Pivotal Phase Research Articles

Breaking down resistance: novel aldosterone synthase inhibitors in the management of resistant hypertension.

This review aims to evaluate the impact of novel aldosterone synthase inhibitors, the first new class of antihypertensives in more than 20 years, on the management of resistant hypertension. We highlight the problem of resistant hypertension in clinical practice and describe the challenging history and development of aldosterone synthase inhibitors. The review highlights clinical trial evidence to-date for all agents in this class, with a key focus on the two most mature agents baxdrostat and lorundrostat which are currently in pivotal Phase 3 trials. Both agents have demonstrated significant dose-dependent reductions in blood pressure, particularly in patients with resistant hypertension and crucially, with a minimal impact on cortisol levels. They have also shown promise with marked blood pressure reductions in patients with varying physiological profiles and few adverse events at optimised doses. However, as would be expected, both drugs are associated with increases in serum potassium levels, necessitating careful monitoring.

Comprehensive Safety Exposure-Response Analysis to Support Ritlecitinib Dose Selection.

Ritlecitinib is a kinase inhibitor drug recently approved for the treatment of alopecia areata (AA) in both adults and adolescents based on a single, combined Phase 2b/3 study. Various QD doses with and without a loading dose have been evaluated in the pivotal Phase 2b/3 study. Therefore, characterization of the ritlecitinib safety profile becomes important to help inform the dose selection within the single Phase 2b/3 trial in conjunction with efficacy analysis. The purpose of this study is to characterize the safety profile of ritlecitinib with comprehensive exposure-response (ER) analyses. The concentration-QTc model was developed using a scientific white paper model, indicating no evidence of ritlecitinib-induced QTc prolongation. The semi-mechanistic PK/PD model well described the longitudinal profile of lymphocytes, indicating ritlecitinib-induced decrease in lymphocytes was marginal and the incidence of Grade 3/4 lymphopenia was predicted to be small across the investigated dose range except for a slight increase in the loading dose regimen. The ritlecitinib-dependent increase in the incidence of infections and rash was successfully described by a Poisson regression model using time-weighted average concentration as an exposure metric, indicating that the dose-dependent increase in the incidence of AEs is not dose-proportionally large in the investigated dose range. Covariate analysis within each model indicated that the safety ER relationship of ritlecitinib is similar across all the patient subgroups and no unique safety risks associated with ritlecitinib are anticipated in adolescent patients. Therefore, this comprehensive safety ER analysis supported the selection of the ritlecitinib 50 mg non-loading dose regimen for AA patients including both adults and adolescents.

Zglp-1 is a novel essential transcriptional regulator for sex reversal in zebrafish

Abstract Sex determination and differentiation play crucial biological roles in sexual reproduction in vertebrates, including zebrafish. Nevertheless, the intricate molecular mechanisms governing these processes have remained enigmatic. In this study, we showed a pivotal role played by zinc finger GATA-like protein-1 (Zglp-1) in sex differentiation in zebrafish. Our findings revealed that homozygous mutants having no Zglp-1 exhibited a female-to-male sex reversal, ultimately resulting in the development of fertile males. Within the pivotal phase of sexual differentiation, zglp-1 −/− zebrafish demonstrated a gene expression pattern that was skewed toward a male phenotype. Notably, the expression of amh was upregulated, while the expression of cyp19a1a was not sustained. Furthermore, our data revealed a direct interaction between the zinc fingers of Zglp-1 and Sf-1, which inhibited the ability of Sf-1 to activate the amh promoter. This interaction was crucial for regulating sex differentiation. Moreover, we observed alterations in gonadal cell proliferation and apoptosis in zglp-1 −/− zebrafish, which partially contributed to the sexual fate selection. Overall, our findings firmly established Zglp-1 as a crucial regulator of sex differentiation in zebrafish, offering deep insights into the intricate molecular mechanisms that govern sex determination and differentiation in vertebrates.

The Role of CPX-351 in the Acute Myeloid Leukemia Treatment Landscape: Mechanism of Action, Efficacy, and Safety.

CPX-351 (also known as VYXEOS® or Vyxeos liposomal) is a dual-drug liposomal encapsulation of cytarabine and daunorubicin in a synergistic 5:1 molar ratio and was the first example that utilized CombiPlex®, a combination drug technology platform. Superior efficacy with CPX-351 in the pivotal phase 3 randomized clinical trial versus its conventional free-drug counterpart led to its approval for the treatment of newly diagnosed therapy-related acute myeloid leukemia (AML) or AML with myelodysplasia-related changes in multiple countries. Emerging evidence indicates that CPX-351 affords additional benefits compared with conventional chemotherapy, including protection against intestinal dysbiosis and fungal colonization, fewer infectious complications, and a lower incidence of cardiotoxicity. This review examines the mechanisms underlying CPX-351's therapeutic effects and highlights its expanding role in AML treatment by summarizing efficacy and safety data from preclinical models, the pivotal clinical trial, and real-world studies. Particular focus is given to recent findings on CPX-351's intestinal and cardioprotective properties, which together strengthen its safety and efficacy profile compared with conventional chemotherapy.

Efficacy and safety results from a pivotal phase 3 trial of DTX401, an AAV8-mediated liver-directed gene therapy, in individuals with glycogen storage disease type Ia (GSDIa)

Efficacy and safety results from a pivotal phase 3 trial of DTX401, an AAV8-mediated liver-directed gene therapy, in individuals with glycogen storage disease type Ia (GSDIa)

High real-world incidence of hepatic dysfunction from cabozantinib plus nivolumab for Japanese patients with metastatic renal cell carcinoma.

The real-world incidence of hepatic dysfunction after combination therapy with cabozantinib plus nivolumab (CABO+NIVO) in Japanese patients with metastatic renal cell carcinoma remains undetermined; hence, this study aimed to determine the incidence of hepatotoxicity in these patients. A total of 48 patients treated with CABO+NIVO were enrolled in this study. Alanine aminotransferase (ALT) levels were used to evaluate liver dysfunction because of its liver specificity. ALT elevation of any grade was found in 30 patients (63%), and grade 3 elevation was found in eight patients (17%). No grade 4 or 5 elevations were observed. Female gender and a higher body mass index were independent predictive factors for ALT elevation. All patients were managed with dose reduction or interruption of cabozantinib and concomitant use of hepatoprotective agents without high-dose corticosteroids. Of the seven patients that underwent cabozantinib rechallenge after grade 3 ALT elevation, only two (23%) required re-interruption due to repeat grade 3 ALT elevation. This is the first study to examine hepatic dysfunction caused by CABO+NIVO in Japanese patients. The incidence of hepatic dysfunction was higher in real-world patients than in global patients found in pivotal phase 3 trials. Cabozantinib appeared to be a major cause of hepatic dysfunction since dose reduction or interruption of cabozantinib without the use of corticosteroids resolved hepatotoxicity. In addition, additional care should be taken when treating female or obese patients with CABO+NIVO.

Adverse Reactions Following First-Dose Administration of Co-Crystal of Tramadol-Celecoxib Versus Tramadol Alone for Moderate-To-Severe Acute Pain.

Phase 3 clinical trials in moderate-to-severe acute pain have shown that co-crystal of tramadol-celecoxib (CTC) has improved efficacy and comparable tolerability versus immediate-release tramadol 50mg alone, with a similar tramadol daily dose, over a 48-h treatment period. However, it is not known how first-dose tolerability compares, giventhat the administered dose of tramadol is higher in CTC 200mg (88mg) versus immediate-release tramadol 50mg. This was explored in a post hoc analysis of a pivotal phase 3 trial. A randomized, double-blind, factorial, active- and placebo-controlled phase 3 trial was conducted in patients with moderate-to-severe acute postoperative pain (NCT03108482) and has been previously reported. This post hoc analysis evaluated the prevalence of the four most common study drug-related, opioid-associated, treatment-emergent adverse reactions reported in phase 3 CTC clinical trials: somnolence, nausea, dizziness, and vomiting. Prevalence was evaluated in 2-h intervals, up to 6h post first dose (just before second-dose administration) of CTC 200mg or immediate-release tramadol 50mg p.o. Descriptive analysis was performed. Each group comprised 183 participants for analysis. The proportions of patients reporting drug-related, treatment-emergent adverse reactions of somnolence, nausea, dizziness, and vomiting were similar between treatment groups at 2, 4, and 6h following the first dose. This post hoc analysis indicates that the higher dose of tramadol (88mg) given in CTC 200mg did not result in an increase in drug-related adverse reactions after first-dose administration, and had a similar tolerability profile, compared with immediate-release tramadol 50mg alone (the lowest dose recommended for the management of moderate-to-severe acute pain). This is in line with earlier findings for the 48-h treatment period of this phase 3 trial and may be explained by CTC's differentiated physiochemical properties related to its co-crystal structure. These findings may have utility for practicing clinicians. ClinicalTrials.gov identifier, NCT03108482.

Anisotropic structure of nanofiber hydrogel accelerates diabetic wound healing via triadic synergy of immune-angiogenic-neurogenic microenvironments.

Anisotropic structure of nanofiber hydrogel accelerates diabetic wound healing via triadic synergy of immune-angiogenic-neurogenic microenvironments.

Fruquintinib for Adult Patients With Metastatic Colorectal Cancer.

Metastatic colorectal cancer (mCRC) represents a major clinical challenge, particularly for refractory patients who have exhausted standard treatments. Fruquintinib is an oral vascular endothelial growth factor receptor (VEGFR) inhibitor that has been approved by FDA for adult patients with mCRC who received prior fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, vascular endothelial growth factor (VEGF) inhibitor therapy, and an epidermal growth factor receptor targeted therapy if RAS wild type. Despite advances in mCRC treatment, patients who progress after standard therapies face limited options. The efficacy of treatments tends to diminish and side effects can be intolerable. There is a need for therapies that can extend survival without worsening quality of life. In the pivotal FRESCO-2 phase 3 trial, 691 patients with heavily pretreated mCRC were studied. Fruquintinib was found to significantly improve survival times, with a median overall survival (OS) of 7.4 months compared with 4.8 months with a placebo. Progression-free survival (PFS) also showed significant improvement with fruquintinib of 3.7 months versus 1.8 months in the placebo group. This was the first trial to show that an oral VEGFR inhibitor can be effective in refractory patients. Fruquintinib represents a new treatment option for patients with mCRC who have limited therapeutic options. Fruquintinib has demonstrated statistically significant improvements in OS and PFS, in heavily pretreated patients. The FRESCO-2 trial demonstrated its efficacy, even in patients previously treated with trifluridine-tipiracil or regorafenib, showing a 34% reduction in OS and improved PFS. Fruquintinib, approved by FDA for heavily pretreated patients with mCRC, addresses an unmet need in this population. Future research should focus on optimizing its integration into treatment plans and identifying biomarkers for personalized therapy.

GS-011 Linerixibat significantly improves cholestatic pruritus in primary biliary cholangitis: results of the pivotal phase 3 GLISTEN trial

GS-011 Linerixibat significantly improves cholestatic pruritus in primary biliary cholangitis: results of the pivotal phase 3 GLISTEN trial

3D reconstruction of a human Carnegie stage 9 embryo provides a snapshot of early body plan formation.

3D reconstruction of a human Carnegie stage 9 embryo provides a snapshot of early body plan formation.

LBO-001 Norucholic acid for the treatment of primary sclerosing cholangitis: 96-week analysis of a pivotal phase 3 trial

LBO-001 Norucholic acid for the treatment of primary sclerosing cholangitis: 96-week analysis of a pivotal phase 3 trial

Systemic treatment in patients with hepatocellular carcinoma and advanced liver dysfunction.

Systemic therapy represents the standard of care treatment for patients with advanced hepatocellular carcinoma (HCC). Given the increased risk of death from cirrhosis-related complications in patients with advanced liver dysfunction, pivotal phase III trials traditionally limited inclusion to patients with Child-Pugh class A, where death is more likely to be attributed to HCC progression. Therefore, Western guidelines recommend the use of systemic therapies primarily in patients with preserved liver function. However, patients with HCC and Child-Pugh class B are commonly encountered in clinical practice, but due to limited prospective evidence, there is no clear guidance on their optimal management.In this recent advances article, we discuss how the clinical course of cirrhosis can affect eligibility to treatment in the modern era of systemic therapy for HCC, elaborate on strategies to improve liver function in HCC patients by targeting cirrhosis-related and tumour-related factors and summarise the current literature on systemic therapy in HCC patients with Child-Pugh class B. Based on this information, we finally propose a clinical algorithm on how to systematically approach patients with HCC and advanced liver dysfunction in clinical practice.

FROM COMMENTARY TO LITERARY CRITICISM: JIN SHENGTAN’S INFLUENCE ON VIETNAMESE CRITICAL WORKS OF VIETNAMESE LITERARY FIGURES NGUYỄN VĂN SIÊU, PHẠM QUỲNH, AND DƯƠNG BÁ TRẠC

<p>Jin Shengtan was a prominent literary critic in China during the Ming–Qing period. He laid the foundation for a personalized system of literary criticism that emphasized emotional response, aesthetic intuition, and humanistic values in engaging with literary works. This paper explores the influence of Jin Shengtan on Vietnamese literary critical thought in the 19th century through three representative figures: Nguyễn Văn Siêu, Phạm Quỳnh, and Dương Bá Trạc. By analyzing their commentaries, essays, and artistic perspectives, the study reveals how Jin Shengtan’s ideas were adapted and localized in the Vietnamese context. This process contributed to the development of a distinctively Vietnamese mode of literary criticism—emotionally rich and deeply humanistic.<br />In doing so, the paper sheds light on a pivotal transitional phase from traditional commentary to modern critical thinking in early 20th-century Vietnamese literature.</p><p> </p><p><strong> Article visualizations:</strong></p><p><img src="/-counters-/soc/0908/a.php" alt="Hit counter" /></p>

Abstract 2130: Optimization of tarlatamab step-up dosing regimen to mitigate cytokine release syndrome using quantitative systems pharmacology modeling

Abstract Tarlatamab is a DLL3/CD3 bispecific T-cell engager (TCE) recently approved by the FDA for the treatment of extensive-stage small cell lung cancer (ES-SCLC). The dosing follows a step-up regimen for the first cycle, with 1 mg given on day 1, and 10 mg given on days 8 and 15. A similar step-up dosing regimen, but with 100 mg instead of 10 mg, was also tested in a pivotal phase 2 trial (Ahn et al. N Engl J Med. 2023 Nov 30;389(22):2063-2075). The alternative step-up dose or step-up regimen were not investigated in the study. The aim of our work was to explore the alternative step-up regimens of tarlatamab, predicting trimer (complex of TCE with target receptors) kinetics in the tumor using quantitative systems pharmacology (QSP) modeling. The QSP model integrated pharmacokinetics of tarlatamab, its distribution into the tumor of patients with ES-SCLC, binding with CD3 expressed by T-cells and DLL3 expressed by cancer cells, formation of trimer in the immunological synapse between T-cell and cancer cell, turnover of free and bound receptors, trimer internalization. Predicted peak trimer levels in the tumor are associated with cytokine release syndrome (CRS) incidence following tarlatamab administration. Higher peak levels of trimer are predicted for the doses and regimens causing more frequent CRS events. The model showed that 1 mg is the optimal step-up dose for the regimens tested in clinical trials since lower doses led to a higher peak trimer level after second dose (10 mg given on day 8). However, split dosing of the 1st or 2nd doses and a longer step-up schedule decreased the peak trimer levels following tarlatamab administration. Splitting the first dose in the approved regimen resulted in a reduction of peak trimer by 30-40%, thus mitigating CRS incidence. Administration of the 0.5 mg on day 1 and 0.5 mg on day 4 also caused a minor decrease of peak trimer level after administration of 10 mg on day 8. A substantial reduction of the maximal level of the trimer after the second dose was predicted for the step-up regimen with 100 mg if the second dose given on day 8 is 3 mg instead of 100 mg. This dose optimization might lower the probability of CRS grade 3 events observed in patients treated with 100 mg. Split-dose regimens and regimens with more than one step-up dose allow for minimizing CRS incidence without compromising the efficacy of TCEs. QSP modeling is a useful tool to investigate various doses and regimens of bispecific and multispecific antibodies. Citation Format: Oleg Demin Jr, Galina Kolesova, Dmitry Shchelokov. Optimization of tarlatamab step-up dosing regimen to mitigate cytokine release syndrome using quantitative systems pharmacology modeling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2130.

Exposure to high altitude leads to disturbances in host metabolic homeostasis: study of the effects of hypoxia-reoxygenation and the associations between the microbiome and metabolome.

This study investigated alterations in hematological parameters, gut microbiota composition, and fecal and plasma metabolic profiles among high-altitude residents during reoxygenation periods of 1 week, 1 month, and 4 months to elucidate the effects of reoxygenation on human physiology and metabolism. Exposure to high altitudes alters intestinal flora, plasma and fecal metabolites, disrupting their metabolic balance. Distinct differences in amino acid, lipid, energy, immune, cofactor, and vitamin metabolism pathways were detected between high- and low-altitude populations, with a partial recovery of disparities during reoxygenation. Although the gut microbiota exhibited limited adaptive homeostasis to altitude variations, the abundance of microbial taxa and the expression levels of fecal metabolites during the initial reoxygenation phase, particularly during the first week, were sensitive to the reoxygenated environment. Through 16S rRNA gene sequencing and bioinformatics analysis, operational taxonomic units (OTUs) were annotated at the genus level, revealing that the genera Barnesiella, Parabacteroides, and Megasphaera, along with plasma L-arginine, S1P, and alpha-D-glucose, emerged as potential biomarkers for the first week of reoxygenation among high-altitude populations. Notably, a marked change in oxidative stress levels and an increase in antioxidant capacity were observed in high-altitude residents during early reoxygenation. Tyrosine metabolism, which is jointly regulated by the plasma and fecal metabolites and gut microbiota, plays an important role under high-altitude conditions during initial reoxygenation. Additionally, the plasma metabolites pyridoxine and hypoxanthine and the Rothia genus correlated significantly with high-altitude deacclimatization syndrome scores during the first week of reoxygenation.IMPORTANCEOur research focuses on the prompt activation of tyrosine metabolism in plasma following reoxygenation, along with the regulatory mechanisms employed by the intestinal microbiota and the metabolism of feces to modulate this metabolic process. Notably, in the initial stages of reoxygenation, specific microbial genera such as Barnesiella, Parabacteroides, and Megasphaera, alongside plasma biomarkers including L-arginine, S1P, and alpha-D-glucose, emerge as pivotal players. Additionally, our findings reveal a distinct hematological profile characterized by a decrease in the MCHC and increases in the MCV and RDW-SD during the first week of reoxygenation, and this temporal window marked a crucial juncture in the plasma metabolome. Whereas the first month of reoxygenation signified a pivotal phase in the gut microbiome's adaptation to altered environmental conditions, as evidenced by alterations in alpha diversity.

Immunogenicity and safety of a multi-human dose formulation of Biological E's 14-valent pneumococcal polysaccharide conjugate vaccine (PNEUBEVAX 14®) administered to 6-8-week-old healthy infants: a phase 3, single-blind, randomized, active-controlled study.

Pneumococcal conjugate vaccines (PCVs) have considerably reduced the burden of invasive pneumococcal disease (PD) worldwide. Consequently, though, there has been an increase in non-vaccine serotype-induced PD particularly at both the extremes of age. Biological E has developed a 14-valent PCV (PNEUBEVAX 14®) that includes additional serotypes 22F and 33F. PNEUBEVAX 14® was shown to be safe, immunogenic, and non-inferior to Prevenar-13® (PCV-13) when administered to infants in a pivotal phase 3 trial. In this study, the multi-dose presentation of PNEUBEVAX 14® with 2-phenoxyethanol as a preservative was assessed for safety and immunogenicity in infants. This was a phase 3, single-blind, randomized, active-controlled study in 6-8-week-old healthy infants, conducted at three sites across India. The safety and immunogenicity of multi-dose presentation of PNEUBEVAX 14® were assessed in a 6-10-14-week dosing schedule, with 300 infants randomized to receive either PNEUBEVAX 14® or PCV-13. Safety-wise solicited local reactions and systemic events, unsolicited adverse events (AEs), serious AEs, and medically attended AEs (MAAEs) were recorded and analyzed. Immunogenicity was assessed by measuring anti-pneumococcal capsular polysaccharide (anti-PnCPS) immunoglobulin G (IgG) antibodies for all 14 serotypes, as well as cross-reactivity to serotype 6A. The safety aspects of the multi-dose presentation of PNEUBEVAX 14® and PCV-13 were comparable with 23.3% of subjects having AEs in each of the two arms. There were no serious AEs, medically attended AEs, or deaths in either of the two study arms. Reported AEs were mild and solicited in nature, with injection site swelling and injection site pain being the most common AEs in both arms. The multi-dose presentation of PNEUBEVAX 14® was found to induce a robust immune response, including the new serotypes 22F and 33F. Importantly, PNEUBEVAX 14® also induced cross-reactive antibodies against serotype 6A. The multi-dose presentation of PNEUBEVAX 14® is both safe and immunogenic when administered to 6-8-week-old infants in a 6-10-14-week dosing schedule. These results extend the findings of a pivotal phase 3 study of the single-dose presentation of PNEUBEVAX 14® that showed that it was safe, robustly immunogenic, and non-inferior to PCV-13 in the same age group and dosing schedule. Taken together, these data suggest that both the single-dose and multi-dose presentations of PNEUBEVAX 14® can be safely administered to infants to prevent pneumococcal disease caused by Streptococcus pneumoniae. https://ctri.nic.in/Clinicaltrials/pmaindet2.php?EncHid=NTk0MzA=&Enc=&userName=, identifier CTRI/2021/10/037067.

Effects of Fe and Zn alone and combined treatment on Triticum aestivum L. seed germination

Seed germination represents a pivotal phase in crop production, exhibiting pronounced sensitivity to abiotic stresses. In this study, wheat seeds of the ‘Ningchun 4’ variety were subjected to treatments involving zinc (Zn) chloride and iron (Fe) chloride, both individually and in combination. The impacts of these treatments on Fe and Zn accumulation, starch mobilization, antioxidant responses, and nitric oxide (NO) metabolism during seed germination were thoroughly examined. Individual application of Fe or Zn significantly inhibited and delayed wheat seed germination, which was accompanied by elevated levels of starch, sucrose, and soluble sugars, as well as increased reactive oxygen species and malondialdehyde concentrations. Concurrently, total amylase and α-amylase activities were downregulated, while antioxidant enzyme activities and the expression of TaCAT, TaAPX, and TaGR were upregulated. Seeds treated solely with Fe exhibited excessive Fe accumulation, heightened Fe2+ content, and diminished Zn content. Conversely, these trends were reversed in seeds treated with Zn alone. Furthermore, reduced NO levels were associated with downregulated nitrate reductase and nitric oxide synthase activities, alongside decreased expression of their corresponding genes in response to Fe exposure. Notably, the above effects induced by Zn alone were less severe compared to those induced by Fe stress. Importantly, the addition of Zn (100 µM or 250 µM) significantly alleviated the detrimental effects of Fe on several parameters in germinating seeds. The results from NO fluorescent probe staining corroborated the quantitative NO measurements across different treatments. In conclusion, an appropriate concentration of Zn effectively promoted the germination of Fe-stressed wheat seeds by mitigating Fe accumulation, attenuating oxidative damage, and enhancing starch mobilization during seed germination.

Brief Report: Final overall survival and long-term safety of lorlatinib in patients with ALK-positive non-small cell lung cancer from the pivotal phase 2 study

IntroductionLorlatinib is a potent, brain-penetrant, third-generation inhibitor of anaplastic lymphoma kinase (ALK) and ROS1 tyrosine kinases with broad coverage of ALK resistance mutations. We present overall survival (OS) and long-term safety of lorlatinib in patients with advanced ALK-positive non-small cell lung cancer (NSCLC) from the final analyses of the pivotal phase 2 study. MethodsAdults with ALK-positive NSCLC, enrolled in expansion cohorts based on prior therapy (EXP1-5), received lorlatinib 100 mg orally once daily in continuous 21-day cycles. The primary endpoint was objective response rate; secondary endpoints included OS and safety. ResultsThirty patients were enrolled in EXP1 (treatment naïve), 59 in EXP2-3A (disease progression following crizotinib ± chemotherapy), 28 in EXP3B (disease progression following one second-generation ALK tyrosine kinase inhibitor [TKI] ± chemotherapy), 111 in EXP4-5 (disease progression following ≥2 ALK TKIs ± chemotherapy), and 139 in EXP3B-5 (disease progression following ≥1 ALK TKI ± chemotherapy). Median OS was not reached (NR) (95% CI, NR-NR) in EXP1, NR (95% CI, 51.5-NR) in EXP2-3A, 37.4 months (95% CI, 12.3-NR) in EXP3B, 19.2 months (95% CI, 15.4-30.2) in EXP4-5, and 20.7 months (95% CI, 16.1-30.3) in EXP3B-5. All-cause adverse events leading to dose reduction were reported in 77 (28%) patients, temporary treatment discontinuation in 158 (57%), and permanent discontinuation in 35 (13%). ConclusionsAfter a minimum follow-up of 5 years, final analyses from the global phase 2 study confirmed substantial activity, prolonged OS, and generally consistent safety findings with lorlatinib in treatment-naïve and previously treated patients with ALK-positive NSCLC.

PRGN-2012 gene therapy in adults with recurrent respiratory papillomatosis: a pivotal phase 1/2 clinical trial.

PRGN-2012 gene therapy in adults with recurrent respiratory papillomatosis: a pivotal phase 1/2 clinical trial.