Coorticosteroid Regimen in Patients With Anti-PD-1/PD-L1 Induced Pneumonitis

This is a prospective interventional open-label randomized trial. The patients treated with anti-

PD-1 (programmed-death receptor type 1) or anti-PD-L1 (programmed-death ligand) antibodies in case of new acute onset interstitial changes or new seriuos respiratory system related symptoms will be recruited for this study to perform diagnostics. At the recruitment the patient will be randomized 1:1 to investigatory or control arm, the randomization will be stratified upon three criteria:

1. severity of suspected pneumonitis at baseline (grade 2 vs. grade 3-4)
2. response for oncological treatment (partial response (PR) and complete response (CR) vs. stable disease (SD) and progression disease (PD))
3. chronic respiratory system disorders Both groups will be treated in the same way in terms of diagnostic procedures. In case of interstitial lung diseases related to immune checkpoint inhibitor is confirmed with the severity of grade 2-4 in the modified CTCAE criteria the patient will get the treatment, accordingly to the randomization: ARM A - INVESTIGATORY GROUP the start dose will be 1-4 mg/kg of body weight of prednisone, depending on clinical condition and pneumonitis severity, the induction treatment will last for 5-7 days, in case of severe condition - no improvement after 48-72 h of initial treatment - introduction of immunosuppressive agent is recommended - cyclophosphamide, mofetil mycophenolate or infliximab. A continuation treatment with dose tapering is than recommended, starting from 60mg q 24h of prednisone for 2-4 weeks, and dropping the dose 10mg q 24 h not faster than over 14 days; the maintenance dose of prednisone 10mg q 24 h should be hold for 8 weeks and withdraw should last for 4 weeks. This arm will be treated with corticosteroid for at least 12-24 weeks.

ARM B - CONTROL GROUP the starting dose will be 1-4mg/kg of body weight of prednisone , depending on clinical condition and pneumonitis severity, the induction treatment will last 5-7 days; in case of severe condition - no improvement after 48-72 h of initial treatment - introduction of immunosuppressive agent is recommended: cyclophosphamide, mofetil mycophenolate or infliximab. A continuation treatment with dose tapering is than planned, starting from oral dose of 30-60mg q 24h of prednisone, and dose reduction of 10mg q 24 h each 1 week. This arm will be treated for 6-12 weeks.

During the treatment and after its termination the function of respiratory system, interstitial changes in radiologic examinations, anticancer response, survival time, pneumonitis relapse and glucocorticosteroid side effects will be monitored and evaluated. The observation will last up to 52 weeks.

1. Diagnostic period The screening for the study will involve patients with newly diagnosed interstitial changes in chest radiological examination or in patient with new respiratory system related symptoms. The radiological changes must be confirmed in chest computed tomography (CT). In case on inclusion criteria are meet the patient will be randomized and will begin the diagnostic process.

In both groups the diagnostic process will be the same, based upon the existing recommendations it will involve:

1. detailed medical history and physical examination;
2. laboratory tests: CBC, CRP, PCT, ALT, AST, CK, LDH, Na, K, Ca, glucose, proteinogram, flow cytometry, IgG and IgM levels, anti-nuclear antibodies (immunofluorescence, dilution), cytomegalovirus (CMV) polymerase-chain reaction (PCR), IgG and IgM for Legionella pneumophila, Chlamydia pneumoniae, Mycoplasma pneumoniae, QuantiferonTB-GOLD, NT- proBNP, troponin T;
3. arterialized blood gas panel;
4. in case it was not yet performed - chest computed tomography with contras enhancement with exclusion of pulmonary embolism;
5. 12-lead electrocardiograph
6. spirometry, full body plethysmography with carbon monoxide diffusion, 6-minute walk test
7. flexible bronchoscopy with:

   1. culture for aerobic bacteria
   2. culture for Mycobacterium tuberculosis (TB), TB PCR,
   3. culture for funguses, Aspergillus antigen, PCR and immunofluoroscopic examination for Pneumocystis jiroveci (PCP)
   4. bronchoalveolar lavage (BAL) with BAL fluid cell analysis
   5. transbronchial lung biopsy with forceps or nitrogen-criobiopsy, exclusion of CMV pneumonia and neoplasm progression, histological examination for pneumonitis histological pattern; bronchoalveolar lavage and lung biopsy will be performed only in patient with no clinical contradictions.

      Interstitial lung diseases related to immune checkpoint inhibitor, i.e. interstitial pneumonia related to checkpoint inhibitor or immunotherapy, i.e. pneumonitis: definition:

      the appearance of new radiological changes in chest examination (chest CT or plain radiogram proved with chest CT) after being exposed (treated) with anti-PD-1 or anti-PD-L1 monoclonal antibody, the radiological changes can be described as interstitial: ground glass opacities, consolidations with air bronchogram, interstitial septa thickening, central lobular nodules with perilymphatic distribution; the changes cannot be explained with neoplasm progression, active respiratory infection, heart failure or one of the above is not a sole explanation for the changes. The radiological changes are sometimes accompanied with respiratory system related symptoms. Each case need detailed differential and diagnosis of pneumonitis diagnosis can be made established after active exclusion of other potential causes. Good reaction for glucocorticosteroid treatment makes the diagnosis more likely.

      The severity of pneumonitis should be based on 5 point scale based on the modified Common Terminology for Adverse Events (CTC AE) v. 5 criteria:

      Grade 1 (G1) Interstitial changes with no symptoms and no progression in follow-up examination after few days.

      Grade 2 (G2) Interstitial changes without respiratory failure with mild to moderate respiratory symptoms.

      Each case of asymptomatic relapse. Grade 3 (G3) Interstitial changes with acute respiratory failure and the need of oxygen therapy.

      Grade 4 (G4) Interstitial changes with acute respiratory failure and the need of mechanical ventilation.

      Grade 5 (G5) Death related to acute interstitial pneumonitis.

      The diagnostics and treatment of patient should be based on patients condition and conducted in pulmonology or intensive care unit (ICU) department. The treatment should always be driven by the most likely diagnosis and the participation in the study should not delay any procedure or medication administration.

      In cases when radiological changes were discovered and severity is grade 1 it is recommended to perform a follow up chest radiograph after 5-7 days to see the dynamics and reassess the severity.

      2. Induction treatment General rules: The treatment is conducted based on patients condition in ICU or pulmonology department. The commence of glucocorticosteroid administration should take place with no delay in patient with high suspicion of grade 4 pneumonitis (max. 12 h after the beginning of diagnostics), in case of grade 3 pneumonitis the time to the initiation of treatment should last less than 24 h, and in grade 2 pneumonitis the diagnostics should last no longer than 5 days. The induction treatment last for 5-7 days.

      In case of elevated inflammatory markers, clinical, laboratory or microbiological signs of infection accompanying pneumonitis it is recommended to administer antibiotics. Antibiotics will not be routinely used in the whole study population.

      Arm A: initial dose in grade 2 is 1 mg/kg of body weight of oral prednisone, in grade 3-4 - 2- 4mg/kg of body weight of intravenous methylprednisolone, depending on severity and clinical condition. Induction treatment for 5-7 days; in cases of severe course - bad condition and no improvement after initial 48-72 h - introduction of cyclophosphamide, mycophenolate mofetile or infliximab.

      Arm B: initial dose in grade 2 is 1 mg/kg of body weight of oral prednisone, in grade 3-4 - 2- 4mg/kg of body weight of intravenous methylprednisolone, depending on severity and clinical condition. Induction treatment for 5-7 days; in cases of severe course - bad condition and no improvement after initial 48-72 h - introduction of cyclophosphamide, mycophenolate mofetile or infliximab.

      Dosage and administration: Preferred intravenous corticosteroid is methylprednisolone, the dosage range is 1-4 mg/kg of body weight, but in case 4mg/kg is considered a flat dose of 500mg q 24 h is recommended. The medication will be diluted in saline, it will be administered in single daily dose.

      The preferred oral medication is prednisone, dosage is 1mg/kg of body weight, but not more than 60mg, administered in single dose daily.

      The administration of cyclophosphamide, mycophenolate mofetile or infliximab will be based on case-by-case decision of multidisciplinary board and dosage will be based on the summary of the medical product characteristics.

      3. Maintenance treatment General rules: the treatment should start the last day of induction treatment if intravenous corticosteroid was administered, in case of oral induction treatment it should start the next day after induction in over. It is based on oral medication, administered in one daily dose in the morning. In case of grade 2 pneumonitis the immunotherapy re-challenge is possible after the dose of 10mg q 24h of prednisone is reached. The dose modification should be considered in case of serious side effects of steroid therapy.

      During glucocorticosteroid therapy no routine prophylaxis of pneumocystis pneumonia is recommended, and the administration of co-trimoxazole should be analyzed case by case; it should be considered in cases of positive PCR results for Pneumocystis jiroveci and in patient with T C4+ cells depletion in flow cytometry - less than 200 cells per microliter. During steroid therapy osteoporosis prophylaxis can be considered. We do not recommend antifungal prophylaxis.

      Arm A: The maintenance treatment with oral agent, the general rules must be meet - tapering starts at the dose of 60mg q 24 h of prednisone for 2-4 weeks, the reduction is not faster than 10mg each 14 days, the maintenance dose if flat 10mg q 24 h dose for 8 weeks and the withdraw should be slow over 4 weeks. The treatment should last 12-24 weeks or longer. The detailed dose of daily prednisone is presented in Tables.

      Arm B: Treatment with oral agent, based on general rules - the tapering starts at the dose of 30- 60 mg q 24h of prednisone, the reduction is no faster than 10mg each 7 days, the treatment lasts between 6 and 12 weeks. The detailed dosage proposition is presented in the Tables.

      Dosage and administration: The preferred oral agent is prednisone, in single daily dose administered in the morning. The recommended dose of co-trimoxazole in case of PCP prophylaxis is 960mg q2d administered on Monday, Wednesday and Friday; it should last until 10mg q 24h of prednisone is reached.

      4. Relapse treatment In case of relapse suspicion the workup should be the same as initial starting from the diagnostic period. The treatment scheme is as in Arm A.

      5. Follow-up period The observation starts from the first day of the maintenance therapy. The clinical and radiological follow-up is planned each 4-6 weeks during the first 24 weeks and then each 12 weeks. The observation will last up to 52 weeks. In the follow-up points steroid side effects, anticancer response, treatment efficacy and signs of relapse will be evaluated, using:

1) detailed history and physical examination 2) chest radiogram

In the 12 weeks (t12) and 52 weeks (t52) point follow-up extra procedures to exaluate the endpoint will be performed:

1. chest computed tomography
2. arterialized blood gas panel
3. spirometry, full body plethysmography with carbon monoxide diffusion, 6-minute walk test

Eligibility Criteria:
Inclusion Criteria:

1. age over 18 years old
2. histological or cytological confirmation of solid cancer
3. treatment with anti-PD-1 or anti-PD-L1 antibody in monotherapy or in combination with cytotoxic chemotherapy or antiangiogenic agents like anti-vascular epitheliar growth factor antibodies
4. acute onset respiratory symptoms or lung changes in radiologic examinations which were not present before immunotherapy was introduced e. signed informed consent

Exclusion Criteria:

1. concomitant or previous treatment with anti-CTLA4 or other immunotherapeutic agents
2. active untreated tuberculosis
3. the use of glucocorticosteroids in the dose equivalent to 10mg q 24h or more of prednisone in the last 4 weeks in indication other than pneumonitis or different immune related adverse event d. withdraw of consent