Original studyA Phase II Trial of Saracatinib, an Inhibitor of src Kinases, in Previously-Treated Advanced Non–Small-Cell Lung Cancer: The Princess Margaret Hospital Phase II Consortium
Introduction
Non–small-cell lung cancer (NSCLC) is the most common cause of cancer death in North America. After first-line platinum-doublet combination chemotherapy, those patients who do not receive maintenance therapy may be eligible to receive additional treatment at the time of disease progression. Standard second-line chemotherapies are docetaxel1 and pemetrexed.2 Both these agents, in histology-unselected populations, lead to an objective response rate of less than 10%, a median survival of approximately 8 months, and a median progression-free survival of 3 months. Although some patients benefit from these agents, a large proportion does not, and more effective therapies are needed.
The src family of nonreceptor tyrosine kinases consists of 9 homologues, some of which (such as src and fyn) are ubiquitously expressed,3 and which integrate a number of cellular signaling pathways.4 Increased src tyrosine kinase activity in tumors is felt to contribute to the malignant phenotype, mediating processes such as migration, adhesion and proliferation, and src expression has been noted to increase as the disease progresses.5 Thus inhibition of dysregulated src may be a relevant therapeutic strategy.
Saracatinib (AZD0530, AstraZeneca, Macclesfield, UK), is an orally available inhibitor of multiple members of the src family of kinases, with IC50 values in the low nanomolar range. Additionally, it has moderate activity against Abl (IC50 30 nmol/L) and wild-type epidermal growth factor receptor (EGFR) tyrosine kinase (66 nmol/L), and more potent activity against certain mutated EGFR variants, such as L858R (5 nmol/L).6 It has demonstrated antitumor activity in preclinical models, predominantly by greater inhibition of cancer cell motility rather than inhibition of cell growth.6 In lung cancer models, saracatinib significantly impaired cell migration and invasion.7 The recommended phase II dose from the phase I study8 was 175 mg/d. The most common toxicities observed in the dose-finding study were asthenia, diarrhea and anemia; 2 episodes of pneumonitis were observed which were deemed possibly related to study therapy. This trial evaluated saracatinib in patients with previously-treated NSCLC. It was felt that saracatinib would have antimetastatic and cytostatic, but not necessarily cytotoxic, activity. Because it was unclear whether, as a single-agent, saracatinib would induce objective responses, the proportion of patients progression-free at 16 weeks was chosen as the primary end point. This magnitude of disease stabilization was felt by the investigators to be clinically relevant in this setting.
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Patients
This open-label, multicenter phase II study (NCT00638937) evaluated the activity of saracatinib in patients who had previously obtained at least stabilization of disease with first-line platinum-based combination chemotherapy for advanced, incurable NSCLC. Chemotherapy administered as adjuvant treatment or as part of a chemoradiation regimen for locally-advanced disease counted as treatment for advanced disease if the patient relapsed within 12 months of this therapy. Patients who were
Patients
Between July 2008 and October 2011, 37 patients were accrued at 3 sites in Canada (Table 1). All patients received at least 1 dose of study therapy and are included in the safety analysis. Thirty-one patients were evaluable for the primary end point: 1 patient was ineligible (determined on pathology review to have cervical cancer, not NSCLC), 3 withdrew consent without progression or toxicity that would mandate discontinuation after 6 doses, 1 and 2 cycles of therapy, respectively, and 2 were
Discussion
In this phase II trial in patients with platinum-pretreated advanced NSCLC, saracatinib demonstrated unexpected objective responses. In keeping with the phase I experience, fatigue and gastrointestinal complaints were the most common adverse events. These were, for the most part, easily managed, only rarely of grade-3 severity, and only infrequently required a dose interruption or reduction. One episode of pneumonitis possibly related to saracatinib was observed. Patients with advanced NSCLC
Conclusion
Although this clinical trial did not meet its prespecified end point for declaring saracatinib an active agent in the second-line setting in NSCLC, it did show some evidence of single-agent activity, warranting further study. Unfortunately, mutational analyses were hampered by limited availability of samples. In particular, there was insufficient material to analyze from the patient who had a 29% reduction in tumor measurements and was undergoing saracatinib therapy for more than 1 year or to
Disclosure
V. Hirsh reports receiving honoraria from AstraZeneca for advisory boards. F. Shepherd reports receiving consultancy fees from AstraZeneca. G. Goss reports receiving consultancy fees and research funding from AstraZeneca. All other authors report no conflicts of interest relevant to this manuscript.
Acknowledgments
Supported by contracts HHSN261201100032C/NO1-CM-2011-00032.
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Phosphoproteomic Analysis Identified Mutual Phosphorylation of FAK and Src as a Mechanism of Osimertinib Resistance in EGFR-Mutant Lung Cancer
2024, JTO Clinical and Research ReportsLncTx: A network-based method to repurpose drugs acting on the survival-related lncRNAs in lung cancer
2021, Computational and Structural Biotechnology JournalCitation Excerpt :A phase II trial showed that 4 out of 37 patients had stable disease for at least four months, and an additional two patients had partial response. This result suggested that a subset of NSCLC patients may have benefitted from saracatinib given that the molecular subtypes have been unclear [75]. Therefore, using ENSG00000268650 as a saracatinib therapeutic response biomarker may be worth further investigations in the future.
An exploratory randomized-controlled trial of the efficacy of the Src-kinase inhibitor saracatinib as a novel analgesic for cancer-induced bone pain
2019, Journal of Bone OncologyCitation Excerpt :The majority of adverse events were mild (83%) and needed observation only and no intervention (CTC grade 1), 14% were grade 2 adverse events and there was one grade 3 event that required hospitalization (incoherence in a patient randomized to placebo; subsequently diagnosed as progressive brain disease and unrelated to the study medication). In the saracatinib-treated group, the majority of the adverse events (73%) affected the gastrointestinal system, with 13% being neurological and 9% fatigue, in keeping with the known adverse event profile of saracatinib [26–39]. One patient experienced alopecia which led to her stopping the trial.
A randomised, placebo-controlled trial of weekly paclitaxel and saracatinib (AZD0530) in platinum-resistant ovarian, fallopian tube or primary peritoneal cancer
2014, Annals of OncologyCitation Excerpt :Saracatinib (AZD0530) is an orally available, dual Src/Abl kinase inhibitor, with high selectivity for Src and Abl, but relatively weak affinity for other tyrosine and serine-threonine kinases [12]. Although its single-agent activity in solid malignancies is limited [13–17], there was an RR of 24% when given in combination with weekly paclitaxel in a phase I study [18]. We thus conducted a multicentre, randomised phase II study of saracatinib in combination with weekly paclitaxel in women with recurrent, platinum-resistant ovarian cancer.