Marianna Koczywas

Small Cell Lung Cancer

Neuroendocrine tumors account for approximately 20% of lung cancers; most (≈15%) are small cell lung cancer (SCLC). These NCCN Clinical Practice Guidelines in Oncology for SCLC focus on extensive-stage SCLC because it occurs more frequently than limited-stage disease. SCLC is highly sensitive to initial therapy; however, most patients eventually die of recurrent disease. In patients with extensive-stage disease, chemotherapy alone can palliate symptoms and prolong survival in most patients; however, long-term survival is rare. Most cases of SCLC are attributable to cigarette smoking; therefore, smoking cessation should be strongly promoted.

Multicenter, Double-Blind, Placebo-Controlled, Randomized Phase II Trial of Gemcitabine/Cisplatin Plus Bevacizumab or Placebo in Patients With Malignant Mesothelioma

PURPOSE Gemcitabine plus cisplatin is active in malignant mesothelioma (MM), although single-arm phase II trials have reported variable outcomes. Vascular endothelial growth factor (VEGF) inhibitors have activity against MM in preclinical models. We added the anti-VEGF antibody bevacizumab to gemcitabine/cisplatin in a multicenter, double-blind, placebo-controlled randomized phase II trial in patients with previously untreated, unresectable MM. PATIENTS AND METHODS Eligible patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 and no thrombosis, bleeding, or major blood vessel invasion. The primary end point was progression-free survival (PFS). Patients were stratified by ECOG performance status (0 v 1) and histologic subtype (epithelial v other). Patients received gemcitabine 1,250 mg/m(2) on days 1 and 8 every 21 days, cisplatin 75 mg/m(2) every 21 days, and bevacizumab 15 mg/kg or placebo every 21 days for six cycles, and then bevacizumab or placebo every 21 days until progression. RESULTS One hundred fifteen patients were enrolled at 11 sites; 108 patients were evaluable. Median PFS time was 6.9 months for the bevacizumab arm and 6.0 months for the placebo arm (P = .88). Median overall survival (OS) times were 15.6 and 14.7 months in the bevacizumab and placebo arms, respectively (P = .91). Partial response rates were similar (24.5% for bevacizumab v 21.8% for placebo; P = .74). A higher pretreatment plasma VEGF concentration (n = 56) was associated with shorter PFS (P = .02) and OS (P = .0066), independent of treatment arm. There were no statistically significant differences in toxicity of grade 3 or greater. CONCLUSION The addition of bevacizumab to gemcitabine/cisplatin in this trial did not significantly improve PFS or OS in patients with advanced MM.

Carboplatin and Paclitaxel in Combination With Either Vorinostat or Placebo for First-Line Therapy of Advanced Non–Small-Cell Lung Cancer

PURPOSE Vorinostat, a histone deacetylase inhibitor, exerts anticancer effects by both histone and nonhistone-mediated mechanisms. It also enhances the anticancer effects of platinum compounds and taxanes in non-small-cell lung cancer (NSCLC) cell lines. This phase II randomized, double-blinded, placebo-controlled study evaluated the efficacy of vorinostat in combination with carboplatin and paclitaxel in patients with advanced-stage NSCLC. PATIENTS AND METHODS Patients with previously untreated stage IIIB (ie, wet) or IV NSCLC were randomly assigned (2:1) to carboplatin (area under the curve, 6 mg/mL x min) and paclitaxel (200 mg/m(2) day 3) with either vorinostat (400 mg by mouth daily) or placebo. Vorinostat or placebo was given on days 1 through 14 of each 3-week cycle to a maximum of six cycles. The primary end point was comparison of the response rate. Results Ninety-four patients initiated protocol therapy. Baseline patient characteristics were similar between the two arms. The median number of cycles was four for both treatment arms. The confirmed response rate was 34% with vorinostat versus 12.5% with placebo (P = .02). There was a trend toward improvement in median progression-free survival (6.0 months v 4.1 months; P = .48) and overall survival (13.0 months v 9.7 months; P = .17) in the vorinostat arm. Grade 4 platelet toxicity was more common with vorinostat (18% v 3%; P < .05). Nausea, emesis, fatigue, dehydration, and hyponatremia also were more frequent with vorinostat. CONCLUSION Vorinostat enhances the efficacy of carboplatin and paclitaxel in patients with advanced NSCLC. HDAC inhibition is a promising therapeutic strategy for treatment of NSCLC.

A Multicenter Phase II Study of Ganetespib Monotherapy in Patients with Genotypically Defined Advanced Non–Small Cell Lung Cancer

Purpose: Ganetespib is a novel inhibitor of the heat shock protein 90 (Hsp90), a chaperone protein critical to tumor growth and proliferation. In this phase II study, we evaluated the activity and tolerability of ganetespib in previously treated patients with non–small cell lung cancer (NSCLC). Experimental Design: Patients were enrolled into cohort A (mutant EGFR), B (mutant KRAS), or C (no EGFR or KRAS mutations). Patients were treated with 200 mg/m2 ganetespib by intravenous infusion once weekly for 3 weeks followed by 1 week of rest, until disease progression. The primary endpoint was progression-free survival (PFS) at 16 weeks. Secondary endpoints included objective response (ORR), duration of treatment, tolerability, median PFS, overall survival (OS), and correlative studies. Results: Ninety-nine patients with a median of 2 prior systemic therapies were enrolled; 98 were assigned to cohort A (n = 15), B (n = 17), or C (n = 66), with PFS rates at 16 weeks of 13.3%, 5.9%, and 19.7%, respectively. Four patients (4%) achieved partial response (PR); all had disease that harbored anaplastic lymphoma kinase (ALK) gene rearrangement, retrospectively detected by FISH (n = 1) or PCR-based assays (n = 3), in crizotinib-naïve patients enrolled to cohort C. Eight patients (8.1%) experienced treatment-related serious adverse events (AE); 2 of these (cardiac arrest and renal failure) resulted in death. The most common AEs were diarrhea, fatigue, nausea, and anorexia. Conclusions: Ganetespib monotherapy showed a manageable side effect profile as well as clinical activity in heavily pretreated patients with advanced NSCLCs, particularly in patients with tumors harboring ALK gene rearrangement. Clin Cancer Res; 19(11); 3068–77. ©2013 AACR.

Phase II Study of Belinostat (PXD101), a Histone Deacetylase Inhibitor, for Second Line Therapy of Advanced Malignant Pleural Mesothelioma

Background: Belinostat (PXD 101) is a novel inhibitor of class I and II histone deacetylases. This class of compounds has demonstrated anticancer activity in malignant mesothelioma. We conducted a phase II study of belinostat in patients with relapsed malignant pleural mesothelioma. Methods: Patients with advanced mesothelioma, progression with one prior chemotherapy regimen and Eastern Cooperative Oncology Group performance status 0–2 were eligible. Belinostat was administered at 1000 mg/m2 intravenously over 30 minutes on days 1–5 of every 3 week cycle. The primary end point was response rate. The Simon two-stage design was used. Disease assessments were performed every two cycles. Results: Thirteen patients were enrolled. Baseline characteristics were: median age of 73 years; Eastern Cooperative Oncology Group performance status 0 (n = 4), 1 (8) and 2 (1). A median of two cycles of therapy were administered. Disease stabilization was seen in two patients. No objective responses were noted and the study did not meet criteria to proceed to the second stage of accrual. Median survival was 5 months with a median progression-free survival of 1 month. Salient toxicities included nausea, emesis, fatigue, and constipation. One patient died as a consequence of cardiac arrhythmia which was deemed ‘possibly’ related to therapy. Conclusions: Belinostat is not active as monotherapy against recurrent malignant pleural mesothelioma. Evaluation of combination strategies or alternate dosing schedules may be necessary for further development of this novel agent in mesothelioma.

A Phase II Study of AT-101 (Gossypol) in Chemotherapy-Sensitive Recurrent Extensive-Stage Small Cell Lung Cancer

Background: AT-101 is an oral inhibitor of the antiapoptotic Bcl proteins (Bcl-2, Bcl-XL, Bcl-W, and Mcl-1) and an inducer of the pro-apoptotic proteins noxa and puma. We studied the efficacy of AT-101 in patients with recurrent chemosensitive extensive-stage small cell lung cancer (SCLC). Methods: Patients with recurrent “sensitive” SCLC (defined as no progression during and no disease recurrence <2 months after completion of first-line platinum-based chemotherapy) were eligible. AT-101 was administered 20 mg orally daily for 21 of 28 days each cycle for up to six cycles. The primary end point was the objective response rate. Results: At the time of planned interim evaluation, none of the 14 evaluable patients enrolled in the first stage had any response to therapy, and the study was closed permanently for further accrual. Three patients (21%) achieved stable disease after two cycles of therapy. Grade 3 toxicities included anorexia, fatigue, and nausea/vomiting. Conclusions: AT-101 is not active in patients with recurrent chemosensitive SCLC.

A phase 2 trial of dacomitinib (PF-00299804), an oral, irreversible pan-HER (human epidermal growth factor receptor) inhibitor, in patients with advanced non-small cell lung cancer after failure of prior chemotherapy and erlotinib

This phase 2 trial (ClinicalTrials.gov identifier NCT00548093) assessed the efficacy, safety, and impact on health‐related quality of life of dacomitinib (PF‐00299804), an irreversible tyrosine kinase inhibitor (TKI) of human epidermal growth factor receptors (EGFR)/HER1, HER2, and HER4, in patients with KRAS wild‐type non–small cell lung cancer (NSCLC).

Phase II Study of Cediranib (AZD 2171), an Inhibitor of the Vascular Endothelial Growth Factor Receptor, for Second-Line Therapy of Small Cell Lung Cancer (National Cancer Institute #7097)

Background: Inhibition of angiogenesis is a novel strategy for the treatment of cancer. We evaluated the safety and efficacy of cediranib, a potent small molecule inhibitor of the vascular endothelial growth factor receptor, in patients with refractory or recurrent small cell lung cancer (SCLC). Methods: Patients with SCLC with progression after prior platinum-based chemotherapy only; performance status (PS) of 0 to 2; and adequate bone marrow, renal, and hepatic function were included. The dose of cediranib was 45 mg PO once a day for the first 12 patients and was reduced to 30 mg PO once a day for the subsequent patients because of intolerance of the higher dose. Treatment was given on a daily continuous schedule. The primary end point was determination of the response rate. Results: Twenty-five patients were enrolled. Patient characteristics were as follows: 13 men; median age 61 years; PS 0 (12 pts), PS 1 (12 pts). A median of two cycles were administered. Salient grade 3/4 toxicities were fatigue, diarrhea, hypertension, proteinuria, and elevated liver enzymes. Tolerability was better with the 30 mg dose once a day. Nine patients had stable disease, but none had a confirmed partial response. The median progression-free survival and overall survival were 2 and 6 months, respectively. Response criteria to proceed to full accrual were not met. Increase in circulating endothelial cell count was noted at the time of progression in several patients. Conclusions: Cediranib failed to demonstrate objective responses in recurrent or refractory SCLC at the dose and schedule evaluated. The 45 mg dose was intolerable in a majority of SCLC patients.

Phase II Trial of Atezolizumab As First-Line or Subsequent Therapy for Patients With Programmed Death-Ligand 1–Selected Advanced Non–Small-Cell Lung Cancer (BIRCH)

Purpose BIRCH was designed to examine the efficacy of atezolizumab, a humanized anti-programmed death-ligand 1 (PD-L1) monoclonal antibody, in advanced non-small-cell lung cancer (NSCLC) across lines of therapy. Patients were selected on the basis of PD-L1 expression on tumor cells (TC) or tumor-infiltrating immune cells (IC). Patients and Methods Eligible patients had advanced-stage NSCLC, no CNS metastases, and zero to two or more lines of prior chemotherapy. Patients whose tumors expressed PD-L1 using the SP142 immunohistochemistry assay on ≥ 5% of TC or IC (TC2/3 or IC2/3 [TC or IC ≥ 5% PD-L1-expressing cells, respectively]) were enrolled. Atezolizumab 1,200 mg was administered intravenously every 3 weeks. Efficacy-evaluable patients (N = 659) comprised three cohorts: first line (cohort 1; n = 139); second line (cohort 2; n = 268); and third line or higher (cohort 3; n = 252). The primary end point was independent review facility-assessed objective response rate (ORR; Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1). Secondary end points included median duration of response, progression-free survival, and overall survival (OS). Results BIRCH met its primary objective of demonstrating a significant ORR versus historical controls. With a minimum of 12 months of follow-up, the independent review facility-assessed ORR was 18% to 22% for the three cohorts, and 26% to 31% for the TC3 or IC3 subgroup; most responses are ongoing. Responses occurred regardless of EGFR or KRAS mutation status. The median OS from an updated survival analysis (minimum of 20 month follow up) for cohort 1 was 23.5 months (26.9 months for TC3 or IC3 patients); the median OS in cohorts 2 and 3 was 15.5 and 13.2 months, respectively. The safety profile was similar across cohorts and consistent with previous atezolizumab monotherapy trials. Conclusion BIRCH demonstrated responses with atezolizumab monotherapy in patients with PD-L1-selected advanced NSCLC, with good tolerability. PD-L1 status may serve as a predictive biomarker for identifying patients most likely to benefit from atezolizumab.

Barriers to pain assessment and management in cancer survivorship.

IntroductionHealthcare providers frequently lack the knowledge and skills to provide optimal pain management for cancer survivors. Scientific evidence and clinical guidelines are lacking in the management of chronic, persistent pain in survivors. The purpose of this article is to describe pain-related issues of cancer survivors using case presentations of selected patients enrolled in a randomized trial to eliminate barriers to pain management.Materials and methodsCase presentations were selected from a National Cancer Institute-funded study that utilizes patient and professional educational content derived from the clinical guidelines of the National Comprehensive Cancer Network. Case presentation criteria included a pain rating of ≥6 and diagnosis of Stage I, II, or III of the following cancers: breast, colon, lung, or prostate cancer. Cases are presented based on the study’s framework of patient, professional, and system-related barriers to optimal pain relief.ResultsAcross all three case presentations, barriers such as fear of side effects from pain medications, fear of addiction, lack of professional knowledge of the basic principles of pain management, and lack of timely access to pain medications due to reimbursement issues are prevalent in cancer survivorship.ConclusionsChronic pain syndromes related to cancer treatments are common in cancer survivors. Patient, professional, and system-related barriers that are seen during active treatment continue to hinder optimal pain relief during survivorship.Implications for cancer survivorsHealthcare providers must acknowledge the impact of chronic, persistent pain on the quality of cancer survivorship. Clinical as well as scientific efforts to increase knowledge in chronic pain management will improve the symptom management of cancer survivors.