FDA Approves Lung Cancer Drug Alimta

(AP)10/28,2004 - The Food and Drug Administration approved a cancer drug made by pharmaceutical giant Eli Lilly and Co. to treat advanced non-small cell lung cancer in patients who have undergone chemotherapy.

According to the American Cancer Society, non-small cell lung cancer is the leading cause of cancer-related deaths in the nation. By the time most patients arrive for treatment, the cancer is widespread.

The drug, Alimta, in clinical trials was found to shrink tumors as effectively as another cancer drug, Taxotere. But Alimta did so with fewer troubling side effects, including hair loss, depressed blood count and hospitalizations for subsequent infection.

The treatment, 500 mg every 21 days, costs patients $3,900 per month, according to the company.

"There's no question, the survival was comparable to the survival with the best drugs we have," said Dr. Paul Bunn, director of the University of Colorado Cancer Center and principal investigator for several of the drug's clinical trials. "As a doctor, this drug is as good as anything else we have. It does benefit patients."

Alimta Improves Life of Lung Cancer Patients

A new version of an old class of chemotherapy drugs offers a better quality of life than the standard medication used for patients with recurrent lung cancer, researchers say.

Alimta® will likely benefit many non-small cell lung cancer patients because the majority of the 174,000 Americans diagnosed with the disease each year experience a recurrence, says Roy Herbst, M.D., chief of Thoracic Oncology at M. D. Anderson.

"Lung cancer is a very devastating disease and the therapies can be hard on patients," Herbst says. “While this new drug does not seem to increase survival at this late stage compared to the current standards, patients have far fewer side effects.”

Nationwide trial finds advantages over standard

Herbst and his M. D. Anderson colleagues took part in a nationwide clinical trial that led to the Aug. 19 approval of Alimta by the Food and Drug Administration. Under the direction of Frank Fossella, M.D., professor in the Department of Thoracic/Head & Neck Medical Oncology, the group tested the drug in 20 patients and found it offered significant benefits.

The trial compared Alimta withTaxotere, the current standard therapy for recurrent non-small cell lung cancer, and found that patients taking Alimta had fewer alternations in their blood counts and fewer side effects than those taking Taxotere. Side effects from Taxotere include myelosuppression, anemia, fatigue, anorexia and infection.

In fact, researchers found that only one in 50 patients taking Alimta had significant side effects, and that it can reduce tumor size as well as Taxotere.

Herbst says Alimta, already used for mesothelioma treatment since earlier this year, is now being used at M. D. Anderson for lung cancer. “We are beginning to offer it to patients,” he says. “Alimta is permitted for use in patients with stage 3 or 4 small-cell lung cancer who have had prior but unsuccessful chemotherapy treatment.”

Herbst says his group is also planning to open future clinical trials at M. D. Anderson using Alimta, including a study that will test it in combination with radiation therapy for treatment of lung cancer. He also suggests that it can someday potentially be used in first line therapy for non-small cell lung cancer based on data from his group.

Drug improves vitamin supplements

Alimta is a refinement of one of the oldest classes of chemotherapy drugs known as “anti-folates” that block folate, a B vitamin involved in making new genetic material. While it reduces the ability of cancer cells to reproduce and grow, the therapy can also harm normal cells, so patients are given extra supplements of folate and B12, to reduce the drug’s toxicity.

“If you supplement this drug with vitamin B12 and folate, the patients do extremely well,” Herbst says. An added benefit is that the drug is given to patients through an intravenous catheter in a procedure that lasts only ten minutes, and is administered only once every three weeks.

The drug’s possibilities have expanded to other diseases. Alimta also received FDA approval to treat malignant pleural mesothelioma, a type of lung cancer associated with asbestos exposure. M. D. Anderson researchers also participated in clinical trials that led to approval of use of Alimta for mesothelioma.

“It is a promising drug that will further help our patients who suffer from this all too common and devastating disease,” Herbst says.

Alimta Approved in the European Union for Two Cancer Indications

First and Only Chemotherapy Approved for Malignant Pleural Mesothelioma and New Option for a Common Form of Lung Cancer

INDIANAPOLIS (USA), 22 Sep. (PRNewswire) -

Eli Lilly and Company announced today that its chemotherapy agent, Alimta(R) (pemetrexed), has been granted marketing authorization by the European Commission (EC) for two distinct cancer indications. This regulatory first for Lilly, means that Alimta can be offered to two patient groups each battling devastating forms of cancer. The product launch and availability of Alimta will vary in each European Member State.

Alimta, in combination with cisplatin, now becomes the first and only approved chemotherapy in the European Union to help patients with malignant pleural mesothelioma live longer(1). Alimta, given as a single agent, is also an important new second-line treatment for patients suffering from non-small cell lung cancer(2).

"Alimta represents a true breakthrough in cancer care pushing the boundaries of conventional therapies with an innovative scientific approach. Alimta provides efficacy and when given with folic acid and B12 offers controlled side effects. Vitamin supplementation helps patients remain healthy enough to complete the full-recommended course of therapy -- increasing the opportunity Alimta has to work," said Christian Manegold, M.D., Professor at Ruprecht-Karls-University and a consultant in Hematology/Oncology for the Thoracic Hospital in Heidelberg, Germany. "By providing a balance of proven efficacy and controlled side effects, Alimta will help positively change the way chemotherapy is perceived."

Cytotoxic chemotherapy, which kills cells to combat cancer, has been the foundation of advanced cancer therapy for decades. Alimta, a cytotoxic chemotherapy, is a novel multitargeting antifolate that simultaneously blocks at least three separate enzymes essential to the survival of cancer cells. A team of researchers led by Lilly discovered that vitamin supplementation of folic acid and B12 given with Alimta significantly reduces the frequency and severity of the drug's side effects without compromising its ability to kill cancer cells.

Specifically, Alimta was approved today in combination with cisplatin, a common chemotherapy agent, for the treatment of malignant pleural mesothelioma (MPM), a cancer in the lining of the lungs for patients who have not received prior chemotherapy and are not candidates for surgery. Alimta was also approved as a single agent therapy for patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) after previous chemotherapy. The administration for Alimta is a convenient 10-minute infusion, once every three weeks.

"We are extremely pleased by the European Commission's approval of Alimta in Europe. This is an historical day -- two patient groups benefit from today's approval," said Edmundo Muniz, M.D., Ph.D., oncology leader at Lilly. "We now have a very strong non-small cell lung cancer franchise led by Gemzar in the first-line metastatic setting and Alimta in the second-line metastatic setting. Oncology is an area of tremendous unmet medical need, and we are committed to being a leader in developing new therapies for patients."

Clinical research of Alimta is ongoing in first-line non-small cell lung cancer and in combination with radiation. Small cell lung, breast, colon, ovarian and gastric cancers are also being researched.

Alimta for Malignant Pleural Mesothelioma Patients

Malignant pleural mesothelioma is a rare cancer of the lining of the lungs. The disease is often associated with asbestos exposure and has a long latency period -- usually between 20 and 40 years. Most people are not diagnosed until the cancer is in advanced stages and treatment with surgery or radiation is not an option. It is estimated that between 10,000 and 15,000 people around the world are diagnosed annually with malignant pleural mesothelioma.

The now approved combination of Alimta and cisplatin was compared to cisplatin alone in a clinical trial of 448 patients from 19 countries -- the largest trial to date among patients with malignant pleural mesothelioma. Results showed overall survival increased 30 percent (12.1 months for Alimta/cisplatin versus 9.3 months for cisplatin alone), and that 50.3 percent of patients treated with Alimta/cisplatin were alive a year later compared to 38.0 percent treated with cisplatin alone(1). Both the median and one-year advantages seen with the combination regimen of Alimta plus cisplatin were statistically significant.

The most common side effects when Alimta is used in combination with cisplatin are disorders of the blood and lymphatic system, gastrointestinal disorders, fatigue, sensory disorders of the nervous system, renal and urinary disorders, rash and hair loss.

Alimta in Non-Small Cell Lung Cancer

According to the 2003 World Health Organization Cancer Report, lung cancer is the world's most common cancer and the leading cause of cancer death for both men and women. There will be 1.2 million cases diagnosed this year around the world. The number of patients receiving treatment beyond the first-line in non-small cell lung cancer is steadily increasing and new therapy options are desperately needed in this setting.

Alimta was studied in a Phase III global clinical trial, the largest ever reported in second-line NSCLC, involving 571 randomized patients whose non-small cell lung cancer advanced beyond the first chemotherapy regimen. Among the patients enrolled in this study, 288 received docetaxel (75 mg/m2 on day one of a 21-day cycle; one-hour infusion) and 283 received Alimta (500 mg/m2 on day one of a 21-day cycle; 10-minute infusion; supplemented with vitamin B12 and folic acid). The primary endpoint was overall survival and secondary endpoints included toxicity, response rate, and progression-free survival.

In this study Alimta showed a survival rate comparable to that of docetaxel but with a more favorable side effect profile. Alimta caused significantly less neutropenia (an abnormal decrease in white blood cells) and hospitalization for neutropenia with fever, as well as less hair loss compared to docetaxel.

Patients on Alimta compared to therapy with docetaxel did show an increased transient elevation in Alanine Transaminase (ALT), a laboratory measurement of liver function. When Alimta is given as a single agent the most common side effects include disorders of the blood and lymphatic system, gastrointestinal disorders, fatigue, rash and desquamation (peeling of the skin).

Gemzar® and Platinol® Neoadjuvant Chemotherapy May Improve Outcome of Pneumonectomy for Mesothelioma

Researchers from Switzerland have reported the outcomes of 19 patients with mesothelioma scheduled to be treated with extrapleural pneumonectomy and radiation therapy after neoadjuvant chemotherapy with Gemzar® (gemcitabine) and Platinol® (cisplatin). The details of this report appeared in the September 1, 2004 issue of the Journal of Clinical Oncology .

In the recent past, standard therapy for mesothelioma was surgery and radiotherapy. However, the use of doublet chemotherapy regimens has become the standard approach, with the active agents being Alimta®, Gemzar® and Platinol® and possibly Paraplatin®. The role of neoadjuvant chemotherapy has been less well defined and there have been no randomized trials comparing surgery to no surgery for potentially operable mesothelioma. However, most patients have disease that cannot be removed with surgery.

In the current study, 19 patients were scheduled to receive neoadjuvant therapy with Gemzar® and Platinol® followed by extrapleural pneumonectomy and post-operative radiation therapy. Sixteen of the 19 patients underwent surgery and 13 patients received post-operative radiation therapy. They reported that the overall response rate to chemotherapy was 32%, with the major toxicity being thrombocytopenia. The median time to disease progression was less than 12 months and the median survival was approximately 23 months. Importantly, two patients remain alive and disease-free at 41 and 38 months after therapy.

Comments: These data suggest that neoadjuvant chemotherapy, surgery and post-operative radiation therapy are feasible in selected patients with advanced mesothelioma. However, it is not clear what role each of these components has in the management of advanced mesothelioma. It is impressive that there are two long-term survivors from this group. However, only randomized trials can determine if these three modalities are necessary for successful treatment of mesothelioma.

Reference: Weder W, Kestenholz, Taverna C, et al. Neoadjuvant chemotherapy followed by extrapleural pneumonectomy in Malignant Mesothelioma. Journal of Clinical Oncology. 2004;22:3451-3457.

Positive Trial Details : Adding Pemetrexed to Cisplatin Improves Survival in Malignant Pleural Mesothelioma

Laurie Barclay, MD

July 18, 2003 - Adding pemetrexed (Alimta) to cisplatin improved survival for patients with malignant pleural mesothelioma, according to the results of a randomized phase III trial published in the July 15 issue of the Journal of Clinical Oncology.

"For the first time we have a therapy for mesothelioma that makes a difference," lead author Nicholas J. Vogelzang, MD, from the University of Chicago Cancer Research Center in Illinois, says in a news release. "This is a first step, a small step to be sure, but a step in the right direction. It should encourage patients to keep trying and inspire physicians to focus more attention on this frustrating disease."

Of 456 chemotherapy-naive patients who were not eligible for curative surgery, 226 received pemetrexed 500 mg/m2 and cisplatin 75 mg/m2 on day 1, 222 received cisplatin alone, and eight never received therapy. Both treatment regimens were given intravenously every 21 days.

Median survival time was 12.1 months in the pemetrexed/cisplatin arm and 9.3 months in the cisplatin group (hazard ratio for death, 0.77; P = .02). Patients in the pemetrexed/cisplatin group also fared better in terms of median time to progression (5.7 months vs. 3.9 months; P = .001) and response rates (41.3% vs. 16.7%; P < .0001).

After 117 patients had enrolled, folic acid and vitamin B12 were added in the pemetrexed/cisplatin group, resulting in a significant reduction in toxicities including neutropenia, severe diarrhea, and severe mouth ulcers. Addition of these vitamins did not adversely affect survival time.

Study limitations include failure to control second-line therapy and lack of double-blind design, which could bias outcome measurements.

Eli Lilly and Company, the maker of Alimta, supported this study and employs one of its authors.

"This trial establishes pemetrexed and cisplatin as a new standard in systemic therapy for mesothelioma," Valerie Rusch, MD, from Memorial Sloan-Kettering Cancer Center in New York City, writes in an accompanying editorial. "It is now reasonable to state that effective chemotherapy exists for malignant pleural mesothelioma, dispelling the profound sense of nihilism surrounding treatment of this disease."

She suggests that future studies should apply this regimen to patients in earlier stages and should add other antineoplastic agents or targeted therapies for patients with advanced disease.

Two such follow-up trials are ongoing at the University of Chicago Hospitals. One is testing cisplatin plus pemetrexed, followed by surgery and radiation therapy, in patients with earlier-stage disease who potentially could be cured by surgery and radiation alone. A second study is testing a combination of pemetrexed plus gemcitabine.

"Although the pemetrexed plus cisplatin chemotherapy regimen is a clear advance in the treatment of malignant pleural mesothelioma, it hardly represents a home run in this difficult disease," Dr. Rusch writes.

J Clin Oncol. 2003;21:2636-2644

Reviewed by Gary D. Vogin, MD

Alimta®

On February 4, 2004, the FDA approved pemetrexed for injection (Alimta®, made by Eli Lilly and Company) in combination with cisplatin for the treatment of patients with malignant pleural mesothelioma whose disease is either unresectable or who are not otherwise candidates for curative surgery.

Safety and efficacy were demonstrated in one multicenter, randomized trial in 456 patients comparing the combination of Alimta and cisplatin with cisplatin alone. Supplementation with vitamin B12 and folic acid was instituted during the trial to decrease adverse effects. Subsequently, all patients, including previously enrolled patients, were given vitamin supplementation.

In an analysis of all patients who were randomized and treated, the combination of Alimta and cisplatin was associated with a statistically significant improvement in survival compared to cisplatin alone. The median survivals were 12.1 versus 9.3 months, respectively (p = 0.020). This superiority in the combination arm was also demonstrated in the fully vitamin supplemented subgroup. The median survivals were 13.3 and 10.0 months in the combination and cisplatin alone groups, respectively (p = 0.051).

The principal adverse effects of the Alimta plus cisplatin regimen were myelosuppression (in which the bone marrow produces fewer blood cells), fatigue, nausea, vomiting, and dyspnea (difficulty breathing). Most grade 3-4 adverse effects were significantly reduced by vitamin supplementation without any efficacy decrement.

Alimta, 500 mg/m2, was diluted in 100 mL normal saline and administered as a 10-minute intravenous infusion. Approximately 30 minutes after Alimta administration, cisplatin, 75 mg/m2 over 2 hours, was administered. Both drugs were given every 21 days.

Folic acid, 350 to 1000 micrograms orally, was given daily, beginning 1 to 3 weeks prior to the first chemotherapy dose and continued daily for one to three weeks after treatment discontinuation. A vitamin B12 injection, 1000 micrograms intramuscularly, was administered one to three weeks before the first chemotherapy dose and repeated approximately every nine weeks until treatment discontinuation.

Dexamethasone 4 mg (or an equivalent corticosteroid) twice daily was administered orally for skin rash prophylaxis to all patients one day prior to, on the day of, and one day after each Alimta dose.

Full prescribing information is available, including clinical trial information, safety, dosing, drug-drug interactions and contraindications.

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