Retrospective Assessment of a Serum Proteomic Test in a Phase III Study Comparing Erlotinib plus Placebo with Erlotinib plus Tivantinib (MARQUEE) in Previously Treated Patients with Advanced Non-Small Cell Lung Cancer.

BACKGROUND: The VeriStrat test provides accurate predictions of outcomes in all lines of therapy for patients with non-small cell lung cancer (NSCLC). We investigated the predictive and prognostic role of VeriStrat in patients enrolled on the MARQUEE phase III trial of tivantinib plus erlotinib (T+E) versus placebo plus erlotinib (P+E) in previously treated patients with advanced NSCLC. METHODS: Pretreatment plasma samples were available for 996 patients and were analyzed by matrix-assisted laser desorption/ionization-time of flight mass spectrometry to generate VeriStrat labels (good, VS-G, or poor, VS-P). RESULTS: Overall, no significant benefit in overall survival (OS) and progression-free survival (PFS) were observed for the addition of tivantinib to erlotinib. Regardless of treatment arm, patients who were classified as VS-G had significantly longer PFS (3.8 mo for T+E arm, 2.0 mo for P+E arm) and OS (11.6 mo for T+E, 10.2 mo for P+E arm) than patients classified as VS-P (PFS: 1.9 mo for both arms, hazard ratio [HR], 0.584; 95% confidence interval [CI], 0.468-0.733; p < .0001 for T+E, HR, 0.686; 95% CI, 0.546-0.870; p = .0015 for P+E; OS: 4.0 mo for both arms, HR, 0.333; 95% CI, 0.264-0.422; p < .0001 for T+E; HR, 0.449; 95% CI, 0.353-0.576; p < .0001 for P+E). The VS-G population had higher OS than the VS-P population within Eastern Cooperative Oncology Group (ECOG) performance score (PS) categories. VS-G patients on the T+E arm had longer PFS, but not OS, than VS-G patients on the P+E arm (p = .0108). Among EGFR mutation-positive patients, those with VS-G status had a median OS more than twice that of any other group (OS: 31.6 mo for T+E and 22.8 mo for P+E), whereas VS-P patients had similar survival rates as VS-G, EGFR-wild type patients (OS: 13.7 mo for T+E and 6.5 mo for P+E). CONCLUSION: In these analyses, VeriStrat showed a prognostic role within EGOC PS categories and regardless of treatment arm and EGFR status, suggesting that VeriStrat could be used to identify EGFR mutation-positive patients who will have a poor response to EGFR tyrosine kinase inhibitors. IMPLICATIONS FOR PRACTICE: This study suggests that VeriStrat testing could enhance the prognostic role of performance status and smoking status and replicates findings from other trials that showed that the VeriStrat test identifies EGFR mutation-positive patients likely to have a poor response to EGFR tyrosine kinase inhibitors (TKIs). Although these findings should be confirmed in other populations, VeriStrat use could be considered in EGFR mutation-positive patients as an additional prognostic tool, and these results suggest that EGFR mutation-positive patients with VeriStrat "poor" classification could benefit from other therapeutic agents given in conjunction with TKI monotherapy.

Symptomatic toxicities experienced during anticancer treatment: agreement between patient and physician reporting in three randomized trials.

PURPOSE: Information about symptomatic toxicities of anticancer treatments is not based on direct report by patients, but rather on reports by clinicians in trials. Given the potential for under-reporting, our aim was to compare reporting by patients and physicians of six toxicities (anorexia, nausea, vomiting, constipation, diarrhea, and hair loss) within three randomized trials. PATIENTS AND METHODS: In one trial, elderly patients with breast cancer received adjuvant chemotherapy; in two trials, patients with advanced non-small-cell lung cancer received first-line treatment. Toxicity was prospectively collected by investigators (graded by National Cancer Institute Common Toxicity Criteria [version 2.0] or Common Terminology Criteria for Adverse Events [version 3]). At the end of each cycle, patients completed the European Organisation for Research and Treatment of Cancer quality-of-life questionnaires, including toxicity-related symptom items. Possible answers were "not at all," "a little," "quite a bit," and "very much." Analysis was limited to the first three cycles. For each toxicity, agreement between patients and physicians and under-reporting by physicians (ie, toxicity reported by patients but not reported by physicians) were calculated. RESULTS: Overall, 1,090 patients (2,482 cycles) were included. Agreement between patients and physicians was low for all toxicities. Toxicity rates reported by physicians were always lower than those reported by patients. For patients who reported toxicity (any severity), under-reporting by physicians ranged from 40.7% to 74.4%. Examining only patients who reported "very much" toxicity, under-reporting by physicians ranged from 13.0% to 50.0%. CONCLUSION: Subjective toxicities are at high risk of under-reporting by physicians, even when prospectively collected within randomized trials. This strongly supports the incorporation of patient-reported outcomes into toxicity reporting in clinical trials.

Dacomitinib compared with placebo in pretreated patients with advanced or metastatic non-small-cell lung cancer (NCIC CTG BR.26): a double-blind, randomised, phase 3 trial.

BACKGROUND: Dacomitinib is an irreversible pan-HER tyrosine-kinase inhibitor with preclinical and clinical evidence of activity in non-small-cell lung cancer. We designed BR.26 to assess whether dacomitinib improved overall survival in heavily pretreated patients with this disease. METHODS: In this double-blind, randomised, placebo-controlled, phase 3 trial, we enrolled adults (aged ≥18 years) with advanced or metastatic non-small-cell lung cancer from 75 centres in 12 countries. Eligible patients had received up to three previous lines of chemotherapy and either gefitinib or erlotinib, and had assessable disease (RECIST 1.1) and tumour tissue samples for translational studies. Patients were stratified according to centre, performance status, tobacco use, best response to previous EGFR tyrosine-kinase inhibitor, weight loss within the previous 3 months, and ethnicity, and were then randomly allocated 2:1 to oral dacomitinib 45 mg once-daily or matched placebo centrally via a web-based system. Treatment continued until disease progression or unacceptable toxicity. The primary outcome was overall survival in the intention-to-treat population; secondary outcomes included overall survival in predefined molecular subgroups, progression-free survival, the proportion of patients who achieved an objective response, safety, and quality of life. This study is completed, although follow-up is ongoing for patients on treatment. This study is registered with ClinicalTrials.gov, number NCT01000025. FINDINGS: Between Dec 23, 2009, and June 11, 2013, we randomly assigned 480 patients to dacomitinib and 240 patients to placebo. At the final analysis (January, 2014), median follow-up was 23·4 months (IQR 15·6-29·6) for patients in the dacomitinib group and 24·4 months (11·5-38·9) for those in the placebo group. Dacomitinib did not improve overall survival compared with placebo (median 6·83 months [95% CI 6·08-7·49] for dacomitinib vs 6·31 months [5·32-7·52] for placebo; hazard ratio [HR] 1·00 [95% CI 0·83-1·21]; p=0·506). However, patients in the dacomitinib group had longer progression-free survival than those in the placebo group (median 2·66 months [1·91-3·32] vs 1·38 months [0·99-1·74], respectively; HR 0·66 [95% CI 0·55-0·79]; p<0·0001), and a significantly greater proportion of patients in the dacomitinb group achieved an objective response than in the placebo group (34 [7%] of 480 patients vs three [1%] of 240 patients, respectively; p=0·001). Compared with placebo, the effect of dacomitinib on overall survival seemed similar in patients with EGFR-mutation-positive tumours (HR 0·98, 95% CI 0·67-1·44) and EGFR wild-type tumours (0·93, 0·71-1·21; pinteraction=0·69). However, we noted qualitative differences in the effect of dacomitinib on overall survival for patients with KRAS-mutation-positive tumours (2·10, 1·05-4·22) and patients with KRAS wild-type tumours (0·79, 0·61-1·03; pinteraction=0·08). Compared with placebo, patients allocated dacomitinib had significantly longer time to deterioration of cough (p<0·0001), dyspnoea (p=0·049), and pain (p=0·041). 185 (39%) of 477 patients who received dacomitinib and 86 (36%) of 239 patients who received placebo had serious adverse events. The most common grade 3-4 adverse events were diarrhoea (59 [12%] patients on dacomitinib vs no controls), acneiform rash (48 [10%] vs one [<1%]), oral mucositis (16 [3%] vs none), and fatigue (13 [3%] vs four [2%]). INTERPRETATION: Dacomitinib did not increase overall survival and cannot be recommended for treatment of patients with advanced non-small-cell lung cancer previously treated with chemotherapy and an EGFR tyrosine-kinase inhibitor. FUNDING: Canadian Cancer Society Research Institute and Pfizer.

Nondisruptive p53 mutations are associated with shorter survival in patients with advanced non-small cell lung cancer.

PURPOSE: TP53 mutations in early-stage non-small cell lung cancer (NSCLC) may be associated with worse survival but their prognostic role in advanced NSCLC is controversial. In addition, it remains unclear whether mutated patients represent a clinically homogeneous group. EXPERIMENTAL DESIGN: We retrospectively examined TP53 mutations and outcome in a training cohort of 318 patients with stage IIIB-IV NSCLC: 125 epidermal growth factor receptor (EGFR) wild-type (wt) and 193 EGFR mutated (mut). An independent validation cohort of 64 EGFR-mut patients was subsequently analyzed. Mutations were classified as "disruptive" and "nondisruptive" according to their predicted degree of disturbance of the p53 protein structure and function. RESULTS: In the training cohort, TP53 mutations were found in 43 of the 125 EGFR-wt patients (34.4%). Of these, 28 had nondisruptive TP53 mutations and a median overall survival (OS) of 8.5 months, compared with 15.6 months for the remaining 97 patients (P=0.003). In the EGFR-mut group, TP53 mutations were found in 50 of the 193 patients (25.9%). The OS for the 26 patients with TP53 nondisruptive mutations was 17.8 months versus 28.4 months for the remaining 167 patients (P=0.04). In the validation cohort, the 11 patients with nondisruptive TP53 mutations had a median OS of 18.1 months compared with 37.8 months for the 53 remaining patients (P=0.006). In multivariate analyses, nondisruptive TP53 mutations had an independent, significant association with a shorter OS. CONCLUSIONS: Nondisruptive mutations in the TP53 gene are an independent prognostic factor of shorter survival in advanced NSCLC.

Rationale and design of MILES-3 and MILES-4 studies: two randomized phase 3 trials comparing single-agent chemotherapy versus cisplatin-based doublets in elderly patients with advanced non--small-cell lung cancer.

BACKGROUND: Platinum-based chemotherapy is the cornerstone of treatment of advanced non-small-cell lung cancer (NSCLC) patients, but the efficacy of adding cisplatin to single-agent chemotherapy remains to be demonstrated in prospective phase III trials dedicated to elderly patients. Furthermore, the superiority of cisplatin/pemetrexed over cisplatin/gemcitabine in non-squamous NSCLC has not been confirmed prospectively. We present the rationale and design of two open-label, multicenter, randomized phase III trials for elderly patients with advanced NSCLC∶ Multicenter Italian Lung cancer in the Elderly Study (MILES)-3 and MILES-4. The aim is to evaluate the efficacy of adding cisplatin to single-agent chemotherapy (both trials) and the efficacy of pemetrexed versus gemcitabine in non-squamous tumors (MILES-4). PATIENTS AND METHODS: Both trials are dedicated to first-line therapy of patients older than 70 years with advanced NSCLC, ECOG performance status 0-1. In the MILES-3 trial, patients are randomized in a 1∶1 ratio to gemcitabine or cisplatin/gemcitabine. In the MILES-4 study patients with non-squamous histology are randomized, in a factorial design with 1∶1∶1∶1 ratio, to four arms: gemcitabine (A), cisplatin/gemcitabine (B), pemetrexed (C), cisplatin/pemetrexed (D). Two comparisons are planned∶ A+C vs B+D to test the role of cisplatin; A+B vs C+D to test the role of pemetrexed. Primary endpoint of both trials is overall survival. Secondary and exploratory endpoints include progression-free survival, response rate, toxicity, and quality of life. CONCLUSIONS: MILES-3 and MILES-4 results will add important evidence about the role of cisplatin-based doublets and pemetrexed in the first-line therapy of elderly patients with advanced NSCLC.

Changes in pulmonary function tests predict radiological response to chemotherapy in malignant pleural mesothelioma.

OBJECTIVES: Response to chemotherapy in malignant pleural mesothelioma (MPM) is usually evaluated by radiological criteria, but no common agreement exists on their validity, yet. The cytoreductive effect of chemotherapy on pleural thickening may make the lung more expansible, reducing the restrictive ventilatory impairment. The aim of this study was to evaluate the changes in pulmonary function following chemotherapy in patients with MPM and to correlate these findings with radiological changes. METHODS: Between 2004 and 2011, 62 consecutive patients (74% males, median age 63 years) were prospectively investigated. Modified RECIST criteria were used for radiological evaluation of response to chemotherapy. All patients underwent pulmonary function tests before and after three cycles of platinum-based chemotherapy. Changes between baseline and post-chemotherapy pulmonary function values (Δ) and their differences were assessed by means of Student's paired and unpaired t-test, respectively. Receiver operating characteristic (ROC) curve analysis was performed on spirometric parameters significantly associated with response. RESULTS: Thirty (48.4%) patients had a radiological stable disease (S), 23 (37.1%) a partial response (R) and 9 (14.5%) a progressive disease (P). ΔFEV1%pred (R: 18.1 ± 18.5%; S: 0.5 ± 9.3%; P: -11 ± 13.5%; P < 0.0001), ΔFVC%pred (R: 16.1 ± 11.8%; S: 0.4 ± 11.2%; P: -9.2 ± 14.6%; P < 0.0001) and ΔVC%pred (R: 12.9 ± 15.7%; S: 1.5 ± 12.1%; P: -6.1 ± 13.2%; P = 0.001) were significantly associated with radiological response. A significant correlation was observed between ΔFEV1%pred (r = 0.46, P = 0.01), ΔFVC%pred (r = 0.43, P = 0.02) and % change in linear tumour measurement. ROC curve analysis using dichotomized radiological response (P/S vs R) as classification variables showed AUC = 0.88 (95%CI: 0.77-0.95) for ΔFEV1%pred (optimal cut-off value: +7%, sensitivity: 83%, specificity: 82%, PPV: 73%, NPV: 89%) and AUC = 0.86 (95%CI: 0.75-0.94) for ΔFVC%pred (optimal cut-off value: +6%, sensitivity: 82%, specificity: 74%, PPV: 64%, NPV: 88%). CONCLUSIONS: Dynamic lung volumes and radiological changes after chemotherapy seem directly related. Lung function changes could be an additional tool to better evaluate the response to chemotherapy in MPM.

Second and third line treatment in advanced non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related deaths worldwide. About 50% of the patients present locally advanced or metastatic disease at the time of diagnosis. First line therapy usually consists of a combination of cisplatin or carboplatin with a third-generation agent (paclitaxel, docetaxel, gemcitabine, or vinorelbine) that results in less than 5% 5-year survival (Goldstraw et al., 2007). Recently a different approach based on histological subtype has been introduced in the first line treatment of NSCLC: in the non-squamous histotypes, cisplatin plus pemetrexed, compared to the cisplatin plus gemcitabine combination, showed a better outcome, leading to its introduction in the first line treatment setting. In recent years advances in the second and third line treatments have led to a prognostic improvement. Two cytotoxic agents, docetaxel and pemetrexed, are approved as NSCLC second line treatment, and a new class of drugs against specific molecular targets -- tyrosine Kinase inhibitors (TKI) -- has emerged as an alternative to conventional treatment. Many trials are ongoing to assess the activity of new drugs, alone or in combination with other agents, or new combinations of third-generation chemotherapeutic agents.

Phase II study of pemetrexed plus carboplatin in malignant pleural mesothelioma.

PURPOSE: This multicenter, phase II clinical study was conducted to evaluate the activity of the combination of pemetrexed and carboplatin in patients with malignant pleural mesothelioma (MPM). PATIENTS AND METHODS: Chemotherapy-naive patients with measurable disease and adequate organ function, who were not eligible for curative surgery, received pemetrexed 500 mg/m2 and carboplatin area under the plasma concentration-time curve of 5 mg/mL/min, administered intravenously every 21 days. All patients received folic acid and vitamin B12 supplementation. Pemetrexed was provided within the Expanded Access Program. RESULTS: A total of 102 patients were enrolled. An objective response was achieved in 19 patients (two complete and 17 partial responses), for a response rate of 18.6% (95% CI, 11.6% to 27.5%). Forty-eight patients (47.0%; 95% CI, 37.1% to 57.2%) had stable disease after treatment. Overall, 67 patients (65.7%) achieved disease control (95% CI, 55.6% to 74.8%). Median time to progression was 6.5 months; median overall survival time was 12.7 months. Compliance to treatment was excellent, with a relative dose-intensity of 97% for pemetrexed and 98% for carboplatin. Toxicity was mild, with grade 3 or 4 neutropenia occurring in 9.7% of total cycles and grade 3 or 4 anemia occurring in 3.5% of total cycles. Nonhematologic toxicity was negligible. CONCLUSION: Treatment with pemetrexed and carboplatin was active and well tolerated in patients with MPM. Disease control rate, time to disease progression, and overall survival were similar to the results achieved with the standard regimen of pemetrexed and cisplatin, suggesting that the carboplatin combination could be an alternative option for these patients.

Stanford V regimen plus consolidative radiotherapy is an effective therapeutic program for bulky or advanced-stage Hodgkin's disease.

Since September 1996, 48 untreated patients with bulky or advanced-stage Hodgkin's disease received the 12-week Stanford V chemotherapy regimen followed by consolidation radiotherapy at a dose of 36 Gy to bulky mediastinal disease and 30.6 Gy to the initial sites of disease > or =3 cm in transverse diameter. After the combined therapy, 46 of 48 (96%) achieved complete remissions. With a median follow-up of 48 months, the 5-year overall survival was 95% and freedom from progression 86%. There were no treatment-related deaths. All but one premenopausal female patient (who received pelvic and inguinal irradiation) recovered normal menses. Until now no case of secondary leukemia or myelodysplasia was observed. Our results confirm that the Stanford V regimen with consolidation radiotherapy is safe and effective in patients with bulky or advanced-stage Hodgkin's disease, achieving very high remission and overall 5-year survival rates. Longer follow-up is necessary to evaluate the extent of all complications.

Gemcitabine combined with carboplatin in patients with malignant pleural mesothelioma: a multicentric phase II study.

BACKGROUND: Malignant pleural mesothelioma (MPM) is increasing rapidly worldwide. Currently, pemetrexed plus cisplatin chemotherapy showed a survival advantage versus cisplatin alone. No impact on patient survival of surgery, radiotherapy, or their combination has been demonstrated. METHODS: Eight centers in northeastern Italy participated in a Phase II multicenter study. Chemotherapy was comprised of carboplatin area under the concentration-time curve 5 on Day 1 and gemcitabine 1000 mg/m(2) on Days 1, 8, and 15. This cycle was repeated every 4 weeks. RESULTS: Between July 1996 and September 2000, 50 patients were treated. Of the sample, 68% were males, 88% had a Eastern Cooperative Oncology Group performance status score of 0-1, 56% had Stage I-II disease, 68% had epithelioid histology, and 62% had no previous treatments. The delivered dose intensity of gemcitabine was 617 mg/m(2) per week, which was 82% of the planned dose (750 mg/m(2) per week). For carboplatin, the delivered dose intensity was 80 mg/m(2) per week. Overall, 44% of 15th day doses were omitted or reduced. Twenty-six percent of the patients had partial responses (95% confidence interval: 15-40%) and 24% had disease progression. None of the patients had complete responses. The median response duration was 55 weeks (range, 13-113 weeks). Patients had good clinical benefit. For example, 46% had improved dyspnea, 40% improved in weight, and 26% experienced pain reduction. Patients developed Grade 3-4 leukopenia during 18 cycles (11%) of chemotherapy. Grade 3-4 thrombocytopenia occurred more frequently, i.e., there were 24 episodes (15%) among 17 patients. Grade 3 anemia developed among patients during eight cycles (5%). None of the patients developed Grade 3-4 nonhematologic toxicity. The median survival of this sample of patients was 66 weeks with 53%, 30%, and 20% of patients alive at 1, 2, and 3 years, respectively. The median progression-free survival period was 40 weeks. CONCLUSIONS: The gemcitabine/carboplatin combination is a valid option in the treatment of MPM due to its acceptable toxicity profile, the good response rate, and the clinical benefit to patients. Minor adjustments in schedule (3-week cycles instead of 4-week cycles) would permit a more optimal treatment administration.