Alteration of the Nucleotide Excision Repair (NER) Pathway in Soft Tissue Sarcoma.

Clinical responses to anticancer therapies in advanced soft tissue sarcoma (STS) are unluckily restricted to a small subgroup of patients. Much of the inter-individual variability in treatment efficacy is as result of polymorphisms in genes encoding proteins involved in drug pharmacokinetics and pharmacodynamics. The nucleotide excision repair (NER) system is the main defense mechanism for repairing DNA damage caused by carcinogens and chemotherapy drugs. Single nucleotide polymorphisms (SNPs) of NER pathway key genes, altering mRNA expression or protein activity, can be significantly associated with response to chemotherapy, toxicities, tumor relapse or risk of developing cancer. In the present study, in a cohort of STS patients, we performed DNA extraction and genotyping by SNP assay, RNA extraction and quantitative real-time reverse transcription PCR (qPCR), a molecular dynamics simulation in order to characterize the NER pathway in STS. We observed a severe deregulation of the NER pathway and we describe for the first time the effect of SNP rs1047768 in the ERCC5 structure, suggesting a role in modulating single-stranded DNA (ssDNA) binding. Our results evidenced, for the first time, the correlation between a specific genotype profile of ERCC genes and proficiency of the NER pathway in STS.

Association of Systemic Steroid Treatment and Outcome in Patients Treated with Immune Checkpoint Inhibitors: A Real-World Analysis.

BACKGROUND: Immune-related adverse events (irAEs) are inflammatory side effects, which can occur during immune-checkpoint(s) inhibitors (ICIs) therapy. Steroids are the first-line agents to manage irAEs because of their immunosuppressive properties. However, it is still debated whether or when steroids can be administered without abrogating the therapeutic efforts of immunotherapy. METHODS: We retrospectively evaluated 146 patients with metastatic non-small cell lung cancer (NSCLC), melanoma and renal cell carcinoma (RCC) treated with ICIs. We assessed the progression-free survival (PFS) of patients treated with steroids due to an irAE compared to a no-steroid group. RESULTS: The early treatment with steroid (within the first 30 days from the beginning of immunotherapy) was not related to a shorter PFS (p = 0.077). Interestingly, patients who were treated with steroids after 30 days from the start of immunotherapy had significantly longer PFS (p = 0.017). In a multivariate analysis, treatment with steroids after 30 days was an independent prognostic factor for PFS (HR: 0.59 [95% CI 0.36-0.97], p = 0.037). CONCLUSIONS: This retrospective study points out that early systemic steroids administration to manage irAEs might not have a detrimental effect on patient clinical outcome in NSCLC, melanoma and RCC patients.

Head and neck melanoma: the eyelid region has a better prognosis and easier management: a retrospective survey and systematic review.

Eyelid melanoma (EM) is a malignant neoplasm accounting for around 1% of eyelid malignancies. Because of its rarity, most of our knowledge of EM is currently based on studies of cutaneous melanomas located elsewhere. Accordingly, this study aimed to specifically evaluate EM characteristics, management strategies, and prognosis. A retrospective study was carried out on patients diagnosed with EM at Careggi University Hospital, Florence between May 2012 and May 2022. In addition, a systematic review of relevant literature was conducted, encompassing studies published from 2013 to 2023. Clinical, histopathological, therapeutical, and prognostic data were analyzed to assess the metastasis rate and the 5-year survival rate of patients with EM. Separate data were extracted for in situ and invasive disease. Our original study included 19 patients diagnosed with EM with a 5-year survival rate of 100% for in situ and 83.3% for invasive EM. The literature review identified five poorly detailed large database reviews and 14 original studies on EM with an overall 5-year survival rate of 79.7%. The present research indicates that EM is a challenging malignancy, but has a relatively better prognosis and easier management than other melanomas of the head and neck region. These are probably related to the anatomical location which leads to early diagnosis. Therefore, EM should be considered as a specific disease requiring dedicated treatment. Based on the personal authors' experience and comprehensive overview of the current knowledge, a dedicated protocol is proposed.

Neutrophil-to-Eosinophil Ratio Predicts the Efficacy of Avelumab in Patients With Advanced Urothelial Carcinoma Enrolled in the MALVA Study (Meet-URO 25).

BACKGROUND: Neutrophil-to-eosinophil ratio (NER) has been described to be associated with outcomes to immune checkpoint inhibitors (ICI) in several tumor types, but less is known about its role of in the response to avelumab in advanced urothelial cancer (aUC). Thus, we reported outcomes by NER of aUC patients treated with avelumab as maintenance after initial response to platinum-based chemotherapy and enrolled in the Maintenance with AVeLumAb ([MALVA] in advanced urothelial neoplasms in response to first-line chemotherapy: an observational retrospective study) study (Meet-URO 25). PATIENTS AND METHODS: Median NER at baseline and after 3 cycles of avelumab were calculated. Progression-free survival (PFS) and overall survival (OS) by NER were reported. RESULTS: At the cutoff date (April 15, 2023), a total of 109 patients were included. The median NER was 28.05 at baseline and 24.46 after 3 cycles of avelumab, respectively. Median PFS was not reached for patients with baseline NER less than the median (

Bone Metastases in Renal Cell Carcinoma: Impact of Immunotherapy on Survival.

Background/Aim: We performed a multicenter retrospective observational study to investigate the impact of immune checkpoint inhibitors (ICIs) on the survival of patients with bone metastases (BMs) from renal cell cancer (RCC). Patients and Methods: A total of 98 patients with metastatic RCC (mRCC) treated with ICIs were retrospectively enrolled. All patients received standard treatments with nivolumab alone or in combination with ipilimumab from December 2015 to March 2022. The primary endpoint was median overall survival (OS). Results: Forty-three patients (44%) had radiological evidence of BMs. No statistically significant difference in OS was reported between the BM population and the entire population (p=0.254). Conclusion: Our study suggests some degree of ICI activity to treat patients with BMs from RCC, historically associated with a poorer prognosis.

Immune checkpoint blockade with anti-programmed cell death 1 (PD-1) monoclonal antibody (mAb) cemiplimab: ongoing and future perspectives in rare genital cancers treatment.

Cemiplimab is a highly potent, hinge-stabilized human IgG4 monoclonal antibody (mAb) targeting programmed cell death 1 (PD-1) receptor approved for patients with locally advanced or metastatic cutaneous squamous cell carcinoma (SCC) who are not candidates for curative surgery or curative radiation. Recently, the phase 3 trial EMPOWER-Cervical 1 has investigated cemiplimab in patients with recurrent/metastatic cervical cancer. At interim analysis, overall survival (OS), progression free survival (PFS) and objective response rate (ORR) in overall and SCC populations favored cemiplimab over single agent chemotherapy. Cervical SCCs are the first for incidence among Human Papilloma Virus (HPV) related neoplasms and are highly correlated (about 95%) with the viral infection. Similarly, penile and vulvar SCC may develop on chronic HPV infections or on dermatological chronic conditions (ie, lichen). The molecular and viral similarities between external genital SCC and SCC originating from the cervical epithelium could be the rationale for using cemiplimab to treat locally advanced or metastatic penile and vulvar SCC as well. Some retrospective data have shown that cemiplimab may provide objective response and clinical benefit to some patients with penile or vulvar SCC and is overall safe to utilize in this population. Given the complexity of the immune activation and the considerable variability in tumor biology across patients and tumor types, the identification of biomarkers to warrant patient selection needs to be further explored. Ongoing clinical trials will hopefully shed light on the treatment paradigm of these rare tumors too, with special regard to the ideal combination and sequencing of immunotherapeutic strategies.

Pharmacogenomics of soft tissue sarcomas: New horizons to understand efficacy and toxicity.

Clinical responses to anticancer therapies in advanced soft tissue sarcoma (STS) are unfortunately limited to a small subset of patients. Much of the inter-individual variability in treatment efficacy and risk of toxicities is as result of polymorphisms in genes encoding proteins involved in drug pharmacokinetics and pharmacodynamics. Therefore, the detection of pharmacogenomics (PGx) biomarkers that might predict drug response and toxicity can be useful to explain the genetic basis for the differences in treatment efficacy and toxicity among STS patients. PGx markers are frequently located in transporters, drug-metabolizing enzyme genes, drug targets, or HLA alleles. Along this line, genetic variability harbouring in the germline genome of the patients can influence systemic pharmacokinetics and pharmacodynamics of the treatments, acting as predictive biomarkers for drug-induced toxicity and treatment efficacy. By linking drug activity to the functional complexity of cancer genomes, also systematic pharmacogenomic profiling in cancer cell lines and primary STS samples represents area of active investigation that could eventually lead to enhanced efficacy and offer a powerful biomarker discovery platform to optimize current treatments and improve the knowledge about the individual's drug response in STS patients into the clinical practice.

Castration-resistant prostate cancer with bone metastases: toward the best therapeutic choice.

The treatment landscape for metastatic castration-resistant prostate cancer has evolved extremely in recent years and several drug classes are now available. Nonetheless, the lack of validated predictive biomarkers makes therapeutic choice and the best sequential approach difficult. The location of the metastatic site could be a valid criterion for choosing among the treatment options available. Although bone remains the most frequent metastatic site and a possible target for many drugs, recent data suggest a profound shift in the disease spectrum with visceral metastases increasing incidence. This review describes the presently available and ongoing therapies for patients with CRPC and bone metastases, focusing on the role of bone metastases as a possible driver for selecting therapies in these patients.

Prognostic value of normal sodium levels in patients with metastatic renal cell carcinoma receiving tyrosine kinase inhibitors.

Background: Although serum sodium concentration, particularly hyponatremia, has been shown to be a prognostic marker of survival in metastatic renal cell carcinoma (mRCC), the impact of normal sodium levels has not been investigated. Herein, we investigate the influence of normonatremia in mRCC patients treated with tyrosine kinase inhibitors (TKIs). Materials and methods: For this retrospective study, the clinical and biochemical data of patients treated with first-line TKIs for mRCC were available from seven Italian cancer centers. We collected natremia levels at baseline and first evaluation after treatment excluding patients with sodium levels outside the normal range (<135 or >145 mEq/L). The remaining patients were subdivided into two groups according to the median sodium value: natremia patients with <140 mEq/L (n = 132) and baseline natremia patients with ≥140 mEq/L (n = 185). Subsequently, we analyzed the impact of sodium levels on response rate (RR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). PFS and OS were estimated through the Kaplan-Meier method, and differences between groups were examined by the log-rank test. Univariate and multivariate Cox regression analyses were applied to evaluate the prognostic factors for PFS and OS. Results: Of the 368 patients, 317 were included in the analysis, 73.1% were men, and the median age was 67 years (range 36-89). When comparing patients with baseline natremia ≥140 mEq/L (n = 185) to patients with natremia <140 mEq/L (n = 132), the PFS was 15 vs. 10 months (p < 0.01) and the OS was 63 vs. 36 months, respectively (p = 0.02). On the first evaluation, patients with serum sodium ≥140 mEq/L had longer PFS (15 vs. 10 months, p < 0.01) and OS (70 vs. 32 months, p < 0.01) than patients with levels <140 mEq/L. Moreover, clinical outcomes showed a significant improvement in patients with natremia ≥140 mEq/L compared with patients with levels <140 mEq/L both at baseline and first evaluation: PFS was 19 vs. 11 months (p < 0.01) and OS was 70 vs. 36 months (p < 0.01), respectively. Conclusions: To the best of our knowledge, this is the first study to investigate the impact of normonatremia in mRCC. We found that serum sodium levels <140 mEq/L at baseline and first assessment are independently associated with worse PFS and OS in mRCC patients treated with TKIs in the first-line setting.

Effect of systemic therapies or best supportive care after disease progression to both nivolumab and cabozantinib in metastatic renal cell carcinoma: The Meet-Uro 19BEYOND study.

BACKGROUND: Nivolumab and cabozantinib are currently approved agents in metastatic renal cell carcinoma (mRCC) but there are no data available for patients progressing to both treatments. The aim of this study was to compare active therapeutic options and best supportive care (BSC) after progression to nivolumab and cabozantinib in mRCC. METHODS: In this retrospective study, we selected 50 patients from eight Italian centers. The primary endpoint of the study was the overall survival (OS) of patients on active treatment versus BSC. Secondary endpoints were the progression-free survival (PFS) and objective response rate (ORR). The efficacy of active therapy was also investigated. RESULTS: After progression to both nivolumab and cabozantinib, 57.1% of patients were given active treatment (mainly everolimus and sorafenib) while 42.9% received BSC. The median OS was 13 months (95% CI: 4-NR) in actively treated patients and 3 months (95% CI: 2-4) in BSC patients (p = 0.001). Patients treated with sorafenib had better disease control than those treated with everolimus (stable disease: 71.4% vs. 16.7%, progression disease: 14.3% vs. 58.3%; p = 0.03), with no significant differences in PFS (5 and 3 months, 95% CI: 1-6 vs. 2-5; p = 0.6) and OS (12 and 4 months, 95% CI: 3-NR vs. 2-NR; p = 0.2). CONCLUSION: After treatment with both nivolumab and cabozantinib, the choice of a safe active systemic therapy offered better outcomes than BSC.

Safety of Immune Checkpoint Inhibitors in Elderly Patients: An Observational Study.

BACKGROUND: Immunotherapy has completely changed the treatment of solid tumors. Although immune checkpoint inhibitors (ICIs) seem to be an appealing alternative to chemotherapy, especially in elderly patients, due to a more tolerable toxicity profile, they can lead to a peculiar variety of immune-related adverse events (irAEs). However, data on tolerability and outcome of ICIs in the elderly are lacking due to poor accrual in clinical trials of these patients. METHODS: We performed a retro-prospective analysis on patients treated with single agent anti-PD-L1/PD-1 at the Clinical Oncology Unit, Careggi University Hospital, from March 2016 to March 2020. Data on the treatment responses, type and severity of irAEs, as well as the corticosteroids (CCS) dosage used for irAEs and the discontinuation rate, were described per each patient, according to two different age-based cohorts of patients (< or ≥70 years). RESULTS: We reported a lower incidence of all-grade toxicity in elderly compared to younger patients (64.9% vs. 44.9%, p = 0.018). The two age-cohorts showed a different profile of irAEs. Endocrine irAEs were significantly higher in younger patients (39.7% vs. 21.7%, p = 0.002), while dermatologic toxicities were more common in the older group (35.0% vs. 11.3%, p = 0.047). Use of CCS and treatment discontinuation rate do not differ significantly between the two age groups. CONCLUSION: Our findings suggest that treatment with ICIs in elderly populations is safe and feasible. Patients over 70 years are more prone to develop skin irAEs, while younger patients are more subject to experience endocrine toxicities.

No Impact of NRAS Mutation on Features of Primary and Metastatic Melanoma or on Outcomes of Checkpoint Inhibitor Immunotherapy: An Italian Melanoma Intergroup (IMI) Study.

AIMS: It is debated whether the NRAS-mutant melanoma is more aggressive than NRAS wildtype. It is equally controversial whether NRAS-mutant metastatic melanoma (MM) is more responsive to checkpoint inhibitor immunotherapy (CII). 331 patients treated with CII as first-line were retrospectively recruited: 162 NRAS-mutant/BRAF wild-type (mut/wt) and 169 wt/wt. We compared the two cohorts regarding the characteristics of primary and metastatic disease, disease-free interval (DFI) and outcome to CII. No substantial differences were observed between the two groups at melanoma onset, except for a more frequent ulceration in the wt/wt group (p = 0.03). Also, the DFI was very similar in the two cohorts. In advanced disease, we only found lung and brain progression more frequent in the wt/wt group. Regarding the outcomes to CII, no significant differences were reported in overall response rate (ORR), disease control rate (DCR), progression free survival (PFS) or overall survival (OS) (42% versus 37%, 60% versus 59%, 12 (95% CI, 7-18) versus 9 months (95% CI, 6-16) and 32 (95% CI, 23-49) versus 27 months (95% CI, 16-35), respectively). Irrespectively of mutational status, a longer OS was significantly associated with normal LDH, <3 metastatic sites, lower white blood cell and platelet count, lower neutrophil-to-lymphocyte (N/L) ratio. Our data do not show increased aggressiveness and higher responsiveness to CII in NRAS-mutant MM.

Anti-PD1 antibodies in patients aged ≥ 75 years with metastatic melanoma: A retrospective multicentre study.

BACKGROUND: Advanced age is associated with comorbidities and immune system impairment, which may influence the efficacy and tolerability of immune checkpoint inhibitors. There is evidence that anti-PD1 antibodies in advanced melanoma are equally effective in patients >65 years. However, data on patients >75 years are lacking as co-morbidities and logistics often exclude them from clinical trials. METHODS: We retrospectively reviewed the clinical records of older patients with advanced melanoma undergoing any-line treatment with an anti-PD1 (nivolumab/pembrolizumab) to investigate its clinical effectiveness and toxicity in a real-life setting. Clinical response was assessed using RECIST criteria and toxicity was evaluated according to CTCAE 4.0. Progression-free survival (PFS) and overall survival (OS) were estimated with the Kaplan-Meier method and the Cox model was used to assess potential prognostic factors. RESULTS: 174 patients were considered; 59.2% males, median age 79 years (range 75-93). The majority had a performance status of 0 and normal lactate dehydrogenase (LDH) levels (55.2% and 52.4%, respectively). 69.1% had multiple co-morbidities. 56.9% received nivolumab. 36.7% of cases showed an objective response and the disease control rate was 56.3%. Median OS was 17.2 months [95% CI: 8.87-not reached] and a better prognosis was observed for patients with normal LDH (p < .001) and lower performance status (p < .001). Treatment was well tolerated, only 11 patients experiencing severe (grade 3/4) toxicity. There were no treatment-related deaths. Adverse events were managed with corticosteroids and additional immunosuppressive agents were unnecessary. CONCLUSIONS: Anti-PD1 antibodies appear effective and well tolerated in older patients with advanced melanoma.

Immunotherapy of brain metastases: breaking a "dogma".

Until very few years ago, the oncology community dogmatically excluded any clinical potential for immunotherapy in controlling brain metastases. Therefore, despite the significant therapeutic efficacy of monoclonal antibodies to immune check-point(s) across a wide range of tumor types, patients with brain disease were invariably excluded from clinical trials with these agents. Recent insights on the immune landscape of the central nervous system, as well as of the brain tumor microenvironment, are shedding light on the immune-biology of brain metastases.Interestingly, retrospective analyses, case series, and initial prospective clinical trials have recently investigated the role of different immune check-point inhibitors in brain metastases, reporting a significant clinical activity also in this subset of patients. These findings, and their swift translation in the daily practice, are driving fundamental changes in the clinical management of patients with brain metastases, and raise important neuroradiologic challenges. Along this line, neuro-oncology undoubtedly represents an additional area of active investigation and of growing interest to support medical oncologists in the evaluation of clinical responses of brain metastases to ICI treatment, and in the management of neurologic immune-related adverse events.Aim of this review is to summarize the most recent findings on brain metastases immunobiology, on the evolving scenario of clinical efficacy of ICI therapy in patients with brain metastases, as well as on the increasing relevance of neuroradiology in this therapeutic setting.

Multicentric retrospective analysis of platinum-pemetrexed regimens as first-line therapy in non-squamous non-small cell lung cancer patients: A "snapshot" from clinical practice.

BACKGROUND: The major challenge for treating non-squamous (non-Sq) non-small cell lung cancer (NSCLC) patients without actionable biomarkers is the actual selection of proper treatment, weighing expected clinical outcomes and safety profile. METHODS: Consecutive non-Sq NSCLC patients were treated with platinum-pemetrexed (PP) doublets in clinical practice. Subgroup analyses were conducted in patients treated with standard (s)PP and modified (m)PP doublets (because of age, performance status, and/or comorbidities) and in patients treated with cisplatin-based and carboplatin-based PP doublets. Activity, efficacy, safety, and toxicities were evaluated. RESULTS: From November 2009 to April 2017, 111 patients were treated: 87 (78.4%) with sPP and 24 (21.6%) with mPP; 76 (68.5%) with cisplatin-based and 35 (31.5%) with carboplatin-based regimens. The objective response rate (ORR), median progression-free survival (PFS), and median overall survival (OS) were 49.0%, 7, and 13 months in the entire patient population, respectively. We found no significant differences in ORR, median PFS, and median OS between sPP and mPP. Cisplatin-based PP showed higher ORR (53.7%) versus carboplatin-based PP (38.7%) and longer PFS (7 vs. 6 months; P = 0.028) and OS (18 vs. 11 months; P = 0.006). We confirm that carboplatin has a better toxicity profile than cisplatin. The received dose-intensities were ~80% of standard full doses. CONCLUSIONS: Accurate management allowed us to treat the majority of advanced non-Sq NSCLC patients with PP combination therapy without significant differences in ORR, median PFS, and median OS. Even considering the selection bias, our data seems to confirm the greater effectiveness of cisplatin-based over carboplatin-based regimens.

Family history of cancer as surrogate predictor for immunotherapy with anti-PD1/PD-L1 agents: preliminary report of the FAMI-L1 study.

AIM: Tumors related to hereditary susceptibility seem to have an immunosensitive phenotype. MATERIALS & METHODS: We conducted a multicenter retrospective study, to investigate if family history of cancer, multiple neoplasms and early onset of cancer could be related to clinical outcomes of anti-PD-1/PD-L1 therapy. Activity and efficacy data of 211 advanced cancer patients (kidney, non-small-cell lung cancer, melanoma, urothelium, colorectal and HeN), treated at seven Italian centers with anti-PD-1/PD-L1 agents, were analyzed. RESULTS: In this preliminary report at multivariate analyses, positive family history of cancer showed a statistically significant relationship with a better objective response rate (p = 0.0024), disease control rate (p = 0.0161), median time to treatment failure (p = 0.0203) and median overall survival (p = 0.0221). Diagnosis of multiple neoplasms significantly correlates only to a better disease control rate, while interestingly non-early onset of cancer and sex (in favor of female patients) showed significant correlation with a better median overall survival (p = 0.0268 and p = 0.0272, respectively). CONCLUSION: This pilot study seems to individuate easily available patient's features as possible predictive surrogates of clinical benefit for anti-PD-1/PD-L1 treatments. These preliminary results need to be confirmed with a greater sample size, in prospective trials with immunotherapy.

INfluenza Vaccine Indication During therapy with Immune checkpoint inhibitors: a transversal challenge. The INVIDIa study.

AIM: Considering the unmet need for the counseling of cancer patients treated with immune checkpoint inhibitors (CKI) about influenza vaccination, an explorative study was planned to assess flu vaccine efficacy in this population. METHODS: INVIDIa was a retrospective, multicenter study, enrolling consecutive advanced cancer outpatients receiving CKI during the influenza season 2016-2017. RESULTS: Of 300 patients, 79 received flu vaccine. The incidence of influenza syndrome was 24.1% among vaccinated, versus 11.8% of controls; odds ratio: 2.4; 95% CI: 1.23-4.59; p = 0.009. The clinical ineffectiveness of vaccine was more pronounced among elderly: 37.8% among vaccinated patients, versus 6.1% of unvaccinated, odds ratio: 9.28; 95% CI: 2.77-31.14; p < 0.0001. CONCLUSION: Although influenza vaccine may be clinically ineffective in advanced cancer patients receiving CKI, it seems not to negatively impact the efficacy of anticancer therapy.

Extraordinary and prolonged erlotinib-induced clinical response in a patient with EGFR wild-type squamous lung cancer in third-line therapy: a case report.

Several small molecules, epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs), such as gefitinib, erlotinib and afatinib, have been demonstrated to significantly improve clinical outcomes in patients with advanced EGFR-mutated non-small cell lung cancer (NSCLC), but erlotinib activity in EGFR wild-type squamous carcinoma is still highly debated. Here, we describe a prolonged and unexpected clinical response to erlotinib in a male former heavy cigarette smoker with wild-type EGFR squamous-cell cancer.

The comparison of outcomes from tyrosine kinase inhibitor monotherapy in second- or third-line for advanced non-small-cell lung cancer patients with wild-type or unknown EGFR status.

BACKGROUND: Second-line treatment for advanced non-small-cell lung cancer (NSCLC) patients includes monotherapy with a third-generation cytotoxic drug (CT) or a tyrosine kinase inhibitor (TKI). These options are the actual standard for EGFR wild-type (WT) status, as patients with EGFR mutations achieve greater benefit by the use of TKI in first-line treatment. Some clinical trials and meta-analyses investigated the comparison between CT and TKI in second-line, but data are conflicting. METHODS: We designed a retrospective trial to gather information about TKI sensitivity in comparison with CT. We selected from clinical records patients treated with at least 1 line of CT and at least 1 line of TKI. We collected data about age, sex, performance status, comorbidity, smoking status, histotype, metastatic sites, EGFR status, treatment schedule, better response and time-to-progression (TTP) for each line of treatment and overall survival (OS). RESULTS: 93 patients met selection criteria. Mean age 66,7 (range: 46-84). M/F ratio is 3:1. 39 EGFR-WT and 54 EGFR-UK. All patients received erlotinib or gefitinib as second-line treatment or erlotinib as third-line treatment. No TTP differences were observed for both second-line (HR:0,91; p = 0,6333) and third-line (HR:1.1; p = 0,6951) treatment (TKI vs CT). A trend of a benefit in OS in favor of 3rd-line TKI (HR:0,68; p = 0,11). CONCLUSIONS: This study explores the role of TKIs in EGFR non-mutated NSCLC patients. OS analysis highlights a trend to a benefit in patients who received TKI in third-line, even if this result is statistically non-significant. Further analysis are needed to find an explanation for this observation.