Lo que un reumatólogo debe saber de inmunoterapia contra el cáncer, abreviado

1. Lo que un reumatólogo debe saber de la inmunoterapia del cáncer Mauricio Lema Medina MD Clínica de Oncología Astorga / Clínica SOMA, Medellín, Colombia Cartagena, 22/03/2019

2. Onconerd

3. Cancer Immunotherapy Mechanism of action

4. Immunoediting Elimination Equilibrium Escape Complete destruction of cancer cells Cancer growth stalled Cancer growth unhindered Disis ML, Semin Oncol, 2014

5. The goal of cancer immunotherapy is to boost or restore the ability of the immune system to detect and destroy cancer cells by overcoming the mechanisms by which tumors evade and suppress the immune response, Disis ML, Semin Oncol, 2014

6. The goal of cancer immunotherapy is to boost or restore the ability of the immune system to detect and destroy cancer cells by overcoming the mechanisms by which tumors evade and suppress the immune response, Disis ML, Semin Oncol, 2014

7. Immunoediting Elimination Equilibrium Escape Complete destruction of cancer cells Cancer growth unhindered Disis ML, Semin Oncol, 2014 Immunotherapy

8. Célula tumoral PD-1 PD-L1 PD-L2 Receptor de células T MHC-1 CD28 Shp-2 B7.1 Célula Dendrítica Antígeno tumoral Linfocito T CD8+/Citotóxico

9. Célula tumoral PD-1 PD-L1 PD-L2 Receptor de células T MHC-1 CD28 Shp-2 B7.1 Célula Dendrítica Antígeno tumoral Linfocito T CD8+/Citotóxico Receptor de célula T (TCR) MHC II y antígeno MHC II: Major histocompatibility complex

10. T-Cell activation Célula tumoral PD-1 PD-L1 PD-L2 Receptor de células T MHC-1 CD28 Shp-2 B7.1 Célula DendríticaLinfocito T CD8+/Citotóxico Co-estimuladora CD28 Co-estimuladora B7.1

11. Célula tumoral PD-1 PD-L1 PD-L2 Receptor de células T MHC-1 CD28 Shp-2 B7.1 Célula DendríticaLinfocito T CD8+/Citotóxico CTLA-4 Co-estimuladora B7.1 T-Cell brake

12. Célula tumoral PD-1 PD-L1 PD-L2 Receptor de células T MHC-1 CD28 Shp-2 B7.1 Célula DendríticaLinfocito T CD8+/Citotóxico CTLA-4 Co-estimuladora B7.1 T-Cell brake Anti-CTLA-4

13. Célula tumoral PD-1 PD-L1 PD-L2 Receptor de células T MHC-1 CD28 Shp-2 B7.1 Célula DendríticaLinfocito T CD8+/Citotóxico CTLA-4 Co-estimuladora B7.1 Restablishes T-Cell functionality Anti-CTLA-4

14. Célula dendrític a Célula T MHC TCR B7 CD28 CTLA-4 Célula T Células Dendrítica s Interacción de Células Presentadoras de antígeno – Células T Anti- CTLA-4 Bloqueo del CTLA-4 Los anticuerpos anti CTLA-4 restablecen la respuesta antitumoral de linfocitos T Ipilimumab Tremelimumab

15. T-Cell/Drugs Ligands Where Action CTLA-4 B7.1 (CD80) APC Immune response inhibited CTLA-4 B7.2 (CD86) APC Immune response inhibited Ipilimumab anti-CTLA-4 T-Cells Immune response restored Tremelimumab anti-CTLA-4 T-Cells Immune response restored

16. Effector T-Cells

17. Tumor Cell PD-1 PD-L1 PD-L2 Receptor de células T MHC-1 CD28 Shp-2 B7.1 MHC class I + Ag

18. Tumor Cell PD-1 PD-L1 PD-L2 Receptor de células T MHC-1 CD28 Shp-2 B7.1 CD8+ T-Cell MHC class I + Ag T-Cell receptor) +++

19. Effector T- Cell activation Célula tumoral PD-1 PD-L1 PD-L2 Receptor de células T MHC-1 CD28 Shp-2 B7.1 CD8+ T-Cell MHC class I + Ag T-Cell receptor +++

20. Célula tumoral PD-1 PD-L1 PD-L2 Receptor de células T MHC-1 CD28 Shp-2 B7.1 Linfocito T CD8+/Citotóxico IFN-γ IFN-γR PD-1 +++

21. Tumor PD-L1 (PD- L2) expression occurs when there is continuous Gamma IFN exposure Célula tumoral PD-1 PD-L1 PD-L2 Receptor de células T MHC-1 CD28 Shp-2 B7.1 Linfocito T CD8+/Citotóxico IFN-γ IFN-γR PD-L1 PD-1 - - - Anti tumor immunity Stalled

22. Célula tumoral PD-1 PD-L1 PD-L2 Receptor de células T MHC-1 CD28 Shp-2 B7.1 Linfocito T CD8+/Citotóxico PD-L1 PD-1 - - - Anti-PD1

23. Célula tumoral PD-1 PD-L1 PD-L2 Receptor de células T MHC-1 CD28 Shp-2 B7.1 Linfocito T CD8+/Citotóxico PD-L1 PD-1 +++ Anti-PD1 T-Cell action restored

24. Célula tumoral PD-1 PD-L1 PD-L2 Receptor de células T MHC-1 CD28 Shp-2 B7.1 Linfocito T CD8+/Citotóxico PD-L1 PD-1 - - - Anti-PD-L1

25. Célula tumoral PD-1 PD-L1 PD-L2 Receptor de células T MHC-1 CD28 Shp-2 B7.1 Linfocito T CD8+/Citotóxico PD-L1 PD-1 +++ Anti-PD-L1 T-Cell action restored

26. Droga Mecanismo de acción Pembrolizumab Anti-PD1 Nivolumab Anti-PD1 Avelumab Anti-PD-L1 Durvalumab Anti-PD-L1 Atezolizumab Anti-PD-L1 Célula T Célula tumoral MHCTCR PD-1 PD-L1 Cancer cell T-cell

27. T-Cell/Drugs Ligands Where (Ligands) Action CTLA-4 B7.1 (CD80) APC Immune response inhibited CTLA-4 B7.2 (CD86) APC Immune response inhibited Ipilimumab anti-CTLA-4 T-Cells Immune response restored Tremelimumab anti-CTLA-4 T-Cells Immune response restored PD1 PD-L1 Tumor cells Immune response inhibited PD1 PD-L2 Tumor cells Immune response inhibited Nivolumab PD1 T-Cell Immune response restored Pembrolizumab PD1 T-Cell Immune response restored Atezolizumab PD-L1 Tumor cells… Immune response restored Avelumab PD-L1 Tumor cells Immun response restored Durvalumab PD-L1 Tumor cells Immune response restored

28. Immune Checkpoint Inhibitors Main Clinical Indications

29. Advanced Melanoma Hodi FS, NEJM, 2010 Ipilimumab gp100 (“placebo”) n= 676 Ipilimumab mOS: 10 mo gp100 mOS: 6.4 HR: 0.68 Unresectable stage III or IV melanoma, whose disease had progressed while they were receiving therapy for metastatic disease

30. CM 066: Advanced Melanoma 418 previously untreated patients who had metastatic melanoma without a BRAFmutation to receive nivolumab or dacarbazine The primary end point was overall survival. Robert C, NEJM, 2015

31. KN 006:Advanced Melanoma 834 previously untreated patients who had metastatic melanoma to receive pembrolizumab or ipilimumab The primary end point was PFS and OS. Robert C, NEJM, 2015

32. Advanced Melanoma 945 previously untreated patients with unresectable stage III or IV melanoma to nivolumab alone, nivolumab plus ipilimumab, or ipilimumab alone. Progression-free survival and overall survival were coprimary end points. Larkin J, NEJM, 2015

33. Adjuvant Melanoma 906 patients (≥15 years of age) who were undergoing complete resection of stage IIIB, IIIC, or IV melanoma to receive Nivolumab or Ipilimumab Weber J, NEJM, 2017

34. CM17: Advanced Squamous NSCLC, 2nd-Line 272 patients to receive nivolumab, or docetaxel, The primary end point was overall survival. Brahmer J, NEJM, 2015

35. CM17/57: Advanced NSCLC, 2nd-Line ≥3 years’ follow-up Vokes EE, Ann Oncol 2018

36. •Untreated stage IV NSCLC •PD-L1 TPS ≥50% •ECOG PS 0-1 •No activating EGFR mutation or ALK translocation •No untreated brain metastases •No active autoimmune disease requiring systemic therapy 1:1 Pembrolizumab Platinum-doublet Chemotherapy KEYNOTE-024 Primary endpoint: OS Reck, M., Rodríguez-Abreu, D., Robinson, A. G., Hui, R., Csőszi, T., Fülöp, A., … Brahmer, J. R. (2016). Pembrolizumab versus Chemotherapy for PD-L1–Positive Non–Small- Cell Lung Cancer. New England Journal of Medicine, 375(19), 1823–1833. https://doi.org/10.1056/NEJMoa1606774 In patients with advanced NSCLC and PD-L1 expression on at least 50% of tumor cells, pembrolizumab was associated with significantly longer progression-free and overall survival and with fewer adverse events than was platinum-based chemotherapy.

37. KeyNote 189 - Pembrolizumab plus Chemotherapy in Metastatic Non–Small-Cell Lung Cancer Gandhi, L., Rodríguez-Abreu, D., Gadgeel, S., Esteban, E., Felip, E., De Angelis, F., … Garassino, M. C. (2018). Pembrolizumab plus Chemotherapy in Metastatic Non–Small-Cell Lung Cancer. New England Journ Metastatic nonsquamous NSCLC No sensitizing EGFR or ALKmutations Treatment-naive for metastatic NSCLC ECOG PS 0/1 Measurable disease Tumor sample for PD-L1 status available No CNS metastasis symptoms No significant autoimmune disease/treatment 2:1 Stratification Smoking history By PD-L1 expression (<1% vs ≥1%) Cisplatin vs Carboplatin Pembrolizumab + Pemetrexed + Platin Pemetrexed + Platin Endpoints: Coprimary endpoints OS / PFS (by central review)

39. PACIFIC: Durvalumab after Chemoradiotherapy in Stage III Non–Small-Cell Lung Cancer. Vicente, D., Murakami, S., Hui, R., … Özgüroğlu, M. (2017). Durvalumab after Chemoradiotherapy in Stage III Non–Small-Cell Lung Cancer. New England Journal of Medicine, 377(20), 1919–1929. h Stage III unresectable NSCLC Non-progressors after chemo-radiation ECOG PS 0/1 No significant autoimmune disease No prior exposure to immunotherapy 2:1 Durvalumab 10 mg/kg q2w, up to 1 yr Placebo q2w, up to 1 yr Endpoints: Coprimary endpoints PFS and OS

40. PACIFIC: Durvalumab after Chemoradiotherapy in Stage III Non–Small-Cell Lung Cancer. Vicente, D., Murakami, S., Hui, R., … Özgüroğlu, M. (2017). Durvalumab after Chemoradiotherapy in Stage III Non–Small-Cell Lung Cancer. New England Journal of Medicine, 377(20), 1919–1929. h

41. CM141: Recurrent Squamous Head and Neck Ca 361 patients with recurrent squamous-cell carcinoma of the head and neck whose disease had progressed within 6 months after platinum-based chemotherapy to receive nivolumab or standard, single-agent systemic therapy Ferris RL, NEJM, 2016

42. Median OS for Patients With mRCC Treated With Nivolumab 1-yr OS: 70% 2-yr OS: 50% Drake CG, et al. ASCO 2013. Abstract 4514. 100 80 60 40 20 0 OS(%) Mos Since Treatment Initiation 510 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 Pts at Risk, n 034 33 28 28 23 19 14 12 8 8 8 8 8 5 2 0 0 Died/Treated 15/34 Median, Mos (95% CI) > 22 (13.60 - NE)

43. Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma. N Engl J Med. 2015;373(19):1803-1813. doi:10.1056/NEJMoa1510665. CHECKMATE 025: Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma 821 patients with Advanced clear-cell renal carcinoma for which they had received previous treatment with one or two regimens of antiangiotenic tehrapy Endpoints OS Nivolumab 3 mg/kg IV q2w Everolimus 10 mg QD

44. 44 Overall survival HR, hazard ratio; NE, not estimable. Median OS, months (95% CI) Nivolumab (N = 410) 25.0 (21.8–NE) Everolimus (N = 411) 19.6 (17.6–23.1) HR (98.5% CI), 0.73 (0.57–0.93) P = 0.0018 0 3 6 129 15 18 21 24 27 30 33 0.0 0.3 0.1 0.2 0.4 0.5 0.6 0.7 0.8 0.9 1.0 OverallSurvival(Probability) Nivolumab Everolimus ▪ The risk of death was reduced by 27% in patients in the nivolumab treatment group compared with those in the everolimus group ▪ Study stopped after planned interim analysis (398 deaths) because assessment by an independent data monitoring committee concluded that the study met its primary endpoint, demonstrating superior OS for nivolumab This means that patients are more likely to live when treated with nivolumab versus everolimus Months

45. Bellmunt J, de Wit R, Vaughn DJ, et al. Pembrolizumab as Second-Line Therapy for Advanced Urothelial Carcinoma. N Engl J Med. 2017;376(11):1015-1026. doi:10.1056/NEJMoa1613683. KEYNOTE 045: Pembrolizumab as Second-Line Therapy for Advanced Urothelial Carcinoma 542 patients with Advanced urothelial cancer Recurrent or refractary to cisplatin-based chemotherapy Endpoints OS/PFS Pembrolizumab 200 mg IV q3w Investigators choice of second-line chemotherapy (Paclitaxel, Vinflumine, Docetaxel)

46. Bellmunt J, de Wit R, Vaughn DJ, et al. Pembrolizumab as Second-Line Therapy for Advanced Urothelial Carcinoma. N Engl J Med. 2017;376(11):1015-1026. doi:10.1056/NEJMoa1613683. KEYNOTE 045: Pembrolizumab as Second-Line Therapy for Advanced Urothelial Carcinoma

47. Boosting the Potential for Immune Response With Combination Therapies Control Targeted therapies/Chemotherapy Survival Time Modified from Ribas A, et al. Clin Cancer Res. 2012;18:336-341.

48. Survival Time Modified from Ribas A, et al. Clin Cancer Res. 2012;18:336- 341. Survival Pattern with Chemotherapy and Immune checkpoint blockade Immune checkpoint Chemotherapy

49. CM 067: Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma Larkin J, NEJM, 2015 945 previously untreated patients with unresectable stage III or IV melanoma to nivolumab alone, nivolumab plus ipilimumab, or ipilimumab alone.

50. CM 214: Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma Motzer R, NEJM, 2018 1096 patients were assigned to receive nivolumab plus ipilimumab or sunitinib

51. Survival Time Inspired by Ribas A, et al. Clin Cancer Res. 2012;18:336- 341. Survival Pattern with Chemotherapy and Immune checkpoint blockade Immune checkpoint + Chemotherapy Chemotherapy

52. Evolving indications

53. Gastroesophageal cancer Breas cancer (TNBC) Hodgkin’s lymphomaMerkel-cell carcinoma Microsatellite-instability (tumor agnostic) SCLC NHL ThyroidHCC

54. Immunotherapy dosages, schedules, and combinations

55. Ipilimumab • YERVOY® (IPILIMUMAB) ESTÁ INDICADO PARA EL TRATAMIENTO DE MELANOMA NO RESECABLE O METASTÁSICO

56. Nivolumab • TRATAMIENTO ADYUVANTE DEL MELANOMA OPDIVO® ESTÁ INDICADO PARA EL TRATAMIENTO ADYUVANTE DE PACIENTES CON MELANOMA ESTADÍO IIIB/IIIC Y IV CON ALTO RIESGO DE RECURRENCIA, QUE HAN SIDO SOMETIDOS A RESECCIÓN COMPLETA. • MELANOMA IRRESECABLE O METASTÁSICO OPDIVO® COMO MONOTERAPIA O EN COMBINACIÓN CON IPILIMUMAB ESTÁ INDICADO PARA EL TRATAMIENTO DE PACIENTES CON MELANOMA AVANZADO (IRRESECABLE O METASTÁSICO) EN ADULTOS. • CÁNCER DE PULMÓN METASTÁSICO DE CÉLULAS NO PEQUEÑAS OPDIVOTM (NIVOLUMAB) ESTÁ INDICADO PARA EL TRATAMIENTO DE PACIENTES CON CÁNCER DE PULMÓN METASTÁSICO DE CÉLULAS NO PEQUEÑAS (CPNM O NSCLC, POR SUS SIGLAS EN INGLÉS) QUE MUESTRA PROGRESIÓN DURANTE O DESPUÉS DE LA QUIMIOTERAPIA BASADA EN PLATINO. PREVIO A RECIBIR OPDIVOTM, LOS PACIENTES CON MUTACIONES TUMORALES GENÓMICAS DE EGFR O ALK DEBEN HABER PRESENTADO PROGRESIÓN DE LA ENFERMEDAD CON UNA TERAPIA APROBADA PARA ESTAS MUTACIONES • CARCINOMA DE CÉLULAS RENALES OPDIVOTM (NIVOLUMAB) ESTÁ INDICADO PARA EL TRATAMIENTO DE PACIENTES CON CARCINOMA AVANZADO DE CÉLULAS RENALES (RCC, POR SUS SIGLAS EN INGLÉS) QUE HAN RECIBIDO TERAPIA ANTI-ANGIOGÉNICA PREVIA. • CARCINOMA DE CÉLULAS ESCAMOSAS DE CABEZA Y CUELLO (SCCHN) OPDIVO ESTÁ INDICADO PARA EL TRATAMIENTO DE PACIENTES CON CARCINOMA DE CÉLULAS ESCAMOSAS DE CABEZA Y CUELLO (SCCHN, POR SUS SIGLAS EN INGLÉS) RECURRENTE O METASTÁSICO QUE HAN SUFRIDO PROGRESIÓN DE LA ENFERMEDAD DURANTE O LUEGO DE UNA TERAPIA BASADA EN PLATINO.

57. Pembrolizumab • KEYTRUDA® (PEMBROLIZUMAB) ESTÁ INDICADO PARA EL TRATAMIENTO DE PACIENTES CON MELANOMA NO RESECABLE O METASTÁSICO. • CARCINOMA DE PULMÓN DE CÉLULAS NO PEQUEÑAS KEYTRUDA COMO MONOTERAPIA ESTÁ INDICADO PARA EL TRATAMIENTO DE PRIMERA LÍNEA DE PACIENTES CON CARCINOMA DE PULMÓN DE CÉLULAS NO PEQUEÑAS (NSCLC, POR SUS SIGLAS EN INGLÉS) METASTÁSICO, CUYOS TUMORES EXPRESAN PD-L1 CON UN ?50% DE PUNTUACIÓN DE PROPORCIÓN DE CÉLULAS TUMORALES (PPT), DETERMINADO POR UNA PRUEBA VALIDADA, SIN ABERRACIONES TUMORALES GENÓMICAS DE EGFR O ALK. • KEYTRUDA, EN COMBINACIÓN CON QUIMIOTERAPIA CON PEMETREXED Y PLATINO, ESTÁ INDICADO PARA EL TRATAMIENTO DE PRIMERA LÍNEA DE PACIENTES CON NSCLC NO ESCAMOSO, METASTÁSICO, SIN ABERRACIONES GENÓMICAS TUMORALES DE EGFR O ALK. • KEYTRUDA, EN COMBINACIÓN CON CARBOPLATINO Y PACLITAXEL O NAB-PACLITAXEL, ESTÁ INDICADO PARA EL TRATAMIENTO DE PRIMERA LÍNEA DE PACIENTES CON NSCLC ESCAMOSO, METASTÁSICO. • KEYTRUDA COMO MONOTERAPIA ESTÁ INDICADO PARA EL TRATAMIENTO DE PACIENTES CON NSCLC AVANZADO, CUYOS TUMORES EXPRESAN PD-L1 CON UN ?1% PPT, DETERMINADO MEDIANTE UNA PRUEBA VALIDADA Y QUE HAN RECIBIDO QUIMIOTERAPIA CON PLATINO. LOS PACIENTES CON ABERRACIONES TUMORALES GENÓMICAS DE EGFR O ALK DEBEN HABER RECIBIDO LA TERAPIA PREVIA PARA ESTAS ABERRACIONES ANTES DE RECIBIR KEYTRUDA. • CARCINOMA UROTELIAL KEYTRUDA ESTÁ INDICADO PARA EL TRATAMIENTO DE PACIENTES CON CARCINOMA UROTELIAL LOCALMENTE AVANZADO O METASTÁSICO, QUE HAN RECIBIDO QUIMIOTERAPIA QUE CONTIENE PLATINO.

58. ICI dosages Trial ICI arm Ipilimumab Nivolumab Pembrolizumab Hodi Ipilimumab 3 mg/kg q21d x4 CM 066 Nivolumab 3 mg/kg q14d KN 006 Pembrolizumab 3 mg/kg q21d KN 189 Pembrolizumab 200 mg q21d CM 066 Ipilimumab + Nivolumab 3 mg/kg q21d x4 1 mg/kg q21d x4, then 3 mg/kg q14d CM 214 Ipilimumab + Nivolumab 1 mg/kg q21d x4 3 mg/kg q21d x4, then 3 mg/kg q14d Newer trials Nivolumab 480 mg q28d

59. Immune-related Adverse Events irAEs

60. Eventos Adversos Relacionados con Autoinmunidad Observados Con los Inhibidores del Retén Inmunológico Minchot JM, et al. Eur J Cancer. 2016;54:139-148. Photo courtesy of Elizabeth R. Plimack, MD, MS. Uveitis Inflamación orbital PneumonitisHipotiroidismo Hepatitis Rash y vitiligo Pancreatitis Diabetes autoinmune Insuficiencia adrenal Enterocolitis Artralgia Xerostomía Hipofisitis

61. Cinética del inicio y resolución de los eventos adversos cutáneos y gastrointestinales relacionados con terapia anti-PD-1/PD-L1 Weber JS, et al. J Clin Oncol. 2016;[Epub ahead of print]. *Cualquier grado. Cutáneos* GI* Tiempo mediano (Semanas) 35 30 25 20 15 10 5 0 0 10 20 30 40 Proporciónaproximadade pacientes(%)

62. Weber JS, et al. J Clin Oncol. 2016;[Epub ahead of print]. *Cualquier grado. Tiempo mediano (Semanas) Proporciónaproximadade pacientes(%) 8 7 6 5 4 3 2 0 0 10 20 30 40 Endocrino* Hepatico* Pulmonar* Renal* 1 Cinética del inicio y resolución de los eventos adversos menos communes relacionados con terapia anti-PD-1/PD-L1

63. Management Algorithms Used for Diarrhea/Colitis Following Anti–PD-1 Treatment* Grade 1 Administer supportive care Continue Monitor for worsening symptoms; educate pt to report immediately If symptoms worsen: treat as grade 2 or 3/4 *Diarrhea and colitis to varying severity. Grades correspond to NCI CTCAE v4.0. Nivolumab [package insert]. 2016. Postow MA, et al. N Engl J Med. 2015;372:2006-2017. clinicaloptions.com/immuneAEtool Slide credit: clinicaloptions.com Nivolumab Symptomatic treatment Steroids Follow-up

64. Management Algorithms Used for Diarrhea/Colitis Following Anti–PD-1 Treatment* If > 5 days: 0.5-1 mg/kg/day prednisone equivalents followed by taper† Resume if: AE remains at grade 0/1 after steroid taper Discontinue if: No improvement or symptoms worsen and increase to 1-2 mg/kg/day prednisone equivalents Grade 2 Hold treatment Administer supportive care Slide credit: clinicaloptions.com *Diarrhea and colitis to varying severity. Grades correspond to NCI CTCAE v4.0. †Consider prophylactic antibiotics. Nivolumab [package insert]. 2016. Postow MA, et al. N Engl J Med. 2015;372:2006-2017. clinicaloptions.com/immuneAEtool Nivolumab Symptomatic treatment Steroids Follow-up

65. Management Algorithms Used for Diarrhea/Colitis Following Anti–PD-1 Treatment* Grade 3 Hold tx; consider discontinuing Discontinue 1-2 mg/kg/day prednisone equivalents followed by taper† Resume if: AE remains at grade 0/1 after steroid taper Discontinue if: If symptoms persist > 3-5 days or recur Add noncorticosteroid immunosuppressive Grade 4 Nivolumab Symptomatic treatment Steroids Follow-up *Diarrhea and colitis to varying severity. Grades correspond to NCI CTCAE v4.0. †Add antibiotics; for grade 3, consider hospital admission; for grade 4, hospitalization is recommended. Nivolumab [package insert]. 2016. http://clinicaloptions.com/immuneAEtool Consider lower-GI endoscopy

66. Case 1: Complications on Anti–PD-1 Therapy ▪ Pt presents with dyspnea, a nonproductive cough, and a fever that he has had for the past 2 wks 8 mos after starting therapy

67. Algorithm for Managing Immune-Related Pneumonitis on PD-1/PD-L1 Inhibitor Therapy Grade 1 Radiographic changes only Grade 2 Mild to moderate new symptoms Grade 3-4 Severe new symptoms: new/worsening hypoxia, life threatening ▪ Consider delay of I-O therapy ▪ Monitor symptoms every 2-3 days ▪ Consider pulmonary and infectious disease consults ▪ Delay I-O therapy per protocol ▪ Pulmonary and ID consults ▪ Monitor symptoms and consider hospitalization ▪ 1-2 mg/kg/day prednisone equivalents ▪ Bronchoscopy? Biopsy? ▪ Discontinue I-O therapy ▪ Hospitalize ▪ Pulmonary and ID consults ▪ 1-2 mg/kg/day prednisone equivalents ▪ Antibiotics? ▪ Bronchoscopy? Biopsy? ▪ Reimage at least every 3 wks ▪ If worsens: treat as grade 2-4 ▪ Reimage every 1-3 days ▪ If improves: when symptoms near baseline, taper steroids over ≥ 1 mo and resume I-O therapy ▪ Antibiotics? ▪ If worsens: treat as grade 3/4 ▪ If improves to baseline, taper steroids over > 6 wks ▪ If no improvement after 48 hrs or worsens: add additional immunosuppression References in slidenotes.

68. Gastrointestinal Immune-Related AE Management Algorithm ▪ Rule out noninflammatory cause – If noninflammatory cause, treat appropriately and continue immunotherapy ▪ Risk of bowel perforations – Opiates/narcotics may mask – Avoid infliximab ▪ May switch from IV to PO steroids taking into account lower bioavailability Villadolid J, et al. Transl Lung Cancer Res. 2015;4:560-575. Michot JM, et al. Eur J Cancer. 2016;54:139-148. Linardou H, et al. Ann Transl Med. 2016;4:272. Grade 1 Diarrhea: < 4 stools/day over baseline Colitis: asymptomatic Grade 2 Diarrhea: 4-6 stools/day over baseline; IV fluids indicated < 24 hrs; not interfering with ADL Colitis: abdominal pain, blood in stool Grade 3/4 Diarrhea (G3): ≥ 7 stools/day over baseline, incontinence; IV fluids ≥ 24 hrs; interfering with ADL Colitis (G3): severe abdominal pain; medical intervention indicated, peritoneal signs G4: life threatening, perforation ▪ Continue I-O therapy per protocol ▪ Symptomatic treatment ▪ Delay I-O therapy per protocol ▪ Symptomatic treatment ▪ Discontinue I-O therapy per protocol ▪ 1.0-2.0 mg/kg/day methylprednisolone IV or IV equivalent ▪ Add prophylactic antibiotics for opportunistic infections ▪ Consider lower endoscopy ▪ Close monitoring for worsening symptoms. ▪ Educate pt to report worsening immediately ▪ If worsens: treat as grade 2 or 3/4 If improves: ▪Continue steroids until grade 1, then taper over at least 1 mo If persists > 3-5 days or recurs after improvement; ▪Add infliximab 5 mg/kg (if no contradiction). Note: Infliximib should not be used in cases of perforation or sepsis Grade of Diarrhea/Colitis (NCI CTCAE v4) Management Follow-up If improves to grade 1: resume I-O therapy per protocol If persists > 5-7 days or recurs: ▪0.5-1.0 mg/kg/day methylprednisolone or PO equivalent ▪When symptoms improve to grade 1, taper steroids over at least 1 mo, consider prophylactic antibiotics for opportunistic infections, and resume I-O therapy per protocol. If worsens or persists > 3-5 days with oral steroids: Treat as grade 3/4

69. Common Immune-Related AEs Associated With Checkpoint Inhibitors Pneumonitis (anti–PD-1) Reticular erythematous rash Perivascular lymphocyte infiltrate extending into epidermis Rash (anti–CTLA-4)[1] Bowel edema and ulceration in the descending colon Gastrointestinal AEs (anti–CTLA-4)[2] Colonoscopy Histopathology Focal active colitis (left) with crypt destruction, loss of goblet cells, and neutrophilic infiltrates in the crypt epithelium (right) 1. Hodi FS, et al. Proc Natl Acad Sci U S A. 2003;100:4712-4717. 2. Maker AV, et al. Ann Surg Oncol. 2005;12:1005-1016.

70. Clinical features, predictive correlates, and pathophysiology of immune-related adverse events in immune checkpoint inhibitor treatments in cancer: a short review Yoest J, Immunotargets Ther, 2017 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5644546/

71. Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: American Society of Clinical Oncology Clinical Practice Guideline Brahmer J, JCO, 2018https://ascopubs.org/doi/full/10.1200/JCO.2017.77.6385

72. Toxicity Ipilimumab Anti PD(L)1 Ipi + Nivo Comment Skin toxicity G1/2: +++/G3/4: + G1/2: ++/G3/4: + G3/4: 1-3% in all groups Diarrhea G1/2: +++/G3/4: ++ G1/2: +/G3/4:+ G1/2: ++++/G3/4: ++ Intestinal perforation: 1% Hepatitis G1/2: +/G3/4:+ G1/2: +/G3/4:+ G1/2: +++/G3/4:++ G3/4 in 15% with Nivo + Ipi Pneumonitis G1/2: +/G3/4:+ G1/2: ++/G3/4:+ G1/2: ++/G3/4:++ Up to 10% Significant endocrinopathies G1/2: ++/G3/4:++ G1/2: ++/G3/4:+ G1/2: ++/G3/4:++ Hypophysitis higher in Ipi. Overall: 10% Hypothyroidism G1/2/3: +++ G1/2/3: +++ G1/2/3: +++ Very frequent Arthritis + ++ +++ Polymyalgia-like + ++ +++ Myositis + ++ +++ Rare, but may be fatal Acute Kidney Injury + + ++ G3/4: 1.6% with Nivo + Ipi Neurologic toxicities + + ++ 12% in Nivo + Ipi Hematologic toxicities + + ++ Cardiovascular toxicities + + + Less than 0.1%, potentially fatal Occular toxicity + + ++ Up to 1% in Nivo + Ipi Brahmer J, Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: American Society of Clinical Oncology Clinical Practice Guideline , JCO, 2018 Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy

73. Rash/Inflammatory dermatitis Grade 1 Symptomatic treatment Continue ICI Grade 2 Symptomatic treatment Continue ICIWithold Rx Grade 3 Symptomatic treatment Continue ICIWithold Rx IV steroids Specialist Grade 4 Symptomatic treatment Continue ICIWithold Rx IV steroids Specialist Discontinue ICI Discontinue ICI

75. Colitis Grade 1 Symptomatic treatment Continue ICI Grade 2 Symptomatic treatment Continue ICIWithold Rx Grade 3 Symptomatic treatment Anti PD(L)1Withold Rx Steroids Specialist Grade 4 Symptomatic treatment Anti PD(L)1)Withold Rx IV steroids Specialist Anti CTLA4 Anti CTLA4 SpecialistSteroids Recommended Not recommended Consider Infliximab for protracted Grade 4

77. Hepatitis Grade 1 Continue ICI Grade 2 Continue ICIWithold Rx Grade 3 Symptomatic treatment Withold Rx Steroids Specialist Grade 4 Symptomatic treatment Anti PD(L)1)Withold Rx IV steroids Specialist Anti CTLA4 Anti CTLA4 SpecialistSteroids Recommended Not recommended Consider Infliximab Anti PD(L)1)

79. Pneumonitis Grade 1 Continue ICI Grade 2 Continue ICIWithold Rx Grade 3 Symptomatic treatment Withold Rx Steroids Specialist Grade 4 Symptomatic treatment Anti PD(L)1)Withold Rx IV steroids Specialist Anti CTLA4 Anti CTLA4 Specialist Recommended Not recommended Consider Anti PD(L)1) Withold Rx Symptomatic treatment Steroids For severe pneumonitis: infliximab, mycophenolate, cyclophosphamide

81. Pneumonitis Grade 1 Continue ICI Grade 2 Continue ICIWithold Rx Grade 3 Symptomatic treatment Withold Rx Steroids Specialist Grade 4 Symptomatic treatment Anti PD(L)1)Withold Rx IV steroids Specialist Anti CTLA4 Anti CTLA4 Specialist Recommended Not recommended Consider Anti PD(L)1) Withold Rx Symptomatic treatment Steroids For severe pneumonitis: infliximab, mycophenolate, cyclophosphamide

82. Endocrinopathies • Headaches that will not go away or unusual pattern • Vision changes • Rapid heartbeat • Increased sweating • Extreme tiredness or weakness • Muscle aches • Weight gain or weight loss • Dizziness or fainting • Feeling more hungry or thirsty than usual • Hair loss • Changes in mood or behavior, such as decreased sex drive, irritability, or forgetfulness • Feeling cold • Constipation • Voice gets deeper • Urinating more often than usual • Nausea or vomiting • Abdominal pain

84. Hypothyroidism Grade 1 Continue ICI Grade 2 Continue ICIWithold Rx Grade 3 Symptomatic treatment Withold Rx Steroids Specialist Grade 4 Symptomatic treatment Anti PD(L)1)Withold Rx Steroids Specialist Anti CTLA4 Anti CTLA4 Specialist Recommended Not recommended Consider Anti PD(L)1) Symptomatic treatment SteroidsSymptomatic treatment

86. Arhtritis Grade 1 Continue ICI Grade 2 Continue ICIWithold Rx Grade 3 Symptomatic treatment Withold Rx Steroids Specialist Grade 4 Symptomatic treatment Anti PD(L)1)Withold Rx Steroids Specialist Anti CTLA4 Anti CTLA4 Specialist Recommended Not recommended Consider Anti PD(L)1) Symptomatic treatment Steroids For severe arthritis: consider methotrexate, lenflunomide, biologics Symptomatic treatment

88. Polymyalgia-like syndrome Grade 1 Continue ICI Grade 2 Continue ICIWithold Rx Grade 3 Symptomatic treatment Withold Rx Steroids Specialist Grade 4 Symptomatic treatment Anti PD(L)1)Withold Rx Steroids Specialist Anti CTLA4 Anti CTLA4 Specialist Recommended Not recommended Consider Anti PD(L)1) Symptomatic treatment Steroids For severe polymyalgia like syndrome: consider methotrexate, lenflunomide, biologics Symptomatic treatment

90. Myositis Grade 1 Continue ICI Grade 2 Continue ICIWithold Rx Grade 3 Symptomatic treatment Withold Rx Steroids Specialist Grade 4 Symptomatic treatment Anti PD(L)1)Withold Rx Steroids Specialist Anti CTLA4 Anti CTLA4 Specialist Recommended Not recommended Consider Anti PD(L)1) Symptomatic treatment Steroids For severe myositis: consider methotrexate, azathioprine, IVIG, plasmapheresis Symptomatic treatment

92. Acute Kidney injury Grade 1 Continue ICI Grade 2 Continue ICIWithold Rx Grade 3 Symptomatic treatment Withold Rx Steroids Specialist Grade 4 Symptomatic treatment Anti PD(L)1)Withold Rx Steroids Specialist Anti CTLA4 Anti CTLA4 Recommended Not recommended Consider Anti PD(L)1) Symptomatic treatment SteroidsSymptomatic treatment Withold Rx Specialist

94. Neurologic toxicity Grade 1 Continue ICI Grade 2 Continue ICIWithold Rx Grade 3 Symptomatic treatment Withold Rx Steroids Specialist Grade 4 Symptomatic treatment Anti PD(L)1)Withold Rx Steroids Specialist Anti CTLA4 Anti CTLA4 Recommended Not recommended Consider Anti PD(L)1) Symptomatic treatment SteroidsSymptomatic treatment Withold Rx Specialist

96. Autoimmune hemolytic anemia Grade 1 Continue ICI Grade 2 Continue ICIWithold Rx Grade 3 Symptomatic treatment Withold Rx Steroids Specialist Grade 4 Symptomatic treatment Anti PD(L)1)Withold Rx Steroids Specialist Anti CTLA4 Anti CTLA4 Recommended Not recommended Consider Anti PD(L)1) SteroidsSymptomatic treatment Specialist

97. Cardiac toxicity Grade 1 Symptomatic treatment Anti PD(L)1)Withold Rx Steroids Specialist Anti CTLA4 Recommended Not recommended Consider For severe pneumonitis: infliximab, mycophenolate, ATG

98. Venous thromboembolism Grade 1 Continue ICI Grade 2 Continue ICIWithold Rx Grade 3 Symptomatic treatment Withold Rx Anticoag Specialist Grade 4 Symptomatic treatment Anti PD(L)1)Withold Rx Anticoag Specialist Anti CTLA4 Anti CTLA4 Recommended Not recommended Consider Anti PD(L)1) AnticoagSymptomatic treatment Specialist

100. https://www.clinicaloptions.com/oncology/programs/irae-management/interactive-decision-support-tool/nccn-idst/page-1

106. irAEs in the medical literature?

107. Adverse Events Associated with Immune Checkpoint Blockade in Patients with Cancer: A Systematic Review of Case Reports Abdel-Wahab N, PLoS One 2016

111. Do AEs improve cancer outcomes in ICIs?

112. Early Immune-Related Adverse Events and Association with Outcome in Advanced Non-Small Cell Lung Cancer Patients Treated with Nivolumab: A Prospective Cohort Study. Teraoka S, J Thorac Oncol, 2017 n=43 NSCLC

113. Pre-existing autoimmune disease and the risk of irAE among patients receiving checkpoint inhibitors for cancer? https://www.ncbi.nlm.nih.gov/pubmed/30877325 Kehl KL, Cancer Immunol Immunother, 2019

114. Kehl KL, Cancer Immunol Immunother, 2019

117. Pre-existing autoimmune disease was not associated with time to any hospitalization after initiating ICI therapy, but it was associated with a modest increase in hospitalizations with irAE diagnoses and with corticosteroid treatment. Kehl KL, Cancer Immunol Immunother, 2019

118. Safety of Programmed Death–1 Pathway Inhibitors Among Patients With Non–Small- Cell Lung Cancer and Preexisting Autoimmune Disorders Leonardi JC, JCO, 2018

119. Safety of Programmed Death–1 Pathway Inhibitors Among Patients With Non– Small-Cell Lung Cancer and Preexisting Autoimmune Disorders Leonardi JC, JCO, 2018

120. Safety of Programmed Death–1 Pathway Inhibitors Among Patients With Non– Small-Cell Lung Cancer and Preexisting Autoimmune Disorders Leonardi JC, JCO, 2018

121. Conclusions • ICIs are life-saving to many patients with advanced malignancies • Melanoma • NSCLC • Genitourinary • Head and Neck… and others

122. Conclusions • Immune-related adverse-events (irAEs) are more severe with anti- CTLA4 and combination ICIs • Early recognition and intervention of irAEs can prevent greater morbidity and mortality • In case of doubt: stop ICI, initiate steroids… • irAEs are not required for “clinical activity” of ICIs

123. Conclusions • Patients with pre-existing (potentially severe) autoimmune conditions were systematically excluded from ICI clinical trials • But there is some evidence that ICIs can be safely used in patients with a history of autoimmune disease • Especially, if in “clinical remission” for > 2 years • All these patients need to be CLOSELY followed by rheumatology (as well)

125. Onconerd

Lo que un reumatólogo debe saber de inmunoterapia contra el cáncer, abreviado

Recommended

Recommended

More Related Content

What's hot

What's hot (20)

Similar to Lo que un reumatólogo debe saber de inmunoterapia contra el cáncer, abreviado

Similar to Lo que un reumatólogo debe saber de inmunoterapia contra el cáncer, abreviado (20)

More from Mauricio Lema

More from Mauricio Lema (20)

Recently uploaded

Recently uploaded (20)

Lo que un reumatólogo debe saber de inmunoterapia contra el cáncer, abreviado

Editor's Notes