Pemetrexed Maintenance Therapy Research Articles

Abstract CT280: FURVENT, Phase 3 trial testing furmonertinib vs chemotherapy as first-line treatment for advanced NSCLC with EGFR exon 20 insertions (FURMO-004)

Abstract Introduction: EGFR exon 20 insertion mutations occur in approximately 2% of non-small cell lung cancer (NSCLC) and overall account for approximately 9% of all the EGFR mutations in NSCLC (Robichaux et al., 2021). Current first-line standard of care for NSCLC patients with these mutations is platinum-based chemotherapy (NCCN NSCLC, 2023). Furmonertinib is an oral, highly brain penetrant, broadly active mutant-selective EGFR inhibitor that targets EGFR exon 20 insertions and other EGFR mutations (Musib et al., NACLC 2022). Furmonertinib recently obtained FDA Breakthrough Therapy Designation for the first line treatment of patients with advanced NSCLC with EGFR ex20ins based on the data from the FAVOUR study. Promising preliminary clinical activity was observed in the FAVOUR study testing furmonertinib (240 mg daily [QD]) in patients with treatment naïve locally advanced or metastatic NSCLC, with EGFR exon 20 insertion (ex20ins) mutations showing confirmed overall response rate (ORR) of 78.6% (n=28) by blinded independent central review (BICR) with a preliminary median DOR of 15.2 months (Han et al., WCLC 2023). In previously treated patients both the 240 mg and 160 mg QD dose levels were active with confirmed ORR of 46.2% (n=26) and 38.5% (n=26) respectively, and included patients harboring near and far loop mutations.Furmonertinib showed a generally well-tolerated safety profile with expected EGFR-TKI class toxicities. Additional furmonertinib preclinical data in uncommon EGFR mutations, including P-loop and αC-helix Compressing (PACC) and ex20ins mutations will be presented at the AACR 2024 Annual Meeting (Nilsson et al., AACR 2024 Abstract #4174). Methods: The FURVENT (FURMO-004) study is a registrational global, phase 3, randomized, multicenter, open-label study. Eligible patients havetreatment-naïve, locally advanced or metastatic non-squamous NSCLC with EGFR exon 20 insertion mutations. Key inclusion criteria include documented EGFR exon 20 insertion mutation and measurable disease per RECIST 1.1. Key exclusion criteria include prior systemic anticancer therapy in the locally advanced or metastases setting or any prior EGFR TKI therapy. Approximately 375 patients will be randomized 1:1:1 to receive furmonertinib 160 mg QD, furmonertinib 240 mg QD, or platinum-based chemotherapy (cisplatin or carboplatin plus pemetrexed for 4 cycles followed by pemetrexed maintenance therapy). Stratification factors include the history or presence of central nervous system metastases at baseline, geographic region, and sex at birth. Patients from the platinum-based chemotherapy arm with documented disease progression are eligible to participate in the crossover phase of this trial to furmonertinib therapy. The primary endpoint is progression-free survival comparing between the treatment arms (furmonertinib 160 mg or 240 mg vs chemotherapy) based on BICR assessment. The key secondary endpoint is overall survival. Study enrollment is ongoing. Clinical trial information: NCT05607550. Citation Format: Alexander Spira, Byoung Chul Cho, Enriqueta Felip, Edward Garon, Koichi Goto, Melissa Lynne Johnson, Natasha B. Leighl, Antonio Passaro, David Planchard, Sanjay Popat, James Yang, Xiaoqian Lu, Yong Jiang, Jack Huang, Morgan Lam, Marcin Kowanetz, Shirley Wang, John Le, Jerry Hsu, Caicun Zhou. FURVENT, Phase 3 trial testing furmonertinib vs chemotherapy as first-line treatment for advanced NSCLC with EGFR exon 20 insertions (FURMO-004) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT280.

Efficacy and safety of epidermal growth factor receptor tyrosine kinase inhibitors combined with chemotherapy as first-line treatment for epidermal growth factor receptor-mutant advanced non-small cell lung cancer

Objective: To observe the clinical efficacy and safety of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) combined with chemotherapy as first-line treatment for EGFR mutant advanced non-small cell lung cancer (NSCLC). Methods: It was a retrospective, single-arm real-world study and a total of 39 patients with stage ⅢB to Ⅳ EGFR mutant NSCLC diagnosed in Cancer Hospital of Chinese Academy of Medical Sciences from July 2018 to December 2020 were collected. There were 16 males and 23 females, the age ranged from 25 to 73 years, with a median age of 53 years. All patients received EGFR-TKIs synchronously combined with pemetrexed and platinum-containing chemotherapy for 4-6 cycles as first-line treatment, followed by EGFR-TKI monotherapy with or without pemetrexed maintenance therapy. The objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) and adverse reactions were evaluated. Median follow-up time was 18.6 months (95%CI: 16.2-21.0 months). The Kaplan-Meier method was used for survival analysis. Results: The ORR was 61.5% (24/39), the DCR was 94.9% (37/39) and the median PFS was 16.4 months (95%CI: 12.1-20.7 months). The main adverse reactions were liver function injury (59.0%, 23/39), myelosuppression (43.6%, 17/39), skin reaction (25.6%, 10/39), gastrointestinal reaction (17.9%, 7/39), fatigue (12.8%, 5/39) and kidney injury (5.1%, 2/39). Most of the patients had grade 1-2 adverse reactions, and the rate of grade 3 adverse events were 12.8%(5/39), which were effectively alleviated after symptomatic support treatment, no grade 4 serious adverse events occurred. Conclusion: EGFR-TKIs synchronously combined with chemotherapy followed by EGFR-TKI monotherapy with or without pemetrexed maintenance therapy has a certain therapeutic effect and fairly good safety, which can prolong PFS in patients with EGFR mutated advanced NSCLC.

Anlotinib combined with pemetrexed and carboplatin as first-line treatment in driver-gene negative advanced non-squamous non-small cell lung cancer: ALTER L012.

e21147 Background: Anlotinib is a novel multitarget tyrosine kinase inhibitor and can be conveniently orally administered. In the phase III trial ALTER 0303, anlotinib significantly improved overall survival (OS) and progression-free survival (PFS) in advanced NSCLC patients. The study aimed to explore the efficacy and safety of anlotinib combined with carboplatin and pemetrexed followed by anlotinib combined with pemetrexed maintenance in advanced EGFR/ALK wild-type non-squamous non-small-cell lung cancer (nsq-NSCLC). Methods: This multicenter (n = 6), single-arm clinical trial recruited patients with wild-type EGFR/ALK advanced nsq-NSCLC who received first-line therapy between March 2019 and February 2021. Patients received anlotinib (12 mg p.o., QD d1 to 14, 21 days per cycle) combined with pemetrexed (500 mg/m, iv, d1, Q3W) + carboplatin (AUC = 5, iv, d1, Q3W) for 4 cycles followed by anlotinib and pemetrexed maintenance until disease progression (PD). The primary endpoint was PFS. Secondary endpoints are OS, objective response (ORR), disease control rate (DCR) and safety. Results: Between Mar 2019 and Feb 2021, 44 patients were enrolled and 38 of them have received at least one tumor assessment. The median age was 62 (range: 33-75) years. Most of the patients were non-smoker (68.4%). The median follow-up was 13.6 (range: 12.3-14.9) months. Median PFS was 10.5 (95%CI: 4.1, 17.0) months, and median OS was 23.4 (95%CI: NE, NE) months. The DCR and ORR were 94.7% and 60.5%, respectively. Twelve participants had treatment-related adverse events (TEAEs) of grade > 3. The most common Grade 3 AEs were hypertension (23.7%), neutropenia (19.4%), and bone marrow hypocellular (10.5%). Seven patients discontinued treatment, including two during induction and five during maintenance. No grade 5 TRAE was recorded. In the non-smoker participants, the median PFS was 14.5 (95%CI: 4.0-25.0) months. Conclusions: This study finds that anlotinib plus pemetrexed and carboplatin followed by anlotinib plus pemetrexed maintenance therapy might be a promising treatment for patients with wild-type EGFR/ALK advanced nsq-NSCLC. The combination was well tolerated, and the AEs were manageable. Clinical trial information: NCT03790228.

Molecular profiling of non-small-cell lung cancer patients with or without brain metastases included in the randomized SAFIR02-LUNG trial and association with intracranial outcome

IntroductionLung cancer remains the most frequent cause of brain metastases (BMs) and is responsible for high morbidity and mortality. Intracranial response to systemic treatments is inconsistent due to several mechanisms: genomic heterogeneity, blood–tumor barrier, and the brain-specific microenvironment. We conducted a study using data from the SAFIR02-LUNG trial. The primary objective was to compare the molecular profiles of non-small-cell lung cancer (NSCLC) with or without BMs. The secondary objective was to explore central nervous system (CNS) outcomes with various maintenance treatment regimens. MethodsIn total, 365 patients harboring interpretable molecular data were included in this analysis. Clinical and biological data were collected. Genomic analyses were based on array-comparative genomic hybridization and next-generation sequencing (NGS) following the trial recommendations. ResultsBaseline genomic analyses of copy number variations identified a 24-gene signature specific to lung cancer BM occurrence, all previously known to take part in oncogenesis. NGS analysis identified a higher proportion of KRAS mutations in the BM-positive group (44.3% versus 32.3%), especially G12C mutations (63% versus 47%). Protein interaction analyses highlighted several functional interactions centered on EGFR. Furthermore, the risk of CNS progression was decreased with standard pemetrexed maintenance therapy. The highest rate of CNS progression was observed with durvalumab, probably because of the specific intracranial immune microenvironment. ConclusionThis work identified a 24-gene signature specific to lung cancer with BM. Further studies are needed to precisely determine the functional implications of these genes to identify new therapeutic targets for the treatment of lung cancer with BM.

Analysis of the Efficacy of Pemetrexed Maintenance Therapy in Patients with Malignant Pleural Mesothelioma

背景与目的恶性胸膜间皮瘤（malignant pleural mesothelioma, MPM）是原发于胸膜且恶性程度高的一类肿瘤。晚期胸膜间皮瘤预后差，中位生存时间不超过15个月。一线标准化疗方案推荐是含培美曲塞的双药联合，加或不加贝伐珠单抗。目前一线标准化疗有效的患者能否从培美曲塞维持化疗中获益，尚无统一结论。本研究旨在探索培美曲塞单药维持在一线标准化疗有效的晚期MPM患者的疗效及安全性。方法收集中国医学科学院肿瘤医院2013年1月-2018年1月确诊的一线培美曲塞联合铂类化疗4个-6个周期，且疾病未进展的MPM患者，共40例。根据患者后续是否进行培美曲塞单药维持治疗，将患者分为培美曲塞单药维持组（n=22）和观察组（n=18）。末次随访时间为2020年1月。主要研究终点为无进展生存时间（progression free survival, PFS），次要终点为总生存时间（overall survival, OS）、培美曲塞单药治疗的疗效以及不良反应发生情况。结果培美曲塞维持治疗组较观察组中位PFS有所延长（8.5个月vs 3个月，P=0.008），而中位OS无明显差异（26.4个月vs 15.7个月，P=0.177）；两组的客观缓解率（objective response rate, ORR）分别为22.7%和0%。维持治疗组3级-4级不良反应包括1例（4.5%）患者出现4级中性粒细胞减少，1例（4.5%）患者出现3级中性粒细胞减少，1例（4.5%）患者出现4级贫血，3级恶心及食欲减低的发生率为4.5%。结论培美曲塞单药维持治疗对于一线使用培美曲塞联合铂类化疗有效的MPM患者，中位PFS有获益，且耐受性可。

148P A phase II study of tislelizumab plus chemotherapy in EGFR mutated advanced non-squamous NSCLC patients failed to EGFR TKI therapies: First analysis

BackgroundAlthough EGFR tyrosine kinase inhibitors (TKI) have improved the survival of EGFR mutated NSCLC pts, drug resistance inevitably develops in almost all pts. Tislelizumab (tis), an anti-PD-1 mAb, has shown improved efficacy when combined with chemotherapy in pts with advanced EGFR-wt NSCLC with a tolerable safety profile. This study aims to evaluate the efficacy and safety of tis plus chemotherapy in EGFR-mut nsq-NSCLC pts failed to EGFR TKI therapies.MethodsThis multicenter, single-arm, phase II study enrolled pts with EGFR sensitizing mutations who have failed prior EGFR-TKI therapies. Pts were treated with tis plus carboplatin and nab-paclitaxel Q3W for up to 4 cycles, followed by tis plus pemetrexed maintenance therapy. Primary endpoint was 1-year PFS rate, and secondary endpoints included ORR, DCR and safety, etc. First analysis is planned at 7 weeks after 50% planned enrollment (33 pts) for early efficacy and safety.ResultsTable: 148PResponseTotal (N=32)EGFR mutation#Prior EGFR TKI treatmentprior anti-angiogenesis treatmentExon 19del (N=17)Exon 21 L858R (N=14)1/2nd and 3rd TKI (N=17)1/2nd or 3rd TKI (N=15)Yes (N=10)No (N=22)BoR, n (%)PR19 (59.4%)∗12 (70.6%)6 (42.9%)10 (58.8%)9 (60.0%)7 (70.0%)12 (54.6%)SD10 (31.3%)3 (17.7%)7 (33.3%)5 (29.4%)5 (33.3%)1 (10.0%)9 (40.9%)PD3 (9.4%)2 (11.8%)1 (7.1%)2 (11.8%)1 (6.7%)2 (20.0%)1 (4.6%)ORR19 (59.4%)12 (70.6%)6 (42.9%)10 (58.8%)9 (60.0%)7 (70.0%)12 (54.6%)DCR29 (90.6%)15 (88.2%)13 (92.9%)15 (88.2%)14 (93.3%)8 (80.0%)21 (95.5%)BOR, best overall response; PR, partial response; SD, stable disease; PD, progressive disease; ORR, objective response rate; DCR, disease control rate*Including 4 unconfirmed PR;#1 pts with exon 18 G719X was PR. Open table in a new tab ConclusionsTislelizumab plus chemotherapy has preliminarily shown a promising anti-tumor efficacy with manageable safety profile for EGFR TKI failure pts. Efficacy and safety of the combination will be continuously monitored.Clinical trial identificationNCT04405674.Legal entity responsible for the studyThe authors.FundingBeiGene (Beijing), Co. Ltd.DisclosureAll authors have declared no conflicts of interest. BackgroundAlthough EGFR tyrosine kinase inhibitors (TKI) have improved the survival of EGFR mutated NSCLC pts, drug resistance inevitably develops in almost all pts. Tislelizumab (tis), an anti-PD-1 mAb, has shown improved efficacy when combined with chemotherapy in pts with advanced EGFR-wt NSCLC with a tolerable safety profile. This study aims to evaluate the efficacy and safety of tis plus chemotherapy in EGFR-mut nsq-NSCLC pts failed to EGFR TKI therapies. Although EGFR tyrosine kinase inhibitors (TKI) have improved the survival of EGFR mutated NSCLC pts, drug resistance inevitably develops in almost all pts. Tislelizumab (tis), an anti-PD-1 mAb, has shown improved efficacy when combined with chemotherapy in pts with advanced EGFR-wt NSCLC with a tolerable safety profile. This study aims to evaluate the efficacy and safety of tis plus chemotherapy in EGFR-mut nsq-NSCLC pts failed to EGFR TKI therapies. MethodsThis multicenter, single-arm, phase II study enrolled pts with EGFR sensitizing mutations who have failed prior EGFR-TKI therapies. Pts were treated with tis plus carboplatin and nab-paclitaxel Q3W for up to 4 cycles, followed by tis plus pemetrexed maintenance therapy. Primary endpoint was 1-year PFS rate, and secondary endpoints included ORR, DCR and safety, etc. First analysis is planned at 7 weeks after 50% planned enrollment (33 pts) for early efficacy and safety. This multicenter, single-arm, phase II study enrolled pts with EGFR sensitizing mutations who have failed prior EGFR-TKI therapies. Pts were treated with tis plus carboplatin and nab-paclitaxel Q3W for up to 4 cycles, followed by tis plus pemetrexed maintenance therapy. Primary endpoint was 1-year PFS rate, and secondary endpoints included ORR, DCR and safety, etc. First analysis is planned at 7 weeks after 50% planned enrollment (33 pts) for early efficacy and safety. ResultsTable: 148PResponseTotal (N=32)EGFR mutation#Prior EGFR TKI treatmentprior anti-angiogenesis treatmentExon 19del (N=17)Exon 21 L858R (N=14)1/2nd and 3rd TKI (N=17)1/2nd or 3rd TKI (N=15)Yes (N=10)No (N=22)BoR, n (%)PR19 (59.4%)∗12 (70.6%)6 (42.9%)10 (58.8%)9 (60.0%)7 (70.0%)12 (54.6%)SD10 (31.3%)3 (17.7%)7 (33.3%)5 (29.4%)5 (33.3%)1 (10.0%)9 (40.9%)PD3 (9.4%)2 (11.8%)1 (7.1%)2 (11.8%)1 (6.7%)2 (20.0%)1 (4.6%)ORR19 (59.4%)12 (70.6%)6 (42.9%)10 (58.8%)9 (60.0%)7 (70.0%)12 (54.6%)DCR29 (90.6%)15 (88.2%)13 (92.9%)15 (88.2%)14 (93.3%)8 (80.0%)21 (95.5%)BOR, best overall response; PR, partial response; SD, stable disease; PD, progressive disease; ORR, objective response rate; DCR, disease control rate*Including 4 unconfirmed PR;#1 pts with exon 18 G719X was PR. Open table in a new tab BOR, best overall response; PR, partial response; SD, stable disease; PD, progressive disease; ORR, objective response rate; DCR, disease control rate *Including 4 unconfirmed PR; #1 pts with exon 18 G719X was PR. ConclusionsTislelizumab plus chemotherapy has preliminarily shown a promising anti-tumor efficacy with manageable safety profile for EGFR TKI failure pts. Efficacy and safety of the combination will be continuously monitored. Tislelizumab plus chemotherapy has preliminarily shown a promising anti-tumor efficacy with manageable safety profile for EGFR TKI failure pts. Efficacy and safety of the combination will be continuously monitored.

P40.01 Maintenance Anlotinib After Induction Therapy With Platinum-Based Chemotherapy for Advanced Non-Small-Cell Lung Cancer: A Phase 2 Study

Patients (pts) with advanced non-squamous non-small-cell lung cancer (NSCLC) benefit from pemetrexed maintenance therapy after induction therapy with platinum-based chemotherapy. However, Pemetrexed needs to be given intravenously, and it has more serious and high incidence of side effects such as bone marrow suppression, rash and so on. This is the first trial to assess anlotinib as maintenance therapy after induction therapy with platinum-based chemotherapy in advanced NSCLC.

P14.02 Phase III Trial of Pembrolizumab-Chemotherapy Versus Pembrolizumab in First-Line of Advanced NSCLC with PD-L1 ≥50%: PERSEE

Single agent antibodies against PD-(L)1 (ICI) have become since 2017 a standard of care for first-line treatment of stage IV NSCLC with PD-L1 TPS ≥50%. Recent phase III trials assessing chemotherapy-ICI combinations have shown an overall survival (OS) benefit for the combination therapy over chemotherapy alone regardless PD-L1 level of expression. In Europe, both single agent ICI and chemotherapy-ICI strategies are approved if PD-L1 TPS ≥50%. The aim of PERSEE trial is to compare head-to-head chemotherapy-pembrolizumab combinations vs. pembrolizumab monotherapy in patients with PD-L1 TPS ≥50%. PERSEE trial is a multicenter, prospective, open label, randomized phase III study that evaluates the superiority of chemotherapy-pembrolizumab combination over pembrolizumab single agent in first-line treatment for patients with PD-L1 TPS ≥50% NSCLC. Main inclusion criteria are stage IV or stage III NSCLC ineligible to local treatment, locally assessed PD-L1 TPS ≥50%, no known EGFR mutation or ALK or ROS1 rearrangements, ECOG performance status 0 or 1. Patients with brain metastases are included if they are asymptomatic or treated if symptomatic. Patients in the chemotherapy-immunotherapy arm receive four induction cycles once every 3 weeks with pembrolizumab 200 mg combined with cisplatin 75 mg/m2 or carboplatin area under the curve (AUC) 5 mg/mL/min, pemetrexed 500 mg/m2 for non-squamous NSCLC or carboplatin AUC 6 mg/mL/min, paclitaxel 200 mg/m2 for squamous NSCLC. Responders or patients with stable disease will receive pembrolizumab up to a maximum of 35 cycles and pemetrexed maintenance therapy for non-squamous NSCLC until disease progression or unacceptable toxicity. Patients in the immunotherapy alone arm receive pembrolizumab 200 mg once every 3 weeks for a maximum of 35 cycles. Primary endpoint is centrally assessed progression-free survival (PFS) according to RECIST 1.1. Secondary endpoints include overall survival, response rate, duration of response and safety. A central assessment of PD-L1 (22C3 clone) will be performed retrospectively. Assuming a hazard ratio of 0.7 for PFS in favor of chemotherapy-pembrolizumab and an expected median PFS of 7.1 months in the control group, the required sample size is 262 randomized patients (131 patients per treatment arm) for the observation of 249 events based on a 3-year recruitment period and a 5-year study period. Randomization will be stratified on tumor histology (squamous versus non squamous) and presence or absence of brain metastases. Trial will be opened in 30 centers in France and inclusions started on December 22, 2020. Recruitment is expected to end in December 2023. Clinical trial information: NCT04547504 ▪▪▪ ▪▪▪

Duration of pemetrexed maintenance therapy with or without pembrolizumab is associated with risk of renal toxicity in patients with metastatic nonsquamous NSCLC.

e21205 Background: Use of maintenance pemetrexed with pembrolizumab is the standard of care among patients with metastatic nonsquamous NSCLC without EGFR or ALK alterations treated with the KEYNOTE-189 regimen. Whether the addition of pembrolizumab to pemetrexed maintenance alters the risk of renal toxicity is not well characterized. Methods: A single center retrospective study was performed. The frequency of acute kidney injury as well as the rates of discontinuation due to renal injury was assessed. Acute renal injury was defined as ≥ 0.3 increase in serum creatinine (sCr) above the upper limit of normal or a rise in sCr ≥ 1.5 times baseline per KDIGO criteria. A Fisher exact test was conducted to compare the rate of renal injury between the two groups. Logistic regression adjusting for performance status, prior lines of treatment, and number of maintenance cycles was performed. Results: We identified 114 patients who received either maintenance pemetrexed or pemetrexed + pembrolizumab. The median number of cycles for the maintenance pemetrexed and pemetrexed + pembrolizumab groups was 5 and 7 cycles respectively. Of these, 41% (47/114) patients developed acute renal injury during their treatment course. Renal injury was seen in 14.3% (5/35) patients who received single agent pemetrexed maintenance and 25% (3/12) who received maintenance pemetrexed + pembrolizumab with no significant difference in the rates of renal injury between both arms (p = 0.403). Among patients who developed acute renal injury, 9% (4/47) permanently discontinued maintenance due to nephrotoxicity. All patients who permanently discontinued therapy received maintenance pemetrexed alone. When adjusting for covariates, ECOG performance status and number of prior lines of therapy did not increase the risk of renal toxicity. Logistic regression analysis identified that the rate of renal injury was significantly associated with the number of maintenance cycles received (p-value = 0.017, OR = 1.14, 95% CI 1.03 - 1.29). The odds of developing renal injury were 1.14 times higher with each additional cycle of maintenance therapy received. Conclusions: Renal injury is common among patients treated with patients receiving maintenance therapy. The addition of pembrolizumab to maintenance pemetrexed did not significantly increase the rate of renal injury. The risk of renal injury appears to correlate with the total number of maintenance cycles received suggesting a cumulative risk of nephrotoxicity over time.

Efficacy and safety of pemetrexed maintenance chemotherapy for advanced non-small cell lung cancer in a real-world setting.

BackgroundPemetrexed maintenance therapy offers a survival benefit in patients with nonprogressive advanced nonsquamous non-small cell lung cancer (NSCLC) with good tolerability. This study was designed to analyze the efficacy and safety of pemetrexed maintenance chemotherapy in advanced nonsquamous NSCLC patients in a real-world setting.MethodsThe response rate (RR) and adverse events in 71 nonsquamous NSCLC patients treated with pemetrexed-based chemotherapy were observed until disease progression or unacceptable toxicities. Measures of survival were analyzed during follow-up.ResultsOf 69 efficacy-evaluable patients, the objective response rate (ORR) was 46.4% and the disease control rate (DCR) was 98.6%. ORR showed no significant difference between patients who received pemetrexed as first-line therapy and those who received pemetrexed as second-line or higher treatment. The median treatment cycle for all patients was 8. The median progression-free survival (PFS) was 9.5 months (m) and median overall survival (OS) was 30.5 m. The univariate and multivariate analyses showed that the number of chemotherapy cycles was an independent factor for PFS. The most common adverse reactions were grade 1 to 2 hematologic toxicities, gastrointestinal reactions, and liver enzyme abnormalities. Only 1 patient experienced a grade 3 gastrointestinal event.ConclusionsPemetrexed maintenance chemotherapy can improve PFS in patients with advanced nonsquamous NSCLC with good tolerability.

PD-L1 expression is a promising predictor of survival in patients with advanced lung adenocarcinoma undergoing pemetrexed maintenance therapy

This study aimed to identify potential predictive factors for the survival of advanced lung adenocarcinoma patients undergoing pemetrexed maintenance therapy. 122 advanced lung adenocarcinoma patients who received pemetrexed maintenance therapy were retrospectively analyzed. Kaplan–Meier method with Log-rank test was used for survival analysis. Univariate and multivariate Cox regression were performed to evaluate prognostic factors for overall survival (OS) and progression-free survival (PFS). Bivariate correlation analysis was used for exploratory purpose. For the whole cohort of 122 patients, median PFS was 11.97 months (95% CI 10.611–13.329) and estimated median OS was 45.07 months (95% CI 31.690–58.450). The mPFS of ALK-positive patients was superior to negative patients (18.27 vs. 11.90 months; P = 0.039). Patients with ECOG PS 0 (14.4 vs. 11.1 months; p = 0.040) and patients with single-organ metastasis (19.0 vs. 11.0 months; p = 0.014) had prolonged median PFS. Compared with the low PD-L1 expression group, PFS of high PD-L1 expression group were improved (13.6 vs. 11.1 months, p = 0.104, at 1% cut-off; 17.5 vs. 11.1 months, p = 0.009, at 10% cut-off; and 27.5 vs. 11.4 months, p = 0.005, at 50% cut-off). No differences were found between EGFR positive and negative patients. PD-L1 expression was an independent prognostic factor for both PFS and OS times (PFS: HR, 0.175; P = 0.001; OS: HR, 0.107; P = 0.036). Bivariate correlation showed a significant positive correlation between PD-L1 expression and PFS (correlation coefficient R = 0.485, P < 0.001). High PD-L1 expression could be a potential effective predictor for favorable survival of advanced lung adenocarcinoma patients undergoing pemetrexed maintenance therapy.

Survival Benefit and Genetic Profile of Pemetrexed as Initial Chemotherapy in Selected Chinese Patients With Advanced Lung Adenocarcinoma.

Objective: This study investigated survival in selected Chinese patients with advanced lung adenocarcinoma who received initial chemotherapy with pemetrexed. We also explored the relationship between genetic biomarkers and pemetrexed efficacy.Methods: We retrospectively collected patients (n = 1,047) enrolled in the Chinese Patient Assistance Program from multiple centers who received pemetrexed alone or combined with platinum as initial chemotherapy and continued pemetrexed maintenance therapy for advanced lung adenocarcinoma from November 2014 to June 2017. The outcomes were duration of treatment (DOT) and overall survival (OS). Clinical features were analyzed for their influence on the treatment effect and prognosis. Next-generation sequencing (NGS) was performed to identify genetic biomarkers associated with the efficacy of pemetrexed.Results: The median DOT was 9.1 months (95% CI: 8.5–9.8), and the median OS was 26.2 months (95% CI: 24.2–28.1). OS was positively correlated with DOT (r = 0.403, P < 0.001). Multivariable analysis showed that smoking status and Eastern Cooperative Oncology Group (ECOG) performance status (PS) were independently associated with DOT; smoking status, ECOG PS, targeted therapy, and EGFR/ALK/ROS1 status were independently associated with OS. NGS in 22 patients with available samples showed genes with high mutation rates were: TP53 (54.5%), EGFR (50.0%), MYC (18.2%), and PIK3CA (13.6%). When grouped based on progression-free survival (PFS) reported in the PARAMOUNT study, the DOT > 6.9 months set was associated with PIK3CA, ALK, BRINP3, CDKN2A, CSMD3, EPHA3, KRAS, and RB1 mutations, while ERBB2 mutation was observed only in the DOT ≤ 6.9 months set.Conclusion: This study shows that initial chemotherapy with pemetrexed is an effective regimen for advanced lung adenocarcinoma in selected Chinese patients. There is no specific genetic profile predicting the benefit of pemetrexed found by NGS. Biomarkers predicting the efficacy of pemetrexed need further exploration.

A phase III, open-label, randomized study of atezolizumab in combination with carboplatin + paclitaxel + bevacizumab compared with pemetrexed + cisplatin or carboplatin with stage IV non-squamous non-small cell lung cancer (NSCLC) with activating EGFR mutation or ALK translocation (ATLAS Trial).

TPS9636 Background: In patients with activating EGFR mutations and ALK fusion, target specific tyrosine kinase inhibitor (TKI) showed significant survival improvement compared to the cytotoxic chemotherapy. However, the questions remain which combination strategy will be the best option for the patients who have failed from TKI. Especially, the role of an immune checkpoint inhibitor (ICI) in this population is still unclear. This study is designed and conducted based on the recent subgroup analyses from the IMpower 150 study which showed the positive clinical outcomes of atezolizumab combined with VEGF inhibitor and conventional cytotoxic chemotherapy in EGFR mutation and ALK translocation. Methods: This study is the phase III, open-label, multicenter study of atezolizumab in combination with bevacizumab + carboplatin + paclitaxel (ABCP, Arm A) compared with pemetrexed + cisplatin or carboplatin (Arm B). The study population will be randomized to either Arm A (n = 152) or Arm B (n = 72) based on two stratification factors, EGFR vs. ALK and presence of brain metastases. In Arm A, patients will be treated with 4 or 6 cycles of ABCP followed by maintenance atezolizumab and bevacizumab every three weeks. In Arm B, pemetrexed maintenance therapy will be applied every three weeks after 4 or 6 cycles of pemetrexed + cisplatin or carboplatin. As key inclusion criteria, the patients must be diagnosed with stage IV non-squamous non-small cell lung cancer with either activating EGFR mutation or ALK translocation. All the patients need to be cytotoxic chemotherapy naïve and must have experienced disease progression to treatment with at least one EGFR or ALK TKI. If the patients have T790M mutation after 1st or 2nd generation EGFR TKI, second line 3rd generation EGFR TKI treatment is mandatory. The number of T790M positive patients is restricted to under 30% of the entire study population. The primary endpoint is progression-free survival and the major secondary endpoints are overall survival, objective response rate and duration of response. A total of 228 subjects will be enrolled to detect a hazard ratio of 0.67. The first subject received treatment in Aug. 2019 and 19 patients receive the treatment. This study is opened in 3 sites and expected to be opened at 18 sites in South Korea. The time point for the primary analyses is Q3. 2022. Clinical trial information: NCT03991403 .

336P - Pembrolizumab plus chemotherapy versus pembrolizumab monotherapy for PD-L1-positive advanced non-small cell lung cancer in the real world

BackgroundImmune checkpoint inhibitor (ICI) plus Chemotherapy has now become the new standard treatment for non-small-cell lung cancer (NSCLC). However, little is known about comparison of ICI plus Chemotherapy and ICI monotherapy in the real world. MethodsPatients with PD-L1-positive, advanced NSCLC treated with pembrolizumab plus chemotherapy (C group) or pembrolizumab monotherapy (M group) at Sendai Kousei Hospital between May 2015 to June 2019 were included in our study. C group received different treatments depending on histology: Patients with squamous NSCLC were received carboplatin and either paclitaxel or nanoparticle albumin-bound [nab]–paclitaxel plus pembrolizumab followed by pembrolizumab maintenance therapy. Patients with non-squamous NSCLC were received pemetrexed and a platinum-based drug plus pembrolizumab followed by pembrolizumab plus pemetrexed maintenance therapy. Two groups were evaluated with respect to adverse event (AE) profiles, objective response rate (ORR), disease control rate (DCR) and progression-free survival (PFS). ResultsThe following were observed: patient background (C group/ M group) number of cases 13/ 38 cases, median age 64/ 73 years old, male 76.9/71.1 %, Performance Status 0 or 1/ 2/ ≧3 (13/ 0/ 0) / (36/ 2/ 0), median observation period 5.1/ 7.4 months, development of AEs 100/ 84.2 %, development of immune-rerated AEs (irAEs) 61.5/ 84.2 %, development of irAEs ≥ grade 3 7.7/ 21.1 %. There was no significant difference in the ORR (38.5/ 55.2 %; p = 0.199) and DCR (100/89.5 %; p = 0.561) between two groups. Three months PFS were 100 % in combination group and 76.3 % in monotherapy group. Median PFS wasn’t significant different between the two groups (5.9/ 9.2 months; p = 0.193). PFS within 3 months of treatment start of C group tended to be better than M group. ConclusionsMedian PFS wasn’t significantly different between the two groups, probably due to the short observation period. PFS within 3 months of treatment start of C group tended to be better than M group. C group had more AEs than M group. However, the frequency of severe irAEs in C group was similar to M group. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureS. Sugawara: Honoraria (self): Ono Pharmaceutical; Honoraria (self): Bristol-Myers Squib; Honoraria (self): MSD; Honoraria (self): AstraZeneca; Honoraria (self): Chugai Pharma; Honoraria (self): Nippon Boehringer Ingelheim; Honoraria (self): Pfizer; Honoraria (self): Taiho Pharmaceutical; Honoraria (self): Eli Lilly and Company; Honoraria (self): Novartis; Honoraria (self): Kyowa Hakko Kirin. Y. Toi: Honoraria (self): Ono Pharmaceutical; Honoraria (self): MSD; Honoraria (self): AstraZeneca. Y. Kawashima: Honoraria (self): Chugai Pharma. A. Nakamura: Honoraria (self): MSD; Honoraria (self): Chugai Pharma; Honoraria (self): AstraZeneca. S. Yamanda: Honoraria (self): Kyowa Hakko Kirin; Honoraria (self): Novartis; Honoraria (self): AstraZeneca; Honoraria (self): Taiho Pharmaceutical. Y. Kimura: Honoraria (self): Nippon Boehringer Ingelheim. All other authors have declared no conflicts of interest.

THE RISK OF TREATMENT WITH PEMETREXED PLUS PLATINUM FOLLOWED BY MAINTENANCE WITH PEMETREXED FOR PATIENTS WITH ADVANCED NONSQUAMOUS NON-SMALL CELL LUNG CANCER CONCURRENT WITH INTERSTITIAL LUNG DISEASE

SESSION TITLE: Wednesday Abstract Posters SESSION TYPE: Original Investigation Posters PRESENTED ON: 10/23/2019 09:45 AM - 10:45 AM PURPOSE: Pemetrexed plus platinum followed by pemetrexed maintenance has been one of the standard first-line treatments in advanced nonsquamous non-small cell lung cancer (NSCLC), but little was known regarding its safety and efficacy for patients with interstitial lung disease (ILD). The aim of this study was to assess the safety and efficacy profiles of pemetrexed plus platinum with and without pemetrexed maintenance for patients with advanced nonsquamous NSCLC and concurrent ILD. METHODS: 24 patients with advanced nonsquamous NSCLC and preexisting ILD received pemetrexed and platinum doublet therapy with and without pemetrexed maintenance in a first-line setting between December 2009 and June 2016. Their clinical outcomes were retrospectively investigated. RESULTS: Of the 24 patients analyzed, 18 did not progress after 4 cycles of pemetrexed and platinum doublet therapy and 6 received pemetrexed maintenance. The median progression-free survival time was 4.7 months, and the median overall survival time was 9.5 months in the analysis for all patients. The median number of pemetrexed maintenance cycles was 2 (range: 2-4 cycles), but pemetrexed maintenance therapy did not improve the median OS. AE-ILD occurred in 3 cases during the doublet therapy and in 2 cases during the maintenance therapy. Treatment-related deaths occurred in one case during the doublet therapy and in 2 cases during the maintenance. CONCLUSIONS: Combination chemotherapy of pemetrexed plus platinum with pemetrexed maintenance has a high risk of AE-ILD in patients with advanced nonsquamous NSCLC and preexisting ILD. We recommend not administering pemetrexed as maintenance therapy for patients with preexisting ILD. CLINICAL IMPLICATIONS: We recommend not administering pemetrexed as maintenance therapy for patients with preexisting ILD. DISCLOSURES: No relevant relationships by Hiroyuki Amano, source=Web Response No relevant relationships by TETSUO FUJITA, source=Web Response No relevant relationships by Satoshi Hirano, source=Web Response No relevant relationships by TSUGUKO KUROKI, source=Web Response No relevant relationships by makoto nakamura, source=Web Response No relevant relationships by SUKEYUKI NAKAMURA, source=Web Response No relevant relationships by YUKA SHIRAISHI, source=Web Response No relevant relationships by Hiroshi Tabeta, source=Web Response

Mature, real world progression-free survival (PFS) and overall survival (OS) milestones in stage IV, non-squamous, non-small cell lung cancer patients (nsqNSCLC) treated with first line pemetrexed(Pem)/platinum(Plat) followed by pem+/-bevacizumab(Bev) maintenance.

e20721 Background: Pemetrexed maintenance therapy is associated with superior survival in stage IV nsqNSCLC patients. We have observed long term disease control in some patients treated with at least one cycle of Pem/Plat with potential for maintenance pem. There are no reports of data regarding long term PFS and OS in patients treated with Pem regimens. The objectives of our retrospective analysis are to determine the frequency of long term disease control on Pem maintenance and to identify parameters associated with longer PFS/OS. Methods: We included all patients with Stage IV nsqNSCLC who received at least one cycle of pem/plat between May 2010 and Nov 2013. We identified 240 patients from our database and analyzed their demographics, lab values, dates of therapy, and dates of progression. PFS/OS was estimated by the Kaplan-Meier method and associations with patient characteristics were assessed by log-rank tests and Cox proportional hazards analysis. The shortest potential follow up was 5 years. Results: Median age was 66 years, 60% were female, and 72% were Caucasian. Baseline ECOG performance status was 0(22%), 1(50%) and ≥ 2(22%). Median PFS was 6.2 months. At 1, 2, 3, 4, and 5 years of follow up absence of disease progression was seen in 33%, 14%, 7.5%, 4%, and 3%, respectively. Additionally, in terms of OS at 1-5 years, we observed 54.5%, 35%, 21%, 14%, and 11%. Lower baseline neutrophil: lymphocyte ratio (NLR) was strongly associated with improved PFS when using NLR≤5 vs &gt; 5 (median PFS 13.2 mo vs 5.6 mo) Additionally, baseline Hemoglobin (mean = 12.03 g/dL, HR = .904, p = .0046) and Albumin (mean 3.3 g/dL, HR = .7722, p = .024) were associated with better PFS. Conclusions: The similarity in median PFS in our patients (6.2 mo) and clinical trial data suggests that our group of real world patients did not have uniquely favorable baseline characteristics. However, the patients most likely to reach long PFS/OS milestones had favorable baseline prognostic indicators suggesting that this patient subset might also be most likely to benefit from the recently approved regimen which combined Pembrolizumab with Pemetrexed/Carboplatin.

164P - PD-L1 expression affect the efficacy of pemetrexed maintenance therapy in real-world patients with advanced non-squamous NSCLC

164P - PD-L1 expression affect the efficacy of pemetrexed maintenance therapy in real-world patients with advanced non-squamous NSCLC

Predictive factors for long-term responders of pemetrexed maintenance treatment in non-small cell lung cancer.

BackgroundWe determined the clinical characteristics and predictive factors of long‐term response to pemetrexed maintenance therapy as first‐line treatment for non‐small cell lung cancer (NSCLC).MethodsA total of 950 advanced NSCLC patients received pemetrexed (500 mg/m2) plus cisplatin (60 mg/m2) (Pem‐Cis) induction chemotherapy every three weeks as first‐line treatment between January 2010 and August 2018. Patients who did not show progression after four cycles of Pem‐Cis and received at least one cycle of pemetrexed maintenance were recruited (n = 199).ResultsPatients were divided into subgroups according to total cycles of pemetrexed: ≤ 10 (F10, n = 134) and > 10 (M10, n = 65). The M10 group had a higher proportion of patients with stage M1a (intrathoracic metastasis alone) and exhibited lower levels of thymidylate synthase (TS) than the F10 group (median H‐score 10.0% vs. 60.0%; P = 0.031). Further subgrouping identified extreme responders: ≤ 7 (F7, n = 101) and ≥ 20 (M20, n = 26) cycles. The M20 group showed lower mean serum CEA levels before (17.5 vs. 147.0; P = 0.099) and after (6.9 vs. 53.2; P = 0.001) Pem‐Cis treatment, and a higher incidence of normalization after Pem‐Cis (abnormal 41.7% vs. 68.5%; P = 0.015). M1a stage, normalization of CEA levels after Pem‐Cis, and lower TS H‐score were predictors of progression‐free survival in patients administered pemetrexed maintenance.ConclusionM1a stage and lower TS expression were predictors of long‐term response to pemetrexed maintenance. CEA normalization after Pem‐Cis could be an additional surrogate marker of positive response to long‐term treatment.

Treatment patterns, duration and outcomes of pemetrexed maintenance therapy in patients with advanced NSCLC in a real-world setting

Objectives: In patients with non-squamous non-small-cell lung cancer (NSCLC), maintenance therapy regimens, including pemetrexed, have been shown to prolong overall survival (OS) and progression-free survival (PFS). The purpose of this study was to describe real-world maintenance use of pemetrexed and associated outcomes in patients with advanced NSCLC.Methods: This was a retrospective, observational study that used longitudinal, demographically and geographically diverse electronic health record data in the United States. Eligible patients were adults with advanced non-squamous NSCLC who had received maintenance treatment with pemetrexed monotherapy or pemetrexed plus bevacizumab. Descriptive statistics were used to describe the patient population and multivariable logistic regression was used to identify the factors associated with duration of maintenance therapy. Kaplan–Meier curves and Cox regression models were used for time-to-event analysis.Results: Patients receiving pemetrexed maintenance therapy were treated with either pemetrexed monotherapy (66.0%) or pemetrexed plus bevacizumab (34.0%). Carboplatin and pemetrexed (37.9%) or carboplatin, pemetrexed and bevacizumab (36.1%) were the most commonly used first-line therapies observed. The majority (84.9%) of these maintenance patients responded to first-line therapy. The median duration of maintenance therapy was 6.0 months for pemetrexed and bevacizumab and 4.1 months for pemetrexed monotherapy. The median OS from the start of first-line therapy of the total study cohort was 21.5 months (95% CI 20.0, 22.9).Conclusion: Real-world effectiveness of pemetrexed maintenance therapy is similar to that observed in published randomized controlled trials, confirming a role for pemetrexed maintenance in eligible patients in clinical practice.

Clinical case of long-term pemetrexed-based chemotherapy treatment for pulmonary adenocarcinoma (ALA +)

The article describes a clinical case of ALK-positive non-small cell lung cancer and its long-term treatment with a chemotherapy drug pemetrexed as first-line regimen followed by pemetrexed maintenance therapy.