Non-platinum Therapy Research Articles

Patterns of pembrolizumab use for recurrent cervical cancer.

e17528 Background: Pembrolizumab was approved for treatment of recurrent or metastatic cervical cancer (CC) as a single agent after chemotherapy in 2018 and in combination with chemotherapy in 2021, but little is known about how it has been actually used in clinical care. We examined real-world use of pembrolizumab for recurrent CC. Methods: The Merative MarketScan Research Databases were used to identify newly diagnosed CC patients who underwent primary hysterectomy or radiation between 2017-2022. Utilization of systemic therapy was assessed at the time of primary/adjuvant therapy and at first recurrence. Primary/adjuvant chemotherapy was defined as the use of chemotherapy within 4 months of the first cancer claim. First-line (1L) systemic therapy for recurrence was defined as the introduction of a new agent after a gap of > 3 months for patients who received adjuvant/primary chemotherapy or after 4 months from primary hysterectomy or radiation. Treatment for recurrence was classified as platinum alone, platinum-based combination therapy and non-platinum therapy. The use of targeted therapy (bevacizumab) and immunotherapy (pembrolizumab, nivolumab) was noted. Patterns and duration of use of each agent are described. Results: A total of 2727 patients were identified, including 1259 (46.2%) who underwent primary hysterectomy and 1468 (53.8%) treated with primary radiotherapy. Chemotherapy for recurrent CC was initiated in 339 patients (12.4%). Treatment for recurrence was noted in 9.7% of those treated initially with hysterectomy and in 14.8% of those with primary radiotherapy. Among patients treated for recurrence, 24.8% received platinum alone, 52.5% received a platinum-based combination, and 22.7% received non-platinum regimens. A total of 41 patients (12.1%) received pembrolizumab after recurrence, including 7.1% who received pembrolizumab alone, 2.1% who received pembrolizumab in combination with platinum, and 2.9% who received pembrolizumab with non-platinum therapy. Pembrolizumab was used after recurrence in 15.7% of patients who received chemotherapy during primary therapy compared to 7.1% of those who did not receive primary chemotherapy. Use of pembrolizumab was 11.4% in 2018, 17.6% in 2019, 14.0% in 2020, 8.8% in 2021, and 11.8% in 2022. The median duration of 1L chemotherapy for recurrence was 2.3 months (IQR, 1.0-5.8) overall, and 4.3 months (IQR, 2.4, 9.8) for patients treated with pembrolizumab. Patients who had not received primary/adjuvant chemotherapy had a longer duration of treatment with pembrolizumab than those who had received upfront chemotherapy, median 7.5 (IQR 3.9-9.8) versus 4.0 (IQR 2.2-11.0) months, respectively. Conclusions: Platinum-based chemotherapy remains the predominant therapy for recurrent CC. Pembrolizumab use is increasing for patients with recurrent cervical cancer. Longer follow-up is necessary to further evaluate its post-approval usage.

Abstract P1-18-28: Phase IV study evaluating effectiveness and safety of talazoparib in patients with locally advanced or metastatic HER2 negative breast cancer and a BRCA1 or BRCA2 mutation (ViTAL)

Abstract Background: Talazoparib (TALA) is a highly potent PARP inhibitor that has demonstrated clinical benefit in the phase III EMBRACA trial for patients with germline BRCA1 or BRCA2-mutation and a locally advanced or metastatic HER2 negative (HER2-) breast cancer (BC). Methods: ViTAL is an ambispective, multi-center longitudinal, phase IV study that aims to ensure the effectiveness and safety of TALA in the real-world setting among patients with locally advanced or metastatic HER2- BC, with somatic or germline BRCA mutation (sBRCA or gBRCA). This study includes two cohorts: - Cohort 1: patients treated through the French Early Access Program from November 2018 to September 2019. Inclusion of patients with sBRCA mutation was allowed. - Cohort 2: patients treated according to the European Marketing Approval granted 21/09/2021. The primary endpoint is Time to Treatment Discontinuation (TTD) for TALA defined as Time between the date of first dose of TALA and the date of last dose or death. Results: We present the results of Cohort 1 in which includes 85 patients. Patients’ characteristics are as follows: median age 50 years; 46% triple negative BC and 54% ER+ BC; 47% BRCA1-mutated and 53% BRCA2-mutated; 94% gBRCA and 6% sBRCA; 95% ECOG PS 0 or 1; 31% premenopausal status; 40% de novo metastatic BC (mBC). Visceral, bones and central nervous system metastases were found in 61%, 54% and 11% of patients, respectively. No breast or ovarian cancer in first degree relative was found in 35 patients (41%). The median number of prior cytotoxic regimen was 2, 15% were chemo-naïve for mBC; 35% received prior platinum in the neoadjuvant, adjuvant or metastatic setting. For patients with ER+/HER2- mBC the median number of prior endocrine therapy was 2 and 74% of these patients received a CDK4/6 inhibitor prior to TALA. The median follow-up was 17.4 months [range 15.7-20.5]. Of 85 treated patients, 66 patients (78%) experienced permanent discontinuation of TALA due to progressive disease (88%), toxicity (8%), cancer-related death (3%), or other reasons (1.5%). The median TTD for TALA was 9.0 months [range 6.0-11.0] with 35% of patients still in under treatment at 12 months. At least one adverse event (AEs) was recorded in 71% of patients. Hematologic AEs (any grade) occurred in 44% of patients (anemia for 26%, thrombocytopenia for 9%, neutropenia for 8%). The most common non-hematologic AEs were alopecia (6%) and asthenia (5%). Related serious hematologic AEs occurred in 7 (8%) patients including 6 (7%) with anemia. Related serious non-hematologic AEs (vomiting, pyelonephritis) were seen in 2 patients (2%). AEs associated with temporary drug interruption, dose modification and permanent drug discontinuation occurred in 32 (38%), 16 (19%), and 5 (8%) patients respectively. After discontinuation of TALA, 83% of patients received a subsequent treatment with a TTD of 2.4 months [range 1.7-3.3]. The most common subsequent treatments were non-platinum chemotherapy (64%) and platinum therapy (24%). Conclusions: The TTD of 9 months is consistent with the outcomes and safety results of the EMBRACA study. ViTAL, the first real-word study with TALA confirms its interest in locally advanced or metastatic HER2- BC. Analysis of Cohort 2 will occur when data are mature. (Ref Litton JK, Rugo HR, Ellt J et al. Talazoparib in Patients with Advanced Breast Cancer and a Germline BRCA Mutation. N Engl J Med. 2018; 379:753-763. Citation Format: Delphine Loirat, Marie Duboys de Labarre, Christine Essner, Ioana Hrab, Jean-Christophe Thery, Christelle Jouannaud, Cristian Villanueva, Perrine Vuagnat, Pauline Soibinet-Oudot, Anne Creisson, Audrey Mailliez, Jean-Loup Mouysset, Laura Salabert, Nadine Dohollou, Jean-David Fumet, Thibault De La Motte Rouge, Jean-Michel Vauthier, Maylis Decrop, Pascal Pujol. Phase IV study evaluating effectiveness and safety of talazoparib in patients with locally advanced or metastatic HER2 negative breast cancer and a BRCA1 or BRCA2 mutation (ViTAL) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-18-28.

Platinum-based chemotherapy for pancreatic cancer: impact of mutations in the homologous recombination repair and Fanconi anemia genes.

Background:Mutations in homologous recombination (HR) and Fanconi anemia (FA) genes may predispose to pancreatic cancer (PC) and enable the prediction of sensitivity to platinum-based chemotherapy. FOLFIRINOX is a standard treatment option for non-selected PC patients and could be effective due to undiagnosed DNA repair deficiency. Here, we aimed to determine the frequency of mutations in genes involved in the HR and FA pathways, evaluate their clinical implications, and determine the objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) of PC patients treated with platinum.Methods:We performed targeted DNA sequencing of 30 genes (ABRAXAS1, ATM, ATR, BARD1, BLM, BRCA1, BRCA2, BRIP1, CDKN2A, CHEK1, CHEK2, FANCC, FANCF, FANCG, FANCI, FANCL, FANCM, MRE11A, NBN, PALB2, PTEN, RAD50, RAD51C, RAD51D, RAD52, RAD54B, RBBP8, RINT1, SLX4, and XRCC2) for 543 PC patients.Results:In BRCA/PALB2-mutated patients with advanced PC (33 patients, 6.1%), the PFS and OS were higher for first-line platinum therapy than for non-platinum therapy [PFS: HR = 0.28, 95% confidence interval (CI) = 0.10–0.81, p = 0.02; OS: HR = 0.31, 95% CI = 0.08–1.16, p = 0.08]. Among 93 patients (17.1%) with mutations in other HR/FA genes, no statistically significant difference in PFS and OS was observed between first-line platinum therapy and non-platinum therapy (PFS: HR = 0.83, 95% CI = 0.43–1.62, p = 0.59; OS: HR = 0.58, 95% CI = 0.28–1.22, p = 0.15). For patients with early PC, no prognostic value was observed for BRCA1/2, PALB2, or other HR/FA genes mutations. Moreover, a personal history of breast, ovarian, pancreatic, or prostate cancer was identified as the only independent predictor of the risk of BRCA/PALB2 mutations (HR = 5.83, 95% CI = 2.16–15.73, p < 0.01).Conclusion:Mutations in the BRCA1/2 and PALB2 genes increase the sensitivity of PC to platinum agents. Thus, alterations in these genes in PC patients must be determined prior to anticancer therapy.

Pembrolizumab with low-dose carboplatin for recurrent platinum-resistant ovarian, fallopian tube, and primary peritoneal cancer: survival and immune correlates

BackgroundAnti-programmed death 1 (PD1)/programmed cell death ligand 1 (PD-L1) therapies have shown modest activity as monotherapy in recurrent ovarian cancer. Platinum chemotherapies induce T-cell proliferation and enhance tumor recognition. We...

First and Second Line Chemotherapeutic Regimens for Non-Small Cell Lung Carcinomas - The Efficacy of Platinum, Non-Platinum and Combination Therapy: A Literature Review.

Non-small cell lung carcinomas (NSCLC) account for a major part of all lung cancer diagnoses. The current literature review is aimed to analyze the varied chemotherapeutic treatment regimens available and to provide a standard for their use in the present and future scenarios. The current literature review focuses on platinum, non-platinum and combination therapeutic modalities, in the first and second line setting. The review also ensures that docetaxel and/or gemcitabine is a part of the study. A PubMed search for NSCLC identified 70,077 articles. A total of 36 research articles were obtained following the application of keywords and inclusion/exclusion criteria to narrow down our search to meet with the research objective. These articles consider NSCLC and chemotherapeutic treatment modalities as its primary endpoint. These 36 articles included 15 randomized clinical trials, five randomized control trials, five retrospective cohort studies, one case-control study, six review articles and four observational studies. Our analysis shows that there is an increasing potential for the use of non-platinum based drugs in the clinical setting with an efficacy that is at par with that of platinum-based treatment modalities. In fact, the studies have proven a greater advantage with the use of combination therapy (non-platinum + platinum), which can be readily applied as an alternative in the clinical setting while the use of non-platinum drugs (other than docetaxel) as a monotherapy or in combination with other non-platinum based drugs does require further research.

Treatment of recurrent epithelial ovarian cancer.

The majority of patients with advanced ovarian cancer progress after first-line therapy and require further treatment. Tumor biology, prior chemotherapy, responses to previous therapy, performance status, and toxicity are the characteristics that influence treatment choice. These criteria have been linked to the time between relapse and last platinum therapy: the platinum-free interval. Today, patients are classified as either those who are eligible for a new platinum-based therapy or those for whom platinum is not an option. A nonplatinum regimen should be administered to patients who are not candidates for platinum re-treatment. This group includes patients with early relapse after, or progression during, previous platinum-based chemotherapy and patients with platinum intolerability. A single agent such as weekly paclitaxel, pegylated liposomal doxorubicin (PLD), gemcitabine, or topotecan represents the standard. For patients not treated with bevacizumab in the first line, this drug should be added to chemotherapy. For patients for whom platinum rechallenge is an option (because they are potentially platinum-responsive), different strategies are available with the incorporation of biological drugs targeting angiogenesis or the mechanisms of DNA repair. A BRCA mutation status predicts a better response to platinum and poly(adenosine diphosphate-ribose) polymerase (PARP) inhibition. PARP inhibitors and antiangiogenic drugs have proven efficacy as maintenance therapy after chemotherapy and concurrently with chemotherapy, respectively. These agents have changed current practice, although few biomarkers are available to guide decisions. Patients potentially responsive to platinum who cannot receive the drug again can be treated with a combination of trabectedin and PLD, the most active nonplatinum therapy in this setting.

Clinical outcomes in ovarian cancer patients receiving three versus more cycles of chemotherapy after neoadjuvant treatment and interval cytoreductive surgery

ObjectivesTo compare clinical outcomes for stage IIIC and IV ovarian cancer patients receiving neoadjuvant chemotherapy and interval cytoreductive surgery followed by up to three versus more cycles of post-operative chemotherapy.MethodsWe...

Efficacy of platinum-based regimens as the first-line therapy in Chinese patients with advanced TNBC and deleterious BRCA1/2 mutations.

e12565 Background: Platinum-based therapy remains an effective treatment for triple-negative breast cancer (TNBC), however, the usage is largely limited due to its side effect and rapidly developed drug resistance. High prevalence of BRCA1/2 mutations are reported in TNBC. Here we explored efficacy of platinum-based regimens as the first-line treatment for Chinese patients (pts) with advanced TNBC, and analyzed its association with mutations of germline BRCA1/2 (gBRCA). Methods: We retrospectively analyze 220 patients diagnosed as advanced TNBC who were treated at the Dept. of Breast Oncology, Peking University Cancer Hospital in 2013-2018, and routinely evaluated by RECIST 1.1. Statistical analysis is performed in R 3.5.1. Cox proportional-hazard models are used for survival analysis. Results: 129 pts received non-platinum chemotherapy (NPCT) as the first-line therapy, and 91 pts received platinum-based chemotherapy (PBCT). The clinical benefit rate (CBR) and median PFS were not statistically different between NPCT and PBCT groups The median OS was 30.0 and 22.5 months for PBCT and NPCT group respectively (P = 0.09, HR = 0.70). Among them, 114 pts had BRCA gene tested, of which 14 had deleterious gBRCA mutations, 7 in each group. In PBCT group, the CBR was 85.7% and 35.1% for pts with and without deleterious gBRCA mutations respectively (P = 0.04). The median PFS, OS were 14.9 months and 5.3months (P = 0.001), 26.5 and 15.5 months (P = 0.16) for pts with and without the gBRCA mutations. No significant difference was observed between NPCT pts with and without gBRCA mutations as regards the CBR, PFS and OS. PBCT Pts had significantly more grade 3-4 anaemia (5.5% vs 0%) and thrombocytopenia (8.8% vs 0%) while higher percentage of palmar-plantar erythrodysesthesia (PPE) (12.4% vs 0%) and peripheral neuropathy (8.6% vs 1.1%) were observed in NPCT pts. Conclusions: The efficacy of platinum-based regimens as the first-line treatment of advanced TNBC insignificantly differs from that of non-platinum therapy. However, they are more effective for patients with deleterious gBRCA mutations, suggesting a BRCA1/2 genetic testing may be warranted for such patients.

Adherence to treatment recommendations and outcomes for women with ovarian cancer at first recurrence

ObjectiveTreatment selection for recurrent ovarian cancer is typically based on the duration of time between the completion of adjuvant, platinum-based therapy and the time of recurrence, the platinum free interval (PFI). We examined the use of, and outcomes associated with platinum-based chemotherapy based on the PFI in women with recurrent ovarian cancer. MethodsThe Surveillance, Epidemiology, and End Results-Medicare database was used to identify women aged >65years with epithelial ovarian cancer who underwent surgery and platinum-based chemotherapy and who developed a recurrence >3months after the completion of adjuvant therapy. Patients were stratified by PFI into 3 groups: PFI <6months, PFI 7–12months, and PFI >12months. Multivariable models were used to examine predictors of use of platinum-based therapy and survival for each group. ResultsA total of 2369 patients were identified. In women with a PFI of ≤6months, treatment consisted of platinum-based combination therapy in 28.2%, single agent platinum in 5.2% and non-platinum therapy in 66.6%. Corresponding rates of these treatments among women with a PFI of 7–12months were 39.7%, 12.4% and 47.9%, respectively; the rates were 57.6%, 13.2% and 29.3% in those with a PFI of >12months, respectively. Median survival was 13, 18, and 27months for patients with a PFI of ≤6months, 7–12months, and >12months, respectively (P<0.0001). For all three groups, platinum combination therapy was associated with decreased risk of death compared to non‑platinum based therapy. ConclusionPlatinum free interval is a strong predictor of survival in elderly women with recurrent ovarian cancer. There is widespread variation in treatment selection for women with recurrent ovarian cancer with many women receiving non-guideline based regimens.

Treatment of recurrent ovarian cancer

Despite optimal surgery and appropriate first-line chemotherapy, ∼70%–80% of patients with epithelial ovarian cancer will develop disease relapse. The same modalities as used primarily are available for treatment of recurrent ovarian cancer (ROC). The rationale for repetitive surgery in ROC was based on a stable body of retrospective data; however, prospective data were missing. Now, preliminary data from the prospective AGO-DESKTOP III give evidence that surgery for ROC seems to be of benefit for selected patients with platinum-sensitive relapse undergoing complete resection. With respect to systemic therapy, tumor histology, BRCA status, the platinum-free interval (PFI) and previous treatment with bevacizumab (anti-VEGF monoclonal antibody) are considered the most important features that influence treatment choice in ROC. In patients with resistant or refractory relapse (PFI < 6 months), monotherapy with a non-platinum drug or participation in clinical trials is indicated. The association of non-platinum monotherapy with bevacizumab, followed by maintenance has been approved in this setting in some European countries due to PFS benefit. In patients with partially sensitive relapse (PFI between 6 and 12 months), two options are available: platinum doublets or non-platinum therapy (single agent or combination). The pegylated liposomal doxorubicin/trabectedin combination represents a viable alternative in patients that cannot receive platinum. In platinum-sensitive patients, treatment with platinum-based combinations is associated with PFS advantage compared with single agents or non-platinum combinations. The presence of germline or somatic BRCA mutations allows platinum-responsive patients to optimize chemotherapy efficacy and prolonging PFS by the use of olaparib (PARP inhibitor) given as maintenance therapy until progression. In patients not pretreated with bevacizumab in first line, the carboplatin/gemcitabine/bevacizumab combination, followed by maintenance is a viable alternative in platinum-sensitive patients (PFI> 6 months). The integration of surgery, with a ‘personalized’ approach by the use of antiangiogenic agent and of PARP inhibitors is affecting survival of patients with recurrent disease and will help epithelial ovarian cancer to become a chronic disease.

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]

Routine Clinical Practice for Patients With Recurrent Ovarian Carcinoma

Treatment options for patients with recurrent ovarian carcinoma are diverse, and different therapies are recommended based on platinum-free interval (PFI). Data examining the association between platinum sensitivity, treatment strategy, and outcomes are limited, particularly for partially platinum-sensitive (PPS) patients. This study characterized clinical features and outcomes in patients with recurrent ovarian carcinoma in the context of sensitivity to platinum-based therapy. Anonymized case records were obtained from eligible European medical sites. Eligible patients were 18 years or older with epithelial ovarian carcinoma who had received 1 or more platinum-based therapies and had 1 or more subsequent relapses. Patient records were categorized by PFI and analyzed based on demographic and clinical data using descriptive statistics. There was no difference between PFI in PPS patients receiving platinum versus nonplatinum therapy (8.9 [range, 6.0-12.0] and 8.3 [range, 6.0-11.3] months, respectively). Overall survival in patients with platinum-sensitive, PPS, platinum-resistant, and platinum-refractory disease was 43.0 (95% confidence interval [95% CI], 25.1-42.3), 20.5 (95% CI, 17.7-24.8), 12.7 (95% CI, 10.4-14.2), and 9.8 (95% CI, 6.6-14.9) months, respectively. Among PPS patients, overall survival was 23.5 (95% CI, 18.4-37.3) and 18.7 (95% CI, 11.0-23.5) months for those who received platinum and nonplatinum-based therapy, respectively. No demographic or clinical characteristics were identified that indicated a difference between PPS patients who received platinum-based therapy versus those who did not. Partially platinum-sensitive patients with recurrent ovarian carcinoma who received platinum-based therapy had improved outcomes compared with those who did not. No clear demographic criteria for choosing platinum- versus nonplatinum-based therapy for PPS patients were identified from patient records.

Chemotherapy for advanced non-small cell lung cancer in the elderly population.

Approximately 50% of patients with newly diagnosed non-small cell lung cancer (NSCLC) are over 70 years of age at diagnosis. Despite this fact, these patients are underrepresented in randomized controlled trials (RCTs). As a consequence, the most appropriate regimens for these patients are controversial, and the role of single-agent or combination therapy is unclear. In this setting, a critical systematic review of RCTs in this group of patients is warranted. To assess the effectiveness and safety of different cytotoxic chemotherapy regimens for previously untreated elderly patients with advanced (stage IIIB and IV) NSCLC. To also assess the impact of cytotoxic chemotherapy on quality of life. We searched the following electronic databases: Cochrane Central Register of Controlled Trials (CENTRAL; 2014, Issue 10), MEDLINE (1966 to 31 October 2014), EMBASE (1974 to 31 October 2014), and Latin American Caribbean Health Sciences Literature (LILACS) (1982 to 31 October 2014). In addition, we handsearched the proceedings of major conferences, reference lists from relevant resources, and the ClinicalTrial.gov database. We included only RCTs that compared non-platinum single-agent therapy versus non-platinum combination therapy, or non-platinum therapy versus platinum combination therapy in patients over 70 years of age with advanced NSCLC. We allowed inclusion of RCTs specifically designed for the elderly population and those designed for elderly subgroup analyses. Two review authors independently assessed search results, and a third review author resolved disagreements. We analyzed the following endpoints: overall survival (OS), one-year survival rate (1yOS), progression-free survival (PFS), objective response rate (ORR), major adverse events, and quality of life (QoL). We included 51 trials in the review: non-platinum single-agent therapy versus non-platinum combination therapy (seven trials) and non-platinum combination therapy versus platinum combination therapy (44 trials). Non-platinum single-agent versus non-platinum combination therapy Low-quality evidence suggests that these treatments have similar effects on overall survival (hazard ratio (HR) 0.92, 95% confidence interval (CI) 0.72 to 1.17; participants = 1062; five RCTs), 1yOS (risk ratio (RR) 0.88, 95% CI 0.73 to 1.07; participants = 992; four RCTs), and PFS (HR 0.94, 95% CI 0.83 to 1.07; participants = 942; four RCTs). Non-platinum combination therapy may better improve ORR compared with non-platinum single-agent therapy (RR 1.79, 95% CI 1.41 to 2.26; participants = 1014; five RCTs; low-quality evidence).Differences in effects on major adverse events between treatment groups were as follows: anemia: RR 1.10, 95% 0.53 to 2.31; participants = 983; four RCTs; very low-quality evidence; neutropenia: RR 1.26, 95% CI 0.96 to 1.65; participants = 983; four RCTs; low-quality evidence; and thrombocytopenia: RR 1.45, 95% CI 0.73 to 2.89; participants = 914; three RCTs; very low-quality evidence. Only two RCTs assessed quality of life; however, we were unable to perform a meta-analysis because of the paucity of available data. Non-platinum therapy versus platinum combination therapy Platinum combination therapy probably improves OS (HR 0.76, 95% CI 0.69 to 0.85; participants = 1705; 13 RCTs; moderate-quality evidence), 1yOS (RR 0.89, 95% CI 0.82 to 0.96; participants = 813; 13 RCTs; moderate-quality evidence), and ORR (RR 1.57, 95% CI 1.32 to 1.85; participants = 1432; 11 RCTs; moderate-quality evidence) compared with non-platinum therapies. Platinum combination therapy may also improve PFS, although our confidence in this finding is limited because the quality of evidence was low (HR 0.76, 95% CI 0.61 to 0.93; participants = 1273; nine RCTs).Effects on major adverse events between treatment groups were as follows: anemia: RR 2.53, 95% CI 1.70 to 3.76; participants = 1437; 11 RCTs; low-quality evidence; thrombocytopenia: RR 3.59, 95% CI 2.22 to 5.82; participants = 1260; nine RCTs; low-quality evidence; fatigue: RR 1.56, 95% CI 1.02 to 2.38; participants = 1150; seven RCTs; emesis: RR 3.64, 95% CI 1.82 to 7.29; participants = 1193; eight RCTs; and peripheral neuropathy: RR 7.02, 95% CI 2.42 to 20.41; participants = 776; five RCTs; low-quality evidence. Only five RCTs assessed QoL; however, we were unable to perform a meta-analysis because of the paucity of available data. In people over the age of 70 with advanced NSCLC who do not have significant co-morbidities, increased survival with platinum combination therapy needs to be balanced against higher risk of major adverse events when compared with non-platinum therapy. For people who are not suitable candidates for platinum treatment, we have found low-quality evidence suggesting that non-platinum combination and single-agent therapy regimens have similar effects on survival. We are uncertain as to the comparability of their adverse event profiles. Additional evidence on quality of life gathered from additional studies is needed to help inform decision making.

Chemotherapy for advanced non-small cell lung cancer in the elderly population.

Approximately 50% of patients with newly diagnosed non-small cell lung cancer (NSCLC) are over 70 years of age at diagnosis. Despite this fact, these patients are underrepresented in randomized controlled trials (RCTs). As a consequence, the most appropriate regimens for these patients are controversial, and the role of single-agent or combination therapy is unclear. In this setting, a critical systematic review of RCTs in this group of patients is warranted. To assess the effectiveness and safety of different cytotoxic chemotherapy regimens for previously untreated elderly patients with advanced (stage IIIB and IV) NSCLC. To also assess the impact of cytotoxic chemotherapy on quality of life. Search methods: We searched the following electronic databases: Cochrane Central Register of Controlled Trials (CENTRAL; 2014, Issue 10), MEDLINE (1966 to 31 October 2014), EMBASE (1974 to 31 October 2014), and Latin American Caribbean Health Sciences Literature (LILACS) (1982 to 31 October 2014). In addition, we handsearched the proceedings of major conferences, reference lists from relevant resources, and the ClinicalTrial.gov database.Selection criteria: We included only RCTs that compared non-platinum single-agent therapy versus non-platinum combination therapy, or non-platinum therapy versus platinum combination therapy in patients over 70 years of age with advanced NSCLC. We allowed inclusion of RCTs specifically designed for the elderly population and those designed for elderly subgroup analyses.Data collection and analysis: Two review authors independently assessed search results, and a third review author resolved disagreements. We analyzed the following endpoints: overall survival (OS), one-year survival rate (1yOS), progression-free survival (PFS), objective response rate (ORR), major adverse events, and quality of life (QoL). We included 51 trials in the review: non-platinum single-agent therapy versus non-platinum combination therapy (seven trials) and non-platinum combination therapy versus platinum combination therapy (44 trials).Non-platinum single-agent versus non-platinum combination therapyLow-quality evidence suggests that these treatments have similar effects on overall survival (hazard ratio (HR) 0.92, 95% confidence interval (CI) 0.72 to 1.17; participants = 1062; five RCTs), 1yOS (risk ratio (RR) 0.88, 95% CI 0.73 to 1.07; participants = 992; four RCTs), and PFS (HR 0.94, 95% CI 0.83 to 1.07; participants = 942; four RCTs). Non-platinum combination therapy may better improve ORR compared with non-platinum single-agent therapy (RR 1.79, 95% CI 1.41 to 2.26; participants = 1014; five RCTs; low-quality evidence).Differences in effects on major adverse events between treatment groups were as follows: anemia: RR 1.10, 95% 0.53 to 2.31; participants = 983; four RCTs; very low-quality evidence; neutropenia: RR 1.26, 95% CI 0.96 to 1.65; participants = 983; four RCTs; low-quality evidence; and thrombocytopenia: RR 1.45, 95% CI 0.73 to 2.89; participants = 914; three RCTs; very low-quality evidence. Only two RCTs assessed quality of life; however, we were unable to perform a meta-analysis because of the paucity of available data.Non-platinum therapy versus platinum combination therapyPlatinum combination therapy probably improves OS (HR 0.76, 95% CI 0.69 to 0.85; participants = 1705; 13 RCTs; moderate-quality evidence), 1yOS (RR 0.89, 95% CI 0.82 to 0.96; participants = 813; 13 RCTs; moderate-quality evidence), and ORR (RR 1.57, 95% CI 1.32 to 1.85; participants = 1432; 11 RCTs; moderate-quality evidence) compared with non-platinum therapies. Platinum combination therapy may also improve PFS, although our confidence in this finding is limited because the quality of evidence was low (HR 0.76, 95% CI 0.61 to 0.93; participants = 1273; nine RCTs).Effects on major adverse events between treatment groups were as follows: anemia: RR 2.53, 95% CI 1.70 to 3.76; participants = 1437; 11 RCTs; low-quality evidence; thrombocytopenia: RR 3.59, 95% CI 2.22 to 5.82; participants = 1260; nine RCTs; low-quality evidence; fatigue: RR 1.56, 95% CI 1.02 to 2.38; participants = 1150; seven RCTs; emesis: RR 3.64, 95% CI 1.82 to 7.29; participants = 1193; eight RCTs; and peripheral neuropathy: RR 7.02, 95% CI 2.42 to 20.41; participants = 776; five RCTs; low-quality evidence. Only five RCTs assessed QoL; however, we were unable to perform a meta-analysis because of the paucity of available data. In people over the age of 70 with advanced NSCLC who do not have significant co-morbidities, increased survival with platinum combination therapy needs to be balanced against higher risk of major adverse events when compared with non-platinum therapy. For people who are not suitable candidates for platinum treatment, we have found low-quality evidence suggesting that non-platinum combination and single-agent therapy regimens have similar effects on survival. We are uncertain as to the comparability of their adverse event profiles. Additional evidence on quality of life gathered from additional studies is needed to help inform decision making.

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.

Prolonging the platinum-free interval (PFI) with trabectedin to allow retreatment with platinum-based chemotherapy in patients with platinum-refractory and -resistant recurrent ovarian cancer (PROC).

e16543 Background: Dose-dense therapy and administration of sequential non-platinum agents in PROC plays a role in reverting platinum-resistance and may improve the prognosis of such patients over years (Bamias A, 2013). The PFI extension is one of the current strategies to improve survival in partially platinum-sensitive (PPS) ROC, with a PFI 6-12 months (Poveda A, 2011). Trabectedin is a minor groove DNA-binder, which may play a role in reverting platinum resistance in patients with PROC and PPS ROC. Methods: Trabectedin 1.1-1.5 mg/m2as single agent was given as a 3-h infusion every 3 weeks with antiemetic and steroid premedication. Tumor response was assessed every 12 weeks. Results: Overall, 27 patients (24 with PROC and 3 with PPS ROC) treated from 2003 to 2013 in a single institution were included in the analysis. The patients had a median age of 63 years (range 45-81), most had serous-papillary (67%), clear-cell (11%), endometrioid (7%) and other (15%) histological subtypes and received a median of 5 prior chemotherapy lines (range: 1-9), 89% of whom also received other non-platinum agents. A median of 4.9 trabectedin cycles (range 1-14) was given. The overall response rate (ORR) was 15%, with a median duration of response of 16.5 weeks (range 5.86-44.43), while 41% of patients achieved stable disease (SD) lasting ≥4 months as best response. Thirteen of 27 patients were retreated with platinum-based chemotherapy after progression with trabectedin treatment. The ORR to platinum retreatment was 54% (n = 7) and SD was achieved in 8% (n = 1) of these patients, for an overall clinical benefit of 61%. Conclusions: Intercalation of a non-platinum therapy with trabectedin prior to subsequent platinum rechallenge may contribute to prolong PFI and to re-sensitize the patients with PROC and PPS ROC to further platinum-based therapies leading to a significant clinical benefit. Further prospective studies are warranted to determine the contribution of sequential treatments with trabectedin in patients with PROC and PPS ROC.

Current and Potential Treatments for Cervical Cancer

Cervical cancer is the third most common carcinoma in women worldwide. Despite increasing efforts to improve therapy in this disease, a significant proportion of women still die, mostly from recurrent or chemoresistant disease. This review discusses current treatments for early cervical cancer, advanced disease, and recurrent cervical cancer, and covers concurrent chemoradiation, neoadjuvant chemotherapy before surgery and radiation, single agent treatment, combination treatment, platinum-based and non-platinum based therapy. We also discuss promising therapeutics trategies for cervical cancer including targeted therapy, cell-based therapy, combined siRNA and chemotherapy, and immunotherapy.

Anaplastic Lymphoma Kinase Gene Rearrangements in Non-small Cell Lung Cancer are Associated with Prolonged Progression-Free Survival on Pemetrexed

To explore whether the progression-free survival (PFS) with pemetrexed differs between anaplastic lymphoma kinase (ALK)-positive and other major molecular subtypes of non-small cell lung cancer. In an ALK-enriched population, patients with metastatic non-small cell lung cancer were screened by ALK fluorescence in situ hybridization and for epidermal growth factor receptor (EGFR) and KRAS mutations. Triple-tested, pemetrexed-treated patients (monotherapy or combination therapy) were identified and PFS with pemetrexed captured retrospectively. Eighty-nine eligible cases were identified (19 ALK fluorescence in situ hybridization positive, 12 EGFR mutant, 21 KRAS mutant, and 37 triple negatives). Eighty-three cases (93%) were adenocarcinomas, two were adenosquamous, one squamous, and three had large cell histology. None of the ALK-positive patients had received crizotinib before pemetrexed. Pemetrexed was first-line therapy in 48% (72% as platinum-based combinations). Median PFS (95% confidence interval) data were EGFR mutant (5.5 months; 1-9), KRAS mutant (7 months; 1.5-10), ALK positive (9 months; 3-12), and triple negative (4 months; 3-5). In a multivariate analysis adjusting for line of therapy, mono- versus platinum and nonplatinum combination therapy, age, sex, histology, and smoking status, the only variable associated with prolonged PFS on pemetrexed was ALK+ (hazard ratio = 0.36 [95% confidence interval: 0.17-0.73], p = 0.0051). In this exploratory analysis, ALK-positive patients have a significantly longer PFS on pemetrexed compared with triple-negative patients, whereas EGFR or KRAS mutant patients do not. This information should be considered when sizing randomized studies in ALK-positive patients that involve pemetrexed. Pemetrexed should also be prioritized as a cytotoxic to explore further in patients with known ALK-positive disease.

Weekly paclitaxel (wP) as single agent or in combination with weekly topotecan (wT) or carboplatin (C) in patients with resistant ovarian cancer (ROC): The phase II CARTAXHY randomized trial from GINECO

5557 Background: For ROC patients (pts) with early progression during or after (&lt; 6 months) platinum and 3 weekly P, use of single non-platinum agent including wP is standard (Kristensen G, et al. J Clin Oncol 26: 2008 abstr 5508). Few randomized trials have explored combination therapy in this setting. Methods: Pts with ROC after a first or second line including a platinum and a taxane were randomized to receive wP (80 mg/m2/week) alone or in combination with wT (3mg/m2/week) or C (AUC 5 every 4 weeks). The primary end-point was the comparison of progression-free survival (PFS) between single non-platinum agent and combination therapy (wP+wT or wP+C). Secondary objectives included safety, QoL, response rate (RR) and overall survival. Results: From April 2004 to August 2008, 165 pts were accrued (wP 57, wP+wT 57, wP+C 51). Median number of cycles and P dose-intensity (mg/m2/week) was 4.6 and 70, 4.2 and 63 in monotherapy and combination therapy arms respectively. Non-hematological toxicity was not different between the arms, except an excess of hypersensitivity reactions in the wP+C arm. Grade 3–4 neutropenia (48 vs 13% of pts), and anemia (24 vs 6%) were more frequent in combination therapy than in single agent arm and similar with wT or C combination. Febrile neutropenia was experienced by 5 pts treated with combination therapy. Discontinuation from drug treatment was more frequent with combination therapy (24% of pts) than with monotherapy (4%), mainly due to hematotoxicity. RR was 34, 38 and 39% for wP, wP+wT and wP+C respectively. Median PFS of pts treated with single agent (112 days) was not significantly different from those treated with combination therapy (149 days) (p = 0,62) and was similar in wP+wT (152 days) or wP+C (146 days) arms. Treatment with single non-platinum agent or combination therapy was not found an independent parameter when added to a Cox model including prognostic variables. Conclusions: Combination therapy (CT) in platinum resistant ovarian cancer was found more toxic than weekly paclitaxel and the PFS advantage from CT was not statistically significant. No significant financial relationships to disclose.

A phase II trial of SNS-595 in women with platinum resistant epithelial ovarian cancer

5582 Background: SNS-595 is under clinical investigation in acute leukemia and ovarian cancer. Clinical responses have been observed in these indications, and in non-small cell and small cell lung cancers. SNS-595 is a replication-dependent DNA damaging agent that causes irreversible G2 arrest and apoptosis via DNA intercalation and topoisomerase II inhibition. A phase 2 study of single agent SNS-595 in ovarian cancer was initiated based on phase 1 clinical activity in patients (pts) with ovarian cancer, including one partial response (PR). Methods: Pts had advanced platinum resistant (progressed during or relapsed within 6 months of platinum based therapy) epithelial ovarian cancer who had progressive disease after 1 or 2 prior platinum containing regimens; pts could have received an additional biologic or non-platinum therapy after becoming platinum-resistant. A GOG PS of 0–1 and adequate hematologic, hepatic and renal status were required. Pts received 48 mg/m2 SNS-595 by 10 minute IV infusion on Day 1...