Anales de la RANM

19 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 downstaging after neoadjuvant therapy were unfavorable prognostic factors in univariate analyses. Clinical N2 status, multiple N2 nodes, and cell type of adenocarcinoma showed poor prognosis but were not statistically significant. Postoperative chemotherapy showed good prognosis but was not statistically significant. Multivariate analysis showed that significant favorable prognostic factors were complete resection and adjuvant chemotherapy (19). Experience of Memorial Sloan-Kettering Cancer Center confirms survival is significantly influenced by patient age, the median survival for complete resection 27.8 months compared with 11.4 months for incomplete resection, pathologic stage with 3-year survival for N0/N1 was 43.3% and 25.5% for N2 patients (20). An emerging hallmark of cancer is immunoevasion— the cancer cell’s ability to avoid destruction by the immune system. The three general categories of immunoevasive mechanisms include: (A) an insufficient number of T cells generated within the lymphoid compartment; (B) an insufficient number of T cells extravasating into the tumor; and (C) inhibition of T cells in the tumor microenvironment. The tumor microenvironment, in turn, offers three main immunoevasive tools: (1) surface membrane proteins that function as immune checkpoints, including PD-1, CTLA-4, lymphocyte-activation gene 3 (LAG-3) protein, T-cell immunoglobulin and mucin domain–containing protein 3 (TIM-3), B- and T-lymphocyte attenuator (BTLA), and the adenosine A2a receptor (A2aR); (2) the relationship between selected soluble factors and metabolic alterations, such as IL-10, transforming growth factor beta, adenosine, indoleamine 2,3-dioxygenase (IDO), and arginase; and (3) inhibitory cells, including cancer- associated fibroblasts (CAFs), regulatory T cells, myeloid-derived suppressor cells (MDSCs), and tumor-associated macrophages. The immune response and the use of strategies to upregulate surface proteins, including programmed death 1 (PD-1), is a new approach for the treatment of tumors. PD-L1 overexpression has been observed in 40% - 50% of all NSCLC tumours, on the set of all stages and histologies (21). Targeted therapy to PD-1 receptor and to PD-L1 ligands is intended to inhibit their intervention and is an attractive therapeutic option in the locally advanced NSCLC stage, which can reactivate the host immune responses and allow good long-term control of the tumor (22). In lung cancer, inhibition of the Check Point PD-1 pathway with antibodies directed against PD-1 or against its ligand, PD-L1, has showed preliminary and encouraged results that suggest a "class effect" and validate this pathway as a therapeutic target in NSCLC. Results from cohorts of heavily pretreated NSCLC patients in phase I studies showed objective responses dose dependent, ranging from 10% to 32% (23). Inhibition of the Checkpoint PD-1 pathway with antibodies against PD-1 or PD-L1 produces long lasting tumor response and stable disease as well, for more than 6 months. Exploratory analysis of PD-L1 tumor expression and treatment response have confirmed the prevalence of > 40% of PD-L1 expression in NSCLC. Some studies suggest an association between treatment response and PD-L1 tumor expression before treatment. However, PD-L1 expression role as a biomarker for response has not yet been validated. Immunotherapy with antibodies anti-PD-1 and anti-PD-L1 in many different tumors types has been, in general, well tolerated. Frequent adverse events related to the drug are limited episodes of grade 1 or 2 fatigue, diarrhea, rash, pruritus, nausea and decreased appetite. In clinical trials, grade 3 or 4 adverse events related to the treatment occur in < 15% of patients. Inmune related adverse events treatment related are infrequent (<2%) and include pneumonitis, vitiligo, colitis, hepatitis, thyroiditis and hypophysitis (24) Numerous ongoing trials are evaluating the combinationof chemotherapyandcheckpointblockade in solid tumors, including melanoma, NSCLC, and SCLC. In untreated metastatic melanoma, a phase III study showed that ipilimumab (at 10 mg/kg) plus dacarbazine improved OS compared with dacarbazine alone (11.2 vs 9.1 months, respectively), but this was at the expense of higher toxicity and there was no ipilimumab-alone comparator arm. A phase II study showed that phased but not simultaneous ipilimumab plus platinum doublet chemotherapy (carboplatin/ paclitaxel) improved immune-related PFS in patients with stage IIIB or IV NSCLC and extensive-stage SCLC, when compared with chemotherapy alone (25, 26). The choice of chemotherapy and dosing schedule are thus critical to optimizing outcomes of checkpoint blockade and chemotherapy combinations. With this in mind, a phase I four-cohort study evaluated first- line nivolumab at 10 mg/kg (N10) vs 5 mg/kg (N5) in combination with gemcitabine/cisplatin (N10) in advanced squamous-cell NSCLC, pemetrexed/ cisplatin (N10) in advanced nonsquamous NSCLC, and paclitaxel/carboplatin (N5 vs N10) in combined cohorts of squamous and nonsquamous NSCLC (27). The toxicity profile was additive, representing effects of both nivolumab and chemotherapy. The ORR, PFS, and 1-year OS outcomes were acceptable. In particular the 1-year OS rate was 85% for the N5 paclitaxel/ carboplatin group and 87% for the N10 pemetrexed/ cisplatin group, which may reflect a positive signal. A phase Ib study enrolled untreated patients with locally advanced or metastatic NSCLC to three treatment arms of atezolizumab plus chemotherapy, including carboplatin/pemetrexed, carboplatin/ paclitaxel, and carboplatin/nab-paclitaxel (28). Atezolizumab at 15 mg/kg every 3 weeks was administered with standard chemotherapy for 4 to 6 cycles followed by atezolizumab maintenance or atezolizumab/pemetrexed maintenance in the IMMUNOTHERAPY IN TREATMENT OF CANCER