Ivana Sullivan

ALK inhibitors in non-small cell lung cancer: the latest evidence and developments.

The treatment of patients with advanced non-small cell lung cancer (NSCLC) harbouring chromosomal rearrangements of ALK (anaplastic lymphoma kinase) was revolutionized by crizotinib, a small molecule inhibitor of ALK, ROS1 and MET. Unfortunately, the disease progressed within the first 12 months in most of the patients because of the development of crizotinib resistance in the majority of patients and the emergence of acquired resistance mutations in most of them. Many of them had been reported even before its approval leading to the rapid development of second-generation ALK inhibitors for crizotinib-resistant NSCLC. In the last few years, novel potent ALK inhibitors with promising results and a good toxicity profile have become available: ceritinib (LDK378), alectinib (RG7853/AF-802/RO5424802/CH5424802), brigatinib (AP26113), entrectinib (RXDX-101, NMS-E628), PF-06463922, ASP3026, TSR-011, X-376/X-396 and CEP-28122/CEP-37440. Moreover, HSP90 (90 kDa heat shock protein) inhibitors have demonstrated clinical activity in patients with ALK+ NSCLC. This review focuses on the molecular and clinical properties of this new generation of ALK inhibitors under development in the clinic.

Next-Generation EGFR Tyrosine Kinase Inhibitors for Treating EGFR-Mutant Lung Cancer beyond First Line.

Tyrosine kinase inhibitors (TKIs) against the human epidermal growth factor receptor (EGFR) are now standard treatment in the clinic for patients with advanced EGFR mutant non-small-cell lung cancer (NSCLC). First-generation EGFR TKIs, binding competitively and reversibly to the ATP-binding site of the EGFR tyrosine kinase domain, have resulted in a significant improvement in outcome for NSCLC patients with activating EGFR mutations (L858R and Del19). However, after a median duration of response of ~12 months, all patients develop tumor resistance, and in over half of these patients this is due to the emergence of the EGFR T790M resistance mutation. The second-generation EGFR/HER TKIs were developed to treat resistant disease, targeting not only T790M but EGFR-activating mutations and wild-type EGFR. Although they exhibited promising anti-T790M activity in the laboratory, their clinical activity among T790M+ NSCLC was poor mainly because of dose-limiting toxicity due to simultaneous inhibition of wild-type EGFR. The third-generation EGFR TKIs selectively and irreversibly target EGFR T790M and activating EGFR mutations, showing promising efficacy in NSCLC resistant to the first- and second-generation EGFR TKIs. They also appear to have lower incidences of toxicity due to the limited inhibitory effect on wild-type EGFR. Currently, the first-generation gefitinib and erlotinib and second-generation afatinib have been approved for first-line treatment of metastatic NSCLC with activating EGFR mutations. Among the third-generation EGFR TKIs, osimertinib is today the only drug approved by the Food and Drug Administration and the European Medicines Agency to treat metastatic EGFR T790M NSCLC patients who have progressed on or after EGFR TKI therapy. In this review, we summarize the available post-progression therapies including third-generation EGFR inhibitors and combination treatment strategies for treating patients with NSCLC harboring EGFR mutations and address the known mechanisms of resistance.

Osimertinib in the treatment of patients with epidermal growth factor receptor T790M mutation-positive metastatic non-small cell lung cancer: clinical trial evidence and experience

Patients with advanced epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC) are particularly sensitive to treatment with first- or second-generation EGFR tyrosine kinase inhibitors such as gefitinib, erlotinib and afatinib, which block the cell-signaling pathways that drive the growth of tumor cells. Unfortunately, the majority of patients develop resistance to them after a median duration of response of around 10 months, and in over half of these patients the emergence of the EGFR T790M resistance mutation is detected. Osimertinib is an oral, highly selective, irreversible inhibitor of both EGFR-activating mutations and the T790M-resistance mutation, while sparing the activity of wild-type EGFR. This article reviews clinical trial development of osimertinib in patients with NSCLC, presenting efficacy and safety evidence for its value in the EGFR T790M mutation-positive population and in different settings, including patients with metastatic disease. The preclinical background of clinically acquired resistance to osimertinib is presented and the combination tactics being investigated in an attempt to circumvent this are addressed.

Targeting ALK-rearranged non-small-cell lung cancer: an update

Medical Oncology Department, Hospital de la Santa Creu i Sant Pau, Carrer Sant Quintí 89, 08026, Barcelona, Spain Medical Oncology Department, Gustave Roussy, 114 rue Édouard Vaillant, 94805, Villejuif Cedex, France *Author for correspondence: Tel.: +33 0 142 115 005; Fax: +33 0 142 116 064; david.planchard@gustaveroussy.fr

High-dose chemotherapy plus autologous stem cell transplation (HDCT/ SCT) in patients with sarcoma: A single institution experience.

10042 Background: Chemotherapy is the standard treatment in high risk advanced sarcomas. The role of HDCT/SCT is controversial in this patients (pt). We described our experience and long term results in sarcoma patients treated into a compassionate use program. METHODS From 12/1988 to 09/2007, 22 pt (16 male, 6 female) with advanced undifferentiated round cell soft tissue or bone sarcoma (15 (68%) Ewing S, 7 (32%) rhabdomyosarcoma) underwent HDCT/SCT; 10 pt had advanced locoregional sarcomas, 12 pt metastatic disease at onset.A minimum of 4x106 CD34+/kg cells were collected. 18 pt received conditioning HDCT regimen with (cyclophosphamide 1500 mg/m2, carboplatin 350 mg/m2, etoposide 400 mg/m2) iv x 3 d.; In 4 pt treated with double HDCT/SCT (tandem), conditioning was ifosfamide 2,500 mg/m2, carboplatin 360 mg/m2, etoposide 310 mg/m2 iv × 4 d. Only pts with CR and maximum PR to previous treatments were included (17 RC, 5 PR). One PR pt was included with an early progression before 1st ASCT. Eighteen pt received HDTC as 1st line treatment, 4 pt in recurrent disease. Previous treatment included CT (VAC-IE, others), surgery and/or RT. RESULTS Median follow-up was 39,8 m. Median age: 22 years (17 - 34); Post-HDCT/SCT all pt developed toxicity: grade (G) 4 hematologic, G 3-4 gastrointestinal, neutropenic fever. Severe venooclusive disease in 2. Two pt transplant-related death. After SCT 16 pt (80%) were CR, 1 (5%) PR, and 3 (15%) PD. The median PFS was 18.4 m (95%CI: 13.3-23.5). Median OS was 35 m (95% CI: 0-137). In the univariate analysis, PFS was significant according to sex (men: 18 vs 3m, p= 0.05) and complete response to HDCT (30m vs 3m, p= 0.002), and remains independent factors in the multivariate analysis. Age, histology and response to previous treatment showed a trend towards significance. Complete response to HDCT was the only independent significant factor for OS (143.5m vs 7.8m, p= 0.002). CONCLUSIONS HDCT is feasible without long term toxicities in this series. Disease response to HDCT was the best predictor for survival. Out of clinical trial, this treatment should not be considered an standard treatment, although it could be an option in selected patients.