Ponatinib has potent activity against native and mutant BCR-ABL1, including BCR-ABL1T315I. The pivotal phase 2 Ponatinib Ph+ ALL and CML Evaluation (PACE) trial evaluated efficacy and safety of ...ponatinib at a starting dose of 45 mg once daily in 449 patients with chronic myeloid leukemia (CML) or Philadelphia chromosome–positive acute lymphoblastic leukemia (ALL) resistant/intolerant to dasatinib or nilotinib, or with BCR-ABL1T315I. This analysis focuses on chronic-phase CML (CP-CML) patients (n = 270) with 56.8-month median follow-up. Among 267 evaluable patients, 60%, 40%, and 24% achieved major cytogenetic response (MCyR), major molecular response (MMR), and 4.5-log molecular response, respectively. The probability of maintaining MCyR for 5 years was 82% among responders. Dose reductions were implemented in October 2013 to decrease the risk of arterial occlusive events (AOEs); ≥90% of CP-CML patients who had achieved MCyR or MMR maintained response 40 months after elective dose reductions. Estimated 5-year overall survival was 73%. In CP-CML patients, the most common treatment-emergent adverse events were rash (47%), abdominal pain (46%), thrombocytopenia (46%), headache (43%), dry skin (42%), and constipation (41%). The cumulative incidence of AOEs in CP-CML patients increased over time to 31%, while the exposure-adjusted incidence of new AOEs (15.8 and 4.9 per 100 patient-years in years 1 and 5, respectively) did not increase over time. These final PACE results demonstrate ponatinib provides durable and clinically meaningful responses, irrespective of dose reductions, in this population of heavily pretreated CP-CML patients. This trial was registered at www.clinicaltrials.gov as #NCT01207440.
•Ponatinib continued to provide deep, durable responses in heavily pretreated patients with CP-CML.•Tolerability was acceptable in this heavily pretreated population with 5 years of follow-up.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Summary Background Ponatinib has shown potent activity against chronic myeloid leukaemia that is resistant to available treatment, although it is associated with arterial occlusion. We investigated ...whether this activity and safety profile would result in superior outcomes compared with imatinib in previously untreated patients with chronic myeloid leukaemia. Methods The Evaluation of Ponatinib versus Imatinib in Chronic Myeloid Leukemia (EPIC) study was a randomised, open-label, phase 3 trial designed to assess the efficacy and safety of ponatinib, compared with imatinib, in newly diagnosed patients with chronic-phase chronic myeloid leukaemia. Patients from 106 centres in 21 countries were randomly assigned (1:1, with stratification by Sokal score at diagnosis) using an interactive voice and web response system to receive oral ponatinib (45 mg) or imatinib (400 mg) once daily until progression, unacceptable toxicity, or other criteria for withdrawal were met. Eligible patients were at least 18 years of age, within 6 months of diagnosis, and Philadelphia chromosome-positive by cytogenetic assessment, with Eastern Cooperative Oncology Group performance status of 0–2, and had not previously been treated with tyrosine kinase inhibitors. The primary endpoint was major molecular response at 12 months. Patients who remained on study and had molecular assessments at specified timepoints were studied at those timepoints. Safety analyses included all treated patients, as per study protocol. This trial is registered with ClinicalTrials.gov , number NCT01650805. Findings Between Aug 14, 2012, and Oct 9, 2013, 307 patients were randomly assigned to receive ponatinib (n=155) or imatinib (n=152). The trial was terminated early, on Oct 17, 2013, following concerns about vascular adverse events observed in patients given ponatinib in other trials. Trial termination limited assessment of the primary endpoint of major molecular response at 12 months, as only 13 patients in the imatinib group and ten patients in the ponatinib group could be assessed at this timepoint; the proportion of patients achieving a major molecular response at 12 months did not differ significantly between the two groups (eight 80% of ten patients given ponatinib and five 38% of 13 patients given imatinib; p=0·074). 11 (7%) of 154 patients given ponatinib and three (2%) of 152 patients given imatinib had arterial occlusive events (p=0·052); arterial occlusive events were designated serious in ten (6%) of 154 patients given ponatinib and in one (1%) of 152 patients given imatinib (p=0·010). The data monitoring committee criterion for risk assessment (significant difference in serious grade 3 or 4 ischaemic events between groups) was not met (five 3% of 154 vs one 1% of 152; p=0·21). Grade 3 or 4 adverse events observed in more than 5% of patients in the ponatinib group were increased lipase (22 14% of 154 vs three 2% of 152 with imatinib), thrombocytopenia (19 12% of 154 vs ten 7% of 152 with imatinib), rash (ten 6% of 154 vs two 1% of 152 with imatinib). In the imatinib group, grade 3 or 4 adverse events observed in more than 5% of patients were neutropenia (12 8% of 152 vs five 3% of 154 with ponatinib) and thrombocytopenia (ten 7% of 152 vs 19 12% of 154 with ponatinib). Serious adverse events that occurred in three or more patients given ponatinib were pancreatitis (n=5), atrial fibrillation (n=3), and thrombocytopenia (n=3). No serious adverse event occurred in three or more patients given imatinib. Interpretation The efficacy of ponatinib treatment of newly diagnosed chronic-phase chronic myeloid leukaemia compared with imatinib could not be assessed due to trial termination, but preliminary data suggest there might be benefit, although with more arterial occlusive events than with imatinib at the doses studied. Because the EPIC trial was terminated early, efficacy of ponatinib in this setting remains to be established. Funding ARIAD Pharmaceuticals.
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In this ongoing Phase 1/2 study (NCT01667133), we evaluated ponatinib and assessed its recommended dose in Japanese patients with chronic myeloid leukemia (CML) resistant/intolerant to dasatinib or ...nilotinib, or with Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph
+
ALL) resistant/intolerant to ≥1 tyrosine kinase inhibitor (TKI). The primary endpoints were safety of the recommended dose (Phase 1) and major cytogenetic response (MCyR) by 12 months in chronic-phase CML (CP-CML) patients or major hematologic response (MaHR) by 6 months in patients with advanced phase disease (Phase 2). MCyR was achieved/maintained by 12 months in 65% of CP-CML patients; MaHR was achieved by 6 months in 61% of patients with advanced phase disease. The most common nonhematologic grade 3/4 treatment-emergent adverse event (AE) was hypertension (37%); common hematologic grade 3/4 AEs were thrombocytopenia (57%), neutropenia (34%), and leukopenia (26%). Overall, five (14%) patients experienced arterial occlusive events (AOEs); no grade 5 AOEs were reported. The steady-state accumulation ratio of ponatinib (based on area under the curve) ranged from 2.6 (15 mg/day) to 1.3 (45 mg/day). In summary, ponatinib demonstrated efficacy in Japanese patients with CML and Ph
+
ALL resistant/intolerant to prior TKI treatment; safety data support a recommended starting dose of 45 mg/day in these patients.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Background: Ponatinib, an oral tyrosine kinase inhibitor with potent activity against native and mutant BCR-ABL1, is approved for patients with refractory chronic myeloid leukemia (CML) or ...Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) for whom no other tyrosine kinase inhibitor (TKI) therapy is indicated, or for patients with the T315I mutation.
The efficacy and safety of ponatinib in patients with resistant/refractory hematologic malignancies were evaluated in a phase 1 trial (NCT00660920). Here, we report 4-year follow-up data from chronic-phase (CP)-CML patients; final data (approximately 5-year follow-up) will be presented.
Methods: In this open-label, dose-escalation, phase 1 trial, 81 patients with resistant/refractory hematologic malignancies (CP-CML, 43 patients; accelerated-phase CML, 9 patients; blast-phase CML, 8 patients; Ph+ ALL, 5 patients) were enrolled. Patients were treated with ponatinib at a starting dose of 2 mg/d - 60 mg/d; intra-patient dose escalation was permitted. In Oct 2013, dose reduction instructions were provided in response to an observed accumulation of arterial occlusive events (AOEs) with longer follow-up across the ponatinib clinical program. For data presented herein, the data cutoff date is 2 Feb 2015, with median follow-up of 53.1 months (range, 1.7 - 69.9 months) for CP-CML patients.
Results: Among CP-CML patients, at baseline, median age was 55 years and median time since diagnosis was 6.6 years; BCR-ABL1 kinase domain mutations were reported in 63% of patients, with T315I confirmed at a central laboratory in 28% of patients. Patients were heavily pretreated, with 37% having received 2 prior TKIs and 60% having received ≥3 prior TKIs. Of 43 CP-CML patients, 22 (51%) remained on ponatinib treatment at data cutoff. Adverse events (AEs; 26%) and disease progression (9%) were the most common reasons for discontinuation of treatment. Cumulative response rates were: major cytogenetic response (MCyR), 72%; complete cytogenetic response (CCyR), 65%; major molecular response (MMR; assessed at a central laboratory), 56%; molecular response 4 (MR4), 42%; MR4.5, 28%. Responses were durable (Table), with median durations of response not reached for MCyR, CCyR, and MMR. Among patients who received ponatinib at starting doses of ≤30 mg/d (n = 15), MCyR was achieved by 67%, CCyR by 53%, and MMR by 47%; ponatinib dose was ≤30 mg/d in all but one of these patients at the time of response. Of 19 patients who were ongoing and in MCyR as of Oct 2013, 13 had their dose reduced; all 13 dose-reduced patients maintained MCyR at data cutoff. Of the 22 ongoing patients at the time of the present analysis, 18 (82%) had CCyR and 17 (77%) had MMR or better (MMR, 6 patients; MR4, 1 patient; MR4.5, 9 patients; MR5, 1 patient) as their response at the data cutoff; 14/22 (64%) ongoing patients were receiving 15 mg/d as their current dose as of the data cutoff. Rash (65%), fatigue (63%), abdominal pain (58%), headache (58%) and arthralgia (53%) were the most common treatment-emergent AEs. The incidence of AOEs (any/serious) was 40%/30% (by subcategory: cardiovascular, 30%/21%; cerebrovascular, 9%/7%; peripheral vascular, 14%/9%).
Conclusions: With median follow-up of over 4 years in this phase 1 study, ponatinib continues to provide clinical benefit to heavily pre-treated CP-CML patients, approximately half of whom continue to receive ponatinib, with a majority in deep response that has been long-lasting; final study data will be presented. The most common treatment-emergent AEs were consistent with the AE profile across the clinical program. Potential for long-term benefit, demonstrated herein, versus risk should be considered when using ponatinib in this patient population.
Study sponsor: ARIAD Pharmaceuticals, Inc.
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Mauro:BMS: Consultancy, Honoraria; ARIAD: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria. Cortes:ARIAD: Consultancy, Research Funding; Bristol-Myers Squib: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding. Kantarjian:Bristol-Myers Squibb: Research Funding; Amgen: Research Funding; ARIAD: Research Funding; Pfizer Inc: Research Funding; Delta-Fly Pharma: Research Funding; Novartis: Research Funding. Shah:ARIAD: Research Funding; BMS: Research Funding; Daiichi-Sankyo: Research Funding; Pfizer: Research Funding; Plexxikon: Research Funding. Flinn:Janssen: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Gilead Sciences: Research Funding; ARIAD: Research Funding; RainTree Oncology Services: Equity Ownership. Rivera:ARIAD: Employment, Equity Ownership. Lustgarten:ARIAD: Employment, Equity Ownership. Santillana:ARIAD: Employment, Equity Ownership. Heinrich:Novartis: Consultancy, Patents & Royalties, Research Funding; Pfizer: Consultancy; Bayer: Research Funding; BMS: Research Funding; Blueprint Medicines: Consultancy; MolecularMD: Consultancy, Equity Ownership; ARIAD: Consultancy, Research Funding; Onyx: Consultancy. Druker:Agios: Honoraria; Ambit BioSciences: Consultancy; ARIAD: Patents & Royalties, Research Funding; Array: Patents & Royalties; AstraZeneca: Consultancy; Blueprint Medicines: Consultancy, Equity Ownership, Other: travel, accommodations, expenses ; BMS: Research Funding; CTI: Equity Ownership; Curis: Patents & Royalties; Cylene: Consultancy, Equity Ownership; D3 Oncology Solutions: Consultancy; Gilead Sciences: Consultancy, Other: travel, accommodations, expenses ; Lorus: Consultancy, Equity Ownership; MolecularMD: Consultancy, Equity Ownership, Patents & Royalties; Novartis: Research Funding; Oncotide Pharmaceuticals: Research Funding; Pfizer: Patents & Royalties; Roche: Consultancy. Deininger:Pfizer: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Gilead: Research Funding; Incyte: Consultancy, Membership on an entity’s Board of Directors or advisory committees; BMS: Consultancy, Research Funding; CTI BioPharma Corp.: Membership on an entity’s Board of Directors or advisory committees; Celgene: Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Ariad: Consultancy, Membership on an entity’s Board of Directors or advisory committees. Talpaz:Novartis: Research Funding; Incyte Corporation: Other: Travel expense reimbursement, Research Funding; Ariad: Other: Expense reimbursement, travel accomodation expenses, Research Funding; Pfizer: Consultancy, Other: travel accomodation expenses, Research Funding.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Indolent non-Hodgkin lymphoma (iNHL) remains largely incurable and often requires multiple lines of treatment after becoming refractory to standard therapies. Duvelisib was approved by the Food and ...Drug Administration for relapsed or refractory (RR) chronic lymphocytic leukemia or small lymphocytic lymphoma (SLL) and RR follicular lymphoma (FL) after two or more prior systemic therapies. On the basis of the activity of duvelisib, a first-in-class oral dual inhibitor of phosphoinositide 3-kinase-δ,-γ, in RR iNHL in a phase I study, the safety and efficacy of duvelisib monotherapy was evaluated in iNHL refractory to rituximab and either chemotherapy or radioimmunotherapy.
Eligible patients had measurable iNHL (FL, SLL, or marginal zone B-cell lymphoma) double refractory to rituximab (monotherapy or in combination) and to either chemotherapy or radioimmunotherapy. All were treated with duvelisib 25 mg orally twice daily in 28-day cycles until progression, unacceptable toxicity, or death. The primary end point was overall response rate (ORR) using the revised International Working Group criteria for malignant lymphoma.
This open-label, global phase II trial enrolled 129 patients (median age, 65 years; median of three prior lines of therapy) with an ORR of 47.3% (SLL, 67.9%; FL, 42.2%; MZL, 38.9%). The estimated median duration of response was 10 months, and the estimated median progression-free survival was 9.5 months. The most frequent any-grade treatment-emergent adverse events (TEAEs) were diarrhea (48.8%), nausea (29.5%), neutropenia (28.7%), fatigue (27.9%), and cough (27.1%). Among the 88.4% of patients with at least one grade 3 or greater TEAE, the most common TEAEs were neutropenia (24.8%), diarrhea (14.7%), anemia (14.7%), and thrombocytopenia (11.6%).
In the DYNAMO study, oral duvelisib monotherapy demonstrated clinically meaningful activity and a manageable safety profile in heavily pretreated, double-refractory iNHL, consistent with previous observations. Duvelisib may provide a new oral treatment option for this patient population of which many are elderly and in need of additional therapies.
In trials with failure-time outcomes, statistical information is determined by accumulated events. Interim and final analyses are performed after a prespecified number of events have been observed. ...It is of interest to predict when a prespecified number of events will be observed based on accumulating data. We propose a fully Bayesian nonparametric approach in modeling the survival probabilities. We compare the accuracy and precision of this approach to proposed parametric and semi-parametric methods. In summary, the proposed method offers greater flexibility and based on our studies has the ability to match or outperform existing methods.
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BFBNIB, DOBA, GIS, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Introduction
In chronic lymphocytic leukemia (CLL), prognostic factors, such as genetic alterations and lines of treatment, have been well studied with chemoimmunotherapy and are advancing with ...ibrutinib, venetoclax, and PI3K inhibitors. Duvelisib (DUV) is a first-in-class, oral, dual PI3K-δ,γ inhibitor approved by the US FDA in 2018 for the treatment of relapsed or refractory (R/R) CLL/small lymphocytic lymphoma (SLL) after ≥ 2 prior therapies and for follicular lymphoma after ≥ 2 prior systemic therapies. In heavily pretreated patients who received ≥ 2 prior regimens in the phase 3 DUO study, PFS was significantly extended with DUV vs ofatumumab (OFA; 16.4 vs 9.1 months) regardless of del(17p) and/or TP53 mutation status. In DUO, approximately one-third of DUV-treated patients had received only 1 prior therapy that consisted of either chemotherapy or chemoimmunotherapy. We evaluated the impact of baseline prognostic cytogenetic and molecular markers in the subgroup of patients who received 1 prior therapy in the DUO trial.
Methods
Patients with R/R CLL/SLL were treated with DUV 25 mg BID (n = 160) or OFA (n = 159) in the DUO trial. Patients who had 1 prior therapy before DUV (n = 64) or OFA (n = 58) were studied. PFS, ORR, and rates of treatment discontinuation in patients who received 1 prior therapy were evaluated based on cytogenetic and molecular markers at baseline. Fresh whole blood from screening or cycle 1 day 1 was evaluated at central laboratories for the following prognostic markers: IGHV mutation, del(17p), TP53 mutation, del(11q), del(13q), and trisomy 12.
Results
Before entry into the DUO trial, nearly all of the patients in the 1 prior therapy study group had received chemotherapy (DUV, 90.6%; OFA, 96.6%), and the majority had received a chemotherapy + anti-CD20 antibody regimen (DUV, 62.5%; OFA, 72.4%). DUV demonstrated a more favorable PFS than OFA in patients with either del(11q) (median PFS, 24.8 vs 9.2 months; HR, 0.34; P = .0318), the absence of del(13q) (median PFS, 12.7 vs 10.5 months; HR, 0.40; P = .0110), or unmutated (U)-IGHV (median PFS, 12.7 vs 11.1 months; HR, 0.67; P = .0754). DUV-treated U-IGHV patients had numerically longer PFS compared with mutated (M)-IGHV patients (median PFS, 12.7 vs 6.2 months; HR, 1.19; P = 0.6417). No significant differences in PFS were observed between DUV and OFA in patients with del(17p)/TP53 (DUV, n = 19; OFA, n = 22) or trisomy 12 (DUV, n = 13; OFA, n = 11). DUV also demonstrated a favorable ORR compared with OFA in patients with del(11q) (83.3% vs 55.6%; OR, 8.36), the absence of del(13q) (66.7% vs 37.5%; OR, 3.90) or U-IGHV (65.9% vs 50.0%; OR, 2.20).
The rate of discontinuationdue to adverse events (AEs) was similar among DUV-treated patients regardless of the presence or absence of cytogenetic markers del(11q), del(13q), del(17p) and/or TP53, and trisomy 12. The rate of discontinuation due to AEs in DUV-treated M-IGHV patients was significantly higher than in those with U-IGHV (83.3% n/N = 10/12 vs 36.4% n/N = 16/44; P = .010) with a median exposure of 14.6 vs 44.9 weeks, respectively, potentially influencing the shorter PFS observed in the M-IGHV patient subgroup. Nearly all DUV-related AEs of special interest leading to discontinuation within the M-IGHV subgroup were immune related (diarrhea n = 1, transaminase elevation n = 1, colitis n = 3, dermatitis n = 2, pneumonitis n = 2). An increased risk of autoimmune AEs in M-IGHV patients was previously reported with idelalisib given frontline (Lampson et al. Blood 2016).
Conclusions
Patients with R/R CLL/SLL and del(11q), U-IGHV, or the absence of del(13q) demonstrated extended PFS and a higher ORR with DUV vs OFA in the second-line setting; therefore, these prognostic markers are potential identifiers of patients who would benefit from DUV treatment. Patients with M-IGHV had a higher rate of discontinuation due to immune-related AEs in the second-line setting. As such, the use of prognostic markers continues to have value in selection of therapy for patients with CLL/SLL treated with novel agents, including in ongoing clinical studies with DUV.
Brown:Gilead, Loxo, Sun Pharmaceuticals, Verastem: Research Funding; Janssen, Teva Pharmaceuticals: Honoraria; Abbvie, Acerta, Astra-Zeneca, Beigene, Catapult Therapeutics, Dynamo Therapeutics, Genentech/Roche, Gilead, Juno/Celgene, Kite, Loxo, Octapharma, Novartis, Pfizer, Pharmacyclics, Sunesis, TG Therapeutics, Verastem: Consultancy; Morphosys, Invectys (Data Safety Monitoring Board): Membership on an entity's Board of Directors or advisory committees. Sprott:SMOC Therapeutics: Employment, Equity Ownership; Verastem Oncology: Employment, Equity Ownership. Lustgarten:Verastem: Employment. Weaver:Verastem Oncology: Employment, Equity Ownership, Patents & Royalties: Inventor; Hillstream Biopharma: Consultancy, Equity Ownership; FemtoDx: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: Inventor. Danilov:Genentech: Consultancy, Research Funding; Janssen: Consultancy; Abbvie: Consultancy; Pharmacyclics: Consultancy; Verastem Oncology: Consultancy, Other: Travel Reimbursement , Research Funding; Gilead Sciences: Consultancy, Research Funding; Seattle Genetics: Consultancy; Celgene: Consultancy; Aptose Biosciences: Research Funding; Takeda Oncology: Research Funding; TG Therapeutics: Consultancy; Bayer Oncology: Consultancy, Research Funding; Bristol-Meyers Squibb: Research Funding; MEI: Research Funding; AstraZeneca: Consultancy, Research Funding; Curis: Consultancy.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
In the phase III DUO trial, duvelisib, an oral dual PI3K-δ,γ inhibitor, demonstrated significantly improved efficacy versus ofatumumab median (m) progression-free survival (PFS), 13.3 vs. 9.9 months ...(HR, 0.52;
< 0.0001); overall response rate ORR, 74% vs. 45% (
< 0.0001), with a manageable safety profile in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). We report results from patients with progressive disease (PD) after ofatumumab who crossed over to duvelisib in the DUO trial.
Patients with radiographically confirmed PD after ofatumumab received duvelisib 25 mg twice daily in 28-day cycles until PD, intolerance, death, or study withdrawal. The primary endpoint was ORR per investigator. Secondary endpoints included duration of response (DOR), PFS, and safety.
As of December 14, 2018, 90 ofatumumab-treated patients in the DUO trial prior to crossover had an ORR of 29%, mDOR of 10.4 months, and mPFS of 9.4 months. After crossover, 77% of patients (69/90) achieved a response, with an mDOR of 14.9 months and mPFS of 15.7 months. Patients with del(17p) and/or
mutations had similar outcomes ORR, 77% (20/26); mPFS, 14.7 months. Notably, 73% of patients (47/64) with disease previously refractory to ofatumumab achieved a response. The most frequent any-grade/grade 3/4 treatment-emergent adverse events were diarrhea (47%/23%), neutropenia (26%/23%), pyrexia (24%/4%), cutaneous reactions (23%/4%), and thrombocytopenia (10%/6%).
Duvelisib demonstrated high response rates with good durability and a manageable safety profile in patients with R/R CLL/SLL who progressed on ofatumumab, including patients with high-risk disease and disease previously refractory to ofatumumab.
Background: Ponatinib is a potent oral tyrosine kinase inhibitor (TKI) active against native and mutant forms of BCR-ABL. It is approved for patients with resistant or intolerant CML or Ph+ ALL, or ...with the T315I mutation, which renders other TKIs ineffective. The USPI recommends a starting dose of 45 mg/day, with consideration of lower starting doses in patients with selected comorbidities. In the US, ponatinib is available exclusively through a specialty pharmacy that maintains prescribing data for all US ponatinib-treated patients. Analyses of dispensed ponatinib prescriptions for CP-CML patients show that median therapy duration exceeds 1.5 years but is variable across groups; examination of demographic, clinical and physician characteristics may reveal predictors of therapy duration.
Methods: We performed a retrospective analysis of patients starting treatment with ponatinib over the 2.5-year period from 01 January 2014 and 30 June 2016 using data from referring physicians, patient intake forms and pharmacy dispensing records. Gender (M/F), age (</≥65 years), reported T315I status (Y/N), line of therapy (2nd-5th), most recent prior TKI (imatinib, nilotinib, dasatinib, or bosutinib), starting dose (15, 30 or 45 mg/day), prescribing physician practice type (academic/community), and number of ponatinib patients treated by physician (1, 2, 3 or more) were examined as predictors of therapy duration using Kaplan-Meier (K-M) techniques and log-rank tests; multivariable, stepwise, proportional-hazard regression was used to generate adjusted hazard ratios and identify primary drivers of therapy duration.
Results: 475 US patients identified with CP-CML initiated treatment with ponatinib over this 2.5-year period; K-M median time on therapy was 20.7 months. About one-half of patients were male (Table) and most were aged <65 years. Only 10% were reported to have the T315I mutation, most were in their 3rd or 4th line of therapy, and had most commonly switched from dasatinib; nearly one-half had a starting dose of 45 mg/day. Slightly more than one-half of prescribing physicians were in academic settings, and more than three-quarters had only one ponatinib patient. When examining each predictor individually, only gender was a significant predictor of time on therapy (Table), with women having significantly shorter duration than men. There was also a trend for T315I patients to have longer duration than non-T315I. In analyses adjusted for other covariates, non-T315I patients had significantly shorter duration (hazard ratio HR: 2.09; p=0.033), as did those whose most recent TKI was not imatinib (HR nilotinib v imatinib: 3.61; dasatinib v imatinib 4.72; bosutinib v imatinib 1.85; overall p=0.001). Women had a borderline significantly shorter duration than men (HR: 1.40; p= 0.085) and versus 2nd line, patients in 3rd (HR: 0.67) and 4th (HR: 0.68) line had longer duration, while 5th line had shorter (HR: 1.45; overall p=0.054).
Conclusions: Real-world US data for CP-CML patients receiving ponatinib show that a number of subgroups have median duration on ponatinib exceeding 2 years, but suggest drivers of therapy duration may be complex including both disease (e.g. T315I, prior line of tx) and patient (e.g. sex) related factors.
Study sponsor: ARIAD Pharmaceuticals, Inc.
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Mauro:Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria; ARIAD: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. McGarry:ARIAD: Employment, Equity Ownership. Lustgarten:ARIAD: Employment, Equity Ownership. Huang:ARIAD: Employment, Equity Ownership.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
This large, multicenter trial compared temsirolimus with interferon alfa alone and with a combination of the two drugs in patients with newly diagnosed metastatic renal-cell cancer and a poor ...prognosis. As compared with interferon alfa or combination therapy, temsirolimus was associated with a moderate improvement in survival among these high-risk patients.
As compared with interferon alfa or combination therapy, temsirolimus was associated with a moderate improvement in survival among patients with newly diagnosed metastatic renal-cell cancer and a poor prognosis.
Renal-cell carcinoma accounts for 2.6% of all cancers in the United States, and nearly 39,000 new cases of this disease and 13,000 associated deaths were expected in 2006.
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Surgical resection is the mainstay of treatment for tumors that are confined to the kidney. Distant metastases develop in about one third of patients, and most of these cases cannot be cured. Interleukin-2 and interferon alfa, alone or in combination, are the main treatments for metastatic renal-cell carcinoma. Treatment with these agents results in a median survival of 12.0 to 17.5 months.
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These cytokines, however, have limited efficacy and substantial toxicity, . . .
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