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28-02-2019 | Lung cancer | At a glance | Article

At a glance: CheckMate lung cancer trials

Nivolumab – an anti-PD-1 agent – is being evaluated in the CheckMate trials for the treatment of various malignancies, either as a single agent or in combination with the CTLA-4 inhibitor ipilimumab.

Here we round up the 21 trials focusing on non-small-cell lung cancer (NSCLC) and the three small-cell lung cancer (SCLC) trials, with top-line results outlined where available. For trials consisting of multiple solid tumor cohorts, we focus on just the NSCLC and SCLC cohorts in this guide.

The drug manufacturer Bristol-Myers Squibb (New York, USA) is the main sponsor of all trials and the nivolumab dose used in the trials is 3 mg/kg given every 2 weeks as an intravenous infusion unless otherwise specified.

NSCLC trials

CheckMate 063: Ongoing

Phase II

Patient population: Previously treated advanced or metastatic squamous NSCLC

Comparator: None

https://clinicaltrials.gov/ct2/show/NCT01721759

This single-arm study showed that nivolumab was active in patients who had received at least two prior lines of therapy and had a manageable safety profile. Around 15% of study participants achieved an objective response, the median duration of which had not been reached at the time of analysis.

The findings were published in The Lancet Oncology in February 2015.

CheckMate 017: Ongoing

Phase III

Patient population: Previously treated stage IIIB/IV squamous NSCLC

Comparator: Docetaxel

https://clinicaltrials.gov/ct2/show/NCT01642004

The trial results, published in The New England Journal of Medicine in July 2015, showed significantly improved overall survival (OS), overall response rate, and progression-free survival (PFS) with nivolumab over docetaxel in this population of patients who had received one prior line of therapy.

Health-related quality of life (HRQoL) results from this trial were published in the Journal of Thoracic Oncology in November 2017, and showed that nivolumab improved HRQoL and symptom burden.

Additionally, researchers have pooled data from CheckMate 017 and 057, and reported the 2- and 3-year outcomes (in the Journal of Clinical Oncology and Annals of Oncology, respectively), showing sustained OS improvement with the PD-1 inhibitor versus the taxane.

Related news stories:

CheckMate 057: Ongoing

Phase III

Patient population: Previously treated stage IIIB/IV or recurrent nonsquamous NSCLC

Comparator: Docetaxel

https://clinicaltrials.gov/ct2/show/NCT01673867

Treatment with nivolumab significantly prolonged OS relative to docetaxel in patients who had progressed during or after platinum-based chemotherapy, according to the report published in The New England Journal of Medicine in October 2015. The response rate was also higher with nivolumab, but PFS was longer with docetaxel.

Similar to CheckMate 017, nivolumab was associated with improved HRQoL, as reported in the European Journal of Cancer in August 2018.

Additionally, researchers have pooled data from CheckMate 057 and 017, and reported the 2- and 3-year outcomes (in the Journal of Clinical Oncology and Annals of Oncology, respectively), showing sustained OS improvement with the PD-1 inhibitor versus the taxane.

Related news stories:

CheckMate 012: Ongoing

Phase I

Patient population: Stage IIIB/IV NSCLC

Comparator: None

https://clinicaltrials.gov/ct2/show/NCT01454102

This multicohort study is evaluating the safety and efficacy of nivolumab, at a range of doses, as first-line or maintenance therapy, alone and in combination with other regimens.

Two sets of results from this study were published in the Journal of Clinical Oncology in June 2016, with the first showing durable responses and a tolerable safety profile with nivolumab monotherapy in treatment-naïve patients. The second set of results showed that nivolumab could be combined with standard platinum-based doublet chemotherapy in the first line to promising effect, although discontinuation as a result of toxicities tended to be greater than would be expected with either nivolumab or chemotherapy alone.

In December 2016, The Lancet Oncology published a report on the subcohort of patients with previously untreated disease who were given nivolumab alongside the CTLA-4 inhibitor ipilimumab at a dose of 1 mg/kg every 6 or 12 weeks, with high response rates and durable responses in both groups.

Related news story: First-line nivolumab promising in advanced NSCLC

CheckMate 026: Ongoing

Phase III

Patient population: Treatment-naïve stage IV or recurrent NSCLC with ≥1% PD-L1-positive tumor cells

Comparator: Investigator’s choice of platinum-based chemotherapy

https://clinicaltrials.gov/ct2/show/NCT02041533

As reported in The New England Journal of Medicine in June 2017, nivolumab treatment did not significantly prolong the primary endpoint of PFS relative to chemotherapy in the primary efficacy analysis population of patients with a PD-L1 expression level of at least 5%. Overall survival was also comparable, but nivolumab had better tolerability.

Related news story: No PFS advantage with nivolumab in advanced NSCLC patients selected by PD-L1 expression

CheckMate 171: Ongoing

Phase II

Patient population: Previously treated stage IIIB/IV squamous NSCLC

Comparator: None

https://clinicaltrials.gov/ct2/show/NCT02409368

In this open-label study – the results of which were presented at the 2017 ESMO Congress – no new safety signals were observed with nivolumab monotherapy. Of note, the tolerability of nivolumab in older patients aged 70 years and above and those with a poor performance status was comparable to that in the overall population.

CheckMate 153: Ongoing

Phase IIIb/IV

Patient population: Previously treated stage IIIB/IV NSCLC

Comparator: Continuous nivolumab

https://clinicaltrials.gov/ct2/show/NCT02066636

CheckMate 153 evaluated the clinical benefit of a fixed duration of nivolumab versus continuous treatment. As reported at the 2017 ESMO Congress, participants who were randomly assigned to continue nivolumab after a year of treatment were significantly less likely to progress than those who stopped at the 1-year mark; the corresponding median PFS durations were unreached and 10.3 months.

Other results from this trial have also been reported. A poster presented at the 2016 IASLC 17th World Conference on Lung Cancer showed that the toxicity profile of nivolumab in older (≥70 years) and poor performance status (ECOG score of 2) patients is similar to in the overall study population. And in another poster – presented at the 2016 IASLC 7th Latin American Conference on Lung Cancer and published in Cancer Chemotherapy and Pharmacology in February 2018 – a 30-min infusion of nivolumab was shown to have a comparable safety profile to a 60-min infusion.

CheckMate 370: Ongoing

Phase I/II

Patient population: Locally advanced or stage IV NSCLC

Comparator: Standard of care, best supportive care, investigator’s choice of chemotherapy

https://clinicaltrials.gov/show/NCT02574078

This trial comprises several sub-trials assessing nivolumab, given either as a single agent or alongside standard of care treatments, in the maintenance or first-line setting in patients with advanced NSCLC.

In March 2018, the Journal of Thoracic Oncology published results from the cohort investigating the first-line combination of nivolumab 240 mg every 2 weeks plus crizotinib 250 mg twice daily in patients with ALK translocation-positive disease. Thirty-eight percent of the initial 13 participants developed severe hepatotoxicities and discontinued treatment, as a result of which enrollment to the group was closed.

CheckMate 568: Ongoing

Phase II

Patient population: Treatment-naïve stage IV NSCLC

Comparator: None

https://clinicaltrials.gov/show/NCT02659059

This two-part trial aims to investigate the response to the combination of nivolumab and ipilimumab, and also the safety and tolerability of adding chemotherapy to the duo.

As presented in April 2018 at the American Association for Cancer Research Annual Meeting, data from this trial were used to establish a tumor mutational burden (TMB) cutoff of 10 mutations/Mb or higher, as used in the CheckMate 227 trial, to delineate the TMB-positive population. The findings have since been published in the Journal of Clinical Oncology.

CheckMate 227: Recruiting

Phase III

Patient population: Chemotherapy-naïve stage IV or recurrent NSCLC

Comparator: Platinum-based doublet chemotherapy

https://clinicaltrials.gov/show/NCT02477826

The co-primary endpoint of PFS in patients with a high TMB (≥10 mutations/Mb) was significantly better with nivolumab plus ipilimumab than with chemotherapy, at 1-year rates of 42.6% versus 13.2%. These results were presented at the American Association for Cancer Research Annual Meeting 2018 and simultaneously published in The New England Journal of Medicine.

The trial is also investigating the efficacy of nivolumab alone and alongside doublet chemotherapy versus chemotherapy.

Related news story: Nivolumab plus ipilimumab benefits shown in highly mutated advanced NSCLC

CheckMate 078: Ongoing

Phase III

Patient population: Chemotherapy-treated stage IIIB/IV or recurrent NSCLC

Comparator: Docetaxel

https://clinicaltrials.gov/ct2/show/study/NCT02613507

The findings of the trial, conducted predominantly in Chinese patients, were reported at the American Association for Cancer Research Annual Meeting 2018 and showed that median OS was significantly improved with nivolumab versus docetaxel, at 12.0 and 9.6 months, respectively. The researchers say that the results were consistent with those of the pivotal global CheckMate 017/057 studies.

The following NSCLC trials are ongoing, but have not reported any results so far.

CheckMate 907: Ongoing

Phase II

Patient population: Previously treated advanced or metastatic NSCLC

Comparator: None 

https://clinicaltrials.gov/ct2/show/NCT03090737

The primary endpoint of this safety study is the incidence of grade 3–4 and grade 5 treatment-related adverse events. Information regarding the dose/s of nivolumab being tested is not available at present.

CheckMate 870: Ongoing

Phase III

Patient population: Previously treated stage IIIB/IV NSCLC

Comparator: None

https://clinicaltrials.gov/ct2/show/NCT03195491

The primary objective of this study is to investigate the safety and tolerability of nivolumab monotherapy given at a dose of 240 mg every 2 weeks in the second or third line to Asian patients recruited from China, Thailand, and the USA.

CheckMate 384: Ongoing

Phase IIIb/IV

Patient population: Stage IIIb/IV NSCLC; previously treated with nivolumab 3 mg/kg or 240 mg every 2 weeks for up to a year

Comparator: Nivolumab 240 mg every 2 weeks

https://clinicaltrials.gov/show/NCT02713867

The trial aims to show that a dose of 480 mg every 4 weeks for nivolumab is noninferior to the 240 mg every 2 weeks regimen.

CheckMate 592: Recruiting

Phase II

Patient population: Treatment-naïve stage IV or recurrent NSCLC

Comparator: None

https://clinicaltrials.gov/show/NCT03001882

This study is exploring the biologic effects and biomarkers of the combination of nivolumab and ipilimumab.

CheckMate 9LA: Recruiting

Phase III

Patient population: Treatment-naïve stage IV or recurrent NSCLC

Comparator: Chemotherapy

https://clinicaltrials.gov/ct2/show/NCT03215706

The trial aims to evaluate overall survival with the addition of nivolumab and ipilimumab to chemotherapy in the first-line treatment of stage IV or recurrent NSCLC.

CheckMate 816: Recruiting

Phase III

Patient population: Resectable stage IB–IIIA NSCLC

Comparator: Platinum-based doublet chemotherapy

https://clinicaltrials.gov/show/NCT02998528

CheckMate 816 is a neoadjuvant trial that will assess the efficacy and safety of supplementing platinum-based doublet chemotherapy with nivolumab, and will also pit the combination of nivolumab and ipilimumab against chemotherapy.

CheckMate 722: Recruiting

Phase III

Patient population: EGFR mutation-positive stage IV or recurrent NSCLC that has progressed on EGFR–TKI therapy

Comparator: Platinum-based doublet chemotherapy

https://clinicaltrials.gov/ct2/show/NCT02864251

Participants with an EGFR mutation but without the T790M resistance mutation will be randomly assigned to receive nivolumab either alongside platinum-based doublet chemotherapy or ipilimumab, or just chemotherapy, with PFS as the primary endpoint.

CheckMate 817: Recruiting

Phase IV

Patient population: Treatment-naïve stage IV or recurrent NSCLC

Comparator: None

https://clinicaltrials.gov/show/NCT02869789

This study of nivolumab plus ipilimumab has three cohorts; the primary objective of two cohorts is to evaluate the number and proportion of participants who experience high-grade adverse events. The third cohort will comprise patients with a high TMB and will assess the objective response rate.

CheckMate 169: Discontinued

Phase – n/a

Patient population: Previously treated stage IIIb/IV squamous or nonsquamous NSCLC

Comparator: None

https://clinicaltrials.gov/ct2/show/NCT02475382

This expanded-access program was set up to provide access to single-agent nivolumab in Brazil and Canada. The program has been discontinued.

Results from the Canadian cohort of the program were presented at the 2017 IASLC 18th World Conference on Lung Cancer, and showed a safety profile in older patients and those with poor functional status that was consistent with the overall population.

CheckMate 955: Withdrawn

Phase Ib/II

Patient population: Chemotherapy-naïve stage IV or recurrent NSCLC

Comparator: None

https://clinicaltrials.gov/ct2/show/NCT03048136

This trial was investigating the safety of combining either a flat or weight-based dose of nivolumab with ipilimumab.

SCLC trials

CheckMate 032: Ongoing

Phase I/II

Patient population: Advanced or metastatic solid tumors

Comparator: None

https://clinicaltrials.gov/ct2/show/NCT01928394

This is a multi-cohort trial assessing the safety and efficacy of nivolumab, given as a single agent or with ipilimumab, in patients with advanced or metastatic solid tumors. Participants received nivolumab and ipilimumab, with both given at a dose of 1 or 3 mg/kg every 2 or 3 weeks.

The findings of the SCLC cohort were published in The Lancet Oncology in June 2016 and showed that previously treated patients with limited- or extended-stage disease achieved durable responses with both regimens, which also had manageable safety profiles.

An analysis restricted to individuals who were receiving nivolumab monotherapy in the third- or later-line demonstrated similar results to the main cohort. These findings appeared in the Journal of Thoracic Oncology in October 2018.

Another analysis – published in Cancer Cell in May 2018 – showed that outcomes in response to nivolumab, either given alone or alongside ipilimumab, were better for patients with high TMB (≥248 mutations) versus low (0 to <143 mutations) or medium (143–247 mutations) TMB.

Related news story: FDA announces approvals for metastatic SCLC, unresectable HCC

CheckMate 331: Ongoing

Phase III

Patient population: Relapsed SCLC after first-line platinum-based chemotherapy

Comparator: Topotecan or amrubicin chemotherapy

https://clinicaltrials.gov/ct2/show/NCT02481830

As reported at the ESMO Immuno-Oncology Congress in December 2018, the trial did not meet its primary endpoint of showing a significant OS improvement with second-line nivolumab – given at a dose of 240 mg every 2 weeks – versus chemotherapy. The researchers note, however, that the OS curves appeared to separate after 12 months, indicating “possible long-term benefit for some patients.”

CheckMate 451: Ongoing

Phase III

Patient population: Extensive-stage disease SCLC that has been treated with first-line chemotherapy

Comparator: Placebo

https://clinicaltrials.gov/ct2/show/NCT02538666

The sponsor announced in November 2018 that the trial did not meet its primary endpoint of improvement in OS with a maintenance regimen of nivolumab 1 mg/kg plus ipilimumab 3 mg/kg versus placebo in patients who had disease control after chemotherapy.

The trial is also investigating maintenance with single-agent nivolumab; these results have not yet been reported.

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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