As knowledge and understanding of molecular pathways has gradually increased, the search for new and promising targets for tumor therapy has begun. New drug weapons targeting these are currently being evaluated, while the evaluation of these novel agents in the early clinical development phase has improved considerably. With relevant molecular evidence being collected at an exponential rate, targeted cancer prevention and intervention is believed to have a meteoric rise in the next decade. A number of valuable results from clinical trials have established a target area for targeted cancer therapies across a wide range of tumor types. These include, small molecular inhibitors of receptors and enzyme binding sites, and also intravenous administration of monoclonal antibodies to block specific interactions between ligands and their receptors. However, a number of studies at this year’s ESMO congress took a preliminary, longer-term view of the future of new drugs that could improve cancer treatment. In a prostate cancer symposium, data from a proof-of-concept study showed that a new androgen receptor (AR) antagonist called ODM-201 reduced prostate-specific antigen (PSA) levels in patients with progressive castration prostate cancer. In this dose escalation trial, 87% of patients who received ODM-201 (n=15) had reduced PSA levels at 12 weeks. “These early results are very promising,” said study author Christophe Massard, MD, PhD, from the Institut de Roussy in Jewish Town, France, who added that “ODM-201 may be a new option for hormone therapy, and its utility and safety profile looks very promising.” Unlike other AR antagonists, there are no clinical data showing that ODM-201 has minimal or no qualifying neurological effects and lacks some of the agonistic activity found on bicalutamide. massard noted, “These results need to be confirmed in a larger number of patients treated.” Data presented at the DevelopmentalTherapeutics meeting also provided insight into future treatments for non-small cell lung cancer (NSCLC). Professor Enriqueta Felip from the University of Waldheim School of Medicine presented data from a phase 2 trial showing the activity of the HSP90 inhibitor-AUY922, which is distributed in advanced NSCLC patients with ALK-positive or EGFR mutations.HSP90 is a protein chaperone associated with NSCLC pathogenesis HSP90 is a protein chaperone associated with NSCLC pathogenesis, including ALK and EGFR. 57% of NSCLC patients exhibit ALK positivity, and EGFR mutations are seen in approximately 10-17% of cases. In this study, 121 patients with prior NSCLC treatment received a one-hour infusion of AUY922 (70 mg/m2) once a week while stratified by molecular status of ALK positive, EGFR variant, KRAS variant or EGFR/KRAS/ALK wild type. AUY922 was associated with an acceptable safety profile while clinical activity in both ALK-positive and EGFR-mutant patients, with 7/22 (32%) patients and 7/35 (20%) patients in partial remission in both groups, respectively. Of particular note, Professor Felip highlighted the improvement in EGFR variant patients just after receiving EGFR receptor tyrosine kinase inhibitor therapy, with a median PFS rate of 45% at week 18, compared to 21% in patients who did not receive TKI as their immediate pre-AUY922 therapy. “These data support that there is greater development of AUY922 in NSCLC,” commented Prof. Felip, “and the expansion to target the EGFR variant level is still moving forward, while more studies are planned to confirm these effective signals. ” She added. With this, Dr. Scott Gettinger from Yale University School of Medicine in New Haven, USA, presented the first dose investigation of the ALK/EGFR inhibitor, AP26113, in humans with advanced malignancies. AP26113 is a novel, synthetic, orally active TKI that is thought to inhibit both ALK-positive and EGFR-variant forms of activity, as well as TKI-resistant forms, including L1196M (ALK) and T790M (EGFR). However, AP26113 does not inhibit the immobilized form of EGFR. this dose-finding study is advancing on a current registry of 34 patients, 29 of whom have NSCLC. although these are primarily grade 1/2, their most common adverse effects are nausea, fatigue and diarrhea. The initial efficacy data show activity in ALK-positive patients receiving the 60 mg dose, both on the fixed and resistant forms of crizotinib, and remission in EGFR variant patients receiving the 120 mg dose. therapy; and EGFR-mutant NSCLC patients who are susceptible to EGFR-targeted therapy. The next presentation was made by Dr. Alice Shaw from Harvard Medical School, Boston, USA, who presented the first phase 1 study in humans on LDK378, a novel, potent small molecule ALK inhibitor, and showed that it promotes tumor regression in ALK-positive NSCLC xenograft models. The primary objective of this study was to determine the maximum tolerated dose (MTD) and safety range in adult patients with advanced malignancies with cryptic genes in ALK who either had improved efficacy with ALK inhibitors or were previously untreated. She also emphasized that “high levels of activity at doses of 400 mg or higher were seen in patients who showed improvement after crizotinib therapy. Next, Dr. Makoto Nishio from the Cancer Institute Hospital of JapaneseFoundation for Cancer Research (Institute) Thoracic Oncology Center in Tokyo, Japan, presented data to support the potential of CH5424802 as a new therapeutic opportunity for patients with ALK-positive NSCLC. Dr. Nishio explained that the phase 2 portion of the trial – the phase 1 trial – showed that CH5424802, an oral ALK inhibitor, was well tolerated and also showed good efficacy in previously treated patients with ALK-positive NSCLC. In the phase 2 portion of the trial, 46 patients with ALK-positive NSCLC who had advanced or metastatic disease and no prior ALK inhibitor therapy received 300 mg of CH5424802 twice a day, unless disease worsened or non-palliative toxicity developed before discontinuation. Overall, three patients were in complete remission and another 36 were in partial remission. In addition, 40 patients are still receiving study treatment, and Dr. Nishio suggests that treatment with CH5424802 was well tolerated, while discontinuation due to treatment-related adverse effects occurred in only three patients. “CH5424802 is a new and potent ALK inhibitor for NSCLC.” Dr. Nishio concluded. Last year, the FDA approved the ALK tyrosine kinase inhibitor, crizotinib, for the treatment of patients with advanced NSCLC with shifted ALK genes, as determined by an FDA-approved genetic trial. This is the first new FDA-approved drug that can be used continuously for several years in advanced NSCLC, while there is a great enthusiasm among patients and practitioners (physicians) for this approval. With this advancement in targeted therapies, we are entering an exciting period, although it appears that we have only scratched the surface of individualized therapy. However, as we keep moving forward with molecular chemotherapy, it will be extremely important to discover trials of molecular interactions (who to test, which to test, and when to test), especially for those with positive intent but only in small, specific patient populations.