tbuckley/cabot-search huggingface dataset:
Randomized phase III study comparing suspension or continuation of PD-1 pathway blockade for patients with advanced non-small-cell lung cancer (SAVE study: JCOG1701).
Authors: Yasushi Goto, Tomonori Mizutani, Yuta Sekino, Shogo Nomura, Noriko Yanagitani, Hiroki Izumi, Yukio Hosomi, Tatsuro Fukuhara, Yuka Fujita, Toshiaki Takahashi, Haruhiko Fukuda, Yuichiro Ohe
Journal: Journal of Clinical Oncology (2024)

TPS8659 Background: The advent of immune checkpoint inhibitors (ICIs) targeting the PD-1 pathway, including nivolumab, pembrolizumab, and atezolizumab, has significantly improved the efficacy outcomes, namely progression-free survival (PFS) and overall survival (OS), in the treatment of advanced non-small cell lung cancer (NSCLC). This improvement is underscored by the observation that some patients (pts) who responded to ICIs continued to show a response even after discontinuing the treatment. Consequently, cessation of ICIs may not adversely impact OS, while potentially reducing immune-related toxicity and financial burden. Methods: The JCOG1701 is a multi-institutional, two-armed, open-label, randomized phase III trial. The objective of this study is to confirm the non-inferiority of suspension of ICIs to their continuation in patients with advanced or recurrent NSCLC who have shown a positive response to ICIs for 12 months or longer. For patients in the suspension arm who experience disease progression, re-initiation of immune checkpoint inhibitors (ICIs) is conducted. The patients were randomized in a 1:1 ratio to either the continuation or discontinuation arms. Randomization was performed by the minimization method using the institution, histology (squamous vs. non-squamous), and drug/timing parameters (first-line pembrolizumab/atezolizumab vs. second-line atezolizumab vs. second-line nivolumab vs. second-line pembrolizumab vs. combined therapy with chemotherapy) as adjustment factors. The primary endpoint of the trial is OS, while secondary endpoints include PFS, time to treatment failure of strategy, response rate, PFS post resumption of ICIs, and safety. In the periodical blinded monitoring, the pooled Kaplan-Meier curve for OS seemed significantly better than planned. This motivated to change the primary analysis method from hazard ratio to a difference in 6-year restricted mean survival time with a non-inferiority margin of 5.6 months. With one-sided alpha of 5% and power of 70%, the study aimed to enroll 172 patients assuming that 2-year OS is 94% in both arms. As of Jan 2024, 162 patients have been randomized, with full enrollment projected by Nov 2024. The trial is registered in the Japan Registry for Clinical Trials as jRCT1031190032. An ancillary study exploring the predictive and prognostic role of circulating tumor DNA is also planned. The findings of the JCOG1701 will provide data for making more informed treatment decisions in advanced NSCLC, specifically related to the continuation or suspension of ICIs. Clinical trial information: CRB3180009 .
TOP: A phase III, multicentre, randomized controlled study comparing osimertinib in combination with carboplatin and pemetrexed to osimertinib monotherapy for untreated patients with advanced non-squamous (Non-sq) non-small cell lung cancer (NSCLC) with concurrent EGFR and TP53 mutations.
Authors: Yunpeng Yang, Weineng Feng, Wei Jiang, Lu Huang, Yanqiu Zhao, Lili Chen, Yong Fang, Mei Ji, Tingting Zhang, Junfei Zhu, Li Zhang
Journal: Journal of Clinical Oncology (2024)

TPS8662 Background: Osimertinib is the current standard first-line treatment for advanced non-sq NSCLC with sensitive EGFR mutations. However, previous studies demonstrated that patients with concurrent EGFR and TP53 mutations had suboptimal clinical benefit with EGFR-TKI monotherapy. FLAURA2 study showed that osimertinib plus pemetrexed and platinum-based chemotherapy significantly improved progression-free survival (PFS) compared with osimertinib monotherapy for EGFR-mutated advanced NSCLC patients. Further study is needed to better understand the benefits of the FLAURA2 model for patients with concurrent mutations. The objective of this study is to determine whether osimertinib plus chemotherapy could improve efficacy compared with osimertinib monotherapy in patients with concurrent EGFR and TP53 Mutations. Methods: This is a phase III, randomized, open-label trial in patients with advanced Non-sq NSCLC harboring EGFR mutations (exon 19 deletion or L858R) and TP53 mutations, with a performance status of 0 to 1, and planned to receive first-line therapy. Eligible patients will be randomized 1:1 to osimertinib monotherapy arm (osimertinib 80 mg orally per day) or combination therapy arm (osimertinib 80 mg orally per day plus pemetrexed 500 mg/m 2 and carboplatin area under curve 5 intravenously every 3 weeks for four cycles, followed by maintenance pemetrexed and osimertinib). Randomization will be stratified by PS score (0 vs. 1), brain metastases status (yes vs. no) and mutation type (exon 19 deletion vs. L858R). The primary end point is PFS per RECIST 1.1 assessed by investigator. Secondary end points include overall survival, objective response rate, duration of response, adverse events and quality of life. Exploratory endpoint is correlation between concurrent mutations other than TP53 and efficacy, and the resistance mechanisms to combination therapy revealed by dynamic ctDNA profiling. Approximately 170 PFS events will be required to detect hazard ratio of 0.65 with 80% power at a two-sided significance level of 0.05. 292 patients will be enrolled. Until February 1, 2024, 204 patients have been enrolled, the last patient is expected to be enrolled in June 2024. Clinical trial information: NCT04695925 .
INTerpath-001: Pembrolizumab with V940 (mRNA-4157) versus pembrolizumab with placebo for adjuvant treatment of high-risk stage II-IV melanoma.
Authors: Jeffrey S. Weber, Jason J. Luke, Matteo S. Carlino, Muhammad Adnan Khattak, Robert S. Meehan, Michelle Brown, Jinchun Zhang, Clemens Krepler, J Paul Duic, Georgina V. Long
Journal: Journal of Clinical Oncology (2024)

TPS9616 Background: The anti−PD-1 antibody pembrolizumab is approved as adjuvant therapy for stage IIB-C and stage III melanoma by AJCC 8th ed, following complete resection. Adjuvant pembrolizumab has improved recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) in patients with high-risk melanoma, but many patients experience disease recurrence. In the randomized phase 2b KEYNOTE-942 study, the individualized neoantigen therapy V940 showed improved RFS and DMFS when used in combination with pembrolizumab versus pembrolizumab monotherapy in patients with stage III or IV melanoma. INTerpath-001 (NCT05933577) is a double-blind phase 3 randomized controlled trial designed to evaluate the efficacy and safety of adjuvant pembrolizumab plus V940 versus pembrolizumab plus placebo in patients with resected high-risk stage II-IV melanoma. Methods: Eligible patients are aged ≥18 years with surgically resected stage IIB or IIC (pathologic or clinical), III, or IV cutaneous melanoma per AJCC 8th ed and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients are ineligible if they have received any prior systemic therapy and if more than 13 weeks has elapsed between last surgical resection and first dose of pembrolizumab. Patients with ocular or mucosal melanoma and past or current in-transit metastases or satellitosis are excluded. All patients must provide a blood sample and a formalin-fixed, paraffin-embedded tumor sample for sequencing. Patients will be stratified by risk (IIB, IIC, IIIA, and IIIB vs IIIC/D and IV) and age (&lt;65 years vs ≥65 years). Approximately 1089 patients will be randomly assigned 2:1 to receive pembrolizumab 400 mg plus V940 1 mg or pembrolizumab 400 mg with placebo. Pembrolizumab will be administered intravenously every 6 weeks and v940 or placebo will be administered intramuscularly every 3 weeks. Treatment will continue for up to 9 doses or until disease recurrence, unacceptable toxicity, or patient withdrawal. The primary end point is RFS by investigator review. Secondary end points are DMFS by investigator review, overall survival, safety and tolerability, and quality of life. Hazard ratios and 95% CIs will be estimated using a stratified Cox regression model with the Efron method of handling ties. Between-treatment differences will be evaluated using a stratified log-rank test. Enrollment is ongoing. Clinical trial information: NCT05933577 .
A phase III, open-label, multicenter, randomized controlled trial of tunlametinib versus investigator-selected chemotherapy in patients with advanced NRAS-mutant melanoma who had previously received immunotherapy.
Authors: Xiaoting Wei, Weizhen Zhang, Meiyu Fang, Zhengyun Zou, Jing Chen, Zhiguo Luo, Hongqi Tian, Zhongwei Jia, Jun Guo, Lu Si
Journal: Journal of Clinical Oncology (2024)

TPS9606 Background: NRAS-mutant melanoma is an aggressive subtype with worse prognosis. However, no targeted therapy has been approved to date worldwide. Tunlametinib (HL-085) has showed an encouraging efficacy (confirmed ORR:34.8%, mPFS:4.2 months) with a manageable safety profile in phase II pivotal registrational study, which was published in ASCO 2023 annal meeting (NO.:9510). Here, we present the design of phase III randomized controlled study. Methods: This is a multicenter, two-arm, open-label, randomized controlled phase III confirmatory clinical trial to evaluate the efficacy and safety of tunlametinib in comparison with the combination chemotherapy of investigator's choice in advanced NRAS-mutant melanoma patients who had previously received immunotherapy. A total of 165 subjects from about 12 sites in China will be included and randomly assigned to the corresponding treatment group in 2:1 ratio. Two stratification factors before randomization: LDH level and whether have received chemotherapy. The key inclusion criteria included: a) Patients with unresectable stage III or metastatic IV melanoma confirmed by histology or cytology; b) History of immunotherapy failure or could not tolerate immunotherapy; c) Be able to provide NRAS mutation positive test report at baseline and provide sufficient histological specimens for NRAS mutation confirmation by central laboratory. Experimental group subjects will receive continuous administration of tunlametinib 12mg BID, 28 days per cycle. Control group subjects will receive one of the following regimens which according to investigator's choice (paclitaxel plus carboplatin, or temozolomide plus cisplatin, or dacarbazine plus cisplatin) , 28 days per cycle. The two groups will receive continuous therapy until disease progression or intolerable toxicity. The primary endpoint is progression-free survival which assessed by independent radiology review committee. Secondary endpoints included overall survival, objective response rate, disease control rate, duration of response, safety, pharmacokinetics and exposure-response. Exploratory endpoints are to evaluate quality of life between two groups and to development a companion diagnostic kit for NRAS gene mutations detection. This study is currently open for enrollment. Clinical trial information: NCT06008106 .
Randomized phase II trial of pembrolizumab/lenvatinib (P+L) +/- responder fecal microbiota transplant (R-FMT) in PD-1 relapsed/refractory (R/R) cutaneous melanoma (MEL).
Authors: Diwakar Davar, Hong Wang, Drew Hurd, Madison Nguyen, Marc B. Schwartz, Howard M. Dubner, Yana G. Najjar, Jason J. Luke, John M. Kirkwood, Giorgio Trinchieri, Hassane M. Zarour
Journal: Journal of Clinical Oncology (2024)

TPS9607 Background: A significant portion of patients (pts) with advanced MEL develop resistance to immune checkpoint inhibitors (ICI). The gut microbiome is a major tumor-extrinsic regulator of ICI response. In mice, gut microbiota modulate therapeutic activity of ICI, and administration of certain gut commensals or responder-derived fecal microbiota transplantation (R-FMT) promotes anti-PD-1 efficacy in melanoma-bearing mice. In the LEAP-004 trial, P+L produced 21% ORR in PD-1 R/R MEL with Gr3+ TRAE 45.6%. Longitudinal analyses of gut microbiome samples from ICI-treated cancer pts suggests key species including Actinobacteria and Firmicutes are associated with favorable response. We and others have previously demonstrated that microbiome modulation using R-FMT reversed PD-1 non-response in PD-1 R/R MEL. In PD-1 naïve MEL, healthy donor FMT (hdFMT) augments benefit of PD-1 monotherapy. We hypothesized that intestinal dysbiosis mediates PD-1 resistance in PD-1 R/R MEL, microbiome modulation may reverse TKI toxicity, and that R-FMT may resensitize MEL to PD-1 blockade. Methods: This is an investigator-initiated, randomized, phase II trial of P+L vs. P+L+R-FMT in PD-1 R/R MEL. Pts must have measurable disease per RECIST v1.1, no active CNS metastases (or if present, previously treated and stable on repeat imaging), and no contraindications to FMT administration. R-FMT is derived from non-obese, advanced MEL with durable response (mPFS ≥24 months) following prior PD-1 ICI, with no recent (≤1 month) antibiotic exposure. Donors are screened broadly for infectious agents including SARS-CoV-2 using bookend screening. R-FMT is processed to make fecal infusates and orally bioavailable capsules. Eligible pts are randomized 1:1 to either P+L [P 200mg every 3 weeks (Q3W) along with L 20mg orally once daily] or P+L+R-FMT. R-FMT is administered endoscopically on D1, and D42, and thereafter via capsules until progression or unacceptable toxicity. Response is assessed at D73, and thereafter Q12W. Pts undergo biopsies at baseline and W8, with optional biopsy at progression. Primary endpoint: ORR assessed using RECIST v1.1 by Blinded Independent Central Review (BICR). Secondary endpoints include: safety, progression-free survival (PFS), overall survival (OS), and landmark PFS/OS. Key translational endpoints include immune activation (tumor tissue, blood), metagenomic engraftment, and transcriptomic analyses of intestinal luminal myeloid cells and exfoliome. The null hypothesis that the true ORR is 20% will be tested versus a one-sided alternative hypothesis of ≥50%. This design has a type I error rate 0.10 and power 0.8 when the true response rate is 0.25. Enrollment has commenced. Clinical trial information: NCT06030037 .
Reduced dose fludarabine/cyclophosphamide lymphodepletion for tumor-infiltrating lymphocytes therapy (LN-144, lifileucel) in metastatic melanoma.
Authors: Muhammad Umair Mushtaq, Haitham Abdelhakim, Luke Selby, Sunil H. Abhyankar, Joseph McGuirk, Gary C. Doolittle
Journal: Journal of Clinical Oncology (2024)

TPS9608 Background: Metastatic melanoma (MM) patients who have progressed following immune checkpoint inhibitors (ICI; anti–PD-1/CTLA-4 therapy) and targeted agents (BRAF/MEK inhibitors) have limited treatment options and dismal prognosis. An autologous tumor-infiltrating lymphocytes (TIL) therapy (LN-144, lifileucel) has demonstrated efficacy and durable responses in heavily pretreated advanced melanoma. In a phase II study of TIL therapy (lifileucel) with traditional lymphodepletion (LD), using fludarabine 25 mg/m2 for 5 days and cyclophosphamide (Cy) 60 mg/kg for 2 days, in 153 MM patients previously treated with ICI and BRAF/MEK inhibitors, an overall response rate (ORR) of 31% was noted, and the median duration of response (DOR) was not reached after 27.6 month follow up. We hypothesize that a reduced dose of Flu/Cy LD for TIL therapy will have similar TIL expansion and persistence post-infusion, resulting in similar efficacy with a reduced toxicity profile. Methods: Study NCT06151847 is a single-center, open-label phase II pilot trial evaluating the efficacy, in vivo persistence, and safety of TIL therapy after reduced dose Flu/Cy LD. Key inclusion criteria include unresectable or metastatic melanoma (stage IIIC-IV) with disease progression after one or more lines of therapy. Four of the 12 planned patients have been enrolled as of February 2, 2024. Central TIL manufacturing from at least a 1.5 cm tumor specimen involves ex vivo expansion through cell culture in the presence of the interleukin (IL)-2 and an anti-CD3 monoclonal antibody (1-150 x10 9 viable cells). Patients will receive an outpatient reduced-dose Flu/Cy LD regimen of Flu (30 mg/m 2 on days -4, -3, -2, -1) and Cy (750 mg/m 2 on days -4, -3, -2). Infusion of TIL will be performed on day 0 followed by high-dose IL-2 (600,000 IU/kg up to 6 doses). The primary objective will be to ascertain TIL persistence using T-cell receptor (TCR) sequencing at day 42 which will be compared to historical data already generated utilizing traditional Flu/Cy LD. The secondary objectives will be to evaluate the efficacy parameters including ORR, DOR, progression-free survival (PFS), and overall survival (OS), and the safety profile of TIL in combination with a reduced dose Flu/Cy LD regimen. Exploratory objectives will involvecorrelative analyses to characterize the immunome and microenvironment. If TIL persistence is roughly equivocal between the reduced and high-dose Flu/Cy LD regimens, the design of a larger-scale trial using reduced-dose Flu/Cy LD for TIL therapy may be considered. Study follow-up will continue for one year. Clinical trial information: NCT06151847 .
A pilot trial of autologous tumor infiltrating lymphocytes (lifileucel, LN-144) for patients with asymptomatic melanoma brain metastases.
Authors: Allison Betof Warner, James William Smithy, Michael A. Postow, Katherine Panageas, Adam Jacob Schoenfeld, Jedd D. Wolchok, Alexander Noor Shoushtari
Journal: Journal of Clinical Oncology (2024)

TPS9603 Background: Melanoma brain metastases (MBM) are a leading cause of morbidity and mortality for patients with advanced melanoma. Modern systemic therapies are insufficient at controlling MBM, resulting in median overall survival (OS) of &lt;1 year. Adoptive T cell therapy, using tumor infiltrating lymphocytes (TIL), has demonstrated efficacy in treating advanced melanoma. Lifileucel (LN-144), an autologous TIL product, was recently shown to be safe and effective for patients with PD-1 refractory melanoma. However, no trials have yet explored lifileucel in patients with active MBM. Methods: This single-center pilot trial (NCT05640193) aims to enroll 10 pts with asymptomatic MBM from non-uveal melanoma to receive lifileucel. Patients must have ≥1 intracranial lesion measuring 5-30mm visible on MRI to be used as a target lesion for modified (m)RECIST measurement, progression on prior anti-PD-1 therapy (with or without anti-CTLA-4), progression on targeted therapy (if BRAF V600E/K-mutated), ECOG PS ≤1, ≥1 resectable lesion(s) (≥1.5 cm), recovered from prior surgery/anticancer treatment-related AEs (grade ≤1). Patients are ineligible if they have symptomatic MBM and/or require corticosteroids of ≥10 mg/day of prednisone or equivalent. Lifileucel is generated from resected tumor in a centralized GMP process. The regimen includes nonmyeloablative lymphodepletion with cyclophosphamide 750 mg/m 2 on days 1-3 and fludarabine 30 mg/kg on days 1-4 (reduced dose compared with standard lifileucel protocol), lifileucel infusion, and up to 6 doses of high-dose IL-2. The primary endpoint is feasibility, defined as ≥7/10 patients who undergo tumor resection successfully receiving lifileucel infusion. Secondary endpoints are safety, feasibility of manufacturing lifileucel in patients with MBM, and brain metastasis response rate (BMRR) per mRECIST 1.1. Exploratory endpoints include overall objective response rate by mRECIST 1.1, best extracranial response rate, intracranial progression-free survival (PFS), overall PFS, OS. Extensive correlative analyses of peripheral blood mononuclear cells, plasma, tumors, and cerebrospinal fluid are planned to better understand MBM growth, treatment resistance, and response of the central nervous system to lifileucel. Clinical trial information: NCT05640193 .
Sotorasib versus pembrolizumab in combination with platinum doublet chemotherapy as first-line treatment for metastatic or locally advanced, PD-L1 negative, <i>KRAS</i> G12C-mutated NSCLC (CodeBreaK 202).
Authors: Fabrice Barlesi, Enriqueta Felip, Sanjay Popat, Benjamin J. Solomon, Juergen Wolf, Bob T. Li, Yi-Long Wu, Keith Kerr, Hiroaki Akamatsu, David Ross Camidge, Ravi G. Gupta, Alison Meloni, Tian Dai, Hossein Borghaei
Journal: Journal of Clinical Oncology (2024)

TPS8653 Background: The 5-year progression free survival (PFS) rate of patients with metastatic, PD-L1 negative, non-small cell lung cancer (NSCLC) remains poor, ranging from approximately 2% to 10% with standard immunotherapy-based treatment regimens. Based on promising anti-tumor activity in the phase 1 CodeBreaK 101 study, with partial responses observed in 62% (8/13) of PD-L1 negative patients in the first-line setting, we hypothesize that sotorasib plus platinum doublet chemotherapy will demonstrate durable clinical response and improved outcomes in this population. CodeBreaK 202 (NCT05920356) is a global phase 3 randomized study evaluating the efficacy of sotorasib versus pembrolizumab in combination with platinum doublet chemotherapy as first-line treatment for metastatic or locally advanced, PD-L1 negative, KRAS G12C-mutated NSCLC. Methods: Patients will be randomized 1:1 to either sotorasib 960 mg once daily or pembrolizumab administered in combination with carboplatin and pemetrexed for 4 cycles, followed by maintenance treatment with sotorasib or pembrolizumab administered in combination with pemetrexed. Key eligibility criteria include treatment-naïve metastatic or locally advanced stage IIIB/C disease that is not amenable to definitive chemoradiation, PD-L1 &lt;1% expression, presence of KRAS G12C mutation, non-squamous tumor histology, and absence of actionable genomic alterations such as EGFR mutations and ALK rearrangements. Patients with both treated and untreated brain metastases are eligible if clinically asymptomatic. The primary endpoint is PFS per RECIST v1.1 by blinded independent central review (BICR). Key secondary endpoints include overall survival and objective response rate. Exploratory endpoints include intra-cranial PFS per RANO-BM criteria. Approximately 750 patients are planned to be enrolled and recruitment began on November 18, 2023. Contact Amgen Medical Information for more information: medinfo@amgen.com . Clinical trial information: NCT05920356 .