ABSTRACT: Non–small-cell lung cancer (NSCLC) remains a difficult-to-treat malignancy, and durable long-term survival is elusive for patients with advanced-stage disease. Chemotherapy, especially with platinum-based combinations, is the mainstay of treatment, yet these regimens yield only modest response and survival rates. Outcomes of recent clinical trials have shown that histology, mutation analyses, and biomarkers have an impact on the selection and combination of chemotherapeutic agents. Oral tyrosine kinase inhibitors and monoclonal antibodies are now part of the treatment schema. Other changes to the treatment paradigm include the duration of treatment and the use of maintenance therapy. Additionally, chemotherapy is now employed in earlier-stage disease in neoadjuvant, adjuvant, and combined-modality treatments. The aim of this article is to review the current systemic treatments for NSCLC.
A variety of agents and drug combinations (see Table 1) are used for the management of patients with non–small-cell lung cancer (NSCLC), depending on the stage of the disease and a number of patient factors that will be discussed in this article.
Doublet Therapy: Histology Matters
Cisplatin-based combinations (doublets) continue to be the cornerstone of treatment for patients with advanced NSCLC, following results of early studies that demonstrated a modest 1-year survival benefit (20% to 25%) with this modality. For years, researchers have tried to determine the most effective doublet therapy, in terms of patient response and survival. Results of phase III clinical trials have shown equivocal response and survival rates in NSCLC patients treated with third-generation agents—such as the taxanes (paclitaxel and docetaxel(Drug information on docetaxel)), gemcitabine(Drug information on gemcitabine), and vinorelbine—combined with a platinum (either cisplatin or carboplatin(Drug information on carboplatin)).
In 2008, Scagliotti et al published the findings of their phase III study comparing the efficacy of cisplatin(Drug information on cisplatin)-based doublets (gemcitabine, pemetrexed(Drug information on pemetrexed) [Alimta]) in untreated patients with advanced-stage NSCLC. Although both combinations had equivocal efficacy, the main finding of the meta-analysis was that patients with either adenocarcinoma or large cell carcinoma who had received cisplatin-pemetrexed had better survival rates than those treated with cisplatin-gemcitabine. It should be noted that patients with squamous cell carcinoma treated with the cisplatin-gemcitabine combination had improved survival rates compared with patients who received the cisplatin-pemetrexed doublet. This study was the first to demonstrate survival differences based on histology. Based on the results of this phase III clinical trial, histology is a significant factor in selection of chemotherapeutic agents for patients with untreated, advanced-stage NSCLC.
There is still some question as to which platin (cisplatin or carboplatin) is the more effective agent. Numerous studies have tried to answer this question.[2,4–6] Both drugs have benefits and toxicities. Treatment with cisplatin requires pre- and post-treatment hydration, thus prolonging the treatment time. Side effects of cisplatin include, but are not limited to, nausea, vomiting, neurotoxicity, nephrotoxicity, and ototoxicity. Nausea and vomiting are better controlled with newer antiemetic medications.
Carboplatin side effects are milder nausea and vomiting (compared with cisplatin) and hematologic issues such as thrombocytopenia. Both drugs are associated with hypersensitivity reactions.
Results of a meta-analysis demonstrated better response and prolonged survival for patients who received cisplatin-based therapy. There was not a higher incidence of severe (grade 3 or 4) side effects in the cisplatin group compared with those who received carboplatin. The American Society of Clinical Oncology (ASCO) and the National Comprehensive Cancer Network (NCCN) guidelines support using either cisplatin or carboplatin for patients with advanced NSCLC; therefore, treatment planning for the patient with NSCLC is determined by histology, performance status, age, and comorbidities.
For years, researchers have been investigating various combinations of drugs and other means of overcoming the plateau effect of standard chemotherapy. Early clinical trials using three cytotoxic chemotherapy agents (triplet therapy) were tried, with the result that triplet therapy was more toxic and did not improve survival rates compared with doublet therapy.[9,10] The consensus among investigators is that newer agents, with a different toxicity profile and mechanism of action, are needed to improve the response and survival rates.[7,11,12] Some targeted therapies, such as the monoclonal antibodies bevacizumab(Drug information on bevacizumab) (Avastin) and cetuximab(Drug information on cetuximab) (Erbitux), have been combined with chemotherapy in clinical trials.
In 2006, the US Food and Drug Administration (FDA) approved bevacizumab as first-line treatment for advanced NSCLC in combination with carboplatin and paclitaxel(Drug information on paclitaxel). Bevacizumab is a recombinant monoclonal antibody that prevents vascular endothelial growth factor (VEGF) from binding to its receptor, thereby slowing tumor growth and preventing metastasis. Results of a phase III clinical trial randomizing untreated patients with advanced NSCLC to carboplatin and paclitaxel with or without bevacizumab demonstrated a survival benefit for patients who received all three drugs. Subsequent clinical trials have also shown response and survival benefit with the addition of bevacizumab to doublet chemotherapy. Both the ASCO and NCCN treatment guidelines recommend combining bevacizumab with chemotherapy, based on clinical trial findings.[14,15]
Cetuximab has also been studied in clinical trials. It targets the epidermal growth factor receptor (EGFR) pathway at the extracellular level, preventing ligands from binding with the EGFR receptors. The results of two phase III clinical trials demonstrated slightly improved response and survival rates for those who received cetuximab with chemotherapy.[17,18] Currently, cetuximab is approved for the treatment of metastatic colorectal cancer and squamous cell head and neck cancer, but not for advanced NSCLC.
Tyrosine Kinase Inhibitors as First-Line Therapy
Small tyrosine kinase inhibitors (TKIs) target the intracellular EGFR pathways, thereby blocking downstream signaling as well as growth and proliferation of cancer. Two such agents are gefitinib(Drug information on gefitinib) (Iressa) and erlotinib (Tarceva). Results of phase III randomized clinical trials comparing chemotherapy plus an oral TKI (gefitinib, erlotinib) against chemotherapy alone did not show improved survival with addition of the oral TKI.[19–22] Therefore, oral TKIs in combination with chemotherapy were not approved for first-line treatment of patients with advanced NSCLC.
Recent studies have evaluated the oral TKIs as monotherapy (single-agent) first-line treatment for advanced NSCLC. One large phase III trial, the Iressa Pan-Asia Study (IPASS), randomized untreated East Asian patients to chemotherapy (carboplatin and paclitaxel) or gefitinib; the results demonstrated improved response and progression-free survival rates for patients who received gefitinib.
Another phase III randomized clinical trial evaluated erlotinib vs carboplatin-gemcitabine as first-line treatment for NSCLC. This was a smaller study in which 549 patients were screened but 384 patients were excluded because their tumor did not express the EGFR-activating mutation (exon 19 deletion or exon 21 L858R point mutation); therefore, 165 patients were randomized to the two arms. Once again, the results demonstrated longer progression-free survival for patients who received erlotinib. Based on the findings from these two studies, and from other clinical trials that demonstrated longer survival with an oral EGFR TKI agent over chemotherapy, the NCCN recommends erlotinib as first-line therapy in patients whose tumors express the EGFR-activating mutation.
Crizotinib (Xalkori), another small-molecule agent, may also be used as first-line treatment providing that the patient’s tumor expresses the EML4-ALK mutation, and that this mutation status is known at the time of treatment intiation. (Crizotinib was approved by the FDA in August 2011 for treatment of NSCLC patients whose tumors express the EML4-ALK mutation.) If the mutation status is not known (the mutation test results are pending), then the oncologist can delay treatment (if the patient agrees to wait) until notified of the results or just begin treatment with other agents. If, after treatment is started, the patient’s tumor does express the EML4-ALK mutation, then crizotinib could be used after initial treatment is completed (see section on Second and Third-Line Therapy). NCCN guidelines recommend crizotinib as first-line therapy for patients with the EML4-ALK mutation.