Non-platinum Doublet Research Articles

Could S-1-based non-platinum doublet chemotherapy be a new option as a second-line treatment for advanced non-small cell lung cancer patients? A multicenter retrospective study.

For patients who have contraindications to or have failed checkpoint inhibitors, chemotherapy remains the standard second-line option to treat non-oncogene-addicted advanced non-small cell lung cancer (NSCLC). This study aimed to investigate the efficacy and safety of S-1-based non-platinum combination in advanced NSCLC patients who had failed platinum doublet chemotherapy. During January 2015 and May 2020, advanced NSCLC patients who received S-1 plus docetaxel or gemcitabine after the failure of platinum-based chemotherapy were consecutively retrieved from eight cancer centers. The primary endpoint was progression-free survival (PFS). The secondary endpoint was overall response rate (ORR), disease control rate (DCR), overall survival (OS), and safety. By using the method of matching-adjusted indirect comparison, the individual PFS and OS of included patients were adjusted by weight matching and then compared with those of the docetaxel arm in a balanced trial population (East Asia S-1 Trial in Lung Cancer). A total of 87 patients met the inclusion criteria. The ORR was 22.89% (vs. 10% of historical control, p < 0.001) and the DCR was 80.72%. The median PFS and OS were 5.23 months (95% CI: 3.91-6.55 months) and 14.40 months (95% CI: 13.21-15.59 months), respectively. After matching with a balanced population in the docetaxel arm from the East Asia S-1 Trial in Lung Cancer, the weighted median PFS and OS were 7.90 months (vs. 2.89 months) and 19.37 months (vs. 12.52 months), respectively. Time to start of first subsequent therapy (TSFT) from first-line chemotherapy (TSFT > 9 months vs. TSFT ≤ 9 months) was an independent predictive factor of second-line PFS (8.7 months vs. 5.0 months, HR = 0.461, p = 0.049). The median OS in patients who achieved response was 23.5 months (95% CI: 11.8-31.6 months), which was significantly longer than those with stable disease (14.9 months, 95% CI: 12.9-19.4 months, p < 0.001) or progression (4.9 months, 95% CI: 3.2-9.5 months, p < 0.001). The most common adverse events were anemia (60.92%), nausea (55.17%), and leukocytopenia (33.33%). S-1-based non-platinum combination had promising efficacy and safety in advanced NSCLC patients who had failed platinum doublet chemotherapy, suggesting that it could be a favorable second-line treatment option.

Trabectedin plus pegylated liposomal doxorubicin in patients with disease progression after PARP inhibitor maintenance: a real-life case–control study

ObjectivePoly (ADP-ribose) polymerase (PARP) inhibitor resistance is problematic in epithelial ovarian cancer management and sequencing strategies may be performed to overcome this issue. In this context, our study evaluated the...

Real-world use and survival outcomes of immune checkpoint inhibitors in older adults with non-small cell lung cancer.

Limited data exist regarding the characteristics and survival outcomes of older adults with non-small cell lung cancer (NSCLC) who receive immune checkpoint inhibitors in routine oncology practice. Using the Surveillance, Epidemiology, and End Results-Medicare linked database, we identified 1256 patients aged ≥65years who were diagnosed with pathologically confirmed stage I to stage IV NSCLC between 2002 and 2015 and initiated nivolumab or pembrolizumab in 2016. We examined patient characteristics and overall survival from the time of immune checkpoint inhibitor initiation through December 31, 2017. The median patient age at the time of immune checkpoint inhibitor initiatiton was 75.3years (interquartile range, 8.5). A substantial percentage of patients were initially diagnosed with stage IV disease (42.6%) and had ≥2 comorbid conditions (48.7%). Using a claims-based proxy, 11.5% of patients had poor performance status and 12.6% had a history of autoimmune conditions. The median overall survival after initiation of immune checkpoint inhibitor was 9.3months (95% CI, 8.5-10.5months). The 1-year survival rate was 43.0% (95% CI, 40.2-45.7%). In multivariable analyses, multiple comorbid conditions, squamous histology, a history of nonplatinum doublet systemic therapy, recent radiotherapy, and a shorter time from initial diagnosis to treatment initiation were found to be statistically significantly associated with an increased hazard of death. Demographics, poor performance status, and prior autoimmune conditions were not significantly associated with the hazard of death. Many older adults with NSCLC who initiated immune checkpoint inhibitors had multiple comorbidities, a history of autoimmune disease, or poor performance status. Factors associated with poor prognosis among patients with advanced NSCLC were also associated with worse survival in older adults treated with immune checkpoint inhibitors.

Real-world use and survival outcomes of immune checkpoint inhibitors in patients with non-small cell lung cancer.

e14111 Background: Little is known about the real-world use and survival outcomes of immune checkpoint inhibitors among elderly patients with non-small cell lung cancer (NSCLC). Methods: Using the SEER-Medicare data, we identified 1,338 patients who were diagnosed with pathologically confirmed stage 1-4 NSCLC between 2002 and 2015 and initiated nivolumab or pembrolizumab in 2016. We examined the association of patient and disease characteristics, and treatment history with overall survival, from initiation through December 31, 2017. We estimated survival curves using the Kaplan-Meier method and identified predictors of survival using multivariable Cox proportional hazards regression. Results: The median age at immune checkpoint inhibitor initiation was 74.8 years. The majority of patients were initially diagnosed with stage 4 disease (42.7%). Median time from diagnosis to initiation were 13.9 and 19.0 months for those initially diagnosed with stage 4 and 1-3 disease, respectively. Median overall survival was 9.5 months. In multivariable analyses, multiple comorbid conditions, squamous histology, history of non-platinum doublet systemic therapy, recent radiation therapy, and shorter time from initial diagnosis to initiation were statistically significantly associated with increased hazard of death (Table). Demographics, stage at initial diagnosis, and prior oral targeted therapy were not significantly associated with the hazard of death. Conclusions: Real-world data show that factors that are generally related to poor prognosis remain predictors of survival in elderly patients treated with immune checkpoint inhibitors.[Table: see text]

Abstract A018: Patient-derived xenograft (PDX) models of NSCLC reflect clinical drug responses and predict effective treatments for patients

Abstract Background: Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related mortality and prognosis remains poor despite the availability of numerous therapies. Integration of drug screening and sequencing in PDX models may allow for improved understanding of mechanisms of resistance (de novo and acquired), identification of biomarkers, and optimization of therapeutic strategies for NSCLC patients. In this study, we evaluated the response of NSCLC PDX models to multiple therapies and correlated responses to known clinical outcomes and molecular characteristics. Methods: PDX models were developed from 86 patients with NSCLC and evaluated by next-generation sequencing for genomic alterations (mutations, amplifications/deletions, fusions, and gene expression changes). Models were screened against different therapies including first-line platinum and nonplatinum doublets and triplets, second-line single agent docetaxel and pemetrexed (second-line therapies), and EGFR-targeted inhibitors. Tumor regression (TR) values and RECIST criteria were determined and correlated with known literature-based response rates (RR) as well as individual patient outcomes. Results: Eighty-eight PDX models from 86 patients were interrogated. To date, 63 (72%) models have been sequenced and 39 screened against standard-of-care therapies. There was robust concordance in mutational and allelic frequency profiles between patient tumors and corresponding PDX models. Based on PDX tumor growth, regression (CR/PR RECIST) was observed for at least one regimen in 50% (12/24) of models screened against first-line therapies and 25% (2/8) screened against second-line docetaxel or pemetrexed. No tumor regression was observed in any NSCLC model treated with the EGFR inhibitor, erlotinib (0%, 0/15), despite EGFR amplification and the absence of KRAS mutations. Nine PDX responses could be correlated to clinical outcomes, with 89% (8/9) accurately reflecting patient responses to the same treatment. Conclusion: Our study demonstrated the strong alignment between PDX model response to standard-of-care therapies and patient clinical outcomes, which highlights the potential application of PDX models for translational modeling and utilizing cohorts of PDX models for clinical trial simulation. The responses of these models to different lines of therapy reflected corresponding patient outcomes both at an individual and population level. Comprehensive sequencing (WES and RNA) and standard-of-care drug testing of these PDX models is planned and could allow a deeper understanding of such mechanisms. In this context, application of PDX models to drug development and stratification of clinical trial patients for treatment will continue to evolve. Citation Format: Daniel Ciznadija, Igor Astaturov, Haiying Cheng, Nir Peled, Jennifer Jaskowiak, Angela Davies, David Sidransky. Patient-derived xenograft (PDX) models of NSCLC reflect clinical drug responses and predict effective treatments for patients [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A018.

Outcomes of ERCC1 high locally advanced esophageal cancer patients treated with non-platinum vs platinum based CRT.

192 Background: ERCC1 is a DNA excision repair enzyme which repairs the DNA adduct damage caused by platinum and hence high levels of ERCC1 has been associated with platinum resistance. Thus utility of platinum as a first line chemotherapy in esophageal cancers with high ERCC1 levels is controversial. SWOG S0356 trial noted a significantly low 2 year overall survival of 37% for platinum based CRT in ERCC1 high esophageal carcinomas, yet no studies have identified the alternative first line chemotherapy. Our Program utilized combined irinotecan 65mg/m2 on D1 and D8 and nab-paclitaxel 100mg/m2with concurrent radiation therapy of 50.4Gy for ERCC1 high esophageal cancers at the treating physician’s discretion. We compared the differences in survival with non-platinum versus platinum CRT. Methods: Retrospective analysis from 2011 to 2016 identified 25 locally advanced esophageal cancer patients in whom ERCC1 levels were checked. Out of this 25 patients 23 had high ERCC1 levels and 2 had low ERCC1 levels. Patients with low ERCC1 were excluded. Patients with high ERCC1 levels received either non-platinum or platinum CRT as neo-adjuvant, adjuvant or definitive chemotherapy. Results: Patient characteristics: Male 69.5%, female 30.5%, squamous 43.4%, adenocarcinoma 52.1%, other 4.5%, operable 39%, non-operable 61%. Non-platinum therapy was utilized for 69.5% and platinum based therapy for 30.5% of the patients. Kaplan-Meier analysis for survival showed clear separation of the curves around 2 years. Median overall survival of non-platinum doublet was not reached during a median follow up of 22 months. Overall survival at 2 years was 57%. The median overall survival for the platinum doublet was 22 months and the 2 year overall survival was 42%. (p = 0.22). Hazard ratio (HR) 0.48(95% CI 0.14-1.58 p = 0.23) .This statistical non significance was due to small sample size. Conclusions: Abraxane and irinotecan showed improved overall survival in the ERCC1 high group when compared with platinum based therapy demonstrated both in our population and the SWOG 0356 trial. [Table: see text]

Final Overall Survival Analysis of the Phase III Randomized Trial of Chemotherapy with and Without Bevacizumab for Advanced Cervical Cancer: a Nrg Oncology - Gynecologic Oncology Group Study

ABSTRACT Aim: On August 14, 2014, the United States Food and Drug Administration approved bevacizumab for women with advanced cervical cancer. This regulatory milestone was due to GOG protocol 240 having met its primary endpoint with the arms administering chemotherapy plus bevacizumab resulting in significantly improved overall survival (OS) compared to chemotherapy alone. These results were publically announced following a data freeze on Dec 12, 2012 when 271 deaths had occurred. We now report the planned final analysis of OS. Methods: Phase III randomized clinical trial using a 2x2 factorial design to determine whether chemotherapy plus bevacizumab and/or the non-platinum chemotherapy doublet (topotecan plus paclitaxel) improves OS in women with recurrent/persistent and metastatic cervical cancer. The primary endpoints were OS and toxicity with secondary endpoints being PFS and response. We calculated that we would need to enroll approximately 450 patients with approximately 346 deaths expected to provide the study with 90% power to detect a reduction in the risk of death of at least 30% with either experimental treatment, with the one-sided type I error rate limited to 2.5% for each regimen. Results: The median age was 49 yrs and groups were well-balanced for disease status (70-73% recurrent), prior chemoradiation (74-75%), and in-field pelvic recurrence (53-54%). Gastrointestinal (GI) perforations were reported in 3.2% of patients receiving bevacizumab, all of whom had prior radiotherapy. GI-vaginal fistula occurred in 8.2% of patients treated with bevacizumab vs. 0.9% of those treated with chemotherapy alone. Grade 3+ venous thromboembolic events were reported in 10.6% (chemotherapy plus bevacizumab) vs 5.4% (chemotherapy alone). On March 7, 2014, 348 deaths had occurred and the regimens administering bevacizumab continued to demonstrate a significant improvement in OS over chemotherapy alone: 16.8 mos vs 13.3 mos; HR 0.765 (95% CI: 0.62, 0.95; p = 0.0068). Conclusions: The benefit conferred by the incorporation of bevacizumab is sustained beyond 50 months as evidenced by the survival curves remaining separated. Bevacizumab is the first targeted agent to be granted regulatory approval in the U.S. for treatment of a gynecologic cancer. Disclosure: K.S. Tewari: Contracted research: Endocyte, Amgen, Genentech Speaker's Bureau: Vermillion Advisory Board: Genentech, Caris Extramural funding: National Cancer Institute, Intuitive Surgical Inc.; R.T. Penson: Advisory Board: Genentech; A. Oaknin: Advisory Board: Roche; B.J. Monk: Advisory Board: Genentech/Roche. All other authors have declared no conflicts of interest.

169O - Et: a Randomized, Multicenter, Phase III Trial of Platinum Versus Nonplatinum Chemotherapy, After Ercc1 Stratification, in Patients with Advanced/Metastatic Non-Small Cell Lung Cancer (Nsclc)

ABSTRACT Aim: Increased expression of excision repair cross-complementing group 1 (ERCC1) protein might be associated with platinum resistance in NSCLC, based on retrospective and meta-analyses findings. We conducted the first ever trial to prospectively evaluate ERCC1 as a predictive marker: to assess whether non-platinum therapy is superior to platinum for ERCC1 + ve, and non-inferior for ERCC1-ve tumors. Methods: Pts with stage IIIB/IV NSCLC (chemo-naive, tissue biopsy available, ECOG PS 0-1) were randomised to receive either platinum-based or non-platinum doublet chemotherapy, after ERCC1 stratification using a recommended monoclonal antibody (clone 8F1) assessed centrally. Pts with squamous (sq) histology had cisplatin/gemcitabine (CG) or paclitaxel/gemcitabine (PG); non-squamous (non-sq) pts had cisplatin/pemetrexed (CP) or paclitaxel/pemetrexed (PP), every 3 wks for up to 6 cycles. Primary endpoint was overall survival (OS). From 2012, we concurrently used another recommended antibody (clone 3F2) specific for XPF/ERCC1 protein complex. Results: 648 pts were recruited from 85 UK centres. Baseline characteristics were balanced for both sq (n = 177) and non-sq (n = 471) pts. Recruitment stopped in 2012 for sq pts because PG OS was inferior to CG, regardless of ERCC1 status: median OS 7.7 vs 11.2 months, HR = 1.54 (95% CI 1.05-2.26, P = 0.03). We stopped accrual in 2013 when main trial objective could not be met for non-sq pts: preliminary OS HR for ERCC1 + ve tumors 1.08 (95%CI 0.75-1.54, P = 0.68), median OS 9.7 (PP) vs 10.9 (CP) months. For ERCC1-ve tumors, HR 0.94 (0.62-1.43, P = 0.79), median OS 9.5 (PP) vs 8.4 (CP) months. HRs using XPF antibody were ERCC1 + ve tumors 1.10 (0.76-1.61, p = 0.61), and ERCC1-ve tumors 1.21 (0.65-2.24, p = 0.54). Findings for progression-free survival were similar. ERCC1 positive rate in non-sq pts was 54% (8F1) or 71% (XPF); 28% of pts had discordant ERCC1 status. Grade 3/4 hematological toxicities were less common with non-platinum therapy: 31% (CG) vs 17% (PG), and 22% (CP) vs 17% (PP). Conclusions: Selecting platinum or non-platinum chemotherapy prospectively based on either of two recommended ERCC1 antibodies in advanced NSCLC did not influence survival. Our prospective data support recent concerns over the reliability of current ERCC1 antibody performance as a predictive biomarker of resistance to platinum-based therapy. Disclosure: All authors have declared no conflicts of interest.

Chemotherapy in the treatment of metastatic, persistent, and recurrent cervical cancer.

Patients with cervical cancer represent a vulnerable population with limited chemotherapeutic options. This year, two large trials focusing on detection/screening and treatment of advanced stage cervical cancer were featured in the opening plenary session of the American Society of Clinical Oncology Annual Meeting. As such, a review of the evolution of chemotherapy in the treatment of this disease is warranted. Following the establishment of cisplatin as an effective single-agent regimen in patients with advanced stage, recurrent, or persistent cervical cancer, several platinum-containing combinations were studied. Ultimately, the adoption of cisplatin chemosensitizing radiation resulted in relative 'cisplatin resistance' and the concept of nonplatinum doublets emerged as an active area of investigation. In an era of biologics, combined therapy with cytotoxic drugs and molecular targeted agents, as well as the use of nonplatinum doublets, represent an exciting area yet to be fully explored.

Phase III randomized clinical trial of cisplatin plus paclitaxel vs the non-platinum chemotherapy doublet of topotecan plus paclitaxel in women with recurrent, persistent, or advanced cervical carcinoma: A Gynecologic Oncology Group study

Phase III randomized clinical trial of cisplatin plus paclitaxel vs the non-platinum chemotherapy doublet of topotecan plus paclitaxel in women with recurrent, persistent, or advanced cervical carcinoma: A Gynecologic Oncology Group study

A phase II trial of a cremophor-free, polymeric micelle formulation of paclitaxel and gemcitabine in patients with advanced non-small cell lung cancer.

e19129 Background: Non-platinum doublet paclitaxel and gemcitabine has shown efficacy on par with platinum-based doublet regimens as first-line chemotherapy in advanced non-small cell lung cancer patients. Genexol-PM is a Cremorphor EL(CrEL)-free polymeric micelle formulation of paclitaxel. This study was designed to evaluate the efficacy and safety of Genexol-PM and gemcitabine combination in advanced non-small cell lung cancer patients. Methods: This is a single-arm, single-center phase II study. Patients with advanced NSCLC received Genexol-PM at 230mg/m2 on day 1 and gemcitabine 1000mg/m2 on day 1 and day 8 of a 3-week cycle as first-line chemotherapy. Six cycles of chemotherapy were administered unless there is a disease progression. The primary endpoint was response rate. Results: Forty-three patients received the study drugs with median of 4 cycles per patient (range, 1-6). Among 35 patients who received more than one cycle, mean dose intensity of CrEL-free paclitaxel and gemcitabine was 209 mg/m2/3-week and 1,853 mg/m2/3-week respectively. Overall response rate was 46.5%. The median progression free survival was 4.0 months (95% CI 2.0-6.0 months) and median overall survival was 14.8 months (95% CI 9.1-20.5 months). 18 patients (51%) experienced grade 3/4 adverse events, including neutropenia or febrile neutropenia (n=7), pneumonia (n=3), asthenia (n=3), peripheral neuropathy (n=2), diarrhea (n=1), skin rash (n=1), myalgia (n=1), pulmonary thromboembolism (n=1), LV dysfunction (n=1), and dyspnea with sudden death (n=1). Adverse events leading to drug discontinuation were occurred in 9 patients, among which 2 patients were died of adverse events (pneumonia, dyspnea with sudden death). Conclusions: CrEL-free paclitaxel in combination with gemcitabine demonstrated comparable antitumor activity with less emetogenicities in non-small cell lung cancer patients. Clinical trial information: NCT01770795.

1308P - Pkm2 Expression May Predict Chemosensitivity to Cisplatin-Based Chemotherapy in Metastatic Non-Small Cell Lung Cancer (NSCLC)

ABSTRACT Background Tumor cells have been shown to express exclusively the embryonic M2 isoform of pyruvate kinase (PKM2). Overexpression of PKM2 has been correlated with cisplatin resistance in cell lines and xenograft models. We evaluated the predictive significance of PKM2 in patients with stage IV NSCLC. Methods PKM2 mRNA expression was analysed by RT-qPCR in microdissected FFPE primary tumors from 305 NSCLC patients (148 as training set and 157 as experimental set) treated with front-line cisplatin-based chemotherapy and 85 patients treated with a non-platinum doublet (as validation set). Results The patients' characteristics were all typical for metastatic NSCLC (median age 61 years, 86% males, 64% adenocarcinomas and 28% squamous cell carcinomas, ECOG PS 0-1: 83%). PKM2 was successfully amplified in all specimens. Progression Free Survival (PFS) was significantly lower in patients with overexpression of PKM2 (4.9 vs. 6.4 months for high and low expression, respectively, p = 0.028) in the training set and the results were confirmed in the experimental set (3.7 vs. 5.9 months, p = 0.006). Similarly, median overall survival (mOS) was significantly decreased in patients with upregulation of PKM2 in both sets: 10.1 vs 17.0 months in the training set (p = 0.01) and 8.3 vs 16.8 months in the experimental sets (p = 0.003), for high and low expression, respectively. In contrast, there was no statistical difference in terms of PFS (5.6 vs. 5.9 months, p = 0.431) and mOS (9.8 vs. 10.1 months, p = 0.512) between low and high PKM2 expression in the validation group. Multivariate analysis revealed that PKM2 high mRNA expression could be emerged as an independent factor associated with decreased PFS (training set: HR = 1.6, p = 0.02; experimental set: HR = 2.1, p = 0.013) and mOS (training set: HR = 1.9, p = 0.02; experimental set: HR = 2.6, p = 0.001), but not in the validation set (PFS: HR = 1.1, p = 0.627; mOS: HR = 0.96, p = 0.495). Conclusions These results indicate that the PKM2 mRNA expression may be used as a predictive factor for sensitivity to cisplatin-based chemotherapy. Disclosure All authors have declared no conflicts of interest.

Non-platinum doublets were as effective as platinum-based doublets for chemotherapy-naïve advanced non-small-cell lung cancer in the era of third-generation agents

The aim was to compare the efficacy between doublets of third-generation agents (non-platinum) and doublets of platinum plus a third-generation agent (platinum-based) for chemotherapy-naïve advanced non-small-cell lung cancer (NSCLC). We conducted a literature-based meta-analysis to compare the efficacy between doublets of third-generation agents and doublets of platinum plus a third-generation agent for chemotherapy-naïve advanced NSCLC. The primary end point was overall survival, and the secondary end points were progression-free survival (PFS) and response rate. Subgroup analyses were also conducted by different non-platinum doublet regimens or different platinum-based doublets. A descriptive review for toxicity was performed. Sixteen randomized controlled trials were identified ultimately. Results demonstrated that the efficacy of non-platinum doublets was comparable with platinum-based doublets according to the overall survival (HR = 1.03, 95 % CI = 0.98-1.08, p = 0.29). Subgroup analyses by different non-platinum doublets also showed the efficacy of all the third-generation doublets, such as vinorelbine plus gemcitabine, vinorelbine plus paclitaxel, gemcitabine plus paclitaxel, and gemcitabine plus docetaxel, was comparable with platinum-based doublets (HR = 1.00, 95 % CI = 0.78-1.27, p = 0.98; HR = 0.97, 95 % CI = 0.80-1.18, p = 0.79; HR = 1.05, 95 % CI = 0.99-1.12, p = 0.11; HR = 1.01, 95 % CI = 0.92-1.10, p = 0.87; respectively). Subgroup analyses by different platinum-based doublets indicated that the efficacy of the third-generation doublets were equal to both cisplatin-based doublets and carboplatin-based doublets (HR = 1.08, 95 % CI = 1.00-1.17, p = 0.05; HR = 1.00, 95 % CI = 0.94-1.05, p = 0.94; respectively). The secondary end points indicated that platinum-based doublets might have an advantage in PFS but not in response rate (HR = 1.06, 95 % CI = 1.01-1.12, p = 0.03; RR = 0.99, 95 % CI = 0.90-1.08, p = 0.81; respectively). Non-platinum doublets were as effective as platinum-based doublets with different toxicity profile for chemotherapy-naïve advanced NSCLC in the era of third-generation agents.

Final report of an open-label phase II trial of bevacizumab plus docetaxel and gemcitabine in metastatic, previously untreated nonsquamous non-small cell lung cancer (NSCLC).

e18046 Background: Platinum and non-platinum doublet chemotherapy has similar efficacy in advanced NSCLC patients (pts). Bevacizumab (B) improves outcomes when added to platinum doublets, but its safety and efficacy in combination with non-platinum doublets is unknown. This study was designed to test the combination of B, docetaxel (D), and gemcitabine (G) in first-line treatment of advanced NSCLC. Methods: Pts with metastatic, non-squamous NSCLC, PS 0-1, and measurable disease by RECIST were enrolled in this open-label, single arm phase II trial. Pts received D (75 mg/m2) on d1, G (900 mg/m2) on d1 &amp; 8, and B (15 mg/kg) on d1 every 21d for up to 6 cycles, followed by B maintenance until progression or 12 mos total. Pts received growth factor d9. CT scans were performed every 6 wks. The primary endpoint was 1-yr progression-free survival (PFS), with secondary endpoints of safety, objective response rate (ORR), overall PFS, and overall survival (OS). Pts with tumor cavitation, untreated brain metastases, and hemoptysis were excluded. Planned enrollment was 46. Results: 13 pts were enrolled from 12/2009 to 4/2011. Pt characteristics: Median age 63 (35-69), 85% male, PS 0 (38%), PS 1 (62%). The median # of cycles of chemotherapy was 6 (1-6), median # cycles of B was 4 (1-15), with 2 pts coming off study prior to the first evaluation (1 grade 5 encephalopathy, 1 grade 4 febrile neutropenia). 5 pts (38%) had chemo dose reduction and 4 (31%) discontinued treatment for toxicity. 3 pts (23%) discontinued B prior to progression, 2 for tumor cavitation and 1 for grade 1 hemoptysis. The grade 3-5 non-hematologic toxicity rate was 69%, with 6 pts (46%) hospitalized with pneumonitis/pneumonia felt possibly related to study drugs. At this point enrollment was halted for safety concerns. The 1-yr PFS was 8%, and the median PFS was 6.9 mos (95% CI 2.0-NYR). 11 pts were evaluable for response, and 6 pts had partial responses for an ORR of 55%. The median OS was NYR with median follow up of 10.9 mos. Conclusions: The combination of B, D, and G was not tolerable at the doses and schedule used in this study. A formal phase I trial is needed if this combination is to be investigated further.

Non-platinum doublets versus single agents in non-small cell lung cancer (NSCLC) patients with elderly age and/or poor performance status: a meta-analysis

Objective The aim of the study was to compare the efficacies and toxicities of non-platinum doublets (doublets group) with a non-platinum single agent (single-agent group) in previously untreated advanced non-small cell lung cancer (NSCLC) patients with elderly age and/or poor performance status (PS).

Changing the Paradigm in the Treatment of Platinum-Sensitive Recurrent Ovarian Cancer: From Platinum Doublets to Nonplatinum Doublets and Adding Antiangiogenesis Compounds

The optimal treatment for women with recurrent epithelial ovarian cancer is evolving. The objective of this review is to outline the transition away from platinum doublets toward nonplatinum combinations and review emerging data on antiangiogenesis therapy in this setting. Recently published and presented data as well as ongoing clinical trials are discussed. Current clinical practice largely harmonizes with a paradigm that outlines a treatment algorithm for recurrent ovarian cancer based on the duration of platinum-free exposure. In this model, patients whose penultimate platinum compound exposure (platinum-free interval [PFI]) is longer than 6 months are generally offered a platinum agent or a platinum-containing doublet; those with a shorter interval are usually treated with a single nonplatinum agent. This is based on the simple contention that better clinical outcomes will be realized with platinum in those deemed platinum sensitive (PFI >6 months). However, it is becoming clear from various phase II and phase III clinical studies that the performance of many nonplatinum chemotherapeutic agents is also influenced by this parameter (PFI). Indeed, although definitive comparisons of nonplatinum drugs to novel cytotoxic agents are lacking, the clinical activity of these compounds might approach or exceed that of platinum agents. Although recognized by clinicians, the dichotomy that determines therapy based on PFI has not been formally accepted by the US Food and Drug Administration in all cases of drug labeling. For instance, whereas the combination of gemcitabine and carboplatin is now approved for patients with platinum-sensitive recurrent ovarian cancer, traditionally used platinum-resistant (PFI <6 months) agents such as topotecan and pegylated liposomal doxorubicin are also approved by the US Food and Drug Administration as single agents in platinum-sensitive patients. Furthermore, the nonplatinum doublet pegylated liposomal doxorubicin and trabectedin has recently documented comparable activity to platinum combinations among patients with a PFI of longer than 6 months. To that end, the most prolific developmental therapeutics arena in ovarian cancer is biologically targeted therapy, particularly angiogenesis inhibitors. Although it is unknown if the clinical activity from these new agents will respect the chemotherapy-sensitive dichotomy, it is clear that they have the potential to augment efficacy, possibly in both traditionally chemosensitive and chemoresistant phenotypes. The term platinum sensitive should probably be replaced by chemotherapy sensitive, particularly as new nonplatinum agents and combinations are identified as active in this setting. Nonplatinum doublets are effective in treating platinum-sensitive recurrent disease, and adding antiangiogenesis agents to these combinations is a research priority.

MO19390 (SAiL): Safety and efficacy of first-line bevacizumab (Bv)-based therapy in advanced non-small cell lung cancer (NSCLC)

8043 Background: MO19390 (SAiL) is a single-arm, multicenter, international trial evaluating the safety and efficacy of first-line Bv in combination with a range of chemotherapy regimens in over 2,000 patients (pts). Methods: Primary endpoint was safety; secondary endpoints included time to disease progression (TTP) and overall survival (OS). Pts with untreated locally advanced, metastatic or recurrent non-squamous NSCLC (ECOG PS 0–2) received Bv (7.5 or 15mg/kg) with standard chemotherapy for up to six cycles, then non-progressors proceeded to receive Bv until disease progression. Results: This analysis (data cut-off July 2008) was based on 2,008 pts with a median age of 59. Pts (%) were: male 60.1; stage IIIB/IV 19.5/80.5 (no data 3 pts); adenocarcinoma/large cell/other 85.8/7.1/7.1; ECOG PS 0/1/2 38.1/56.1/5.8. Pts received a median of 6 Bv cycles and 4 chemotherapy cycles. 26.7% of pts experienced grade ≥3 serious adverse events (SAEs); 8.3% of pts experienced grade ≥3 SAEs related to Bv. Adverse events (AEs) of special interest (all grades) included bleeding (27.6%), hypertension (19.3%), proteinuria (14.6%), thromboembolism (8.6%), CHF (2.9%) and GI perforation (1.2%). The incidence of AEs of special interest (all grades) was comparable across the various types of chemotherapy regimens: carboplatin doublets (50.6%)/cisplatin doublets (49.9%)/non-platinum doublets (41.7%)/monotherapy (37.5%). No new safety signals were reported. Trial data were not deemed mature enough to provide efficacy results. Conclusions: SAiL confirms that Bv-based therapy has a well-established and manageable safety profile. Clinical outcomes obtained in this real-life population are consistent with those seen in the pivotal trials of bevacizumab (Avastin) in NSCLC (E4599 and AVAiL), and compare favorably with historical data. Updated efficacy results for 2,147 pts will be presented, based upon an additional 5 months’ follow-up. [Table: see text]

Promising Survival in Patients with Recurrent Non-small Cell Lung Cancer Treated with Docetaxel and Gemcitabine in Combination as Second-Line Therapy

Lung cancer is the leading cause of cancer death in men and women, and current second-line chemotherapy regimens yield relatively poor response and survival rates. We hypothesized that the combination of weekly docetaxel (D) and gemcitabine (G) would show activity in the second-line setting. We therefore conducted a phase II trial evaluating this regimen in patients with relapsed or progressive non-small cell lung cancer (NSCLC) after first-line platinum-based therapy. Patients with recurrent NSCLC, adequate physiologic indices, and exposure to one prior platinum-based regimen were eligible. Docetaxel 40 mg/m intravenous (IV) and gemcitabine (G) 800 mg/m IV weekly were administered on day 1 and 8 every 21 days. In the absence of dose-limiting toxicity, G was escalated on an intrapatient basis to 1 g/m/wk. The primary endpoint was response rate (RR); event-free (EFS) and overall survival were secondary endpoints. Thirty-five patients (median age 61 years; 20 [57%] male) were accrued. Most (88%) had previously received carboplatin/paclitaxel, 31.4% in combination with a third investigational agent, more than half (57.1%) had prior radiation. The median number of cycles was four. RR was 23%. Median EFS was 5.7 months and median overall survival was 12.5 months. Patients who had their cancer diagnosed more than or equal to 12 months before entering the trial had superior EFS (13.7 months versus 4.8 months). Toxicity was acceptable. There were no treatment-related deaths. A nonplatinum doublet with GD is feasible and effective in the treatment of recurrent, platinum-exposed NSCLC patients. RR and survival are promising.

Efficacy and side effects of cisplatin- and carboplatin-based doublet chemotherapeutic regimens versus non-platinum-based doublet chemotherapeutic regimens as first line treatment of metastatic non-small cell lung carcinoma: A systematic review of randomized controlled trials

Evidence suggests that platinum-based regimens confer a better survival in patients with non-small cell lung carcinoma (NSCLC). However, evidence is lacking regarding the specific effects of cisplatin or carboplatin when compared to non-platinum-based doublets. Meta-analysis of all randomized trials comparing non-platinum-based with platinum-based doublet regimens given as first-line treatment for NSCLC. Relative risks were calculated for all outcomes ascertained. Sensitivity analysis, using methodological quality of the trials and different measures of effect, was undertaken. Seventeen trials, comprising 4920 patients were included. The use of platinum-based doublet regimens was associated with a slightly higher survival at 1 year (RR=1.08, 95% CI 1.01-1.16, p=0.03), better partial response (RR=1.11, 95% CI 1.02-1.21, p=0.02), with a higher risk of anemia, nausea, and neurotoxicity. Cisplatin-based doublet regimens improved survival at 1 year (RR=1.16, 95% CI 1.06-1.27, p=0.001), complete response (RR=2.29, 95% CI 1.08-4.88, p=0.03), partial response (RR=1.19, 95% CI 1.07-1.32, p=0.002) with an increased risk of anemia, neutropenia, neurotoxicity and nausea. Conversely, carboplatin-based doublet regimens did not increase survival rate at 1 year (RR=0.95, 95% CI 0.85-1.07, p=0.43). There was a statistically significant difference between the effect of cisplatin compared to carboplatin (p=0.05). Carboplatin-based doublet regimen included a higher risk of anemia and thrombocytopenia, but no increased nausea and/or vomiting, contrarily to cisplatin. Sensitivity analyses showed that the results were robust to the exclusion of lesser quality trials and the choice of the measure of effect. We provide additional evidence that cisplatin, but not carboplatin-based doublet regimens are associated with a slightly better survival compared to non-platinum-based doublet regimens. Side effects of cisplatin- and carboplatin-based regimens differ between each other and when compared to non-platinum doublets. Although this analysis has limitations, it may provide valuable information to clinicians when choosing the appropriate regimen for patients with non-small cell lung cancer.

A randomized phase II study of carboplatin and paclitaxel (CP) versus gemcitabine and vinorelbine (GV) in performance status (PS) 2 patients with advanced non-small cell lung cancer (NSCLC): West Japan Thoracic Oncology Group 00

18060 Background: Although doublet chemotherapy is a standard treatment regimen for PS 0–1 patients with advanced non- small cell lung cancer (NSCLC), the optimal chemotherapy for PS 2 patients with advanced NSCLC still remains to be established. We conducted a randomized phase II study to compare the efficacy and safety of a platinum-doublet regimen (CP) versus a non-platinum doublet regimen (GV) in PS 2 patients with advanced NSCLC. Methods: Chemotherapy-naive patients with stage IIIB (malignant effusion) and IV NSCLC were eligible for this study. The patients were randomly assigned to carboplatin area under the curve of 6 plus paclitaxel 200 mg/m2 on day 1 every 3 weeks (the CP arm) or gemcitabine 1000 mg/m2 plus vinorelbine 25 mg/m2 on days 1 and 8 every 3 weeks (the GV arm). The primary endpoint was the 1-year survival rate while the secondary endpoints were the response rate, the time to progression and the quality-of-life (QOL). The sample size was 41 assessable patients in each arm. Results: Of the 89 patients enrolled, 84 were assessable for efficacy and toxicity: 41 patients (median age 65 years, male/female 30/11, stage IIIB/IV 7/34) in the CP arm and 43 patients (median age 67 years, male/female 31/12, stage IIIB/IV 7/36) in the GV arm. The overall response and 1-year survival rates were 29.3% (95% CI, 16.1 to 45.5%) and 22% (95% CI, 9.3 to 34.6%) for the CP and 20.9% (95% CI, 10 to 36%) and 27.9% (95% CI, 14.5 to 41.3%) for the GV arm, respectively. The median survival time and time to progression were 5.9 and 2.9 months, respectively, for the CP arms and 6 and 2.6 months for the GV arm. The selected Grade 3/4 toxicity in the CP and GV arms included neutropenia (67.5% vs 65.1%, respectively), anemia (12.5% vs 30.2%), thrombocytopenia (7.5% vs 11.6%), febrile neutropenia (17.1% vs 11.6%), infection (29.3% vs 23.3%), pneumonitis (4.9% vs 11.6%), liver dysfunction (2.5% vs 9.3%), and neuropathy (5.1% vs 0%). The QOL improved after each treatment and it was similar between the two arms. Conclusions: Both CP and GV appear to be active in PS 2 patients with advanced NSCLC . The toxicity profiles were different between the two arms. [Table: see text]