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Abstract
Background CheckMate 817, a phase 3B study, evaluated flat-dose nivolumab plus weight-based ipilimumab in patients with metastatic non-small cell lung cancer (NSCLC). Here, in this research, we report on first-line treatment in patients with Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0–1 (cohort A) and special populations (cohort A1: ECOG PS 2; or ECOG PS 0–1 with untreated brain metastases, renal impairment, hepatic impairment, or controlled HIV infection).
Methods Cohorts A and A1 received nivolumab 240 mg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks. The primary endpoint was the incidence of grade 3–4 and grade 5 immune-mediated adverse events (IMAEs; adverse events (AEs) deemed potentially immune-related, occurring <100 days of last dose, and treated with immune-modulating medication (except endocrine events)) and treatment-related select AEs (treatment-related AEs with potential immunological etiology requiring frequent monitoring/intervention, reported between first dose and 30 days after the last dose) in cohort A; efficacy endpoints were secondary/exploratory. In cohort A1, safety/efficacy assessment was exploratory.
Results The most common grade 3–4 IMAEs were pneumonitis (5.1%), diarrhea/colitis (4.9%), and hepatitis (4.6%) in cohort A (N=391) and diarrhea/colitis (3.5%), hepatitis (3.5%), and rash (3.0%) in cohort A1 (N=198). The most common grade 3–4 treatment-related select AEs were hepatic (5.9%), gastrointestinal (4.9%), and pulmonary (4.6%) events in cohort A and gastrointestinal (4.0%), skin (3.5%), and endocrine (3.0%) events in cohort A1. No grade 5 IMAEs or treatment-related select AEs occurred. Treatment-related deaths occurred in 4 (1.0%) and 3 (1.5%) patients in cohorts A and A1, respectively. Three-year overall survival (OS) rates were 33.7% and 20.5%, respectively.
Conclusions Flat-dose nivolumab plus weight-based ipilimumab was associated with manageable safety and durable efficacy in cohort A, consistent with data from phase 3 metastatic NSCLC studies. Special populations of cohort A1 including patients with ECOG PS 2 or ECOG PS 0–1 with untreated brain metastases had manageable treatment-related toxicity and clinically meaningful 3-year OS rate.
Trial registration number NCT02869789.
- Immunotherapy
- Clinical Trials, Phase III as Topic
- Programmed Cell Death 1 Receptor
- CTLA-4 Antigen
- Lung Neoplasms
Data availability statement
Data are available upon reasonable request. Bristol Myers Squibb policy on data sharing may be found at https://www.bms.com/researchers-and-partners/independent-research/data-sharing-request-process.html.
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- Immunotherapy
- Clinical Trials, Phase III as Topic
- Programmed Cell Death 1 Receptor
- CTLA-4 Antigen
- Lung Neoplasms
WHAT IS ALREADY KNOWN ON THIS TOPIC
Immunotherapy regimens, including programmed death-1/programmed death ligand 1 regimens alone or in combination with other immune checkpoint inhibitors and/or chemotherapy, have improved survival outcomes for patients with metastatic non-small cell lung cancer (NSCLC). Combination nivolumab and ipilimumab treatment has shown promising benefit in patients with metastatic NSCLC, but there are limited prospective studies that evaluate the safety and efficacy of this combination in patients with poorer prognosis, including those with Eastern Cooperative Oncology Group performance status (ECOG PS) ≥2, or those with ECOG PS 0–1 plus untreated brain metastases, organ dysfunction, or positive HIV status.
WHAT THIS STUDY ADDS
The CheckMate 817 trial is the first to show that first-line combination flat-dose nivolumab plus weight-based ipilimumab has a tolerable safety profile and durable efficacy in patients with metastatic NSCLC. Additionally, CheckMate 817 is the first prospective study to evaluate patients with metastatic NSCLC and patient subgroups that are typically excluded from phase 3 randomized controlled trials: those with ECOG PS 2, or ECOG PS 0–1 plus untreated brain metastases, renal or hepatic impairment, or positive HIV status.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
These results support the use of combination nivolumab and ipilimumab as a first-line treatment for patients with metastatic NSCLC, including patients who were ECOG PS 2, or ECOG PS 0–1 and had untreated brain metastases, renal or hepatic impairment, or positive HIV status.
Introduction
First-line immunotherapy targeting programmed death-1 (PD-1) or its ligand (PD-L1) alone or in combination with other treatment modalities has improved overall survival (OS) for patients with metastatic non-small cell lung cancer (NSCLC) having no epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor aberrations.1 Nivolumab (a PD-1 inhibitor) and ipilimumab (a cytotoxic T-lymphocyte antigen-4 inhibitor) are immune checkpoint inhibitors with distinct, but complementary mechanisms of action.2 3 Nivolumab restores antitumor T-cell function while ipilimumab induces de novo antitumor T-cell responses, including an increase in memory T cells.4–7 In the randomized, open-label, phase 3 CheckMate 227 study, first-line, weight-based nivolumab plus ipilimumab provided durable OS benefit versus chemotherapy in patients with metastatic NSCLC and tumor PD-L1 expression ≥1% or <1%, regardless of histology.8 Four-year OS rates with nivolumab plus ipilimumab were 29% and 24% in patients with tumor PD-L1 expression ≥1% and <1%, respectively.8 Nivolumab plus ipilimumab has been approved in the USA and other countries for the first-line treatment of adults with metastatic NSCLC expressing PD-L1 ≥1% and no sensitizing targetable EGFR or ALK aberrations, and is recommended by the National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology (NCCN Guidelines®) and European Society for Medical Oncology Guidelines as first-line treatment regardless of PD-L1 expression or histology.2 3 9–12
Nivolumab plus ipilimumab combination therapy underwent additional dose optimization for NSCLC indications in order to improve the safety profile seen particularly with the ipilimumab 3 mg/kg every 3-week (Q3W) dose that was developed to treat malignant melanoma.13 CheckMate 012 was a phase 1 trial with multiple treatment arms designed to identify an optimal dose and schedule of nivolumab plus ipilimumab for metastatic NSCLC. In CheckMate 012, nivolumab 1 mg/kg Q3W plus ipilimumab 3 mg/kg Q3W and nivolumab 3 mg/kg Q3W plus ipilimumab 1 mg/kg Q3W dosing regimens had poor tolerability, while nivolumab 3 mg/kg every 2 weeks (Q2W) plus ipilimumab 1 mg/kg every 6 weeks (Q6W) was tolerable with promising clinical benefit.14 Therefore, to assess the clinical safety of flat-dose nivolumab in combination with ipilimumab, nivolumab (240 mg Q2W) plus ipilimumab (1 mg/kg Q6W) was evaluated in CheckMate 817. A fixed-dosing regimen increases convenience to patients while minimizing dosing errors and dosage preparation time and reducing overall healthcare burden.15 Another key unmet need is to improve clinical outcomes in patients with metastatic NSCLC and poorer prognosis, such as those with Eastern Cooperative Oncology Group performance status (ECOG PS) ≥2, or those with ECOG PS 0–1 and either untreated brain metastases, organ dysfunction, or positive HIV status, who are often excluded from prospective clinical trials.16 17 Data on safety and efficacy of immunotherapy in these patient populations are limited, and effective therapeutic options for these patients are a high unmet need. Reported herein are safety and efficacy findings with flat-dose nivolumab plus weight-based ipilimumab in patients with metastatic NSCLC in cohorts A (ECOG PS 0–1) and A1 (ECOG PS 2; or ECOG PS 0–1 with untreated brain metastases, renal or hepatic impairment, or positive HIV status) of CheckMate 817.
Methods
Patients
Detailed eligibility criteria are summarized in online supplemental table S1. Briefly, eligible patients in cohorts A and A1 had histologically confirmed stage IV or recurrent NSCLC (per the seventh edition of the International Association for the Study of Lung Cancer Classification) with no prior systemic therapy for advanced or metastatic disease. Following a protocol amendment in November 2016, patients with EGFR mutations or ALK translocations sensitive to available therapy were excluded. In cohort A, eligible patients had ECOG PS 0–1, adequate renal and hepatic function, negative HIV status, and no active or untreated brain metastases. In cohort A1, eligible patients either had ECOG PS 2 or ECOG PS 0–1 with one of the following: untreated asymptomatic brain metastases, renal impairment (creatinine clearance: 20–39 mL/min), hepatic impairment (aspartate aminotransferase/alanine aminotransferase: 3.0–5.0×upper limit of normal and/or total bilirubin 1.5–3.0×upper limit of normal), or controlled HIV infection.
Supplemental material
Study design and treatment
CheckMate 817 is a phase 3B, multicenter, open-label, single-arm, multicohort, safety study conducted at 135 study sites across North America, Europe, and South America. Patients in cohorts A and A1 received nivolumab (240 mg Q2W) plus ipilimumab (1 mg/kg Q6W) intravenously until disease progression, unacceptable toxicity, withdrawal of consent, or for up to 2 years (online supplemental figure S1). Dose delay criteria are summarized in online supplemental table S2.
Cumulative time to onset of immune-mediated adverse events (IMAEs) (A), cumulative time to resolution of IMAEs (B), and IMAEs over time (C) in cohort A.
Endpoints and assessments
The primary endpoint was the proportion of patients with grade 3–4 and grade 5 immune-mediated adverse events (IMAEs) and treatment-related select adverse events (AEs) in cohort A. Secondary endpoints included efficacy in cohort A: OS, and Response Evaluation Criteria in Solid Tumors V.1.1-defined investigator-assessed progression-free survival (PFS), objective response rate (ORR), and duration of response (DOR); efficacy by tumor PD-L1 expression (≥1% and <1%) was exploratory. In cohort A1, efficacy and safety assessments were exploratory.
IMAEs were AEs deemed potentially immune-related by the investigator (regardless of causality), occurring within 100 days of the last dose, and treated with immune-modulating medication, except for endocrine events, which were included in the analysis regardless of method of treatment. Treatment-related select AEs were treatment-related AEs (TRAEs) with a potential immunological etiology requiring frequent monitoring/intervention, and included events reported between first dose and 30 days after last dose of study drug. Grade 3–4 and grade 5 IMAEs and treatment-related select AEs were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, V.4.0. Events leading to death ≤24 hours from onset were documented as grade 5. Events leading to death >24 hours after onset were reported with the worst grade before death. Additional details are included in online supplemental methods.
Statistical analysis
Based on previous reports on the incidence of grade 3–4 treatment-related select AEs (≤5% per category) with weight-based dosing of nivolumab (3 mg/kg Q2W) plus ipilimumab (1 mg/kg Q6W),14 a sample size of approximately 400 patients in cohort A was estimated to allow detection of safety events with incidence rates of 1% and 0.5% with >98% and >86% probability, respectively. In cohort A1, a sample size of 30 patients for each special population subgroup was estimated to allow detection of safety events with an incidence rate of 5% with a probability of approximately 79%.
Safety and efficacy were analyzed in all patients who received ≥1 dose of study drug. OS, PFS, and DOR were summarized by Kaplan-Meier methodology and reported as medians with two-sided 95% CIs, per the Brookmeyer and Crowley method. Survival rates were estimated using the Kaplan-Meier method and expressed with two-sided 95% CIs per the Greenwood formula. Confirmed ORRs were summarized by binomial response rates with corresponding two-sided 95% exact CIs, per the Clopper-Pearson method. Statistical analyses were conducted using SAS software V.9.4 (SAS Institute).
Results
Patients and treatment
Starting November 2016, 391 (cohort A) and 198 (cohort A1) patients received ≥1 dose of treatment (online supplemental figure S2). Cohort A1 included 139 patients with baseline ECOG PS 2, and 68 patients with ECOG PS 0–1 plus one of the following: untreated brain metastases (n=49), renal impairment (n=9), hepatic impairment (n=7), or positive HIV status (n=4). One patient had both untreated brain metastases and positive HIV status; 9 patients with untreated brain metastases or comorbidities in cohort A1 also had ECOG PS 2. Of these 10 patients, 5 were enrolled when study eligibility criteria allowed inclusion of patients with ≥1 special population criteria; 5 patients had protocol deviations. Patients belonging to multiple subgroups were included in each of the subgroups for all analyses. At database lock (February 19, 2021), all patients in both cohorts had discontinued or completed treatment; treatment discontinuation was mainly due to disease progression or study drug toxicity (online supplemental table S3). Median (range) duration of treatment was 4.0 (<0.1–25.8) months in cohort A and 2.8 (<0.1–25.4) months in cohort A1 (online supplemental table S4). Subsequent systemic therapy was received by 139 (35.5%) and 53 (26.8%) patients in cohorts A and A1, subsequent chemotherapy by 120 (30.7%) and 43 (21.7%), and subsequent immunotherapy by 32 (8.2%) and 14 (7.1%) patients, respectively, (online supplemental table S5). The minimum and median follow-up in cohorts A and A1 were 40.9/43.9 months and 33.9/38.1 months, respectively.
Overall survival (OS) and progression-free survival (PFS) in cohort A. (A) OS and (B) PFS, overall and by tumor programmed death ligand 1 (PD-L1) expression, and (C) OS by tumor histology.
In cohort A, most patients had stage IV disease (88.0%) and non-squamous histology (71.9%); 55.5% had ECOG PS 1, and 49.3% had tumor PD-L1 expression ≥1% (table 1). Of eight patients (2.0%) with EGFR-positive mutation status, three had sensitizing mutations (two patients were enrolled before protocol amendment exclusion; one was protocol deviation). In cohort A1, 93.4% of the patients had stage IV disease and 70.2% had non-squamous histology, and 44.4% had tumor PD-L1 expression ≥1%; neither of the two patients with EGFR-positive mutation status had a sensitizing mutation. In cohort A1 subgroups, baseline characteristics, excluding protocol-defined differences, were largely similar to those in cohort A1 overall (table 1).
Patient demographics and baseline characteristics
Cohort A
Safety
In patients with ECOG PS 0–1, any-grade TRAEs were reported in 301 (77.0%), grade 3–4 TRAEs in 138 (35.3%), and any-grade TRAEs leading to treatment discontinuation of at least one study drug in 93 (23.8%) patients (table 2). Four treatment-related deaths (1.0%) occurred (cardiac failure secondary to immune-mediated rhabdomyolysis of heart and other muscles (n=1), autoimmune esophagitis (n=1), autoimmune hepatitis (n=1), and Guillain–Barré syndrome (n=1)). The most common grade 3–4 IMAEs were pneumonitis (5.1%), diarrhea/colitis (4.9%), and hepatitis (4.6%) (table 2). The most common grade 3–4 treatment-related select AEs were hepatic (5.9%), gastrointestinal (4.9%), and pulmonary (4.6%) events. No grade 5 IMAEs or treatment-related select AEs were reported. Times to onset and resolution of IMAEs are shown in figure 1. Systemic corticosteroids were primarily used for the management of IMAEs, with treatment lasting <1 week to 1.5 months (online supplemental table S6). Most patients did not require any other immune-modulating medications for IMAE management.
Safety summary for patients treated with nivolumab plus ipilimumab in cohort A
Efficacy
In cohort A, median (95% CI) OS was 16.8 months (14.6 to 22.4), with a 3-year OS rate (95% CI) of 33.7% (29.0% to 38.5%) (figure 2A); median (95% CI) PFS was 5.8 months (4.5 to 7.6) with a 3-year PFS rate (95% CI) of 20.1% (15.9% to 24.7%) (figure 2B). ORR (95% CI) was 37.3% (32.5% to 42.3%) and median (95% CI) DOR was 27.6 months (20.4 to 34.3); 41% (32% to 50%) of responders had an ongoing response at 3 years (online supplemental table S7).
In patients with tumor PD-L1 expression ≥1% and <1%, respectively, median (95% CI) OS was 21.0 months (14.2 to 30.8) and 15.3 months (12.5 to 19.2) (figure 2A); median (95% CI) PFS was 7.1 months (4.2 to 9.3) and 5.3 months (4.1 to 6.3) (figure 2B). ORR (95% CI) was 43.8% (36.3% to 51.4%) and 30.9% (24.3% to 38.2%) (online supplemental table S7); median (95% CI) DOR was 29.9 months (15.2 to 39.8) and 25.8 months (16.8 to 34.3); and 45% (32% to 56%) and 35% (22% to 49%) of responders had an ongoing response at 3 years. Data trends were generally similar in patients with tumor PD-L1 ≥50% with median (95% CI) OS of 21.4 months (11.8 to 41.1) and median (95% CI) PFS was 8.4 months (5.4 to 14.8); however the sample size for patients with tumor PD-L1 ≥50% was small (online supplemental table S7).
In patients with non-squamous and squamous histology, respectively, median (95% CI) OS was 20.1 months (15.4 to 27.3) and 13.7 months (9.4 to 21.4) (figure 2C); median (95% CI) PFS was 5.8 months (4.2 to 8.3) and 5.5 months (4.1 to 8.2). ORR (95% CI) was 38.1% (32.4% to 44.0%) and 35.5% (26.6% to 45.1%); and median (95% CI) DOR was 27.6 months (18.9 to 39.8) and 29.9 months (13.7 to 37.2).
Cohort A1 (special populations)
Safety
In cohort A1, any-grade TRAEs were reported in 135 (68.2%), grade 3–4 TRAEs in 58 (29.3%), and TRAEs leading to treatment discontinuation of at least one study drug in 32 (16.2%) patients (table 3). Three treatment-related deaths (1.5%) were reported, all in patients with ECOG PS 2 (myasthenic syndrome secondary to immunotherapy (n=1), interstitial diffuse pneumonitis (n=1), and polymyositis (n=1)). The most common grade 3–4 IMAEs were diarrhea/colitis (3.5%), hepatitis (3.5%), and rash (3.0%). The most common grade 3–4 treatment-related select AEs were gastrointestinal (4.0%), skin (3.5%), and endocrine (3.0%) events. No grade 5 IMAEs or treatment-related select AEs were reported. Times to onset and resolution of IMAEs are reported in figure 3. Use of systemic corticosteroids for IMAE management was overall similar to that reported in cohort A (online supplemental table S6).
Safety summary for patients treated with nivolumab plus ipilimumab in cohort A1
Cumulative time to onset of immune-mediated adverse events (IMAEs) (A), cumulative time to resolution of IMAEs (B), and IMAEs over time (C) in cohort A1.
Among patients with ECOG PS 2, any-grade and grade 3–4 TRAEs were reported in 89 (64.0%) and 38 (27.3%) patients, respectively; 20 (14.4%) patients discontinued treatment due to TRAEs (table 3). The most common grade 3–4 IMAEs were rash (3.6%), hepatitis (3.6%), diarrhea/colitis (2.2%) and pneumonitis (2.2%). The most common grade 3–4 treatment-related select AEs were skin (4.3%), endocrine (3.6%), hepatic (2.9%), and gastrointestinal (2.9%) events (table 3).
Safety profile for patients with ECOG PS 0–1 and untreated brain metastases, organ impairment, or positive HIV status is reported in table 3. Among patients with untreated brain metastases, any-grade or grade 3–4 TRAEs were reported in 38 (77.6%) and 18 (36.7%) patients, respectively; 11 (22.4%) discontinued treatment due to TRAEs. The most common grade 3–4 IMAEs were diarrhea/colitis (6.1%), hepatitis (4.1%), and pneumonitis (4.1%); the most common grade 3–4 treatment-related select AEs were gastrointestinal (6.1%) and pulmonary (4.1%) events (table 3). Of nine patients with baseline renal impairment, two had grade 2 increased blood creatinine during the study; one was treatment-related and led to treatment discontinuation, while the other was not treatment-related. Among seven patients with baseline hepatic impairment, one experienced grade 3 treatment-related hepatotoxicity, which led to treatment discontinuation. Another patient with bilirubin elevated at baseline and a history of toxic liver cirrhosis experienced grade 3 increased bilirubin and grade 5 aggravated biliary cirrhosis, both of which were deemed unrelated to study treatment by the investigator. All four patients with HIV-positive status remained on concomitant antiretroviral medications throughout the study.
Efficacy
In cohort A1, median (95% CI) OS was 9.9 months (7.0 to 13.7) with a 3-year OS rate (95% CI) of 20.5% (15.0% to 26.6%) (figure 4A); median (95% CI) PFS was 3.9 months (2.8 to 5.4) with a 3-year PFS rate (95% CI) of 9.4% (5.2% to 15.3%) (figure 4B). Specifically, in patients with ECOG PS 2, median (95% CI) OS was 9.0 months (5.5 to 12.9) with a 3-year OS rate (95% CI) of 18.7% (12.4% to 26.0%) (figure 4C); median (95% CI) PFS was 3.6 months (2.8 to 5.4) and the 3-year PFS rate (95% CI) was 6.3% (1.9% to 14.4%) (figure 4D). ORR (95% CI) was 20.9% (14.4% to 28.6%) and median (95% CI) DOR was 15.5 months (9.8 to 29.3); 28% (12% to 47%) of responders had an ongoing response at 30 months (table 4). In patients with untreated brain metastases, median (95% CI) OS was 12.8 months (7.7 to 25.9) with a 3-year OS rate (95% CI) of 21.0% (10.9% to 33.4%) (figure 4C). Median (95% CI) PFS was 2.8 months (1.7 to 8.0); the 3-year PFS rate (95% CI) was 14.2% (5.4% to 27.1%) (figure 4D). ORR (95% CI) was 32.7% (19.9% to 47.5%) and median (95% CI) DOR was 12.6 months (6.7 to not reached); 39% (15% to 64%) of responders had an ongoing response at 3 years (table 4). For the nine patients with renal impairment, OS ranged from 1.4 to 45.3+ months; five patients experienced a partial response. For the seven patients with hepatic impairment, OS ranged from 0.4 to 35.5+ months; one patient experienced a partial response. OS in the four patients with HIV-positive status ranged from 7.0 to 41.4+months; two patients experienced a partial response.
Overall survival (OS) and progression-free survival (PFS) in cohort A1. (A) OS and (B) PFS, overall and by tumor programmed death ligand 1 (PD-L1) expression, (C) OS and (D) PFS, overall and in patients with Eastern Cooperative Oncology Group performance status (ECOG PS) 2 and untreated brain metastases. *Asymptomatic, untreated.
Tumor response in cohort A1
Median (95% CI) OS by tumor PD-L1 expression levels were 6.9 months (3.6 to 12.8), 10.5 (7.0 to 15.6), and 13.3 (7.9 to 30.1) for tumor PD-L1 ≥1%, tumor PD-L1 <1%, and tumor PD-L1 ≥50%, respectively, (figure 4A for tumor PD-L1 ≥1% and <1%). Median (95% CI) for PFS were 3.3 months (2.8 to 6.0), 3.9 (2.6 to 6.2), and 9.6 (2.8 to 16.4) for tumor PD-L1 ≥1%, tumor PD-L1 <1%, and tumor PD-L1 ≥50%, respectively, (figure 4B for tumor PD-L1 ≥1% and <1%). ORR was similar in patients with tumor PD-L1 ≥1% and those with tumor PD-L1 <1% (27.6% and 24.2%, respectively; table 4). In patients with tumor PD-L1 ≥50%, responses were generally similar except for ORR (40.6%; online supplemental table S8).
Discussion
Concerns regarding excess treatment-related immune toxicity have influenced the use of combination nivolumab plus ipilimumab for metastatic NSCLC in clinical practice; therefore, clinical trials optimizing dosing and schedule are important. In CheckMate 817, the safety and efficacy of flat-dose nivolumab plus weight-based ipilimumab in cohort A (patients with metastatic NSCLC and ECOG PS 0–1) was consistent with that reported for weight-based nivolumab plus weight-based ipilimumab.14 18 19
Clinical trials usually exclude patients from special populations, including patients with ECOG PS 0–1 and untreated brain metastases, organ dysfunction, or chronic viral infections; there is a paucity of prospective clinical trial data to guide clinicians in treating patients with metastatic NSCLC from special populations. We report some of the first prospective safety and efficacy data for patients from special populations receiving any type of combination immunotherapy. Of particular interest, fixed-dose nivolumab plus weight-based ipilimumab had a tolerable safety profile and clinically meaningful 3-year OS in special populations of patients with metastatic NSCLC, including in patients with ECOG PS 2, untreated asymptomatic brain metastases, renal impairment, hepatic impairment, or controlled HIV infection.
Since the approval of nivolumab plus ipilimumab for advanced melanoma, optimization of dose and administration schedule of these agents for the treatment of various cancers has enabled clinicians to appropriately manage TRAEs. In metastatic NSCLC, nivolumab 3 mg/kg Q2W plus ipilimumab 1 mg/kg Q6W demonstrated a more favorable safety profile with similar efficacy benefits compared with regimens incorporating higher dosing of ipilimumab.14 18 19 In the present study, no new safety signals were identified. IMAEs and treatment-related select AEs were primarily grade 1–2 with no grade 5 events reported. IMAEs occurred early after treatment initiation and resolved quickly with management based on guidelines that have been developed using data from various clinical studies.20
Immunotherapy-based regimens have shown long-term clinical benefit across numerous studies and have become the standard of care for the first-line treatment of patients with metastatic NSCLC without targetable mutations, with treatment choice influenced by tumor PD-L1 expression.10 11 Anti-PD-(L)1 monotherapy has demonstrated OS benefit versus standard chemotherapy in patients with tumor PD-L1 expression ≥50%,21–23 whereas immunotherapy plus chemotherapy or dual immunotherapy with nivolumab plus ipilimumab18 24–29 have shown benefit regardless of tumor PD-L1 expression or histology. Although efficacy endpoints were secondary in cohort A of CheckMate 817, nivolumab plus ipilimumab resulted in long-term OS benefit (with one-third of the patients alive at 3 years) and durable responses (with over 40% of the responders maintaining response at 3 years) across tumor PD-L1 expression and histology subgroups, consistent with the results of the CheckMate 227 study at similar follow-up times.8 It is worth noting that in patients with high unmet needs, that is, those with tumor PD-L1 expression <1% or with squamous histology, 3-year OS rates remained above 20%, as seen with this regimen in the CheckMate 227 study. Furthermore, in CheckMate 227, response with nivolumab plus ipilimumab at 6 months was associated with long-term OS benefit: 70% and 82% of the patients with ≥1% and <1% tumor PD-L1 expression who were in response at 6 months were alive at 3 years, supporting the durability of efficacy benefit with this immunotherapy combination regimen.30
CheckMate 817 is the first prospective study to evaluate the clinical profile of dual immunotherapy in patient populations that have poor prognosis31 and are often excluded from clinical trials.17 Safety in the overall cohort A1, as well as in the ECOG PS 2 and untreated brain metastases subgroups, was comparable with that in cohort A. Most patients with renal and hepatic impairment did not experience worsening of renal and hepatic functions, respectively. All four patients with HIV-positive status could continue treatment with antiretroviral medications throughout the study. Although efficacy was lower in cohort A1 than in cohort A, likely due to the prognostic impact of ECOG PS 2 and brain metastases, encouraging clinical activity was observed regardless of tumor PD-L1 expression in cohort A1 overall as well as in subgroups. Limited data sets in patients with ECOG PS 2 have shown median OS ranging from 3.0 to 9.8 months with single-agent PD-1 inhibitor therapy in the first-line or later-line settings.32–38 Despite 56% of the patients with ECOG PS 2 having tumor PD-L1 expression <1% in this study, these patients, who received dual immunotherapy with a minimum follow-up of 3 years, had a median OS of 9.0 months, 6% PFS rate, median DOR of 15.5 months (9.8–29.3), and approximately 20% of the patients had a clinically meaningful 3-year OS rate. Taken together, these findings for the first time prospectively demonstrate promising efficacy in these patient populations of high unmet need.
Immunotherapy has shown promise in the treatment of NSCLC among patients with brain metastases; however, most of the data relate to patients with treated brain metastases or are based on non-prospective analyses.39–45 Median OS with anti-PD-(L)1 agents as monotherapy, dual immunotherapy, or dual immunotherapy plus chemotherapy in this patient population ranges from 8.6 to 19.9 months.39–43 45 Exploratory analyses in patients with metastatic NSCLC and previously treated brain metastases from the phase 3 CheckMate 227 and CheckMate 9LA studies have shown durable and long-term survival benefits with the nivolumab plus ipilimumab combination with or without chemotherapy. In CheckMate 227, over one-third of the patients with treated brain metastases were alive at 3 years46; similarly in CheckMate 9LA, 35% of the patients with treated brain metastases were alive at 2 years.47 Importantly, of the responders in these studies, nearly 40% maintained their response at the indicated landmarks. In contrast, data on untreated brain metastases in NSCLC are limited. In a small phase 2 study with single-agent pembrolizumab, median OS of 9.9 months and a 2-year OS rate of 34% were reported.48 49 Although findings across studies should be interpreted with caution due to different study designs and patient populations, the long-term OS benefit and durability of responses (39% of responders maintaining response at 3 years) reported with nivolumab plus ipilimumab in patients with asymptomatic untreated brain metastases in CheckMate 817 are promising and continue to reflect the biologic effect of ipilimumab on the immune system. Encouraging clinical activity was also noted in patients with renal and hepatic impairment and HIV-positive status, although these subgroups had small patient numbers.
Although CheckMate 817 was a prospective study, conclusions were limited by its single-arm design. Additionally, intracranial benefit among patients with brain metastases could not be assessed given data collection limitations. Furthermore, the subgroups of renal impairment, hepatic impairment, and HIV-positive status had limited patient numbers and provide descriptive analysis only.
In conclusion, flat-dose nivolumab plus weight-based ipilimumab among patients with ECOG PS 0–1 was associated with manageable safety and durable efficacy, consistent with outcomes with weight-based nivolumab plus weight-based ipilimumab in metastatic NSCLC.14 18 19 Among patients with ECOG PS 2 or with ECOG PS 0–1 and untreated brain metastases, organ impairment, or positive HIV status, safety was comparable with that in patients with ECOG PS 0–1 and encouraging long-term durable clinical activity was reported. These results support the use of flat-dose nivolumab plus weight-based ipilimumab for the first-line treatment of patients with metastatic NSCLC, including those with ECOG PS 2, or with ECOG PS 0–1 and asymptomatic untreated brain metastases, renal impairment, hepatic impairment, or HIV-positive status.
Data availability statement
Data are available upon reasonable request. Bristol Myers Squibb policy on data sharing may be found at https://www.bms.com/researchers-and-partners/independent-research/data-sharing-request-process.html.
Ethics statements
Patient consent for publication
Ethics approval
Approval from an institutional review board or independent ethics committee was obtained at all 135 sites. Example: Site: Metrohealth, PI: Ila Tamaskar, IRB ID: CR00000190. Participants gave informed consent to participate in the study before taking part.
Acknowledgments
The authors thank the patients and their families, as well as the clinical study teams, for making this study possible. The authors also thank Ayman Nassar for his contributions as trial physician. This study was sponsored by Bristol Myers Squibb (Princeton, New Jersey, USA) and ONO Pharmaceutical (Osaka, Japan). The PD-L1 IHC 28-8 pharmDx assay was developed in collaboration with Dako. Professional medical writing assistance was provided by Michele Jacob, PhD and Meenakshi Subramanian, PhD of Evidence Scientific Solutions, and was funded by Bristol Myers Squibb.
References
Supplementary materials
Supplementary Data
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Footnotes
Presented at This work was partially presented at the 19th World Conference on Lung Cancer (Toronto, Canada, September 23–26, 2018), 20th World Conference on Lung Cancer (Barcelona, Spain, September 7–10, 2019), and European Society for Medical Oncology Congress 2019 (Barcelona, Spain, September 27–October 1, 2019).
Contributors Study concept and design: NER, SL, HC, JF, AA, and LP-A. Acquisition and analysis: All authors. Interpretation of the data: All authors. Statistical analysis: SL. Drafting of the manuscript/critical revision of the manuscript for important intellectual content: All authors. NER and LP-A act as the guarantors for the overall content.
Funding This work was supported by Bristol Myers Squibb (Princeton, New Jersey, USA).
Competing interests NER reports receiving consulting fees from AstraZeneca, Bristol Myers Squibb, Genentech, Jazz, Lilly, Merck, Regeneron and Roche; and other fees (honoraria) from Bristol Myers Squibb. CA-V reports interests (clinical trials, as principal investigator) with AbbVie, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, GlaxoSmithKline, Janssen, MSD, Novartis, Roche, and Sanofi; other fees (consultant/advisor) from AbbVie, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, FoundationOne, GlaxoSmithKline, Janssen, Lilly, MSD, Novartis, Pfizer, Roche, Sanofi, and Takeda; and, as speaker (conferences and invitations) for AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Lilly, Novartis, Pfizer, and Roche. JWG reports receiving grants/research support from Advaxis, AstraZeneca, Bristol Myers Squibb, Genentech and Merck; and other fees (consultant/advisor) from AstraZeneca, Bristol Myers Squibb, and Genentech. EF reports receiving grants/research support for the institution from Merck; other fees (consultant/advisor) from Amgen, AstraZeneca, Bayer, Beigene, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, F. Hoffmann-La Roche, GlaxoSmithKline, Janssen, Medical Trends, Merck Serono, Merck Sharp & Dohme, Peptomyc, Pfizer, Puma Biotechnology, Regeneron, Sanofi and Takeda for Advisory Board and Syneos Health for Data Safety and Monitoring; other fees (honoraria) from Amgen, AstraZeneca, Bristol Myers Squibb, Eli Lilly, F. Hoffmann-La Roche, Janssen, Medscape, Merck Serono, Merck Sharp & Dohme, Peervoice, Pfizer, Springer and Touch Medical; and other fees (personal) from Grifols as an independent member of the board. T-EC reports personal fees from Bristol Myers Squibb, during the conduct of the study; personal fees from Amgen, Astellas Pharma, AstraZeneca, Boehringer Ingelheim, Genzyme, Ipsen, Janssen, Lilly, Merck Serono, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Sanofi and Servier; and personal fees from Bristol Myers Squibb, outside the submitted work. MRGC reports receiving consulting fees from AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Janssen, Lilly, MSD, Novartis, Pfizer, Roche and Takeda; other fees (honoraria) from AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Janssen, Lilly, MSD, Novartis, Pfizer, Roche and Takeda; and support for attending meetings for AstraZeneca, Bristol Myers Squibb, Lilly, MSD, Pfizer and Roche. KJ reports receiving consulting fees from Amgen and Novartis; and other fees (honoraria) from AstraZeneca, Bristol Myers Squibb, Janssen, Merck, Pfizer and Takeda. FB reports personal fees from AstraZeneca, Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Eli Lilly Oncology, Hoffmann-La Roche Ltd, Novartis, Merck, MSD, Pierre Fabre, Pfizer and Takeda. SB reports no conflicts of interest. ER reports receiving other fees (honoraria) from Bristol Myers Squibb. LU reports receiving other fees (scholarship) for coursework in Molecular Oncology at the Institute of Bioscience Madrid. J-SA reports receiving grants/research support for the institution from Bristol Myers Squibb, Merck and Roche; other fees (honoraria) from AstraZeneca, Novartis, Pfizer and Sanofi; and participation on Data Safety Monitoring Board or Advisory Board for AstraZeneca, Bristol Myers Squibb, Merck, Novartis, Pfizer and Roche. CZ reports no conflicts of interest. KV reports receiving grants/research support from Bristol Myers Squibb; other fees (honoraria) from Bristol Myers Squibb; support for attending meetings for AstraZeneca, Bristol Myers Squibb and Merck; patents planned/issued/pending on behalf of Ghent University; and participation on Data Safety Monitoring Board or Advisory Board for Amgen, AstraZeneca, Bristol Myers Squibb and Merck. OAF reports receiving other fees (honoraria) from Bristol Myers Squibb of Chile. ACF reports receiving fees (honoraria) from MSD; and participation on Data Safety Monitoring Board or Advisory Board for AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Janssen-Cilag, MSD, Pfizer, Roche, and Takeda. AS-G reports no conflicts of interest. OJ-V reports receiving other fees (honoraria) from AstraZeneca, Bristol Myers Squibb, Lilly, MSD, Roche and Takeda; and participation on Data Safety Monitoring Board or Advisory Board for AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Lilly, MSD and Takeda. HL reports receiving personal fees from Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, MSD, Novartis, Pfizer and Roche. EP reports no conflicts of interest. DRS reports all support for present manuscript from Bristol Myers Squibb; receiving grants/research support from Aeglea Biotherapeutics, Agios, Apollomics, Arcus Biosciences, Arrys Therapeutics, Astellas Pharma, AstraZeneca, Bayer, BeiGene, BIND Therapeutics, BioNTech RNA Pharmaceuticals, Blueprint Medicine, Boehringer Ingelheim, Bristol Myers Squibb, Calithera Biosciences, Celgene, Celldex Therapeutics, Clovis, Cyteir Therapeutics, Daiichi Sankyo, Denovo Biopharma, Eisai, Elevation Oncology, EMD Serono, Evelo Biosciences, G1 Therapeutics, Genentech/Roche, GlaxoSmithKline, GRAIL, Hutchison MediPharma, ImClone Systems, Incyte, Ipsen, Janssen, Kronos Bio, Lilly, Loxo, MacroGenics, MedImmune, Merck, Molecular Template, Nektar, Neon, Novartis, Novocure, Oncologie, Pfizer, PTC Therapeutics, PureTech Health, Razor Genomics, Repare Therapeutics, Rgenix, Takeda, Tarveda, Tesaro, Tizona Therapeutics, UT Southwestern, and Verastem; and other fees (consultant/advisor) from Amgen, AstraZeneca, BeiGene, Bristol Myers Squibb, Curio Science, EMD Serono, Evidera, Exelixis, Genentech/Roche, GlaxoSmithKline, Intellisphere, Ipsen, Janssen, Jazz Pharmaceuticals, Lilly, Mirati Therapeutics, Molecular Templates, Novartis, Novocure, Pfizer, Puma Biotechnology, Regeneron and Sanofi-Aventis. SA reports receiving other fees (consultant/advisor) from Bristol Myers Squibb. MM reports other fees (honoraria) from Bristol Myers Squibb, MSD and Merck Serono; support for attending meetings for Alfasigma, AstraZeneca, Bristol Myers Squibb, Eli Lilly, GlaxoSmithKline, Incyte, Merck, MSD, Pierre Fabre, Roche, Sanofi, and Sciclone; participation on Data Safety Monitoring Board or Advisory Board for Alfasigma, Amgen, AstraZeneca, Bristol Myers Squibb, Eli Lilly, GlaxoSmithKline, Incyte, Merck, Pierre Fabre, Roche, Sanofi, and Sciclone; and has stock in Epigen Therapeutics and Theravance. SL is a Bristol Myers Squibb employee and has stock in Bristol Myers Squibb. HC is a Bristol Myers Squibb employee and has stock in Bristol Myers Squibb. JF is a Bristol Myers Squibb employee and has stock in Bristol Myers Squibb. AA is a Bristol Myers Squibb employee and has stock in Bristol Myers Squibb. LP-A reports receiving grants/research support for the institution from AstraZeneca, Bristol Myers Squibb, MSD and Pfizer; other fees (consultant/advisor) from Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, GlaxoSmithKline, Ipsen, Janssen, Lilly, Merck, Mirati, MSD, Novartis, Pfizer, Pharmamar, Roche, Sanofi, Servier and Takeda; other fees (honoraria) from AstraZeneca, Janssen, Merck and Mirati; and other (leadership/fiduciary) from Altum Sequency and Genomica.
Provenance and peer review Not commissioned; externally peer reviewed.
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