Cycles Of First-line Platinum-based Chemotherapy Research Articles

Four versus six cycles of platinum-based chemotherapy for advanced Urothelial carcinoma in the era of immune checkpoint inhibitors: A retrospective cohort study (FOCUS, KCSG-GU23-08)

IntroductionThis study aimed to assess the survival outcomes of four versus six cycles of first-line platinum-based chemotherapy (PBCT) in the era of immune checkpoint inhibitor (ICI) for patients with advanced urothelial carcinoma (UC). Patients and MethodsPatients with histologically confirmed advanced UC were allocated to either the 4-cycle PBCT (C4) or 6-cycle PBCT (C6) groups and retrospectively analyzed. After the planned cycles, active surveillance was conducted every 6–8 weeks, followed by second-line treatments, including ICIs, upon progression. The primary endpoint was overall survival (OS). ResultsOf the 161 patients initiated with PBCT between September 2016 and February 2023, 27 were deemed ineligible, leaving 134 patients for analysis (C4, n = 58; C6, n = 77). Baseline characteristics, including cisplatin eligibility, were similar between the groups. With a median follow-up of 23.7 months (95 % confidence interval (CI), 20.3–27.1), no significant difference was observed in OS between the C6 and C4 groups (18.7 months vs. 17.0 months; hazard ratio (HR) 1.27, P = 0.343). In multivariate analysis adjusted for sex, initial presentation, metastatic lesion, and ECOG PS, no significant difference was observed between the C6 and C4 groups (HR 1.29, 95 % CI, 0.78–2.14, P = 0.315). ConclusionsThis study showed that four cycles of PBCT do not differ from six cycles regarding OS.

A case of pagetoid spread of urothelial carcinoma with notable reduction achieved through enfortumab vedotin, resulting in complete surgical resection.

Secondary extramammary Paget's disease is a rare condition associated with the contiguous extension of tumor cells from the underlying adnexal structures, genitourinary, or gastrointestinal tracts. We report the case of an 80-year-old female with a 7-year history of urothelial carcinoma who presented with erythema of the labia majora. The diagnosis was pagetoid spread of urothelial carcinoma. The patient declined surgical resection of the lesion. She underwent nine cycles of first-line platinum-based chemotherapy and received one course of pembrolizumab for metastatic urothelial carcinoma. As the lesion progressively enlarged, third-line therapy with enfortumab vedotin was initiated, which resulted in significant tumor reduction. This allowed for a successful surgical complete resection of the tumor. Enfortumab vedotin was highly effective and demonstrated dramatic efficacy for controlling extramammary Paget's disease secondary to urothelial carcinoma.

Optimal Number of Cycles of First-line Platinum-based Chemotherapy for Metastatic Urothelial Carcinoma.

In recent years, switch maintenance after platinum-based chemotherapy has been a standard of care. However, the appropriate number of systemic chemotherapy cycles against advanced-stage urothelial carcinoma (UC) remains unclear. This study assessed the survival outcomes of first-line platinum-based chemotherapy according to treatment cycles in patients with metastatic disease. We retrospectively evaluated patients with metastatic bladder and upper urinary tract cancer who received platinum-based combination therapy. Overall survival (OS) was evaluated using the Kaplan-Meier method and the log-rank test. Of 179 patients, 47 (26.3%) were women, and 73 (40.8%) had upper urinary tract cancer. Furthermore, 47 (26.3%) who were not eligible for cisplatin received carboplatin. The median number of treatment cycles was 3 (range=1-14 cycles). The rates of progressive disease within two cycles, from two to four cycles, and from four to six cycles were 18.4%, 19.2%, and 30.6%, respectively. The median OS of patients with 2, 3, 4, 5-6, and ≥7 treatment cycles were 8.6, 14.3, 21.3, 24.4, and 26.1 months, respectively. The OS did not significantly differ between patients receiving four treatment cycles and those receiving ≥5 treatment cycles. In patients with disease control (complete or partial response or stable disease) receiving ≥4 treatment cycles, there was no significant difference in terms of OS between patients receiving four cycles and those receiving six cycles. Four cycles of first-line platinum-based chemotherapy can be effective in patients with metastatic UC.

A retrospective study on optimal number of cycles of the first-line platinum-based chemotherapy for metastatic urothelial carcinoma

Recently, switch maintenance with avelumab has been approved for the treatment of advanced or metastatic urothelial carcinoma (UC), with no progression after four to six cycles of first-line platinum-based chemotherapy. However, the optimal number of cycles of platinum-based chemotherapy has not been determined. To analyze the clinical characteristics of patients with advanced UC who were treated with platinum-based chemotherapy and investigate the association between the number of cycles of the treatment and the patients' overall survival. A total of 124 patients with advanced UC who were treated with first-line platinum-based chemotherapy at Osaka City University Hospital between April 2009 and January 2020 were retrospectively reviewed. Of the 124 patients, clinical information regarding overall survival was available for 115 patients. The median age was 72 years (range, 43-95 years). Only 59 patients (51.3 %) were treated with gemcitabine and cisplatin, and 52 patients (45.2 %) were treated with gemcitabine and carboplatin. The median number of cycles was three (1-8), and the percentage of patients who discontinued chemotherapy due to progressive disease was 80.3%, 64.0%, and 86.4% in those receiving one to three, four, and five or more cycles, respectively. Moreover, no difference in overall survival was observed between patients who received four cycles and those who received five or more cycles at both univariate and multivariate levels. The present study shows that five or more cycles of first-line platinum-based chemotherapy did not prolong overall survival compared with four cycles, suggesting that four cycles of chemotherapy might be sufficient, considering the new treatment strategy involving switch maintenance with avelumab.

Randomized phase II study of niraparib plus best supportive care (BSC) versus BSC alone as maintenance treatment in patients with advanced urothelial carcinoma (UC) whose disease did not progress after first-line platinum-based chemotherapy (PBCT): The Meet-URO12 trial.

442 Background: Niraparib is an oral inhibitor of poly ADP-ribose polymerase (PARP) enzymes. Based on the association of mutations in homologous recombination repair (HRR) genes with platinum sensitivity, aim of this phase II trial was to compare maintenance treatment with niraparib plus BSC vs. BSC alone in pts with advanced UC who obtain objective response (OR) or stable disease (SD) with first-line PBCT. Methods: Meet-URO12 is a randomized phase II multicentre trial enrolling pts with advanced transitional cell UC, without evidence of progression after 4-6 cycles of first-line PBCT (cisplatin or carboplatin). Pts were randomized (2:1) to experimental arm A (niraparib 300 or 200 mg daily according to body weight and baseline platelets, plus BSC) or control arm B (BSC alone). Primary endpoint was progression-free survival (PFS). 77 pts were planned and 65 PFS events were needed to detect Hazard Ratio 0.57, with 80% power and one-tailed alpha 0.1. Accrual was prematurely stopped due to availability of avelumab in the same setting, and protocol was amended to perform analysis with ≥ 40 PFS events. Molecular characteristics, including alteration of HRR genes, were assessed in formalin-fixed paraffin-embedded tumour samples using the FoundationOne CDx assay. Results: Between Aug 2019 and Mar 2021, 58 pts were randomized in 14 Italian centers (39 assigned to arm A and 19 to arm B); 1 pt assigned to arm A did never start niraparib. Median age was 69y (44-84); ECOG PS0 65.5%/ PS1 34.5%; best response with PBCT OR 55.2%/ SD 44.8%. As of Aug 2021, after a median follow-up of 8.5 mos, 47 PFS events were recorded. Median PFS was 2.1 mos in arm A and 2.4 mos in arm B (HR 0.92; 95%CI 0.49 – 1.75, p=0.81). 6-months progression-free rate was 28.2% and 26.3%, respectively. Time to treatment failure for pts who started niraparib was 2.4 mos. Out of 47 pts with molecular info, 21 (44.7%) had HRR alterations: 6 (12.8%) known pathogenic mutations and 15 (31.9%) variants of unknown significance. In pts with pathogenic mutations, median PFS was 2.0 mos in arm A and 1.9 mos in arm B. In pts with any HRR mutation, median PFS was 2.0 mos in arm A and 2.0 mos in arm B. Any grade≥3 treatment-emergent adverse event (AE) was reported in 25/38 pts (65.8%) in arm A and in 3/19 pts (15.8%) in arm B. 18/38 pts (47.4%) needed dose reduction of niraparib. Most common AEs with niraparib were anemia (50.0%, G3 10.5%), thrombocytopenia (36.8%, G3-4 15.8%), neutropenia (21.1%, G3 5.3%), fatigue (31.6%, G3 15.8%), constipation (31.6%, G3 2.6%), mucositis (13.2%, G3 2.6%), nausea (13.2%, G3 2.6%). Conclusions: Maintenance niraparib plus BSC did not prolong PFS, as compared with BSC alone, among pts with urothelial cancer without progression after first-line PBCT. Clinicaltrials.gov Identifier. NCT03945084. Clinical trial information: NCT03945084.

Phase II open-label study of S-588410 as maintenance monotherapy after first-line platinum-containing chemotherapy in patients with advanced or metastatic urothelial carcinoma.

440 Background: S-588410 is a cancer peptide vaccine composed of 5 human leukocyte antigen (HLA)-A*24:02-restricted epitope peptides derived from 5 cancer-testis antigens: DEPDC1, MPHOSPH1, URLC10, CDCA1 and KOC1; all of which are highly expressed in urothelial carcinoma. This study aimed to evaluate the effect of S-588410 maintenance therapy on peptide-specific cytotoxic T-lymphocyte (CTL) induction in patients with advanced or metastatic urothelial carcinoma after first-line platinum-based chemotherapy. Methods: An open-label, multicenter phase II trial was performed across 62 sites in Japan, the United Kingdom, France and Bulgaria (EudraCT 2013-005274-22). Eligible patients had completed ≥4 cycles of first-line platinum-based chemotherapy without disease progression. HLA-A*24:02-positive patients received S-588410 (1 mg of each of 5 peptides mixed with Montanide ISA 51 VG) subcutaneously weekly for 12 weeks, then every 2 weeks for up to 2 years. HLA-A*24:02-negative patients were enrolled in an observation group and did not receive study drug. The primary endpoint for the S-588410 group was the CTL induction rate at 12 weeks, defined as the proportion of patients who showed increased CTL activity for ≥1 peptide. Secondary endpoints included CTL induction rate after 1 year, antitumor effect defined by immune-related response criteria, progression-free survival (PFS), overall survival (OS), and safety. Results: A total of 81 patients with platinum-sensitive advanced or metastatic urothelial carcinoma were enrolled (S-588410 group, n=45; observation group, n=36) between April 2014 and November 2017. Most patients were male and Asian with a mean age of 67 years. CTLs were induced in 42 (93.3%) patients who received S-588410 for 12 weeks (P<0.0001, one-sided binomial test where the CTL induction rate is ≤50% as the null hypothesis). The CTL induction rate steadily increased to 95.6% within 48 weeks. CTL activity was high for the DEPDC1, MPHOSPH1 and URLC10 peptides. The response rate (immune-related complete response [CR] or partial response [PR]) was 8.9% (4/45 patients) in the S-588410 group and 0% in the observation group. Tumor imaging showed gradual (PR, n=3) and durable (CR, n=1) tumor shrinkage after ≥36 weeks in the S-588410 group. Median PFS was 18.1 weeks in the S-588410 group and 12.5 weeks in the observation group. Median OS was 71 and 99 weeks, respectively. The most frequent treatment-emergent adverse event was injection site reaction (42/45 patients [93.3%]; Grades 1–3). Pyrexia, rash and pruritus were also observed in the S-588410 group, but not the observation group. Conclusions: S-588410 showed a potent immune response and acceptable safety profile in patients with advanced or metastatic urothelial carcinoma, potentially offering a clinical benefit as post-chemotherapy maintenance therapy. Clinical trial information: EudraCT 2013-005274-22.

Maintenance chemotherapy is effective in patients with metastatic triple negative breast cancer after first-line platinum-based chemotherapy

Platinum-based chemotherapy (PBCT) has gained an important position as a first-line treatment for metastatic triple-negative breast cancer (mTNBC). We assessed whether maintenance chemotherapy maintenance was superior to observation after first-line PBCT in patients with mTNBC. A total of 265 patients with mTNBC who had exhibited non-PD after 4-6 cycles of firstline PBCT at the Fudan University Shanghai Cancer Center from January 2008 to April 2019 were retrospectively analyzed. 107 patients who did not receive additional treatment were defined as the control observation group, and the remaining 158 patients who continued to receive maintenance therapy were defined as the maintenance treatment group. The median progression-free survival (PFS) time in the maintenance group was 9.63 months, which was significantly longer than the PFS time of 7.47 months in the observation group (HR 0.49, 95% CI: 0.37-0.67, P<0.0001). The median overall survival (OS) of the observation group and the maintenance group was 25.37 months and 31.27 months, respectively (HR 0.65, 95% CI: 0.44-0.95, P=0.019). The survival benefit was still present after adjusting baseline characteristics. Moreover, multivariate analyses suggested that maintenance chemotherapy is an independent predictive factor for both PFS and OS. Interaction and stratified analyses showed no difference in the PFS with between the single-drug maintenance strategy, single agent or doublet group and the doublet-drug maintenance group. The most common adverse event in this study was hematologic toxicity. Except for hand-foot syndrome (0 vs. 7.6%, P=0.004), the incidence of other adverse events was not significantly different between the observation and maintenance groups. After achieving non-PD with the first-line PBCT in mTNBC patients, chemotherapy maintenance may provide OS benefit prior to the era of biologicals.

A Real-World Study of Maintenance Chemotherapy vs. Observation in Patients with Metastatic Triple Negative Breast Cancer after Achieving Disease Control with First-Line Platinum-Based Chemotherapy

Background: The platinum-based chemotherapy (PBCT) has gained its important position in the first-line treatment of metastatic triple-negative breast cancer (mTNBC). We accessed whether maintenance chemotherapy is superior to observation after first-line PBCT in patients with mTNBC. Patients and Methods: From January 2008 to November 2016, a total of 232 patients with mTNBC exhibited disease control with 4-6 cycles of first-line PBCT in the Fudan University Shanghai Cancer Center were retrospectively analyzed. 87 patients remained without any treatment were defined as a control observation group, and the remaining 145 patients continued to receive maintenance therapy were allocated into the maintenance treatment group. Findings: The median PFS time in the maintenance group was 9.6 months, which was significantly longer than the 7.7 months in the observation group (HR 0.47, 95% CI 0.34-0.65, P<0.0001). The median OS in the two groups was 23.9 months and 30.1 months, respectively (HR 0.67, 95% CI 0.45-0.98, P=0.029). Interaction and stratified analyses showed no difference in the PFS between the single drug maintenance group and the doublet drug maintenance group. The most common adverse event in this study was the hematologic toxicity. Except hand-foot syndrome (0 vs. 8.3%, P=0.003), the incidence of other adverse events was not significantly different between the two groups. Interpretation: After achieving disease control with first-line PBCT in mTNBC patients, maintenance chemotherapy is recommended. Funding Statement: This study was supported by the Shanghai Municipal Science and Technology Commission Guidance Project, P.R. China (contract no. 18411967800)；Shanghai Municipal Commission of Health and Family Planning (grant no. 201640069); Shanghai Natural Science Foundation (grant no. 17ZR1405700); and research grant from Shanghai Hospital Development Center (grant no. SHDC12018X03). Declaration of Interests: The Author(s) declare(s) that there is no conflict of interest. Ethics Approval Statement: This study was approved by the Regional Ethics Committee of our hospital and informed consent was obtained from all patients.

Vinflunine in Advanced Transitional Cell Cancer of the Urothelial Tract: A Potential Option for Maintenance Therapy? A Case Series

Introduction: Vinflunine is a microtubule inhibitor approved in Europe as second-line treatment of advanced transitional cell cancer of the urothelium (TCCU). The inability to continue with a first-line platinum-based regimen beyond 6 cycles suggested investigating the use of vinflunine as switch maintenance therapy in patients with response or stable disease after first-line therapy. Methods: Patients with advanced TCCU and documented disease control after 3-6 cycles of first-line platinum-based chemotherapy received vinflunine maintenance therapy within 6 weeks of the last cycle. Our analysis aimed to examine the performance of vinflunine in terms of activity and safety in such a patient population. Results: 28 consecutive patients were studied. After a median follow-up of 25 months, vinflunine was associated with a median progression-free survival of 9 months (range 4 to > 16 months) and a disease control rate of 64%; median overall survival was not reached. Treatment was well tolerated, with no unexpected safety events. The most common adverse events of grade ≥ 3 were neutropenia (21%) and constipation (14%); no toxicity-related death occurred. Conclusions: Our results suggest that vinflunine may be a suitable maintenance treatment option for TCCU patients who received a maximum of 6 cycles of platinum-based chemotherapy commonly used as first-line treatment.

Randomised Phase 2 study of maintenance linsitinib (OSI-906) in combination with erlotinib compared with placebo plus erlotinib after platinum-based chemotherapy in patients with advanced non-small cell lung cancer

Background:Maintenance therapy is important in advanced/metastatic non-small cell lung cancer (NSCLC). Erlotinib as switch maintenance following platinum-based chemotherapy increases survival. Cross-talk between the epidermal growth factor receptor and insulin-like growth factor receptor (IGFR) pathways mediate resistance to individual receptor blockade. This study compared maintenance linsitinib plus erlotinib vs erlotinib plus placebo in patients with NSCLC.Methods:In this Phase II randomised trial, patients without progression following four cycles of first-line platinum-based chemotherapy (N=205) received continuous schedule maintenance oral linsitinib 150 mg or placebo BID combined with erlotinib 150 mg QD for 21-day cycles. The primary endpoint was progression-free survival (PFS).Results:The study was unblinded early due to linsitinib non-superiority. No difference was found between the two treatment groups in median PFS of 125 days linsitinib vs 129 days placebo (P=0.601); no difference in overall survival (OS) was observed. Tolerability was similar, although in the linsitinib group, treatment-related adverse events and discontinuations were more frequent. No drug–drug interaction was implicated.Conclusions:Linsitinib maintenance therapy added to erlotinib did not improve PFS or OS in non-progressing NSCLC patients. This highlights the need for robust biomarkers of response for combinations that incorporate IGFR-targeted therapies in maintenance or other therapeutic settings.

Six versus fewer planned cycles of first-line platinum-based chemotherapy for non-small-cell lung cancer: a systematic review and meta-analysis of individual patient data

Platinum-based chemotherapy is the standard first-line treatment for patients with advanced non-small-cell lung cancer. However, the optimum number of treatment cycles remains controversial. Therefore, we did a systematic review and meta-analysis of individual patient data to compare the efficacy of six versus fewer planned cycles of platinum-based chemotherapy. All randomised trials comparing six versus fewer planned cycles of first-line platinum-based chemotherapy for patients with advanced non-small-cell lung cancer were eligible for inclusion in this systematic review and meta-analysis. The primary endpoint was overall survival. Secondary endpoints were progression-free survival, proportion of patients with an objective response, and toxicity. Statistical analyses were by intention-to-treat, stratified by trial. Overall survival and progression-free survival were compared by log-rank test. The proportion of patients with an objective response was compared with a Mantel-Haenszel test. Prespecified analyses explored effect variations by trial and patient characteristics. Five eligible trials were identified; individual patient data could be collected from four of these trials, which included 1139 patients-568 of whom were assigned to six cycles, and 571 to three cycles (two trials) or four cycles (two trials). Patients received cisplatin (two trials) or carboplatin (two trials). No evidence indicated a benefit of six cycles of chemotherapy on overall survival (median 9·54 months [95% CI 8·98-10·69] in patients assigned to six cycles vs 8·68 months [8·03-9·54] in those assigned to fewer cycles; hazard ratio [HR] 0·94 [95% CI 0·83-1·07], p=0·33) with slight heterogeneity between trials (p=0·076; I(2)=56%). We recorded no evidence of a treatment interaction with histology, sex, performance status, or age. Median progression-free survival was 6·09 months (95% CI 5·82-6·87) in patients assigned to six cycles and 5·33 months (4·90-5·62) in those assigned to fewer cycles (HR 0·79, 95% CI 0·68-0·90; p=0·0007), and 173 (41·3%) of 419 patients assigned to six cycles and 152 (36·5%) of 416 patients assigned to three or four cycles had an objective response (p=0·16), without heterogeneity between the four trials. Anaemia at grade 3 or higher was slightly more frequent with a longer duration of treatment: 12 (2·9%) of 416 patients assigned to three-to-four cycles and 32 (7·8%) of 411 patients assigned to six cycles had severe anaemia. Six cycles of first-line platinum-based chemotherapy did not improve overall survival compared with three or four courses in patients with advanced non-small-cell lung cancer. Our findings suggest that fewer than six planned cycles of chemotherapy is a valid treatment option for these patients. None.

Association ofHMGB1andHMGB2genetic polymorphisms with lung cancer chemotherapy response

The aim of the present study was to investigate the association of genetic polymorphisms in high mobility group box 1 and 2 (HMGB1 and HMGB2, respectively) with platinum-based chemotherapy responses in Chinese lung cancer patients. In total, 338 Chinese lung cancer patients (154 responders and 184 non-responders) were recruited to the study. All patients received at least two cycles of first-line platinum-based chemotherapy. Three tagging single nucleotide polymorphisms (SNPs) of HMGB1 and two tagging SNPs of HMGB2 were detected in patients. We found that rs1412125 and rs2249825 of HMGB1 were significantly associated with the platinum-based chemotherapy response in both recessive and genotypic models. In addition, rs1412125 showed significant association with platinum-based chemotherapy response for the subgroup of patients aged >55years in additive, recessive and genotypic models. No significant associations were detected between other SNPs and the platinum-based chemotherapy response. The HMGB1 SNPs (rs1412125 and rs2249825) were associated with platinum-based chemotherapy responses in Chinese lung cancer patients. In conclusion, HMGB1 SNPs may serve as potential biomarkers for predicting the efficacy of platinum-based chemotherapy.

The possibility of traditional chinese medicine as maintenance therapy for advanced nonsmall cell lung cancer.

Lung cancer has become the leading cause of cancer deaths, with nonsmall cell lung cancer (NSCLC) accounting for around 80% of lung cancer cases. Chemotherapy is the main conventional therapy for advanced NSCLC. However, the disease control achieved with classical chemotherapy in advanced NSCLC is usually restricted to only a few months. Thus, sustaining the therapeutic effect of first-line chemotherapy is an important problem that requires study. Maintenance therapy is given for patients with advanced NSCLC if three is no tumor progression after four to six cycles of first-line platinum-based chemotherapy. However, selection of appropriate maintenance therapy depends on several factors, while traditional Chinese medicine (TCM) as maintenance therapy is recommended for all kinds of patients. It has been demonstrated that TCM can prolong the survival time, improve the quality of life (QOL), and reduce the side effects for advanced NSCLC. Although the trials we searched about TCM serving as maintenance therapy is only 9 studies, the results indicate TCM can prolong the progression free survival (PFS) and improve the QOL. So it is possible for TCM to be as maintenance therapy for advanced NSCLC. More rigorous trials are required to further verify its efficacy.

Outcome of platinum-based chemotherapy for non-small-cell lung cancer patients with pleural dissemination detected during surgery

Pleural dissemination detected by computed tomography (CT) is considered to be unfavorable for patients with non-small-cell lung cancer (NSCLC). However, the prognosis of NSCLC patients who are diagnosed with pleural dissemination at the time of surgery has yet to be adequately elucidated. To assess the outcomes of platinum-based chemotherapy in NSCLC patients in whom pleural dissemination was detected during exploratory thoracotomy with or without a videoscope, the clinical records of NSCLC patients who were admitted to Shizuoka Cancer Center between September, 2002 and April, 2009 were reviewed. A total of 19 patients were included in this study, 12 males and 7 females, with a median age of 65 years. All patients were diagnosed with adenocarcinoma and 6 were epidermal growth factor receptor (EGFR) gene mutation-positive. The median number of treatment cycles of first-line platinum-based chemotherapy was 4 (range, 1-6 cycles) and the objective response rate was 21% [95% confidence interval (CI): 8.5-43]. The median progression-free and overall survival were 10.4 (95% CI: 6.3-18.4) and 50.5 months (95% CI: 32.5-98.0), respectively. Of the 18 patients with reported disease progression, 9 (50%) developed locoregional tumor progression. In conclusion, NSCLC patients in whom pleural dissemination is detected during surgery tend to have a favorable prognosis for survival. Systemic chemotherapy and additional local treatment may improve their clinical outcomes.

A Multicenter Randomized Phase IIb Efficacy Study of Vx-001, a Peptide-Based Cancer Vaccine as Maintenance Treatment in Advanced Non–Small-Cell Lung Cancer: Treatment Rationale and Protocol Dynamics

We present the treatment rationale and study design of a multicenter, open-label, randomized, 2-arm, phase IIb study. Patients with stage IV or recurrent stage I to III non–small-cell lung cancer (NSCLC) whose disease does not progress after 4 cycles of first-line platinum-based chemotherapy will be randomized in a 1:1 ratio to 1 of 2 study arms. Patients will receive the cancer vaccine Vx-001 + Montanide ISA51 VG (Seppic, Paris, France) adjuvant subcutaneously, at a dose of 2 mg, or placebo + Montanide ISA51 VG adjuvant subcutaneously. The vaccination protocol comprises 2 injections with the TYR-Vx001 or placebo (1 at day 0 and another at week 3) and 4 injections with the ARG-Vx001 or placebo, at weeks 6, 9, 12, and 15. After the treatment assessment at week 18, patients will receive the ARG-Vx001 or placebo every 12 weeks starting from week 27 until disease progression, unacceptable toxicity, withdrawal of informed consent, or death. The primary end point of this study is the survival rate at 12 months. Secondary end points include time-to-event comparison of overall survival and comparison of time to treatment failure. Exploratory objectives include comparison of disease control rate after the end of subsequent second-line treatments, comparisons of vaccine immune responses, comparison of survival rate at 12 months in patients with vaccine-induced immune response detected after the second and sixth injections, identification of biomarkers on lymphocytes and on tumors, and comparison of safety and tolerability.

Insulin-Like Growth Factor Receptor

The insulin-like growth factor (IGF) signaling axis plays an essential role in the balance between cellular proliferation and apoptosis. Higher levels of IGF receptor are seen in lung tumor cells than normal tissue. IGF-1 receptor (IGFR-1R) and its ligand IGF-2 is overexpressed in non-small cell lung cancer (NSCLC). Elevated levels of IGF-1 in plasma are associated with an increased risk of developing lung cancer, and IGF-1R has been shown to promote the proliferation of lung cancer cells in vitro. 1 IGF-1R can hybridize with other membrane receptors leading to the activation of different tyrosine kinase domains. 2 The central role that the IGFR pathway plays in various signaling pathways in tumor cells makes the IGF axis an attractive target for therapeutic intervention. Dr. Pollak presented an overview of the science of the IGFR to establish the rationale for the development of this class of drugs for the treatment of NSCLC. There are a number of possible avenues through which the effects of IGF can be inhibited. These strategies include antibodies directed against IGF ligand, IGF-1R tyrosine kinase inhibitors, and antibodies targeting the IGF-1R. The approach of blocking the IGF-1 receptor tyrosine kinase pathway and the insulin receptor (IR) via signal transduction inhibitors is also undergoing clinical evaluation. IMC-A12 IMC-A12 is a fully humanized IgG1 monoclonal antibody with a half-life of 15 to 21 days that targets the IGF-1 receptor. 3 Both weekly and q21-day schedules are being explored. There are three ongoing randomized phase II trials with differentfirst-line platinum-based regimens including a trial that is comparing gemcitabine, carbopatin with the addition of IMC-A12, cetuximab, or both, and another evaluating carboplatin, paclitaxel bevacizumab with or without IMC-A12 in nonsquamous NSCLC. There is one randomized first-line trial of etoposide, cisplatin with or without either IMC-A12 or the hedgehog inhibitor GDC-0449 in extensive disease small cell lung cancer (EDSCLC). The combination of erlotinib plus A12 was closed due to toxicity of the combination. Currently, no additional toxicity or efficacy data are available. AMG-479 Phase I studies established thrombocytopenia as the dose-limiting toxicity of AMG-479, a fully human monoclonal antibody to IGF-1R. 4 AMG-479 is being evaluated in the front-line setting in combination with etoposide and carboplatin or cisplatin in a randomized phase I/II trial in patients with EDSCLC. Patients will receive up to six cycles of the combination then single-agent AMG 479 as maintenance therapy until disease progression. Preliminary results indicate that AMG-479 can be safely combined with etoposide and cisplatin (or carboplatin) in this patient population without impact on the delivery of AMG-479 or the chemotherapy. Activity in the phase I portion was similar to reported with chemotherapy alone. 5 The phase II portion of the trial has completed accrual and results are pending. MK-0646 MK-0646 is a fully humanized monoclonal IgG1 antibody that selectively binds to the IGF-1 receptor and not to the insulin receptor. 6 The recommended phase II dose is 10 mg/kg weekly. An overview of the compound and the design of several clinical trials were presented. In the randomized phase II IMPACT study, MK-0646 is being evaluated in combination with pemetrexed (500 mg/m 2 ) and cisplatin (75 mg/m 2 ) as first-line therapy in patients with stage IIIB or IV nonsquamous NSCLC. The phase I/II design of MK-0646 plus cisplatin and etoposide in patients with treatment-naive EDSCLC was also presented. Both studies are ongoing but not actively recruiting participants.

The role of pemetrexed as maintenance treatment in advanced NSCLC: a Phase III randomized trial

A randomized Phase III trial tested the efficacy of pemetrexed as maintenance treatment in patients with advanced non-small-cell lung cancer (NSCLC) who were without progression after completing four cycles of first-line platinum-based chemotherapy. The primary endpoint of the trial was progression-free survival (PFS). Pemetrexed was significantly better than placebo both in terms of PFS and overall survival. The study was not designed as a direct comparison between ‘early’ and ‘delayed’ administration of pemetrexed because there was no mandatory cross-over in the control arm, in which less than 20% of patients actually received pemetrexed as second-line. However, a relevant proportion of patients with advanced NSCLC, due to early death or clinical deterioration, will never be able to receive a second-line treatment after disease progression. At the end of first-line treatment, the immediate administration of a drug that has not been received before (instead of adopting the ‘wait and watch’ approach based on stopping treatment until disease progression) could be a positive strategy, allowing patients to receive early one more potentially active drug without an unacceptable increase in toxicity. This strategy should be discussed with patients. Prespecified analysis of efficacy by tumor histology showed a significant interaction between treatment and histology, with pemetrexed producing significant and clinically meaningful benefit compared to placebo in the non-squamous group, without efficacy in patients with squamous tumors.

Assessment of the Prognostic Relevance of Serum Anti-p53 Antibodies in Epithelial Ovarian Cancer

The objective of this study was to assess the prognostic relevance of preoperative serum anti-p53 antibodies in epithelial ovarian cancer. These autoantibodies were detected with a new generation enzyme-linked immunosorbent assay in blood samples preoperatively drawn from 86 patients with this malignancy. Serum anti-p53 antibodies were found in 3 (10.0%) of the 30 patients with stage I–II and 15 (26.8%) of the 56 patients with stage III–IV epithelial ovarian cancer (P= 0.09). We assessed in detail 44 patients with stage III–IV disease who underwent six cycles of first-line platinum-based chemotherapy. A pathological complete response at second-look was achieved by none of the 15 patients with serum anti-p53 antibodies compared to 24.1% of the 29 patients without autoantibodies (P= 0.09). However, the preoperative serum anti-p53 antibody status had no prognostic relevance for progression-free survival and survival. In conclusion, the assessment of preoperative serum anti-p53 antibodies seems to have a limited clinical value in the management of patients with advanced epithelial ovarian cancer.