Clinical trialPhase 3Lung cancer

Pembrolizumab Plus Pemetrexed and Platinum in Nonsquamous Non–Small-Cell Lung Cancer: 5-Year Outcomes From the Phase 3 KEYNOTE-189 Study

J Clin Oncol · 2023616 patients

Garassino MC, Gadgeel S, Speranza G, Felip E, Esteban E, Dómine M, et al. J Clin Oncol. 2023. 41:1992-1998

Study type: Clinical trial
Study name: KEYNOTE-189
Phase: Phase 3
Design: Randomised, double-blind, placebo-controlled trial (2:1); 5-year updated report
Sample size: 616 patients
Source: J Clin Oncol · 2023
Trial registration: NCT02578680

In plain words

For the most common type of advanced lung cancer (non-squamous) that has no targetable mutation, adding the immunotherapy drug pembrolizumab to chemotherapy almost doubled the chance of being alive after 5 years (about 19% versus 11%). Patients who completed the full two years of treatment more often had a lasting response.

Key results

19.4% vs 11.3%

5-year overall survival

Overall survival HR 0.60; 95% CI 0.50–0.72

HR 0.50

Progression-free survival

95% CI 0.42–0.60; 5-year PFS 7.5% vs 0.6%

48.3% vs 19.9%

Objective response

95% CI 43.4–53.2 vs 14.7–26.0

12.7 months vs 7.1 months

Median duration of response

Range 1.‎1+‎ to 68.‎3+‎ vs 2.4 to 31.5

17.0 months vs 9.1 months

Progression-free survival 2 (PFS2)

HR 0.54; 95% CI 0.45–0.65

86.0%

Response in patients who completed 35 cycles (57 patients)

3-year survival after completing 35 cycles: 71.9%

Drugs in this study:Carboplatin (Paraplatin)Cisplatin (Platinol)Pembrolizumab (Keytruda)

Dose and schedule cards

Pembrolizumab + pemetrexed + platinum (KEYNOTE-189)

Metastatic non-squamous NSCLC without EGFR or ALK alterations, any PD-L1 level; first-lineCycle length: Every 21 daysOn the page “Lung cancer” · Advanced NSCLC without a driver alteration: first-line

Metastatic non-squamous NSCLC without EGFR or ALK alterations, any PD-L1 level; first-line

Drug	Dose	Route	Schedule
Induction: 4 cycles of 21 days
Pembrolizumab	200 mg	IV (30 min)	Day 1 (first)
Pemetrexed	500 mg/m²	IV (10 min)	Day 1 (after pembrolizumab)
Cisplatin or carboplatin	75 mg/m² or AUC 5	IV	Day 1 (last)
Maintenance
Pembrolizumab + pemetrexed	200 mg + 500 mg/m²	IV	Every 3 weeks

Cycle length: Every 21 days
Duration: Pembrolizumab for a maximum of 24 months (35 cycles); pemetrexed until progression or intolerable toxicity

Sources: FDA labels for pembrolizumab and pemetrexed; 5-year results.

On the page “Lung cancer” · Advanced NSCLC without a driver alteration: first-line

Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.

Treatment arms and regimens

1Pembrolizumab + pemetrexed–platinum (410 patients)

Induction (4 cycles, every 21 days): pembrolizumab 200 mg IV (before chemotherapy) + pemetrexed 500 mg/m² IV + investigator's choice of cisplatin 75 mg/m² or carboplatin AUC 5 IV, all on day 1.

Maintenance: pembrolizumab 200 mg + pemetrexed 500 mg/m² IV every 3 weeks; pembrolizumab for a maximum of 35 cycles (about 2 years) and pemetrexed until disease progression or unacceptable toxicity. Continuing pembrolizumab after RECIST-defined progression was allowed in clinically stable patients with clinical benefit. A second course of single-agent pembrolizumab for up to 17 cycles (about 1 year) was allowed on progression after completing 35 cycles (with a best response of stable disease or better) or after a confirmed complete response (after at least 8 cycles of pembrolizumab and 2 cycles beyond the complete response).

Pemetrexed premedication: folic acid 350 to 1000 µg orally (at least 5 doses in the 7 days before the first pemetrexed dose, continued throughout treatment and until 21 days after the last dose); vitamin B12 1000 µg intramuscularly in the week before the first dose and then every 3 cycles; dexamethasone 4 mg orally twice a day (or equivalent) on the day before, the day of and the day after pemetrexed.

2Placebo + pemetrexed–platinum (206 patients)

IV saline placebo in place of pembrolizumab, with the same chemotherapy: pemetrexed 500 mg/m² + cisplatin 75 mg/m² or carboplatin AUC 5, day 1 every 21 days for 4 cycles; then placebo + pemetrexed 500 mg/m² every 3 weeks until progression. The same vitamin supplements and dexamethasone. On progression confirmed by independent central review, crossover to single-agent pembrolizumab was allowed (84 patients crossed over within the study; effective crossover rate including off-study anti-PD-‎(L)1 therapy 57.3%).

Source of the regimen details: Full text of the paper (PMC10082311), ClinicalTrials.gov NCT02578680 (folic acid, vitamin B12 and dexamethasone doses) and the FDA label for Keytruda (DailyMed, section 14, KEYNOTE-189).

Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.

Study population

Adults with stage IV non-squamous NSCLC (histologically or cytologically confirmed) without previous systemic therapy for metastatic disease, without EGFR or ALK alterations, with any level of PD-L1 expression, ECOG performance status 0 or 1, measurable disease, a life expectancy of at least 3 months and adequate organ function. Exclusion criteria: predominantly squamous histology, autoimmune disease requiring systemic treatment in the past 2 years, conditions requiring immunosuppression, lung radiotherapy of more than 30 Gy in the past 6 months. Randomisation was stratified by smoking status, choice of platinum and PD-L1 expression (TPS less than 1% versus 1% or more).

Endpoints

Primary endpoints: overall survival and progression-free survival. Other endpoints: objective response, duration of response and safety.

Safety and side effects

Almost all patients had an adverse event (99.8% versus 99.0%). Immune-mediated adverse events and infusion reactions occurred in 27.9% of the pembrolizumab group and 13.4% of the placebo group. According to the FDA label (405 patients on pembrolizumab): pembrolizumab was discontinued for adverse events in 20% of patients (most common causes: pneumonitis 3% and acute kidney injury 2%) and interrupted in 53% (most common cause neutropenia 13%). Selected grade 3–4 adverse events (pembrolizumab versus placebo): fatigue/asthenia 12% versus 6%, diarrhoea 5% versus 3%, nausea 3.5% in both groups. In the 57 patients who completed 35 cycles, grade 3/4 adverse events occurred in 66.7% and there were no grade 5 events.

Clinical significance and place in guidelines

KEYNOTE-189 made pembrolizumab plus pemetrexed–platinum one of the first-line standards for metastatic non-squamous NSCLC without EGFR/ALK mutations, at any PD-L1 level (FDA approval in 2018), and it is recommended in the ESMO and NCCN guidelines. In tumours with PD-L1 ≥50%, single-agent immunotherapy (KEYNOTE-024) is also an option.

Limitations

Extensive crossover of control-group patients to immunotherapy (effective rate 57.3%) makes the overall survival difference look smaller than it is; patients with targetable mutations and poor performance status were not enrolled; the 5-year analyses are descriptive.

Original article (DOI)PubMed ClinicalTrials.gov

This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.