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Silver bullet treatments in lung cancer

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In lung cancer, even patients presenting with early, more manageable disease have a low five-year survival rate. A Scottish analysis reported that 50 per cent of lung cancer patients are dead within four months of diagnosis. The predominant histologic type of lung cancer is non-small cell lung cancer (NSCLC), and approximately 30 per cent of newly diagnosed patients with NSCLC present with stages I-IIIA disease.

In 1995, the NSCLC Collaborative Group in the US reported a meta-analysis evaluating the role of cisplatin-based chemotherapy in curatively resected NSCLC. There was an absolute benefit in survival of five per cent at five years in favour of adjuvant cisplatin-based chemotherapy, but it failed to achieve statistical significance. Five major cisplatin-based trials have been reported since the 1995 meta-analysis.

Three of these trials defined a specific regimen to be used, whereas two trials allowed physicians a choice of regimen. The only regimen considered to be a “modern” platinum-based regimen was cisplatin plus vinorelbine, and only two of the trials mandated treatment with this regimen. Four of the five trials allowed adjuvant thoracic radiotherapy (TRT) to be delivered following chemotherapy.

Maintenance therapy in lung cancer refers to the use of an active therapeutic agent for extended duration following frontline induction therapy for patients with advanced stage NSCLC. Multiple clinical trials have shown a beneficial role for maintenance therapy especially in select patient groups characterised by histology and/or molecular profile.

The first real evidence that a molecular marker could predict treatment outcome in NSCLC came about in the early 2000s with the targeted drugs that inhibited the epidermal growth factor receptor (EGFR).

A substantial percentage of lung cancers express cell surface EGFRs. Activation of these cell surface receptors has been shown in experimental systems to result in the growth and progression of the malignancy.

These mutations within the EGFR-tyrosine kinase(TK) domain are more commonly observed in patients with the following clinical characteristics: (a) adenocarcinoma histology (particularly bronchioloalveolar subtype); (b) no prior history of smoking; (c) female sex; and (d) Asian ethnicity.

In 1995, it was shown that erlotinib can prolong survival in patients with non–small cell lung cancer after first-line or second-line chemotherapy. Further trials have since shown that Tarceva produces similar efficacy to chemotherapy in second-line settings, although results are not directly comparable because of different patient populations.

The discovery that somatic mutations in the EGFR gene are found in a subset of lung adenocarcinomas and are associated with sensitivity to the EGFR tyrosine kinase inhibitors (TKI) generated excitement among clinicians and researchers. This information has allowed us to gain insight into the pathogenesis and treatment of this subset of lung tumours.

Coupled with the observation that KRAS mutations are associated with resistance to gefitinib or erlotinib, these studies validate the hope for personally tailored molecular therapy in the near future.

Although platinum-based doublet chemotherapy remains the cornerstone for the first-line treatment of metastatic NSCLC, several phase II and III trials have been conducted utilising EGFR TKIs in this setting. Patients with advanced NSCLC who are life long never-smokers, those with EGFR mutations, and those with bronchioloalveolar cell carcinoma histology seem to have promising efficacy with first-line therapy with EGFR TKIs compared with unselected groups of patients receiving the same agents.

The IPASS study, for example, found that gefitinib was superior to carboplatin–paclitaxel as an initial treatment for pulmonary adenocarcinoma among non-smokers or former light smokers in East Asia. The presence in the tumour of a mutation of the EGFR gene is a strong predictor of a better outcome with gefitinib, according to IPASS.

In patients with newly diagnosed NSCLC, meanwhile, erlotinib can significantly extend progression-free survival, according to the interim results of a phase III trial.

An independent data-monitoring committee recommended that the European Randomised Trial of Tarceva vs Chemotherapy be stopped early because it met its primary endpoint. The data showed that, compared with a platinum-based chemotherapy regimen, erlotinib significantly extended progression-free survival in patients with NSCLC tumours with EGFR-activating mutations.

Monoclonal antibodies

Cetuximab is a humanised monoclonal antibody to the extracellular domain of EGFR. It is already approved for colorectal cancer refractory to irinotecan. Single agent cetuximab resulted in disease control in seven of 29 patients with EGFR expressing NSCLC in one trial. Phase I/II data suggested that cetuximab is well tolerated in combination with both first-line platinum-based chemotherapy and with second-line docetaxel.

In the E4599 trial, patients receiving bevacizumab plus paclitaxel and carboplatin (PC) vs PC alone were 16 per cent more likely to be alive at one year and 53 per cent more likely to be alive at two years. This trial (lung cancer cells) showed the highest 1- and 2-year overall survival rates observed to date in first-line non-squamous NSCLC.

EML4-ALK

The EML4-ALK fusion gene was identified in 2007 by a group of Japanese investigators headed by Dr Hiroyuki Mano, who identifed a novel fusion gene from a surgical specimen of a patient with lung adenocarcinoma. The fusion of the EMLY and ALK genes results in increased activity of ALK, which was already known to be implicated in a certain type of lymphoma.

Subsequent studies have identified that patients with the EML4-ALK fusion gene tend to be younger than the average lung cancer patient, are more likely to be light or never smokers, and have adenocarcinomas. While these clinical characteristics are also shared by patients with EGFR mutations, patients with EML4-ALK do not have EGFR mutations.

PF-02341066 is a phase II trial that will evaluate the safety and efficacy of Pfizer’s oral MET and ALK inhibitor PF-02341066 in patients with advanced NSCLC with a specific gene profile involving the ALK gene. This trial will also allow patients from a phase III trial who received standard of care chemotherapy to receive PF-02341066.

In summary, translational biology should be at the core of new treatment development  – as this is how novel targets for therapy are identified. These novel therapies are resulting in individualised patient treatments and maximising response rates, symptom control and survival. n

References on request

Professor Ken O’Byrne, Consultant Medical Oncologist, Lung Cancer Team, Blackrock Clinic and Thoracic Oncology Research Group, St James’s Hospital, Dublin and Trinity College Dublin

 

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