Correction to: Afatinib in advanced NSCLC: a profile of its use.

[This corrects the article DOI: 10.1007/s40267-018-0482-6.].

Afatinib in advanced NSCLC: a profile of its use.

Afatinib [Giotrif® (EU); Gilotrif® (USA)] is an orally administered, irreversible inhibitor of the ErbB family of tyrosine kinases that provides an important first-line treatment option for advanced non-small cell lung cancer (NSCLC) with activating epidermal growth factor receptor (EGFR) mutations (i.e. EGFRactMUT+), and an additional treatment option for squamous NSCLC that has progressed following first-line platinum-based chemotherapy. Relative to gefitinib in the first-line treatment of EGFRactMUT+ advanced lung adenocarcinoma, afatinib prolonged progression-free survival (PFS) and time to treatment failure (TTF), but not overall survival (OS). Afatinib also prolonged PFS, but not OS, versus cisplatin-based chemotherapy in this setting; however, afatinib improved OS versus chemotherapy in the subgroup of patients with deletions in exon 19. As a second-line treatment for advanced squamous NSCLC, afatinib prolonged PFS and OS compared with erlotinib, regardless of EGFR mutation status. Afatinib had a predictable and manageable tolerability profile.

Atogepant: First Approval.

Atogepant (Qulipta™) is an orally administered, small-molecule, calcitonin gene-related peptide (CGRP) receptor antagonist being developed by AbbVie for the prophylaxis of migraine. In September 2021, atogepant was approved in the USA for the preventive treatment of episodic migraine in adults. The drug is also in phase 3 clinical development for the preventive treatment of migraine in various other countries. This article summarizes the milestones in the development of atogepant leading to this first approval for the preventive treatment of episodic migraine in adults.

Chiglitazar: First Approval.

Chiglitazar (Bilessglu®) is an orally administered, non-thiazolidinedione small-molecule agonist of α, δ and γ peroxisome proliferator-activated receptors (PPARs) being developed by Chipscreen Biosciences for the treatment of type 2 diabetes (T2D) and non-alcoholic steatohepatitis. In October 2021, chiglitazar was approved in China for use as an adjunct to diet and exercise to improve glycaemic control in adult patients with T2D. The drug is also in phase 2 clinical development in China for the treatment of non-alcoholic steatohepatitis. This article summarizes the milestones in the development of chiglitazar leading to this first approval for the treatment of T2D.

Asciminib: First Approval.

Asciminib (Scemblix®) is an orally administered, small molecule, selective allosteric inhibitor that targets the myristoyl pocket of the BCR-ABL1 tyrosine kinase and is being developed by Novartis for the treatment of haematological malignancies, including Philadelphia chromosome-positive (Ph+) chronic myeloid leukaemia (CML). The drug is active against a number of the single catalytic-site mutations, such as T315I, that confer resistance to conventional tyrosine kinase inhibitors (TKIs) that bind to the ATP-binding site of BCR-ABL1. In October 2021, asciminib monotherapy was granted accelerated approval for the treatment of adults with Ph+ CML in chronic phase (CML-CP), previously treated with ≥ 2 TKIs, and full approval for the treatment of adults with Ph+ CML-CP with the T315I mutation. The drug is under regulatory review for use as monotherapy in CML in the EU, and is in phase 1-3 development exploring its potential in first-line, later-line and paediatric patients with CML. This article summarizes the milestones in the development of asciminib leading to this first approval for the treatment of adults with Ph+ CML-CP, previously treated with ≥ 2 TKIs, and Ph+ CML-CP with the T315I mutation.

Anifrolumab: First Approval.

Anifrolumab (anifrolumab-fnia; Saphnelo™) is a monoclonal antibody antagonist of the type 1 interferon receptor (IFNAR). It is being developed by AstraZeneca (under license from Medarex, now Bristol-Myers Squibb) for the treatment of autoimmune disorders, including systemic lupus erythematosus (SLE) and lupus nephritis, the underlying pathogenesis of which involves type 1 interferon. In July 2021, intravenous anifrolumab was approved in the USA for the treatment of adult patients with moderate to severe SLE who are receiving standard therapy. Anifrolumab (intravenous or subcutaneous) continues to be assessed in clinical studies in SLE in various countries, and the intravenous formulation is under regulatory review in the EU and Japan. This article summarizes the milestones in the development of anifrolumab leading to this first approval for the treatment of moderate to severe SLE.

Odevixibat: First Approval.

Odevixibat (Bylvay™) is a small molecule inhibitor of the ileal bile acid transporter being developed by Albireo Pharma, Inc. for the treatment of various cholestatic diseases, including progressive familial intrahepatic cholestasis (PFIC). In July 2021, odevixibat received its first approval in the EU for the treatment of PFIC in patients aged ≥ 6 months, followed shortly by its approval in the USA for the treatment of pruritus in patients aged ≥ 3 months with PFIC. Odevixibat is also in clinical development for the treatment of other cholestatic diseases, including Alagille syndrome and biliary atresia, in various countries. This article summarizes the milestones in the development of odevixibat leading to this first approval for PFIC.

Belzutifan: First Approval.

Belzutifan (Welireg™) is an oral small molecule inhibitor of hypoxia-inducible factor (HIF)-2α being developed by Peloton Therapeutics for the treatment of solid tumours, including renal cell carcinoma (RCC) with clear cell histology (ccRCC) and von Hippel-Lindau (VHL) disease-associated RCC. In August 2021, belzutifan received its first approval in the USA for the treatment of patients with VHL disease who require therapy for associated RCC, central nervous system (CNS) haemangioblastomas or pancreatic neuroendocrine tumours (pNET), not requiring immediate surgery. Clinical studies of belzutifan (as monotherapy or combination therapy) in other indications, including ccRCC, pNET and phaeochromocytoma/paraganglioma, are also underway in various countries. This article summarizes the milestones in the development of belzutifan leading to this first approval for certain VHL disease-associated tumours.

Furmonertinib: First Approval.

Furmonertinib mesylate (hereafter furmonertinib) [Ivesa®] is a selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) being developed by Allist Pharmaceuticals for the treatment of patients with EGFR mutation-positive non-small cell lung cancer (NSCLC). In March 2021, furmonertinib received its first approval in China for the treatment of patients with locally advanced or metastatic NSCLC with confirmed EGFR T790M mutation whose disease has progressed during or after EGFR TKI therapy. Furmonertinib (as monotherapy and/or combination therapy) continues to be assessed in phase I/II and phase III trials for NSCLC with EGFR mutation in China, and its clinical development is also underway/planned in China and elsewhere for NSCLC with various EGFR mutations. This article summarizes the milestones in the development of furmonertinib leading to this first approval for EGFR T790M-positive NSCLC.

Disitamab Vedotin: First Approval.

Disitamab vedotin (Aidixi®) is an antibody-drug conjugate comprising a monoclonal antibody against human epidermal growth factor receptor 2 (HER2) conjugated via a cleavable linker to the cytotoxic agent monomethyl auristatin E. Disitamab vedotin is being developed by RemeGen for the treatment of solid tumours, including gastric cancer; Seagen has the right to develop disitamab vedotin globally outside of RemeGen's territory. In June 2021, disitamab vedotin received its first Biologics License Application (BLA) approval in China for the treatment of patients with HER2-overexpressing (defined as IHC2+ or 3+) locally advanced or metastatic gastric cancer (including gastroesophageal junction adenocarcinoma) who have received at least two systemic chemotherapy regimens. Disitamab vedotin as monotherapy or combination therapy is also in clinical development for the treatment of other solid tumours globally, including urothelial cancer in China and the USA, and biliary tract cancer, non-small cell lung cancer and HER2-positive and HER2-low expressing breast cancer in China. This article summarizes the milestones in the development of disitamab vedotin leading to this first approval for locally advanced or metastatic gastric cancer.

Casirivimab/Imdevimab: First Approval.

Casirivimab/imdevimab (Ronapreve™; REGEN-COV™) is a co-packaged combination of two neutralizing immunoglobulin gamma 1 (IgG1) human monoclonal antibodies (casirivimab and imdevimab) against the spike protein of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19). Casirivimab/imdevimab received its first emergency use authorization for the treatment of COVID-19 in November 2020 in the USA, with similar authorizations subsequently granted in various other countries, including India, Canada, and Switzerland. In February 2021, casirivimab/imdevimab was granted a positive scientific opinion in the EU for the treatment of COVID-19. In July 2021, casirivimab/imdevimab received its first approval in Japan for the treatment of mild or moderate COVID-19, followed in August 2021 by its conditional approval for the prophylaxis and treatment of acute COVID-19 infection in the UK. The combination was also granted provisional determination in Australia in August 2021, indicating its eligibility to be considered for provisional registration for COVID-19 treatment and prevention. This article summarizes the milestones in the development of casirivimab/imdevimab leading to these first approvals for COVID-19.

Difelikefalin: First Approval.

Difelikefalin (Korsuva™) is a synthetic peptide agonist of the kappa opioid receptor being developed by Cara Therapeutics for the treatment of pruritus. In August 2021, intravenous difelikefalin was approved in the USA for the treatment of moderate-to-severe pruritus associated with chronic kidney disease (CKD) in adults undergoing haemodialysis. Intravenous difelikefalin has also been evaluated for CKD-associated pruritus in patients undergoing haemodialysis in various other countries, with Marketing Authorization Application under regulatory review in the EU and a phase III trial ongoing in Japan. Clinical studies of an oral formulation of difelikefalin have also been completed or are underway in pruritus indications, including pruritus associated with atopic dermatitis, notalgia paraesthetica or primary biliary cholangitis. This article summarizes the milestones in the development of difelikefalin leading to this first approval for CKD-associated pruritus in adults undergoing haemodialysis.

Abrocitinib: First Approval.

Abrocitinib (Cibinqo®) is an oral small-molecule inhibitor of Janus kinase 1 (JAK1) being developed by Pfizer for the treatment of moderate-to-severe atopic dermatitis (AD). In September 2021, abrocitinib was approved in the UK and Japan for the treatment of moderate-to-severe AD in adults and adolescents 12 years and older who are candidates for systemic therapy. Abrocitinib has also received a positive CHMP opinion in the EU for the treatment of moderate-to-severe atopic dermatitis in adults who are candidates for systemic therapy. Regulatory applications for the drug have also been submitted for review to several other countries, including the USA and Australia. This article summarizes the milestones in the development of abrocitinib leading to this first approval for the treatment of moderate-to-severe AD.

Doxycycline 40 mg capsules (30 mg immediate-release/10 mg delayed-release beads): anti-inflammatory dose in rosacea.

Anti-inflammatory dose doxycycline 40 mg capsules (30 mg immediate-release and 10 mg delayed-release beads) provide a sub-antimicrobial dose that reduces the inflammatory response in patients with rosacea without producing drug concentrations required to treat bacterial diseases. The efficacy of oral, anti-inflammatory dose doxycycline 40 mg capsules once daily in the treatment of adults with rosacea was demonstrated in two pivotal large, randomized, double-blind, placebo-controlled, multicenter trials. After 16 weeks' therapy, anti-inflammatory dose doxycycline 40 mg was significantly more effective in improving rosacea than placebo, providing a greater reduction in the total inflammatory lesion count (primary endpoint) than placebo. Anti-inflammatory dose doxycycline 40 mg was associated with a rapid onset of action, achieving a significantly greater decrease in total inflammatory lesion count than placebo by the first follow-up visit at week 3 in both studies. Maximum anti-inflammatory efficacy appears to be achieved with doxycycline 40 mg capsules once daily, as no additional improvement in rosacea symptoms was achieved with oral doxycycline 100 mg once daily (usual antibacterial dosage) in a small, randomized, double-blind trial. Anti-inflammatory dose doxycycline 40 mg was generally well tolerated in clinical trials, with most adverse events being of mild to moderate intensity.

Apremilast: A Review in Oral Ulcers of Behçet's Disease.

The oral phosphodiesterase 4 inhibitor apremilast (Otezla®) is indicated for the treatment of oral ulcers associated with Behçet's disease in some countries, including the USA (where it is the first agent approved for the disease) and Japan. In phase 2 and 3 trials in adults with this chronic and debilitating disorder, 12 weeks of treatment with apremilast 30 mg twice daily reduced the number and pain of oral ulcers and disease activity relative to placebo, with these clinical benefits being accompanied by improvements in health-related quality of life (HR-QOL). Benefits of apremilast were seen regardless of baseline patient/disease characteristics and in Japanese patients, and were sustained over up to 64 weeks of treatment. Apremilast was generally well tolerated, with gastrointestinal adverse events being among the most common tolerability issues. Emerging real-world data also support the drug's use in this setting. Thus, for patients with oral ulcers associated with Behçet's disease, apremilast provides an effective and generally well tolerated approved treatment option.

Cemiplimab: A Review in Advanced Cutaneous Squamous Cell Carcinoma.

Cemiplimab (Libtayo®) is an antibody immunotherapy that stimulates an anti-cancer response via programmed cell death protein-1 (PD-1) blockade. It is the first approved treatment in the USA and EU for patients with locally advanced (laCSCC) or metastatic (mCSCC) cutaneous squamous cell carcinoma who are not candidates for curative surgery or curative radiotherapy. Approval was based largely on positive results from the phase II EMPOWER-CSCC 1 trial in this patient population. In this pivotal trial, treatment with intravenous cemiplimab 3 mg/kg once every 2 weeks or 350 mg once every 3 weeks resulted in a clinically significant objective response rate across laCSCC and mCSCC patient groups. Furthermore, responses appear to be durable, as the median duration of response has not yet been reached. Similarly, the median overall survival has also not yet been reached as of the latest data cut-off date. The safety and tolerability profile of cemiplimab was acceptable, with most immune-related adverse events being clinically manageable with appropriate therapy or discontinuation of cemiplimab. Overall, cemiplimab has a durable, clinically significant effect and an acceptable tolerability and safety profile. As the first approved treatment for this indication, cemiplimab represents a welcome therapeutic advance for patients with advanced CSCC.

Cenegermin: A Review in Neurotrophic Keratitis.

Cenegermin (Oxervate™), an ophthalmic solution containing 20 µg/mL of recombinant human nerve growth factor (rhNGF), is the first drug to be approved for the treatment of neurotrophic keratitis (NK; also referred to as neurotrophic keratopathy). In the registration trials, the majority of adults with moderate or severe NK experienced complete corneal healing after up to 8 weeks of topical cenegermin therapy. The rate of complete corneal healing was generally higher, and that of disease progression was lower, with cenegermin than with vehicle. Although the drug provided no statistically significant benefit over vehicle in terms of corneal sensitivity or visual acuity after 8 weeks of treatment, few patients with corneal healing experienced disease recurrence over 48 weeks of follow-up. Longer-term data are needed to definitively determine the efficacy of cenegermin with respect to these outcomes; further investigation into cenegermin re-treatment following disease recurrence would also be beneficial. Cenegermin had no detrimental impact on health-related quality of life (in contrast to some surgical treatments) and was generally well tolerated. Cenegermin is thus a welcomed non-surgical treatment option approved for this rare and challenging degenerative disease.

Correction to: Cemiplimab: A Review in Advanced Cutaneous Squamous Cell Carcinoma.

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Exemestane: a review of its use in postmenopausal women with breast cancer.

Exemestane (Aromasin) is an orally active steroidal irreversible inactivator of the aromatase enzyme indicated as an adjuvant treatment in postmenopausal women with estrogen receptor-positive early-stage breast cancer following 2-3 years of adjuvant treatment with tamoxifen, and for the treatment of advanced breast cancer in postmenopausal women whose disease has progressed following tamoxifen or other antiestrogen therapy. Exemestane is effective for the treatment of postmenopausal women with early-stage or advanced breast cancer. In early-stage disease, switching to exemestane for 2-3 years after 2-3 years of adjuvant tamoxifen treatment was more effective in prolonging disease-free survival than continuing tamoxifen therapy, although it was not associated with an overall survival benefit, except in those with estrogen receptor-positive or unknown receptor status disease when nodal status, hormone replacement therapy (HRT) and chemotherapy use were adjusted for. Moreover, preliminary data suggest that the efficacy of exemestane is generally no different to that of tamoxifen in the primary adjuvant treatment of early-stage breast cancer, although exemestane may be better in prolonging the time to distant recurrence. In advanced disease, exemestane showed equivalent efficacy to megestrol in patients with disease refractory to tamoxifen and an efficacy not significantly different from that of fulvestrant in those refractory to a nonsteroidal aromatase inhibitor. Available data, some of which are limited, suggest exemestane is also effective in the first-line hormonal treatment of advanced breast cancer in postmenopausal women. Exemestane is generally well tolerated, although the potential bone fracture risk of the drug requires further investigation. Results from directly comparative trials indicating the efficacy, tolerability and bone fracture risk of exemestane relative to third-generation aromatase inhibitors and other agents in both early-stage and advanced disease, as well as the optimal sequence of endocrine therapies, are awaited with interest. In the meantime, switching to exemestane should be considered in postmenopausal women who have received 2-3 years of adjuvant tamoxifen treatment for early-stage breast cancer, and is an emerging treatment option for postmenopausal women with advanced breast cancer refractory to one or more antiestrogen therapies.

Amlodipine/valsartan/hydrochlorothiazide: fixed-dose combination in hypertension.

Amlodipine/valsartan/hydrochlorothiazide (HCTZ) is a fixed-dose combination of the well established antihypertensive agents amlodipine (a calcium channel antagonist), valsartan (an angiotensin II receptor antagonist), and HCTZ (a thiazide diuretic). In patients with moderate or severe hypertension, triple combination therapy with amlodipine + valsartan + HCTZ produced significantly greater reductions from baseline in mean sitting systolic and diastolic BP (msSBP and msDBP) than either valsartan + HCTZ, amlodipine + HCTZ, or amlodipine + valsartan in a large, 8-week, randomized, double-blind, multinational, phase III trial. Furthermore, the proportion of patients achieving overall BP control at endpoint was significantly greater with the triple combination regimen than with any of the dual regimens, with significantly more triple combination recipients achieving msSBP and msDBP control at each assessment throughout the trial. Subgroup analyses of this study suggested that amlodipine + valsartan + HCTZ was generally more effective in reducing BP and providing overall BP control than the dual combination therapies, irrespective of age, race, gender, ethnicity, or hypertension severity. Several smaller studies provide data that support the efficacy of amlodipine + valsartan + HCTZ in patients whose BP is inadequately controlled with amlodipine + valsartan, amlodipine + HCTZ, or valsartan + HCTZ dual combination therapy. Treatment with amlodipine + valsartan + HCTZ for up to 8 weeks was generally well tolerated in the large, phase III trial, with most adverse events being transient and of mild to moderate severity.