Breaking barriers: bridging the gap in lung cancer trials through inclusive representation
Editorial Commentary

Breaking barriers: bridging the gap in lung cancer trials through inclusive representation

Julian A. Marin-Acevedo1, Sonam Puri2

1Division of Medical Oncology, Department of Internal Medicine, Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, IN, USA; 2Division of Medical Oncology, Department of Internal Medicine, The Huntsman Cancer Institute at the University of Utah, Salt Lake City, UT, USA

Correspondence to: Sonam Puri, MD. Assistant Professor of Medicine, Division of Medical Oncology, Department of Internal Medicine, The Huntsman Cancer Institute at the University of Utah, 2000 Circle of Hope Drive, Salt Lake City, UT 84112, USA. Email: Sonam.Puri@hci.utah.edu.

Comment on: : Ready NE, Audigier-Valette C, Goldman JW, et al. First-line nivolumab plus ipilimumab for metastatic non-small cell lung cancer, including patients with ECOG performance status 2 and other special populations: CheckMate 817. J Immunother Cancer 2023;11:e006127.

Keywords: Immunotherapy; lung cancer trials; comorbidities

Received: 08 November 2023; Accepted: 08 January 2024; Published online: 05 February 2024.

doi: 10.21037/actr-23-58

Introduction

Immune checkpoint inhibitors (ICIs) are a standard component in the treatment of advanced/metastatic non-small cell lung cancer (NSCLC). When used alone or in combination with chemotherapy, ICIs are associated with durable responses, improved survival, and acceptable toxicities (1-3). A significant number of patients, however, do not benefit from the use of ICIs, even in the presence of tumor features suggesting otherwise [e.g., high tumor mutational burden (TMB) or high expression of programmed death-ligand 1 (PD-L1)] (4). To overcome this limitation, concurrent use of ICIs with different mechanisms of action has been evaluated. The combination of ipilimumab [anti-cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4)] with nivolumab [anti-programmed death 1 (PD-1)] in the CheckMate 067 trial in melanoma patients, for example, showed a higher overall response rate (ORR) and improved overall survival (OS) than ipilimumab alone (5). Similarly, two phase III clinical trials in patients with stage IV or recurrent NSCLC, showed that ipilimumab with nivolumab resulted in higher ORR and OS compared to chemotherapy (Table 1) (6,7). In CheckMate 227, patients received either ipilimumab (at a dose of 1 mg/kg every 6 weeks) with nivolumab (at a dose of 3 mg/kg every 2 weeks), nivolumab single agent (at a dose of 240 mg every 2 weeks), or platinum-doublet chemotherapy every 3 weeks (6). In CheckMate 9LA, patients received either ipilimumab (at a dose of 1 mg/kg every 6 weeks) with nivolumab (at a dose of 360 mg every 3 weeks) combined with platinum-based chemotherapy for two cycles, or platinum-based chemotherapy alone (7). Both trials, however, only evaluated patients with optimal hepatic and renal function, without central nervous system (CNS) disease involvement or with previously treated CNS disease, and those without significant comorbidities (6,7). These patients do not always reflect the real-world NSCLC population, making the reproducibility of these findings challenging in clinical practice (8-10).

Table 1

Clinical trials of ipilimumab with nivolumab in patients with advanced NSCLC

Trial Inclusion criteria Population Intervention Efficacy Toxicities (grade 3–4)
Median OS, months Median PFS, months ORR Median DOR, months
CM-227 Squamous or non-squamous histology PD-L1 ≥1%
Stage IV or recurrent NSCLC without prior systemic therapy for advanced/metastatic disease Cohort A (n=396) Nivolumab 3 mg/kg Q2 weeks + ipilimumab 1 mg/kg Q6 weeks 17.1 5.1 35.9% 23.2 35.5% including rash (2.3%), fatigue (2.0%), diarrhea (1.5%), and anemia (1.3%)
ECOG 0 or 1 Cohort B (n=396) Nivolumab 240 mg Q2 weeks 15.7 4.2 27.5% 15.5 19.4% including rash (0.8%), diarrhea (0.5%), fatigue (0.5%), and anemia (0.5%)
No EGFR mutations or ALK translocations Cohort C (n=397) Platinum-doublet chemotherapy Q3 weeks for up to four cycles 14.9 5.6 30.0% 6.2 36.4% including anemia (10.6%), neutropenia (8.5%), nausea/vomiting (4.4%), and fatigue (1.0%)
No untreated or symptomatic CNS metastases PD-L1 <1%
No HIV, previous malignancy, autoimmune diseases, hepatitis B or hepatitis C Cohort D (n=187) Nivolumab 3 mg/kg Q2 weeks + ipilimumab 1 mg/kg Q6 weeks 17.2 5.1 27.3% 18 27.0% including diarrhea (2.2%), anemia (1.6%),
fatigue (1.1%), and vomiting (0.5%)
Cohort E (n=177) Nivolumab 360 mg Q3 weeks + platinum-doublet chemotherapy Q3 weeks for up to four cycles 15.2 5.6 37.9% 8.3 55.8% including anemia (17.4%), neutropenia (13.4%), fatigue (4.7%), and nausea/vomiting (4.6%)
Cohort F (n=186) Platinum-doublet chemotherapy Q3 weeks for up to four cycles 12.2 4.7 23.1% 4.8 35% including anemia (13.7%), neutropenia (11.5%), nausea/vomiting (4.3%), and fatigue (2.2%)
CM-9LA Squamous or non-squamous histology Cohort A (n=361) Nivolumab 360 mg Q3 weeks + ipilimumab 1 mg/kg Q6 weeks + histology-based platinum-doublet chemotherapy Q3 weeks for two cycles 15.6 (all), 15.8 (PD-L1 ≥1%), 16.8 (PD-L1 <1%), 17.0 (non-squamous), and 14.5 (squamous) 6.7 (all), 7.1 IPD-L1 ≥1%), 5.6 (PD-L1 <1%), 7.0 (non-squamous), and 5.6 (squamous) 38.2% (all), 43.3% (PD-L1 ≥1%), 31.1% (PD-L1 <1%),
33.3% (non-squamous), and 48.7% (squamous)		 11.3 (all), 11.0 (PD-L1 ≥1%), not reached (PD-L1 <1%), 15.8 (non-squamous), and 10.4 (squamous) 47% including increased amylase/lipase (9%), neutropenia (7%), anemia (6%), diarrhea (4%), rash (2%), and vomiting (2%)
Stage IV or recurrent NSCLC without prior systemic therapy for advanced/metastatic disease
ECOG 0–1 Cohort B (n=358) Histology-based platinum-doublet chemotherapy alone Q3 weeks for four cycles 10.9 (all), 10.9 (PD-L1 ≥1%), 9.8 (PD-L1 <1%), 11.9 (non-squamous), and 9.1 (squamous) 5.0 (all), 4.7 (PD-L1 ≥1%), 4.6 (PD-L1 <1%), 5.6 (non-squamous), and 4.3 (squamous) 27.5% (PD-L1 ≥1%), 20.2% (PD-L1 <1%), 22.0% (non-squamous), and 31.3% (squamous) 5.6 (all), 5.4 (PD-L1 ≥1%), 4.3 (PD-L1 <1%), 8.8 (non-squamous), and 3.9 (squamous) 38% including anemia (14%), neutropenia (9%), thrombocytopenia (3%), and asthenia (2%)
No HIV, previous malignancy, autoimmune diseases, hepatitis B or hepatitis C
CM-817 Squamous or non-squamous histology Cohort A (n=391) ECOG 0–1, adequate renal/hepatic function, no HIV infection, no active or untreated brain metastasis 16.8 (all), 21 (PD-L1 ≥1%),
15.3 (PD-L1 <1%), 20.1 (non-squamous), and 13.7 (squamous)		 5.8 (all), 7.1 (PD-L1 ≥1%), 5.3 (PD-L1 <1%), 5.8 (non-squamous), and 5.5 (squamous) 37.3% (all), 43.8% (PD-L1 ≥1%), 30.9% (PD-L1 <1%),
38.1% (non-squamous), 35.5% (squamous)		 27.6 (all), 29.9 (PD-L1 ≥1%), 25.8 (PD-L1 <1%), 27.6 (non-squamous), and 29.9 (squamous) 35.3% including pneumonitis (5.1%), diarrhea/colitis (4.9%), and hepatitis (4.6%)
Stage IV or recurrent NSCLC without prior systemic therapy for advanced/metastatic disease Cohort A1 ECOG 2 or ECOG 0–1 with either untreated asymptomatic brain metastasis, renal impairment (CrCl 20–39 mL/min), hepatic impairment (AST or ALT 3.0–5.0 times ULN, and/or TB 1.5–3.0 times ULN), or controlled HIV infection 9.9 (all), 6.9 (PD-L1 ≥1%), 13.3 (PD-L1 ≥50%), 10.1 (PD-L1 <1%), 9.0 (ECOG PS 2), and 12.8 (untreated brain metastasis) 3.9 (all), 3.3 (PD-L1 ≥1%), 9.6 (PD-L1 ≥50%), 3.9 (PD-L1 <1%), 3.6 (ECOG PS 2), and 2.8 (untreated brain metastasis) 25.8% (all), 27.6% (PD-L1 ≥1%), 24.2% (PD-L1<1%),
40.6% (PD-L1 ≥50%), 20.9% (ECOG PS 2), 32.7%
(untreated brain metastasis)		 13.5 (all), 15.5 (ECOG PS 2), and 12.6 (untreated brain metastasis) 29.3%, including diarrhea/colitis (3.5%), hepatitis (3.5%), and rash (3.0%):
• ECOG PS 2: 27.3% including rash (3.6%), hepatitis (3.6%), diarrhea/colitis (2.2%), and pneumonitis (2.2%);
• Untreated brain metastasis: 36.7% including diarrhea/colitis (6.1%), hepatitis (4.1%), and pneumonitis (4.1%)
• Renal impairment: none
• Liver impairment: two patients had hepatotoxicity, deemed unrelated to therapy
ECOG 0–2 OS: Renal impairment, 1.4 to over 45.3; 5 patients had a PR
No EGFR mutations or ALK translocations OS: Liver impairment, 0.4 to over 35.5; 1 patient had a PR
OS: HIV, 7.0 to over 41.4; 2 patients had a PR
All patients Nivolumab (240 mg Q2 weeks) + ipilimumab (1 mg/kg Q6 weeks) until disease progression, unacceptable toxicity, withdrawal of consent, or for up to 2 years

ALT, alanine aminotransferase; AST, aspartate aminotransferase; CM, CheckMate; CNS, central nervous system; CrCl, creatinine clearance; DOR, duration of response; ECOG PS, Eastern Cooperative Oncology Group performance status; HIV, human immunodeficiency virus; NSCLC, non-small cell lung cancer; ORR, overall response rate; OS, overall survival; PD-L1, programmed death-ligand 1; PFS, progression-free survival; PR, partial response; TB, total bilirubin; ULN, upper limits of normal.

CheckMate 817

CheckMate 817 is a phase IIIB, multicenter, open-label, single-arm study that evaluated the use of standard-flat-dose nivolumab (240 mg every 2 weeks) with ipilimumab (1 mg/kg every 6 weeks) in patients with untreated, stage IV or recurrent NSCLC (11). All patients were treated until disease progression, unacceptable toxicity, withdrawal of consent, or for up to two years. There were two cohorts evaluated. Cohort A included individuals with an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0–1, previously treated or without CNS involvement, no history of human immunodeficiency virus (HIV), and no renal and/or hepatic impairment. The primary endpoint for this cohort was safety, and the secondary endpoints were OS, progression-free survival (PFS), ORR, and duration of response (DOR). Cohort A1 evaluated patients with an ECOG PS of 2 or those with an ECOG of 0–1 and either untreated brain metastasis, controlled HIV infection, renal impairment, or hepatic impairment. Both safety and efficacy were exploratory in this cohort (11).

Table 1 summarizes the results of CheckMate 817.

Among the 391 patients in cohort A, 138 (35.3%) experienced grade 3–4 immune-related adverse events (irAEs) including pneumonitis (5.1%), diarrhea/colitis (4.9%), and hepatitis (4.6%). There were 4 patients (1%) who died from irAE complications including rhabdomyolysis of the heart, hepatitis, esophagitis, and Guillain-Barré syndrome. With a median follow-up of 43.9 months, the median OS was 16.8 months and the 3-year OS rate was 33.7%. The median PFS was 5.8 months, the ORR was 37.3%, and the median DOR was 27.6 months (11). Those with tumor PD-L1 levels of ≥1% had a median OS of 21 months, a median PFS of 7.1 months, and an ORR of 43.8%, while those with levels <1% had a median OS of 15.3 months, a median PFS of 5.3 months, and an ORR of 30.9%.

Among the 198 patients from cohort A1, there were 139 patients with an ECOG PS of 2 and 68 with an ECOG PS of 0–1 and untreated brain metastases (n=49), renal impairment (n=9), hepatic impairment (n=7), or HIV (n=4). Grade 3–4 toxicities were reported in 58 patients (29.3%) including diarrhea/colitis (3.5%), hepatitis (3.5%), and rash (3.0%). There were 3 (1.5%) reported toxicity-related deaths, all in the ECOG PS 2 subgroup: a case of myasthenic syndrome, a case of pneumonitis, and a case of polymyositis. With a median follow-up of 38.1 months, the median OS was 9.9 months, the 3-year OS rate was 20.5%, the median PFS was 3.9 months, the ORR was 25.8%, and the median DOR was 13.5 months. Interestingly, patients with PD-L1 levels <1% had a median OS of 10.5 months and those with PD-L1 levels of ≥50% had a median OS of 13.3 months, compared to those with levels ≥1% that had a median OS of only 6.9 months. Similarly, the median PFS was 3.9 months for those with PD-L1 levels <1% and 9.6 months for those with levels ≥50%, compared to 3.3 months for those with levels ≥1% (11).

In the ECOG PS 2 subgroup, grade 3–4 irAEs were seen in 38/139 patients (27.3%), the median OS was 9.0 months, the 3-year OS rate was 18.7%, the median PFS was 3.6 months, the ORR was 20.9%, and the median DOR was 15.5 months. In those with untreated brain metastases, grade 3–4 toxicities were seen in 18/49 patients (36.7%), the median OS was 12.8 months, the 3-year OS rate was 21%, the median PFS was 2.8 months, the ORR was 32.7%, and the median DOR was 12.6 months. Of note, therapy-associated CNS benefit was not assessed due to data collection limitations. The limited number of patients with renal impairment, hepatic dysfunction, and HIV subgroups only allowed for descriptive analyses. In those with renal impairment, there were no grade 3–4 toxicities and the OS ranged from 1.4 to 45.3 months. In the hepatic impairment subgroup, two patients developed grade 3 hepatotoxicity but these were deemed unrelated to ipilimumab/nivolumab by the investigator. The OS ranged from 0.4 to 35.5 months. For those with HIV, toxicities were not described and the OS ranged from 7.0 to 41.4 months (11).

Applying CheckMate 817 to clinical practice

CheckMate 817 evaluated the safety and efficacy of standard-flat-dose nivolumab using 240 mg every 2 weeks as an alternative to a weight-base dosing approach. While weight-based dosing is commonly used to overcome the variability in drug levels among patients, standard dosing offers a convenient alternative that reduces preparation time, dosing errors, and burden in therapy administration (12). When used as monotherapy, standard doses of nivolumab using 240 mg every 2 weeks or 480 mg every 4 weeks are safe, effective, and Food and Drug Administration (FDA)-approved (12,13). When combined with ipilimumab, approved doses of nivolumab in NSCLC include 3 mg/kg every 2 weeks and 360 mg every 3 weeks. While CheckMate 817 suggests that nivolumab 240 mg every 2 weeks in combination with ipilimumab could be a safe and effective alternative to weight-based dosing, the applicability of this regimen is less obvious. Compared to the currently approved standard dosing given every 3 weeks, standard doses of nivolumab given every 2 weeks could result in an increased number of visits, infusions, patient non-compliance, and possibly healthcare costs (11,14).

Evaluating the nivolumab and ipilimumab combination in underrepresented patients was another objective of CheckMate 817. The stringent criteria used by clinical trials have been called into question before as these favor the selection of patients that do not represent the “real-world” cancer population (15). For instance, only 35% of clinical trials include patients with an ECOG PS of 0–2, but up to 40% of patients with NSCLC have an ECOG of at least 2 (8,15). While lower ECOG PS tends to have higher rates of toxicities, treatment discontinuation, and death, data suggests that including these patients in clinical trials does not adversely impact the outcomes of the studies (16). CheckMate 817 and other small studies suggest that ICIs are well tolerated and that the inferior outcomes seen in these patients are likely a reflection of the underlying disease rather than the medications per se (11,17-19). Further, a recent phase III clinical trial (IPSOS) showed that using atezolizumab could offer superior outcomes and better tolerability than single-agent chemotherapy in those with an ECOG PS of 2–3 or in those with an ECOG PS of 0–1 who have significant comorbidities (20).

CNS involvement is another significant complication of NSCLC. Up to 50% of patients with NSCLC develop brain metastases during their illness (9). Unfortunately, those with known, active, or symptomatic CNS disease are frequently excluded from clinical trials (15). While a small, phase II clinical trial suggested that pembrolizumab could have a CNS ORR ~30% and a DOR of 5.7 months in those with untreated, asymptomatic brain metastasis whose NSCLC tumors PD-L1 levels are ≥1%, larger prospective data is lacking (21). A recent analysis from CheckMate 227 suggests that ipilimumab-nivolumab provides an OS (17.4 months) and systemic ORR (32%) advantage over chemotherapy alone (13.7 months, and 26%, respectively) in individuals with previously treated brain metastasis (22). The CNS efficacy of this combination in NSCLC patients with untreated brain metastases, however, is unclear. CheckMate 817 suggests that ipilimumab-nivolumab combination is safe and systemically effective in those with untreated brain metastasis (11). Whether this combination provides any intracranial benefit remains unknown, because the data collection limitations did not allow for assessment of intracranial responses. Further, this study did not evaluate the role of other therapies (i.e., radiation) to determine if the benefit of ICIs in these patients was in addition to, or in place of other treatments.

While the co-existence of serious comorbidities (e.g., cardiovascular disease, respiratory illnesses, diabetes, HIV, hepatitis B, hepatitis C, or renal insufficiency) and NSCLC is another common problem, only a minority of cancer trials include these patients (10,15). Small retrospective analyses suggest that ICIs are safe and effective in individuals with underlying HIV, renal impairment, or hepatic disease, but prospective data is also lacking (23,24). Even the IPSOS trial that evaluated patients with serious comorbidities excluded those with HIV, hepatitis B or C, and those with an elevated serum creatinine (20). CheckMate 817 suggests that ipilimumab-nivolumab is safe and effective in these populations, however, these endpoints were exploratory, the number of patients was extremely low, and the analysis of these cohorts was descriptive which restricts the interpretation and applicability of these results (11).

One interesting finding from CheckMate 817 was the lack of clear correlation seen between PD-L1 levels and outcomes in those with low ECOG PS or serious comorbidities (11). While the number of patients was limited, this finding calls into question the role PD-L1 levels alone have in predicting response to immunotherapy in this population. Novel proteomic tests have demonstrated a better correlation with outcomes when compared to PD-L1 levels in individuals with advanced NSCLC treated with immunotherapy (25). These tests could be prospectively studied in NSCLC patients with lower ECOG PS levels or serious comorbidities for whom immunotherapy is being considered.

Conclusions

CheckMate 817 evaluated the administration, safety, and efficacy of ipilimumab combined with flat-dose nivolumab in patients with advanced/metastatic NSCLC and included a subset of individuals that are often excluded from clinical trials. While this study suggests standard-dose nivolumab is a feasible and safe alternative to the already approved weight-based regimen, flat-dose nivolumab every 2 weeks could result in an increased number of infusions, costs, and healthcare burden compared to a flat-dose nivolumab given every 3 weeks. CheckMate 817 also suggests that ipilimumab-nivolumab combination is likely safe and effective in individuals with lower ECOG PS, untreated asymptomatic CNS disease, HIV, hepatic disease, and renal impairment. It also suggests that PD-L1 levels may not correlate with immunotherapy response in these patients. Unfortunately, some limitations restrict the applicability and interpretability of these results. First, safety and efficacy were exploratory endpoints in this cohort. Second, there were data collection limitations that restricted the assessment of intracranial benefit from ipilimumab-nivolumab combination. Third, the number of patients with serious comorbidities (i.e., HIV, renal, and hepatic impairments) only allowed for a descriptive analysis. Lastly, the single-arm design of the study did not allow assessing the impact of this therapy compared to other treatments or placebo. Despite these limitations, CheckMate 817 is one of the few trials that increase awareness of the need to expand the enrollment of underrepresented populations. In the future, clinical trials should consider using less stringent inclusion criteria and expanding the number of trials focusing on underrepresented populations. This will likely result in increased accrual, better representation of real-world NSCLC patients, and perhaps, more accurate and applicable results for clinical practice.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-23-58/prf

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-23-58/coif). S.P. has participated in advisory boards for Pfizer, G1 therapeutics, BMS, Novocure and Jazz Pharmaceutics; and receives consulting fees from them. She has received support for travel from Dava Oncology. The other author has no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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doi: 10.21037/actr-23-58
Cite this article as: Marin-Acevedo JA, Puri S. Breaking barriers: bridging the gap in lung cancer trials through inclusive representation. AME Clin Trials Rev 2024;2:16.

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