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: Completed
Phase 2 | |
Patient population: Previously treated advanced or metastatic squamous NSCLC | Comparator: None |
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: Completed
Phase 3 | |
Patient population: Previously treated stage IIIB/IV squamous NSCLC | Comparator: Docetaxel |
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 in 2017 and Annals of Oncology in 2018, respectively), showing sustained OS improvement with the PD-1 inhibitor versus the taxane.
Subsequent pooled analyses of the two trials showed that the rates of 4- and 5-year OS continued to be higher with nivolumab than docetaxel. The findings were published in The Lancet Oncology in 2019 and the Journal of Clinical Oncology in 2021, respectively.
CheckMate 057: Completed
Phase 3 | |
Patient population: Previously treated stage IIIB/IV or recurrent nonsquamous NSCLC | Comparator: Docetaxel |
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 showed sustained OS improvement with the PD-1 inhibitor versus the taxane at 2 and 3 years. See the CheckMate 017 section for details.
Subsequent pooled analyses of the two trials also showed the continued benefit of nivolumab with respect to 4- and 5-year. Details in the CheckMate 017 section above.
CheckMate 012: Completed
Phase 1 | |
Patient population: Stage IIIB/IV NSCLC | Comparator: None |
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.
A pooled analysis of long-term data from two cohorts of CheckMate 012, part 1 of CheckMate 227 and 568, and cohort A of CheckMate 817 showed that first-line nivolumab plus ipilimumab achieved a 3-year OS rate of 35% and a median OS of 18.6 months after a minimum follow-up of 29.1–58.9 months. The authors say in the 2022 Annals of Oncology publication that these results “further support this first-line treatment option for advanced NSCLC.”
CheckMate 026: Completed
Phase 3 | |
Patient population: Treatment-naïve stage IV or recurrent NSCLC with ≥1% PD-L1-positive tumor cells | Comparator: Investigator’s choice of platinum-based chemotherapy |
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.
CheckMate 171: Completed
Phase 3 | |
Patient population: Previously treated stage IIIB/IV squamous NSCLC, including older patients and those with a poor PS | Comparator: None |
In this open-label study – the results of which were presented at the 2017 ESMO Congress and subsequently published in the European Journal of Cancer in 2020 – 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 an ECOG performance status (PS) of 2 was comparable to that in the overall population.
OS was similar for all treated and older patients aged at least 70 years and 75 years, at medians of 10.0 months versus 10.0 and 11.2 months, respectively, but was poorer for those with an ECOG PS of 2, at 5.2 months.
CheckMate 153: Completed
Phase 3b/4 | |
Patient population: Previously treated stage IIIB/IV NSCLC, including older patients and those with a poor PS | Comparator: Continuous nivolumab |
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. The results were published in the Journal of Clinical Oncology in 2020, with updated estimates of median PFS (24.7 vs 9.4 months) and OS data (median, unreached vs 32.5 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 PS (ECOG score of 2) patients is similar to that in the overall study population. These results were subsequently published in the Journal of Thoracic Oncology in 2019, with the publication also including OS data that showed a comparable median OS for the full cohort and the subgroup aged 70 years or older, at 9.1 and 10.3 months, respectively. In line with the CheckMate 171 findings, median OS was poorer for patients with an ECOG PS of 2, at 4.0 months.
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: Completed
Phase 1/2 | |
Patient population: Locally advanced or stage IV NSCLC | Comparator: Standard of care, best supportive care, investigator’s choice of chemotherapy |
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: Completed
Phase 2 | |
Patient population: Treatment-naïve stage IV NSCLC | Comparator: None |
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 in 2019.
Pooled data from three first-line studies of nivolumab plus ipilimumab – parts 1 of CheckMate 227 and 568 and cohort A of CheckMate 817 – at a minimum follow-up of 31 months further supported the tolerability of the combination, in all treated patients as well as those aged at least 75 years. The analysis was published in the Journal of Thoracic Oncology in 2022.
The researchers additionally included two cohorts from CheckMate 012 and showed favorable OS with the combination at the 3-year mark. See the CheckMate 012 section for the details.
CheckMate 227: Ongoing
Phase 3 | |
Patient population: Chemotherapy-naïve stage IV or recurrent NSCLC | Comparator: Platinum-based doublet chemotherapy |
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 other primary endpoint of the trial was OS in patients positive for PD-L1 (expression levels ≥1%), and this was significantly prolonged with dual checkpoint blockade relative to chemotherapy, at respective medians of 17.1 and 14.9 months. The findings were similar in patients with PD-L1 expression levels below 1%. These results appeared in The New England Journal of Medicine in 2019.
The combination of nivolumab plus ipilimumab was further supported by the patient-reported outcome (PRO) data in the high TMB and PD-L1-positive populations, which were reported in the European Journal of Cancer in 2019 and the Journal of Thoracic Oncology in 2021, respectively, and showed delayed deterioration and improvements in HRQoL and symptoms relative to chemotherapy.
Nivolumab plus ipilimumab also showed durable efficacy, with OS benefits seen relative to chemotherapy in the PD-L1-positive and negative populations after 4 years (hazard ratios [HRs]=0.76 and 0.64, respectively) and 5 years (HRs=0.77 and 0.65), as reported in the Journal of Thoracic Oncology in 2021 and the Journal of Clinical Oncology in 2022, respectively.
Data from the Asian subgroup, published in ESMO Open in 2022, demonstrated a consistent benefit of the dual immunotherapy regimen at the 3-year mark regardless of PD-L1 expression levels.
Pooled analyses of results from part 1 of this trial along with those from CheckMate 568 part 1, 817 cohort A, and 012 demonstrated the long-term efficacy and tolerability of nivolumab plus ipilimumab. Details in the CheckMate 568 and 012 sections.
The study authors reported 5-year results from part 1 of CheckMate 227 in 2023, showing durable clinical benefit of first-line nivolumab plus ipilimumab in Japanese patients, independent of tumor PD-L1 expression (International Journal of Clinical Oncology), and those with brain metastases at intake (Journal of Thoracic Oncology).
CheckMate 078: Ongoing
Phase 3 | |
Patient population: Chemotherapy-treated stage IIIB/IV or recurrent NSCLC | Comparator: Docetaxel |
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. These results were subsequently published in the Journal of Thoracic Oncology in 2019.
Longer-term follow-up from the trial continued to show the superiority of nivolumab over docetaxel at 2 and 3 years, with median OS times of 11.9 versus 9.5 months at both timepoints, as reported in Lung Cancer in 2020 and 2021, respectively.
CheckMate 907: Completed
Phase 2 | |
Patient population: Previously treated advanced or metastatic NSCLC | Comparator: None |
This study investigated the safety profile of a flat dose of nivolumab, 480 mg every 4 weeks, in patients who had received at least one prior line of therapy. As reported at the 2021 World Conference on Lung Cancer, there was one case each of grade 3–4 treatment-related skin and gastrointestinal toxicity and no grade 5 events. The researchers commented that the safety profile was comparable to that of weight-based dosing used in the registrational trials.
CheckMate 870: Completed
Phase 3 | |
Patient population: Previously treated stage IIIB/IV NSCLC | Comparator: None |
In this study, conducted in Asian (mainly Chinese) patients, treatment with a flat dose of nivolumab – 240 mg every 2 weeks – was well tolerated, with a low incidence of grade 3–4 treatment-related adverse events (TRAEs) and no grade 5 TRAEs. Reporting the findings in Therapeutic Advances in Medical Oncology in 2022, the investigators said that the dosing regimen was also efficacious, with median PFS and OS times of 3.6 and 14.7 months, respectively.
CheckMate 384: Completed
Phase 3b/4 | |
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 |
An interim analysis of CheckMate 384 – presented at the 2019 ASCO-SITC Clinical Immuno-Oncology Symposium – indicated the comparable efficacy and tolerability of the 480 mg every 4 weeks and the 240 mg every 2 weeks regimens of nivolumab, supporting the former “as a more convenient dosing option” in this setting.
CheckMate 592: Ongoing
Phase 2 | |
Patient population: Treatment-naïve stage IV or recurrent NSCLC | Comparator: None |
Results from this biomarker trial were presented at the 2022 ESMO Immuno-Oncology Congress and demonstrated that responses to first-line nivolumab plus ipilimumab were better among patients with a tissue TMB of at least 10 mutations/Mb (ORR, 51.0 vs 21.8%) or a blood TMB of at least 21 mutations/Mb (47.4 vs 24.5%) relative to those with lower levels.
CheckMate 9LA: Ongoing
Phase 3 | |
Patient population: Treatment-naïve stage IV or recurrent NSCLC | Comparator: Chemotherapy |
The study met its primary endpoint of a significant improvement in OS with the addition of two cycles of chemotherapy to nivolumab 360 mg every 3 weeks plus ipilimumab 1 mg/kg every 6 weeks versus four cycles of chemotherapy, at a median of 15.6 versus 10.9 months after a median follow-up of 13.2 months. These data were published in The Lancet Oncology in January 2021.
The 2-year update, which was conducted at a median follow-up of 30.7 months and reported in ESMO Open in October 2021, indicated the continued benefit of the dual immunotherapy plus chemotherapy combination. The median OS times in the experimental and control groups were similar to those in the initial analysis, at 15.8 and 11.0 months, respectively, and the corresponding 2-year OS rates were 38% and 25%.
PROs at a minimum follow-up of a year, presented at the ESMO Virtual Congress 2020, also supported nivolumab, ipilimumab plus chemotherapy as a first-line option in this setting, with continued benefit observed after a minimum follow-up of 2 years (European Journal of Cancer, 2023).
An analysis focused on the subgroup enrolled in Japan and China pointed to a consistent OS benefit of the chemoimmunotherapy regimen in Asian patients (published in the International Journal of Clinical Oncology in 2022). Another subgroup analysis – conducted at a minimum follow-up of 3 years and published in 2022 in the Journal of Thoracic Oncology – showed an OS advantage for participants with baseline brain metastases and those with select somatic mutations.
The 2023 ASCO Annual Meeting saw the presentation of 4-year data from the trial, which continued to show the durable efficacy of adding nivolumab plus ipilimumab to chemotherapy irrespective of tumor PD-L1 expression or histology.
CheckMate 816: Ongoing
Phase 3 | |
Patient population: Resectable stage IB–IIIA NSCLC | Comparator: Platinum-based doublet chemotherapy |
In this neoadjuvant trial, the co-primary endpoint of event-free survival (EFS) and pathologic complete response were significantly improved by supplementing platinum-based chemotherapy with nivolumab at a dose of 360 mg every 3 weeks relative to chemotherapy alone, at medians of 31.6 versus 20.8 months and rates of 24.0% versus 2.2%, respectively. The surgical outcomes also provided support for the use of nivolumab as its addition did not lead to surgical delays or complications. These findings appeared in The New England Journal of Medicine in 2022.
The EFS advantage offered by adding nivolumab to neoadjuvant chemotherapy was maintained in the 3-year follow-up presented at the European Lung Cancer Congress 2023, with a 3-year rate of 57% versus 43% with chemotherapy alone.
CheckMate 722: Completed
Phase 3 | |
Patient population: EGFR mutation-positive stage IV or recurrent NSCLC that has progressed on EGFR–TKI therapy | Comparator: Platinum-based doublet chemotherapy |
As reported at the ESMO Asia Congress 2022, this trial did not meet its primary endpoint – PFS was not significantly improved for previously treated patients with EGFR-mutated NSCLC who received nivolumab plus chemotherapy versus chemotherapy alone. The researchers noted, however, that there were trends toward benefits in certain subgroups, such as those who had received just one prior line of EGFR–TKI therapy.
CheckMate 817: Completed
Phase 3b/4 | |
Patient population: Treatment-naïve stage IV or recurrent NSCLC | Comparator: None |
As reported in the Journal for ImmunoTherapy of Cancer in 2023, treatment with flat-dose nivolumab (240 mg every 2 weeks) plus weight-based ipilimumab (1 mg/kg every 6 weeks) had manageable safety and antitumor activity in the cohort of patients with an ECOG PS of 0–1 (cohort A) as well as in the cohort with an ECOG PS of 2 or 0–1 plus untreated brain metastases, renal impairment, hepatic impairment, or controlled HIV infection (cohort A1).
Data from cohort A of this trial were pooled with those from CheckMate 227 part 1, 568 part 1, and 012, and demonstrated the long-term efficacy and tolerability of nivolumab plus ipilimumab. Details in the CheckMate 568 and 012 sections.
CheckMate 169: Discontinued
Phase – n/a | |
Patient population: Previously treated stage IIIb/IV squamous or nonsquamous NSCLC | Comparator: None |
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 1b/2 | |
Patient population: Chemotherapy-naïve stage IV or recurrent NSCLC | Comparator: None |
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 1/2 | |
Patient population: Advanced or metastatic solid tumors | Comparator: None |
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 extensive-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 a high TMB (≥248 mutations) versus a low (0 to <143 mutations) or medium (143–247 mutations) TMB.
In October 2019, the trial investigators reported in the Journal of Thoracic Oncology that the ORR was significantly higher for previously treated SCLC patients who received nivolumab plus ipilimumab than nivolumab alone (21.9 vs 11.6%), but median OS times were comparable (28.4 vs 29.0 months).
CheckMate 331: Completed
Phase 3 | |
Patient population: Relapsed SCLC after first-line platinum-based chemotherapy | Comparator: Topotecan or amrubicin chemotherapy |
As reported at the ESMO Immuno-Oncology Congress in December 2018, with subsequent publication in the Annals of Oncology in 2021, 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: Completed
Phase 3 | |
Patient population: Extensive-stage disease SCLC that has been treated with first-line chemotherapy | Comparator: Placebo |
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 up to four cycles of first-line chemotherapy. These results were subsequently published in the Journal of Clinical Oncology in 2021.
The trial is also investigating maintenance with single-agent nivolumab; these results have not yet been reported.
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