Raffaele Califano

A phase I study of the safety and tolerability of olaparib (AZD2281, KU0059436) and dacarbazine in patients with advanced solid tumours

Background:Poly adenosine diphosphate (ADP)-ribose polymerase (PARP) is essential in cellular processing of DNA damage via the base excision repair pathway (BER). The PARP inhibition can be directly cytotoxic to tumour cells and augments the anti-tumour effects of DNA-damaging agents. This study evaluated the optimally tolerated dose of olaparib (4-(3--4-fluorophenyl) methyl-1(2H)-one; AZD2281, KU0059436), a potent PARP inhibitor, with dacarbazine and assessed safety, toxicity, clinical pharmacokinetics and efficacy of combination treatment.Patients and methods:Patients with advanced cancer received olaparib (20–200 mg PO) on days 1–7 with dacarbazine (600–800 mg m−2 IV) on day 1 (cycle 2, day 2) of a 21-day cycle. An expansion cohort of chemonaive melanoma patients was treated at an optimally tolerated dose. The BER enzyme, methylpurine-DNA glycosylase and its substrate 7-methylguanine were quantified in peripheral blood mononuclear cells.Results:The optimal combination to proceed to phase II was defined as 100 mg bd olaparib with 600 mg m−2 dacarbazine. Dose-limiting toxicities were neutropaenia and thrombocytopaenia. There were two partial responses, both in patients with melanoma.Conclusion:This study defined a tolerable dose of olaparib in combination with dacarbazine, but there were no responses in chemonaive melanoma patients, demonstrating no clinical advantage over single-agent dacarbazine at these doses.

Biomarker Utility of Circulating Tumor Cells in Metastatic Cutaneous Melanoma

The incidence of melanoma is increasing worldwide. Advances in targeted agents and immunotherapy have improved outcomes in metastatic disease, but biomarkers are required to optimize treatment. We determined the prevalence of circulating tumor cells (CTCs) and explored their utility as prognostic and pharmacodynamic biomarkers. A total of 101 patients with metastatic cutaneous melanoma were recruited prospectively. CTC number was determined using the CellSearch platform and melanoma kits in samples taken at baseline and serially during treatment. CTC numbers ranged between 0 and 36 per 7.5 ml blood; 26% of patients had ≥ 2 CTCs. Baseline CTC number was prognostic for median overall survival (OS) in univariate analysis (2.6 vs. 7.2 months (P<0.011) for patients with ≥ 2 CTCs vs. <2 CTCs, respectively). In multivariate analysis, CTC number was an independent prognostic biomarker of OS (hazard ratio (HR) 2.403, 95% confidence interval (CI) 1.303-4.430, P=0.005). Patients receiving treatment in whom CTC number remained ≥ 2 CTCs during treatment had shorter median OS than those who maintained <2 CTCs (7 vs. 10 months, HR 0.34, 95% CI 0.14-0.81, log-rank test P=0.015). In conclusion, CTC number in metastatic cutaneous melanoma patients is prognostic for OS with a cutoff of 2 CTCs per 7.5 ml blood. CTC number measured before and throughout treatment provided additional prognostic information. Larger studies are warranted to confirm CTC biomarker utility in melanoma patients.

Management of small cell lung cancer: recent developments for optimal care.

Small cell lung cancer (SCLC) represents approximately 13% of all lung cancer diagnoses and the incidence has reduced over the last 20 years. Treatment of SCLC remains challenging because of its rapid growth, early dissemination and development of drug resistance during the course of the disease.Chemotherapy remains the cornerstone of treatment for limited (LD) and extensive disease (ED), with concurrent chemotherapy and radical thoracic radiotherapy representing the best treatment option for fit patients with LD. Platinum-based chemotherapy is the treatment of choice in fit patients with good organ function, and the radiosensitizing effect of cisplatin is critically important for concurrent chemoradiotherapy in LD. Anthracycline-containing regimens represent a viable alternative for patients where platinum-based chemotherapy is contraindicated.Patients who relapse or progress after first-line chemotherapy have a very poor prognosis. Second-line therapy may produce a modest clinical benefit. Maintenance chemotherapy has not been shown to convincingly improve outcomes for SCLC. A number of targeted agents have been investigated in LD and ED, mostly in unselected populations, with disappointing results. Prophylactic cranial irradiation has been shown to reduce the incidence of brain metastases and prolong survival for both LD and ED without negative impact on quality of life (QOL) and cognitive function. Ongoing trials will shed some light on the impact of thoracic radiotherapy on QOL, symptom control and survival in ED SCLC patients who benefitted from first-line chemotherapy.

Prognostic and Predictive Value of K-RAS Mutations in Non-Small Cell Lung Cancer

Non-small cell lung cancer (NSCLC) is a heterogeneous disease, caused by the presence of different clinically relevant molecular subtypes. Genetic mutations are emerging as potential biomarkers of response and treatment selection in patients with NSCLC.Over the past few years, activating mutations of epidermal growth factor receptor (EGFR) have been recognized as the most important predictor of response to EGFR tyrosine kinase inhibitors (TKIs) such as gefitinib and erlotinib and also as a favourable prognostic factor.The RAS genes, including H-RAS, K-RAS and N-RAS, encode a family of proteins regulating cell growth, differentiation and apoptosis. Mutations in the K-RAS gene, mainly in codons 12 and 13, have been found in 20–30% of NSCLC tumor samples and occur most commonly, but not exclusively, in adenocarcinoma histology and in heavy smokers. In NSCLC, the presence of K-RAS mutations has generally been considered to be associated with worse prognosis and resistance to systemic therapy in the adjuvant as well as the metastatic setting. In early stage NSCLC, the prognostic role of K-RAS mutations has been evaluated in several studies without definitive conclusion. On the other hand, in advanced NSCLC, the presence of K-RAS mutations identifies a subgroup of patients who do not respond to EGFR-TKI therapy but, at the same time, a positive survival effect from EGFR-TKIs cannot be excluded in these patients. Similarly, K-RAS mutational status does not predict benefit from the anti-EGFR monoclonal antibody cetuximab, highlighting the biological difference between lung cancer and colorectal cancer. As a result of the lack of conclusive data, K-RAS mutations do not represent a validated biomarker for the negative selection of patients who are candidates for anti-EGFR therapy. The aim of this article is to review and discuss the data on the prognostic and predictive value of K-RAS mutations in NSCLC.

Outcomes of small-cell lung cancer patients treated with second-line chemotherapy: A multi-institutional retrospective analysis

BACKGROUND Patients with small-cell lung cancer (SCLC) that progress after first-line chemotherapy have a poor prognosis and the evidence of a benefit from second-line (SL) chemotherapy is limited. Patients relapsing or progressing more than 90 days after completion of first-line treatment are considered platinum sensitive and may be rechallenged with platinum-based chemotherapy. Topotecan is approved as SL treatment independent of time to progression. This retrospective analysis evaluates the clinical outcomes of SCLC patients who received SL chemotherapy after platinum-etoposide chemotherapy. PATIENTS AND METHODS We retrospectively reviewed 161 patients who received SL chemotherapy for SCLC. Patients were divided into four subgroups by type of SL treatment: (1) platinum-based rechallenge; (2) anthracycline-based regimens; (3) topotecan; (4) other single agents. The endpoints were overall survival (OS), progression-free survival (PFS) and response rate (RR). Survival curves were plotted using the Kaplan-Meier method. The Cox proportional hazard model was used for multivariate analysis to investigate factors influencing survival. RESULTS The median age was 63. There were 125 males and 36 females. Eastern Cooperative Oncology Group performance status (ECOG-PS) was 0, 1 and 2 in 12.5%, 62.5% and 25% of patients, respectively. Platinum sensitive/platinum resistant/platinum refractory/unknown=121/29/3/8 patients. Median time to SL chemotherapy was 6.9 months. The median PFS from starting second-line treatment was 4.3 months and median OS was 5.8 months. The overall RR was 22.9%. There was a trend toward higher RR (34.5% vs 17.5%, p for trend: 0.06) and OS (9.2 months vs 5.8 months, p=0.08) for patients with sensitive disease who were rechallenged with platinum-based chemotherapy. A multivariate analysis that adjusted for the time to SL treatment showed that a platinum-containing regimen achieves better RR, PFS and OS independently of the time to SL chemotherapy and that response to first-line treatment and PS at SL are the only independent prognostic factors. CONCLUSIONS The outcome for second-line therapy for SCLC was poor and benefit appeared to be limited to those patients with good PS and rechallenged with platinum-based chemotherapy. Platinum-based rechallenge should be considered as a standard comparator in future randomized controlled trials of SL chemotherapy.

Phase III randomised trial of doxorubicin-based chemotherapy compared with platinum-based chemotherapy in small-cell lung cancer

This randomised trial compared platinum-based to anthracycline-based chemotherapy in patients with small-cell lung cancer (limited or extensive stage) and ⩽2 adverse prognostic factors. Patients were randomised to receive six cycles of either ACE (doxorubicin 50 mg/m2 i.v., cyclophosphamide 1 g/m2 i.v. and etoposide 120 mg/m2 i.v. on day 1, then etoposide 240 mg/m2 orally for 2 days) or PE (cisplatin 80 mg/m2 and etoposide 120 mg/m2 i.v. on day 1, then etoposide 240 mg/m2 orally for 2 days) given for every 3 weeks. For patients where cisplatin was not suitable, carboplatin (AUC6) was substituted. A total of 280 patients were included (139 ACE, 141 PE). The response rates were 72% for ACE and 77% for PE. One-year survival rates were 34 and 38% (P=0.497), respectively and 2-year survival was the same (12%) for both arms. For LD patients, the median survival was 10.9 months for ACE and 12.6 months for PE (P=0.51); for ED patients median survival was 8.3 months and 7.5 months, respectively. More grades 3 and 4 neutropenia (90 vs 57%, P<0.005) and grades 3 and 4 infections (73 vs 29%, P<0.005) occurred with ACE, resulting in more days of hospitalisation and greater i.v. antibiotic use. ACE was associated with a higher risk of neutropenic sepsis than PE and with a trend towards worse outcome in patients with LD, and should not be studied further in this group of patients.

Beyond EGFR and ALK inhibition: unravelling and exploiting novel genetic alterations in advanced non small-cell lung cancer.

During the last decade, thoracic oncology has witnessed an unprecedented outburst of knowledge regarding molecular biology of non small-cell lung cancer (NSCLC). The implementation of high-throughput sequencing analysis and genomic technologies has led to the identification of novel molecular events that characterize NSCLC transformation and may represent critical oncogenic drivers amenable to targeted therapy. Among these, the presence of activating mutations of the epidermal growth factor receptor (EGFR) gene and of chromosomic rearrangements in the anaplastic-lymphoma kinase (ALK) proto-oncogene, have been the first well characterized genetic alterations with corresponding targeted agents to enter the clinical arena. Nevertheless, in the recent years a number of other oncogenic drivers beyond EGFR and ALK inhibition have emerged as novel molecular targets with potential therapeutic implications, including mutations in the genes KRAS, BRAF, HER2, PI3KCA and DDR2, as well as ROS1 and RET rearrangements and MET, HER2 and FGFR1 gene amplifications. The aim of this review is to provide comprehensive information on the novel therapeutic targets identified by recent preclinical evidence and to discuss developments in molecular treatments targeting these oncogenic drivers or actionable mutations beyond EGFR and ALK in advanced NSCLC.

Targeted therapies in small cell lung cancer: a review

Small cell lung cancer (SCLC) is an aggressive form of lung cancer that is characterized by a rapid doubling time, early onset of dissemination and high sensitivity to chemotherapy. Despite the potential for cure in patients with limited disease with concurrent chemoradiation and an initial good response to chemotherapy in extensive disease, there is a high chance of disease relapse with an overall poor median survival for both stages. With increasing translational research and a better understanding of the molecular basis of cancer, a number of molecular targets have been identified in various preclinical studies. This review summarizes potentially viable targets and new agents that have been developed and employed in recent, ongoing and future clinical trials to attempt to improve clinical outcomes in this disease.

Expert Consensus on the Management of Adverse Events from EGFR Tyrosine Kinase Inhibitors in the UK

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) such as gefitinib, erlotinib, and afatinib are standard-of-care for first-line treatment of EGFR-mutant advanced non-small cell lung cancer (NSCLC). These drugs have a proven benefit in terms of higher response rate, delaying progression and improvement of quality of life over palliative platinum-based chemotherapy. The most common adverse events (AEs) are gastrointestinal (GI) (diarrhoea and stomatitis/mucositis) and cutaneous (rash, dry skin and paronychia). These are usually mild, but if they become moderate or severe, they can have a negative impact on the patient’s quality of life (QOL) and lead to dose modifications or drug discontinuation. Appropriate management of AEs, including prophylactic measures, supportive medications, treatment delays and dose reductions, is essential. A consensus meeting of a UK-based multidisciplinary panel composed of medical and clinical oncologists with a special interest in lung cancer, dermatologists, gastroenterologists, lung cancer nurse specialists and oncology pharmacists was held to develop guidelines on prevention and management of cutaneous (rash, dry skin and paronychia) and GI (diarrhoea, stomatitis and mucositis) AEs associated with the administration of EGFR-TKIs. These guidelines detail supportive measures, treatment delays and dose reductions for EGFR-TKIs. Although the focus of the guidelines is to support healthcare professionals in UK clinical practice, it is anticipated that the management strategies proposed will also be applicable in non-UK settings.

Third-Line Chemotherapy in Small-Cell Lung Cancer: An International Analysis

INTRODUCTION Small-cell lung cancer is an aggressive disease for which the mainstay of treatment is chemotherapy. Despite good initial responses most patients will relapse. Some will receive second-line therapy with clinical benefit, but for third-line chemotherapy there is little evidence to guide treatment decisions and the benefits of treatment are unknown. This study investigated the treatment of SCLC in the third-line setting. PATIENTS AND METHODS An international, multicenter retrospective analysis of patients who received at least 3 lines of chemotherapy for their SCLC was performed. RESULTS From 2000 to 2010, 120 patients were identified from 5 centers: median age 61, 40% (n = 72) limited stage, and 79% (n = 95) Eastern Cooperative Oncology Group performance status of 0 to 1. Only 22% of these patients received 3 distinct lines of chemotherapy. The remainder were rechallenged with a chemotherapy regimen used at least once previously. Six percent received platinum-based chemotherapy in all 3 lines. In third-line, response rate was 18% and median overall survival was 4.7 months. Factors associated with longer survival included normal baseline LDH levels and response to second-line chemotherapy. On multivariate analysis only normal baseline LDH retained statistical significance. Thirty-five patients went on to receive chemotherapy beyond the third line. CONCLUSION Few SCLC patients receive 3 chemotherapy lines. Most patients were rechallenged with a similar regimen at least once. Response and survival in the third-line setting are modest. Lack of response to second-line chemotherapy and elevated baseline LDH level might predict lack of benefit from third-line treatment. This data set does not include patients receiving fewer lines for comparison.