tbuckley/cabot-search huggingface dataset:
Exposure-response (ER) analyses of efficacy and safety of trastuzumab deruxtecan (T-DXd) to inform dosing recommendation in<i> HER2-</i>mutant non-small cell lung cancer (NSCLC).
Authors: Amit Khatri, Daniel Polhamus, Enoch Cobbina, Ramon Garcia, Todd Yoder, Malaz Abutarif, Tushar Garimella
Journal: Journal of Clinical Oncology (2024)

e20545 Background: T-DXd, a novel human epidermal growth factor receptor 2 (HER2) targeting antibody drug conjugate, was evaluated at doses of 5.4 and 6.4 mg/kg every three weeks in Phase 1 or 2 trials in HER2 mutant (HER2m) NSCLC subjects, including Destiny-Lung01 (DL-01) and DL-02 trials 1,2 . ER analyses of key efficacy and safety endpoints were conducted to support the dosing recommendation of T-DXd in HER2m NSCLC. Methods: Exposure-efficacy (EE) analysis was performed using confirmed objective response (cORR) data from HER2m NSCLC in Phase 1-2 trials (N = 181). The dataset included primary analysis data cut from DL-01 1 and interim analysis data cut from DL-02. Exposure-safety (ES) analyses of T-DXd were performed, using pooled data from 11 Phase 1-3 trials (N = 1850) across tumor types, including DL-01 and DL-02, for safety endpoints of adverse events (AEs) associated with dose reduction or discontinuation, Grade3+ (G3+) AEs, serious AEs, G3+Anemia, G3+neutropenia, G3+thrombocytopenia, adjudicated any grade interstitial lung disease (ILD), and G3+ ILD. cORR and all safety endpoints, except ILD were analyzed by logistic regression; any grade ILD was analyzed by parametric time-to-event analysis. The T-DXd or DXd exposure metric and numerous patient-specific covariates were tested in the analysis. Results: T-DXd exposure had a positive but shallow relationship with cORR. The predicted cORR varied from 57% (95% credible interval (CrI): [36, 77]) to 65% (95% CrI: [41, 84]) across 5 th and 95 th percentile of T-DXd exposure respectively. No clinically meaningful difference in cORR was estimated across 5.4 and 6.4 mg/kg doses with predicted cORR values of 53% (95% CrI: [44, 60]) and 55% (95% CrI: [47, 62]) at T-DXd doses of 5.4 mg/kg and 6.4 mg/kg, respectively. ES relationships were consistent with previous T-DXd ES analyses in breast cancer (BC). Model-predicted AE rates were lower (up to 9%) in 5.4 mg/kg compared to the 6.4 mg/kg dose. Model-predicted safety at 5.4 mg/kg dose in HER2m NSCLC was similar to the approved dose of 5.4 mg/kg in BC. Conclusions: The ER analyses showed no clinically meaningful difference in efficacy between 5.4 and 6.4 mg/kg doses of T-DXd; and safety events were lower in 5.4 mg/kg, thus supporting the 5.4 mg/kg recommended dose for HER2m NSCLC. These findings were later confirmed based on primary analysis in DL-02 2 and support the utility of ER analyses in dosing recommendation. Reference: Li BT et al. N Engl J Med 2022;386:241-51 Goto K et al. J Clin Oncol 41:4852-4863. Clinical trial information: NCT03505710 , NCT04644237 .
Role of celecoxib in reducing cognitive impairment in patients receiving definitive chemoradiation for head and neck carcinoma: A phase II randomized placebo controlled trial (CELCI-HN study).
Authors: Aparna Sharma, ATUL SHARMA, Alok Thakar, Suman Bhasker, Kapil Sikka, Amit Chirom Singh, Rajeev Kumar, Raja Pramanik, Vaibhav Patil, akash kumar, Babita Kataria, Abhinav Singhal, Smriti Panda, Aman Sharma, Yousra Izzuddeen, Chethan R
Journal: Journal of Clinical Oncology (2024)

TPS12150 Background: Head and neck squamous cell carcinoma (HNSCC) is common in the Indian subcontinent and majority (65%) patients present in an advanced stage. Chemotherapy related cognitive impairment (CRCI) is a poorly defined and underestimated phenomenon in the HNSCC population. Through this study, we are attempting to establish evidence of activity of agents targeting neuro-inflammation in reducing or halting cognitive decline associated with definitive chemoradiotherapy for head and neck malignancies without adding to treatment-associated toxicity. This study can potentially aid in developing a cost effective approach with a readily available and cheap agent like celecoxib in improving the quality of life in this cohort of patients. Methods: This is a single center, double blinded placebo controlled phase 2 randomized trial. We intend to randomize 92 non metastatic HNSCC patients registered at a large tertiary cancer center of North India {Department of Medical Oncology (Head and Neck Cancer Clinic, All India Institute of Medical Sciences-National Cancer Institute, India)} planned for definitive chemoradiation (CTRT) with or without induction chemotherapy. Patients in the experimental arm will receive celecoxib 100 mg or matched placebo tablet orally twice a day starting with day 1 of initiation of definitive chemoradiotherapy/induction chemotherapy for a duration of 6 months or until unacceptable toxicity. Our primary objective is to determine the activity of celecoxib versus placebo in reducing cognitive decline in patients undergoing definitive CTRT with or without induction chemotherapy in HNSCC through patient reported outcome tools (FACT cog questionnaire). Secondary objectives include assessment of adverse event profile (measured using CTCAE v5.0), objective assessment of neurocognitive decline using neuropsychological battery of tests, to identify predictors of cognitive decline on the basis of site of malignancy, radiation dose to the base of skull and brainstem, age, comorbidities and educational status. Tertiary objective include evaluation of inflammatory biomarkers e.g serum COX-2, serum Interleukin and tumor necrosis factors-alpha levels at the end of therapy and on follow up. Clinical trial information: CTRI/2022/09/045579.
Guard 01: A randomized, multicentre, controlled trail on the prophylactic use of efbemalenograstim alfa for concurrent chemo-radiotherapy induced neutropenia.
Authors: Yuanyuan Chen, QiWen Li, Chunyan Chen, Yi Ouyang, Ming Chen
Journal: Journal of Clinical Oncology (2024)

TPS12155 Background: Concurrent chemo-radiotherapy plays a crucial role in the treatment of various advanced-stage malignant tumors. However, it is often associated with significant hematologic toxicity, especially leukopenia and neutropenia, which may lead to treatment interruptions, reduced efficacy, and even severe infections. Efbemalenograstim alfa is a novel long-acting recombinant human granulocyte colony stimulating factor (rhG-CSF) combined of an immunoglobulin (Ig) G2-Fc fragment and two rhG-CSF molecules. Although efbemalenograstim alfa has been confirmed to be effective in the prevention of chemotherapy induced neutropenia by a number of clinical studies, its prophylactic efficacy during concurrent chemo-radiotherapy was seldom investigated. Guard-01 is aimed to evaluate the effectiveness and safety of primary preventive use of efbemalenograstim alfa in concurrent chemo-radiotherapy. Methods: This study is a multicenter, open-label, randomized, controlled clinical trial involving 120 patients who are planned to receive definitive concurrent chemo-radiotherapy with non-small cell lung cancer, small cell lung cancer, esophageal cancer, nasopharyngeal carcinoma, head and neck squamous cell carcinoma, or cervical cancer. Patients will be randomized into efbemalenograstim alfa arm or control arm in a 1:1 ratio on the first day of the first concurrent chemo-radiotherapy cycle. The stratification factor is chemotherapy regimen of the patients. Approximately 48 (±4) hours after the completion of each chemotherapy cycle, patients in the efbemalenograstim alfa arm will receive efbemalenograstim alfa (20 mg per dose, subcutaneous injection) for prevention. Patients in the control arm will receive rhG-CSF (5 μg/kg/day) when the absolute neutrophil count (ANC) is less than 1.0×10 9 /L, and treatment will be discontinued when ANC reaches ≥5×10 9 /L. The primary endpoint is the incidence of grade ≥3 neutropenia (ANC&lt;1.0×10 9 /L) during concurrent chemo-radiotherapy. The trial is opened in November 2023 and will be conducted in 8 hospitals with the aim of recruiting 120 evaluable patients (4 patients are recruited untilled 29-Jan-2024). Clinical trial information: ChiCTR2300077504.
Association between clinical and disease characteristics and detectable or undetectable baseline ctDNA in patients with metastatic uveal melanoma.
Authors: Paul D. Nathan, Laura Collins, Richard D. Carvajal, Piruntha Thiyagarajah, Ryan J. Sullivan, Joseph J Sacco
Journal: Journal of Clinical Oncology (2024)

9537 Background: Tebentafusp, a bispecific soluble TCR specific for a gp100 peptide, is licensed for the treatment of metastatic uveal melanoma (mUM) in HLA-A*02:01+ individuals. 82% of patients (pts) with mUM in the IMCgp100-102 (previously treated; 2L+) and 61% in IMCgp100-202 (frontline; 1L) studies, respectively, had detectable baseline ctDNA. There is a strong relationship between decrease in ctDNA by 9 weeks and overall survival (OS) [Carvajal 2022; Hassel &amp; Piperno-Neumann 2023]. Patients with undetectable baseline ctDNA had improved survival despite having macroscopic disease. In this study, we report the characteristics of baseline ctDNA undetectable vs detectable disease. Methods: Disease characteristics of 202 1L (Study 202) and 117 2L+ (Study 102) pts who had baseline undetectable or detectable ctDNA (unDNA vs detDNA) were compared in a post-hoc unplanned analysis. ctDNA detection was analysed at baseline and up to week 9 on tebentafusp using targeted mPCR-NGS assay for mutations in 15 genes including GNAQ, GNA11, SF3B1, CYSLTR2, PLCB4 and EIF1AX. Largest lesion size groups (≤ 3 cm, 3-8 cm, &gt; 8 cm) were defined by American Joint Committee on Cancer 7 th Ed. Presence of oncogenic mutations in GNAQ, GNA11, SF3B1 and BAP1 were assessed by WES on metastatic tissue biopsies. Results: Baseline ctDNA levels increased in association with size of largest lesion regardless of number of prior therapies. However, there was an association between disease burden (defined by largest lesion size) and unDNA vs detDNA in both studies, with all pts with largest liver lesion &gt; 8 cm having detDNA. In Study 202, % of the population with unDNA vs detDNA was 50% vs 50% for ≤ 3cm and 27% vs 73% for 3.1-8 cm. While OS was similar for unDNA &amp; detDNA in pts with ≤ 3cm lesions, OS was longer for pts with unDNA vs detDNA who had baseline tumor size 3.1-8 cm in both studies (Table). Within this 3.1-8 cm group, pts with unDNA tended to have lower LDH, AST, and ALP. Initial analysis showed no difference in the frequency of GNAQ, GNA11, SF3B1 or BAP1 mutations between unDNA and detDNA groups. Further data on somatic mutation defined groups and RNAseq gene expression in unDNA and detDNA groups will be presented. Conclusions: Patients with unDNA were more likely to have smaller disease burden than those with detDNA; however, many pts with unDNA had a significant burden of metastatic disease. Baseline unDNA was associated with improved OS outcome vs detDNA in pts with 3.1-8 cm baseline metastatic deposits, but not in pts with ≤ 3cm disease. No association was seen between oncogenic background of GNAQ/GNA11/SF3B1/BAP1 and unDNA vs detDNA. Clinical trial information: NCT02570308 ; NCT03070392 . [Table: see text]
Safety and efficacy of PEG-rhG-CSF as primary prophylaxis against neutropenia induced by combination chemotherapy regimens involving oral chemotherapy agents in gastrointestinal cancer patients: A prospective, exploratory, non-randomized controlled study.
Authors: Jun Zhao, Hui Wang, Gehong Zhang, Xiaoling Zhang, Yunyi Du, Ning Ma, Wei Yang, Bo Yang, Yangjun Gao, Mei Wang, Linlin Cai, Tingting Feng, Na Zhang, Suxia Yang, Xiaobo Guo, Ouxiang Wang
Journal: Journal of Clinical Oncology (2024)

e24107 Background: The safety and efficacy of PEGylated recombinant human granulocyte colony-stimulating factor (PEG-rhG-CSF) for prevention of chemotherapy-induced neutropenia (CIN) in patients undergoing oral chemotherapy remain unclear. This study investigated the safety and efficacy of PEG-rhG-CSF as primary prophylaxis against CIN in gastrointestinal (GI) cancer patients receiving combination chemotherapy regimens involving oral chemotherapy agents. Methods: This is a prospective, single-center, open-label, exploratory, non-randomized controlled study. GI cancer patients receiving two consecutive cycles of IV oxaliplatin (150mg/m 2 on day 1) combined with oral capecitabine 1000mg/m 2 or tegafur gimeracil oteracil potassium capsule 40-60mg twice daily on days 1-14 every 3 weeks. PEG-rhG-CSF (6mg) was administered subcutaneously 24 hours post-oxaliplatin treatment in the PEG-rhG-CSF group, while the control group did not receive it. The primary endpoint was safety, and secondary endpoints included CIN incidence and neutropenic complications. The study was registered with the Chinese Clinical Trial Registry (registration number ChiCTR2100054854). Results: Between March 2022 and January 2023, a total of 49 patients was screened, and 43 patients completed the treatment (26 in PEG-rhG-CSF group and 17 in control group). The average age was 61.4 years, with 90.7% males and 83.7% having gastric cancer. Baseline characteristics were similar between the two groups. The overall adverse events (AE) did not differ statistically (88.5% vs. 88.2%, p = 1.000), with grade £2 fatigue and nausea being the most common AEs. Grade 3 platelet reduction showed no significant difference between the two groups (7.69% vs. 17.65%, p = 0.432). Four cases of bone pain (15.4%) and five cases of injection site reactions below grade 3 (19.2%) were observed in the PEG-rhG-CSF group. Grade ≥2 CIN was significantly lower in the PEG-rhG-CSF group (3.84% vs. 58.82%, p &lt; 0.001). One case in the PEG-rhG-CSF group required antibiotic treatment due to febrile neutropenia. Regarding neutropenic complications, the PEG-rhG-CSF group exhibited lower proportion of chemotherapy delay (3.85% vs. 35.29%, p &lt; 0.001) and dose reduction (1.92% vs. 23.53%, p = 0.002). Rescue treatment with rhG-CSF for grade 3/4 CIN was significantly less frequent in the PEG-rhG-CSF group (1.92% vs. 23.53%, p = 0.002). Conclusions: Primary prophylaxis with PEG-rhG-CSF in GI cancer patients undergoing oral capecitabine/tegafur gimeracil oteracil potassium may be safe, without an increased chemotherapy-related AEs, and is associated with a reduced grade ≥2 CIN. Clinical trial information: ChiCTR2100054854.
First-line of penpulimab and chemotherapy for advanced non-melanoma cutaneous carcinoma: A single center, single arm, exploratory study.
Authors: Jing Xu, Dongyuan Zhu, Zengjun Liu, Jinfang Cui, Mengyao Liu, Wenyu Hu, Ni Xu, Minghuan Li, Heng Fu, Junkai Zhao
Journal: Journal of Clinical Oncology (2024)

e21510 Background: Non-melanoma cutaneous carcinoma is a rare subtype malignancy including basal cell carcinoma, squamous cell carcinoma and appendage carcinoma. This study aims to explore the efficacy and safety of penpulimab combined with chemotherapy in advanced non-melanoma cutaneous carcinoma. Methods: Patients were eligible if they were aged 18 through 80 years; had histologically confirmed basal cell carcinoma, squamous cell carcinoma and appendage carcinoma with TNM clinical stage IIIB-IV; had received no previous systemic therapy. Penpulimab (200mg, every 21 days) was given on day 1 until disease progression, unacceptable toxic effects, withdrawal of consent, death, or initiation of new antitumor therapy, whichever occurred first. Fluorouracil (2.5g/m 2 ) and cisplatin or nedaplatin (75mg/m 2 ) were given for 6 cycles. The primary endpoint was objective response rate (ORR) defined by the RECIST v1.1 guideline, and the secondary endpoints included disease control rate (DCR), progression free survival (PFS), overall survival (OS) and adverse effects (AEs). Results: 15 patients were enrolled from June 3, 2021, through December 24, 2023. The median age was 66 years (range, 42-78 years). 13 patients were males (86.7%) and 2 were females (13.3%). There were 7 cases of appendage carcinoma (46.7%), 6 cases of squamous cell carcinoma (40%), and 2 cases of basal cell carcinoma (13.3%). Among them, there were 4 cases of stage IIIB (26.7%) and 11 cases of stage IV (73.3%). Among the 15 patients, 12 underwent efficacy evaluation, including 4 partial response (PR), 5 stable disease (SD), and 4 progression disease (PD). The objective response rate was 33.3%, and the disease control rate was 66.7%. There was 8 patients experienced disease progression, with a median progression free survival of 3.83 (range,1.5-18.7) months. 4 patients died, and the median overall survival has not yet been reached. AEs related to any component of the trial regimen occurred in 13 (86.7%) patients, the most frequent AEs were grade 1-2. The most common AEs included nausea/vomiting (86.7%), fever (26.7%), thrombocytopenia (26.7%), leukopenia (26.7%), anemia (20%), hypothyroidism (13.3%), hypokalemia (6.7%), rash (6.7%). Only two patients (13.3%) refused therapy because of experiencing unacceptable nausea/vomiting. Conclusions: Penpulimab combined with chemotherapy achieved high response rate and disease control rate in the treatment of newly diagnosed advanced non-melanoma cutaneous carcinoma, with good safety, and may become a new treatment option. Disclosure: All authors have declared no conflicts of interest. Clinical trial information: ChiCTR2200063777.
Prevention of pemetrexed-induced rash with low-dose dexamethasone in patients with NSCLC receiving immunotherapy: A prospective, single-arm clinical trial.
Authors: Jing Zhang, Xue Zhou, Yuming Jia, Shenglan Huang, Qiu Wang, Mao-Qiong Jiang, Ting Li, Jian Jiang, Zhong Liqiang, Xujuan Ye, Kaijian Lei
Journal: Journal of Clinical Oncology (2024)

e20596 Background: Pemetrexed is highly active in non-small cell lung cancer (NSCLC). Rashes associated with pemetrexed are more commonly than other chemotherapies. It is recommended that patients receive pemetrexed are required dexamethasone as a pretreatment. However, the immunosuppressive effects of dexamethasone especially high doses of glucocorticoids may reduce the efficacy of immune checkpoint inhibitors (ICIs). This study aims to prospectively evaluate the efficacy of low-dose dexamethasone in pretreatment of pemetrexed-induced rash, particularly in NSCLC patients receiving immunotherapy. Methods: This is a prospective, single-arm clinical trial that enrolled NSCLC patients scheduled to receive chemotherapy including pemetrexed, with/without immunotherapy. Patients received low-dose dexamethasone: 8mg, 4mg, 2 mg of dexamethasone for 3 days recpectively from the day preceding pemetrexed (the recommended administration is 8 mg/day of dexamethasone for 3 days) . Rash severity is described according to CTCAE v5.0 (Common toxicity criteria for adverse events version 5.0). The primary endpoint was the 3-week incidence of rash after pemetrexed. Results: A total of forty-seven stage IIB-IVB patients were enrolled between February 2022 and December 2023, including eighteen patients were combined with immunotherapy. They all received the low-dose dexamethasone regimen prior to a total of 149 cycles of chemotherapy. The incidence of skin rash after 3 weeks was of 7 episodes in 149 cycles (4.70%), 7 patients (12.77%) presented rash. In the eighteen patients receiving immunotherapy, rash within 3 weeks after pemetrexed administration occurred in 4 episodes in 72 cycles (5.56%), 4 patients ( 22.22%) presented rash. And one patient presented two episodes of cutaneous toxicity. Most skin rash episodes were of grade 1 (approximately 85%), while the rest were grade 2 (approximately 15%). No grade 3 or 4 skin rash was reported in the entire study population. Most cutaneous toxicities occurred during the first or second cycle. The incidence of rash in this study was significantly lower than the rate of 67.5-93% reported in patients treated without corticosteroids and did not increase compared with the rate of 14-56% reported in patients treated with corticosteroids. Conclusions: Administration of low-dose dexamethasone (8mg, 4mg, 2 mg of dexamethasone for 3 days from the day preceding pemetrexed) significantly reduces the incidence of rash after pemetrexed. The regimen may provide a standard preventive strategy for pemetrexed-induced rash, especially in NSCLC patients combined with immunotherapy(This study is registered with the Chinese Clinical Trial Registry (ChiCTR2400079622). Clinical trial information: ChiCTR2400079622.
Preliminary results from a multi-center phase Ib/II study of RC48-ADC combined with tislelizumab as neoadjuvant treatment in patients with HER2 positive locally advanced muscle-invasive urothelial bladder cancer (Hope-03).
Authors: Feng Wen, Ping Tan, Tianhai Lin, Peng Zhang, Yali Shen
Journal: Journal of Clinical Oncology (2024)

e16595 Background: To evaluate the safety and efficacy of RC48-ADC, a humanized anti-HER2 antibody conjugated with monomethyl auristatin E, and tislelizumab, a PD-1 antibody, as a novel neoadjuvant treatment combination in patients with HER2 positive locally advanced muscle-invasive bladder cancer (MIBC). The study design has been presented at 2022 ESMO Asia meeting. The preliminary results would be reported this time. Methods: This is a Ib/II, multi-center, open-label, single-arm study (ChiECRCT20210564). 51 patients with pathological and imaging diagnosed cT2-4bN0-3M0-1a HER2 positive MIBC will be included. RC48-ADC is given every 2 weeks with a maximum dose of 120mg intravenously, and tislelizumab is given every three weeks at the dose of 200mg intravenously. Treatment efficacy will be performed by imaging and transurethral resection of tumors after the neoadjuvant treatment. Patients without disease progression will receive radical cystectomy or bladder-sparing therapies based on individual risk profiles and preferences. The primary endpoints are clinical complete remission rate (cCR, T0/Ta/Tis), pathological complete remission rate (pCR) and safety. The secondary endpoints are disease control rate (DCR), overall survival (OS), local recurrence free survival (LRFS), distant metastasis free survival (DMFS) and quality of life. Results: Until now, 18 patients were included successfully, with 3 female patients and 15 male patients. And the median age was 64.47 years old. Of them, 7 patients were HER2(2+), and 11 patients were HER2(3+). The clinical stages were T2-4aN0-3M1a. Sixteen patients had the primary efficacy evaluation by now. After the neoadjuvant treatment, 7 patients were T0, 4 patients Tis, 2 patients partial response (PR), 2 patients stable disease (SD) and 1 patient suffered from progress of local disease. Hence the cCR rate was 68.75%, and the DCR was 90.91%. Fourteen patients chose radiotherapy as bladder-sparing therapy and no evidence of tumor in 6 patients who received treatment efficacy after radiotherapy. Two patients received radical cystectomy and pT3N0M0 was achieved for both. No patient died so far. For safety analysis, 4 patients suffered from immune-related adverse event, namely, grade 2 myositis, grade 1 elevated transaminase and grade 1 hyperthyroidism which led to treatment interruption of tislelizumab. And 10 patients experienced RC48-ADC related toxicities, including grade 1 elevated transaminase, grade 1 erythra and grade 1 paresthesia. No treatment related dose reduction happened. Conclusions: The novel neoadjuvant combination of RC48-ADC and tislelizumab showed promising down stage efficacy in patients with HER2 positive locally advanced MIBC and the toxicities were manageable, which would be verified by the final analysis. Clinical trial information: ChiECRCT20210564.