CurrentAetnaPolicy 0687

Pemetrexed (Alimta)

Clinical policy defining Aetna's coverage, continuation, exclusions, dosing, and coding for pemetrexed (Alimta and alternatives) for commercial medical plans.

Policy Summary

PayerAetna

PolicyPemetrexed (Alimta)

Policy CodePolicy 0687

Change TypeNo material changes

Effective Date07/16/2004

Next Review Date09/26/2024

Key ActionObtain prior authorization and document indication, regimen, vitamin B12 and folic acid supplementation, and planned dosing schedule.

SourceLink

POLICY UPDATE CHANGES

No material clinical or coverage changes in this revision.

>10FDA/compendial indications

500 mg/m2Common dose

CrCl ≥45Renal threshold

≥1500Minimum ANC

J9305...HCPCS J-codes listed

Coverage Criteria

Trek Health ingests and normalizes Transparency in Coverage data and payer policy updates to give provider organizations a clear view of how commercial reimbursement behaves across markets, payers, and services. Our platform transforms raw payer disclosures into structured intelligence that supports contract evaluation, payer negotiations, and service line strategy. By combining market benchmarks with ongoing policy visibility, Trek helps teams identify variability, risk, and opportunity in commercial reimbursement. The result is faster insight, stronger negotiating positions, and more informed financial decisions.

Initial Therapy

Covered when ANY of the following indications are met:

Covered Indications: 1. Bladder cancer — locally advanced, metastatic, or relapsed transitional cell urothelium cancer, as second-line treatment; 2. Cervical cancer — persistent, recurrent, or metastatic cervical cancer; 3. Ovarian, fallopian tube, or primary peritoneal cancer (specified histologies) — persistent or recurrent epithelial ovarian cancer, fallopian tube cancer, primary peritoneal cancer, carcinosarcoma (malignant mixed Mullerian tumors), clear cell carcinoma of the ovary, grade 1 endometrioid carcinoma, low-grade serous carcinoma/ovarian borderline epithelial tumor (low malignant potential), or mucinous carcinoma of the ovary, as single-agent therapy; 4. Pleural or peritoneal mesothelioma (including pericardial and tunica vaginalis testis) when pemetrexed is used as a single agent or in combination with cisplatin or carboplatin, or in combination with bevacizumab or durvalumab and a platinum agent; 5. Non-squamous non-small-cell lung cancer (NSCLC), including leptomeningeal metastases; 6. Primary central nervous system (CNS) lymphoma, as a single agent; 7. Thymomas and thymic carcinomas, as a single agent.

See exclusions for squamous NSCLC

Malignant peritoneal mesothelioma

Covered when ALL of the following are met (peritoneal mesothelioma / re-challenge context):

Malignant peritoneal mesothelioma: Pemetrexed plus cisplatin systemic therapy may be used in first-line or re-challenge settings when patient performance status and general health permit; pemetrexed monotherapy has been used following CRS/HIPEC and pemetrexed re-challenge (with or without cisplatin) has reported disease control and prolonged survival in select cases.

Evidence from case reports and small series; UpToDate notes pemetrexed+carboplatin may be preferred in palliative setting for less toxicity

Maintenance therapy — Non-Small Cell Lung Cancer

Maintenance pemetrexed is supported when ALL of the following are met:

Maintenance pemetrexed criteria: 1) Histologically or cytologically confirmed locally advanced or metastatic non-squamous NSCLC; 2) Disease has not progressed after 4 cycles of platinum-based first-line chemotherapy; 3) Patient has ECOG performance status 0-2 and adequate bone marrow, renal, and hepatic function; 4) Concomitant supplementation with folic acid and vitamin B12 initiated and corticosteroid prophylaxis administered per labeling; 5) Dosing consistent with FDA labeling (500 mg/m2 IV on Day 1 of each 21-day cycle).

Based on FDA approval and randomized trial evidence showing improved PFS and OS in non-squamous histology

Evidence-based coverage conclusions and required precautions

Clinical conclusions and implications drawn from cited studies:

Bevacizumab plus pemetrexed-platinum: Multiple analyses including a Bayesian network meta‑analysis found no consistent efficacy advantage to adding bevacizumab to pemetrexed‑platinum; authors concluded routine addition is unjustified based on available RCT data.

Zhao et al. Bayesian NMA

Real-world evidence for carboplatin/pemetrexed + bevacizumab: A retrospective cohort (n=4,724) observed improved median overall survival with addition of bevacizumab to carboplatin/pemetrexed (12.1 vs 8.6 months; HR 0.80), but authors cautioned about potential unmeasured confounding and missing performance status data.

Bagley et al. real‑world study

Elderly patients (>=75) pemetrexed ± bevacizumab: Randomized phase II in elderly patients found no PFS or OS benefit adding bevacizumab; response rate increased but with higher costs and hematologic toxicity.

Fukuda et al.

Pemetrexed + nintedanib in mesothelioma: Phase III LUME‑Meso did not meet its primary PFS end‑point; no confirmed benefit and increased certain adverse events (eg, neutropenia, pulmonary embolism).

Scagliotti et al.

Pemetrexed + radiotherapy for brain metastases: Small non‑randomized comparative study reported higher response and local control rates and improved short‑term survival for pemetrexed combined with stereotactic radiotherapy versus radiotherapy alone; validation in larger studies is needed.

Zhang et al.

TroVax + pemetrexed-cisplatin in MPM: Phase II single‑arm trial met immunologic primary end‑point with 95.6% immune response in per‑protocol analysis and acceptable safety; further phase III study warranted.

Lester et al.

Dosing prerequisites: Prior to initiating pemetrexed, initiate folic acid and vitamin B12 supplementation and administer corticosteroids the day before, day of, and day after pemetrexed; dose reductions or discontinuation may be required for toxicities from prior cycles.

Prescribing information guidance

Coding

Other related CPT codesCPT

96365
96366
96367
96368
96379
96409
96411
96413
96415
96416

1–10 of 11

1/2

HCPCS codes covered if selection criteria are metHCPCSCovered

J9305	Injection, pemetrexed, 10 mg.
J9294	Injection, pemetrexed (hospira) not therapeutically equivalent to j9305, 10 mg.
J9296	Injection, pemetrexed (accord) not therapeutically equivalent to j9305, 10 mg.
J9297	Injection, pemetrexed (sandoz), not therapeutically equivalent to j9305, 10 mg.
J9314	Injection, pemetrexed (teva) not therapeutically equivalent to J9305, 10 mg.
J9322	Injection, pemetrexed (bluepoint) not therapeutically equivalent to j9305, 10 mg.
J9323	Injection, pemetrexed ditromethamine, 10 mg.
J9324	Injection, pemetrexed (pemrydi rtu), 10 mg.
J9035	Injection, bevacizumab, 10 mg.
J9045	Injection, carboplatin, 50 mg.

1–10 of 12

1/2

ICD-10 codes covered if selection criteria are metICD-10Covered

C33 - C34.92	Malignant neoplasm of trachea, bronchus and lung [non-small-cell lung cancer (NSCLC) only- not small cell lung cancer] [covered for non squamous cell non-small cell lung cancer only].
C37	Malignant neoplasm of thymus [thymic carcinoma].
C38.4	Malignant neoplasm of pleura.
C45.0	Mesothelioma of pleura.
C45.1	Mesothelioma of peritoneum [persistent or recurrent].
C45.2	Mesothelioma of pericardium.
C45.7	Mesothelioma of other sites [tunica vaginalis testis mesothelioma].
C45.9	Mesothelioma, unspecified.
C48.2	Malignant neoplasm of peritoneum, unspecified [primary peritoneal cancer].
C53.0 - C53.9	Malignant neoplasm of cervix uteri.

1–10 of 13

1/2

HCPCS codes not coveredHCPCSNot Covered

81291

MTHFR (5,10-methylenetetrahydrofolate reductase) (eg, hereditary hypercoagulability) gene analysis, common variants (eg, 677T, 1298C).

ICD-10 codes not covered for indications listedICD-10Not Covered

C15.3 - C15.9	Malignant neoplasm of esophagus.
C16.0 - C16.9	Malignant neoplasm of stomach [gastric].
C18.0 - C20	Malignant neoplasm of colon, rectosigmoid junction, and rectum [colorectal].

Creatinine clearance

Creatinine clearance threshold>= 45 mL/min

Source guidancePatients must have creatinine clearance >=45 mL/min for initial, maintenance, and recurrent pemetrexed dosing per prescribing recommendations

Implication for dosingDo not initiate a new cycle if CrCl <45 mL/min; document calculated creatinine clearance prior to each cycle

ANC (Absolute Neutrophil Count)

Absolute neutrophil count (ANC) threshold>= 1500 cells/mm3

Monitoring requirementObtain CBC including ANC prior to each cycle; document nadir and recovery as appropriate

Cycle initiation implicationDo not begin a new cycle unless ANC >=1500 cells/mm3

Platelet count

Platelet count threshold>= 100,000 cells/mm3

Monitoring requirementPerform platelet count prior to each cycle and document values in authorization record

Cycle initiation implicationDo not begin a new cycle unless platelets >=100,000 cells/mm3

Laboratory thresholds to start a new cycle

Laboratory thresholds to start a new cycleANC >=1500 cells/mm3; Platelets >=100,000 cells/mm3; Creatinine clearance >=45 mL/min

Documentation expectationCBC with ANC and platelet count plus calculated creatinine clearance should be documented prior to each cycle

Action on failing thresholdsIf thresholds not met, delay cycle and consider dose modification per prescribing information

Provider Actions and Documentation

Prior Authorization

Prior Authorization Required

Prior authorization required for pemetrexed (J-code billed under commercial medical plans). Prior authorization should indicate the requested indication, regimen, and supporting documentation; pemetrexed is covered only for specified indications in this policy and is excluded for squamous NSCLC.

Document indication (diagnosis code and stage)
Submit prior regimen details and prior chemotherapy status where applicable
Include planned regimen and dosing (e.g., pemetrexed 500 mg/m2 with cisplatin 75 mg/m2 for mesothelioma)

Prior Authorization

Mesothelioma Regimen — Prior Authorization Details

For pleural or peritoneal mesothelioma, prior authorization should reflect the standard mesothelioma regimen when applicable (for example, pemetrexed 500 mg/m2 IV on Day 1 of each 21‑day cycle in combination with cisplatin 75 mg/m2 IV) and must document that pemetrexed will be used as single agent or in combination with platinum agents or with bevacizumab/durvalumab plus platinum as allowed by the policy.

Specify whether single-agent or combination therapy is requested
Include prior therapy status and intent (first-line, subsequent-line)
Provide dosing schedule and supportive supplementation plan

Documentation Required

Bevacizumab Add‑on Assessment

If bevacizumab is being requested as an add-on to a pemetrexed‑platinum regimen, include rationale and supporting evidence; routine addition of bevacizumab to pemetrexed‑platinum is not routinely supported by the evidence and should be justified in the prior authorization documentation.

Provide clinical justification and references if requesting bevacizumab add‑on
Include pertinent real‑world outcomes or patient-specific factors (e.g., presence of brain metastases, hemoptysis, anticoagulation)

Documentation Required

Continuation of Therapy Requirements

Continuation of therapy requires documentation that the member has not experienced unacceptable toxicity and that the disease has not progressed on the current pemetrexed regimen; dose reductions or discontinuation due to toxicity must be documented.

Document tumor response or stability and absence of progression
Provide records of toxicities and any dose modifications with rationale

Documentation Required

Baseline and Pre‑cycle Laboratory Thresholds

Baseline and pre‑cycle laboratory thresholds must be documented in the medical record prior to each cycle: ANC ≥ 1500 cells/mm3, platelet count ≥ 100,000 cells/mm3, and creatinine clearance ≥ 45 mL/min. Periodic renal and hepatic chemistries and CBC monitoring (including nadir and recovery where available) should be provided.

Attach most recent CBC with differential and platelet count prior to dosing
Provide creatinine clearance (or serum creatinine and weight for calculation) and liver chemistries

Documentation Required

Supportive Care and Monitoring

Supportive care and monitoring documentation is expected: initiation and continuation of folic acid (400–1000 mcg daily starting 7 days before first dose and continued through treatment and 21 days after last dose), intramuscular vitamin B12 (1000 mcg IM within the week before first dose and every 9 weeks thereafter), and corticosteroid prophylaxis (dexamethasone as indicated). Monitor CBC, renal and hepatic function per prescribing information.

Document initiation dates and ongoing supplementation schedule for folic acid and vitamin B12
Include corticosteroid prophylaxis plan (eg, dexamethasone schedule)
Provide recent laboratory monitoring results (CBC, chemistries)

Documentation Required

Documentation of Diagnosis and Performance Status

Document histologic or cytologic confirmation of diagnosis, staging (eg, stage III/IV for NSCLC not amenable to curative therapy or mesothelioma stage), and ECOG performance status (preferably 0–2 where indicated). Include prior lines of chemotherapy and relevant prior treatment responses.

Attach pathology report confirming histology/cytology
Provide staging documentation and ECOG performance status assessment
Include prior treatment history and dates

Note

Reference Sources and Prescribing Information

Reference the prescribing information and key clinical guidelines or literature when supporting requests: Alimta (Eli Lilly) and other pemetrexed prescribing information, Pemfexy and Pemrydi RTU labeling, NCCN guidelines, FDA approvals, and relevant trials/reviews (eg, Vogelzang 2003 mesothelioma trial; maintenance pemetrexed NSCLC studies). Include citations in the PA submission as appropriate.

Attach relevant prescribing information (Alimta, Pemfexy, Pemrydi RTU)
Cite NCCN guideline sections or pivotal trials used to justify therapy

Note

Other Provider Actions

No additional provider actions specified in these source chunks beyond the documentation, prior authorization, monitoring, and supportive care items above.

Covered Regimens and Dosing

inv-62: first-line

First-line NSCLC: Pemetrexed 500 mg/m2 IV on Day 1 every 21 days as part of first-line therapy for metastatic or locally advanced non‑squamous NSCLC (single agent or in combination with pembrolizumab and platinum; contraindicated in squamous histology and requires creatinine clearance ≥45 mL/min).CrCl ≥ 45 mL/min

Dosing and renal threshold per labeled guidance

inv-63: first-line

First-line mesothelioma: Pemetrexed 500 mg/m2 IV Day 1 every 21 days in combination with cisplatin 75 mg/m2 IV Day 1 for malignant pleural mesothelioma; folic acid and vitamin B12 supplementation and corticosteroid prophylaxis per prescribing information.

FDA‑approved regimen for pleural mesothelioma

inv-64: salvage

Salvage/PCNSL and re‑challenge: Pemetrexed has single‑agent activity in relapsed/refractory primary CNS lymphoma and has been used as re‑challenge therapy in peritoneal mesothelioma; consider higher doses and individualized dosing in PCNSL trials and re‑challenge where prior response and performance status permit.

Evidence from small trials and case reports/series

inv-65: first-line

First-line NSCLC (cisplatin combo): Pemetrexed plus cisplatin is an approved first‑line option for locally advanced/metastatic non‑squamous NSCLC; dosing per labeling and histology‑specific benefit observed in trials.

Phase III data support use in non‑squamous histology

inv-66: second-line

Second-line or maintenance: Single‑agent pemetrexed is a standard second‑line option for advanced NSCLC and is FDA‑approved for maintenance therapy after 4 cycles of platinum‑based first‑line chemotherapy in non‑squamous histology, with demonstrated PFS and OS benefit.

FDA approval and randomized trial evidence

inv-67: first-line

Bevacizumab caution: Adding bevacizumab to pemetrexed‑platinum regimens lacks consistent RCT evidence of benefit; Bayesian NMA concluded Pem‑Pt + B showed no significant differences versus Pem‑Pt for key outcomes and routine addition is unjustified.

Zhao et al.; Pem‑Pt + B not clearly superior

Indication	Regimen / Dose & Schedule	Coverage stance
Non-squamous non-small cell lung cancer (first-line, maintenance, or recurrent non-squamous disease)
Pemetrexed 500 mg/m2 IV on Day 1 of each 21-day cycle; may be given as single agent or in combination with pembrolizumab and a platinum agent. Maintenance dosing continued until disease progression or unacceptable toxicity. Creatinine clearance ≥45 mL/min required.
Covered with criteria

Indication	Regimen / Dose & Schedule	Coverage stance
Pleural or peritoneal mesothelioma (includes pleural mesothelioma as FDA‑approved indication)
Pemetrexed 500 mg/m2 IV on Day 1 of each 21-day cycle in combination with cisplatin; continue until disease progression or unacceptable toxicity. (Pemrydi RTU administered undiluted over 10 minutes.)
Covered with criteria

Indication	Regimen / Dose & Schedule	Supportive measures	Coverage stance
Malignant pleural mesothelioma (initial therapy)
Pemetrexed 500 mg/m2 IV on Day 1 of each 21-day cycle + cisplatin 75 mg/m2 IV on Day 1; regimens administered every 21 days.
Folic acid and vitamin B12 supplementation plus corticosteroid prophylaxis per prescribing information; dose reductions as needed for toxicity.
Covered with criteria (FDA‑approved regimen)

Indication	Regimen / Dose & Schedule	Evidence context / notes	Coverage stance
Malignant peritoneal mesothelioma (systemic therapy; first-line or re‑challenge)
Pemetrexed with cisplatin (dose per mesothelioma regimens, e.g., pemetrexed 500 mg/m2 IV Day 1 + cisplatin 75 mg/m2 IV Day 1) or pemetrexed monotherapy in selected cases; use where performance status permits.
Evidence from case reports and small series supports activity and re‑challenge in select patients; UpToDate notes pemetrexed+carboplatin may be preferred in palliative setting for less toxicity.
Covered with criteria (limited evidence; patient selection required)

Indication	Regimen / Note	Coverage stance
Head and neck cancer — initial treatment for recurrent/metastatic disease
Cisplatin + pemetrexed: UpToDate and NCCN do not recommend or list pemetrexed as an initial standard regimen for head and neck cancer; regimen not recommended as initial treatment.
Not covered (not recommended)

Indication	Regimen / Dose	Coverage stance
Locally-advanced or metastatic non-squamous NSCLC — first-line in combination with cisplatin
Pemetrexed 500 mg/m2 IV on Day 1 + cisplatin 75 mg/m2 IV on Day 1 every 21 days.
Covered with criteria

Indication	Regimen / Dose & Schedule	Supportive measures	Coverage stance
Maintenance therapy for non-squamous NSCLC after induction chemotherapy
Pemetrexed 500 mg/m2 IV on Day 1 of each 21-day cycle until disease progression or unacceptable toxicity (after 4 cycles of platinum-based first-line chemotherapy).
Folic acid and vitamin B12 supplementation and corticosteroid prophylaxis per labeling; dosing per FDA-approved maintenance regimen.
Covered with criteria

Indication	Regimen / Note	Coverage stance
Extensive-stage small-cell lung cancer (first-line)
Pemetrexed-carboplatin has been studied (pemetrexed 500 mg/m2 IV Day 1 + carboplatin AUC 5) but was inferior to etoposide-carboplatin in phase III trials with worse OS and PFS.
Not covered (not recommended / inferior regimen)

Indication	Regimen / Note	Coverage stance
Thymomas and thymic carcinomas — second-line systemic therapy
Pemetrexed, with or without prednisone, per NCCN recommendations as a second‑line systemic therapy option.
Covered with criteria (per NCCN guidance)

Indication	Regimen / Note	Evidence / Rationale	Coverage stance
Advanced non-squamous NSCLC — carboplatin/pemetrexed with or without bevacizumab
Carboplatin + pemetrexed ± bevacizumab (regimens vary; pemetrexed dosing commonly 500 mg/m2 IV Day 1 every 21 days).
Real-world retrospective data show an OS association favoring addition of bevacizumab (median OS 12.1 vs 8.6 months; HR 0.80) but randomized trial/NMA evidence is inconclusive; clinical judgment required.
Mixed / case-by-case coverage (clinical justification required)

Indication	Regimen / Note	Trial result	Coverage stance
Unresectable epithelioid malignant pleural mesothelioma — investigational combination
Pemetrexed + cisplatin combined with nintedanib (nintedanib 200 mg twice daily on days 2–21 in trial) added to standard pemetrexed/cisplatin induction and maintenance in LUME-Meso.
Phase-III LUME-Meso did not meet the primary PFS endpoint (no PFS benefit) and showed increased certain adverse events.
Not covered / not supported (trial primary end-point not met)

Indication	Regimen / Required supportive care	Dose modification guidance	Coverage stance
Pemetrexed monotherapy or pemetrexed-containing chemotherapy across covered indications
Pemetrexed 500 mg/m2 IV Day 1 every 21 days with mandatory folic acid and intramuscular vitamin B12 supplementation and corticosteroid prophylaxis per prescribing information.
Dose reductions or discontinuation may be required based on toxicities from preceding cycle; follow prescribing information for adjustments.
Covered with criteria (supplementation and monitoring required)

Indication / Trial context	Regimens studied / examples	Coverage stance
Various malignancies included in clinical trials and references cited
Multiple pemetrexed-containing regimens studied in trials (examples: pemetrexed + cisplatin; pemetrexed + carboplatin; pemetrexed + carboplatin + bevacizumab; pemetrexed + cisplatin + nintedanib; maintenance pemetrexed), as referenced in the literature list.
Informational / trial-based — coverage determined by specific indication and criteria

Biomarker Requirements

EGFR or ALK

EGFR/ALK requirementNo EGFR or ALK genomic tumor aberrations for use in combination with pembrolizumab and platinum chemotherapy

ContextApplies to initial treatment of metastatic non-squamous NSCLC in combination with pembrolizumab and platinum

Provider actionConfirm tumor genomic testing for EGFR and ALK prior to initiating combination regimen

EGFR mutation; MTHFR 677 C>T

EGFR mutation contextEGFR-mutant NSCLC patients with leptomeningeal metastasis had longer post-LM survival when pemetrexed was used after LM

MTHFR 677 C>TMeta-analysis found MTHFR 677 C>T does not predict pemetrexed effectiveness for PFS/OS, but the T allele may increase hematologic toxicity

Clinical implicationMTHFR polymorphism testing is considered investigational for predicting pemetrexed benefit; T allele may warrant closer hematologic monitoring

EGFR mutation (exon 19 deletion, exon 21 L858R)

EGFR exon-specific benefitSubgroup analyses show patients with EGFR exon 19 deletion or exon 21 L858R may benefit in PFS when pemetrexed-based chemotherapy is added to gefitinib

Evidence sourcePooled analysis of randomized trials demonstrated improved PFS (EGFR exon 19: HR 0.50; exon 21 L858R: HR 0.46) with combination therapy

Clinical considerationConsider combination gefitinib plus pemetrexed-based chemotherapy for selected patients with exon 19 or 21 sensitizing mutations based on multidisciplinary judgment

Definitions and Prescribing Notes

Pemetrexed (Alimta) is a multitargeted antifolate approved by the FDA for non‑squamous non‑small cell lung cancer (NSCLC) and for use in combination with cisplatin for unresectable malignant pleural mesothelioma; it is also used compendially for a variety of other malignancies. Labeling and the policy require folic acid and vitamin B12 supplementation and corticosteroid prophylaxis to reduce toxicity, and dosing commonly cited is 500 mg/m2 IV on Day 1 of each 21‑day cycle.

Pemetrexed mechanism (overview)

Mechanism of actionAlimta (pemetrexed) is a pyrimidine-based folate analog that inhibits multiple enzymes in folate metabolism and DNA synthesis

Clinical relevanceMultitargeted antifolate activity may overcome resistance to agents targeting single folate enzymes

Indications linkMechanism supports use in multiple solid tumors including NSCLC and mesothelioma per compendial references

Supportive supplementation

Folic acid supplementationFolic acid 400-1000 mcg orally daily beginning 7 days before first dose and continued during therapy and for 21 days after last dose

Vitamin B12 supplementationVitamin B12 1000 mcg IM during the week before the first dose and every 3 cycles thereafter; subsequent injections may be given the same day as pemetrexed

Corticosteroid prophylaxisDexamethasone 4 mg PO twice daily for 3 days beginning the day before administration to reduce cutaneous reactions

Pemetrexed mechanism (specific enzymes)

Multi-targeted antifolate targetsInhibits thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltransferase (GARFT)

Pharmacologic effectInterrupts both purine and pyrimidine synthesis pathways contributing to antitumor activity

Therapeutic implicationExplains observed activity in mesothelioma and non-squamous NSCLC and rationale for combination with platinum agents

FDA‑approved dosing (mesothelioma)

FDA‑approved mesothelioma dosing500 mg/m2 IV on Day 1 of each 21-day cycle with folic acid and vitamin B12 supplementation

Administration noteInfuse over approximately 10 minutes and give cisplatin 75 mg/m2 beginning 30 minutes after pemetrexed when combined

Supportive measuresCorticosteroid premedication and vitamin supplementation required to reduce toxicity

Maintenance therapy

Definition of maintenance therapyAdministration of pemetrexed after disease control (no progression) following 4 cycles of platinum-based first-line chemotherapy

Dosing for maintenance500 mg/m2 IV on Day 1 of each 21-day cycle until disease progression or unacceptable toxicity

Eligibility criteriaHistologically/cytologically confirmed non-squamous NSCLC, ECOG PS 0-2, adequate organ function, and documented supplementation per labeling

Candidate for pemetrexed (NSCLC)

Candidate population (NSCLC)Patients with histologic or cytologic confirmation of stage III/IV non-squamous NSCLC not amenable to curative therapy

Performance status and organ functionECOG PS 0-2 and adequate bone marrow, renal, and hepatic function required

Use settingsFirst-line in combination with platinum chemotherapy and pembrolizumab (no EGFR/ALK aberrations), maintenance after platinum therapy, or recurrent/metastatic disease after prior chemotherapy

LUME-Meso Trial

LUME-Meso Trial designPhase-III randomized, double-blind trial of pemetrexed plus cisplatin with nintedanib versus placebo in unresectable epithelioid malignant pleural mesothelioma

Enrollment458 patients randomized; primary end-point investigator-assessed PFS in the ITT population

Outcome notePrimary PFS end-point was not met in the phase-III portion

TroVax

TroVax study contextPhase-II single-arm trial evaluating TroVax vaccine with pemetrexed-cisplatin in malignant pleural mesothelioma

Immunologic primary end-pointPer-protocol analysis: 22/23 patients (95.6%) developed humoral or cellular immune response to 5T4

Clinical outcomesDisease control observed in 87% (PR 17.4%, SD 69.6%); median PFS 6.8 months and median OS 10.9 months

Pemetrexed (product names and uses)

Product names and indicationsPemetrexed (antifolate) marketed as Alimta, Pemfexy, Pemrydi; used IV for malignant pleural mesothelioma and non-squamous NSCLC

Administration routeIntravenous infusion (standard 500 mg/m2 dosing referenced)

Supportive requirementsFolic acid, vitamin B12 supplementation and corticosteroid prophylaxis per prescribing information

Line of Therapy Mapping

inv-62: first-line

First-line NSCLC dosing: Pemetrexed 500 mg/m2 IV Q21 days as single agent or with pembrolizumab and platinum; maintenance dosing until progression or unacceptable toxicity; ensure creatinine clearance ≥45 mL/min prior to administration.CrCl ≥ 45 mL/min

Per dosing and administration guidance

inv-63: first-line

First-line mesothelioma dosing: Pemetrexed 500 mg/m2 IV Q21 days in combination with cisplatin 75 mg/m2 IV Q21 days; folic acid and vitamin B12 supplementation and corticosteroid prophylaxis required per labeling.

FDA‑approved regimen

inv-64: salvage

Salvage/regional uses: Pemetrexed has activity in relapsed/refractory PCNSL (higher doses studied) and has been used as re‑challenge systemic therapy in diffuse malignant peritoneal mesothelioma with reported disease control in case series; consider on a case‑by‑case basis with documentation of prior response and performance status.

Evidence limited to small trials and case reports

inv-65: first-line

First-line cisplatin combination: Pemetrexed plus cisplatin is an approved first‑line option for locally advanced/metastatic non‑squamous NSCLC; dosing per labeling with histology‑specific benefit.

Phase III data

inv-66: second-line

Second-line/maintenance: Single‑agent pemetrexed is an established second‑line therapy and is FDA‑approved as maintenance for non‑squamous NSCLC after 4 cycles of platinum‑based therapy with demonstrated improvements in PFS and OS in non‑squamous histology.

FDA approval and pivotal trial evidence

inv-67: first-line

Bevacizumab add‑on assessment: Routine addition of bevacizumab to pemetrexed‑platinum regimens is not supported by NMA of RCTs; clinicians may consider bevacizumab addition based on individual patient factors and real‑world data but must document rationale and risks.

Zhao et al.; Bagley real‑world findings require cautious interpretation

OpenPayer

Pemetrexed (Alimta)

Coverage Criteria

Coding

Provider Actions and Documentation

Covered Regimens and Dosing

Biomarker Requirements

Definitions and Prescribing Notes

Line of Therapy Mapping

Revision History