CheckMate 817: expanding the pool of patients eligible for immune checkpoint inhibitor therapy in advanced non-small cell lung cancer

Background

The treatment landscape has changed greatly in recent years since immune checkpoint inhibitors (ICIs) were first introduced into treatment algorithms for advanced non-small cell lung cancer (NSCLC) patients progressing on, or after first-line therapy (1,2). Multiple trials have evaluated ICI therapy alone, or in combination with chemotherapy, demonstrating improvements in progression-free survival (PFS), overall survival (OS), and quality of life, with an acceptable safety and toxicity profile (3-5). Long-term follow-up of these trials report that 20–30% of patients remain alive at 5 years (6-8). Pembrolizumab alone (patients with PD-L1 expression ≥50%) (5), or in combination with platinum-based chemotherapy (patients with PD-L1 expression <50%) (3,9), nivolumab plus ipilimumab (4), or nivolumab, ipilimumab plus two cycles of platinum-based chemotherapy (10), atezolizumab (11), and newer agents such as cemiplimab (12), have all been incorporated into first-line therapy of advanced NSCLC. The exception to this is NSCLC patients with tumors harboring driver mutations such as EGFR or ALK.

Initial trials of ICI therapy used weight-based dosing in determining the recommended doses for clinical practice (13,14). However, fixed dosing, using standard vial sizes, has the potential to reduce drug wastage and dosing errors. Pharmacokinetic (PK) data showed that fixed dosing of pembrolizumab resulted in similar drug exposure to weight-based dosing (15). Based on these PK analyses, fixed-dose schedules have been more widely adopted. No randomized trials though, have compared patient outcomes, or toxicity from fixed, vs. weight-based dosing.

Gaps in knowledge exist though, in the implementation of ICI therapy into everyday practice. Clinical trial eligibility criteria often exclude many patients who are routinely considered for therapy. Patients with Eastern Cooperative Oncology Group performance status (ECOG PS) 2 or higher are excluded from the majority of clinical trials in lung cancer, based on analysis of trials, such as ECOG 1594, that demonstrated patients with PS 2 had higher toxicity and poor OS (16). Additional subgroups of patients, including those with untreated brain metastasis or major co-morbidities such as hepatic and renal dysfunction, as well as human immunodeficiency virus-1 (HIV-1), are also generally ineligible. This creates uncertainty concerning both efficacy and toxicity for such patients who may be offered therapy in routine clinical practice.

CheckMate 817

CheckMate 817 was a multi-cohort non-randomized phase 3b trial designed to address some of the gaps described above (17). It was conducted at 135 study sites across North America, Europe, and South America. Both cohorts evaluated the safety of fixed-dose nivolumab 240 mg every 2 weeks plus weight-based ipilimumab 1 mg/kg every 6 weeks. Treatment continued until disease progression, unacceptable toxicity, or withdrawal of consent, up to a maximum of 2 years. Cohort A included good PS [0–1] patients receiving first-line therapy for metastatic NSCLC. Efficacy was a secondary outcome in cohort A. The second cohort (cohort A1) evaluated populations of patients typically ineligible for NSCLC clinical trials including patients with ECOG PS 2, or alternatively ECOG PS 0–1 plus untreated brain metastasis, renal (creatinine clearance 20–39 mL/min) or hepatic [aspartate aminotransferase/alanine aminotransferase (AST/ALT) 3–5 times upper limit normal (ULN), or bilirubin 1.5–3.0 times ULN] impairment, or controlled HIV infection. Patients with EGFR mutations or ALK translocations sensitive to available therapy were initially eligible but excluded following a protocol amendment based on emerging data.

The primary outcome for both cohorts was the incidence of grade 3–5 immune-mediated adverse events (IMAEs) and treatment-related select adverse events (AE) in cohort A. Efficacy outcomes were secondary in cohort A and exploratory in cohort A1. These included OS, investigator-assessed PFS, objective response rate (ORR) based on Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, and duration of response (DoR). Efficacy by tumor PD-L1 expression (≥1% and <1%) was exploratory.

Baseline characteristics, excluding protocol-defined differences in the study populations, were broadly similar between cohorts A (n=391) and A1 (n=198; PS 2, n=139; PS 1, n=20; and comorbidity, n=39). The non-squamous histology population was 71.9% vs. 70.2%. PD-L1 expression ≥1% was 49.3% and 44.4%.

Safety information for cohort A and cohort A1 is summarized in Table 1. Treatment-related adverse events (TRAEs) occurred frequently in both groups. Grade 3–4 TRAEs occurred in about one-third of patients and were similar in both cohorts. These resulted in treatment discontinuation of at least one study drug in approximately one in five patients. The most common grade 3–4 IMAEs in both cohorts were pneumonitis, diarrhea/colitis, hepatitis, and skin rash. The profile of grade 3–4 treatment-related select AEs was similar (hepatic, gastrointestinal, pulmonary, skin, and endocrine). The authors report no grade 5 IMAEs, or treatment-related select AEs (defined as death within 24 hours of onset of an event). However, 4 treatment-related deaths (1.0%) occurred in cohort A [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)] and 3 treatment-related deaths (1.5%) were reported in cohort A1, all in patients with ECOG PS 2 [myasthenic syndrome secondary to immunotherapy (n=1), interstitial diffuse pneumonitis (n=1), and polymyositis (n=1)].

Efficacy data are summarized in Table 2. Not surprisingly, higher efficacy was observed in cohort 1 (patients typically eligible for inclusion in clinical trials). Overall response rate (ORR) was 37.3% with a median DoR of 27.6 months. Median OS was 16.8 months with 33.7% alive at 3 years. In cohort A1 (poor PS, or comorbid health issues), ORR was only 20.9%, with median DoR of 15.5 months. Median OS was 9.9 months with only 20.5% alive at 3 years. Efficacy data were similar for ECOG 2 patients with no comorbidities and ECOG 1 patients with brain metastases. There were only small numbers of patients with other comorbidities, making it difficult to reach any conclusions.

In exploratory analyses, efficacy varied according to PD-L1 expression. In cohort A, median OS was 21.0 months in patients with PD-L1 ≥1% and 15.3 months in patients with PD-L1 <1%. The association of PD-L1 expression and OS was less clear in cohort A1, with a median OS of 6.9 months in patients with PD-L1 ≥1% and 10.5 months in patients with PD-L1 <1%. PFS and ORR were generally higher in patients with PD-L1 positive tumors. The impact of histology was only reported for Cohort A. Patients with non-squamous NSCLC had longer OS than patients with squamous histology (median OS, 20.1 vs. 13.7 months). PFS, ORR, and DoR were similar regardless of histology.

What are the implications of CheckMate 817?

The combination of nivolumab and ipilimumab is already an established therapeutic option for patients with advanced NSCLC. Both CheckMate 227 (4) and CheckMate 9LA (10) demonstrated that nivolumab plus ipilimumab, either alone or in combination with two cycles of platinum-based chemotherapy, results in improved OS in comparison to platinum-based chemotherapy. Ipilimumab dosing of 1 mg/kg in lung cancer trials has remained unchanged since early phase trials of the combination (18). However, recent trials of the combination, including CheckMate 9LA (10) and CheckMate 743 in mesothelioma (19), have employed fixed dosing of nivolumab, either 240 mg every 2 weeks, or 360 mg every 3 weeks. PK data suggest similar drug exposure with fixed dosing of ICIs, in comparison to weight-based dosing (15), but there are less data on patient outcomes such as toxicity and efficacy.

CheckMate 817 provides reassurance that fixed dosing of nivolumab does not have a major impact on therapeutic outcomes. Patients in cohort A were similar to the patient populations in the major randomized trials, CheckMate 227 and CheckMate 9LA. While direct comparisons across trials are not possible, the profile of adverse effects with flat dosing appears similar to that seen with weight-based dosing. The rate of grade 3–4 TRAE in CheckMate 227 (32.8%) is similar to that observed in CheckMate 817 (35.3%). The rate of treatment discontinuation was slightly higher in CheckMate 817 (23.8% vs. 18.1%). Similar efficacy was also observed in the two trials. The median OS and 3-year OS in the current trials was 16.8 months and 33.7%, in comparison to CheckMate 227 (PD-L1 ≥1%: median OS, 17.1 months and 3-year OS, 33%; PD-L1 <1%: median OS, 17.4 months and 3-year OS, 33%). Similar ORR (37.3%) and DoR (median, 27.6 months) were observed in comparison to CheckMate 227 (PD-L1 ≥1%: ORR, 36% and median DoR, 24.5 months; PD-L1 <1%: ORR, 27% and median DoR, 19.4 months).

One might conclude from CheckMate 817, that fixed dosing of nivolumab in combination with weight-based dosing of ipilimumab is safe and effective and should be implemented across the board. However, the issue is more complex. This approach is employed across many ongoing trials of ICIs including nivolumab and ipilimumab, pembrolizumab, atezolizumab, durvalumab, and cemiplimab. This approach may limit drug wastage and improve safety. However, the decision to use fixed vs. weight-based dosing depends on whether one considers the perspective of the prescriber, vs. the payer. It is also important to consider whether there are economic implications from fixed dosing. An economic model of fixed dosing for pembrolizumab for patients with NSCLC in the US reported that weight-based dosing may save approximately US dollars (USD) 0.825 billion annually in drug costs (20). It is unclear whether drug wastage was accounted for in this model though. Some publicly funded healthcare systems, such as Ontario Health in Canada, have taken a cost-minimization approach and adopted a hybrid dosing system using weight-based dosing for patients up to 80 kg, with fixed dosing for patients with higher body weights. These decisions are driven by concerns about overall budget impact.

Clinical trial populations are often restrictive, with many patients ineligible for trials. CheckMate 817 also provides information on safety and efficacy of nivolumab and ipilimumab in such patients typically excluded from clinical trials in NSCLC, including poor PS patients, patients with untreated brain metastases, or comorbidities such as hepatic or renal dysfunction and HIV infections. Old data reported that ECOG PS 2 predicted greater toxicity from chemotherapy and worse OS (16). Subsequently, PS 2 patients were excluded from many subsequent trials. However, there are trials in NSCLC focusing on patients with PS 2, that demonstrate improved OS with platinum-based doublets (21) and many of these patients are candidates for treatment in everyday clinical practice.

The data from cohort A1 of CheckMate 817 provide reassurance that those patients with PS 2, or co-morbidities do not experience significantly greater adverse events with nivolumab and ipilimumab, than good PS patients. The patients in cohort A1 may represent a select group. However, the incidence of grade 3–4 IMAE, TRAEs, and the rate of treatment-related discontinuation of at least one drug are all similar, or better, than that observed in cohort A. It is apparent though, that these patients have a worse prognosis. Their median OS and 3-year OS were lower than those observed with patients in cohort A. In itself, this is not predictive of lower benefit from therapy, but likely reflective of worse prognosis. However, patients in cohort A1 had a lower ORR, shorter DoR, and shorter median PFS. Not surprisingly, patients in cohort A1 appear less likely to receive subsequent lines of therapy. These all raise questions about whether the benefit of nivolumab and ipilimumab is lower than in good PS patients. CheckMate 817 does not provide any information about the relative efficacy of nivolumab and ipilimumab in comparison to other treatment options for poor PS patients, such as platinum-based chemotherapy alone, other chemotherapy and immunotherapy combinations, or single-agent pembrolizumab, atezolizumab, or cemiplimab in patients with tumor PD-L1 expression ≥50%. The data are supportive of the need for a randomized clinical trial in these patient populations typically excluded from clinical trials.

CheckMate 817 is a further trial supportive of the benefit of nivolumab and ipilimumab in advanced NSCLC. The trial does leave several questions unaddressed. There are no randomized data examining efficacy outcomes for the comparison of fixed vs. weight-based dosing. This seems very unlikely to happen, as fixed dosing has already been widely adopted, as it is simpler, reduces drug wastage, is less subject to medication dosing errors, and has become standard for dosing in ongoing clinical trials. The number of patients with brain metastasis is small in this study (n=49), however, the median OS was 12.8 months, which is better than the historical survival data for patients with untreated, or treated brain metastasis (22). Intracranial responses are seen in patients with brain metastases from metastatic melanoma, treated with nivolumab and ipilimumab (23). CheckMate 817 though, does not provide any data on the likelihood of intracranial response. It would be crucial to understand the likelihood of brain metastases responding to nivolumab and ipilimumab when considering whether the initiate systemic therapy or radiation in patients with asymptomatic brain metastases from NSCLC.

The trial was designed to provide safety information for patients with hepatic or renal dysfunction treated with nivolumab and ipilimumab. Previous case series in the setting of chronic kidney disease did not demonstrate excess renal toxicity (24). Unfortunately, the number of patients with hepatic or renal dysfunction in CheckMate 817 was very small. Only seven patients with hepatic impairment and nine with renal impairment were included in this study. Two of nine patients with renal impairment experienced increased creatinine, although only one was deemed related. Two of seven patients with hepatic impairment had liver toxicity, although only one was considered related. This leaves uncertainty about the potential risks of treating these patient populations.

In summary, CheckMate 817 adds information to what is already known about nivolumab and ipilimumab therapy in advanced NSCLC and probably expands the population of eligible patients who might be treated in the community. No new safety concerns were identified, with fixed dosing of nivolumab in combination with weight-based dosing of ipilimumab. Fixed dose nivolumab plus ipilimumab appears safe in NSCLC patients with untreated brain metastases but more information is needed about intracranial efficacy to better inform decisions about immunotherapy vs. radiation for this group of patients. Lastly, there is an ongoing need for information regarding the safety of these agents in patients with significant renal or hepatic dysfunction.

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-23-42/prf

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-23-42/coif). P.M.E. receives honoraria from the following companies for speaking or advisory board meetings: AstraZeneca, BMS, Eli Lilly, Jazz, Jannsen, Merck, Novartis, Pfizer, Roche, Sanofi. He is also the Chair of the Ontario Cooperative Oncology Group DSMC, a member of Ontario Health-Cancer Cancer Ontario Provincial Guideline Group, and Thoracic Malignancy Advisory Group, as well as an executive member of the Canadian Cancer Trials Group Lung DSG. 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/.

References

1. Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer. N Engl J Med 2015;373:1627-39. [Crossref] [PubMed]
2. Herbst RS, Baas P, Kim DW, et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet 2016;387:1540-50. [Crossref] [PubMed]
3. Gandhi L, Rodríguez-Abreu D, Gadgeel S, et al. Pembrolizumab plus Chemotherapy in Metastatic Non-Small-Cell Lung Cancer. N Engl J Med 2018;378:2078-92. [Crossref] [PubMed]
4. Hellmann MD, Paz-Ares L, Bernabe Caro R, et al. Nivolumab plus Ipilimumab in Advanced Non-Small-Cell Lung Cancer. N Engl J Med 2019;381:2020-31. [Crossref] [PubMed]
5. Reck M, Rodríguez-Abreu D, Robinson AG, et al. Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. N Engl J Med 2016;375:1823-33. [Crossref] [PubMed]
6. Brahmer JR, Lee JS, Ciuleanu TE, et al. Five-Year Survival Outcomes With Nivolumab Plus Ipilimumab Versus Chemotherapy as First-Line Treatment for Metastatic Non-Small-Cell Lung Cancer in CheckMate 227. J Clin Oncol 2023;41:1200-12. [Crossref] [PubMed]
7. Garassino MC, Gadgeel S, Speranza G, et al. Pembrolizumab Plus Pemetrexed and Platinum in Nonsquamous Non-Small-Cell Lung Cancer: 5-Year Outcomes From the Phase 3 KEYNOTE-189 Study. J Clin Oncol 2023;41:1992-8. [Crossref] [PubMed]
8. Reck M, Rodríguez-Abreu D, Robinson AG, et al. Updated Analysis of KEYNOTE-024: Pembrolizumab Versus Platinum-Based Chemotherapy for Advanced Non-Small-Cell Lung Cancer With PD-L1 Tumor Proportion Score of 50% or Greater. J Clin Oncol 2019;37:537-46. [Crossref] [PubMed]
9. Paz-Ares L, Luft A, Vicente D, et al. Pembrolizumab plus Chemotherapy for Squamous Non-Small-Cell Lung Cancer. N Engl J Med 2018;379:2040-51. [Crossref] [PubMed]
10. Paz-Ares L, Ciuleanu TE, Cobo M, et al. First-line nivolumab plus ipilimumab combined with two cycles of chemotherapy in patients with non-small-cell lung cancer (CheckMate 9LA): an international, randomised, open-label, phase 3 trial. Lancet Oncol 2021;22:198-211. [Crossref] [PubMed]
11. Herbst RS, Giaccone G, de Marinis F, et al. Atezolizumab for First-Line Treatment of PD-L1-Selected Patients with NSCLC. N Engl J Med 2020;383:1328-39. [Crossref] [PubMed]
12. Sezer A, Kilickap S, Gümüş M, et al. Cemiplimab monotherapy for first-line treatment of advanced non-small-cell lung cancer with PD-L1 of at least 50%: a multicentre, open-label, global, phase 3, randomised, controlled trial. Lancet 2021;397:592-604. [Crossref] [PubMed]
13. Garon EB, Rizvi NA, Hui R, et al. Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med 2015;372:2018-28. [Crossref] [PubMed]
14. Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 2012;366:2443-54. [Crossref] [PubMed]
15. Freshwater T, Kondic A, Ahamadi M, et al. Evaluation of dosing strategy for pembrolizumab for oncology indications. J Immunother Cancer 2017;5:43. [Crossref] [PubMed]
16. Sweeney CJ, Zhu J, Sandler AB, et al. Outcome of patients with a performance status of 2 in Eastern Cooperative Oncology Group Study E1594: a Phase II trial in patients with metastatic nonsmall cell lung carcinoma. Cancer 2001;92:2639-47. [Crossref] [PubMed]
17. 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. [Crossref] [PubMed]
18. Hellmann MD, Rizvi NA, Goldman JW, et al. Nivolumab plus ipilimumab as first-line treatment for advanced non-small-cell lung cancer (CheckMate 012): results of an open-label, phase 1, multicohort study. Lancet Oncol 2017;18:31-41. [Crossref] [PubMed]
19. Baas P, Scherpereel A, Nowak AK, et al. First-line nivolumab plus ipilimumab in unresectable malignant pleural mesothelioma (CheckMate 743): a multicentre, randomised, open-label, phase 3 trial. Lancet 2021;397:375-86. [Crossref] [PubMed]
20. Goldstein DA, Gordon N, Davidescu M, et al. A Phamacoeconomic Analysis of Personalized Dosing vs Fixed Dosing of Pembrolizumab in Firstline PD-L1-Positive Non-Small Cell Lung Cancer. J Natl Cancer Inst 2017; [Crossref] [PubMed]
21. Zukin M, Barrios CH, Pereira JR, et al. Randomized phase III trial of single-agent pemetrexed versus carboplatin and pemetrexed in patients with advanced non-small-cell lung cancer and Eastern Cooperative Oncology Group performance status of 2. J Clin Oncol 2013;31:2849-53. [Crossref] [PubMed]
22. Ali A, Goffin JR, Arnold A, et al. Survival of patients with non-small-cell lung cancer after a diagnosis of brain metastases. Curr Oncol 2013;20:e300-6. [Crossref] [PubMed]
23. Tawbi HA, Forsyth PA, Algazi A, et al. Combined Nivolumab and Ipilimumab in Melanoma Metastatic to the Brain. N Engl J Med 2018;379:722-30. [Crossref] [PubMed]
24. Herz S, Höfer T, Papapanagiotou M, et al. Checkpoint inhibitors in chronic kidney failure and an organ transplant recipient. Eur J Cancer 2016;67:66-72. [Crossref] [PubMed]