NEVENWERKINGEN ONDER IMMUNOTHERAPIE

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2 NEVENWERKINGEN ONDER IMMUNOTHERAPIE AANPAK EN DIAGNOSTIEK 14 OKTOBER 2017 Ximena Elzo Kraemer Medisch Oncoloog geintegreerd Kankercentrum Gent Klinische Studiedienst Oncologie

3 Immunotherapy Immunotherapy with monoclonal antibodies (MoAbs)targeting: cytotoxic T lymphocyte-associated antigen 4 (CTLA4) Ipilimumab the programmed death-1 receptor (PD-1) and its ligand PD-L1 Nivolumab (PD-1) Pembrolizumab (PD-1) Atezolizumab (PD-L1)

4 Nevenwerkingen Aanvallen eigen orgaansystemen Anders dan chemotherapie nevenwerkingen Vaak mild en zelflimiterend, maar kunnen ernstig of levensbedreigend zijn en soms blijvend (endocrinopathies) Meestal binnen de eerste weken na opstart

5 Nevenwerkingen Toxicities from immune checkpoint inhibitors (ICPis)can be divided into: infusion reactions and immune-related adverse events (iraes)

6 Immune related adverse events can affect any organ system

7 Ipilimumab-associated immune-related toxicities Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up Ann Oncol. 2017;28(suppl_4):iv119-iv142. doi: /annonc/mdx225 Ann Oncol The Author Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For Permissions, please

8 antipd1 IKG-symposium

9 Combination of CTLA4 and PD-1/PD-L1 blockade immune-related toxicities Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up Ann Oncol. 2017;28(suppl_4):iv119-iv142. doi: /annonc/mdx225 Ann Oncol The Author Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For Permissions, please

10 Algemene richtlijnen IKG-symposium

11 Principes van behandeling IKG-symposium

12 Welke? Graad 1-2: check voor elke volgende kuur Pruritis Rash Leverfunctiestoornissen Diarree Endocrinopathies Hypophysitis Thyroiditis Antralgieën

13 Levels of evidence I Evidence from at least one large randomised, controlled trial of good methodological quality (low potential for bias) or meta-analyses of well-conducted randomised trials without heterogeneity II Small randomised trials or large randomised trials with a suspicion of bias (lower methodological quality) or meta-analyses of such trials or of trials demonstrated heterogeneity III IV V Prospective cohort studies Retrospective cohort studies or case control studies Studies without control group, case reports, expert opinions Levels of evidence and grades of recommendation (adapted from the Infectious Diseases Society of America-United States Public Health Service Grading System)

14 a Grades of recommendation A Strong evidence for efficacy with a substantial clinical benefit, strongly recommended B Strong or moderate evidence for efficacy but with a limited clinical benefit, generally recommended C Insufficient evidence for efficacy or benefit does not outweigh the risk or the disadvantages (adverse events, costs,...). optional D Moderate evidence against efficacy or for adverse outcome, generally not recommended E Strong evidence against efficacy or for adverse outcome, never recommended By permission of the Infectious Diseases Society of America [88].

15 Huidtoxiciteit

16 Huidtoxiciteit

17 Huidtoxiciteit

18 Table 1. Grading of rash, pruritus and hypopigmentation according to Common Terminology Criteria of Adverse Events, version Grade Rash Pruritus Hypopigmentation 1 Macular or papular eruption covering <10% BSA with or without symptoms (e.g., pruritus, burning, tightness) Mild or localized; topical intervention indicated Hypopigmentation or depigmentation covering <10% BSA; no psychosocial impact 2 Macular or popular eruption covering 10 30% BSA with or without symptoms (e.g., pruritus, burning, tightness); limiting instrumental ADL 3 Macules/papules covering >30% BSA with or without associated symptoms; limiting self-care ADL Intense or widespread; intermittent; skin changes from scratching (e.g., edema, population, excoriations, lichenification, oozing/ crusts); oral intervention indicated; limiting instrumental ADL Intense or widespread; constant; limiting self care ADL or sleep; oral corticosteroid or oral immunosuppressive therapy indicated 4 Generalized exfoliative, ulcerative, or bullous dermatitis 5 Death Hypopigmentation or depigmentation covering >10% BSA; associated psychosocial impact

19 Huidtoxiciteit

20 Immune-related skin toxicity (ESMO-guidelines) For grade 1 2 skin AEs, continue (at least 1 week) with ICPis. Start topical emollients, antihistamines in the case of pruritus and/or topical (mild strength) corticosteroid creams. Reinitiate ICPi when grade 1. For grade 3 skin AEs, interrupt ICPi and start immediate treatment with topical emollients, antihistamines and high strength corticosteroid creams [II, B]. For grade 4 skin AEs, discontinue ICPi (permanently), consider admitting patient and always consult dermatologist immediately. Start i.v. corticosteroids [1 2 mg/kg (methyl)prednisone] and taper based on response of AE [II, B].

21 Gastro-intestinale toxiciteit

22 Gastrointestinaltoxicity (ESMO-guidelines) In patients with non-severe diarrhea (grade 1), ICPi can be continued. Treatment with antidiarrheal medication (e.g. loperamide) should be prescribed [IV V, B]. In grade 2 diarrhea, ICPi should be interrupted and the patient should start with corticosteroids depending on the severity and other symptoms (either budesonide or oral corticosteroids 1 mg/kg). In the case of no improvement within 3 5 days, colonoscopy should be carried out and, in the case of colitis, infliximab 5 mg/kg should be administered [IV V, B]. In patients with severe diarrhea (grade 3 to 4), permanently discontinue ICPi. Admit patient to the hospital and initiate (methyl)prednisone 2 mg/kg i.v. Add MMF if improvement is observed within 2 3 days. Consult a hepatologist if no improvement under double immunosuppression. Other immunosuppressive drugs to consider are ATG and tacrolimus. Consult or refer patient to an experienced center. Taper over 6 weeks under close monitoring of liver tests [IV V, B].

23 Immune-related endocrinopathies (ESMO-guidelines) In symptomatic hyperthyroism patients, usually grade 1 or 2, interrupt ICPi, start beta-blocker therapy (propranolol or atenolol/metoprolol). Restart ICPi when asymptomatic [IV V, B]. In the case of hypothyroidism, rarely > grade 2, start HRT depending on the severity ( μg/day). Increase the dose until TSH is normal. In the case of inflammation of the thyroid gland, start prednisone orally 1 mg/kg. Taper based on recovery of clinical symptoms. Consider interruption of ICPi treatment when symptomatic [IV V, B]. In the case of hypophysitis (rarely > grade 2), when headache, diplopia or other neurological symptoms are present, start (methyl)prednisone 1 mg/kg orally and taper over 2 4 weeks. Start HRT depending on the affected hormonal axis (levothyroxine, hydrocortisol, testosterone) [V, B]. In patients with type I DM grade 3 to 4 [ketoacidotic (sub)coma], admit to hospital immediately and start treatment of newly onset type I DM [I, A]. Role of corticosteroids in preventing complete loss of insulin producing cells is unknown and not recommended

24 Hepatitis

25 Immune-related hepatotoxicity (ESMO-guidelines) For grade 2 hepatitis, withhold ICPi and monitor AST/ALT levels closely (1 2 times/week). When no improvement over 1 week, start (methyl)prednisone (0.5 1 mg/kg). Taper over several weeks under close monitoring of AST/ALT and bilirubin [IV V, B]. For grade 3 hepatitis, discontinue ICPi and immediately start with (methyl)prednisone 1 2 mg/kg. When no improvement in 2 3 days, add MMF (1000 mg 3 daily). Taper immunosuppression over 4 6 weeks under close monitoring of AST/ALT and bilirubin [IV V, B]. For grade 4 hepatitis, permanently discontinue ICPi, admit patient to the hospital and initiate (methyl)prednisone 2 mg/kg i.v. Add MMF if no improvement is observed within 2 3 days. Consult hepatologist if no improvement under double immunosuppression. Other immunosuppressive drugs to consider are ATG and tacrolimus. Consult or refer patient to an experienced centre. Taper over 6 weeks under close monitoring of liver tests [IV V, B].

26 Pneumonitis

27 Immune-related pneumonitis (ESMO-guidelines) In grade 1 and 2 pneumonitis, interrupt ICPi therapy, try to rule out infection and start with prednisone 1 2 mg/kg orally. Taper over 4 6 weeks [IV V, B]. In grade 3 and 4 pneumonitis, discontinue ICPi permanently, admit the patient to the hospital, even ICU if necessary and immediately start highdose (methyl)prednisone 2 4 mg/kg i.v. Add infliximab, MMF or cyclophosphamide in the case of deterioration under steroids. Taper over a period of 4 6 weeks [IV V, B].

28 Duurzame responsen als nevenwerkingen IKG-symposium

29 Impact of immunosuppression on efficacy The need for immunosuppressive therapy to manage iraes does not appear to affect the response to checkpoint inhibition with either anti-pd-1 antibodies or ipilimumab. Anti-PD-1 antibodies IrAEs are significantly less frequent with the anti-pd-1 antibodies compared with ipilimumab. In an analysis of 576 patients with advanced melanoma treated in four clinical trials, 24 percent received immunosuppressive therapy for the management of treatment-related adverse events [3]. There was no significant difference in the objective response rate between those who received immunosuppressive treatment and those who did not (29.8 versus 31.8 percent). The median duration of response was not reached in those with immunosuppressive therapy, compared with 22 months in those not requiring immunosuppressive therapy. Ipilimumab The most extensive data with ipilimumab come from a single-institution experience that analyzed the incidence of iraes and treatment outcomes in 298 melanoma patients treated with ipilimumab (3 mg/kg) outside of a clinical trial setting [4]. IrAEs were seen in 254 patients (85 percent), and 103 patients (35 percent) required corticosteroids. Anti-tumor necrosis factor-alpha therapy was used in 29 cases (10 percent) who did not respond promptly to corticosteroids. The median overall survival was 16.5 months, and the estimated two-year survival rate was 39 percent for the entire cohort. Overall survival was the same in patients who had an irae compared with those without an irae, and there was no difference between those requiring corticosteroids and those not requiring immunosuppressive therapy. The time to treatment failure, defined as the need for alternative therapy or death, was 5.7 months for the entire cohort. As with overall survival, there were no significant differences between those with and without an irae or between those treated with corticosteroids and those not receiving corticosteroids.

30 Weinig voorkomende toxiciteit

31 Cardiac toxicity (ESMO-guidelines) When a myocarditis is suspected, admit the patient and immediately start high-dose (methyl)prednisone (1 2 mg/kg). In the case of deterioration, consider adding another immunosuppressive drug (MMF or tacrolimus) [V, B].

32 Neurological toxicity (ESMO-guidelines) In the case of mild neurological AEs, withhold ICPi and perform work-up (MRI scan, lumbar puncture) to define nature of neurotoxicity. In the case of deterioration or severe neurological symptoms, admit the patient and start (methyl)prednisone 1 2 mg/kg orally or i.v. In the case of Guillain- Barré or myasthenia-like symptoms, consider adding plasmapheresis or i.v. Ig [V, B].

33 Hematologic Auto-immuun anaemia neutropenia thrombocytopenia

34 Rheumatological toxicity (ESMO-guidelines) For mild arthralgia, start NSAIDs, and in the case of no improvement, consider low dose steroids (10 20 mg prednisone). In the case of severe polyarthritis, refer patient to or consult a rheumatologist and start prednisone 1 mg/kg. Sometimes infliximab or another anti-tnfα drug is required for improvement of arthritis [V, B].

35 Renal toxicity (ESMO-guidelines) In case of nephritis, rule out other causes of renal failure first. Interrupt or permanently discontinue ICPi depending on the severity of the renal insufficiency. Stop other nephrotoxic drugs. Start (methyl)prednisone 1 2 mg/kg. Consider renal biopsy to confirm diagnosis [V, B].

36 Vaccinaties

37 Vaccinaties Geen vaccinaties met levende verzwakte organismen: bv: rubella, mazelen, gele koorts, enz. Opletten bij contact met personen, die een levend verzwakt organisme, oraal gegeven: rotavirus bij kinderen. Griepvaccin: vooralsnog wordt het aangeraden, niet de nasale vorm, echter

38 Griepvaccin Immune response and adverse events to influenza vaccine in cancer patients undergoing PD-1 blockade: Metastatic cancer pts treated with at least one dose of either nivolumab or pembrolizumab were vaccinated with a trivalent inactive influenza vaccination between October and November We included 23 pts and 7 age-matched healthy controls. 16 pts had a diagnosis of non-small cell lung cancer, 3 pts had renal cell carcinoma and 3 pts a malignant melanoma. 12 pts (52.2%) experienced an irae. 6 pts (26.1%) had grade 3 or 4 (G3/4) iraes. Conclusion: The seasonal influence vaccination reaches a protective range in these pts. Unexpectedly, however, an increased rate of clinically relevant iraes was observed. Confirmation in a larger population and mechanistic understanding is required.

39 Take Home Message

40 DANK!