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checkpoint inhibitor; immune checkpoint inhibitor; PD-1/PD-L1 inhibitor

Indications: - cancer immunotherapy - treatment of melanoma, renal cell carcinoma, non-small cell lung cancer, bladder cancer, Hodgkin lymphoma, & colon cancers caused by DNA mismatch-repair deficiency [1] - many solid tumors with mismatch-repair mutations & progressive disease despite therapy respond to checkpoint-inhibitor (PD-L1 inhibitor) treatment with pembrolizumab (Keytruda) [3] - objective radiographic responses in 53% of patients [3] - complete responses in 21% [3] - treatment of virtually any lung cancer [11] - communities of intestinal bacteria influence response to checkpoint inhibitors in patients with non-small cell lung carcinoma [25] Monitor: - echocardiogram to monitor myocarditis [14] Adverse effects: - may increase risk of autoimmune disease - rheumatoid arthritis & polymyalgia rheumatica associated with ipilimumab (Yervoy), nivolumab (Opdivo), pembrolizumab (Keytruda) [6] - wide range of immune-related adverse effects [7] - all checkpoint inhibitors associated with diabetes mellitus type 1 & adrenal insufficiency [23] - immune checkpoint inhibitor therapy is not associated with increased mortality in cancer patients with COVID-19 [20] - autoimmune hepatitis [14] - lymphocytic hypophysitis [14] - hyperprogression of cancer [21] - neurological complications (3%) [4] - myopathy, neuropathy - cerebellar ataxia - internuclear ophthalmoplegia - retinopathy - headache - colitis, diarrhea, hepatitis, hypophysitis, rash more common with CTLA-4 inhibitors [17] - pneumonitis, hypothyroidism, arthralgia, vitiligo more common with PD-1 inhibitors [8,17] - myocarditis [9,12], pericarditis [14] - thyroid dysfunction, hypothyroidism 13.4%, hyperthyroidism 9.5% [19] - cutaneous manifestations - maculopapular rash, pruritus, vitiligo (most common) - xanthems, lichenoid reactions, psoriasis, bullous disorders [24] - psoriasis after PD-1/PD-L1 inhibitors [27] - Stevens-Johnson syndrome or toxic epidermal necrolysis [24] - sclerodermoid reaction, morphea* - multiple studies suggest a favorable association of subtypes of cutaneous manifestations with clinical response & survival [24] - small increase in incidence of pulmonary embolism in patients with metastatic lung cancer 17% vs 14.6% [26] * guidelines for management of toxicity [10] - discontinuation of drug + high-dose IV glucocorticoid [14] * toclizumab for glucocorticoid-resistant morphea [22] Mechanism of action: - when T cells are activated, the activated T cells paradoxically produce 'checkpoint' proteins that then abort the T-cell attack - checkpoint inhibitors facilitate an uninhibited T-cell response to tumor antigens [1] - 3 checkpoint proteins are CTLA-4, PD-1 & PD-L1 - PD-1 is an inhibitory receptor expressed on activated tumor-specific CD4+ helper T-cells & CD8+ cytotoxic T-cells - its major ligand PD-L1 is expressed in many human cancers [5] - inhibition of PD-1 unleashes immunological response of tumor-specific T-cells on tumor cells expressing PD-L1 [5] Notes: - ipilimimab targets CTLA-4 treats melanoma, DLBCL, RCC - tremelimumab targets CTLA-4 (investigational) - nivolumab targets PD-1 treats DLBCL, HNSCC, NSCLC, Hodgkin's, melanoma, others - pembrolizumab targets PD-1 treats DLBCL, HNSCC, NSCLC, Hodgkin's, melanoma, others - cemiplimab targets PD-1 treats cutaneous SCC - atezolizumab targets PD-L1 treats NSCLC, urothelial cancer - avelumab targets PD-L1 treats Merkel cell carcinoma, urothelial cancer - darvalumalb targets PD-L1 treats NSCLC, urothelial cancer

Interactions

drug interactions drug adverse effects of checkpoint inhibitor(s)

Related

cancer immunotherapy programmed cell death protein 1; PDL1 receptor; protein PD-1; CD273 receptor; CD274 receptor; hPD-1 (PDCD1, hPD-1, CD279)

Specific

atezolizumab (Tecentriq) avelumab (Bavencio) cemiplimab (Libtayo) durvalumab (Imfinzi) ipilimumab (Yervoy) nivolumab (Opdivo) pembrolizumab (Keytruda) sugemalimab

General

antineoplastic agent (chemotherapeutic agent) biological response modifier; immune factor; immunomodulator; biomodulator

References

  1. Komaroff AL Immunotherapy to Fight Cancer Begins to Work. NEJM Journal Watch. June 16, 2015 Massachusetts Medical Society (subscription needed) http://www.jwatch.org - Sharma P and Allison JP. The future of immune checkpoint therapy. Science 2015 Apr 3; 348:56. PMID: 25838373 - Le DT et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med 2015 May 30 PMID: 26028255
  2. Cappelli LC et al. Inflammatory arthritis and sicca syndrome induced by nivolumab and ipilimumab. Ann Rheum Dis 2017 Jan; 76:43 PMID: 28000525 Free Article
  3. Le DT, Durham JN, Smith KN et al. Mismatch-repair deficiency predicts response of solid tumors to PD-1 blockade. Science 2017 Jun 8 PMID: 28596308
  4. George J Neurological Events Rare with Anti-PD-1 Therapy More cases expected as immunotherapy for metastatic cancer expands. MedPage Today. September 05, 2017 https://www.medpagetoday.com/Neurology/GeneralNeurology/67694
  5. Topalian SL Targeting Immune Checkpoints in Cancer Therapy. JAMA. Published online September 8, 2017 PMID: 28885639 http://jamanetwork.com/journals/jama/fullarticle/2653953
  6. Belkhir R, Burel SL, Dunogeant L et al. Rheumatoid arthritis and polymyalgia rheumatica occurring after immune checkpoint inhibitor treatment. Ann Rheum Dis 2017 Oct; 76:1747 PMID: 28600350 http://ard.bmj.com/content/76/10/1747
  7. Postow MA, Sidlow R, Hellmann MD. Immune-Related Adverse Events Associated with Immune Checkpoint Blockade. N Engl J Med 2018; 378:158-168. January 11, 2018 PMID: 29320654 http://www.nejm.org/doi/full/10.1056/NEJMra1703481
  8. Khoja L, Day D, Wei-Wu Chen T, Siu LL, Hansen AR. Tumour- and Class-specific Patterns of Immune-Related Adverse Events of Immune Checkpoint Inhibitors. Ann Oncol. 2017;28(10):2377-2385. PMID: 28945858 https://www.medscape.com/viewarticle/890539
  9. Johnson DB, Balko JM, Compton ML et al Fulminant Myocarditis with Combination Immune Checkpoint Blockade. N Engl J Med. 2016 Nov 3;375(18):1749-1755. PMID: 27806233 Free PMC Article
  10. Fuerst ML New Guidelines Outline Management of Immunotherapy Side Effects. Emerging patterns suggest checkpoint inhibitors may cause problems in several organ systems. MedPage Today. ASCO Reading Room. Feb 8, 2018 https://www.medpagetoday.com/reading-room/asco/immunotherapy/71026 - Haanen J, Carbonnel F, Kerr RK et al Management of Toxicities from Immunotherapy: ESMO Clinical Practice Guidelines Ann Oncol (2017) 28 (suppl 4): iv119-iv142 http://www.esmo.org/Guidelines/Supportive-and-Palliative-Care/Management-of-Toxicities-from-Immunotherapy
  11. Kris MG. Checkpoint Inhibitors Have a Role for 'Virtually Every Patient' With Lung Cancer. Medscape. Apr 25, 2018. https://www.medscape.com/viewarticle/895557
  12. Mahmood SS et al. Myocarditis in patients treated with immune checkpoint inhibitors. J Am Coll Cardiol 2018 Apr 24; 71:1755. PMID: 29567210 https://www.sciencedirect.com/science/article/pii/S0735109718333680 - Tocchetti CG et al. Cardiac toxicity in patients treated with immune checkpoint inhibitors: It is now time for cardio-immuno-oncology. J Am Coll Cardiol 2018 Apr 24; 71:1765 PMID: 29567211 https://www.sciencedirect.com/science/article/pii/S0735109718333692
  13. Smith M. Checkpoint Blocker Plus Chemo Slows NSCLC Progress No significant OS improvement in interim analysis of IMpower131 trial. MedPage Today. June 02, 2018 https://www.medpagetoday.com/meetingcoverage/asco/73236 - Jotte RM et al IMpower131: Primary PFS and safety analysis of a randomized phase III study of atezolizumab + carboplatin + paclitaxel or nab-paclitaxel vs carboplatin + nab-paclitaxel as 1L therapy in advanced squamous NSCLC. American Society of Clinical Oncology (ASCO) 2018: Abstract LBA9000.
  14. Medical Knowledge Self Assessment Program (MKSAP) 17, 18, 10, American College of Physicians, Philadelphia 2015, 2018, 2022. - Medical Knowledge Self Assessment Program (MKSAP) 19 Board Basics. An Enhancement to MKSAP19. American College of Physicians, Philadelphia 2022
  15. Johnson DB, Chandra S, Sosman JA Immune Checkpoint Inhibitor Toxicity in 2018 JAMA. 2018;320(16):1702-1703 PMID: 30286224 https://jamanetwork.com/journals/jama/fullarticle/2706415
  16. Byun DJ, Wolchok JD, Rosenberg LM, Girotra M. Cancer immunotherapy - immune checkpoint blockade and associated endocrinopathies. Nat Rev Endocrinol. 2017 Apr;13(4):195-207. Review. PMID: 28106152 Free PMC Article
  17. Marin-Acevedo JA, Chirila RM, Dronca RS. Immune Checkpoint Inhibitor Toxicities. Mayo Clinic Proc. July 2019. 94(7):1321-1329 PMID: 31272574
  18. Lou N. Cardiac Echo Tracks Checkpoint Inhibitor Damage - Global longitudinal strain can flag cardiac injury before EF falls. MedPage Today. Feb 03, 2020 https://www.medpagetoday.com/cardiology/chf/84682 - Awadalla M, Mahmood SS, Groarke JD et al Global longitudinal strain and cardiac events in patients with immune checkpoint inhibitor-related myocarditis. J Am Coll Cardiol Feb 2020; 75(5). PMID: 32029128 http://www.onlinejacc.org/content/75/5/467 - Abraham TP, Aras MA Echo-strain to check up on checkpoint inhibitors. J Am Coll Cardiol Feb 2020; 75(5) PMID: 32029129 http://www.onlinejacc.org/content/75/5/479
  19. Monaco K How Prevalent Is Checkpoint Inhibitor Thyroid Dysfunction, Really? - Real-world data offer word of caution for oncologists. MedPage Today. April 1, 2020 https://www.medpagetoday.com/meetingcoverage/endo/85750 - Quandt Z et al Finding the Needles in the Haystack: Harnessing the Electronic Health Record to Find Thyroid Immune Related Adverse Events. ENDO 2020; Abstract SAT-418
  20. Worcester S Immune Checkpoint Inhibitors Don't Increase Death Risk for COVID-19 Cancer Patients. Medscape - Aug 07, 2020. https://www.medscape.com/viewarticle/935370
  21. Park HJ, Kim KW, Won SE et al Definition, Incidence, and Challenges for Assessment of Hyperprogressive Disease During Cancer Treatment With Immune Checkpoint Inhibitors. A Systematic Review and Meta-analysis. JAMA Netw Open. 2021;4(3):e211136. March 24 PMID: 33760090 Free article https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2777859 - Sehgal K Hyperprogression in Patients With Cancer Receiving Immune Checkpoint Inhibitors. JAMA Netw Open. 2021;4(3):e211839. PMID: 33760084 Free article https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2777853
  22. Blaise M, Cardot-Leccia N, Seitz-Polski B et al Tocilizumab for Corticosteroid-Refractory Immune Checkpoint Inhibitor- Induced Generalized Morphea. JAMA Dermatol. Published online November 30, 2022. PMID: 36449277 https://jamanetwork.com/journals/jamadermatology/fullarticle/2798842
  23. NEJM Knowledge+ Complex Medical Care - Barroso-Sousa R, Barry WT, Garrido-Castro AC et al Incidence of Endocrine Dysfunction Following the Use of Different Immune Checkpoint Inhibitor Regimens: A Systematic Review and Meta-analysis. JAMA Oncol. 2018 Feb 1;4(2):173-182. PMID: 28973656 PMCID: PMC5838579 Free PMC article.
  24. Du Y, Wu W, Chen M et al Cutaneous Adverse Events and Cancer Survival Prognosis With Immune Checkpoint Inhibitor Treatment. A Systematic Review and Meta-Analysis. JAMA Dermatol. Published online September 6, 2023. PMID: 37672255 https://jamanetwork.com/journals/jamadermatology/fullarticle/2808778
  25. Guglielmi G Gut microbiome discovery provides roadmap for life-saving cancer therapies. The balance between bacterial communities in the gut affects the likelihood of a positive response to drugs called checkpoint inhibitors. Nature News. June 24, 2024 https://www.nature.com/articles/d41586-024-02070-9 - Derosa L, Iebba V, Silva CAC et al. Custom scoring based on ecological topology of gut microbiota associated with cancer immunotherapy outcome. Cell. 2024. Jun 20;187(13):3373-3389.e16 PMID: 38906102 Free article. https://www.cell.com/cell/fulltext/S0092-8674(24)00538-5
  26. Kahn K Checkpoint Inhibitors for Lung Cancer Linked to Pulmonary Embolism. Study raises questions about how to assess patient risk, experts say. MedPage Today. October 8, 2024 https://www.medpagetoday.com/meetingcoverage/chest/112306
  27. Kneisel K Watch for Psoriasis After Cancer Immunotherapy, Study Says. PD-1/PD-L1 inhibitors singled out for association. MedPage Today November 7, 2024 https://www.medpagetoday.com/dermatology/psoriasis/112783