Treatment of lung large cell neuroendocrine carcinoma.

Lung large cell neuroendocrine carcinoma (L-LCNEC) is a rare, aggressive, and difficult-to-treat tumor. It is classified as a neuroendocrine subtype of large cell lung carcinoma (LCLC) belonging to the non-small cell lung cancer (NSCLC) group, but it is also included in the neuroendocrine tumor (NET) group. Most of the available data related to its treatment derive from retrospective analyses or small case series. For patients with L-LCNEC, prognosis is generally very poor. In early stages (I-II-III), surgery is recommended but does not seem to be sufficient. Platinum-based adjuvant chemotherapy may be useful while the role of neoadjuvant chemotherapy is still not well defined. In patients with advanced L-LCNEC, the chemotherapy regimens used in SCLC still remain the standard of treatment, but results are not satisfactory. Due to their peculiar clinical and biological features and the lack of literature data, there is an emerging need for a consensus on the best treatment strategy for L-LCNEC and for the identification of new therapeutic options. In this review, we will discuss the key aspects of L-LCNEC management with the aim to clarify the most controversial issues.

Machine Learning Using Real-World and Translational Data to Improve Treatment Selection for NSCLC Patients Treated with Immunotherapy.

(1) Background: In advanced non-small cell lung cancer (aNSCLC), programmed death ligand 1 (PD-L1) remains the only biomarker for candidate patients to immunotherapy (IO). This study aimed at using artificial intelligence (AI) and machine learning (ML) tools to improve response and efficacy predictions in aNSCLC patients treated with IO. (2) Methods: Real world data and the blood microRNA signature classifier (MSC) were used. Patients were divided into responders (R) and non-responders (NR) to determine if the overall survival of the patients was likely to be shorter or longer than 24 months from baseline IO. (3) Results: One-hundred sixty-four out of 200 patients (i.e., only those ones with PD-L1 data available) were considered in the model, 73 (44.5%) were R and 91 (55.5%) NR. Overall, the best model was the linear regression (RL) and included 5 features. The model predicting R/NR of patients achieved accuracy ACC = 0.756, F1 score F1 = 0.722, and area under the ROC curve AUC = 0.82. LR was also the best-performing model in predicting patients with long survival (24 months OS), achieving ACC = 0.839, F1 = 0.908, and AUC = 0.87. (4) Conclusions: The results suggest that the integration of multifactorial data provided by ML techniques is a useful tool to select NSCLC patients as candidates for IO.

Poziotinib for EGFR and HER2 exon 20 insertion mutation in advanced NSCLC: Results from the expanded access program.

BACKGROUND: The treatment of metastatic non-small-cell lung cancer (mNSCLC) patients with EGFR/HER2 exon 20 insertion mutation (i-mut) remains an unmet clinical need. Poziotinib, a new generation tyrosine kinase inhibitor, is currently under investigation as a potential targeted therapy. This compassionate study of its use aims to describe the activity/toxicity of poziotinib in mNSCLC with EGFR/HER2-exon-20-i-mut. PATIENTS AND METHODS: NSCLC patients who were treated either with EGFR or HER2 exon 20-i-mut within an expanded access program were included in this study. Poziotinib (16 mg or less) was administrated orally quaque die (QD). The primary end-point was the overall response rate (ORR) assessed by central review using RECIST v1.1, and secondary end-points were median progression free survival (PFS), disease control rate (DCR), median overall survival (OS) and toxicity. RESULTS: The median age of all the 30 patients was 58 years (25-80 years), most of them were females (73%); ECOG 0-1 (83%), EGFR i-mut (73%) and pre-treated (83%). 73% started with poziotinib at a dose of 16 mg. At data cut-off, 22 of 33 patients (73%) experienced a progress in the disease and 12 of 30 (40%) died. Median PFS was 5.6 months (95% CI: 3.6-6.7 months) and the mOS 9.5 months (95% CI: 5.3 - not-reached months). The ORR was 30% (EGFR/HER2: 23/50%) and DCR 80%. G3 AEs were reported in 66% of the patients and were found with skin rash (50%), diarrhoea (17.6%), mucositis (7%) and paronychia (3%). G5, possibly associated with pneumonitis might also have occurred. CONCLUSIONS: Poziotinib exhibited effects in mNSCLC patients with EGFR/HER2-exon 20-i-mut. The toxicity rate was high leading to frequent dose interruption and reduction, thereby reducing mPFS in patients with good ORR/DCR. ZENITH20 trial is now being used to evaluate the low dose and new scheduled dose (e.g. bis in die (BID)).

EPSILoN: A Prognostic Score for Immunotherapy in Advanced Non-Small-Cell Lung Cancer: A Validation Cohort.

BACKGROUND: Beyond programmed death ligand 1 (PD-L1), no other biomarkers for immunotherapy are used in daily practice. We previously created EPSILoN (Eastern Cooperative Oncology Group performance status (ECOG PS), smoking, liver metastases, lactate dehydrogenase (LDH), neutrophil-to-lymphocyte ratio (NLR)) score, a clinical/biochemical prognostic score, in 154 patients treated with second/further-line immunotherapy. This study's aim was to validate EPSILoN score in a different population group. METHODS: 193 patients were included at National Cancer Institute of Milan (second-line immunotherapy, 61%; further-line immunotherapy, 39%). Clinical/laboratory parameters such as neutrophil-to-lymphocyte ratio and lactate dehydrogenase levels were collected. Kaplan-Meier and Cox hazard methods were used for survival analysis. RESULTS: Overall median progression-free survival and median overall survival were 2.3 and 7.6 months, respectively. Multivariate analyses for Progression-Free Survival (PFS) identified heavy smokers (hazard ratio (HR) 0.71, p = 0.036) and baseline LDH < 400 mg/dL (HR 0.66, p = 0.026) as independent positive factors and liver metastases (HR 1.48, p = 0.04) and NLR ≥ 4 (HR 1.49, p = 0.029) as negative prognostic factors. These five factors were included in the EPSILoN score which was able to stratify patients in three different prognostic groups, high, intermediate and low, with PFS of 6.0, 3.8 and 1.9 months, respectively (HR 1.94, p < 0.001); high, intermediate and low prognostic groups had overall survival (OS) of 24.5, 8.9 and 3.4 months, respectively (HR 2.40, p < 0.001). CONCLUSIONS: EPSILoN, combining five baseline clinical/blood parameters (ECOG PS, smoking, liver metastases, LDH, NLR), may help to identify advanced non-small-cell lung cancer (aNSCLC) patients who most likely benefit from immune checkpoint inhibitors (ICIs).

Exploiting FAsting-mimicking Diet and MEtformin to Improve the Efficacy of Platinum-pemetrexed Chemotherapy in Advanced LKB1-inactivated Lung Adenocarcinoma: The FAME Trial.

Advanced lung adenocarcinoma with inactive liver kinase B1 (LKB1) tumor suppressor protein is associated with poor response to immune checkpoint inhibitors and molecularly targeted agents, and with dismal patient prognosis. LKB1 is a central orchestrator of cancer cell metabolism, and halts tumor growth/proliferation during metabolic stress. Recent preclinical evidence suggests that LKB1-inactive lung adenocarcinoma is highly sensitive to metformin, a safe and low-cost antidiabetic compound that inhibits mitochondrial oxidative phosphorylation. The effects of metformin can be enhanced by nutrient deprivation (ie, glucose, amino acids), which reduces intracellular levels of ATP and anabolic precursors and can be achieved by the fasting mimicking diet (FMD). Noticeably, metformin also prevents resistance to cisplatin in preclinical in vitro and in vivo models of LKB1-inactive lung adenocarcinoma. Based on such preclinical evidence, the phase II FAME trial was designed to test the hypothesis that the addition of metformin, with or without cyclic FMD, to standard platinum-based chemotherapy improves the progression-free survival of patients with advanced, LKB-1 inactive lung adenocarcinoma. Enrolled patients will be randomized in a 1:1 ratio to receive cisplatin/carboplatin and pemetrexed with the addition of metformin alone (Arm A) or metformin plus FMD (Arm B). The FAME study will use a "pick-the-winner" design with the aim of establishing which of the 2 experimental treatments is superior in terms of antitumor efficacy and safety. The primary assumption of the study is that the combination of the 2 experimental treatments shall improve median progression-free survival from 7.6 months (historical data with chemotherapy alone) to 12 months. Secondary study endpoints are: objective response rate, overall survival, treatment tolerability, and compliance to the experimental treatment.

Syndrome of inappropriate anti-diuretic hormone secretion in cancer patients: results of the first multicenter Italian study.

BACKGROUND: Hyponatremia in cancer patients is often caused by the syndrome of inappropriate antidiuretic hormone secretion (SIADH). The aim of this observational multicenter study was to analyze the medical and economic implications of SIADH in this setting. METHODS: This study included 90 oncological patients from 28 Italian institutions that developed SIADH between January 2010 and September 2015. Data on clinical-pathological characteristics, anticancer therapies, hyponatremia, and related treatments were statistically analyzed. RESULTS: The majority were lung cancer patients (73%) with metastatic disease at the onset of hyponatremia (83%). A total of 76 patients (84%) were hospitalized because of SIADH and less than half (41%) received tolvaptan for SIADH treatment. The duration of hospitalization was significantly longer in patients who did not receive tolvaptan and in those who do not reach sodium normalization during hospitalization. Patients who experienced a second episode of hyponatremia following tolvaptan dose modification/discontinuation presented a significantly lower serum sodium value at the time of hospitalization and minimum sodium value during hospitalization compared with patients who had not experienced another episode. The severity of hyponatremia, defined as minimum sodium value during hospitalization with a cut-off value of 110 mmol/l, and not obtaining sodium correction during hospitalization significantly correlated with overall survival rate. CONCLUSIONS: Hyponatremia due to SIADH could result in longer hospitalization and in a decreased overall survival when not adequately treated, and tolvaptan represents an effective treatment with a potential effect of both improving overall survival and decreasing duration of hospitalization.

Oral maintenance metronomic vinorelbine versus best supportive care in advanced non-small-cell lung cancer after platinum-based chemotherapy: The MA.NI.LA. multicenter, randomized, controlled, phase II trial.

BACKGROUND: Oral vinorelbine administered at the maximum tolerated dose has already showed activity and a good safety profile in advanced non-small-cell lung cancer (NSCLC). The MA.NI.LA study was a phase II, multicenter, randomized, controlled trial that aimed to assess the effects of a 'switched maintenance' regimen with oral metronomic vinorelbine (OMV) in patients with NSCLC who had not progressed after first-line platinum-based chemotherapy. PATIENTS AND METHODS: Patients were randomly assigned in a 1:1 ratio to either OMV (50 mg three-times weekly) as maintenance treatment or best supportive care (BSC). The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective disease control rate (DCR, CR + PR + SD), safety and quality of life. RESULTS: In total, 61 and 59 patients were assigned to OMV and BSC, respectively. At a median follow-up of 23.9 (IQR 10.2-38.2) months, patients treated with OMV reported a significantly lower progression rate compared to patient in the BSC arm (89% [54/61] vs 96% [56/58]; HR 0.73; 90% CI 0.53-0.999, p = 0.049). Median PFS for patients treated with vinorelbine was 4.3 months (95% CI 2.8-5.6) vs 2.8 months (95% CI 1.9-4.5) for patients receiving BSC. This benefit was specifically evident in patients aged ≥70 years, in current smokers, and in those who reported disease stabilization as best response to induction chemotherapy. OS and response rate and quality of life were similar in the two arms. Drop-out rate for major toxicity with OMV was unexpectedly high (25%, 14/61) mainly due to grade 3-4 neutropenia (11%, 7/61). Conclusions In patients with unselected NSCLC achieving disease control after platinum-based chemotherapy switch maintenance therapy with OMV prolonged PFS compared to BSC; however, the optimal dose of OMV requires further investigation.

Small-Cell Lung Cancer: Clinical Management and Unmet Needs New Perspectives for an Old Problem.

Small cell lung cancer is a highly aggressive, difficult to treat neoplasm. Among all lung tumors, small cell lung cancers account for about 20%. Patients typically include heavy smokers in 70s age group, presenting with symptoms such as intrathoracic tumors growth, distant spread or paraneoplastic syndromes at the time of diagnosis. A useful and functional classification divides small cell lung cancers into limited disease and extensive disease. Concurrent chemo-radiotherapy is the standard treatment for limited disease, with improved survival when combined with prophylactic cranial irradiation. Platinum compounds (cisplatin/carboplatin) plus etoposide remain the cornerstone for extensive disease. Nevertheless, despite high chemo- and radio-sensitivity of this cancer, nearly all patients relapse within the first two years and the prognosis is extremely poor. A deeper understanding about small cell lung cancer carcinogenesis led to develop and test a considerable number of new and targeted agents but the results are currently weak or insufficient. To date, small cell lung cancer is still a challenge for researchers. In this review, key aspects of small cell lung cancer management and controversial points of standard and new treatments will be discussed.

Epidermal growth factor receptor tyrosine kinase inhibitors for the treatment of central nervous system metastases from non-small cell lung cancer: the present and the future.

Lung cancer is one of the major causes of cancer related mortality worldwide. Brain metastases (BM) complicate clinical evolution of non-small cell lung cancer (NSCLC) in approximately 25-40% of cases, adversely influencing quality of life (QoL) and overall survival (OS). Systemic therapy remains the standard strategy for metastatic disease. Nevertheless, the blood-brain barrier (BBB) makes central nervous system (CNS) a sanctuary site. To date, the combination of chemotherapy with whole brain radiation therapy (WBRT), surgery and/or stereotactic radiosurgery (SRS) represents the most used treatment for patients (pts) with intracranial involvement. However, due to their clinical conditions, many pts are not able to undergo local treatments. Targeted therapies directed against epidermal growth factor receptor (EGFR), such as gefitinib, erlotinib and afatinib, achieved important improvements in EGFR mutated NSCLC with favorable toxicity profile. Although their role is not well defined, the reported objective response rate (ORR) and the good tolerance make EGFR-tyrosine kinase inhibitors (TKIs) an interesting valid alternative for NSCLC pts with BM, especially for those harboring EGFR mutations. Furthermore, new-generation TKIs, such as osimertinib and rociletinib, have already shown important activity on intracranial disease and several trials are still ongoing to evaluate their efficacy. In this review we want to highlight literature data about the use and the effectiveness of EGFR-TKIs in pts with BM from NSCLC.

Systemic approach to malignant pleural mesothelioma: what news of chemotherapy, targeted agents and immunotherapy?

Malignant pleural mesothelioma is a rare cancer with a cause-effect relationship to asbestos exposure. The prognosis is poor and chemotherapy seems the best treatment option. In the last two decades a deeper understanding of mesothelioma carcinogenesis and invasiveness mechanisms has prompted research efforts to test new agents in patients with malignant pleural mesothelioma, but the results have been modest. Attractive preclinical data disappointed in subsequent experimental phases. Other promising agents failed to improve patient outcomes due to high toxicity. Interesting suggestions have come from preliminary data on immunotherapy. Several trials are ongoing and the results are eagerly awaited. The aim of this review is to discuss the most recent news on systemic therapy for advanced malignant pleural mesothelioma.

Is there evidence for different effects among EGFR-TKIs? Systematic review and meta-analysis of EGFR tyrosine kinase inhibitors (TKIs) versus chemotherapy as first-line treatment for patients harboring EGFR mutations.

Three EGFR tyrosine kinase inhibitors have been compared to standard chemotherapy as up-front treatment in patients with advanced EGFR-positive NSCLC. We performed a systematic review and meta-analysis using indirect comparisons to estimate the risk/benefit associated with each drug. EGFR-TKIs fared better than chemotherapy in terms of PFS. The relative probability of overall response was gefitinib versus erlotinib 0.96 (95% CI 0.69-1.34), gefitinib versus afatinib 0.91 (95% CI 0.67-1.23), erlotinib versus afatinib 0.94 (95% CI 0.65-1.35). Indirect comparisons for safety showed the RR for diarrhea gefitinib versus erlotinib 0.80 (95% CI 0.63-1.01), gefitinib versus afatinib 0.29 (95% CI 0.20-0.41), erlotinib versus afatinib 0.36 (95% CI 0.25-0.54); for rash gefitinib versus erlotinib 1.00 (95% CI 0.82-1.22), gefitinib versus afatinib 0.41(95% CI 0.25-0.65), erlotinib versus afatinib 0.41 (95% CI 0.25-0.66); for hypertransaminasemia gefitinib versus erlotinib 2.29 (95% CI 1.63-3.23). Our analysis showed that all treatments had similar efficacy but they differ for toxicities.

Emerging toxicities in the treatment of non-small cell lung cancer: ocular disorders.

The treatment of advanced disease (stage IIIb and IV) of non-small cell lung cancer (NSCLC) is based on systemic treatment with platinum-based chemotherapy or biological compounds depending on the disease molecular profile. In the last few years, intensive investigational efforts in anticancer therapy have led to the registration of new active chemotherapeutic agents, combination regimens, and biological drugs, expanding choices for customizing individual treatment. However, the introduction of new drugs in the clinical setting has led to several new toxicities, creating some difficulties in daily management. Among these, ocular toxicity is generally overlooked as more common toxicities such as myelosuppression, stomatitis, diarrhea, vomiting, "hand-foot syndrome", and neurological alterations attract greater attention. Ophthalmic complications from cytotoxic chemotherapeutics are rare, transient, and of mild/moderate intensity but irreversible acute disorders are possible. The best way to prevent potential irreversible visual complications is an awareness of the potential for ocular toxicity because dose reductions or early drug cessation can prevent serious ocular complications in the majority of cases. However, given the novelty of many therapeutic agents and the complexity of ocular pathology, oncologists may be unfamiliar with these adverse effects of anticancer therapy. Although toxicities from chemotherapy are generally intense but short lasting, toxicities related to targeted drugs are often milder but longer lasting and can persist throughout treatment. Here we review the principal clinical presentations of ocular toxicity arising from chemotherapy [1-3], target therapies [4], and newly developed drugs and provide some recommendations for monitoring and management of ocular toxicity.