We identified novel gene fusions in patients with lung cancer harboring the kinase domain of the NTRK1 gene that encodes the TRKA receptor. Both the MPRIP-NTRK1 and CD74-NTRK1 fusions lead to constitutive TRKA kinase activity and are oncogenic. Treatment of cells expressing NTRK1 fusions with inhibitors of TRKA kinase activity inhibited autophosphorylation of TRKA and cell growth. Three of 91 lung cancer patients (3.3%), without known oncogenic alterations, assayed by NGS or FISH demonstrated evidence of NTRK1 gene fusions.

ZD1839 was well tolerated, with DLT observed at a dose well above that at which antitumor activity was seen. Pharmacokinetic analysis confirmed that ZD1839 was suitable for administration as a once-daily oral tablet formulation. Phase II monotherapy and phase III combination trials in NSCLC are being conducted to investigate further the efficacy, tolerability, and optimal daily dose of ZD1839.

Colorectal cancer (CRC) is increasingly appreciated as a heterogeneous disease, with factors such as microsatellite instability (MSI), cancer subsite within the colon versus rectum, and age of diagnosis associated with specific disease course and therapeutic response. Activating oncogenic mutations in KRAS and NRAS are common in CRC, driving tumor progression and influencing efficacy of both cytotoxic and targeted therapies. The RAS mutational spectrum differs substantially between tumors arising from distinct tissues. Structure-function analysis of relatively common somatic RAS mutations in G12, Q61, and other codons is characterized by differing potency and modes of action. Here we show the mutational profile of KRAS , NRAS , and the less common HRAS in 13,336 CRC tumors, comparing the frequency of specific mutations based on age of diagnosis, MSI status, and colon versus rectum subsite. We identify mutation hotspots, and unexpected differences in mutation spectrum, based on these clinical parameters.

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LBA8002 Background: B when added to chemotherapy, and E alone, each lead to improved survival in the treatment of patients (pts) with NSCLC (Sandler et al, NEJM 2006, 355:2542–2550; Shepherd et al, NEJM 2005, 353:123–132). Pre-clinical and clinical data (Herbst, J Clin Oncol 2007, 25: 4743–4750) suggest that the combination of B and E may improve the efficacy of NSCLC treatment. This potential was demonstrated in the BETA (B in combination with E compared with E alone for treatment of advanced NSCLC after failure of standard first-line chemotherapy) trial, a phase III trial in which progression free survival (PFS) was improved for patients treated with B + E (Hainsworth, Thoracic Oncol 2008, 3(11) Supp. 4:S302). Methods: The ATLAS study was designed to evaluate B + E (150 mg daily) versus B alone, following B + platin-containing doublet chemotherapy, in pts with stage IIIb/IV NSCLC. Enrolled pts were B-eligible, including pts with treated brain metastases, and pts anticoagulated with low molecular weight heparin(s). Pts with peripheral and/or extra-thoracic squamous tumors were also eligible. Pts received 4 cycles of B (15 mg/kg every 3 weeks) with chemotherapy. Pts who had not experienced disease progression (DP) or significant toxicity were then randomized to receive B + E or B + placebo (P). The primary objective of ATLAS was to compare PFS in pts receiving B + E versus B + placebo. Secondary objectives included the assessment of safety, and overall survival. A data safety monitoring committee (DSMC) monitored safety and efficacy. Results: 1,160 patients were enrolled and 768 randomized from May 2005 to May 2008. The DSMC recommended stopping the trial at the second planned interim efficacy analysis, because it met the primary endpoint. The median PFS after randomization was 4.8 mos for (B + E) vs. 3.7 mos for (B + P), HR= 0.722 (95% CI: 0.592–0.881), p = 0.0012. The safety profile for B + E was consistent with known profiles for B and E. Conclusions: E added to B treatment after chemotherapy with B significantly improves the PFS of patients treated in the first-line setting for locally advanced, recurrent, or metastatic NSCLC. [Table: see text]

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Rearrangements involving the gene have been detected in dozens of cancer types using next-generation sequencing. Patients whose tumors harbor rearrangements or fusions respond to treatment with crizotinib and alectinib, including tumors not normally associated with mutations, such as non-Langerhans cell histiocytosis or renal cell carcinoma. Comprehensive genomic profiling using next-generation sequencing can detect targetable fusions irrespective of tumor type or fusions partner.

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