tbuckley/cabot-search huggingface dataset:
Atezolizumab in patients (pts) with tumor mutational burden (TMB)–high tumors from the TAPISTRY trial.
Authors: Rafal Dziadziuszko, Fabrice Barlesi, Jeong Eun Kim, Shirish M. Gadgeel, Maciej Krzakowski, Jae Ho Jeong, Gennaro Daniele, David Chen, Youyou Hu, Timothy R. Wilson, Brian P. Simmons, David Morgan Thomas
Journal: Journal of Clinical Oncology (2024)

LBA2509 Background: Studies have suggested that pts with TMB-high tumors could derive clinical benefit from atezolizumab, a PD-L1 inhibitor; however, these studies used inconsistent TMB cutoffs. We report efficacy and safety data of atezolizumab in adult and pediatric pts with TMB-high advanced/metastatic solid tumors from Cohort D of the TAPISTRY trial (NCT04589845), using two TMB cutoffs: ≥13 mutations [mut]/Mb and ≥16 mut/Mb. Methods: TAPISTRY is a phase II, global, open-label, multicohort basket trial evaluating the efficacy and safety of multiple therapies in pretreated pts with advanced/metastatic solid tumors. Pts in Cohort D had advanced unresectable/metastatic, PD-L1 inhibitor-naïve, TMB-high (≥13 mut/Mb) solid tumors. Atezolizumab was given every 21 days, at 1200 mg in pts ≥18 years old, and at ≥15 mg/kg (up to 1200 mg) in pts &lt;18 years old. Tumor responses were assessed per RECIST v1.1. Primary endpoint: objective response rate (ORR) by independent review committee (IRC) in pts with TMB ≥16 mut/Mb. Secondary endpoints included ORR by IRC in pts with TMB ≥13 mut/Mb, duration of response (DoR), progression-free survival (PFS), overall survival (OS) and safety. Results: At data cut-off (Nov 9, 2023), 150 pts with TMB ≥13 mut/Mb were enrolled. In the safety-evaluable population (n = 148), median age was 63 years (range 11–86); 56% of pts were male, and 56% had received ≥2 prior lines of therapy (median 2; range 0–14). The efficacy-evaluable population included 129 pts with TMB ≥13 mut/Mb (TMB ≥16 mut/Mb; n = 111); the most common tumor types were colorectal (n = 40; 31%), breast, and gastroesophageal cancer (n = 11 each; 9%). Key outcomes are presented (Table). After a median follow-up of 9.8 months, ORR by IRC was comparable between pts with TMB ≥16 mut/Mb (22.5%) and pts with TMB ≥13 mut/Mb (20.2%). Responses were seen across a variety of tumor types. DoR 6- and 12-month event-free rates were 79% and 72%, respectively. Median PFS was short, suggesting fast disease progression in non-responders. Fatigue (22%) and anemia (20%) were the most common adverse events. Safety of atezolizumab was consistent with its known profile. Conclusions: Atezolizumab was well tolerated and led to antitumor activity in pts with TMB-high solid tumors. Responses were seen across a variety of tumor types. Clinical trial information: NCT04589845 . [Table: see text]
Covalent FAPI PET enables accurate management of medullary thyroid carcinoma: A prospective single-arm comparative clinical trial.
Authors: Ziren Kong, Zhu Li, Xi-Yang Cui, Wang Jian, Mengxin Xu, Yang Liu, Junyi Chen, Song Ni, Xiaowei Fan, Jiazhao Huang, Yansong Lin, Xinfeng Lin, Tianyu Men, Changming An, Nan Li, Chen Liu, Yi-Ming Zhu, Zhi Yang, Zhibo Liu, Shaoyan Liu
Journal: Journal of Clinical Oncology (2024)

LBA6018 Background: Localizing medullary thyroid carcinoma (MTC) lesions is crucial for treatment decision, but the detection using the current imaging modalities is unsatisfied. Previously, we reported a 68 Ga-labeled targeted covalent radiopharmaceutical fibroblast activation protein inhibitor ( 68 Ga-TCR-FAPI), which demonstrated improved and sustained tumor targeting. This study aimed to head-to-head compare the 68 Ga-TCR-FAPI PET-CT and the currently approved 18 F-FDG PET-CT in detecting MTC. Methods: This was a prospective, single-center, open-labeled, single-arm comparative imaging trial. MTC patients with serum calcitonin&gt;10 pg/ml and without targeted therapy were eligible. Serum calcitonin level, 68 Ga-TCR-FAPI PET-CT and 18 F-FDG PET-CT were acquired within a maximum interval of 30 days. Images were independently interpreted by 3 readers to calculate the patient-based and region-based detection rate. Quantitative PET parameters were calculated from the lesion ROI and compared between 68 Ga-TCR-FAPI and 18 F-FDG PET-CT. The accuracy of imaging findings was validated on lesions with histopathology or calcitonin-based follow-up. The primary outcome was patient-based detection rate, and the secondary outcome included region-based detection rates, metabolic parameters comparison and diagnostic accuracy. Results: 50 patients were enrolled between May 11 th , 2023 and Feb. 1 st , 2024. 68 Ga-TCR-FAPI exhibited significantly higher patient-based detection rate than 18 F-FDG PET-CT (98% vs. 66%, p=0.0002). Detection rates were also superior for 68 Ga-TCR-FAPI in head and neck (72% vs. 50%, p=0.0098), thorax (50% vs. 34%, p=0.0269), abdomen (28% vs. 10%, p=0.0077) and skeleton (54% vs. 16%, p&lt;0.0001). On quantitative analysis, SUV max was significantly higher in 68 Ga-TCR-FAPI PET-CT than 18 F-FDG PET-CT (11.71±9.16 vs. 2.55±1.73, p&lt;0.0001). Diagnostic accuracy was substantially greater with 68 Ga-TCR-FAPI PET-CT than 18 F-FDG PET-CT (96.7% vs. 43.3%, p&lt;0.0001) based on 60 histopathological validated lesions from 15 patients who underwent surgery. Notably, 60% (30/50) patients directly benefited from 68 Ga-TCR-FAPI PET-CT, with 66.7% (10/15) experiencing changes in surgical plans, and 100% (6/6) of the newly diagnosed MTC with R0 resection achieved biochemical cure at 1-month post-surgery. Conclusions: 68 Ga-TCR-FAPI PET-CT displayed higher detection rate, metabolic value and diagnostic accuracy than 18 F-FDG PET-CT in MTC patients, and should be integrated into MTC evaluation at initial diagnosis and persistent disease. Clinical trial information: NCT06084767 . [Table: see text]
KROCUS: A phase II study investigating the efficacy and safety of fulzerasib (GFH925) in combination with cetuximab in patients with previously untreated advanced KRAS G12C mutated NSCLC.
Authors: Vanesa Gregorc, Maria González-Cao, Stefania Salvagni, Anna Koumarianou, Ignacio Gil-Bazo, Michele Maio, Santiago Viteri, Margarita Majem, Vanesa Gutiérrez, Reyes Bernabe Caro, Miguel F. Sanmamed, Huaqiang Zhu, Haige Shen, Yu Wang, Rafael Rosell
Journal: Journal of Clinical Oncology (2024)

LBA8511 Background: Fulzerasib (GFH925), a KRAS G12C inhibitor, showed substantial efficacy in previously treated NSCLC patients (pts) as monotherapy. Activation of epidermal growth factor receptor (EGFR) is identified to be one of the dominant mechanisms for KRAS inhibition resistance. Preclinical evidence showed synergistic activity in KRAS G12C mutant NSCLC modeling using fulzerasib in combination with cetuximab. Here we report the first results for a KRAS G12C inhibitor combined with an anti-EGFR antibody in NSCLC pts as front-line treatment. Methods: KROCUS (NCT05756153) was an open-label, single-arm, multi-center, Phase II study with the primary objective to evaluate the efficacy of fulzerasib in combination with cetuximab in pts with previously untreated advanced NSCLC harboring KRAS G12C mutation. Secondary objectives included safety/tolerability, pharmacokinetics and biomarkers. Pts were enrolled to receive fulzerasib (oral, 600 mg BID) and cetuximab (intravenous, 500 mg/m 2 , every two weeks [Q2W]) combination treatment in a 28-day cycle. Results: As of Jan. 30, 2024, a total of 27 pts (median age: 68 yrs old; 55.6% female) were treated, 11 (40.7%) with baseline brain metastases. Of 20 pts who had at least one post-treatment tumor assessment, ORR was 80.0% (95% CI: 56.3, 94.3, including one CR), of whom eight pts had ≥ 50% tumor shrinkages in the target lesions. Disease control rate (DCR) was 100% (95% CI: 83.2, 100.0). Five out of seven pts (71.4%) with brain metastases achieved PRs. Nine pts with baseline PD-L1 expression tested (six TPS≥1% and three TPS &lt;1%) all achieved PRs. The overall safety profile of the combination was favorable. Treatment-related adverse events (TRAEs) of any grade occurred in 21 (77.8%) pts. 5 pts (18.5%) experienced G3 TRAEs and no G4 or 5 TRAEs. Three pts (11.1%) had dose reduction/interruption with fulzerasib due to TRAEs but no pts discontinued treatment while one pt (3.7%) had dose reduction/interruption and three (11.1%) discontinued cetuximab due to TRAEs. Table 1 shows the most common TRAEs or G3 TRAEs. Conclusions: The preliminary data from ongoing KROCUS study has demonstrated very promising efficacy and favorable safety profile of fulzerasib + cetuximab in the first line setting of KRAS G12C mutated NSCLC. More data will be generated to provide clinical evidence supporting this combination as a potential frontline therapy. Clinical trial information: NCT05756153 . [Table: see text]
Neoadjuvant nivolumab (NIVO) + chemotherapy (chemo) vs chemo in patients (pts) with resectable NSCLC: 4-year update from CheckMate 816.
Authors: Jonathan Spicer, Nicolas Girard, Mariano Provencio, Changli Wang, Tetsuya Mitsudomi, Mark M. Awad, Everett E. Vokes, Janis M. Taube, Lorena Lupinacci, Gene B. Saylors, Fumihiro Tanaka, Moishe Liberman, Sung Yong Lee, Aurelia Alexandru, Manolo D’Arcangelo, Phuong Tran, Javed Mahmood, Vishwanath Suresh Gharpure, Apurva Bhingare, Patrick M. Forde
Journal: Journal of Clinical Oncology (2024)

LBA8010 Background: The phase 3 CheckMate 816 study established neoadjuvant NIVO + chemo as a standard of care for eligible pts with resectable NSCLC. Here, we report the 4-year survival update from this study, representing the longest follow-up among all global phase 3 studies evaluating neoadjuvant or perioperative immunotherapy-based treatments. Methods: Adults with stage IB (≥ 4 cm)–IIIA (per AJCC v7) resectable NSCLC, ECOG PS ≤ 1, and no known EGFR/ ALK alterations were randomized 1:1 to receive NIVO 360 mg + chemo Q3W or chemo alone Q3W for 3 cycles, followed by surgery. Event-free survival (EFS) and pathologic complete response (pCR; both per blinded independent review) were primary endpoints and were both statistically significant. Overall survival (OS) was a key secondary endpoint. Exploratory analyses included efficacy by pCR status and extent of resection. Results: At the 23 Feb 2024 database lock (median follow-up, 57.6 mo), NIVO + chemo continued to improve EFS vs chemo (median, 43.8 mo vs 18.4 mo; HR [95% CI], 0.66 [0.49–0.90]); 4-year EFS rates were 49% vs 38%. EFS favored NIVO + chemo vs chemo regardless of whether pts had lobectomy or pneumonectomy (Table), with 56%–57% vs 40%–43% of pts without disease recurrence at 4 years. NIVO + chemo also continued to show OS improvement vs chemo (HR [98.36% CI], 0.71 [0.47–1.07]; P = 0.0451; median OS was not reached [NR] in both arms, and the significance boundary was not met at this interim analysis). An OS improvement of 13% was sustained over time for NIVO + chemo vs chemo; 4-year OS rates were 71% vs 58%. Pts in the NIVO + chemo arm who had pCR continued to have improved OS vs those who did not (HR [95% CI], 0.08 [0.02–0.34]); 4-year OS rates, 95% vs 63%); a similar trend was seen in the chemo arm, although few pts had pCR with chemo (n = 4). No new safety signals were observed at this update. Additional survival analyses in pt subgroups and by ctDNA levels will be presented. Conclusions: In this 4-year analysis from CheckMate 816, neoadjuvant NIVO + chemo sustained EFS and OS separation vs chemo over time and demonstrated the long-term survival benefit of having pCR in pts with resectable NSCLC. These data provide the first understanding of the long-term benefits of neoadjuvant immunotherapy when added to chemo, reinforcing neoadjuvant NIVO + chemo as a standard of care, and providing a benchmark to assess the benefits of all perioperative immunotherapy-based treatments. Clinical trial information: NCT02998528 . [Table: see text]
Rates of pathologic complete response (pCR)after neoadjuvant datopotamab deruxtecan (Dato): Results from the I-SPY2.2 trial.
Authors: Jane Lowe Meisel, Katia Khoury, Amy Jo Chien, Anne M. Wallace, Mili Arora, Mariya Rozenblit, Nicole Olivia Williams, Rita Nanda, Virginia F. Borges, Erica Michelle Stringer-Reasor, Judy Caroline Boughey, Chaitali Nangia, Christos Vaklavas, Laura van 't Veer, Angela DeMichele, Nola Hylton, Douglas Yee, Christina Yau, Laura Esserman
Journal: Journal of Clinical Oncology (2024)

LBA509 Background: I-SPY2.2 is a multicenter phase 2 platform sequential multiple assignment randomized trial (SMART) evaluating novel experimental regimens in the neoadjuvant breast cancer setting. The novel therapy is given as first in a sequence (Block A), followed by standard chemo/targeted therapies (Block B/C) if indicated. The goal is to identify agents that lead to pCR after novel targeted agents alone, or in sequence with optimal therapy assigned based on the tumor response predictive subtype (RPS). RPS incorporates expression-based immune, DNA repair deficiency (DRD), and luminal signatures with hormone receptor (HR) and HER2 status to classify patients by subtype: S1: HR+HER2-Immune-DRD-; S2: HR-HER2-Immune-DRD-; S3: HER2-Immune+; S4: HER2-Immune-DRD+; S5: HER2+/non-Luminal; S6: HER2+/Luminal. Methods: RPS S1, S2, S3 and S4 were eligible for assignment to Dato in Block A. Patients (pts) were followed by MRI during treatment (at 3, 6 and 12 weeks after start of Blocks A and B). Predicted responders by MRI and biopsy at the end of Block A or B have the option of going to surgery early, otherwise they proceed to next treatment Block (B +/- C). Randomization to Block B includes a taxane-based regimen specific to the RPS, and options include S1: paclitaxel; S2 and S3: paclitaxel + carboplatin + pembrolizumab; S4: paclitaxel + carboplatin vs. paclitaxel + carboplatin + pembrolizumab. Patients who did not go to surgery after Block B proceeded to Block C (AC or AC + Pembrolizumab if HR-HER2-). The primary endpoint is pCR. Efficacy is evaluated within each RPS and HR+HER2- and HR-HER2- signatures. To estimate the arm's efficacy as a stand-alone therapy, we use a Bayesian covariate-adjusted model to estimate the pCR rate and compare the posterior distribution to a subtype-specific fixed threshold. This model uses pCR data when available and MRI data when pCR is not. To estimate pCR rate in the context of a multi-decision treatment regimen, we use a Bayesian model based on if and when a pCR occurred in the trial. The posterior is compared to a subtype-specific dynamic control generated from historical I-SPY data. Results: 103 pts were randomly assigned to the Dato arm between August 2022 and August 2023. All patients have proceeded beyond Block A; 33 went to surgery after Dato alone. The efficacy results for Dato as a stand-alone therapy are summarized in Table. Conclusions: Dato monotherapy was active, particularly in the HR-HER2- signature, but did not meet the pre-specified threshold for graduation in I-SPY 2.2. Clinical trial information: NCT01042379 . [Table: see text]
IMpower010: Final disease-free survival (DFS) and second overall survival (OS) interim results after ≥5 years of follow up of a phase III study of adjuvant atezolizumab vs best supportive care in resected stage IB-IIIA non-small cell lung cancer (NSCLC).
Authors: Heather A. Wakelee, Nasser K. Altorki, Caicun Zhou, Tibor Csőszi, Ihor O. Vynnychenko, Oleksandr Goloborodko, Achim Rittmeyer, Martin Reck, Alex Martinez-Marti, Hirotsugu Kenmotsu, Yuh-Min Chen, Antonio Chella, Shunichi Sugawara, Chenqi Fu, Marcus Ballinger, Yu Deng, Minu K Srivastava, Elizabeth Bennett, Barbara Jenifer Gitlitz, Enriqueta Felip
Journal: Journal of Clinical Oncology (2024)

LBA8035 Background: IMpower010 (NCT02486718) met its primary endpoint of significant DFS improvement with atezo vs BSC after adj chemotherapy in resected NSCLC in the PD-L1 TC ≥1% and all-randomized stage II-IIIA populations, leading to worldwide approval of adj atezo for PD-L1 TC ≥1% or PD-L1 TC ≥50% stage II-IIIA NSCLC. At OS IA1, a trend favoring atezo was seen in the PD-L1 TC ≥1% stage II-IIIA population. Here we report findings from the DFS FA and OS IA2. Methods: The IMpower010 study design has been previously described (Felip et al, Lancet 2021). The primary DFS and secondary OS endpoints were tested hierarchically: DFS in the PD-L1 TC ≥1% (SP263) stage II-IIIA, then in the all-randomized stage II-IIIA, and then in the intent-to-treat (ITT; stage IB-IIIA) populations, followed by OS in the ITT population. Secondary endpoints included 3- and 5-y DFS and DFS in the PD-L1 TC ≥50% (SP263) stage II-IIIA population. OS in the ITT population could only be formally tested if the significance boundary for DFS in that population was crossed. Results: At the DFS FA and OS IA2 (clinical cutoff date: Jan 26, 2024), with a minimum follow-up of 60 mo, DFS and OS for the PD-L1 TC ≥1% and TC ≥50% stage II-IIIA populations were consistent with previously observed benefit; the difference in median (m) DFS between arms in the PD-L1 TC ≥1% population was 31.2 mo (Table). In the ITT population, the significance boundary for DFS was not crossed and OS was similar between arms, although data were immature. The safety profile of atezo was consistent with prior analyses. Conclusions: These results provide the first cancer immunotherapy data with ≥5 y of follow-up from a Phase III study in resectable NSCLC. Although the statistical boundary for the ITT population was not crossed, DFS benefit with adj atezo continues to translate into a positive OS trend vs BSC in the PD-L1 TC ≥1% and TC ≥50% stage II-IIIA populations. These results further support the use of adj atezo in PD-L1–selected populations. Clinical trial information: NCT02486718 . [Table: see text]
Results from a randomised, open-label trial of a multimodal intervention (exercise, nutrition and anti-inflammatory medication) plus standard care versus standard care alone to attenuate cachexia in patients with advanced cancer undergoing chemotherapy.
Authors: Tora S. Solheim, Barry J A Laird, Trude R. Balstad, Guro Birgitte Stene, Vickie Baracos, Asta Bye, Olav Dajani, Andrew Eugene Hendifar, Florian Strasser, Martin Robert Chasen, Matthew Maddocks, Melanie R. Simpson, Eva Skovlund, Gareth Owen Griffiths, Jonathan Hicks, Janet Shirley Graham, Fiona Kyle, Joanna Bowden, Marie T. Fallon, Stein Kaasa
Journal: Journal of Clinical Oncology (2024)

LBA12007 Background: Cancer cachexia arises from the interaction between the host and the tumour, triggering an inflammatory response that leads to weight and appetite loss, diminished physical activity, reduced treatment efficacy and survival. Combining interventions to address inflammation, weight loss, and physical activity is proposed as an effective strategy. Building on a promising pilot study, we conducted the MENAC (Multimodal Exercise Nutrition Anti-inflammatory Cachexia) trial to comprehensively evaluate this approach in patients with lung and pancreatic cancer undergoing systemic anti-cancer treatment (SACT). Methods: MENAC was an investigator-initiated, multicentre, open label, randomised phase 3 trial conducted at 17 sites in 4 countries. Patients with stage III or IV lung or pancreatic cancer receiving SACT with non-curative intent were randomly assigned (1:1) to a multimodal intervention consisting of nutritional counselling plus fish oil containing oral nutritional supplements, physical exercise [endurance and strength] and non-steroidal anti-inflammatory drugs [NSAIDs]) versus standard care. Randomisation was stratified by country, cancer type and stage. Primary Objective: To assess differences between arms in change in body weight. Secondary Objectives: To assess differences in muscle mass (measured by CT L3 technique) and physical activity (assessed through step counts using ActivPAL activity meter) between arms. Assessments were conducted at basline (pre-randomisation) and at endpoint (after 6 weeks). Results: From May 2015 to February 2022, 212 patients were enrolled (105 to multimodal treatment, 107 standard care). Over 6 weeks, weight stabilised in patients assigned to multimodal treatment compared with those assigned to standard care (mean weight change [SD] 0.05 kg [3.8] vs – 0.99 kg [3.2], respectively) with a mean difference in weight change of -1.04, 95 % CI -2.02 to -0.06, p=0.04. There was no conclusive difference in muscle mass (mean change [SD] -6.5cm 2 [ 10.1] vs -6.3cm 2 [11.9], p=0.93) or in mean step counts [SD] (-377.7 [2075] vs -458 [1858], p=0.89). There were 28 and 24 reported SAEs in the intervention and control arm respectively, no SUSARs were reported. Conclusions: A multimodal cachexia intervention stabilised weight compared to standard care at six weeks. There was no difference in physical activity or muscle mass between trial arms. Clinical trial information: NCT02330926 .
Long term results of phase 3 randomized study evaluating the addition of low dose nivolumab to palliative chemotherapy in head and neck cancer.
Authors: Vijay Maruti Patil, Vanita Noronha, Nandini Sharrel Menon, Minit Jalan Shah, Zoya Ravish Peelay, Kavita Prakash Nawale, Priyanka Bhagyavant, Riddhi Sawant, Manali Kolkur, Kumar Prabhash
Journal: Journal of Clinical Oncology (2024)

LBA6054 Background: The addition of low-dose nivolumab to metronomic chemotherapy (MC) improved 1-year overall survival in relapsed and refractory head and neck squamous cell carcinoma (HNSCC). However, sustained benefit over the long term is an important aspect of immunotherapy and it has never been studied in a prospective randomized study for low-dose nivolumab. Methods: This was an open-label randomized phase 3 superiority study. Adult patients (age= or &gt;18 years), ECOG PS (0-1), relapsed -recurrent or newly diagnosed advanced HNSCC, and normal organ functions were eligible. Patients were randomly assigned 1:1 to oral metronomic chemotherapy consisting of methotrexate 9 mg/m2 weekly, celecoxib 200 mg twice daily, and erlotinib 150 mg daily, with (TMC-I) or without (TMC) with intravenous nivolumab 20 mg flat dose once-every-3-weeks. Systemic therapy was continued till the development of intolerable side effects or progression of disease. The primary endpoint was overall survival (OS). Landmark analysis was performed to compare OS between 2 arms. Results: The median follow-up was 32.5 months (95% CI 29.6-32.7). The 1 year, 2 year and 2.5 year OS were 20% (95%CI 11.9-29.7) versus 35.5% (95%CI 25-46.2) {Hazard ratio (HR)= 0.6534, 95%CI 0.4473 -0.956: P=0.028}, 5.3% (95%CI 1.7-12.3) versus 18.4 %(95%CI 10.7-27.8) {HR= 0.6318, 95%CI 0.4476 -0.8919: P=0.009} and 5.3% (95%CI 1.7-12.3) versus 17.1 % (95%CI 9.66.-26.3) {HR= 0.6379, 95%CI 0.4524 -0.8993: P=0.01} in the TMC and the TMC-I arms respectively. The benefit of the addition of nivolumab was independent of other factors like age, gender, ECOG PS, Site of malignancy, time to failure, PDL1 score, and previous exposure to platinum (Table). Conclusions: The addition of low-dose nivolumab to triple metronomic chemotherapy leads to a tripling of OS thus suggesting that even low-dose nivolumab has sustainable benefits. The benefit observed is irrespective of known prognostic factors in HNSCC. Clinical trial information: CTRI/2020/11/028953 . [Table: see text]