Eli Lilly and Company announced that patients may receive Alimta (pemetrexed for injection) as a maintenance therapy following first-line Alimta plus cisplatin for locally advanced or metastatic nonsquamous non-small cell lung cancer (NS NSCLC). The FDA approved the label inclusion of phase III data that demonstrated progression-free and overall survival advantages in the continuation maintenance setting for these patients.

Appropriate patients can now start with Alimta plus cisplatin and continue with Alimta in the maintenance setting in advanced or metastatic NS NSCLC. Alimta is indicated for the maintenance treatment of patients with locally advanced or metastatic NS NSCLC whose disease has not progressed after four cycles of platinum-based first-line chemotherapy. Alimta is not indicated for patients with squamous-cell NSCLC. Myelosuppression is usually the dose-limiting toxicity with Alimta therapy.

"Continuation maintenance" involves continuing one of the same medicines prescribed in first-line treatment as maintenance therapy, in an effort to extend survival. It is the most recent addition to a new paradigm of maintenance treatment for advanced nonsquamous non-small cell lung cancer. Prior to the use of maintenance treatment, physicians typically treated a patient with four to six cycles of chemotherapy and then waited until the disease returned or worsened before resuming treatment.

"The approval provides patients and physicians with a new regimen that has demonstrated an improvement in overall survival. A survival benefit was previously established for Alimta for the first-line treatment of advanced nonsquamous non-small cell lung cancer in combination with cisplatin, and now as a single-agent for continuation maintenance treatment," said Richard Gaynor, vice president, product development and medical affairs for Lilly Oncology. "This is the first study to show a survival advantage for continuation maintenance, and it reinforces the role of Alimtain treating patients with advanced nonsquamous NSCLC."

In October 2011, the European Commission granted approval for the use of Alimta as a single agent for continuation maintenance in patients with advanced NS NSCLC based on progression-free survival and preliminary overall survival. On September 21, 2012, the Committee for Medicinal Products for Human Use (CHMP) in the European Union issued a positive opinion for a label update for Alimta in the continuation maintenance setting for certain patients with advanced nonsquamous non-small cell lung cancer after initial treatment with Alimta plus cisplatin.

The FDA and European Commission approvals were based on results from PARAMOUNT, a global, multicenter, double-blind phase III trial, the final results of which were shared in an oral presentation at the American Society of Clinical Oncology (ASCO) annual meeting in Chicago, Illinois. PARAMOUNT was the first study to evaluate the first-line use of Alimta plus cisplatin therapy followed immediately by the use of Alimta as a single-agent in the continuation maintenance setting.

A total of 939 patients with advanced nonsquamous NSCLC were enrolled in the study and received Alimta (500 mg/m2 on day one of a 21-day cycle) in combination with cisplatin (75 mg/m2) induction therapy. All patients received vitamin B12, folic acid and dexamethasone. Patients whose disease had not progressed during the Alimta plus cisplatin induction and who had an ECOG performance status of 0-1 (n=539) were randomized two-to-one to receive Alimta maintenance (500 mg/m2 on day one of a 21-day cycle) plus best supportive care (n=359) or placebo plus best supportive care (n=180) until disease progression. Of the patients whose disease had not progressed during Alimta plus cisplatin induction therapy and who were randomized to receive maintenance therapy, 44 per cent versus 42 per cent achieved a complete or partial response to induction therapy and 53 per cent versus 53 per cent had stable disease after induction treatment in the Alimta and placebo arms, respectively.

Final results of the PARAMOUNT trial demonstrated a statistically significant 22 per cent reduction in the risk of death (HR=0.78; 95 per cent CI: 0.64—0.96; p=0.02) with Alimta, compared to placebo. This reduction in the risk of death resulted in an improved median overall survival from the time patients were randomized of 13.9 months median for patients receiving Alimta, compared to 11.0 months median for patients on the placebo arm.

Median progression-free survival measured from randomization was 4.1 months on the Alimta arm as compared to 2.8 months on the placebo arm with a hazard ratio of 0.62. Stated another way, the study showed that patients on the Alimta continuation maintenance arm had a 38 per cent improvement of survival without disease worsening, compared to the placebo arm.

The most severe adverse reactions (grades 3-4) with Alimta as a single agent versus placebo, respectively, for these patients in the maintenance setting were anaemia (4.8 per cent vs 0.6 per cent); neutropenia (3.9 per cent vs 0 per cent); fatigue (4.5 per cent vs 0.6 per cent).

Common adverse reactions (all grades) with Alimta as a single agent versus placebo, respectively, were anaemia (15 per cent vs 4.8 per cent); neutropenia (nine per cent vs 0.6 per cent); fatigue (18 per cent vs 11 per cent); nausea (12 per cent vs 2.4 per cent); vomiting (six vs 1.8 per cent); mucositis/stomatitis (five per cent vs 2.4 per cent); edema (five per cent vs 3.6 per cent).

In 2004, Alimta received consecutive approvals: it was the first agent to be approved in combination with cisplatin as a treatment for patients with malignant pleural mesothelioma, whose disease is unresectable or who are otherwise not candidates for curative surgery, and then as a single agent for the second-line treatment of patients with locally advanced or metastatic NSCLC after prior chemotherapy treatment.

In 2008, Alimta, in combination with cisplatin, was approved as a first-line treatment for locally advanced or metastatic NSCLC for patients with nonsquamous histology. At the time of the first-line approval, the FDA also approved a change to the second-line indication. Alimta is now indicated as a single agent for the treatment of patients with locally advanced or metastatic, nonsquamous NSCLC after prior chemotherapy.

In 2009, Alimta was approved as a maintenance therapy for locally advanced or metastatic NSCLC, specifically for patients with a nonsquamous histology whose disease has not progressed after four cycles of platinum-based first-line chemotherapy.

Alimta is not indicated for treatment of patients with squamous cell NSCLC. Myelosuppression is usually the dose-limiting toxicity with Alimta therapy.