For Physicians
New Treatment Strategies for Advanced Lung Cancer
The incidence and mortality rates of lung cancer in this country have declined substantially, especially for men 1. Furthermore, important controversial questions regarding treatment have been resolved, and the discovery and use of certain biological agents have had a major impact on the natural history of this disease for a significant subset of patients.
Locally Advanced Intrathoracic Disease
Locally advanced NSCLC is considered inoperable when there is direct invasion of the mediastinum, major blood vessels, heart, vertebral body, or involvement of multi-station lymph nodes. In this setting randomized studies showed that the addition of chemotherapy to radiation improved overall survival, and that although more toxic, outcomes were better when treatment was concurrent rather than sequential 2. In fact, five year survivals of 15-20% were possible for the percentage of patients with good initial performance status. Administration of a targeted agent like gefitinib (Iressa®) with or after chemoradiation has not improved survival, but cetuximab (Erbitux®) currently is being tested in this setting 3.
Advanced Metastatic NSCLC
Initial Therapy
Two drug combination chemotherapy (a “doublet”) using either cis- or carboplatin as the backbone, together with another chemotherapy agent, has become standard therapy for advanced disease. An important clinical trial compared four commonly used two-drug platinum-based regimens and found equal efficacy for all four 4. Several third generation chemotherapy agents, when combined with a platinum compound, have shown similar results. Although two drug regimens clearly are better than single agents, trials of triple agents did not produce prolongation of overall survival 1, but instead just added more toxicity. Therefore, a platinum-based doublet remains the standard.
Role of Histology
For many years, all histological types of NSCLC were treated with similar regimens. Recently, differences in sensitivity to chemotherapy have been found to be related to certain tumor histological types. For example, a clinical trial of 1,700 subjects compared initial therapy with cisplatin/pemetrexed (Alimta®) to standard cisplatin/gemcitabine (Gemzar®) and observed a statistically improved overall survival in the former arm only for adenocarcinomas 5. In addition, the preliminary results of a phase III trial of carboplatin with either nab paclitaxel (Abraxane®) or standard paclitaxel (Taxol®) reported a marked difference in response rate for squamous cancer treated with nab paclitaxel (41% vs. 24%) 6. Furthermore, bevacizumab (Avastin®) is associated with an unacceptably high incidence of hemoptysis when administered with chemotherapy for squamous cell NSCLC, but not with adenocarcinoma.
Maintenance Therapy
The optimal duration of chemotherapy for responding patients or those with at least stable non-progressive disease has been controversial. The question was whether to stop and wait after a fixed number of cycles (4 to 6), or to continue the same therapy until disease progression. Randomized trials eventually showed that continuing therapy until progression did not have an advantage over a fixed number of cycles followed by observation and re-treatment at relapse 1. Recently, with clear evidence that either maintenance chemotherapy, or targeted therapy (Tarceva®) delay NSCLC progression, observation until relapse has been replaced. Docetaxel (Taxotere®) maintenance is beneficial if instituted immediately after standard doublet therapy. The permetrexed (Alimta®) vs. placebo trial demonstrated a modest but statistically superior progression-free and overall survival with pemetrexed maintenance 8, leading to approval by the FDA for this regimen. The targeted agent erlotinib (Tarceva®) also has been approved for maintenance based on improvement in progression-free and overall survival 9. The administration of bevacizumab (Avastin®) or cetuximab (Erbitux®) for many months after the completion of chemotherapy induction remains an unproved regimen, although common in clinical practice 1. Presently there is evidence from meta-analyses that that patients benefit from maintenance therapy provided they have a reasonable performance status and either are responding or have stable disease after initial chemotherapy.
EGFR Inhibitors
The epidermal growth factor receptor (EGFR, Erb-1, HER1) is a member of a family of four receptor tyrosine kinases (TK). EGFR is activated mainly by epidermal growth factor and transforming growth factor-α, plus several other ligands, leading to downstream cellular signaling and resultant DNA synthesis and cell proliferation. Since overexpression and overactivity of EGFR have been noted in 40-80% of cases of NSCLC, it was logical to develop agents that target the EGFR tyrosine kinase domain as potential treatment for NSCLC. Clinical trials with these inhibitors, gefitinib and erlotinib, initially reported objective responses in about 10% of advanced cases. The most definitive trial was performed by the National Cancer Institute of Canada, which reported improvement of progression-free and overall survival with erlotinib 11, results that led to the approval of erlotinib for the second-line treatment NSCLC.
A remarkable observation was made during subset analyses of these and several other trials: an extraordinary response rate and survival benefit was noted for women never-smokers of Asian ethnicity with adenocarcinoma histology. A search for the molecular explanation found that this subset had tumors with activating mutations of the EGFR tyrosine kinase genes at exon 19 and 21, which made them uniquely susceptible to tyrosine kinase inhibitors. Their response rates and overall survival to initial therapy with erlotinib were 66% and 27 months, and survival was even higher (39 mos) when combined with standard chemotherapy12. About 40% of Asians and 10% of Caucasians with NSCLC have these activating mutations. In this subset of patients, the results with a relatively simple oral tyrosine kinase inhibitor have been so dramatic that it has become increasingly commonplace for major pathology laboratories to test all tumors for activating EGFR mutations, and to initiate erlotinib as front-line therapy in patients that exhibit these genetic changes.
Other Targeted Therapies
Cetuximab is a monoclonal antibody that targets the extracellular domain of EGFR. When combined with platinum-based chemotherapy, a very modest survival improvement of 1.2 mo. over chemotherapy alone was noted, regardless of KRAS or EGFR mutations 13. The FDA has approved bevacizumab for nonsquamous NSCLC based on a study that compared this anti-VEGF antibody plus chemotherapy to chemotherapy alone; the combination resulted in a modest improvement in overall survival, but at the price of increased toxicity, especially in older patients 14.
Activation of the ALK Pathway
An area of great excitement has been the discovery of an inversion within chromosome 2 that results in a fusion gene in about 5% of NSCLC cases. This includes portions of the EMLA4 and ALK genes and results in the activation of the enzyme anaplastic lymphoma kinase (ALK), which in turn triggers a dominant oncogenic pathway that drives these tumors. The small molecule tyrosine kinase inhibitor, crizotinib, inhibits ALK kinase. When crizotinib was used in an early trial of 119 patients with an ALK translocation, an outstanding response rate of 61% was noted; actually, the response rate was 80% if no prior therapy had been given, and 82% in Asians. Some exceptional reductions in gross tumor size were noted. Median duration of response was 48 weeks and overall survival has not yet been reached. Preclinical evidence suggests that for ALK positive patients crizotinib is more effective than chemotherapy. However, a definitive answer to this will not be available until the recently completed Phase III trial comparing the ALK inhibitor to chemotherapy in this subset of NSCLC has been analyzed 15.
Conclusion
During the past few years the results of important clinical research have improved the process by which oncologists select the most effective chemotherapy regimens for NSCLC. Furthermore, the identification of key molecular pathways that drive tumor activity has led to the development of important agents that target and inhibit these pathways. In some instances this targeted therapy has resulted in extraordinary responses, which likely signifies the beginning of an exciting new era.
References