Maintenance Pemetrexed Research Articles

Brief Report: Impact of Maintenance Pemetrexed Cessation on Clinical Outcomes of Patients With Metastatic Nonsquamous NSCLC

IntroductionCombination chemoimmunotherapy including pemetrexed and a PD(L)1 inhibitor is a common first-line systemic therapy approach for patients with metastatic nonsquamous NSCLC. Patients often discontinue maintenance pemetrexed due to adverse effects, and little is known about the impact of maintenance pemetrexed cessation on real-world progression-free survival (rwPFS) and overall survival (OS). MethodsA total of 121 patients with stage IV or recurrent, metastatic nonsquamous NSCLC treated at Vanderbilt University Medical Center (VUMC) were included in this retrospective analysis. Patients diagnosed between July 2017 and September 2023 were included if they received maintenance pemetrexed and pembrolizumab. Patients were divided into two groups: those who stopped pemetrexed due to toxicity and those who did not. rwPFS and OS were measured from time of stage IV or metastatic diagnosis to the date of radiographic progression or death, respectively. ResultsAmong patients with stage IV or recurrent, metastatic NSCLC (n = 121), who remained on maintenance pemetrexed and pembrolizumab (n = 68), the median rwPFS was 11.7 months (95% confidence interval [CI]: 7.47–not applicable [NA]) compared with 24.3 months (95% CI, 19.37–NA) among patients who stopped maintenance pemetrexed (n = 53) (p = 0.1). The median OS in the same patient groups was 25.8 months (95% CI: 13.8–NA) compared with 36.4 months (95% CI: 26.9–NA) (p = 0.15), respectively. ConclusionsIn this study of patients with metastatic nonsquamous NSCLC who received maintenance pemetrexed and pembrolizumab, patients who stopped pemetrexed due to toxicity experienced similar outcomes to those who continued with pemetrexed. The optimal duration of maintenance chemotherapy should be further evaluated in the immunotherapy era.

Impact of maintenance pemetrexed cessation on clinical outcomes of patients with metastatic non-squamous NSCLC.

8568 Background: Combination chemoimmunotherapy including pemetrexed and a PD(L)1 inhibitor is a common first line systemic approach for patients with metastatic non-squamous non-small cell lung cancer (NSCLC). Patients often discontinue maintenance pemetrexed due to adverse effects, and little is known about the impact of maintenance pemetrexed cessation on progression free survival (PFS) and overall survival (OS). Methods: 121 patients with stage IV or recurrent, metastatic non-squamous NSCLC treated at VUMC were included in this retrospective analysis. Patients diagnosed between 7/2017- 9/2023 were included if they received maintenance pemetrexed and pembrolizumab. Patients were divided into two groups: those who stopped pemetrexed due to toxicity and those who did not. PFS and OS were measured from time of stage IV or metastatic diagnosis to the date of radiographic progression or death, respectively, and compared with the Kaplan Meier method. Results: Among patients with stage IV or recurrent, metastatic NSCLC (n = 121), who remained on maintenance pemetrexed and pembrolizumab (n=68), the median PFS was 11.7 months (95% CI, 7.47-NA) compared to 24.3 months (95% CI, 19.4-NA) among patients who stopped maintenance pemetrexed (n=53; p=0.1). The median OS in the same patient groups was 25.8 months (95% CI, 13.8-NA) compared to 36.4 months (95% CI, 26.9-NA) (p=0.15), respectively. Among patients with stage IV disease at diagnosis (n = 97), the median PFS among patients who did not stop pemetrexed was 8.7 months (95% CI, 7.2–NA) compared to 24.3 months (95% CI, 17.3-NA) for patients who stopped pemetrexed (p=0.089). The median OS in these groups were 21 months (95% CI, 13.6-NA) and 38.6 months (95%, 28.0-NA) (p=0.054), respectively. Conclusions: In this study of patients with metastatic non-squamous NSCLC who received maintenance pemetrexed and pembrolizumab, patients who stopped pemetrexed due to toxicity experienced similar outcomes to those who continued with pemetrexed. The necessity of continuation of maintenance chemotherapy should be further evaluated in the immunotherapy era. [Table: see text]

Outcomes for pembrolizumab stratified by pemetrexed maintenance post pembrolizumab-platinum-pemetrexed induction in metastatic non-small-cell lung cancer.

Aim: We assessed treatment patterns and outcomes in patients with metastatic nonsquamous non-small-cell lung cancer (mNSCLC) who initiated first-line pembrolizumab-platinum-pemetrexed (induction) in US community oncology settings. Methods: Patients initiating induction were retrospectively identified. Patients continuing pembrolizumab afterward underwent chart review. Clinical outcomes were described by maintenance pemetrexed exposure after inverse probability of treatment weighting (IPTW). Results: Median induction pembrolizumab and pemetrexed durations were 5.1 and 4.2months. Among patients continuing pembrolizumab after induction, 64% received maintenance pemetrexed. Common discontinuation reasons for induction pemetrexed were completion of planned therapy (79%) and partial response (68%) and progressive disease (38%) and toxicity (29%) for maintenance pemetrexed. After IPTW, median overall survival and real-world progression-free survival were longer in patients continuing pembrolizumab with versus without maintenance pemetrexed (20.3 vs 12.0months and 10.3 vs 5.8months, respectively). Conclusion: Patient characteristics and planned treatment decisions affect maintenance pemetrexed utilization in the community oncology setting.

Phase III randomized controlled trial of gefitinib versus chemotherapy in EGFR-positive treatment-naïve metastatic lung cancer: Long-term outcome after eight years

Background: This was the first Phase III randomized study comparing an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), gefitinib, to standard-of-care chemotherapy (pemetrexed + carboplatin followed by pemetrexed maintenance) in advanced EGFR-mutated lung cancer. The initial interim analysis showed the superiority of gefitinib over chemotherapy in terms of progression-free survival (PFS), objective response rate (ORR), and safety. Objectives: We aimed to evaluate the long-term outcomes. Our primary endpoint was to evaluate the overall survival (OS) and the secondary endpoints were progression-free survival 2 (PFS2) and duration of response (DOR). Materials and Methods: This was a Phase III open-label, randomized, parallel-group study conducted in the Department of Medical Oncology, Tata Memorial Hospital, Mumbai, India, in patients with EGFR mutation-positive treatment-naïve Stage IIIB or IV lung adenocarcinoma. Patients were randomized to gefitinib (250 mg orally daily) or carboplatin (area under the curve 5) and pemetrexed (500 mg/m2) chemotherapy, followed by maintenance pemetrexed (500 mg/m2). Results: Between February 2012 and April 2016, 290 patients were randomized:145 to each arm. At a median follow-up of 104 months, all 290 (100%) patients had progressed, and 287 (99%) deaths had occurred. The median OS in the gefitinib arm was 19.5 months (95% confidence interval [CI], 16.7-24.8) compared to 22.6 months (95% CI, 19.2-25.2) in the chemotherapy arm; hazard ratio [HR], 1.11; 95% CI, 0.87-1.39; P, 0.423. The median PFS2 in the gefitinib arm was 15.5 months (95% CI, 13.5-18.1) compared to 12.5 months (95% CI, 11.1-14.5) in the chemotherapy arm; HR, 0.86 (95% CI, 0.66-1.13); P, 0.270. The median DOR was improved in the gefitinib arm (7.6 months; 95% CI, 5.45-9.88) compared to 3.9 months (95% CI, 3.49-6.35) in the chemotherapy arm; HR, 0.59; 95% CI, 0.42-0.82; P, 0.002. The 5-year survival was 4.1% in the gefitinib arm versus 6.8% in the chemotherapy arm. Conclusions: This study establishes the advantages of first-line EGFR TKI therapy over chemotherapy in terms of a durable response and numerically superior PFS2. Due to crossover post-progression, there was is no significant difference in OS (Clinical Trials Registry of India number: CTRI/2015/08/006113).

Circulating tumor DNA to guide furmonertinib monotherapy or combination therapy in advanced EGFR mutant non-small cell lung cancer (NSCLC): A randomized, open-label, multicenter study (FOCUS-C).

TPS9150 Background: Detection of EGFR ctDNA after several weeks EGFR-TKIs treatment was an effective method to identify prognosis of advanced EGFR mutant NSCLC patients. Patients with uncleared EGFR ctDNA had shorter progression-free survival (PFS) ( Mack PC et al; CCR 2022). However, whether they can benefit from EGFR-TKI combination therapy has not been reported. Furmonertinib (AST2818), a potent, orally bioavailable, highly brain penetrant, third generation EGFR-TKI with unique chemical structure designed to improve potency and specificity, showed superior efficacy compared with gefitinib as first-line therapy in EGFR mutant NSCLC along with an acceptable safety profile without new signals ( Shi, YK et al.; Lancet Respir Med 2022). We hypothesized that monitoring clearance of EGFR ctDNA in blood could rationally guide subsequent monotherapy or combination therapy with furmonertinib and will improve outcomes in patients with uncleared EGFR ctDNA. Methods: The FOCUS-C study is a multicenter, open-label, randomized study. Patients who are aged 18 years or older and have histologically confirmed, locally advanced or metastatic, stage IIIB, IIIC, or IV unresectable NSCLC with EGFR exon 19 deletions (19Del) or exon 21 Leu858Arg mutation (L858R) on tissue biopsy and plasma will be treated with furmonertinib. Eligible patients with uncleared EGFR 19Del or L858R ctDNA after 3 weeks furmonertinib treatment will be stratified according to EGFR mutation (19Del or L858R), central nervous system metastases (with or without) and detectable accompanying gene aberrances in plasma (with or without) and randomly assigned (2: 2: 1) to receive furmonertinib or furmonertinib plus chemotherapy (pemetrexed and carboplatin for 4 cycles followed by maintenance pemetrexed) or furmonertinib plus chemotherapy plus bevacizumab (pemetrexed, carboplatin and bevacizumab for 4 cycles followed by maintenance pemetrexed and bevacizumab) in 21-day cycles until disease progression, the occurrence of intolerable toxicities, withdrawal of consent, or other discontinuation reasons judged by the investigators. The primary endpoint is PFS between furmoneritnib plus chemotherapy versus furmonertinib alone. Secondary endpoints include PFS, objective response rate, duration of response, disease control rate, overall survival and safety. Several exploratory endpoints will also be evaluated based on ctDNA detection by next-generation sequencing (Genecast, Wuxi, China). The study is enrolling. 34 patients had been enrolled till 2nd Feb 2023. Clinical trial information: NCT05334277 .

An intelligent machine learning model for real-time early detection of undesirable cancer events: AIM2REDUCE.

1557 Background: Cancer and its treatment cause undesirable cancer events (UCEs). Automated warning systems could reduce the frequency and severity of UCEs by alerting the healthcare team and allocating preventative interventions. Most previous studies predicted single UCEs at the initiation of treatment. In AIM2REDUCE, we developed and evaluated a general-purpose system for predicting UCEs during outpatient systemic anti-cancer therapy. Methods: Each time a patient receives treatment, AIM2REDUCE applies machine learning to the preceding data in the electronic medical record (EMR) to predict future UCEs. We identified patients treated for aerodigestive cancers from the EMR at Princess Margaret Cancer Centre, who were randomly split into development, validation, and test cohorts. Features included cancer diagnosis, treatment sessions with doses, laboratory tests, and patient-reported symptoms. UCEs are listed in the Table. We trained LASSO regression and random forests models in the training cohort and tuned hyperparameters in the validation cohort using Bayesian optimization. We evaluated performance across discrimination, calibration, and net benefit in the test cohort. Results: The cohort included 5,760 patients who received 175,565 treatment sessions, with 13,612,746 unique data points across 102 features. Of these patients, 2,352 (40.8%) were female, the median age was 64.0 years (interquartile range 14.0), the most common diagnoses were lung cancer (2,071, 36.0%) and pancreatic cancer (926, 16.1%), and the most common treatment regimens were weekly gemcitabine (433, 7.5%) and maintenance pemetrexed (417, 7.2%). The Table shows the performance of AIM2REDUCE. Conclusions: We demonstrate that longitudinal machine learning systems trained using EMR data can accurately predict a wide range of UCEs. Based on these results, automated warning systems should be implemented and evaluated in real-time clinical practice. [Table: see text]

Complete response to nivolumab in Kirsten rat sarcoma virus oncogene KRAS-G12C mutant metastatic lung adenocarcinoma: a case report

BackgroundThe advent of immunotherapies has ushered in a new era in the treatment of non-small cell lung carcinoma. Although immunotherapies are associated with improved clinical outcomes, studies report a median overall survival of 11 months with progression-free survival of 2.5 months with the use of nivolumab for pretreated metastatic non-small cell lung cancer. Herein, we describe a case of advanced non-small cell lung carcinoma that has shown exceptional response to immunotherapy, with the patient being in complete response for the past 6 years since commencement of nivolumab.Case presentationWe report the case of a 58-year-old female Caucasian, an ex-smoker with 40-pack-year history of smoking, who presented with cough and chest pain and was subsequently diagnosed with metastatic pulmonary adenocarcinoma. The tumor was positive for Kirsten rat sarcoma virus oncogene KRAS-G12C mutation and had high programmed death-1 ligand expression. She was commenced on first-line chemotherapy with carboplatin and gemcitabine with disease response, then continued on maintenance pemetrexed. She was then commenced on immunotherapy with nivolumab, with complete response for a total of 6 years. She does not report any adverse events. Currently, she shows no evidence of recurrence of non-small cell lung carcinoma.ConclusionThe exceptional response to immunotherapy seen in this case may be explained by the presence of Kirsten rat sarcoma virus oncogene mutation, which is associated with enhanced clinical response to programmed death-1 ligand inhibitors. This report emphasizes the urgent need for further studies evaluating the role of Kirsten rat sarcoma virus oncogene mutation in determining the clinical efficacy of immunotherapies. This would enable us to make effective evidence-based clinical interventions in the treatment of non-small cell lung carcinoma.

Abstract CT552: RATIONALE 304: Tislelizumab (TIS) plus chemotherapy versus chemotherapy alone as first-line (1L) treatment for non-squamous (non-sq) NSCLC in patients (pts) aged 65-75 years

Abstract Background: Primary results from the Phase 3 RATIONALE-304 study (NCT03663205) showed efficacy and a manageable safety/tolerability profile for TIS, an anti-programmed cell protein 1 monoclonal antibody, plus chemotherapy, as 1L treatment for non-sq NSCLC. We report results from pts aged 65-75 years. Methods: In RATIONALE-304, eligible pts (18-75 years) were treatment-naïve and had locally advanced or metastatic non-sq NSCLC. Pts were stratified by disease stage and programmed death-ligand 1 expression, and randomized 2:1 to receive TIS (200 mg intravenously [IV]) plus platinum (carboplatin AUC 5 or cisplatin 75 mg/m2 IV) plus pemetrexed 500 mg/m2 every three weeks for 4-6 cycles followed by maintenance TIS plus pemetrexed (Arm A), or platinum pemetrexed for 4-6 cycles followed by maintenance pemetrexed (Arm B). Progression-free survival (PFS) by independent review committee (IRC), objective response rate (ORR), and safety were assessed in pts aged 65-75 years. Results: In total, 97 pts aged 65-75 years were randomized to Arm A (60 pts) or Arm B (37 pts). The median age of pts was 68.0 years, and 76 pts (78.4%) were male. PFS was longer, and ORR higher, in Arm A vs Arm B (Table). Overall, 59 pts in Arm A, and 37 pts in Arm B experienced ≥ 1 treatment-emergent adverse event (TEAE). In Arm A, Grade ≥ 3 TEAEs occurred in 43 (72.9%) pts aged 65-75 years vs 150 (67.6%) aged ≥ 18 years, and in Arm B, 18 (48.6%) pts aged 65-75 years vs 59 (53.6%) pts aged ≥ 18 years. TEAEs leading to permanent discontinuation of any component of study treatment occurred in 19 (32.2%) pts in Arm A, and 5 (13.5%) pts in Arm B. 21 (35.6%) pts receiving TIS experienced ≥ 1 immune-related TEAE. Conclusions: Observed improvements in PFS and ORR support the treatment benefits of TIS in combination with platinum and pemetrexed chemotherapy in pts aged 65-75 with advanced non-squamous NSCLC. The safety profile of TIS in pts aged 65-75 years was similar to the safety profile for all pts in the overall study population. Table Arm A (N=60) Arm B (N=37) PFS Events (%) 27 (45.0) 20 (54.1) HR (95% CI) 0.727 (0.407, 1.297) - Median, months (95% CI) 9.7 (5.75, 11.53) 7.7 (4.21, 9.76) ORR, % (95% CI) 53.3 (40.0, 66.3) 40.5 (24.8, 57.9) HR, hazard ratio Citation Format: Shun Lu, Jie Wang, Yan Yu, Xinmin Yu, Yanping Hu, Zhiyong Ma, Xingya Li, Wu Zhuang, Yunpeng Liu, Weidong Li, Jiuwei Cui, Dong Wang, Wangjun Liao, Mengzhao Wang, Jianying Zhou, Zhehai Wang, Yuping Sun, Wanyu He, Yuanyuan Bao. RATIONALE 304: Tislelizumab (TIS) plus chemotherapy versus chemotherapy alone as first-line (1L) treatment for non-squamous (non-sq) NSCLC in patients (pts) aged 65-75 years [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT552.

Abstract CT555: Pembrolizumab vs chemotherapy in Chinese patients with PD-L1-positive NSCLC: 4-year update from KEYNOTE-042 China study

Abstract Background: In the global, phase 3 KEYNOTE-042 study, pembrolizumab (pembro) significantly prolonged OS vs chemotherapy (chemo) in patients (pts) with previously untreated advanced/metastatic NSCLC with PD-L1 TPS ≥1% without EGFR/ALK alterations. Among pts enrolled in China, pembro prolonged OS (HR; 95% CI) vs chemo in pts with PD-L1 TPS ≥50% (0.63; 0.43-0.94), TPS ≥20% (0.66; 0.47-0.92), and TPS ≥1% (0.67; 0.50-0.89). We present efficacy and safety outcomes with an additional 14 calendar mo of follow-up in Chinese pts in KEYNOTE-042. Methods: Pts enrolled in China in the KEYNOTE-042 global (NCT02220894) and China extension (NCT03850444) studies were randomized 1:1 to pembro 200 mg Q3W for ≤35 cycles or carboplatin+paclitaxel or pemetrexed with optional pemetrexed maintenance (nonsquamous only). Primary endpoints were OS in pts with PD-L1 TPS ≥50%, ≥20%, and ≥1%. Eligible pts who completed 35 cycles of pembro could receive a second course of pembro. No alpha was allocated to the China extension analysis. Results: 262 pts with PD-L1 TPS ≥1% were randomized in China to pembro (n = 128) or chemo (n = 134). Median time from randomization to data cutoff (Apr 28, 2021) was 47.2 (range, 39.8-56.1) mo. Pembro prolonged OS (HR, 95% CI) vs chemo in pts with PD-L1 TPS ≥50% (0.66, 0.45-0.95), ≥20% (0.68, 0.49-0.93), and ≥1% (0.67, 0.51-0.89; Table). 19.5% and 68.8% of pts in the pembro and chemo groups experienced treatment-related grade 3-5 AEs. Among 22 pts who completed 35 cycles of pembro, ORR was 81.8% (95% CI, 59.7%-94.8%); estimated OS rate 4 y after randomization was 69.1%. At data cutoff, 79 pts in each group had begun subsequent therapy; 4 pts began a second course of pembro. Conclusion: Similar to the global KEYNOTE-042 study, first-line pembro continues to prolong OS and provide durable response in pts in China with advanced/metastatic PD-L1-positive NSCLC without EGFR/ALK alterations after nearly 4 y of follow-up. Pembro monotherapy remains a standard of care in these pts. Table PD-L1 TPS ≥50% PD-L1 TPS ≥20% PD-L1 TPS ≥1% Pembro n = 72 Chemo n = 74 Pembro n = 101 Chemo n = 103 Pembro n = 128 Chemo n = 134 OS, median (95% CI), mo 24.5 (17.4-34.3) 13.8 (10.1-18.3) 21.9 (17.4-27.0) 13.5 (10.1-17.9) 20.2 (17.4-25.3) 13.5 (10.1-17.9) OS, HR (95% CI) 0.66 (0.45-0.95) 0.68 (0.49-0.93) 0.67 (0.51-0.89) OS 4-y rate (95% CI), % 23.4 (13.5-34.8) 13.6 (6.1-24.1) 22.5 (14.2-31.9) 14.4 (8.0-22.6) 21.3 (14.1-29.5) 12.7 (7.2-19.7) ORRa (95% CI), % 41.7 (30.2-53.9) 24.3 (15.1-35.7) 34.7 (25.5-44.8) 24.3 (16.4-33.7) 32.0 (24.1-40.9) 24.6 (17.6-32.8) DOR, median (range), mo 16.5 (1.4+ to 47.1+) 11.7 (1.6+ to 46.9+) 16.5 (1.4+ to 47.1+) 10.9 (1.6+ to 46.9+) 16.0 (1.4+ to 47.1+) 10.9 (1.1+ to 46.9+) DOR ≥2-y, % 36.9 34.0 37.4 25.6 36.7 25.0 DOR, duration of response; HR, hazard ratio; TPS, tumor proportion score. ‘+’ indicates no PD by time of last assessment. aPer RECIST v1.1 by blinded independent central review. Citation Format: Yi-Long Wu, Yun Fan, JianYing Zhou, Li Zhang, Qing Zhou, Wei Li, ChengPing Hu, GongYan Chen, Xin Zhang, CaiCun Zhou, Carmen González Arenas, Wei Fu, Helen Wu, Tony Mok. Pembrolizumab vs chemotherapy in Chinese patients with PD-L1-positive NSCLC: 4-year update from KEYNOTE-042 China study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT555.

AcceleRET Lung: A phase 3 study of first-line pralsetinib in patients with RET fusion–positive advanced/metastatic NSCLC.

TPS9159 Background: RET gene fusions have been identified as oncogenic drivers in multiple tumor types, including 1–2% of non-small cell lung cancer (NSCLC). Pralsetinib is a potent, selective RET inhibitor, approved in the US and EU for the treatment of metastatic RET fusion–positive NSCLC based on the phase 1/2 ARROW study (NCT03037385). In the ARROW study (data cutoff: Nov 6, 2020), patients who initiated 400 mg once daily (QD) of pralsetinib after platinum-based chemotherapy achieved an overall response rate (ORR) of 62%, per independent central review. In the treatment-naïve group, the ORR was 79%. Most treatment-related adverse events were grade 1–2 across the entire safety population treated at 400 mg QD (n=471). AcceleRET Lung, an international, open-label, randomized, phase 3 study (NCT04222972), will evaluate the efficacy and safety of pralsetinib versus standard of care (SOC) for first-line treatment of advanced/metastatic RET fusion–positive NSCLC. Abstracts for this study were previously submitted to the European Lung Cancer Congress 2020, the American Society of Clinical Oncology 2020 annual meeting, and 2020 World Conference on Lung Cancer. Methods: Approximately 226 patients with metastatic RET fusion–positive NSCLC will be randomized 1:1 to oral pralsetinib (400 mg QD) or SOC (non-squamous histology: platinum/pemetrexed ± pembrolizumab followed by maintenance pemetrexed ± pembrolizumab [at investigator’s discretion]; squamous histology: platinum/gemcitabine or platinum + pembrolizumab + paclitaxel/nab-paclitaxel followed by maintenance pembrolizumab). Stratification factors include intended use of pembrolizumab, history of brain metastases, and Eastern Cooperative Oncology Group Performance Status. Key eligibility criteria include no prior systemic treatment for advanced/metastatic NSCLC; RET fusion–positive tumor by local or central assessment; no additional actionable oncogenic drivers; no prior selective RET inhibitor; measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Patients with central nervous system metastases were permitted if asymptomatic and on a stable dose of corticosteroids. Cross-over to receive pralsetinib upon disease progression will be permitted for patients randomized to SOC. The primary endpoint is progression-free survival (blinded independent central review; RECIST v1.1). Secondary endpoints include ORR, overall survival, duration of response, disease control rate, clinical benefit rate, time to intracranial progression, intracranial ORR, safety/tolerability and quality of life evaluations. Identification of potential biomarkers of antineoplastic activity and resistance was an exploratory endpoint. Recruitment has begun with sites (active or planned) in North America, Central America, Europe and Asia. Clinical trial information: NCT04222972.

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.

Veliparib Plus Carboplatin and Paclitaxel Versus Investigator's Choice of Standard Chemotherapy in Patients With Advanced Non–Squamous Non–Small Cell Lung Cancer

BackgroundThis open-label Phase III trial (NCT02264990) evaluated the PARP inhibitor, veliparib, combined with carboplatin/paclitaxel versus chemotherapy alone for first-line treatment of patients with advanced non–squamous non–small cell lung cancers (NSCLC). A 52-gene expression classifier (LP52) previously shown to identify patients more likely to respond to veliparib was evaluated as a planned correlative analysis. Materials and MethodsAdult current or former smokers with advanced non–squamous NSCLC were randomized 1:1 to veliparib (120 mg daily for 7 days/cycle) with carboplatin and paclitaxel or to investigators’ choice of platinum doublet chemotherapy (up to 6, 21-day cycles), with optional pemetrexed maintenance. Prospective analysis of the LP52 signature was conducted using a clinical Qiagen/HTG assay. The primary endpoint was overall survival (OS) in LP52+ patients. ResultsOverall, 595 patients received veliparib + carboplatin/paclitaxel (n = 298) or chemotherapy alone (n = 297); 13% (n = 40) in each arm were LP52+. The primary endpoint was not met; median OS was 11.2 months with veliparib + carboplatin/paclitaxel versus 9.2 months with chemotherapy alone in the LP52+ subgroup (hazard ratio [HR] 0.644, 95% confidence interval [CI]: 0.396-1.048; P = .113). In the overall population, median OS was 12.1 months in both arms (HR 0.986, 95% CI: 0.827-1.176; P = .846). No new safety signals were observed. ConclusionIn patients with non–squamous NSCLC, there was no significant improvement in OS with veliparib + carboplatin/paclitaxel versus chemotherapy alone, although a trend toward improved OS in the LP52+ population suggests this subgroup may benefit from veliparib. Statistical power was limited due to the small sample size.

Survival outcomes of alternate dosing schedule of pemetrexed as maintenance therapy in NSCLC: Single institution experience

BackgroundMaintenance therapy with pemetrexed has shown survival benefit in patients with advanced stage non-small cell lung cancer (NSCLC). The recommended dose schedule is 500 mg/m 2 in 21-day cycles. Prolonged treatment with maintenance pemetrexed can result in cumulative toxicities. We sought to compare treatment outcomes in patients receiving an alternate maintenance schedule in realworld practice. MethodsThis single-center, retrospective study investigated patients with advanced stage (IIIB and IV) NSCLC receiving at least two doses of maintenance pemetrexed from May 1, 2011 to June 30, 2016. The objective was to compare time on treatment with maintenance pemetrexed therapy initiated at a standard schedule (q3 weeks) versus an alternate schedule (q4 weeks or longer). Also evaluated were progressionfree survival (PFS) and overall survival (OS) differences between the two groups. Results129 patients were included, of whom 40 started the alternate schedule no later than cycle 3 of treatment (29 of 40 patients initiated maintenance treatment on the alternate schedule). Average time on maintenance treatment for patients appeared to be longer in the patients who received the alternate schedule regimen (195 vs 263 days, p =0.008). OS trended towards better survival among patients receiving the alternate schedule regimen (11.9 vs 18.1 months, p =0.3). Limiting the analysis to ALK wildtype, the patients showed a similar trend, with median PFS (7.6 vs 11.5 months, p =0.46) and OS (11.9 vs 17.6 months, p =0.38), still favoring the alternate schedule. ConclusionsThe alternate dosing schedule of maintenance pemetrexed (q4 weeks or longer) is feasible and not detrimental to OS. Future investigations evaluating the optimal administration schedule of maintenance pemetrexed is warranted.

Risk factors of nephrotoxicity of maintenance pemetrexed in patients with metastatic non-squamous non-small cell carcinoma of lung

BackgroundNephrotoxicity is one of the concerns of prolonged maintenance therapy with pemetrexed. No reversible risk factors for pemetrexed-induced nephrotoxicity have been identified in previous studies. Identification of such factors would be clinically meaningful to maximize the chemotherapeutic benefits by avoiding premature termination of maintenance therapy which might otherwise result from the development of renal impairment. MethodsThis was a retrospective single-center cohort study conducted in Queen Mary Hospital in Hong Kong. The study included 134 patients with advanced stage non-squamous NSCLC that received first line pemetrexed-platinum doublets followed by maintenance pemetrexed. The primary endpoint was the occurrence of nephrotoxicity. The risk factors of nephrotoxicity were identified. ResultsPresence of non-evacuated third-space fluid during treatment course (OR 4.185, 95% CI = 1.150–15.191, p-value 0.030), the use of cisplatin (instead of carboplatin) during the induction phase (OR 8.761, 95% CI = 1.684–45.577, p-value 0.010) and receiving more than 15 cycles of maintenance pemetrexed (OR 3.839, 95% CI = 1.022–14.413, p-value 0.046) were identified as independent risk factors to the development of nephrotoxicity associated with maintenance pemetrexed use. ConclusionsIn order to reduce the risk of development of nephrotoxicity in NSCLC patient receiving first-line pemetrexed-platinum doublets, third-space fluid should be evacuated and carboplatin should be chosen over cisplatin whenever possible.

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.

FP13.04 KEYNOTE-042 3-Year Survival Update: 1L Pembrolizumab vs Platinum-Based Chemotherapy for PD-L1+ Locally Advanced/Metastatic NSCLC

In the KEYNOTE-042 study (NCT02220894), pembrolizumab significantly improved OS vs platinum-based chemotherapy as first-line treatment for locally advanced/metastatic NSCLC without sensitizing EGFR/ALK alterations with PD-L1 tumor proportion score (TPS) ≥1%. We present updated data from KEYNOTE-042 with >3 years follow-up from randomization, including an exploratory analysis of time to progression on next-line therapy (PFS-2). Outcomes in patients who completed 35 cycles of pembrolizumab and in those who received second-course treatment are also reported. Patients were randomized 1:1 to pembrolizumab 200 mg Q3W for 35 cycles or chemotherapy (carboplatin area under the curve 6/5 plus paclitaxel 200 mg/m2 or pemetrexed 500 mg/m2) Q3W for 4‒6 cycles with optional pemetrexed maintenance (nonsquamous only). Randomization was stratified by region (East Asia vs non–East Asia), histology (squamous vs nonsquamous), ECOG PS (0 vs 1), and PD-L1 TPS (≥50% vs 1%–49%). The primary endpoint was OS in prespecified TPS groups (≥50%, ≥20%, and ≥1%). Secondary endpoints included PFS, ORR, and safety. Patients randomized to pembrolizumab who completed 35 treatment cycles with SD or better or stopped treatment after confirmed CR could receive second-course pembrolizumab after PD if eligibility criteria were met. No alpha was assigned to these analyses. 1274 patients were randomized (pembrolizumab, n=637; chemotherapy, n=637). As of February 21, 2020, median (range) time from randomization to database cutoff was 46.9 (35.8‒62.1) months. Efficacy results are summarized in the Table. Treatment-related grade 3‒5 AEs occurred in 120 (18.9%) vs 256 patients (41.6%) in the pembrolizumab vs chemotherapy groups. 102 patients completed 35 cycles (∼2 years) of pembrolizumab. 86/102 (84.3%) had CR (n=2) or PR (n=84) as best response. 80/102 (78.4%) patients were alive at time of analysis. 1-year OS after completion of 35 cycles was 91.1% in patients with PD-L1 TPS ≥1%. Among 26 patients who received second-course pembrolizumab; ORR after initiation of second-course treatment was 15.4% (all PR), and the disease-control rate (CR+PR+SD) was 76.9%. 21/26 (80.8%) patients were alive at data cutoff.TableEfficacyPD-L1 TPS ≥50%PD-L1 TPS ≥20%PD-L1 TPS ≥1%Pembro (N=299)Chemo (N=300)Pembro (N=413)Chemo (N=405)Pembro (N=637)Chemo (N=637)Median OS,a,b mo (95% CI)20.0 (15.9‒24.2)12.2 (10.4‒14.6)18.0 (15.5‒21.5)13.0 (11.6‒15.3)16.4 (14.0‒19.6)12.1 (11.3‒13.3)HR (95% CI)0.68 (0.57‒0.82)0.75 (0.64‒0.88)0.80 (0.71‒0.90)3-y OS rate,a % (95% CI)31.3 (26.1‒36.6)18.4 (14.2‒23.0)28.3 (24.1‒32.8)18.8 (15.1‒22.8)25.3 (22.0‒28.7)16.7 (13.8‒19.7)Median PFS,a,b, c mo (95% CI)6.5 (5.9‒8.6)6.5 (6.2‒7.6)6.2 (5.1‒7.4)6.8 (6.3‒8.1)5.5 (4.3‒6.2)6.8 (6.4‒7.7)HR (95% CI)0.85 (0.72‒1.02)0.95 (0.82‒1.10)1.05 (0.93‒1.18)3-y PFS rate,a % (95% CI)14.5 (10.5‒19.0)5.3 (3.0‒8.7)13.2 (10.0‒16.9)4.7 (2.7‒7.5)11.0 (8.6‒13.7)4.1 (2.6‒6.2)Median PFS-2,a,d mo (95% CI)15.0 (11.6‒19.2)10.1 (8.9‒11.2)12.9 (10.9‒15.5)10.2 (9.0‒11.3)11.3 (10.1‒12.9)9.3 (8.6‒10.2)HR (95% CI)0.62 (0.52‒0.74)0.66 (0.57‒0.77)0.73 (0.65‒0.82)ORR,b %39.1 (33.6‒44.9)32.3 (27.1‒37.9)33.2 (28.6‒37.9)29.1 (24.8‒33.8)27.3 (23.9‒31.0)26.7 (23.3‒30.3)Median DOR,a mo (95% CI)27.3 (2.1+ to 56.0+)10.8 (1.8+ to 49.6+)22.3 (2.1+ to 56.0+)10.8 (1.8+ to 49.6+)22.3 (2.1+ to 56.0+)8.4 (1.8+ to 49.6+)Chemo, chemotherapy; Pembro, pembrolizumab. “+” indicates no progressive disease at the time of last disease assessment. aKaplan-Meier estimate. bOS and PFS were calculated from the time of randomization. cPer RECIST v1.1 by blinded independent central review. dPFS-2 was defined as time from randomization to subsequent disease progression after initiation of new anticancer therapy, or death from any cause, whichever occurred first. Open table in a new tab Chemo, chemotherapy; Pembro, pembrolizumab. “+” indicates no progressive disease at the time of last disease assessment. aKaplan-Meier estimate. bOS and PFS were calculated from the time of randomization. cPer RECIST v1.1 by blinded independent central review. dPFS-2 was defined as time from randomization to subsequent disease progression after initiation of new anticancer therapy, or death from any cause, whichever occurred first. With long-term follow-up, first-line pembrolizumab monotherapy continued to show improved OS, ORR and PFS-2 outcomes compared with platinum-based chemotherapy in patients with locally advanced/metastatic PD-L1–positive NSCLC without sensitizing EGFR/ALK alterations, with a manageable safety profile. Patients who completed 35 cycles of pembrolizumab had durable responses, and second-course pembrolizumab was feasible and associated with antitumor activity. These findings continue to support first-line pembrolizumab in patients with locally advanced/metastatic PD-L1–positive NSCLC without sensitizing EGFR/ALK alterations.

High lymphocyte population-related predictive factors for a long-term response in non-small cell lung cancer patients treated with pemetrexed: a retrospective observational study

BackgroundRegimens combining pemetrexed (PEM) and immune checkpoint inhibitors (ICIs) targeting programmed cell death-1 (PD-1) or programmed death-ligand 1 (PD-L1) are widely used for the treatment of advanced non-squamous non-small-cell lung cancer (NSq-NSCLC). Recently, PEM was shown to induce immunogenic cell death (ICD) and to enhance immune-regulatory genes. Some patients demonstrate an extremely long-term response to PEM. It is possible that the continued response in these patients is dependent on not only the pharmacological induction of cytotoxic cell death but also antitumor immunity. However, factors that can predict outcomes associated with long-term PEM administration using blood test results have not yet been elucidated. We investigated the clinical characteristics and predictive factors in patients with advanced NSq-NSCLC who underwent long-term PEM maintenance therapy.MethodsIn total, 504 patients with advanced NSq-NSCLC who received PEM combination therapy/monotherapy (n = 414) or paclitaxel (PTX) combination therapy (n = 90) between January 2010 and November 2019 were recruited; 381 patients were retained for the final analysis. Patients treated with PEM (n = 301) were divided into subgroups according to the total cycles of PEM (≥ 17 [n = 25] for the long-term administration group and ≤ 16 [n = 276] for the intermediate/short-term group) and compared with another population (n = 80) treated with PTX combination regimen. We investigated clinical features and predictive biomarkers, focusing on immune-regulatory factors, absolute lymphocyte count (ALC), neutrophil-to-lymphocyte ratio (NLR), and PD-1 and PD-L1 expression, to predict long-term response to PEM.ResultsThe long-term PEM administration group exhibited a higher ALC and a lower NLR than the shorter-term group did. Both these markers displayed greater association with progression-free survival and overall survival in the PEM combination therapy group than in the PTX combination therapy group. Increased PD-1 lymphocytes were associated with the long-term PEM response group, as PD-L1 expression in tumors was associated with a high incidence of immune-related adverse effects following ICI administration.ConclusionsALC, NLR, and PD-1 expression are PEM-mediated predictive biomarkers that are indirectly related to tumor immunity and can provide useful predictive information on the long-term response to PEM in patients with NSq-NSCLC.

PUL01.02 AcceleRET Lung: A Phase 3 Study of First-Line Pralsetinib in Patients with RET-Fusion+ Advanced/Metastatic NSCLC

RET gene fusions have been identified as oncogenic drivers in multiple tumor types, including 1–2% of non-small cell lung cancer (NSCLC). The investigational oral RET inhibitor, pralsetinib, potently and selectively targets oncogenic RET alterations, including those that confer resistance to multi-kinase inhibitors. In the registration-enabling phase 1/2 study (ARROW; NCT03037385), patients with RET-fusion+ NSCLC treated with pralsetinib 400 mg once daily (QD) after platinum-based chemotherapy (n=80) achieved an overall response rate (ORR) of 61% (95% CI 50, 72; two responses pending confirmation) per independent central review. In addition, an ORR of 73% (all centrally confirmed responses) was attained in the systemic treatment naïve cohort (n=26). Most treatment-related adverse events were grade 1–2 across the entire safety population treated with pralsetinib 400 mg QD (N=354). AcceleRET Lung, an international, open-label, randomized, phase 3 study, will evaluate the efficacy and safety of pralsetinib versus standard of care (SOC) in first-line treatment of advanced/metastatic RET fusion+ NSCLC (NCT04222972). This abstract was previously submitted to and presented at the American Society of Clinical Oncology 2020 annual meeting (May 29 to June 2, 2020). Approximately 250 patients with advanced/metastatic RET-fusion+ NSCLC will be randomized 1:1 to pralsetinib 400 mg QD or SOC (non-squamous histology: platinum/pemetrexed ± pembrolizumab followed by maintenance pemetrexed ± pembrolizumab; squamous histology: platinum/gemcitabine). Stratification factors include intended use of pembrolizumab, history of brain metastases, and Eastern Cooperative Oncology Group Performance Status 0 vs 1. Key eligibility criteria include no prior systemic treatment for advanced/metastatic NSCLC; RET-fusion+ tumor by local or central assessment, no additional actionable oncogenic drivers, no prior treatment with a selective RET inhibitor, and measurable disease per RECIST v1.1. Cross-over to receive pralsetinib upon disease progression will be permitted for patients randomized to SOC. The primary endpoint is progression-free survival (blinded independent central review; RECIST v1.1). Secondary endpoints include ORR, overall survival, duration of response, disease control rate, clinical benefit rate, time to intracranial progression, intracranial ORR, safety/tolerability, and quality of life. Recruitment has begun with sites (active or planned) in North America, Europe, Asia, and Australia.

Randomized clinical trial of pembrolizumab vs chemotherapy for previously untreated Chinese patients with PD-L1-positive locally advanced or metastatic non-small-cell lung cancer: KEYNOTE-042 China Study.

In the global KEYNOTE‐042 study (Clinicaltrials.gov, NCT02220894), pembrolizumab significantly improved overall survival (OS) vs chemotherapy in patients with previously untreated programmed death ligand 1 (PD‐L1)‐positive locally advanced/metastatic non–small‐cell lung cancer (NSCLC) without EGFR/ALK alterations. We present results from patients in KEYNOTE‐042 enrolled from China in the global or extension study (NCT03850444; protocol identical to global study). Patients were randomized 1:1 (stratified by ECOG performance status 0 vs 1, squamous vs nonsquamous histology and PD‐L1 tumor proportion score [TPS] ≥50% vs 1%‐49%) to 35 cycles of pembrolizumab 200 mg every 3 weeks (Q3W) or investigator's choice of 4 to 6 cycles of carboplatin plus paclitaxel or pemetrexed Q3W with optional pemetrexed maintenance for nonsquamous tumors. Primary endpoints were OS in patients with PD‐L1 TPS ≥50%, ≥20% or ≥1%. Two hundred sixty‐two patients (pembrolizumab, n = 128; chemotherapy, n = 134) were enrolled from China. At data cutoff (February 21, 2020; median follow‐up, 33.0 [range, 25.6‐41.9] months), pembrolizumab was shown to improve OS vs chemotherapy in patients with PD‐L1 TPS ≥50% (hazard ratio [95% CI], 0.63 [0.43‐0.94]), TPS ≥20% (0.66 [0.47‐0.92]) and TPS ≥1% (0.67 [0.50‐0.89]). Grade 3 to 5 treatment‐related adverse events occurred less frequently with pembrolizumab vs chemotherapy (19.5% vs 68.8%). In 22 patients who completed 35 cycles of pembrolizumab, objective response rate was 77.3% and median duration of response was 27.6 months. Consistent with the global KEYNOTE‐042 study, pembrolizumab improved OS vs chemotherapy in this study of Chinese patients with locally advanced/metastatic NSCLC and PD‐L1 TPS ≥1%, supporting first‐line pembrolizumab monotherapy for PD‐L1‐positive advanced/metastatic NSCLC in China.

CheckMate 743: A Glimmer of Hope for Malignant Pleural Mesothelioma

CheckMate 743: A Glimmer of Hope for Malignant Pleural Mesothelioma