Pablo Martínez

Serum tumor markers CEA, CYFRA21-1, and CA-125 are associated with worse prognosis in advanced non-small-cell lung cancer (NSCLC).

BACKGROUND Serum tumor markers are considered a negative prognostic factor in early-stages NSCLC but its role in advanced disease is controversial. The aim of this study is to analyze the prognostic value of tumor markers in advanced NSCLC. PATIENTS AND METHODS Two hundred and seventy seven patients diagnosed in our institution were retrospectively reviewed. Baseline prognostic factors analyzed were gender, histology and brain metastases. RESULTS Baseline patients characteristics: median age 63 years (30-81 years); males 84.4%, stage IV: 61.7%; adenocarcinoma 38.6%, squamous carcinoma 22.4%. High levels of CEA, CYFRA21-1, and CA125 levels were detected in 179 (55.9%), 119 (65%), and 129 (46.6%) patients respectively. Significant higher levels of CEA and CA125 at baseline were present in adenocarcinoma (P < .05). PFS in patients with elevated CEA, CYFRA21-1, and CA125 was 5.3 months (m), 3.5 m and 4.6 m versus 7.4 m, 6.2 m and 7.5 m in patients with normal levels (P < .05). The OS in patients with high and normal levels of tumor markers was 10.0 m vs 14.0 m (P = 0.085) for CEA; 5.6 vs 12.1 m for CYFRA21-1 (P = .002), and 8.7 vs 14.0 (P = .03) for CA125. In the multivariate analysis high levels of tumor markers, histology and clinical stage were significant correlated with worse prognostic. Patients with all the tumor markers elevated presented the worst prognosis (3.6 m for PFS and 7.1 m for OS, P < .001). CONCLUSION In our analysis, high levels of tumor markers at baseline are correlated with worse survival in stage III-IV NSCLC patients.

Analysis of Expression of Programmed Cell Death 1 Ligand 1 (PD-L1) in Malignant Pleural Mesothelioma (MPM)

Background The increasing incidence and poor outcome associated with MPM requires finding effective treatment for this disease. PD1/PD-L1 pathway plays a central role in tumor immune evasion and appears to be predictive and prognostic marker. PD-L1 is expressed in many different human cancers but its role in MPM has yet to be established. The aim of this study is to evaluate the expression of PD-L1 in MPM. Methods 119 MPM patients (p) from two institutions between November 2002 and February 2014 were reviewed. Formalin-fixed, paraffin-embedded tissue was stained with anti-PD-L1 (clone E1L3N). Cases showing more than 1% of tumor cells expression of PD-L1 were considered positive. Results PD-L1 was analyzed in 77 p with tumor tissue available and was positive in 20.7% p (14 samples in membrane, 16 in cytoplasm and 4 in immune infiltrate). PD-L1 intensity was weak in 56.2%, moderate in 25% and strong in 18.7% p. There was a significant relationship between PD-L1 expression and histology (PD-L1 expression 37.5% in no-epithelioid tumor and 13.2% in epithelioid; p=0.033). The median survival in p PD-L1 positive was 4.79 vs 16.3 months in p PD-L1 negative (p=0.012). Conclusions We have shown PD-L1 is expressed in 20% of patients, associated with no epithelioid histology and poor prognostic in MPM. Our results suggest PD-L1 warrants further exploration in selecting p for immunotherapy.

Clinical surrogate markers of survival in advanced non-small cell lung cancer (NSCLC) patients treated with second–third line erlotinib

BACKGROUND Inhibition of the EGFR pathway is a useful strategy in the treatment of patients with advanced NSCLC. The aim of this study is to assess predictive clinical parameters of efficacy. METHODS AND PATIENTS Sixty-two patients with advanced NSCLC were treated with erlotinib as second-third line (150 mg/day). Baseline patient characteristics were: performance status (PS) 1: 92%; median age, 58 years; males, 73%; adenocarcinoma, 45%; current/former smokers, 83%. During erlotinib treatment, 35% of patients had no rash, 32.3% had grade 1 rash, 26% had grade 2 rash and 6.5% patients developed grade 3 rash. RESULTS For patients with grades 2-3 rash vs. those with grades 0-1 rash, time to tumor progression (TTP) and overall survival (OS) were 92 vs. 41 days (p=0.0381) and 244 vs. 131 days (p=0.011), respectively. For patients with non-smoking history and current/former smokers, TTP and OS were 136 vs. 42 days (p=0.0015) and 324 vs. 133 days (p=0.0242), respectively. In addition, rash grade and smoking history were found to have a highly significant impact on TTP and OS, according to the Cox model. CONCLUSIONS Grade > or =2 rash and non-smoking history are associated with improved TTP and OS in advanced NSCLC patients treated with erlotinib.

A phase Ib, dose-finding study of erlotinib in combination with a fixed dose of pertuzumab in patients with advanced non-small-cell lung cancer

BACKGROUND Pertuzumab, a dimerization inhibitor of human epidermal growth factor receptor 2 (HER2), has demonstrated pharmacodynamic activity, with stable disease in non-small-cell lung cancer. Combining erlotinib and pertuzumab may enhance antitumor activity. This study aimed to establish the recommended dosing of the erlotinib and pertuzumab combination; assess safety, preliminary efficacy, and pharmacokinetics; and analyze biomarkers. PATIENTS AND METHODS Fifteen patients with stage IIIb/IV non-small-cell lung cancer who failed chemotherapy were recruited. The patients received erlotinib (days -8 to -1), then combination therapy (21-day cycles for 6 cycles). Pertuzumab was given intravenous at 840 mg, then 420 mg once every three weeks, with erlotinib given daily (100 or 150 mg). RESULTS No dose-limiting toxicities were observed. Adverse events were generally grade 1/2 and manageable. The objective response rate was 20% (3/15 patients; 2 responders had mutant HER1, 1 responder had wild-type HER1), median overall progression-free survival was 9.3 weeks. High HER1, HER2, and HER3 messenger RNA expression correlated with increased progression-free survival. Combination therapy did not affect erlotinibs pharmacokinetics; however, pertuzumab mean exposures (maximum concentration, 231 mg/L; area under the concentration-time curve from 0 to 21 days, 1780 mg*d/L) were slightly higher than in previous studies. CONCLUSIONS Combination therapy was well tolerated in patients with good performance status, with encouraging efficacy. A loading dose of pertuzumab 840 mg followed by 420 mg once every three weeks plus daily erlotinib 150 mg appears to be the most appropriate regimen for this combination.

How to integrate current knowledge in selecting patients for first line in NSCLC

Non-small-cell lung cancer (NSCLC) accounts for 80% of all lung cancer, which is the leading cause of cancer mortality. The majority of NSCLC patients present with advanced disease at diagnosis. Standard chemotherapy using platinum-containing doublets has reached a therapeutic plateau with a median survival of ~1 year. The development of more effective strategies in the first-line setting remains challenging. In selected chemotherapy-naïve, advanced, non-squamous patients, the combination of bevacizumab with chemotherapy was shown to produce better outcomes than chemotherapy alone. The potential benefit of maintenance/sequential treatment after initial platinum-based chemotherapy should be discussed in detail with each patient. Epidermal growth factor receptor (EGFR) mutation determination should be carried out in subgroups of patients characterized by a high prevalence of sensitizing mutations. When a mutation is present, first-line treatment with an EGFR tyrosine kinase inhibitor may be considered. Finally, a phase I study using an oral ALK inhibitor has produced promising results in NSCLC patients with ALK rearrangements, indicating that ALK represents a new therapeutic target in a molecularly defined subset of NSCLC. Ongoing studies in first-line therapy are focusing on targeted therapies and patient selection.

Ganitumab for the treatment of small-cell lung cancer

Introduction: Small-cell lung cancer (SCLC) accounts for 15 – 20% of all lung cancer cases with few advances made in the systemic treatment and outcomes for extensive-stage SCLC. Many strategies have been evaluated over the past 15 years but none of these approaches has resulted in improved survival rates for patients with SCLC. The IGF receptor (IGF-R) pathway represents a potential actionable target in SCLC patients. Indeed, the IGF-R pathway is involved in cancer development and progression and regulates different vital processes including fetal development, growth and metabolism. Areas covered: This review provides an overview of insulin inhibitors and the strategies undertaken in recent years with SCLC. Specifically, the article discusses ganitumab and its applicability to SCLC patients. Expert opinion: At present, there is a lack of therapeutic choices for patients with advanced SCLC. Unfortunately, ganitumab, administered in combination with chemotherapy, demonstrated no clinical activity in patients with SCLC, although it could have utility with other cancers. Furthermore, insulin inhibitors may have some utility in the treatment of SCLC and further studies are required to identify subsets of patients most likely to benefit from their use. The authors also believe that it is important to determine the exact role of the IGF pathway in the pathogenesis and propagation of SCLC.

Abstract A254: A phase 1 safety and pharmacokinetic (PK) study of PI3K/TORC1/TORC2 inhibitor, XL765 (SAR245409), in combination with erlotinib in patients (pts) with advanced solid tumors

Background: XL765 is an oral, selective inhibitor of Class I PI3Ks, as well as TORC1 and TORC2. The PI3K pathway is frequently dysregulated in cancer cells and has been implicated as a mediator of resistance to EGFR inhibitors. In preclinical studies, XL765 has demonstrated dose‐dependent target modulation in tumor xenograft models. In an ongoing Phase 1 single agent clinical study, XL765 has exhibited robust pharmacodynamic activity in diverse solid tumors. Methods: Pts with advanced solid tumors are enrolled in successive cohorts of 3 to receive escalating doses of XL765 in combination with erlotinib. Cycles consist of 28 days of XL765 and erlotinib, each given qd. During the ongoing dose‐escalation phase of the study there is a 14‐day run‐in period of erlotinib monotherapy. Cycle 1 safety data determine dose limiting toxicities (DLTs). Tumor response is evaluated every 8 weeks. Results: As of 24Aug2009, 14 pts with advanced solid tumors have been enrolled: NSCLC (11), CRC (1), liposarcoma (1), and endometrial adenocarcinoma (1). Most of the NSCLC pts have been previously treated with erlotinib before entering the study. Pts have been treated at 2 dose levels of XL765 (30 and 50 mg) administered once‐daily in combination with 100 mg erlotinib. No DLTs or study treatment‐related SAEs have been reported. As of 03Aug2009, AEs have been reported for 7 pts. Grade 3 adverse events of nausea, vomiting, and anorexia considered related to study treatment were observed in one pt dosed at 30 mg qd. The PK of XL765 given in combination with erlotinib is consistent with that observed for XL765 given alone (Exelixis study XL765‐001). Likewise, XL765 does not appear to alter the PK of erlotinib. In skin biopsies, substantial post‐dose reductions were evident in phosphorylation of AKT, the mTOR substrate 4EBP1, and EGFR. For example, progressive pharmacodynamic effects were evident in serial skin biopsies from a pt with EGFR‐mutant NSCLC previously treated with erlotinib who has remained on study through 26 weeks, culminating in decreases in pAKT‐T308 (72%), p4EBP1 (57%), pERK (73%), and pEGFR (50%) at Day 85 post‐start of combination dosing (50 mg XL765/100 mg erlotinib). Pharmacodynamic analyses of paired tumor biopsies are in progress. Of the first 9 patients enrolled, five have remained on study for at least 12 weeks. Conclusions: XL765 in combination with erlotinib is generally well tolerated at doses up to 50 mg XL765/100 mg erlotinib, with no apparent drug‐drug PK interaction, and results in robust simultaneous inhibition of PI3K and EGFR signaling. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A254.

Pembrolizumab in recurrent advanced cervical squamous carcinoma

No definitive cure is known for recurrent, persistent or metastatic cervical carcinoma. Chemotherapy remains the standard of care, although available options are scarce and do not provide satisfactory results. Immune checkpoint inhibitors have shown a strong and prolonged response in several types of cancer, although only in a subset of patients. Defining the profile of the patients likely to benefit from such treatment is a subject of active research. Here, we present a case of a heavily pretreated patient with recurrent advanced squamous cell carcinoma of the cervix who had exhausted all available treatment options and showed a striking response to the immune checkpoint inhibitor pembrolizumab.

Brain metastases: the need for a more tailored approach in non-small-cell lung cancer patients

Brain metastases are quite common in cancer patients and their incidence has increased over the last two decades. That may be due to both improvements in diagnostic methods and longer survival of metastatic patients. The most common primary site for patients with brain metastases is the lung and approximately 20% of patients with non-small-cell lung cancer (NSCLC) will develop brain metastases at some point in the course of their disease. Most patients with brain metastases are symptomatic at diagnosis and their presence should be suspected in any patient with a history of lung cancer who presents with a new neurological sign or symptom. Magnetic resonance imaging is the test of choice for diagnosing brain metastases because of its superior resolution and accuracy compared with computed tomography. Overall, the outcome for NSCLC patients who develop brain metastases remains poor, with an average survival of 3–6 months. A number of prognostic indexes have been proposed and validated with a view to predicting more accurately the prognosis of patients with brain metastases [1]. Essentially, all these index scores help us to better select patients for the different options available to treat brain metastases: surgery, stereotactic radiosurgery, whole brain radiotherapy, chemotherapy and corticosteroids. However, these index scores are less than perfect and more precise prognostic tools are clearly needed. For patients with single or 1–3 brain metastases as the