Edward S Kim Assistant Professor, Department of Thoracic and Head and Neck Medical Oncology, M.D. Anderson Cancer Center

Originally printed in:
» US Oncological Disease 2006 -June 2006

The field of lung cancer therapy remains dynamic. In the last several years, erlotinib (Tarceva, Genentech/OSI Pharmaceuticals) and pemetrexed (Alimta, Eli Lilly and Company) have gained approval for the treatment of lung cancer, and drugs such as bevacizumab have demonstrated success in combination with chemotherapy as first-line therapy against NSCLC. As more novel drugs and treatments continue to receive approval, strategies other than chemotherapy may be integrated into the frontline setting. Because previous clinical trials combining biologic therapies with chemotherapy have not been successful in improving survival, discoveries defining certain patient populations (e.g. those with specific biomarker abnormalities of the epidermal growth factor receptor (EGFR)) may allow earlier treatment with biologic compounds in selected patients.

In the past decade, several drugs have been identified with single-agent activity against NSCLC, showing partial response (PR) rates consistently in the range of 20–30%. These include docetaxel (Taxotere, Sanofi-Aventis), paclitaxel, gemcitabine (Gemzar, Eli Lilly), vinorelbine (Navelbine, GlaxoSmithKline), and irinotecan (Camptosar, Pfizer). As they have been identified, followup studies have been conducted with these newer drugs in combination with platinum compounds (cisplatin and/or carboplatin) demonstrating increased efficacy when these drugs are administered concurrently with another chemotherapeutic agent (doublet therapy).

Frontline Therapy

In most cases, phase III trials comparing numerous platinum-based doublets have failed to demonstrate superiority of one single combination regimen. Paclitaxel/cisplatin (PC) was compared to gemcitabine/ cisplatin (GC), docetaxel/cisplatin (DC), paclitaxel/ carboplatin (PCb) in the Eastern Cooperative Oncology Group (ECOG) E1594. This trial reported objective response rate (ORR) of 19%, median survival of 7.9 months, and one- and two-year survival rates of 33% and 11%, respectively, with no significant differences in the ORR and survival between PC and the other three regimens. In contrast, Rosell et al. published the results of a 618-patient trial of the combination of PC versus PCb; the combination of PC was associated with a significantly superior median survival (9.8 vs 8.2 months).Toxicities were low and comparable in the two arms. Moreover, the combination of vinorelbine/cisplatin (VC) was compared to PCb in the SWOG 9509 trial, and demonstrated similar response rates and median survival; less toxicity was noted in the PCb group, although there was no significant difference in quality of life (QOL).

The largest front-line trial reported to date in advanced lung cancer is the TAX 326 trial, which enrolled 1,218 patients with a good performance status; DC or docetaxel plus carboplatin (DCb) was compared with a control regimen of VC every four weeks. The mean age of the patients was 60 years, 75% were men, and approximately two-thirds had stage IV disease. Unlike the previous trials, TAX 326 demonstrated a survival benefit in one of the treatment arms. For DC versus VC, median survival was 11.3 months versus 10.1 months which reached significance (P<0.05); one-year survival was 46% versus 41%; and two-year survival was 21% versus 14%; all favoring DC. Global QOL, measured by the EuroQOL5D Scale, was better for the DC regimen (p=0.016). For DCb versus VC, median survival was 9.4 months versus 9.9 months; one-year survival was 38% versus 40%; and two-year survival was 18% versus 14%. The DCb arm showed global QOL benefits, measured by both the EuroQOL5D (p=0.001) and the Lung Cancer Symptom Scale (p=0.016). Performance status was better maintained in both docetaxel-containing arms, and weight loss of 10% or more was less frequent in these arms (7% vs 15%; p<0.001).

ECOG 4599 (phase II/III trial) recently reported on the addition of bevacizumab to PCb therapy in patients with advanced, metastatic, or recurrent non-squamous cell NSCLC. In this trial, 878 patients were randomized to receive either PC, or the same chemotherapy plus bevacizumab on day one every three weeks. After six cycles, chemotherapy was discontinued and patients in the experimental arm received single-agent bevacizumab. Patients excluded from E4599 were those at an increased risk of bleeding with bevacizumab as demonstrated by the phase II trial: patients with squamous histology, brain metastasis, or gross hemoptysis. Significant improvement in median survival (12.5 months vs 10.2 months),ORR (27% vs 10%), and time-to-tumor progression (TTP) (6.4 months vs 4.5 months) were observed, all favoring the bevacizumab arm. As expected, a higher incidence of bleeding was associated with bevacizumab administration (4.5% vs 0.7%).