment groups despite the increased myelosuppression that was expected in the more intense treatment group (100% experience grade 3 or greater hematologic toxicity vs. 89.9%). Among patients who achieve ANC>1000, those receiving LMS regimens did have a decrease in time to achieve this benchmark, though statistically it was not significant (median: 16 days vs. 21 days, p = 0.243). ConclusionWhile limited by the small sample size, it appears that the combination of TKIs with either IMS or LMS treatment regimens will achieve high CR rates. In our study OS was improved compared to historical controls prior to the introduction of TKIs and this includes a number of patients who did not undergo HSCT (Fielding AK, et al. Blood 2009; 113:4489-4496). It appears that in older patients who receive LMS regimens may not have inferior outcomes compared to younger patients who received IMS despite being far less likely to undergo HSCT in CR1. This finding may potentially prove to be significant given that up to 50% of patients with ALL older than 60 years of age are Ph+. [Display omitted] [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Different Strategies for First-Line Treatment of Chronic Myeloid Leukaemia: An Economic Analysis

AbstractAbstract 4696 Purpose:To evaluate the economic outcome of conventional and targeted therapies of patients with chronic myelogenous leukemia (CML). Methods:Two Markov simulation models were designed to measure the cost and quality-adjusted life years (QALYs) for newly diagnosed CML patients whether to be administered conventional therapy or six tyrosine kinase inhibitors (TKIs) based strategies. Clinical and utility data were taken mostly from the literature by a MEDLINE search. Costs were based on local charges. The primary output was reported in terms of incremental cost-effectiveness ratios (ICERs). Sensitivity analyses were performed to examine the robustness of the model output. The impact of patient assistance program (PAP) was assessed. Results:The imatinib plus peginterferon-Á switch 2nd TKIs strategy yielded the most health benefits for newly diagnosed CML patients when compared with the conventional, imatinib switch 2nd TKIs, imatinib switch conventional, imatinib plus IFN-Á switch conventional, nilotinib switch conventional and dasatinib switch conventional strategies (figure 1). Marginal cost-effectiveness was $79,134 or $17,600 per QALY gained relative to conventional strategy without or with PAP (figure 2). Both the nilotinib and dasatinib based strategies were more expensive yet less effective than the alternative strategies and were therefore dominated. Model outputs were sensitive to the cost of TKIs. Conclusion:Imatinib and imatinib plus peginterferon-Á based strategies are potentially more cost-effective and 2nd-generation TKIs may be preferred in the setting of imatinib failure. Patient assistant program in health resource limited setting might notably improve the economic outcome of TKIs based therapies. [Display omitted] [Display omitted] Disclosures:No relevant conflicts of interest to declare.

A comparison of ARMS and direct sequencing for EGFR mutation analysis and Tyrosine Kinase Inhibitors treatment prediction in body fluid samples of Non-Small-Cell Lung Cancer patients

BackgroundEpidermal growth factor receptor (EGFR) mutation is strongly associated with the therapeutic effect of tyrosine kinase inhibitors (TKIs) in patients with non-small-cell lung cancer (NSCLC). Nevertheless, tumor tissue that needed for mutation analysis is frequently unavailable. Body fluid was considered to be a feasible substitute for the analysis, but arising problems in clinical practice such as relatively lower mutation rate and poor clinical correlation are not yet fully resolved.MethodIn this study, 50 patients (32 pleural fluids and 18 plasmas) with TKIs therapy experience and with direct sequencing results were selected from 220 patients for further analysis. The EGFR mutation status was re-evaluated by Amplification Refractory Mutation System (ARMS), and the clinical outcomes of TKIs were analyzed retrospectively.ResultsAs compared with direct sequencing, 16 positive and 23 negative patients were confirmed by ARMS, and the other 11 former negative patients (6 pleural fluids and 5 plasmas) were redefined as positive, with a fairly well clinical outcome (7 PR, 3 SD, and 1 PD). The objective response rate (ORR) of positive patients was significant, 81.3% (direct sequencing) and 72.7% (ARMS) for pleural fluids, and 80% (ARMS) for plasma. Notably, even reclassified by ARMS, the ORR for negative patients was still relatively high, 60% for pleural fluids and 46.2% for plasma.ConclusionsWhen using body fluids for EGFR mutation analysis, positive result is consistently a good indicator for TKIs therapy, and the predictive effect was no less than that of tumor tissue, no matter what method was employed. However, even reclassified by ARMS, the correlation between negative results and clinical outcome of TKIs was still unsatisfied. The results indicated that false negative mutation still existed, which may be settled by using method with sensitivity to single DNA molecule or by optimizing the extraction procedure with RNA or CTC to ensure adequate amount of tumor-derived nucleic acid for the test.