Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitors (TKIs) have changed the paradigm of treatment in non-small cell lung cancer (NSCLC). The molecular biology study of EGFR has led to clinical trials that select patients more accurately, regarding the presence of EGFR activating mutations. Nonetheless, a lack of response or a temporary condition of the response has been detected in patients on EGFR TKIs. This has urged to study potential resistance mechanisms underneath. The most important ones are the presence of secondary mutations in EGFR, such as T790M, or the overexpression of mesenchymal-epithelial transition factor (MET) that may explain why patients who initially respond to EGFR TKIs, may ultimately become refractory. Several approaches have been taken and new drugs both targeting EGFR resistance-mutation or MET are currently being developed. Here we review and update the EGFR biological pathway as well as the clinical data leading to approval of the EGFR TKIs currently in the market. New compounds under investigation targeting resistance mutations or dually targeting EGFR and other relevant receptors are also reviewed and discussed.

Introduction: Preoperative chemotherapy remains an experimental approach in patients (pts) with locally advanced colon cancer (LACC) that is being actively tested in ongoing randomised trials. We assessed the feasibility and preliminary evidence of activity of incorporating a direct monitoring of 5-FU levels based on pharmacokinetic-(PK) guided dose adjustments. Methods: Radiologically-staged LACC pts (T4 or T3 with >5mm invasion beyond the muscularis propia), were planned to receive 4 cycles of Oxaliplatin (85mg/m2), Leucovorin (400 mg/m2), bolus 5-FU (400 mg/m2) and infusional 5-FU (initial dose of 2400mg/m2 in 46h and subsequent cycles tailored according to PK monitoring in order to reach a target 5-FU area under the curve (AUC) between 20-30 mg·h·L-1) on a biweekly basis. Surgery was scheduled 4 to 6 weeks after the completion of chemotherapy treatment. All pts were staged at baseline and before surgery. Pathological tumor regression was graded according to the MSKCC classification. Toxicity was reported according to the NCI-CTCAE 4.0. Results: From March 2011 to August 2013, 19 pts (M/F: 13/6; median age 60) with LACC were evaluated. Median dose of 5-FU was 5000 mg. 78.9% of the pts required a 5-FU dose increase to reach the target AUC. Median 5-FU plasma clearance was 199,58 L/h. Side effects profile included G3 neutropenia (6 pts), G2 diarrhea (5 pts), G2 nausea (3 pts) and G2 asthenia (5 pts). Neoadjuvant treatment was discontinued in 2 pts due to small bowel obstruction requiring surgery. No progressive disease was observed during preoperative chemotherapy. A radiological dowstaging was achieved in 11 pts (58%). All pts underwent surgery (laparoscopy-assisted 50%) with an R0 resection rate of 89.47%. There were no treatment-related deaths. Pathological responses (MSKCC score) included grades 4, 3+ and 3 in 10.5%, 15.78% and 21% of pts, respectively. Median number of harvested nodes was 23 (7-51) with a ypN0 rate of 79%. Median time to hospital discharge was 9 days. After a median follow-up of 15 months (6-35), the 12-month actuarial PFS and OS were 76.5% and 97.4%, respectively. Conclusion: Preoperative PK-adjusted FOLFOX in LACC pts is safe and well tolerated, achieving major pathological responses in almost 50% the pts and a remarkable R0 resection rate. This strategy may be an alternative in the management of patients with LACC but further research seems warranted. Almost 80% of the patients required a dose increase to achieve target dose levels.

Interesting neurological and cytological response rates after intrathecal (i.t) liposomal cytarabine have been observed in patients with leptomeningeal carcinomatosis (LMC) from solid tumors. However, the potential use of those responses as early predictors of time-to-progression (TTP) and overall survival (OS) is unexplored. 27 consecutive patients with LMC treated with 50 mg i.t liposomal cytarabine under compassionate drug use were retrospectively studied. All patients received i.t treatment every 2 weeks during induction and every 4 weeks during maintenance periods. Neurological and cytological responses were assessed before every liposomal cytarabine cycle. Most of the patients were female (17/27) diagnosed with breast cancer (15/27). A complete neurological response was seen among 11 % of the patients; partial response in 22 % of the patients; stable disease in 30 % of the patients and progressive disease in 37 % of them. Cytological assessment was available in 11/27 patients showing a 26 % complete response rate. The median time to neurological and cytological response was 15 days and 14 days, respectively. Patients showing a combined neurological and cytological response showed a significantly longer median TTP (122 vs. 3 days; p = 0.001) and OS (141 vs. 3 days; p = 0.002) compared to those showing both neurological and cytological progression. No grade 4 toxicities were recorded. According to these preliminary results, early neurological and cytological responses may be further studied as early predictors of TTP and OS in patients receiving i.t liposomal cytarabine for LMC.

Background: Frontline treatment of metastatic castration-resistant prostate cancer (mCRPC) consists of docetaxel-based chemotherapy. The median time to progression (TTP) from chemotherapy initiation is 6 to 8 months. Ketoconazole, a nonspecific cytochrome P17 inhibitor (CYP17i), blocks adrenal androgen synthesis. Low-dose ketoconazole (LDK), (200 mg three times daily [t.d.s]) has shown activity in mCRPC after progression to androgen deprivation. The role of a CYP17i after docetaxel treatment in the maintenance setting has been unexplored. Methods: We identified 38 patients with mCRPC who showed progression to luteinizing hormone releasing-hormone agonists (LHRHa) and who were treated with a median of 7 cycles of frontline three-weekly docetaxel (75 mg/m(2)) plus prednisone (10 mg/d) and LHRHa. Medical charts of 20 patients who showed no progression to docetaxel were reviewed. After the last docetaxel cycle, 10 patients received LDK maintenance treatment plus prednisone (10 mg/d) and LHRHa, whereas 10 patients received LHRHa alone. TTP was the primary endpoint. Results: After a follow-up of 27 months, disease in all patients receiving LHRHa alone progressed, whereas 8/10 patients progressed to maintenance therapy. Median TTP from docetaxel initiation was 11.5 months (95% confidence interval [CI], 6.3-16.6) for maintenance therapy and 9.2 months (95% CI, 8.5-9.9) for LHRHa alone (P = .047). The maintenance treatment was well tolerated. Only 1 patient experienced a grade 4 adverse event due to a nonsymptomatic pulmonary embolism. Conclusion: This is the first study evaluating a CYP17i for maintenance therapy after docetaxel therapy. We showed a 2-month significant benefit in TTP for patients with mCRPC treated with LDK maintenance therapy after docetaxel, with a favorable toxicity profile. A large prospective randomized study using a CYP17i is warranted.