The Low-down on Gefitinib

With the rising incidence of lung cancer there is an unmet need to provide effective therapy for advanced lung cancer that does not have the toxicity burden of conventional chemotherapy and radiotherapy. Divya Pamnani reviews Gefitinib as a treatment option for lung cancer, in addition to evaluating the research backing it up

According to the Indian Society of Medical and Paediatric Oncology (ISMPO), lung cancer is gaining epidemic proportions in India. It is considered amongst the five 'most prevalent' cancers in the country. The increased prevalence of the 'smoking epidemic' in India is resulting in many more Indians now developing the disease. Over 50,000 new lung cancer cases are diagnosed every year. Unfortunately, about 70 per cent of them are diagnosed at advanced stages, mostly amongst the middle-aged and elderly. Lung cancer has become the number one cancer among men at six (New Delhi, Mumbai, Kolkata, Bhopal and Ahmedabad) of the 12 population-based cancer registries in India. The primary cause of lung cancer in up to 90 per cent of patients is tobacco. What is also worrying is that the incidence and mortality from lung cancer in women is rising as well.

The Role of EGFR in Cancer

The Epidermal Growth Factor Receptor (EGFR) is a trans-membrane receptor, of the tyrosine kinase receptor family, involved in cell proliferation, growth, migration, invasion and survival. These receptors are bound by ligands, forming ligand-receptor dimers that signal within the cell, activating receptor auto-phosphorylation through tyrosine kinase activity. Auto-phosphorylation triggers a series of intracellular pathways that may result in cancer-cell proliferation, blocking apoptosis, activating invasion and metastasis. The receptor is structurally composed of three principal domains– extra cellular ligand-binding domain, trans-membrane domain, intracellular domain with intrinsic Tyrosine Kinase (TK) activity. Depending on the molecular site of action, anti-EGFR agents are classified into monoclonal antibodies and small-molecule Tyrosine Kinase inhibitors (TKIs). Monoclonal Antibodies (MAbs) are anti-EGFR agents that act on the extracellular ligand-binding domain. In comparison, small-molecule TKIs act on the intracellular cellular domain. Function of the EGFR is dysregulated in the vast majority of human epithelial tumors and, thus, it constitutes an attractive target for the development of novel anticancer treatments. Abnormalities in EGFR signaling are most common in carcinomas of the lung, colon and breast. In tumor cells, the EGF receptor is activated by additional mechanisms such as over-expression of the receptor, lingand-independent receptor dimerisation and autocrine ligand production. Mutant forms of EGF receptor gene re-arrangements further result in ligand-independent constitutive receptor activation, and impaired receptor down regulation. Currently, two classes of EGFR antagonists have been successfully tested in phase III trials and are now in clinical use— anti-EGFR MAbs and small-molecule EGFR-TKIs.

Current Status of Gefitinib

"Gefitinib has the potential to replace intravenous chemotherapy in selected patients. Imagine getting the response without significant side effects" - Dr Purvish Parikh Chairperson, Lung Cancer Guidelines Committee of ICMR, Government of India

Gefitinib is currently approved in various countries as third-line treatment for non-small cell lung cancer that has failed to respond to platinum-based chemotherapy as well as newer chemotherapeutic agents called taxanes, such as docetaxel. Initially, Gefitinib started out with promising results in phase II trials and was the first anti-EGFR agent that was shown to have clinically important anti-tumour activity in patients with non-small-cell lung cancer who failed to show response to one or more chemotherapy regimens. These trials led to accelerated approval by the the Food and Drug Administration (FDA) in May 2003 to endorse Gefitinib as third-line therapy for patients with locally advanced or metastatic chemotherapy resistant non-small-cell lung cancer. However, after preliminary results of the phase III ISEL study (Iressa Survival Evaluation in Lung Cancer trial), a landmark trial for Gefitinib, were released, the US FDA withheld the drug from the market. This study failed to show the efficacy of Gefitinib in improving survival. This phase III randomised trial tested Gefitinib versus placebo in patients with non-small cell lung cancer, with failed chemotherapy treatments. Results showed that median survival did not differ significantly between the Gefitinib and placebo treatment arms. In June 2005, on the basis of ISEL study results, and the lack of survival benefit displayed by Gefitinib, the FDA restricted the use of Gefitinib to patients participating in a clinical trial or continuing to benefit from treatment already initiated. Essentially, after an accelerated approval, Gefitinib was then dubiously deemed as an investigational drug in the US, as well as in the European Union. Currently, Gefitinib is marketed in several countries in Asia including Japan, Korea, China, now India and a few others. Despite the lack of survival benefit of Gefitinib over placebo, retrospective sub-group analysis of the ISEL study sample population lead to some important findings. Drug responses were significantly more frequent in women, in patients with adenocarcinoma, and in patients with no history of smoking.

Gefitinib in India: A Different Stand

Another important finding resulting from sub-group analysis of the ISEL study sample population was that Gefitinib was found to have survival benefit in Asians, which explains why Gefitinib is approved in Asian countries. With such promising findings for patients of Asian origin, investigators in India undertook a retrospective ad hoc analysis of clinical data from the experience with Gefitinib in Indian patients that were enrolled in the ISEL study as well as the Iressa Expanded-Access Program (EAP). Median survival for Indian patients with chemotherapy resistant non-small cell lung cancer was 6.4 months with Gefitinib and 5.1 months with placebo, yielding a survival benefit of 1.3 months. The objective response rate in these patients was 14 per cent with Gefitinib versus zero per cent with placebo.

The tolerability data from Indian patients were consistent with the overall study population - that Gefitinib resulted in unwanted side effects with the most common ones being diarrhoea and acne form skin rash. No unexpected adverse events were observed. In conclusion Gefitinib in Indians with refractory NSCLC was reasonably well tolerated with a statistically significant survival benefit.

'Geffy, Inhibits EGFR, not life', the marketing slogan for Gefitinib used by Intas Biopharmaceuticals Limited, capitalises on the quality of life advantage that this drug has over traditionally available treatments like chemotherapy and radiation. Gefitinib, recently launched in India and to be marketed by Intas as 'Geffy,' administered as an oral tablet, has the potential to enhance the treatment and management of the rising lung cancer burden. Current treatment options in India for advanced lung cancer are limited, thus, as with any new drug launched in Indian market, this one is also very welcome.

Gefitinib might not exactly be the stuff of headlines world over, but in India with limited treatment options, a 2.5 million cancer burden, and an increasingly high lung cancer incidence, this novel approach is bound to bring hope to the treatment and management of lung cancer. With companies like Intas taking a risk, it will eventually mean more treatment choices for patients. With India, drug efficacy need not necessarily be measured by statistical analysis, but simply by patients getting cured.

Why Gefitinib Appears Selective

So far, what we have learned mostly from the ISEL study and trials that followed is that patient responsiveness to Gefitinib is associated with being Asian, female, never having smoked, and adenocarcinoma. What is the common link between these patient sub-groups? The answer is EGFR mutations. Most of these patient groups harbored somatic EGFR deletions conferring tumor sensitivity to these agents. Clinical evidence from numerous studies indicates that EGFR mutations are potential predictive factors of response to Gefitinib for patients with non-small cell lung cancer (NSCLC). Essentially the same EGFR mutations that give rise to the tumors are what confer sensitivity to Gefitinib treatment. The discovery of such mutations represents a dramatic step toward developing tailor made strategies to treat lung cancer, depending on the existence of EGFR mutations. Researchers in the US are currently conducting trials based on EGFR mutations screening, identifying tumors and patients likely to respond to Gefitinib treatment, and assessing treatment response. In conclusion, Gefitinib is not a 'one-size-fits-all' kind of therapy, but its success has been demonstrated in select patients with specific EGFR mutations, and in such cases responses were rapid and dramatic. Clinical trials in the US are yet to elucidate on the promise of EGFR mutation screening and the role of determining the genetic signatures of tumors, which could perhaps be the key to the future of personalised treatment for lung cancer. Lastly, the final test to answering the conundrum of response or lack thereof to Gefitinib treatment, is comparing standard chemotherapy treatments and Gefitininb, in a genotype-selected population, claim researchers at Harvard Medical School, who are at the forefront of such cancer research.

Gefitinib and Breast Cancer

Recent studies of a phase II clinical trial conducted at the University of Texas MD Anderson Cancer Center, Houston show that Gefitinib (Iressa) may improve the effectiveness of hormonal therapy for the treatment of specific types of metastatic breast cancer. These findings show promise for the treatment of advanced breast cancer as well as the entire class of EGFR tyrosine kinase inhibitors. This study compared anastrozole (Arimidex) and Gefitinib versus anastrozole and placebo. All of the women enrolled in the study were newly diagnosed with metastatic breast cancer and were hormone receptor-positive and oestrogen receptor HER-2-negative. The primary endpoint was progression-free survival. Results of study conferred a higher progression free survival time for the anastrozole plus Gefitinib arm versus anastrozole plus placebo, by a positive difference of 6.3 months, which represented a 45 per cent reduction in risk. The drawback was that patients in the combination arm of Gefitinib plus anastrozole had a higher rate of adverse events. Investigators of this study conclude that findings of this study show the possibility of adding EGFR inhibitor targeted therapy to enhance the benefit for hormonal therapy, giving another option for breast cancer afflicted women who are hormone receptor-positive, HER-2-negative with metastatic disease.

Looking Ahead: EGFR and VEGF Inhibition Combined

Vascular Endothelial Growth Factor (VEGF) and epidermal growth factor receptor (EGFR) inhibitors possibly hold the key to targeted therapies in several tumor types. Since the implication of tyrosine kinase enzyme in cellular signaling, therapeutic agents targeting abnormal activation of tyrosine kinases, are taking centre stage as goals for cancer therapy. Vascular endothelial growth factor receptor (VEGFR) and EGFR are tyrosine kinase receptors. A close relationship exists between the ligand VEGF and the EGF receptor. VEGF signaling is up-regulated by EGFR expression and, conversely, VEGF up-regulation appears to contribute to resistance to EGFR inhibition. Thus, inhibition of both pathways could improve antitumor efficacy and overcome resistance to EGFR inhibition that certain tumors display.

Preclinical studies have shown that VEGF and EGFR inhibitors can have additive effects and that combined inhibition can have better results. These trials have also produced promising data- combining the anti-VEGF monoclonal antibody bevacizumab with the anti-EGFR antibody cetuximab or the EGFR tyrosine kinase inhibitor erlotinib increases benefit compared with either of these anti-EGFR agents alone or combined with chemotherapy. The promise of this novel approach to anticancer therapy is yet to be further replicated and elucidated by large ongoing clinical trials.

(The author has done her Bachelor of Science in Psychology and Biology atthe University of Texas at Austin. She can be contacted at pamnani.divya@gmail.com)