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Objectives Treatment options for malignant pleural mesothelioma (MPM) are limited but some studies on immune checkpoint inhibitors (ICIs) in MPM have reported antitumor activity. Very little is known about immune-related predictive factors. Materials and methods Here we report the case of a 45-year-old woman presenting with dyspnea and evidence of pleural effusion. She was diagnosed with malignant epithelioid pleural mesothelioma with brain metastasis and peritoneal carcinosis, refractory to initial standard chemotherapy treatment. Because of high PDL1 expression (100 %), she was treated with the anti-PD1 agent, pembrolizumab. Results Chemotherapy with cisplatin and pemetrexed was started, imaging studies showing stable disease after 3 treatment cycles. The patient underwent pleural decortication but rapidly progressed and thus started chemotherapy with carboplatin and gemcitabine. After 2 cycles she experienced seizures caused by a brain metastasis. This secondary lesion was surgically removed and confirmed as a metastasis from mesothelioma. Samples from both the primary tumor and the metastasis were molecularly characterized, the pleural sample proving ALK-positive and the brain sample, ALK-negative. PD-L1 was positive in 10 % of tumor cells in the pleural biopsy and 100 % in the brain lesion. Next generation sequencing analysis was negative for both samples. It was decided to start alectinib. Disease progression (peritoneal carcinosis and liver metastases) was documented after one month followed by complete bowel obstruction and recurrence in the site of the brain surgery. Alectinib was stopped and supportive care begun with parenteral nutrition via nasogastric tube. Pembrolizumab was started and after 15 days the patient’s condition had significantly improved, enabling recanalization and restoration of enteral nutrition. Imaging displayed complete response of the brain metastasis, peritoneal carcinosis, bone lesions and mediastinal nodal metastases. A partial response was documented in the pleural and pulmonary nodules, with stable liver metastases. The patient is still undergoing immunotherapy and has no cancer-related symptoms. Conclusions Our findings indicate that the use of immunotherapy in MPM warrants further investigation. Furthermore, the impressive clinical response obtained by our patient suggests that immune checkpoint inhibitors could help in the management of the disease after the failure of other treatments.

Crizotinib is an anaplastic lymphoma kinase (ALK)-tyrosine kinase inhibitor (-TKI) that represents the standard first-line treatment of patients with ALK-rearranged (ALK-positive) advanced non-small cell lung cancer (NSCLC). In this setting, crizotinib has demonstrated a response rate of roughly 75% and a median progression-free survival just under one year. However, acquired resistance will emerge in virtually all crizotinib-treated patients, whose management may require a diversified approach according to the pace of the disease and/or the site(s) of disease progression. Crizotinib beyond disease progression is an option in patients with oligoprogressive disease, especially in presence of isolated central nervous system (CNS) relapse, provided that local ablative therapy (mainly radiotherapy) to the brain is administered. On the other hand, novel more potent and highly selective ALK-TKIs with demonstrated anti-tumor activity (CNS included) in crizotinib-refractory patients have been made available in recent years. Therefore, clinicians may well consider switching to a second-generation ALK-TKI as treatment option in case of progression on crizotinib. Therapeutic chances are more limited for patients who progress after crizotinib and a second-generation ALK-TKI, for whom both a third-generation ALK-TKI or pemetrexed-based chemotherapy could prove beneficial, while evidence in support of the use of immunotherapy in patients pretreated with ≥1 ALK-TKI is lacking.

Recent advances in the understanding of non-small cell lung cancer (NSCLC) biology have revealed a number of 'targetable' genetic alterations that underlie cancer growth and survival in specific patients subgroups. The anaplastic lymphoma kinase (ALK) gene rearrangement identifies a population of NSCLCs in whom dysregulation of ALK-tyrosine kinase (-TK) leads to uncontrolled proliferation of cancer cells, thus providing the basis for the therapeutic use of ALK-TK inhibitors (-TKIs) in ALK-rearranged (-positive) disease. Crizotinib was the first ALK-TKI to undergo clinical development in ALK-positive advanced NSCLC, in which it has been shown to greatly outperform the best available chemotherapy regimen in either second- or first-line setting. More recently, the novel second-generation ALK-TKI ceritinib has been shown to be highly active in either crizotinib-pretreated or -naïve population. Nevertheless, as mechanisms of resistance to crizotinib and ALK-TKIs in general are being progressively elucidated, the treatment landscape of ALK-positive NSCLC is expected to evolve rapidly. In the present review we will briefly discuss the current knowledge of ALK-positive advanced non-small cell lung cancer. Also, we will touch upon new developments on drugs/combination regimens aimed at inhibiting the ALK-TK, in an attempt to delineate how treatment of ALK-positive disease may change in the next future.

Introduction This retrospective study was undertaken to investigate the impact of specific mutant KRAS on clinical outcome to either gefitinib or erlotinib (EGFR tyrosine kinase inhibitor, EGFR-TKI) in patients with EGFR wild type (WT) advanced non-small cell lung cancer (NSCLC). Methods Patients with an EGFR WT genotype who were treated with an EGFR-TKI for advanced disease at our Institution were identified. Simultaneous availability of KRAS mutation status was required for study inclusion. Results Sixty-seven patients were eligible. Median age was 60 years (39–84), and 10 patients (14.9%) had received an EGFR-TKI as upfront therapy. Overall, the median progression-free survival (PFS) and overall survival (OS) were 2.9 months and 18.0 months, respectively. KRAS mutant patients ( n =18) experienced a significantly shorter PFS compared with those carrying a KRAS WT genotype ( n =49) (1.6 months vs 3.0 months, respectively, P =0.04; HR=1.92). However, within the KRAS mutant group a great variability in terms of sensitivity to treatment was noted (PFS ranging from 0.7 months to 38.7 months). KRAS codon 13 mutant patients ( n =4) experienced the worse outcome when compared with KRAS codon 12 mutants ( n =14) and KRAS WT patients ( P P =0.01 for PFS and OS, respectively). Conclusions Though we found that EGFR WT/ KRAS mutant advanced NSCLC patients are associated with an increased resistance to treatment, specific mutant KRAS may account for differential sensitivity to an EGFR-TKI. KRAS codon 13 mutants are those who seem to experience the worse clinical outcome.

Lung cancer is the most common cancer in the world today, in terms of both incidence and mortality. Non-small cell lung cancer (NSCLC) accounts for about 85% of all lung cancers, and the majority of people diagnosed with NSCLC have locally advanced or metastatic disease. Treatment algorithms have rapidly changed in the last 10 years because of the introduction of new chemotherapeutic and targeted agents in clinical practice. SUN is a 1-year longitudinal observational multicenter study that has consecutively enrolled patients affected by stage IIIB or IV NSCLC with the aim to describe the pattern of care and evolving approaches in the treatment of advanced NSCLC. 987 consecutive NSCLC patients were enrolled between January 2007 and March 2008 at the 74 participating centers throughout Italy and a 12-month follow-up was performed. Cyto-histological diagnosis was performed mainly by broncoscopy with only 24% by CT-scan guided fine-needle aspiration biopsy. 91.4% of the patients received a first-line medical treatment and 8.6% supportive care only. Median age of patients receiving first-line treatment was 66 years. First-line chemotherapy consisted of a single agent in 20% of patients and combination chemotherapy in 80%. The most frequently used chemotherapy regimens were cisplatin plus gemcitabine and carboplatin plus gemcitabine. Median survival of patients receiving first-line chemotherapy was 9.1 months. 32% percent of patients received a second-line treatment that consisted of chemotherapy in 71% of cases and erlotinib in 29%. Overall third-line treatment was given to 7.3% of patients. These results showed a pattern of care for advanced NSCLC that reflects the current clinical practice in Italy at the study time with a high adherence to the International guidelines by the Italian Oncologists. Keywords Advanced NSCLC; Observational study; Chemotherapy; Platin-based chemotherapy; Pemetrexed; Docetaxel; Targeted therapy; Erlotinib

Summary Chemotherapy has reached a therapeutic plateau in the treatment of advanced non-small cell lung cancer (NSCLC), and effective, better-tolerated treatment strategies are needed. An improved understanding of the molecular processes underlying tumor biology has led to the development of therapies that target these processes. Intracellular signaling pathways related to the vascular endothelial growth factor and the epidermal growth factor receptor both play a central role in tumorigenesis as well as tumor growth, and are therefore rational targets for anti-cancer drug development. Various agents that target these pathways are in clinical development. Some of these have already changed treatment practice in NSCLC, most notably the monoclonal antibody, bevacizumab, in combination with chemotherapy in the first-line setting and the small-molecule tyrosine-kinase inhibitors, erlotinib and gefitinib, in the second-line setting. We will review the clinical data for various novel therapies and identify how these agents are improving outcomes in the first- and second-line treatment of advanced NSCLC.

Lung cancer remains the leading cause of cancer-related mortality in the western world. Non-small-cell lung cancer (NSCLC) accounts for approximately 80% of these thoracic malignancies, with 1.2 million new cases diagnosed worldwide each year. The vast majority of NSCLC patients present with disease that is beyond the scope of surgical cure and are, therefore, candidates for palliative chemotherapy, which has been the subject of intensive investigation in recent years. Although platinum-based therapies modestly improve survival and palliate some tumour-related symptoms in patients with locally advanced or metastatic NSCLC, at times the chemotherapy-related side effects outweigh the benefits. Consequently, the identification of new regimens that maintain the same level of efficacy as platinum-based combinations but offer a better toxicity profile is a key goal in this important area of medicine.

Lung cancer accounts for about 28% of all cancer-related deaths. Non-small cell lung cancer (NSCLC) constitutes 80% of all lung cancer cases, and in 70% of patients, the disease is diagnosed when it is locally advanced or metastatic. In these situations, chemotherapy has played only a minor role in modifying the natural history according to a 1995 meta-analysis. New drugs such as gemcitabine, vinorelbine, and the taxanes have been combined with cisplatin and tested in several phase-II and phase-III clinical trials versus cisplatin alone and different cisplatin/new drug combinations. Overall, the data seem to confirm that, despite a possible increase in response rate, no major difference in long-term survival has been achieved. Moreover, toxicity and cost may be significant with some of the combinations and schedules. While the combination of cisplatin and gemcitabine seems to be fairly active and better tolerated, we all look forward to the results of ongoing studies on the association of these regimens with the new biological drugs.

Background: Small cell lung cancer (SCLC) is a chemoresponsive tumor but overall survival remains poor even in limited disease (LD). With the aim of eradicating chemoresistant tumor cells and reducing toxicity, we investigated in this phase II trial the feasibility and outcome of a sequential approach of induction chemotherapy (CT) followed, in responding patients with LD-SCLC, by intensified platinum-based CT and concurrent thoracic irradiation (TI). Materials and methods: We treated 55 consecutive LD-SCLC patients with three 21-day cycles of cyclophosphamide, epiadriamycin and vincristine (CEV) as induction CT. In 44 (80%) patients there was an objective response and they received treatment intensification consisting of TI and concomitant CT with carboplatin and etoposide plus recombinant granulocite colony stimulating factor. Twenty-five (57%) patients were submitted to twice-daily thoracic irradiation (TDTI; 1.5 Gy per fraction, to a total dose of 45 Gy) and 19 (43%) to once-daily thoracic irradiation (ODTI; 2 Gy per fraction, to a total dose of 50 Gy). Results: Median follow up was 75 months (range, 42–102). Of 44 patients submitted to intensification with TI plus CT, 32 (73%) had a complete and 12 (27%) a partial response. Median overall survival of all 55 patients was 17 months with actuarial survival probabilities of 2 and 5 years, 32 and 25%, respectively. Analysis of patient sub-groups showed a 5-month median survival in non-responders, 19 in TDTI and 17 in ODTI patients, respectively. Two and 5 year survival probabilities were 0% in non-responders, 40 and 35% in TDTI and 39 and 21% in ODTI patients, respectively. At present, 13 of 44 responders are still alive, of which nine (20%) have been progression-free from 45 to 93 months (median 60). Treatment failure was registered in 31 (70%) of 44 patients who received both induction and intensification treatment. One-half of patients had intrathoracic recurrence, eight of which only local and the remaining seven local and distant. Fourteen (32%) patients had brain metastases. Grade 3–4 neutropenia occurred in 24 (55%) patients with no differences between treatment groups. Grade 3 esophagitis was registered in four (9%) patients: in 3/25 (12%) and 1/19 (5%) of those who received TDTI and ODTI, respectively (P=not significant). Acute radiation pneumonitis occurred in three (12%) patients submitted to TDTI. No clinically debilitating pulmonary fibrosis, permanent esophageal stricture or toxic death was observed. Conclusions: In LD-SCLC patients late concurrent CT plus TI is feasible and effective. Our long-term results are similar to the best reported in the literature. Despite the high incidence of complete response obtained, however, one-half of the patients had intrathoracic relapse and one-third brain metastases.

A poor prognosis for patients with Stage IIIA clinical N2 treated by surgery alone has led clinical researchers to find a new treatment modality to improve the curative potential of surgery. Many Phas II trials have been carried out with induction chemo- or chemo-radiotherapy prior to surgery. From June 1988 to July 1991, 46 patients with non-small cell lung cancer (NSCLC) Stage IIIA clinical N2 entered a Phase II induction-chemotherapy trial. Patients received 2-3 cycles of high-dose cisplatin and etoposide. Forty-five were evaluable for response; the response rate was 82% (37/45: 3 CR, 34 PR). Toxicity was primarily hematologic. Surgical resection was performed in 35 patients; radical resection was possible in 28 patients (62%); three patients were incompletely resected and two patients were only explored. Three deaths were surgery-related. Median survival was 24.5 months with a 2-year survival of 53%. Cisplatin with etoposide is an active and safe induction chemotherapy regimen for NSCLC Stage IIIA N2 with a high response rate. The median survival seems to be prolonged and therefore, randomized trials are needed to compare this approach with other treatment modalities.