Evolution of First-Line Immune Checkpoint Inhibition in Advanced or Metastatic Solid Tumors - Episode 1

Overview of Immune Checkpoint Inhibitors in NSCLC

Overview of T-cell immune regulation

Pathways involved in T-cell regulation

Antigen-presenting cells (APCs) activate T-cell receptors via the major histocompatibility complex, but T-cell activation is ultimately controlled by costimulatory and coinhibitory molecules on T cells.1 Molecules that costimulate T-cell activation include CD28, ICOS, and TNFRSF4.2 Coinhibitory molecules that reduce T-cell activation include CTLA-4, PD-1, T-cell receptor with Ig and ITIM domains protein, LAG-3, TIM-3, BTLA.3 These coinhibitory receptors act as immune checkpoints, downregulating T-cell activation.1

Role of CTLA-1 and PD-1 in T-cell regulation

CTLA-4 and PD-1 are key immune checkpoint molecules that attenuate T-cell activation.1 CTLA-4, which is stored in effector T cells, is rapidly relocated to the cell surface through exocytosis of vesicles containing CTLA-4 when the costimulatory molecule CD28 interacts with CD80 and CD86 located on APCs.4 When released, CTLA-4 competitively inhibits CD28 and also may remove CD80 and CD86 from APCs, leading to reduced T-cell activation.5 After activation occurs, T cells express the coinhibitory molecule PD-1.1 Once expressed, PD-1 interacts with its ligands, PD-L1 and PD-L2, and inhibits T-cell proliferation, cytokine production, and survival.1,4

Immune regulation in cancer cells

Cancer evasion of immunity

T cells are central to anticancer immunity, yet tumors are able induce environments that lead to T-cell dysregulation.6,7 The high antigen loads, particularly of PD-L1, produced by cancer cells result in chronic stimulation of tumor-infiltrating lymphocytes (TILs).6-8 This persistent stimulation can result in T-cell exhaustion and dysregulation of immune function.7,9 In non– small cell lung cancer (NSCLC) disease progression, CD8+ T cells shift from a pre-exhausted to exhausted state while regulatory T-cell (Treg) activation increases.10 Tregs constitutively express CTLA-4 and suppress T-cell activation, possibly through downregulation of CD80 and CD86 on APCs.4

CTLA-4 and PD-1 in NSCLC

In cancer, dysregulation of immune function and disease progression are correlated with changes in the expression of coinhibitory molecules on TILs.7,10,11 In a comparison of CD8+ T cells from patients with NSCLC and healthy donors, the coinhibitory molecules PD-1, CTLA-4, TIM-3, LAG-3, and BTLA were found at higher levels in TILs.7 PD-1 was expressed at the highest levels with disease progression, while the cumulative expression of the other coinhibitory molecules increased with disease stage.7 Guo et al also found an increase in PD-1 and CTLA-4 expression in exhausted CD8+ T cells.10 Exhausted CD4+ cells also expressed high levels of PD-1, whereas Tregs had increased levels of CTLA-4.10

Immune checkpoint inhibitors

Rationale for ICI in cancer

The increased expression of coinhibitory molecules in TILs makes them ideal targets for immune checkpoint inhibitors (ICIs).12 ICIs interact with coinhibitory molecules or their ligands and reactivate T-cell immune function.7,13 The first CTLA-4 inhibitor, ipilimumab, was approved by the FDA for use in melanoma in 2010, followed by the approval of nivolumab, a PD-1 inhibitor, for the treatment of lung adenocarcinoma.13

Overview of ICI monotherapies for NSCLC

Currently approved ICIs for NSCLC as of October 2022 are shown in Table 1.13-20 The CTLA-4 inhibitor ipilimumab is approved as combination therapy with nivolumab, while nivolumab is indicated for use in combination with ipilimumab or as a single agent in patients with disease progression after chemotherapy.14,15 All of the approved therapies, except durvalumab, are indicated as first-line treatment in specific patient populations.14-20 Cemiplimab is a PD-1 inhibitor specifically indicated for patients with high PD-L1 levels (≥50%).17 The National Comprehensive Cancer Network recommends immunohistochemical testing for PD-L1 expression in all patients with metastatic NSCLC due to survival benefits seen with pembrolizumab as a first-line therapy.21

Table 1. FDA Immune Checkpoint Inhibitors Approved for NSCLC13-20

aSee full prescribing information for indication.

bPD-L1 status determined by an FDA-approved test.

NSCLC, non–small cell lung cancer

Rationale for combining CTLA-4 and PDL-1 inhibitors

Synergistic effects of CTLA-4 and PD-1/PD-L1 inhibitor combination therapy

The combined use of ICIs is supported by studies that have shown increased levels of many coinhibitory molecules in TILs.7,10 CTLA-4 and PD-1 are the most prominent coinhibitory molecules found in exhausted CD8+ and CD4+ T cells from advanced NSCLC tumors.10 In CheckMate 227 (NCT02477826), a phase 3 study in untreated adult patients with stage IV or recurrent NSCLC, patients treated with ipilimumab and nivolumab had longer progression-free survival and greater overall survival (OS) compared with patients treated with chemotherapy alone.22 These results led to FDA approval of the first combined CTLA-4/PD-1 immune checkpoint blockade therapy for NSCLC.14,15

Ongoing clinical trials of combination therapies for NSCLC

Clinical trials of new combinations of CTLA-4 and PD-1/PD-L1 inhibitors are shown in Table 2.23-31 Novel ICI combinations include ipilimumab and cemiplimab, botensilimab and balstilimab, and pembrolizumab with either ipilimumab or ONC-382.23-27 An additional phase 1 trial will investigate a novel ICI formulation, a bispecific monoclonal antibody for both CTLA-4 and PD-1 inhibition.28 A phase 3 trial of a CTLA-4/PD-L1 inhibitor combination, tremelimumab plus durvalumab, used as a first-line treatment did not meet its primary end points in patients with PD-L1 expression levels ≥25%.32 Tumor mutational burden (TMB) was found to be a better predictor of OS. Other clinical and mechanistic studies of NSCLC have found TMB to be more predictive than PD-L1 of immune dysfunction and treatment success.33

Table 2. Clinical Trials Combining CTLA-4 and PD-1/PD-L1 Inhibitors in NSCLC23-31

NSCLC, non–small cell lung cancer


Clinical trials of ICI monotherapy and combination therapy have demonstrated survival benefits in patients with advanced or metastatic NSCLC. As our understanding of the coinhibitory responses of T cells to the tumor microenvironment continues to grow, additional therapeutic combinations of ICIs will likely be identified.


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2. Smith-Garvin JE, Koretzky GA, Jordan MS. T cell activation. Annu Rev Immunol. 2009;27:591-619. doi:10.1146/annurev.immunol.021908.132706

3. Chen L, Flies DB. Molecular mechanisms of T cell co-stimulation and co-inhibition. Nat Rev Immunol. 2013;13(4):227-242. doi:10.1038/nri3405. Published correction appears in Nat Rev Immunol. 2013;13(7):542.

4. Buchbinder EI, Desai A. CTLA-4 and PD-1 pathways: similarities, differences, and implications of their inhibition. Am J Clin Oncol. 2016;39(1):98-106. doi:10.1097/COC.0000000000000239

5. Seidel JA, Otsuka A, Kabashima K. Anti-PD-1 and anti-CTLA-4 therapies in cancer: mechanisms of action, efficacy, and limitations. Front Oncol. 2018;8:86. doi:10.3389/fonc.2018.00086

6. Kim N, Kim HK, Lee K, et al. Single-cell RNA sequencing demonstrates the molecular and cellular reprogramming of metastatic lung adenocarcinoma. Nat Commun. 2020;11(1):2285. doi:10.1038/s41467-020-16164-1

7. Thommen DS, Schreiner J, Müller P, et al. Progression of lung cancer is associated with increased dysfunction of T cells defined by coexpression of multiple inhibitory receptors. Cancer Immunol Res. 2015;3(12):1344-1355. doi:10.1158/2326-6066.CIR-15-0097

8. Wu M, Huang Q, Xie Y, et al. Improvement of the anticancer efficacy of PD-1/PD-L1 blockade via combination therapy and PD-L1 regulation. J Hematol Oncol. 2022;15(1):24. doi:10.1186/s13045-022-01242-2

9. Wherry EJ. T cell exhaustion. Nat Immunol. 2011;12(6):492-499. doi:10.1038/ni.2035

10. Guo X, Zhang Y, Zheng L, et al. Global characterization of T cells in non–small-cell lung cancer by single-cell sequencing. Nat Med. 2018;24(7):978-985. doi:10.1038/s41591-018-0045-3. Published correction appears in Nat Med. 2018;24(10):1628.

11. Fourcade J, Sun Z, Pagliano O, et al. CD8(+) T cells specific for tumor antigens can be rendered dysfunctional by the tumor microenvironment through upregulation of the inhibitory receptors BTLA and PD-1. Cancer Res. 2012;72(4):887-896. doi:10.1158/0008-5472.CAN-11-2637

12. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12(4):252-264. doi:10.1038/nrc3239

13. Shiravand Y, Khodadadi F, Kashani SMA, et al. Immune checkpoint inhibitors in cancer therapy. Curr Oncol. 2022;29(5):3044-3060. doi:10.3390/curroncol29050247

14. Yervoy. Prescribing information. Bristol Myers Squibb; 2022. Accessed November 1, 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/125377s110lbl.pdf

15. Opdivo. Prescribing information. Bristol Myers Squibb; 2022. Accessed November 1, 2022. https://packageinserts.bms.com/pi/pi_opdivo.pdf

16. Keytruda. Prescribing information. Merck; 2022. Accessed November 1, 2022. https://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_pi.pdf

17. Libtayo. Prescribing information. Regeneron; 2022. Accessed November 1, 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/761097s007lbl.pdf

18. FDA approves cemiplimab-rwlc for non–small cell lung cancer with high PD-L1 expression. FDA. February 22, 2021. Accessed October 15, 2022. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-cemiplimab-rwlc-non-small-cell-lung-cancer-high-pd-l1-expression

19. Tecentriq. Prescribing information. Genentech; 2022. Accessed November 1, 2022. https://www.gene.com/download/pdf/tecentriq_prescribing.pdf

20. Imfinzi. Prescribing information. AstraZeneca; 2022. Accessed November 1, 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/761069s018lbl.pdf

21. NCCN. Clinical Practice Guidelines in Oncology. Non–small cell lung cancer, version 5.2022. Accessed October 15, 2022. https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf.

22. 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(21):2020-2031. doi:10.1056/NEJMoa1910231

23. REGN2810 (anti-PD-1 antibody), platinum-based doublet chemotherapy, and ipilimumab (anti-CTLA-4 antibody) versus pembrolizumab monotherapy in patients with lung cancer. ClinicalTrials.gov. Updated August 13, 2021. Accessed October 18, 2022. https://clinicaltrials.gov/ct2/show/NCT03515629?term=NCT03515629&cond=nsclc&draw=2&rank=1

24. A study of REGN2810 and ipilimumab in patients with lung cancer. ClinicalTrials.gov. Updated November 17, 2021. Accessed October 18, 2022. https://clinicaltrials.gov/ct2/show/NCT03430063?term=NCT03430063&cond=nsclc&draw=2&rank=1

25. Fc-engineered anti-CTLA-4 monoclonal antibody in advanced cancer. ClinicalTrials.gov. Updated September 16, 2022. Accessed October 18, 2022. https://clinicaltrials.gov/ct2/show/NCT03860272?term=NCT03860272&cond=nsclc&draw=2&rank=1

26. Study of pembrolizumab given with ipilimumab or placebo in participants with untreated metastatic non–small cell lung cancer (NSCLC) (MK-3475-598/KEYNOTE-598). ClinicalTrials.gov. Updated October 4, 2022. Accessed October 18, 2022. https://clinicaltrials.gov/ct2/show/NCT03302234?term=NCT03302234&cond=nsclc&draw=2&rank=1

27. Safety, PK and efficacy of ONC-392 in monotherapy and in combination of anti-PD-1 in advanced solid tumors and NSCLC (PRESERVE-001). ClinicalTrials.gov. Updated October 13, 2022. Accessed October 18, 2022. https://clinicaltrials.gov/ct2/show/NCT04140526?term=NCT04140526&cond=nsclc&draw=2&rank=1

28. A study of XmAb®20717 in subjects with selected advanced solid tumors (DUET-2). ClinicalTrials.gov. Updated July 22, 2022. Accessed October 18, 2022. https://clinicaltrials.gov/ct2/show/NCT03517488?term=NCT03517488&cond=nsclc&draw=2&rank=1

29. Durvalumab and tremelimumab with or without high or low-dose radiation therapy in treating patients with metastatic colorectal or non–small cell lung cancer. ClinicalTrials.gov. Updated July 19, 2022. Accessed October 18, 2022. https://clinicaltrials.gov/ct2/show/NCT02888743?term=NCT02888743&cond=nsclc&draw=2&rank=1

30. Phase III open label first line therapy study of MEDI 4736 (durvalumab) with or without tremelimumab versus SOC in non small-cell lung cancer (NSCLC) (MYSTIC). ClinicalTrials.gov. Updated October 6, 2022. Accessed October 18, 2022. https://clinicaltrials.gov/ct2/show/NCT02453282

31. A global study to assess the effects of MEDI4736 (durvalumab), given as monotherapy or in combination with tremelimumab determined by PD-L1 expression versus standard of care in patients with locally advanced or metastatic non small cell lung cancer (ARCTIC). ClinicalTrials.gov. Updated October 10, 2022. Accessed October 18, 2022. https://clinicaltrials.gov/ct2/show/NCT02352948?term=NCT02352948&cond=nsclc&draw=2&rank=1

32. Rizvi NA, Cho BC, Reinmuth N, et al; MYSTIC Investigators. Durvalumab with or without tremelimumab vs standard chemotherapy in first-line treatment of metastatic non–small cell lung cancer: the MYSTIC phase 3 randomized clinical trial. JAMA Oncol. 2020;6(5):661-674. doi:10.1001/jamaoncol.2020.0237. Published correction appears in JAMA Oncol. 2020;6(11):1815.

33. Ready N, Hellmann MD, Awad MM, et al. 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. doi:10.1200/JCO.18.01042