Glasdegib In Combination Research Articles

501O Glasdegib in combination with temozolomide and radiotherapy in patients with newly diagnosed glioblastoma: Phase Ib/II GEINO 1602 trial

501O Glasdegib in combination with temozolomide and radiotherapy in patients with newly diagnosed glioblastoma: Phase Ib/II GEINO 1602 trial

Glasdegib plus intensive or non-intensive chemotherapy for untreated acute myeloid leukemia: results from the randomized, phase 3 BRIGHT AML 1019 trial

This is the primary report of the randomized, placebo-controlled phase 3 BRIGHT AML 1019 clinical trial of glasdegib in combination with intensive chemotherapy (cytarabine and daunorubicin) or non-intensive chemotherapy (azacitidine) in patients with untreated acute myeloid leukemia. Overall survival (primary endpoint) was similar between the glasdegib and placebo arms in the intensive (n = 404; hazard ratio [HR] 1.05; 95% confidence interval [CI]: 0.782–1.408; two-sided p = 0.749) and non-intensive (n = 325; HR 0.99; 95% CI: 0.768–1.289; two-sided p = 0.969) studies. The proportion of patients who experienced treatment-emergent adverse events was similar for glasdegib versus placebo (intensive: 99.0% vs. 98.5%; non-intensive: 99.4% vs. 98.8%). The most common treatment-emergent adverse events were nausea, febrile neutropenia, and anemia in the intensive study and anemia, constipation, and nausea in the non-intensive study. The addition of glasdegib to either cytarabine and daunorubicin or azacitidine did not significantly improve overall survival and the primary efficacy endpoint for the BRIGHT AML 1019 phase 3 trial was not met. Clinical trial registration: ClinicalTrials.gov: NCT03416179.

Real-World Observational Study of Outcomes for Acute Myeloid Leukemia (AML) in Patients Treated with Glasdegib or Venetoclax in US Community Oncology Practices

Introduction: Glasdegib (GLAS) and venetoclax (VEN) were approved by the FDA in Nov 2018 for the treatment of AML in patients (pts) who are ≥75 years old or who have comorbidities that preclude intensive induction chemotherapy. Data related to the clinical outcomes of pts who receive these agents in the community oncology setting are limited. We conducted a retrospective, observational study to assess US real-word (RW) patient characteristics and clinical outcomes for pts who received a GLAS- or VEN-based regimen as first line (1L) therapy for AML. This study was observational and not designed or powered to compare characteristics or outcomes between pts treated with GLAS and those treated with VEN. We present RW findings comparing to the respective pivotal clinical trial populations (the BRIGHT AML 1003 trial which evaluated GLAS and the VIALE-A trial which evaluated VEN), including an exploratory analysis to match the characteristics of the RW cohorts to the clinical trials. Methods: A retrospective, observational, US multi-site, cohort chart review of adult pts who initiated 1L therapy for AML between 01 Dec 2018 and 31 Dec 2019 was conducted. Eligible pts had at least 6 months (mo) of follow-up since initiation of 1L (unless the pt died within this follow-up time, with known date of death), known cytogenetic risk profile, and had at least 1 bone marrow biopsy completed following index therapy initiation. Index therapy was either a GLAS- or VEN-based regimen (with low-dose cytarabine [LDAC], azacytidine [AZA), or decitabine). Pts treated in a clinical trial were excluded. The treating physician extracted all data for a given patient, including demographics, clinical characteristics, treatment patterns and dosing, transfusions, follow-up, disease response, and clinical outcomes. Results: 50 pts treated with GLAS as 1L therapy for AML, most of whom (82.0%) received GLAS in combination with LDAC, were followed for a median of nearly 7 mo, 28% of whom were still alive at data collection. The median age at initiation of 1L GLAS was 77 (47-89) years. Approximately half of 1L GLAS pts had an ECOG-PS of 0 or 1 at 1L therapy initiation. The median overall survival (mOS) for pts who received 1L GLAS was 6.9 mo (95% CI: 5.4-8.9); for comparison, the mOS for 88 GLAS- treated pts in the BRIGHT AML 1003 clinical trial was 8.8 mo. The median duration of follow-up was shorter in the RW cohort versus the trial (6.9 vs 27.1 mo). ECOG-PS 3 and poor cytogenetic risk score was noted in a greater proportion of RW 1L GLAS cohort vs BRIGHT AML 1003 trial (14% vs 0% and 58% vs 41%, respectively). The mOS for a subset of RW pts who matched all eligibility criteria for BRIGHT AML 1003 was 7.7 mo. 83 RW pts treated with VEN as 1L therapy for AML, the majority of whom (61.5%) received VEN in combination with AZA, were followed for a median of 8.4 mo and 38.6% of these pts were reported to be alive at data collection. The median age at initiation of VEN was 73 years and ECOG-PS of 0 or 1 was reported for 44.6% pts, 2 for 47.0% and 3 for 8.4%. The mOS of pts treated with 1L VEN was 8.4 mo (95% CI: 5.7-16.2); this compared to 286 VEN-treated pts in the VIALE-A trial with a mOS of 14.1 mo. The VEN RW cohort has shorter follow up compared to VIALE-A (8.4 mo vs 20.5). In comparison to pts treated with VEN in the VIALE-A trial, a greater proportion of pts in the RW VEN cohort had ECOG-PS scores of 2 or 3 (55.4% vs 45%) and poor cytogenetic risk (49.4% vs 36%). When the RW VEN cohort was matched to the eligibility criteria for VIALE-A, the RW mOS was not reached (n=23). Conclusions: In this RW observational study, the pt clinical and cytogenetic characteristics in the RW cohorts were less favorable for both GLAS and VEN than those observed in their respective clinical trials. In the RW, mOS was 1.9 mo lower for GLAS and 5.7 mo lower for VEN versus their respective clinical trials. This study was not comparative between GLAS and VEN, and indeed the pt populations were different with a higher median age and a higher proportion of ECOG-PS 3 in the GLAS RW cohort than the VEN RW cohort; the main combination agent also differed (LDAC or AZA). The settings and populations evaluated in these studies were unique and offer novel insights into the RW treatment patterns and effectiveness of both therapeutic options. Outcomes may be explained by differences in the characteristics of the RW cohorts and the eligibility criteria between the clinical trials.

Safety and efficacy of glasdegib in combination with temozolomide and radiotherapy in patients with newly diagnosed glioblastoma: Phase Ib/II GEINO 1602 trial.

2060 Background: Hedgehog signaling through Smoothened (SMO) protein in gliomas promotes cell cycle progression and leads to glioma stem cells (GSCs) maintenance, which constitutes one of the key hallmarks for glioblastoma (GB) resistance against anticancer therapies. Glasdegib, a SMO inhibitor, may disrupt GSCs and lead to enhanced efficacy of the Stupp scheme. Methods: Newly diagnosed GB pts received glasdegib with standard radiotherapy (RT)/ temozolomide (TMZ) followed by maintenance with glasdegib monotherapy. The primary objective was to determine the recommended phase 2 dose (RP2D) in a 3+3 dose escalation (DE) strategy in phase Ib and overall survival (OS) in phase II. Secondary objectives included progression-free (PFS) according to RANO criteria, safety, changes in performance status, and exploratory biomarker analysis. Results: Between 2018 and 2020, 79 GB pts were enrolled and 78 received at least one dose of glasdegib. In DE, 4 pts received Glasdegib at 100 mg/QD and 6 pts received 75 mg/QD. DLTs were reported in 3/4 pts in 100 mg dose level, and 1/6 pts in 75 mg dose level, declaring 75 mg/QD of glasdegib as RP2D. For phase II, 68 additional pts were treated at 75 mg/QD dose. The median age was 55 years (range: 28-78), 54% were male, 45% were MGMT unmethylated, and 1 pts had an IDH1/2 mutation. Glasdegib treatment lasted a median of 6 m (range: 0.5-21.9). Overall, 72 (97.3%) pts completed concomitant therapy, 65 (87.8%) started adjuvant therapy, 28 (37.8%) completed adjuvant therapy, and 23 (31.1%) continued glasdegib monotherapy. Treatment combination was discontinued due to treatment-related adverse events (TRAEs) in 9 (12.2%) pts. For those pts that received RT/TMZ combined with glasdegib at 75 mg/QD dose, 7 (9.5%) presented grade (G) ≥3 hematological TRAEs during concomitant treatment and 2 (3.1%) during the adjuvant treatment. There were no G≥3 TRAEs of any type during the maintenance phase. Neutrophil count decrease G≥3 was reported in 6 (8.1%) pts and platelet count decrease G≥3 in 7 (9.5%) pts. Cutaneous events G≥3 were reported in 3 (4.1%) pts. ECOG, Minimental and Barthel indexes, were maintained when comparing baseline with end of treatment (p = 0.181, 0.25 and 0.346 respectively). Stabilization was the most common response, reported in 60 (81.1%) pts. After a median follow up of 7.8 m (range 0.7-25.9), median PFS was 6.9 m (95% CI: 6.1-8.5). The 6-m PFS rate was 62.1% (95% CI: 50.9-75.8) and the 18 m OS rate was 63.3% (95% CI: 47.5-84.4). Conclusions: The addition of glasdegib to standard RT and TMZ was safe. Glasdegib monotherapy showed no G ≥3 TRAEs. Most patients had disease stabilization, with a promising preliminary PFS and OS for newly diagnosed GBM. Final survival results are awaited. Clinical trial information: NCT03466450.

EXPERIENCE OF GLASDEGIB IN PATIENTS WITH ELDERLY ACUTE MYELOID LEUKEMIA

Acute myeloid leukemia (AML) is characterized by the increase of high levels of myeloid cells in the bone marrow. In general, AML is a disease of older adults. Many adults with AML are unable to receive intensive chemotherapy because of its toxicity.In this study, it was aimed to retrospectively evaluate patients with AML who were treated Glasdegib-based regimens in our center. Case 1: A 75-year-old male patient was diagnosed with congestive heart failure + AML, and idarubicin and cytarabine chemotherapy protocol was started. The patient started to receive covid treatment due to covid lung involvement. The patient, whose treatment was interrupted for 1 month, received the second course as LDAC + glasdegib. In the bone marrow biopsy performed after the 5th cycle, it is observed in remission. Case 2: An 82-year-old male patient was diagnosed with chronic renal failure. With a diagnosis of AML intermediate risk LDAC+glasdegib treatment was given to the patient who did not go into remission after 4 cycles of decitabine treatment. The patient, who was followed in remission after 4 cycles, died due to pneumonia. Case 3: A 76-year-old male patient has a diagnosis of cerebrovascular disease. The patient, who was followed up in remission after 2 courses of azacitidine with a diagnosis of medium risk AML, was approved for glasdegib in the 3rd course of treatment, and he is being followed up with the 3rd course of LDAC+glasdegib therapy. The data of the patients who were treated Glasdegib-based regimens with the diagnosis of AML in the Bozyaka Training and Research Hospital Department of Hematology were scanned retrospectively from their files. In our 3 patients, 1 person died due to pneumonia, but the patient was being followed in remission. Our other 2 patients are still being actively followed up with LDAC + glasdegib treatments. In 2018, the FDA approved glasdegib, a Hedgehog signaling pathway inhibitor, in adults 75 years of age or older with a diagnosis of AML or those with comorbidities that preclude the use of low-dose cytarabine plus intensive induction chemotherapy. Approval is based on interim results from the phase 2 BRIGHT 1003 study evaluating glasdegib in combination with LDAC or LDAC alone. The median OS was 4.9 months for LDAC versus 8.8 months in patients treated with glasdegib+LDAC. This difference represented an approximately 50% reduction in mortality in patients treated with glasdegib+LDAC. The final result of the BRIGHT 1003 study confirmed that glasdegib LDAC significantly improved OS compared to LDAC alone (hazard ratio, 0.495 [95% CI, 0.325-0.752]; P =0.0004). Also, the addition of glasdegib to LDAC did not cause a significant increase in adverse events.

Glasdegib in combination with low-dose Cytarabine for the outpatient treatment of relapsed or refractory acute myeloid leukemia in unfit patients.

We retrospectively collected clinical data on 31 relapsed or refractory acute myeloid leukemia (R/R AML) patients who were treated with outpatient glasdegib and low-dose Cytarabine (LDAraC) at our institution. The median age was 67 years (45–86). The median Eastern Cooperative Oncology Group performance status was 2 (1–3). The patients had previously received a median number of 2 (1–4) treatment lines, 61% (19/31) had been treated with intensive chemotherapy, 29% (9/31) had relapsed after allogeneic stem cell transplantation, and 45% (14/31) had had venetoclax exposure. Adverse cytogenetics were identified in 45% (14/31) of the cases. The CR + CRp rate was 21% (6/29) among evaluable patients. The median overall survival was 3.9 months for all patients. Different median overall survival times were observed in responders, patients achieving stable disease and those diagnosed with progressive disease: not reached vs 3.9 months vs 0.8 months, respectively (p < 0.001). The most common adverse events were pneumonia (29%, 9/31), sepsis (23%, 7/31), and febrile neutropenia (16%, 5/31). Glasdegib + LDAraC is a fairly safe, non-intensive, outpatient regimen inducing complete remission and resulting in prolonged survival in some R/R AML patients.

The cost-effectiveness of glasdegib in combination with low-dose cytarabine, for the treatment of newly diagnosed acute myeloid leukemia in adult patients who are not eligible to receive intensive induction chemotherapy in Canada

Aim The clinical efficacy and safety of DAURISMO (glasdegib) combined with low-dose cytarabine (LDAC) were demonstrated in the BRIGHT AML 1003 study among newly diagnosed acute myeloid leukemia patients who are not eligible to receive intensive chemotherapy. This study aims to evaluate its cost-effectiveness versus LDAC alone and azacitidine from a Canadian payer perspective. Materials and Methods A partitioned-survival model was developed with three health states: progression-free survival (PFS), relapse/progression and death. Clinical inputs were obtained from the BRIGHT AML 1003 study for glasdegib and LDAC, and from the two trial publications and indirect treatment comparison for azacitidine. Drug acquisition/administration, disease management, adverse event and end-of-life costs were considered. All costs were measured in Canadian dollars. Cost-effectiveness of glasdegib + LDAC was assessed against LDAC alone in main population, and against azacitidine by bone marrow blasts (BMB). A weighted average ICER was calculated to represent the current treatment use of Canadian clinical practice. The reference-case analysis was conducted probabilistically, and numerous probabilistic scenario analyses were conducted. Results The incremental cost-effectiveness ratios (ICERs) compared to LDAC alone was CAD $177,065 (a mean gain of 0.41 QALYs and an incremental cost of CAD $72,695), to azacitidine in 20–30% and >30% BMB group were CAD $178,201 (a mean gain of 0.34 QALYs and an incremental cost of CAD $59,889) and dominant (a mean gain of 0.28 QALYs while reducing costs by CAD $7,856) respectively, resulting in a weighted average ICER of CAD $81,310 per QALY. Limitations and conclusions Though uncertainties remain with the generated PFS curve, the derived azacitidine curves, administration and vial wastage, the model has been built under the best available evidence and relied on clinical opinions where there were data gaps. The weighted average ICER suggests that glasdegib + LDAC is cost-effective at a CAD $100,000 willingness-to-pay threshold.

Trial in Progress: Glad-AML - a Randomized, Phase 2 Trial of Glasdegib with Two Standard Decitabine Regimens for Older Patients with Newly-Diagnosed, Poor-Risk Acute Myeloid Leukemia

Trial in Progress: Glad-AML - a Randomized, Phase 2 Trial of Glasdegib with Two Standard Decitabine Regimens for Older Patients with Newly-Diagnosed, Poor-Risk Acute Myeloid Leukemia

AML-207: Glasdegib in Combination with Azacitidine in Patients with Untreated Higher-Risk Myelodysplastic Syndromes, Acute Myeloid Leukemia, and Chronic Myelomonocytic Leukemia: Effects on Marrow Recovery and Transfusion Independence

Context Glasdegib + azacitidine (AZA) showed promising remission rates and overall survival with a generally well-tolerated and manageable safety profile in an analysis of BRIGHT MDS & AML 1012 ( NCT02367456 ) in patients with higher-risk myelodysplastic syndromes (MDS), acute myeloid leukemia (AML), and chronic myelomonocytic leukemia (CMML). Objective Here, we evaluate early hematopoietic recovery and transfusion independence with glasdegib + AZA in BRIGHT MDS & AML 1012. Design Phase 1b, open-label study. Data cut-off: September 11, 2019. Setting Multicenter study at centers in Europe and North America. Patients Untreated patients with AML, higher-risk MDS, and CMML ineligible for intensive chemotherapy received glasdegib + AZA. Interventions Glasdegib 100 mg QD; AZA 75 mg/m2/D on D1-7 q28D. Main outcome measures Here we report the recovery of absolute neutrophil count (ANC), hemoglobin, and platelets, as well as rates of transfusion. Results Among patients with MDS (n=30; including 3 with CMML), median duration of treatment was 5.0 months (range, 0.4–15.5). Recovery occurred as early as Cycle 1 for ANC (≥1000/μL, 57%; ≥500/μL, 75%), hemoglobin (≥10 g/dL, 31%; ≥9 g/dL, 62%) and platelets (≥100,000/μL, 59%; ≥50,000/μL, 83%). Early platelet recovery correlated with response to treatment; 54% (7/13) of patients with platelets ≥ 100,000/μL at Cycle 2, D1 achieved complete or partial remission vs 0% (0/13) of patients with Conclusions Glasdegib + AZA shows promising rates of survival with early marrow recovery in the up-front treatment of patients with MDS, AML and CMML ineligible for intensive chemotherapy. The association between hematopoietic recovery and efficacy in the MDS cohort merits further study. Sponsor Pfizer.

The comparative effectiveness of glasdegib in combination with low-dose cytarabine versus azacitidine by bone marrow blasts counts among patients with newly-diagnosed acute myeloid leukemia who are ineligible for intensive chemotherapy.

e19512 Background: Acute myeloid leukemia (AML) is an orphan disease with one of the lowest five-year survival rates among myeloid malignancies. Recently, a randomized, open label study among previously untreated, chemotherapy-ineligible AML patients demonstrated improved overall survival (OS) among patients treated with glasdegib (GLAS) + LDAC compared with LDAC alone. Two trials of AZA vs. conventional care regimens report data by bone marrow blast (BMB) counts: one with 20-30% and the other with &gt;30%. In the absence of head-to-head comparisons, this study aims to perform the indirect treatment comparison between GLAS+LDAC and AZA by BMB counts. Methods: As there were potential imbalances between the GLAS and AZA trials and within the AZA trial arms in the baseline characteristics (e.g. poor cytogenetics% and de novo%), simulated treatment comparisons (STCs) for GLAS+LDAC vs. LDAC were performed to derive robust estimation by adjusting for the imbalances in the baseline effect modifiers. Afterwards, the classical network meta-analysis (NMA) was conducted. To derive the hazard ratio (HR) of GLAS+LDAC vs. AZA, three NMAs were conducted in each BMB group. Each NMA used a different HR of GLAS+LDAC vs. LDAC: 1) an unadjusted HR (classical NMA), 2) an STC adjusted HR adjusting for potential imbalances between the trials, and 3) an STC adjusted HR additionally accounting for potential imbalances between arms within the AZA trial. Results: In the 20-30% BMB group (N = 30), the OS HRs of GLAS+LDAC vs. AZA resulting from the three respective NMAs were as follows: 1) 0.46 [95% confidence interval: 0.10-2.14], 2) 0.31 [0.06-1.69], and 3) 0.36 [0.06-2.15]. In the &gt; 30% BMB group (N = 80), the HRs were 1) 0.69 [0.39-1.20], 2) 0.48 [0.23-0.97], and 3) 0.48 [0.24-1.00]. All the HRs suggest that patients with GLAS+LDAC have a survival advantage over patients with AZA. Conclusions: Both the classical NMAs and the NMAs based on the STC adjusted HRs correcting for the potential imbalances at baseline suggest that GLAS+LDAC may be preferred over AZA as a treatment option for previously untreated chemotherapy-ineligible AML patients regardless of BMB counts. [Table: see text]

Glasdegib in combination with azacitidine (AZA) in patients (pts) with untreated higher-risk myelodysplastic syndromes (MDS), acute myeloid leukemia (AML) and chronic myelomonocytic leukemia (CMML): Effects on marrow recovery and transfusion independence.

7526 Background: Glasdegib, an oral inhibitor of the Hedgehog signaling pathway, is approved in the USA in combination with low-dose cytarabine to treat pts with newly diagnosed AML unable to receive intensive chemotherapy due to comorbidities or age (≥75 years). Glasdegib + AZA showed promising remission rates and overall survival with a generally well-tolerated and manageable safety profile in an analysis of BRIGHT MDS &amp; AML 1012 in pts with MDS, AML and CMML. Here we evaluate early hematopoietic recovery and transfusion independence with glasdegib + AZA in this ongoing Phase Ib study. Methods: Untreated pts with MDS, AML and CMML ineligible for intensive chemotherapy received glasdegib (100 mg QD) + AZA (75 mg/m2/D on D1–7 q28D). Data cutoff: Sept 11, 2019. Results: Among pts with MDS (n=30; including 3 with CMML), median duration of treatment was 5.0 months (range, 0.4–15.5). Recovery of absolute neutrophil count (ANC), hemoglobin (Hb) and platelets at 2 thresholds started in cycle (Cyc) 1 (Table). Early platelet recovery correlated with response to treatment; 54% (7/13) of pts with platelets ≥100,000/µL at Cyc 2, D1 achieved complete or partial remission vs 0% (0/13) of pts with &lt;100,000/µL, P=0.002. Start of Cyc 2 was delayed due to AEs in 8% (2/26) of pts. 54% (7/13) of evaluable pts transfusion dependent at baseline (BL) became transfusion independent. Among pts with AML (n=30), median duration of treatment was 5.0 months (range, 0.3–14.9). ANC, Hb and platelet recoveries started in Cyc 1 (Table). 9% (2/23) of pts had Cyc 2 dose delays due to AEs. 64% (9/14) of evaluable pts transfusion dependent at BL became transfusion independent. Clinical trial information: NCT02367456 . Conclusions: Glasdegib + AZA shows promising rates of survival with early marrow recovery in the up-front treatment of pts with MDS, AML and CMML ineligible for intensive chemotherapy. The association between early hematopoietic recovery and efficacy in the MDS cohort merits further study. [Table: see text]

Overall Survival of Glasdegib in Combination with Low-Dose Cytarabine and Azacitidine By Bone Marrow Blasts Among Adult Patients with Previously Untreated Acute Myeloid Leukemia: Comparative Effectiveness Using Indirect Treatment Comparisons

Introduction Acute myeloid leukemia (AML) is an orphan disease with one of the lowest five-year survival rates among myeloid malignancies in United States adults. Older AML patients face a much lower 5-year survival rate than their younger counterparts (8% for those aged 60-65 years vs. 38% for those under 45 years). Current therapies are limited and historically include low-dose cytarabine (LDAC), decitabine, azacitidine (AZA) and best supportive care. A phase II randomized study (Cortes et al, 2019) among previously untreated AML patients who are not eligible for intensive chemotherapy demonstrated improved overall survival (OS) in patients treated with glasdegib (GLAS) in combination with low-dose cytarabine (LDAC) compared to patients receiving LDAC alone. There are two trials comparing AZA with conventional care regimens that report data by bone marrow blasts (BMB) count: Fenaux et al. (2010) for patients with 20-30% BMB and Dombret et al (2015) for patients with over 30% BMB. In clinical practice, AZA may be restricted to the 20-30% BMB population, which is important to consider when comparing treatment options. Therefore, as there are currently no head-to-head comparisons for GLAS+LDAC vs AZA, two separate indirect treatment comparisons (ITCs) were performed in different BMB populations (i.e., 20-30% and &gt;30% BMB). ITCs is an accepted method to support evidence-based comparative effectiveness decision making and ultimately help to optimize treatment and outcomes of patients with previously untreated AML. Method ITCs were conducted in a classical frequentist statistical framework based on the Bucher method. Patient-level data of the Cortes study (data-cut: January 2017) was divided into two subgroups in terms of BMBs, 20-30% (n=30) and &gt;30% (n=80) to match the patient population of Fenaux et al (n=34) and Dombret et al (n=399) accordingly. GLAS+LDAC and AZA were compared in terms of overall survival and results were reported in terms of hazard ratio (HR) with corresponding 95% confidence intervals (95% CI). AZA was chosen as the reference treatment in the ITC. Results In the 20-30% BMB population, the estimated OS HR of GLAS-LDAC in comparison to AZA was 0.46 (95% CI: 0.10-2.14). In the &gt;30% BMB population, the estimated OS HR of GLAS-LDAC in comparison to AZA was 0.61 (95% CI: 0.35-1.08). Conclusion These ITCs suggest that GLAS+LDAC is trending towards being a better treatment option for improving OS in patients with AML compared with AZA, irrespective of the level BMB. These results are consistent with previously published ITC results for this treatment comparison. The results of this ITC should, however, be interpreted with caution due to methodological limitations. First, the relatively small number of patients and deaths result in high uncertainty (as exemplified by the 95% CIs) and, second, patient baseline characteristics (including cytogenetic risk, ECOG status and de novo status) between trial arms and over the different trials were either imbalanced or not reported. While more research is needed, current evidence suggests that GLAS+LDAC may be the preferred treatment option for previously untreated AML patients irrespective of BMB levels. Disclosures Van Beekhuizen: Ingress-health: Consultancy, Other: funding from Pfizer. Bell:Pfizer Inc.: Employment, Equity Ownership. Gezin:Ingress-health: Consultancy, Other: funding from Pfizer. Cappelleri:Pfizer: Employment, Equity Ownership. Heeg:Ingress-Health: Employment. Selya-Hammer:Pfizer Inc: Employment, Equity Ownership. Charaan:Pfizer Inc: Employment, Equity Ownership. Chan:Pfizer Inc: Employment, Equity Ownership.

Clinical Benefit of Glasdegib in Combination with Azacitidine or Low-Dose Cytarabine in Patients with Acute Myeloid Leukemia

Clinical Benefit of Glasdegib in Combination with Azacitidine or Low-Dose Cytarabine in Patients with Acute Myeloid Leukemia

Budget Impact of Glasdegib in Combination with Low-Dose Cytarabine for the Treatment of First-Line Acute Myeloid Leukemia in the United States

I ntroduction Acute myeloid leukemia (AML) is an orphan disease and has one of the lowest five-year survival rates among myeloid malignancies in United States (US) adults (28.3% on average, 5% of which are aged 65 years or older). Older patients with AML have few treatment options and are often not candidates for intensive induction chemotherapy, therefore novel therapeutic strategies are needed. A phase II randomized study (Cortes et al. 2019) among newly diagnosed AML patients who were not candidates for intensive induction chemotherapy demonstrated improved overall survival (OS) in patients treated with glasdegib in combination with low-dose cytarabine (LDAC) compared to patients receiving LDAC alone. The present analysis estimated the budget impact of including glasdegib combined with LDAC as first-line treatment for these AML patients from a US health plan perspective. Methods The budget impact was assessed using a decision analytic model that compared the current market environment where glasdegib + LDAC was not included with a new market environment where glasdegib + LDAC was included. The comparators in the model were LDAC alone, azacitidine, decitabine, and venetoclax combined with LDAC, azacitidine or decitabine. The budget impact was calculated based on epidemiology inputs, market share inputs, clinical inputs and all relevant cost inputs (i.e. drug and administration cost, medical resource use cost, adverse event cost). The base case was calculated for a US commercial health plan of 1 million members with a time horizon of 3 years. The main outcomes were total costs of current and new market environments, incremental budget impact, incremental cost per member per month (PMPM) and incremental cost per treated patient per month (PTPPM). Both deterministic sensitivity analyses and scenario analyses were performed to assess the uncertainty of the structure and inputs of the model. Results The analysis estimated an eligible patient population of 19 AML patients per year (per million members) who are not candidates for intensive induction chemotherapy. Of these: 2, 4 and 6 patients were estimated to receive glasdegib + LDAC in years 1, 2 and 3, respectively. In the base case, the incremental budget impact of glasdegib + LDAC was $179,290 in year 1, $262,694 in year 2 and $346,098 in year 3. This translated into an incremental cost PMPM of $0.0149, $0.0219, and $0.0288 in years 1, 2, and 3, respectively. The model results were most sensitive to the mean OS of glasdegib + LDAC. Conclusions The introduction of glasdegib + LDAC as a treatment for newly diagnosed AML patients who are not candidates for intensive induction chemotherapy has a small impact on the budget of US payers, given the small size of the eligible patient population. The model results suggest glasdegib + LDAC provides an alternative treatment option while extending life at minimal incremental cost for health plans. As such, glasdegib + LDAC may provide substantial value for money spent on treatment of these AML patients in the US for which treatment options are few. Disclosures Pham: Pfizer: Consultancy, Other: funding from Pfizer. Milev:Evidera: Consultancy, Other: funding from Pfizer. Li:Evidera: Consultancy, Other: funding from Pfizer. Zou:Evidera: Consultancy, Other: funding from Pfizer. Hu:Ingress-health: Consultancy, Employment, Other: funding from Pfizer. Heeg:Ingress-Health: Employment. Bell:Pfizer Inc.: Employment, Equity Ownership.

A Phase 1b Study of Glasdegib in Combination with Azacitidine in Patients with Untreated Higher-Risk Myelodysplastic Syndromes, Acute Myeloid Leukemia, and Chronic Myelomonocytic Leukemia

A Phase 1b Study of Glasdegib in Combination with Azacitidine in Patients with Untreated Higher-Risk Myelodysplastic Syndromes, Acute Myeloid Leukemia, and Chronic Myelomonocytic Leukemia

Overall survival of glasdegib in combination with low-dose cytarabine, azacitidine, and decitabine among adult patients with previously untreated AML: comparative effectiveness using simulated treatment comparisons.

BackgroundUntil recently, treatments for older patients with AML ineligible to receive intensive chemotherapies were limited to hypomethylating agents, low-dose cytarabine (LDAC), or clinical trials. In 2018, the FDA approved combination glasdegib (GLAS) plus LDAC based on Phase II results demonstrating improved overall survival (OS) versus LDAC alone in previously untreated AML. However, no randomized clinical trials have directly compared GLAS + LDAC with other AML treatments.ObjectiveUsing both indirect treatment comparison (ITC) and simulated treatment comparison (STC), which adjusts for baseline differences between trials, the comparative effectiveness of GLAS + LDAC was compared with hypomethylating agent azacitidine (AZA) or decitabine (DEC).MethodsA systematic literature review identified published trials of AZA or DEC versus LDAC among older AML patients ineligible for high-intensity chemotherapy. In addition to standard and covariate-adjusted ITC, STC was performed following guidance from the NICE Decision Support Unit (DSU). Using individual patient data from the Phase II GLAS + LDAC study, population-specific OS hazard ratios (HR) for GLAS + LDAC versus AZA or DEC were compared. Furthermore, covariate-adjusted ITC (Cox multivariate models) and STC were repeated using GLAS + LDAC versus LDAC data propensity-weighted for within-trial mean cytogenetic risk. As this initial step was not specified in the DSU, results from this second method were compared to the first STC following DSU guidance only.ResultsStandard ITC and STC both demonstrated significantly improved OS for GLAS + LDAC versus either AZA or DEC. Adjusting for key covariates, STC stepwise exponential models demonstrated GLAS + LDAC superiority to both AZA (HR=0.424; 95% CI: 0.228, 0.789) and DEC (HR=0.505; 95% CI: 0.269, 0.949). These significant results held using full or step-wise approaches, following DSU guidance only or the weighted STC approach.ConclusionUsing ITC and STC, GLAS + LDAC demonstrated superior OS to AZA or DEC in an adult population with previously untreated AML for whom intensive chemotherapy is not an option.

Low-Dose Cytarabine With or Without Glasdegib in Newly Diagnosed Patients with Acute Myeloid Leukemia: Long-Term Analysis of a Phase 2 Randomized Trial

Glasdegib is an oral inhibitor of the Hedgehog signaling pathway. Following the BRIGHT AML 1003 trial (NCT01546038) primary results, glasdegib in combination with low-dose cytarabine (LDAC) was approved in the US for the treatment of newly diagnosed acute myeloid leukemia (AML) in patients unable to receive intensive chemotherapy due to comorbidities or age (≥75 years).

Abstract LB-009: Biomarkers correlating with overall survival (OS) and response to glasdegib and intensive or nonintensive chemotherapy in patients with acute myeloid leukemia (AML)

Abstract Background: The Smoothened inhibitor glasdegib (GLAS) was recently approved in combination with low-dose cytarabine (LDAC) in adults with AML when intensive chemotherapy is not an option. GLAS in combination with intensive chemotherapy has also been well tolerated and shown clinical activity, and is undergoing further evaluation. This analysis aimed to identify molecular drivers that predict overall response (OR) and OS with GLAS. Materials and Methods: We included AML patients receiving LDAC alone or with GLAS 100 mg QD (nonintensive arm) or GLAS 100 mg QD &amp; 7+3 (intensive arm) from Phases 1b and 2 of a multicenter study (NCT01546038). We assessed correlation of OS/OR with mRNA expression of 19 genes, expression levels of 38 cytokines, and mutations in 109 genes. For correlation analyses, a cut-off &amp;lt; or ≥ the median was used for gene expression and cytokine levels and mutated or not for gene mutations. Results: Within the nonintensive arm (LDAC + GLAS, n=68; LDAC, n=30), improved OS with GLAS + LDAC correlated with lower FOXM1 and MSI2, and higher BCL2 and CCND2 expression. For cytokines, lower levels of 6CKINE, BAFF, ICAM-1, MIP-1α, MIP-1β and MMP-3 correlated with improved OS. The low number of responders in the LDAC arm (n=2) prevented correlation analysis of mRNA or cytokines; however, within the LDAC + GLAS arm, OR correlated with high PTCH1 levels, and high EOTAXIN but low BAFF levels. In the intensive arm (GLAS &amp; 7+3, n=59), higher PTCH1 expression correlated with improved OS (median OS 10.8 vs 39.5 months) but no significant correlations were found with OR; no cytokines correlated with OS or with OR. For gene mutation, in the nonintensive arm (LDAC + GLAS, n=65; LDAC alone, n=25), OS differed with PLEKHH1 and STAG2 mutation status, but no genes correlated with OR. In the intensive arm (n=55), mutations in FLT3, TP53, CEP170, PHF6, and ANKRD26 correlated with OS. Patients in this arm with FLT3 mutations (including ITD) responded better vs wild type FLT3 (median OS 13.4 months vs unreached for FLT3 mutant). We also examined mRNA expression and cytokine levels at various times after starting treatment: statistically significant changes included modulation of SMO, BDNF, ITAC, and IL-23 levels in the nonintensive arm, and SMO, MYCN, CDKN1A, and a number of cytokines including IL-8, TNF-α and IL-5 in the intensive arm. Conclusions: In this analysis, expression levels of a select number of genes and circulating cytokines implicated in AML appear to correlate with OS and OR. The improved response with FLT3 mutations and high PTCH1 expression levels in the intensive arm, along with the analysis appearing to indicate modulation of select genes (eg SMO) and cytokines in both arms while on treatment, deserves further investigation. These preliminary findings will need to be verified in larger randomized trials, which are on-going. Citation Format: Akil Merchant, Catriona Jamieson, Michael Heuser, Geoffrey Chan, Panpan Wang, Keith A. Ching, Jillian Johnson, Thomas O’Brien, Jorge E. Cortes. Biomarkers correlating with overall survival (OS) and response to glasdegib and intensive or nonintensive chemotherapy in patients with acute myeloid leukemia (AML) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-009.

Phase 1/2 trial of glasdegib in patients with primary or secondary myelofibrosis previously treated with ruxolitinib

Glasdegib is a potent and selective oral inhibitor of the Hedgehog pathway. We report data from the single-arm, lead-in cohort of an open-label phase 1b/2 trial of glasdegib in patients with primary/secondary myelofibrosis (MF) previously treated with at least one Janus kinase inhibitor (JAKi). Patients received glasdegib 100 mg orally once daily until there was no further clinical benefit. Primary endpoints included adverse events (AEs). Secondary endpoints included patients with spleen volume reduction (SVR) ≥35% at week 24, patients with ≥50% total symptom score (TSS) reduction, and pharmacokinetics. All 21 treated patients had one or more AE and five (23.8%) had serious AEs. Most common (>30%) AEs were dysgeusia (61.9%), muscle spasms (57.1%), alopecia (38.1%), fatigue (33.3%), and decreased appetite (33.3%). Although no patient had ≥35% SVR at week 24, one patient previously treated with ruxolitinib had an SVR of 32.9%. At week 12, two (9.5%) patients had ≥50% reduction in TSS from baseline and ˜40% had ≥20% reduction. One patient had an anaemia response. Following administration of glasdegib 100 mg once daily, the median time to peak plasma concentrations at steady-state generally occurred at 1 h post-dose. The safety profile of glasdegib monotherapy was manageable in patients with primary/secondary MF. Further study of glasdegib in combination with JAKi in a MF population may be warranted.

Glasdegib for the treatment of adult patients with newly diagnosed acute myeloid leukemia or high-grade myelodysplastic syndrome who are elderly or otherwise unfit for standard induction chemotherapy.

On November 21, 2018, the U.S. Food and Drug Administration (FDA) approved glasdegib in combination with low-dose cytarabine (LDAC), for the treatment of newly diagnosed acute myeloid leukemia (AML) in patients > 75 years old or who have comorbidities that would be prohibitive of intensive induction chemotherapy. Glasdegib is a small-molecule inhibitor of a component of the hedgehog (HH) pathway, an upregulated pathway in leukemia and leukemia stem cells that is associated with relapse, drug resistance and poor survival. Preclinical studies suggested that glasdegib could sensitize AML cells to chemotherapy. FDA approval was based on a randomized, placebo-controlled, phase II trial in elderly or infirmed adults with new AML, unable to receive intensive induction chemotherapy, in whom the addition of glasdegib to LDAC nearly doubled the median overall survival compared with LDAC alone. In this report, we examine the preclinical development of glasdegib, its pharmacology and the clinical investigation that demonstrated its safety and efficacy, resulting in its approval. Additionally, we highlight ongoing investigation and future applications of this therapy.