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, as a single agent.

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

* 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 vs placebo 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

  1. 21 days x 4 cycles = 84 days/28 days = 3 months.
  1. Values for PFS given based on independent review (ALIMTA n=387, Placebo n=194).
  2. HRs are adjusted for multiplicity but not for stratification variables.
  3. Includes adenocarcinoma, large cell carcinoma, and other histologies except those with squamous cell type.
  4. HRs are not adjusted for multiplicity.
  5. Primary diagnosis of NSCLC not specified as adenocarcinoma, large cell carcinoma, or squamous cell carcinoma.

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 vs placebo 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.

ECOG=Eastern Cooperative Oncology Group; IV=intravenous; PS=performance status.

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 seen2

Adverse reactions occurring in ≥5% of patients receiving ALIMTA in study JMEN

Table showing ALIMTA safety profile in switch maintenance (JMEN)

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

  1. NCI CTCAE version 3.0.

NCI CTCAE=National Cancer Institute 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 dose reductions for ALIMTA maintenance therapy in advanced nonsquamous NSCLC

There is no recommended dose for patients whose creatinine clearance is less than 45 mL/min.

  • Initiate folic acid 400 mcg to 1000 mcg orally once daily, beginning 7 days before the first dose of ALIMTA and continuing until 21 days after the last dose of ALIMTA
  • Patients must also receive one intramuscular injection of vitamin B12 (1 mg) 1 week prior to the first dose of ALIMTA and every 3 cycles thereafter. Do not substitute oral vitamin B12 for intramuscular vitamin B12
  • Patients should receive dexamethasone 4 mg orally twice daily for 3 consecutive days, beginning the day before each ALIMTA administration

NS=nonsquamous

Dosing modifications1

Dose reductions for ALIMTA as a single agent

Recommended dosage modifications for adverse reactionsa

Table showing dose reductions for ALIMTA maintenance therapy in advanced nonsquamous NSCLC
  1. National Cancer Institute Common Toxicity Criteria for Adverse Events version 2 (NCI CTCAE v2).

Dosing modification notes

  • In patients with creatinine clearances between 45 mL/min and 79 mL/min, avoid administration of ibuprofen for 2 days before, the day of, and 2 days following administration of ALIMTA. Monitor patients more frequently for myelosuppression, renal, and gastrointestinal toxicity, if concomitant administration of ibuprofen cannot be avoided
  • Obtain complete blood count on days 1, 8, and 15 of each cycle. Assess creatinine clearance prior to each cycle. Do not administer ALIMTA if the creatinine clearance is less than 45 mL/min
  • Delay initiation of the next cycle of ALIMTA until recovery of nonhematologic toxicity to grade 0-2, ANC is 1500 cells/mm3 or higher, and platelet count is 100,000 cells/mm3 or higher
  • Upon recovery, modify the dosage of ALIMTA in the next cycle as specified in the table above

ANC=absolute neutrophil count.

References
  1. ALIMTA (pemetrexed for injection) [package insert]. Indianapolis, IN: Eli Lilly and Company; 2017.
  2. Ciuleanu T, et al. Lancet. 2009;374(9699):1432-1440.

ALIMTA/cisplatin for malignant pleural mesothelioma

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

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

Overall survival (OS) (all randomized and treated, N=448)

KM curve, median overall survival, all randomized MPM patients: ALIMTA/cisplatin vs cisplatin
  1. HRs are not adjusted for stratification variables.

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

OS (fully supplemented, n=331)2

KM curve, median overall survival in fully supplemented MPM patients: ALIMTA/cisplatin vs cisplatin
  1. HRs are not adjusted for stratification variables.
  2. Not a prespecified analysis.

ALIMTA MPM trial (JMCH) 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

† Patients with MPM who had received no prior chemotherapy were randomized into two treatment groups. At least one dose of protocol-specified therapy was given and treatment continued until disease progression or intolerable toxicity.

‡ 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.

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

Adverse reactions occurring in ≥5% of fully supplemented subgroup of patients receiving ALIMTA/cisplatin in study JMCHa

Table of all grades and grades 3/4 toxicities in fully supplemented patients: ALIMTA/cisplatin vs cisplatin
  1. In study JMCH, 226 patients received at least one dose of ALIMTA/cisplatin and 222 patients received at least one dose of cisplatin. This table represents the patients treated with ALIMTA/cisplatin (168 patients) or cisplatin alone (163 patients) who received full supplementation with folic acid and vitamin B12 during study therapy.
  2. NCI CTCAE version 2.0.

NCI CTCAE=National Cancer Institute Common Terminology Criteria for Adverse Events.

Dosing and administration for ALIMTA in combination with cisplatin1

The recommended dose of ALIMTA is 500 mg/m2 as an IV infusion over 10 minutes administered prior to cisplatin on day 1 of each 21-day cycle.

Dosing table for ALIMTA/cisplatin in malignant pleural mesothelioma

There is no recommended dose for patients whose creatinine clearance is less than 45 mL/min.

  • Initiate folic acid 400 mcg to 1000 mcg orally once daily, beginning 7 days before the first dose of ALIMTA and continuing until 21 days after the last dose of ALIMTA
  • Patients must also receive one intramuscular injection of vitamin B12 (1 mg) 1 week prior to the first dose of ALIMTA and every 3 cycles thereafter. Do not substitute oral vitamin B12 for intramuscular vitamin B12
  • Patients should receive dexamethasone 4 mg orally twice daily for 3 consecutive days, beginning the day before each ALIMTA administration

Dosing modifications1

Dose reductions for ALIMTA in combination with cisplatin

Recommended dosage modifications for adverse reactionsa

Dose reduction table for ALIMTA/cisplatin
  1. National Cancer Institute Common Toxicity Criteria for Adverse Events version 2 (NCI CTCAE v2).

Dosing modification notes

  • In patients with creatinine clearances between 45 mL/min and 79 mL/min, avoid administration of ibuprofen for 2 days before, the day of, and 2 days following administration of ALIMTA. Monitor patients more frequently for myelosuppression, renal, and gastrointestinal toxicity, if concomitant administration of ibuprofen cannot be avoided
  • Obtain complete blood count on days 1, 8, and 15 of each cycle. Assess creatinine clearance prior to each cycle. Do not administer ALIMTA if the creatinine clearance is less than 45 mL/min
  • Delay initiation of the next cycle of ALIMTA until recovery of nonhematologic toxicity to grade 0-2, ANC is 1500 cells/mm3 or higher, and platelet count is 100,000 cells/mm3 or higher
  • Upon recovery, modify the dosage of ALIMTA in the next cycle as specified in the table above
  • For dosing modifications for cisplatin, refer to the prescribing information for cisplatin

ANC=absolute neutrophil count.

References
  1. ALIMTA (pemetrexed for injection) [package insert]. Indianapolis, IN: Eli Lilly and Company; 2017.
  2. Vogelzang NJ, et al. J Clin Oncol. 2003;21(14):2636-2644.
Indications and Important Safety Information

Indications for ALIMTA® (pemetrexed for injection)

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

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, as a single agent.

ALIMTA is indicated for the treatment of patients with recurrent metastatic nonsquamous non-small cell lung cancer (NSCLC) after prior chemotherapy, as a single agent.

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

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

Important Safety Information for ALIMTA

Contraindication

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

WARNINGS AND PRECAUTIONS

Myelosuppression and Increased Risk of Myelosuppression without Vitamin Supplementation

  • ALIMTA can cause severe myelosuppression resulting in a requirement for transfusions and which may lead to neutropenic infection. The risk of myelosuppression is increased in patients who do not receive vitamin supplementation.
  • Prior to treatment with ALIMTA, patients must be instructed to initiate supplementation with oral folic acid. Intramuscular injections of vitamin B12 are also required prior to ALIMTA treatment. Folic acid and vitamin B12 supplementation should be continued during treatment and for 21 days after the last dose of ALIMTA as they may reduce the severity of treatment-related hematologic and gastrointestinal toxicities. Obtain a complete blood count at the beginning of each cycle. Do not administer ALIMTA until the ANC is at least 1500 cells/mm3 and platelet count is at least 100,000 cells/mm3. Permanently reduce ALIMTA in patients with an ANC of less than 500 cells/mm3 or platelet count of less than 50,000 cells/mm3 in previous cycles.
  • In Studies JMDB and JMCH, among patients who received vitamin supplementation, incidence of Grade 3-4 neutropenia was 15% and 23%, the incidence of Grade 3-4 anemia was 6% and 4%, and incidence of Grade 3-4 thrombocytopenia was 4% and 5%, respectively. In Study JMCH, 18% of patients in the ALIMTA arm required red blood cell transfusions compared to 7% of patients in the cisplatin arm. In Studies JMEN, PARAMOUNT, and JMEI, where all patients received vitamin supplementation, incidence of Grade 3-4 neutropenia ranged from 3% to 5%, and incidence of Grade 3-4 anemia ranged from 3% to 5%.

Renal Failure

  • ALIMTA can cause severe, and sometimes fatal, renal toxicity. Determine creatinine clearance before each dose and periodically monitor renal function during treatment with ALIMTA.
  • The incidences of renal failure in clinical studies in which patients received ALIMTA with cisplatin were: 2.1% in Study JMDB and 2.2% in Study JMCH. The incidence of renal failure in clinical studies in which patients received ALIMTA as a single agent ranged from 0.4% to 0.6% (Studies JMEN, PARAMOUNT, and JMEI).
  • Withhold ALIMTA in patients with a creatinine clearance of less than 45 mL/min.

Bullous and Exfoliative Skin Toxicity

  • Serious and sometimes fatal, bullous, blistering and exfoliative skin toxicity, including cases suggestive of Stevens-Johnson Syndrome/Toxic epidermal necrolysis can occur with ALIMTA. Permanently discontinue ALIMTA for severe and life-threatening bullous, blistering or exfoliating skin toxicity.

Interstitial Pneumonitis

  • Serious interstitial pneumonitis, including fatal cases, can occur with ALIMTA treatment. Withhold ALIMTA for acute onset of new or progressive unexplained pulmonary symptoms such as dyspnea, cough, or fever pending diagnostic evaluation. If pneumonitis is confirmed, permanently discontinue ALIMTA.

Radiation Recall

  • Radiation recall can occur with ALIMTA in patients who have received radiation weeks to years previously. Monitor patients for inflammation or blistering in areas of previous radiation treatment. Permanently discontinue ALIMTA for signs of radiation recall.

Increased Risk of Toxicity with Ibuprofen in Patients with Renal Impairment

  • Exposure to ALIMTA is increased in patients with mild to moderate renal impairment who take concomitant ibuprofen, increasing the risks of adverse reactions of ALIMTA. In patients with creatinine clearances between 45 mL/min and 79 mL/min, avoid administration of ibuprofen for 2 days before, the day of, and 2 days following administration of ALIMTA. If concomitant ibuprofen use cannot be avoided, monitor patients more frequently for ALIMTA adverse reactions, including myelosuppression, renal, and gastrointestinal toxicity.

Embryo-Fetal Toxicity

  • Based on findings from animal studies and its mechanism of action, ALIMTA can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, intravenous administration of pemetrexed to pregnant mice during the period of organogenesis was teratogenic, resulting in developmental delays and increased malformations at doses lower than the recommended human dose of 500 mg/m2. Advise pregnant women of the potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment with ALIMTA and for 6 months after the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with ALIMTA and for 3 months after the final dose.

DRUG INTERACTIONS

  • Ibuprofen increases exposure (AUC) of pemetrexed. In patients with creatinine clearance between 45 mL/min and 79 mL/min:
    • Avoid administration of ibuprofen for 2 days before, the day of, and 2 days following administration of ALIMTA.
    • Monitor patients more frequently for myelosuppression, renal, and gastrointestinal toxicity, if concomitant administration of ibuprofen cannot be avoided.

ADVERSE REACTIONS

  • Severe adverse reactions (grades 3-4) occurring in fully vitamin supplemented patients with locally advanced or metastatic nonsquamous non-small cell lung cancer (NSCLC) receiving ALIMTA in combination with cisplatin versus gemcitabine in combination with cisplatin for initial treatment (JMDB), respectively, were neutropenia (15% vs 27%); fatigue (7% vs 5%); nausea (7% vs 4%); vomiting (6% vs 6%); anemia (6% vs 10%); thrombocytopenia (4% vs 13%); anorexia (2% vs 1%); creatinine elevation (1% vs 1%); diarrhea (1% vs 2%); stomatitis/pharyngitis (1% vs 0%); and constipation (1% vs 0%).
  • Common adverse reactions (all grades) occurring in ≥5% fully vitamin supplemented patients with locally advanced or metastatic nonsquamous non-small cell lung cancer (NSCLC) receiving ALIMTA in combination with cisplatin versus gemcitabine in combination with cisplatin for initial treatment (JMDB), 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%); stomatitis/pharyngitis (14% vs 12%); alopecia (12% vs 21%); diarrhea (12% vs 13%); thrombocytopenia (10% vs 27%); creatinine elevation (10% vs 7%), sensory neuropathy (9% vs 12%); taste disturbance (8% vs 9%); rash/desquamation (7% vs 8%); and dyspepsia/heartburn (5% vs 6%).
  • Severe adverse reactions (grades 3-4) occurring in patients with non-progressive locally advanced or metastatic nonsquamous non-small cell lung cancer (NSCLC) receiving ALIMTA as a single agent versus placebo as maintenance treatment (JMEN), respectively, following non-ALIMTA containing platinum-based induction therapy were anemia (3% vs 1%); neutropenia (3% vs 0%); fatigue (5% vs 1%); nausea (1% vs 1%); anorexia (2% vs 0%); infection (2% vs 0%); mucositis/stomatitis (1% vs 0%); diarrhea (1% vs 0%); and sensory neuropathy (1% vs 0%).
  • Common adverse reactions (all grades) occurring in ≥5% patients with non-progressive locally advanced or metastatic nonsquamous non-small cell lung cancer (NSCLC) receiving ALIMTA as a single agent versus placebo as maintenance treatment (JMEN), respectively, following non-ALIMTA containing platinum-based induction therapy were fatigue (25% vs 11%); nausea (19% vs 6%); anorexia (19% vs 5%); anemia (15% vs 6%); increased rash/desquamation (10% vs 3%); ALT (10% vs 4%); sensory neuropathy (9% vs 4%); vomiting (9% vs 1%); increased AST (8% vs 4%); mucositis/stomatitis (7% vs 2%); neutropenia (6% vs 0%); diarrhea (5% vs 3%); and infection (5% vs 2%).
  • Severe adverse reactions (grades 3-4) occurring in patients with non-progressive locally advanced or metastatic nonsquamous non-small cell lung cancer (NSCLC) receiving ALIMTA as a single agent versus placebo as maintenance treatment (PARAMOUNT), respectively, following ALIMTA plus cisplatin induction therapy were anemia (4.8% vs 0.6%); fatigue (4.5% vs 0.6%); neutropenia (3.9% vs 0%); nausea (0.3% vs 0%); and mucositis/stomatitis (0.3% vs 0%).
  • Common adverse reactions (all grades) occurring in ≥5% patients with non-progressive locally advanced or metastatic nonsquamous non-small cell lung cancer (NSCLC) receiving ALIMTA as a single agent versus placebo as maintenance treatment (PARAMOUNT), respectively, following ALIMTA plus cisplatin induction therapy were fatigue (18% vs 11%); anemia (15% vs 4.8%); nausea (12% vs 2.4%); neutropenia (9% vs 0.6%); vomiting (6% vs 1.8%); mucositis/stomatitis (5% vs 2.4%); and edema (5% vs 3.6%).
  • Severe adverse reactions (grades 3-4) occurring in fully supplemented patients with recurrent metastatic nonsquamous non-small cell lung cancer (NSCLC) receiving ALIMTA as a single agent versus docetaxel as 2nd-line treatment after prior chemotherapy (JMEI), respectively, were neutropenia (5% vs 40%); fatigue (5% vs 5%); anemia (4% vs 4%); nausea (3% vs 2%); anorexia (2% vs 3%); vomiting (2% vs 1%); thrombocytopenia (2% vs 0%); increased ALT (2% vs 0%); increased AST (1% vs 0%); and stomatitis/pharyngitis (1% vs 1%).
  • Common adverse reactions (all grades) occurring in ≥5% of fully supplemented patients with recurrent metastatic nonsquamous non-small cell lung cancer (NSCLC) receiving ALIMTA as a single agent versus docetaxel as 2nd-line treatment after prior chemotherapy (JMEI), 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/desquamation (14% vs 6%); diarrhea (13% vs 24%); neutropenia (11% vs 45%); fever (8% vs 8%); thrombocytopenia (8% vs 1%); increased ALT (8% vs 1%); pruritus (7% vs 2%); increased AST (7% vs 1%); constipation (6% vs 4%); and alopecia (6% vs 38%).
  • Severe adverse reactions (grades 3-4) occurring in fully supplemented subgroup of patients with malignant pleural mesothelioma (MPM) receiving ALIMTA in combination with cisplatin versus cisplatin alone (JMCH), respectively, were neutropenia (23% vs 3%); nausea (12% vs 6%); vomiting (11% vs 4%); fatigue (10% vs 9%); thrombocytopenia (5% vs 0%); dehydration (4% vs 1%); anemia (4% vs 0%); diarrhea (4% vs 0%); stomatitis/pharyngitis (3% vs 0%); creatinine elevation (1% vs 1%); anorexia (1% vs 1%); constipation (1% vs 1%); dyspepsia (1% vs 0%); sensory neuropathy (0% vs 1%); rash (1% vs 0%); and creatinine clearance decrease (1% vs 2%).
  • Common adverse reactions (all grades) occurring in ≥5% of fully supplemented subgroup of patients with malignant pleural mesothelioma (MPM) receiving ALIMTA in combination with cisplatin versus cisplatin alone (JMCH), respectively, were nausea (82% vs 77%); vomiting (57% vs 50%); neutropenia (56% vs 13%); fatigue (48% vs 42%); anemia (26% vs 10%); thrombocytopenia (23% vs 9%); stomatitis/pharyngitis (23% vs 6%); anorexia (20% vs 14%); diarrhea (17% vs 8%); creatinine clearance decreased (16% vs 18%); rash (16% vs 5%); constipation (12% vs 7%); creatinine elevation (11% vs 10%); alopecia (11% vs 6%); sensory neuropathy (10% vs 10%); conjunctivitis (5% vs 1%); dyspepsia (5% vs 1%); dehydration (7% vs 1%); and taste disturbance (8% vs 6%).

USE IN SPECIFIC PATIENT POPULATIONS

  • Lactation: There is no information regarding the presence of pemetrexed or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production. Because of the potential for serious adverse reactions in breastfed infants from ALIMTA, advise women not to breastfeed during treatment with ALIMTA and for one week after last dose.
  • Males of Reproductive Potential: ALIMTA may impair fertility in males of reproductive potential. It is not known whether these effects on fertility are reversible.
  • Pediatric Use: The safety and effectiveness of ALIMTA in pediatric patients have not been established. Adverse reactions observed in pediatric patients studied were similar to those observed in adults.
  • Patients with Renal Impairment: ALIMTA is primarily excreted by the kidneys. Decreased renal function results in reduced clearance and greater exposure (AUC) to ALIMTA compared with patients with normal renal function. No dose is recommended for patients with creatinine clearance less than 45 mL/min.
  • Geriatric: The incidences of Grade 3-4 anemia, fatigue, thrombocytopenia, hypertension, and neutropenia were higher in patients 65 years of age and older as compared to younger patients: in at least one of five randomized clinical trials.

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

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