What's new in drug therapy

The following material represents a subset of new drugs, drug approvals, drug warnings, and drugs removed from the market from the past six months. This is not a complete list; it includes those topics considered by the authors and editors to be of particular interest or importance. For a complete list of new drug approvals, see /lco/action/index/newapprovals/patch_f (an additional subscription may be required).

You can check drug interactions by going to the drug interactions program included with UpToDate.

GENERAL DRUG THERAPY

Reversal strategy for intracerebral hemorrhage associated with direct factor Xa inhibitors (May 2024)

The optimal reversal strategy for direct factor Xa inhibitors (apixaban, edoxaban, rivaroxaban) in acute intracerebral hemorrhage (ICH) is uncertain. In the ANNEXA-I trial, which randomly assigned 530 patients with factor Xa inhibitor-associated ICH to andexanet alfa or standard care (typically including a prothrombin complex concentrate [PCC]), patients assigned to andexanet had higher rates of hemostasis than those assigned to standard therapy (67 versus 53 percent) [1]. However, thrombotic events, including ischemic stroke and myocardial infarction, were more common with andexanet (10.3 versus 5.6 percent). Mortality and functional outcomes at 30 days were similar. Based on these results, we individualize selection of andexanet alfa or PCC for direct factor Xa inhibitor reversal in acute ICH and other life-threatening bleeding; previously, we favored andexanet in most cases. Andexanet may restore hemostasis more effectively than PCC but is associated with higher thrombotic risk. (See "Reversal of anticoagulation in intracranial hemorrhage", section on 'Reversal agent options'.)

Updated guidelines for the management of acne vulgaris (May 2024)

The American Academy of Dermatology published updated guidelines for the management of acne vulgaris [2]. The guidelines continue to support multiple treatment measures, such as combined use of topical agents with different mechanisms of action; limited duration of antibiotic treatment; topical or systemic antibiotic treatment only in conjunction with topical benzoyl peroxide; and oral isotretinoin treatment for severe acne, acne that has not responded adequately to standard oral or topical treatment, and acne associated with psychosocial burden or scarring. (See "Acne vulgaris: Overview of management", section on 'Treatment principles'.)

Hepatitis C virus antiviral treatment for patients with opioid use disorder (May 2024)

Despite concerns about adherence to antiviral therapy among individuals with opioid use disorder, hepatitis C virus (HCV) treatment can be highly successful in this population, particularly in nontraditional care settings. In a cluster-randomized trial that included 600 individuals with chronic HCV infection who were engaged in an opioid treatment program, provision of antiviral therapy through the program, directed by an HCV specialist over telemedicine, increased rates of antiviral initiation (92 versus 40 percent) and sustained virologic response (85 versus 30 percent) compared with traditional referral to a specialist clinic for treatment [3]. These data highlight the impact of reducing barriers to care for individuals with opioid use disorder and support our recommendation to treat all patients for chronic HCV, regardless of active drug use. (See "Patient evaluation and selection for antiviral therapy for chronic hepatitis C virus infection", section on 'Active drug use'.)

Calcitonin gene-related peptide antagonists as a first-line preventive therapy for migraine (April 2024)

Several calcitonin gene-related peptide (CGRP) antagonists available for migraine prevention have frequently been reserved for patients with an inadequate response to initial therapy. However, in a position statement by the American Headache Society, CGRP antagonists are now considered among first-line therapies for migraine prevention, based on cumulative evidence of efficacy, safety, and tolerability from several clinical trials, meta-analyses, and postapproval open-label cohort studies [4]. They may be effective for patients with severe symptoms or frequent migraines and may provide earlier benefit than other preventive agents, and the formulations given by injection may also be helpful for those who have difficulty with daily dosing. However, cost or insurance approval may limit access to these agents as first-line therapy for some patients. (See "Preventive treatment of episodic migraine in adults", section on 'Choosing pharmacologic therapy'.)

Tailored clinical alerts in the intensive care unit (March 2024)

Clinical decision support systems are commonly used in hospital settings to assist in medication ordering, but numerous low-yield alerts can lead to alarm fatigue and lack of benefit. In a randomized trial conducted in nine intensive care units (ICUs) in the Netherlands among 9887 patients, ICU-tailored drug-drug interaction alerts reduced administrations of high-risk drug combinations relative to control (26.2 versus 35.6 per 1000 drug administrations, respectively) [5]. Tailoring alert systems to be relevant to the clinical setting may result in meaningful improvements in care. (See "Prevention of adverse drug events in hospitals", section on 'Computerized physician order entry'.)

The Preventing Risk of Cardiovascular Disease EVENTS (PREVENT) calculator (February 2024)

Guidelines for primary prevention of cardiovascular disease (CVD) recommend using a risk calculator to estimate atherosclerotic CVD (ASCVD) risk. However, risk calculators derived from older databases may not reflect current risk in diverse populations. To provide contemporary estimates of ASCVD risk, the PREVENT calculator was derived and validated in over 6.6 million adults to estimate 10- and 30-year risks of CVD and its subtypes, heart failure and ASCVD [6,7]. The PREVENT calculator inputs include standard CVD risk measures (eg, age, sex, body mass index, diabetes, lipid levels, smoking history, blood pressure, and kidney function); the full model also includes albuminuria, hemoglobin A1C, and zip code (which estimates social deprivation). The PREVENT calculator is a valuable tool for individualizing risk assessment and discussing the primary prevention of ASCVD with patients. (See "Atherosclerotic cardiovascular disease risk assessment for primary prevention in adults: Our approach", section on 'Choosing a risk calculator'.)

Effects of tirzepatide discontinuation on weight (February 2024)

Glucagon-like peptide 1-based therapies for the treatment of obesity result in substantial weight loss. Although earlier data suggested that stopping treatment with semaglutide results in weight regain, it was unclear whether the same occurs with tirzepatide. Among adults with obesity who had previously lost weight (21 percent mean weight reduction) during a 36-week, open-label trial of tirzepatide, those randomly assigned to continue tirzepatide for 52 weeks experienced additional weight loss, whereas those assigned to placebo partially regained (-5.5 versus +14 percent mean weight change, respectively) [8]. These results, in line with those of previous studies, suggest that most individuals with obesity who opt for pharmacotherapy will require long-term treatment for weight loss maintenance. (See "Obesity in adults: Drug therapy", section on 'Duration of therapy'.)

Low- versus high-dose calcium supplements and risk of preeclampsia (January 2024)

In populations with low baseline dietary calcium intake, the World Health Organization recommends 1500 to 2000 mg/day calcium supplementation for pregnant individuals to reduce their risk of developing preeclampsia. However, a recent randomized trial that evaluated low (500 mg) versus high (1500 mg) calcium supplementation in over 20,000 nulliparous pregnant people residing in two countries with low dietary calcium intake found low and similar rates of preeclampsia in both groups [9]. These findings suggest that a 500 mg supplement is sufficient for preeclampsia prophylaxis in these populations. For pregnant adults in the United States, we prescribe 1000 mg/day calcium supplementation, which is the recommended daily allowance to support maternal calcium demands without bone resorption. (See "Preeclampsia: Prevention", section on 'Calcium supplementation when baseline dietary calcium intake is low'.)

Semaglutide and cardiovascular outcomes (January 2024)

Semaglutide and other glucagon-like peptide 1 receptor agonists can reduce rates of adverse cardiovascular events in individuals with type 2 diabetes who have established cardiovascular disease or are at high risk of cardiovascular disease. In a newly published trial of 17,604 individuals with overweight or obesity and cardiovascular disease but not diabetes, once-weekly subcutaneous semaglutide 2.4 mg reduced rates of adverse cardiovascular outcomes compared with placebo (6.5 versus 8.0 percent) [10]. Discontinuation of the study drug due to side effects occurred more often with semaglutide (17 versus 8 percent). For individuals with overweight or obesity and established cardiovascular disease, semaglutide is a particularly attractive option for chronic weight management. (See "Obesity in adults: Drug therapy", section on 'Cardiovascular benefits'.)

Guidelines for fever management in critically ill patients (November 2023)

Updated guidelines on the management of fever in the intensive care unit have been recently published by the Society for Critical Care Medicine and the Infectious Diseases Society of America [11]. Differences with the previous guidelines include an emphasis on the use of core methods when feasible (eg, pulmonary artery catheter, bladder, esophageal) and oral or rectal measurement when not feasible. Also promoted was the use of bedside imaging (eg, ultrasonography) in the evaluation process and biomarkers to facilitate duration of antimicrobial therapy. We agree with the recommendations, most of which were based upon weak evidence. (See "Fever in the intensive care unit", section on 'Temperature measurement'.)

DRUG OR INDICATION WITHDRAWALS

Sodium phenylbutyrate-taurursodiol withdrawn from market (April 2024)

Sodium phenylbutyrate-taurursodiol (PB-TURSO) was approved by the US Food and Drug Administration for patients with amyotrophic lateral sclerosis (ALS) in September 2022 after an initial placebo-controlled trial of 137 participants showed a slowing in clinical deterioration at 24-week follow-up. However, the company has indicated that a confirmatory trial involving 664 participants with ALS failed to confirm the efficacy of PB-TURSO at 48 weeks (unpublished data) [12]. In response, in April 2024, the medication was withdrawn from the market by the manufacturer in Canada and the United States [13]. PB-TURSO may continue to be available for some patients already on therapy and trial participants. (See "Disease-modifying treatment of amyotrophic lateral sclerosis", section on 'Sodium phenylbutyrate-taurursodiol'.)

Copanlisib withdrawn from the market (November 2023)

While previously approved by the US Food and Drug Administration for the treatment of multiply relapsed follicular lymphoma (FL), the phosphoinositide 3-kinase (PI3K) inhibitor copanlisib has been voluntarily withdrawn from the market by its manufacturer [14]. While initial studies suggested efficacy, subsequent studies did not confirm a favorable risk-to-benefit ratio. There are now no PI3K inhibitors with regulatory approval for FL. Patients who began treatment with copanlisib and are experiencing benefit with acceptable levels of toxicity may choose to continue the drug; the manufacturer is exploring access options. (See "Treatment of relapsed or refractory follicular lymphoma", section on 'Other novel agents'.)

ADVERSE REACTIONS AND WARNINGS

Severe hypocalcemia with denosumab therapy in dialysis-treated patients (February 2024)

Denosumab use is not restricted in individuals with osteoporosis who have advanced kidney disease. However, concerns remain regarding the risk of severe hypocalcemia in such patients. In a cohort study of 2804 female patients (aged ≥65 years) with osteoporosis and undergoing dialysis, severe hypocalcemia (serum calcium <7.5 mg/dL [1.9 mmol/L] or hypocalcemia requiring emergency care) occurred in a higher proportion of patients who initiated denosumab compared with those who initiated an oral bisphosphonate (12-week weighted cumulative incidence 41.1 versus 2 percent, respectively) [15]. Denosumab also was associated with a higher incidence of very severe hypocalcemia (serum calcium <6.5 mg/dL [1.6 mmol/L]). A boxed warning about risk of severe hypocalcemia in individuals with advanced kidney disease, especially patients on dialysis, has been added for brand name denosumab (Prolia) [16], underscoring the need for greater caution and increased monitoring during treatment. (See "Denosumab for osteoporosis", section on 'Hypocalcemia'.)

Hearing impairment after teprotumumab for thyroid eye disease (January 2024)

Teprotumumab, an insulin-like growth factor 1 receptor inhibitor, is a relatively new, effective treatment for moderate-to-severe thyroid eye disease. In the initial clinical trials, hearing abnormalities were reported in approximately 10 percent of patients, but audiograms were not routinely performed. In a subsequent prospective study evaluating hearing outcomes before and after teprotumumab therapy in 52 patients, 21 percent had a decline in hearing on audiometry immediately after completing therapy, which persisted after six months in 5 patients [17]. Most patients with hearing loss had baseline hearing dysfunction. It is important to discuss potential adverse hearing effects prior to initiating therapy and review symptoms at each visit. It is reasonable to obtain baseline audiometry in all patients and repeat in individuals who report any change in hearing. (See "Treatment of thyroid eye disease", section on 'Teprotumumab'.)

Risk of fractures with benzodiazepine receptor agonists (January 2024)

Benzodiazepine receptor agonists (BZRAs), including benzodiazepines and nonbenzodiazepine BZRAs such as zolpidem, can cause excess drowsiness and imbalance leading to falls and fractures. In a recent meta-analysis of 20 observational studies in over six million individuals, BZRAs were associated with increased risk of osteoporotic fractures across a range of drug classes and fracture types, with odds ratios ranging from 1.2 to 1.4 [18]. Most but not all studies included adults 50 years of age or older. These data reinforce the need for caution in prescribing BZRAs for insomnia and other indications, particularly in older adults. (See "Pharmacotherapy for insomnia in adults", section on 'Special populations'.)

Rare secondary T cell lymphomas after chimeric antigen receptor (CAR)-T cell therapy (December 2023)

Chimeric antigen receptor (CAR)-T cell therapy is effective for treatment of relapsed or refractory B cell lymphomas, multiple myeloma, and other disorders, but it may be associated with severe and potentially fatal adverse effects (AEs). Reports are now emerging of secondary T cell lymphomas in patients treated with CD19- and B cell maturation antigen (BCMA)-directed CAR-T cell therapy, some of which have CAR-positive malignant cells [19]. Although rare, the actual incidence is not well defined and it is uncertain if they are associated with all CAR-T cell products. US Food and Drug Administration (FDA)-approved CAR-T cell products include warnings about potential secondary malignancies, but at present, no regulatory action has been taken and no product has been recalled. Patients receiving CAR-T cell therapy should be monitored for development of new malignancies, and any such events should be reported to the manufacturer and to the FDA AE Reporting System (FAERS) [20]. The overall benefits of CAR-T cell products continue to outweigh potential risks for approved uses, but patients should be monitored and events reported. (See "Diffuse large B cell lymphoma (DLBCL): Suspected first relapse or refractory disease in patients who are medically fit", section on 'Relapse <12 months or primary refractory DLBCL'.)

Macular changes related to pentosan polysulfate sodium (November 2023)

Macular eye disease has been reported in patients who have taken pentosan polysulfate sodium (PPS), which is used for the treatment of interstitial cystitis. In a prospective cohort study of 26 eyes with PPS maculopathy and >3000 g cumulative PPS exposure, progression of macular changes continued 13 to 30 months after drug cessation [21]. Median visual acuity decreased slightly; most patients reported progression of symptoms, including difficulty in low-light environments and blurry vision. These results indicate that PPS maculopathy progresses despite drug discontinuation, underscoring the importance of regular screening for maculopathy in patients with current or prior PPS exposure. (See "Interstitial cystitis/bladder pain syndrome: Management", section on 'Pentosan polysulfate sodium as alternative'.)

RECENT APPROVALS - ANTIMICROBIALS

Taurolidine catheter locks for the prevention of hemodialysis catheter-related bloodstream infections (December 2023)

Catheter-related bloodstream infections (CRBSIs) are an important cause of morbidity and mortality in patients on hemodialysis. In a randomized trial of nearly 800 patients on maintenance hemodialysis via a tunneled central venous catheter, a catheter lock solution containing taurolidine, an antimicrobial agent, plus heparin reduced the incidence of CRBSI compared with a heparin control lock solution (2 versus 8 percent) over a mean of 200 days [22]. No trial participants used chlorhexidine-coated catheter caps, which are commonly used to reduce the risk of CRBSI. Based on these results, taurolidine lock solutions are a reasonable alternative to chlorhexidine-coated catheter caps to help prevent CRBSIs in select patients. (See "Tunneled hemodialysis catheter-related bloodstream infection (CRBSI): Management and prevention", section on 'Methods we use'.)

RECENT APPROVALS - DERMATOLOGIC AND ALLERGY THERAPIES

Omalizumab for food allergy (March 2024)

Most food allergy reactions can be prevented with careful avoidance, but accidental exposures and reactions can still occur. There are also substantial burdens associated with avoidance. In a multicenter, placebo-controlled randomized trial in 177 children aged 1 to 17 years with multiple food allergies, patients assigned to omalizumab, an anti-immunoglobulin E (anti-IgE) monoclonal antibody, plus allergen avoidance had an increased reaction threshold on oral food challenge, compared with avoidance alone [23]. These findings suggest that omalizumab may offer some protection from accidental food exposures and contributed to US Food and Drug Administration approval for this indication [24]. However, its ability to induce permanent tolerance is untested, its use is costly, and administration requires subcutaneous injections at regular intervals indefinitely. For most patients with food allergy, we suggest allergen avoidance alone rather than avoidance plus omalizumab. (See "Food allergy management: Allergen-nonspecific therapies", section on 'Efficacy' and "Management of IgE-mediated food allergy: An overview", section on 'Choice of strategy'.)

Topical roflumilast for seborrheic dermatitis (January 2024)

Seborrheic dermatitis is a chronic, relapsing dermatitis involving areas rich in sebaceous glands (eg, scalp, face) that requires repeated or long-term maintenance treatment with topical anti-inflammatory agents. In a randomized trial that included 226 adults with moderate to severe seborrheic dermatitis, topical roflumilast, a potent phosphodiesterase-4 inhibitor with anti-inflammatory properties, was more effective than vehicle in achieving an Investigator Global Assessment score of clear/almost clear at eight weeks (74 versus 41 percent, respectively) [25]. Treatment was generally well tolerated. These findings contributed to approval by the US Food and Drug Administration of roflumilast 0.3% foam for the treatment of seborrheic dermatitis in adults and children older than nine years [26]. (See "Seborrheic dermatitis in adolescents and adults", section on 'Topical anti-inflammatory agents'.)

RECENT APPROVALS - ENDOCRINE AND KIDNEY DISEASE THERAPIES

Tirzepatide for weight loss in adults (March 2024)

The US Food and Drug Administration recently approved subcutaneous tirzepatide, a dual glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor agonist, for chronic weight management [27]. Two randomized trials in adults with obesity demonstrated mean losses of 15 to 21 percent body weight with the highest dose of tirzepatide (15 mg weekly) [28,29]. In the larger of the two trials, over 80 percent of participants in all tirzepatide treatment groups (5 to 15 mg weekly) lost ≥5 percent of body weight, compared with 35 percent of those assigned to placebo [28]. Dose-related gastrointestinal side effects (nausea, diarrhea, constipation) were common but generally mild. Although direct comparisons are limited, the magnitude of weight loss with tirzepatide appears greater than that with other agents; thus, we consider tirzepatide a preferred medication for chronic weight management. (See "Obesity in adults: Drug therapy", section on 'Efficacy for weight loss'.)

RECENT APPROVALS - HEMATOLOGIC AND ANTICOAGULANT

Zanubrutinib plus obinutuzumab in multiply relapsed follicular lymphoma (April 2024)

Zanubrutinib, a Bruton tyrosine kinase inhibitor, has received regulatory approval by the US Food and Drug Administration for use with obinutuzumab in patients with multiply relapsed follicular lymphoma (FL) [30]. Approval was based on results from a randomized trial in which >200 patients who had received two or more prior systemic therapies for FL experienced improved overall response rates and progression-free survival with the addition of zanubrutinib to obinutuzumab. Toxicities with zanubrutinib were modest. Although we prefer other combinations, including lenalidomide with either rituximab or obinutuzumab, for multiply relapsed FL, we consider zanubrutinib plus obinutuzumab to be an acceptable alternative or later-line option. (See "Treatment of relapsed or refractory follicular lymphoma", section on 'Zanubrutinib plus obinutuzumab'.)

CAR-T cell therapy for multiply relapsed CLL (April 2024)

The US Food and Drug Administration recently granted accelerated approval of the CD19-directed chimeric antigen receptor T (CAR-T) cell therapy lisocabtagene maraleucel for patients with relapsed or refractory chronic lymphocytic leukemia (CLL) after two or more lines of systemic therapy including a Bruton tyrosine kinase inhibitor and a BCL2 inhibitor [31]. Approval was based on accumulating evidence from single-arm prospective trials that show variable response rates and duration of response; remissions have lasted over a decade in some patients with persistent CAR-T cells. This population has few therapeutic alternatives, and we consider CAR-T cell therapy an option for fit patients who meet these criteria. However, given the toxicity, complexity, and cost, the decision is individualized and highly dependent on an estimation of complication risk and the needs and wishes of the patient. (See "Treatment of relapsed or refractory chronic lymphocytic leukemia", section on 'Chimeric antigen receptor T cells'.)

Pegcetacoplan self-injector for adults with paroxysmal nocturnal hemoglobinuria (November 2023)

Pegcetacoplan is a pegylated peptide that can inhibit both intravascular and extravascular hemolysis in adults with paroxysmal nocturnal hemoglobinuria (PNH). The US Food and Drug Administration (FDA) recently approved pegcetacoplan in a single-use self-injector for use by the patient or caregiver after training in preparation and administration [32]. As with other complement inhibitors, pegcetacoplan is contraindicated in patients with severe infections, and the FDA label has a boxed warning about increased risk for meningococcal infections. We consider the pegcetacoplan self-injector an acceptable method for treatment of adults with symptomatic PNH. (See "Treatment and prognosis of paroxysmal nocturnal hemoglobinuria", section on 'Pegcetacoplan'.)

RECENT APPROVALS - NEUROLOGIC AND PSYCHIATRIC

Givinostat for Duchenne muscular dystrophy (April 2024)

The histone deacetylase inhibitor givinostat was recently approved by the US Food and Drug Administration for the treatment of Duchenne muscular dystrophy (DMD) in patients six years of age and older. Approval was based on results from a small randomized trial, which suggest that givinostat may slow DMD progression [33]. Benefit was found on only one outcome (the four-stair climb test), as shown by a smaller performance decline from baseline to 72 weeks for the givinostat group compared with placebo (1.25 versus 3.03 seconds); statistical significance was marginal. Adverse effects of givinostat include gastrointestinal disturbances, thrombocytopenia, elevated triglycerides, fever, and potential QTc interval prolongation. While givinostat may be used in combination with glucocorticoid therapy and genetic therapies, its role in the treatment of DMD remains to be defined, and further data are needed to confirm benefit. (See "Duchenne and Becker muscular dystrophy: Glucocorticoid and disease-modifying treatment", section on 'Givinostat'.)

Vamorolone for Duchenne muscular dystrophy (December 2023)

Glucocorticoid treatment with prednisone or deflazacort for Duchenne muscular dystrophy (DMD) is associated with improved motor function, but adverse effects include weight gain, slowing of growth, and bone loss. Vamorolone, a novel steroid, was designed to reduce adverse effects of glucocorticoid therapy for DMD. In the VISION-DMD trial, vamorolone treatment led to improvement on several motor outcomes compared with placebo, while efficacy was similar compared with prednisone [34]. Prednisone treatment (but not vamorolone) led to growth deceleration and bone biomarker abnormalities. Based on these findings, the US Food and Drug Administration approved vamorolone for children age ≥2 years with DMD [35]. We suggest glucocorticoid treatment for children with DMD and anticipate using vamorolone as an alternative to prednisone and deflazacort. (See "Duchenne and Becker muscular dystrophy: Glucocorticoid and disease-modifying treatment", section on 'Benefits of glucocorticoid therapy'.)

RECENT APPROVALS - ONCOLOGIC

Nogapendekin alfa inbakicept for BCG-unresponsive non-muscle invasive bladder cancer (May 2024)

For patients with Bacillus Calmette-Guerin (BCG) unresponsive non-muscle invasive bladder cancer (NMIBC), studies are evaluating novel therapies such as nogapendekin alfa inbakicept (NAI), an interleukin 15 superagonist antibody cytokine fusion protein. In an open-label trial in over 150 patients with BCG-unresponsive NMIBC, among the subgroup of 82 patients with carcinoma in situ (CIS), intravesical NAI plus BCG demonstrated a complete response rate of 71 percent and two-year overall survival (OS) of 94 percent [36]. Among the 72 patients with papillary disease only, two-year OS was 92 percent. Based on these data, the US Food and Drug Administration approved intravesical NAI in combination with BCG for the treatment of adult patients with BCG-unresponsive NMIBC with CIS with or without papillary tumors [37]. (See "Treatment of recurrent or persistent non-muscle invasive urothelial carcinoma of the bladder", section on 'Nogapendekin alfa inbakicept'.)

Tovorafenib in BRAF-altered pediatric low-grade gliomas (May 2024)

Tovorafenib is a first-in-class oral type II RAF inhibitor recently approved by the US Food and Drug Administration for treatment of relapsed or refractory pediatric low-grade glioma (LGG) harboring a BRAF V600E mutation or BRAF fusion or rearrangement [38]. In a phase II trial among 69 such patients (50 percent with optic pathway glioma), response rates ranged from 51 to 67 percent depending on response criteria, with a median duration of response of 14 to 17 months [39]. Tovorafenib is now one of several targeted therapy options for children with recurrent/progressive BRAF-altered LGG; ongoing phase III trials are investigating these agents in the upfront setting versus chemotherapy. (See "Optic pathway glioma", section on 'Role of MAPK pathway inhibition'.)

BCMA-directed CAR-T cell therapy for relapsed multiple myeloma (May 2024)

The US Food and Drug Administration has expanded the indications for B cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR) T cell therapy in relapsed or refractory multiple myeloma (MM), to allow use earlier in the disease course given progression-free survival benefits:

● Ciltacabtagene autoleucel is now approved after at least one line of systemic therapy, including an immunomodulatory agent and a proteasome inhibitor, that is refractory to lenalidomide [40].

● Idecabtagene vicleucel is now approved after two or more prior lines of therapy, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody [41].

However, we do not typically offer CAR-T cell therapy after just one line of systemic therapy, given risks that include neurotoxicity and T cell lymphoma. A possible exception is high-risk MM with progression without response to a four-drug combination that includes an anti-CD38 monoclonal antibody. (See "Multiple myeloma: Treatment of second or later relapse", section on 'Chimeric antigen receptor T cells'.)

Tislelizumab for treatment-refractory metastatic esophageal squamous cell carcinoma (March 2024)

For patients with treatment-refractory metastatic esophageal squamous cell carcinoma (SCC), studies are evaluating the efficacy of immune checkpoint inhibitors (ICIs). In a randomized trial in over 500 patients with advanced or metastatic esophageal SCC who progressed on initial platinum-based chemotherapy, tislelizumab, a programmed cell death 1 (PD-1) inhibitor, improved overall survival relative to paclitaxel, docetaxel, or irinotecan (median 8.6 versus 6.3 months), with less toxicity [42]. Based on these data, tislelizumab was approved by the US Food and Drug Administration for the treatment of adult patients with unresectable or metastatic esophageal SCC after prior systemic chemotherapy that did not include a PD-1 or programmed cell death ligand 1 (PD-L1) inhibitor [37], and we also consider it to be an acceptable option in this population. (See "Second- and later-line systemic therapy for metastatic gastric and esophageal cancer", section on 'Tislelizumab'.)

Pembrolizumab with chemoradiation in locally advanced cervical cancer (March 2024)

Trials are investigating the use of immune checkpoint inhibitors in locally advanced cervical cancer. In a randomized trial among 598 patients with International Federation of Gynecology and Obstetrics (FIGO) 2014 stage III to IVA cervical cancer, the addition of pembrolizumab to weekly cisplatin and radiation (external beam followed by brachytherapy) improved 12-month progression-free survival (81 versus 70 percent) [43,44]. Overall survival data are not mature. Pembrolizumab now has regulatory approval in the United States in combination with chemoradiotherapy for patients with FIGO 2014 stage III to IVA cervical cancer. This includes patients who, irrespective of lymph node involvement, have tumor invasion of the lower vagina (with or without extension onto pelvic sidewall), hydronephrosis/nonfunctioning kidney, or spread to adjacent pelvic organs. (See "Management of locally advanced cervical cancer", section on 'Incorporation of pembrolizumab for select patients with more advanced disease'.)

Tumor-infiltrating lymphocyte therapy in metastatic melanoma (March 2024)

Tumor-infiltrating lymphocyte (TIL) therapy is an autologous infusion of T cells that are produced and expanded ex vivo from a tumor specimen obtained via metastasectomy. Treatment includes nonmyeloablative chemotherapy prior to TIL therapy and interleukin 2 after TIL infusion. The US Food and Drug Administration recently approved the use of TIL therapy in patients with unresectable or metastatic melanoma after progression on a programmed cell death-1 (PD-1) inhibitor and a BRAF inhibitor (if BRAF V600 mutation positive) [45]. Earlier data comparing TIL therapy to ipilimumab in this population demonstrated improved progression-free survival. We now offer TIL to such patients if they have an excellent performance status. (See "Systemic treatment of metastatic melanoma lacking a BRAF mutation", section on 'Tumor-infiltrating lymphocytes'.)

Maintenance eflornithine in high-risk neuroblastoma (January 2024)

For patients with high-risk neuroblastoma (HRNBL), there is interest in investigating novel maintenance therapies such as eflornithine, an ornithine decarboxylase inhibitor. In an externally controlled analysis of almost 100 patients with HRNBL who completed multimodality treatment and maintenance immunotherapy, extended maintenance therapy with eflornithine was associated with improved overall survival (hazard ratio 0.38) [46]. Based on these data, the US Food and Drug Administration approved eflornithine as maintenance therapy in patients with HRNBL who achieve at least a partial response to prior systemic agents and complete maintenance immunotherapy. Since maintenance eflornithine is not standard across all institutions, this agent may be offered on a case-by-case basis. (See "Treatment and prognosis of neuroblastoma".)

Repotrectinib in advanced ROS1-positive NSCLC (January 2024)

Studies are evaluating novel tyrosine kinase inhibitors (TKIs) in advanced ROS1-positive non-small cell lung cancer (NSCLC). In a study of repotrectinib in 71 patients with such cancers who were naïve to TKIs, the median progression-free survival (PFS) was 36 months and the 18-month overall survival (OS) rate was 88 percent. Among 56 patients with one prior TKI and no chemotherapy, the median PFS was 9 months and OS was 25 months [47]. These data contributed to regulatory approval of repotrectinib in the United States [48]. We consider repotrectinib to be an acceptable initial treatment option for patients with advanced ROS1-positive NSCLC. (See "Personalized, genotype-directed therapy for advanced non-small cell lung cancer", section on 'ROS1 rearrangements'.)

Toripalimab plus gemcitabine and cisplatin in metastatic nasopharyngeal carcinoma (December 2023)

In patients with metastatic nasopharyngeal carcinoma (NPC), the addition of immunotherapy to chemotherapy has been promising in early phase trials. In a placebo-controlled trial in 289 patients with recurrent of metastatic NPC, the addition of the novel checkpoint inhibitor toripalimab to gemcitabine and cisplatin improved median progression-free survival (21 versus 8 months) and overall survival (not reached versus 34 months, hazard ratio 0.63) [49]. Grade ≥3 treatment-related toxicities were similar between the two groups (90 percent). Based on these data, the US Food and Drug Administration approved toripalimab in combination with gemcitabine and cisplatin in patients with metastatic NPC, and we suggest its use as the initial treatment strategy for such patients. (See "Treatment of recurrent and metastatic nasopharyngeal carcinoma", section on 'Rationale for addition of immunotherapy'.)

Mirvetuximab soravtansine in folate receptor alpha-positive ovarian cancer (December 2023)

Mirvetuximab soravtansine (MIRV) is a folate receptor (FR) alpha-directed antibody and microtubule inhibitor conjugate that is being evaluated for platinum-resistant, FR alpha-positive epithelial ovarian cancer (EOC). In a randomized trial of MIRV versus investigator's choice chemotherapy in 453 patients with such cancers, MIRV improved objective response rates (42 versus 16 percent), progression-free survival (5.6 versus 4.0 months), and overall survival (16.5 versus 12.8 months) [50]. Grade ≥3 adverse events were less common in the MIRV group (42 versus 54 percent). Based on these results, MIRV has regulatory approval in the United States for FR alpha-positive, platinum-resistant EOC that has been treated with one to three prior systemic treatment regimens. (See "Medical treatment for relapsed epithelial ovarian, fallopian tube, or peritoneal cancer: Platinum-resistant disease", section on 'Mirvetuximab soravtansine'.)

Belzutifan for advanced clear cell renal carcinoma (January 2023)

For patients with advanced clear cell renal carcinoma (RCC), studies are evaluating targeted agents such as belzutifan, a small molecule inhibitor of hypoxia-inducible factor 2 alpha (HIF-2a). In a randomized trial in approximately 750 patients with treatment-refractory advanced or metastatic clear cell RCC, belzutifan improved progression-free survival (PFS) over everolimus (18-month PFS 23 versus 9 percent) and was well tolerated [51]. Based on these data, the US Food and Drug Administration approved belzutifan for patients with advanced RCC following treatment with an immune checkpoint inhibitor and a vascular endothelial growth factor tyrosine kinase inhibitor. (See "Systemic therapy for advanced and metastatic clear cell renal carcinoma", section on 'Belzutifan'.)

RECENT APPROVALS - OTHER

Resmetirom for metabolic dysfunction-associated steatohepatitis (MASH) (April 2024)

Therapeutic options for adults with metabolic dysfunction-associated steatohepatitis (MASH) are expanding. In a trial comparing two doses of resmetirom (a thyroid hormone receptor-beta agonist) with placebo in nearly 1000 adults with MASH and liver fibrosis stage F1B, F2, or F3, resmetirom resulted in higher rates of MASH resolution at 52 weeks (100 mg, 80 mg, placebo: 30, 26, and 10 percent, respectively) [52]. Resmetirom also increased the percentage of patients in whom fibrosis improved by at least one stage (100 mg, 80 mg, placebo: 26, 24, and 14 percent, respectively). However, the treatment groups had more diarrhea and nausea. We anticipate using resmetirom as an option for patients with MASH and F2 or F3 fibrosis who do not achieve sustained weight loss. (See "Management of metabolic dysfunction-associated steatotic liver disease (nonalcoholic fatty liver disease) in adults", section on 'Pharmacologic therapies'.)

Budesonide oral suspension for eosinophilic esophagitis (March 2024)

In patients with eosinophilic esophagitis (EoE), use of topical glucocorticoids has been limited by lack of regulatory approval and potentially inconsistent drug delivery. Budesonide oral suspension is a formulation that was recently approved by the US Food and Drug Administration for treating EoE in adults and pediatric patients ages 11 years and older [53,54]. Approval was informed by clinical trials showing that topical budesonide resulted in higher rates of histologic remission and symptomatic improvement compared with placebo. We anticipate using budesonide oral suspension as the preferred topical glucocorticoid for treating EoE. (See "Treatment of eosinophilic esophagitis (EoE)", section on 'Topical glucocorticoids'.)

Mirikizumab for moderate to severe ulcerative colitis (August 2023, Modified January 2024)

Therapeutic options for adults with moderate to severe ulcerative colitis (UC) are expanding. In an induction trial comparing mirikizumab (a monoclonal antibody that targets the p19 subunit of interleukin-23) with placebo in nearly 1300 patients, mirikizumab (300 mg intravenously every four weeks) resulted in higher rates of clinical remission after 12 weeks (24 versus 13 percent) [55]. In the maintenance trial including over 500 patients, mirikizumab (200 mg subcutaneously every four weeks) resulted in higher rates of clinical remission after 40 weeks (50 versus 25 percent). Based on these data, the US Food and Drug Administration approved mirikizumab for moderate to severe UC [56]. We anticipate using mirikizumab as first- or second-line therapy for adults with moderate to severe UC. (See "Management of moderate to severe ulcerative colitis in adults", section on 'Anti-interleukin antibody-based therapy'.)

COVID-19 MANAGEMENT

Limited benefit of nirmatrelvir-ritonavir in non-high-risk individuals with mild-to-moderate COVID-19 (May 2024)

Although nirmatrelvir-ritonavir reduces COVID-19-associated hospitalization and death in patients at high risk for severe disease, the benefit in lower-risk patients is uncertain. The EPIC-SR trial evaluated nirmatrelvir-ritonavir among 1200 outpatients who either had no risk factors for severe disease (and were unvaccinated or vaccinated) or had at least one risk factor but were vaccinated; median age was 42 years, and only 5 percent were 65 years old or older [57]. In the trial, nirmatrelvir-ritonavir did not reduce duration of symptoms, the risk of hospitalization from COVID-19, or all-cause mortality compared with placebo. We continue to suggest against treating patients who are not at high risk for severe disease. (See "COVID-19: Management of adults with acute illness in the outpatient setting", section on 'Efficacy and rationale'.)

Pemivibart for prevention of COVID-19 in selected immunocompromised patients (April 2024)

Monoclonal antibodies have been used as adjunctive pre-exposure prophylaxis to reduce the risk of COVID-19 in individuals expected to have suboptimal response to vaccination, although emergence of variants that escape neutralization limit their utility. In March 2024 in the United States, the novel monoclonal antibody pemivibart received emergency use authorization (EUA) to prevent COVID-19 in individuals age 12 years or older (weighing at least 40 kg) who have moderate-to-severe immunocompromising conditions (table 1) [58]. Pemivibart is active against JN.1, the dominant SARS-CoV-2 variant. We suggest pemivibart in individuals at the highest risk for vaccine nonresponse (eg, those with hematologic malignancy or recent history of transplantation) as long as it remains active against the main circulating variants. (See "COVID-19: Epidemiology, virology, and prevention", section on 'Limited role for monoclonal antibodies in selected patients'.)

Ensitrelvir for mild to moderate COVID-19 (March 2024)

Although nirmatrelvir-ritonavir reduces hospitalization and death from COVID-19,drug interactions preclude its use in some patients. Ensitrelvir is an oral protease inhibitor that prevents SARS-CoV-2 replication and has fewer drug interactions. In a randomized, double-blinded trial of over 1800 patients with mild to moderate COVID-19 (majority vaccinated) in Asia in early 2022, five days of ensitrelvir reduced time to symptom resolution by one day compared with placebo [59]. Since only two participants (one in each arm) had a COVID-19-related hospitalization within the 28-day study period, it is unknown whether the drug prevents hospitalizations or death from COVID-19. Ensitrelvir is approved for emergency use in Japan; it is undergoing US Food and Drug Administration approval process in the United States. (See "COVID-19: Management of adults with acute illness in the outpatient setting", section on 'Therapies of limited or uncertain benefit'.)

VACCINES

Impact of the RTS,S/AS01 malaria vaccine in national immunization programs (April 2024)

The RTS,S/ASO1 vaccine for prevention of malaria was incorporated into national immunization programs in Ghana, Kenya, and Malawi in 2019. A recent trial randomly assigned geographical clusters in these countries to receive early or delayed vaccination; three doses (months 0, 1, and 2) were administered to more than 490,000 children age five to nine months [60]. Early vaccination reduced all-cause mortality by 9 percent and rates of hospital admission for severe malaria by 32 percent. Evaluation is ongoing to assess the impact of a fourth (booster) dose administered at 24 months. Efforts to broaden malaria vaccine administration should be accelerated. (See "Malaria: Epidemiology, prevention, and control", section on 'RTS,S/ASO1 vaccine'.)

Second dose of a 2023-2024 COVID-19 vaccine for individuals 65 years and older (April 2024)

In the United States, a single dose of an updated 2023-2024 formula COVID-19 vaccine is recommended for all immunocompetent adults and adolescents, regardless of prior vaccination history. In February 2024, the Centers for Disease Control and Prevention (CDC) updated its guidance to recommend a second dose (at least four months after the prior dose) for individuals 65 years and older [61]. Rates of COVID-19-associated hospitalization and death are higher in this age group than in any other, and the repeat dose is intended to improve protection by restoring the waning immune response; the 2023-2024 vaccine elicits response against currently circulating variants. Our recommendations are consistent with those of the CDC. (See "COVID-19: Vaccines", section on 'Adults 65 years and older'.)

Investigational single-dose dengue virus vaccine (March 2024)

Two dengue virus vaccines are commercially available, CYD-TDV (Dengvaxia) and TAK-003 (Qdenga); both require multiple doses. In a phase III randomized trial of another vaccine (TV003/Butantan-DV), vaccine efficacy of a single dose was 80 percent with minimal serious adverse effects [62]. The vaccine was effective regardless of baseline dengue serostatus. These results show promise for a single-dose vaccine that is suitable for use in children and adults without regard to prior dengue immunity. It is not yet commercially available. (See "Dengue virus infection: Prevention and treatment", section on 'Investigational vaccines'.)

2024 immunization schedule for adults (January 2024)

The United States Centers for Disease Control and Prevention has published the 2024 immunization schedule for adults (figure 1 and figure 2) [63]. Respiratory syncytial virus (RSV) vaccine is a new addition to the schedule; it is recommended for pregnant people 32 to 36 weeks' gestation during RSV season and is an option for adults ≥60 years of age. Mpox vaccine has also been added and is recommended for adults of all ages who are at risk for infection. Other changes include updates to COVID-19, polio, and meningococcal vaccine recommendations. Our approach to immunization is largely consistent with these updated recommendations. (See "Standard immunizations for nonpregnant adults", section on 'Immunization schedule for nonpregnant adults'.)