Challenging mNSCLC Stamp and Photo of Rock ClimberChallenging mNSCLC Stamp and Photo of Rock Climber

Indicated in combination with pembrolizumab (pembro) and platinum chemotherapy as an initial treatment for nonsquamous metastatic non-small cell lung cancer (mNSCLC)

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

Combined strength for extending survival

A 1st-line option for any PD-L1 level: ALIMTA/platinum + KEYTRUDA® (pembrolizumab) is the first approved chemotherapy/immunotherapy combination to significantly extend overall survival (OS) vs ALIMTA/platinum.1-3

The phase III KEYNOTE-189 study included patients with all programmed death-ligand 1 (PD-L1) expression levels.

With ALIMTA/platinum + KEYTRUDA, it’s possible to cut the risk of death in half vs ALIMTA/platinum.1,2

Co-primary endpoint: Median OS in KEYNOTE-189 (ITT population) (after a median 10.5 months of follow-up)

KM curve showing median OS in exploratory subgroup of the ITT population of KEYNOTE-189.
  • Number of patients with events observed with ALIMTA/platinum + KEYTRUDA: 127 (31%)
  • Number of patients with events observed with ALIMTA/platinum + placebo: 108 (52%)

Co-primary endpoint

Median progression-free survival (PFS)c

ALIMTA/platinum + KEYTRUDA (n=410): 8.8 months (95% CI: 7.6-9.2); ALIMTA/platinum + placebo (n=206): 4.9 months (95% CI: 4.7-5.5); HRa=0.52 (95% CI: 0.43-0.64); P<0.0001b

Select Important Safety Information

Contraindication

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

Secondary endpoints

Overall response rate (ORR)c,d

ALIMTA/platinum + KEYTRUDA (n=410): 48% of patients (95% CI: 43-53), Complete response: 0.5%, Partial response: 47%; ALIMTA/platinum + placebo (n=206): 19% of patients (95% CI: 14-25), Complete response: 0.5%, Partial response: 18%; P<0.0001e

Duration of responsec

ALIMTA/platinum + KEYTRUDA (n=410): Median 11.2 months (range 1.1+, 18.0+ months); ALIMTA/platinum + placebo (n=206): Median 7.8 months (range 2.1+, 16.4+ months)

a Based on the stratified Cox proportional hazard model.

b Based on stratified log-rank test.

c PFS, ORR, and duration of response were assessed by BICR.

d Response: Best objective response as confirmed complete response or partial response.

e Based on Miettinen and Nurminen method stratified by PD-L1 status, platinum chemotherapy, and smoking status.

BICR=blinded independent central review; CI=confidence interval; HR=hazard ratio; ITT=intention-to-treat; NE=not estimable; NR=not reached.

View Trial Design

Select Important Safety Information

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.

Median OS across all PD-L1 expression categories2,3

The subgroup analyses in the KEYNOTE-189 trial were prespecified but were exploratory and not error-controlled or appropriately powered; therefore, treatment differences cannot be regarded as statistically significant.

In KEYNOTE-189, the efficacy results from the exploratory subgroup analysis by PD-L1 expression level showed improvement with ALIMTA/platinum + KEYTRUDA as compared to ALIMTA/platinum + placebo.

Exploratory analysis of median OS in PD-L1 TPS subgroups: PD-L1 TPS ≥50%*

KM curve showing median OS in exploratory subgroup of patients with PD-L1 TPS ≥50% in KEYNOTE-189.

Exploratory analysis of median OS in PD-L1 TPS subgroups: PD-L1 TPS <50%

  • PD-L1 TPS 1%-49%: ALIMTA/platinum + KEYTRUDA (n=128): Median OS was NR (95% CI: NE); ALIMTA/platinum + placebo (n=58): 12.9 months (95% CI: 8.7-NE); HR=0.55 (95% CI: 0.34-0.90)
  • PD-L1 TPS <1%: ALIMTA/platinum + KEYTRUDA (n=127): 15.2 months (95% CI: 12.3-NE); ALIMTA/platinum + placebo (n=63): 12.0 months (95% CI: 7.0-NE); HR=0.59 (95% CI: 0.38-0.92)

12-month OS rate3

  • PD-L1 TPS 1%-49%: ALIMTA/platinum + KEYTRUDA: 71.5%; ALIMTA/platinum + placebo: 50.9%
  • PD-L1 TPS <1%: ALIMTA/platinum + KEYTRUDA: 61.7%; ALIMTA/platinum + placebo: 52.2%

* The PD-L1 TPS was defined as the percentage of tumor cells with membranous PD-L1 expression.2

TPS=tumor proportion score.

Select Important Safety Information

Warnings and Precautions

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. Withhold ALIMTA in patients with a creatinine clearance of less than 45 mL/min.

ALIMTA/platinum + KEYTRUDA significantly improved PFS in 1st line compared to ALIMTA/platinum.1,2

Co-primary endpoint: Median PFSa in KEYNOTE-189 (ITT population)

The phase III KEYNOTE-189 study included patients with all PD-L1 expression levels.

KM curve showing median PFS in the ITT population of KEYNOTE-189.
  • Number of patients with events observed with ALIMTA/platinum + KEYTRUDA: 244 (60%)
  • Number of patients with events observed with ALIMTA/platinum + placebo: 166 (81%)

An estimated 34.1% of patients treated with ALIMTA/platinum + KEYTRUDA were alive and progression-free at 12 months (95% CI: 28.8-39.5) compared to 17.3% of patients treated with ALIMTA/platinum + placebo (95% CI: 12.0-23.5).2

a PFS was assessed by BICR

b Based on the stratified Cox proportional hazard model.

c Based on stratified log-rank test.

Select Important Safety Information

Warnings and Precautions

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.

ORRa with ALIMTA/platinum + KEYTRUDA was more than double that of ALIMTA/platinum.1,2

Secondary endpoint: ORRb in KEYNOTE-189 (ITT population)

The phase III KEYNOTE-189 study included patients with all PD-L1 expression levels.

Bar chart showing ORR in the ITT population of KEYNOTE-189.

a Response: Best objective response as confirmed complete response or partial response.

b ORR was assessed by BICR.

c Based on Miettinen and Nurminen method stratified by PD-L1 status, platinum chemotherapy, and smoking status.

Additional secondary endpoint: Median duration of responsea

Bar chart showing median duration of response in KEYNOTE-189.

a Duration of response was assessed by BICR.

KEYNOTE-189 efficacy results by PD-L1 expression levels2-4

The subgroup analyses in the KEYNOTE-189 trial were prespecified but were exploratory and not error-controlled or appropriately powered; therefore, treatment differences cannot be regarded as statistically significant.

Table showing median OS, median PFS, and ORR by PD-L1 TPS % exploratory subgroups in KEYNOTE-189.

* The PD-L1 TPS was defined as the percentage of tumor cells with membranous PD-L1 expression.2

a PFS and ORR were assessed by BICR.

Select Important Safety Information

Warnings and Precautions

Serious interstitial pneumonitis: 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.

KEYNOTE-189 study design1,2,5

  • The phase III KEYNOTE-189 study included patients with all PD-L1 levels
  • After initial therapy, ALIMTA and KEYTRUDA were continued until disease progression or unacceptable toxicity (or up to 35 cycles for KEYTRUDA)2

KEYNOTE-189 was a phase III, randomized, multicenter, double-blind, active-controlled study investigating the safety and efficacy of ALIMTA/platinum chemotherapy (cisplatin or carboplatin [carbo]) + KEYTRUDA (n=410) vs ALIMTA/platinum chemotherapy + placebo (n=206) in previously untreated patients with nonsquamous mNSCLC.

Chart showing study design of KEYNOTE-189.

Primary endpoints

  • OS and PFS as assessed by BICR using RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ

Secondary endpoints

  • ORR and duration of response as assessed by BICR using RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ

Select patient characteristics

  • 49% age 65 years or older; median age 64 years (range 34 to 84)
  • 31% had tumor PD-L1 expression TPS <1% (negative)
  • 72% received carboplatin
  • 12% were never smokers

Exclusion criteria

  • Patients with autoimmune disease that required systemic therapy within 2 years of treatment
  • Patients with a medical condition that required immunosuppression
  • Patients who had received more than 30 Gy of thoracic radiation within the prior 26 weeks

ALK=anaplastic lymphoma kinase; AUC=area under the curve; EGFR=epidermal growth factor receptor;
IV=intravenous; R=randomization; RECIST=Response Evaluation Criteria in Solid Tumors.

The continuous regimen with ALIMTA + KEYTRUDA, which included 4 cycles in combination with platinum (cisplatin or carboplatin), was integral to the efficacy results in KEYNOTE-189.1

The uninterrupted treatment regimen in KEYNOTE-189 demonstrated significant improvements in OS, PFS, and ORR compared to continuous treatment with ALIMTA + placebo (including 4 platinum combination cycles).1,2

Graphic for ALIMTA/platinum + KEYTRUDA that says, “Staying the course.”

In KEYNOTE-189:4

The median number of cycles was similar between ALIMTA and KEYTRUDA.

  • Patients received a median of 9 cycles of ALIMTA (in both the cisplatin and carbo groups)
  • Patients received a median of 11 cycles of KEYTRUDA in the cisplatin group and 10 cycles in the carbo group

The percentage of patients who received ≥5 doses was similar between ALIMTA and KEYTRUDA.

  • 77% of patients in the ALIMTA/platinum + KEYTRUDA arm received ≥5 doses of ALIMTA
  • 79% of patients received ≥5 doses of KEYTRUDA

Safety profile for ALIMTA/platinum (cisplatin or carboplatin) + KEYTRUDA1,2

Clinical adverse reactions occurring in ≥20% of patients in KEYNOTE-1891

Table showing adverse reactions from KEYNOTE-189.
  • In KEYNOTE-189, 23.0% of patients (n=93/405) in the ALIMTA/platinum + KEYTRUDA group discontinued ALIMTA due to adverse reactions vs 11.4% of patients (n=23/202) in the ALIMTA/platinum + placebo group1,6
  • The most common clinical adverse reactions resulting in discontinuation of ALIMTA in the ALIMTA/platinum + KEYTRUDA group were acute kidney injury (3%) and pneumonitis (2%)1

a Graded per NCI CTCAE version 4.03.

b Includes asthenia and fatigue.

c Includes genital rash, rash, rash generalized, rash macular, rash maculo-papular, rash papular, rash pruritic, and rash pustular.

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

Laboratory abnormalities worsened from baseline in ≥20% of patients in KEYNOTE-1891

Table showing laboratory abnormalities from KEYNOTE-189.

a Graded per NCI CTCAE version 4.03.

b Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: ALIMTA/KEYTRUDA/platinum chemotherapy (range: 381 to 401 patients) and placebo/ALIMTA/platinum chemotherapy (range: 184 to 197 patients).

National Comprehensive Cancer Network® (NCCN®) recommendations for nonsquamous mNSCLC7

Chart showing the Category 1 recommendations by NCCN Guidelines.

† Category 1: Based on high-level evidence (eg, randomized phase III trials), there is uniform NCCN consensus that the intervention is appropriate.

FDA-Approved Indication1

ALIMTA is indicated in combination with pembrolizumab (pembro) and platinum chemotherapy for the initial treatment of patients with nonsquamous metastatic non-small cell lung cancer (mNSCLC) with no EGFR or ALK genomic tumor aberrations.

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

Preclinical studies of the immunomodulatory effects of ALIMTA in murine models provide insight into a mechanistic rationale for its use with immunotherapy.8,9

In murine models, ALIMTA caused immunogenic cell death of tumor cells and enhanced T-cell activation/mitochondrial function, leading to an intratumor gene expression signature indicative of increased immune activation. Preclinical studies demonstrated that ALIMTA:

Table showing results from preclinical studies of ALIMTA.

ALIMTA. A foundational component of the 1st-line nonsquamous mNSCLC treatment landscape.1

Image of a lung with cancer

As the only folate analog metabolic inhibitor approved to treat nonsquamous mNSCLC, ALIMTA inhibits key intracellular folate-dependent metabolic processes essential for cell replication.1

Image of a clipboard with a magnifying glass

To date, ALIMTA has been used in 228 non-small cell lung cancer (NSCLC) clinical trials in the US, and has been studied in 16 NSCLC trials with immunotherapies.10

Image of an IV bag

ALIMTA/platinum is the only chemotherapy backbone FDA-approved for use with KEYTRUDA in first line nonsquamous mNSCLC.1

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

Combining ALIMTA/platinum with KEYTRUDA in 1st line may help you change outcomes without changing the dosing you may already know.1,2

Dosing and administration for ALIMTA when used in combination with cisplatin or carboplatin and KEYTRUDA1

Table of dosing recommendations for ALIMTA with cisplatin or carboplatin + KEYTRUDA in first-line.

Following completion of platinum-based therapy, treatment with ALIMTA (with or without KEYTRUDA) is administered until disease progression or unacceptable toxicity.

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
  • Administer vitamin B12, 1 mg intramuscularly, 1 week prior to the first dose of ALIMTA and every 3 cycles thereafter. Subsequent vitamin B12 injections may be given the same day as treatment with ALIMTA. Do not substitute oral vitamin B12 for intramuscular vitamin B12
  • Administer dexamethasone 4 mg orally twice daily for 3 consecutive days, beginning the day before each ALIMTA administration
  • 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

NS=nonsquamous.

Dosing modifications1

Dose reductions for:

  • ALIMTA in combination with cisplatin or carboplatin and KEYTRUDA

Recommended dosage modifications for adverse reactionsa

Table showing dosing modifications for adverse reactions with ALIMTA.

Dosing modification notes

  • 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, carboplatin, and KEYTRUDA, refer to the respective prescribing information for each medication

a NCI CTCAE version 2.0.

References

  1. ALIMTA (pemetrexed for injection) [package insert]. Indianapolis, IN: Eli Lilly and Company; 2019.
  2. Gandhi L, et al. N Engl J Med. 2018;378(22):2078-2092.
  3. Gandhi L. KEYNOTE-189: Randomized, double-blind, phase 3 study of pembrolizumab or placebo plus pemetrexed and platinum as first-line therapy for metastatic NSCLC. Presented at: AACR Annual Meeting; April 14-18, 2018; Chicago, IL.
  4. Gandhi L, et al. N Engl J Med. 2018;378(22)(suppl):2078-2092.
  5. KEYTRUDA (pembrolizumab) [package insert]. Whitehouse Station, NJ: Merck & Co., Inc.; 2018.
  6. Data on file, Eli Lilly and Company. DOF-PM-US-0005.
  7. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Non-Small Cell Lung Cancer V.3.2019. © National Comprehensive Cancer Network, Inc 2019. All rights reserved. Accessed February 5, 2019. To view the most recent and complete version of the guidelines, go online to NCCN.org. NCCN makes no warranties of any kind whatsoever regarding their content, use, or application and disclaims any responsibility for their application or use in any way.
  8. Novosiadly RD, et al. Pemetrexed enhances anti-tumor efficacy of PD-1 pathway blockade by promoting intra-tumor immune response via immunogenic tumor cell death and T cell-intrinsic mechanisms. Presented at: AACR Annual Meeting; April 14-18, 2018; Chicago, IL.
  9. Novosiadly RD, et al. Pemetrexed enhances anti-tumor efficacy of PD-1 pathway blockade by promoting intra-tumor immune response via immunogenic tumor cell death and T cell-intrinsic mechanisms. Presented at: IASLC WCLC Annual Meeting; September 23-26, 2018; Toronto, Canada.
  10. National Institutes of Health (NIH). ClinicalTrials.gov. https://clinicaltrials.gov. Accessed January 30, 2019.
Indications and Important Safety Information

Indications for ALIMTA® (pemetrexed for injection)

ALIMTA is indicated in combination with pembrolizumab (pembro) and platinum chemotherapy for the initial treatment of patients with nonsquamous metastatic non-small cell lung cancer (mNSCLC) with no EGFR or ALK genomic tumor aberrations.

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

ALIMTA is indicated as a single agent 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.

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

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

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 (Grade 3-4) occurring in ≥20% of patients with metastatic nonsquamous non-small cell lung cancer (NSCLC) receiving ALIMTA in combination with pembrolizumab and platinum chemotherapy (carboplatin or cisplatin) versus ALIMTA with platinum chemotherapy + placebo for initial treatment (KEYNOTE-189), respectively, were fatigue (12% vs 6%); diarrhea (5% vs 3%); dyspnea (3.7% vs 5%); vomiting (3.7% vs 3%); nausea (3.5% vs 3.5%); rash (2% vs 2.5%); decreased appetite (1.5% vs 0.5%); constipation (1% vs 0.5%); and pyrexia (0.2% vs 0%).

Common adverse reactions (all grades) occurring in ≥20% of patients with metastatic nonsquamous non-small cell lung cancer (NSCLC) receiving ALIMTA in combination with pembrolizumab and platinum chemotherapy (carboplatin or cisplatin) versus ALIMTA with platinum chemotherapy + placebo for initial treatment (KEYNOTE-189), respectively, were nausea (56% vs 52%); fatigue (56% vs 58%); constipation (35% vs 32%); diarrhea (31% vs 21%); decreased appetite (28% vs 30%); rash (25% vs 17%); vomiting (24% vs 23%); cough (21% vs 28%); dyspnea (21% vs 26%); and pyrexia (20% vs 15%).

Severe adverse reactions (Grade 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 (Grade 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 (Grade 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 (Grade 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 (Grade 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 the 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 full Prescribing Information and Patient Prescribing Information.

PM_HCP_ISI_All_30JAN2019