TOSSICITA’ POLMONARI
Lucio Buffoni
buffonil75@gmail.com Oncologia AOU San Luigi
Orbassano
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.
Gefitinib
• Incidenza 1% (Asia 3-6%);
• Fattori predisponenti:
Fumo; Maschi;
Età avanzata;
Malattie polmonari sottostanti;
Malattie cardiologiche.
• Tempo insorgenza medio: 24-31 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.
Immuno
PD-1 Inhibitors - Safety
Felip E et al, ESMO 2014
Keynote 001: pembrolizumab
CheckMate 063: nivolumab
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
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%
Docetaxel 88%
54%
Neutropenia – 31%
Fatigue – 29%
Nausea – 26%
0%
Keynote 010 Pembrolizumab 2 mg/kg dose
63%
13%
Fatigue – 20%
Pruritis – 11%
appetite – 11%
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
UNIVERSITY OF TORINO –DEPARTMENT OF ONCOLOGY
Adverse Events: KN024 Pembro I linea
Reck M, NEJM 2016
All grade G>3
Naidoo J et al, JCO 2016
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
Pneumonitis in Patients Treated With Anti–PD1/PDL1 Therapy
(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
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
Pneumonitis in Patients Treated With Anti–PD1/PDL1 Therapy
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
After nodal progression (laterocervical lymph nodes), the patient was evaluated within MK-3475-010 clinical trial.
PD-L1 expression on diagnostic tissue was evaluated and described.
The patient was randomized to treatment with MK 3475 2 mg/Kg q3weeks. I cycle started on 23 Jan 2014
… appearance and increase of bilateral ground glass areas
After 3 cycles After 6 cycles After 9 cycles
After 12 cycles After 18 cycles
CT scan during treatment
Baseline
Decreased Diffusing Capacity (DLCO) – Asymptomatic patient
Baseline After 17 cycles
Pulmonary function testing
Stop MK - 3475
Evaluation for broncoscopy, cultures and pulmonary functions tests
From the trial… Instructions for symptomatic patients with pneumonitis
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.
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
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
UNIVERSITY OF TORINO –DEPARTMENT OF ONCOLOGY
