DUMAS: Neo-Adjuvant Immunotherapy for Pancoast Tumors

This is an open-label, phase II, single-arm, multi-centre clinical trial.

The total sample size is 40 patients. The population to be included are previously untreated patients with histologically- or cytologically- documented NSCLC diagnosed with Pancoast tumor.

Patients will receive Nivolumab 360mg + Paclitaxel 200mg/m2 + Carboplatin AUC6 for 3 cycles every 21 days (+/- 3 days) as neoadjuvant treatment followed by surgery and 6 months of adjuvant treatment with Nivolumab 480 mg Q4W (+/- 3 days) if applicable and depending on surgery results. Patients that will not receive adjuvant treatment will start follow up phase after end of treatment visit. Follow up for all patients must be done for 2 years.

The primary objective is to evaluate the complete resection (R0) rate after induction treatment defined as the absence of residual tumor in patients treated with neoadjuvant chemo-immunotherapy.Secondary objectives and endpoint are Overall survival rate at 24 months and disease-free survival rate at 24 months.

Patient accrual is expected to be completed within 2 years excluding a run-in-period of 3 months. Treatment and follow-up are expected to extend the study duration to a total of 5 years. The study will end once survival follow-up has concluded.

Inclusion criteria

• 1. Previously untreated patients with histologically- or cytologically- documented NSCLC diagnosed with Pancoast tumor according to 8th edition of the TNM (stages IIB, IIIA and T3N2 (IIIB) patients)
• 2. PET/CT including IV contrast (CT of diagnostic quality) will be performed at baseline (28 days +10 before enrollment) to rule out the presence of distant disease. Also, a brain CT-SCAN or brain MRI will be done at baseline
• 3. Positive mediastinal lymph nodes by PET-CT must be confirmed histologically. Mediastinal involvement may be considered without the need for histological confirmation when there is a mass of lymph nodes in which the margins cannot be distinguished
• 4. Measurable or evaluable disease (according to RECIST 1.1 criteria)
• 5. ECOG (Performance status) 0-2
• 6. Patients with a life expectancy of at least more than 12 weeks
• 7. Patients aged > 18 years and ≤ 75 years
• 8 Screening laboratory values must meet the study criteria and should be obtained within 14 days prior to enrollment
• 9. Correct lung function without bronchodilators, defined by forced expiratory volume in 1 second (FEV1) >40% of the predicted normal volume, and a pulmonary diffusing capacity for carbon monoxide (DLCO) >40% of the predicted normal value
• 10. All patients are notified of the investigational nature of this study and signed a written informed consent in accordance with institutional and national guidelines, including the Declaration of Helsinki prior to any trial-related intervention
• 11. Women of childbearing potential, including women who had their last menstrual period in the last 2 years, must have a negative serum or urine pregnancy test within 7 days before enrollment.
• 12. All sexually active men and women of childbearing potential must use an effective contraceptive method during the study treatment and for a period of at least 12 months following the last administration of trial drugs
• 13. Patient capable of proper therapeutic compliance and accessible for correct follow-up.

Exclusion criteria

• 1. Patients that receive previous treatment with antineoplastic drugs, chest radiotherapy, or previous surgery for lung cancer or for another reason
• 2. Pleural or pericardial effusion: Both will be considered indicative of metastatic disease unless proven otherwise. Those that, even being cytologically negative for malignancy, are exudates, will also be excluded. Patients with pleural effusion not visible on chest X-ray or too small to perform diagnostic puncture safely may be included.
• 3. Patients with a weight loss >10% in the 3 months prior to the study entry
• 4. All patients carrying activating mutations in the TK domain of EGFR or any variety of alterations in the ALK gene or ROS1 mutations.
• 5. Patients with active, known or suspected autoimmune disease. Subjects with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune thyroiditis only requiring hormone replacement or unexpected conditions of recurrence in the absence of an external trigger are allowed to be included.
• 6. Patients with symptomatic neuropathy > grade 1 according to the CTCAE v5.0 and that were not related to the tumor
• 7. Patients with a condition requiring systemic treatment with either corticosteroids (>10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of enrollment. Inhaled or topical steroids, and adrenal replacement steroid doses > 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease.
• 8. Patients with a history of interstitial lung disease cannot be included if they have symptomatic ILD (Grade 3-4) and/or poor lung function. In case of doubt please contact trial team.
• 9. Patients with other active malignancy requiring concurrent intervention and/or concurrent treatment with other investigational drugs or anticancer therapy
• 10. Patients with uncontrolled comorbidities that may affect the clinical trial compliance
• 11. Patients with previous malignancies (except non-melanoma skin cancers, and the following in situ cancers: bladder, gastric, colon, endometrial, cervical/dysplasia, melanoma, or breast) are excluded unless a complete remission was achieved at least 5 years prior to study entry and no additional therapy is required during the study period.
• 12. Any medical, mental, neurological or psychological condition which in the opinion of the investigator would not permit the patient to complete the study or understand the patient information sheet.
• 13. Patients in any psychological, familiar, sociological or geographical situation that may hinder compliance with the study protocol and/or the follow up
• 14. Patients who have had prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways
• 15. Patients with positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection
• 16. Patients with known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).
• 17. Patients with know hypersensitivity to drugs with a structure similar to the study drug and/or history of allergy to study drug components excipients
• 18. Women who are pregnant or in the period of breastfeeding
• 19. Sexually active men and women of childbearing potential who are not willing to use an effective contraceptive method during the study