tbuckley/cabot-search huggingface dataset:
Association between achieving adequate antenatal care and health-seeking behaviors: A study of Demographic and Health Surveys in 47 low- and middle-income countries
Authors: Boshen Jiao, Isabelle Iversen, Ryoko Sato, Clint Pecenka, Sadaf Khan, Ranju Baral, Margaret E. Kruk, Catherine Arsenault, Stéphane Verguet
Journal: PLoS Medicine (2024)

Background Antenatal care (ANC) is essential for ensuring the well-being of pregnant women and their fetuses. This study models the association between achieving adequate ANC and various health and health-seeking indicators across wealth quintiles in low- and middle-income countries (LMICs). Methods and findings We analyzed data from 638,265 women across 47 LMICs using available Demographic and Health Surveys from 2010 to 2022. Via multilevel logistic regression analyses adjusted for a series of confounding variables and country and wealth quintile fixed effects, we estimated the projected impact of achieving adequate ANC utilization and quality on a series of health and health care indicators: facility birth, postnatal care, childhood immunizations, and childhood stunting and wasting. Achieving adequate levels of ANC utilization and quality (defined as at least 4 visits, blood pressure monitoring, and blood and urine testing) was positively associated with health-seeking behavior across the majority of countries. The strongest association was observed for facility birth, followed by postnatal care and child immunization. The strength of the associations varied across countries and wealth quintiles, with more significant ones observed in countries with lower baseline ANC utilization levels and among the lower wealth quintiles. The associations of ANC with childhood stunting and wasting were notably less statistically significant compared to other indicators. Despite rigorous adjustments for potential confounders, a limitation to the methodology is that it is possible that unobserved variables may still impact outcomes. Conclusions Strengthening ANC is associated with improved use of other health care in LMICs. ANC could serve as a critical platform for improving health outcomes for mothers and their children, emphasizing its importance beyond direct impact on maternal and neonatal mortality.
An open-label, multicenter phase 1 study to characterize safety, tolerability, preliminary antitumor activity, and pharmacokinetics of VIP236 monotherapy in patients with advanced cancer.
Authors: Andrae L. Vandross, Brian N. Stein, Jermaine Coward, Sunil Sharma, Amy J. Johnson, Joseph Birkett, Xin Huang, Melanie M. Frigault, Hans-georg Lerchen, Beatrix Stelte-Ludwig, Tasheda Navarro, Jim Peck, Wyatt Gross, Raquel Izumi, Ahmed M. Hamdy, Ildefonso Rodriguez Rivera
Journal: Journal of Clinical Oncology (2024)

TPS3168 Background: VIP236, a first-in-class SMDC, consists of an αvβ3 integrin small molecule binder, a peptide linker cleaved by neutrophil elastase (NE) in the tumor microenvironment (TME), and a camptothecin (CPT) payload VIP126 which was optimized for high permeability and low efflux. The overall drug design strategy for VIP236 is targeted delivery to the TME and tumors expressing α V β 3 integrin on their cell surface with release of the optimized CPT derivative by NE also present in the TME. VIP126, when delivered as a component of VIP236, is anticipated to kill tumor cells while reducing effects to normal tissue. VIP236 exhibits convincing single agent in vivo antitumor efficacy and acceptable tolerability in multiple human tumor cell line- and patient- derived xenograft models in mice, including breast, colorectal, small cell lung, gastric, metastatic breast and metastatic colon cancer. In three gastric cancer xenograft models, VIP236 caused statistically significant tumor growth inhibition across the models independent of HER2 status. VIP236 outperformed an anti-HER2 ADC, trastuzumab deruxtecan, in all three models. Methods: This trial in progress is an open-label, global, multicenter Phase 1 study to characterize safety, tolerability, preliminary antitumor activity and pharmacokinetics of VIP236 monotherapy in subjects with advanced cancer. Enrollment includes all comer patients with histologically confirmed advanced or metastatic solid tumors that are relapsed or refractory to standard of care. Subjects must have exhausted all available standard therapies or be deemed ineligible for potential available therapies. Frequency, severity, and relationship to study drug of any treatment-emergent adverse events or abnormalities of laboratory tests will be studied. Tumor response will be assessed using RECIST 1.1 criteria. The following dose schedules are being evaluated: 1) Cohorts 1, 2a, and 3a: A cycle is 21 days 1-hour intravenous (IV) infusions on a 2 days on/5 days off schedule with no pause between cycles. 2) Cohorts 2b, 3b, 4b, 5b, 6b, 7b, and 8b: A cycle is 21 days of VIP236 given as a 1-hour IV infusion once every three weeks (Q3W) with no pause between cycles. 3) Cohorts 1, 2a, 3a, 2b, 3b and 4b have been completed. Enrollment continues in the Q3W cohorts. Clinical trial information: NTC05371054.
The design, preclinical study and phase I dose escalation plan of a HER2 targeted immunoliposome (HF-K1) for HER2 low solid tumor treatment.
Authors: Shanshan Jin, Xiaochen Zhang, Yunlu Jia, Yongchao Dai, Fengwei Xu, Yongfeng Huang, Xun Wang, Hailong Wu, Yu Shao, Jinfeng Long, Anjie Zheng, Yuhong Xu
Journal: Journal of Clinical Oncology (2024)

3035 Background: Doxorubicin liposome formulations are being used extensively in the clinic in anthracycline chemotherapy with reduced cardiotoxicity. However, they did not improve clinical outcome because the cancer cell uptake of PEG-coated liposomes is poor. So, the concept of coating antibodies on the liposome surface was initiated and they were named immunoliposomes. There have been numerous studies conducted world-wide for the development of immunoliposomes but none have progressed to late-stage development. Our work draws on the experiences of these prior studies with a new perspective. Since the mechanism of immunoliposomes is similar to those of ADCs, we sought to compare immunoliposomes with ADCs containing the same cancer cell binding domain, for target cell binding capability, binding affinity as well as in vivo distribution, tumor tissue accumulation, and anti-tumor activities. The lessons learned from the success of many ADC products may be applicable to the development of immunoliposomes. Methods: The antibody to liposome ratio (ALR) and the drug to lipid ratio (DLR) of the immunoliposomes were selected by in vitro and in vivo anti-cancer activity screening. Cell lines with different HER2 expression levels were used to study immunoliposome binding, cell uptake, drug delivery and cytotoxicity. PK, drug distribution, efficacy and toxicities studies were conducted in respective CDX and PDX mice and non-rodent models. Based on these studies, a phase I dose escalation study plan was designed and the study is now ongoing. Results: HF-K1 was designed to have an average of 10 anti-HER2 Fab on each liposome surface and approximately 2300 doxorubicin molecules inside. The equivalent drug to antibody ratio (DAR) is 230. HF-K1 can bind to cancer cells with different levels of HER2 expression with similar kinetics and induces cells death at IC50s of 0.35-6.46 μg/ml Fab concentration. It has a long circulation behavior and enhanced permeability and retention (EPR) in tumor tissues. The clearance T1/2 of HF-K1 in mice and monkey is 12.78 h and 47.12 h, respectively. Evaluation of HF-K1 activity in vivo showed significant tumor growth inhibition &gt;95% at the equivalent antibody dose of 3.6 mg/kg in various mouse tumor models including HER2 low and HER2 very low (HER2-). Similar activities were shown by ADCs including T-DM1 and DS-8201a at about 10 mg/kg. Conclusions: The encouraging preclinical data supported a clinical trial starting with dose escalation at equivalent antibody doses of 0.72 mg/m2, 2.16 mg/m2, 5.4 mg/m2, 10.8 mg/m2, 16.2 mg/m2, and 21.6 mg/m2. The study is ongoing to determine the safety, tolerability, PK, and preliminary antitumor efficacy in participants with HER2 positive or HER2 low expression advanced solid tumors (NCT05861895). Clinical trial information: NCT05861895 .
Pooled safety analysis of sacituzumab govitecan (SG) in multiple solid tumor types.
Authors: Hope S. Rugo, Sara M. Tolaney, Aditya Bardia, Javier Cortes, Frederik Marmé, Peter Schmid, Lisa A. Carey, Sibylle Loibl, Kevin Kalinsky, Joyce O'Shaughnessy, Sara A. Hurvitz, Theresa Valdez, Ya Meng, Wendy Verret, Scott T. Tagawa
Journal: Journal of Clinical Oncology (2024)

3029 Background: SG is an antibody-drug conjugate targeted to Trop-2 that received approval for treatment of previously treated metastatic triple negative breast cancer (mTNBC) and HR+/HER2- mBC in multiple countries and accelerated approval for previously treated metastatic urothelial cancer (mUC) in the US. In multiple clinical trials, SG has demonstrated significantly improved efficacy compared to standard of care therapies and a consistent, manageable safety profile with limited treatment discontinuations from adverse events (AEs). We present an analysis of pooled safety data from patients (pts) treated with SG in clinical trials, including differences by UGT1A1 polymorphisms. Methods: Safety data for pts treated with SG (10 mg/kg, days 1 and 8 every 21-day cycle) were pooled from 4 clinical trials of multiple solid tumors, including mTNBC, HR+/HER2- mBC, and mUC: ASCENT (NCT02574455), TROPiCS-02 (NCT03901339), TROPHY-U-01 (NCT03547973), and IMMU-132-01 (NCT01631552). Treatment-emergent AEs (TEAEs) were defined as any AE that started on or after first dose date until ≤ 30 days after last dose date. Results: The pooled analysis included 1063 pts; &gt; 99% experienced any-grade TEAEs, and 76% experienced grade ≥ 3 TEAEs (Table). The most common any-grade TEAEs were nausea (64%), diarrhea (64%), neutropenia (61%), and fatigue (51%). The most common grade ≥ 3 TEAEs were neutropenia (46%), anemia (12%), leukopenia (11%), and diarrhea (11%). Febrile neutropenia occurred in 6% of pts (both any-grade and grade ≥ 3). TEAEs led to SG dose reduction in 31% and SG discontinuation in 7% of pts. The most common TEAEs that led to discontinuation were neutropenia, diarrhea, pneumonia, and fatigue (1% each). In pts with available UGT1A1 genotypes, *28/*28 was associated with a higher rate of grade ≥ 3 TEAEs and TEAEs leading to dose reduction and SG interruption compared to *1/*1 and *1/*28 (Table). Conclusions: The results of the pooled safety analysis of pts treated with SG were consistent with previous clinical trials, with neutropenia remaining the most common grade ≥ 3 TEAE. Neutropenia and diarrhea were generally manageable, and the rate of TEAEs leading to discontinuation was low. The *28/*28 UGT1A1 genotype was associated with higher rates of grade ≥ 3 TEAEs, as previously observed. This is the largest SG safety analysis published to date, providing further support for SG as a treatment with a consistent and manageable safety profile. Clinical trial information: NCT02574455 , NCT03901339 , NCT03547973 , NCT01631552 . [Table: see text]
CLAMP: A phase II prospective study of camrelizumab combined with pegaspargase, etoposide, and high-dose methotrexate in patients with natural killer (NK)/T-cell lymphoma.
Authors: Tao Liu, Qiuhui Li, Xia Mao, Haibo Zhou, Youhong Dong, Fang Zhu, Xinxiu Liu, Gang Wu, Min Xiao, Liling Zhang
Journal: Journal of Clinical Oncology (2024)

7002 Background: Immune checkpoint blockades have been investigated and show promising results in natural killer (NK)/T-cell lymphoma (NKTCL) patients. This study explored the efficacy and safety of camrelizumab, a PD-1 monoclonal antibody, combined with pegaspargase, etoposide, and high-dose methotrexate (CLAMP) in the treatment of NKTCL patients. Methods: This single-arm, phase 2 study enrolled patients with NKTCL. Patients were divided into two groups: group A, early-stage (Ann Arbor staging I/II) patients; group B, advanced-stage (Ann Arbor staging III/IV) and RR patients. Group A received involved-field radiotherapy combined with 3-4 cycles of CLAMP treatment. Group B received 6 cycles of CLAMP treatment. CLAMP regimen was administrated as follows: pegaspargase 2500 U/m 2 d1, etoposide 100 mg/m 2 per day d1-3, HD-MTX 3 g/m 2 d4, camrelizumab 200 mg d7. Results: A total of 41 patients, including 36 newly diagnosed and 5 relapsed NKTCL, were enrolled in this study from July 2020 to December 2022. 14 patients presented with high-risk central nervous system (CNS) infiltration with 2-4 risk factors of the NKPI (Ann Arbor stage III or IV, presence of B symptoms, regional lymph node involvement, elevated lactate dehydrogenase). One patient had complied hemophagocytic lymphohistiocytosis (HLH). On treatment completion, the overall cohort showed a complete remission (CR) rate of 87.80% (36/41) and a partial remission (PR) rate of 7.32% (3/41), giving an overall response rate (ORR) of 95.12% (39/41). The ORR for group A patients was 100% (19/19) and 90.91% (20/22) for group B patients; only 2 patients in group B progressed during the treatment. The patient with HLH obtained CR and was disease-free for more than 12 months. No patients developed HLH or CNS involvement during the follow-up period. At a median follow-up of 21 months, 5 patients (12.20%) died; among them, 3 patients died of disease progression, and 2 patients died of infection unrelated to treatment. The 2-year progression-free survival (PFS) and 2-year overall survival (OS) rates for the whole cohort were 72.81% and 88.03%, respectively. The 2-year PFS rates for group A and group B were 91.67% and 53.83%, respectively. The 2-year OS rates for group A and group B were 91.67% and 77.53%, respectively. Hematologic toxicity was common, yet nonhematologic toxicity was mild and could be well controlled by supportive treatments, except 2 patients had delayed methotrexate metabolism and received dialysis. No treatment-related death was observed. Conclusions: The CLAMP regimen is effective and safe and seems to reduce the incidence of CNS involvement and HLH. The CLAMP regimen may be a promising option in the treatment of NKTCL lymphoma. Clinical trial information: ChiCTR2100051208.
Mefatinib as first-line treatment of EGFR sensitizing mutation-positive non-small-cell lung cancer: A phase III efficacy and biomarker study.
Authors: Jia Yu, Caicun Zhou, Wang Kai, Qiming Wang, Hongrui Niu, Cheng-Zhi Zhou, Panwen Tian, Wu Zhuang, Jie Li, Jing Wang, Xu Sun, Bing Yu, Chaonan Zhu, Jianghua Chen, June Xu
Journal: Journal of Clinical Oncology (2024)

8546 Background: Mefatinib is an irreversible and highly effective EGFR and HER2 dual inhibitor. Although EGFR tyrosine kinase inhibitors are standard 1 st line therapy for EGFR mutated non-small cell lung cancer (NSCLC), co-mutations, such as TP53 are associated with shorter PFS of EGFR TKI. Methods: Patients newly diagnosed with EGFR exon 19 deletion (19 del) or exon 21 L858R mutant (L858R), stage IIIB/IV NSCLC were enrolled and randomized at 2:1 ratio to receive mefatinib 60 mg PO QD or gefitinib 250 mg PO QD; The primary endpoint of the study was progression-free survival (PFS) per independent review committee (IRC). Archival tumor samples were analyzed using a 150 genes next-generation sequencing panel for biomarker analysis. Results: 336 eligible patients were assigned to receive mefatinib (n = 223) or gefitinib (n = 113). The median PFS of mefatinib was longer than gefitinib (13.73 vs. 9.66 months, hazard ratio [HR] = 0.68, P= 0.0024) and even longer in L858R subgroup (13.73 vs. 8.28 months, HR = 0.55). The data on overall survival (OS) were immature at the cut-off date ( &lt; 40% events). 288 patients (189 in mefatinib and 99 in gefitinib) had available tumor samples for exploratory biomarker analysis. TP53 mutations were the most common disruptive concurrent alterations (45%). In patients with co-occurring disruptive mutations, mefatinib showed significant improvement in PFS compared to gefininib (12.55 vs 9.56 months, HR = 0.56, P= 0.0005; 12.55 vs 12.39 months, HR = 0.65, P= 0.0753 in 19del; and 13.70 vs 8.28 months, HR = 0.44, P= 0.0004 in L858R); Similarly, OS benefit of mefatinib was observed compared to gefitinib (not reached vs 26.68 months, HR = 0.54, P= 0.0045; not reached vs not reached, HR = 0.75, P= 0.4121 in 19del; and not reached vs 20.01 months, HR = 0.40, P= 0.0006 in L858R). Mefatinib had a favorable safety profile, with only 5.8% of patients experiencing dose reduction and less than 5% discontinuing treatment. Conclusions: Mefatinib is a new frontline option for EGFRmutant NSCLC. Co-occurring disruptive mutations caused decreased therapeutic efficacy of gefitinib, but had minimal impact on the PFS and OS of mefatinib. Comparing to gefitinib, PFS and OS improvements of mefatinib were most pronounced in patients with EGFR L858R mutation, especially those with disruptive co-occurring mutations. EGFR 19del or L858R mutation alone may not be sufficient to inform optimized front line therapies. Further studies are warranted to verify functional concurrent mutations for a better individualized precision medicine. Clinical trial information: CTR20192297.
Comparison of ICI plus chemotherapy or ipilimumab plus nivolumab based therapy for patients with NSCLC with TPS (1-49%): TOPGAN2023-01.
Authors: Takehiro Tozuka, Hisashi Tanaka, Tomonori Makiguchi, Yosuke Kawashima, Tomohiro Oba, Ryosuke Tsugitomi, Junji Koyama, Yuichi Tambo, Shinsuke Ogusu, Masafumi Saiki, Hiroshi Gyotoku, Tsukasa Hasegawa, Eisaku Miyauchi, Tomoaki Sonoda, Ryota Saito, Katsumi Nakatomi, Toshio Sakatani, Keita Kudo, Yuko Tsuchiya-Kawano, Makoto Nishio
Journal: Journal of Clinical Oncology (2024)

8550 Background: Nowadays,immune checkpoint inhibitor (ICI) plus chemotherapy is a standard treatment for non-small cell lung cancer (NSCLC) without targetable oncogene alternations. Recently, ipilimumab plus nivolumab-based therapies (CM227 or CM9LA) are also used as standard treatments for NSCLC. Whether ICI plus chemotherapy (ICI-chemo) or ipilimumab plus nivolumab-based therapy (I-N) is better for patients with NSCLC with PD-L1 tumor proportion score (TPS) 1-49% has not been investigated. Here, we report the results of real-world data in NSCLC patients with PD-L1 TPS 1-49%. Methods: We conducted a multicenter (19 centers in Japan) retrospective cohort study. NSCLC patients with PD-L1 TPS 1-49% who received ICI-chemo or I-N as first-line systemic therapy between January 2018 and March 2022 were eligible. Patients with major epidermal growth factor receptor mutations or anaplastic lymphoma kinase rearrangements were excluded. Results: A total of 401 patients were enrolled: median (range) age 69 (35-90) years; 322 (80.3%) male; ECOG PS 0-1, 372 (92.7%); PS ≥2, 29 (7.3%); 233 (58.1%) adenocarcinoma; PD-L1 TPS 1-24%, 312 (77.8%); 25-49%, 82 (20.4%); 1-49% (details are unknown), 7 (1.8%); ICI-chemo 308 (76.8%); I-N, 93 (23.2%). The median overall survival (OS) was 21.0 months (95%CI, 16.7–27.5) in the ICI-chemo group and 20.0 months (95%CI, 15.1–not reached) in the I-N therapy group, respectively. After propensity score matching, there were no differences in OS and progression-free survival (PFS) between ICI-chemo group (n=92) and I-N group (n=92) (OS: HR, 0.83; 95% CI, 0.54-1.26; p=0.38, PFS: HR, 0.72; 95% CI, 0.52-1.00; p=0.05). Among patients with PD-L1 TPS 25-49%, there was a tendency for better OS in the ICI-chemo group (OS: HR, 0.30; 95% CI, 0.09–0.85, p=0.02). In contrast, among PD-L1 TPS 1-24%, significant difference in OS was not observed. Regarding safety, treatment discontinuation due to adverse events was observed 26.2% in the ICI-chemo group and 41.9% in the I-N group. Treatment related death was seen in 4.5% of the ICI-chemo group and in 3.2% of the I-N group. Pneumonitis was seen in 13.9% of the ICI-chemo group and in 17.6% of the N-I group. Conclusions: In real-world data for NSCLC with PD-L1 TPS 1-49%, there were no significant differences in both OS and PFS between ICI-chemo group and I-N group. Toxicity discontinuation rate was higher in I-N group. Based on the subgroup-analysis results, ICI-chemo might be better for NSCLC with PD-L1 TPS 25-49%. Clinical trial information: UMIN000016441.
Long-term efficacy and safety of larotrectinib in patients with TRK fusion lung cancer.
Authors: Alexander E. Drilon, Shivaani Kummar, Jessica Jiyeong Lin, Daniel Shao-Weng Tan, Victor Moreno, Serge Leyvraz, Biswajit Dubashi, Haresh KP, Domnita-Ileana Burcoveanu, Natascha Neu, Chiara E. Mussi, Lin Shen
Journal: Journal of Clinical Oncology (2024)

8570 Background: NTRK gene fusions are oncogenic drivers in lung cancer and other cancers. Larotrectinib is the highly selective and central nervous system (CNS)-active TRK inhibitor approved for use in patients with TRK fusion cancer based on a robust and durable overall response rate (ORR) in patients with various tumor types. Here, we report long-term efficacy and safety in a cohort of patients with TRK fusion lung cancer treated with larotrectinib. Methods: Patients with TRK fusion lung cancer treated with larotrectinib in two clinical trials (NCT02122913, NCT02576431) were included. Larotrectinib was administered at 100 mg twice daily. Response was assessed by an independent review committee (IRC) per RECIST v1.1. Results: As of July 20, 2023, 32 patients with a median age of 55.5 years (range 25-81) with TRK fusion lung cancer were enrolled, including 12 patients with CNS metastases at baseline. NTRK gene fusions were identified by next-generation sequencing in all 32 patients. The gene fusions involved NTRK1 (n=24; 75%) and NTRK3 (n=8; 25%). Patients had received a median of two prior lines of systemic therapies; one patient was treatment-naïve. The ORR per IRC was 66% (95% confidence interval [CI] 47-81): four complete responses, 17 partial responses, seven stable disease, two progressive disease, and two not evaluable. Median time to first response was 1.8 months (range 1.5-7.3). Median duration of response (DoR) was 33.9 months (95% CI 9.5-not estimable [NE]); median follow-up was 25.8 months. Median progression-free survival (PFS) was 22.0 months (95% CI 9.9-NE); median follow-up was 27.7 months. Median overall survival (OS) was 39.3 months (95% CI 17.2-NE); median follow-up was 32.9 months. The 48-month rates for DoR, PFS, and OS were 47% (95% CI 19-76), 34% (95% CI 11-56), and 38% (95% CI 13-64), respectively. Duration of treatment ranged from 2 to 75+ months. At the data cutoff, 11 patients had progressed; six patients continued treatment post-progression for ≥4 weeks due to continued clinical benefit. Treatment-related adverse events (TRAEs) were predominantly Grade 1/2. Grade 3/4 TRAEs were reported in nine patients. One patient discontinued treatment due to TRAEs (increased alanine aminotransferase, aspartate aminotransferase and gamma-glutamyltransferase). Conclusions: Larotrectinib continued to demonstrate rapid and durable responses, extended survival benefit, and a favorable safety profile in patients with advanced TRK fusion lung cancer. These results support the wider adoption of next-generation sequencing panels that include NTRK gene fusions in patients with lung cancer to identify those who may benefit from targeted treatment. Clinical trial information: NCT02122913 , NCT02576431 .