Francesca Mazzoni

Bevacizumab in non-small cell lung cancer.

Lung cancer continues to be the leading cause of cancer death in Western countries. The median survival time for advanced non-small cell lung cancer (NSCLC) remains poor and chemotherapy is the treatment of choice for most patients with metastatic NSCLC. Platinum-based chemotherapy has long been the standard of care for advanced NSCLC. The formation of new blood vessels (angiogenesis) is needed for the growth and invasiveness of primary tumours, and plays an important role in metastatic growth. Vascular endothelial growth factor (VEGF) has emerged as a key potential target for the pharmacological inhibition of tumour angiogenesis. This review discusses current data and the future potential of bevacizumab, a recombinant humanized monoclonal antibody that binds VEGF, in the treatment of NSCLC.Results from a phase II study showed that the addition of bevacizumab to the first-line chemotherapy with paclitaxel and carboplatin (CP) may increase the overall survival (OS) and the time to progression in advanced NSCLC. Based on these promising results, a randomized phase III trial compared the combination of bevacizumab with CP versus CP alone in the treatment of advanced non-squamous NSCLC. The combination of CP plus bevacizumab led to a statistically significant increase in median OS and progression-free survival (PFS) compared with CP alone, with a response rate (RR) in the CP arm of 15% compared with 35% in the bevacizumab plus CP arm (p < 0.001). More recently, the randomized AVAIL (Avastin in Lung Cancer) study, which evaluated cisplatin with gemcitabine plus bevacizumab in two different dosages versus chemotherapy alone in 1043 patients with recurrent or advanced non-squamous NSCLC, reported a significant increase of PFS, RR and duration of response for both of the bevacizumab-containing arms. Bevacizumab has also been investigated in combination with erlitonib as second-line treatment in two small early phase trials, with interesting results.Bevacizumab was generally well tolerated in clinical trials; the main treatment-associated adverse events were neutropenia and haemorrhage, especially in the lung, but also at other sites. Several trials that incorporate bevacizumab in combination with new active drugs in NSCLC are ongoing and should further help to define the place of bevacizumab in the therapy of NSCLC.

Phase II trial of customized first line chemotherapy according to ERCC1 and RRM1 SNPs in patients with advanced non-small-cell lung cancer.

OBJECTIVES Customized chemotherapy has several advantages: patients are more likely to be treated with the most effective agents and can be spared the toxicity of ineffective drugs. Based on the literature, excision repair cross complementation group 1 (ERCC1) and ribonucleotide reductase M1 (RRM1) genes represent predictive biomarkers of response to platinum compound and gemcitabine, in NSCLC. MATERIALS AND METHODS We had planned a phase II trial (Simon design) to evaluate combination chemotherapy according to single nucleotide polymorphisms (SNPs) of ERCC1 (118T/C and 8092C/A) and RRM1 (-37C/A and -524T/C) in naïve patients affected by advanced NSCLC. ERCC1 and RRM1 SNPs assessment was performed in peripheral blood lymphocytes (PBLs). Combination chemotherapy was selected based on ERCC1 and RRM1 SNPs: we assume that patients with one or two C alleles at position 118 and with one or two A alleles at position 8092 in ERCC1 gene would correspond to Cisplatin non-responder and than with two A alleles at -37 and two C alleles at -524 in RRM1 gene to gemcitabine non-responder. Four schedules were provided: cisplatin+gemcitabine, cisplatin+docetaxel, gemcitabine+docetaxel; docetaxel+vinorelbine. Primary endpoint was overall response (ORR) in the intention-to-treat population. RESULTS 42 patients were enrolled from January 2010 to November 2011; 40 patients received at least 1 cycle of chemotherapy; median age was 66 years (range: 47-72); 36(90%) had stage IV, 4(10%) IIIB; 23(58%) had adenocarcinoma, 14(35%) squamous carcinoma. Twenty-five (62%) patients received treatment A, 3(8%) treatment B, 11(28%) treatment C, 1(23%) treatment D. ORR was 55%, analysis in squamous patients subgroups showed 71.4% ORR. The median follow-up was 19.7 months, PFS was 23 weeks (95% CI = 15-26) and OS was 40.4 weeks (95% CI = 32-55). Treatment was well tolerated. CONCLUSION We observed an increase of ORR in NSCLC patients when they were treated with chemotherapy according to ERCC1 and RRM1 SNPs status.

From clinical trials to clinical practice: predictors of response to erlotinib in advanced non-small cell lung cancer patients pretreated with chemotherapy.

BACKGROUND Inhibition of the epidermal growth factor receptor pathway with tyrosine kinase inhibitors can improve outcome of patients with advanced non-small cell lung cancer after first-line chemotherapy. The use of clinical characteristics and molecular markers may permit the identification of patients who are more likely to benefit from erlotinib. PATIENTS AND METHODS Retrospective analysis of unselected patients with metastatic non-small cell lung cancer who had previously failed on at least one line of chemotherapy and treated at our institution with erlotinib (150 mg/day orally) until disease progression. Mutations of epidermal growth factor receptor (exon 19-21) and KRAS (codon 12-13) genes were screened with high-resolution melting analysis and identified with direct sequencing. RESULTS Fifty-three patients were included in the study. The disease control rate was 38%. Median progression-free survival and median overall survival were 4 and 15 months, respectively. Skin rash, diarrhea and mucositis were the most common toxicities of erlotinib. In 19 patients, erlotinib dose was reduced for toxicity. The disease control rate and progression-free survival were significantly better in non-smokers, responders to chemotherapy and patients with epidermal growth factor receptor mutations. Overall survival was longer in patients with skin toxicity and epidermal growth factor receptor mutations. CONCLUSIONS In our experience, epidermal growth factor receptor mutations, response to previous chemotherapy and non-smoking status were predictors of higher disease control rate and longer progression-free survival. Overall survival was significantly longer in patients with epidermal growth factor receptor mutations and skin toxicity.

Phase II trial of single-agent oral vinorelbine in elderly (≥70 years) patients with advanced non-small-cell lung cancer and poor performance status

BACKGROUND Elderly patients with advanced non-small-cell lung cancer (NSCLC) with poor performance status (PS) are a special population requiring particular attention. Single-agent oral vinorelbine could be an attractive option. PATIENTS AND METHODS A total of 43 patients with stage IIIB-IV NSCLC and Eastern Cooperative Oncology Group (ECOG) PS of two or more with good functional status were prospectively recruited. Oral vinorelbine was administered at the dose of 60 mg/m(2) on days 1-8 every 3 weeks. Primary end points were response rate and safety. RESULTS Overall response rate was 18.6% with 8 partial responses; 18 of 43 (41.8%) experienced stable disease lasting >12 weeks and 17 of 43 (39.6%) disease progression for an overall clinical benefit of 60.4%. Median time to progression was 4.0 (range 2-22) months and median overall survival 8.0 (range 3-35) months. Treatment was well tolerated. Of 187 cycles, we did not observe any grade 3/4 toxicity with the exception of a single not-febrile G3 neutropenia. Regardless of severity, main toxic effects observed were nausea in 48.1% and vomiting in 22.9% of patients, anemia in 43.2%, fatigue in 32.6% and leukopenia in 23.2%. CONCLUSION Single-agent oral vinorelbine is extremely safe in elderly patients with advanced NSCLC and ECOG PS of two or more and may represent a valid option in this very special population.

Efficacy and safety of rechallenge treatment with gefitinib in patients with advanced non-small cell lung cancer

OBJECTIVES Although patients with advanced non-small cell lung cancer (NSCLC) and an activating epidermal growth factor receptor (EGFR) mutation benefit from the use of EGFR-tyrosine kinase inhibitors (TKI), most of them progress within 12 months from treatment start due to acquired resistance. In clinical practice, many physicians frequently offer these patients retreatment with EGFR-TKIs after a chemotherapy break, based on small or retrospective studies. MATERIALS AND METHODS A phase II trial was conducted in patients with stage III/IV NSCLC, to assess the efficacy, safety and impact on quality of life (QoL) and disease-related symptoms of gefitinib rechallenge. Eligible patients had initially responded to first-line gefitinib and progressed after second-line chemotherapy. RESULTS Of 61 enrolled patients, 73.8% were female, 100% had EGFR-mutated adenocarcinoma and 67.2% were never-smokers. Thirty-two (52.5%) patients obtained a clinical benefit, with 3 (4.9%) achieving a partial response and 29 (47.5%) having stable disease. Median progression-free survival was 2.8 months, overall survival 10.2 months and duration of gefitinib treatment 3.6 months. The most common all grade-adverse events were diarrhea (27.6%), nausea and/or vomiting (20.3%), rash (14.7%) and dyspnea (10.3%); no new toxicities were apparent. CONCLUSION Findings from this study indicate that gefitinib rechallenge offers modest benefit and may be taken into consideration only for patients for whom no other treatment option exists.

Primary Cardiac Angiosarcoma: A Fatal Disease

A 42-year-old man with a cardiac tamponade underwent an urgent pericardiotomy that showed tumoral tissue, covering the surface of the right atrium. The tumor was then partially excised, and the histological examination revealed the presence of a moderately-differentiated angiosarcoma. The patient was then referred to the oncology unit and scheduled for a chemotherapy schedule including Epirubicin (60 mg/m2, on days 1 and 2) plus Ifosfamide (2000 mg/m2, on days 1 to 3) and Uromitexan (2000 mg/m2 at hours 0, 4, 8 after IFO). All drugs were administered every three weeks. After two cycles, a restaging work-up revealed a partial remission. The treatment was continued for another two cycles. A new evaluation by cardiac MRI evidenced a local and distant (lung) progression of disease. The patient died after three months. This paper confirms that cardiac angiosarcoma is a fatal disease, and the prognosis is usually 6–11 months from time of diagnosis.

Skin metastasis from typical carcinoid tumor of the lung.

Carcinoids are neuroendocrine tumors that may arise within any organ, although they are more commonly found in the gastrointestinal tract and in the bronchopulmonary tract. They are generally characterized by an indolent clinical course but may in some instances metastatise to regional lymph nodes or to distant sites. We herein describe a rather infrequent case of a 60‐year‐old man with a skin metastasis from a typical carcinoid of the lung. We discuss the histopathological and immunohistochemical features in the context of previous literature and comment issues related to difficulties in the differential diagnosis. Dermatopathologists should be familiar with the metastatic carcinoid profile in order to avoid potential misdiagnoses and to properly address the patient management when the skin metastasis represents the first manifestation of an internal disease.

Primary resistance to osimertinib due to SCLC transformation: Issue of T790M determination on liquid re-biopsy

OBJECTIVES EGFR T790M mutation is the most common mechanism of resistance to first-/second-generation EGFR tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC) and could be overcome by third-generation EGFR-TKIs, such as osimertinib. Liquid biopsy, a non-invasive technique used to test the presence of the resistant mutation, may help avoiding tissue re-biopsy. However, analysing only circulating-free DNA, information about other less frequent and coexisting resistance mechanisms may remain unrevealed. MATERIALS AND METHODS All patients reported in this series participated in the ASTRIS trial, a real world treatment study testing the efficacy of osimertinib (80mg os die) in advanced T790M-positive NSCLC progressed to prior EGFR-TKI. Patients were considered eligible to osimertinib if T790M positive on tissue or plasma samples. In our patients, EGFR molecular testing on blood sample was conducted with digital droplet PCR (ddPCR). RESULTS We report our experience of five patients treated with osimertinib after T790M detection on liquid biopsy that presented a disease progression at first tumor assessment mediated by SCLC transformation, as evidenced at tissue re-biopsies. All patients showed low ratio T790M/activating mutation in the blood before osimertinib (lower than 0.03). For three patients, EGFR mutational analysis was T790M-negative when re-assessed by using a less sensitive method (therascreen®) on the same liquid biopsy sample analysed by ddPCR before osimertinib therapy. CONCLUSION Although liquid biopsy is a relevant tool to diagnose T790M presence in NSCLC patients resistant to EGFR-TKI, in case of a low ratio T790M/activating mutation, tissue biopsy should be considered to exclude the presence of SCLC transformation and/or other concomitant resistance mechanisms.

Patients with NSCLC may display a low ratio of p.T790M vs. activating EGFR mutations in plasma at disease progression: implications for personalised treatment

Introduction NSCLC harboring activating mutations of EGFR is highly sensitive to first-line EGFR-tyrosine kinase inhibitors (TKIs), but drug resistance depending on the EGFR mutation p.T790M will occur in about 50-60% of patients. Detailed information on the amount of p.T790M plasmatic level associated with resistance to EGFR-TKIs and guidance to treatment with p.T790M-effective TKI depending on these levels, is lacking. Methods This study enrolled p.T790M-positive patients (n=49) affected by EGFR-mutated NSCLC at progression to first-line EGFR-TKIs and, in selected cases (n=5), after second-line treatment with osimertinib. Cell-free circulating tumor DNA (cftDNA) was extracted from plasma and the quantitative analysis of EGFR ex19del, p.L858R and p.T790M was performed by digital droplet PCR. Results The mean amount of mutated alleles at progression to first-line EGFR-TKIs was 108,492 copies/ml for ex19del, 97,336 copies/ml for p.L858R, but only 8,754 copies/ml for p.T790M. There was no significant correlation between progression-free survival and the ratio of p.T790M over EGFR activating mutations. The analysis of cftDNA in 5 patients treated with osimertinib revealed a marked decrease of all EGFR mutant alleles. Conclusions The amount of p.T790M in plasma can be much lower than activating EGFR mutations. Despite this finding, osimertinib is effective in p.T790M-positive patients. These results indicate that clones driving resistance to EGFR-TKIs represent a minority among cells bearing activating EGFR-mutations. In addition, the identification of a threshold level of p.T790M is not a strict requirement for the selection of patients to be treated with osimertinib, since treatment showed a decrease in all EGFR mutated cells.

Osteonecrosis of the jaw and angiogenesis inhibitors: a revival of a rare but serous side effect

Osteonecrosis of the jaw (ONJ) is a rare treatment related side effect that was firstly described in 2002 through a case report in metastatic bone cancer patient treated with bisphosphonates (BPs) therapy. ONJ is defined as an eight weeks or longer clinical finding of exposed bone in the oral cavity without response to appropriate therapy. The diagnosis is mainly clinical but often requires a radiological confirmation with an orthopantomography. So it must be made by a dental specialist with sufficient experience on ONJ and requires a detailed anamnestic exploration of comorbidities and treatments history. In particular, ONJ affects a wide number of oncologic patients treated with BPs for bone metastatic cancers and, more recently, with anti-angiogenic drugs. The aim of this this paper is to describe diagnosis and classification of this rare but serious side effect and its pathophysiology. In particular, we provide a detailed description of clinical evidences upon the relationship between anti-angiogenic drugs and ONJ. Considering the evolving of cancer epidemiology with a greater number of cancer surviving patients, this side effect always deserves more attention. We conclude that ONJ must be always carefully investigated and prevented with a multidisciplinary approach involving oncologist, radiation oncologist and skilled dental practitioner when a cancer patient must begin a BP or an antiangiogenic treatment.