Addition of Bevacizumab to Erlotinib as First-Line Treatment of Patients With EGFR-Mutated Advanced Nonsquamous NSCLC: The BEVERLY Multicenter Randomized Phase 3 Trial.

INTRODUCTION: Adding bevacizumab to erlotinib prolonged progression-free survival (PFS) of patients with EGFR-mutated advanced NSCLC in the Japanese JO25567 trial, but limited data were available in non-Asian patients. BEVERLY is an Italian, multicenter, randomized, phase 3 investigating the addition of bevacizumab to erlotinib as first-line treatment of advanced EGFR-mutated NSCLC. METHODS: Eligible patients were randomized 1:1 to erlotinib plus bevacizumab or erlotinib alone. Investigator-assessed PFS and blinded independent centrally reviewed PFS were coprimary end points. With 80% power in detecting a 0.60 hazard ratio and two-sided α error of 0.05, 126 events of 160 patients were needed. The trial was registered as NCT02633189 and EudraCT 2015-002235-17. RESULTS: From April 11, 2016, to February 27, 2019, a total of 160 patients were randomized to erlotinib plus bevacizumab (80) or erlotinib alone (80). At a median follow-up of 36.3 months, median investigator-assessed PFS was 15.4 months (95% confidence interval [CI]: 12.2-18.6) with erlotinib plus bevacizumab and 9.6 months (95% CI: 8.2-10.6) with erlotinib alone (hazard ratio = 0.66, 95% CI: 0.47-0.92). Blinded independent centrally reviewed PFS analysis confirmed this result. A statistically significant interaction with treatment effect was found for smoking habit (p = 0.0323), with PFS prolongation being clinically significant only among current or previous smokers. Hypertension (grade ≥3: 24% versus 5%), skin rash (grade ≥ 3: 31% versus 14%), thromboembolic events (any grade: 11% versus 4%), and proteinuria (any grade: 23% versus 6%) were more frequent with the combination. CONCLUSIONS: The addition of bevacizumab to first-line erlotinib prolonged PFS in Italian patients with EGFR-mutated NSCLC; toxicity was increased with the combination but without unexpected safety issues.

Pembrolizumab for First-Line Treatment of Advanced Non-Small-Cell Lung Cancer: Analysis of Prognostic Factors of Outcomes.

BACKGROUND: In advanced non-small-cell lung cancer, without activating mutations and with PD-L1≥50%, Pembrolizumab monotherapy is the therapeutic standard in Europe. OBJECTIVE: To evaluate retrospectively the safety and efficacy of this drug and to investigate potential prognostic factors in daily clinical practice. METHODS: From September 2017 to September 2019, 205 consecutive patients from 14 Italian Medical Oncology Units were enrolled in the study. Gender, Age (> or <70 years), ECOG-PS (0-1 or 2), histology (squamous or nonsquamous), presence of brain, bone and liver metastases at baseline, PD-L1 score (>90% or <90%), smoking status (never or former or current) were applied to the stratified log-rank. Cox's proportional hazards model was used for multivariate analysis. RESULTS: At a median follow-up of 15.2 months, median progression-free and overall survival (mPFS and mOS) were 9.2 months (95% C.I., 4.8-13.5) and 15.9 months (95% C.I., not yet evaluable), respectively. Patients with Eastern Cooperative Oncology Group performance status (ECOG-PS) 2 had mPFS of 2.8 months (95% C.I., 2.1-3.4) and mOS of 3.9 months (95% C.I., 2.5-5.3). Patients with liver metastases at diagnosis had an mPFS of 3.2 months (95% C.I., 0.6-5.8) and an mOS of 6.0 months (95% C.I., 3.7-8.4). At multivariate analysis for OS gender, ECOG-PS 2, and presence of liver metastases were independent prognostic factors. CONCLUSION: Patients with ECOG-PS 2 derived little benefit from the use of first-line pembrolizumab. In patients with liver metastases, the association of pembrolizumab with platinum-based chemotherapy could be a better option than pembrolizumab alone.

Metabolomics to Assess Response to Immune Checkpoint Inhibitors in Patients with Non-Small-Cell Lung Cancer.

In the treatment of advanced non-small cell lung cancer (NSCLC), immune checkpoint inhibitors have shown remarkable results. However, not all patients with NSCLC respond to this drug treatment or receive durable benefits. Thus, patient stratification and selection, as well as the identification of predictive biomarkers, represent pivotal aspects to address. In this framework, metabolomics can be used to support the discrimination between responders and non-responders. Here, metabolomics was used to analyze the sera samples from 50 patients with NSCL treated with immune checkpoint inhibitors. All the samples were collected before the beginning of the treatment and were analyzed by NMR spectroscopy and multivariate statistical analyses. Significantly, we show that the metabolomic fingerprint of serum acts as a predictive "collective" biomarker to immune checkpoint inhibitors response, being able to predict individual therapy outcome with > 80% accuracy. Metabolomics represents a potential strategy for the real-time selection and monitoring of patients treated with immunotherapy. The prospective identification of responders and non-responders could improve NSCLC treatment and patient stratification, thus avoiding ineffective therapeutic strategies.

Incidence of T790M in Patients With NSCLC Progressed to Gefitinib, Erlotinib, and Afatinib: A Study on Circulating Cell-free DNA.

BACKGROUND: Insights into the mechanism of resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) could provide important information for further patient management, including the choice of second-line treatment. The EGFR T790M mutation is the most common mechanism of resistance to first- and second-generation EGFR TKIs. Owing to its biologic relevance in the response of non-small-cell lung cancer (NSCLC) to the selective pressure of treatment, the present study investigated whether the occurrence of T790M at progression differed among patients receiving gefitinib, erlotinib, or afatinib. PATIENTS AND METHODS: The present retrospective study included patients with NSCLC with an EGFR activating mutation, who had received gefitinib, erlotinib, or afatinib as first-line treatment. Plasma samples for the analysis of cell-free DNA were taken at disease progression and analyzed using a digital droplet polymerase chain reaction EGFR mutation assay. RESULTS: A total of 83 patients were enrolled; 42 had received gefitinib or erlotinib and 41afatinib. The patient characteristics were comparable across the 2 groups. The median time to progression (TTP) was 14.4 months for the gefitinib and erlotinib group and 10.2 months for the afatinib group (P = .09). Of the 83 patients, 47 (56.6%) were positive for the T790M in plasma. A greater incidence of T790M was observed in patients with progression during gefitinib or erlotinib therapy compared with patients treated with afatinib (33 [79%] vs. 14 [34%], respectively; odds ratio, 7.1; 95% confidence interval, 2.7-18.5; P = .0001). CONCLUSIONS: Although gefitinib, erlotinib, and afatinib showed a comparable TTP in patients receiving first-line therapy, the incidence of T790M differed among them, as demonstrated by the present study, which could have implications for the choice of second-line treatment.

Oral maintenance metronomic vinorelbine versus best supportive care in advanced non-small-cell lung cancer after platinum-based chemotherapy: The MA.NI.LA. multicenter, randomized, controlled, phase II trial.

BACKGROUND: Oral vinorelbine administered at the maximum tolerated dose has already showed activity and a good safety profile in advanced non-small-cell lung cancer (NSCLC). The MA.NI.LA study was a phase II, multicenter, randomized, controlled trial that aimed to assess the effects of a 'switched maintenance' regimen with oral metronomic vinorelbine (OMV) in patients with NSCLC who had not progressed after first-line platinum-based chemotherapy. PATIENTS AND METHODS: Patients were randomly assigned in a 1:1 ratio to either OMV (50 mg three-times weekly) as maintenance treatment or best supportive care (BSC). The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective disease control rate (DCR, CR + PR + SD), safety and quality of life. RESULTS: In total, 61 and 59 patients were assigned to OMV and BSC, respectively. At a median follow-up of 23.9 (IQR 10.2-38.2) months, patients treated with OMV reported a significantly lower progression rate compared to patient in the BSC arm (89% [54/61] vs 96% [56/58]; HR 0.73; 90% CI 0.53-0.999, p = 0.049). Median PFS for patients treated with vinorelbine was 4.3 months (95% CI 2.8-5.6) vs 2.8 months (95% CI 1.9-4.5) for patients receiving BSC. This benefit was specifically evident in patients aged ≥70 years, in current smokers, and in those who reported disease stabilization as best response to induction chemotherapy. OS and response rate and quality of life were similar in the two arms. Drop-out rate for major toxicity with OMV was unexpectedly high (25%, 14/61) mainly due to grade 3-4 neutropenia (11%, 7/61). Conclusions In patients with unselected NSCLC achieving disease control after platinum-based chemotherapy switch maintenance therapy with OMV prolonged PFS compared to BSC; however, the optimal dose of OMV requires further investigation.

Screening for Frailty in Older Patients With Early-Stage Solid Tumors: A Prospective Longitudinal Evaluation of Three Different Geriatric Tools.

BACKGROUND: Frailty increases the risk of adverse health outcomes and/or dying when exposed to a stressor, and routine frailty assessment is recommended to guide treatment decision. The Balducci frailty criteria (BFC) and Fried frailty criteria (FFC) are commonly used, but these are time consuming. Vulnerable Elders Survey-13 (VES-13) score of ≥7, a simple and resource conserving function-based scoring system, may be used instead. This prospective study evaluates the performance of VES-13 in parallel with BFC and FFC, to identify frailty in elderly patients with early-stage cancer. METHODS: Patients aged ≥70 years with early-stage solid tumors were classified as frail/nonfrail based on BFC (≥1 criteria), FFC (≥3 criteria), and VES-13 (score ≥ 7). All patients were assessed for functional decline and death. RESULTS: We evaluated 185 patients. FFC had a 17% frailty rate, whereas BFC and VES-13 both had 25%, with poor concordance seen between the three geriatric tools. FFC (hazard ratio = 1.99, p = .003) and VES-13 (hazard ratio = 2.81, p < .001) strongly discriminated for functional decline, whereas BFC (hazard ratio = 3.29, p < .001) had the highest discriminatory rate for deaths. BFC and VES-13 remained prognostic for overall survival in multivariate analysis correcting for age, tumor type, stage, and systemic treatment. CONCLUSIONS: A VES-13 score of ≥7 is a valuable discriminating tool for predicting functional decline or death and can be used as a frailty-screening tool among older cancer patients in centers with limited resources to conduct a comprehensive geriatric assessment.

Gastric cancer metastatic to the pituitary gland: a case report.

Neoplasms from almost every tissue have been reported to metastasize to the pituitary. Gastric carcinoma is a rare cause of metastases in pituitary gland. Gastric carcinoma will be the primary tumor in less than 2% of patients with pituitary gland metastases. We report the case of a 60-years old white man with liver metastasis from gastric cancer with fair presentation symptoms of pituitary gland metastasis. Basal endocrinological work-up showed corticotroph, gonadotroph, somatotroph and thyrotroph cell insufficiency; serum PRL was elevated and no deficit of the ADH level was observed. Despite the hormonal deficits the patient did not report any specific symptom. After diagnosis the patient began thyroid and adrenal-replacement therapy and was referred to Radiotherapy Unit for treatment on the sellar and pituitary gland region.

Selection of chemotherapeutic drugs in adjuvant programs based on molecular profiles: where do we stand?

Tumors have usually been classified by their morphologic appearances. Unfortunately, these current classification schemes have serious drawbacks. They are not able to stratify similar histopathological appearances that will follow significantly different clinical courses or respond differently to chemotherapy. The information that a specific molecular profile correlates with important clinical endpoints should permit physicians to take treatment decisions based on the molecular characteristics of each tumor. Lessons from the metastatic setting have been translated to the adjuvant setting, and several strategies have been evaluated in clinical trials. The expression of estrogen receptors (ER) in breast cancer enables physicians to make treatment decisions related to the use of hormonal manipulations. In this context, the challenge is to define a suitable subgroup of patients who will benefit from the addition of chemotherapy. Otherwise, the lack of ER expression predicts no benefit from hormonotherapy. In this setting chemotherapy plays a central role. The selection of the most appropriate regimen based on HER-2 status remains an uncertain strategy. However, the expression of the oncoprotein HER-2 has been linked to the probability of response to the target-designed monoclonal antibody trastuzumab. The role of trastuzumab in the adjuvant setting is supported by the early results of three large clinical trials presented at the American Society Clinical Oncology meeting in 2005. These trials have shown a striking impact of trastuzumab on the main endpoints such as disease-free survival and overall survival. In this context, the integration of trastuzumab with taxane and anthracycline-based-chemotherapy seems to be the appropriate choice. This review will combine data from breast cancer biology with clinical evidence coming from large phase III trials in the attempt to propose a molecular targeted approach to the adjuvant treatment strategy of early breast cancer patients.

Folinic acid, 5-fluorouracil and etoposide after curative resection for gastric cancer.

BACKGROUND/AIMS: The aim of this study was to evaluate the survival benefit of adjuvant chemotherapy with etoposide, leucovorin and 5-fluorouracil (ELF) in gastric cancer patients undergoing previous surgery with a curative intent. METHODOLOGY: The clinical outcome of 49 patients with resected gastric cancer treated with adjuvant chemotherapy was compared with that of 85 surgically treated historical controls who did not receive any adjuvant treatment. The chemotherapy regimen consisted of six cycles of daily 1-hour intravenous infusions of folinic acid 100 mg/m2 and 5-FU 400 mg/ m2, and a 2-hour infusion of etoposide 100 mg/m2, for three days every 28 days. RESULTS: The 5-year relapse-free survival was 32% in the adjuvant arm and 27% in the control arm (p = 0.6). At the last follow-up, there were 32 deaths in the adjuvant arm and 60 in the control arm. The median duration of survival was respectively 23 and 19 months, and the 5-year survival rates were 34% and 29% (p = 0.4). The chemotherapy was well tolerated. CONCLUSIONS: Our data suggest that ELF adjuvant treatment is a safe and well tolerable combination chemotherapy in patients with resected gastric cancer, but it does not seem to improve prognosis in comparison with historical controls.

Analysis of biochemical bone markers as prognostic factors for survival in patients with hormone-resistant prostate cancer and bone metastases.

OBJECTIVES: To investigate the prognostic value of some conventional bone markers and a number of other factors in terms of the survival of patients with hormone-resistant prostate cancer and bone metastases treated with chemotherapy. METHODS: The data of 141 patients were analyzed to verify the influence of the following factors on survival: bone-alkaline phosphatase, type I collagen propeptide, the carboxyterminal telopeptide of type I collagen, the urinary calcium/creatinine ratio, patient age, Karnofsky performance status, pathologic grade, duration of response to primary hormonal therapy, prostate-specific antigen, hemoglobin, lactate dehydrogenase, and extent of bone disease. RESULTS: When all the variables were simultaneously analyzed using the multivariate proportional hazard model, only Karnofsky performance status (P <0.005) and duration of response to primary hormonal therapy (P <0.0001) remained statistically significant. CONCLUSIONS: The results of this study suggest that bone-alkaline phosphatase, type I collagen propeptide, the carboxyterminal telopeptide of type I collagen, and the urinary calcium/creatinine ratio are not prognostic of survival in patients with hormone-resistant prostate cancer and bone metastases treated with chemotherapy.

Weekly low-dose docetaxel in advanced hormone-resistant prostate cancer patients previously exposed to chemotherapy.

OBJECTIVE: The aim of this study was to evaluate the activity and tolerability of docetaxel in patients with hormone-resistant prostate cancer previously exposed to chemotherapy. METHODS: We enrolled 27 patients with hormone-resistant prostatic cancer that had progressed during first-line chemotherapy. The primary end-point was palliative response defined as a 2-point reduction in the 6-point present pain intensity scale, and an improvement in Karnofsky performance status of one 10-point category. The treatment consisted of weekly docetaxel 25 mg/m(2) body surface area administered by means of a 1-hour intravenous infusion with corticosteroid premedication. RESULTS: The primary criterion of palliative response was met in 13 patients (48%) after eight treatment cycles; its median duration was 6 months (range 1-8). Mean global quality of life improved in 8 and 10 patients after respectively four and eight treatment cycles. After a median follow-up of 8 months, 21 patients had died: the median survival was 9+ months (range 2-18). Weekly docetaxel was very well tolerated: grade 3 neutropenia occurred in 1 patient and grade 3 anemia in 2. CONCLUSIONS: Weekly low-dose docetaxel is an effective and well-tolerated treatment for patients with hormone-resistant prostate cancer previously exposed to chemotherapy.

Weekly low-dose docetaxel in advanced non-small cell lung cancer previously treated with two chemotherapy regimens.

BACKGROUND: The role of salvage chemotherapy in advanced non-small cell lung cancer (NSCLC) is still controversial, but the recent development of a number of active antineoplastic agents has created new possibilities for disease management. The aim of this study was to evaluate the activity and safety of weekly docetaxel treatment in patients with advanced NSCLC previously treated with two chemotherapy regimens. PATIENTS AND METHODS: The study involved 26 patients with histologically documented stage IIIB, IV or recurrent metastatic NSCLC previously treated with two non-taxane based-chemotherapy regimens. They all received docetaxel 25 mg/m(2)/week administered as a 1-h infusion in an outpatient setting with corticosteroid premedication. RESULTS: Fourteen of the 26 patients (54%) had distant metastases and 12 (46%) chest-localised disease. Six patients (23%; confidence interval: 9.8-44.1%) showed a partial response, 8 (31%) stable disease, and 12 (46%) progressive disease. The median time to progression was 4 months (range 2-8), and the median survival was 7+ months (range 3-13+). There were no statistically significant differences between the global quality of life scores recorded at baseline and those recorded after subsequent cycles. The treatment was very well tolerated. CONCLUSION: The results of this study suggest that weekly low-dose docetaxel is effective, well tolerated and maintains a relatively good quality of life in patients with advanced NSCLC previously exposed to two chemotherapy regimens.

High-affinity HLA-A(*)02.01 peptides from parathyroid hormone-related protein generate in vitro and in vivo antitumor CTL response without autoimmune side effects.

Parathyroid hormone-related protein (PTH-rP), a protein produced by prostate carcinoma and other epithelial cancers, is a key agent in the development of bone metastases. We investigated whether the protein follows the self-tolerance paradigm or can be used as a target Ag for anticancer immunotherapy by investigating the immunogenicity of two HLA-A(*)02.01-binding PTH-rP-derived peptides (PTR-2 and -4) with different affinity qualities. PTH-rP peptide-specific CTL lines were generated from the PBMC of two HLA-A(*)02.01(+) healthy individuals, stimulated in vitro with PTH-rP peptide-loaded autologous dendritic cells and IL-2. The peptide-specific CTLs were able to kill PTH-rP(+)HLA-A(*)02.01(+) breast and prostate carcinoma cell lines. The two peptides were also able to elicit a strong antitumor PTH-rP-specific CTL response in HLA-A(*)02.01 (HHD) transgenic mice. The vaccinated mice did not show any sign of side effects due to cell-mediated autoimmunity or toxicity. In this study we describe two immunogenic and toxic-free PTH-rP peptides as valid candidates for the design of peptide-based vaccination strategies against prostate cancer and bone metastases from the most common epithelial malignancies.

Folinic acid, 5-fluorouracil and mitomycin C in metastatic breast cancer patients previously treated with at least two chemotherapy regimens.

PURPOSE: To assess the activity and safety of combined folinic acid (FA), 5-fluorouracil (5-FU) and mitomycin C (MMC) in metastatic breast cancer patients previously treated with at least two chemotherapy regimens. PATIENTS AND METHODS: A total of 104 consecutive patients were enrolled for treatment with FA 100 mg/m(2) plus 5-FU 400 mg/m(2) i.v. on days 1-5, and MMC 3 mg/m(2) on days 3-5 (FFM). The cycles were repeated every 21 days until progression, severe toxicity or patient refusal. RESULTS: Of the 104 patients, 96 were evaluable for response and toxicity. The overall response rate was 43% (95% confidence interval 32.8-53.2%); 40 patients achieved stable disease (42%) and 15 progressed (15%). In a retrospectively defined subgroup of patients with clinical resistance to taxanes (12 patients) or anthracyclines (14 patients), the response rate was 42%. The median time to progression was 8 months (3-18 months), and the median overall survival was 10.5+ months (2-36 months). The most common treatment-related adverse events were stomatitis, neutropenia, nausea/vomiting and diarrhea. Stomatitis, neutropenia and thrombocytopenia were the only grade 4 treatment-related adverse events, and occurred in no more than 3% of patients. CONCLUSION: The tested FFM regimen seems to offer a valid option for patients with metastatic breast cancer who have been pretreated with two or more chemotherapeutic lines or who have failed on regimens containing anthracyclines or taxanes.