Standard treatment for GVHD is glucocorticoids, but for glucocorticoid-refractory GVHD, no intervention has emerged as standard second-line treatment. This trial with 329 patients compared ...ruxolitinib with control (chosen from among 10 possible therapies) in patients with glucocorticoid-refractory chronic GVHD. Response at week 24 was 50% with ruxolitinib as compared with 26% with control therapy.
Acquired resistance to approved tyrosine kinase inhibitors limits their clinical use in patients with gastrointestinal stromal tumor (GIST). This study investigated the safety, tolerability and ...efficacy of alpelisib, a phosphatidylinositol 3-kinase inhibitor, used in combination with imatinib in patients with advanced GIST who had failed prior therapy with both imatinib and sunitinib.
This phase 1b, multicenter, open-label study consisted of 2 phases: dose escalation and dose expansion. Dose escalation involved 200 mg once daily (QD) alpelisib, initially, followed by 250 and 350 mg. These were combined with 400 mg QD imatinib until maximum tolerated dose (MTD) and/or a recommended phase 2 dose (RP2D) of alpelisib in combination with imatinib was determined. This MTD/RP2D dose was tested to evaluate the clinical activity of this combination in dose expansion.
Fifty-six patients were enrolled, 21 and 35 in the dose escalation and expansion phases, respectively. The MTD of alpelisib given with imatinib was determined as 350 mg QD. Combination treatment showed partial response in 1 (2.9%) and stable disease in 15 (42.9%) patients. Median progression-free survival was 2 months (95% CI 1.8-4.6). Overall, 92.9% patients had adverse events (AEs) while 46.4% had grade 3/4 AEs, hyperglycemia being the most common (23.2%).
The MTD of alpelisib was estimated as 350 mg QD when used in combination with imatinib 400 mg QD after oral administration in patients with advanced GIST. The safety and tolerability profile of this combination was acceptable; however, the combination did not demonstrate sufficient clinical activity to justify additional clinical testing.
ClinicalTrials.gov NCT01735968 (date of initial registration 28/11/2012).
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The etiopathogenesis of Crohn's disease (CD) and ulcerative Colitis (UC), the two major forms of inflammatory bowel disease (IBD), is still unknown. Although the exact cause and mechanisms of both ...IBD have yet to be completely understood, it is widely accepted that both CD and UC result from an inappropriate immune response that occurs in genetically susceptible individuals as the result of a complex interaction among environmental factors, microbial factors, and the intestinal immune system. In the last few years a tremendous advance in knowledge of the mechanisms underlying intestinal inflammation in IBD has been achieved, leading to new therapeutic targets and novel drugs. These new therapeutic weapons have been specifically designed to selective shut down intestinal inflammation at different levels. Aim of this review is to summarize the recent advances in IBD pathophysiology and the new therapeutic targets and drugs that are changing the IBD clinical management.
Overall response rate (ORR) is commonly used as key endpoint to assess treatment efficacy of chronic graft versus host disease (cGvHD), either as ORR at week 24 or as best overall response rate (BOR) ...at any time point up to week 24 or beyond. Both endpoints as well as duration of response (DOR) were previously reported for the REACH3 study, a phase 3 open-label, randomized study comparing ruxolitinib (RUX) versus best available therapy (BAT). The comparison between RUX and BAT was performed on ORR and BOR using all randomized patients, while DOR was derived for the subgroup of responders only. Here we illustrate the application of the probability of being in response (PBR), a graphical method presenting simultaneously the time to first response and subsequent failure using all randomized patients. In REACH3, PBR showed an earlier time to first response, a higher probability of being in response and a longer duration of response for RUX compared to BAT. PBR is a clinically easily interpretable measurement and can serve as a novel efficacy endpoint to assess treatments for chronic graft versus host disease.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Crohns disease (CD) is a chronic inflammatory disorder which may involve any part of gastrointestinal tract. Chronic inflammation is primarily due to an immunological imbalance between pro- and ...anti-inflammatory cytokines, and with a defective apoptosis of lamina propria T cells. Amongst the pro-inflammatory cytokines tumor necrosis factor-α (TNF-α) seems to play a central role in pathogenesis of CD. Over the last years, increasing knowledge on the pathogenesis of CD together with progresses in bio-technology have led to the development of a number of biological agents targeting specific molecules involved in gut inflammation, most importantly TNF-α and its receptors. The aim of this paper is to critically review the rationale and state-of-the art for the use TNF-α inhibitors in the treatment of CD.
Introduction: Corticosteroids (CS) are the standard first-line treatment for patients (pts) with chronic graft-versus-host disease (cGvHD), but pts can be unresponsive or become refractory to or ...dependent on CS (SR/D).Ruxolitinib (RUX), a JAK1/2 inhibitor, is approved for the treatment of pts ≥12 years of age with SR/D-cGVHD, based on the primary outcomes from the randomized, phase III REACH3 (NCT03112603) study, which demonstrated the superior efficacy of RUX vs best available treatment (BAT) in pts with SR/D-cGVHD. Here, we present the final, long-term efficacy and safety outcomes from REACH3. Methods: Pts ≥12 years of age with moderate or severe SR/D-cGVHD were randomized 1:1 to receive either RUX 10 mg twice daily (BID) or investigator-selected BAT and followed for 3 years, till discontinuation or death. The primary analysis was conducted at week 24 (Cycle 7 Day 1 C7D1) in randomized pts, then pts entered the extension period (C7-39) in which they continued treatment, switched from BAT to RUX (crossover cohort), or discontinued treatment and entered long-term survival follow-up (FU). Failure-free survival (FFS; key secondary endpoint), duration of response (DOR), overall survival (OS), non-relapse mortality (NRM), malignancy relapse (MR), and safety were analyzed at 3 years (week 156; final data cut off 15 Dec 2022). Overall response rate (ORR) and best overall response (BOR) during the crossover treatment period were analyzed for pts who switched from BAT to RUX on or after C7D1. Results: Of 329 pts randomized, 53 completed the treatment period and 276 discontinued, 115 entered survival FU (RUX: 73/165; BAT:42/164); 70 pts crossed over from BAT to RUX of which 16 completed the crossover treatment period and 24 entered survival FU. Median FFS was longer in the RUX vs BAT arms (38.4 vs 5.7 months; hazard ratio HR=0.361, 95% confidence interval CI: 0.268, 0.485) with 12-month FFS probabilities of 64.0% (95% CI: 56.1, 70.8) and 28.8% (95% CI: 21.8, 36.1), respectively. Median OS was not reached and there was no difference in risk of death between the arms (HR=0.851, 95% CI: 0.544, 1.331) Table 1. Median DOR was 6.4 months (95% CI: 4.9, 11.4) in the BAT arm but was not reached for the RUX arm; notably, the probability of maintaining DOR at 3 years was higher in RUX (59.6%; 95% CI: 50.4, 67.6) vs BAT (26.7%; 95% CI: 18.5, 35.5). NRM event rates were similar between the arms (RUX: 29/165; BAT 34/164), and MR events were similar and low in both arms (13/156 and 11/160, RUX and BAT respectively) up to 3 years. The ORR at week 24 after crossover from BAT to RUX was 50.0% (95% CI: 37.8, 62.2), including complete response (CR) in 4 (5.7%) pts and partial response (PR) in 31 (44.3%) pts. The BOR during crossover was 81.4% (95% CI: 70.3, 89.7), including CR of 7.1% and PR of 74.3%; disease progression only occurred in 1 pt. Almost all pts treated during the main treatment period (RUX: 100%; BAT: 93.7%) experienced ≥1 adverse event (AE) and, in general, AE rates were higher in the RUX vs BAT arms Table 2, likely due to prolonged FU and exposure to RUX (median exposure to treatment of 52.9 weeks vs. 24.1 weeks for RUX and BAT, respectively).Anemia was the most common AE (RUX: 33.9%; BAT: 15.8%) and grade ≥3 AE for RUX (17.6% vs BAT 9.5%, respectively); grade ≥3 neutropenia, thrombocytopenia, alanine aminotransferase increase, and gamma-glutamyltransferase increase were also ≥5% higher for RUX than BAT. Anemia (24.2%; grade ≥3, 10.3%) and thrombocytopenia (3.8%) were the most common RUX and BAT treatment-related AEs, respectively. Infections, excluding tuberculosis, were the most common AE of special interest (77.6% vs. 68.4%; grade ≥3, 31.5% and 26.6%, for RUX and BAT, respectively). On-treatment deaths were mainly due to cGvHD (n/N, RUX: 10/18; BAT 6/12). Conclusions: After 3 years of treatment in REACH3, the longer FFS and higher DOR with RUX vs BAT indicated that cGVHD was more in control with RUX treatment. Notably, efficacy was demonstrated in pts who switched from BAT to RUX with an ORR similar to that in pts randomized to RUX. RUX was well tolerated with no unexpected toxicities and safety that was consistent with earlier studies. Overall, the long-term control of cGVHD and tolerability of RUX was demonstrated for pts ≥12 years of age with SR/D-cGvHD.
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BACKGROUND
Approximately 50% of patients (pts) who receive initial cGVHD therapy are steroid refractory or dependent (SR/D); standard second-line therapy has yet to be established. Quality of life ...(QOL) in these pts is poor and worsens with disease severity.
In the phase 3 REACH3 study in SR/D cGVHD (NCT03112603), RUX demonstrated superior efficacy compared with BAT, with a higher overall response rate at wk 24 (primary endpoint), longer failure-free survival, and a higher proportion of pts with a significant improvement in symptoms on the cGVHD-specific modified Lee Symptom Scale (mLSS; 24.2% vs 11.0% at wk 24; P=0.001) (Zeiser NEJM 2021).
Given the significant impact of symptoms on QOL, the collection of PROs is recommended by NIH consensus criteria, and assessing QOL via PRO measures specifically designed to capture cGVHD symptoms (ie, the mLSS) is important in evaluating treatment. We present an analysis of PROs in REACH3 and compare mLSS subscale results with objective organ responses (data cutoff: May 8, 2020).
METHODS
Pts ≥12 years old with moderate or severe SR/D cGVHD were randomized (1:1) to RUX 10 mg twice daily or investigator-selected BAT (prespecified from 10 options). Randomized treatment was administered for ≥6 cycles (28 d/cycle) along with corticosteroids ± a calcineurin inhibitor. Addition or initiation of a new systemic agent for cGVHD was considered treatment failure.
PROs were collected at baseline and at 4-wk intervals through wk 24 or until treatment failure or discontinuation from the main study period. The rate of responders per improvement of ≥7 points from baseline in mLSS summary score (0 no symptoms to 100 worst symptoms) at wk 24 was a key secondary endpoint (alpha controlled). Additional endpoints were individual organ response and changes in other PROs (Functional Assessment of Cancer Therapy-Bone Marrow Transplantation FACT-BMT, EQ-5D-5L, Patient Global Impression of Severity PGIS, Patient Global Impression of Change PGIC). mLSS data at wk 24 were available for 55.8% of RUX pts (92/165) and 53.0% of BAT pts (87/164) (see Table for pts evaluable for other PROs) .
RESULTS
A total of 329 pts received RUX (n=165) or BAT (n=164). Baseline characteristics, including symptom burden, were balanced between arms; 48% and 52% of pts had moderate or severe cGVHD, respectively. The baseline median summary mLSS score was 18.7 (RUX) vs 18.5 (BAT), indicating a moderate symptom burden.
More pts receiving RUX had an mLSS response at wk 24, at any time up to wk 24, and for ≥2 consecutive visits than those receiving BAT (Table). RUX was associated with a rapid and continued reduction in mean summary mLSS symptom score, whereas only an initial reduction at wk 4 was seen with BAT (Figure 1). In subset analysis, mLSS response was similar in RUX pts with moderate and severe cGVHD. Among pts achieving a complete or partial cGVHD response, those treated with RUX were more likely to have an mLSS response (RUX, 40.2%; BAT, 28.6%).
Response rates in mLSS subscales were higher with RUX vs BAT (odds ratio, >1.7; P<0.05, except lung). Greater mean reductions were observed with RUX vs BAT at wk 24 across all 7 mLSS subscales; improvements in organ-specific subscales corresponded with higher objective responses in the respective organ at wk 24 in both arms (Figure 2). As demonstrated by reductions on the Psych and Energy subscales, overall symptom burden not directly tied to organ responses was also better with RUX than BAT.
More pts receiving RUX than BAT reported “no symptoms” (28.6% vs 17.3%) according to PGIS and were “very much better” or “moderately better” (63.1% vs 39.5%) based on PGIC. RUX treatment also had a positive effect on non-cGVHD-specific PRO measures (EQ-5D-5L and FACT-BMT) at wk 24.
CONCLUSIONS
Compared with BAT, RUX resulted in more substantial improvement in PROs, with rapid, continued symptom improvement and benefits across mLSS subscales, indicating that RUX is superior to BAT not only in physician-assessed responses but also in terms of treating patients' cGVHD symptoms. EQ-5D-5L and FACT-BMT scores were numerically higher with RUX than BAT, but the smaller changes suggest that these measures are too generic to fully capture the impact of cGVHD on QOL while confirming that multidimensional QOL was not reduced with RUX or BAT. Importantly, the pt experience of organ-specific symptom improvements was consistent with physician-assessed objective organ responses and both were greater with RUX.
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Lee: Amgen: Research Funding; AstraZeneca: Research Funding; Incyte: Other: Membership on Steering Committee, Research Funding; Kadmon: Research Funding; Novartis: Research Funding; Pfizer: Consultancy, Research Funding; Syndax: Research Funding; Takeda: Research Funding; 4SC: Consultancy; EMD Serono: Consultancy, Research Funding; Genzyme: Consultancy; Merck Sharpe Dohme: Consultancy; Regeneron: Consultancy; Sanofi: Consultancy; BMS: Research Funding; Wolters Kluwer: Research Funding. Locatelli: Miltenyi: Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Medac: Speakers Bureau; Jazz Pharamceutical: Speakers Bureau; Takeda: Speakers Bureau. Ayuk: Gilead: Honoraria; Mallinckrodt/Therakos: Honoraria, Research Funding; Takeda: Honoraria; Janssen: Honoraria; Celgene/BMS: Honoraria; Miltenyi Biomedicine: Honoraria; Novartis: Honoraria. Zuckerman: Gilead Sciences: Honoraria, Speakers Bureau; Novartis: Honoraria; AbbVie: Honoraria; BioSight Ltd: Honoraria; Orgenesis Inc.: Honoraria; Janssen: Honoraria; Cellect Biotechnology: Honoraria. Pidala: Pharmacyclics: Other: Clinical trial support, Research Funding; BMS: Other: Clinical trial support, Research Funding; Novartis: Other: Clinical trail support; Takeda: Other: Clinical trail support; Jannssen: Other: Clinical trial support; Johnson and Johnson: Other; AbbVie: Other; BMS: Other; Incyte: Consultancy; Regeneron: Consultancy; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Clinical trial support; CTI Biopharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Clinical trial support; Syndax: Consultancy, Membership on an entity's Board of Directors or advisory committees. Hamad: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Zeiser: Incyte, Mallinckrodt, Novartis: Honoraria, Speakers Bureau. Bhatt: Incyte: Current Employment. Gowda: Novartis: Current Employment. Han: Novartis: Current Employment. Stefanelli: Novartis: Current Employment, Current equity holder in publicly-traded company. Zuurman: Novartis: Current Employment. Teshima: Pfizer Inc.: Honoraria; Astellas Pharma Inc.: Research Funding; TEIJIN PHARMA Limited: Research Funding; Merck Sharp & Dohme: Membership on an entity's Board of Directors or advisory committees; Nippon Shinyaku Co., Ltd.: Research Funding; Bristol Myers Squibb: Honoraria; Gentium/Jazz Pharmaceuticals: Consultancy; Takeda Pharmaceutical Company: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis International AG: Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; CHUGAI PHARMACEUTICAL CO., LTD.: Research Funding; Kyowa Kirin Co.,Ltd.: Honoraria, Research Funding; Janssen Pharmaceutical K.K.: Other; Fuji pharma CO.,Ltd: Research Funding; Sanofi S.A.: Research Funding.
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IJS, IMTLJ, KILJ, NLZOH, NUK, SAZU, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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