Overview

What is the optimal therapy for patients with advanced non-small cell lung cancer?

Five years ago, a platinum-based doublet for 4-6 cycles was considered standard first-line therapy for advanced non-small cell lung cancer (NSCLC). Overall response rates were 25%, with a median survival of 9 months and a 2-year survival of 10%. Hundreds of studies were performed, including dozens of large phase III trials, all of which failed to show any advantage for one chemotherapy regimen over another. This led to wide acceptance of the concept that we had reached a "chemotherapy plateau" in advanced NSCLC. Molecular genotyping was unheard of, and few oncologists made any distinction between the various histologies of lung cancer when choosing treatments. Clinicians also felt strongly that following 4-6 cycles of first-line chemotherapy, a treatment hiatus or "break" was indicated. Patients were then observed carefully and, when signs or symptoms of progression arose, second-line treatment was begun. The results of recent trials of therapies targeted against vascular endothelial growth factor (VEGF) and the epidermal growth factor receptor (EGFR) challenge many of these assumptions.

In 2009, the paradigms for how we treat advanced NSCLC are changing.

"Maintenance" antibody therapy

The Eastern Cooperative Oncology Group (ECOG) study E4599 was a randomized trial comparing 4 cycles of carboplatin/paclitaxel to the same chemotherapy given with concurrent bevacizumab, followed by maintenance single-agent bevacizumab until progression.¹ The FLEX trial shared nearly the same design, but used cetuximab given concurrently with chemotherapy (cisplatin/navelbine) and then as single-agent maintenance therapy.2 Both studies met their primary end point of prolonged overall survival (OS) as compared to chemotherapy alone. Both studies also included "maintenance" antibody therapy in their design. The one key difference was that maintenance bevacizumab was given every 3 weeks while maintenance cetuximab was given weekly. Today, many oncologists feel that if they are to combine antibody therapy with chemotherapy, maintenance treatment with the antibody is indicated since this was the design of the study arm that showed superior survival. As a result, maintenance bevacizumab has become widely used in the US, and maintenance cetuximab may well follow if this agent is approved by the US Food and Drug Administration (FDA) for this indication. It is important to remember, however, that the maintenance phase of these protocols has not been assessed in terms of its independent contribution to patient benefit.

"Early" second-line chemotherapy

Concurrent with the pivotal antibody studies, a number of trials examining the optimal timing of second-line treatment have matured and are now being reported. In the YEAR trial, Fidias et al reported that immediate docetaxel following 4 cycles of carboplatin/gemcitabine led to improved PFS. At the 2009 American Society of Clinical Oncology (ASCO) meeting, Belani et al reported that maintenance pemetrexed following 4 cycles of platinum-based chemotherapy showed improvements in OS and PFS in patients with non-squamous tumors.⁴ In July of 2009 this approach was given a green light by the FDA with the approval of maintenance pemetrexed following 4 cycles of platinum-based chemotherapy. Finally, the SATURN study, also reported at ASCO 2009, showed that immediate erlotinib following platinum-based chemotherapy similarly improves PFS.⁵ These three recent studies support the concept of giving second-line therapy soon after 4 cycles of platinum-based therapy rather than waiting for progression.

If maintenance therapy with bevacizumab or cetuximab improves outcome, and immediate initiation of second-line therapy also improves outcome, how do we integrate these 2 concepts in the optimal approach for our patients? One hint comes from the ATLAS study.⁶ These results suggest that giving erlotinib with bevacizumab as maintenance therapy after 4 cycles of concurrent chemotherapy/bevacizumab is superior to the same chemotherapy/bevacizumab regimen followed by maintenance bevacizumab alone. Thus, for at least our bevacizumab-eligible population, we have some guidance. But is the ATLAS approach better than early second-line pemetrexed or docetaxel? This is unclear for now but hopefully will be addressed in future trials. For the bevacizumab-ineligible population, can we consider earlysecond-line pemetrexed, erlotinib, or docetaxel as standard therapy? What if the patient is on maintenance cetuximab — which approach should be chosen in this setting? Clearly, more data are needed.

Optimal first-line treatment for adenocarcinoma and squamous cell carcinoma

While chemotherapy timing is an area of great interest, use of tumor histology and EGFR mutational genotype also have made great inroads in first-line therapy. Scagliotti et al have shown that cisplatin/pemetrexed is superior to cisplatin/gemcitabine for patients with adenocarcinoma and inferior for those with squamous cell carcinoma.⁷ This has led to a first-line indication for platinum/pemetrexed in adenocarcinoma patients and, equally important, a revision of the pemetrexed label in the second-line setting to omit squamous cell patients. It is important to note that it is not clear if pemetrexed is superior to a taxane or vinca alkaloid for adenocarcinomas, and both remain options. In 2009 Patel et al reported their results of using carboplatin/pemetrexed/bevacizumab followed by "maintenance" pemetrexed/bevacizumab.8 Encouraging RR and PFS were reported in this single arm phase III study. It should be remembered that the Patel trial differed from the Belani approach in that it used the same chemotherapy agent to partner with platinum as was used in maintenance. Thus, it is not clear if the results of these two trials are comparable. Patel does give us some preliminary safety data on the use of pemetrexed with bevacizumab in lung cancer; a particularly attractive option for non-squamous patients.

• For bevacizumab-eligible adenocarcinoma patients, it is not yet known whether they should receive carboplatin/paclitaxel/bevacizumab followed by maintenance bevacizumab/erlotinib, or the Patel regimen of carboplatin/pemetrexed/bevacizumab followed by maintenance bevacizumab/pemetrexed.⁸ Fortunately, a large US trial is about to begin comparing these two approaches.
• For bevacizumab-ineligible adenocarcinomas patients, it is not yet known whether platinum/pemetrexed followed by early erlotinib (SATURN) should be standard, or whether these patients should receive platinum/ vinorelbine with cetuximab. In the squamous situation, if a taxane is used as initial chemotherapy, the best maintenance approach is not yet established.

Clearly, we are in a time of uncertainty.

First-line therapy for EGFR-mutation positive patients clarified in 2008

We have known for some time that first-line treatment with either erlotinib or gefitinib produces very high response rates with impressive PFS and OS results in single-arm studies. In 2008, Mok et al reported the results of the IPASS study, which showed that in clinically selected patients (mostly Asian, never-smokers with adenocarcinoma) first line gefitinib was superior to chemotherapy (carboplatin/paclitaxel).⁹ Most notably, the benefit appeared to be restricted to those patients who harbored an EGFR mutation. In mutation-negative patients, chemotherapy is the preferred initial therapy. Thus, for EGFR mutation-positive patients, a single-agent tyrosine kinase inhibitor (TKI) is a very reasonable first choice. Research efforts in this group of patients are aimed at preventing the emergence of resistance in order to prolong the PFS from first-line therapy.

Advances are also being made in the use of molecular diagnosis and classification of lung cancer subtypes in order to improve upon standard histological methods. For example, the recent analysis of microRNA expression levels in patients with NSCLC led to the identification of a highly specific marker, hsa-miR-205, for squamous cell carcinoma.¹⁰ Detection of hsa-miR-205 by polymerase chain reaction (PCR) was found to be highly specific for squamous histology (96% sensitivity, 90% specificity). Such molecular diagnostics may aid in the accurate subclassification of NSCLC patients and the selection of histology-dependent therapies.

It is important not to overstate the magnitude of progress these recent developments have brought to the treatment of advanced lung cancer. Except for patients with EGFR mutations (only 10% in the US), response rates hover at 35%, median survival is 12 months, and 2-year survival is about 20%. These are better than 5 years ago, but only marginally. We need to continue to seek new targets and new drugs. What we can say is that monoclonal antibodies, early second-line treatment, and histology-based approaches now play a role in the treatment of advanced lung cancer.

This monograph presents recent data on studies assessing maintenance therapy and early second-line therapies in NSCLC. Discussion of several case studies follow, illustrating treatment decisions for individual patients and outstanding issues physicians should consider in assessing treatment options.

NEXT > >