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Non-small cell lung cancer research

As drug research focuses on the derangement of molecular pathways and into biomarkers associated with treatment response, increasingly therapies are being matched to the patient
xray-lungs

Lung cancer is the most frequent cause of cancer-related death worldwide. Non-small cell lung cancer (NSCLC) accounts for approximately 85 per cent of all lung cancers, with the major risk factor for it being tobacco smoking. Treatment of NSCLC with systemic chemotherapy has some efficacy for improving cancer-related symptoms and quality of life compared with best supportive care. However, NSCLC generally has not shown the gains in survival and response observed in other tumour types in recent years. Thus, there has been a significant amount of research into the derangement of molecular pathways in NSCLC and biomarkers associated with treatment response, ushering treatment into the age of personalised medicine by allowing patients to be divided into subgroups likely to respond to targeted therapies.

Specific inhibitors
The Lung Cancer Mutation Consortium presented results of its tumour sequencing effort at the American Society of Clinical Oncology (ASCO) 2011 congress, having identified mutations in 54 per cent of cases of NSCLC, with several mutations occurring at a high enough frequency to warrant development of specific inhibitors. Epidermal growth factor receptor (EGFR) mutations were detected in 17 per cent of tumours, while anaplastic lymphoma kinase (ALK) mutations were observed in seven per cent of tumours. The most frequently observed gene affected by mutations was KRAS, though targeting of this gene has been difficult thus far. Of note, KRAS mutations are associated with resistance to anti-EGFR treatments, particularly erlotinib (Tarceva; Roche) and gefitinib (Iressa; AstraZeneca). Based on the prevalence of these and other mutations, a number of targeted therapies have recently reached the market or are in development for NSCLC.

EGFR inhibitors are most effective when targeted at patients with EGFR-activating mutations, which promote tumour growth. Two orally active EGFR tyrosine kinase inhibitors, erlotinib and gefitinib, are currently approved for the treatment of NSCLC. Erlotinib is indicated as a second-line therapy for locally advanced or metastatic NSCLC in the US and the EU, and was approved as a first-line monotherapy for locally advanced or metastatic NSCLC in the EU in September 2011, while gefitinib is approved for all lines of therapy in the treatment of locally advanced or metastatic NSCLC in the EU. However, AstraZeneca has withdrawn its accelerated New Drug Application (NDA) for gefitinib as a therapy for NSCLC in the US and does not intend to seek approval.

Data presented at ASCO 2011 showed that erlotinib was effective in patients with NSCLC displaying activating EGFR mutations. In the European EURTAC study, erlotinib was associated with a significant increase in progression-free survival versus standard platinum-based chemotherapy, with durations of 9.7 and 5.2 months, respectively (hazard ratio 0.37). Data from this study was the first prospective data in non-Asian patients and was similar to data from erlotinib studies in Asian patients and studies of gefitinib. However, crossover of patients from the chemotherapy arm to the erlotinib arm was permitted at progression, which may interfere with the final analysis of overall survival.

Several other agents targeting EGFR are currently in development, including cetuximab (Erbitux; ImClone, Bristol-Myers Squibb), afatinib (Tovok; Boehringer Ingelheim) and dacomitinib (Pfizer).

Prospects for Cetuximab
Cetuximab is a chimeric anti-EGFR monoclonal antibody which blocks EGFR-induced tyrosine kinase activation, interrupting EGFR signalling, and has been approved for colorectal and head and neck cancer in a number of countries. Cetuximab is currently in preregistration as a first-line therapy for NSCLC in combination with other chemotherapy agents in the US and EU, and is in phase III development as a second-line therapy in the US and Canada. Submissions in the EU are based on an analysis of EGFR expression levels in the tumours of patients who participated in the phase III FLEX study. This showed a significant increase in response rate from 28.1 per cent to 44.4 per cent in patients receiving cetuximab in combination with platinum-based chemotherapy. The prospects for cetuximab are promising, with inThought forecasting a 72 per cent probability of approval in NSCLC.

Boehringer Ingelheim's afatinib is an orally bioavailable irreversible inhibitor of EGFR and the closely related HER2, and is expected to have broader anti-tumour activity than first-generation EGFR inhibitors. Boehringer Ingelheim is conducting the phase III LUX trial programme to assess the efficacy of afatinib in NSCLC. The phase IIb/III LUX-Lung 1 study assessed the efficacy and tolerability of afitinib in 585 patients who had previously failed treatment with erlotinib or gefitinib, but received no more than two lines of chemotherapy. Afitinib did not achieve the primary endpoint of extending survival, but was associated with objective improvements, including delayed disease progression and improvements in cancer-related symptoms in a population which would not otherwise have any treatment options.

Five other phase III trials in the LUX programme are still ongoing, with Boehringer Ingelheim assessing afitinib as both first- and second-line therapy for NSCLC; inThought projects a 55 per cent probability of approval in this indication.

Pfizer is developing dacomitinib, a pan-HER tyrosine kinase inhibitor. Much like afatinib, dacomitinib is an irreversible inhibitor of EGFR and HER2, 3 and 4. Dacomitinib is currently in phase III development as a second-line monotherapy for advanced NSCLC in the US, and is in phase II development as first- and second-line monotherapy in various countries. Encouraging results from a phase II trial comparing dacomitinib and erlotinib were presented at ASCO in 2010, with the trial meeting its primary endpoint of progression-free survival. Dacomitinib was significantly more effective than erlotinib, with progression-free survival durations of 12.4 and eight months, respectively.

ALK and c-met Inhibitors
The genes for two other receptor tyrosine kinases, ALK (anaplastic lymphoma kinase) and c-Met have also been identified as targets for the treatment of NSCLC. The transcription product of c-Met (mesenchymal epithelial transition growth factor) is hepatocyte growth factor receptor (HGFR). HGFR has been found to be expressed in 41–72 per cent of NSCLC tumours, while MET mutations have been identified in 8–13 per cent and MET amplification in 5–10 per cent. ALK mutations occur at a much lower rate than c-Met mutations, with an estimated prevalence of 2–7 per cent of patients with NSCLC, though ALK translocations are more prevalent in light smokers or those who have never smoked with NSCLC, occurring at a rate of up to 20–30 per cent. The presence of ALK translocations is often mutually exclusive of EGFR and KRAS mutations and predicts a poor response to EGFR tyrosine kinase inhibitors, such as erlotinib.

Pfizer is developing crizotinib (Xalkori), a dual inhibitor of both c-Met and ALK, which was approved for the treatment of NSCLC in the US in August 2011, and is either awaiting registration or in phase III development in the EU and other countries elsewhere. Despite its approval in the US, results from phase III studies of crizotinib are not yet available. Pfizer has presented positive preliminary results from a study in 82 patients with advanced ALK-positive NSCLC, with objective clinical response and disease control rates of 57 per cent and 87 per cent, respectively, at eight weeks. Analysis of the trial is ongoing, as the median progression-free survival duration has not yet been reached.

Another c-Met targeting drug currently under development is tivantinib, the result of a collaboration between ArQule, Daiichi Sankyo and Kyowa Hakko Kirin. Again, tivantinib is an orally bioavailable small molecule inhibitor of c-Met, and is currently in phase III trials as a second- or third-line combination therapy in patients with late-stage NSCLC. A combination of tivantinib and erlotinib is being compared with erlotinib alone in two phase III trials. The MARQUEE trial aims to recruit 988 patients with previously treated, unresectable, locally advanced or metastatic, non-squamous NSCLC, while the ATTENTION trial is recruiting 460 patients with previously treated, locally advanced or metastatic, non-squamous NSCLC with wild-type EGFR. The primary endpoint of both studies is overall survival. InThought rates tivantinib as having a 58 per cent probability of approval.

Finally, Genentech is developing MetMAb, an anti-c-Met monoclonal antibody for NSCLC, which is currently in phase II development as second- and third-line therapy for NSCLC. Results from a phase II study of 137 patients, assessing MetMAb in combination with erlotinib, were released in May 2011. Though MetMAb failed to improve progression-free survival in the overall patient population, the addition of MetMAb to erlotinib almost doubled the duration of progression-free survival compared with erlotinib alone in patients with high Met protein levels. Along with the announcement of these results, Genentech reported that it plans to initiate a phase III trial of MetMAb later in 2011, though this trial does not appear to have been initiated yet. InThought currently forecasts a 51 per cent probability of approval for MetMAb, along with an estimated approval date of February 2014.

Conclusion
The therapies discussed here represent only a fraction of the targeted treatments currently being developed for NSCLC, with a variety of others being investigated. For example, a number of compounds in phase III development are aimed at blocking tumour angiogenesis by inhibiting varying combinations of vascular endothelial growth factor receptors, platelet-derived growth factor receptors and fibroblast growth factor receptors. Compounds in earlier phases of development act at an even wider range of targets, though it will be several years before their effectiveness becomes apparent. Either way, it seems that the era of personalised medicine for NSCLC is finally arriving.


The Author
R&D Pipeline was written by Bernard Kerr of inScience Communications, a Wolters Kluwer business, using data derived from Adis R&D Insight, Clinical Trials Insight (www.adisinsight.com) and inThought™ (www.in-thought.com). For further information on Adis services, please contact Daniela Ranzani on +39 02 423 4562 or email Daniela.Ranzani@wolterskluwer.com

21st November 2011

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