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Risdiplam is an oral, survival of motor neuron 2 (SMN2) pre-mRNA splicing modifier approved for the treatment of spinal muscular atrophy (SMA). SUNFISH (NCT02908685) Part 2, a Phase 3, randomized, double-blind, placebo-controlled study, investigated the efficacy and safety of risdiplam in type 2 and non‑ambulant type 3 SMA. The primary endpoint was met: a significantly greater change from baseline in 32-item Motor Function Measure (MFM32) total score was observed with risdiplam compared with placebo at month 12. After 12 months, all participants received risdiplam while preserving initial treatment blinding. We report 24-month efficacy and safety results in this population. Month 24 exploratory endpoints included change from baseline in MFM32 and safety. MFM‑derived results were compared with an external comparator. At month 24 of risdiplam treatment, 32% of patients demonstrated improvement (a change of ≥ 3) from baseline in MFM32 total score; 58% showed stabilization (a change of ≥ 0). Compared with an external comparator, a treatment difference of 3.12 (95% confidence interval [CI] 1.67–4.57) in favor of risdiplam was observed in MFM-derived scores. Overall, gains in motor function at month 12 were maintained or improved upon at month 24. In patients initially receiving placebo, MFM32 remained stable compared with baseline (0.31 [95% CI – 0.65 to 1.28]) after 12 months of risdiplam; 16% of patients improved their score and 59% exhibited stabilization. The safety profile after 24 months was consistent with that observed after 12 months. Risdiplam over 24 months resulted in further improvement or stabilization in motor function, confirming the benefit of longer-term treatment.

The small molecule risdiplam increased the expression of SMN protein in blood in 21 infants with type 1 spinal muscular atrophy. Post hoc clinical features of sitting ability and respiratory status were reported.

In this randomized noninferiority trial involving patients with rheumatoid arthritis, cardiovascular events and cancers occurred more frequently with tofacitinib than with a TNF inhibitor, and noninferiority of tofacitinib with respect to these end points was not established.

Fibroblast growth factor receptor (FGFR) 2 gene alterations are involved in the pathogenesis of cholangiocarcinoma. Pemigatinib is a selective, potent, oral inhibitor of FGFR1, 2, and 3. This study evaluated the safety and antitumour activity of pemigatinib in patients with previously treated, locally advanced or metastatic cholangiocarcinoma with and without FGFR2 fusions or rearrangements. In this multicentre, open-label, single-arm, multicohort, phase 2 study (FIGHT-202), patients aged 18 years or older with disease progression following at least one previous treatment and an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2 recruited from 146 academic or community-based sites in the USA, Europe, the Middle East, and Asia were assigned to one of three cohorts: patients with FGFR2 fusions or rearrangements, patients with other FGF/FGFR alterations, or patients with no FGF/FGFR alterations. All enrolled patients received a starting dose of 13·5 mg oral pemigatinib once daily (21-day cycle; 2 weeks on, 1 week off) until disease progression, unacceptable toxicity, withdrawal of consent, or physician decision. The primary endpoint was the proportion of patients who achieved an objective response among those with FGFR2 fusions or rearrangements, assessed centrally in all patients who received at least one dose of pemigatinib. This study is registered with ClinicalTrials.gov, NCT02924376, and enrolment is completed. Between Jan 17, 2017, and March 22, 2019, 146 patients were enrolled: 107 with FGFR2 fusions or rearrangements, 20 with other FGF/FGFR alterations, 18 with no FGF/FGFR alterations, and one with an undetermined FGF/FGFR alteration. The median follow-up was 17·8 months (IQR 11·6–21·3). 38 (35·5% [95% CI 26·5–45·4]) patients with FGFR2 fusions or rearrangements achieved an objective response (three complete responses and 35 partial responses). Overall, hyperphosphataemia was the most common all-grade adverse event irrespective of cause (88 [60%] of 146 patients). 93 (64%) patients had a grade 3 or worse adverse event (irrespective of cause); the most frequent were hypophosphataemia (18 [12%]), arthralgia (nine [6%]), stomatitis (eight [5%]), hyponatraemia (eight [5%]), abdominal pain (seven [5%]), and fatigue (seven [5%]). 65 (45%) patients had serious adverse events; the most frequent were abdominal pain (seven [5%]), pyrexia (seven [5%]), cholangitis (five [3%]), and pleural effusion (five [3%]). Overall, 71 (49%) patients died during the study, most frequently because of disease progression (61 [42%]); no deaths were deemed to be treatment related. These data support the therapeutic potential of pemigatinib in previously treated patients with cholangiocarcinoma who have FGFR2 fusions or rearrangements. Incyte Corporation.

In three phase 3 trials involving patients with ulcerative colitis, tofacitinib (an oral, small-molecule Janus kinase inhibitor) was more effective as induction and maintenance therapy than placebo. Infections were more common with tofacitinib. Ulcerative colitis is characterized by an increased frequency of bowel movements and bloody diarrhea, which has a negative effect on quality of life. 1 Current therapies for ulcerative colitis include mesalamine, glucocorticoids, thiopurines, and antagonists to tumor necrosis factor (TNF) and α4β7 integrin. 1 – 5 Many patients do not have a response to these therapies or have a response that is not sustained. Additional treatment options with new mechanisms of action are needed to increase efficacy rates. The Janus kinase (JAK) family comprises four intracellular tyrosine kinases — JAK1, JAK2, JAK3, and nonreceptor tyrosine-protein kinase 2 — that activate signal transducers and . . .

Sotorasib is a selective irreversible inhibitor of the G12C-activated KRAS oncogene, present in approximately 13% of non–small-cell lung cancers. In a single-group, phase 2 trial involving 126 patients with previously treated KRAS p.G12C–mutated NSCLC, 37% had a response (median duration, 11 months). One fifth of patients had grade 3 toxic effects, mainly liver-enzyme abnormalities and diarrhea.

In a trial comparing abrocitinib with placebo and dupilumab, IGA and EASI-75 responses were better with abrocitinib than with placebo at 12 weeks. Itch response at 2 weeks was better with the 200-mg dose of abrocitinib than with dupilumab, but neither abrocitinib dose differed significantly from dupilumab in most other key secondary end-point comparisons at week 16.

Both single-agent ibrutinib and chlorambucil plus obinutuzumab have shown superior efficacy to chlorambucil monotherapy and are standard first-line treatments in chronic lymphocytic leukaemia. We compared the efficacy of the combination of ibrutinib plus obinutuzumab with chlorambucil plus obinutuzumab in first-line chronic lymphocytic leukaemia or small lymphocytic lymphoma. iLLUMINATE is a multicentre, randomised, open-label, phase 3 trial done at 74 academic and community hospitals in Australia, Canada, Israel, New Zealand, Russia, Turkey, the EU, and the USA in patients with previously untreated chronic lymphocytic leukaemia or small lymphocytic lymphoma, either aged 65 years or older or younger than 65 years with coexisting conditions. Patients were randomly assigned (1:1) using a blocked randomisation schedule, stratified by Eastern Cooperative Oncology Group performance status and cytogenetics, to receive ibrutinib plus obinutuzumab (oral ibrutinib [420 mg once daily continuously] combined with intravenous obinutuzumab [100 mg on day 1, 900 mg on day 2, 1000 mg on day 8, and 1000 mg on day 15 of cycle 1 and on day 1 of subsequent 28-day cycles, for a total of six cycles]) or chlorambucil plus obinutuzumab (oral chlorambucil [0·5 mg/kg bodyweight on days 1 and 15 of each 28-day cycle for six cycles] combined with the same obinutuzumab regimen). Allocation concealment was achieved using an interactive web response system. Patients and investigators were not masked to treatment assignment. The primary endpoint was progression-free survival assessed by a masked independent review committee in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov (NCT02264574), and patient enrolment is complete. Between Oct 6, 2014, and Oct 12, 2015, 229 patients were enrolled and randomly assigned to receive ibrutinib plus obinutuzumab (n=113) or chlorambucil plus obinutuzumab (n=116). After a median follow-up of 31·3 months (IQR 29·4–33·2), median progression-free survival was significantly longer in the ibrutinib plus obinutuzumab group (median not reached [95% CI 33·6–non-estimable]) than in the chlorambucil plus obinutuzumab group (19·0 months [15·1–22·1]; hazard ratio 0·23; 95% CI 0·15–0·37; p<0·0001). Estimated 30-month progression-free survival was 79% (95% CI 70–85) in the ibrutinib plus obinutuzumab group and 31% (23–40) in the chlorambucil plus obinutuzumab group. The most common grade 3 or 4 adverse events in both groups were neutropenia and thrombocytopenia. Serious adverse events occurred in 65 (58%) of 113 patients treated with ibrutinib plus obinutuzumab and 40 (35%) of 115 patients treated with chlorambucil plus obinutuzumab. Ibrutinib or chlorambucil treatment-related deaths were reported in one (1%) of 113 patients in the ibrutinib plus obinutuzumab group (sudden death) and one (1%) of 115 patients in the chlorambucil plus obinutuzumab group (neuroendocrine carcinoma of the skin). Ibrutinib plus obinutuzumab is an efficacious and safe chemotherapy-free combination treatment in previously untreated patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma independent of high-risk features and provides an alternative first-line treatment option for these patients. Pharmacyclics LLC, an AbbVie Company, and Janssen Research and Development.

In a study involving patients with non–small-cell lung cancer with a MET exon 14 skipping mutation, the use of tepotinib (a selective MET inhibitor) was associated with a partial response in approximately half the patients. The main adverse event was peripheral edema.

Patients 70 years of age or younger with previously untreated CLL were randomly assigned to receive ibrutinib plus rituximab or chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab. The ibrutinib-based regimen led to prolonged progression-free and overall survival.