Anales de la RANM

21 A N A L E S R A N M R E V I S T A F U N D A D A E N 1 8 7 9 TRATAMIENTO NEOADYUVANTE DEL CÁNCER DE PULMÓN Mariano Provencio Pulla An RANM · Año 2019 · número 136 (01) · páginas 17 a 24 96 weeks (12 cycles) or until unacceptable toxicity, confirmed complete response, confirmed disease progression, or withdrawal of consent. In the absence of clinical deterioration, patients could continue treatment after initial disease progression to allow for patterns of response consistent with immune-related response criteria. In the NSCLC cohort, with a long term median follow-up of 27.5 months (range, 21 to 54 months), median overall survival (OS) across nivolumab doses was 9.9 months. One- and 2-year OS rates were 42% and 24%, respectively, across doses and 56% and 45%, respectively, at the 3 mg/kg dose (n=37) being used for further clinical development. Among 22 (17%) patients with objective responses, estimated median response duration was 17.0 months. Response rates were similar in squamous and non-squamous NSCLC and in patients who received 3 or more prior therapies. Sixteen responding patients discontinued nivolumab for reasons other than progressive disease and 6 (38%) had responses lasting >30 weeks after their last dose. Grade 3-4 treatment-related adverse events occurred in 14% of patients. Three treatment-related deaths (2% of patients) occurred, each associated with pneumonitis (37). Recently, the first randomized trials using nivolumab in comparison to standard of care docetaxel in the second line setting have been reported (39, 40). The first one (checkmate 017) was focusing on squamous histology advanced NSCLC patients. 272 patients were assigned to receive nivolumab at a dose of 3 mg per kilogram of body weight every 2 weeks, or docetaxel at a dose of 75 mg per square meter of body-surface area every 3 weeks. The median overall survival was 9.2 months (95% confidence interval [CI], 7.3 to 13.3) with nivolumab versus 6.0 months (95% CI, 5.1 to 7.3) with docetaxel. The risk of death was 41% lower with nivolumab than with docetaxel (hazard ratio, 0.59; 95% CI, 0.44 to 0.79; P<0.001). At 1 year, the overall survival rate was 42% (95% CI, 34 to 50) with nivolumab versus 24% (95% CI, 17 to 31) with docetaxel. The response rate was 20% with nivolumab versus 9% with docetaxel (P=0.008). The median PFS was 3.5 months with nivolumab versus 2.8 months with docetaxel (hazard ratio for death or disease progression, 0.62; 95% CI, 0.47 to 0.81; P<0.001). The expression of the PD-1 ligand (PD-L1) was neither prognostic nor predictive of benefit. Treatment-related adverse events of Grade 3 or 4 were reported in 7% of the patients in the nivolumab group as compared with 55% of those in the docetaxel group (39). The second trial, checkmate 057 used the same design in the non-squamous subgroup. Patients in the CheckMate 057 study had progressed after treatment with platinum-based doublet chemotherapy (and, if eligible, a tyrosine kinase inhibitor), a guideline-recommended first-line therapy for nonsquamous NSCLC. They were randomly assigned to subsequent treatment with nivolumab (3 mg/kg every 2 weeks; 292 patients) or docetaxel (75 mg/m2 every 3 weeks; 290 patients); both drugs were continued until progression or discontinuation due to toxicity (40). The primary efficacy endpoint of the study was overall survival (OS). Treatment with nivolumab significantly improved median OS, with a hazard ratio for death of 0.73 (95% CI: 0.59, 0.89; P=0.00155) compared with docetaxel. One-year OS was 50.5% with nivolumab versus 39.0% with docetaxel. Other study endpoints included PFS, ORR, and nivolumab efficacy by PD-L1 expression. Significantly more patients had an objective response (19.2% vs. 12.4%; P=0.0235). At the time of the analysis, the median duration of response to nivolumab was 17.1 months, compared with 5.6 months for docetaxel. No difference between nivolumab and docetaxel was observed in median PFS (2.3 months vs. 4.2 months; P=0.393). PD-L1 expression was associated with improved efficacy for patients treated with nivolumab, an effect most dramatically seen in patients with PD-L1 expression 5% or higher and 10% or higher, but evident at PD-L1 expression levels as low as 1% or higher. Also of note, subgroup analysis favoured nivolumab over docetaxel in all categories, except patients 75 years of age or older, never smokers, and those positive for EGFR mutations. Treatment-related adverse reactions of grade 3 to 5 severity occurred at a higher rate with docetaxel (53.7%) than with nivolumab (10.5%). Regarding toxicity, and as a summary, across all clinical trials performed to date using anti-PD‑1 drug monotherapy and in particular nivolumab, the observed incidence of severe pneumonitis is less than 5% with nivolumab monotherapy. Chemotherapy stimulates an immune response against tumors, which may facilitate immunotherapy´s anticancer activity. Evidence of synergy between chemotherapy and immunotherapy was shown in several studies. The feasibility of combining both targeted agents and immunotherapy is also being studied in the CheckMate 012 trial and more recently in CheckMate 227 phase III study. Neoadjuvant administration of two doses of nivolumab in patients with early stage lung cancer led to a major pathological response in 45% of tumors (41) . Major pathological response defined as <10% viable tumor cells in the resected specimen. NADIM Study (CA209-547) (42) is a Phase II, single-arm, open-label multicenter study aimed to assess the feasibility, safety and efficacy of combined neoadjuvant chemotherapy and immunotherapy. (Figure 1) The primary endpoint is the progression- free survival (PFS) at 24 months from diagnosis . Results: (cut-off date 30th June 2018). Available efficacy results for this subset of 30 patients underwent surgery: No intraoperative complications were documented. 7/30 patients had postsurgical complications. There was no post-operative mortality. Clinical results: Tumor responses after neoadjuvant therapy (100% compliance rate), according to RECIST criteria v1.1 assessed per CT-SCAN: -ORR= 21/30 (70%), including 3 Complete Responses (CR)