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08-08-2017 | Non-small cell lung cancer | Article

At a glance: The KEYNOTE lung cancer trials

The PD-1 inhibitor pembrolizumab is being investigated in multiple KEYNOTE trials across different tumor types, either alone or as part of various combinations, leading to a prodigious amount of information.

Here we provide a quick guide to the 11 non-small-cell lung cancer (NSCLC) trials, all of which are sponsored by the drug manufacturer, Merck Sharp & Dohme. Where a trial comprises multiple solid tumor cohorts, we focus on just the NSCLC cohort in this guide.

KEYNOTE-001: Published

Phase I

Patient population: locally advanced or metastatic NSCLC with PD-L1 positivity

Comparator: none

https://clinicaltrials.gov/show/NCT01295827

The results of the NSCLC cohort of the KEYNOTE-001 trial were published in The New England Journal of Medicine in May 2015. They showed that pembrolizumab given at a dose of 2 or 10 mg/kg every 3 weeks or 10 mg/kg every 2 weeks was well tolerated and had antitumor activity regardless of whether patients had received prior therapy or not.

Overall survival (OS) data on the treatment-naïve participants of the same trial, published in the Annals of Oncology in April 2017, showed a median OS time of 22.1 months, with greater benefits for those with a PD-L1 tumor proportion score of at least 50%.


KEYNOTE-010: Published

Phase II/III

Patient population: previously treated advanced NSCLC with ≥1% PD-L1-positive tumor cells

Comparator: docetaxel

https://clinicaltrials.gov/show/NCT01905657

As reported in The Lancet in December 2015, median OS was significantly longer with either the 2 or 10 mg/kg dose of pembrolizumab than with docetaxel 75 mg/m2, all given every 3 weeks. The survival benefit was even greater among patients with PD-L1 expression on at least 50% of tumor cells.

The co-primary endpoint of progression-free survival (PFS) did not differ significantly between the pembrolizumab and docetaxel arms in the overall study population, but pembrolizumab-treated participants with high (≥50%) PD-L1 expression did derive a significant PFS benefit relative to those given the taxane.


KEYNOTE-024: Published

Phase III

Patient population: treatment-naïve metastatic NSCLC with ≥50% PD-L1-positive tumor cells

Comparator: investigator’s choice of five platinum-based chemotherapy regimens

https://clinicaltrials.gov/show/NCT02142738

A prespecified interim analysis showed that pembrolizumab, administered at a fixed dose of 200 mg every 3 weeks, significantly extended the primary endpoint of PFS relative to chemotherapy. OS was also significantly longer with pembrolizumab, with 80.2% of patients alive at 6 months, compared with 72.4% in the chemotherapy group.

These results were published in The New England Journal of Medicine in November 2016.

Related news stories: KEYNOTE-024 demonstrates pembrolizumab superiority for PD-L1-positive NSCLC

Pembrolizumab PFS2, OS results support first-line NSCLC strategy


KEYNOTE-021: Ongoing

Phase I/II

Patient population: treatment-naïve locally advanced or metastatic NSCLC

Comparator: various

https://clinicaltrials.gov/ct2/show/NCT02039674

This is a multicohort study investigating the addition of pembrolizumab to various chemotherapeutic and immunotherapeutic regimens.

The findings of the cohort comparing carboplatin and pemetrexed with or without pembrolizumab were published in The Lancet Oncology in October 2016, and showed a significantly higher objective response rate (ORR) for the pembrolizumab group.

Related news story: Pembrolizumab addition supported in KEYNOTE-021 study


KEYNOTE-025: Completed, not yet published

Phase Ib

Patient population: advanced NSCLC with PD-L1 positivity

Comparator: None

https://clinicaltrials.gov/ct2/show/NCT02007070

The study is evaluating overall response rate in patients given pembrolizumab at a dose of 10 mg/kg on the first day of each 21-day cycle for up to 2 years.


KEYNOTE-011: Currently recruiting

Phase I

Patient population: advanced NSCLC

Comparator: none

https://clinicaltrials.gov/ct2/show/NCT01840579

In this multicohort trial, the researchers are evaluating the safety and tolerability of single-agent pembrolizumab given at three different doses – 2 or 10 mg/kg or 200 mg – and also administered in combination with platinum-based chemotherapy or the CTLA-4 inhibitor ipilimumab.

The study also includes a cohort of patients with advanced solid tumors and another comprising small-cell lung cancer patients with extensive disease.


KEYNOTE-042: Ongoing

Phase III

Patient population: treatment-naïve advanced NSCLC with ≥1% PD-L1-positive tumor cells

Comparator: carboplatin plus paclitaxel or pemetrexed

https://clinicaltrials.gov/ct2/show/NCT02220894

This is a head-to-head comparison, with OS as the primary endpoint, of pembrolizumab 200 mg every 3 weeks versus carboplatin given alongside either paclitaxel or pemetrexed in the first-line advanced NSCLC setting.

 

KEYNOTE-189: Ongoing

Phase III

Patient population: treatment-naïve metastatic nonsquamous NSCLC

Comparator: placebo plus platinum-based chemotherapy and pemetrexed

https://clinicaltrials.gov/ct2/show/NCT02578680

This trial was initiated in response to the encouraging results of the KEYNOTE-021 study. Participants in the experimental arm are receiving pembrolizumab 200 mg every 3 weeks in combination with pemetrexed plus either cisplatin or carboplatin, while the control arm is receiving placebo plus chemotherapy, with a view to assessing PFS.

 

KEYNOTE-407: Currently recruiting

Phase III

Patient population: treatment-naïve metastatic squamous NSCLC

Comparator: carboplatin plus paclitaxel or nab-paclitaxel

https://clinicaltrials.gov/ct2/show/NCT02775435

Study participants will receive carboplatin plus paclitaxel or nab-paclitaxel, with or without pembrolizumab at a dose of 200 mg on the first day of each 21-day cycle, and PFS and OS will be assessed as the co-primary endpoints.

 

KEYNOTE-091: Currently recruiting

Phase III

Patient population: early-stage resectable NSCLC

Comparator: placebo

https://clinicaltrials.gov/ct2/show/NCT02504372

Also known as PEARLS, this trial is exploring treatment with pembrolizumab 200 mg every 3 weeks or placebo in patients with stage IB–IIIA disease who have undergone surgical resection with or without standard adjuvant therapy. The primary endpoint of the trial is disease-free survival.

 

KEYNOTE-032: Ongoing

Phase I

Patient population: locally advanced or metastatic NSCLC; Chinese

Comparator: none

https://clinicaltrials.gov/ct2/show/NCT02835690

Here the focus is on evaluating the safety, tolerability and pharmacokinetics of three doses of pembrolizumab (2 or 10 mg/kg or 200 mg every 3 weeks) in Chinese patients. Efficacy, as indicated by the ORR, duration of response, PFS, and OS, will be investigated as the secondary endpoint.


Summary of approvals

  • Pembrolizumab was initially approved in October 2015 by the US Food and Drug Administration (FDA) for the treatment of advanced NSCLC patients with PD-L1-positive disease that had progressed after other treatments. A companion PD-L1 test received simultaneous approval.

  • A year later, in October 2016, the FDA approved pembrolizumab in the first-line metastatic NSCLC setting, with use restricted to patients with a PD-L1 tumor proportion score of at least 50%.

  • In May 2017, the FDA modified the indication for pembrolizumab to include all patients with nonsquamous metastatic NSCLC, regardless of PD-L1 expression. The PD-1 inhibitor is to be given alongside pemetrexed and carboplatin in the first-line.

    Related news story: Avelumab, pembrolizumab indications expanded 
  • In June 2016, the European Medicines Agency (EMA) adopted a positive opinion regarding the marketing authorization of pembrolizumab for patients with locally advanced or metastatic NSCLC expressing PD-L1 who had received at least one prior chemotherapy regimen. The decision also required patients with EGFR or ALK mutations to have received appropriate therapy for these mutations prior to initiation of the PD-1 inhibitor.

  • Later in the same year, the EMA adopted a new indication such that single-agent pembrolizumab could be given in the first line to metastatic NSCLC patients with a tumor proportion score of at least 50% and no EGFR mutations or ALK alterations.

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