bluuebunny/crossref_metadata_2025_split huggingface dataset:
Standard atezolizumab leads to severe overexposure in real-world patients with lung cancer: How far could we go in extending dosing intervals and saving money?
Authors: Marolleau Sophie , Mogenet Alice , Boeri Clara , Hamimed Mourad , Ciccolini Joseph , Greillier Laurent 
Published: July 2024

3085 Background: Immune checkpoint inhibitors are given as fixed doses, which may lead to drug exposure exceeding the plasma concentrations required for target engagement. If confirmed, this could pave the way for de-escalating treatments without compromising efficacy while reducing drug-costs. Methods: We monitored plasma concentrations of Atezolizumab in 40 real-world patients. A final set of 33 patients with SCLC or NSCLC were available for full PK/PD analysis. Individual PK parameters were derived using a population pharmacokinetics approach. Individual PK parameters allowed to simulate the full concentration-time profiles and to further simulate for each patient the time to reach the target threshold after the first dose of Atezolizumab. In addition, efficacy (RECIST criteria) and immune-related adverse events, (IRAEs, CTCAE grading) were monitored and statistical analysis was performed to search for possible exposure-response relationships. Results: Overall Response Rate was 55% and no severe IRAEs were observed. All patients had Cmin levels significantly above the target threshold on the first cycle of Atezolizumab. The mean Cmax after the first dose on cycle 1 was 426.1 µg/ml and the mean Cmin was 68.5 µg/ml, i.e. 11-time higher than the target threshold associated with target engagement (i.e., 6 µg/ml). The mean AUC at the first cycle was 4763 µg.d/ml. Exposure metrics and PK parameters at baseline and simulated prior RECIST evaluation were tested together with other covariates (i.e. age, sex, smoking, NLR, number of metastatic sites, line of treatment) as possible predictive markers of response or toxicity. None of the parameters related to Atezolizumab pharmacokinetics or exposure levels were associated with efficacy or toxicity, most likely because all patients had plasma levels well above pharmacologically active concentrations. First-line therapy was associated with better response on univariate analysis, but this effect was lost on multivariate analysis. Further simulations based on time required to fall below the efficacy threshold suggest that dosing intervals could be extended from Q7W to Q19W (mean: Q12W). Considering the annual budget for Atezolizumab at our institution, further simulations showed that the annual drug cost could thus be reduced from 2.5 M€ to 0.6 M€ while ensuring that all patients remain above active concentrations. Conclusions: Our study demonstrates in a real-world setting that standard Atezolizumab given as 1200 mg Q3W infusion leads to severe overexposure of the drug. This strong overexposure was not associated with more severe treatment-related toxicities. Finally, our study suggests that PK-guided dosing with Atezolizumab could help customizing the dosing interval while maintaining efficacious trough levels and that Q12W could be an alternate scheduling leading to significant cut in drug costs.
Results of IMPACT 2, a randomized study evaluating molecular profiling and targeted agents in metastatic cancer at MD Anderson Cancer Center.
Authors: Tsimberidou Apostolia Maria , Fu Siqing , Hong David S. , Piha-Paul Sarina A. , Naing Aung , Rodon Ahnert Jordi , Yap Timothy A. , Karp Daniel D. , Dumbrava Ecaterina Elena , Heymach John , Ajani Jaffer A. , Cartwright Carrie , Beck Jennifer , Andersen Clark R. , Kahle Michael , Vining David J. , Ross Jeffrey S. , Chao Calvin Y. , Berry Donald A. , Meric-Bernstam Funda 
Published: July 2024

3153 Background: To address the limitations of exploratory studies, we conducted IMPACT2. The primary endpoint was to compare the progression-free survival (PFS) between patients treated with matched targeted therapies (MTT) selected on the basis of tumor molecular alterations and those whose treatment was not selected on the basis of alteration analysis (non-targeted therapy, NTT). Methods: Patients with metastatic cancer and targetable alterations were randomized between the 2 arms when eligibility criteria were met (Part A, 5/2014-4/2017; sponsor, Foundation Medicine). In Part B (3/2019-9/2023; sponsor, Tempus), patients who declined randomization selected the treatment arm ( NCT02152254 ). PFS/OS analysis (Kaplan Meier, Cox model; reference group, comparison, NTT). All cases were presented at weekly Molecular Tumor Board meetings; initial plan, to randomize 300 of 1,362 enrolled patients. Results: Overall, 829 patients (Parts A, 391; B, 438); were enrolled (med. age 59.5 yrs, range 18-84; men 50%; med. No. of prior therapies 3, range 0-17; most common cancers: gastrointestinal 34%, head/neck 13.5%, gynecologic 10%, sarcoma 9.53%; most common genomic alterations RAS 38%, PI3K 31%, FGFR 28%). In Part A, 69 were randomized (MTT, n=35; NTT, n=34); Part B (MTT, n=11, NTT=13; Selected arm: n=16: MTT, n=13; NTT, n=3). Results are shown (Table). MTT group: median PFS by therapy type: FDA approved/off-label, 4.7 months (95% CI, 2.93, 7.1); investigational, 2.6 months (95% CI, 2.27,4.87), combined FDA approved/investigational, 1.7 months (1.7, NR) (p=0.22). Conclusions: Considering the challenges to randomize patients (doi: 10.1038/s41698-022-00317-0), and that the study was underpowered for its original goal, no differences in response, PFS (primary endpoint), or OS was noted between the 2 arms, possibly because of the advanced stage disease and the complexity of tumor biology that cannot be addressed by randomization. Clinical trial information: NCT02152254 . [Table: see text]
A phase 1 study of HRS-1167 (M9466), a highly selective PARP1 inhibitor, in patients (pts) with advanced solid tumors.
Authors: Wu Lingying , Wang Jing , Li Ning , Zhang Jin , Wang Danbo , Jiang Shusuan , Chen Liang , Li Yongsheng , Zou Dongling , Cui Jiuwei , Yan Min , Wang Wei , Zhao Hongwei , Wang Ying , Wang Xiaojia , Liu Funan , Zhang Youzhong , Wang Jing , Zhang Dapeng , Miao Qingqing 
Published: July 2024

3154 Background: The use of first-generation dual PARP1/2 inhibitors is limited due to their hematological toxicities and inevitable drug resistance. Given that loss of PARP1 is the primary driver of synthetic lethality in homologous recombination repair (HRR) deficient tumors, and PARP2 is largely associated with hematological toxicities, development of next-generation PARPi with selectivity for PARP1 is warranted. Here, we present results of the dose escalation (D-ESC) and dose expansion (D-EXP) parts of a first-in-human study of HRS-1167 (M9466), a highly selective PARP-1 inhibitor, in pts with advanced solid tumors. Methods: Pts were eligible for the D-ESC part if they had advanced solid tumors that had progressed on standard therapies or for which no standard therapies were available. The D-ESC part began with accelerated titration (30 mg; QD) and then switched to the BOIN design (50, 100, 200, and 300 mg; QD). In the D-EXP part, previously treated pts harboring germline or somatic BRCA1/2, PALB2, or RAD51C/D mutations received HRS-1167 at 50, 100, and 200 mg QD. Prior PARPi was allowed. The primary objectives were to assess the safety and tolerability of HRS-1167. Results: As of Nov 20, 2023, 40 pts were enrolled (median lines of prior treatment, 2 [range, 1–5]; prior PARPi, 15.0%). No dose-limiting toxicities occurred, and the maximum tolerated dose was not reached. Grade ≥3 treatment-related adverse events occurred in 12 (30.0%) pts, with the most common being anemia (6 [15.0%]), decreased neutrophil count (5 [12.5%]), and decreased WBC count (5 [12.5%]). Of the 24 pts with HRR mutations who had at least one post-baseline assessment for tumor response, 10 (41.7%) pts had objective responses (8 ovarian cancer, 1 prostate cancer, and 1 pancreatic cancer). PK exposures were approximately dose-proportional. The median Tmax was 1.0–1.5 h, and the mean t1/2 was 10.5–15.0 h following a single dose of HRS-1167 at 30–300 mg. No obvious drug accumulation was observed (Rac, 1.08–1.30 for Cmax; 1.29–1.62 for AUC0-24). Conclusions: HRS-1167 was well-tolerated and exhibited favorable safety and PK profiles in pts with advanced solid tumors, and demonstrated promising anti-tumor activity in pretreated pts with HRR mutations. Clinical trial information: NCT05473624 .
Efficacy and safety of trastuzumab deruxtecan (T-DXd) in patients (pts) with HER2-expressing solid tumors: Results from the bladder cohort of the DESTINY-PanTumor02 (DP-02) study.
Authors: Wysocki Piotr Jan , Jung Kyung Hae , Oh Do-Youn , Doroshow Deborah Blythe , Artamonova Elena , Mammatas Lemonitsa , SU Po-Jung , Moiseyenko Vladimir , Penkov Konstantin , Stroyakovskiy Daniil , Bartolome Jorge , Siena Salvatore , Fielding Anitra , Jung Lindsey , Michelini Flavia , Puvvada Soham D. , Makker Vicky 
Published: July 2024

4565 Background: In DP-02, T-DXd showed robust responses and clinically meaningful survival outcomes in 267 pretreated pts with HER2-expressing solid tumors; the objective response rate (ORR) by investigator (INV) was 37.1% (95% CI 31.3, 43.2). Here we report subgroup analyses in the bladder cohort (urothelial carcinoma including transitional cell carcinoma of the renal pelvis, ureter, urinary bladder, or urethra), and characterize pts with an objective response (OR). Methods: This open-label, Phase 2 study (NCT04482309) evaluated T-DXd (5.4 mg/kg Q3W) in pts with HER2-expressing (immunohistochemistry [IHC] 3+/2+ by local or central testing) locally advanced/metastatic disease after ≥1 systemic treatment (Tx), or without Tx options. The primary endpoint was confirmed ORR by INV. Secondary endpoints included duration of response (DOR), progression-free survival (PFS), disease control rate (DCR), and safety. Exploratory endpoints included efficacy outcomes according to HER2 expression. Results: At data cutoff (June 2023), 41 pts with urothelial cancers had received T-DXd (median [m] follow up [range]: 12.65 [0.4–26.8] months); 27 (65.9%) had received ≥2 prior Tx regimens. 16/41 pts (39.0%; 95% CI 24.2, 55.5) had a confirmed OR by INV; 12 responders had received ≥2 prior Tx regimens, 14 had received prior immunotherapy Tx, and 14 had known PD-L1 immune cell status ≥1%. The Table shows efficacy outcomes in all pts and by HER2 expression (central testing). Grade (G) ≥3 drug-related adverse events occurred in 17/41 (41.5%) pts. Adjudicated drug-related interstitial lung disease / pneumonitis occurred in 4/41 (9.8%) pts (n=1 G1; n=3 G2). Conclusions: T-DXd showed clinically meaningful responses in pretreated pts with urothelial cancers, including across HER2 expression levels (IHC 3+ and 2+). Safety was consistent with the known profile. These data support further evaluation of T-DXd as a potential Tx for pretreated pts with HER2-expressing urothelial cancers. Clinical trial information: NCT04482309 . [Table: see text]
Comparison of clinical outcomes of stable disease with confirmed tumor reduction and RECIST partial response for tebentafusp in metastatic uveal melanoma (mUM).
Authors: Ikeguchi Alexandra , Sato Takami , Butler Marcus O. , Carvajal Richard D. , Sacco Joseph J , Shoushtari Alexander Noor , Hassel Jessica Cecile , Nathan Paul D. , Piulats Josep M. , Johnson Douglas Buckner , Luke Jason J. , Espinosa Enrique , Leyvraz Serge , Collins Laura , Edukulla Ramakrishna , Thiyagarajah Piruntha , Hamid Omid 
Published: July 2024

9529 Background: Tebentafusp (gp100 x CD3) has demonstrated an overall survival (OS) benefit in mUM. Benefit was observed in patients (pts) who achieved a RECIST v1.1 partial response (PR), stable disease (SD) and even progressive disease (PD) (Nathan 2021). In Phase (Ph) 1, some melanoma pts had SD with tumor reduction > 10% that was confirmed at ≥ 1 subsequent scan (referred to as minor response, MR). In Ph 2, an analysis of MR was pre-specified as an endpoint and presented here. Methods: 127 HLA-A*02:01+ pts with previously treated mUM received weekly intravenous tebentafusp following intra-pt dose escalation of 20mcg Week 1, 30mcg Week 2 and 68mcg Week 3+ (NCT02570308; Carvajal 2022). Radiologic assessments were performed every 8 weeks until week 40, then q12 weeks. Tumor assessment was evaluated by a blinded independent review committee per RECISTv1.1. MR was prospectively defined as RECISTv1.1 best response of SD with reduction in sum of target lesions of -10% to -29% and which was confirmed ≥ 4 weeks later. ctDNA levels were assessed using a targeted mPCR-NGS assay for mutations in 15 genes including mUM oncogenes GNAQ, GNA11, SF3B1, CYSLTR2, PLCB4 and EIF1AX (Natera). Molecular response was defined as ≥ 0.5 log [68%] ctDNA reduction by week 9. Data cut off: Oct 2022. Median duration of follow-up was 46 months. Results: Of 127 pts, the clinical benefit rate of PR + SD was 50% (64/127). 25% (32/127) had any tumor reduction that was confirmed on ≥ 1 subsequent scan, including 6 PR (ORR 5%) and 26 SD (20%). 8/26 SD (6% of 127) met the pre-defined threshold for MR, most (5/8) had >20% reduction. The median duration of response for PR and MR were 8.7 months and 10.6 months, respectively. The estimated percent of pts with PR and MR remaining in response at Month 20 were 20% and 33%, respectively. 3/6 PR pts were alive ≥ 3 years vs 3/8. 58% of PR + SD pts with evaluable ctDNA had a molecular response (26/45), including 2/4 PRs and 5/5 MRs. Conclusions: This Ph2 UM study prospectively confirmed that a subset of SD patients had tumor reduction over multiple scans. The frequency of minor response was similar to that of PR and had similar durability, OS and ctDNA molecular response. SD with confirmed tumor reduction is an emerging endpoint for the ImmTAC platform and will be studied in other trials (NCT05549297, NCT04262466). Clinical trial information: NCT02570308 .
Long-term overall survival after isolated liver perfusion with melphalan in patients with isolated liver metastases of uveal melanoma (SCANDIUM trial).
Authors: Nelson Axel , Shafazand Amir , All-Eriksson Charlotta , Cahlin Christian , Elander Nils , Helgadottir Hildur , Kiilgaard Jens Folke , Kinhult Sara , Ljuslinder Ingrid , Mattsson Jan Erik , Rizell Magnus , Sternby Eilard Malin , Ullenhag Gustav J. , Nilsson Jonas A , Ny Lars , Lindner Per , Olofsson Bagge Roger 
Published: July 2024

9532 Background: Uveal melanoma is a rare subtype of melanoma characterized by frequent metastases to the liver. The median survival for patients with liver metastases is less than one year, and there are few systemic treatment options available, providing only small survival benefits. Patients with liver metastases of uveal melanoma were in the SCANDIUM trial randomized to a one-time treatment with isolated hepatic perfusion (IHP) with high dose melphalan and investigator´s choice. We have previously reported that IHP gave significantly superior response rates and progression-free survival compared to best alternative care Furthermore, the primary endpoint, overall survival (OS) rate at 24 months was numerically higher for the IHP treated group (46.5% vs 29.5%), but the difference was not statistically significant. Here we present extended OS follow-up. Methods: In this randomized, controlled, phase III trial, treatment naïve Swedish patients with isolated liver metastases from uveal melanoma were between 2013 and 2021 randomly assigned in a 1:1 ratio to receive a one-time treatment with IHP or best alternative care (control group). No crossover from the control group to the IHP group was allowed. Results: A total of 87 patients were randomized and assigned to either IHP (43 patients) or control (44 patients). In the IHP group, 41 (89%) patients received IHP. In the control group, the first-line treatment was chemotherapy (49%), immunotherapy (39%) or localized treatment interventions (9%). The overall response rate was 40% in the IHP group, with a median duration of response of 13.7 months (95% CI, 11.6-18.3, n=17). At a minimum follow-up of 36 months, the 3-year OS rate was 18.6% (95% CI, 10.0-34.8%) in the IHP group compared to 9.1% (95% CI, 3.6-23.1%) in the control group (p=0.23, fisher exact test), and the 5-year OS rate was 16.3% (95% CI, 8.3-32.1%) compared to 6.8% (95% CI, 2.3-20.3%). The median OS in the IHP group was 21.4 months (95% CI, 19.0-30.4 months) compared to 17.3 months (95% CI, 13.8-22.3 months) in the control group (p=0.11, log-rank test). Conclusions: This extended analysis from the SCANDIUM trial supports long-term efficacy of a one-time treatment with IHP compared to best alternative care in patients with isolated liver metastases of uveal melanoma. Clinical trial information: NCT01785316 .
Real-world outcomes of combined lenvatinib and anti-PD-1 in advanced melanoma: Lenvamel, a multicenter retrospective study of the French Group of Skin Cancers.
Authors: Rousset Perrine , Nardin Charlée , Maubec Eve , Heidelberger Valentine , Picard Alexandra , Gérard Emilie , Kramkimel Nora , Steff Maud , Quéreux Gaëlle , Gaudy-Marqueste Caroline , Lesage Candice , Mignard Claire , Jeudy Geraldine , Jouary Thomas , Saint-Jean Mélanie , Baroudjian Barouyr , Archier Elodie , Mortier Laurent , Lebbe Celeste , Montaudie Henri 
Published: July 2024

9546 Background: Treatment options for patients (pts) with advanced melanoma who experience resistance to immunotherapy (ICI) +- targeted therapy are lacking. Studies suggest the anti-tumour activity of combined pembrolizumab and lenvatinib in pts progressing on ICI. We report the clinical outcomes of combined lenvatinib and anti-PD-1 in this population. Methods: This French multicenter real-world study was conducted from 09/2020 to 07/2023. The primary endpoint was objective response rate (ORR) according to the RECIST criteria (v.1.1). Secondary endpoints were treatment-related adverse events (TRAEs), progression-free survival (PFS), overall survival (OS) and duration of response (DOR). Results: Of the 67 pts included (median age, 69 years; median follow-up, 5.0 months), 85% had stage IV M1c or M1d disease. Baseline characteristics are presented (Table). Overall ORR was 28.4% (95%CI, 18–41%), including 3 complete (4.5%) and 16 partial (23.9%) responses. ORR was 71.4% (95%CI, 29–96%) for mucosal melanoma, 32,8% (95%CI, 21–46%) for pts pre-treated with anti-PD-1 + anti-CTLA-4, and 31,5% (95%CI, 20–46%) for BRAF wild-type melanoma. Median DOR was 3.1 (IQR, 1.3–4.3) months. Median PFS and OS were 3.1 (95% CI, 2.5–3.7) and 9.8 (95% CI, 5.6–13.9) months respectively. Grade 3–4 TRAEs occurred in 16 pts (24%, no grade 5); common TRAEs were fatigue (43.3%), nausea/vomiting (26.8%), diarrhea (20.9%), and hypertension (20.9%). Conclusions: Our study demonstrates an interesting response rate and acceptable safety profile of this combination, with manageable toxicities, in an immuno-refractory population with poor prognostic factors. Pts pre-treated with anti-PD-1+ anti-CTLA-4, and those with BRAF wild-type melanoma seemed to benefit more from this strategy. Our study also provides promising data (considering the small sample) for pts with mucosal melanoma. Our data support this treatment option for refractory melanoma, though not yet approved by the health authorities, and highlight the need for new strategies. [Table: see text]
Pembrolizumab (pembro) for locally advanced (LA) or recurrent/metastatic (R/M) cutaneous squamous cell carcinoma (cSCC): Long-term results of the phase 2 KEYNOTE-629 study.
Authors: Muñoz Couselo Eva , Hughes Brett Gordon Maxwell , Mortier Laurent , Grob Jean-Jacques , Gutzmer Ralf , Roshdy Osama , Gonzalez Mendoza Rene Lazaro , Schachter Jacob , Arance Ana Maria , Grange Florent , Meyer Nicolas , Joshi Abhishek Jagdish , Billan Salem , Ojavee Sven Erik , Yuan Jianda , Gumuscu Burak , Bratland Åse 
Published: July 2024

9554 Background: Pembro monotherapy is approved in certain countries, including the US, for treatment of LA or R/M cSCC based on results from the open-label phase 2 KEYNOTE-629 trial (NCT03284424). Promising antitumor activity was demonstrated with pembro in both the LA and R/M cohorts. ORR (95% CI) was 50.0% (36.1-63.9; 16.7% CRs) in the LA cohort and 35.2% (26.2-45.2; 10.5% CRs) in the R/M cohort. We present data from KEYNOTE-629 with an additional follow-up of 38 mo for LA and R/M cohorts. Methods: Adults with histologically confirmed LA or R/M cSCC, measurable disease per RECIST v1.1 by blinded independent central review (BICR), and ECOG PS 0 or 1 received pembro 200 mg IV every 3 weeks for up to 35 cycles (~2 years). The primary end point was ORR per RECIST v1.1 by BICR. Secondary end points were DOR, DCR (CR + PR + SD ≥12 wks), and PFS per RECIST v1.1 by BICR; OS; and safety. End points were analyzed in pts who received ≥1 dose of pembro. Results: A total of 159 pts were treated with pembro (LA, n = 54; R/M, n = 105). As of September 13, 2023, 33 pts (20.8%) completed treatment and 126 pts (79.2%) discontinued treatment. Median (range) follow-up was 52.4 mo (47.6-56.9) for the LA cohort, 64.7 mo (62.1-69.5) for the R/M cohort, and 63.1 mo (47.6-69.5) in the total population. ORR and DCR are shown in the table. Median DOR (range) was 47.2 mo (1.0+ to 49.9+) in the LA cohort, not reached (NR; 2.7 to 64.2+ mo) in the R/M cohort, and 52.5 mo (1.0+ to 64.2+) in the total population; the proportion of responders with responses ≥12 mo by Kaplan-Meier estimate were 84.8%, 77.8%, and 80.7%, respectively. Median (95% CI) PFS was 14.4 mo (5.5-43.6) in the LA cohort, 5.7 mo (3.1-8.5) in the R/M cohort, and 8.0 mo (5.3-14.4) in the total population; 12-mo rates were 56.7%, 37.3%, and 43.7%, respectively. Median (95% CI) OS was NR (33.3-NR) in the LA cohort, 23.8 mo (13.4-30.9) in the R/M cohort, and 29.8 mo (20.0-42.8) in the total population; 36-mo rates were 62.0%, 39.5%, and 47.0%, respectively. Grade 3-5 treatment-related AEs occurred in 11.3% of pts, and grade 3-5 immune-mediated AEs and infusion reactions occurred in 8.8% of pts. Two pts (1.3%) died due to a treatment-related AE (colitis, cranial nerve disorder). Conclusions: With a median follow-up of more than 5 years, pembro continued to show durable responses in pts with LA or R/M cSCC. No new safety signals were observed. Results from this study continue to support the use of pembro in this pt population. Clinical trial information: NCT03284424 . [Table: see text]