TOSSICITA POLMONARI. Lucio Buffoni Oncologia AOU San Luigi Orbassano

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Renato Simonetti
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1 TOSSICITA POLMONARI Lucio Buffoni Oncologia AOU San Luigi Orbassano

4 TKIs: riduzione fosforilazione di EGFR con concomitante riduzione nei processi di rigenerazione epiteliale e inibizione di EGFR signaling by TKI può alterare i processi di riparazione polmonare del danno.

5 Gefitinib Incidenza 1% (Asia 3-6%); Fattori predisponenti: Fumo; Maschi; Età avanzata; Malattie polmonari sottostanti; Malattie cardiologiche. Tempo insorgenza medio: gg Jap; 42 US Metanalisi Shi L et al, Lung Cancer 2014; > increase of ILD with TKIs use; 22.8% mortality rate among ILD pts; > RR se I linea ma anche in linee avanzate per > rischio da precedente CT. ILD non è una entità unica.

9 Immuno

10 PD-1 Inhibitors - Safety Keynote 001: pembrolizumab CheckMate 063: nivolumab Felip E et al, ESMO 2014 Rizvi NA et al, Lancet Oncology 2015

UNIVERSITY OF TORINO DEPARTMENT OF ONCOLOGY PD-1 Checkpoint Inhibition Phase III Trials II LInes -Toxicities Trial Agent Rx-Related AEs All & Grade 3/4 Most Common Rx-Related AEs Pneumonitis Rate

11 UNIVERSITY OF TORINO DEPARTMENT OF ONCOLOGY PD-1 Checkpoint Inhibition Phase III Trials II LInes -Toxicities Trial Agent Rx-Related AEs All & Grade 3/4 Most Common Rx-Related AEs Pneumonitis Rate Checkmate 017 Nivolumab 58% 7% Fatigue 16% appetite 11% Asthenia 10% All 5% Gr 3/4 0% Docetaxel 86% 55% Neutropenia 33% Fatigue 33% Nausea 23% 0% Checkmate 057 Nivolumab 69% 10% Fatigue 16% Nausea 12% appetite 10% All 3% Gr 3/4 1% Keynote 010 Docetaxel 88% 54% Pembrolizumab 2 mg/kg dose 63% 13% Neutropenia 31% Fatigue 29% Nausea 26% Fatigue 20% Pruritis 11% appetite 11% 0% All 5% Grade 3-5 2% 2 deaths Docetaxel 81% 35% Fatigue 25% Diarrhea 18% appetite 16% 0% Brahmer J et al NEJM 2015; Borgahi H et al NEJM 2015; Herbst R et al Lancet 2015

12 UNIVERSITY OF TORINO DEPARTMENT OF ONCOLOGY Adverse Events: KN024 Pembro I linea All grade G>3 Reck M, NEJM 2016

72% (31 of 43) of cases were grade 1 to 2, and 86% (37 of 43) improved/resolved with drug holding/immunosuppression (worsening

13 Pneumonitis in Patients Treated With Anti PD1/PDL1 Therapy Of 915 patients who received anti PD-1/PD-L1mAbs, pneumonitis developed in 43 (5%) The incidence was higher with combo immunotherapy vs monotherapy (19 of 199 [10%] vs 24 of 716 [3%]; P,01) 72% (31 of 43) of cases were grade 1 to 2, and 86% (37 of 43) improved/resolved with drug holding/immunosuppression (worsening cases were restricted to current and former smokers and were more common in patients with underlying lung conditions) Naidoo J et al, JCO 2016

14 Pneumonitis in Patients Treated With Anti PD1/PDL1 Therapy Because timing of pneumonitis onset varied widely, constant vigilance for the signs and symptoms of this toxicity is required Of note, chest x-ray did not detect a new radiographic abnormality in nearly one quarter of pneumonitis cases, which suggests that it may be an inadequate tool for evaluating suspected pneumonitis FEV1 and diffusing capacity of lung for carbon monoxide (DLCO) adjusted for hemoglobin were completed in a subset of patients at the time of pneumonitis BUT no associations between these parameters and clinical outcomes were seen Naidoo J et al, JCO 2016

Male patient, A.S. 61 years old. Right supraclavicular lymph node FNA (28 May 2012) Diagnosis of adenocarcinoma, Stage IIIB (T1N3M0) ALK: not rearranged, EGFR wt.

16 Male patient, A.S. 61 years old. Right supraclavicular lymph node FNA (28 May 2012) Diagnosis of adenocarcinoma, Stage IIIB (T1N3M0) ALK: not rearranged, EGFR wt. First-line treatment (June 2012 August 2012): Cisplatin 75 mg/mq Pemetrexed 500 mg/mq (3 cycles), shifted to Carboplatin AUC 6 because of GFR reduction. Sequential thoracic mediastinal radiotherapy: DFT 60Gy/30 fr Best response: Stable Disease Maintained until October 2013

17 After nodal progression (laterocervical lymph nodes), the patient was evaluated within MK clinical trial. PD-L1 expression on diagnostic tissue was evaluated and described. The patient was randomized to treatment with MK mg/kg q3weeks. I cycle started on 23 Jan 2014

18 CT scan during treatment Baseline After 3 cycles After 6 cycles After 9 cycles appearance and increase of bilateral ground glass areas After 12 cycles After 18 cycles

19 Pulmonary function testing Baseline After 17 cycles Decreased Diffusing Capacity (DLCO) Asymptomatic patient

20 From the trial Instructions for symptomatic patients with pneumonitis Stop MK Evaluation for broncoscopy, cultures and pulmonary functions tests

21 From the trial Instructions for asymptomatic patients with pneumonitis Despite radiologic images and pulmonary function testing, the patient remained asymptomatic. Neither interruption nor dose reduction were performed. The patient, as per protocol, is still continuing on treatment.

22 Pulmonary toxicity with checkpoint inhibitors Pulmonary irae can present with dyspnoea, cough, fatigue or respiratory failure Grade 1 (asymptomatic radiological changes) may be monitored with no change in immunotherapy treatment. Grade 2: immunotherapy therapy should be withheld and oral steroids commenced (1mg/kg/day prednisolone or equiva- lent) Grade 3-4: hospitalisation and review by a respiratory physician, together with high dose intravenous steroids (2 4 mg/kg/day IV methylprednisolone) M. Howell et al, Lung Cancer 2015

23 UNIVERSITY OF TORINO DEPARTMENT OF ONCOLOGY Conclusioni - Molti farmaci possono causare tossicità polmonare; - Tossicità polmonare: miscellanea di quadri clinico-radiologici; - Soggetti > predisposti > attenzione - TKIs oncogene-addicted 20% - Immunotherapies >20% - Combinazioni? (CT + Immuno; TKIs + Immuno) - Tossicità: curva di apprendimento per riconoscerle, gestirle - Info al paziente - Gruppi Multidisciplinari/specialista di riferimento

24 UNIVERSITY OF TORINO DEPARTMENT OF ONCOLOGY Questions for Pneumologist Dobbiamo indagare meglio le patologie polmonari dei nostri pazienti? Quali in particolare? Esiste una figura di paziente più a rischio? Quando sospetto la tossicità polmonare? Segni/sintomi/esami per diagnosticarla-escluderla Esistono quadri TAC patognomonici? Quando la diagnostico/sospetto fortemente come la gestisco? Quale terapia? Posso riprendere la terapia se si risolve? Open questions

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