A review of the benefit–risk profile of gefitinib in Asian patients with advanced non‐small‐cell lung cancer

ABSTRACT

Background: Improvements in first-line therapy of advanced non-small-cell lung cancer (NSCLC) have increased the need for effective second-line treatment options. In a Phase II trial of the anticancer drug gefitinib (IRESSA), greater efficacy was observed in Japanese compared with non-Japanese patients. Furthermore, results from a placebo-controlled Phase III trial (IRESSA Survival Evaluation in Lung cancer [ISEL]) showed that treatment with gefitinib was not associated with a statistically significant improvement in survival in either the overall or adenocarcinoma co-primary populations, although there was marked heterogeneity in survival outcomes between patient groups, with patients of Asian origin achieving a significant survival benefit with gefitinib compared with placebo.

Objective: To review the benefit:risk profile of gefitinib in Asian patients with advanced NSCLC.

Research design and methods: We identified and reviewed 31 reports (each with ≥ 25 patients) of clinical experience with gefitinib 250?mg/day in Asia involving a total of > 2000 patients with refractory NSCLC in Japan, China, Korea and Taiwan by searching EMBASE and Medline databases for publications between 1 January 2003 and 1 July 2005.

Results and discussion: In the majority of these reports, objective response rates of > 25% and disease control rates of > 60% have been described. Treatment with gefitinib resulted in a median time to progression of > 3 months and a median survival time of > 6 months in most studies. These 31 reports also demonstrated the efficacy of gefitinib in patients with secondary brain metastases, those with poor performance status (PS) and in patients receiving the drug as first-line treatment. Female gender, adenocarcinoma histology, non-smoking history, good PS and the presence of multiple lung metastases are associated with improved responsiveness to gefitinib. Reflecting the results of previous clinical trials, the reports indicate that gefitinib is generally well tolerated by Asian patients. The incidence of interstitial lung disease appears to be higher in Japanese than non-Japanese patients, although the reasons for this are not clear. Recent findings regarding cellular and genetic factors that may underlie the increased responsiveness to gefitinib among Asian patients are discussed.     

Does celecoxib improve the efficacy of chemotherapy for advanced non‐small cell lung cancer?

Aims

Clinical trials have reported conflicting results about whether celecoxib plus chemotherapy improves outcomes over chemotherapy alone in patients with advanced non‐small cell lung cancer.

Methods

We performed a meta‐analysis comparing the primary and secondary endpoints of treatment with celecoxib plus chemotherapy vs. chemotherapy alone in patients with advanced non‐small cell lung cancer.

Results

Six eligible trials (1181 patients) were selected from the 206 studies that were identified initially. A significant difference, favouring celecoxib plus chemotherapy over chemotherapy alone, was observed in the overall response rate [odds ratio (OR) 1.34; 95% confidence interval (CI) 1.08, 1.67; P = 0.009). However, there was no difference in the 1‐year survival rate (OR 1.08; 95% CI 0.86, 1.35; P = 0.512), clinical benefit (OR 1.05; 95% CI 1.88, 1.25; P = 0.613), complete response (OR 0.77; 95% CI 0.39, 1.51; P = 0.446) or partial response (OR 1.22; 95% CI 0.92, 1.63; P = 0.163). Toxicity did not differ significantly with the exception of the occurrence of leucopenia and thrombocytopenia.

Conclusions

Celecoxib plus chemotherapy appeared to improve the overall response rate compared with chemotherapy alone in the treatment of patients with advanced non‐small cell lung cancer. Further prospective randomized controlled trials are now needed.     

A phase II trial of oral 4′ demethoxydaunorubicin (DMDR) in inoperable non small cell lung cancer

Summary 4 Demethoxydaunorubicin, an orally active daunorubicin analogue, was administered to 22 patients with inoperable non small cell lung cancer (NSCLC). Patients were stratified into good and poor risk categories and received doses of 45 mg/m² and 40 mg/m² respectively at 28 day intervals. All 22 patients were evaluable for response: No tumour responses occurred. Therapy was well tolerated. Mild gastrointestinal toxicity occurred in 41% of patients. Leucopenia with a wcc < 3 × 10⁹/L occurred in 33% of patients and thrombocytopenia < 100 × 10⁹/L in 9%. Severe marrow toxicity was rare and there appeared to be no difference in terms of toxicity between the different dose levels. DMDR appears to have no useful clinical activity in NSCLC.     

Feasibility of adding everolimus to carboplatin and paclitaxel,with or without bevacizumab,for treatment-naive,advanced non–small cell lung cancer

Introduction One standard of care for advanced non–small cell lung cancer (NSCLC) is paclitaxel plus carboplatin?±?bevacizumab. This two-step phase I study evaluated the feasibility of adding everolimus to paclitaxel plus carboplatin?±?bevacizumab for advanced NSCLC. Methods Adults with advanced NSCLC naive to systemic therapy were enrolled. A Bayesian dose-escalation model was used to identify feasible daily or weekly everolimus doses given with paclitaxel (200 mg/m² q21 days) and carboplatin (AUC 6 mg/mL/min q21 days) (step 1) and paclitaxel (200 mg/m² q21 days), carboplatin (AUC 6 mg/mL/min q21 days), and bevacizumab (15 mg/kg q21 days) (step 2). Primary endpoint was end-of-cycle 1 dose-limiting toxicity (DLT) rate. Secondary endpoints included safety; relative dose intensities of paclitaxel, carboplatin, and bevacizumab; pharmacokinetics; and tumor response. Results Fifty-two patients were enrolled and received everolimus 5 mg/day plus carboplatin and paclitaxel (step 1 daily; n?=?13); everolimus 30 mg/week plus carboplatin and paclitaxel (step 1 weekly; n?=?13); everolimus 5 mg/day plus carboplatin, paclitaxel, and bevacizumab (step 2 daily; n?=?13); or everolimus 30 mg/week plus carboplatin, paclitaxel, and bevacizumab (step 2 weekly; n?=?13). End-of-cycle 1 DLT rate was 16.7 % (step 1 daily), 30.8 % (step 1 weekly), 30.0 % (step 2 daily), and 16.7 % (step 2 weekly). Cycle 1 DLTs were grade 3 neutropenia, anal abscess, diarrhea, and thrombocytopenia and grade 4 myalgia, cellulitis, neutropenia, febrile neutropenia, pulmonary embolism, and thrombocytopenia. The most common adverse events were neutropenia, fatigue, anemia, and thrombocytopenia. One patient (step 2 daily) experienced complete response, 10 patients partial response. Conclusions The feasible everolimus doses given with carboplatin and paclitaxel?±?bevacizumab were 5 mg/day and 30 mg/week. Neither schedule was very well tolerated in this unselected NSCLC population.     

Phase 2 study of bevacizumab plus carboplatin/nab-paclitaxel followed by bevacizumab plus nab‐paclitaxel for non‐squamous non‐small cell lung cancer with malignant pleural effusion

Investigational New Drugs - Objectives Vascular endothelial growth factor plays an important role in the pathogenesis of malignant pleural effusion (MPE). We previously showed the efficacy of...     

Safety and pharmacokinetic study of <Emphasis Type="Italic">nab</Emphasis>-paclitaxel plus carboplatin in chemotherapy-naïve patients with advanced non–small cell lung cancer

Background Nanoparticle albumin-bound paclitaxel (nab-paclitaxel) is a Cremophor EL–free formulation of paclitaxel newly designed to avoid solvent-related toxicities. We have evaluated the safety, tolerability, pharmacokinetics, and tumor response profile of weekly nab-paclitaxel (100 mg/m²) infusion together with administration of carboplatin at an area under the curve (AUC) of 6 every 3 weeks in Japanese patients with advanced non–small cell lung cancer (NSCLC). Methods Nab-paclitaxel (100 mg/m²) was administered without steroid or antihistamine premedication as a 30-min intravenous infusion once a week in combination with carboplatin at an AUC of 6 on day 1 of repeated 21-day cycles. The pharmacokinetics of both drugs were analyzed, and both adverse events and treatment response were monitored. Results Eighteen patients were enrolled in the study. The most frequent treatment-related toxicities of grade 3 or 4 were neutropenia (67%), leukopenia (50%), and anemia (22%). No severe hypersensitivity reactions were observed despite the lack of premedication, and no unexpected or new toxicities were detected. Pharmacokinetics analysis did not reveal any substantial drug-drug interactions. Seven partial responses were observed among the 18 evaluable patients, yielding a treatment response rate of 38.9%. Conclusions The combination of nab-paclitaxel (100 mg/m²) administered weekly and carboplatin at an AUC of 6 every 3 weeks was well tolerated in Japanese patients with advanced NSCLC. This combination therapy also showed promising antitumor activity and was not associated with relevant pharmacokinetic interactions.     

Phase II trial of esorubicin (4′deoxydoxorubicin,DxDx) in patients with small cell lung cancer

Summary Esorubicin (4-deoxydoxorubicin or DxDx) is an analog of doxorubicin with preclinical antitumor activity and no significant cardiotoxicity in model systems. Eleven patients with small cell lung cancer who had previously received chemotherapy were given esorubicin (25 mg/m² intravenously) every 3 weeks. No major objective responses were observed (95% confidence limits: 0–25%). Nine of the 11 patients had grade 2 or greater toxicity, with 55% of the patients experiencing grade 3 or greater toxicity [myelosuppression (4/11), anemia (2/11) or elevated liver enzymes (3/11)]. Nausea, vomiting, alopecia and intravenous site phlebitis were also seen. Three of the 11 patients received 3 or more course of esorubicin without evidence of significant cardiotoxicity. At this dose and shedule, no significant antitumor response were seen in this population of patients. Esorubicin, with this low response rate and significant toxicity, appears to be of limited utility in this disease.     

Novel agents in the treatment of non-small cell lung cancer: implications for neoadjuvant chemotherapy?

During recent years, we have seen an increasing awareness among physicians about the possibilities of helping patients stricken by non-small cell lung cancer using active intervention with chemotherapeutics. This has emerged mainly from the development of new chemotherapeutics and novel drug combinations with an improved therapeutic ratio better tolerated by the patients. However, these new combinations of chemotherapeutics have proved to be only marginally better in terms of survival than the earlier used cytotoxic agents. Thus, many clinicians consider the effects of systemic therapy on symptom control and improved quality of life to be at least as important as survival when evaluating new drugs or new combinations. It is also obvious that improvements using traditional cytotoxics are slow and that there is a need for novel approaches. The present review focuses on novel drugs that have recently been introduced, or soon await to be included, in the management of advanced lung cancer and which have a potential value for use in neoadjuvant treatment of patients with non-small cell lung cancer, i.e. pemetrexed, EGFR-inhibiting agents, anti-angiogenesis inhibitors and other small molecules.     

Phase II study of docetaxel alternating with cisplatin in chemotherapy-naïve patients with advanced non-small cell lung cancer

The objective of this study was to evaluate a regimen of full doses of docetaxel and cisplatin, using an alternating schedule, as first-line therapy for patients with inoperable non-small cell lung cancer (NSCLC). The standard concomitant schedule does not allow full doses of both drugs to be administered. We wanted to see if there was an advantage to be gained by administering full doses of both docetaxel and cisplatin, using a different schedule. Docetaxel 100 mg/m2 was given once every 6 weeks from week 1 and cisplatin (120 mg/m2 for two doses and 100 mg/m2 thereafter) once every 6 weeks from week 4, for six cycles (three docetaxel and three cisplatin). Thirty-six of the 44 patients enrolled were evaluable for efficacy. Forty-eight percent of the patients had good (KPS 90-100%) performance status. A median of five cycles was administered, for which no dose reductions were necessary. There were 13 of 36 partial responses (36%; 95% CI 21-54%) and 15 of 36 patients achieved stable disease (42%). The median duration of response was 10.5 months, the median time to progression was 4.5 months and the median survival was 9 months. The 1 and 2 year survival rates were 39 and 16%, respectively. The most frequent grade 3-4 toxicities were nausea (23% of patients), vomiting (18%) and neutropenia (77%). Infections were also common, but not severe. The alternating schedule produced response, toxicity and survival figures that compared favorable with those using the concomitant schedule. This study could serve as a model for future studies of non-cisplatin-containing regimens, in which full doses of docetaxel could alternate with full doses of other new agents active against NSCLC.     

Phase Ⅱ trial of gemcitabine plus cisplatin in patients with advanced non-small cell lung cancer

Aim:

To investigate the pharmacodynamics and pharmacokinetics of gemcitabine (dFdC) administered on d 1 and 5 plus cisplatin administered on d 1 in chemonaive patients with stage IIIB or IV non-small cell lung cancer (NSCLC).

Methods:

In each combination cycle, gemcitabine was administered at a dose of 1250 mg/m² as a 30 min intravenous (iv) infusion on d 1 and 5 followed by cisplatin at a dose of 75 mg/m² as a 3 h iv infusion on d 1 every 3 weeks. There was an interval of 1 h between the two infusions. Clinical response and toxicity of the regimen were observed. Furthermore, the plasma concentrations of gemcitabine (dFdC) and its metabolite (dFdU) at different time points were detected during the first cycle of infusion. Pharmacokinetic software (PKS) was used to estimate the pharmacokinetic parameters of gemcitabine and its metabolite dFdU.

Results:

A total of 28 patients was enrolled in the study. The median age was 54 years (range 27–75 years), and most patients were in good clinical condition. Twenty-seven patients received two or more treatment cycles. The overall clinical response rate was 33.3%. The median overall survival time was 13 months. The estimated median time to tumor progression (TTP) was 6.2 months, and the 1-year survival rate was 55.6%. Toxicities were tolerated. The main toxicity was myelosuppression; 35.7% of patients had grade 3/4 hematologic toxicities and 28.6% had grade 3/4 non-hematologic toxicities, which were commonly gastrointestinal responses. The pharmacokinetic parameters of dFdC and dFdU were not different between pre- and post-administration of gemcitabine on d 1 and 5. dFdU was minimal (0.729±0.637 μg/mL) before gemcitabine was infused on d 5, and gemcitabine was not present.

Conclusion:

The regimen is active and well tolerated in chemonaive patients with advanced NSCLC. After gemcitabine was administered on d 1 and 5, the pharmacokinetic parameters of dFdC and dFdU showed no difference from those before the infusion, and dFdU was minimal before gemcitabine was administered on d 5.     

Prolonged-release oxycodone/naloxone in opioid-naïve patients – subgroup analysis of a prospective observational study

Objective: Prolonged-release oxycodone/naloxone (OXN PR) showed improved gastrointestinal tolerability and equivalent analgesic efficacy compared to oxycodone alone in patients with non-cancer pain or cancer pain. This is the first dataset to demonstrate its effectiveness and safety compared to other strong opioids in opioid-naïve patients.

Methods: This is a subgroup analysis of a 4- to 6-week multicenter, observational study. A total of 162 opioid-naïve patients with moderate-to-severe pain of varying etiologies received either OXN PR or other strong opioids (control group). Documented parameters include pain relief (numeric rating scale), bowel function (Bowel Function Index [BFI]), pain-related functional impairment (Brief Pain Inventory Short Form), quality of life (QoL; EuroQol EQ-5D-3L) and a global therapy assessment.

Results: OXN group patients experienced a substantial clinically important reduction in mean pain intensity of 51.4%, compared to a 28.6% reduction in control patients. Although the BFI remained in the reference range in both groups, there was a difference between BFI changes during treatment in favor of OXN PR. The superior effectiveness of OXN PR was paralleled by greater improvements of pain interference and QoL and fewer adverse drug reactions compared to other strong opioids.

Conclusion: The favorable outcomes under real-life conditions suggest that OXN PR provides a valuable option for treatment of moderate-to-severe pain without using weak opioids first.     

The management of skin toxicity during erlotinib in advanced non-small cell lung cancer: how much does it cost?

Abstract

Introduction: The aim of this study is to estimate the costs for the foreseeable management of skin toxicity (papulo-pustular reactions) in patients treated with erlotinib for non-small cell lung cancer (NSCLC) in order to value the direct medical economical impact. No studies like the above have been published until now.

Materials and methods: We retrospectively analyzed all consecutive patients with NSCLC treated with erlotinib at Clinical Oncology Unit of University Hospital of Ferrara, Italy from June 2007 to May 2011. We evaluated severity and median duration of papulo-pustular reactions for each grade and we identified costs for the different therapeutic interventions.

Results: We evaluated 25 patients. Median time follow-up was 18.65 months (range 5.69–88.36). Finally, follow-up 7 patients (28.0%) were alive with metastases and 18 patients (72.0%) were deceased. Nineteen patients (76.0%) developed papulo-pustular reactions: 2 patients (10.5%) mild rash, 11 patients (57.9%) moderate rash and 6 patients (31.6%) severe rash; no case of hospitalization was observed. Median duration of mild rash was 97 days (costs-range: 157.7–452.2 €), median duration of moderate rash was 89 days (costs-range: 438.7–1035.6 €) and median duration of severe rash was 34 days (costs-range: 460.3–1057.2 €).

Conclusions: Our experience, though the analysis of not selected case study, showed that management of skin toxicities related to erlotinib is not so expensive, especially for low grade; therefore, we also recommended to give particular attention to low grade of toxicities for reducing progression to high grade and consequent risk of hospitalization, which really impact on costs.