Stereotactic ablative radiotherapy with nivolumab for early-stage operable non-small cell lung cancer: A phase 2 study.
Authors: Schvartsman Gustavo , Rezende Ana Carolina Pires de , Gomes Diogo Bugano Diniz , Koch Ludmila De Oliveira , Bibas Benoit Jacques , Gomes Oswaldo , Campregher Paulo V , Severino Patricia , Marti Luciana Cavalheiro , Paes Vitor Ribeiro , Chate Rodrigo Caruso , Ribas José Milanez , Ramos Sousa Victor Aurelio , Taranto Patricia , Moura Fernando , Terra Ricardo Mingarini , Samano Marcos Naoyuki 
Published: June 2023

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Background: Surgery is standard of care for patients with stage I non-small cell lung cancer (NSCLC). However, 5-year mortality can reach up to 30%. For patients with contraindication to surgery, treatment with stereotactic ablative radiotherapy (SABR) leads to adequate local tumor control, but has a high rate of regional and distant failure. SABR as neoadjuvant therapy for stage I NSCLC produced a pathologic complete response (pCR) rate of only 60% when surgery was performed after 10 weeks of treatment, demanding improvement in the management of both operable and inoperable early-stage NSCLC. Immune checkpoint inhibitors (ICI) are routinely used in stages III-IV NSCLC, with recent approvals in the peri-operative setting, and may be synergistic with radiotherapy. We hypothesized that neoadjuvant nivolumab plus SABR may improve pCR rate and provide insight to its changes in the tumor microenvironment. Methods: This is a phase 2, single arm, open label study evaluating neoadjuvant treatment for patients with NSCLC of up to 4 cm, with no lymph node involvement (AJCC 8th edition: up to cT2aN0), and adequate surgical conditions. Treatment consisted of nivolumab 360 mg every 3 weeks for 3 doses or unacceptable toxicity. SABR started on D1 of nivolumab, with a duration of 2 to 3 weeks, depending on the lesion size and location (3 x 18 Gy; or 5 x 10 Gy; or 8 x 7.5 Gy). Standard-of-care surgery was performed at 10 (+- 2) weeks after the last radiotherapy dose. The primary endpoint of the study is pCR rate at surgery. Tissue, blood, and stool samples were collected during treatment. Results: We included 25 patients. All but one were cared for in the Brazilian public system. Mean age was 68 years. Mean tumor size was 2.45 cm. Only 3 patients were never-smokers. Surgery was performed as scheduled in all but one patient. pCR rate was 80% (19/24) and MPR rate was 83% (20/24) of patients who underwent surgery. Twenty-nine treatment-emergent adverse events occurred in 13 patients (23 grade 1-2 events, two grade 3 and two grade 5 events, being only one grade 3 diarrhea related to experimental treatment). The single patient who was not operated died during study treatment from relapsed acute alcoholic hepatitis. The other grade 5 event was due to a respiratory infection, both unrelated to treatment. Two patients died from surgical complications 185 and 72 days after surgery, respectively (one with pulmonary artery lesion with subsequent clinical complications and other with thromboembolic events), deemed unrelated to experimental treatment. During follow-up, two additional patients died due to comorbidities, and none relapsed to date. Conclusions: In this trial with patients with significant comorbidities and smoking history from the public system in Brazil, we demonstrated a pCR rate of 80% with SABR + nivolumab. Further studies are warranted to evaluate this strategy versus surgery in operable patients with stage I disease. Clinical trial information: NCT04271384 .