The study randomly assigned 494 patients with primary advanced stage 3 or 4 or first recurrent endometrial cancer to 500 mg dostarlimab (n = 245) or placebo (n = 249) in addition to the usual chemotherapy—carboplatin (AUC, 5 mg/mL/min) and paclitaxel (175 mg/m² BSA)—every 3 weeks for 6 cycles, followed by 1,000 mg dostarlimab or placebo every 6 weeks, continuing treatment for up to 3 years or until disease progression, discontinuation, or death. Of this total, 118 patients had mismatch repair-deficient (dMMR), microsatellite instability-high (MSI-H) tumors. These dMMR–MSI-H tumors occur in 25% to 30% of endometrial cancers; they are marked by increased expression of programmed cell death (PD-1) receptors and its ligands (PD-L1 and PD-L2). Dostarlimab is an immune checkpoint inhibitor targeting the PD-1 receptor.

As of data cutoff, 88 patients in the overall trial population were still receiving treatment in one of the two groups. The researchers examined progression-free survival, as assessed using Response Evaluation Criteria in Solid Tumors (RECIST), and for overall survival. Imaging to assess status of the cancer was performed every 6 weeks to week 25, then every 9 weeks until week 52, and then every 12 weeks until progressive disease was documented in accordance with RECIST. Results were stratified according to MMR-MSI status, whether patients had received previous external pelvic radiotherapy, and disease status.

In the overall population with endometrial cancer, progression-free survival at 24 months was 36.1% with dostarlimab and 18.1% with placebo (hazard ratio [HR], 0.64). Overall survival in the total population at 24 months was 71.3% with dostarlimab and 56.0% with placebo (HR, 0.64). Of the 118 patients with dMMR–MSI-H tumors, progression-free survival at 24 months was 61.4% with dostarlimab and 15.7% with placebo (HR, 0.28). Overall survival in the dMMR–MSI-H population was 83.3% with dostarlimab and 58.7% with placebo (HR, 0.30).

The progression-free survival benefit seen with dostarlimab does not appear to be consistent across all tumor subgroups except in the dMMR–MSI-H population, where the regimen provided a significant benefit, with a 64.1% probability of progression-free survival. Extended follow-up may be necessary to observe a treatment effect in other subgroups, especially in those with stage 3 disease. (Mirza, M. R., et al. (2023). Dostarlimab for primary advanced or recurrent endometrial cancer. New Engl J Med. Retrieved April 2023 from https://www.nejm.org/doi/full/10.1056/NEJMoa2216334?query=main_nav_lg)

Released: April 2023

Nursing Drug Handbook

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An open-label, multicenter, randomized controlled trial conducted at 10 Swiss hospitals is the first reported that compared the two most used anti-inflammatory treatments in these patients. The study, Swissped RECOVERY, was published in The Lancet Child and Adolescent Health, and enrolled 75 patients between May 2021 and April 2022. The patients, children hospitalized with PIMS-TS, were randomized to IV methylprednisolone (10 mg/kg/day for 3 days; n = 37) or IV immunoglobulins (2 g/kg as single dose; n = 38). Patients were eligible for study if the attending practitioner considered them candidates for IV anti-inflammatories; although patients could receive additional anti-inflammatory medications, they had to be observed for at least 24 hours after starting the randomized treatment before doing so. All other treatments given to the patients in the study were reviewed by a committee who were masked as to which treatment group the patient was assigned to.

The study compared the two treatments on length of hospitalization to day 28, death, or discharge, and measured the proportion of patients requiring organ support and the duration of such support. They found few differences between the two treatments. The average length of hospital stay was 6.0 days in both groups. But fewer patients in the methylprednisolone group (10/37; 27%) required respiratory support at any time during treatment compared with patients in the immunoglobulin group (21/38; 55%). When comparing the need for respiratory support after randomization, this possible benefit for methylprednisolone still appeared to hold: 3/37 (8%), compared to 11/38 (29%) in the immunoglobulin group. Other outcomes—duration of respiratory support, need for inotropes, intensive care unit admission, cardiac effects after baseline, major bleeding, and thrombotic events—did not differ significantly between the two groups. No children died, and only one was still hospitalized after 28 days.

These findings need confirmation because the sample size was so small; hopefully, long-term follow-ups of other cohorts in the RECOVERY trial can provide a clearer picture. But they do offer evidence that methylprednisolone could be acceptable as first-line treatment of PIMS-TS, given that it’s a more affordable and more widely available medication. (Welzel, T., et al. (2023). Methylprednisolone versus intravenous immunoglobulins in children with paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS): An open-label, multicentre, randomised trial. Lancet Child Adolesc Health, 7(4), 238–248. Retrieved April 2023 from https://www.thelancet.com/journals/lanchi/article/PIIS2352-4642(23)00020-2/fulltext)

Released: April 2023

Nursing Drug Handbook

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Injection of Jynneos (modified vaccinia Ankhara vaccine) has been shown to be effective in preventing monkeypox; the Centers for Disease Control and Prevention (CDC) has published data estimating how successful vaccination campaigns have been in providing coverage among populations at risk for monkeypox. Despite the administration of more than 1 million doses of Jynneos (734,510 first dose and 452,884 second dose), the CDC finds that these numbers equate to only 23% of those most at risk being fully vaccinated, with 37% having received just one dose. Those at increased risk include the following:

• persons with known or presumed exposure to monkeypox
• men who have sex with men (MSM) and gender-diverse persons (transgender, nonbinary, or other gender-diverse individuals) with multiple recent sexual partners
• MSM and gender-diverse individuals with newly diagnosed sexually transmitted disease
• persons who have had sex at a commercial sex venue or other large social-cultural gathering during the previous 6 months
• those with sexual partners with any of the aforementioned risks
• persons with HIV or other immunosuppression who might be exposed due to any of these scenarios.

The CDC calculated vaccination coverage for each state and U.S. territory, and further determined coverage for various jurisdictions, including major cities. The analysis was done using a numerator created from information on vaccinated individuals in each region and a denominator that represented persons in that region at risk for monkeypox virus exposure. This figure was determined as the number of MSM who met indications for preexposure prophylaxis plus the number of MSM with HIV in the region plus 25% to account for others at risk. Using this formula, only Washington DC is estimated to have achieved at least 50% full (two-dose) vaccine coverage. Those areas with more than 50% single-dose vaccine coverage included these regions:

• Washington, DC (94.8% coverage)
• New York City (88.8% coverage)
• California (61.4% coverage)
• Rhode Island (58.9% coverage)
• Massachusetts (53.9% coverage)
• New York State excluding New York City (50.1% coverage).

Three of these six areas (New York City, California, New York State) were also areas with the highest monkeypox case counts. But in 22 of the regions studied by the CDC, vaccination coverage with one dose was less than 25%. Within this low uptake of the vaccine, a special area of concern is that outreach may be failing to reach those most affected; for example, although approximately 1 in 3 monkeypox cases in the United States occurred in Black persons, only 1 in 8 single-dose recipients were Black. The CDC notes that this less-than-optimal uptake has numerous causes:

• Lower vaccine availability and awareness
• Fewer vaccination providers in those regions
• Lower confidence in vaccines and therefore lower demand
• Concerns about stigma.

The CDC has recently made the vaccine available in an intradermal form under an Emergency Use Authorization, noting that, because each intradermal dose is one-fifth the size of a subcutaneous dose, this strategy can increase availability of the vaccine. But clearly, it’s important to find and use strategies to advance health equity among those most affected by the epidemic. This remains true even as the incidence of infection from this outbreak declines. (Owens, L. E., et al. (2023). JYNNEOS vaccination coverage among persons at risk for Mpox – United States, May 22, 2022 – January 31, 2023. MMWR, 72(13), 342–347. Retrieved April 2023 from https://www.cdc.gov/mmwr/volumes/72/wr/mm7213a4.htm?s_cid=mm7213a4_w)

Released: April 2023

Nursing Drug Handbook

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SMA is caused by a mutation in the SMA1 gene, which codes for survival motor neuron protein, which is critical to maintaining healthy motor neurons. Risdiplam, an orphan drug, is an SMN2 splicing modifier that treats SMA by increasing and sustaining production of SMN protein in the CNS and peripheral tissues.

The SUNFISH trial was designed to evaluate risdiplam effects on motor function. It enrolled 180 patients with SMA, all of whom could sit independently but were not able to walk. It evaluated changes in motor function by measuring motor function on the Motor Function Measure-32 (MFM-32) and the Revised Upper Limb Module (RULM), as well as on the Hammersmith Functional Motor Scale Expanded (HMSE). The study showed a statistically significant change from baseline in MFM-32 score at 12 months in patients treated with risdiplam (n = 120) versus placebo (n = 60). Findings from RULM were also statistically significant in the primary trial, with HMSE hinting at benefits but not reaching significance. The greatest improvement in motor function, as assessed by MFM-32 score, was seen in the youngest age group (ages 2 to 5); 78.1% of those receiving risdiplam showed meaningful improvement compared to 52.9% of those on placebo. In older patients, stabilization is a more realistic goal; the oldest group (ages 18 to 25) showed stabilization in 57.1% of patients in the risdiplam group versus 37.5% of patients in the placebo group. Patients and caregivers also completed the SMA Independence Scale-Upper Limb Module, reporting improvements or stabilization in ability to carry out activities of daily living (ADLs).

The poster presentation at the MDA meeting demonstrated that these findings have remained generally stable over 4 years, with patients maintaining the improvements or stabilization of motor function from the original trial, demonstrating long-term efficacy. The overall rate of adverse events continued to decrease over the 48 months. In addition, patients and caregivers continued to report better performance on the SMA Independence Scale, which measures the assistance required to complete ADLs, such as feeding, brushing teeth, getting dressed, or writing, than before beginning risdiplam treatment. Patients and caregivers reported continuous improvement or stabilization in the level of assistance needed to perform ADLs. (Genentech. Press release. 19 March 2023. New four-year data for Genentech’s Evrysdi reinforce long-term efficacy and safety profile in some of the most severely affected people with types 2 and 3 spinal muscular atrophy (SMA). Retrieved April 2023 from https://www.gene.com/media/press-releases/14985/2023-03-19/new-four-year-data-for-genentechs-evrysd; Genentech. MEDically. Conference report. 19 March 2023. SUNFISH parts 1 and 2: 4-year efficacy and safety of risdiplam in types 2 and 3 SMA. Retrieved April 2023 from https://medically.gene.com/global/en/unrestricted/neuroscience/MDA-2023/mda-2023-poster-day-sunfish-parts-1-and-2-4-year-effica.html; SMA Today. 22 March 2023. MDA 2023: Evrysdi’s motor benefits found to last for 4 years in trial. Retrieved April 2023 from https://smanewstoday.com/news/mda-2023-evrysdi-motor-benefits-last-4-years-sunfish-trial-data/)

Released: April 2023

Nursing Drug Handbook

© 2023 Wolters Kluwer