The primary analysis of the phase 2 OPTIC trial (NCT02467270) demonstrated optimal benefit:risk with response-based ponatinib dosing (45 mg once daily (QD) reduced to 15 mg QD) upon achieving ≤1% BCR::ABL1IS in patients with tyrosine kinase inhibitor-resistant or T315I-positive chronic-phase chronic myeloid leukemia (CP-CML). Here, we report 5-year long-term outcomes. Overall, 283 patients were randomized to 45-mg, 30-mg, or 15-mg QD starting doses (n = 94, 95, and 94, respectively), with dose reduction to 15 mg QD upon response in the 45-mg and 30-mg cohorts. At data cutoff, 61 patients remained on trial. Median follow-up time was 75-78 months. By 5 years, 60%, 41%, and 40% of patients in the 45-mg, 30-mg, and 15-mg cohorts, respectively, achieved ≤1% BCR::ABL1IS. Five-year progression-free survival rates were 63%, 57%, and 60%, respectively, by cohort; overall survival rates exceeded 80%. In patients with a T315I mutation, 5-year rates of ≤1% BCR::ABL1IS, PFS, and OS were highest in the 45-mg cohort. Exposure-adjusted rates of adjudicated arterial occlusive events were 4.1, 3.8, and 2.0 patients per 100 patient-years, respectively, by cohort; results were comparable in T315I-positive patients. These findings support long-term clinical benefit of response-based ponatinib dosing in third-line CP-CML, especially in patients with the T315I mutation.

Introduction: Ponatinib is a third-generation BCR::ABL1 tyrosine kinase inhibitor (TKI) that potently inhibits native and mutant forms of BCR::ABL1, including T315I. The phase 2 OPTIC (NCT02467270) study evaluated a response-based ponatinib dosing strategy to optimize efficacy and improve safety of ponatinib in patients (pts) with chronic-phase chronic myeloid leukemia (CP-CML) whose disease was resistant to ≥2 TKIs or who had the T315I mutation. The 45-mg once-daily (QD) starting dose with dose reduction to 15 mg QD upon achievement of BCR::ABL1IS ≤1% (MR2) was associated with optimal benefit:risk outcomes, resulting in FDA approval of this response-based dosing strategy for the treatment of pts with CP-CML with disease resistant to ≥2 TKIs or with T315I. We present results from the 5-year update of efficacy and safety outcomes from OPTIC. Methods: Pts with CP-CML resistant to ≥2 TKIs or with the T315I mutation were randomized to ponatinib starting doses of 45 mg, 30 mg, and 15 mg QD. Upon achievement of ≤1% BCR::ABL1IS, doses were reduced to 15 mg in the 45-mg and 30-mg cohorts. The primary endpoint was ≤1% BCR::ABL1IS at 12 months; secondary endpoints included molecular response rates and safety outcomes, including arterial occlusive events (AOEs) adjudicated prospectively by an independent review committee. Progression-free survival (PFS) and overall survival (OS) were analyzed by Kaplan-Meier methods. Exploratory mutational analyses were conducted with baseline and end-of-treatment (EOT) blood samples. Results: A total of 283 pts were randomized (45 mg/30 mg/15 mg: n=94/95/94; median age, 48 years [range: 18‒81 years]; male, 50%; race: White 79%, Asian 15%, Black 2%; ethnicity: 74% not Hispanic or Latino; T315I mutation, 24%). Median dose intensity was 27.7, 23.5, and 14.7 mg/day in the 45-mg, 30-mg, and 15-mg cohorts, respectively. As of the data cutoff (May 2, 2024), when the last pt still on study reached at least 5 years of treatment, 73 pts (26%) remained on ponatinib treatment; the most common reasons for treatment discontinuation were adverse event (45 mg/30 mg/15 mg: n=20/19/17), lack of efficacy (n=16/22/28), and progressive disease (n=8/10/7). By 60 months, 60% (56/93), 41% (38/93), and 40% (36/91) of pts in the 45-mg, 30-mg, and 15-mg cohorts, respectively, achieved ≤1% BCR::ABL1IS. Pts with a T315I mutation at baseline also had a higher MR2 rate by 60 months at the 45-mg starting dose (64%; n=25), which was comparable to those with no mutations at baseline (60%; n=50). Median duration of ≤1% BCR::ABL1IS was not reached in any cohort. By 60 months, the rates of ≤0.01% BCR::ABL1IS were 24% (22/93), 18% (17/93), and 19% (17/91) in the 45-mg, 30-mg, and 15-mg starting dose cohorts, respectively, and rates of ≤0.0032% BCR::ABLIS were 13% (12/93), 14% (13/93), and 15% (14/91), respectively. The estimated PFS rates at 60 months were 63%, 57%, and 60% in the 45-mg, 30-mg, and 15-mg cohorts. Estimated OS rates at 60 months were similar across starting dosing cohorts. Among pts who had dose reduction to 15 mg after achieving ≤1% BCR::ABL1IS, 29% (13/45) in the 45-mg cohort and 23% (6/26) in the 30-mg cohort lost the response after dose reduction. Of the pts in the 45-mg and 30-mg cohorts who had dose re-escalation after loss of ≤1% BCR::ABL1IS response, 69% (9/13) and 80% (4/5), respectively, regained a ≤1% BCR::ABL1IS response. The most common grade 3/4 treatment-emergent adverse events were thrombocytopenia (27%), neutropenia (18%), and hypertension (10%). Exposure-adjusted AOE rates per 100 pt-years (95% confidence interval) were similar across the 3 cohorts: 45 mg, 4.1 (1.8-6.4); 30 mg, 3.4 (1.0-5.8); 15 mg, 1.2 (0.0-2.5). For the first time, EOT mutation analyses will be shared. Among 74 pts with no baseline mutation and available EOT data, only 6 had BCR::ABL1 mutations detected; 5 received the 15-mg starting dose and 1 had the 45-mg starting dose (E255K). Conclusion: Long-term results from OPTIC highlight the clinical benefits of ponatinib in patients with CP-CML resistant to ≥2 TKIs or harboring a T315I mutation. These results are consistent with previous OPTIC analyses and demonstrate that the approved ponatinib starting dose of 45 mg QD with reduction to 15 mg QD upon attainment of ≤1% BCR::ABL1IS provides the optimal benefit:risk ratio. Mutation data from EOT samples support ponatinib suppression of emerging mutations at the approved 45-mg starting dose.

This phase 2 study investigated pevonedistat + azacitidine + venetoclax (n = 83) versus azacitidine + venetoclax (n = 81) in patients with newly diagnosed acute myeloid leukemia (AML) ineligible for intensive chemotherapy. The study was stopped early following negative results from PANTHER, which evaluated pevonedistat in higher-risk myelodysplastic syndromes/chronic myelomonocytic leukemia or low-blast AML. Outcomes were analyzed up to the datacut. For pevonedistat + azacitidine + venetoclax versus azacitidine + venetoclax, the median follow-up was 8.44 versus 7.95 months; the complete remission (CR) rate was 45% versus 49%; composite CR (CCR; CR+CR with incomplete blood count recovery) was 77% versus 72%. There were no differences in event-free survival (primary endpoint; hazard ratio [HR]: 0.99; 95% confidence interval [CI]: 0.61-1.60; p = 0.477) or overall survival (HR: 1.42; 95% CI: 0.82-2.49; p = 0.896). In exploratory analyses in IDH-mutated AML, CCR rates were higher with pevonedistat + azacitidine + venetoclax versus azacitidine + venetoclax. Safety was similar between treatment arms. Efficacy/safety with azacitidine + venetoclax was consistent with the phase 3 VIALE-A study. TRIAL REGISTRATION:NCT04266795.

Introduction: BCR::ABL1 tyrosine kinase inhibitors (TKIs) in combination with chemotherapy and/or steroids are standard of care for newly diagnosed Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). Ponatinib is a potent third-generation BCR::ABL1 TKI. The phase 3 PhALLCON study (NCT03589326) is comparing frontline TKIs + chemotherapy in Ph+ ALL. After minimum follow-up of 3 months (mos) for all patients (pts), PhALLCON met its primary endpoint, showing a significantly higher rate of minimal residual disease (MRD)-negative (BCR::ABL1IS ≤0.01%; MR4) complete remission (CR) at end of induction (EOI) with ponatinib vs imatinib (34.4% vs 16.7%; P=0.002) and a safety profile comparable to imatinib. Per study protocol, pts who did not proceed to stem cell transplant or other alternative therapy could receive monotherapy with ponatinib or imatinib after 20 cycles of the chemotherapy combination. We report post hoc analyses of the subset of pts who received maintenance monotherapy post Cycle 20. Methods: Adults with newly diagnosed Ph+ ALL were randomized 2:1 to ponatinib (30 mg once daily [QD] reduced to 15 mg upon achievement of MRD-neg CR at EOI) or imatinib 600 mg QD plus 20 cycles of reduced-intensity chemotherapy (induction: 3 cycles; consolidation: 6 cycles; maintenance combination: 11 cycles), followed by maintenance monotherapy with ponatinib or imatinib starting on Day 1, Cycle 21 until disease progression or unacceptable toxicity. The decision to proceed to monotherapy was solely per investigator's discretion. This post hoc analysis evaluated baseline characteristics, cumulative molecular response rates (MR4: BCR::ABL1IS ≤0.01%; MR4.5: BCR::ABL1IS ≤0.0032%), and safety in pts who received TKI monotherapy post Cycle 20. Data cutoff: Aug 12, 2022. Results: Among 41 pts who initiated TKI monotherapy in Cycle 21, the proportion proceeding to monotherapy was higher with ponatinib (21%; 34/163) vs imatinib (9%; 7/81). Pts who received monotherapy appeared to be older (≥60 y: 56%), and a higher proportion had ECOG score 1 at baseline (68%) compared with the overall population (n=245; ≥60 y: 37%; ECOG 1: 52%); other pt characteristics (female: 63%; region: Europe: 37%, North America: 34%; BCR::ABL1 p190/p210: 71%/20%) were comparable to the overall population (female: 54%; Europe: 42%, North America: 31%; p190/p210: 68%/27%). Among pts who initiated TKI monotherapy at Cycle 21 and had p190/p210 confirmed by central laboratory at baseline, the MRD-negativity (MR4) rate was 53% (16/30) with ponatinib vs 29% (2/7) with imatinib by EOI (Cycle 3) and 97% (29/30) vs 71% (5/7) by end of Cycle 20; the rate of deeper molecular response (MR4.5) was 37% (11/30) vs 29% (2/7) by EOI and 93% (28/30) vs 43% (3/7) by end of Cycle 20. For pts with MR4 at start of Cycle 21 (ponatinib n=26; imatinib n=3), 1 pt (4%) in the ponatinib arm and 1 (33%) in the imatinib arm lost MR4 response after starting monotherapy; by Kaplan-Meier estimates, MR4 was maintained at 12 mos post Cycle 20 in 95% of pts with ponatinib monotherapy vs 67% with imatinib. Median duration of MR4 post Cycle 20 was not reached (NR) in either arm (median follow-up: ponatinib [n=26], 6.1 mos [95% CI: 3.0-11.6]; imatinib [n=3], 18.4 mos [95% CI: 15.7-NR]). Treatment-emergent adverse event (TEAE) rates post Cycle 20 were similar with ponatinib (59%; 20/34) and imatinib (57%; 4/7), as were grade ≥3 TEAE rates (ponatinib: 12% [4/34; hypertension, peripheral arterial occlusive disease, recurrent leukemia, neutropenia, n=1 each]; imatinib: 14% [1/7; depression]). Vascular occlusive events (peripheral arterial occlusive disease and venous thrombosis; both grade 2) occurred in 2/34 pts receiving ponatinib monotherapy; both events resolved following dose reduction or interruption. TEAEs led to few dose modifications post Cycle 20 (ponatinib/imatinib: discontinuation, 1/1; reduction, 1/0; interruption, 3/0). Conclusion: More pts initiated monotherapy maintenance with ponatinib than imatinib. Single-agent ponatinib maintained durable MRD negativity post Cycle 20. Although these post hoc analyses should be interpreted with caution due to the small number of pts entering the maintenance phase, especially in the imatinib arm, and potential selection bias, these data appear to support the continuous clinical benefit and tolerability of ponatinib monotherapy after combination with chemotherapy in pts with newly diagnosed Ph+ ALL.

Abstract Background: Many newly diagnosed patients with AML are ineligible for intensive chemotherapy due to pre-existing comorbidities and older age. VIALE-A, a phase-3 trial with venetoclax (ven) and azacitidine (aza) established this combination as a new standard of care (SOC) for this patient population. The addition of pevonedistat (pevo) to this combination was evaluated in the same patient population in the current trial (NCT04266795). Here we present results of biomarker analyses from baseline and on-treatment bone marrow samples. Methods: Molecular mutational analysis was performed using a next generation sequencing (NGS) panel on baseline bone marrow samples. Combining this data with cytogenetics allowed centralized assignment of risk category based on ELN2017 guidelines. Longitudinal bone marrow aspirate samples were also examined by multi-color flow cytometry for expression of select surface antigen expression and to identify AML leukemic stem cells (LSCs) from the blast population. Results: Eleven genes were selected for analyses based on prevalence and scientific interest, including DNMT3A, ASXL1, TET2, FLT3, and IDH1/2. In contrast to other genes and ELN risk categories, we observed a statistically significant increase (p-value 0.013) in CR+CRi rates for IDH1/2 mutant patients when treated with pevo + ven + aza (95%, n=21) compared to ven+aza control arm (62%, n=21). In addition, we evaluated the prevalence of CD33, CD123 and CLEC12a, targets of current AML developmental therapeutics, in both the blast and LSC populations at baseline. The median (n=120 pts) % blast cells expressing CD33, CD123, or CLEC12a were 89.8%, 63.2%, and 66.0%, respectively. The median (n=78 pts) % LSCs expressing CD33, CD123, or CLEC12a were 48.2%, 90.9%, and 32.0%, respectively. Importantly, we did not see any significant difference in median fluorescence intensity (MFI) or % expression in any of the three proteins after treatment with ven and aza (+/- pevo). Finally, no strong associations were observed between expression levels and either mutations or ELN risk categories. Conclusions: Analyses of biomarker samples as part of the PEVENAZA trial resulted in several insights for not only the pevonedistat program but also for other AML therapeutics in development. The observation that newly diagnosed patients with IDH1/2 mutations may benefit from the addition of pevo to ven+aza is certainly hypothesis-generating but would require further follow-up with higher patient numbers. In addition, baseline CD33, CD123, and CLEC12a expression levels were in line with published studies. Here we have also shown they remain similar after SOC treatment (ven+aza) supporting the development of agents that target these proteins in both first and second line settings for AML. Citation Format: Radha Ramesh, Xiang Fang, Shuli Li, Sharon Friedlander, Farhad Sedarati, Lionel Adès, Nicholas Short, Cristina Papayannidis, Tammie Yeh. Biomarker results from PEVENAZA, a randomized phase 2 study of venetoclax and azacitidine +/- pevonedistat in newly diagnosed AML patients unfit for intensive chemotherapy: Increased efficacy in a subset of patients with IDH1/2 mutations and other observations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5184.

ImportanceIn newly diagnosed Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia (ALL), disease progression due to acquired resistance to first- or second-generation BCR::ABL1 tyrosine kinase inhibitors is common. Ponatinib inhibits BCR::ABL1 and all single-mutation variants, including T315I.ObjectiveTo compare frontline ponatinib vs imatinib in adults with newly diagnosed Ph+ ALL.Design, Setting, and ParticipantsGlobal registrational, phase 3, open-label trial in adults aged 18 years or older with newly diagnosed Ph+ ALL. From January 2019 to May 2022, eligible patients at 77 sites were randomized 2:1 to ponatinib (30 mg/d) or imatinib (600 mg/d) with reduced-intensity chemotherapy, followed by single-agent ponatinib or imatinib after the cycle 20 phase of the trial. The last date of follow-up for this analysis was August 12, 2022.InterventionPatients received ponatinib, 30 mg/d, or imatinib, 600 mg/d, with reduced-intensity chemotherapy, followed by single-agent ponatinib or imatinib after cycle 20. The ponatinib dose was reduced to 15 mg on achievement of minimal residual disease–(MRD) negative complete remission.Main Outcomes and MeasuresThe primary end point of this interim analysis was MRD-negative complete remission (≤0.01% BCR::ABL1 [MR4] centrally assessed by reverse transcriptase–quantitative polymerase chain reaction), with complete remission maintained for at least 4 weeks at the end of cycle 3. The key secondary end point was event-free survival.ResultsOf 245 patients randomized (median age, 54 years; 133 [54.3%] female), 232 (ponatinib, n = 154; imatinib, n = 78) who had p190 or p210 dominant isoforms verified by the central laboratory were analyzed for the primary end point. The MRD-negative complete remission rate (primary end point) was significantly higher with ponatinib (34.4% [53/154]) vs imatinib (16.7% [13/78]) (risk difference, 0.18 [95% CI, 0.06-0.29]; P = .002). At the data cutoff, event-free survival had not met the prespecified number of events. Median event-free survival was not reached in the ponatinib group and was 29 months in the imatinib group. The most common adverse events were similar between treatment groups. Arterial occlusive events were infrequent and comparable between groups (ponatinib, 2.5%; imatinib, 1.2%).Conclusions and RelevancePonatinib demonstrated a superior rate of MRD-negative complete remission at the end of induction vs imatinib when combined with reduced-intensity chemotherapy in adults with newly diagnosed Ph+ ALL. The safety profile of ponatinib was comparable with imatinib.Trial RegistrationClinicalTrials.gov Identifier: NCT03589326

Background: Minimal residual disease (MRD) is an established, prognostic indicator for patients with acute lymphoblastic leukemia (ALL), including Philadelphia chromosome-positive (Ph+) ALL. The objective of this study was to evaluate the association between MRD and long-term outcomes (event-free survival [EFS] and overall survival [OS]) in adult patients with Ph+ ALL receiving first-line therapy. Methods: A systematic literature review (SLR) was performed to identify eligible studies, including interventional and observational studies reporting survival outcomes by MRD status in adults ≥18 years of age with Ph+ ALL receiving first-line therapy. Key outcomes and data elements of interest were EFS, OS, and MRD or MRD-negative complete remission (CR) at end of induction (EOI). Aggregate study-level and individual patient data (IPD) meta-analyses were conducted. The IPD approach included a log-level MRD analysis to evaluate the concordance of deepening levels of molecular response with long-term EFS or OS in patients with CR and an analysis evaluating the utility of MRD-negative CR over CR alone. The analyses were conducted using frequentist and Bayesian approaches with fixed-effects and random-effects models. Kaplan-Meier method with log-rank tests was used for survival analysis. Where applicable, Cox regression method with and without adjustment for prognostic factors were applied. Results: The SLR identified 19 publications (18 unique studies), 10 (9 unique studies) of which had sufficient MRD and EFS/OS data. Nine studies (n=704) were included in the aggregate study-level analysis; 3 of the 9 studies (Phase II AP24534-11-001 [Jabbour et al. 2015], Phase II GIMEMAINCB 84344-201 [Martinelli et al. 2017], and Phase III GRAAPH-2005 RCT [Chalandon et al. 2015]) had IPD available. MRD was assessed by polymerase chain reaction in all 9 studies. Findings from the aggregate study-level meta-analysis demonstrated a significant long-term survival benefit (EFS and OS) in favor of patients with MRD-negative CR. This significant benefit was generally consistent across analysis types (base-case or sensitivity analyses), analytic models (fixed- or random-effects), and approaches (frequentist or Bayesian). Evidence from the IPD analysis, based on patients with CR, was mostly consistent with the aggregate study-level meta-analysis, supporting MRD-negative CR at the EOI as being predictive of EFS or OS. Log-level MRD analysis showed that patients who are in CR with deeper molecular response ( BCR::ABL1/ABL1 ≤0.01%) at EOI have significantly better long-term EFS and OS compared with patients with other levels of MRD (ie, BCR::ABL1/ABL1 >0.01%). This significant long-term survival benefit was also demonstrated in patients with MRD-negative CR ( BCR::ABL1/ABL1 ≤0.01%) at EOI compared with patients who were MRD-positive ( BCR::ABL1/ABL1 >0.01%) ( Table 1) or based on achievement of CR alone (regardless of BCR::ABL1/ABL1 values). Results from the IPD analysis standardized for outcome definition, with and without adjustment for prognostic factors (age, gender, white blood cell count at baseline, and stem cell transplant), were consistent with the findings from the log-level MRD analysis. The analysis showed a significant association between MRD-negative/MRD-negative CR status (ie, BCR::ABL1/ABL1 ≤0.01% threshold) at EOI with improved long-term EFS and OS. The results were significant for EFS in both the adjusted and unadjusted models. The OS results were significant only in the unadjusted model. Conclusions: These analyses indicate that a deeper molecular response at EOI results in better long-term EFS and OS; MRD-negative CR has a greater prognostic value than CR and is strongly associated with long-term EFS and OS in patients with Ph+ ALL. Acknowledgement: The authors acknowledge APHP, who provided the individualized patients data for the GRAAPH study.

Background: Minimal residual disease (MRD) is an established, prognostic indicator for patients with acute lymphoblastic leukemia (ALL), including Philadelphia chromosome-positive (Ph+) ALL. The objective of this study was to evaluate the association between MRD and long-term outcomes (event-free survival [EFS] and overall survival [OS]) in adult patients with Ph+ ALL receiving first-line therapy. Methods: A systematic literature review (SLR) was performed to identify eligible studies, including interventional and observational studies reporting survival outcomes by MRD status in adults ≥18 years of age with Ph+ ALL receiving first-line therapy. Key outcomes and data elements of interest were EFS, OS, and MRD or MRD-negative complete remission (CR) at end of induction (EOI). Aggregate study-level and individual patient data (IPD) meta-analyses were conducted. The IPD approach included a log-level MRD analysis to evaluate the concordance of deepening levels of molecular response with long-term EFS or OS in patients with CR and an analysis evaluating the utility of MRD-negative CR over CR alone. The analyses were conducted using frequentist and Bayesian approaches with fixed-effects and random-effects models. Kaplan-Meier method with log-rank tests was used for survival analysis. Where applicable, Cox regression method with and without adjustment for prognostic factors were applied. Results: The SLR identified 19 publications (18 unique studies), 10 (9 unique studies) of which had sufficient MRD and EFS/OS data. Nine studies (n=704) were included in the aggregate study-level analysis; 3 of the 9 studies (Phase II AP24534-11-001 [Jabbour et al. 2015], Phase II GIMEMAINCB 84344-201 [Martinelli et al. 2017], and Phase III GRAAPH-2005 RCT [Chalandon et al. 2015]) had IPD available. MRD was assessed by polymerase chain reaction in all 9 studies. Findings from the aggregate study-level meta-analysis demonstrated a significant long-term survival benefit (EFS and OS) in favor of patients with MRD-negative CR. This significant benefit was generally consistent across analysis types (base-case or sensitivity analyses), analytic models (fixed- or random-effects), and approaches (frequentist or Bayesian). Evidence from the IPD analysis, based on patients with CR, was mostly consistent with the aggregate study-level meta-analysis, supporting MRD-negative CR at the EOI as being predictive of EFS or OS. Log-level MRD analysis showed that patients who are in CR with deeper molecular response ( BCR::ABL1/ABL1 ≤0.01%) at EOI have significantly better long-term EFS and OS compared with patients with other levels of MRD (ie, BCR::ABL1/ABL1 >0.01%). This significant long-term survival benefit was also demonstrated in patients with MRD-negative CR ( BCR::ABL1/ABL1 ≤0.01%) at EOI compared with patients who were MRD-positive ( BCR::ABL1/ABL1 >0.01%) ( Table 1) or based on achievement of CR alone (regardless of BCR::ABL1/ABL1 values). Results from the IPD analysis standardized for outcome definition, with and without adjustment for prognostic factors (age, gender, white blood cell count at baseline, and stem cell transplant), were consistent with the findings from the log-level MRD analysis. The analysis showed a significant association between MRD-negative/MRD-negative CR status (ie, BCR::ABL1/ABL1 ≤0.01% threshold) at EOI with improved long-term EFS and OS. The results were significant for EFS in both the adjusted and unadjusted models. The OS results were significant only in the unadjusted model. Conclusions: These analyses indicate that a deeper molecular response at EOI results in better long-term EFS and OS; MRD-negative CR has a greater prognostic value than CR and is strongly associated with long-term EFS and OS in patients with Ph+ ALL. Acknowledgement: The authors acknowledge APHP, who provided the individualized patients data for the GRAAPH study.

Topic: 2. Acute lymphoblastic leukemia - Clinical Background: The standard of care in patients with newly diagnosed Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL) is BCR::ABL1 tyrosine kinase inhibitors (TKIs) in combination with chemotherapy or steroids. Treated with first- or second-generation TKIs, patients eventually progress due to emergence of resistance. Multiple studies have reported promising minimal residual disease (MRD) negativity (neg) rates and survival outcomes with ponatinib in combination with chemotherapy or chemotherapy-free regimens. Aims: PhALLCON (NCT03589326), the first randomized study comparing TKIs in patients with Ph+ ALL, evaluates ponatinib versus imatinib in combination with reduced-intensity chemotherapy. Methods: This phase 3 open-label study randomized newly diagnosed Ph+ ALL adult patients 2:1 to receive ponatinib (30 mg once daily [QD]) or imatinib (600 mg QD) with reduced-intensity chemotherapy through end of induction (EOI), consolidation, and post-consolidation. After post-consolidation, patients received single-agent ponatinib or imatinib until disease progression or unacceptable toxicity. The composite primary endpoint was MRD-neg (BCR::ABL1 ≤0.01%) complete remission (CR) for 4 weeks at EOI. Event-free survival (EFS: any-cause death, failure to achieve CR by EOI, relapse from CR) was a key secondary endpoint. Results: A total of 245 pts were randomized to ponatinib (n=164) or imatinib (n=81); median age was 54 years (37% ≥60 years). At data cutoff (Aug 2022), 78 patients (ponatinib vs imatinib: 42% vs 12%) were on study treatment; the top 3 reasons for discontinuation were hematopoietic stem cell transplantation (30% vs 37%), adverse events (12% vs 12%), and lack of efficacy (7% vs 26%). Median follow-up was 20 months vs 18 months (ponatinib vs imatinib). The primary endpoint was met (Table), with a significantly higher MRD-neg CR rate at EOI for ponatinib vs imatinib (34% vs 17%; P=0.0021). Additionally, MRD-neg rate regardless of CR at EOI was significantly higher for ponatinib vs imatinib (43% vs 21%; P=0.0017). Median duration of MRD-neg and time to treatment failure were not reached for ponatinib and were 20.9 months and 21.9 months, respectively, for imatinib. EFS data were not mature; however, the median EFS was reached in imatinib and not in ponatinib, with a trend toward improvement (hazard ratio [HR] 0.65, 95% confidence interval [CI] 0.39–1.10). The treatment-emergent adverse event (TEAE) rates (any-grade and Grade 3/4/5) were comparable between treatment arms. Most common any-grade hematologic TEAEs were anemia (ponatinib 72%, imatinib 67%) and platelet count decrease (ponatinib 68%, imatinib 69%). The most common Grade 3/4 nonhematologic TEAEs were headache (ponatinib and imatinib 43%) and nausea (ponatinib 35%, imatinib 50%). Incidence of arterial occlusive events (AOEs) were infrequent and similar between the arms (Table). Summary/Conclusion: Ponatinib was superior to imatinib in combination with reduced-intensity chemotherapy in the front-line setting for patients with Ph+ ALL, with a significantly higher MRD-neg CR rate at EOI. Ponatinib was associated with deeper and more durable responses, with a trend toward improved EFS and comparable safety vs imatinib.Keywords: Ph+ ALL

Background: G and D have both shown efficacy in patients (pts) with NSCLC; G + D may improve durability of response. Methods: This Phase 1 dose escalation (Part A) and expansion (Part B) study (NCT0208811) assessed G 250 mg once daily + D 3 mg/kg (Part A) or 10 mg/kg (Parts A + B) every 2 weeks in pts with locally advanced/metastatic NSCLC. Part A pts were all comers who had failed to respond/relapsed following standard treatment (Tx). Part B pts had sensitising EGFR mutations and were tyrosine kinase inhibitor naïve: Arms 1 + 1a received G + D; Arm 2 received G (4 weeks) before G + D. Primary objective: safety/tolerability. Secondary objectives: pharmacokinetics (PK), pharmacodynamics, immunogenicity (anti-drug antibodies [ADAs]) and efficacy. Exploratory objective: evaluation of biomarkers (e.g. tumour programmed cell death ligand-1 [PD-L1]) and relationship with efficacy. Results: There were no dose limiting toxicities in Part A (n = 16) and D 10 mg/kg was used in Part B. In Part B (n = 40) all pts had possible Tx related adverse events (TRAEs; Table): diarrhoea (68%) and elevated alanine aminotransferase (ALT; 58%) were the most common TRAEs; elevated ALT (20%) and aspartate aminotransferase (15%) were the most common TRAEs leading to discontinuation. PK were as expected, inhibition of soluble PD-L1 was observed in all pts and no Tx emergent ADAs were observed. In Arms 1 + 1a, most patients achieved objective response (63.3%; 95% confidence intervals [CI]: 43.9, 80.1), median duration of response was 9.2 months (95% CI: 3.7, 14.0) and median progression-free survival (mPFS) was 10.1 months (95% CI: 5.5, 15.2; Table). PD-L1 expression ≥20% was associated with numerical improvements in mPFS (Table).Table84O Summary of safety, exposure, efficacy and exploratory analysesSafetyArm 1 (n = 10)Arm 1a (n = 20)Arm 2 (n = 10)Any grade AE, n (%)10 (100.0)20 (100.0)10 (100.0)Grade ≥3 AE, n (%)5 (50.0)15 (75.0)8 (80.0)Any grade TRAE, n (%)10 (100.0)20 (100.0)10 (100.0)Grade ≥3 TRAE, n (%)4 (40.0)11 (55.0)7 (70.0)Any grade TRAE leading to treatment discontinuation, n (%)010 (50.0)6 (60.0)Grade ≥3 TRAEaOne cycle equalled 28 days. leading to treatment discontinuation, n (%)09 (45.0)5 (50.0)ExposureArm 1 (n = 10)Arm 1a (n = 20)Arm 2 (n = 10)Median cyclesaOne cycle equalled 28 days. of D, n10.53.06.0Median total G treatment duration, months (min, max)12.0 (5, 13)5.7 (1, 12)7.1 (1, 13)EfficacyArm 1 (n = 10)Arm 1a (n = 20)Arm 2 (n = 10)Achieved OR, % (95% CI)80.0 (44.4, 97.5)55.0 (31.5, 76.9)70.0 (34.8, 93.3)Median DoR, months (95% CI)8.8 (3.0, 14.8)7.4 (3.7, 20.7)12.6 (5.5, 20.4)Median PFSbPatients with progression events: Arm 1, n = 9; Arm 1a, n = 16; Arm 2, n = 8; PD-L1 positive, n = 8; PD-L1 negative, n = 22., months (95% CI)10.5 (4.6, 17.0)9.3 (4.6, 15.2)12.0 (2.7, 15.6)PD-L1 statuscDetermined using fresh and archival baseline tumour biopsies (archival biopsies permitted in Arm 1a only) and SP263 Roche Tissue Diagnostics protocol: PD-L1 positivity was defined as tumour cell PD-L1 expression ≥20%; negative was defined as PD-L1 expression <20%. Results from Arms 1, 1a, and 2 were combined for this analysis.Positive (n = 12)Negative (n = 24)Median PFSbPatients with progression events: Arm 1, n = 9; Arm 1a, n = 16; Arm 2, n = 8; PD-L1 positive, n = 8; PD-L1 negative, n = 22., months (95% CI)15.9 (2.8, 21.3)9.1 (5.5, 11.9)HR (95% CI)0.461dHR was not statistically significant and should be interpreted with caution due to low patient numbers. AE, adverse event; CI, confidence interval; D, durvalumab; DoR, duration of response; G, gefitinib; HR, hazard ratio; max, maximum; min, minimum; n, number of patients; OR, objective response; PD-L1, programmed cell death ligand-1; PFS, progression-free survival; TRAE, treatment-related adverse event. (0.187, 1.029)a One cycle equalled 28 days.b Patients with progression events: Arm 1, n = 9; Arm 1a, n = 16; Arm 2, n = 8; PD-L1 positive, n = 8; PD-L1 negative, n = 22.c Determined using fresh and archival baseline tumour biopsies (archival biopsies permitted in Arm 1a only) and SP263 Roche Tissue Diagnostics protocol: PD-L1 positivity was defined as tumour cell PD-L1 expression ≥20%; negative was defined as PD-L1 expression <20%. Results from Arms 1, 1a, and 2 were combined for this analysis.d HR was not statistically significant and should be interpreted with caution due to low patient numbers. AE, adverse event; CI, confidence interval; D, durvalumab; DoR, duration of response; G, gefitinib; HR, hazard ratio; max, maximum; min, minimum; n, number of patients; OR, objective response; PD-L1, programmed cell death ligand-1; PFS, progression-free survival; TRAE, treatment-related adverse event. Open table in a new tab Conclusions: G + D had a high discontinuation rate due to liver related TRAEs and there was no additional benefit vs historical data for G alone. However, tumours expressing PD-L1 had favourable PFS and could be investigated further. Clinical trial identification: NCT02088112; March 14, 2014. Editorial acknowledgement: Medical writing support, under the direction of the authors, was provided by Lauren McNally, MSci, of CMC CONNECT, a division of McCann Health Medical Communications Ltd, Glasgow, UK, with funding from AstraZeneca PLC, in accordance with Good Publication Practice (GPP3) guidelines. Legal entity responsible for the study: MedImmune LLC (a wholly owned subsidiary of AstraZeneca PLC). Funding: AstraZeneca PLC. Disclosure: T. Yeh, W. Tang, M. Tang, H.K. Angell, M.P. Roudier, M. Marotti: Employee: AstraZeneca. R. Taylor: Employee, contractor: AstraZeneca. D.L. Gibbons: Advisory boards/research funding: AstraZeneca. All other authors have declared no conflicts of interest.

CDK9 (cyclin-dependent kinase 9) regulates RNA transcription through its phosphorylation of RNA polymerase II and subsequent release from a “paused” elongation state, resulting in transcriptional activity. A transient inhibition of CDK9 activity will significantly impact transcripts with a short half-life, which includes the transcript for MCL1, an anti-apoptotic protein. AZD4573 is a highly potent and selective CDK9 inhibitor. We have previously reported that AZD4573 treatment results in dose-dependent inhibition of pSer2 of RNA polymerase II, reductions in MCL1 mRNA and protein, and an increase in cleaved caspase 3, resulting in cell death of hematological tumor cell lines and regressions in AML/DLBCL in vivo models [Cidado et. al., AACR Annual Meeting, Abstract 310 (2018)].

The human IgG1 monoclonal antibody D blocks interaction of PD-L1 with PD-1 and CD-80 with high affinity and selectivity. This Phase I open-label multicentre study (NCT02088112) was initiated to evaluate D in combination with the EGFR TKI G in NSCLC. Expansion phase data are reported. The ongoing expansion phase combines D 10 mg/kg every 2 weeks plus G 250 mg once-daily in TKI naïve NSCLC pts with sensitising EGFR mutations. Arm 1 (10 pts): concurrent D plus G; Arm 2 (10 pts): 4 weeks of priming G monotherapy followed by concurrent D plus G. Primary endpoint: safety and tolerability. Secondary endpoints: tumour response (RECIST 1.1); pharmacokinetics (PK); pharmacodynamics (PD); immunogenicity. Pt demographics were similar across Arms (table). At data cut off (15 Sept 2015), follow-up was ≥3 months for all pts. G plus D combination was tolerable (most frequently reported treatment-related adverse events [AEs] of any grade: see table). Treatment-related CTC Grade 3–4 AEs led to discontinuation in 4 pts, all from Arm 2: increased ALT and/or AST (n = 3), pneumonitis (n = 1). Investigator-determined best objective response rate in 19 evaluable pts at ≥8 weeks: Arm 1 77.8% (7/9); Arm 2 80.0% (8/10) (table). No significant PK or PD interactions were observed nor anti-drug antibodies detected.Tabled 1Expansion PhaseArm 1 (N = 10)Arm 2 (N = 10)DemographicsMale, n (%)5 (50.0)5 (50.0)Median age, years (range)54.5 (27–68)66.0 (57–76)Never-smoker, n (%)4 (40.0)6 (60.0)Exon 19 deletion, n (%)6 (60.0)5 (50.0)Exon 21 L858R, n (%)4 (40.0)4 (40.0)Treatment-related AEs (occurring in ≥4 pts in any Arm)Total, naNumber of pts reporting ≥1 AE.10 (100)10 (100)Diarrhoea, n (%)8 (80.0)6 (60.0)ALT increased, n (%)7 (70.0)6 (60.0)AST increased, n (%)4 (40.0)5 (50.0)Pruritus, n (%)4 (40.0)6 (60.0)Dry skin, n (%)3 (30.0)5 (50.0)Nausea, n (%)4 (40.0)1 (10.0)Rash, n (%)6 (60.0)4 (40.0)Tumour responsebn = 19 pts with tumour data available for analysis.Arm 1Arm 2(N = 9)(N = 10)Best objective response ratecComplete + partial response., n (%)7 (77.8)8 (80.0)Complete response, n (%)1 (11.1)0 (0.0)Partial response, n (%)6 (66.7)8 (80.0)Stable disease ≥8 weeks, n (%)2 (22.2)1 (10.0)Not evaluable, n (%)0 (0.0)0 (0.0)AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; pts, patients.a Number of pts reporting ≥1 AE.b n = 19 pts with tumour data available for analysis.c Complete + partial response. Open table in a new tab AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; pts, patients. D 10 mg/kg plus G 250 mg was generally tolerated, with encouraging activity observed in TKI naïve NSCLC pts with sensitising EGFR mutations, supporting continued evaluation of this combination.

Gefitinib (IRESSA™) has been approved as early as 2002 for the treatment of advanced NSCLC patients in over 90 countries. However, during the historical development of gefitinib, paired lung biopsies were challenging to collect and the evaluation of phosphorylated EGFR (pEGFR) inhibition in tumour samples was therefore extremely limited. We recently had an opportunity to revisit and evaluate pEGFR inhibition in the context of a gefitinib+durvalumab combination trial (NCT02088112) where pre- and post-treatment biopsies were collected in TKI-naïve patients with tumours harbouring EGFR mutations (i.e. L858R/Del19) in the dose expansion part of the study. There were two arms in the dose expansion. Patients in Arm 1 were treated immediately with gefitinib+durvalumab; patients in Arm 2 were treated with gefitinib alone for 28 days (d) before starting the combination. For Arm 1, biopsies were collected at pre-treatment and at 10 d after combination treatment. For Arm 2, biopsies were collected at pre-treatment, 10 d after gefitinib alone and 10 d after combination (i.e. d 38). Biopsies were analysed for pEGFR/Y1173 by IHC and manually scored for membrane and cytoplasmic staining. There were 20 patients in dose expansion, 10 patients/arm. However, a number of the post-treatment biopsies contained little or no tumour cells, resulting in the final analysis of 3 tumour pairs for Arm 1 (combination) and 8 tumour pairs for Arm 2 (gefitinib run-in). Although baseline pEGFR levels were lower than expected, the majority (6/8) of the paired samples from Arm 2 and all (3/3) of the paired samples from Arm 1 showed pEGFR inhibition after 10 d of treatment, suggesting not only pEGFR inhibition by gefitinib but no antagonism by durvalumab with regard to gefitinib's mechanism of action. Paired tumour biopsies from gefitinib- and gefitinib+durvalumab-treated patients suggested inhibition of pEGFR after 10 d of treatment, consistent with the observation of rapid tumour reductions in these patients. Analysis of immune biomarkers is ongoing (e.g. PD-L1) and will also be presented.

3047 Background: MEDI4736 is a human IgG1 monoclonal antibody which blocks PD-L1 binding to PD-1 and CD-80 with high affinity and selectivity. A Phase I open-label multicenter study was initiated to evaluate MEDI4736 combined with the EGFR tyrosine kinase inhibitor (TKI) gefitinib in NSCLC (NCT02088112). Dose escalation phase data are reported. Methods: Key eligibility criteria included: locally advanced/metastatic NSCLC of any EGFR mutation status, relapsed/refractory/intolerant of standard treatment; ≤ 4 prior therapies. Cohort A received MEDI4736 3 mg/kg (starting dose) every 2 weeks plus gefitinib 250 mg once-daily (QD). If no dose-limiting toxicities were observed, Cohort B received MEDI4736 at a higher dose of 10 mg/kg every two weeks plus gefitinib 250 mg QD. Primary endpoint: safety/tolerability and recommended dose of the MEDI4736 plus gefitinib combination. Secondary endpoints included: tumor response (RECIST 1.1); pharmacokinetics (PK); immunogenicity. Results: Of 10 pts (Cohort A = 3; Cohort B = 7): 4 male; 4 Asian; median age 58.5 years. Maximum tolerated dose was not reached, and no dose limiting toxicities were observed. Adverse events (AEs) were observed in all pts; treatment-related CTC Grade 3-4 AEs in 3 pts led to study discontinuation: dyspnea/hypoxia (Cohort A; 1 pt), myalgia/fatigue and elevated ALT (Cohort B; 1 pt each). These AEs resolved upon discontinuation and standard management guidelines. Two unrelated deaths occurred in Cohort B. No PK interactions were observed nor anti-drug antibodies detected with the drug combination. Of 7 pts with ≥ 1 8-week tumor assessment; 3 pts had reduction in tumor size (Cohort A = 2; Cohort B = 1). Conclusions: MEDI4736 (3 and 10 mg/kg) plus gefitinib was generally well tolerated in pts with NSCLC in the escalation phase, with early clinical activity observed in these heavily pre-treated pts. Preliminary data support continued evaluation of MEDI4736 10 mg/kg with gefitinib 250 mg as the recommended expansion phase dose in pts with EGFR sensitized mutation-positive/TKI naïve NSCLC. Sponsored by MedImmune, global biologics R&D arm of AstraZeneca Clinical trial information: NCT02088112.

Abstract Activation of the Ras/Raf/MEK/MAP kinase pathway is implicated in uncontrolled cell proliferation and tumor growth. Inappropriate activation of the RAS pathway can occur through several distinct mechanisms, including activating mutations in Ras and B-raf, or activated growth factor-signaling, cytokines and stress responses. Mutated, oncogenic forms of Ras are found in 50% of colon, 90% of pancreatic, and 30% of lung cancers. Also, B-Raf mutations have been identified in more than 60% of malignant melanomas and from 40-70% of papillary thyroid cancers. MEK, a dual specific kinase, is a key player in this pathway; it is downstream of both Ras and Raf and activates ERK1/2 through phosphorylation of key tyrosine and threonine residues. These data suggest that targeting MEK can inhibit cancer cell signaling mediated by a wide variety of signals, making MEK an attractive target for the treatment of cancer. We have discovered ARRY-162, a novel ATP-uncompetitive inhibitor of MEK 1/2, which is un-competitive with respect to ATP. ARRY-162 has nanomolar activity against purified MEK enzyme (IC50 = 12 nM) and is highly selective. It has been evaluated against 220 serine/threonine and tyrosine kinases with no inhibitory activity observed up to 20 μM. ARRY-162 inhibits both basal and induced levels of ERK phosphorylation in numerous cancer cell lines with IC50s as low as 5 nM. ARRY-162 is especially potent at inhibiting the cell proliferation of mutant B-Raf and Ras cell lines such as HT29, Malme-3M, SK-MEL-2, COLO 205, SK-MEL-28 and A375 (IC50s from 30-250 nM). In vivo, ARRY-162 has demonstrated efficacy in several xenograft tumor models in mice, including HT29, BxPC3, MIA PaCa2, A549, LoVo, Calu6, DU145 and COLO 205. In the HT29 and in the COLO 205 colon carcinoma models, dose-dependent inhibition of tumor growth (up to 75% TGI) was observed at doses ranging from 3 to 30 mg/kg, QD, PO for 21 days. In the Colo-205 colon carcinoma model, significant tumor regressions were observed with 50% partial responses and 13% complete responses at 30 mg/kg, PO, QD. In the BxPC3 pancreatic carcinoma model (which does not harbor either Ras or Raf mutations), tumor growth inhibition (∼70% TGI) and 13% partial responses were seen at doses of 30 mg/kg, QD, PO for 21 days. Consistent with ARRY-162's mechanism of action, tumor growth inhibition correlates with decreased phospho-ERK levels in tumor xenografts. In addition to its potency against MEK, this compound demonstrates other desirable attributes for development including good physical chemical characteristics, low clearance, medium-to-high Caco-2 permeability and minimal predicted drug-drug interactions. With preclinical efficacy and safety studies on ARRY-162 completed, this compound has entered clinical development for treatment of cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2515.

The dual-specificity kinases MEK 1/2 play key roles in tumorgenesis by activating the serine/threonine kinases ERK 1/2. These kinases play critical roles in cellular proliferation, differentiation, apoptosis, migration, and invasion. As such, inhibition of MEK 1/2 is an attractive mechanism for anti-cancer therapy and several small molecule inhibitors have entered human clinical trials, including AZD6244 (ARRY-142886). We have discovered AZD8330 (ARRY-424704), a novel, selective, highly efficacious, uncompetitive MEK 1/2 inhibitor with superior drug-like properties. In cell-free kinase assays, AZD8330 inhibits MEK with an IC50 of 7 nM, and has no inhibitory activity against over 200 other kinases at concentrations up to 10 \#956;M. AZD8330 demonstrates sub-nano molar potency in mechanistic (pERK) and low to sub-nano-molar potency in functional (proliferation) assays in MEK inhibitor sensitive cell lines. In a Calu-6 rat xenograft PK/PD model a single, 1.25 mg/kg oral dose of AZD8330 inhibits ERK phosphorylation by > 90% for between 4 and 8 hours. In pharmacokinetic studies, the high permeability, low predicted hepatic Cl and solubility of AZD8330 translates to high %F and long plasma half-life in rat and dog , 63 and 77% and 10 and 11 hours, respectively following oral administration. The pharmacodynamic and pharmacokinetic properties of AZD8330 result in impressive efficacy at low doses in rodent models of cancer. Doses as low as 0.4 mg/kg once daily are sufficient for > 80% tumour growth inhibition in the Calu-6 nude rat xenograft model. Comparison of once and twice daily dosing schedules indicate similar efficacy for both. In multiple-dose toxicity studies, oral dosing of AZD8330 has an acceptable overall safety profile in the rat and the dog. AZD8330 is currently in Phase I clinical trials for the treatment of cancer. Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 3696.