Correlations of response rate and progression-free survival with overall survival in immunotherapy trials for metastatic non-small-cell lung cancer: an FDA pooled analysis.

BACKGROUND: Radiographic changes might not fully capture the treatment effects of immune checkpoint inhibitors (ICIs). We aimed to assess correlations of overall response rate and progression-free survival with overall survival in trials of ICIs for metastatic non-small-cell lung cancer (NSCLC). METHODS: To assess trial-level and patient-level correlations of overall response rate and progression-free survival with overall survival, we conducted a pooled analysis of first-line randomised trials (including patients aged ≥18 years with metastatic squamous and non-squamous NSCLC and an Eastern Cooperative Oncology Group performance status of 0-1) submitted to the US Food and Drug Administration from June 24, 2016, to March 16, 2021. Eligible trials evaluated at least one ICI in the experimental group versus chemotherapy in the control group. At the trial level, we used weighted linear regression to derive coefficients of determination (R2). At the patient level, we used Cox proportional hazards models to compare overall survival between responders versus non-responders per Response Evaluation Criteria in Solid Tumours (version 1.1). FINDINGS: A total of 13 trials including 9285 patients evaluated ICIs alone or in combination with chemotherapy versus chemotherapy alone. At the trial level, the R2 was 0·61 (95% CI 0·32-0·84) for correlation of overall response rate with overall survival and 0·70 (0·40-0·89) for correlation of progression-free survival with overall survival. Correlations ranged from weak to moderate when evaluating subgroups by PD-L1 expression and were consistent across trials evaluating ICIs alone or in combination with chemotherapy. At the patient level, responders had longer overall survival than non-responders (hazard ratio [HR] 0·28 [95% CI 0·26-0·30]). Among responders, overall survival was longer in patients enrolled in experimental groups than in control groups (HR 0·54 [95% CI 0·48-0·61]). INTERPRETATION: Correlations of overall response rate and progression-free survival with overall survival were generally moderate in this pooled analysis. The findings support routine analysis of mature overall survival data, where feasible, in first-line randomised trials of ICIs for metastatic NSCLC. FUNDING: US Food and Drug Administration.

Polyacrylonitrile and polyethersulfone based co-axial electrospun nanofibers for fluoride removal from contaminated stream.

Coaxial electrospun polyacrylonitrile (PAN) and polyethersulfone (PES) based nanofibers were prepared and was used for filtration of fluoride from drinking water for the first time. Well defined fiber geometry was obtained at 1 ml/h of core polymer, i.e., PES flow rate, 1.4 ml/h of shell polymer, i.e., PAN flow rate, voltage of 22 kV, while the distance between the needle tip and the collector was 15-17 cm. Increase in bead like structure in fiber strands was observed with higher PAN concentration, while it decreased for lower PES concentration, thereby giving an optimum composition (6 wt% PAN and 10 wt% PES) for uniform fiber morphology. This nanofiber, abbreviated as N2 acted as an ultrafiltration membrane having permeability in the lower range, i.e., 0.5 × 10-11 m/s Pa and its fluoride removal efficacy was 46%. Fibers were also hydrophilic with considerable porous nature. Uptake of fluoride by this N2 nanofibers were evident from binding energy of 685.2 eV during XPS analysis. It is probable that nitrile and sulfone groups present in the core and shell of the nanofibers played an active in fluoride uptake, which was estimated as 110 mg/g at 298 K. Isoelectric point was in alkaline range which promoted negative fluoride ion uptake on positive nanofiber surface. Lead played higher masking effect in the uptake of fluoride in comparison to arsenic as coexisting ion. Dynamic cross flow filtration was also studied with this nanofiber in both synthetic and real life feed solution.

FDA Approval Summary: Amivantamab for the Treatment of Patients with Non-Small Cell Lung Cancer with EGFR Exon 20 Insertion Mutations.

The FDA granted accelerated approval for amivantamab-vmjw (hereafter referred to as amivantamab), a bispecific antibody directed against EGFR and mesenchymal-epithelial transition receptor, on May 21, 2021, for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with EGFR exon 20 insertion mutations whose disease has progressed on or after platinum-based chemotherapy. Approval was based on results of an ongoing, multicenter, nonrandomized, open-label, multicohort clinical trial (CHRYSALIS, NCT02609776), demonstrating a substantial overall response rate (ORR) and durable responses, with an ORR of 40% [95% confidence interval (CI): 29-51] and a median response duration of 11.1 months (95% CI: 6.9-not evaluable). Guardant360 CDx was contemporaneously approved as a companion diagnostic for this indication to identify EGFR exon 20 insertion mutations in plasma specimens. The most notable safety finding was the high incidence (66%) of infusion-related reactions, which is addressed in both the Dosage and Administration and Warnings and Precautions sections of the product label. Other common adverse reactions (occurring in ≥20% of patients) were rash, paronychia, musculoskeletal pain, dyspnea, nausea and vomiting, fatigue, edema, stomatitis, cough, and constipation. The approval of amivantamab was the first approval of a targeted therapy for patients with advanced NSCLC harboring EGFR exon 20 insertion mutations.

FDA Approval Summary: Pemigatinib for Previously Treated, Unresectable Locally Advanced or Metastatic Cholangiocarcinoma with FGFR2 Fusion or Other Rearrangement.

On April 17, 2020, the FDA granted accelerated approval to pemigatinib (PEMAZYRE, Incyte Corporation) for the treatment of adults with previously treated, unresectable locally advanced or metastatic cholangiocarcinoma with an FGFR2 fusion or other rearrangement as detected by an FDA-approved test. Approval was based on FIGHT-202 (NCT02924376), a multicenter open-label single-arm trial. Efficacy was based on 107 patients with locally advanced unresectable or metastatic cholangiocarcinoma whose disease had progressed on or after at least one prior therapy and had an FGFR2 gene fusion or rearrangement. Patients received pemigatinib, 13.5 mg orally, once daily for 14 consecutive days, followed by 7 days off therapy. Safety was based on a total of 466 patients, 146 of whom had cholangiocarcinoma and received the recommended dose. Efficacy endpoints were overall response rate (ORR) and duration of response (DOR) determined by an independent review committee using RECIST 1.1. ORR was 36% (95% confidence interval: 27-45). Median DOR was 9.1 months. The most common adverse reactions were hyperphosphatemia, alopecia, diarrhea, nail toxicity, fatigue, dysgeusia, nausea, constipation, stomatitis, dry eye, dry mouth, decreased appetite, vomiting, arthralgia, abdominal pain, hypophosphatemia, back pain, and dry skin. Ocular toxicity and hyperphosphatemia are important risks of pemigatinib. The recommended dosage is 13.5 mg orally once daily for 14 consecutive days followed by 7 days off therapy in 21-day cycles. FDA also approved the FoundationOne CDX (Foundation Medicine, Inc.) as a companion diagnostic for patient selection.

A review on pectinase properties, application in juice clarification, and membranes as immobilization support.

Pectic substances cause haziness and high viscosity of fruit juices. Pectinase enzymes are biological compounds that degrade pectic compounds. Nontoxicity and ecofriendly nature make pectinases excellent biocatalysts for juice clarification. However, the poor stability and nonreusability of pectinases trim down the effectiveness of the operation. The immobilization techniques have gained the attention of researchers as it augments the properties of the enzymes. Literature has reported the stability improvement of enzymes like lipase, laccase, hydrogen peroxidase, and cellulase upon immobilization on the membrane. However, only a few research articles divulge pectinase immobilization using a membrane. The catalysis-separation synergy of membrane-reactor has put indelible imprints in industrial applications. Immobilization of pectinase on the membrane can enhance its performance in juice processing. This review delineates the importance of physicochemical and kinematic properties of pectinases relating to the juice processing parameters. It also includes the influence of metal-ion cofactors on enzymes' activity. Considering the support and catalytic-separation facets of the membrane, the prediction of the membrane as support for pectinase immobilization has also been carried out.

FDA Approval Summary: Cabozantinib for Differentiated Thyroid Cancer.

On September 17, 2021, the FDA approved cabozantinib (Cabometyx; Exelixis, Inc.) for the treatment of adult and pediatric patients 12 years of age and older with locally advanced or metastatic differentiated thyroid cancer (DTC) that has progressed following prior VEGFR-targeted therapy and who are radioactive iodine (RAI)-refractory or ineligible. This is the first approval for patients with RAI-refractory locally advanced or metastatic DTC who have progressed following prior therapy and the first approval in pediatric patients with DTC. The approval was based on data from COSMIC-311 (Study XL184-311, NCT03690388), an international, randomized, double-blind trial in which patients with locally advanced or metastatic RAI-refractory DTC that progressed during or following treatment with at least one VEGFR-targeting tyrosine kinase inhibitor were treated with either cabozantinib 60 mg orally once daily (N = 170) or placebo with best supportive care (N = 88). The primary efficacy outcome measures were progression-free survival (PFS) and overall response rate (ORR) by blinded independent central review per RECIST 1.1. The median PFS was 11.0 months [95% confidence interval (CI), 7.4-13.8] in the cabozantinib arm compared with 1.9 months (95% CI, 1.9-3.7) in the control arm, with an HR of 0.22 (95% CI, 0.15-0.31). The endpoint of ORR was not met. No new safety signals were identified with the exception of hypocalcemia, which was added as a warning in the product labeling.

FDA Approval Summary: Nivolumab in Combination with Ipilimumab for the Treatment of Unresectable Malignant Pleural Mesothelioma.

On October 2, 2020, FDA approved nivolumab with ipilimumab as first-line treatment for adult patients with unresectable malignant pleural mesothelioma (MPM). The approval was based on results from Study CA209743 (CHECKMATE-743), an open-label trial of patients with MPM randomized to receive nivolumab and ipilimumab for up to 2 years (n = 303) or six cycles of chemotherapy with cisplatin or carboplatin plus pemetrexed (n = 302). Overall survival (OS) was improved for patients who received nivolumab and ipilimumab, with a median OS of 18.1 months [95% confidence interval (CI), 16.8-21.5] compared with 14.1 months (95% CI: 12.5-16.2; HR, 0.74; 95% CI, 0.61-0.89; P = 0.002), for patients who received chemotherapy. The magnitude of benefit was larger for patients with non-epithelioid versus epithelioid histology. Additional clinical pharmacology data support an alternative dosing regimen of nivolumab than evaluated in the trial, which will reduce the number of required treatment visits. This application was reviewed under FDA's Project Orbis, in collaboration with Australia's Therapeutic Goods Administration, Switzerland's Swissmedic, Health Canada, and Brazil's National Health Surveillance Agency or ANVISA (Agência Nacional de Vigilância Sanitária). Nivolumab and ipilimumab is the first drug regimen approved by FDA for MPM since 2004.

FDA Approval Summary: Pralsetinib for the Treatment of Lung and Thyroid Cancers With RET Gene Mutations or Fusions.

The FDA granted accelerated approval for pralsetinib on September 4, 2020 for non-small cell lung cancer (NSCLC) and December 1, 2020 for thyroid cancer, for: (i) adult patients with metastatic RET fusion-positive NSCLC, (ii) adult and pediatric patients ≥12 years of age with advanced or metastatic RET-mutant medullary thyroid cancer who require systemic therapy, and (iii) adult and pediatric patients ≥12 years of age with advanced or metastatic RET fusion-positive thyroid cancer who require systemic therapy and who are radioactive iodine refractory (if radioactive iodine is appropriate). Approval was based on the results of a multicenter, open-label, multi-cohort clinical trial (ARROW, NCT03037385), demonstrating substantial overall response rates (ORR) and durable responses in patients with RET-altered tumors. ORRs within the approved patient populations ranged from 57% [95% confidence interval (CI), 46-68] in patients with RET fusion-positive NSCLC previously treated with platinum chemotherapy to 89% (95% CI, 52-100) in patients with RET fusion-positive thyroid cancer, with response duration of at least 6 months in most responders. The product label includes warnings and precautions for pneumonitis, hypertension, hepatotoxicity, hemorrhagic events, tumor lysis syndrome, risk of impaired wound healing, and embryo-fetal toxicity. This article summarizes the major considerations during FDA review leading to the approval of pralsetinib.

Defluoridation using novel chemically treated carbonized bone meal: batch and dynamic performance with scale-up studies.

Novel defluoridating adsorbent was synthesized by chemical treatment of carbonized bone meal using aluminum sulfate and calcium oxide. Precursor for chemical treatment was prepared by partial carbonization of raw bone meal at 550 °C for 4 h. Maximum fluoride removal capacity was 150 mg/g when carbonized bone meal (100 g/L) was treated with aluminum sulfate (500 g/L) and calcium oxide (15 g/L). Morphological analysis revealed formation of a coating layer consisting of aluminum compounds on the precursor surface. This was verified by stretching frequency of aluminum hydroxide (602 cm-1) in the infrared spectra. Presence of hydroxylapatite (2θ = 30° and 2θ = 24°) and aluminum mineral phases (2θ = 44°) in the adsorbent were identified from the X-ray diffractograms. Adsorption capacity decreased from 150 mg/g (30 °C) to 120 mg/g (50 °C) indicating exothermic adsorption. Adsorption experiments under batch kinetic mode were simulated using shrinking core model. Effective fluoride diffusivity in the adsorbent and the mass transfer coefficient were estimated as 5.8 × 10-12 m2/s and 9 × 10-4 m/s, respectively. Desorption was maximum at basic pH and desorption efficiency was decreased by 31% after third cycle. Dynamic filtration with artificially fluoride-spiked solution showed that the empty bed contact time for a packed column with equal weight of carbonized and chemically treated adsorbent was 4.7 min and number of bed volumes treated (till WHO limit of 1.5 mg/L) was 340 for a column of 3-cm diameter and 18-cm length. The system was successfully tested using contaminated groundwater from an affected area. Fixed-bed column experiments were simulated from the first principles using convective pore diffusion-adsorption model for both synthetic solution and contaminated groundwater. Axial dispersion coefficient was found to be one order of magnitude less than the pore diffusivity indicating dominance of fluoride diffusion within porous network of adsorbent. The developed adsorbent exhibited antibacterial property as well.

Novel carbonized bone meal for defluoridation of groundwater: Batch and column study.

Low cost naturally available bone meal was carbonized and its fluoride adsorption capacity was explored. Carbonized bone meal (CBM) produced at 550°C, 4 h carbonization time and a heating rate of 60°C/min, showed fluoride adsorption capacity of 14 mg g-1. Adsorbent was characterized using scanning electron microscopy, X-ray diffraction, X-ray fluoroscence, thermogravimetric analysis and Fourier transform infrared spectroscopy to highlight its physical and chemical properties. Best fluoride uptake capacity was observed for 0.2 mm particle size, 7 g L-1 adsorbent concentration and at pH 6.5. Fluoride uptake was endothermic and chemisorption in nature. Effective diffusivity and mass transfer coefficient were obtained as 6 × 10-11 m2 s-1 and 9 × 10-5 m s-1 from shrinking core model. Sulphate and carbonate showed the highest interference effect on adsorption of fluoride by CBM. Maximum desorption was observed at basic pH (pH 12). Fixed bed study was performed and effect of different parameters (bed height, inlet flow rate and initial concentration) was investigated. Efficiency of the adsorbent using real life fluoride contaminated groundwater solution was also observed.

Effect of different operating conditions in cloud point assisted extraction of thymol from Ajwain (Trachyspermum Ammi L.) seeds and recovery using solvent.

Cloud point assisted extraction of thymol from water extract of Ajwain (Trachyspermum Ammi L.) seeds has been reported. Effects of different operating conditions, i.e., concentration of surfactant, heating time and temperature in extraction efficiency were investigated. It was observed that maximum extraction efficiency of thymol was achieved with 30% (v/v) of SPAN 80 surfactant, 45 min of heating at 65 °C. Recovery of thymol from the surfactant complex was optimal at 1:3 coacervate phase to solvent (acetone) volume ratio. A semi-empirical correlation was proposed at the optimum time to predict the concentration of surfactant and temperature required for a desired yield.

A socio-economic study along with impact assessment for laterite based technology demonstration for arsenic mitigation.

Arsenic contamination mitigation technologies have been adsorption-based, but the most widely-used and traditionally available adsorbents suffered inherent limitations, including cost infeasibility and problems associated with regeneration and disposal of the spent adsorbent. The present technology is based on indigenously developed activated laterite prepared from the naturally and abundantly available material, and can hence easily be scaled up for community usage and large scale implementation. The total arsenic removal capacity is 32.5mg/g, which is the highest among all naturally occurring arsenic adsorbents. A major issue in earlier adsorbents was that during regeneration, the adsorbed arsenic would be released back into the environment (leaching), and would eventually contaminate the groundwater again. But the adsorbent in this filter does not require regeneration during its five-year lifespan and does not leach upon disposal. An attempt is made to test and demonstrate the practical implementation of the technology - its effectiveness and viability in three community (primary schools - one in Malda and two in north 24 Parganas, West Bengal, India) and 20 household filters, catering to over 5000 people in different areas of West Bengal exposed to high arsenic contamination of groundwater (ranging from 0.05 to 0.5mg/l). The work also focuses on the social impact of the real life technological solution on the lives on the affected people in the worst hit arsenic affected communities, perhaps the greatest public health risk emergency of the decade.

Application of novel, low-cost, laterite-based adsorbent for removal of lead from water: Equilibrium, kinetic and thermodynamic studies.

Contamination of groundwater by carcinogenic heavy metal, e.g., lead is an important issue and possibility of using a natural rock, laterite, is explored in this work to mitigate this problem. Treated laterite (TL- prepared using hydrochloric acid and sodium hydroxide) was successfully utilized for this purpose. The adsorbent was characterized using scanning electron microscopy (SEM), X-ray diffraction (XRD), energy dispersive X-ray (EDX), and Fourier Transform Infrared Spectroscopy (FTIR) to highlight its physical and chemical properties. Optimized equilibrium conditions were 1 g L(-1) adsorbent concentration, 0.26 mm size and a pH of 7 ± 0.2. Monolayer adsorption capacity of lead on treated laterite was 15 mg/g, 14.5 and 13 mg g(-1) at temperatures of 303 K, 313 K and 323 K, respectively. The adsorption was exothermic and physical in nature. At 303 K, value of effective diffusivity of (De) and mass transfer co-efficient (Kf) of lead onto TL were 6.5 × 10(-10) m(2)/s and 3.3 × 10(-4) m/s, respectively (solved from shrinking core model of adsorption kinetics). Magnesium and sulphate show highest interference effect on the adsorption of lead by TL. Efficacy of the adsorbent has been verified using real-life contaminated groundwater. Thus, this work demonstrates performance of a cost-effective media for lead removal.