Jurnal Internasional Fase 3 uji coba DUO: duvelisib vs ofatumumab pada CLL / SLL yang kambuh dan refrakter
The main efficacy endpoint for this study is PFS as determined by IRC, with ORR and OS as the key secondary endpoints. With a median overall follow-up of 22.4 months for the duvelisib and ofumumab arms, the median PFS by a blinded review of IRC was significantly longer for the duvelisib arm compared with the arm of materumab (13.3 months vs. 9.9 months, HR = 0.52, P <.0001 id="xref-fig-2-1" class="xref-fig" href="#F2"> Figure 1A). Estimates of the possibility of developing progressively at 6 months and 12 months were 78% and 60%, respectively, in the duvelisib arm, and 72% and 39% in the arm ofatumumab. An increase in PFS with duvelisib compared with ofatumumab was also observed per investigator assessment (17.6 months vs. 9.7 months, HR = 0.40, P <.0001 id="xref-fig-2-2" class="xref-fig" href="#F2"> Figure 1B). PFS was also extended with duvelisib in several subgroups of CLL / SLL examined, including patients with high-risk cytogenetic markers ( Figure 2A ). In the subset of patients with del (17p) / TP53 mutations, the median PFS by IRC assessment was 12.7 months with duvelisib vs. 9.0 months for ofumumab (HR = 0.40, P ] = .0002), with estimates of the probability of being development-free at 6 months and 12 months from 73% and 55% with duvelisib, and 63% and 30% with ofatumumab ( Figure 2B ). With the investigator's assessment, the median PFS in patients with del (17p) / TP53 mutation was 13.8 months with duvelisib and 9.5 months with ofumumab (HR = 0.41, P = .0003) with estimates of the probability of being development-free at 6 months and 12 months 77% and 66% with duvelisib, and 53% and 33% with ofatumumab ( Figure 2C ). Duvelisib maintained favorable odds ratios relative toumumab for all subgroups analyzed, including refractory / early relapse (HR = 0.51), baseline 4 cytopenia (HR = 0.14), and previous anticancer therapy in the last 12 months (HR = 0.40)
PFS in selected study subgroups. (A) Plots and forest hazard ratios for PFS per IRC assessment on duvelisib or ofatumumab monotherapy for a predetermined subgroup in the study population in total Kaplan-Meier curves from PFS per IRC (B) assessment and researcher assessment (C) in a subgroup of patients with del (17p) /  TP53 mutations. In this high-risk subgroup, the median PFS was 12.7 months and 9.0 months (HR = 0.40, P = .0002) by IRC and 13 ratings , 8 months and 9.5 months (HR = 0.41, P = .0003) by researchers assessing for duvelisib and ofatumumab, respectively. “Refractory / early relapse” shows early refractory / relapse to analog purine-based therapy, “previous anticancer therapy” shows the most recent previous anticancer therapy from randomization, LCL, low confidence limit, UCL, above the confidence limit.
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ORR per assessment of IRC response to duvelisib was also significantly higher than ofatumumab (73.8% vs 45.3%; P <.0001 id="xref-fig-4-1" class="xref-fig" href="#F4"> Figure 3). In the duvelisib arm, almost all responses were PR (72.5%) with the exception of 2 patients: 1 patient achieved CR (0.6%) and 1 patient reached PRwL (0.6%). The response in the ofatumumab arm was also dominated by PR (44.7%) with CR (0.6%) in 1 patient (additionally Table 2). Duvelisib treatment was very effective in targeting lymph node compartments, with lymph node response with 85.0% IRC assessment (95% CI, 79.5-90.5) compared to 15.7% (95% CI, 10, 1-21.4) in the arm ofatumumab ( P <.0001 id="xref-fig-4-2" class="xref-fig" href="#F4"> Figure 3). The median OS was not achieved in the two treatment groups with a probability of 12 months survival of 86% (HR = 0.99; 95% CI, 0.65-1.50) for both treatments (supplement Figure 2).
AE was assessed during the treatment period of each arm. Median treatment exposure was about twice as long as patients treated with duvelisib (average duration of 50 week) compared with patients treated with patients treated with diatumumab (median duration of 23 weeks) Per protocol, treatment ofumumab did not exceed 12 doses (∼6 months) specified in the prescription information ofatumum.On the cutoff data, 49% of patients treated with duvelisib has received more than one year of treatment, with 31% and 12% receiving 1.5 years and 2 years of treatment, respectively AE that occurs in ≥10% of patients during each AE reporting period (i.e., not suitable exposure) is presented in 1945-1946 Table 3. Almost all patients in both arms experienced AE. The most common hematological AEs with duvelisib and ofumumab were neutropenia (33% and 21%), anemia (23% and 10%), d thrombocytopenia (15% and 6%), respectively. The most commonly reported nonhematologic AE with duvelisib is diarrhea (51%), fever (29%), nausea (23%), and cough (21%). Colitis, as a different event of diarrhea, was reported in 13% with 8% of patients experiencing diarrhea that immediately preceded and / or overlapped with the occurrence of colitis. The median time for the first event of diarrhea or inflammation of the large intestine is ∼4 months and 7 months, respectively. With ofatumumab, infusion-related reactions (19%), cough (14%), and diarrhea, rash, and fatigue (12% each) were the most common non-hematological AE.
AE 3grade 3 occurred in 87% of patients with dual arm and 48% of patients with atumum arm. In the duvelisib arm, the most common severe events were neutropenia (30%), diarrhea (15%), pneumonia (14%), and anemia (13%). In the ofumumab arm, only neutropenia (17%) occurred in ≥10% of patients. As previously observed in the phase 1 study, 22 24 Severe immune-related toxicity (3grade 3) was recorded in patients treated with duvelisib. In this phase 3 study, the occurrence of severe immune-related toxicity included colitis (12%) and pneumonitis, alanine transaminase, or increased aspartate transaminases (3% each). Although this event was primarily managed by dose interruption, 60% of patients with pneumonitis or colitis received steroid therapy with resolution reported in almost all patients at the time of data cutoff. None of these events were fatal.
Infection AE was more frequently reported in the duvelisib arm (69% vs 43%) with pneumonia (18%) and URTI (16%) representing the most common events. [Jj9002] P jirovecii pneumonia occurred in 3 patients treated with duibisib and 1 patient treated with diatumumab, 3 of whom did not receive prophylaxis at the time of their infection although needed per protocol and 1 patient treated with duvelisib who did not continue prophylaxis. because of intolerance. Of patients treated with duvelisib who stopped treatment because AE, colitis and diarrhea were the only AEs that occurred in pada5% of patients (both 5%). Treatment of treatment discontinuation from other toxicity related to pneumonitis (2%) and increased aspartate transaminase levels (1%) are rare.
Serious AE is summarized in supplements Table 3. Pneumonia is the most frequently reported serious AE in both treatments. arm (duvelisib 15%; ofatumumab 3%). There were 19 fatal AEs on the duvelisib arm (supplement Table 4), 4 of which were assessed by researchers related to drug studies: staphylococcal pneumonia (n = 2) and sepsis and general health deterioration (n = 1 each). In the ofumumab arm, 7 patients experienced fatal AE, although none was associated with treatment ofatumumab.
Twenty-four chemokines and cytokines were measured in patient serum samples, and percent median changes from baseline to cycle 2 days 1 determined to assess treatment-related effects associated with targeting leukemia cells and tumor microenvironment, 29 30 as described in the Additional methods section. Sixteen chemokines were significantly reduced from baseline in patients treated with duvelisib ( P <.05 id="xref-fig-5-1" class="xref-fig" href="#F5"> Figure 4). Patients treated with ofatumumab had rates that did not decrease statistically from baseline, while patients treated with duvelisib experienced a very significant decrease in levels: CCL1 ( P <.0001 ccl17=""> P <.0001 cxcl10=""> P <.0002 cxcl11=""> P <.0009 cxcl9=""> P  P 50% median decreased in patients treated with duvelisib.
In this phase 3 of the DUO study, duvelisib monotherapy was produced in statistically significant improvement in PFS and ORR, including those with del (17p) / TP53 mutations. Activity and subgroup analysis for both efficacy end points. In the duvelisib arm, the median use investigator response was not more than IRC-assessed PFS (17.6 months vs. 13.3 months). This difference is likely to reflect the inherent differences in the methodologies used to determine progression between the 2 evaluator groups. With the IRC PFS based largely on radiological data, the investigator-derived PFS, incorporating both radiological and real-time clinical assessments, as would be applied in the standard oncology care setting, is likely to be more clinically relevant PFS. Clinically meaningful reductions in target lymph nodes (85%), representing a statistically significant treatment effect over breastfeeding (16%) ( P
Design-based, the treatment period for duvelisib was longer than atumumab (median exposure 50 weeks vs. 23 weeks), which resulted in more than a year of treatment, 49%, 31%, and 12% received more than a year , 18 months, and 2 years of treatment, respectively The duvelisib AE was observed with the drug safety profile to date, 22 24 with the majority of AEs presenting as grade 1 or 2 events Many of the more common AEs, such as cytopenics and constitutional symptoms, are also well-recognized complications of CLL / SLL Similar to other B-cell receptors pathway inhibitors, infections (particularly pneumonias and URTIs) s) 31 [32,902] 32 were frequently observed on duvelisib, representing the most common severe and serious AEs; 3 patients were edited because of treatment-related infections. Although a well-recognized major cause of morbidity and mortality in CLL given the inherent inherent to the disease immunology 33  34 and induced immunosuppression therapy, infections remain an important risk with duvelisib treatment . The protocol requirement for PIirovecii pneumonia prophylaxis may have mitigated the risks of these opportunistic infections, which have been reported with other B-cell receptor inhibitors. 35 ⇓ ⇓  ⇓ –  39 Of interest, the three treated patients who experienced because of protocol deviations or medication intolerance.  Several prespecified AEs of interest in possible immunomodulatory effects of PI3K-δ / γ inhibition 40  ⇓ ⇓ ] – 45 were closely monitored in this study. The incidences of neutropenia, diarrhea, colitis, transaminase elevations, pneumonitis, and radiation therapy were moderate and manageable with early intervention and dose modification as required per protocol. Of these, colitis was the most commonly observed severe (3grade 3) event, reported in 12% of two treated patients, and severe cases of pneumonitis, transaminase elevations, and toxic skin eruption / rash were reported in
Malignant B- cell proliferation and survival in CLL / SLL is promoted by PI3K. 10 [ – 12 The PI3K-δ / γ is composed of the tumor microenvironment where they provide supportive signaling. 13 19 [1945 – 16 As a dual PI3K-δ / γ inhibitor, duvelisib has the potential to target cell autonomous mitogenic and survival signaling, as well as supportive tumor microenvironment that further enables CLL proliferation. 30 46 An analysis of patient blood protein profiles showed significant reductions in the levels of serum chemokines and cytokines associated with malignant B cells, stable and proliferation in CLL 24 Considering the dual inhibitor action of duvelisib, the pattern of chemokine signaling within the inhibition of both PI3K-δ and PI3K-γ the tumor microenvironment.
This report of the DUO study data represents a second phase randomized trial to examine the safety and efficacy of oral PI3K inhibitors in relapsed CLL patients. In a prior study, ideal, an oral inhibitor of the PI3K-of isoform, in combination with rituximab, showed improved PFS compared with rituximab monotherapy (not reached vs. 5.5 months) and response rate (81% vs 13%) in patients with relapsed CLL who have clinically significant coexisting medical conditions. 47 such as cytopenias, constitutional symptoms, and diarrhea at the same time as rituximab arm, Similar rates in the duvelisib arm of the DUO trial. However, at the time of the trial trial, patients with the ideal of rituximab arm had only received a median of 3.8 months compared with a lot of exposure from two years of nearly a year in the DUO trial. This large difference in drug exposure and observation periods makes it difficult to compare incidences across trials. Additionally, the timing of immune-mediated toxicities, such as colitis and pneumonitis, which tend to emerge with a longer drug exposure, may be more accurately represented. Interestingly, however, the incidence of high-grade transaminitis was low in this study. The AE profile with two levels of monotherapy remains consistent across studies 22 23 and manageable with appropriate intervention via dose modifications, routine medical care, and prophylactic measures. Additional characterization of key safety events are associated with the use of idealism 40 and inhibitors as a whole 41 .
The anti-CD20 monoclonal antibody ofatumumab is approved as a treatment for relapsing CLL at the time of study initiation. However, the use of single-agent agents for the treatment of relapsed CLL has been completed in recent years, which are the most popular agents that target the B-cell receptor pathway. In a combination with rituximab, an oral BTK inhibitor, received in 2014 full approval based on a phase 3 randomized study demonstrating a significantly improved PFS compared withumumab (median PFS not reached vs. 8.1 months [HR = 0.22]).  7 Treatment indices have since expanded to include ibrutinib use as a frontline CLL therapy. Although it is an effective and well-tolerated therapy, it is not curative, and treatment discontinuations because of disease progression and drug intolerance have been described in published reports. 48 19 – 50 or have resistance or intolerance to currently available, targeted therapies, or have comorbidities that may preclude their safe use, there are critical medical needs for additional, novel, targeted therapies for patients with RR CLL / SLL, especially those with del (17p) / TP53 mutations. These combined safety and efficacy results suggest that treatment can be effective in additional therapeutic options.
The authors of the patients and families who participated in this study. Veristat Inc. provided biostatistical programming support. The Henion of Acumen Medical Communications LLC team provided medical writing and editorial assistance, and John provided graphics support.
Contribution: I.W.F. provided primary authorship, trial design input, and data interpretation; I.F., P.H., M.M., Z.N., A.I., G.E., J.D., B.J.K., C.S.T., Z.G., F.O., S.L., F.B., M.S., N.L., U.J., P.G., F.C., C.A.P., A.P.S., A.F.C., and S.S. enrolled patients, researched and contributed to / edited the manuscript; V.M.K. analyzed data and wrote and / or edited the manuscript; B.T. provided statistical outputs; and D.T.W. performed pharmacodynamic analysis and data interpretation.
Conflict-of-interest disclosure: I.W.F. received funds from the institutions for trial participation from Agios, ArQule, Beigene, Calithera, Celgene, Constellation, Curis, Forma, Forty Seven, Genentech, Gilead, Incyte, Infinity, Janssen, KITE, Merck, Novartis, Pfizer, Pharmacyclics, Portola, Seattle Genetics, Takeda, TG Therapeutics, Trillium, and Verastem. M.M. received personal fees from Janssen and Roche and personal fees and nonfinancial support from AbbVie and Gilead. U.J. received research funding and personal fees from Gilead, Celgene, Roche, and Novartis and personal fees from AbbVie. P.G. received research funding and personal fees from Abbvie, Janssen, and Gilead; research funding from Novartis; and personal fees from Acerta / Astra Zeneca and Beigene. A.F.C. received from Gilead personal fees and received personal fees from Verastem. D.T.W. is employee of Verastem Oncology. V.M.K. was employee of Infinity Pharmaceuticals and was a consultant for Verastem Oncology. B.T. was a consultant to Verdict Oncology when the analyses were performed.