ALIMTA switch maintenance therapy in advanced nonsquamous* NSCLC

ALIMTA is indicated for the maintenance treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer (NSCLC) whose disease has not progressed after four cycles of platinum-based first-line chemotherapy.

Limitation of Use: ALIMTA is not indicated for the treatment of patients with squamous cell non-small cell lung cancer.

Myelosuppression is usually the dose-limiting toxicity with ALIMTA therapy.

* Includes adenocarcinoma, large cell carcinoma, and other histologies except those with squamous cell type.

JMEN trial: Efficacy in advanced NSCLC by histologic subgroups1,2

Table showing efficacy results from the JMEN trial by histologic subgroups: ALIMTA + BSC vs placebo + BSC in switch maintenance

All endpoints were measured from the date of randomization, after completion of induction therapy.

Within the switch maintenance (JMEN) trial design, ALIMTA/cisplatin was not included as an induction therapy.2

Primary endpoint: Median progression-free survival (months) (95% CI) in the JMEN trial following 3 months of induction therapya

† 21 days x 4 cycles = 84 days/28 days = 3 months.

  1. Values for PFS are given based on independent review (ALIMTA + BSC n=387, placebo + BSC n=194).
  2. Includes adenocarcinoma, large cell carcinoma, and other histologies except those with squamous cell type.
  3. The subgroup of "Other" represents patients with a primary diagnosis of NSCLC whose disease did not clearly qualify as adenocarcinoma, large cell carcinoma, or squamous cell carcinoma.
  4. An HR <1.0 indicates that the result is better in the ALIMTA arm than in the placebo arm. An HR >1.0 indicates that the result is better in the placebo arm than in the ALIMTA arm.
  5. Unadjusted hazard ratios are provided.

BSC=best supportive care; CI=confidence interval; HR=hazard ratio; OS=overall survival; PFS=progression-free survival.

JMEN trial: ALIMTA advanced NSCLC switch maintenance study design1,2

A multicenter, randomized, placebo-controlled, double-blind phase III study

Diagram showing JMEN trial design: ALIMTA + BSC vs placebo + BSC in switch maintenance

Within the ALIMTA switch maintenance (JMEN) trial design, ALIMTA/cisplatin was not included as an induction therapy.2

All endpoints were measured from the date of randomization, which was after completion of four cycles of induction chemotherapy.

CR=complete response; IV=intravenous; PR=partial response; SD=stable disease.

ALIMTA safety profile in switch maintenance (JMEN)1,2

Increases in adverse reactions (all grades) were seen with longer exposure; however, no clinically relevant differences in grades 3/4 adverse reactions were seen1

Table showing ALIMTA safety profile in switch maintenance (JMEN)

Within the ALIMTA switch maintenance (JMEN) trial design, ALIMTA/cisplatin was not included as induction therapy.2

  1. For the purpose of this table, a cutoff of 5% was used for inclusion of all events where the reporter considered a possible relationship to ALIMTA.
  2. Refer to NCI CTCAE version 3.0 for each grade of toxicity.

CTCAE=Common Terminology Criteria for Adverse Events.

Dosing and administration for ALIMTA as a single agent1

The recommended dose of ALIMTA is 500 mg/m2 IV on day 1 of each 21-day cycle.

Table showing ALIMTA maintenance dose for advanced nonsquamous NSCLC; 500 mg/m² over 10 minutes every 21 days
  • Instruct patients to initiate folic acid 400 mcg to 1000 mcg orally once daily beginning 7 days before the first dose of ALIMTA. Continue folic acid during the full course of therapy and for 21 days after the last dose of ALIMTA
  • Patients must also receive one intramuscular injection of vitamin B12 (1000 mcg) 1 week prior to the first dose of ALIMTA and every 3 cycles thereafter
  • Patients should receive dexamethasone 4 mg by mouth twice daily the day before, the day of, and the day after ALIMTA administration

NS=nonsquamous

Dosing modifications1

Dose reductions for ALIMTA as a single agent

Table showing dose reductions for ALIMTA maintenance therapy in advanced nonsquamous NSCLC
  1. These criteria meet the CTC version 2.0 (NCI 1998) definition of ≥ CTC grade 2 bleeding.
  2. NCI Common Toxicity Criteria (CTC).
  3. Excluding neurotoxicity.
  4. Patients should discontinue therapy if grade 3 or 4 neurotoxicity is experienced.
  • Complete blood cell counts including platelet counts should be performed on all patients receiving ALIMTA. Patients should be monitored for nadir and recovery, which were tested in the clinical study before each dose and on days 8 and 15 of each cycle. Patients should not begin a new cycle of treatment unless the ANC is ≥1500 cells/mm3, the platelet count is ≥100,000 cells/mm3, and creatinine clearance is ≥45 mL/min. Periodic chemistry tests should be performed to evaluate renal and hepatic function
  • Dose adjustments at the start of a subsequent cycle should be based on nadir hematologic counts or maximum nonhematologic toxicity from the preceding cycle of therapy
  • If patients develop nonhematologic toxicities (excluding neurotoxicity) ≥ grade 3, ALIMTA should be withheld until resolution to less than or equal to the patient's pretherapy value. Treatment should be resumed according to the guidelines listed in the dosing modifications table shown above
  • ALIMTA therapy should be discontinued if a patient experiences any hematologic or nonhematologic grade 3 or 4 toxicity after 2 dose reductions or immediately if grade 3 or 4 neurotoxicity is observed
  • ALIMTA should not be administered to patients with a creatinine clearance <45 mL/min
References
  1. ALIMTA (pemetrexed for injection) [package insert]. Indianapolis, IN: Eli Lilly and Company; 2013.
  2. Ciuleanu T, et al. Lancet. 2009;374(9699):1432-1440.

ALIMTA/cisplatin for malignant pleural mesothelioma

ALIMTA in combination with cisplatin is indicated for the treatment of patients with malignant pleural mesothelioma (MPM) whose disease is unresectable or who are otherwise not candidates for curative surgery.

Myelosuppression is usually the dose-limiting toxicity with ALIMTA therapy.

ALIMTA/cisplatin demonstrated a statistically significant, clinically relevant survival advantage over cisplatin alone in patients with MPM.1,2

Overall survival (all randomized and treated, n=448)*

KM curve, median overall survival, all randomized MPM patients: ALIMTA/cisplatin vs cisplatin

Similar results were seen in the analysis of patients (n=303) with confirmed histologic diagnosis of MPM.

Objective tumor response for MPM is difficult to measure and response criteria are not universally agreed upon. However, based upon prospectively defined criteria, the objective tumor response rate for ALIMTA/cisplatin was greater than the objective tumor response rate for cisplatin alone.1

Secondary endpoint: Median time to progressive disease (months) (95% CI)

ALIMTA/cisplatin (n=226): 5.7 (4.9-6.5); cisplatin (n=222): 3.9 (2.8-4.4); HR: 0.68; P=0.001†,2

Secondary endpoint: Objective response rate (95% CI)

ALIMTA/cisplatin (n=226): 41.3% (34.8-48.1); cisplatin (n=222): 16.7% (12.0-22.2)2

* Kaplan-Meier estimates of survival time.

P value refers to comparison between arms.

CI=confidence interval; HR=hazard ratio.

View Trial Design

ALIMTA/cisplatin demonstrated an improved clinically relevant survival advantage over cisplatin alone in patients with MPM.1,2

Overall survival (fully supplemented, n=331)*

KM curve, median overall survival in fully supplemented MPM patients: ALIMTA/cisplatin vs cisplatin

* Kaplan-Meier estimates of survival time.

P value refers to comparison between arms.

‡ Supplementation with oral (PO) folic acid and intramuscular (IM) B12 before first dose of ALIMTA and throughout treatment. Corticosteroids should also be used as supplementation the day before, the day of, and the day after ALIMTA administration.

ALIMTA MPM trial study design: ALIMTA/cisplatin vs cisplatin1,2

One of the largest multicenter, randomized phase III trials to be conducted in MPM

ALIMTA MPM trial design: ALIMTA/cisplatin vs cisplatin

‡ After 117 patients were treated, white cell and GI toxicity led to a change in protocol whereby all patients were given folic acid and vitamin B12 supplementation.

§ Patients were randomized into two treatment groups.

IV=intravenous.

Patient vitamin supplementation status in the MPM trial2

Table of patient vitamin supplementation in the MPM trial: ALIMTA/cisplatin vs cisplatin

Vitamin supplementation (folic acid and vitamin B12) During the trial, vitamin supplementation was added to help reduce the frequency and severity of certain side effects. This resulted in subsets of patients who either never or partially received vitamin supplementation, or were fully supplemented with vitamins.

ALIMTA safety profile in MPM1

Summary of all grades and grades 3/4 toxicities in fully supplemented patients: ALIMTA/cisplatin vs cisplatin in MPM

Table of all grades and grades 3/4 toxicities in fully supplemented patients: ALIMTA/cisplatin vs cisplatin
  1. For the purpose of this table, a cutoff of 5% was used for inclusion of all events where the reporter considered a possible relationship to ALIMTA.
  2. Refer to NCI CTC version 2.0 for each grade of toxicity except the term "creatinine clearance decreased," which is derived from the CTC term "renal/genitourinary—other."
  3. According to NCI CTC version 2.0, this adverse event term should be reported only as grade 1 or 2.

CTC=Common Toxicity Criteria.

Dosing and administration for ALIMTA in combination with cisplatin1

The recommended dose of ALIMTA is 500 mg/m2 IV on day 1 of each 21-day cycle in combination with cisplatin 75 mg/m2 IV, beginning cisplatin 30 minutes after ALIMTA administration.

Dosing table for ALIMTA/cisplatin in malignant pleural mesothelioma
  • Instruct patients to initiate folic acid 400 mcg to 1000 mcg orally once daily beginning 7 days before the first dose of ALIMTA. Continue folic acid during the full course of therapy and for 21 days after the last dose of ALIMTA
  • Patients must also receive one intramuscular injection of vitamin B12 (1000 mcg) 1 week prior to the first dose of ALIMTA and every 3 cycles thereafter
  • Patients should receive dexamethasone 4 mg by mouth twice daily the day before, the day of, and the day after ALIMTA administration

Dosing modifications1

Dose reductions for ALIMTA in combination with cisplatin

Dose reduction table for ALIMTA/cisplatin
  1. These criteria meet the CTC version 2.0 (NCI 1998) definition of ≥ CTC grade 2 bleeding.
  2. NCI Common Toxicity Criteria (CTC).
  3. Excluding neurotoxicity.
  4. Patients should discontinue therapy if grade 3 or 4 neurotoxicity is experienced.
  • Complete blood cell counts including platelet counts should be performed on all patients receiving ALIMTA. Patients should be monitored for nadir and recovery, which were tested in the clinical study before each dose and on days 8 and 15 of each cycle. Patients should not begin a new cycle of treatment unless the ANC is ≥1500 cells/mm3, the platelet count is ≥100,000 cells/mm3, and creatinine clearance is ≥45 mL/min. Periodic chemistry tests should be performed to evaluate renal and hepatic function
  • Dose adjustments at the start of a subsequent cycle should be based on nadir hematologic counts or maximum nonhematologic toxicity from the preceding cycle of therapy
  • If patients develop nonhematologic toxicities (excluding neurotoxicity) ≥ grade 3, ALIMTA should be withheld until resolution to less than or equal to the patient's pretherapy value. Treatment should be resumed according to the guidelines listed in the dosing modifications table shown above
  • ALIMTA therapy should be discontinued if a patient experiences any hematologic or nonhematologic grade 3 or 4 toxicity after 2 dose reductions or immediately if grade 3 or 4 neurotoxicity is observed
  • ALIMTA should not be administered to patients with a creatinine clearance <45 mL/min
  • In the event of neurotoxicity, the recommended dose adjustments for ALIMTA and cisplatin are shown above. Patients should discontinue therapy if grade 3 or 4 neurotoxicity is experienced
References
  1. ALIMTA (pemetrexed for injection) [package insert]. Indianapolis, IN: Eli Lilly and Company; 2013.
  2. Vogelzang NJ, et al. J Clin Oncol. 2003;21(14):2636-2644.

Indications for ALIMTA® (pemetrexed for injection)

ALIMTA® (pemetrexed for injection) is indicated in combination with cisplatin therapy for the initial treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer.

ALIMTA is indicated for the maintenance treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer whose disease has not progressed after four cycles of platinum-based first-line chemotherapy.

ALIMTA is indicated as a single agent for the treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer after prior chemotherapy.

Limitation of Use: ALIMTA is not indicated for the treatment of patients with squamous cell non-small cell lung cancer.

ALIMTA in combination with cisplatin is indicated for the treatment of patients with malignant pleural mesothelioma whose disease is unresectable or who are otherwise not candidates for curative surgery.

Important Safety Information for ALIMTA

Myelosuppression is usually the dose-limiting toxicity with ALIMTA therapy.

Contraindication

ALIMTA is contraindicated in patients who have a history of severe hypersensitivity reaction to pemetrexed.

Warnings and Precautions

Prior to treatment with ALIMTA, patients must be instructed to initiate supplementation with oral folic acid. Additionally, intramuscular injections of vitamin B12 are also required prior to ALIMTA treatment. Folic acid and vitamin B12 supplementation should be continued throughout treatment as they may reduce the severity of treatment-related hematologic and GI toxicities.

Dexamethasone or its equivalent should be administered the day before, the day of, and the day after ALIMTA treatment.

ALIMTA can suppress bone marrow function, as manifested by neutropenia, thrombocytopenia, and anemia (or pancytopenia). Reduce doses for subsequent cycles based on hematologic and nonhematologic toxicities.

ALIMTA should not be administered to patients with a creatinine clearance <45 mL/min. One patient with severe renal impairment (creatinine clearance 19 mL/min) who did not receive folic acid and vitamin B12 died of drug-related toxicity following administration of ALIMTA alone.

Caution should be used when administering NSAIDs concurrently with ALIMTA to patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 79 mL/min). Patients with mild to moderate renal insufficiency should avoid taking NSAIDs with short elimination half-lives for a period of 2 days before, the day of, and 2 days following administration of ALIMTA. In the absence of data regarding potential interaction between ALIMTA and NSAIDs with longer half-lives, all patients taking these NSAIDs should interrupt dosing for at least 5 days before, the day of, and 2 days following ALIMTA administration. If concomitant administration of NSAIDs is necessary, patients should be monitored closely for toxicity, especially myelosuppression, renal, and gastrointestinal toxicity. No dose adjustment of ALIMTA is needed with concomitant NSAIDs in patients with normal renal function.

Do not initiate a cycle of treatment in patients unless the ANC is ≥1500 cells/mm3, the platelet count is ≥100,000 cells/mm3, and creatinine clearance is ≥45 mL/min.

Pregnancy Category D—ALIMTA may cause fetal harm when administered to a pregnant woman. Women should be apprised of the potential hazard to the fetus and should be advised to use effective contraceptive measures to prevent pregnancy during treatment with ALIMTA.

Drug Interactions

See Warnings and Precautions for specific information regarding NSAID administration in patients with renal insufficiency.

Concomitant administration of nephrotoxic drugs or substances that are tubularly secreted could result in delayed clearance of ALIMTA.

Use in Specific Patient Populations

It is recommended that nursing be discontinued if the mother is being treated with ALIMTA or discontinue the drug, taking into account the importance of the drug for the mother.

Efficacy of ALIMTA in pediatric patients has not been demonstrated. The most common toxicities reported in the studied pediatric patients were hematological (leukopenia, neutropenia/granulocytopenia, anemia, thrombocytopenia, and lymphopenia), liver function abnormalities (increased ALT/AST), fatigue, and nausea.

Dosage and Administration Guidelines

Complete blood cell counts, including platelet counts and periodic chemistry tests, which include renal and hepatic function tests, should be performed on all patients receiving ALIMTA.

Dose adjustments at the start of a subsequent cycle should be based on nadir hematologic counts or maximum nonhematologic toxicity from the preceding cycle of therapy. Modify or suspend therapy according to the Dosage Reduction Guidelines in the full Prescribing Information.

Abbreviated Adverse Reactions (% incidence) – 1st-line advanced nonsquamous non-small cell lung cancer (NS NSCLC)

The most severe adverse reactions (grades 3-4) with ALIMTA in combination with cisplatin versus gemcitabine in combination with cisplatin, respectively, for the 1st-line treatment of patients with advanced nonsquamous non-small cell lung cancer (NSCLC) were neutropenia (15% vs 27%); leukopenia (5% vs 8%); thrombocytopenia (4% vs 13%); anemia (6% vs 10%); fatigue (7% vs 5%); nausea (7% vs 4%); vomiting (6% vs 6%); anorexia (2% vs 1%); creatinine elevation (1% vs 1%); and diarrhea (1% vs 2%).

Common adverse reactions (all grades) with ALIMTA in combination with cisplatin versus gemcitabine in combination with cisplatin, respectively, were nausea (56% vs 53%); fatigue (43% vs 45%); vomiting (40% vs 36%); anemia (33% vs 46%); neutropenia (29% vs 38%); anorexia (27% vs 24%); constipation (21% vs 20%); leukopenia (18% vs 21%); stomatitis/pharyngitis (14% vs 12%); alopecia (12% vs 21%); diarrhea (12% vs 13%); thrombocytopenia (10% vs 27%); neuropathy/sensory (9% vs 12%); taste disturbance (8% vs 9%); rash/desquamation (7% vs 8%); dyspepsia/heartburn (5% vs 6%); and creatinine elevation (10% vs 7%).

Abbreviated Adverse Reactions (% incidence) – Maintenance in advanced NS NSCLC following non-ALIMTA containing, platinum-based induction therapy

The most severe adverse reactions (grades 3-4) with ALIMTA as a single agent versus placebo, respectively, for the maintenance treatment of patients with locally advanced nonsquamous non-small cell lung cancer (NS NSCLC) following non-ALIMTA containing platinum-based induction therapy were anemia (3% vs 1%); neutropenia (3% vs 0%); leukopenia (2% vs 1%); fatigue (5% vs 1%); nausea (1% vs 1%); anorexia (2% vs 0%); mucositis/stomatitis (1% vs 0%); diarrhea (1% vs 0%); infection (2% vs 0%); and neuropathy-sensory (1% vs 0%).

Common adverse reactions (all grades) with ALIMTA as a single agent versus placebo, respectively, after non-ALIMTA containing platinum-based induction therapy were anemia (15% vs 6%); neutropenia (6% vs 0%); leukopenia (6% vs 1%); increased ALT (10% vs 4%); increased AST (8% vs 4%); fatigue (25% vs 11%); nausea (19% vs 6%); anorexia (19% vs 5%); vomiting (9% vs 1%); mucositis/stomatitis (7% vs 2%); diarrhea (5% vs 3%); infection (5% vs 2%); neuropathy-sensory (9% vs 4%); and rash/desquamation (10% vs 3%).

Abbreviated Adverse Reactions (% incidence) – Maintenance in advanced NS NSCLC following ALIMTA plus cisplatin induction therapy

The most severe adverse reactions (grades 3-4) with ALIMTA as a single agent versus placebo, respectively, for the maintenance treatment of patients with locally advanced nonsquamous non-small cell lung cancer (NS NSCLC) following ALIMTA plus cisplatin induction therapy were anemia (4.8% vs 0.6%); neutropenia (3.9% vs 0%); and fatigue (4.5% vs 0.6%).

Common adverse reactions (all grades) with ALIMTA as a single agent versus placebo, respectively, following ALIMTA plus cisplatin induction therapy were anemia (15% vs 4.8%); neutropenia (9% vs 0.6%); fatigue (18% vs 11%); nausea (12% vs 2.4%); vomiting (6% vs 1.8%); mucositis/stomatitis (5% vs 2.4%); and edema (5% vs 3.6%).

Abbreviated Adverse Reactions (% incidence) – 2nd-line advanced NS NSCLC

The most severe adverse reactions (grades 3-4) with ALIMTA as a single agent versus docetaxel, respectively, for the 2nd-line treatment of patients with advanced non-small cell lung cancer (NSCLC) were neutropenia (5% vs 40%); leukopenia (4% vs 27%); thrombocytopenia (2% vs 0%); anemia (4% vs 4%); fatigue (5% vs 5%); nausea (3% vs 2%); anorexia (2% vs 3%); vomiting (2% vs 1%); increased ALT (2% vs 0%); increased AST (1% vs 0%); and stomatitis/pharyngitis (1% vs 1%).

Common adverse reactions (all grades) with ALIMTA as a single agent versus docetaxel, respectively, were fatigue (34% vs 36%); nausea (31% vs 17%); anorexia (22% vs 24%); anemia (19% vs 22%); vomiting (16% vs 12%); stomatitis/pharyngitis (15% vs 17%); rash (14% vs 6%); diarrhea (13% vs 24%); leukopenia (12% vs 34%); thrombocytopenia (8% vs 1%); increased ALT (8% vs 1%); increased AST (7% vs 1%); constipation (6% vs 4%); fever (8% vs 8%); pruritus (7% vs 2%); alopecia (6% vs 38%); and neutropenia (11% vs 45%).

Abbreviated Adverse Reactions (% incidence) – MPM

The most severe adverse reactions (grades 3-4) with ALIMTA in combination with cisplatin versus cisplatin alone, respectively, for the treatment of patients with malignant pleural mesothelioma (MPM) were neutropenia (23% vs 3%); leukopenia (15% vs 1%); thrombocytopenia (5% vs 0%); anemia (4% vs 0%); nausea (12% vs 6%); vomiting (11% vs 4%); fatigue (10% vs 9%); creatinine elevation (1% vs 1%); stomatitis/pharyngitis (3% vs 0%); anorexia (1% vs 1%); diarrhea (4% vs 0%); constipation (1% vs 1%); dyspepsia (1% vs 0%); dehydration (4% vs 1%); neuropathy-sensory (0% vs 1%); rash (1% vs 0%); and creatinine clearance decrease (1% vs 2%).

Common adverse reactions (all grades) with ALIMTA in combination with cisplatin versus cisplatin alone, respectively, were neutropenia (56% vs 13%); leukopenia (53% vs 17%); anemia (26% vs 10%); thrombocytopenia (23% vs 9%); nausea (82% vs 77%); vomiting (57% vs 50%); fatigue (48% vs 42%); creatinine elevation (11% vs 10%); creatinine clearance decreased (16% vs 18%); conjunctivitis (5% vs 1%); anorexia (20% vs 14%); diarrhea (17% vs 8%); constipation (12% vs 7%); dyspepsia (5% vs 1%); dehydration (7% vs 1%); neuropathy-sensory (10% vs 10%); taste disturbance (8% vs 6%); rash (16% vs 5%); alopecia (11% vs 6%); and stomatitis/pharyngitis (23% vs 6%).

For safety and dosing guidelines, see complete Warnings and Precautions, Adverse Reactions, and Dosage and Administration sections in the Prescribing Information and Patient Prescribing Information.

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