Carboplatin, pemetrexed and pembrolizumab

First-line chemo-immunotherapy for advanced non-squamous NSCLC (KEYNOTE-189)

For clinicians and students · Regimen tutorial · Lung cancer · 8 min read · last reviewed September 30, 2026

Key points

Induction is 4 cycles every 21 days of pembrolizumab, pemetrexed 500 mg/m2 and carboplatin AUC 5. Maintenance pembrolizumab plus pemetrexed follows, for up to 35 pembrolizumab doses (about 2 years) in total.
Pembrolizumab is 200 mg flat every 3 weeks in KEYNOTE-189 and eviQ. BC Cancer uses 2 mg/kg (maximum 200 mg), and 400 mg every 6 weeks is a licensed alternative.
Pemetrexed needs folic acid daily and vitamin B12 IM (every 9 weeks, or every 3 cycles), plus dexamethasone to prevent rash. Without vitamins, severe myelosuppression and mucositis are much more common.
Pemetrexed is renally cleared. Hold it if CrCl is below 45 mL/min, and avoid NSAIDs around dosing.
Confirm non-squamous histology and rule out EGFR, ALK, ROS1 and other actionable drivers before starting. Checkpoint inhibitors before or with TKIs can be harmful.
Immune-related adverse events can occur at any time, including after the last dose. Check TSH and liver tests each cycle.

Indications

This regimen is first-line treatment for advanced or metastatic non-squamous NSCLC when all of the following apply:

No sensitising EGFR mutation, ALK or ROS1 rearrangement, or other actionable driver for which targeted therapy is preferred. BC Cancer excludes EGFR, ALK and ROS1 explicitly. Guidelines also expect testing for BRAF, RET, MET, NTRK, KRAS G12C and HER2 before first-line decisions.
No prior treatment in the advanced setting.
ECOG 0–2 (BC Cancer) or 0–1 (eviQ).
Access to a centre with expertise in managing immune-related adverse events (irAEs).

The regimen is used regardless of PD-L1 expression. It is especially valuable at PD-L1 below 50%, and remains an option at 50% or above when rapid response is needed.

Exclusions (BC Cancer): relapse on or within 6 months of neoadjuvant or adjuvant immunotherapy, or within 12 months of adjuvant platinum.

Cautions: active autoimmune disease, chronic immunosuppression (more than 10 mg prednisone per day), organ transplant, and prior lung radiotherapy.

Cisplatin 75 mg/m² can replace carboplatin in fit patients (same protocol, cisplatin option).

Regimen table

Induction: Cycles 1–4, every 21 days (eviQ ID 3510 v9; BC Cancer LUAVPPPMB carboplatin option)

Drug	Dose	Route	Day	Notes
Pembrolizumab	200 mg flat (eviQ, KEYNOTE-189). BC Cancer: 2 mg/kg, maximum 200 mg, dose-banded	IV in 50 mL NS over 30 min, 0.2 micron in-line filter	Day 1	Give first
Pemetrexed	500 mg/m²	IV in 100 mL NS over 10 min	Day 1	Vitamin premedication is mandatory
Carboplatin	AUC 5 (Calvert: dose = AUC × [GFR + 25])	IV over 30 min (BC Cancer) or 30–60 min (eviQ)	Day 1	See GFR note below

Maintenance: from Cycle 5, every 21 days (BC Cancer LUAVPPMBM; eviQ Cycles 5–35)

Drug	Dose	Route	Day	Notes
Pembrolizumab	200 mg (or 2 mg/kg, maximum 200 mg, per BC Cancer)	IV over 30 min	Day 1	Up to 35 doses or 2 years in total, including induction
Pemetrexed	500 mg/m²	IV over 10 min	Day 1	Continue until progression or toxicity. If pemetrexed is not tolerated, pembrolizumab may continue alone

Cycle length: 21 days. Number of cycles: 4 induction cycles, then maintenance to a maximum of 35 pembrolizumab doses (every 3 weeks) or 18 doses (every 6 weeks). BC Cancer starts maintenance 21 to 42 days after the last induction cycle.

Where the protocols differ:

Pembrolizumab dose: weight-based in BC Cancer, flat in eviQ.
Extended dosing of 400 mg every 6 weeks is licensed. BC Cancer allows 6-weekly pembrolizumab in maintenance through its single-agent protocols.
The SCIMMUNE protocol notes that extended-interval dosing has similar pharmacokinetics, efficacy and safety.
GFR for Calvert:
BC Cancer uses the Cockcroft-Gault formula or a nuclear renogram, with estimated GFR capped at 125 mL/min.
eviQ, following ADDIKD, prefers measured GFR or BSA-adjusted eGFR. It does not cap at 125, but strongly recommends direct measurement or dose capping when the AUC 5 dose would exceed 750 mg.
Retreatment: BC Cancer allows pembrolizumab retreatment for 1 more year at progression, if the initial course was completed without progression.

Premedication & supportive care

Vitamin supplementation (mandatory):
BC Cancer: folic acid 0.4 mg PO daily and vitamin B12 1000 mcg IM every 9 weeks. Start at least 7 days before Cycle 1 and continue until 21 days after the last pemetrexed dose.
eviQ: folic acid 500 mcg PO daily and hydroxocobalamin 1000 mcg IM every 3 cycles. eviQ allows starting either 5–7 days before or at the same time as Cycle 1, based on PEMVITASTART.
The vitamins reduce pemetrexed-related neutropenia, febrile neutropenia and mucositis.
Dexamethasone for pemetrexed rash:
BC Cancer induction: dexamethasone 8–12 mg PO before treatment, then 4 mg PO every 12 hours for 4 doses.
BC Cancer maintenance: 4 mg PO twice daily for 3 days, starting the day before pemetrexed. Treatment may proceed even if doses were missed.
eviQ: 4 mg twice daily on the day before and Days 1–2 (with Day 3 optional in induction), which also serves as the antiemetic steroid.
Short steroid courses for these indications are accepted with immunotherapy.
Antiemetics:
Induction: BC Cancer uses its highly emetogenic protocol. eviQ rates carboplatin AUC 5 as moderate (AUC above 4) and gives an NK1 antagonist, a 5-HT3 antagonist and dexamethasone.
Maintenance: low emetogenic risk.
Avoid NSAIDs. They reduce pemetrexed clearance. Hold short-acting NSAIDs for about 2 days before and after pemetrexed (longer for long-acting agents), especially if CrCl is below 80 mL/min.
Pembrolizumab infusion reactions: no routine premedication. After a prior reaction, BC Cancer premedicates with diphenhydramine 50 mg PO, acetaminophen 325–975 mg PO and hydrocortisone 25 mg IV 30 minutes before treatment.
Growth factors: not routine. Consider after febrile neutropenia per local guidance.
Carboplatin hypersensitivity: eviQ rates the risk as high and rising with the number of cycles. Rechallenge only through a desensitisation protocol.

Key toxicities

Myelosuppression: neutropenia, thrombocytopenia (carboplatin) and anaemia, which is cumulative and frequent in maintenance.
Pemetrexed:
Rash, mucositis and fatigue.
Renal impairment and acute kidney injury. KEYNOTE-189 reported more AKI in the pembrolizumab arm.
Rising transaminases, oedema, epiphora and conjunctivitis.
Carboplatin: nausea, thrombocytopenia, hypersensitivity (often after multiple cycles) and hypomagnesaemia.
Pembrolizumab irAEs:
Common: hypothyroidism and hyperthyroidism, rash and pruritus, diarrhoea or colitis, pneumonitis (important in lung cancer, where it can be confused with infection or progression), hepatitis, nephritis, and arthralgia.
Rare but serious: hypophysitis, adrenal insufficiency, type 1 diabetes with DKA, myocarditis, myositis, myasthenia gravis, encephalitis, and severe skin reactions (SJS/TEN).
Overlapping toxicities: diarrhoea, rash, rising LFTs and creatinine can come from chemotherapy or immunotherapy. A structured work-up is needed before choosing between holding pemetrexed and giving steroids.
Pseudoprogression: uncommon (about 5% per eviQ). Consider confirmatory imaging 4–6 weeks later in a patient who is clinically well.

Monitoring

Baseline (BC Cancer):
CBC and differential, creatinine, ALP, ALT, bilirubin, LDH, sodium, potassium.
TSH and morning cortisol.
Chest X-ray.
eviQ suggests considering a baseline ECG and troponin.
Also check glucose, and consider HBV, HCV and HIV serology and a pregnancy test where relevant.
Before each cycle: CBC and differential, creatinine (for CrCl), liver panel, electrolytes and TSH.
As indicated: cortisol, ACTH, lipase, glucose, free T4, sex hormones, CK, troponin, ECG, and chest imaging for new respiratory symptoms.
Imaging: restage every 2–3 cycles (6–9 weeks) during induction and early maintenance, then less often.
Between visits: BC Cancer offers optional weekly nurse telephone assessment for irAE symptoms.

Dose-modification principles

Summarized from BC Cancer LUAVPPPMB and LUAVPPMBM. Defer to your local protocol.

Day 1 counts: if ANC is below 1.5 × 10⁹/L or platelets are below 100 × 10⁹/L, delay chemotherapy.
Renal (by CrCl):
45 mL/min or more: full-dose pemetrexed.
Below 45 mL/min: hold pemetrexed, whichever platinum is used.
With the cisplatin option, 45–60 mL/min means cisplatin 80% or a switch to carboplatin.
Mucositis: at grade 3–4, give pemetrexed at 50% of the previous dose. Discontinue after two dose reductions.
Other grade 3 or higher chemotherapy toxicity: delay until it resolves, then resume at a 25% lower dose if appropriate.
Pembrolizumab:
Never dose-reduced. Toxicity is managed by holding or discontinuing it and giving immunosuppression per SCIMMUNE and the ASCO, ESMO and SITC irAE guidelines.
Discontinue permanently after a grade 3–4 infusion reaction.
See the checkpoint inhibitor irAE primer.

Key trials & evidence

KEYNOTE-021 cohort G (Langer, Lancet Oncol 2016): this randomised phase 2 cohort showed a higher response rate when pembrolizumab was added to carboplatin and pemetrexed.
KEYNOTE-189 (Gandhi, NEJM 2018):
Design: 616 patients received pembrolizumab 200 mg every 3 weeks plus pemetrexed and platinum (cisplatin or carboplatin) × 4, then pembrolizumab + pemetrexed maintenance, compared with placebo plus chemotherapy.
Results: overall survival improved markedly (HR 0.49 at the first analysis), and progression-free survival improved. The benefit was seen in every PD-L1 category, including below 1%.
Crossover to pembrolizumab at progression was allowed.
KEYNOTE-189 5-year update (Garassino, JCO 2023): the overall survival benefit persisted. 5-year overall survival was about 19% compared with about 11% for chemotherapy. Patients who completed 35 cycles had durable responses.
PARAMOUNT (Paz-Ares, Lancet Oncol 2012; OS in JCO 2013): established pemetrexed continuation maintenance, the backbone of the maintenance phase.
Alternatives, depending on PD-L1 and fitness: single-agent pembrolizumab or other checkpoint inhibitors for PD-L1 of 50% or more. Other regimens include nivolumab-ipilimumab with two chemotherapy cycles (CheckMate 9LA), atezolizumab-bevacizumab-carboplatin-paclitaxel (IMpower150), and cemiplimab-chemotherapy. For squamous histology, carboplatin-paclitaxel/nab-paclitaxel-pembrolizumab (KEYNOTE-407) is used.

Clinical pearls

Don't start immunotherapy before driver results are back when a driver is likely, for example in never-smokers or adenocarcinoma with EGFR or ALK risk. Starting osimertinib after recent checkpoint inhibitor exposure raises the risk of severe pneumonitis and hepatotoxicity.
Start the vitamins at diagnosis. Folic acid and B12 can be started as soon as pemetrexed is likely. Current evidence (PEMVITASTART) supports not delaying Cycle 1 for the vitamin lead-in.
Watch creatinine closely in maintenance. Cumulative pemetrexed nephrotoxicity is common. Dropping pemetrexed and continuing pembrolizumab alone is a valid option.
Screen for NSAID use at every visit, including over-the-counter ibuprofen.
Suspect pneumonitis early. New cough or dyspnoea on treatment should prompt a CT and a low threshold to hold treatment. Do not assume progression or infection without imaging and clinical review.
Keep checking TSH. Thyroiditis often presents as transient hyperthyroidism followed by permanent hypothyroidism. The usual management is to replace levothyroxine and continue pembrolizumab.
Write down the treatment end date. Record the 35-dose / 2-year cap and the pembrolizumab dose count in the treatment plan so treatment stops on time.

Sources

For your patients

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