Efficacy and safety of long-acting pasireotide or everolimus alone or in combination in patients with advanced carcinoids of the lung and thymus (LUNA): an open-label, multicentre, randomised, phase 2 trial.

BACKGROUND: There are no data from prospective studies focused exclusively on patients with advanced lung and thymic carcinoids. We aimed to assess the efficacy and safety of long-acting pasireotide and everolimus, administered alone or in combination, in patients with advanced carcinoids of the lung or thymus. METHODS: LUNA was a prospective, multicentre, randomised, open-label, phase 2 trial of adult patients (aged >18 years) with advanced (unresectable or metastatic), well differentiated carcinoid tumours of the lung or thymus, with radiological progression within 12 months before randomisation, and a WHO performance status of 0-2. At each centre, the investigator or their designee registered each patient using an interactive voice recognition system into one of the three treatment groups. The randomisation allocation sequence was generated by an external company; patients were randomly assigned (1:1:1) to receive treatment with long-acting pasireotide (60 mg intramuscularly every 28 days), everolimus (10 mg orally once daily), or both in combination, for the core 12-month treatment period. Patients were stratified by carcinoid type (typical vs atypical) and line of study treatment (first line vs others). The primary endpoint was the proportion of patients progression-free at month 9, defined as the proportion of patients with overall lesion assessment at month 9 showing a complete response, partial response, or stable disease according to local Response Evaluation Criteria in Solid Tumors, version 1.1, assessed in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study drug and had at least one post-baseline safety assessment. The trial is registered with ClinicalTrials.gov, number NCT01563354. The extension phase of the study is ongoing. FINDINGS: Between Aug 16, 2013, and Sept 30, 2014, 124 patients were enrolled from 36 centres in nine countries: 41 were allocated to the long-acting pasireotide group, 42 to the everolimus group, and 41 to the combination group. At month 9, the proportion of patients with an overall lesion assessment of complete response, partial response, or stable disease was 16 of 41 patients (39·0%, 95% CI 24·2-55·5) in the long-acting pasireotide group, 14 of 42 patients (33·3%, 19·6-49·5) in the everolimus group, and 24 of 41 patients (58·5%, 42·1-73·7) in the combination group. The most common grade 1-2 adverse events with a suspected association with long-acting pasireotide monotherapy were diarrhoea (15 [37%] of 41), hyperglycaemia (17 [41%]), and weight loss (8 [20%]); those with a suspected association with everolimus monotherapy were stomatitis (26 [62%] of 42) and diarrhoea (16 [38%]); and those suspected to be associated with combination treatment were hyperglycaemia (27 [66%] of 41]), diarrhoea (19 [46%]), and asthenia (8 [20%]). The most common grade 3-4 adverse events with a suspected association with long-acting pasireotide monotherapy were γ-glutamyltransferase increased (four [10%] of 41 patients), diarrhoea (three [7%]), and hyperglycaemia (three [7%]); those for everolimus were hyperglycaemia (seven [17%] of 42 patients), stomatitis (four [10%]), and diarrhoea (three [7%]); those for combination treatment were hyperglycaemia (nine [22%] of 41 patients) and diarrhoea (four [10%]). 11 patients died during the core 12-month treatment phase or up to 56 days after the last study treatment exposure date: two (5%) of 41 in the long-acting pasireotide group, six (14%) of 42 in the everolimus group, and three (7%) of 41 in the combination group. No deaths were suspected to be related to long-acting pasireotide treatment. One death in the everolimus group (acute kidney injury associated with diarrhoea), and two deaths in the combination group (diarrhoea and urinary sepsis in one patient, and acute renal failure and respiratory failure in one patient) were suspected to be related to everolimus treatment. In the latter patient, acute renal failure was not suspected to be related to everolimus treatment, but respiratory failure was suspected to be related. INTERPRETATION: The study met the primary endpoint in all three treatment groups. Safety profiles were consistent with the known safety profiles of these agents. Further studies are needed to confirm the antitumour efficacy of the combination of a somatostatin analogue with everolimus in lung and thymic carcinoids. FUNDING: Novartis Pharma AG.

Selumetinib: a promising pharmacologic approach for KRAS-mutant advanced non-small-cell lung cancer.

Selumetinib is a potent and selective inhibitor of MEK1 and 2 that is currently being clinically developed for the treatment of several human malignancies. Initially administered as free-base suspension, a more convenient Hyd-sulfate capsule formulation has recently been developed. Phase I studies revealed that acneiform dermatitis was the dose-limiting toxicity of both the free-base and capsule formulation given two-times a day at the maximum tolerated doses of 100 and 75 mg, respectively, with the capsule formulation resulting into a significantly higher drug bioavailability. Importantly, as a MEK inhibitor, selumetinib could be particularly effective in tumors with a hyperactivated Ras/Raf/MEK/ERK pathway, which might be the case of KRAS-mutant non-small-cell lung cancers (NSCLCs). Accordingly, a recent randomized Phase II study evaluating docetaxel plus selumetinib or placebo in KRAS-mutant pretreated advanced NSCLC patients has demonstrated a significant improvement in terms of response rate, progression-free survival and patient-reported outcomes in favor of the combination arm. These positive results support further clinical evaluation of selumetinib in NSCLC, and confirmatory ongoing and future trials will assess its role according to KRAS-mutation status and in combination regimens with other targeted agents.

Inflamed Tumor Phenotype as Predictor of Long-Term Response to Pembrolizumab in an EGFR-Mutated Non-Small Cell Lung Cancer (NSCLC) Patient with Acquired Resistance to Afatinib: a Case Report and Review of the Literature.

Treatment with immune checkpoint inhibitors (ICIs) that target the programmed cell death 1/programmed cell death ligand-1 (PD-1/PD-L1) axis is usually ineffective in patients with epidermal growth factor receptor (EGFR)-mutated advanced non-small cell lung cancer (NSCLC), either as first-line treatment or in later lines. By contrast, especially for patients with common EGFR mutations (exon 19 deletion/L858R point mutation), an orally bioavailable EGFR tyrosine kinase inhibitor (EGFR-TKI) is the best upfront therapy, being able to provide response rates well above 50% and a median progression-free survival ranging from 11 to 19 months, depending on whether a second-generation (e.g., afatinib) or a third-generation (i.e., osimertinib) EGFR-TKI is used. Unfortunately, treatment options for these patients at the time of acquired resistance are limited. As for afatinib-pretreated patients, those who develop a T790M mutation may benefit from osimertinib, whereas platinum-based chemotherapy is the preferable therapeutic strategy for T790M-negative patients as well as for patients who progress on osimertinib administered as first-line therapy. Here, we describe the case of an exon-19-deleted patient who experienced a complete response to the anti-PD-1 agent pembrolizumab upon the development of T790M-negative acquired resistance to afatinib. Furthermore, we discuss this case in the context of the existing literature, especially focusing on the importance of evaluating multiple markers of immune response post-EGFR-TKI and prior to ICI treatment in order to select the best treatment strategy in this clinical scenario.

Higher TLR7 Gene Expression Predicts Poor Clinical Outcome in Advanced NSCLC Patients Treated with Immunotherapy.

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of lung cancer. However, their clinical benefit is limited to a minority of patients. To unravel immune-related factors that are predictive of sensitivity or resistance to immunotherapy, we performed a gene expression analysis by RNA-Seq using the Oncomine Immuno Response Assay (OIRRA) on a total of 33 advanced NSCLC patients treated with ICI evaluating the expression levels of 365 immune-related genes. We found four genes (CD1C, HLA-DPA1, MMP2, and TLR7) downregulated (p < 0.05) and two genes (IFNB1 and MKI67) upregulated (p < 0.05) in ICI-Responders compared to ICI-Non-Responders. The Bayesian enrichment computational analysis showed a more complex interaction network that involved 10 other genes (IFNA1, TLR4, CD40, TLR2, IL12A, IL12B, TLR9, CD1E, IFNG, and HLA-DPB1) correlated with different functional groups. Five main pathways were identified (FDR < 0.0001). High TLR7 expression levels were significantly associated with a lack of response to immunotherapy (p < 0.0001) and worse outcome in terms of both PFS (p < 0.001) and OS (p = 0.03). The multivariate analysis confirmed TLR7 RNA expression as an independent predictor for both poor PFS (HR = 2.97, 95% CI, 1.16-7.6, p = 0.023) and OS (HR = 2.2, 95% CI, 1-5.08, p = 0.049). In conclusion, a high TLR7 gene expression level was identified as an independent predictor for poor clinical benefits from ICI. These data could have important implications for the development of novel single/combinatorial strategies TLR-mediated for an efficient selection of "individualized" treatments for NSCLC in the era of immunotherapy.

High PD-L1/IDO-2 and PD-L2/IDO-1 Co-Expression Levels Are Associated with Worse Overall Survival in Resected Non-Small Cell Lung Cancer Patients.

Programmed death ligand 1 (PD-L1) expression is a predictive biomarker of the success of PD-1/PD-L1 inhibitor therapy for patients with advanced non-small cell lung cancer (NSCLC) but its role as a prognostic marker for early-stage resectable NSCLC remains unclear. We studied gene expression levels of immune-related genes PD-1, PD-L1, PD-L2, IDO-1, IDO-2 and INFγ in tumor tissue of surgically resected NSCLC and correlated the finding with clinicopathological features and patient outcomes. A total of 191 consecutive early-stage NSCLC patients who underwent curative pulmonary resection were studied. The mRNA expression levels of immune-related genes were evaluated by quantitative reverse transcription polymerase chain reaction (qRT-PCR) using RT2 Profiler PCR Arrays (Qiagen). PD-1, PD-L2 and IDO-2 gene expression levels were significantly higher in patients with squamous histology (p = 0.001, p = 0.021 and p < 0.001; respectively). PD-1, PD-L1 and IDO-2 gene expression levels were significantly higher in patients with higher stage (p = 0.005, p = 0.048 and p = 0.002, respectively). The univariate analysis for recurrence-free survival (RFS) and overall survival (OS) showed that patients with higher levels of three-genes (PD-L1/PD-L2/INFγ) (hazard ratio (HR)) 1.90 (95% confidence interval (CI), 1.13-3.21), p = 0.015) were associated with a worse RFS, while patients with higher levels of both genes (PD-L1/IDO-2) or (PD-L2/IDO-1) were associated with a worse OS (HR 1.63 95% CI, 1.06-2.51, p = 0.024; HR 1.54 95% CI, 1.02-2.33, p = 0.04; respectively). The multivariate interaction model adjusted for histology and stage confirmed that higher levels of three genes (PD-L1/PD-L2/INFγ) were significantly associated with worse RFS (HR 1.98, p = 0.031) and higher levels of both genes (PD-L1/IDO-2) and (PD-L2/IDO-1) with worse OS (HR 1.98, p = 0.042, HR 1.92, p = 0.022). PD-L1/IDO-2 and PD-L2/IDO-1 co-expression high levels are independent negative prognostic factors for survival in early NSCLC. These features may have important implications for future immune-checkpoint therapeutic approaches.

Sensitivity to Immune Checkpoint Blockade in Advanced Non-Small Cell Lung Cancer Patients with EGFR Exon 20 Insertion Mutations.

Besides platinum-based chemotherapy, no established treatment option exists for advanced non-small-cell lung cancer (NSCLC) patients with EGFR exon 20 (Ex20ins) insertion mutations. We sought to determine the clinical outcome of patients with this EGFR mutation subtype in the immunotherapy era. Thirty NSCLCs with EGFR Ex20ins mutations were identified, of whom 15 had received immune checkpoint blockade (ICB) treatment as monotherapy (N = 12), in combination with chemotherapy (N = 2) or with another immunotherapeutic agent (N = 1). The response rate was observed in 1 out of 15 patients (6.7%), median progression-free survival (PFS) was 2.0 months and median overall survival (OS) was 5.3 months. A trend towards an inferior outcome in terms of PFS and OS was observed for patients receiving ICB treatment in the first versus second line setting (PFS: 1.6 months versus 2.7 months, respectively, p = 0.16-OS: 2.0 months versus 8.1 months, respectively, p = 0.09). Median OS from the time of diagnosis of advanced disease was shorter for patients treated with ICB versus those who did not receive immunotherapy (12.9 months versus 25.2 months, respectively, p = 0.08), which difference remained associated with a worse survival outcome at multivariate analysis (p = 0.04). Treatment with ICB is poorly effective in NSCLCs with EGFR Ex20ins mutations, especially when given in the first-line setting. This information is crucial in order to select the optimal treatment strategy for patients with this subtype of EGFR mutation.

Detection of EGFR Mutations in Plasma Cell-Free Tumor DNA of TKI-Treated Advanced-NSCLC Patients by Three Methodologies: Scorpion-ARMS, PNAClamp, and Digital PCR.

Analysis of circulating cell-free tumor DNA (cftDNA) has emerged as a specific and sensitive blood-based approach to detect epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer (NSCLC) patients. Still, there is some debate on what should be the preferential clinical method for plasma-derived cftDNA analysis. We tested 31 NSCLC patients treated with anti-EGFR tyrosine kinase inhibitors (TKIs), at baseline and serially during therapy, by comparing three methodologies in detecting EGFR mutations (L858R, exon 19 deletion, and T790M) from plasma: scorpions-amplification refractory mutation system (ARMS) methodology by using EGFR Plasma RGQ PCR Kit-QIAGEN, peptide nucleic acid (PNA) clamp and PANA RealTyper integration by using PNAClamp EGFR-PANAGENE, and digital real time PCR by using QuantStudio 3D Digital PCR System-Thermo Fisher Scientific. Specificity was 100% for all three mutations, independently from the platform used. The sensitivity for L858R (42.86%) and T790M (100%) did not change based on the method, while the sensitivity for Del 19 differed markedly (Scorpion-ARMS 45%, PNAClamp 75%, and Digital PCR 85%). The detection rate was also higher (94.23%) as measured by Digital PCR, and when we monitored the evolution of EGFR mutations over time, it evidenced the extreme inter-patient heterogeneity in terms of levels of circulating mutated copies. In our study, Digital PCR showed the best correlation with tissue biopsy and the highest sensitivity to attain the potential clinical utility of monitoring plasma levels of EGFR mutations.

Listening understanding and acting (lung): focus on communicational issue in thoracic oncology.

BACKGROUND: In the field of oncological assistance, nowadays we have to deal with a complex scenario where patients got used to obtain a huge amount of information through internet or social media and to apply them in performing their health-related decisions. This landscape requires that clinicians become able to handle therapeutical approaches and adequate skills in communication tools to satisfy the current needs. Our project aimed to build a communication model based on clinical oncologists' real experiences in order to find a simple way to share with patients all the innovative therapeutical opportunities today available in lung cancer. The final goal is to design a flexible and personalized model adaptable to clinician's personal characteristics and to the specific patient he is facing. We applied both traditional educational tools and innovative techniques in order to make the results effective and applicable to support peer learning. METHODS: The first step consisted in a Board synthesized the definition of the diagnostic process, the identification of treatment strategies and any potential communication barrier clinicians may face dealing with patients. The second step consisted in teamwork including a theoretical part and a training part. In the third step we produce five training videos and video interviews regarding communication praxis and a "Small communication manual". The last step consisted in the publication of the produced material on website and its diffusion through the social media. RESULTS: In medicine, the universal application of a single model of communication does not represent the optimal solution. By contrary, the availability of simple and practical suggestions to improve the communicative style could allow clinicians to abandon stereotyped formulas identically repurposed to all patients. The "from bottom to top" training, starting from real-life to take advantage of the clinician's experience, give the clinicians the possibility to meditate about their own communicative style and to train in the context of a protected environment. Applying these rules, we design an effective communication model, based on healthcare humanization, which could represent a fundamental support for the patient in order to be gently driven by the clinician to the most appropriate therapeutical choice, balancing efficacy and quality of life. The relational training may improve the quality of clinician-patient communication and could be widespread to other clinicians through the media. CONCLUSIONS: Considering the innovative therapeutical options available, particularly for lung cancer patients, and the increasing access of health-related information through internet or social media the clinician-patient communication has become crucial to support the achievement of the most appropriate therapeutical choice for the patient, facing the intricate illness experience. Building a shareable and easy-to-apply communication model represents a challenge aimed to help clinicians and including technology not as a threat, but as a positive tool.

The safety of nivolumab for the treatment of advanced non-small cell lung cancer.

INTRODUCTION: Immune checkpoint blockaders (ICBs) act by unbalancing the immune system, thus favoring the development of an immune-mediated antitumor effect. ICBs targeting the programmed cell death receptor-1 (PD-1) have recently been investigated in a number of advanced tumors, including non-small cell lung cancer (NSCLC). Nivolumab, a fully human IgG4 kappa directed against PD-1, has been the first ICB to be approved for second-line treatment of advanced NSCLC. Areas covered: In this review we focus on the clinical development of nivolumab for the treatment of advanced NSCLC, with an emphasis on its safety profile. In addition, we summarize the most common types of immune-related adverse events (irAEs) associated with nivolumab, mainly due to organ inflammation secondary to autoimmunity. Expert opinion: Nivolumab is the preferred treatment option for platinum-pretreated advanced NSCLC, having convincingly shown higher efficacy compared with standard docetaxel chemotherapy in phase III trials. The same trials showed far less incidence of either any grade and severe treatment-related AEs with nivolumab compared with chemotherapy. IrAEs associated with nivolumab are rarely severe in intensity, and often resolve with prompt management. Future studies will explore nivolumab in combination strategies with either platinum-based chemotherapy or other ICBs in treatment-naïve advanced NSCLC patients.

Pharmacotherapeutic options for treating brain metastases in non-small cell lung cancer.

INTRODUCTION: Central nervous system (CNS) metastases represent an important cause of morbidity and mortality in non-small cell lung cancer (NSCLC) patients. Local approaches of neurosurgery (usually for single brain lesions), whole brain radiotherapy, and stereotactic radiosurgery are often withheld for the treatment of NSCLC-derived brain metastases (BMs). However, systemic treatment is consistently emerging as an option for patients with asymptomatic BMs, which could allow for delaying cranial radiotherapy at symptomatic/radiological progression. AREAS COVERED: Chemotherapy, monoclonal antibodies, tyrosine-kinase inhibitors (TKIs) for molecularly selected NSCLCs, such as epidermal growth factor receptor (EGFR)-mutant and anaplastic lymphoma kinase (ALK)-rearranged diseases, and immune checkpoint inhibitors are all systemic treatments that have shown activity against NSCLC-derived CNS metastases. Among these, EGFR- and ALK-TKIs will be discussed more in detail owing to their superior efficacy in this context. EXPERT OPINION: Up-front systemic treatment should be considered for patients with asymptomatic, multiple BMs, as recently acknowledged by the European Society of Medical Oncology guidelines. Nevertheless, it must be emphasized that the best treatment strategy for NSCLC-derived BMs has to be defined within a multidisciplinary team.

Future options for ALK-positive non-small cell lung cancer.

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.

Clinical impact of sequential treatment with ALK-TKIs in patients with advanced ALK-positive non-small cell lung cancer: Results of a multicenter analysis.

OBJECTIVES: Anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC) is sensitive to treatment with an ALK-tyrosine kinase inhibitor (-TKI). However, the benefit of sequential treatment with a 2nd ALK-TKI in patients who fail a 1st ALK-TKI has been poorly addressed. MATERIALS AND METHODS: We collected the data of 69 advanced ALK-positive NSCLCs who were treated with one or more ALK-TKIs at three Italian institutions. The clinical outcome of treatment with an ALK-TKI and the patterns of treatment upon failing a 1st ALK-TKI were recorded. RESULTS: Objective response rate (ORR) and median progression-free survival (PFS) on a 1st ALK-TKI (mostly crizotinib) were 60.9% and 12 months, respectively. Of the 50 patients who progressed on a 1st ALK-TKI, 22 were further treated with a 2nd ALK-TKI (either ceritinib or alectinib), for whom an ORR of 86.4% and median PFS of 7 months, respectively, were reported. Conversely, 13 patients underwent rapid clinical/radiographic disease progression leading to death shortly after discontinuation of the 1st ALK-TKI, 7 patients were managed with a 1st ALK-TKI beyond progression, and 8 patients transitioned to other systemic treatments (mostly chemotherapy). Post-progression survival (PPS) significantly favored the 22 patients who were sequentially treated with a 2nd ALK-TKI over those who transitioned to other systemic treatments (P=0.03), but not versus those who were treated with a 1st ALK-TKI beyond progression (P=0.89). CONCLUSION: Sequential treatment with a 2nd ALK-TKI is effective in patients who fail a 1st ALK-TKI. Continuous ALK-inhibition upon failing a 1st ALK-TKI may be associated with improved clinical outcome.

miRNAs and resistance to EGFR-TKIs in EGFR-mutant non-small cell lung cancer: beyond 'traditional mechanisms' of resistance.

Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) have dramatically changed the prognosis of advanced non-small cell lung cancers (NSCLCs) that harbour specific EGFR activating mutations. However, the efficacy of an EGFR-TKI is limited by the onset of acquired resistance, usually within one year, in virtually all treated patients. Moreover, a small percentage of EGFR-mutant NSCLCs do not respond to an EGFR-TKI, thus displaying primary resistance. At the present time, several mechanisms of either primary and acquired resistance have been elucidated, and new drugs are currently under preclinical and clinical development in order to overcome resistance to treatment. Nevertheless, there still remains much to be thoroughly investigated, as so far research has mainly focused on the role of proteincoding genes involved in resistance to EGFR-TKIs. On the other hand, in line with the data underscoring the relevance of non-coding RNAs in the pathogenesis of lung cancer and modulation of response to systemic therapies, microRNAs (miRNAs) have been supposed to play an important role in resistance to EGFR-TKIs. The aim of this review is to briefly summarise the existing relationship between miRNAs and resistance to EGFR-TKIs, and also focusing on the possible clinical applications of miRNAs in reverting and overcoming such resistance.

Double-blind evaluation of analgesic efficacy of orally administered diclofenac, nefopam, and acetylsalicylic acid (ASA) plus codeine in chronic cancer pain.

The analgesic efficacy and toxicity of oral diclofenac sodium 50 mg (q.i.d.) vs. nefopam 60 mg (q.i.d.) and a combination of 640 mg ASA and 40 mg codeine (q.i.d.) in cancer patients with moderate to severe chronic pain has been evaluated in a randomized double-blind study. Planned duration of treatment was 10 days. Pain intensity was evaluated by a visual analog scale. The length of patient participation in the trial, the patient's final global evaluation and the incidence of side effects were also evaluated. Ninety-nine patients were enrolled in the study. All treatments produced a statistically significant pain relief (P less than 0.01) without differences among groups but only 26 of 99 patients (26.3%) completed the planned treatment period. Mean time in the study was 4.65 days. Inefficacy and side effects were the main reasons for premature treatment interruption. Patients treated with nefopam had a significantly shorter period in the study than patients treated with the other 2 treatments. Adverse effects were slightly more frequent with the nefopam and ASA + codeine regimens. The 3 therapeutic regimens appear to be similar as to analgesic efficacy, but diclofenac presents the advantage of a slightly better safety profile than nefopam and the ASA + codeine combination.

Long-term results of induction chemotherapy followed by concurrent chemotherapy and thoracic irradiation in limited small cell lung cancer.

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.

Clinical outcome with platinum-based chemotherapy in patients with advanced nonsquamous EGFR wild-type non-small-cell lung cancer segregated according to KRAS mutation status.

BACKGROUND: We hypothesized that KRAS mutations function as a marker of poor sensitivity to first-line platinum-based chemotherapy in patients with advanced nonsquamous EGFR wild-type (WT) non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Consecutive advanced nonsquamous EGFR WT NSCLCs treated at the Medical Oncology of Perugia with simultaneous assessment of KRAS mutation status were eligible. Anaplastic lymphoma kinase (ALK) gene status was known in roughly half of the patients who had KRAS WT. RESULTS: Two hundred four patients were included. Among them, the 77 individuals carrying a KRAS-mutant phenotype experienced a significantly inferior outcome in terms of response rate (P = .04), disease control rate (P = .05), and progression-free survival (PFS) (P = .05) compared with the EGFR WT/KRAS WT population. The association between KRAS mutation and shorter PFS remained statistically significant at multivariate analysis (hazard ratio [HR], 1.45). In addition, patients with KRAS mutations reported a significantly shorter overall survival (OS) compared with patients with EGFR WT/KRAS WT/ALK negativity (n = 64) (P = .02). Among patients with KRAS mutations, those harboring a mutation at codon 13 (n = 12) performed worse than those with a mutation at codon 12 (n = 62) in terms of both PFS and OS (P = .09 for both). CONCLUSION: KRAS mutation appears to negatively affect sensitivity to first-line platinum-based chemotherapy in patients with advanced nonsquamous EGFR WT NSCLC. Studies on larger case series are needed to address differences in clinical outcome according to the type of mutation.

Impact of specific mutant KRAS on clinical outcome of EGFR-TKI-treated advanced non-small cell lung cancer patients with an EGFR wild type genotype.

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<0.0001 and 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.

Association of cytidine deaminase and xeroderma pigmentosum group D polymorphisms with response, toxicity, and survival in cisplatin/gemcitabine-treated advanced non-small cell lung cancer patients.

BACKGROUND: Selecting patients according to key genetic characteristics may help to tailor chemotherapy and optimize the treatment in non-small cell lung cancer (NSCLC). Genetic variations in drug metabolism may affect the clinical response, toxicity, and prognosis of NSCLC patients treated with cisplatin/gemcitabine-based therapy. PATIENTS AND METHODS: We evaluated seven single-nucleotide polymorphisms of six genes CDA Lys27Gln (A/C); CDA C435T; ERCC1 C118T; XRCC3 Thr241Met (C/T); XPD Lys751Gln (A/C); P53 Arg72Pro (G/C), and RRM1 C524T in 192 chemotherapy-naive patients with advanced NSCLC treated with cisplatin/gemcitabine-based regimen by TaqMan probe-based assays with 7300 Real-Time PCR System, using genomic DNA extracted from blood samples. RESULTS: The CDA 435 T/T genotype was significantly associated with better response (p = 0.03). The CDA 435 C/T genotype was associated with a significantly increased risk of nonhematological toxicity of grade ≥3 (p = 0.02) after adjusting for performance status, age, and type of treatment regimen. In the multivariate Cox model, the XPD 751 C/C genotype was a significant prognostic factor of longer progression-free survival (p = 0.006). CONCLUSION: Our data suggest polymorphic variations of drug metabolic gene were associated with response and toxicity of cisplatin/gemcitabine-based therapy and progression-free survival of patients with advanced NSCLC.