Iressa (gefitinib) Improves Progression-free Survival over Standard Chemotherapy in Patients with NSCLC with EGFR Mutations.

Researchers from Japan have reported that Iressa (gefitinib) alone improves outcomes of patients with non–small cell lung cancer (NSCLC) with epithelial growth factor receptor (EGFR) mutations compared with patients receiving Paraplatin (carboplatin) and Taxol (paclitaxel). The details of this study were presented at the Joint ECCO 15 – 34th ESMO Multidisciplinary Congress in Berlin, September 20-24, 2009.

Oral Iressa (gefitinib) is approved in the United States as a single-agent treatment for patients with advanced NSCLC who have failed platinum- and taxane-based treatment. Iressa is a selective inhibitor of EGFR-tyrosine kinase. Epidermal growth factor receptor is expressed, overexpressed, or dysregulated in many human solid tumors, including NSCLC. Activation of this receptor is believed to promote tumor growth by blocking apoptosis and by increasing cell proliferation, adhesion and invasive capacity, and motility. Responsive lung tumors are likely to be adenocarcinomas or bronchio-alveolar carcinomas and occur more frequently in non-smokers and women. Responses also occur more frequently in patients with specific mutations of EGFR. Recently, researchers from Asia have reported that first-line treatment with Iressa improves progression-free survival (PFS) over combination treatment with Paraplatin and Taxol in advanced NSCLC among nonsmokers and former light smokers.

The current study included 198 patients with NSCLC with sensitive EGFR mutations who had received no prior chemotherapy. They were randomly allocated to receive Iressa alone or Paraplatin and Taxol.

Overall response rate was 74.5% for patients receiving Iressa versus 29% for patients receiving Paraplatin and Taxol. Grade 4 neutropenia occurred in 1% of patients receiving Iressa and 33% of patients receiving chemotherapy. Grade 3-4 liver dysfunction occurred in 33% of patients receiving Iressa versus 1% receiving chemotherapy. Grade 3 neuropathy occurred in 0% of patients receiving Iressa and 5% of patients receiving chemotherapy. PFS was 10.4 months following Iressa treatment versus 5.5 months for chemotherapy. Overall survival was 28.0 months for patients receiving Iressa and 23.6 months for patients receiving chemotherapy (P=0.357).

This study shows that Iressa improves PFS in patients with NSCLC with EGFR mutations compared with conventional chemotherapy. These authors suggest that Iressa be considered the new standard treatment for “sensitive EGFR mutation-positive NSCLC patients.”

Non-small cell lung cancer (NSCLC) is the most common cause of cancer mortality in men and women in Singapore.Chemotherapy and biologically targeted agents can extend survival only modestly for these patients; therefore, discovery of novel ways to prolong the disease course is a top research priority.

The epidermal growth factor receptor (EGFR) signaling pathway plays a central role in the neoplastic transformation of NSCLC and promotes cancer cell survival, metastasis, and angiogenesis. The predominance of EGFR signaling in NSCLC makes the pathway an attractive candidate for the development of targeted therapeutics. Over the last three years, the FDA has approved two drugs for salvage treatment of NSCLC, gefitinib (Iressa ®, formerly known as ZD1839) and erlotinib (Tarceva ®, formerly known as OSI-774). Both are small molecule orally-bioavailable tyrosine kinase inhibitors (TKIs) of the EGFR TK domain, and have been shown to improve survival compared to placebo in asian patients when administered after failure of first or second line chemotherapy for advanced NSCLC.

Non-small cell lung cancer (NSCLC) is the most common cause of cancer mortality in men and women in Singapore.Chemotherapy and biologically targeted agents can extend survival only modestly for these patients; therefore, discovery of novel ways to prolong the disease course is a top research priority.

The epidermal growth factor receptor (EGFR) signaling pathway plays a central role in the neoplastic transformation of NSCLC and promotes cancer cell survival, metastasis, and angiogenesis. The predominance of EGFR signaling in NSCLC makes the pathway an attractive candidate for the development of targeted therapeutics. Over the last three years, the FDA has approved two drugs for salvage treatment of NSCLC, gefitinib (Iressa ®, formerly known as ZD1839) and erlotinib (Tarceva ®, formerly known as OSI-774). Both are small molecule orally-bioavailable tyrosine kinase inhibitors (TKIs) of the EGFR TK domain, and have been shown to improve survival compared to placebo in asian patients when administered after failure of first or second line chemotherapy for advanced NSCLC.

Recently, it was found that somatic mutations in the EGFR gene sensitize NSCLC tumors to TKIs. These mutations are present in approximately 50 % of asian patients with NSCLC. Retrospective studies suggest that patients harboring a mutation may derive greater clinical benefit from treatment with TKIs than patients without a mutation.

Nevertheless, all patients that benefit from TKI treatment ultimately develop resistance to therapy manifesting as progression of their cancer, after which there remains few, if any treatment options. Hence, there would be vast clinical utility in understanding the mechanisms of TKI resistance and developing strategies to reverse or prevent it.

We have preliminary data which shows that the combination of hydroxychloroquine and gefitinib results in delayed acquired resistance to gefitinib in cell lines that harbour the EGFR mutation. In addition, the addition of hydroxychloroquine to gefitinib can result in reversal of acquired resistance to gefitinib. Much parallel has been observed in resistance mechanisms between NSCLC cell lines and molecular changes observed in patients thus far.

The long term aim therefore is to examine the efficacy of this combination in delaying acquired resistance to gefitinib in NSCLC patients.

First, however, the MTD and DLT of each drug when used in combination therapy will be examined in this study. The other aim is to examine the pharmacokinetic effect and interactions of hydroxychloroquine on gefitinib, and vice versa. Gefitinib is usually well tolerated, with main toxicities of rash and diarrhoea. Hydroxychloroquine is also FDA approved and widely used and generally well-tolerated for rheumatological conditions.