Cisplatin Pemetrexed Research Articles

True Benefits of Immune Checkpoint Inhibitors in the Treatment of Malignant Pleural Mesothelioma in Japan.

In February 2004, the Food and Drug Administration (FDA) was the first to approve the combination of cisplatin (CDDP) and pemetrexed (PEM) as standard first-line chemotherapy for untreated, unresectable malignant pleural mesothelioma (MPM). However, after that approval, no progress was made in the standard first-line treatment of MPM for almost 15 years. Positive results from a phase 3 study (Mesothelioma Avastin Cisplatin Pemetrexed Study: MAPS) verifying the effect of bevacizumab, an anti-angiogenesis agent added to CDDP/PEM for unresectable MPM, were published in The Lancet in December 2015; however, this did not lead to approval by national drug regulatory agencies. Furthermore, no second-line treatment was established for cases refractory to CDDP/PEM. In August 2018, the Pharmaceuticals and Medical Devices Agency of Japan was the first in the world to approve monotherapy with nivolumab, an immune checkpoint inhibitor (ICI), for previously unresectable, advanced, or recurrent MPM. Following Japan, in October 2020, the FDA approved the combination of nivolumab and ipilimumab for the treatment of previously untreated, unresectable MPM. In this article, we review the transition of drug treatment for MPM, in light of the historical background, focusing on the benefits of ICIs.

VEGFR2 and CD34 expression associated with longer survival in patients with pleural mesothelioma in the IFCT-GFPC-0701 MAPS phase 3 trial

ObjectivesVEGF/VEGFR autocrine loop is a hallmark of pleural mesothelioma (PM). We thus assayed the prognostic and predictive values of VEGFR-2 [vascular endothelial growth factor receptor 2 or Flk-1] and CD34, a marker of endothelial cells, in samples from patients accrued in the Mesothelioma Avastin Cisplatin Pemetrexed Study ('MAPS', NCT00651456). Materials and MethodsVEGFR2 and CD34 expression were assayed using immunohistochemistry in 333 MAPS patients (74.3%), and their prognostic value was evaluated in terms of overall survival (OS) and progression-free survival (PFS) in univariate and multivariate analyses, before validation by bootstrap methodology. ResultsPositive VEGFR2 or CD34 staining was observed in 234/333 (70.2%) and 322/323 (99.6%) of tested specimens, respectively. VEGFR2 and CD34 staining correlated weakly, yet significantly, with each other (r = 0.36, p < 0.001). High VEGFR2 expression or high CD34 levels were associated with longer OS in PM patients in multivariate analysis (VEGFR2: adjusted [adj.] hazard ratio [HR]: 0.91, 95% confidence interval [CI] [0.88; 0.95], p < 0.001; CD34: adj. HR: 0.86, 95 %CI [0.76; 0.96], p = 0.010), with only high VEGFR2 expression resulting in significantly longer PFS (VEGFR2: adj. HR: 0.96, 95 %CI [0.92; 0.996], p = 0.032). Stability of these results was confirmed using bootstrap procedure. Nevertheless, VEGFR2 expression failed to specifically predict longer survival in bevacizumab-chemotherapy combination trial arm, regardless of whether the VEGFR2 score was combined or not with serum VEGF concentrations. ConclusionVEGFR2 overexpression independently correlated with longer OS or PFS in PM patients, such biomarker deserving prospective evaluation as stratification variable in future clinical trials.

Comparison of 3 Randomized Clinical Trials of Frontline Therapies for Malignant Pleural Mesothelioma

Some recently proposed frontline therapies for malignant pleural mesothelioma (MPM) are very costly, yet their impact on quality of life and overall survival of these patients remains arguable. Given the high social toll of this aggressive occupational cancer, it is paramount to establish the real clinical benefit of these treatments. To directly compare and analyze the statistical robustness of the 3 randomized clinical trials (RCTs) of frontline therapies recommended for MPM since 2003. This comparative effectiveness study assessed the following phase 3 RCTs: the Mesothelioma Cisplatin Pemetrexed Study (MPS) of cisplatin plus pemetrexed vs cisplatin; the Mesothelioma Avastin Cisplatin Pemetrexed Study (MAPS) of cisplatin plus pemetrexed plus bevacizumab vs cisplatin plus pemetrexed; and the CheckMate743 (CM743) study of nivolumab plus ipilimumab vs cisplatin plus pemetrexed. Data collection dates for the RCTs ranged from April 1999 to April 2018. Data for this study were analyzed from February to October 2021. Patient selection criteria, superiority of the intervention groups, survival-inferred fragility index, and censoring patterns in each RCT. A total of 1501 patients were included in the analysis (1170 men [77.9%]; range of median age for treatment groups, 60 [IQR, 19-84] to 69 [IQR, 65-75] years). A virtual comparison of overall survival in MAPS vs the CM743 study showed no statistically significant difference (hazard ratio [HR], 0.97 [95% CI, 0.79-1.20]; P = .79), and the survival-inferred fragility index in the intention-to-treat (ITT) populations was as low as 0.22% of the total sample size in MPS, -0.45% of the total sample size in MAPS, and 0.99% of the total sample size in the CM743 trial. Moreover, reverse restricted mean survival time (RMST) analysis of overall survival using RMST-difference (RMST-D) demonstrated differential censoring in the ITT population of the CM743 trial favoring the control group (0.56 [95% CI, 0.18-0.94]; P = .004) and in the nonepithelioid group (reverse RMST-D, 0.90 [95% CI, 0.001-1.79]; P = .048). This comparative effectiveness study found no survival benefit in the CM743 trial over MAPS, despite the inclusion of patients with worse prognosis in the latter trial. Moreover, the statistical conclusions of all the examined trials were shown to be extremely fragile, and the findings of differential censoring in the CM743 trial and in the ITT nonepithelial subset raised additional areas of concern. These findings suggest that selection criteria, fragility, and censoring patterns may affect the original conclusions drawn for the respective trials, casting a shadow on the real benefit. This model of analysis lays a rigorous groundwork extendable to trials of all cancer treatments before their registration.

Osimertinib plus platinum–pemetrexed in newly diagnosed epidermal growth factor receptor mutation-positive advanced/metastatic non-small-cell lung cancer: safety run-in results from the FLAURA2 study

BackgroundThe phase III FLAURA2 (NCT04035486) study will evaluate efficacy and safety of first-line osimertinib with platinum–pemetrexed chemotherapy versus osimertinib monotherapy in epidermal growth factor receptor mutation-positive (EGFRm) advanced/metastatic non-small-cell lung cancer (NSCLC). The safety run-in, reported here, assessed the safety and tolerability of osimertinib with chemotherapy prior to the randomized phase III evaluation.Patients and methodsPatients (≥18 years; Japan: ≥20 years) with EGFRm locally advanced/metastatic NSCLC received oral osimertinib 80 mg once daily (QD), with either intravenous (IV) cisplatin 75 mg/m2 or IV carboplatin target area under the curve 5, plus pemetrexed 500 mg/m2 every 3 weeks (Q3W) for four cycles. Maintenance was osimertinib 80 mg QD with pemetrexed 500 mg/m2 Q3W until progression/discontinuation. The primary objective was to evaluate safety and tolerability of the osimertinib–chemotherapy combination.ResultsThirty patients (15 per group) received treatment [Asian, 73%; female, 63%; median age (range) 61 (45-84) years]. Adverse events (AEs) were reported by 27 patients (90%): osimertinib–carboplatin–pemetrexed, 100%; osimertinib–cisplatin–pemetrexed, 80%. Most common AEs were constipation (60%) with osimertinib–carboplatin–pemetrexed and nausea (60%) with osimertinib–cisplatin–pemetrexed. In both groups, 20% of patients reported serious AEs. No specific pattern of AEs leading to dose modifications/discontinuations was observed; one patient discontinued all study treatments including osimertinib due to pneumonitis (study-specific discontinuation criterion). Hematologic toxicities were as expected and manageable.ConclusionsOsimertinib–chemotherapy combination had a manageable safety and tolerability profile in EGFRm advanced/metastatic NSCLC, supporting further assessment in the FLAURA2 randomized phase.

Choroidal metastases: case report and review

AbstractIntroduction:Choroidal metastases are the most frequent intraocular secondary tumours, with a prevalence of 2–7% according to the literature. Our aim was to review a clinical case of choroidal metastasis.We present a case of a 63-year-old male patient diagnosed in 2018 with lung adenocarcinoma cT4N0M1. The patient had three metastases in the brain, which were successfully treated with radiosurgery (RS). The patient was treated with chemotherapy with pemetrexed–cisplatin schedule. Five months after diagnosis, the patient presented with decreased vision in the right eye. After ophthalmologic evaluation, he was diagnosed with a right choroidal metastasis, which was treated with external beam radiotherapy with 20 Gy in five fractions, resulting in improved visual acuity and a complete clinical and radiological response.The patient took part in a clinical trial that continued with systemic chemotherapy. Twenty-two months after radiotherapy to the eye, the patient has good visual acuity without any side effects.Conclusions:Choroidal metastasis treated with radiotherapy achieves good local control, with limited side effects, allowing an improvement in visual acuity and consequently, an improvement in the patient´s quality of life.

CheckMate 743: A Glimmer of Hope for Malignant Pleural Mesothelioma

CheckMate 743: A Glimmer of Hope for Malignant Pleural Mesothelioma

Omental Metastasis from ALK-positive Lung Cancer \u2014 A Case Report

BackgroundNon-small cell lung cancer (NSCLC) is the leading cause of cancer-related deaths worldwide. In Ireland alone, there are over 2500 new cases of lung cancer diagnosed each year. It ranks fourth among the most common cancers and causes 21% of all cancer-related deaths.Lung cancers usually metastasize to the liver, brain, bone, and adrenal glands—rarely affecting the abdomen. To our knowledge, there are 8 previous studies in the literature to date which involve omental metastasis from NSCLC.Case presentationA 73-year-old lady presented with a history of productive cough for 18 months. A chest X-ray showed a suspicious 6 cm mass in the right lower zone. She went on to have an endobronchial biopsy which confirmed a moderately differentiated adenocarcinoma of the lung which was ALK positive. She went on to have staging PET and CT scans and was staged as cT3N2M0. She was not a suitable candidate for surgery so she had radical chemo-radiotherapy with 4 cycles of cisplatin pemetrexed followed by radical dose sequential radiotherapy. Post treatment CT showed the tumor to be more spiculated in appearance. She was ineligible for Durvalumab maintenance therapy due to the extensive pneumonitis following her radiotherapy which required a prolonged course of steroids. Interval scans every 3 months did not show any progression of disease.She presented to the hospital 13 months post her diagnosis with progressive abdominal swelling. Restaging CT scans showed extensive omental infiltration, the presence of multiple peritoneal nodules, and progression of her pulmonary disease with new brain metastasis. Cytological analysis of the ascitic fluid confirmed metastasis followed by omental biopsy which confirmed metastatic ALK-positive NSCLC. She went on to have targeted treatment with alectinib. She tolerated the treatment well. Restaging scans done 3 months later showed good partial response to therapy.ConclusionIn conclusion, ALK-positive NSCLC with metastasis to the omentum is very rare. However, in patients with atypical symptoms like ascites, the possibility of a metastasis must be considered and repeat biopsy is always recommended. A targeted therapy in the selected patients has shown a more durable response than chemotherapy.

Survival analysis of afatinib versus erlotinib for individuals with advanced del19 lung adenocarcinoma with asymptomatic brain metastasis after pemetrexed-cisplatin chemotherapy: a retrospective study.

ObjectiveTo evaluate survival following afatinib (AF) and erlotinib (ER) treatment in advanced del19 lung adenocarcinoma (AD19LA) with asymptomatic brain metastasis (ABM) after pemetrexed–cisplatin chemotherapy (PCC).MethodsData were retrospectively analysed from individuals with AD19LA and ABM after PCC who received AF or ER for 2 years or until intolerable adverse events (AEs), withdrawal, or death. The primary outcome was survival; secondary outcomes were AEs.ResultsThe final analysis included 174 AD19LA individuals (AF: n = 86; ER: n = 88) with a median follow-up of 24.2 months (IQR 2.1–28.3). Significant differences in overall survival (16.2 months [95%CI 15.4–17.1] for AF vs 7.2 months [95%CI 6.3–8.1] for ER) (HR 0.50, 95%CI 0.36–0.71, p<0.0001) and median progression-free survival (9.4 months [95%CI 8.5–9.7] for AF vs 5.6 months [4.7–6.2] for ER) (HR 0.66, 95%CI 0.47–0.94, p=0.02) were observed between the groups. Rates of all-grade AEs were 82.5% for AF and 72.7% for ER, and rates of grade ≥3 AEs were 37.2% for AF and 34.0% for ER.ConclusionCompared with ER, AF treatment may be more beneficial in terms of survival in the management of AD19LA after PCC with a tolerable safety profile.

1440PD - JIPANG study: Randomized phase III study of pemetrexed/cisplatin (PEM/Cis) versus vinorelbine /cisplatin (VNR/Cis) for completely resected p-stage II-IIIA non-squamous non-small cell lung cancer (Ns-NSCLC): Outcomes based on EGFR mutation status

BackgroundThe VNR/Cis chemotherapy doublet has been evaluated in prior positive adjuvant trials in patients with completely resected Ns-NSCLC, whereas no phase III study has so far evaluated PEM/Cis in this population. And there are few data regarding outcomes based on EGFR mutation (EGFRm) status in adjuvant chemotherapies. MethodsPatients with completely resected Ns-NSCLC were randomized in a 1:1 ratio to receive either PEM (500mg/m2, day 1)/Cis (75mg/m2, day 1) or VNR (25mg/m2, days 1 and 8)/Cis (80mg/m2, day 1), and stratified according to sex, age, pathologic stage, EGFRm status and institution. The primary endpoint was recurrence-free survival (RFS), and, the planned sample size was 800 patients in total (Trial Identifier, UMIN000006737). ResultsBetween March 2012 and August 2016, 804 patients were randomized. Of 784 for the efficacy analysis (389 in PEM/Cis and 395 in VNR/Cis), median age was 65/65 years; stage IIIA 52.2%/52.4%; adenocarcinoma, 95.9%/95.9%; and EGFR mutation, 24.1%/24.9%. With a median follow-up of 45.2 months (mo), median RFS was 38.9mo in PEM/Cis and 37.3mo in VNR/Cis with a hazard ratio (HR) of 0.98 (95% CI, 0.81--1.20; log-rank test, P=0.948), whereas HRs in patients with or without EGFRm were 1.38 (95% CI, 0.95--1.99) and 0.87 (95% CI, 0.69--1.09), respectively (Interaction, P=0.046). As for patients without EGFRm, median RFS was 65.2mo in PEM/Cis and 39.9mo in VNR/Cis. The overall survival rate at 3 years was 83.5% versus 87.2% with a HR of 0.98 (95% CI, 0.71 --1.35). Rates of treatment completion were 87.9% (PEM/Cis) and 72.7% (VNR/Cis), respectively (P<0.001). Incidences of grade 3 or 4 febrile neutropenia (11.6/0.3%, P<0.001), neutropenia (81.1/22.8%, P<0.001), and anemia (9.3/2.8%, P<0.001); any grade alopecia (30.1/12.8%, P<0.001). ConclusionsAlthough this phase III study did not meet the primary endpoint, PEM/CDDP had a similar efficacy to VNR/CDDP with a better tolerability as postoperative adjuvant chemotherapy for Ns-NSCLC patients. A significant interaction for RFS was found between treatment and EGFR mutation status. In patients without EGFR mutation, PEM/Cis seems to be a preferable regimen as the adjuvant chemotherapy. Clinical trial identificationUMIN000006737. Legal entity responsible for the studyThe authors. FundingHealth and Labor Sciences Research Grants, The Japan Agency of Medical Research and Development (AMED). DisclosureM. Tsuboi: Honoraria (self): AstraZeneca KK; Honoraria (self): Johnson & Johnson Japan; Honoraria (self): MSD; Honoraria (self): Chugai Pharmaceutical Co., Ltd.; Honoraria (self): Taiho Pharma; Honoraria (self): Eli Lilly Japan; Honoraria (self): Boehringer Ingelheim Japan; Honoraria (self): Ono Pharmaceutical Co., Ltd; Honoraria (self): Bristol-Myers Squibb KK; Honoraria (self): Daiichi-Sankyo; Honoraria (self): Covidien Japan; Honoraria (self): Teijin Pharma; Research grant / Funding (institution): Boehringer Ingelheim Japan. All other authors have declared no conflicts of interest.

Bidirectional chemotherapy allowing surgery and HIPEC for malignant peritoneal mesothelioma.

BackgroundThis case report aims to describe the impact of the bidirectional chemotherapy (BDC) on resecability for initially unresectable malignant peritoneal mesothelioma (MPM).MethodsWe report a case of 55-year-old male with the diagnosis of initially unresecable MPM. The BDC combined intravenous (IV) chemotherapy (Cisplatin–Pemetrexed) and intra peritoneal (IP) chemotherapy (Cisplatin). The response to chemotherapy was assessed by CT – scan and laparoscopy.ResultsInitial evaluation classed the disease as unresecable with PCI at 39. At the reevaluation, CT – scan and laparoscopy showed a macroscopic response, allowing surgery consisting of cytoreductive surgery and hyperthermic intra peritoneal chemotherapy (Doxorubicin and Cisplatin).ConclusionsBDC (IV and IP) has promising results and allows to undergo surgery for selected patients with borderline or initially unresectable MPM.

MST1/Hippo promoter gene methylation predicts poor survival in patients with malignant pleural mesothelioma in the IFCT-GFPC-0701 MAPS Phase 3 trial

BackgroundThe Mesothelioma Avastin Cisplatin Pemetrexed Study (MAPS/NCT00651456) phase 3 trial demonstrated the superiority of bevacizumab plus pemetrexed–cisplatin triplet over chemotherapy alone in 448 malignant pleural mesothelioma (MPM) patients. Here, we evaluated the prognostic role of Hippo pathway gene promoter methylation.MethodsPromoter methylations were assayed using methylation-specific polymerase chain reaction in samples from 223 MAPS patients, evaluating their prognostic value for overall survival (OS) and disease-free survival in univariate and multivariate analyses. MST1 inactivation effects on invasion, soft agar growth, apoptosis, proliferation, and YAP/TAZ activation were investigated in human mesothelial cell lines.ResultsSTK4 (MST1) gene promoter methylation was detected in 19/223 patients tested (8.5%), predicting poorer OS in univariate and multivariate analyses (adjusted HR: 1.78, 95% CI (1.09–2.93), p = 0.022). Internal validation by bootstrap resampling supported this prognostic impact. MST1 inactivation reduced cellular basal apoptotic activity while increasing proliferation, invasion, and soft agar or in suspension growth, resulting in nuclear YAP accumulation, yet TAZ cytoplasmic retention in mesothelial cell lines. YAP silencing decreased invasion of MST1-depleted mesothelial cell lines.ConclusionsMST1/hippo kinase expression loss is predictive of poor prognosis in MPM patients, leading to nuclear YAP accumulation and electing YAP as a putative target for therapeutic intervention in human MPM.

Clinical efficacy and safety of randomized phase 2 trial of pemetrexed-cisplatin or docetaxel-cisplatin plus thoracic intensity-modulated radiation therapy in patients with stage IV lung adenocarcinoma

Objective To evaluate the clinical efficacy and toxicity of concurrent pemetrexed-cisplatin (PP) or docetaxel-cisplatin (DP) with intensity-modulated radiation therapy (IMRT) in patients with stage ⅠV lung adenocarcinoma. Methods Stage IV lung adenocarcinoma patients with unknown EGFR mutation status or wild-type admitted to Guizhou Cancer Hospital from 2011 to 2016 were randomly assigned into the PP (n=50) and DP groups (n=51). All patients received concurrent IMRT of the chest at a prescription dose of 60-70 Gy. Primary endpoint was 1-year survival rate, and secondary endpoint was acute toxicity. Results The overall response rate was 68.0% and 72.5% in the PP and DP groups (χ2=0.250, P=0.617). The median survival time was 19.6 months (95%CI 13.9-25.3) versus 12.1 months (95%CI 10.7-13.5) in the PP and DP groups. The 1-, 2-and 3-year overall survival rates were 72.0% versus 52.9%, 28.0% versus 17.6%, and 16.0% versus 13. 7%, respectively in the PP and DP groups (P=0.049). In the PP and DP groups, the incidence of grade 3-4 leukopenia was declined by 48% and 63%(P=0.098), and the incidence of grade 3-4 neutropenia was decreased by 34% and 65%(P=0.002), the incidence of grade 3-4 anemia was reduced by 38% and 10%(P=0.024), and the incidence of grade 3-4 thrombocytopenia was declined by 40% and 14%(P=0.003). The incidence rate of grade 2 pneumonitis (P=0.625) and grade 3 esophagitis (P=0.484) were similar in both groups. No patients experienced ≥grade 3 pneumonitis or ≥ grade 4 radiation esophagitis. Conclusions Pemetrexed-cisplatin combined with chemoradiotherapy yields higher clinical efficacy compared with docetaxel-cisplatin plus concurrent chemoradiation in the treatment of stage ⅠV lung adenocarcinoma. The incidence of radiation pneumonitis and esophagitis is similar. The incidence and severity of hematological toxicity does not significantly differ between two groups. Treatment-related toxicity is tolerable in both groups. Clinical Trial Registration Chinese Clinical Trial Registry (ChiCTR-TRC-13004184). Key words: Stage IV lung adenocarcinoma; Radiotherapy; Intensity-Modulated; Pemetrexed; Docetaxel; Phase 2 trial

Tumor burden (TB) and treatment exposure (TE) in patients (pts) with malignant pleural mesothelioma (MPM) receiving nintedanib (N)/placebo (P) in combination with first-line pemetrexed/cisplatin (PEM/CIS) in phase II of the LUME-Meso study.

8566Background: In the double-blind, placebo-controlled phase II/III LUME-Meso trial, N was combined with up to 6 cycles of PEM/CIS, followed by N monotherapy until progression or toxicity. The primary analysis of phase II showed improved progression-free survival (primary endpoint) with N vs P (hazard ratio (HR) = 0.56; 95% confidence interval (CI): 0.34–0.91; p = 0.017); for overall survival HR = 0.77; 95% CI 0.46–1.29. We evaluated outcomes in the combination and monotherapy phases to understand better the overall study results. Methods: Pts with unresectable MPM (ECOG PS 0–1), stratified by histology, were randomized 1:1 to receive ≤6 cycles PEM (500 mg/m2)/CIS (75 mg/m2) Day 1 + N or P; 200 mg bid, Days 2–21), followed by N or P monotherapy maintenance. TE was analyzed for PEM/CIS, N and P. TB, measured using sum of diameter by modified RECIST 1.0, was analyzed over time, using a mixed-effects model in pts with at least two imaging datapoints. Results: 87 pts were randomized: 85 pts (N: 44, P: 41) we...

SWOG S0905: A randomized phase II study of cediranib versus placebo in combination with cisplatin and pemetrexed in chemonaive patients with malignant pleural mesothelioma.

8514Background: Anti-angiogenic inhibitors combined with cisplatin-pemetrexed (CP) have shown efficacy in unresectable malignant pleural mesothelioma (MPM). Cediranib, a vascular endothelial growth...

Association between progression-free survival (PFS) rate (PFSR) and overall survival (OS) in LUME-Meso, a study of nintedanib (N) vs. placebo (P) in combination with first-line pemetrexed/cisplatin (PEM/CIS) in patients (pts) with malignant pleural mesothelioma (MPM).

8568Background: We evaluated the relationship between PFSR and OS in the Phase II part of LUME-Meso, a double-blind, placebo-controlled study that showed improved PFS (primary endpoint; hazard rati...

SPS-7 - Nintedanib plus pemetrexed/cisplatin in patients with MPM: Phase II findings from the placebo-controlled LUME-Meso trial

Standard 1st-line treatment for patients (pts) with unresectable malignant pleural mesothelioma (MPM) is pemetrexed/cisplatin (PEM/CIS); median overall survival (OS) is approximately 1 year. Nintedanib (N) is an oral inhibitor of VEGFR, PDGFR and FGFR, and Src and Abl kinases. VEGF and PDGF overexpression are associated with poor prognosis in MPM, and N has shown efficacy in preclinical models. This study evaluated the efficacy and safety of N+PEM/CIS vs placebo (P)+PEM/CIS in pts with MPM. Pts with unresectable MPM (chemo-naive, ECOG PS 0-1) were stratified by histology (epithelioid/biphasic) and randomised 1:1 to receive up to 6 cycles of PEM (500 mg/m2)/CIS (75 mg/m2) on Day 1 plus N or P (200 mg bid) on Days 2-21. Pts without disease progression received maintenance N or P. The primary endpoint was progression-free survival (PFS). 87 pts were randomised to N+PEM/CIS (n = 44) or P+PEM/CIS (n = 43). Pt characteristics were comparable between the groups; 89% had epithelioid MPM. PFS was significantly improved with N vs P (HR = 0.56 [95% CI 0.34-0.91]; p = 0.0174; median PFS 9.4 vs 5.7 months). PFS benefit was also seen in the epithelioid subgroup (HR = 0.51 [95% CI 0.30-0.86]; p = 0.0101). Preliminary OS data favoured N; objective tumour response was observed in 59% of the N arm vs 44% of the P arm (all partial responses). All pts experienced at least one adverse event (AE; any grade), with 7% of the N arm discontinuing due to AEs vs 15% with P. Serious AEs occurred in 36% vs 42% of pts in the N and P arms, respectively. The most common Grade ≥3 AEs (N vs P) were neutropenia (34% vs 10%), alanine aminotransferase increase (14% vs 2%) and gamma glutamyltransferase increase (14% vs 0%). N+PEM/CIS demonstrated clinical efficacy with improved PFS and a tolerable safety profile in pts with unresectable MPM. Based on these promising findings, the study was extended and the Phase III part is recruiting (NCT01907100).

1618PD - Overall survival (OS) and forced vital capacity (FVC) results from the LUME-Meso study of nintedanib (N) + pemetrexed/cisplatin (PEM/CIS) vs placebo (P) + PEM/CIS in chemo-naïve patients (pts) with malignant pleural mesothelioma (MPM)

1618PD - Overall survival (OS) and forced vital capacity (FVC) results from the LUME-Meso study of nintedanib (N) + pemetrexed/cisplatin (PEM/CIS) vs placebo (P) + PEM/CIS in chemo-naïve patients (pts) with malignant pleural mesothelioma (MPM)

Antimetabolites in the treatment of advanced pleural mesothelioma: a network meta-analysis of randomized clinical trials

An indirect comparison of cisplatin-pemetrexed (CP) and cisplatin-raltitrexed (CR) was performed. The Odds Ratios of 10, 15 and 20 month survival rate and response rate were assumed as indexes of efficacy; the Odds Ratio of grade III–IV side effects, and the absolute risk of overall, hematologic and non-hematologic toxicity, were assumed as indexes of safety. The outcomes of 352 patients were analysed. The Odds Ratios and 95% Confidence Interval (95% CI) of 10, 15 and 20 months survival rate and response rate were 1.2 (95% CI 0.65−2.24, p = 0.559), 1.02 (95% CI 0.49−2.12, p = 0.953), 1.13 (95% CI 0.44−2.91, p = 0.805) and 0.56 (95% CI 0.26−1.21, p = 0.141), respectively. An absolute increased risk of grade III–IV side effects was observed for CP: 6% (95% CI 3–9%, p < 0.001), 9% (95% CI 2–16%, p = 0.008) and 3% (95% CI 0–5%, p = 0.035) for overall, hematological and non-hematological toxicity. CP and CR can be considered comparable in terms of efficacy in the treatment of metastatic pleural mesothelioma, with a modest increased risk of grade III–IV side effects for CP.

IFCT-GFPC-1101 trial: A multicenter phase III assessing a maintenance strategy determined by response to induction chemotherapy compared to continuation maintenance with pemetrexed in patients (pts) with advanced non-squamous (NSQ) NSCLC.

9003 Background: Benefit coming from maintenance treatment appears greater for switch maintenance in pts with disease stabilization (SD) while it might be larger for continuation maintenance in pts with objective response (OR). This study assessed a maintenance strategy conditioned by response to cisplatin-gemcitabine (CG): continuation maintenance with G for pts with OR and switch maintenance with pemetrexed (P) for pts with SD compared with a control arm using P continuation maintenance following cisplatin-pemetrexed (CP) induction regimen. Methods: Eligibility criteria included age 18-70 years, PS of 0-1, untreated stage IV NSQ NSCLC without EGFR mutation or ALK rearrangement, ineligibility to bevacizumab. Pts were randomized 1:1 to receive either experimental CG arm: CG (4 cycles) followed by G maintenance in case of OR followed by second-line P or switch maintenance with P for pts with SD, or standard CP arm: 4 cycles CP induction regimen followed by maintenance P. Overall survival (OS) was the primary endpoint; secondary endpoints included PFS, response rate and safety. Results: Between Jul 2012 and Jun 2016, 932 pts were randomized (CG: 467, CP: 465). Pts characteristics were balanced between the arms. 255 pts (54.6%) in the CG arm received maintenance treatment (G: 142, P: 113) while 274 pts (58.9%) received P maintenance in the CP arm. Median number of maintenance cycles was 5 for G and 4 for P in both arms. The OS adjusted HR was 0.97 (95% CI 0.84, 1.13; p=0.72); median OS: 10.9m CG vs. 10.4m CP. The HR for PFS was 0.96 (95% CI 0.84, 1.10; p=0.56); median PFS: 5.0m CG vs. 4.7m CP. Safety profile was as expected during induction chemotherapy. During maintenance, grade ≥3 hematological AEs occurred in 28% and 31% of pts in CG and CP, respectively, with febrile neutropenia (2.4% vs. 1.1%), anemia (9.4% vs. 11.7%), thrombocytopenia (6.7% vs. 5.8%). No grade ≥3 non-hematological AEs occurred in &gt;5% of pts except for asthenia (3.9% CG vs. 5.1% CP). Conclusions: Adapting maintenance strategy according to response to induction chemotherapy does not improve patient outcome. Clinical trial information: NCT01631136.

Mature overall survival (OS) results from the LUME-Meso study of nintedanib (N) + pemetrexed/cisplatin (PEM/CIS) vs placebo (P) + PEM/CIS in chemo-naïve patients (pts) with malignant pleural mesothelioma (MPM).

8506 Background: LUME-Meso is a Phase (Ph) II/III, double-blind, randomized study. N targets MPM by inhibiting VEGFR 1–3, PDGFR α/β, FGFR 1–3, Src and Abl kinases. Primary analysis of the Ph II data demonstrated improved progression-free survival (PFS; hazard ratio [HR]=0.56; 95% confidence interval [CI] 0.34–0.91; p=0.017). Mature Ph 2 OS and updated PFS results are reported here. Methods: Pts with unresectable MPM (ECOG PS 0–1) were stratified by histology (epithelioid/biphasic) and randomized 1:1 to receive ≤6 cycles PEM (500 mg/m2)/CIS (75 mg/m2) Day 1 + N or P (200 mg bid, Days 2–21), followed by N or P monotherapy until progression or toxicity. The primary endpoint was PFS. The primary OS analysis and updated PFS analysis were performed as predefined. Results: 87 pts were randomly assigned (N=44, P=43). OS benefit favored N over P treatment (HR=0.77; 95% CI 0.46–1.29; p=0.319; 62 [71%] OS events) and was greatest in epithelioid pts (HR=0.70; 95% CI 0.40–1.21; p=0.197) with a median (m) OS gain of 5.4 months (mOS [95% CI]: 20.6 [16.2–28.8] N vs 15.2 [12.2–23.6] P). Updated PFS results (HR=0.54; 95% CI 0.33–0.87; p=0.010) also showed greatest benefit for epithelioid pts (HR=0.49; 95% CI 0.30–0.82; p=0.006) with a mPFS gain of 4.0 months (mPFS [95% CI]: 9.7 [7.2–12.4] N vs 5.7 [5.5–7.0] P). Improved forced vital capacity, objective response rates and duration of response were also observed with N treatment. Drug-related adverse events (AEs) in N- vs P-treated pts were 97.7% vs 97.6%. Grade ≥3 AEs of note included neutropenia (27.3% vs 4.9%), ALT (11.4% vs 0) and GGT (6.8% vs 0) elevations, and diarrhea (6.8% vs 0). AEs led to trial discontinuation in only 3 (6.8%) N vs 7 (17.1%) P pts. Conclusions: Mature Ph II OS data show that adding N to standard 1st-line treatment gives a strong signal towards improved OS. Updated PFS confirmed the primary analysis; AEs were manageable. The greatest clinical benefit was observed in pts with epithelioid histology. Median survival of 20.6 months in epithelioid pts treated with N is unprecedented in advanced MPM trials. Ph III is actively recruiting in this pt population. Clinical trial information: NCT01907100.