FDA Approval Summary: Repotrectinib for Locally Advanced or Metastatic ROS1-Positive Non-Small Cell Lung Cancer.

On November 15, 2023, the U.S. Food and Drug Administration (FDA) granted traditional approval to repotrectinib (Augtyro, Bristol Myers Squibb Corporation) for the treatment of adult patients with locally advanced or metastatic receptor tyrosine kinase encoded by the ROS1 gene (ROS1)-positive non-small cell lung cancer (NSCLC). The approval was based on TRIDENT-1, a single-arm trial with multiple cohorts of patients with ROS1 fusion-positive (hereafter "ROS1-positive") NSCLC (NCT03093116), who were either treatment naïve or had received prior ROS1 tyrosine kinase inhibitor (TKI) and/or platinum-based chemotherapy. The primary efficacy outcome measure is objective response rate (ORR) assessed by blinded independent central review (BICR) using response evaluation criteria in solid tumors version 1.1. ORR was assessed in 71 patients who were ROS1 TKI naïve and 56 patients who had received a prior ROS1 TKI. Among the 71 patients who were ROS1 TKI naïve, the ORR was 79% (95% CI, 68-88), median duration of response was 34.1 months (95% CI, 26-NE). In patients who had received a prior ROS1 TKI and no prior chemotherapy, the ORR was 38% (95% CI, 25-52). The median duration of response was 14.8 months (95% CI, 7.6-NE); BICR-assessed responses were observed in CNS metastases in patients in both cohorts and in patients who developed resistance mutations following prior TKI therapy. The most common (>20%) adverse reactions were dizziness, dysgeusia, peripheral neuropathy, constipation, dyspnea, ataxia, fatigue, cognitive disorders, and muscular weakness. A unique feature of this ROS1 TKI approval is the inclusion of robust evidence of efficacy in patients with ROS1-positive NSCLC who had progressed on prior ROS1 TKIs.

US Food and Drug Administration Approval Summary: Elacestrant for Estrogen Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative, ESR1-Mutated Advanced or Metastatic Breast Cancer.

PURPOSE: The US Food and Drug Administration (FDA) approved elacestrant for the treatment of postmenopausal women or adult men with estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-), estrogen receptor 1 (ESR1)-mutated advanced or metastatic breast cancer with disease progression after at least one line of endocrine therapy (ET). PATIENTS AND METHODS: Approval was based on EMERALD (Study RAD1901-308), a randomized, open-label, active-controlled, multicenter trial in 478 patients with ER+, HER2- advanced or metastatic breast cancer, including 228 patients with ESR1 mutations. Patients were randomly assigned (1:1) to receive either elacestrant 345 mg orally once daily (n = 239) or investigator's choice of ET (n = 239). RESULTS: In the ESR1-mut subgroup, EMERALD demonstrated a statistically significant improvement in progression-free survival (PFS) by blinded independent central review assessment (n = 228; hazard ratio [HR], 0.55 [95% CI, 0.39 to 0.77]; P value = .0005). Although the overall survival (OS) end point was not met, there was no trend toward a potential OS detriment (HR, 0.90 [95% CI, 0.63 to 1.30]) in the ESR1-mut subgroup. PFS also reached statistical significance in the intention-to-treat population (ITT, N = 478; HR, 0.70 [95% CI, 0.55 to 0.88]; P value = .0018). However, improvement in PFS in the ITT population was primarily attributed to results from patients in the ESR1-mut subgroup. More patients who received elacestrant experienced nausea, vomiting, and dyslipidemia. CONCLUSION: The approval of elacestrant in ER+, HER2- advanced or metastatic breast cancer was restricted to patients with ESR1 mutations. Benefit-risk assessment in the ESR1-mut subgroup was favorable on the basis of a statistically significant improvement in PFS in the context of an acceptable safety profile including no evidence of a potential detriment in OS. By contrast, the benefit-risk assessment in patients without ESR1 mutations was not favorable. Elacestrant is the first oral estrogen receptor antagonist to receive FDA approval for patients with ESR1 mutations.

FDA Approval Summary: Futibatinib for Unresectable Advanced or Metastatic, Chemotherapy Refractory Intrahepatic Cholangiocarcinoma with FGFR2 Fusions or Other Rearrangements.

On September 30, 2022, the FDA granted accelerated approval to futibatinib for the treatment of adult patients with previously treated, unresectable, locally advanced or metastatic intrahepatic cholangiocarcinoma (iCCA) with FGFR2 fusions or other rearrangements. Approval was based on Study TAS-120-101, a multicenter open-label, single-arm trial. Patients received futibatinib 20-mg orally once daily. The major efficacy outcome measures were overall response rate (ORR) and duration of response (DoR) as determined by an independent review committee (IRC) according to RECIST v1.1. ORR was 42% (95% confidence interval, 32%-52%). Median DoR was 9.7 months. Adverse reactions occurring in ≥30% patients were nail toxicity, musculoskeletal pain, constipation, diarrhea, fatigue, dry mouth, alopecia, stomatitis, and abdominal pain. The most common laboratory abnormalities (≥50%) were increased phosphate, increased creatinine, decreased hemoglobin, and increased glucose. Ocular toxicity (including dry eye, keratitis, and retinal epithelial detachment) and hyperphosphatemia are important risks of futibatinib, which are listed under Warnings and Precautions. This article summarizes the FDA's thought process and data supporting the approval of futibatinib.

Whole Body PBPK Modeling of Remdesivir and Its Metabolites to Aid in Estimating Active Metabolite Exposure in the Lung and Liver in Patients With Organ Dysfunction.

Remdesivir (RDV) is the first drug approved by the US Food and Drug Administration (FDA) for the treatment of coronavirus disease 2019 (COVID-19) in certain patients requiring hospitalization. As a nucleoside analogue prodrug, RDV undergoes intracellular multistep activation to form its pharmacologically active species, GS-443902, which is not detectable in the plasma. A question arises that whether the observed plasma exposure of RDV and its metabolites would correlate with or be informative about the exposure of GS-443902 in tissues. A whole body physiologically-based pharmacokinetic (PBPK) modeling and simulation approach was utilized to elucidate the disposition mechanism of RDV and its metabolites in the lungs and liver and explore the relationship between plasma and tissue pharmacokinetics (PK) of RDV and its metabolites in healthy subjects. In addition, the potential alteration of plasma and tissue PK of RDV and its metabolites in patients with organ dysfunction was explored. Our simulation results indicated that intracellular exposure of GS-443902 was decreased in the liver and increased in the lungs in subjects with hepatic impairment relative to the subjects with normal liver function. In subjects with severe renal impairment, the exposure of GS-443902 in the liver was slightly increased, whereas the lung exposure of GS-443902 was not impacted. These predictions along with the organ impairment study results may be used to support decision making regarding the RDV dosage adjustment in these patient subgroups. The modeling exercise illustrated the potential of whole body PBPK modeling to aid in decision making for nucleotide analogue prodrugs, particularly when the active metabolite exposure in the target tissues is not available.

Nicotine aggravates vascular adiponectin resistance via ubiquitin-mediated adiponectin receptor degradation in diabetic Apolipoprotein E knockout mouse.

There is limited and discordant evidence on the role of nicotine in diabetic vascular disease. Exacerbated endothelial cell dysregulation in smokers with diabetes is associated with the disrupted adipose function. Adipokines possess vascular protective, anti-inflammatory, and anti-diabetic properties. However, whether and how nicotine primes and aggravates diabetic vascular disorders remain uncertain. In this study, we evaluated the alteration of adiponectin (APN) level in high-fat diet (HFD) mice with nicotine (NIC) administration. The vascular pathophysiological response was evaluated with vascular ring assay. Confocal and co-immunoprecipitation analysis were applied to identify the signal interaction and transduction. These results indicated that the circulating APN level in nicotine-administrated diabetic Apolipoprotein E-deficient (ApoE-/-) mice was elevated in advance of 2 weeks of diabetic ApoE-/- mice. NIC and NIC addition in HFD groups (NIC + HFD) reduced the vascular relaxation and signaling response to APN at 6 weeks. Mechanistically, APN receptor 1 (AdipoR1) level was decreased in NIC and further significantly reduced in NIC + HFD group at 6 weeks, while elevated suppressor of cytokine signaling 3 (SOCS3) expression was induced by NIC and further augmented in NIC + HFD group. Additionally, nicotine provoked SOCS3, degraded AdipoR1, and attenuated APN-activated ERK1/2 in the presence of high glucose and high lipid (HG/HL) in human umbilical vein endothelial cells (HUVECs). MG132 (proteasome inhibitor) administration manifested that AdipoR1 was ubiquitinated, while inhibited SOCS3 rescued the reduced AdipoR1. In summary, this study demonstrated for the first time that nicotine primed vascular APN resistance via SOCS3-mediated degradation of ubiquitinated AdipoR1, accelerating diabetic endothelial dysfunction. This discovery provides a potential therapeutic target for preventing nicotine-accelerated diabetic vascular dysfunction.

FDA Approval Summary: Selumetinib for Plexiform Neurofibroma.

On April 10, 2020, the FDA approved selumetinib (KOSELUGO, AstraZeneca) for the treatment of pediatric patients 2 years of age and older with neurofibromatosis type 1 who have symptomatic, inoperable plexiform neurofibromas. Approval was based on demonstration of a durable overall response rate per Response Evaluation in Neurofibromatosis and Schwannomatosis criteria and supported by observed clinical improvements in plexiform neurofibroma-related symptoms and functional impairments in 50 pediatric patients with inoperable plexiform neurofibromas in a single-arm, multicenter trial. The overall reponse rate per NCI investigator assessment was 66% (95% confidence interval, 51-79) with at least 12 months of follow-up. The median duration of response was not reached, and 82% of responding patients experienced duration of response ≥12 months. Clinical outcome assessment endpoints provided supportive efficacy data. Risks of selumetinib are consistent with MAPK (MEK) inhibitor class effects, including ocular, cardiac, musculoskeletal, gastrointestinal, and dermatologic toxicities. Safety was assessed across a pooled database of 74 pediatric patients with plexiform neurofibromas and supported by adult and pediatric selumetinib clinical trial data in cancer indications. The benefit-risk assessment for selumetinib in patients with inoperable plexiform neurofibromas was considered favorable.

FDA Approval Summary: Tucatinib for the Treatment of Patients with Advanced or Metastatic HER2-positive Breast Cancer.

On April 17, 2020, the FDA approved tucatinib in combination with trastuzumab and capecitabine for the treatment of patients with advanced unresectable or metastatic HER2-positive breast cancer, including patients with brain metastases, who have received one or more prior anti-HER2-based regimens in the metastatic setting. This was the first new molecular entity evaluated under Project Orbis, an FDA Oncology Center of Excellence initiative, which supports concurrent review of oncology drugs by multiple global health authorities. Approval was based on the HER2CLIMB trial, which randomized patients to receive tucatinib or placebo with trastuzumab and capecitabine. Tucatinib demonstrated efficacy compared with placebo in progression-free survival [PFS; HR: 0.54; 95% confidence interval (CI): 0.42-0.71; P < 0.00001] and overall survival (OS; HR: 0.66; 95% CI, 0.50-0.87; P = 0.00480). Patients with either treated and stable or active brain metastases made up 48% of the study population. PFS in patients with brain metastases confirmed benefit (HR: 0.48; 95% CI, 0.34-0.69; P < 0.00001). The benefit in patients with brain metastases allowed for inclusion of this specific population in the indication. Important safety signals included diarrhea and hepatotoxicity which are listed under Warnings and Precautions. This article summarizes the FDA thought process and data supporting the favorable benefit-risk profile and approval of tucatinib.

FDA Approval Summary: Alpelisib Plus Fulvestrant for Patients with HR-positive, HER2-negative, PIK3CA-mutated, Advanced or Metastatic Breast Cancer.

On May 24, 2019, the FDA granted regular approval to alpelisib in combination with fulvestrant for postmenopausal women, and men, with hormone receptor (HR)-positive, HER2-negative, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA)-mutated, advanced or metastatic breast cancer as detected by an FDA-approved test following progression on or after an endocrine-based regimen. Approval was based on the SOLAR-1 study, a randomized, double-blind, placebo-controlled trial of alpelisib plus fulvestrant versus placebo plus fulvestrant. The primary endpoint was investigator-assessed progression-free survival (PFS) per RECIST v1.1 in the cohort of trial participants whose tumors had a PIK3CA mutation. The estimated median PFS by investigator assessment in the alpelisib plus fulvestrant arm was 11 months [95% confidence interval (CI), 7.5-14.5] compared with 5.7 months (95% CI, 3.7-7.4) in the placebo plus fulvestrant arm (HR, 0.65; 95% CI, 0.50-0.85; two-sided P = 0.001). The median overall survival was not yet reached for the alpelisib plus fulvestrant arm (95% CI, 28.1-NE) and was 26.9 months (95% CI, 21.9-NE) for the fulvestrant control arm. No PFS benefit was observed in trial participants whose tumors did not have a PIK3CA mutation (HR, 0.85; 95% CI, 0.58-1.25). The most common adverse reactions, including laboratory abnormalities, on the alpelisib plus fulvestrant arm were increased glucose, increased creatinine, diarrhea, rash, decreased lymphocyte count, increased gamma glutamyl transferase, nausea, increased alanine aminotransferase, fatigue, decreased hemoglobin, increased lipase, decreased appetite, stomatitis, vomiting, decreased weight, decreased calcium, decreased glucose, prolonged activated partial thromboplastin time, and alopecia.

Mathematical modeling of the heterogeneous distributions of nanomedicines in solid tumors.

The distribution of nanomedicines inside solid tumors is often restricted to perivascular areas, leaving most distal tumor cells out of reach. This partly explains modest patient benefit of many nanomedicines compared to their free-form counterparts. The objective for this study is to develop a mathematical model to quantitatively analyze this phenomenon and the influencing factors to such perivascular distribution and seek for effective strategies to alleviate this. A spatial tumor distribution model was firstly constructed to mimic the geometrical structure of tumor vessels and the surrounding tumor cells. This tumor model was further integrated with a systemic pharmacokinetics model for nanoparticles. A variety of factors on the tumor spatial distributions of nanomedicines were considered in the model. With the model, we quantified the effect of these influencing factors on tumor delivery efficacy (ID %), the magnitude of heterogeneous distribution (H index), and the effect of enhanced permeability and retention (EPR). In particularly, we compared the spatial distributions of the nanoparticles and the free payloads insides tumors. The model predicted high degrees of distributional heterogeneity for both nanoparticles and free payloads. The degree of heterogeneity and the influencing factors for free payloads were markedly different from those for nanoparticles. We found that nanoparticle diffusion coefficient was the most effective factor in reducing the nanoparticle H index but exerted moderate influence on the free payloads H index. The most effective factor in reducing the H index of free payload was payload diffusion coefficient. The factors that improved free payload distribution were closely associated with higher drug efficacy. In contrast, the factors that improved nanoparticle spatial distributions did not always confer improved anti-tumor efficacy of the delivered drug. These findings highlight the importance of assessing the heterogeneous free payload distribution in tumors for the development of effective nanomedicines.

A Multiscale Physiologically-Based Pharmacokinetic Model for Doxorubicin to Explore its Mechanisms of Cytotoxicity and Cardiotoxicity in Human Physiological Contexts.

PURPOSE: The mechanisms underlying doxorubicin cytotoxicity and cardiotoxicity were broadly explored but remain incompletely understood. A multiscale physiologically-based pharmacokinetic (PBPK) model was developed to assess doxorubicin dispositions at levels of system, tissue interstitial, cell, and cellular organelles. This model was adopted to explore the mechanisms-of-action/toxicity of doxorubicin in humans. METHODS: The PBPK model was developed by analyzing data from mice and the model was verified by scaling up to predict doxorubicin multiscale dispositions in rats and humans. The multiscale dispositions of doxorubicin in human heart and tumors were explicitly simulated to elucidate the potential mechanisms of its cytotoxicity and cardiotoxicity. RESULTS: The developed PBPK model was able to adequately describe doxorubicin dispositions in mice, rats and humans. In humans, prolonged infusion, a dosing regimen with less cardiotoxicity, was predicted with substantially reduced free doxorubicin concentrations at human heart interstitium, which were lower than the concentrations associated with oxidative stress. However, prolonged infusion did not reduce doxorubicin-DNA adduct at tumor nucleus, consistent with clinical observations that prolonged infusion did not compromise anti-tumor effect, indicating that one primary anti-tumor mechanism was DNA torsion. CONCLUSIONS: A multiscale PBPK model for doxorubicin was developed and further applied to explore its cytotoxic and cardiotoxic mechanisms.

Bone morphogenetic protein-4 induced rat hepatic progenitor cell (WB-F344 cell) differentiation toward hepatocyte lineage.

Hepatic progenitor cells are local stem cells in the liver and they can be differentiated into either hepatocytes or cholangiocytes depending on different stimulations. These stimulations include extracellular growth factors and intracellular transcription factors. Bone morphogenetic protein 4 (BMP4) is a member of transforming growth factor beta (TGF-beta) superfamily and was first identified as growth factor to induce ectopic bone formation from skeletal muscle. Role of BMP4 in the liver is still unclear especially its role in hepatic progenitor cells (HPCs) differentiation. BMP4 was used to stimulate rat HPCs (WB-F344 cells) and differentiation of WB-F344 cells was investigated by reverse transcriptase polymerase chain reaction (RT-PCR) and Western blot analysis. Both adenovirus delivered BMP4 and recombinant BMP4 were able to induce expression of hepatocyte markers such as albumin, TAT-1, and G6Pase but not cholangiocyte markers such as beta4-integrin and CK19. BMP4 induced differentiation of WB-F344 cells toward hepatocytes was mediated by increase in phosphorylation of Smad1 and ERK1/2. Moreover, BMP4 also stimulated expression of transcription factor--C/EBP-alpha, which involved in differentiation of WB-F344 cells toward hepatocytes. BMP4 is able to stimulate WB-F344 cells differentiation toward hepatocyte lineage.

Proteome analysis and tissue microarray for profiling protein markers associated with lymph node metastasis in colorectal cancer.

BACKGROUND: Understanding the proteins associated with lymph node metastasis (LNM) in colorectal cancer (CRC) will benefit us in the prediction of CRC prognosis and provide us new potential targets in the intervention of CRC. The aim of this study is to investigate the LNM-associated proteins and to evaluate the clinicopathological characteristics of these target proteins' expression in CRC. METHODS: Fresh tumor and paired normal mucosa from five cases for each group of non-LNM CRC and LNM CRC were analyzed by two-dimensional electrophoresis coupled with MALDI-TOF-MS, followed by Western blotting confirmation. In 40 paraffin-embedded CRC samples, each for non-LNM CRC and LNM CRC, four differentially expressed proteins identified by proteomics analysis were detected by tissue microarray with immunohistochemistry staining to access the clinicopathological characteristics of these proteins in LNM of CRC. RESULTS: Twenty-five proteins were found to be differentially expressed between normal mucosa and CRC tissue. Increased expression levels of heat shock protein-27 (HSP-27), glutathione S-transferase (GST), and Annexin II, but a decreased expression level of liver-fatty acid binding protein (L-FABP), existed in LNM CRC as compared with non-LNM CRC (p<0.01 or p<0.05, respectively). CONCLUSION: The techniques of proteomic analysis combined with tissue microarray provide us a dramatic tool for screening of LNM-associated proteins in cancer research. The increased expression of HSP-27, GST, and Annexin II, but decreased expression of L-FABP, suggests a significantly elevated incidence of LNM in CRC.

Saikosaponin-d attenuates the development of liver fibrosis by preventing hepatocyte injury.

Treatment of liver fibrosis and cirrhosis remains a challenging field. Hepatocyte injury and the activation of hepatic stellate cells are the 2 major events in the development of liver fibrosis and cirrhosis. It is known that several Chinese herbs have significant beneficial effects on the liver; therefore, the purpose of the present study was to investigate the therapeutic effect of saikosaponin-d (SSd) on liver fibrosis and cirrhosis. A rat model of liver fibrosis was established using the dimethylnitrosamine method. Liver tissue and serum were used to examine the effect of SSd on liver fibrosis. A hepatocyte culture was also used to investigate how SSd can protect hepatocytes from oxidative injury induced by carbon tetrachloride. The results showed that SSd significantly reduced collagen I deposition in the liver and alanine aminotransferase level in the serum. Moreover, SSd decreased the content of TGF-beta1 in the liver, which was significantly elevated after dimethylnitrosamine induced liver fibrosis. Furthermore, SSd was able to alleviate hepatocyte injury from oxidative stress. In conclusion, SSd could postpone the development of liver fibrosis by attenuating hepatocyte injury.

Increased Smad1 expression and transcriptional activity enhances trans-differentiation of hepatic stellate cells.

Smad1 is a receptor-activated intracellular signaling protein, which mediates signal transduction of bone morphogenetic proteins. Current study investigated the expression and transcriptional activity of Smad1 during hepatic stellate cell (HSC) activation. Rat HSCs were isolated from rats at 1, 2, 3 and 4 days after gavaged with carbon tetrachloride (CCl(4)) or corn oil. RT-PCR, Western blot, gel-shift assay and luciferase assay were employed to examine Smad1 expression and transcriptional activity, respectively. CCl(4)-cirrhotic liver fat-storing cells-8B (CFSC-8B) cells were infected with recombinant adenoviruses of Smad1 and/or Smad1 shRNA. Both mRNA and protein levels of Smad1 were significantly increased at 48 h after gavage of CCl(4). Gel shift assays demonstrated a significant increase in nuclear Smad1 in day 9 HSCs. Transfection of HSCs with Smad1 responsible luciferase indicated an increase in Smad1 transcriptional activity in day 6 HSCs (1.563 +/- 0.229 in day 6 versus 0.785 +/- 0.192 in day 3). When CFSC-8B cells were infected with adenoviruses with Smad1 or Smad1 short hairpin RNA (shRNA), there was an increase or decrease in Smad1 mRNA and protein, respectively. Smooth muscle alpha-actin expression was increased or decreased according to induction or reduction of Smad1. In conclusion, there were significantly increases in Smad1 expression and transcriptional activity during in vivo activation of hepatic stellate cells.