TOXICITY RELATED TO IO IN LUNG CANCER Dr. Jorge A. Alatorre Alexander Head of the Thoracic Oncology Clinic at Instituto Nacional de Enfermedades Respiratorias American British Cowdray Medical Center Mexico city, Mexico
1947 Sidney Farber ( 1903-1973) Aminopterine: Folic acid Inh Acute Lympholastic Leukemia Schiller JH et al N Engl J Med 2002; 346:92-98
The Magic Bullet
TKI s efficacy FLAURA Immunotherapies Efficacy KEYNOTE 024 ALEX COMBOS: CM 227 & KN 189
BUT. THEY HAVE DIFFERENT TOXICITY PROFILE ALTHOUGH BETTER TOLERATED CHEMO IO tkitkis Habanero Chili Spicy ++++/++++ Chipotle Chili Spicy ++/++++ Poblano Chili Spicy +/++++
IO monotherapy and Combo Toxicity TKI s Toxicity
IO monotherapy and Combo Toxicity TKI s Toxicity
Cancer Immunity Cicle
Cancer Immunity Cicle CTLA-4 is expressed on regulatory T cells (TREG), a type of T cell that suppresses the immune response in the tumour microenvironment. CTLA-4 blockade results in a broad, nonspecific activation of an immune response CTLA-4 PD-1/PD-L1 PD-L1 is frequently upregulated on the tumour cell surface. By targeting T cells more specifically in the tumour microenvironment and tissues, treatment with PD-1 inhibition results in a more restricted spectrum of adverse events compared with CTLA-4 blockade
Immune-related adverse events can affect any organ system The frequency of iraes following immunotherapy is probably underestimated. Most clinical trials follow patients for only a brief time of enrollment Some iraes can have a delayed onset: Thyroiditis (3 years after initiation of anti-ctla4) T1D (from weeks to decades) Champiat S et al. Ann Oncol 2016;27:559-74
PREVENTION: We know the most common General AEs
PREVENTION: We know IRAE s
ANTICIPATE: Know your patient: Measure & Grade General Endocrine Infectious Auto- Antibodies BASAL LABS CBC, Serum Electrolytes, Cr, Liver function Test TSH, T4, T3 HIV, HBV, HCV and CMV ANA, anti-thyiroid
WHAT WE LEARNED FROM MELANOMA: IMMUNE MEDIATED ANTICIPATE: Time Since Development of Adverse Events PD-1 Blockade
ANTICIPATE: Time Since Development of Adverse Events PD-1 Blockade
General Management of irae
General Management of Toxicities: IO GRADE Grade 2 Toxicity Grade 3 or 4 Withheld and should not be resumed until symptoms or toxicity is grade 1 or less Treatment with the checkpoint inhibitor should be permanently discontinued. CORTICOESTEROIDE Prednisone 0.5 mg/kg/day or equivalent should be started if symptoms do not resolve within a week High doses of corticosteroids (prednisone 1 to 2 mg/kg/day or equivalent) should be given. When symptoms subside to grade 1 or less, steroids can be gradually tapered over at least one month. If symptoms do not improve, after approximately three days with IV steroids, administer infliximab (5 mg/kg). If symptoms persist after the first infliximab dose, a second dose of infliximab (5 mg/kg) can be repeated two weeks after the initial dose.
TOXICITIES DUE TO CHECKPOINT INHIBITORS Multidisciplinary Group Only Info of IO (Not Combos with Chemo) 38 Systematic Reviews + 166 primary studies met eligibility criteria Brahmer J et al J Clin Oncol 2018
FATIGUE
Fatigue CLINICAL TRIAL N ALL GRADES 3-4 IPI + NIVO CHECMATE 227 NIVOLUMAB CHECKMATE 227 576 13.2 1.4 391 11 0.5 CHECKMATE 057 287 16 1 PEMBROLIZUMAB KEYNOTE 024 PEMBROLIZUMAB KEYNOTE 10 (2 mg/k) ATEZO + BEV + Che IMPOWER 150 ATEZO OAK DURVA + RT PACIFIC 154 10.4 1.3 339 14 1 400 Pend Pend 425 27 4 475 23.8 0.2
Decreased Apetite CLINICAL TRIAL N ALL GRADES 3-4 IPI + NIVO CHECMATE 227 NIVOLUMAB CHECKMATE 227 576 12.7 0.5 391 6.4 0 CHECKMATE 057 287 10 0 PEMBROLIZUMAB KEYNOTE 024 PEMBROLIZUMAB KEYNOTE 10 (2 mg/k) ATEZO + BEV + Che IMPOWER 150 ATEZO OAK DURVA + RT PACIFIC 154 9.1 0 339 14 1 400 Pend Pend 425 NR NR 475 14 0.2
Skin Reactions
*NR, probably due < 10% FRECUENCY OF RASH/INFLAMATORY DERMATITIS IN NSCLC TRIALS CLINICAL TRIAL N ALL GRADES 3-4 IPI + NIVO CHECMATE 227 NIVOLUMAB CHECKMATE 227 576 16.7% 1.6% 391 11% 0.8% CHECKMATE 057 287 NR * NR* PEMBROLIZUMAB KEYNOTE 024 PEMBROLIZUMAB KEYNOTE 10 (2 mg/k) PEMBROLIZUMAB KEYNOTE 001 ATEZO + BEV + Che IMPOWER 150 154 NR* NR* 339 NR* NR* 495 9.7 0.2 400 PEND NR* ATEZO OAK DURVA + RT PACIFIC 425 NR * NR* 475 12% 0.2%
Grade Definition Management 1 Symptoms do not affect the quality of life or controlled with topical regimen and/or oral antipruritic 2 Inflammatory reaction that affects quality of life and requires intervention based on diagnosis 3 As G2 but with failure to respond to indicated interventions for a G 2 dermatitis 4 All severe rashes unmanageable with prior interventions and intolerable Continue ICPi Treat with topical emollients and/or mild-moderate potency topical corticosteroids Counsel patients to avoid skin irritants and sun exposure Consider holding ICPi and monitor weekly for improvement. If not resolved, interrupt treatment until skin AE has reverted to grade 1 Consider initiating prednisone 1 mg/kg. In addition, treat with topical emollients, oral antihistamines, and medium- to high potency topical corticosteroids Hold ICPi therapy and consult with dermatology. topical emollients, oral antihistamines, and high-potency topical corticosteroidsinitiate (methyl)prednisolone (or equivalent) 1-2 mg/kg Immediately hold ICPi and consult dermatology to determine appropriateness of resuming ICPi (methyl)prednisolone (or equivalent) dosed at 1-2 mg/kg Monitor closely for progression to severe cutaneous adverse reaction.
Not all skin toxicities are bad..... Re-pigmentation
HYPOTHYROIDISM
Hypothyroidism **OAK Trial didn t report Hypothiroisism CLINICAL TRIAL N ALL GRADES 3-4 IPI + NIVO CHECMATE 227 NIVOLUMAB CHECKMATE 227 576 11.6 0.3 391 6.4 0.3 CHECKMATE 057 287 NR NR PEMBROLIZUMAB KEYNOTE 024 PEMBROLIZUMAB KEYNOTE 10 (2 mg/k) ATEZO + BEV + Che IMPOWER 150 ATEZO POPLAR** DURVA + RT PACIFIC 154 9.1 1.3 339 8 0 400 13 <1 425 6% 0.4 475 11.6 0.2
Hypothyroidism Grade Definition Management 1 TSH, 10 miu/l and asymptomatic 2 Moderate symptoms; able to perform ADL; TSH persistently. 10 miu/l 3-4 Severe symptoms, medically significant or lifethreatening consequences, unable to perform ADL Should continue ICPi with close follow-up and monitoring of TSH, FT4 May hold ICPi until symptoms resolve Prescribe thyroid hormone supplementation in symptomatic patients with any degree of TSH elevation or in asymptomatic patients with TSH levels that persist. Hold ICPi, supplementation, Endocrine consultation. May admit for IV therapy if signs of myxedema (bradycardia, hypothermia) Thyroid supplementation and reassessment as in G2
HYPERTHYROIDISM
Hyperthyroidism in IO NSCLC Trials CLINICAL TRIAL N ALL GRADES 3-4 IPI + NIVO CHECMATE 227 NIVOLUMAB CHECKMATE 227 576 NR NR 391 NR NT CHECKMATE 057 287 NR NR PEMBROLIZUMAB KEYNOTE 024 PEMBROLIZUMAB KEYNOTE 10 (2 mg/k) ATEZO + BEV + Che IMPOWER 150 ATEZO OAK DURVA + RT PACIFIC 154 7.8 0 339 4 0 400 4 <1 425 NR NR 475 NR NR
Hyperthyroidism Grade Definition Management 1 Asymptomatic or mild symptoms 2 Moderate symptoms, able to perform ADL 3-4 Severe symptoms, medically significant or lifethreatening consequences, unable to perform ADL Can continue ICPi with close follow-up and monitoring of TSH, FT4 every 2-3 weeks Consider holding ICPi until symptoms return to baseline Consider endocrine consultation (eg, atenolol, propranolol) for symptomatic relief. Corticosteroids are not usually required to shorten duration and consider thionamide (methimazole or PTU) Refer to endocrinology for Graves disease Hold ICPi until symptoms resolve. Endocrine consultationb-blocker (eg, atenolol, propranolol) for symptomatic relief For severe symptoms or concern for thyroid storm, hospitalize patient and initiate prednisone 1-2 mg/kg/d or equivalent consider also use of SSKI or thionamide (methimazole or PTU).
ADRENAL INSUFFICIENCY
Frecuency of Adrenal Insufficiency Between Trials NSCLC CLINICAL TRIAL N ALL GRADES 3-4 IPI + NIVO CHECMATE 227 NIVOLUMAB CHECKMATE 227 576 1 <1 391 NR NR CHECKMATE 057 287 0 0 PEMBROLIZUMAB KEYNOTE 024 PEMBROLIZUMAB KEYNOTE 10 (2 mg/k) ATEZO + BEV + Che IMPOWER 150 ATEZO OAK DURVA + RT PACIFIC 154 NR NR 339 1 0 400 1 <1 425 NR NR 475 0 0
Adrenal Insufficiency Grade Definition Management 1 Asymptomatic or mild symptoms 2 Moderate symptoms, able to perform ADL Consider holding ICPi until patient is stabilized on replacement hormone. Endocrine consultation. Replacement therapy with prednisone (5-10 mg daily) or hydrocortisone (10-20 mg orally every morning, 5-10 mg orally in early afternoon). May require fludrocortisone (0.1 mg/d) for mineralocorticoid replacement in primary adrenal insufficiency Titrate dose up or down as symptoms dictate Hold ICPi until patient is stabilized on replacement hormone Endocrine consultation See in clinic or, for after hours, make an emergency department referral for normal saline (at least 2 L) and IV stress-dose corticosteroids on presentation (hydrocortisone 100 mg) taper stress-dose corticosteroids down to maintenance doses over 7-14 days after discharge. Maintenance therapy as in G1
Adrenal Insufficiency Grade Definition Management 3-4 Severe symptoms, medically significant or lifethreatening consequences, unable to perform ADL Hold ICPi until patient is stabilized on replacement hormone Endocrine consultation See in clinic or, for after hours, make an emergency department referral for normal saline (at least 2 L) and IV stress-dose corticosteroids on presentation(hydrocortisone 100 mg or dexamethasone 4 mg (if the diagnosis is not clear and stimulation testing will be needed) Taper stress-dose corticosteroids down to maintenance doses over 7-14 days after dischargemaintenance therapy as in G1
PNEUMONITIS
Naidoo et al, J Clin Oncol 2016 DIFFERENT PRESENTATIONS
Pneumonitis ** Placebo group had pneumonitis all grades 24.8 & grade 3-4 2.6 (grade 5: 0.4%) CLINICAL TRIAL N ALL GRADES 3-4 IPI + NIVO CHECMATE 227 NIVOLUMAB CHECKMATE 227 NIVOLUMAB CHECKMATE 057 PEMBROLIZUMAB KEYNOTE 024 PEMBROLIZUMAB KEYNOTE 10 (2 mg/k) ATEZO + BEV + Che IMPOWER 150 ATEZO OAK DURVA + RT PACIFIC ** 576 NR NR 391 NR NR 287 NR NR 154 5.8 2.6 339 5 2 400 3 2 425 1 0.7 475 33.9 3.4
PNEUMONITIS
DIARRHEA/COLITIS
Frecuency of Colitis Between Trials in NSCLC CLINICAL TRIAL N ALL GRADES 3-4 IPI + NIVO CHECMATE 227 NIVOLUMAB CHECKMATE 227 576 1 <1 391 NR NR CHECKMATE 057 287 0 0 PEMBROLIZUMAB KEYNOTE 024 PEMBROLIZUMAB KEYNOTE 10 (2 mg/k) ATEZO + BEV + Che IMPOWER 150 ATEZO OAK DURVA + RT PACIFIC 154 1.9 1.3 339 NR NR 400 0.3 0 425 NR NR 475 0 0
Diarrhea/Colitis AMBULATORY HOSPITALIZED
Pillai R et al Cancer 2017
drjorgealatorre@yahoo.com.mx INSTITUTO NACIONAL DE ENFERMEDADES RESPIRATORIAS CENTRO MÉDICO ABC