Expert Opinion
Nasser Hanna, MD
Indiana University
Nasser Hanna, MD, is an assistant professor at Indiana University, medical director for their Thoracic Oncology Program, and chair of the thoracic committee for the Hoosier Oncology Group. Recently, WebMD spoke with Dr Hanna about the current treatment options in previously treated NSCLC, treatment decisions in this setting, and the role of pemetrexed.
What are the standard treatment options for second-line NSCLC?
Three drugs are FDA approved to treat advanced non-small cell lung cancer previously treated with chemotherapy: docetaxel, erlotinib, and pemetrexed (ALIMTA).
ALIMTA as a single agent is indicated for the treatment of patients with locally advanced or metastatic NSCLC after prior chemotherapy. The effectiveness of ALIMTA in second-line NSCLC was based on the surrogate endpoint of response rate. There are no controlled trials demonstrating a clinical benefit, such as a favorable survival effect or improvement of disease-related symptoms.
ALIMTA received accelerated approval by the FDA based on results of a phase III study, which compared pemetrexed vs docetaxel in the second-line setting. This was the largest trial of second-line therapy at that time. Results demonstrated an acceptable side effect profile. The efficacy of ALIMTA when compared to docetaxel in a phase III open-label trial, showed an overall response rate of 9.1% vs 8.8%, median survival of 8.3 vs 7.9 months, median progression-free survival of 2.9 vs 2.9 months, and 1-year survival of 29.7% vs 29.7%, respectively. Please see the table below for additional detail and limitations of the study.[6]
The most common adverse events (grades 3/4) with ALIMTA for the treatment of patients with NSCLC were anemia (8%), leukopenia (5%), neutropenia (5%), thrombocytopenia (2%), infection without neutropenia (6%), fatigue (16%), thrombosis/embolism (3%), cardiac ischemia (3%), anorexia (5%), dyspnea (18%), and chest pain (7%). The most common clinically relevant adverse events (all grades) were fatigue (87%), anorexia (62%), nausea (39%), constipation (30%), vomiting (25%), diarrhea (21%), stomatitis/pharyngitis (20%), dyspnea (72%), chest pain (38%), neuropathy/sensory (29%), infection without neutropenia (23%), and rash (17%).
Briefly describe the pivotal trial of pemetrexed conducted by you and your colleagues. (Hanna N, et al. Randomized phase III trial of pemetrexed versus docetaxel in patients with non–small-cell lung cancer previously treated with chemotherapy. J Clin Oncol. 2004;22:1589-1597.)
The trial consisted of 571 patients, randomized to pemetrexed 500 mg/m2 over about a 10-minute infusion once every 3 weeks vs docetaxel 75 mg/m2. Patients treated with pemetrexed received folic acid and vitamin B12 supplementation to reduce the incidence of mucositis, diarrhea, and myelosuppression and dexamethasone to reduce the incidence of skin rash. Docetaxel was also given with dexamethasone.
What did results of the randomized trial demonstrate about the efficacy of pemetrexed?
The trial demonstrated that the response rates of those agents were comparable: about 8% to 9% confirmed objective response. About 45% of patients on both arms had confirmed stable disease. The time to disease progression, the median survival, and the 1-year survival were the same for both arms of the trial.
The primary endpoint in this study was overall survival. The median survival time was 8.3 months in the ALIMTA treatment arm and 7.9 months in the docetaxel arm, with a hazard ratio of 0.99 (see table above). The study did not show an overall survival superiority of ALIMTA. Non-inferiority of ALIMTA to docetaxel could not be demonstrated, because a reliable and consistent treatment crossover at the time of disease progression may have confounded the survival interpretation. The demonstrated surrogate endpoint, response rate, allowed the conclusion that an effect of ALIMTA on survival is reasonably likely.
In the second-line NSCLC setting, docetaxel has demonstrated improved overall survival compared with best supportive care. Controlled trials demonstrating a survival benefit of ALIMTA are still ongoing.
What did results of the randomized trial demonstrate about the safety and tolerability of pemetrexed?
Results showed pemetrexed has fewer side effects than docetaxel: less alopecia, less grade 1/2 neurosensory toxicity, and less grade 1/2 diarrhea. It did have a slightly higher rate of increase in the liver enzyme ALT, which was not clinically significant (grade 3, 1.9%).
What is the general goal of treatment in the second-line setting?
The goal of treatment in the second-line setting really is palliation. The last thing you want to do when you're trying to give a patient palliation is to induce side effects. These patients are already fatigued, anorexic, and in pain. They have very short life expectancies, so a week in the hospital is really unacceptable in the palliative setting. Stabilizing disease does confer improvement in individual symptoms and may allow patients to spend more time with their families or doing activities they enjoy. Administering drugs that are more convenient, take less time to administer, and result in fewer complications can also benefit patients.
What patient and disease characteristics do you consider when choosing a treatment program in the second-line setting?
Performance status is the most important variable by far when determining whether to treat somebody with chemotherapy in the second-line setting. It is the most predictive of tolerance, efficacy, and survival time. If a patient has a performance status of 0 or 1, particularly if they have benefited in some way from first-line chemotherapy, achieving at least stable disease, perhaps with some symptom improvement, then I think it's very appropriate to treat those patients with second-line chemotherapy.
How do you determine what treatment to use in the second-line treatment of NSCLC?
Based upon the phase III data, pemetrexed is a reasonable choice for the second-line treatment of NSCLC. It's just as active as docetaxel, but it is better tolerated, and it has a 10-minute infusion.
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ALIMTA as a single agent is indicated for the treatment of patients with locally advanced or metastatic non-small cell lung cancer after prior chemotherapy. The effectiveness of ALIMTA in second-line NSCLC was based on the surrogate endpoint, response rate. There are no controlled trials demonstrating a clinical benefit, such as a favorable survival effect or improvement of disease-related symptoms.
In the 2nd-line NSCLC setting, docetaxel has demonstrated improved overall survival compared with best supportive care. Controlled trials demonstrating a survival benefit of ALIMTA are still ongoing.
The most common adverse events (grades 3/4) with ALIMTA for the treatment of patients with NSCLC were anemia (8%), leukopenia (5%), neutropenia (5%), thrombocytopenia (2%), infection without neutropenia (6%), fatigue (16%), thrombosis/embolism (3%), cardiac ischemia (3%), anorexia (5%), dyspnea (18%), and chest pain (7%). The most common clinically relevant adverse events (all grades) were fatigue (87%), anorexia (62%), nausea (39%), constipation (30%), vomiting (25%), diarrhea (21%), stomatitis/pharyngitis (20%), dyspnea (72%), chest pain (38%), neuropathy/sensory (29%), infection without neutropenia (23%), and rash (17%).
