Sequence Of Tyrosine Kinase Inhibitors Research Articles

Executive summary of the American Radium Society appropriate use criteria for brain metastases in epidermal growth factor receptor mutated-mutated and ALK-fusion non-small cell lung cancer.

The American Radium Society (ARS) Central Nervous System (CNS) committee reviewed literature on epidermal growth factor receptor mutated (EGFRm) and ALK-fusion (ALK+) tyrosine kinase inhibitors (TKIs) for the treatment of brain metastases (BrMs) from non-small cell lung cancers (NSCLC) to generate appropriate use guidelines addressing use of TKIs in conjunction with or in lieu of radiotherapy (RT). The panel developed three key questions to guide systematic review: can radiotherapy be deferred in patients receiving EGFR or ALK TKIs at (1) diagnosis or (2) recurrence? Should TKI be administered concurrently with RT (3)? Two literature searches were performed (May 2019 and December 2023). The panel developed 8 model cases and voted on treatment options using a 9-point scale, with 1-3, 4-6 and 7-9 corresponding to usually not appropriate, may be appropriate, and usually appropriate (respectively), per the UCLA/RAND Appropriateness Method. Consensus was achieved in only 4 treatment scenarios, all consistent with existing ARS-AUC guidelines for multiple BrM. The panel did not reach consensus that RT can be appropriately deferred in patients with BrM receiving CNS penetrant ALK or EGFR TKIs, though median scores indicated deferral may be appropriate under most circumstances. Whole brain RT with concurrent TKI generated broad disagreement except in cases with 2-4 BrM, where it was considered usually not appropriate. We identified no definitive studies dictating optimal sequencing of TKIs and RT for EGFRm and ALK+ BrM. Until such studies are completed, the committee hopes these cases guide decision- making in this complex clinical space.

Administering immunotherapy after anti-vascular targeted therapy improves overall survival of patients with metastatic clear cell renal cell carcinoma.

The Food and Drug Administration of the United States has approved several drugs for treating advanced metastatic renal cell carcinoma, including anti-vascular tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs). Options for first-line therapy include monotherapy or combination therapy. However, selecting a suitable first-line and second-line treatments to improve overall survival remains an unresolved issue. To evaluate the overall survival (OS) and progression-free survival (PFS) of patients with metastatic clear cell renal cell carcinoma (mRCC). Patients were divided into several grouped according to the treatment sequence of TKI and anti PD-1 administration. The overall survival benefit was evaluated based on the order of administration of anti PD-1 and TKI. In this retrospective propensity-matched cohort study, we identified 135 patients with mRCC treated at the Affiliated Cancer Hospital of Shandong First Medical University from January 1, 2017, to December 31, 2022. These patients had received anti PD-1 treatment as part of their first or second line of therapy. Statistical analysis was performed from June 1, 2023, to August 1, 2023. The primary outcome measure was OS, from the date of diagnosis to death or the last follow-up. PFS was monitored during treatment. Survival analyses were conducted using Cox proportional hazards regression and Kaplan-Meier estimates. By comparing the complete treatment course of patients, the survival of patients in different groups was compared according to the number of immunotherapy lines. The final cohort comprised 135 patients, of whom 84 received first-line therapy with anti PD-1 (include 6 patients treated with anti PD-1 (tislelizumab, carrelizumab, toripalimab or sintilizumab) alone and 78 patients treated with anti PD-1 combined with anti-vascular TKI (axitinib, sunitinib, solfanitinib or pazopanib)). The remaining 51 patients were treated with anti PD-1 as second-line therapy following an initial regime of TKIs. Patients were initially categorized based on whether anti PD-1 were used in the first-line treatment. It was observed that the OS of patients receiving first-line targeted therapy was higher than those receiving first-line immunotherapy, with a median OS of 33 months versus 15 months. To investigate this outcome further, we refined the patient groups based on the administration sequence of anti PD-1 and TKIs in the treatment regimen. We found that the median PFS of patients with first-line treatments of TKI combined with anti PD-1 was 3.5 months, compared to 14.5 months when TKI combined with anti PD-1 followed first-line TKI (p=0.0092). The median PFS for second-line treatments was 6.5 months versus 15 months (p=0.0014). Similarly, the median OS was 16.66 months and 31.88 months, respectively (p=0.008). This study indicates that administering immunotherapy following anti-vascular therapy significantly enhances both OS and PFS compared to other sequences of therapies. This finding provides valuable insights and robust data support for clinical decision-making regarding treatment sequencing.

Effectiveness of Tyrosine Kinase Inhibitors in Patients with Chronic Myeloid Leukemia in Chronic Phase (CML-CP) after Two or More Prior Tyrosine Kinase Inhibitors

Introduction: Despite the availability of therapies that have broadened treatment choices and improved outcomes for patients with CML-CP, patients who have been treated with ≥2 prior tyrosine kinase inhibitors (TKIs) experience high failure rates due to resistance or intolerance, with outcomes worsening across lines of therapy. Previously presented real-world data on TKI treatment patterns in patients with CML-CP from 3 registries across different countries did not identify a common TKI sequence. Between 12.8% and 35.7% of patients starting treatment with a second line TKI required third line therapy and beyond (3L+) and 32.8% (124/378) of patients in 3L+ discontinued treatment, with treatment intolerance among the most frequent reasons for discontinuation. There is scarce information on response rates in patients treated with ≥2 prior TKIs and no established standard of care exists for these patients. Here we present data collected from CML registries on the effectiveness of different TKIs in patients with CML-CP initiating therapy after ≥2 prior TKI treatments. Methods: This non-interventional, descriptive, retrospective cohort study is based on secondary use of data from 3 existing CML registries (Czech INFINITY, Dutch PHAROS, and Swedish CML register). The observation period was from January 1, 2008, until the last available date of follow-up for each registry (6‒12 years depending on the registry). Patients with CML-CP aged ≥18 years and initiating a TKI after being treated with ≥2 prior TKIs were included in the analysis. Study index date was defined as the start date of treatment for each TKI used in the 3L+ setting. Effectiveness endpoints (major molecular response [MMR, BCR::ABL1IS ≤0.1%] rates by 6 and 12 months and overall survival [OS] rates) were analyzed separately for each TKI. Results for each registry are reported separately. Results: Among patients enrolled in the INFINITY, PHAROS, and Swedish CML registries, 105, 48, and 172 patients, respectively, started 3L+ TKI therapy and were included in this analysis. Across all 3 registries, the most frequently prescribed TKIs in the 3L+ setting were nilotinib (NIL; 52.4%, 58.3%, and 45.3%, respectively) and dasatinib (DAS; 38.1%, 16.7%, and 32.6%, respectively). NIL and DAS were mostly prescribed to patients who had received 2 prior TKIs at index, whereas bosutinib (BOS) and ponatinib (PON) were mostly prescribed in later treatment lines (BOS: 8/12 [66.7%], no data [ND], and 21/48 [43.7%] patients had received 3 prior TKIs at index, respectively; PON: 9/14 [64.3%], 3/8 [37.5%], and 7/19 [36.8%] patients had received 3 prior TKIs at index, respectively). At the time of TKI index, there were more patients already in MMR in the Swedish CML register compared with the other registries (Table 1). For patients not in MMR at the time of TKI index, the highest MMR rates by 12 months across all registries were observed on DAS (12/32 [37.5%], 3/8 [37.5%] and 14/34 [41.2%], respectively), followed by NIL (14/47 [29.8%], 6/21 [28.6%], and 13/46 [28.3%], respectively). MMR rates by 12 months were in general lower for BOS (2/11 [18.2%], ND, 7/21 [33.3%]) and PON (2/11 [18.2%], 2/8 [25.0%], 5/13 [38.5%]) (Table 2). The OS analysis showed that the median survival time was longest for NIL (42.5, ND, and 45.0 months, respectively), followed by DAS (34.5, 68.0, and 40.9 months, respectively). Conclusion: This is the most comprehensive study to date analyzing TKI response rates based on real-world data from patients with CML-CP treated in the 3L+ setting. The number of patients in each registry was low, which may explain the variability of response and limits comparability across TKIs. However, a common pattern of treatment was observed across the 3 countries, with BOS and PON being used more frequently in patients treated with ≥3 prior TKIs; this could explain some of the differences in response rates. In the Swedish CML register, the high number of patients in MMR at the time of TKI switch may suggest that intolerance is a frequent reason for switching TKI; this is consistent with the reasons for discontinuation reported in a previous analysis. This study contributes to the evidence on real-world response rates of TKI treatment in CML-CP. This study was a research collaboration between Novartis and the 3 registries and was funded by Novartis. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Immune checkpoint inhibitors and tyrosine kinase inhibitors in patients with advanced hepatocellular carcinoma: Does the sequence matter?

Combination therapy with immune checkpoint inhibitor (ICI) and antivascular endothelial growth factor (anti-VEGF) is currently the first line treatment for advanced hepatocellular carcinoma (aHCC). However, there are many patients who may not be able to receive combination therapy due to underlying comorbidities or resource limitations. For these patients, systemic treatment options include single agent tyrosine kinase inhibitors (TKIs) or ICI monotherapy. However, whether an optimal sequence of systemic therapy exists remains unknown. We aim to explore the impact of sequencing of TKI and ICI therapy in terms of response rates and to examine the safety of their use in sequential order. Patients with aHCC treated with both ICI and TKI between December 30, 2013 and June 13, 2018 were retrospectively identified. Patients were classified into two groups: those who received TKI in the first-line (TKI1), followed by ICI (ICI2) and those who received ICI (ICI1) in the first-line followed by TKI (TKI2). The primary objective of the study was to identify differences in objective response rate (ORR) and disease control rate (DCR), as evaluated based on response evaluation criteria in solid tumor v1.1 for TKI1, TKI2, ICI1, and ICI2. Secondary objectives included comparison of progression free survival (PFS) for each line of therapy, overall survival (OS) and adverse events (AEs). Twenty-seven and 23 patients were classified into group 1 and 2, respectively. Objective response rates of TKI1 and TKI2 were 3.8% and 17.6%, respectively (p=.28); DCR to TKI1 versus TKI2 was 23.1% versus 35.3% (p=.49). ORRs of ICI1 and ICI2 were 8.7% and 14.3%, respectively (p=.66); DCR to ICI2 versus ICI1 was 56.5% versus 42.9% (p=.37). Median PFS was not significant between TKI1 and TKI2 (PFS 3.06 versus 1.61 months, p=.097) as well as between ICI2 and ICI1 (PFS 1.84 versus 2.37 month, p=.32). Median OS was also not significantly different between both groups (OS 20.63 versus 13.93 months, p=.20) on univariable and multivariable analysis (OS adjusted hazard ratio [HR] 2.07, 95% CI .83-5.18, p=.118). The proportion of patients who experienced adverse events of any grade was similar in both groups (TKI1 59.3% versus TKI2 52.2%; ICI1 78.3% versus ICI2 70.4%). Our study suggests that the sequence of TKI versus ICI therapy in patients with aHCC may not matter, given similar efficacy and toxicity profile when either agent is received in the first or second-line setting. This finding is of value in the real-world setting, where patients may be frail or have comorbidities that render them unable to tolerate combination therapy (ICI and TKI/anti-VEGF). For these patients, sequential exposure to both classes of drugs (ICI and TKI) may be a suitable option.

Abstract 660: Predicting imatinib responses in exon 18 PDGFRA-mutant GIST

Abstract Gastrointestinal stromal tumor (GIST) is the most common GI sarcoma and frequently harbor oncogenic mutations in KIT or platelet derived growth factor receptor alpha (PDGFRA) receptor tyrosine kinases. While type II tyrosine kinase inhibitors (TKIs) revolutionized the treatment of KIT-mutant GIST, they are thought to be ineffective for many PDGFRA-mutant GIST cases. Over 80% of PDGFRA mutations in GIST occur in exon 18 and patients with the most common mutation, D842V, are resistant to imatinib and other type II TKIs, leading to poor outcomes. However, beyond D842V, numerous other PDGFRA exon 18 mutations have been observed. From curated data of a large cohort of PDGFRA-mutant GISTs, we have identified nearly 50 unique PDGFRA exon 18 mutations, including both point mutations and complex indels. Although it is largely unknown how these mutations respond to imatinib, currently most, if not all, PDGFRA exon 18 mutations are assumed to be imatinib resistant. Using cell models, we tested some of the most commonly observed mutations in this cohort. Contrary to dogma, we observed that some exon 18 mutations tested were imatinib sensitive. We also observed that imatinib sensitivity seemed to be dependent on the properties of the residue in the 842-codon position, which encodes a key auto-inhibitory residue. We then hypothesized that imatinib sensitivity of every known or future reported PDGFRA exon 18 mutation might be predicted based on the 842 residue. To test the predictive potential of the 842 residue, we created mutagenic libraries that included every amino acid substitution at the 842 position. We expressed each mutation in Ba/F3 cells and assessed imatinib sensitivity via immunoblotting for phosphorylated-PDGFRA. Overall, 40% of tested mutations were sensitive to imatinib, further debunking the belief that all PDGFRA exon 18 mutations are imatinib resistant. In agreement with our hypothesis, we found that any hydrophobic residue at the 842 position conferred imatinib resistance (IC50 > 100nM), and all other amino acids tested to date were imatinib sensitive (IC50 < 100nM). Based on these data alone, over 55% of the 50 unique mutations identified from our PDGFRA-mutant GIST patient cohort would be predicted to be imatinib sensitive, demonstrating the importance of understanding the biochemical properties of various exon 18 mutations to predict treatment outcomes. Our predictive model would help identify patients with PDGFRA exon 18 mutations that could benefit from using front-line imatinib as an alternative to avapritinib, which has been recently approved for first-line treatment for all PDGFRA exon 18 mutant GIST. Imatinib, which has been used clinically for over 20 years, has a superior safety and tolerability profile compared to avapritinib. This paradigm shifting approach has the potential to transform patient care and outcomes by optimizing the sequencing of TKIs for PDGFRA-mutant GIST patients. Citation Format: Homma M. Khosroyani, Lillian R. Klug, Johanna Falkenhorst, Sebastian Bauer, Michael C. Heinrich. Predicting imatinib responses in exon 18 PDGFRA-mutant GIST [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 660.

P45.05 Sequencing of PD-1 Inhibitors and TKIs in Metastatic NSCLC with MET Exon 14 Skipping Mutation May Influence Survival

The treatment landscape for patients with metastatic non-small cell lung cancer with a MET exon 14 skipping mutation (MET ex14) is rapidly changing, with recent approvals of MET selective tyrosine kinase inhibitors (TKIs) and reports of durable response to immune checkpoint inhibitors (ICI). Currently there are no published data that inform the sequencing of TKIs and ICI regimens. We sought to characterize treatment patterns and sequencing outcomes at 3 Ontario cancer centres.

Sequencing of systemic therapies in advanced NSCLC with MET exon 14 skipping mutation: A multicenter experience.

e21123 Background: The treatment landscape for patients with metastatic non-small cell lung cancer (mNSCLC) with a MET exon 14 skipping mutation ( MET ex14) is rapidly changing, with recent approvals of MET selective tyrosine kinase inhibitors (TKIs) and reports of durable response to immune checkpoint inhibitors (ICI), particularly among those with sarcomatoid histology. Currently there are no published data that inform the sequencing of TKIs and ICI regimens. We sought to characterize treatment patterns and outcomes in this population at 3 Ontario cancer centres. Methods: We reviewed all mNSCLC patients with MET ex14 identified by tissue or plasma NGS in the last 4 years. Patients with EGFR co-mutation or MET amplification alone were excluded. All systemic therapies and outcomes of overall response (ORR), progression free survival (PFS), overall survival (OS), and adverse events (AEs) were captured. Results: We identified 43 patients with MET alterations, of whom 29 had MET ex14: median age 73 years (54-92), 66% female, 79% non-smokers. Tumor histology was adenocarcinoma in 76%, pleomorphic/sarcomatoid in 21% and adenosquamous in 3% of patients. 69% of patients had PD-L1 ≥50%. At presentation, 20% of patients had high disease burden and ECOG ≥2. Among 15 patients who received ICI, ORR with ICI monotherapy was 45% (10/11 had PD-L1 ≥50%) and ORR with ICI plus chemotherapy was 75% (4/4 had PD-L1 0-49%). Responses were seen in 50% of non-smokers (7/12 had PD-L1 ≥50%). The median PFS with ICI was 10.6 months (1.7-NR). MET TKIs were received by 18 patients (16 crizotinib, 1 capmatinib, 1 cabozantinib), with an ORR of 28% (30% amongst those who received crizotinib first line). The median PFS with TKIs was 2.6 months (1.2-8.9). Median OS for the entire cohort was 24.4 months (10.1-48.3). Patients who received initial ICI (n = 13) compared to those who received initial TKI (n = 11) had significantly longer OS (48.3 vs 13.6 months; p = 0.005), not controlled for prognostic factors. All patients who progressed after ICI (9/13) received further treatment while only 50% of patients who progressed after TKI (8/11) received subsequent therapy. 7 patients received TKI therapy after ICI with a median time to TKI of 35 days (24-181). 6 patients (85.7%) experienced an early grade ≥3 AE (4 transaminitis, 2 pneumonitis) resulting in permanent discontinuation of TKI in half of patients. There were no treatment-related deaths. Conclusions: Patients with MET ex14 NSCLC benefit from ICI irrespective of PD-L1 expression and smoking history. ORR and PFS with earlier generation TKIs (crizotinib) were poor. Increased toxicity is seen when a TKI is used after ICI and careful monitoring is necessary. Future studies focusing on the optimal sequencing of TKIs and ICI-containing therapy should be prioritized, as well as broader access to newer generation MET TKIs with greater activity.

Sequence of Second Generation Tyrosine Kinase Inhibitors (TKIs) in the Treatment of Patients with Chronic Phase Philadelphia Chromosome-Positive Chronic Myeloid Leukaemia - Real World Experience in the UK

Sequence of Second Generation Tyrosine Kinase Inhibitors (TKIs) in the Treatment of Patients with Chronic Phase Philadelphia Chromosome-Positive Chronic Myeloid Leukaemia - Real World Experience in the UK

Turning EGFR mutation-positive non-small-cell lung cancer into a chronic disease: optimal sequential therapy with EGFR tyrosine kinase inhibitors.

Four epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), erlotinib, gefitinib, afatinib and osimertinib, are currently available for the management of EGFR mutation-positive non-small-cell lung cancer (NSCLC), with others in development. Although tumors are exquisitely sensitive to these agents, acquired resistance is inevitable. Furthermore, emerging data indicate that first- (erlotinib and gefitinib), second- (afatinib) and third-generation (osimertinib) EGFR TKIs differ in terms of efficacy and tolerability profiles. Therefore, there is a strong imperative to optimize the sequence of TKIs in order to maximize their clinical benefit. Osimertinib has demonstrated striking efficacy as a second-line treatment option in patients with T790M-positive tumors, and also confers efficacy and tolerability advantages over first-generation TKIs in the first-line setting. However, while accrual of T790M is the most predominant mechanism of resistance to erlotinib, gefitinib and afatinib, resistance mechanisms to osimertinib have not been clearly elucidated, meaning that possible therapy options after osimertinib failure are not clear. At present, few data comparing sequential regimens in patients with EGFR mutation-positive NSCLC are available and prospective clinical trials are required. This article reviews the similarities and differences between EGFR TKIs, and discusses key considerations when assessing optimal sequential therapy with these agents for the treatment of EGFR mutation-positive NSCLC.

Chronic myeloid leukemia: sequencing of TKI therapies.

Multiple tyrosine kinase inhibitors (TKIs) are available for managing patients with chronic myeloid leukemia. Although most patients have a favorable outcome with their initial therapy, whether imatinib or a second-generation TKI was used, some will require subsequent use of one or more different TKIs. Such sequencing might be indicated in a reactive way (ie, for patients who have experienced resistance or intolerance to their initial therapy) or in a proactive way (ie, for patients with a somewhat favorable outcome who have not reached an "optimal" outcome). Sequencing of TKIs has become standard practice, and the proper use of sequenced TKIs is likely to optimize outcomes and resource utilization.

ASCO 2013: new developments in lung cancer

At American Society of Clinical Oncology meeting 2013, some new data were presented, which might have a practice-changing potential. Epidermal growth factor receptor mutational testing was successfully performed in plasma samples, giving hope that tumor biopsies might be replaced by a more comfortable blood analysis. Some studies focused on new second-generation anaplastic lymphoma kinase inhibitors, which showed an impressive efficacy even in crizotinib refractory patients in phase I/II studies and support a sequence of tyrosine kinase inhibitors (TKIs) in this sub-entity of non-small-cell lung cancer (NSCLC). Immunological strategies are worth being tested also in lung cancer, as different strategies have proven first signs of efficacy (MUC1 antigen-specific cancer immunotherapy, programmed cell death ligand 1). Finally, a large phase III trial found that a new oral vascular endothelial growth factor receptor, fibroblast growth factor receptor, and platelet-derived growth factor receptor TKI (nintedanib) combined with docetaxel improved outcome in second-line NSCLC patients when compared with docetaxel monotherapy.

Sequential therapy in metastatic renal cell carcinoma: what comes next?

Metastatic renal cell carcinoma (mRCC) is a fast-moving therapeutic field with multiple targeted agents approved and many more in development. In our expert agreement article [1], we evaluated available data together with our clinical experience to consider how we might optimize using targeted therapies in sequence, emphasizing the need continually to address the question, ‘‘what comes next?’’ Crucially, new phase III data presented at the American Society of Clinical Oncology (ASCO) 2011 annual meeting provide level 1 evidence that patients can receive continued clinical benefit when VEGF-targeted tyrosine kinase inhibitors (TKIs) are used sequentially [2, 3]. The randomized, open-label, phase III AXIS study compared second-line axitinib 5 mg bid (titrated to 7, then 10 mg bid, if tolerated) with sorafenib 400 mg bid in 723 patients with mRCC, more than half of whom had previously received the TKI sunitinib (n = 389) [2]. The study met the primary endpoint of superiority for axitinib, with median PFS 6.7 months, compared with 4.7 months for sorafenib (P \ 0.0001). Median PFS was lower in post-sunitinib than in the total patient population for both axitinib (4.8 months) and sorafenib (3.4 months; P \ 0.05 versus axitinib). Notably, and as discussed in our expert agreement article, this phenomenon was also seen in the phase III RECORD-1 study of everolimus in patients previously treated with sorafenib and/or sunitinib—prior sunitinib was prognostic of lower PFS and overall survival in a multivariate analysis [1]. The AXIS and RECORD-1 data, therefore, suggest that pre-treatment with effective VEGF-TKI therapy, such as sunitinib, has a detrimental effect on subsequent outcome with both VEGF-TKI therapy and mTOR inhibition. Therefore, cross-resistance between these two classes may be apparent. A further noteworthy publication at ASCO 2011, from Dr. Mhd Al-Marrawi on behalf of the International mRCC Database Consortium, showed that response to initial TKI therapy did not predict response to further TKI therapy [4]. This study did not report whether the sequence of TKIs received was important, but this question could be addressed in part by performing a similar analysis using the AXIS data—i.e., were ORR/stable disease/PFS with axitinib or sorafenib related to ORR/stable disease/PFS with sunitinib and were there differences between axitinib and sorafenib in this regard? Overall, the findings from AXIS, RECORD-1, and the International mRCC Database Consortium do not support the hypothesis that switching mode of action from VEGF inhibition to mTOR is the logical first step in the face of VEGF resistance. Re-challenging with VEGF-TKI therapy appears to be more attractive as the first treatment manipulation at present. Switching to mTOR as 3rd line or later, which is supported by randomized phase III data, gives us multiple lines of therapy with proven efficacy. On a further note, though it may be tempting to compare the efficacy data from AXIS with those for RECORD-1, there are a number of key differences between the studies, including patient population and study design, and so such comparisons are fundamentally flawed. Patient-reported outcomes from AXIS were also presented at ASCO [3]. Dr. David Cella showed that C. Porta (&) I.R.C.C.S. San Matteo University Hospital Foundation, Pavia, Italy e-mail: c.porta@smatteo.pv.it

Sequential therapies with sorafenib and sunitinib in advanced or metastatic renal cell carcinoma

To investigate whether patients with metastatic renal cell carcinoma benefit from sequential therapies with the tyrosine kinase inhibitors (TKIs) sorafenib and sunitinib. A total of 89 patients were treated in nine German centres between 2002 and 2009. The TKI sequence started as first-, second- or third-line therapy after prior chemo- or immunotherapy. When progression was diagnosed, treatment was switched to the second TKI until further progression. Overall progression-free survival (PFS) of patients receiving sunitinib followed by sorafenib shows no statistically significant difference to patients receiving sorafenib followed by sunitinib (15.4 months vs. 12.1 months). The secondary use of sorafenib resulted in a median PFS of 3.8 months if the TKI sequence had been started as a first-line treatment and of 3.5 months if the TKI sequence had been started second-line treatment. The secondary use of sunitinib resulted in a median PFS of 3.4 and 4.0 months, respectively. OS was 28.8 months for all patients, without a statistically significant difference between the two groups. This study endorses the notion of a clinical benefit of the sequential use of sorafenib and sunitinib and supports observations from previous studies. In terms of the optimal succession of the two TKIs, the study does not allow a definite answer.

Recent Advances and Future Directions in the Management of Metastatic Renal Cell Carcinoma

A better understanding of the molecular biology of renal cell carcinoma (RCC) and the emergence of tyrosine kinase inhibitors (TKIs) have revolutionized the treatment for patients with metastatic RCC (mRCC). Multikinase inhibitors (sunitinib and sorafenib) and the inhibitors of mammalian target of rapamycin (temsirolimus and everolimus) have recently shown superiority over IFN-alpha or placebo; and bevacizumab + IFN-alpha have demonstrated improved activity when compared to IFN-alpha alone in patients with mRCC. Newer anti-vascular endothelial growth factor (VEGF) agents such as axitinib, pazopanib and cediranib are currently under investigation to expand and elucidate future treatment options. Several studies have investigated the synergistic potential of TKIs with a view to blocking multiple signalling pathways simultaneously, but this approach has resulted in a significant increase in toxicity. Sequential TKI administration has demonstrated encouraging results but the optimal sequence of TKIs is yet to be determined. Studies combining TKIs with immunotherapy have resulted in varying degrees of success; with bevacizumab + IFN-alpha being the only studies with positive outcomes. The purpose of this review is to summarize the current evidence supporting the role of TKIs and to discuss potential future directions in the management of mRCC. The role of TKIs as monotherapy, in combination with immunotherapy or other TKIs (combined or sequential approach) will be discussed.

Appropriate sequencing of tyrosine kinase inhibitors in chronic myelogenous leukemia: when to change? A perspective in 2009

Kinase inhibitor therapy options for Philadelphia chromosome positive leukemias have rapidly developed and continue to expand. In 2001, imatinib was approved by the US Food and Drug Administration and revolutionized the treatment of chronic myelogenous leukemia (CML); in 2006 and 2007, approval of dasatinib and nilotinib followed for use in imatinib-resistant or intolerant disease; additional kinase inhibitors continue in development to optimize toxicity and circumvent resistance. Decision-making regarding key questions of initial therapy choice, role of allografting, and changes in therapy remains a fluid discussion; this review aims to give a current perspective. Imatinib remains a highly effective and well characterized choice for patients with CML in chronic phase; long-term toxicity continues to be assessed, and data surrounding stability of response are quite promising. Dasatinib and nilotinib have proven to be highly effective alternate approaches when imatinib is inadequate or intolerable, yet direct comparison in trials is lacking. Limited clinical and molecular data can aid in decision-making between these agents. Multiple options exist today for the treatment of Philadelphia chromosome positive leukemias. Careful monitoring of response and categorization based on guidelines, utilization of molecular diagnostics, particularly kinase domain mutation analysis, as well as early review of allograft options, can allow for efficient and optimal management of the chronic phase CML patient.