Advances in Treatment of Non–Small-Cell Lung Cancer

Over the past year, there have been a number of important developments in the treatment of non-small-cell lung cancer (NSCLC). New data supporting induction chemoradiation therapy and adjuvant chemotherapy were reported. New combinations including chemotherapeutic agents and targeted biologic agents were shown to be active in various stages of disease. Developments in Targeted Therapy Chemoprevention of NSCLC will increase in importance, as small molecules that target specific receptors or mutations may prove to be more effective and better tolerated than standard therapy; while chemoprevention is still a very new concept with many unresolved issues, recent advances in understanding the molecular biology of lung cancer may facilitate development of chemoprevention strategies with a significant impact on NSCLC incidence and mortality. Targeted biologic therapy has continued to mature as an approach that will ultimately permit individualization of treatment and patient-specific combination cocktails. This special supplement to Oncology News International (ONI) presents a compilation of reports on these and other developments in NSCLC published in ONI over the last year.
Targeted biologic agents are under extensive clinical investigation in NSCLC. The HER1/epidermal growth factor receptor (HER1/EGFR) tyrosine kinase inhibitor gefitinib(Drug information on gefitinib) (Iressa) showed activity and produced symptom improvement in phase II studies but provided no survival benefit when added to standard chemotherapy in phase III evaluations in chemotherapy- naive patients (see report, beginning on page 6).
However, based on activity observed in a phase II trial in patients failing platinum-based and docetaxel(Drug information on docetaxel) (Taxotere) chemotherapy (overall 10.6% response rate), gefitinib has received accelerated approval by the US Food and Drug Administration (FDA) as monotherapy in patients with advanced NSCLC previously treated with platinum-based and docetaxel chemotherapy. This approval was itself delayed upon receipt of reports of interstitial lung disease in patients receiving gefitinib in Japan; the FDA concluded that this rare but serious toxicity (approximately 2% incidence in Japan and 0.3% in the US gefitinib expanded-access program, with a mortality rate of 33%) does not outweigh the benefits of treatment in advanced NSCLC (see page 11). Initial studies of the HER1/EGFR tyrosine kinase inhibitor erlotinib (Tarceva), which possibly exhibits some pharmacodynamic properties that are different from gefitinib, indicated activity and durable responses in patients with advanced refractory NSCLC and in patients with largely pretreated bronchoalveolar carcinoma. Erlotinib monotherapy is being evaluated against supportive care in a phase III trial in advanced, refractory disease. It was recently announced that phase III trials assessing the addition of erlotinib to platinum chemotherapy in first-line treatment of advanced disease did not meet the primary end points of improved survival. Although these findings are disappointing, they were not unexpected. Clearly, the combination of these agents with chemotherapy in lung cancer in an unselect population has not shown additive or synergistic activity as seen in the preclinical models. The results also reaffirm the need for identifying subsets of patients who are most likely to respond to treatment with EGFR tyrosine kinase inhibitors and other forms of targeted therapy (see page 9). In this regard, it is of interest that severity of rash has been correlated with prolonged survival in patients treated with erlotinib or with the anti-EGFR monoclonal antibody cetuximab(Drug information on cetuximab) (Erbitux). These findings at least suggest the possibility of using rash as a biomarker to guide dosing of these agents in order to optimize response. Programs assessing clinical samples to identify potential predictive and surrogate markers for response to EGFR inhibitors are underway (see page 16). New Combinations Intriguing data on conventional doublets and novel combinations involving targeted agents have been reported over the past year. A randomized phase II trial in chemotherapy-naive patients with advanced disease indicates that the nonplatinum doublet of vinorelbine (Navelbine)/gemcitabine (Gemzar) produced response rates and survival outcomes similar to carboplatin(Drug information on carboplatin) (Paraplatin)/paclitaxel (Taxol) treatment and resulted in reduced hematologic toxicity (see page 19). The combination of erlotinib and the angiogenesis inhibitor bevacizumab(Drug information on bevacizumab) (Avastin) has shown good activity (25% response) and a very encouraging safety profile in a phase I/II study in patients with recurrent/ metastatic disease (see page 14). Similar good activity of a combination of cetuximab and docetaxel has been reported in a phase II trial in patients resistant to second-line chemotherapy (see page 12). In addition, interim results of a comparative phase II trial in chemotherapy-naive patients indicate that the addition of cetuximab to a standard cisplatin(Drug information on cisplatin)/ vinorelbine regimen resulted in improved response rate (53% vs 32%) compared with the standard regimen, with no major increase in toxicity (see page 17). Adjuvant Therapy The International Adjuvant Lung Cancer Trial has demonstrated that cisplatin-based adjuvant chemotherapy results in significant improvements in 5-year overall survival (4.1% absolute benefit) and diseasefree survival (5.1% absolute benefit) in patients undergoing complete surgical resection for NSCLC. The trial involved 1,867 patients who received a cisplatinbased doublet (with etoposide(Drug information on etoposide), vinorelbine, vinblastine(Drug information on vinblastine), or vindesine(Drug information on vindesine) [Eldisine], depending on study site), or placebo following surgery. Grade 4 toxicity occurred in 23% of the adjuvant group. These data argue strongly for a role of adjuvant therapy in NSCLC. Further investigation will be needed to define patient selection criteria and optimal adjuvant regimens (see page 5). Induction Therapy Findings of the Intergroup Trial 0139 indicate that concurrent chemotherapy, radiation, and surgical resection results in improved progression-free survival compared with chemotherapy/radiation therapy alone. In this trial, 429 patients with T1-3, pN2, M0 disease underwent two cycles of induction therapy with cisplatin/ etoposide and daily radiation and then were randomized to surgery or continued radiation therapy, both followed by two additional cycles of chemotherapy. Median progression-free survival was significantly prolonged (13.4 vs 11.8 months) in the surgery arm. However, no difference in overall survival was observed. In the surgery arm, significantly more patients are alive without progression and significantly more have died without progression. An important finding in this trial is that downstaging of disease from N2 to N0 occurred in a significant proportion of patients, and that N0 status was associated with a marked improvement in survival (53% at 3 years) (see page 27). Docetaxel in First-Line Treatment With Cisplatin Docetaxel was approved for use in combination with cisplatin as first-line treatment in patients with unresectable locally advanced or metastatic NSCLC. The approval was based on a phase III trial in 1,218 patients showing significantly improved overall survival with this combination compared with the standard regimen of cisplatin/vinorelbine (10.9 vs 10.0 months); survival in a third study arm receiving carboplatin/ docetaxel was similar to that in the cisplatin/vinorelbine arm (see page 10). Looking Forward The coming year will bring additional advances in targeted therapy in NSCLC and other cancers. Information about novel combinations and schedules will become available. Ongoing investigations aimed at characterizing patients who respond best to these interventions will yield results that will ultimately enable targeting of therapy to appropriately selected patient subsets. With the FDA approval of gefitinib for use in patients with advanced NSCLC who have received prior platinum-based and docetaxel treatment, we have a demonstration of clinical benefit using the HER1/EGFR inhibition approach. More success of this approach and other targeted approaches is to follow. The greatest excitement in NSCLC research is to combine multiple agents in a patient-specific way; unlike chronic myelogenous leukemia, there is most likely not a single mutation that drives all cases of NSCLC, hence there can be no Gleevec (imatinib mesylate) for this disease-rather, treatment will require a cocktail of agents based on a patient's particular molecular phenotype. Roy S. Herbst, MD, PhD
Associate Professor of Medicine
Chief, Section of Thoracic Medical Oncology
Department of Thoracic/
Head and Neck Medical Oncology
University of Texas M. D. Anderson Cancer Center
Houston, Texas