bluuebunny/crossref_metadata_2025 huggingface dataset:
Development and validation of an LC–MS/MS method for the determination of BLU-945, a fourth-generation EGFR tyrosine kinase inhibitor, in rat and mouse plasma: application to a pharmacokinetic study in rats
Authors: Oh Ji-Hoon , Nguyen Thi-Thao-Linh , Maeng Han-Joo
Published: June 2024

BLU-945, a new-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), is a potential drug candidate for the treatment of non-small-cell lung cancer (NSCLC) in patients with mutations that are resistant to previous generations of EGFR TKI. This compound has been investigated in preclinical and phase 1 dose-escalation studies that require a bioanalytical method for drug quantitation. In this study, an LC–MS/MS method was developed and validated for the quantitation of BLU-945 in rodent plasma and was applied to pharmacokinetic studies. The compound was extracted from plasma samples using a simple protein precipitation method. The method was validated in the linearity range of 1–1000 ng/mL with acceptable accuracy and precision, no matrix effects, and complete extraction recovery. BLU-945 was stable in the plasma quality control samples under various handling and storage conditions. The compound was stable after 4-h incubation in human, mouse, and rat plasma but was extensively metabolized in the microsomal fractions of these species. Furthermore, the validated analytical method was applied to a pharmacokinetic study in rats, revealing that BLU-945 had a high oral bioavailability range (55.91–105.6%) with a nonlinear pharmacokinetic profile up to an oral dose of 20 mg/kg. The validated bioanalytical method and findings of our study represent valuable assets for future investigations and clinical studies of BLU-945.
Pembrolizumab plus nab-paclitaxel and platinum as first-line treatment in patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC): A prospective, single-arm, open-label, phase 2 study.
Authors: Gui Lin , Chen Xinrui , Xie Zucheng , He Xiaohui , Yang Jianliang , Liu Peng , Qin Yan , Shi Yuankai
Published: June 2024

6023

Background: Based on KN-048, pembrolizumab combined with PF regimen has become the first-line standard treatment for R/M HNSCC. KN-B10 confirmed pembrolizumab combined with carboplatin and paclitaxel has a promising effect with manageable safety. This study aims to supplement the efficacy and safety data of pembrolizumab combined with nab-paclitaxel and platinum in the Chinese population. Methods: Untreated R/M HNSCC patients were treated with pembrolizumab 200mg, nab-paclitaxel 260mg/m2, plus cisplatin 75 mg/m2 or carboplatin AUC 5 (only if patients have cisplatin contraindications) on day 1 every 21 days for up to six cycles, followed by pembrolizumab maintenance therapy until progression or intolerable toxicity or completion of 35 cycles. Efficacy was evaluated according to RECIST 1.1, and survival analysis was performed using the Kaplan-Meier method. Adverse events were assessed using the CTCAE 5.0. The primary endpoint was ORR. Secondary endpoints include safety, DCR, OS, and PFS. High-resolution sequencing based on probe capture was performed on eligible patients. Results: Between Sep 15, 2020, and Nov 8, 2023, 67 R/M HNSCC patients were enrolled. Baseline characteristics are shown in the table. The median follow-up time was 12.7 months at the data cut-off date of January 8th, 2023, the ORR was 62.7%, and the DCR was 88.1%. The median PFS and OS were 11.6 months and 18.7 months, respectively. The median DOR was 14.7 months. The most common TRAEs of grade ≥3 were leukopenia (22.4%) and neutropenia (28.4%). Grade≥3 immune-related AEs were pneumonitis (1.5%), hepatitis (1.5%), and enteritis (1.5%). Of the 35 patients with sequencing results, the most common alterations were the TP53 mutation (86%), CDKN2A mutation (22%), FGF19 (26%), FGF4 (20%), FGF3 (20%), and CCND1 (20%) amplification. FGF19, FGF4, FGF3, and CCND1 amplification were associated with poor ORR, and CDKN2A mutation was associated with poor OS. Conclusions: Pembrolizumab combined with nab-paclitaxel and platinum shows encouraging antitumor activity accompanied by a manageable safety profile in untreated R/M HNSCC patients in China. CDKN2A mutation was a potential independent prognostic factors for this patient population. Clinical trial information: NCT04857164 . [Table: see text]
The role and mechanism of circadian clock gene BMAL1 in the proliferation and metastasis of nasopharyngeal carcinoma by inhibition TGF-β1/Smads pathway.
Authors: Chaofen Zhao , Jin Feng , Liu Lina , He Qianyong , Chen Yue , Shang Kai , Li Xiaomei , Xu Xinyu , Luo Xunyan
Published: June 2024

6027

Background: To explore the molecular mechanism of biological clock gene BMAL1 inhibiting the proliferation and metastasis of nasopharyngeal carcinoma(NPC). Methods: 1. IHC detected the expression of BMAL1 in 41 cases of nasopharyngeal chronic inflammatory tissue and 71 cases of NPCtissue. PCR and Western blot measured the expression levels of BMAL1 in NP69 in NPC cells and human immortalized nasopharyngeal epithelial cells, respectively. 2. To detect the effect of BMAL1 on the proliferation capacity of NPCcells in vitro and in vivo; Scratch healing and Transwell invasion migration experiments detected the effect of BMAL1 on the invasion and migration ability of NPCcells in vitro. Fluorescence in vivo imaging and HE staining to determine the transfer of nude mouse tail intravenous injection model. PCR and Western blot detect the effect of BMAL1 on the expression of EMT-related markers at the transcriptional and protein levels in NPC cells. 3. A series of molecular biological means such as bioinformatics technology, ChIP experiment, double luciferase reporter gene experiment, immunofluorescence colocalization experiment and Co-IP were used to verify its mechanism. Results: 1. The expression of BMAL1 in NPCtissues and cells is reduced. The expression of BMAL1 in NPC tissues was associated with the M stage of nasopharyngeal carcinoma patients (p=0.006). 2. Overexpression of BMAL1 can inhibit the proliferation, invasion and migration ability of nasopharyngeal cancer cells, while knocking down BMAL1 is the opposite. Overexpression of BMAL1 inhibits EMT of NPCcells. 3. There are 5 BMAL1 binding sites in the TGF-β1promoter region, and BMAL1 can directly bind to the TGF-β1promoter region, which can inhibit the transcriptional activity of TGF-β1. Overexpression of BMAL1 inhibits TGF-β1/Smads pathway activity. Under the induction of recombinant human TGF-β1, the proliferation ability of NPC cells was enhanced, the activity of TGF-β1/Smads signaling pathway was enhanced, and nasopharyngeal cancer cells underwent EMT, and cell invasion and migration capacity increased. After overexpression of BMAL1, TGF-β1 no longer promotes TGF-β1/Smads signaling pathway activity, EMT is inhibited, and cell invasion and migration ability is weakened. BMAL1 combined with TGF-β1 has certain diagnostic value in predicting whether nasopharyngeal carcinoma metastasis. Conclusions: BMAL1 expression is downregulated in nasopharyngeal carcinoma, and its expression level is related to the development and metastasis of nasopharyngeal carcinoma. BMAL1 can inhibit the proliferation, epithelial-mesenchymal transformation and invasion and metastasis ability of NPC cells, and its mechanism is related to the inhibition of TGF-β1/Smads signaling pathway activity. It is speculated that it may become a new prognostic marker and therapeutic target for nasopharyngeal carcinoma.
Impact of immune-related adverse events (irAE) onset on disease response and survival in patients (pts) with head-neck cancer treated with immune check point inhibitors (ICI).
Authors: Patel Reema , Elghawy Omar , Barsouk Adam , Kaur Varinder
Published: June 2024

6028

Background: ICI or combination chemo-immunotherapy are the mainstay of therapy for metastatic head-neck squamous cell carcinoma (mHNSCC) due to durable responses in certain pts. irAEs have emerged as a new challenge in the management of these pts. Some studies suggest a positive correlation between irAE onset and ICI efficacy in other cancers, however, whether such an association exists in HNSCC remains incompletely explored. Methods: We performed a retrospective, single-center cohort study of pts ≥ 18 years of age, with histologically confirmed mHNSCC who received ≥ 1 dose of ICIs at the University of Virginia Comprehensive Cancer Center, VA, USA between 2013-2022. Demographics, disease and treatment characteristics, and clinical outcomes related to irAEs and ICI re-challenge were analyzed. IrAEs were graded using CTCAE v4.0 criteria by chart review. Independent sample t-tests and chi-square analyses were used for univariate comparisons. Median PFS and OS from ICI therapy initiation were estimated using Kaplan-Meier methodology and censored at date of last follow up. P-values <0.05 were considered statistically significant. Results: Of 1979 pts who received ICI, 110 had mHNSCC (72.7% male; 84.5% White) with a median age of 62.4 years. ICI type included pembrolizumab or nivolumab in 109 pts, and nivolumab/ipilimumab in one pt. 53 (48%) pts experienced any grade irAE and 12 pts (11%) experienced >1 irAE. The most common irAEs were hypothyroidism (30.4%), dermatitis (14.3%), and hepatitis (10.7%). CTCAE ≥G3 irAEs were seen in 22.6% pts (n=12). These included hepatitis (n=3), colitis (n=3), hypothyroidism (n=1), arthritis (n=1), pneumonitis (n=1), adrenal insufficiency (n=1), vasculitis (n=1), and cardiomyopathy (n=1). Men (62% vs 37%, p= 0.015) and pts with prior radiation therapy (83% vs 17%, p=0.047) were more likely to experience irAEs. Treatment interruption/discontinuation occurred in 43% pts with irAEs. Topical/supportive therapy was required in 52.8%, and 35.8% required systemic corticosteroids, with more than half experiencing complete irAE resolution. A statistically significant association was observed between irAE onset and objective response rate (68% vs 39%, p= 0.009). 12 pts underwent ICI re-challenge, resulting in partial response in 3 (25%), stable disease in 4 (33.3%) and progressive disease in 3 (25%) pts. There was no statistically significant difference in PFS (4.9 vs 9.7 months, p = 0.731) or OS (30.5 vs 21 months, p = 0.159) in irAE vs non-irAE groups, respectively. Conclusions: irAEs onset was associated with improved best response to ICI therapy in mHNSCC. Although OS was numerically superior in the irAE group, it did not meet statistical significance. ICI re-challenge is feasible in select pts, however further studies are needed to evaluate long term benefit of ICI re-challenge.
Identifying patients at high risk of recurrence by rebound of plasma Epstein-Barr virus DNA in nasopharyngeal carcinoma.
Authors: Zhang Qixian , Zhou Xin , Xu Tingting , Shen Chunying , Qian Wei , Zhu Lin , Ying Hongmei , He Xiayun , Hu Chaosu , Lu Xueguan
Published: June 2024

6030

Background: About 10-30% of patients with nasopharyngeal carcinoma (NPC) would develop disease recurrence following treatment. The optimal method to screen patients needing early medical intervention remains to be studied. We investigated the potential cut-off values of plasma EBV DNA in identifying patients at high risk of recurrence. Methods: From 2012 to 2020, 950 patients with detectable pre-treatment plasma EBV DNA and undetectable EBV DNA within 3 months after treatment were retrospectively reviewed. Survival outcomes of patients with different plasma EBV DNA rebound patterns were analyzed. The diagnostic performance of different cut-off values was evaluated in patients with ≥ 2 positive tests. Results: The number of patients with continuous negative plasma EBV DNA, only 1 positive test, and ≥ 2 positive tests during post-treatment surveillance were 747, 89, and 114, respectively. Patients with ≥ 2 positive plasma EBV DNA tests had worse PFS, LRRFS, and DMFS when compared with the ones with negative tests ( P < 0.001, P < 0.001, and P < 0.001) and only 1 positive test ( P < 0.001, P < 0.001, and P < 0.001). Superior PFS was observed for patients with negative tests compared to patients with only 1 positive test ( P = 0.006). Of 56 patients with more than 50 copies/ml plasma EBV DNA in both tests, 48 developed recurrences within 4 years. The sensitivity, specificity, PPV, and NPV of this cut-off for recurrence prediction were 35.8%, 99.0%, 85.7%, and 90.4, respectively. Then, the whole population was divided into the low-risk group (≤ 1 positive test), the intermediate-risk group (≥ 2 positive tests and at least one test had < 50 copies/ml) and the high-risk group (≥ 2 positive tests and both tests had ≥ 50 copies/ml). The PFS of the high-risk group was worse than that of the low-risk group ( P < 0.001) and the intermediate-risk group ( P < 0.001). The PFS of the high-risk patients with and without capecitabine or tegafur/gimeracil/oteracil before clinical confirmed relapse were 59.3% and 15.0% ( P = 0.004). Conclusions: NPC patients with ≥ 2 positive tests and ≥ 50 copies/ml in both tests during follow-up were at high risk of relapse. Early medical intervention could bring survival benefits to this cohort.
Long-term outcomes of anlotinib and penpulimab combined with chemotherapy in the treatment of patients with metastatic nasopharyngeal carcinoma that failed definitive platinum-based chemoradiotherapy.
Authors: Huang Shuang , Chen Xiaozhong , Qu Song , Qu Shenhong , Han Yaqian , Yang Kunyu
Published: June 2024

6040

Background: The median progression-free survival (mPFS) of anti-PD-1 monoclonal antibody (mAb) plus gemcitabine (G) and cisplatin (C) in the first-line treatment of metastatic nasopharyngeal carcinoma (M NPC) is still limited in about 10 ~12 months. The tolerance is also unfavorable, especially for patients (pts) who had undergone platinum-based chemoradiotherapy (CRT) previously. We performed a phase 2 study to explore the potency of replacing cisplatin with anloinib (A), a multi-kinase inhibitor in combined with penpulimab (P), a novel anti-PD-1 mAb as the first-line treatment of M NPC for pts with prior explosure of platinum-based CRT. Here we report the updated long term outcomes of this study. Methods: This is a prospective, three cohorts, single-arm study. Eligible pts were aged 18 ~ 75 years old, diagnosed with NPC and developed metastasis after platinum-based CRT. Pts who were diagnosed as having M NPC at the first visit or experienced treatment failure within 6 months after definitive CRT or adjuvant therapy were excluded. Pts were randomized to receive G + A + P (cohort GAP), G + C + A + P (cohort GCAP) or G+C+P (cohort GCP). Gemcitabine (1000mg/m2, d1, d8) and cisplatin (80mg/m2, d1) were given intravenously for 4 to 6 cycles, 3 weeks per cycle. Penpulimab (200mg, d1) and anlotinib (10mg, qd, d1-14) were given intravenously and orally respectively until disease progression, or unacceptable toxicities. The primary endpoint was objective response rate (ORR). Results: 21 pts were randomized to three cohorts in lead-in phase while only cohort GAP was selected into expansion phase to enrolled another 7 pts. Finally, totally 28 pts were enrolled and received study treatment. The data cutoff date was December 1, 2023. The median follow-up was 20.2 month (95% CI: 17.0, 23.4). The results were summered in the table below. In cohort GAP, the confirmed ORR was 92.3% (95% CI: 64.0%, 99.8%) and the mPFS was still not reached (95% CI: NE, NE). The most common Grade 3 treatment-related adverse event (TRAE) was neutrophil count decreased (3 pts). Only one patient occurred Grade 4 TRAE (neutrophil count decreased) and no treatment-related death was observed. Conclusions: The long term outcomes of this phase 2 study preliminarily disclosed the advantage of the treatment regimen including gemcitabine, anlotinib and penpulimab as the first-line treatment of M NPC, especially for pts who had exposed to platinum-based chemotherapy. The further study with more sample size is warranted. Clinical trial information: NCT04736810 . [Table: see text]
Efficacy from the phase 1 study of FID-007, a novel nanoparticle paclitaxel formulation, in patients with head and neck squamous cell carcinoma.
Authors: Chow Lydia D. , Hsu Robert , Nieva Jorge J. , Umayam Rebecca , Smith Bryant Angela , Tsao-Wei Denice , Hsieh Ming , Yin Ray , El-Khoueiry Anthony B. , Thomas Jacob Stephen
Published: June 2024

6042

Background: Patients with recurrent or metastatic squamous-cell carcinoma of the head and neck (HNSCC) have limited treatment options after progression on first-line immunotherapy with or without platinum-based chemotherapy. Taxanes in this setting have historically demonstrated response rates around 14-27%. FID-007 (FID) consists of paclitaxel encapsulated in a polyethyloxazoline (PEOX) polymer excipient designed to enhance PK, biodistribution, and tolerability. This allows the drug to remain in solution until it can enter a cancer cell and preferentially delivers paclitaxel to the tumor through the leaky hyperpermeable vasculature. Preclinically, FID was more effective at lower or comparable taxane doses, including nab-paclitaxel. In the phase I study of FID, we determined 125 mg/m2 as the recommended phase 2 dose. Here we present updated safety and efficacy data with emphasis on pts with HNSCC. Methods: The study evaluated the safety, PK, and preliminary efficacy of FID in pts with advanced solid tumors. The primary objective is to determine the MTD and RP2D. Pts received FID in doses between 15mg/m2 and 160mg/m2 using a 3+3 dose escalation. FID was given IV on Days 1, 8, and 15 of a 28-day cycle. Eligibility included ECOG 0-2, adequate organ function, and < 3 prior lines of cytotoxic therapy. Results: 46 patients were enrolled, of which 9 had HNSCC (2 nasopharynx, 2 sinonasal, 3 oropharynx, 1 oral cavity, and 1 occult primary). Median age (range) was 60 (53-75). ECOG PS was 1 in all HNSCC pts. Median number of prior therapies was 3 (1-5) and all had received prior immune checkpoint inhibitor. All grade treatment related adverse events (TRAEs) in ≥ 25% of pts included rash (72%), alopecia (52%), leukopenia (46%), pruritus (43%), neutropenia (41%), anemia (37%), fatigue (37%), nausea (28%), and anorexia (28%). Grade 3/4 TRAEs occurring in >1 pt were maculopapular rash (35%), neutropenia (20%), leukopenia (20%), anemia (17%), lymphopenia (7%), and febrile neutropenia (4%). No pts experienced > grade 2 peripheral sensory neuropathy; 20% experienced grade 1-2. Across all solid tumors, the overall response rate (ORR) was 17%. In patients with HNSCC, 5 (56%) had a partial response, 2 (22%) had stable disease, and 2 (22%) had PD. Three out of 5 HNSCC patients previously treated with a taxane achieved a partial response. Median duration of treatment was 4 months (1-15). Conclusions: FID demonstrates preliminary evidence of anti-tumor activity in heavily pre-treated HNSCC pts across different primary tumor sites, with an ORR 56%, including those with prior taxane exposure. A phase 2 study of FID with cetuximab in pts with HNSCC is planned to begin enrollment in 2024. Clinical trial information: NCT03537690 .
Characterizing the impact of sarcopenia on treatment response and survival in previously treated recurrent or metastatic nasopharyngeal carcinoma: Insights from a secondary analysis of the KL-A167 randomized trial.
Authors: Liu Zheran , Meng Dou , Li Huilin , Li Dong , Li Zhihui , Cai Lei , Zhou Jitao , Peng Xingchen
Published: June 2024

6046

Background: The relationship between sarcopenia and adverse outcomes among patients with recurrent and metastatic nasopharyngeal carcinoma (R/M NPC) undergoing immunotherapy remains underexplored. This secondary analysis of the KL-A167 clinical trial data aims to elucidate the impact of sarcopenia on treatment efficacy and prognosis in this cohort, while also identifying potential mediating hematological biomarkers. Methods: A cohort of 148 patients enrolled in the KL-A167 clinical trial was analyzed. Logistic and Cox regression models were applied to assess the association between sarcopenia and treatment response, overall survival (OS), and progression-free survival (PFS), with adjustment for clinical prognostic factors. Counterfactual causal mediation analysis was conducted to identify hematological biomarkers potentially mediating the relationship between sarcopenia and prognosis in R/M NPC patients. Results: The presence of sarcopenia was significantly associated with reduced objective response rate (ORR: OR = 0.25, 95% CI = 0.08–0.81, p = 0.020) and disease control rate (DCR: OR = 0.23, 95% CI = 0.07–0.70, p = 0.010). Furthermore, sarcopenia was linked to inferior OS (HR = 2.07, 95% CI = 1.12–3.81, p = 0.020) and PFS (HR = 2.59, 95% CI = 1.48–4.54, p = 0.001). Notably, sarcopenia was characterized by elevated levels of neutrophil count, fibrinogen, and white blood cell count, alongside decreased creatine kinase levels. Fibrinogen emerged as the sole elevated biomarker significantly associated with both OS and PFS. Causal mediation analysis indicated that fibrinogen accounted for 23.5% of the association between sarcopenia and OS and 15.7% of PFS. Conclusions: Sarcopenia significantly correlates with poor treatment response and survival outcomes in patients with R/M NPC receiving immunotherapy. Targeting fibrinogen may offer a novel strategy to mitigate the negative impact of sarcopenia on patient survival.
Mapping the mental health correlates of head and neck cancer: A systemic review and meta-analysis.
Authors: Jiménez Labaig Pablo , Aymerich Claudia , Rullan Antonio , Llop Sandra , Brana Irene , Cacicedo Jon , Harrington Kevin Joseph , Catalan Ana
Published: June 2024

6077

Background: Patients with head and neck cancer (HNC) present particularly high levels of mental health disorders. Yet the actual rate of relevant mental health symptoms and disorders, along with its determinants, remains unclear. Methods: A PRISMA/MOOSE-compliant systematic review and quantitative effects meta-analysis (PROSPERO: CRD42023441432) was conducted to determine the prevalence of depression, anxiety, distress, post-traumatic stress, insomnia and suicide among patients with HNC. MEDLINE, WebofScience, Cochrane Central Register, KCI-Korean Journal, SciELO, Russian Science Citation Index and Ovid/PsycINFO databases were searched from database inception to August 1, 2023. Secondary analyses were used to assess longitudinal trajectories of the samples over time. Results: 208 studies (n=713,527, median age 60.7; 25.5% female) were included. 19.5% patients reported depressive symptoms (95% confidence interval [CI]=17-21%), 17.8% anxiety symptoms (95%CI=14-21%), 34.3% distress (95%CI=29-39%), 17.7% post-traumatic symptoms (95%CI=6-41%) and 43.8% insomnia symptoms (95%CI=35-52%). Diagnostic criteria assessments revealed lower prevalence of disorders: 10.3% depression (95%CI=7-13%), 5.6% anxiety (95%CI=2-10%), 9.6% insomnia (95%CI=1-40%), and 1% post-traumatic stress (95%CI=0-84.5%). Pooled suicide incidence was 161.16 per 100,000 individuals per year (95%CI=82-239). A higher prevalence of anxiety was found in patients undergoing primary chemoradiation compared to surgery, and increased distress in smokers and advanced tumor staging. European samples exhibited lower prevalence of distress. Patients were more likely to be depressed after finishing radiation treatment. Conclusions: Patients with HNC exhibited a notable prevalence of mental health issues across various domains, where suicide emerged as a particular concern. There is a need for improved methods of assessment and intervention for these mental health concerns. Preventive interventions should be implemented before the start of radiation treatments. [Table: see text]
Patients with radioiodine-refractory differentiated thyroid cancer (RAI-R DTC) with BRAF V600E and/or K601E mutation status: A real-world view of effectiveness of lenvatinib monotherapy.
Authors: Worden Francis P. , Wirth Lori J. , Reynolds Neil , Cooper Charley , Rajkovic-Hooley Olivera , Milligan Gary , Pham Phananh , Saal Hakim , Brose Marcia S.
Published: June 2024

6098

Background: Lenvatinib was approved for the treatment of patients RAI-R DTC in the United States (US) in 2015, and the treatment landscape has evolved with agents targeting specific driver mutations. We assessed real-world clinical effectiveness of first line therapy with lenvatinib in patients with BRAF-mutated tumors, wild-type (WT) tumors, and patients who have not been tested for BRAF mutations (BRAF untested tumors). Methods: A retrospective chart review of RAI-R DTC patients in the US who initiated first-line lenvatinib monotherapy between February 13, 2015, and September 30, 2020. Data, including a boosted cohort of patients with BRAF-mutated tumors collected in late 2023, were abstracted from patients’ electronic health records and were de-identified. Descriptive analyses were conducted in patient cohorts with BRAF V600E and/or K601E mutated tumors, wild-type (WT) tumors, and BRAF untested tumors. Best response in first-line therapy was captured, real-world progression-free survival (rwPFS) and real-world overall survival (rwOS) were assessed using Kaplan-Meier methods. Results: Of the 361 patients reviewed, 185 had records showing BRAF mutational status testing. 89 had BRAF V600E and/or K601E mutated tumors, 96 had WT tumors. 176 patients did not have BRAF mutational assessment. Of all subjects, 73.7% were White/Caucasian, 15.2% were African American, and 16.8% were Hispanic/Latino; 27.1% had ECOG performance status ≥2. The median follow-up times for each cohort were 30.0, 18.7 and 18.0 months, showing the longer follow up period for the BRAF-mutated cohort boost. Kaplan-Meier estimation for lenvatinib treatment discontinuation for the three cohorts at 24-months were as shown in the table below. Provider-reported overall response rate (complete or partial response) was 76.4%, 75.0% and 69.3% respectively. The estimated 24-month rwPFS rates (95% CI) were 74.1% (62.2%-82.8%), 61.7% (49.6%-71.8%), and 69.8% (60.9%-77.0%) respectively. Median rwOS was not reached for patients with BRAF-mutated and WT tumors, median OS was 54.2 months for BRAF untested tumors. Estimated rwOS rates at 12- and 48-months were 93.2% (85.4%-96.9%) and 83.9% (73.3%-90.3%) in BRAF-mutated patients, 90.6% (82.8%-95.0%) and 68.5% (53.4%-79.6%) in WT patients, and 90.2% (84.7%-93.8%) and 72.5% (61.6%-80.7%) in BRAF untested patients respectively. Conclusions: In this US real-world experience, the effectiveness of lenvatinib is consistent across a diverse cohort of RAI-R DTC patients with BRAF-mutated, WT, and BRAF untested tumors. This has implications for the first-line use of lenvatinib in BRAF mutated patients. [Table: see text]
Preclinical assessment of IPH6501, a first-in-class IL2v-armed tetraspecific NK cell engager directed against CD20 for R/R B-NHL, in comparison with a CD20-targeting T cell engager.
Authors: Demaria Olivier , Vetizou Marie , Remark Romain , Chiossone Laura , Vagne Constance , Courtois Rachel , Denis Caroline , Maguer Aurélie , Le Floch François , Represa Agnès , Blanchard Alvarez Audrey , Gauthier Laurent , Quaratino Sonia , Paturel Carine , Vivier Eric
Published: June 2024

7030

Background: The therapeutic landscape for relapsed or refractory (R/R) B-cell non-Hodgkin lymphoma (B-NHL) is evolving to include targeted T-cell based immunotherapies, including CD19-targeted CAR-T and CD3xCD20 T-cell engaging (TCE) bispecific antibodies. Yet, there remains an unmet medical need for patients who are refractory to, or ineligible for these treatments. Leveraging natural killer (NK) cells emerges as a promising strategy in hematological malignancies, as shown in a Phase 1 study with IPH6101/SAR’579 in R/R AML (Stein, ASCO 2023; Bajel, ASH 2023). Methods: We developed IPH6501, a tetraspecific antibody-based NK cell engager that simultaneously targets on NK cells the CD16a and NKp46 receptors, the IL-2 receptor with an engineered IL-2 variant (IL2v) and on B-NHL cells the CD20 antigen. This approach boosts NK cell activation and proliferation, cytotoxicity against tumor cells, and cytokine production. The IL-2 variant is designed with mutations that prevent binding to CD25 (IL-2Rα), limiting Treg activation and potential IL-2-related side effects. IPH6501 has been evaluated in mouse, non-human primate, and human-derived models, including cells from R/R B-NHL patients. Results: In vivo studies in non-human primates and tumor mouse models revealed that IPH6501, at well-tolerated doses, significantly boosted peripheral NK cell proliferation, drove their accumulation at tumor locations, and effectively eradicated CD20+ cells in blood and tissues. In human derived-models, IPH6501 significantly induced NK cell proliferation and cytotoxicity. Notably, IPH6501 showed potent activity against a range of B-NHL cell lines, including those with low CD20 expression. In addition, IPH6501 upregulated the expression of activating receptors on NK cells, such as NKG2D, essential for the recognition and killing of malignant cells, thereby introducing another mode of action enabling the elimination of CD20-negative tumor cells. In a comparative analysis with a CD3xCD20 TCE, IPH6501 induced lower cytokine secretion, suggesting a potentially safer profile. Additionally, IPH6501 showed higher killing efficacy compared to the TCE in samples from healthy individuals as well as R/R B-NHL patients, underscoring its therapeutic potential. Conclusions: The preclinical demonstrations of IPH6501 activities across various in vivo models and its effectiveness in ex vivo assays using cells from R/R B-NHL patients provide compelling evidence of its therapeutic potential and tolerability. IPH6501 is emerging as a promising new candidate within the treatment landscape for R/R B-NHL and is currently being investigated in a global, first-in-human phase 1/2 study (NCT 06088654).
Epcoritamab + R-DHAX/C in transplant-eligible patients (pts) with high-risk relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL).
Authors: Karimi Yasmin , Abrisqueta Pau , de Vos Sven , Nijland Marcel , Offner Fritz , Osei-Bonsu Kojo , Rana Ali , Archer Kimberly G. , Song Yaou , Cordoba Raul , Falchi Lorenzo
Published: June 2024

7032

Background: While high-dose therapy (HDT)–autologous stem cell transplant (ASCT) is potentially curative for pts with R/R DLBCL, many do not receive this treatment (tx) due to insufficient response to salvage chemoimmunotherapy; better options are needed. Epcoritamab is a CD3xCD20 bispecific antibody with efficacy and safety in R/R DLBCL as a single agent and in combination. We report updated data from epcoritamab in combination with rituximab, dexamethasone, cytarabine, and oxaliplatin or carboplatin (R-DHAX/C) in pts with R/R DLBCL eligible for HDT-ASCT, including high-risk pts (progressed within 12 mo of initial tx or primary refractory), from EPCORE™ NHL-2 (phase 1/2; NCT04663347). Methods: Adults with R/R CD20+ DLBCL eligible for HDT-ASCT received R-DHAX/C and epcoritamab (2 step-up doses, then 24- or 48-mg full doses) in 21-d cycles (Cs): QW, C1–3. If HDT-ASCT was deferred, pts could continue epcoritamab (21-d C: QW, C4; 28-d Cs: Q2W, C5–9; Q4W, C≥10) until disease progression. Primary endpoint was overall response rate (ORR; Lugano criteria). Results: As of Dec 15, 2023, 29 pts (median age, 58 y) received epcoritamab (24 mg, n=3; 48 mg, n=26) + R-DHAX/C. At baseline, 24 pts (83%) had progressed within 12 mo of initial tx, 19 (66%) had primary refractory disease (no response or relapse within 6 mo of initial tx), and 3 (10%) had prior CAR T. At 27.5 mo median follow-up, 16 (55%) pts had proceeded to HDT-ASCT and 2 (7%) remained on tx. ORR was 76% and complete response (CR) rate was 69% (Table). Median time to response was 1.4 mo (CR, 1.5 mo). At 24 mo, per Kaplan–Meier estimates, 60% of pts remained progression free, while 90% of pts who proceeded to ASCT (n=16) and 60% of pts who continued epcoritamab without ASCT (n=5) remained progression free; additionally, 90% of pts with CR who received ASCT (n=15) and 100% of high-risk pts with CR who received ASCT (n=12) remained in response. An estimated 86% of pts remained alive at 24 mo. The most common tx-emergent AEs (TEAEs) of any grade (G) were thrombocytopenia (76%), anemia (59%), nausea (48%), and neutropenia (48%; febrile neutropenia, 17%). CRS was low grade (38% G1, 7% G2), resolved, and did not lead to tx discontinuation. ICANS (G2) occurred in 1 pt and led to tx discontinuation. There were no fatal TEAEs. Conclusions: Longer follow-up reaffirms the efficacy and feasibility of epcoritamab + R-DHAX/C in ASCT-eligible DLBCL. Response rates were high and most pts proceeded to ASCT. Safety was manageable and consistent with prior data. These results, including new high-risk subgroup analyses, support future evaluation of epcoritamab + R-DHAX/C in ASCT-eligible DLBCL. Clinical trial information: NCT04663347 . [Table: see text]
First-line (1L) treatment of follicular lymphoma (FL) with atezolizumab and obinutuzumab (A+O) +/- radiotherapy (RT): Results from the FLUORO study.
Authors: Chong Geoffrey , Lee Denise , Lee Sze Ting , Grobler Anneke , Khor Richard , Campbell Belinda A. , Thachil Thanuja , Manos Kate , Martynchyk Arina , Douglas Genevieve , Keane Colm , Palmer Jodie , Hawkes Eliza Anne
Published: June 2024

7070

Background: Standard 1L immunochemotherapy in FL is highly effective but not without significant toxicity. Up to 75% of FL patients (pts) have grade 3-5 adverse events (AEs), primarily infection and myelosuppression. More tolerable approaches are needed. PD1/PDL1 inhibitors are active in FL. A+O yield responses in 57% of rituximab-refractory FL pts (Palomba 2017). Our phase 2 study of 1L nivolumab + rituximab in FL yielded 92% overall response rate (ORR), (54% Complete Response (CR)). Toxicity compared favourably with chemotherapy: 41% grade 3-5 AEs (Hawkes 2021). FL is sensitive to low dose RT, with proven abscopal effects, is safe and synergistic with PDL1i (Hawkes 2023), potentially improving treatment efficacy with minimal extra toxicity. This investigator-led, multicentre PET-adapted phase 2 trial assessed A+O +/- RT efficacy for treatment-naïve FL. Methods: ‘FLUORO’ (NCT03245021) is an open-label, multi-centre, phase 2, Simon’s 2-stage study of A+O+/-RT (N = 46; 15 in initial cohort). Key eligibility were stage II-IV grade 1-3A FL requiring therapy; ECOG ≤2; adequate organ function. All pts received 6 cycles (C) of A 1200mg + O 1000mg IV 3-weekly (plus O on C1, days 8 & 15). Pts with < CR on PET post C2 had RT (4Gy) to residual PET-avid disease. Pts with CR or PR(partial response) received 12 cycles 8-weekly maintenance O. Primary endpoint (EP) was CR rate with <5/15 CR deemed futile in 1st stage. Secondary EP included ORR, Progression-free survival (PFS), overall survival (OS) and AEs. Exploratory EP included biomarker studies and PET radiomics. Results: 16 pts were enrolled from 08/2021-10/2022, 1 pt was replaced due to Grade(G) 4 infusion reaction to O requiring cessation. Baseline characteristics included median age 53y (range 33-79), stage IV disease in 81%, B symptoms in 12.5%, 44% had FLIPI >2. Primary EP was met, with CR at end of induction in 13/15 (87%) evaluable pts (ORR 100%). 12 pts (80%) required RT. 2 pts (13%) discontinued due to progressive disease (Table). AEs were mostly G1-2; fatigue 44%, constipation 31%, nausea 25%. fever 25%, abdominal pain 18.6%. SAEs were reported in 7/16 (44%) pts, including grade 3 infections: COVID19 12%, upper respiratory tract 12%, urinary tract 6.2%. Median follow-up is 24m (range 16-28) and ongoing, 16m PFS & OS is 87% & 100%. Biomarker analysis is ongoing. Conclusions: Atezolizumab +Obinutuzumab +/- PET-adapted 4Gy RT yielded high complete response rates with low toxicity in treatment-naïve FL. CR threshold to proceed to stage 2 was met, however was not deemed commercially viable. Clinical trial information: NCT04962126 .[Table: see text]
Impact of extramedullary multiple myeloma on outcomes with idecabtagene vicleucel.
Authors: Zanwar Saurabh , Sidana Surbhi , Shune Leyla , Castaneda Puglianini Omar Alexis , Pasvolsky Oren , Gonzalez Rebecca , Dima Danai , Afrough Aimaz , Kaur Gurbakhash , Davis James A. , Herr Megan , Hashmi Hamza , Forsberg Peter A. , Sborov Douglas W. , Richard Shambavi , Khouri Jack , Lin Yi , Patel Krina K. , Kumar Shaji , Hansen Doris K. ,   US Multiple Myeloma Immunotherapy Consortium
Published: June 2024

7508

Background: Idecabtagene vicleucel (Ide-cel) has demonstrated excellent efficacy in patients with relapsed/refractory multiple myeloma (RRMM). However, outcomes in patients with extramedullary disease (EMD) remain to be better characterized. Methods: We included patients from 11 US academic centers, who were evaluated for EMD and were infused with ide-cel between May 2021 and April 2023. Patients with soft tissue or visceral lesions non-contiguous from bony lesions were classified as having true EMD, with paraskeletal disease classified as non-EMD. Disease responses were evaluated using the IMWG criteria. Time-to-event analyses were performed from the date of ide-cel infusion. Results: Among 351 patients with RRMM treated with ide-cel, 84 (24%) had EMD prior to infusion. Median follow-up for the entire cohort was 18.2 months (95% CI: 17-19.3). Baseline characteristics at ide-cel infusion for EMD and non-EMD cohorts are depicted in the table. For the EMD and non-EMD cohorts, the Day 30 objective response rates (ORR) were 58% vs. 69% (p=0.1), Day 30 ≥complete response rates were 16% vs 24% (p=0.11), the Day 90 ORR were 52% vs 82% (p<0.001), and best ORR were 58% vs 82%, respectively. The median progression-free survival (PFS) was 5.3 months (95% CI: 4.1-6.9) for the EMD cohort vs. 11.1 months (95% CI: 9.2-12.6; p<0.0001) for the non-EMD cohort. The median duration of response for EMD among day 30 responders was 6.4 months (95% CI: 5.1-8.4). In a multivariable analysis, EMD was an independent predictor of inferior PFS [hazard ratio 1.8 (95% CI: 1.2-2.5), p<0.001] after adjusting for ECOG status, revised ISS stage, penta-drug refractoriness, elevated ferritin, prior BCMA-directed therapy and use of bridging therapy. Pattern of progression in the EMD cohort (n=68/84) included EMD site only (21%), hematologic only (22%), or both (57%), with comparable PFS for type of progression (p=0.19). The median overall survival (OS) was 14.8 months [95% CI: 9-Not reached (NR)] for EMD and 26.9 months [95% CI: 26.3 vs NR, p=0.006)] for the non-EMD group. Rates of Grade ≥2 cytokine release syndrome or neurotoxicity syndrome were comparable between the two cohorts. Conclusions: Patients with EMD demonstrate significantly inferior Day 90 ORR and presence of EMD is an independent risk factor for inferior PFS. [Table: see text]
Apixaban versus warfarin for primary thromboprophylaxis in patients with multiple myeloma undergoing immunomodulatory treatment.
Authors: Chang Yu-Cheng , Chiang Cho Han , Tang Zhiting , See Xin Ya , Chiang Cho Hung , Chi Kuan-Yu , Chang Yu , Gao Wenli
Published: June 2024

7548

Background: Immunomodulatory drugs (IMiDs) have been demonstrated to improve clinical outcomes in patients with multiple myeloma (MM), but are associated with an elevated risk of thromboembolism. Existing guidelines recommend low-dose direct oral anticoagulants as an alternative to warfarin for primary thromboprophylaxis in MM. However, the data comparing these two therapies are limited. We aim to compare the efficacy and safety of apixaban versus warfarin in patients with MM undergoing IMiD treatment. Methods: We conducted a retrospective propensity score-matched cohort study using the TriNetX Analytics Network database, which contains de-identified data from over 120 participating healthcare institutions. We included adult patients with MM who underwent IMiD treatment. Patients treated with apixaban were matched in a 1:1 ratio to those treated with warfarin using clinical variables a priori. The primary safety outcomes included all-cause mortality, intracranial hemorrhage, and gastrointestinal bleeding, while the primary efficacy outcomes included thromboembolic events including pulmonary embolism, deep venous thrombosis, and ischemic stroke within a 3-year period following IMiDs initiation. Results: We identified 448 patients on apixaban who were matched to patients on warfarin. In a Cox proportional hazard analysis, apixaban was associated with a 30% lower risk of all-cause mortality compared to warfarin (Hazard ratio (HR), 0.70 [95% CI: 0.56-0.88]).There was a tendency toward a reduced risk of gastrointestinal bleeding in patients treated with apixaban compared to warfarin (HR, 0.58 [95% CI: 0.31-1.08], log-rank p = 0.083). The risk of intracranial hemorrhage was similar between the two groups.The risks of thromboembolic events including pulmonary embolism, deep venous thrombosis, and ischemic stroke were comparable between the apixaban and warfarin cohorts. Conclusions: Apixaban was associated with a lower risk of all-cause mortality and a comparable risk of bleeding and thromboembolism compared with warfarin among MM patients undergoing immunomodulatory treatment. [Table: see text]
Real world outcomes of high dose melphalan conditioning prior to autologous stem cell transplant in extramedullary multiple myeloma vs. multiple myeloma without extramedullary involvement: A single center experience.
Authors: Poei Darin , Parker Graham Blake , Ye Shirley , Tun Han , Ranganathan Raghuveer , Myint Zaw Win
Published: June 2024

7550

Background: Extramedullary multiple myeloma (EMM) is defined as the presence of multiple myeloma plasma cells, which develop outside of the bone marrow. It is an aggressive form of multiple myeloma that is associated with a poor prognosis. The current standard of care for multiple myeloma consists of induction, high dose melphalan autologous stem cell transplant (ASCT), followed by maintenance. However, there is limited data on the outcome of patients with extramedullary multiple myeloma who undergo ASCT. Therefore, we examined the outcomes of high dose melphalan conditioning prior to ASCT in EMM patients compared to multiple myeloma patients without extramedullary involvement (non-EMM) at an academic institution in Los Angeles. Methods: We retrospectively reviewed 246 multiple myeloma patients who underwent ASCT after receiving high dose melphalan conditioning at USC Norris Comprehensive Cancer Center from Jan 2017 to Dec 2022. The cohort was subdivided into 70 EMM patients and 176 non-EMM patients. Outcomes were measured as the status of disease response, which was evaluated at 100 days (D+100) and 365 days (D+365) after the date of transplant. Results: In the EMM group, 1.43% (n=1) was found to have progression at D+100 and 12.86% (n=9) at D+365. In the non-EMM group, 0.57% (n=1) was found to have progression at D+100 and 11.93% (n=21) at D+365. There was no statistical significance between the EMM and non-EMM groups for progression free survival at D+100 (p-0.50) and D+365 (p-0.75). Regarding overall survival, there were 0 deaths observed at D+100 in both the EMM and non-EMM groups. For D+365, the overall survival was 98.57% (n=69) for the EMM group and 99.43% (n=175) for the non-EMM group. There was no statistical significance between the overall survival at D+365 (p-0.14). Conclusions: The EMM cohort exhibited similar rates of progression free survival (87.14% vs. 88.07%) and overall survival (98.57% vs. 99.43%) compared to the non-EMM cohort at one year post ASCT after receiving high dose melphalan conditioning. We observed that there was no significant statistical difference between the EMM and non-EMM cohorts regarding progression-free survival (p-0.75) and overall survival (p-0.14) on day 365. According to our data, high dose melphalan conditioning prior to autologous stem cell transplant is equally as effective for patients with multiple myeloma with or without extramedullary involvement. Future studies with long-term follow-up are recommended to further explore these findings. [Table: see text]
First relapse in patients with multiple myeloma: Outcomes and predictors.
Authors: Seth Sukriti , Kapoor Prashant , Buadi Francis , Binder Moritz , Cook Joselle , Dispenzieri Angela , Dingli David , Fonder Amie L. , Gertz Morie A. , Gonsalves Wilson I. , Hayman Suzanne R. , Hwa Lisa , Hobbs Miriam A. , Kourelis Taxiarchis , Leung Nelson , Lin Yi , Muchtar Eli , Warsame Rahma M. , Rajkumar S. Vincent , Kumar Shaji
Published: June 2024

7558

Background: Survival in patients with multiple myeloma (MM) continues to improve with the newer therapies, but there is no clear evidence of a cure and patients continue to relapse. However, most patients have the most extended period without progression with their first-line therapy, and subsequent therapies often provide a shorter duration of response due to the use of drugs with overlapping mechanisms of action and, more importantly, a shorter first remission, pointing toward more aggressive disease biology. With newer immunotherapies being used at 1st relapse, this may change. We designed this study to explore the natural history of MM after the 1st relapse and define the predictors of outcome after the initial relapse. Methods: We identified all patients in the Mayo Clinic database diagnosed between Jan 2004-June 2019 who had had initial disease progression. The study cohort included 2005 patients. We explored the overall survival (OS) from the time of documented disease progression or the start of second-line treatment in patients who had not met IMWG criteria before second-line therapy. Front-line therapy was grouped into those with either an IMiD or PI, both IMiD and PI, daratumumab with IMiD and PI, and none of these agents. The IMiD and PI were always used with dexamethasone with or without an alkylator. Results: The median age was 63 (range 24-95) years and 60% were male. The median estimated follow-up from diagnosis for all patients was 86 mos. (95% CI; 82, 88) and the median time to progression from the start of therapy was 25 mos. (95% CI; 24, 26). The median OS from the first progression was 45 mos. (95% CI; 42, 50), 36 mos. for those diagnosed before 2009, and 52-53 mos. for those diagnosed later. On univariate analysis, age <70 at 1st relapse, RISS I, novel agents in initial therapy, CR in the first line, diagnosis after 2009, initial remission >18 mos, and initiation of therapy before IMWG progression were all associated with improved OS after 1st relapse (Table). On multivariate analysis, age <70, RISS I, initial remission >18 mos, and initiation of therapy before IMWG progression were all associated with improved OS after 1st relapse. Conclusions: The study provides an estimate of the outcomes and significant predictors of outcomes after 1st relapse in patients with MM. These factors should be taken into consideration when designing clinical trials in this patient population. In particular, these factors identify a high-risk group of patients not always identified by baseline characteristics and should be the focus of future trials. [Table: see text]