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

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.

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References

Facchinetti F, Mazzaschi G, Barbieri F, Passiglia F, Mazzoni F, Berardi R . First-line pembrolizumab in advanced non-small cell lung cancer patients with poor performance status. Eur J Cancer. 2020; 130:155-167. DOI: 10.1016/j.ejca.2020.02.023. View

Hellmann M, Rizvi N, Goldman J, Gettinger S, Borghaei H, Brahmer J . 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. 2016; 18(1):31-41. PMC: 5476941. DOI: 10.1016/S1470-2045(16)30624-6. View

Metro G, Banna G, Signorelli D, Gili A, Galetta D, Galli G . Efficacy of Pembrolizumab Monotherapy in Patients With or Without Brain Metastases From Advanced Non-Small Cell Lung Cancer With a PD-L1 Expression ≥50%. J Immunother. 2020; 43(9):299-306. DOI: 10.1097/CJI.0000000000000340. View

Hodi F, ODay S, Mcdermott D, Weber R, Sosman J, Haanen J . Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010; 363(8):711-23. PMC: 3549297. DOI: 10.1056/NEJMoa1003466. View

Sharma P, Allison J . Dissecting the mechanisms of immune checkpoint therapy. Nat Rev Immunol. 2020; 20(2):75-76. DOI: 10.1038/s41577-020-0275-8. View

Herbst R, Giaccone G, de Marinis F, Reinmuth N, Vergnenegre A, Barrios C . Atezolizumab for First-Line Treatment of PD-L1-Selected Patients with NSCLC. N Engl J Med. 2020; 383(14):1328-1339. DOI: 10.1056/NEJMoa1917346. View

Reck M, Rodriguez-Abreu D, Robinson A, Hui R, Csoszi T, Fulop A . Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. N Engl J Med. 2016; 375(19):1823-1833. DOI: 10.1056/NEJMoa1606774. View

Goldberg S, Schalper K, Gettinger S, Mahajan A, Herbst R, Chiang A . Pembrolizumab for management of patients with NSCLC and brain metastases: long-term results and biomarker analysis from a non-randomised, open-label, phase 2 trial. Lancet Oncol. 2020; 21(5):655-663. PMC: 7380514. DOI: 10.1016/S1470-2045(20)30111-X. View

Passaro A, Spitaleri G, Gyawali B, de Marinis F . Immunotherapy in Non-Small-Cell Lung Cancer Patients With Performance Status 2: Clinical Decision Making With Scant Evidence. J Clin Oncol. 2019; 37(22):1863-1867. DOI: 10.1200/JCO.18.02118. View

10.

West H, McCleod M, Hussein M, Morabito A, Rittmeyer A, Conter H . Atezolizumab in combination with carboplatin plus nab-paclitaxel chemotherapy compared with chemotherapy alone as first-line treatment for metastatic non-squamous non-small-cell lung cancer (IMpower130): a multicentre, randomised, open-label, phase.... Lancet Oncol. 2019; 20(7):924-937. DOI: 10.1016/S1470-2045(19)30167-6. View

11.

Felip E, Ardizzoni A, Ciuleanu T, Cobo M, Laktionov K, Szilasi M . CheckMate 171: A phase 2 trial of nivolumab in patients with previously treated advanced squamous non-small cell lung cancer, including ECOG PS 2 and elderly populations. Eur J Cancer. 2020; 127:160-172. DOI: 10.1016/j.ejca.2019.11.019. View

12.

Gadgeel S, Lukas R, Goldschmidt J, Conkling P, Park K, Cortinovis D . Atezolizumab in patients with advanced non-small cell lung cancer and history of asymptomatic, treated brain metastases: Exploratory analyses of the phase III OAK study. Lung Cancer. 2019; 128:105-112. DOI: 10.1016/j.lungcan.2018.12.017. View

13.

Crino L, Bronte G, Bidoli P, Cravero P, Minenza E, Cortesi E . Nivolumab and brain metastases in patients with advanced non-squamous non-small cell lung cancer. Lung Cancer. 2019; 129:35-40. DOI: 10.1016/j.lungcan.2018.12.025. View

14.

Paz-Ares L, Ciuleanu T, Cobo M, Schenker M, Zurawski B, Menezes J . 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(2):198-211. DOI: 10.1016/S1470-2045(20)30641-0. View

15.

Reck M, Ciuleanu T, Cobo M, Schenker M, Zurawski B, Menezes J . First-line nivolumab plus ipilimumab with two cycles of chemotherapy versus chemotherapy alone (four cycles) in advanced non-small-cell lung cancer: CheckMate 9LA 2-year update. ESMO Open. 2021; 6(5):100273. PMC: 8493593. DOI: 10.1016/j.esmoop.2021.100273. View

16.

Middleton G, Brock K, Savage J, Mant R, Summers Y, Connibear J . Pembrolizumab in patients with non-small-cell lung cancer of performance status 2 (PePS2): a single arm, phase 2 trial. Lancet Respir Med. 2020; 8(9):895-904. DOI: 10.1016/S2213-2600(20)30033-3. View

17.

Ready N, Hellmann M, Awad M, Otterson G, Gutierrez M, Gainor J . First-Line Nivolumab Plus Ipilimumab in Advanced Non-Small-Cell Lung Cancer (CheckMate 568): Outcomes by Programmed Death Ligand 1 and Tumor Mutational Burden as Biomarkers. J Clin Oncol. 2019; 37(12):992-1000. PMC: 6494267. DOI: 10.1200/JCO.18.01042. View

18.

Paz-Ares L, Luft A, Vicente D, Tafreshi A, Gumus M, Mazieres J . Pembrolizumab plus Chemotherapy for Squamous Non-Small-Cell Lung Cancer. N Engl J Med. 2018; 379(21):2040-2051. DOI: 10.1056/NEJMoa1810865. View

19.

Curran M, Montalvo W, Yagita H, Allison J . PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors. Proc Natl Acad Sci U S A. 2010; 107(9):4275-80. PMC: 2840093. DOI: 10.1073/pnas.0915174107. View

20.

Paz-Ares L, Ramalingam S, Ciuleanu T, Lee J, Urban L, Bernabe Caro R . First-Line Nivolumab Plus Ipilimumab in Advanced NSCLC: 4-Year Outcomes From the Randomized, Open-Label, Phase 3 CheckMate 227 Part 1 Trial. J Thorac Oncol. 2021; 17(2):289-308. DOI: 10.1016/j.jtho.2021.09.010. View