Multicenter Real-World Study on Effectiveness and Early Discontinuation Predictors in Patients With Non-small Cell Lung Cancer Receiving Nivolumab.

BACKGROUND: Real-world (RW) evidence on nivolumab in pretreated patients with non-small cell lung cancer (NSCLC) by matching data from administrative health flows (AHFs) and clinical records (CRs) may close the gap between pivotal trials and clinical practice. METHODS: This multicenter RW study aims at investigating median time to treatment discontinuation (mTTD), overall survival (mOS) of nivolumab in pretreated patients with NSCLC both from AHF and CR; clinical-pathological features predictive of early treatment discontinuation (etd), budget impact (BI), and cost-effectiveness analysis were investigated; mOS in patients receiving nivolumab and docetaxel was assessed. RESULTS: Overall, 237 patients with NSCLC treated with nivolumab were identified from AHFs; mTTD and mOS were 4.2 and 9.8 months, respectively; 141 (59%) received at least 6 treatment cycles, 96 (41%) received < 6 (etd). Median overall survival in patients with and without etd were 3.3 and 19.6 months, respectively (P < .0001). Higher number, longer duration, and higher cost of hospitalizations were observed in etd cases. Clinical records were available for 162 patients treated with nivolumab (cohort 1) and 83 with docetaxel (cohort 2). Median time to treatment discontinuation was 4.8 and 2.6 months, respectively (P < .0001); risk of death was significantly higher in cohort 2 or cohort 1 with etd compared with cohort 1 without etd (P < .0001). Predictors of etd were body mass index <25, Eastern Cooperative Oncology Group performance status >1, neutrophile-to-lymphocyte ratio >2.91, and concomitant treatment with antibiotics and glucocorticoids. The incremental cost-effectiveness ratio of nivolumab was 3323.64 euros ($3757.37) in all patients and 2805.75 euros ($3171.47) for patients without etd. Finally, the BI gap (real-theoretical) was 857 188 euros ($969 050.18). CONCLUSION: We defined predictors and prognostic-economic impact of nivolumab in etd patients.

Combi-TED: a new trial testing Tedopi® with docetaxel or nivolumab in metastatic non-small-cell lung cancer progressing after first line.

Despite the positive results obtained by first-line chemoimmunotherapy in patients with metastatic non-small-cell lung cancer (NSCLC), only a few second-line options are available after disease progression. Combi-TED is a phase II international study that will assess the efficacy of Tedopi®, a cancer vaccine, combined with either docetaxel or nivolumab and compared with docetaxel monotherapy in patients with metastatic NSCLC after chemoimmunotherapy. The study, currently in the recruitment phase, will assess 1-year overall survival (primary end point), patient's progression-free survival and overall response rate, as well as the correlation of efficacy with several tumor or blood biomarkers. The results will hopefully provide more information on Tedopi combinational treatment compared with current standard of care in NSCLC patients who fail first-line chemoimmunotherapy. Clinical Trial Registration: NCT04884282 (ClinicalTrials.gov).

Patients with lung cancer that has spread to other parts of the body are usually treated with a combination of chemotherapy and drugs that stimulate the immune system to kill cancer cells, which is referred to as immunotherapy. If after receiving these drugs the cancer still gets worse, patients have only a few treatment options left and are usually treated with chemotherapy only. Researchers will study if a new medicine called Tedopi^®, a vaccine that specifically attacks cancer cells, used together with chemotherapy or immunotherapy, will work better then chemotherapy alone for these patients. The study will monitor how long patients will live after treatment, for how long they will live without their disease getting worse and how many patients will improve after treatment. Moreover, researchers will study if patients present specific features, such as certain molecules in their tumor cells or blood cells, that may indicate that they respond better to certain treatments.

A phase II, open-label, single-arm trial of carboplatin plus etoposide with bevacizumab and atezolizumab in patients with extended-stage small-cell lung cancer (CeLEBrATE study): background, design and rationale.

Based on improved survival from the addition of PD-L1 inhibitors in phase III trials, the combination of immunotherapy and platinum-doublet chemotherapy has become the new standard treatment for extended-stage small-cell lung cancer (ES-SCLC). Furthermore, the antiangiogenetic agent bevacizumab showed a longer progression-free survival by targeting VEGF that has pleiotropic effects, including immunosuppressive ones. We, therefore, hypothesized that targeting angiogenesis would improve the efficacy of chemoimmunotherapy. The CeLEBrATE trial is an open-label, multicenter, phase II study designed to assess the efficacy and safety of the combination of carboplatin and etoposide plus bevacizumab and atezolizumab in treatment-naive patients with ES-SCLC. The primary end point is overall survival rate at 1 year, while secondary end points include overall response rate, progression-free survival and toxicity.

Lay abstract Extended-stage small-cell lung cancer (ES-SCLC) is a highly aggressive lung cancer subtype, accounting for 13­15% of all lung cancers. For several years, the standard treatment for this disease was based on polychemotherapy, with a rapid disease response but with an equally rapid disease progression. The new standard treatment has recently been changed, based on the results of two large clinical trials, which showed the efficacy and safety of the combination of chemotherapy with immunotherapy compared to chemotherapy alone. Nevertheless, prognosis of ES-SCLC remains poor, and new treatment strategies are urgently needed. Therefore, we designed the CeLEBrATE trial to investigate whether the combination of chemotherapy with antiangiogenetic therapy and immunotherapy is safe and could improve survival in patients with ES-SCLC.

The cost-effectiveness of new first-line therapies approved in advanced hepatocellular carcinoma.

The introduction of targeted agents (lenvatinib) and immune-based therapies (atezolizumab in combination with bevacizumab) for first-line advanced hepatocellular carcinoma provided new therapeutic options. The aim of this paper was to assess the cost-effectiveness of lenvatinib and the combination of atezolizumab plus bevacizumab in first-line for advanced hepatocellular carcinoma. Pivotal phase III randomized controlled trials were considered. Incremental cost-effectiveness ratio was calculated as the ratio between the difference of the costs in the intervention and in the control groups (pharmacy costs) and the difference between the effect in the intervention and in the control groups (progression free survival). One thousand four hundred and fifty five patients were included. The lowest cost for month of progression free survival-gain was associated with lenvatinib, with 139.24 € per month progression free survival-gained. Combining pharmacological costs of drugs with the measure of efficacy represented by progression free survival, lenvatinib is a cost-effective treatment in first-line for advanced hepatocellular carcinoma.

Cost-effectiveness of encorafenib plus cetuximab in BRAF V600E-mutated colorectal cancer.

Recently, the introduction of encorafenib in combination with cetuximab was considered as a practice changing in BRAFV600-mutated metastatic colorectal cancer. The aim of this paper was to assess the cost-effectiveness of encorafenib plus cetuximab in the second-line treatment of BRAFV600-mutated metastatic colorectal cancer. BEACON CRC Trail was considered. Incremental cost-effectiveness ratio was calculated as the ratio between the difference of the costs in the intervention and in the control groups (pharmacy costs) and the difference between the effect in the intervention and in the control groups (overall survival). Four hundred forty-one patients were included. Differences in costs between the two arms (encorafenib plus cetuximab vs FOLFIRI plus cetuximab) was 59 501 €, with a cost of 17 500 € per month of overall survival-gain. Combining pharmacological costs of drugs with the measure of efficacy represented by overall survival, at the actual prize encorafenib cannot be considered cost-effectiveness for second-line treatment of BRAFV600-mutated metastatic colorectal cancer.

Is lung ultrasound score a useful tool to monitoring and handling moderate and severe COVID-19 patients in the general ward? An observational pilot study.

Lung ultrasound is a well-established diagnostic tool in acute respiratory failure, and it has been shown to be particularly suited for the management of COVID-19-associated respiratory failure. We present exploratory analyses on the diagnostic and prognostic performance of lung ultrasound score (LUS) in general ward patients with moderate-to-severe COVID-19 pneumonia receiving O2 supplementation and/or noninvasive ventilation. From March 10 through May 1, 2020, 103 lung ultrasound exams were performed by our Forward Intensive Care Team (FICT) on 26 patients (18 males and 8 females), aged 62 (54 - 76) and with a Body Mass Index (BMI) of 30.9 (28.7 - 31.5), a median 6 (5 - 9) days after admission to the COVID-19 medical unit of the University Hospital of Parma, Italy. All patients underwent chest computed tomography (CT) the day of admission. The initial LUS was 16 (11 - 21), which did not significantly correlate with initial CT scans, probably due to rapid progression of the disease and time between CT scan on admission and first FICT evaluation; conversely, LUS was significantly correlated with PaO2/FiO2 ratio throughout patient follow-up [R = - 4.82 (- 6.84 to - 2.80; p < 0.001)]. The area under the receiving operating characteristics curve of LUS for the diagnosis of moderate-severe disease (PaO2/FiO2 ratio ≤ 200 mmHg) was 0.73, with an optimal cutoff value of 11 (positive predictive value: 0.98; negative predictive value: 0.29). Patients who eventually needed invasive ventilation and/or died during admission had significantly higher LUS throughout their stay.

The cost-effectiveness of atezolizumab in first-line for metastatic triple negative breast cancer is heavily linked to PD-L1 level.

The present analysis was conducted to assess the pharmacological costs of atezolizumab as first-line treatment in triple negative metastatic breast cancer (mBC). Pivotal phase III randomized controlled trial (RCT) was considered. Nine hundred and two patients were included. Differences in costs between the 2 arms (atezolizumab plus nabpaclitaxel versus placebo plus nab-paclitaxel) was 17 398 €, with a cost of 7564 €per month of OS-gain in the overall population and 2485 €per month of OS-gain in PD-L1-positive (≥1) population. Combining pharmacological costs of drugs with the measure of efficacy represented by the OS, atezolizumab could be considered cost-effective in first-line treatment for triple-negative mBC only in PD-L1-positive population, but a reduction of costs is mandatory.

The role of fentanyl in the treatment of breakthrough cancer pain: Different biotechnologies, different results and different drug costs.

The aim of this paper was to assess the drug costs of the different biotechnologies (intranasal fentanyl spray (INFS), oral transmucosal fentanyl citrate (OTFC) and fentanyl buccal tablet (FBT)) in the treatment of breakthrough cancer pain (BTCP). We have calculated the mean drug costs (expressed in euros (€)) for patients treated for BTCP. INFS resulted the less expensive towards OTFC and FBT, with 697 440 €versus (vs.) 809 552 €vs. 779 662 €every 100 patients treated for BTCP, respectively. In conclusion, combining drug costs of different biotechnologies (INFS, OTFC and FBT) with the measure of efficacy represented by the reduction of BTCP avoided (incremental cost-effectiveness ratio, ICER), INFS resulted in better cost-effectiveness.

Dose-escalation strategy in refractory metastatic colorectal cancer: A change in terms of cost-effectiveness.

The analysis was conducted to assess the pharmacological costs of regorafenib and trifluridine/tipiracil in the treatment of refractory metastatic colorectal cancer (mCRC). Pivotal phase III randomized controlled trials (RCTs) of regorafenib and trifluridine/tipiracil in the treatment of refractory mCRC were considered. We have also considered the ReDOS trial, in order to verify if the dose-escalation strategy (practice changing for regorafenib) could influences the results. Differences in OS (expressed in months) between the different arms were calculated and compared with the pharmacological costs (at the Pharmacy of our Hospital and expressed in euros (€)) needed to get one month of OS. Trifluridine/tipiracil resulted the less expensive, with 1167.50 €per month OS-gained. The ReDOS trial further reduce costs with 510.41 €per month OS-gained in favour of regorafenib with the escalation-dose strategy. Both regorafenib and trifluridine/tipiracil can be considered economically sustainable treatments for refractory mCRC, apparently with a lower cost of trifluridine/tipiracil. The adoption of a dose-escalation strategy (ReDOS trial) could reverse the situation making regorafenib more cost-effective than trifluridine/tipiracil.

Cost-effectiveness of newer regimens for the prophylaxis of chemotherapy-induced nausea and vomiting: review of the literature and real-world data.

PURPOSE OF REVIEW: To investigate the cost of netupitant and palonosetron (NEPA) in the prophylaxis of chemotherapy-induced nausea and vomiting (CINV) in adults receiving highly emetogenic chemotherapy (HEC) and moderately emetogenic chemotherapy (MEC) for cancer treatment in real life. RECENT FINDINGS: A retrospective analysis of all consecutives patients with advanced lung cancer treated in platinum-based (carboplatin or cisplatin) chemotherapy and with breast cancer treated with anthracycline and cyclophosphamide -based chemotherapy at our Medical Oncology Unit during 4 years was performed. The costs of drugs are at the Pharmacy of our Hospital (&OV0556;). SUMMARY: We evaluated 110 patients with lung cancer and 55 patients with breast cancer. Concerning lung cancer, we have obtained an advantage of 133 &OV0556; in monthly medical costs of NEPA and dexamethasone (DEX) vs. the combination of palonosetron (PALO) and DEX for each patient. Concerning breast cancer, we have obtained an advantage of 78 &OV0556; in monthly medical costs of NEPA and DEX vs. the combination of PALO and DEX for each patient. Combining the medical costs of antiemetic therapy with the measure of efficacy represented by the complete response, the combination of NEPA and DEX is cost-effective for preventing CINV in HEC and MEC cancer treatment.

The introduction of a third CDK4/6 inhibitor does not change the cost-effectiveness profile in first and subsequent-lines after progression or relapse during previous endocrine therapy in patients with hormone receptor positive (HR+)/human epidermal receptor-2 negative (HER-2) advanced or metastatic breast cancer.

The aim of this study was to assess the pharmacological costs of CDK4/6-inhibitors (palbociclib, ribociclib and abemaciclib) in hormone receptor positive (HR+)/human epidermal receptor 2-negative (HER2-) advanced or metastatic breast cancer (BC). We have considered pivotal phase III randomized controlled trials (RCTs) of palbociclib, ribociclib and abemaciclib for the treatment of postmenopausal women with HR+/HER2- advanced or metastatic BC in first-line in association with letrozole or anastrozole (scenario 1) and in subsequent-lines after progression or relapse during previous endocrine therapy (scenario 2).The costs of drugs are at the Pharmacy of our Hospital and are expressed in euros (€). Six phase III RCTs, including 3843 patients, were considered. In the scenario 1, abemaciclib resulted the less expensive at the full dose, with 2246 € per month of progression free survival (PFS)-gained. Overall ribociclib resulted the less expensive considering the reduction in dosage (36.1% in MONALEESA-2 trial versus (vs). 36.0% of palbociclib in PALOMA-2 trial vs. 43.4% of abemaciclib in MONARCH-3 trial). The price was the same for palbociclib and abemaciclib both at full and with dose reduction. In the scenario 2, the situation was similar to the scenario 1, but with lowest costs for ribociclib per month PFS-gained both at full dose (2070 €) and at dose reduction (1391 € and 690 € at 400 mg and 200 mg, respectively). Combining pharmacological costs of drugs with the measure of efficacy represented by the PFS, ribociclib was the less expensive in both scenarios.

From Diagnostic-Therapeutic Pathways to Real-World Data: A Multicenter Prospective Study on Upfront Treatment for EGFR-Positive Non-Small Cell Lung Cancer (MOST Study).

INTRODUCTION: Gefitinib, erlotinib, and afatinib represent the approved first-line options for epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC). Because pivotal trials frequently lack external validity, real-world data may help to depict the diagnostic-therapeutic pathway and treatment outcome in clinical practice. METHODS: MOST is a multicenter observational study promoted by the Veneto Oncology Network, aiming at monitoring the diagnostic-therapeutic pathway of patients with nonsquamous EGFR-mutant NSCLC. We reported treatment outcome in terms of median time to treatment failure (mTTF) and assessed the impact of each agent on the expense of the regional health system, comparing it with a prediction based on the pivotal trials. RESULTS: An EGFR mutation test was performed in 447 enrolled patients, of whom 124 had EGFR mutation and who received gefitinib (n = 69, 55%), erlotinib (n = 33, 27%), or afatinib (n = 22, 18%) as first-line treatment. Because erlotinib was administered within a clinical trial to 15 patients, final analysis was limited to 109 patients. mTTF was 15.3 months, regardless of the type of tyrosine kinase inhibitor (TKI) used. In the MOST study, the budget impact analysis showed a total expense of €3,238,602.17, whereas the cost estimation according to median progression-free survival from pivotal phase III trials was €1,813,557.88. CONCLUSION: Good regional adherence and compliance to the diagnostic-therapeutic pathway defined for patients with nonsquamous NSCLC was shown. mTTF did not significantly differ among the three targeted TKIs. Our budget impact analysis suggests the potential application of real-world data in the process of drug price negotiation. IMPLICATIONS FOR PRACTICE: The MOST study is a real-world data collection reporting a multicenter adherence and compliance to diagnostic-therapeutic pathways defined for patients with epidermal growth factor receptor-mutant non-small cell lung cancer. This represents an essential element of evidence-based medicine, providing information on patients and situations that may be challenging to assess using only data from randomized controlled trials, e.g., turn-around time of diagnostic tests, treatment compliance and persistence, guideline adherence, challenging-to-treat populations, drug safety, comparative effectiveness, and cost effectiveness. This study may be of interest to various stakeholders (patients, clinicians, and payers), providing a meaningful picture of the value of a given therapy in routine clinical practice.

Assessment of Ramucirumab plus paclitaxel as switch maintenance versus continuation of first-line chemotherapy in patients with advanced HER-2 negative gastric or gastroesophageal junction cancers: the ARMANI phase III trial.

BACKGROUND: Platinum/fluoropyrimidine regimens are the backbone of first-line chemotherapy for advanced gastric cancer (AGC). However response rates to first line chemotherapy range from 30 to 50% and disease progression occurs after 4-6 cycles. The optimal duration of first-line therapy is still unknown and its continuation until disease progression represents the standard. However this strategy is often associated with cumulative toxicity and rapid development of drug resistance. Moreover, only about 40% of AGC pts. are eligible for second-line treatment. METHODS: This is a randomized, open-label, multicenter phase III trial. It aims at assessing whether switch maintenance to ramucirumab plus paclitaxel will extend the progression-free survival (PFS) of subjects with HER-2 negative AGC who have not progressed after 3 months of a first-line with a platinum/fluoropyrimidine regimen (either FOLFOX4, mFOLFOX6 or XELOX). The primary endpoint is to compare Progression-Free Survival (PFS) of patients in ARM A (switch maintenance to ramucirumab and placlitaxel) versus ARM B (continuation of the same first-line therapy with oxaliplatin/fluoropyrimidine). Secondary endpoints are: overall survival, time-to-treatment failure, overall response rate, duration of response, percentage of patients that will receive a second line therapy according to arm treatment, safety, quality of life. Exploratory studies including Next-Generation Sequencing (NGS) in archival tumor tissues are planned in order to identify potential biomarkers of primary resistance and prognosis. DISCUSSION: The ARMANI study estimates if patients treated with early swich with ramucirumab plus paclitaxel received benefit when compared to those treated with continuation of first line therapy. The hypothesis is that the early administration of an active, non-cross resistant second-line regimen such as ramucirumab plus paclitaxel may prolong the time in which patients are progression-free, and consequently have a better quality of life. Moreover, this strategy may rescue all those subjects that become ineligible for second-line therapy due to the rapid deterioration of health status after the first disease progression. TRIAL REGISTRATION: ARMANI is registered at ClinicalTrials.gov ( NCT02934464 , October 17, 2016) and EudraCT(2016-001783-12, April 202,016).

FOLFIRINOX is a cost-effective combination chemotherapy in first-line for advanced pancreatic Cancer.

OBJECTIVES: The analysis was conducted to assess the effect of front-line combination chemotherapies on progression free survival (PFS). METHODS: The analysis was restricted to phase III randomized controlled trials (RCTs) in first-line therapy for advanced pancreatic cancer. The European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS) was applied to the above phase III RCTs. We have also calculated differences in PFS between the different arms of each trial and the pharmacological costs necessary to get the benefit in PFS, for each trial. RESULTS: Our study evaluated 11 phase III randomized controlled trials (RCTs), including 4572 patients. Combining the costs of therapy with the measure of efficacy represented by the PFS, we have obtained 74.12 € per month of PFS gained for 5-FU, leucovorin, irinotecan and oxaliplatin (FOLFIRINOX), 90.14 per month of PFS gained for gemcitabine and oxaliplatin (GEMOX) and 4708.70 € per month of PFS gained for the combination of gemcitabine plus nab-pacliatxel against gemcitabine alone. CONCLUSIONS: Combining pharmacological costs with the measure of efficacy represented by PFS, FOLFIRINOX is a cost-effective first-line for advanced pancreatic cancer.

First-line therapies in metastatic colorectal cancer: integrating clinical benefit with the costs of drugs.

PURPOSE: In light of the relevant expenses of pharmacological interventions, it might be interesting to make a balance between the cost of the new drugs administered and the added value represented by the improvement in progression free survival (PFS) in first-line for metastatic colorectal cancer CRC (mCRC). METHODS: Phase III randomized controlled trials (RCTs) that compared at least two first-line chemotherapy regimens for mCRC patients were evaluated. Differences in PFS between the different arms were compared with the pharmacological costs (at the pharmacy of our hospital). The European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS) was applied to the above RCTs. RESULTS: Overall 28 phase III RCTs, including 19,958 patients, were analyzed. The FOLFOX resulted the least expensive (56 € per month of PFS gained) while the addition of irinotecan to FOLFOX (FOLFOXIRI) increased only marginally the costs (90 € per month of PFS gained). Treatments including the monoclonal antibodies showed a cost per month of PFS gained of 2823 € (FOLFIRI with cetuximab in KRAS wild-type patients and liver-only metastases), of € 15,822 (FOLFOX with panitumumab in KRAS wild type), and of 13,383 € (FOLFOX with bevacizumab). According to the ESMO-MCBS, the treatments including an EGFR-inhibitor (cetuximab or panitumumab) were associated with a score of 4, while the inclusion of bevacizumab reached a score of 3. CONCLUSIONS: Our data demonstrate a huge difference in cost per month of PFS gained in modern first-line treatments in mCRC.

Anti-angiogenic agents in second-line treatment for metastatic colorectal cancer: the optimization of pharmacological costs.

PURPOSE: In western Countries, colorectal cancer (CRC) is the second most common cause of death from cancer. In particular, the introduction of active new anti-angiogenic agents for the second-line treatment of metastatic CRC (mCRC) is associated with a relevant increase of costs, and it is therefore important to make a balance between the costs of treatment and the added value represented by the improvement of the clinical parameters of interest such as progression-free survival (PFS). METHODS: The analysis was conducted to assess the effect of second-line therapy with anti-angiogenic agents on the PFS and was restricted to pivotal phase III randomized controlled trials (RCTs). RESULTS: The present analysis evaluated four phase III RCTs, including 3938 patients. Dividing the costs of therapy by the measure of efficacy represented by PFS, we found out that the lowest cost per month of PFS gained (4581 €) was associated with the use of FOLFIRI plus aflibercept. CONCLUSIONS: Combining pharmacological costs of drugs with the measure of efficacy represented by the PFS, aflibercept in combination with FOLFIRI is a cost-effective second-line treatment for patients with mCRC.

Serum LDH predicts benefit from bevacizumab beyond progression in metastatic colorectal cancer.

BACKGROUND: Different antiangiogenics are currently indicated in the second-line treatment of metastatic colorectal cancer (mCRC), following a first-line bevacizumab-containing treatment. The magnitude of benefit is limited, but no predictors of benefit have been identified. METHODS: A total of 184 mCRC patients progressing to a first-line bevacizumab-containing treatment were randomised in the BEBYP study to continue or not the antiangiogenic in combination with a second-line chemotherapy. A subgroup analysis according to baseline serum lactate dehydrogenase (LDH) levels was carried out. RESULTS: A significant interaction effect between LDH levels and treatment was found in terms of progression-free survival (PFS; P=0.002). Although patients with low LDH levels achieved significant PFS benefit from the continuation of bevacizumab (HR: 0.39 (95% CI: 0.23-0.65)), patients with high levels did not (HR: 1.10 (95% CI: 0.74-1.64)). Consistent results were reported in overall survival (OS; P=0.075). CONCLUSIONS: As preclinical evidence suggests that serum LDH may be a marker of tumour angiogenesis activation, low levels may indicate that bevacizumab is still efficacious in inhibiting angiogenesis. Validation of present results in subgroup analyses of other randomised trials of second-line angiogenesis inhibitors is warranted.

Tandem Tetrahydroisoquinoline-4-carboxylic Acid/ß-Alanine as a New Construct Able To Induce a Flexible Turn.

Tetrahydroisoquinoline-4-carboxylic acid, a constrained ß2 -amino acid named ß-TIC, was synthesised for the first time in enantiopure form. The biocatalytic route applied herein represents one of the few successful examples of enzymatic resolution of ß2 -amino acids. Model tetrapeptides, namely, Fmoc-l-Ala-ß-TIC-ß-Ala-l-Val-OBn (Fmoc=fluorenylmethyloxycarbonyl, Bn=benzyl), containing both isomers of ß-TIC, were prepared. Both computational and NMR spectroscopy studies were performed. A reverse-turn conformation was observed in the case of (R)-ß-TIC enantiomer that was obtained in 99 % enantiomeric excess by enzymatic resolution. The ß-TIC/ß-Ala construct represents the first example of a flexible turn mimetic containing a cyclic and an acyclic ß-amino acid. Furthermore, the presence of an aromatic ring of ß-TIC could facilitate non-covalent interactions to increase the potential of this scaffold for the preparation of protein-protein interaction modulators.

The Pharmacological Costs of Second-Line Treatments for Recurrent Ovarian Cancer.

INTRODUCTION: In ovarian cancer, it is uncertain which chemotherapy regimen is more clinically effective and cost-effective for the treatment of recurrence; therefore, it might be interesting to make a balance between the cost of the drugs administered and the difference in progression-free survival (PFS) and overall survival (OS). METHODS: The present evaluation was restricted to pivotal phase 3 randomized controlled trials. We calculated the pharmacological costs necessary to get the benefit in PFS and OS. The costs of drugs are at the pharmacy of our hospital and are expressed in Euros (&OV0556;). We have subsequently applied the European Society for Medical Oncology Magnitude of Clinical Benefit Scale. RESULTS: Our study evaluated 3 phase 3 randomized controlled trials, including 2004 patients. The most relevant increase of costs was associated with the combination chemotherapy including trabectedin, with the highest costs for month of PFS gained (15,836 &OV0556;) and for month of OS gained (7198 &OV0556;), but it substantially differs considering the data of partially platinum-sensitive populations (platinum-free interval of 6-12 months), with 3959 &OV0556; for month of OS gained. CONCLUSIONS: The addition of trabectedin to pegylated liposomal doxorubicin for the treatment of recurrent ovarian cancer can lead to an increase of pharmacological costs. Differently, considering OS in patients with platinum-free interval of 6 to 12 months, there is a halving of pharmacological costs with the addition of trabectedin to pegylated liposomal doxorubicin. These costs are in line with the spending suggested as sustainable (thresholds of <$61,500 per life-year gained).