New weapons in the fight against cancer

The increase in our knowledge and understanding of molecular pathways is leading to the identification of novel and appealing targets in oncology

  • Date: 01 Oct 2012

As such, new drug ‘weapons’ to target these are currently under evaluation and there has been an increase in the assessment of these novel agents at an early stage of clinical development. With molecular evidence accumulating at an exponential rate, there will be a surge in the development of targeted cancer preventions and interventions over the next decade. Promising results from clinical trials identify a spectrum of targeted cancer therapies across a broad range of tumour types. These include both small molecule inhibitors of key receptors and enzyme binding sites, as well as intravenously delivered monoclonal antibodies that block a specific binding interaction between ligands and their receptors. However, some studies presented at this year’s ESMO Congress have provided a first glance at some new drugs that may improve cancer treatment in the coming years even further.

Data presented during a prostate cancer poster discussion session from a proof-of-concept study demonstrated that a novel androgen receptor (AR) antagonist called ODM-201 reduced levels of prostate-specific antigen (PSA) in patients with progressive castration-resistant prostate cancer. In this dose-escalation trial, 87% of patients who received ODM-201 (n=15) experienced a PSA decrease at 12 weeks. “These early results are very promising,” said study author Dr Christophe Massard from Institute Gustave Roussy, Villejuif, France, adding that “ODM-201 might be a new hormonal treatment option, and its efficacy and safety profile seems to be very promising in prostate cancer patients”. Unlike other AR antagonsists, nonclinical data indicate that ODM- 201 has minimal or no brain entrance and lacks the partial agonist activity seen with bicalutamide. “The results need to be confirmed in bigger patient population of course” noted Dr Massard.  Data presented at the Developmental Therapeutics session (29 September 2012) also provided an insight into future cancer treatments for non-small-cell lung cancer (NSCLC). Professor Enriqueta Felip from the Vall d'Hebron University Hospital, Barcelona, Spain, presented data from a Phase 2 trial indicating activity for the HSP90 inhibitor, AUY922, in patients with ALK-rearranged (ALK-positive) or EGFR-mutated advanced NSCLC. HSP90 is a chaperone of client proteins relevant in NSCLC pathogenesis, including both ALK and EGFR. ALK positivity occurs in 5 7% of patients with NSCLC, and EGFR mutation occurs in around 10–17% of cases. In this study, 121 patients with previously treated NSCLC received AUY922 (70 mg/m2) as a once-weekly, 1-hour infusion and were stratified by molecular status – ALK-positive, EGFR-mutant, KRAS-mutant or EGFR/KRAS/ALK wild-type. AUY922 was associated with an acceptable safety profile and clinical activity was demonstrated in both ALK-positive and EGFR-mutant patients, with partial responses in 7/22 (32%) patients and 7/35 (20%) patients, respectively. Of particular note, Professor Felip highlighted that in EGFR-mutated patients who had progressed just after receiving EGFR tyrosine kinase inhibitor (TKI) therapy, the median PFS rate at 18 weeks was 45% versus 21% in patients who had not received a TKI as their immediate pre-AUY922 therapy. “These data support the further development of AUY922 in NSCLC,” Professor Felip commented, “Expansion of the EGFR-mutated stratum is ongoing and further studies are planned to confirm these efficacy signals” she added.

Following this, Dr Scott Gettinger from Yale University School of Medicine, New Haven, USA, presented initial data from a first-in-human dose-finding study of the ALK/EGFR inhibitor, AP26113, in patients with advanced malignancies. AP26113 is a novel, synthetic, orally-active TKI that is thought to inhibit mutant activated forms of ALK-positive and EGFR, as well as TKI-resistant forms including L1196M (ALK) and T790M (EGFR). However, AP26113 does not inhibit native EGFR. This dose-finding study is ongoing with 34 patients currently enrolled, 29 of whom have NSCLC. The most common adverse events were nausea, fatigue and diarrhoea, although these were mostly Grade 1/2. Preliminary efficacy data indicate activity with the 60 mg dose in ALK-positive patients both naïve and resistant to crizotinib and responses to the 120 mg dose in EGFR-mut patients. Dr Gettinger highlighted that the Phase 2 expansion study will include 4 cohorts of patients: those with ALK-positive NSCLC who are naïve or resistant to prior ALK-targeted therapy, patients with EGFR-mutant NSCLC who are resistant to EGFR-targeted therapy and patients with other cancers with abnormalities in ALK or other AP26113 targets.

The next presentation was given by Dr Alice Shaw, from the Harvard Medical School, Boston, USA, who presented a first-in-human Phase 1 study of LDK378, a novel, potent small molecule ALK inhibitor that has demonstrated tumour regressions in ALK-positive NSCLC xenograft models. The primary objective of the study was to determine the maximum tolerated dose (MTD) and safety profile in adult patients with advanced malignancies harboring a genetic alteration in ALK who have either progressed on ALK inhibitor therapy or who were previously untreated. Dr Shaw explained that “daily oral LDK378 appears to be well tolerated and the MTD was 750 mg/day”. She also highlighted that “a high level of activity was seen in patients who had progressed following crizotinib therapy at doses of 400 mg or greater”.

Following this, Dr Makoto Nishio from the Thoracic Oncology Center, Cancer Institute Hospital of Japanese Foundation for Cancer Research, 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 1 part of this Phase 1/2 trial had shown that CH5424802, an oral ALK inhibitor, was also well tolerated and had demonstrated promising efficacy in previously treated patients with ALK-positive NSCLC. In the Phase 2 portion of the trial, 46 patients with ALK-positive NSCLC, advanced or metastatic disease and no prior ALK inhibitor therapy were treated with CH5424802 at 300 mg bid until progressive disease or intolerable toxicity. Overall, 3 people experienced a complete response and a further 36 experienced a partial response. Moreover, 40 patients are still receiving study treatment. Dr Nishio advised that treatment with CH5424802 was well tolerated and treatment-related adverse events leading to discontinuation were observed in only 3 patients. “CH5424802 is a new potent ALK inhibitor for NSCLC”, Dr Nishio concluded.

Last year, the US Food and Drug Administration (FDA) approved the ALK tyrosine kinase inhibitor, crizotinib, for the treatment of patients with advanced NSCLC with translocations of the ALK gene as determined by an FDA-approved companion genetic test. This was the first new FDA-approved drug for advanced NSCLC for a number of years, and there was much enthusiasm about the approval among patients and practitioners. Following on from this targeted therapy, we are entering an exciting time as it seems that we have only scratched the surface of personalised therapy. However, as we move ever forward towards molecularly-defined therapies, it will be critical to work out the interplay of molecular testing (who to test, which test to use, and when to test), particularly for those agents that are effective but only in small, specific groups of patients.