Second-line Platinum-based Chemotherapy Research Articles

Maintenance with mirvetuximab soravtansine plus bevacizumab vs bevacizumab in FRα-high platinum-sensitive ovarian cancer.

At first recurrence, platinum-sensitive ovarian cancer (PSOC) is frequently treated with platinum-based chemotherapy doublets plus bevacizumab, then single-agent bevacizumab. Most patients' disease progresses within a year after chemotherapy, emphasizing the need for novel strategies. Mirvetuximab soravtansine-gynx (MIRV), an antibody-drug conjugate, comprises a folate receptor alpha (FRα)-binding antibody and tubulin-targeting payload (maytansinoid DM4). In FRα-high PSOC, MIRV plusbevacizumab previously showed promising efficacy (objective response rate, 69% [95% CI: 41-89]; median progression-free survival, 13.3months [95% CI: 8.3-18.3]; median duration of response, 12.9months [95% CI: 6.5-15.7]) and safety. The Phase III randomized GLORIOSA trial will evaluate MIRV plusbevacizumab vs. bevacizumab alone as maintenance therapy in patients with FRα-high PSOC who did not have disease progression following second-line platinum-based doublet chemotherapy plus bevacizumab.Clinical Trial Registration: ClinicalTrials.gov ID: NCT05445778; GOG.org ID: GOG-3078; ENGOT.ESGO.org ID: ENGOT-ov76.

Efficacy of poly (ADP-ribose) polymerase inhibitors monotherapy and the impact to subsequent platinum-based chemotherapy in breast cancer susceptibility genes1/2-mutated ovarian cancer patients with secondary platinum-sensitive relapse

BackgroundThe therapeutic effect of poly (ADP-ribose) polymerase inhibitors (PARPi) monotherapy compared with platinum-based chemotherapy, and the impact to subsequent platinum-based chemotherapy after PARPi resistance were inconclusive in breast cancer susceptibility genes (BRCA)1/2-mutated ovarian cancer patients with secondary platinum-sensitive relapse.MethodsBRCA1/2-mutated patients with secondary platinum-sensitive relapse included in this study did not receive any maintenance regimen after first- and second-line platinum-based chemotherapy, and the secondary platinum-free interval (PFI) was more than 6 months. Patients in study group were treated with PARPi monotherapy until disease progression, and patients in control group were treated with platinum-based chemotherapy without restriction. Progression-free survival (PFS) was defined as the time from third-line therapy to disease progression or death, PFS2 was defined as the time from platinum-based chemotherapy after PARPi resistance to next subsequent therapy or death. Post-recurrence survival (PRS) refers to the survival time after secondary platinum-sensitive relapse.ResultsA total of 119 patients were retrospectively analyzed, including 71 (59.7%) in study group and 48 (40.3%) in control group. The objective response rate (ORR: 77.5% vs. 80.0%, p=0.766) and PFS (median: 11.2 vs. 11.0 months, p=0.962) were comparable. The benefit of subsequent platinum-based chemotherapy after PARPi resistance was more pronounced in patients with PARPi treatment for more than 12 months (median PFS2: 8.6 vs. 4.3 months, p=0.040). PARPi monotherapy had no adverse effect on PRS compared with platinum-based chemotherapy (median PRS:41.2 vs. 42.8 months, p=0.323). Compared to patients in control group who had never received PARPi, PARPi monotherapy (median PRS: 41.2 vs. 33.7 months, p=0.019) and post-line treatment with PARPi in the control group (median PRS: 48.1 vs. 33.7 months, p=0.002) could prolong PRS for patients with secondary platinum-sensitive relapse.ConclusionsPARPi monotherapy was similar to platinum-based chemotherapy for BRCA1/2-mutated ovarian cancer patients with secondary platinum-sensitive recurrence, and could improve prognosis.

A randomized phase II clinical trial of talazoparib maintenance therapy in patients with triple-negative breast cancer who showed platinum-sensitivity on first- or second-line platinum-based chemotherapy: KCSG BR21-10.

TPS1132 Background: A potent PARP inhibitor, talazoparib, demonstrated superior clinical activity compared to standard chemotherapy in germline BRCA1/2-mutant advanced breast cancer patients. However, the role of talazoparib treatment in BRCA1/2 wild-type triple-negative breast cancer (TNBC) patients remains undefined, although high incidence of homologous recombination deficiency (HRD) is one of the major characteristics of the TNBC. Previous studies indicated clinical responsiveness to platinum agents is a useful surrogate for HRD that may predict favorable PARP inhibitor response. Here, we present a phase II study to test talazoparib maintenance therapy in germline BRCA1/2 mutation unselected advanced TNBC patients after platinum-based chemotherapy. Methods: The KCSG BR21-10 study (NCT04755868) is a randomized double-blind placebo-controlled phase II clinical trial of talazoparib maintenance therapy in metastatic TNBC patients whose tumor showed platinum-sensitivity to first- or second-line platinum-based chemotherapy. The criteria for platinum-sensitivity were set as follows: remaining complete response (CR), partial response (PR), or stable disease (SD) after 6 to 9 tri-weekly doses or 18 to 27 weekly doses of platinum-based chemotherapy. The eligible TNBC patients are enrolled to the trial after completion of platinum-based therapy and 1:1 randomized to receive talazoparib (once daily 1.0 mg) or placebo maintenance therapy. The patient with any germline BRCA1/2 mutation status is eligible, and randomization stratification factors include line of platinum-based chemotherapy, response to platinum-based chemotherapy, and germline BRCA1/2 mutation status. The talazoparib/placebo maintenance treatment is initiated within 8 weeks after the last platinum chemotherapy. At the time of progression of disease, unblinding can be performed and patients in placebo arm may be eligible for crossover to talazoparib single treatment. The primary endpoint is progression-free survival (PFS) after randomization by RECIST 1.1, and the key secondary endpoints are overall survival, PFS2, objective response rate, adverse events by CTCAE 5.0 criteria, and quality of life. We also planned exploratory study to find predictive biomarker by tumor tissue and blood analysis. The median PFS from the randomization is expected to be 3 months in the placebo maintenance arm and we expect that talazoparib maintenance will improve PFS with hazard ratio of 0.65. It is predicted that a total of 206 patients (103 patients in each arm) are required with the α of 0.05 and power of 0.8 (1-β) by two-sided test, considering monthly 3% dropout rate. Currently, 23 of planned 206 patients have been enrolled. Clinical trial information: NCT04755868 .

Triplet maintenance (olaparib, pembrolizumab, and bevacizumab) in BRCA non-mutated patients with platinum-sensitive recurrent ovarian cancer: A multi-center, single-arm phase II study (OPEB-01).

5584 Background: The optimal treatment of BRCA 1/2 non-mutated patients with platinum-sensitive recurrent ovarian cancer remains unknown. In this study, we evaluated the efficacy and safety of triplet maintenance therapy in BRCA non-mutated patients with platinum-sensitive recurrent ovarian cancer. Methods: BRCA 1/2 non-mutated patients with platinum-sensitive recurrent epithelial ovarian cancer, showing a complete/partial response after second-line platinum-based chemotherapy, were eligible. Triplet maintenance therapy (olaparib, bevacizumab, and pembrolizumab) was administered until disease progression or unacceptable toxicity. The primary endpoint was the progression-free survival (PFS) rate at six months after therapy initiation. The secondary endpoints were PFS, overall survival, and safety. The translational objectives included biomarker evaluation with respect to survival outcomes. Results: Forty-four patients were enrolled (median age 61 years), majority with high-grade serous carcinoma (93.2%) and partial response (75.0%) to second-line chemotherapy. Overall, 54.6% were homologous recombination deficiency (HRD)-positive (genomic instability score ≥ 42) and 63.6% had PD-L1 positive tumors (combined positive score [CPS] ≥ 1). At 6 months, the PFS rate was 88.6% (95% confidence interval [CI] 75.4–96.2). The median PFS has not been reached. The most common ≥ grade 3 treatment-related adverse events (AEs) were anemia (20.5%) and neutropenia (6.8%), but there were no grade 4 AEs. Exploratory analysis demonstrated remarkable survival outcomes regardless of HRD status, whereas patients with PD-L1 CPS ≥ 1 showed improved PFS compared to those with PD-L1 CPS < 1 ( P = 0·032). Analysis of molecular consensus subtype of the pre-treatment tissue samples showed that patients with mesenchymal subtype demonstrated poor PFS, compared to non-mesenchymal subtypes (p = 0.0023). Conclusions: This is the first report on triplet maintenance therapy in BRCA non-mutated platinum-sensitive recurrent ovarian cancer. The results show that the triplet maintenance therapy is efficacious with manageable toxicity, showing a particular promise for patients with molecular consensus subtype other than mesenchymal. Clinical trial information: NCT04361370 .

Hyperthermic intraperitoneal chemotherapy in platinum-sensitive relapsed epithelial ovarian cancer: The CHIPOR randomized phase III trial.

5510 Background: Standard treatment for patients with first platinum-sensitive relapse of epithelial ovarian cancer (EOC) is based on surgery and second-line systemic chemotherapy (CT). The role of hyperthermic intra-peritoneal chemotherapy (HIPEC) remains uncertain. Methods: The CHIPOR multicentric randomized phase III trial (NCT01376752), conducted in 31 institutions, enrolled patients with a first platinum-sensitive relapse (platinum-free interval of ≥6 months) of EOC. Patients were treated with 6 cycles of platinum and taxane based CT ± bevacizumab, and those amenable to a complete cytoreductive surgery at the end of CT were enrolled and randomly assigned to receive HIPEC (cisplatin 75 mg/m² at 41°C for 60 min) or not. Randomization was performed during complete cytoreductive surgery, stratified by center, surgical outcome (no residual disease vs residual <0.25 cm), chemotherapy-free interval before relapse, and PARP inhibitor use (yes vs no). The primary endpoint was overall survival (OS). The target sample size was 404 evaluable patients, providing 80% power at 5% alpha after 268 deaths. Secondary endpoints included progression-free survival (PFS), peritoneal PFS, patient-reported outcomes, safety, and postoperative morbidity and mortality (≤60 days after surgery). Results: Between May 11, 2011, and May 14, 2021, 415 patients were randomized. Baseline characteristics were balanced between treatment arms. At the data cutoff (Jan 8, 2023), with a median follow-up of 6.2 years, 268 patients (65%) had died. Efficacy results are summarized below. Conclusions: HIPEC significantly improves OS and peritoneal PFS of women with first platinum-sensitive relapse of EOC treated with second-line platinum-based CT followed by secondary complete cytoreductive surgery. Ongoing analyses, including patient reported outcome, BRCA status, bevacizumab exposure, and subsequent therapy, will be presented. Clinical trial information: NCT01376752 . [Table: see text]

Structure of residual metastases in patients with advanced testicular non-seminomatous germ cell tumors and incomplete serological and radiological response to chemotherapy

Objective: to analyze histological structure and identify predictors of detecting malignant non-seminoma in residual tumor masses obtained from patients with testicular non-seminomatous germ cell tumors (TNSGCTs) who had not achieved complete serological and radiological response to chemotherapy (CT).Materials and methods. This study included 96 out of 703 patients with TNSGCTs (13.7 %) operated on in N.N. Blokhin National Medical Research Center of Oncology. The inclusion criteria were as follows: verified advanced TNSGCT, elevated levels of alpha-fetoprotein and/or chorionic gonadotropin at the moment of CT initiation, at least 3 completed courses of first-line or second-line platinum-based CT, residual tumor foci after CT visualized with radiological methods, alpha-fetoprotein >7.29 IU/mL or chorionic gonadotropin >5 mIU/mL 3 weeks after the initiation of the last CT course, and surgery after CT. Histological examination of the primary tumors demonstrated that they contained elements of seminoma (n = 14; 14.6 %), teratoma (n = 29; 30.2 %), choriocarcinoma in (n = 23; 23.9 %), embryonal carcinoma (n = 45; 46.9 %), and yolk sac (n = 18; 18.8 %). All study participants received first-line CT; 58 of them (60.4 %) also received second-line CT. All patients underwent surgery after CT, including retroperitoneal lymph node dissection (RPLND) (n = 96; 100 %) and excision of extra-retroperitoneal lesions (n = 8; 8.3 %).Results. Histological examination of excised retroperitoneal masses showed that they contained areas of necrosis and fibrosis (n = 25; 26.0 %), teratoma (n = 29; 30.2 %), and viable malignant non-seminoma (n = 42; 43.8 %). There was a strong positive correlation between the existence of residual malignant non-seminomatous components in retroperitoneal masses and presence of choriocarcinoma (r = 0.300; р = 0.004), as well as the absence of embryonal carcinoma in the primary tumor (r = –0.300; р = 0.004), invasion of retroperitoneal metastases into major vessels and/or adjacent organs (r = 0.243; р = 0.017), and second-line CT prior to RPLND (r = 0.413; р <0.0001). Patients having ≥3 risk factors were significantly more likely to have residual malignant non-seminoma in retroperitoneal masses than patients who had 0–2 risk factors (73.5 % vs 27.3 %; р <0.0001). Excised residual extra-retroperitoneal masses contained areas of necrosis and fibrosis (n = 3; 37.5 %), teratoma (n = 1; 12.5 %), and malignant non-seminoma (n = 4; 62.5 %). Concordant structure of retroperitoneal and extra-retroperitoneal lesions was observed in 4 patients (50.0 %).Conclusion. Malignant non-seminomas were detected in 43.8 % of retroperitoneal and 62.5 % of extra-retroperitoneal residual tumorsremoved after CT in patients with advanced TNSGCTs and incomplete serological and radiological response. Discordant structure of metastases at different locations was observed in 50 % of patients. Our finding can be used to select candidates for surgical excision of residual tumors among these patients.

Olaparib beyond progression compared with platinum chemotherapy after secondary cytoreductive surgery in patients with recurrent ovarian cancer: phase III randomized, open-label MITO 35b study, a project of the MITO-MANGO groups

BackgroundPoly (ADP-ribose) polymerase inhibitors have transformed the management landscape for patients with ovarian cancer, demonstrating remarkable improvements in progression-free survival and overall survival. Unfortunately, most relapses are due to an...

Second-line olaparib maintenance therapy is associated with poor response to subsequent chemotherapy in BRCA1/2-mutated epithelial ovarian cancer: A multicentre retrospective study

IntroductionWith expanded use of poly (adenosine diphosphate-ribose) polymerase inhibitors (PARPi), there is a potential impact of PARPi resistance on platinum resistance. A post-hoc analysis of SOLO2 demonstrated a reduction in response to subsequent platinum-based therapy among patients who received prior olaparib but not placebo. The present multicentre, retrospective, observational study was conducted to determine the effects of olaparib on subsequent therapy for recurrent epithelial ovarian cancer (EOC). Materials and methodsData on EOC patients with BRCA1/2-mutated tumours who received second-line platinum-based chemotherapy between January 2012 and June 2020, at three South Korean institutions (n = 197) were collected. Patients who received olaparib as maintenance therapy after second-line chemotherapy were assigned to the olaparib group (n = 105), and subjects who did not receive olaparib maintenance therapy were assigned to the control group (n = 92). The primary endpoint was time intervals from the date of second disease progression (PFS1) to the date of third disease progression (PFS2), expressed as PFS2 − PFS1. ResultsAs expected, PFS1 in the olaparib group was longer than the control group. However, PFS2 – PFS1 in the olaparib group was significantly shorter than that of the control group (median 7.9 vs. 13.6 m; p = 0.0005). Even when the third-line PARPi maintenance (cross-over) patients were excluded from the control group, the response to subsequent therapy in the olaparib group remained poor (median 7.7 vs. 11.5; p = 0.0422). DiscussionsPatients with platinum-sensitive BRCA1/2 mutated tumours who progressed during olaparib maintenance after second-line chemotherapy were less likely to respond to third-line chemotherapy compared to controls who did not receive olaparib, suggesting that resistance to olaparib may contribute to chemotherapy resistance.

Comparisons of survival outcomes between bevacizumab and olaparib in BRCA-mutated, platinum-sensitive relapsed ovarian cancer: a Korean Gynecologic Oncology Group study (KGOG 3052).

ObjectiveTo compare survival outcomes between bevacizumab (BEV) and olaparib (OLA) maintenance therapy in BRCA-mutated, platinum-sensitive relapsed (PSR) high-grade serous ovarian carcinoma (HGSOC).MethodsFrom 10 institutions, we identified HGSOC patients with germline and/or somatic BRCA1/2 mutations, who experienced platinum-sensitive recurrence between 2013 and 2019, and received second-line platinum-based chemotherapy. Patients were divided into BEV (n=29), OLA (n=83), and non-BEV/non-OLA users (n=36). The OLA and non-BEV/non-OLA users were grouped as the OLA intent group. We conducted 1:2 nearest neighbor-matching between the BEV and OLA intent groups, setting the proportion of OLA users in the OLA intent group from 65% to 100% at 5% intervals, and compared survival outcomes among the matched groups.ResultsOverall, OLA users showed significantly better progression-free survival (PFS) than BEV users (median, 23.8 vs. 17.4 months; p=0.004). Before matching, PFS improved in the OLA intent group but marginal statistical significance (p=0.057). After matching, multivariate analyses adjusting confounders identified intention-to-treat OLA as an independent favorable prognostic factor for PFS in the OLA 65P (adjusted hazard ratio [aHR]=0.505; 95% confidence interval [CI]=0.280−0.911; p=0.023) to OLA 100P (aHR=0.348; 95% CI=0.184−0.658; p=0.001) datasets. The aHR of intention-to-treat OLA for recurrence decreased with increasing proportions of OLA users. No differences in overall survival were observed between the BEV and OLA intent groups, and between the BEV and OLA users.ConclusionCompared to BEV, intention-to-treat OLA and actual use of OLA maintenance therapy were significantly associated with decreased disease recurrence risk in patients with BRCA-mutated, PSR HGSOC.

1591TiP - IFCT-1701 DICIPLE: A randomized phase III trial comparing continuation nivolumab-Ipilimumab doublet immunotherapy until progression versus observation in patients with PDL1-positive stage IV non-small cell lung cancer (NSCLC) after nivolumab-ipilimumab induction treatment

BackgroundWe raise the hypothesis that a STOP and GO strategy with induction by double immunotherapy Nivolumab + Ipilimumab combination during 6 months, followed by observation in patients with disease control (DC) at 6 months, would not be inferior to immunotherapy combination continuation until progression or unacceptable toxicity, in terms of progression-free survival, allowing lower toxicities cumulative rates, better quality of life and lower costs. Such strategy should not penalize overall survival, provided resuming immunotherapy at disease progression before second-line platinum-based chemotherapy. Trial designThis is an open-label, randomized, phase III study in adult (≥18 years) patients, with stage IV non-small cell lung cancer, PD-L1 positive tumors, previously untreated for advanced disease. Subjects will first be locally assessed for PD-L1 expression, using 1% cut-off. Patients with enough tumor samples for central PD-L1 expression assessment, will be given first-line Nivolumab+Ipilumumab combination as followed: Nivolumab administered IV over 30minutes at 3mg/kg every 2 weeks combined with Ipilimumab administered IV over 30minutes at 1mg/kg every 6 weeks.Only patients with DC (objective response or stable disease), confirmed at 6 months, after a 1rst tumor evaluation at 3 months or beyond in case of pseudo-progression needing tumor reassessment, and without drug-related toxicity commanding treatment discontinuation will be randomized 1:1 either to continuation of Nivolumab+Ipilumumab combination until disease progression or unacceptable toxicity, or to clinical and radiological observation from week 24.Subjects receiving Nivolumab+Ipilimumab beyond investigator assessed progression must also continue tumor assessments until treatment discontinuation.Enrollment will end after approximately 868 subjects have been randomized (25/months). The primary endpoint of the study is Progression-Free Survival. Clinical trial identificationNCT03469960. Legal entity responsible for the studyIFCT (French Cooperative Thoracic Intergroup). FundingBristol-Myers Squibb. DisclosureAll authors have declared no conflicts of interest.

Hematopoietic-cell transplantation for lymphoma in the era of genetically engineered cellular therapy: it's not quite time to scrap the old vehicle for the new car.

Second-line platinum-based salvage chemotherapy followed by high-dose chemotherapy and autologous hematopoietic-cell transplantation (AHCT) has remained the standard of care (SOC) for relapsed and primary refractory (r/r) diffuse large B-cell lymphoma (DLBCL) for greater than 2 decades. In the postrituximab era, this strategy has yielded disappointing outcomes for r/r patients with curability in less one-quarter of the patients by intention-to-treat. Given the Food and Drug Administration (FDA) approval of chimeric antigen receptor (CAR) modified T cells directed against CD19 (CD19 CAR T) for DLBCL following two lines of therapy and/or failed AHCT, encouragement with this therapy in the second line for r/r patients has naturally prompted randomized phase III studies against the aforementioned SOC. The predominant hurdle to procession to AHCT is chemotherapy sensitivity after platinum-based salvage therapy. In this review, we will discuss recent investigations to improve response rates in r/r DLBCL with the intent of proceeding to potentially curative AHCT, as well as investigations to decrease progression post-AHCT. In addition, data regarding currently FDA approved CD19 CAR T cells will be reviewed. Within 2-3 years, we will know if the multicenter/multinational studies of CD19 CAR T will replace SOC salvage therapy and AHCT in the second-line. The role of allogeneic HCT will also be briefly reviewed in the context of these therapies.

The concept of platinum sensitivity could be applied to recurrent cervical cancer: a multi-institutional retrospective study from the Japanese Gynecologic Oncology Group.

This study aimed at evaluating the applicability of the concept of platinum sensitivity to recurrent cervical cancer. The clinical information of patients with recurrent cervical cancer, who were initially treated with platinum-based chemotherapy and received second-line platinum-based chemotherapy at the time of recurrence between January 2008 and December 2012, was retrospectively reviewed. A total of 677 patients from 71 medical centers were analyzed. The median overall survival (OS) for patients with platinum-free interval (PFI) of <6, 6-11, 12-17, and ≥18months was 12.1 (95% CI 11.0-14.1) months, 17.4 (15.5-20.4) months, 20.2 (17.9-27.6) months, and 29.9 (26.7-36.0) months, respectively (P<0.0001, log-rank). The best cut-off value of PFI that affected OS was 7months, analyzed by the minimum P value method. The median progression-free survival (PFS) for patients with less than and more than PFI of 7months was 6.2months (95% CI 4.8-9.3) and 21.0months (18.9-24.8) (P<0.0001, log-rank), respectively, and the median OS for patients with less than and more than PFI of 7months was 12.3months (11.2-14.1) and 24.2months (20.8-25.8) (P<0.0001, log-rank). Multivariate analysis revealed that PFI (P<0.0001, HR 0.449, 95% CI 0.369-0.548) alone had a statistically significant association with OS. This study showed that the concept of platinum sensitivity could be applied to recurrent cervical cancer and PFI could be one of the independent prognostic factors for patients with recurrent cervical cancer who have previously been treated with platinum-based chemotherapy.

Real-life clinical practice results with vinflunine in patients with relapsed platinum-treated metastatic urothelial carcinoma: an Italian multicenter study (MOVIE-GOIRC 01\u20132014)

BackgroundVinflunine is the only chemotherapeutic agent shown to improve survival in platinum-refractory patients with metastatic transitional cell carcinoma of the urothelium (TCCU) in a phase III clinical trial, which led to product registration for this indication in Europe. The aim of this study was to assess the efficacy of vinflunine and to evaluate the prognostic significance of risk factors in a large, unselected cohort of patients with metastatic TCCU treated according to routine clinical practice.MethodsThis was a retrospective multicenter study. Italian cancer centers were selected if, according to the Registry of the Italian Medicines Agency (AIFA), at least four patients had been treated with vinflunine between February 2011 and June 2014, after first- or second-line platinum-based chemotherapy. The primary objective was to test whether the efficacy measured by overall survival (OS) in the registration study could be confirmed in routine clinical practice. Multivariate analysis was carried out using Cox proportional hazard model.ResultsA total of 217 patients were treated in 28 Italian centers. Median age was 69 years (IQR 62–76) and 84% were male; Eastern Cooperative Oncology Group performance status (ECOG PS) was ≥ 1 in 53% of patients. The median number of cycles was 4 (IQR 2–6); 29%, 35%, and 36% received an initial dose of 320 mg/m2, 280 mg/m2 or a lower dose, respectively. Median progression-free survival (PFS) and OS for the entire population was 3.2 months (2.6–3.7) and 8.1 months (6.3–8.9). A complete response was observed in six patients, partial response in 21, stable disease in 60, progressive disease in 108, with a disease control rate of 40%. Multivariate analysis showed that ECOG PS, number of metastatic sites and liver involvement were unfavorable prognostic factors for OS. Toxicity was mild, and grade 3–4 adverse effects were mainly: neutropenia (9%), anemia (6%), asthenia/fatigue (7%) and constipation (5%).ConclusionsIn routine clinical practice the results obtained with VFL seem to be better than the results of the registration trial and reinforce evidence supporting its use after failure of a platinum-based chemotherapy.

Systemic Treatment Patterns With Advanced or Recurrent Non–small Cell Lung Cancer in Japan: A Retrospective Hospital Administrative Database Study

PurposeData on the treatment of non–small cell lung cancer (NSCLC) in real-world clinical practice in Japan are limited. This large-scale, retrospective cohort study examined data on patients’ characteristics and systemic therapies for advanced or recurrent NSCLC in routine practice in Japan. MethodsThis study used an electronic health records–based database of health claims and Diagnosis Procedure Combination data from 215 consenting hospitals in Japan. Records from April 2008 to September 2015 were analyzed. Regimens were examined by histology, age, sex, and therapeutic line. Logistic regression analysis was performed to predict which clinical and demographic factors affected patients’ probability of receiving first- or second-line therapy or completing first-line platinum-based chemotherapy. FindingsAmong 16,413 patients, 67.9%, 39.2%, and 22.3% received first-, second-, and third-line systemic treatment, respectively. Treatment was more common in patients aged <75 versus ≥75 years (76.0% vs 51.6%), in female versus male patients (71.6% vs 65.4%), and in patients with nonsquamous versus squamous disease (75.6% vs 61.9%). More than 30 systemic regimens were administered. The most common first-line therapy was platinum-based chemotherapy (nonsquamous, 53.6%; squamous, 73.7%). Non–platinum-based chemotherapy use increased in the second-line setting, but platinum-based chemotherapy use remained high (nonsquamous, 33.9%; squamous, 38.6%). Tyrosine kinase inhibitors were used in 32.0% and 29.4% of patients with nonsquamous NSCLC in the first- and second-line settings, respectively. Switches from first- to second-line platinum-based chemotherapy and from first- to second-line tyrosine kinase inhibitors occurred. Forty-two percent of the patients died during hospitalization. In the logistic regression analysis, factors associated with a decreased likelihood of receiving first-line therapy were male sex, squamous histology, age >75 years, treatment at a general (vs cancer-specific) hospital, worse scores on certain activities of daily living, presence of chronic pulmonary disease, worse Hugh–Jones classification, and positive smoking status. The likelihood of completing first-line platinum-based chemotherapy was increased with greater body mass index, better activities of daily living scores, absence of chronic pulmonary disease, and better Hugh-Jones classification. The likelihood of continuing with second-line therapy was decreased with older age and recurrence of NSCLC. ImplicationsSystemic treatment patterns for advanced or recurrent NSCLC in Japan were varied. Nearly 30% of all patients and approximately half of elderly patients did not receive systemic treatment. Treatment rates declined with subsequent therapeutic lines. Generally, guidelines were followed with first-line treatment administration, but not with second-line administration. These results underscore the need for better guideline adherence and more optimal treatment in and elderly patients and in those receiving later-line treatment in Japan.

Clinical outcomes of platinum-based chemotherapy according to T790M mutation status in EGFR-positive non-small cell lung cancer patients after initial EGFR-TKI failure

BackgroundEmergence of the T790M point mutation in exon 20 of epidermal growth factor receptor (EGFR) is the most common mechanism of resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs). It remains unclear whether the efficacy of platinum-doublet chemotherapy is impacted by the presence of the T790M mutation. The aim of this study is to evaluate the efficacy of platinum-doublet chemotherapy after initial EGFR-TKI failure according to the EGFR T790M in patients with advanced EGFR-mutation-positive non-small cell lung cancer (NSCLC). Patients and methodsWe retrospectively reviewed 50 patients with advanced NSCLC harboring EGFR mutations who underwent rebiopsy to evaluate their T790M mutation status after development of resistance to first-line EGFR-TKIs (gefitinib, erlotinib, or afatinib) and were subsequently treated with second-line platinum-based chemotherapy. ResultsThe median age of patients was 63 years (range, 35–77 years), and 15 (30%) patients were male. Histological examination revealed that all patients had adenocarcinoma, 39 (78%) had stage IV disease, and 11 (22%) patients had postoperative recurrence. Of all, 17 patients (34%) had the T790M mutation by rebiopsy after initial EGFR-TKI failure. The overall response rate (ORR) of platinum-doublet chemotherapy was 24% for both T790M-positive and T790M-negative patients. There was no significant difference in the progression-free survival (PFS) in T790M-positive and T790M-negative patients (median PFS, 6.0 months vs. 5.1 months; 95% confidence interval [CI], 0.1–11.9 vs. 4.4–5.8; hazard ratio [HR], 0.90 [95%CI, 0.49–1.66]; P=0.7210). None of the factors were predictive of platinum-doublet chemotherapy efficacy by the multivariate analysis. ConclusionThere were no differences in clinical outcomes of platinum-based chemotherapy according to the T790M status of NSCLC patients.

Sequential treatment of tyrosine kinase inhibitor and platinum-based doublet chemotherapy on EGFR mutant non-small cell lung cancer: a meta-analysis of randomized controlled clinical trials.

There is debate surrounding which treatment is superior in overall survival (OS) rates in patients with epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC); first-line tyrosine kinase inhibitor (TKI) followed by second-line platinum-based doublet chemotherapy (PCT), or the reverse sequence. Cross treatment of first- and second-line TKI and PCT makes it difficult to deduce which sequence (TKI-PCT or PCT-TKI) is better for OS. Using the keywords “lung cancer” and “EGFR” we identified clinical trials within the PubMed database which were published between January 2006 and November 2016. Basic characteristics and OS with hazard ratio and 95% confidence intervals were searched and analyzed. In total, 457 articles were reviewed and nine clinical trials with 1,876 patients were of sufficient quality for further analysis. Fixed effects models were performed to pool the data in this meta-analysis. All nine studies were open-labeled, multicenter, Phase III randomized controlled clinical trials. The pooled hazard ratio was 0.96 (95% confidence interval: 0.84–1.10) for OS between first-line TKI followed by second-line PCT compared to the reverse sequence. No statistically significant heterogeneity (I2=0, P=0.553) nor publication bias (Egger’s P=0.991) was observed among these studies. In conclusion, there was no OS benefit between first-line TKI followed by second-line PCT compared to the reverse sequence in EGFR mutant NSCLC patients. Chemotherapy was still useful and irreplaceable for the treatment of NSCLC, especially for those patients with EGFR unavailable for testing.

Platinum sensitivity and non-cross-resistance of cisplatin analogue with cisplatin in recurrent cervical cancer.

ObjectiveThe concept of platinum sensitivity and cross-resistance among platinum agents are widely known in the management of recurrent ovarian cancer. The aim of this study was to evaluate two hypotheses regarding the validity of the concept of platinum sensitivity and non-cross-resistance of cisplatin analogue with cisplatin in recurrent cervical cancer.MethodsIn this retrospective study, the clinical data of patients with recurrent cervical cancer, who had a history of receiving cisplatin based chemotherapy (including concurrent chemoradiotherapy [CCRT] with cisplatin) and who received second-line chemotherapy at the time of recurrence between April 2004 and July 2012 were reviewed.ResultsIn total, 49 patients-34 squamous cell carcinomas (69.4%) and 15 non-squamous cell carcinomas (30.6%)-were enrolled. The median age was 53 years (range, 26 to 79 years). Univariate and multivariate analysis showed that a platinum free interval (PFI) of 12 months has a strong relationship with the response rate to second-line chemotherapy. Upon multivariate analysis of survival after second-line platinum-based chemotherapy, a PFI of 12 months significantly influenced both progression-free survival (hazard ratio [HR], 0.349; 95% confidence interval [CI], 0.140 to 0.871; p=0.024) and overall survival (HR, 0.322; 95% CI, 0.123 to 0.842; p=0.021). In patients with a PFI of less than 6 months, the difference of progression-free survival between patients with re-administration of cisplatin (3.0 months) and administration of cisplatin analogue (7.2 months) as second-line chemotherapy was statistically significant (p=0.049, log-rank test).ConclusionThe concept of platinum sensitivity could be applied to recurrent cervical cancer and there is a possibility of noncross-resistance of cisplatin analogue with cisplatin.

Applicability of the Concept of “Platinum Sensitivity” to Recurrent Endometrial Cancer

The platinum-free interval is defined as the period between the completion of platinum-based primary chemotherapy for ovarian cancer and disease recurrence. Platinum sensitivity refers to women with ovarian cancer who have a platinum-free interval of more than 6 months. These women usually undergo platinum-based second-line chemotherapy; response rates range from 27% to 65% with a median survival of 12 to 24 months. Women with a platinum-free interval of less than 6 months are considered to be platinum resistant; response rates in these women to second-line chemotherapy is 10% to 30% with a median survival is 6 to 9 months. There are few data on the efficacy of second-line platinum-based chemotherapy for endometrial cancer. Also, there is no definitive evidence on the applicability of the concept of platinum sensitivity to recurrent endometrial cancer. This multicenter retrospective cohort study investigated the applicability of the concept of platinum sensitivity to recurrent endometrial cancer. The patient population was composed of 262 women with relapsed endometrial cancer who had a history of receiving first-line platinum-based chemotherapy. All had received second-line platinum-based chemotherapy at the time of recurrence between January 2005 and December 2009. The study examined the relationship between platinum-free interval and response to second-line platinum-based chemotherapy, as well as progression-free survival and overall survival after second-line chemotherapy. The initial International Federation of Gynecology and Obstetrics stage classifications for the 262 patients were as follows: I (n = 29), II (n = 23), III (n = 122), and IV (n = 88). Documented tumors included 153 endometrioid adenocarcinomas, 34 serous adenocarcinomas, 17 clear cell adenocarcinomas, 36 carcinosarcomas, and 22 other tumors. After second-line platinum-based chemotherapy, response rates for patients with platinum-free intervals of less than 6 months, 6 to 11 months, 12 to 23 months, and 24 months or more were 25%, 38%, 61%, and 65%, respectively. After second-line platinum-based chemotherapy, the median progression-free survival for patients with platinum-free intervals of less than 12 months and 12 months or more was 4.4 months (95% confidence interval [CI], 3.7–5.8) and 10.3 months (95% CI, 8.2–12.6), respectively (P < 0.0001, log-rank test), and the median overall survival was 13.8 months (95% CI, 10.6–18.1) and 40.9 months (95% CI, 25.3–54.2), respectively (log-rank P < 0.0001). These data show that the platinum-free interval is a predictor of response to second-line platinum-based chemotherapy and of survival in patients with recurrent endometrial cancer. The data indicate that the concept of platinum sensitivity can be applied to recurrent endometrial cancer.

Cost-effectiveness of folfirinox for first-line treatment of metastatic pancreatic cancer.

The accord 11/0402 trial demonstrated that folfirinox (5-fluorouracil, leucovorin, irinotecan, oxaliplatin) is significantly more efficacious than gemcitabine monotherapy in the first-line treatment of metastatic pancreatic cancer (mpc). The present study assessed the cost-effectiveness of first-line folfirinox compared with first-line gemcitabine for public payers in Canada. A Markov model simulated the movement of mpc patients from first-line treatment until death. Overall survival (os) and progression-free survival (pfs) data were derived from accord. Published utility data and Canadian costs were applied based on time in each health state and on treatment-related adverse event (ae) rates. Costs included first- and second-line therapy, monitoring, and costs to treat aes. Two separate analyses were performed. Analysis 1 was based on trial data [first-line folfirinox followed by second-line gemcitabine compared with first-line gemcitabine followed by second-line platinum-based chemotherapy, with use of granulocyte colony-stimulating factor (g-csf) allowed], and analysis 2 used Ontario treatment patterns before folfirinox funding (first-line folfirinox followed by second-line gemcitabine compared with first-line gemcitabine followed by best supportive care, no use of g-csf). Compared with first-line gemcitabine, first-line folfirinox resulted in more life-years and quality adjusted life-years (qalys). Probabilistic sensitivity analysis results showed that, for analyses 1 and 2 respectively, folfirinox has a greater than 85% probability and an approximately 80% probability of being cost-effective at the $100,000 threshold. Compared with gemcitabine, first-line folfirinox significantly prolongs median os. Given the favourable cost per qaly, the improvement in clinical efficacy, and the limited available treatment options, folfirinox represents an attractive cost-effective treatment for mpc.

Applicability of the concept of “platinum sensitivity” to recurrent endometrial cancer: The SGSG-012/GOTIC-004/Intergroup study

ObjectiveThe concept of “platinum sensitivity” has been widely applied in the management of recurrent ovarian cancer. This study aimed to evaluate the applicability of this concept to recurrent endometrial cancer. Patients and methodsIn this multicenter retrospective cohort study, the clinical data of patients with recurrent endometrial cancer, who had a history of receiving first-line platinum-based chemotherapy and who received second-line platinum-based chemotherapy at the time of recurrence between January 2005 and December 2009 were reviewed. ResultsA total of 262 patients from 30 centers with initial FIGO stage classifications of I (29), II (23), III (122), and IV (88) were enrolled. In total, 153 endometrioid adenocarcinomas, 34 serous adenocarcinomas, 17 clear cell adenocarcinomas, 36 carcinosarcomas, and 22 “other” tumors were documented. The response rates for patients with platinum-free intervals of <6months, 6–11months, 12–23months, and ≥24months were 25%, 38%, 61%, and 65%, respectively. The median progression-free survival after second-line platinum-based chemotherapy for patients with platinum-free intervals of <12months and ≥12months was 4.4 (95% confidence interval (CI)=3.7–5.8) months and 10.3 (95% CI=8.2–12.6) months, respectively (log-rank P<0.0001), and the median overall survival was 13.8 (95% CI=10.6–18.1) months and 40.9 (95% CI=25.3–54.2) months, respectively (log-rank P<0.0001). ConclusionPlatinum-free interval is a predictor of response and survival after second-line platinum-based chemotherapy in patients with recurrent endometrial cancer. The concept of “platinum sensitivity” could be applicable to recurrent endometrial cancer.