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08-08-2017 | Non-small cell lung cancer | At a glance | Article

Updated July 2019

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 non-small-cell lung cancer (NSCLC) and small-cell lung cancer (SCLC) trials sponsored by the drug manufacturer Merck Sharp & Dohme. Where a trial comprises multiple solid tumor cohorts, we focus on just the NSCLC and SCLC cohorts in this guide.

NSCLC trials

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 (TPS) of at least 50%.

Three-year results from the trial pointed to a durable effect of the agent on OS, with median OS durations of 22.3 and 10.5 months among treatment-naïve and previously treated participants, respectively. The association between higher PD-L1 levels and better outcomes was also observed in this analysis, which appeared in The Lancet Respiratory Medicine in March 2019.

A secondary analysis of the trial – published in The Lancet Oncology in May 2017 – showed significantly better progression-free survival (PFS) and OS for participants who had previously received radiotherapy relative to those who had not. Individuals with versus without prior receipt of thoracic radiation had a higher incidence of any (63 vs 40%) and treatment-related (13 vs 1%) pulmonary toxicity, but the safety profile was considered acceptable by the researchers.

The trial investigators reported 5-year results at the 2019 ASCO Annual Meeting, with simultaneous publication in the Journal of Clinical Oncology, showing OS rates at this timepoint of 23.2% and 15.5% for treatment-naïve and previously treated participants, respectively.

Related news story: Prolonged survival possible with pembrolizumab in advanced NSCLC

Related expert interviews:

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

The co-primary endpoint of 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 (5.0 and 5.2 months for 2 and 10 mg/kg, respectively, vs 4.1 months).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 (10.4 and 12.7 vs 8.5 months). The survival benefit was even greater among patients with PD-L1 expression on at least 50% of tumor cells.

An updated analysis – conducted at an additional 18 months’ follow-up – showed that the OS benefit afforded by pembrolizumab was maintained not only in the intention-to-treat population, but also in the subgroups of patients with archival or newly collected specimens. These results were published in the Annals of Oncology in January 2019.

As reported in the Journal of Thoracic Oncology in January 2019, health-related quality of life (HRQoL) and symptoms did not worsen or improved over the 12-week assessment period with pembrolizumab versus docetaxel.

A pooled analysis of data from the KEYNOTE-010, -024, and -042 trials was presented at ELCC 2019 and showed that older (≥75 years) patients with a PD-L1 TPS of at least 50% derive a greater OS benefit from pembrolizumab over chemotherapy than younger patients.

Related news story: Conflicting data reported on immunotherapy benefit for older NSCLC patients

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 (median 10.3 vs 6.0 months). OS was also significantly longer with pembrolizumab, with 80.2% of patients alive at 6 months, compared with 72.4% of the chemotherapy group.

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

As seen in KEYNOTE-010, HRQoL was maintained or improved in the pembrolizumab versus chemotherapy groups from baseline to week 15. The article was published in The Lancet Oncology in November 2017.

Data published in the Journal of Clinical Oncology in January 2019 showed that pembrolizumab continued to provide an OS advantage over chemotherapy with prolonged follow-up and despite cross-over from the chemotherapy to the pembrolizumab arm.

A pooled analysis of data from the KEYNOTE-010, -024, and -042 trials was presented at ELCC 2019 and showed that older (≥75 years) patients with a PD-L1 TPS of at least 50% derive a greater OS benefit from pembrolizumab over chemotherapy than younger patients.

Related news stories:

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 for the cohort comparing carboplatin and pemetrexed with or without pembrolizumab (cohort G) were published in The Lancet Oncology in October 2016, and showed a significantly higher objective response rate (ORR; 55 vs 29%) and PFS (median, 13.0 vs 8.9 months) with the addition of pembrolizumab. Additional results from this cohort – published in the Journal of Thoracic Oncology in August 2018 – showed a significant OS improvement with the addition of pembrolizumab at a median follow-up of 24 months (hazard ratio [HR] for death=0.56).

Results from cohorts A–C demonstrated the feasibility of adding pembrolizumab 2 or 10 mg/kg every 3 weeks to carboplatin–paclitaxel, either without or with bevacizumab, and to carboplatin–pemetrexed. According to the article appearing in Lung Cancer in August 2018, the ORRs were 48%, 56%, and 75%, respectively.

Analysis of cohorts E and F of the trial, which included patients with sensitizing EGFR mutations, showed that although the toxicity profile of pembrolizumab–erlotinib was similar to that seen for the individual agents, albeit with no improvement in the ORR versus prior monotherapy studies, the combination of pembrolizumab–gefitinib is not feasible as over two-thirds of patients developed grade 3 or 4 liver toxicity. These results appeared in the Journal of Thoracic Oncology in December 2018.

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

KEYNOTE-025: Published

Phase Ib

Patient population: Platinum-treated advanced NSCLC with PD-L1 TPS ≥1%

Comparator: None

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

The results of this study in Japanese patients were consistent with those of the phase III KEYNOTE-010 trial. Treatment with pembrolizumab at a dose of 10 mg/kg every 3 weeks for up to 2 years led to an ORR of 27% among patients with a PD-L1 TPS of at least 50% and of 22% among those with a TPS of at least 1%. These data were published in Cancer Science in January 2019.

KEYNOTE-042: Published

Phase III

Patient population: Treatment-naïve advanced NSCLC with PD-L1 TPS ≥1%; no EGFR or ALK alterations

Comparator: Carboplatin plus paclitaxel or pemetrexed

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

The primary analysis of the trial showed that pembrolizumab monotherapy – given at a dose of 200 mg every 3 weeks for up to 35 cycles – significantly improves OS relative to chemotherapy regardless of PD-L1 levels. However, as reported in The Lancet in April 2019, the magnitude of benefit varies by PD-L1 TPS, with HRs for death of 0.69, 0.77, and 0.81 for scores of at least 50%, 20%, and 1%, respectively.

A pooled analysis of data from the KEYNOTE-010, -024, and -042 trials was presented at ELCC 2019 and showed that older (≥75 years) patients with a PD-L1 TPS of at least 50% derive a greater OS benefit from pembrolizumab over chemotherapy than younger patients.

Related news stories:

Related expert interview: Expert commentary: Lung cancer highlights, including the KEYNOTE-042 and CCGA studies

KEYNOTE-189: Published

Phase III

Patient population: Treatment-naïve metastatic nonsquamous NSCLC lacking EGFR or ALK alterations

Comparator: Placebo plus platinum-based agent and pemetrexed

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

This trial was initiated in response to the encouraging results of the KEYNOTE-021 study. The primary results – published in The New England Journal of Medicine in April 2018 – showed a significant improvement in OS and PFS with the addition of pembrolizumab 200 mg every 3 weeks to pemetrexed plus either cisplatin or carboplatin, with an HR for death of 0.49 and an HR for progression or death of 0.52 relative to placebo plus chemotherapy. Participants derived a benefit regardless of PD-L1 levels, albeit the PFS benefit did not reach statistical significance amongst those with a TPS below 1%.

Related news story: First-line pembrolizumab plus chemotherapy boosts advanced NSCLC outcomes

KEYNOTE-407: Published

Phase III

Patient population: Treatment-naïve metastatic squamous NSCLC

Comparator: Carboplatin plus paclitaxel or nab-paclitaxel

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

Similar to the results in nonsquamous patients, the addition of pembrolizumab 200 mg every 3 weeks to carboplatin plus paclitaxel or nab-paclitaxel led to a significant improvement in the co-primary endpoints of OS and PFS, with respective HRs of 0.64 and 0.56. The OS and PFS gains with pembrolizumab were observed across all PD-L1 TPS subgroups.

These results appeared in The New England Journal of Medicine in September 2018.

Related news stories:

KEYNOTE-011: Ongoing

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 SCLC patients with extensive disease.

Results from Japanese participants with advanced solid tumors – reported in Investigational New Drugs in March 2016 – demonstrated the tolerability of pembrolizumab 2 or 10 mg/kg given every 2 weeks in this setting. 

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.

KEYNOTE-091: 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-598: Recruiting

Phase III

Patient population: Treatment-naïve metastatic NSCLC with TPS ≥50%

Comparator: Pembrolizumab plus placebo

https://clinicaltrials.gov/ct2/show/NCT03302234

This trial is investigating the effect on OS and PFS of adding either ipilimumab 1 mg/kg every 6 weeks or placebo to pembrolizumab 200 mg every 3 weeks in individuals with stage IV disease and high PD-L1 expression.

KEYNOTE-671: Recruiting

Phase III

Patient population: Resectable stage IIB or IIIA NSCLC

Comparator: Perioperative placebo plus neoadjuvant chemotherapy

https://clinicaltrials.gov/ct2/show/NCT03425643

This study will assess the efficacy of using perioperative pembrolizumab 200 mg on the first day of each 3-week cycle or placebo alongside neoadjuvant platinum doublet chemotherapy in patients with stage IIB or IIIA disease amenable to resection. The co-primary endpoints are event-free survival (EFS) and OS.

KEYNOTE-789: Recruiting

Phase III

Patient population: EGFR-mutated, TKI-resistant, metastatic nonsquamous NSCLC

Comparator: Pemetrexed, platinum-based chemotherapy, and placebo

https://clinicaltrials.gov/ct2/show/NCT03515837

Participants are required to be positive for an activating EGFR mutation (exon 19 deletion or exon 20 L858R point mutation) and resistant to prior tyrosine kinase inhibitor (TKI) treatment; those who harbor the T790M mutation should have previously received osimertinib. Patients with stage IV nonsquamous NSCLC will receive either pembrolizumab 200 mg every 3 weeks or placebo together with pemetrexed and carboplatin or cisplatin, and PFS and OS will be the primary endpoints.

KEYNOTE-799: Recruiting

Phase II

Patient population: Inoperable locally advanced NSCLC

Comparator: None

https://clinicaltrials.gov/ct2/show/NCT03631784

The focus here is to evaluate the incidence of grade 3 or worse pneumonitis in stage III NSCLC patients who are given pembrolizumab 200 mg every 3 weeks alongside thoracic radiotherapy and either paclitaxel plus carboplatin or pemetrexed plus cisplatin, followed by pembrolizumab monotherapy at the same dose for up to 14 cycles. The investigators will also assess ORR as a co-primary endpoint.

KEYNOTE-867: Recruiting

Phase III

Patient population: Unresectable early-stage NSCLC

Comparator: SBRT plus placebo

https://clinicaltrials.gov/ct2/show/NCT03924869

Individuals with inoperable stage I or IIA disease will be treated with stereotactic body radiotherapy (SBRT) plus either pembrolizumab 200 mg every 3 weeks or placebo, with a view to evaluating the co-primary endpoints of EFS and OS.

KEYNOTE-782: Ongoing

Phase II

Patient population: Treatment-naïve metastatic nonsquamous NSCLC

Comparator: None

https://clinicaltrials.gov/ct2/show/NCT03664024

This biomarker study aims to establish whether the tumor mutational burden (TMB) in circulating free DNA can be used to predict response among patients with stage IV nonsquamous NSCLC receiving four cycles of pembrolizumab plus platinum-based doublet chemotherapy, followed by up to 31 cycles of maintenance pembrolizumab and pemetrexed.

KEYNOTE-495: Recruiting

Phase II

Patient population: Treatment-naïve metastatic NSCLC

Comparator: None

https://clinicaltrials.gov/ct2/show/NCT03516981

In this trial, the investigators aim to evaluate the utility of biomarker-based triage in individuals with stage IV disease, where the biomarker will be a combination of gene expression profile and TMB. All participants will receive pembrolizumab plus either lenvatinib, or the anti-LAG3 monoclonal antibodies MK-4280 or MK-1308. The primary endpoint of the study is ORR.

KEYNOTE-593: Recruiting

Phase IV

Patient population: Platinum-naïve (PD-L1 ≥50%) or treated (PD-L1 ≥1%) advanced NSCLC; Indian

Comparator: None

https://clinicaltrials.gov/ct2/show/NCT03715205

This trial will assess the safety of pembrolizumab 200 mg administered every 3 weeks for up to 35 cycles in Indian patients with NSCLC. Those receiving the PD-1 inhibitor in the first line are required to have stage IV disease and high PD-L1 expression (≥50%), whereas previously treated participants can be of stage IIIB, IIIC, or IV and have PD-L1 expression of 1% or greater.

Other trials

In addition, there are various extension studies ongoing that are evaluating the same regimens as the global study in specific populations. Specifically, there are the China extension studies of the KEYNOTE-407 (https://clinicaltrials.gov/ct2/show/NCT03875092) and 042 (https://clinicaltrials.gov/ct2/show/NCT03850444) trials, and the Japan extension study of KEYNOTE-189 (https://clinicaltrials.gov/ct2/show/NCT03950674).

SCLC trials

KEYNOTE-158: Recruiting

Phase II

Patient population: Previously treated advanced SCLC

Comparator: None

https://clinicaltrials.gov/ct2/show/NCT02628067

This is a multicohort trial investigating up to 2 years of treatment with pembrolizumab 200 mg every 3 weeks across various solid tumors. All participants have unresectable and/or metastatic disease that has progressed on standard of care therapy.

KEYNOTE-604: Ongoing

Phase III

Patient population: Untreated extensive-stage SCLC

Comparator: Etoposide, platinum-based chemotherapy, and placebo

https://clinicaltrials.gov/ct2/show/NCT03066778

This trial – in patients with a new diagnosis of extensive-stage SCLC – is assessing the impact on PFS and OS of adding either pembrolizumab 200 mg every 3 weeks or placebo to the standard of care, namely, etoposide plus investigator’s choice of carboplatin or cisplatin.

Summary of approvals

  • In June 2016, the 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 TPS of at least 50% and no EGFR mutations or ALK alterations.
  • In July 2018, the EMA gave the nod to first-line pembrolizumab together with pemetrexed and platinum chemotherapy for metastatic nonsquamous NSCLC patients who are negative for EGFR and ALK alterations. The positive decision for those with squamous NSCLC came in January 2019, allowing the use of pembrolizumab, carboplatin and paclitaxel or nab-paclitaxel in previously untreated individuals.

By Shreeya Nanda

medwireNews is an independent medical news service provided by Springer Healthcare. © 2019 Springer Healthcare part of the Springer Nature group

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