2G Tyrosine Kinase Inhibitors Research Articles

Abstract B154: Safety and preliminary activity of the selective ALK inhibitor NVL-655 in patients with ALK fusion-positive solid tumors

Abstract Background: Oncogenic ALK alterations drive diverse tumor types, including ALK fusions in 3-5% of non-small cell lung cancers (NSCLCs). While 3 generations (1G, 2G, 3G) of ALK tyrosine kinase inhibitors (TKIs) are approved globally for ALK fusion-positive (ALK+) NSCLC, they are limited by acquired ALK resistance mutations, CNS relapses, and for the 3G TKI lorlatinib, neurologic adverse events attributed to off-target TRK inhibition. A rationally designed ALK TKI that overcomes these limitations is needed. Preclinically, NVL-655 is a brain-penetrant, ALK-selective, and TRK-sparing TKI that exhibits activity against diverse ALK fusions and resistance mutations, including lorlatinib-refractory compound mutations. Materials and Methods: ALKOVE-1 (NCT05384626) is a global phase 1/2 trial of NVL-655. The ongoing phase 1 dose escalation enrolls patients (pts) with a previously treated ALK+ solid tumor, including NSCLC treated with ≥1 prior 2G or 3G ALK TKI. Primary objectives are to determine the safety/tolerability, recommended phase 2 dose (RP2D), and if applicable, the maximum tolerated dose (MTD). Additional objectives include assessments of pharmacokinetics (PK), pharmacodynamics, and preliminary activity by investigator-assessed tumor response (RECIST v1.1). Data cut: June 12, 2023. Results: 57 pts (54 NSCLC, 3 other solid tumors) received NVL-655 orally at 15-200 mg once daily (QD). Pts previously received a median of 4 (range: 1-8) prior anticancer therapies, including a 2G or 3G ALK TKI (100%); ≥1 2G ALK TKI + lorlatinib (77%); ≥3 ALK TKIs (53%); and chemotherapy (60%). At baseline, 51% had a history of CNS metastases. 47% had known ALK resistance mutations and 32% had compound ALK mutations, as per available local testing or central analyses of baseline circulating tumor DNA (ctDNA). Treatment-related adverse events (TRAEs) were generally mild; most frequent were nausea (12%), transaminase elevation (12%), fatigue (9%), and constipation (7%). Grade ≥3 TRAEs were transaminase elevation (n=2), CPK elevation (n=1), and fatigue (n=1). NVL-655 PK analyses demonstrated dose-proportional exposure. Partial responses (PR) were observed in 45% (15/33; 8 pending confirmation) of efficacy-evaluable pts with ALK+ NSCLC (15-150 mg QD), in 65% (11/17) with baseline ALK resistance mutations, and in 41% (12/29) post-lorlatinib, including cases with compound resistance mutations. CNS activity, including complete resolution of CNS metastases, has been observed. ctDNA analyses showed reductions, including clearance, of ALK fusion and mutation variants. Neither the MTD nor RP2D has been identified; phase 1 continues. Conclusions: NVL-655 has been well-tolerated up to 200 mg daily with favorable PK. Preliminary activity has been demonstrated in heavily pretreated pts with ALK+ NSCLC, including those who previously received 2G ALK TKI(s) + lorlatinib, with brain metastases, or with single/compound ALK resistance mutations. Citation Format: Jessica J Lin, Melissa Johnson, Enriqueta Felip, Sai-Hong Ignatius Ou, Benjamin Besse, Christina Baik, Julien Mazieres, Yasir Elamin, Joshua E. Reuss, Anna Minchom, Aurelie Swalduz, Nick Pavlakis, Geoffrey Liu, Shirish Gadgeel, D. Ross Camidge, Jennifer A Green, Junwu Shen, John Soglia, Yuting Sun, Viola W Zhu, Alexander Drilon. Safety and preliminary activity of the selective ALK inhibitor NVL-655 in patients with ALK fusion-positive solid tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B154.

ASC4START and ASC4FIRST: Two Ongoing Phase 3 Trials Investigating Asciminib Monotherapy As First-Line Therapy Versus Tyrosine Kinase Inhibitors in Patients with Newly Diagnosed Philadelphia Chromosome-Positive Chronic Myeloid Leukemia in Chronic Phase

Background: The current standard of care (SoC) for newly diagnosed patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP) is treatment with 1 of the 4 tyrosine kinase inhibitors (TKIs) approved for this use (first generation [1G] imatinib [IMA] and second generation [2G] bosutinib [BOS], dasatinib [DAS], and nilotinib [NIL]). Although TKIs have vastly improved treatment outcomes, pts with newly diagnosed CML-CP experience lack of efficacy and intolerance to available treatments. A large number of pts treated with IMA do not achieve major molecular response (MMR) and even fewer pts achieve deep molecular response, a key requirement to attempt treatment-free remission. Treatment with 2G TKIs results in larger proportions of pts achieving deep responses albeit still with a sizeable minority not reaching this goal. Also, many pts are intolerant to 2G TKIs, resulting in therapy switching, frequently multiple times. For pts who remain on treatment, even low-grade adverse events (AEs) may significantly impact quality of life (QoL) given the long-term nature of treatment. Improved treatments with high efficacy and improved tolerability are needed to limit therapy switching, reduce treatment discontinuation, maintain, or improve pt QoL, and allow pts to remain on treatment at an optimal dose for longer duration to achieve deep responses. Asciminib is the first and only approved BCR::ABL1 inhibitor that works by specifically targeting the ABL myristoyl pocket (STAMP). This unique mechanism of action (MoA) has no confirmed overlapping mutation-driven resistance profile with ATP-competitive TKIs. Asciminib shows better selectivity compared to other TKIs, with no known off-target kinase-mediated effects due to its MoA; this translates into improved tolerability. In clinical trials (Hughes et al. N Engl J Med. 2019; Rea et al. Blood 2021), asciminib has demonstrated sustained efficacy and a favorable safety profile over time in pts with Philadelphia chromosome positive (Ph+) CML-CP previously treated with ≥2 TKIs as well as in pts with T315I mutation. Asciminib as monotherapy and in combination with ATP-competitive TKIs is being studied as first-line (1L) treatment in CML. The ongoing ASC4FIRST (NCT04971226) study is investigating the efficacy and safety of asciminib 80 mg once daily (QD) monotherapy vs investigator-selected 1G or 2G TKI in adults with newly diagnosed Ph+ CML-CP ( Table 1). The primary endpoint of ASC4FIRST is MMR rate at 48 weeks. The ongoing ASC4START (NCT05456191) study is focused on pt-centric objectives, assessing the tolerability and efficacy of asciminib vs 2G TKI NIL in adults with newly diagnosed Ph+ CML-CP. The primary endpoint of ASC4START is time to treatment discontinuation due to an AE ( Table 1). Current Status: As of December 20, 2022, the ASC4FIRST study completed recruitment, with 405 pts enrolled worldwide. The end of study (EOS) will occur 5 years from the last pt first treatment in the study. Pts will continue to receive the assigned treatment until the EOS, or until premature discontinuation due to treatment failure, disease progression or intolerance, or due to investigator or participant decision. Between 21 November 2022 and 25 July 2023, 180 pts have been screened for the ASC4START study, with 147 pts randomized to treatment (n=52 France, n=40 Germany, n=9 Bulgaria, n=7 Czechia, n=7 Hungary, n=6 Korea, n=6 Singapore, n=2 Slovakia, n=5 Argentina, n=3 Greece, n=2 each from Slovakia, Malaysia, and Oman, and n=1 each from the USA, Italy, Romania, UK, Jordan, and Canada). Recruitment is ongoing. Patients will be treated until approximately 64 discontinuations of either study treatment due to an AE have been recorded. Conclusions: With demonstrated efficacy and improved tolerability compared to ATP-binding TKIs, asciminib has the potential to become the therapy of choice for CML in 1L, enabling newly diagnosed patients to remain on therapy with improved QoL and overall survival, and reducing the need for therapy switching, ultimately allowing patients to achieve optimal milestone responses and reach treatment goals. Findings from these two trials will provide comprehensive evidenceon the use of asciminib as 1L therapy for newly diagnosed pts with Ph+ CML-CP.

Prospective Assessment of Co-Morbidities and Framingham Risk Score in Newly Diagnosed Chronic Myeloid Leukemia (CML) Patients and Its Impact on Clinical Outcomes Following Frontline TKI Therapy: Toronto CML Genomic Alliance in Greater Toronto Area & Ontario (TCGA-GTA)

Introduction Front-line (1L) tyrosine kinase inhibitor (TKI) drug selection is a pearl of clinical practice in CML. It requires consideration of multiple aspects including the goal of therapy, potency of the drug as well as comorbidity of the patient (pt). Contemporary CML practice emphasizes the importance of comorbidity for TKI selection. However, such data is scarce particularly the prevalence of comorbidity and its impact on 1L drug selection. We are developing a shared care model with community hematologists in Greater Toronto Area (TCGA-GTA). Newly diagnosed CML pts in the community will be referred to the study core center for prospective enrolment into the CML registry, informed consenting for genetic testing/future research, and evaluation of baseline comorbidity. Pt will return to referring hematologists for management of CML, including 1L TKI treatment as per standard of care, and is scheduled to visit the study center at 6 and 12 months, then annually for 10 years. It gives us a unique opportunity to evaluate the impact of comorbidity on 1L TKI drug selection. Patients and method Adult pts with newly diagnosed CML of any phase within 2 months of diagnosis are eligible for the study unless they are not able to visit study core center. Comorbidities and Framingham risk score (FRS) were assessed at the time of initial evaluation. Mutation profile testing is done by a bar-coded error-corrected sequencing platform for 40 genes developed at the Ontario Institute for Cancer Research. Cumulative incidence of molecular response with 2 log (MR2), 3 log (MR3), 4 log reduction or deeper (MR4), and treatment failure (TF) were calculated using cumulative incidence method considering competing risk. Event-free survival (EFS) was defined as time from start of TKI until TKI stop/switch, TF or death. Failure-free survival (FFS) was defined as time from start of TKI to TF [primary resistance, loss of complete cytogenetic response, new additional cytogenetic abnormalities (ACAs), and progression to accelerated or blasts phase (AP/BP)] or death. Results From November 2020 until June 31, 2023 (data cutoff), a total of 77 pts were enrolled in the study. The median follow-up time was 12 months. The frequency of 1L TKI selection was as follows: IMATINIB (IM) (n=23, 30%), DASATINIB (n=25, 32%), NILOTINIB (n=22, 29%), BOSUTINIB (n=1, 1%), ASCIMINIB (n=6, 8%). Majority of the pts were male (n=51, 66%). Ninety-three percent of pts were in chronic phase at diagnosis, while 4% and 3% were in AP and BP, respectively. Presence of ACAs was detected in 18 pts (23%), 10 of which were high risk, while 6% (n=5) were not evaluable. The baseline clinical and disease characteristics of pts on 1L IM vs other TKIs (2G-TKI) are summarised in Table 1. Of note, pts on IM were significantly older with higher FRS and comorbidities, including coronary artery disease, diabetes mellitus, and hypertension. The OS of all pts at 1 year was 98.5% (95% confidence interval 90%-99.8%). At 1 year, pts with intermediate to high risk FRS had lower FFS (73.2% vs 86.5%, p=0.037) while history of hyperlipidemia was associated with lower EFS (59.3% vs 81.5%, p=0.023) and 6 times more likely to stop or switch therapy due to intolerance or resistance (HR 5.9, p=0.002). Baseline comorbidities did not demonstrate signifincant impact on MR2 and MR3 at 1 year but pts with low FRS were more likely to achieve MR4 within 1 year (22.3% vs 0%, p=0.023). Age did not affect any of the clinical and molecular endpoints. Compared to 2G-TKI, IM had worse EFS (HR 3.93, p=0.003), FFS (HR 5.66, p=0.011), and MR2 (47.3% vs 84.4%, p=0.003) at 1 year. Further, IM pts experienced higher rate of any side effects compared to those on 2G-TKI (69.6% vs 31.5%, p=0.003). Conclusion The TCGA-GTA study provides valuable insights into the impact of comorbidity on selection of 1L TKI and its outcome in a real-world setting. Pts who are older and with higher FRS and comorbidities tend to receive 1L IM. However, pts on 1L 2G TKIs are more likely to reach treatment goals faster with lower probability of TF. The present study did not reach a clear conclusion whether the worse outcomes in the pts receiving IM are from IM treatment or concurrent risk factors such as age and comorbidities, thus further study with an expanded cohort and longer follow-up is required. Elderly pts or those with comorbidities would need alternative treatment with better efficacy and tolerability, such as Asciminib, that can overcome comorbidity issues in the future.

Real-world Management of CML: Outcomes and Treatment Patterns.

Chronic myeloid leukemia (CML) is a disease that previously signified a poor prognosis, but treatment options and outcomes have improved over the last several decades. Despite this, challenges remain in optimal management in clinical practice, as the characteristics in trial populations differ from patients who are treated in a real-world setting. This review describes recent updates in real-world treatment patterns and outcomes in patients with CML. Several analyses describing real-world practice patterns show that tyrosine kinase inhibitors (TKIs) are the most commonly prescribed agents in multiple lines of therapy. First-generation (1G) and second-generation (2G) TKIs are the most commonly prescribed, even in the third line and beyond. Third-generation (3G) TKIs are typically utilized in patients with resistant disease who are younger with fewer comorbidities. Hematopoietic stem cell transplant (HSCT) is utilized significantly less, given other treatment options available. The goals of treatment with CML have shifted to quality of life, cost savings, and treatment-free response (TFR). Despite clear guidelines for attempting TFR, discontinuation practice patterns remain inconsistent. TKIs are the mainstay of CML treatment, including those in later lines of therapy. In real-world practice, several challenges still remain with regard to optimal management. Specifically, ideal sequencing of treatments, side effect profiles of tyrosine kinase inhibitors (TKIs), current role and timing of transplant, and adherence to recommendations for attempting to achieve a treatment-free response (TFR). A national registry could characterize these practice patterns in order to find ways to optimize care for CML patients.

ASC2ESCALATE: A US phase 2, single-arm, dose-escalation study of asciminib monotherapy in patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP) previously treated with 1 prior tyrosine kinase inhibitor (TKI).

TPS7082 Background: ATP–competitive TKIs extend life expectancy in CML; yet up to 40% of newly diagnosed pts with CML-CP stop first-line (1L) therapy by 5 years due to resistance or intolerance and switch to second-line (2L) therapy. There is also an unmet need to overcome high rates of resistance in 2L. Studies show some pts with resistance achieve responses with higher doses of TKIs, while use of another second-generation (2G) TKI may not clinically benefit pts with resistance to a 2G TKI. Asciminib is the 1st BCR:ABL1 inhibitor that Specifically Targets the ABL Myristoyl Pocket (STAMP), giving it activity against most BCR:ABL1 mutations imparting resistance to ATP-competitive TKIs. Asciminib was 1st approved in the US for patients with CML-CP after ≥2 TKIs at 80 mg once daily (QD) and 40 mg twice daily (BID) and CML-CP with the T315I mutation at 200 mg BID. In the phase 3 ASCEMBL study, asciminib 40 mg BID showed superior efficacy vs bosutinib 500 mg QD in pts with CML-CP after ≥2 prior TKIs at weeks 24 (major molecular response [MMR], 25.5% vs 13.2%) and 96 (MMR, 37.6% vs 15.8%) and favorable tolerability with > 2 years’ follow-up. The phase 1 dose-finding X2101 trial investigated asciminib doses of 80-200 mg QD and 10-200 mg BID; the maximum tolerated dose of asciminib was not reached and no differing safety signals were noted in patients receiving 200 mg BID vs the total treatment population. Here, we describe the phase 2 ASC2ESCALATE trial investigating efficacy and safety of 2L asciminib with dose escalation in pts with CML-CP (NCT05384587). Methods: This is a phase 2, open-label, multicenter, single-arm, dose-escalation study in the US. Adults with CML-CP without the T315I mutation with treatment resistance/failure ( BCR:ABL1IS > 10% with 6-12 months of 1L treatment or > 1% with > 12 months of 1L treatment ) or intolerance ( BCR:ABL1IS > 0.1%) with ≥6 months of treatment with 1 prior ATP-competitive TKI are eligible. All pts start treatment with asciminib 80 mg QD. For pts not achieving BCR:ABL1IS ≤1% at 6 months, dose will be escalated to 200 mg QD if pts do not have grade ≥3 or persistent grade 2 toxicity refractory to optimal management. For those without MMR at 12 months, either dose escalation from 80 to 200 mg QD or from 200 mg QD to 200 mg BID will occur or pts can be switched to an investigator’s agent of choice and taken off study treatment. Pts achieving MMR at 12 months will continue asciminib at their current dose. Pts continuing to derive clinical benefit from asciminib per investigator assessment may receive post-trial access. Recruitment for this study began August 2022 with an estimated enrollment of 92 pts with CML-CP across ≈40 sites. The primary endpoint is MMR at 12 months. Secondary endpoints include additional efficacy outcomes at 3, 6, 18, and 24 months and safety measures. Clinical trial information: NCT05384587 .

Efficacy and Safety Results from ASC4MORE, a Randomized Study of Asciminib (ASC) Add-on to Imatinib (IMA), Continued IMA, or Switch to Nilotinib (NIL) in Patients (Pts) with Chronic-Phase Chronic Myeloid Leukemia (CML-CP) Not Achieving Deep Molecular Responses (DMRs) with ≥1 Year of IMA

INTRODUCTION: With the evolving CML treatment landscape, improvement in quality of life and treatment-free remission have become important therapy goals in CML-CP. In the 1st line (1L), more pts are able to achieve DMRs with 2nd-generation (2G) tyrosine kinase inhibitors (TKIs) than IMA. However, 30% to 60% of pts treated with 2G TKIs do not achieve DMR after 5 y of therapy, and 2G TKIs are associated with increased toxicity. Safe and effective treatment options are needed in early lines to help more pts achieve durable DMR. ASC is the 1st BCR::ABL1 inhibitor to Specifically Target the ABL Myristoyl Pocket (STAMP). ASC was 1st approved in the US for the treatment of adult pts with Philadelphia chromosome-positive CML-CP after ≥2 prior TKIs and pts with the T315I mutation. In the phase 3 ASCEMBL study, ASC led to superior major molecular response vs bosutinib (BOS) at wk 24 and 96. More pts on ASC vs BOS achieved MR4 (wk 24: 10.8% vs 5.3%; wk 48: 10.8% vs 3.9%; wk 96: 17.2% vs 10.5%) and MR4.5 (wk 24: 8.9% vs 1.3%; wk 48: 7.6% vs 1.3%; wk 96: 10.8% vs 5.3%). ASC demonstrated a favorable safety profile. Here, we present results from the ASC4MORE study (NCT03578367) of ASC add-on to IMA vs continued IMA vs switch to NIL in pts not achieving DMR with ≥1 y of 1L IMA (cutoff: Jan 10, 2022). METHODS: In this open-label, multicenter, qualitative trial, eligible adults with CML-CP were randomized 1:1:1:1 to receive ASC (40 or 60 mg once daily [QD]) add-on to IMA 400 mg QD, continue IMA 400 mg QD, or switch to NIL 300 mg twice daily. The primary endpoint was MR4.5 rate at wk 48. Pts in the IMA arm could switch to the ASC 60-mg QD add-on arm if they had not achieved MR4.5 at wk 48; data from these pts will be analyzed separately and are not part of the current analysis. Pts must have received 1L IMA 400 mg QD for ≥1 y with BCR::ABL1IS >0.01% to ≤1% at randomization. Pts were excluded if they met failure criteria (per European LeukemiaNet 2013), had previous treatment with any TKIs other than IMA, or had achieved DMR at any time with IMA. RESULTS: Eighty-four pts were randomized to receive ASC 40- or 60-mg QD add-on to IMA, continue IMA, or switch to NIL (n=21 each); baseline characteristics were mostly well-balanced between arms. At cutoff, 85.7%, 76.2%, 23.8%, and 61.9% of pts, respectively, remained on treatment, with median (range) durations of exposure of 104.7 (27-160), 94.0 (1-148), 78.9 (1-146), and 53.4 (50-142) wk, respectively. Top reasons for discontinuation were pt decision in the ASC 40-mg add-on arm (9.5%), AEs in the ASC 60-mg add-on and NIL arms (14.3% and 23.8%, respectively), and physician decision in the IMA arm (57.1%) (pts who crossed over to the ASC 60-mg add-on arm were considered discontinued for IMA arm). In the 40-mg ASC add-on, 60-mg ASC add-on, IMA, and NIL arms, respectively, 19.0%, 28.6%, 0%, and 4.8% of pts were in MR4.5 at wk 48, with 42.9%, 28.6%, 0%, and 23.8% in MR4 at wk 48. DMRs were achieved earlier in pts receiving ASC 40- and 60-mg add-on vs NIL; median time to MR4.5 was 12.1, 12.4, and 24.6 wk, respectively (Figure). The Kaplan-Meier-estimated rate of maintaining MR4.5 for ≥48 wk was 60.0%, 80.0%, and 66.7% in the 40- and 60-mg ASC add-on and NIL arms, respectively. As expected in these pts tolerating IMA for ≥1 y, ASC add-on was associated with higher rates of adverse events (AEs), serious AEs, and discontinuations than continued IMA, but less than switching to NIL. AEs leading to discontinuation in the 40-mg add-on, 60-mg ASC add-on, IMA, and NIL arms were reported in 4.8%, 14.3%, 0%, and 23.8% of pts, respectively, with dose adjustments/interruptions occurring in 28.6%, 33.3%, 5.0%, and 23.8%, respectively. There were no new or worsening safety findings with ASC (Table). CONCLUSIONS: More pts achieved DMR at wk 48 with ASC add-on to IMA vs continued IMA or switch to NIL in pts not achieving DMR with IMA alone for ≥1 y. In this population of pts tolerating IMA for ≥1 y, ASC add-on was generally well tolerated. While not powered to identify the best arm for achievement of DMR in this setting, the high rate of DMR in the ASC add-on arms is promising. Further studies are needed to assess if ASC alone can provide equivalent efficacy and better tolerability vs add-on to IMA. Ongoing studies are assessing ASC monotherapy in 1L, including ASC4FIRST (NCT04971226) and ASC4START. ASC may provide an important early-line treatment option to help more pts safely achieve rapid and deep responses and reduce therapy switching. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Dynamics of Response and Response Factors in Patients (Pts) with Chronic Myeloid Leukemia in Chronic Phase (CML-CP) after ≥2 Prior Tyrosine Kinase Inhibitors (TKIs) in the Phase 3 Ascembl Study

Introduction: Asciminib is the 1st BCR::ABL1 inhibitor that works by Specifically Targeting the ABL Myristoyl Pocket (STAMP). Based on the phase 3 ASCEMBL trial, asciminib was FDA approved for the treatment of adult pts with Philadelphia chromosome-positive CML-CP after ≥2 TKIs and for pts with the T315I mutation. In ASCEMBL, after ≥2 years of follow-up, asciminib continues to demonstrate superior efficacy, safety, and tolerability compared with bosutinib (BOS), with more pts on asciminib remaining on treatment and continuing to benefit from therapy over time. In a preplanned subgroup analysis, major molecular response (MMR; BCR::ABL1IS ≤0.1%) rates were consistently higher with asciminib than BOS across major demographic and prognostic subgroups. Here we describe exploratory analyses aimed to characterize the efficacy of asciminib over time and compared with BOS (data cutoff for ASCEMBL wk 96 analysis: October 6, 2021). Methods: Eligible pts with intolerance or treatment failure (lack of efficacy) per European LeukemiaNet (ELN) 2013 recommendations were randomized 2:1 to asciminib 40 mg twice daily or BOS 500 mg once daily, stratified by baseline major cytogenetic response status. Per ELN 2013, pts with BCR::ABL1IS >10% at wk 24 were considered to have lack of efficacy and discontinued therapy. Analyses included molecular response at different time points according to baseline BCR::ABL1IS, cumulative incidence of MMR/BCR::ABL1IS ≤1% in nonresponder pts by wk 24, and logistic regression to assess baseline characteristics as predictive factors of MMR achieved early (by wk 24) vs late (after wk 24). MMR rate at wk 96 according to prior TKIs and reason of discontinuation was analyzed with asciminib and BOS. Results: Of 60 pts on asciminib with BCR::ABL1IS ≤10% at baseline, 18 (30.0%), 24 (40.0%), and 36 (60.0%) reached MMR at wk 12, 24, and 96, respectively, and 38 (63.3%), 45 (75.0%), and 47 (78.3%) reached BCR::ABL1IS ≤1% at wk 12, 24, and 96, respectively. Of 97 pts with BCR::ABL1IS >10% at baseline, 10 (10.3%), 16 (16.5%), and 23 (23.7%) reached MMR at wk 12, 24, and 96, respectively, and 28 (28.9%), 32 (33.0%), and 29 (29.9%) reached BCR::ABL1IS ≤1% at wk 12, 24, and 96 (Table 1). Per protocol, twenty-one (21.6%) pts had BCR::ABL1IS >10% at wk 24 and discontinued treatment per protocol. Of 18 pts on asciminib with BCR::ABL1IS >1% by wk 24, the estimated cumulative incidence of BCR::ABL1IS ≤1% (95% CI) was 22.2% (6.5%-43.6%) by 1 year and 38.9% (16.4%-61.0%) by 2 years. Of 56 pts on asciminib without MMR by wk 24 and who were still on asciminib after wk 24, the estimated cumulative incidence of MMR (95% CI) was 17.9% (9.1%-29.0%) by 1 year and 37.9% (25.1%-50.6%) by 2 years. No baseline characteristics were identified as independent predictive factors of early vs late MMR. Overall MMR rates at wk 96 were higher with asciminib than BOS regardless of the last prior TKI received (imatinib, 55.6% vs 14.3%; nilotinib, 40.9% vs 35.7%; dasatinib, 37.1% vs 10.5%; radotinib, 50.0% vs 0%; ponatinib, 20.0% vs 11.8%) and higher in pts who discontinued their last TKI due to intolerance (asciminib, n=59; BOS, n=22) vs resistance (asciminib, n=95; BOS, n=54). A higher proportion of pts who were resistant to the prior lines of 2nd-generation (2G) TKIs received before randomization, achieved MMR with asciminib vs BOS, respectively, at wk 96: 34.3% vs 7.7% with 1 prior 2G TKI; 35.0% vs 16.7% with ≥2 prior 2G TKIs (Table 2). Conclusions: Responses continued to deepen over time with asciminib in pts with CML-CP after ≥2 prior TKIs, with additional pts achieving MMR at later time points. Pts on asciminib achieved MMR regardless of the last TKI and reason for discontinuation (resistance/intolerance), and overall MMR rates at wk 96 were higher with asciminib than BOS across all last prior TKIs. In pts with resistance to all prior lines of 2G TKIs, MMR rates at wk 96 were higher with asciminib than BOS and comparable to the previously published MMR rate of all pts randomized to receive asciminib (37.6 %). Overall, these results demonstrate that pts who continued asciminib therapy beyond wk 24 have a considerable probability of achieving MMR at later time points. The efficacy of asciminib after treatment failure on 2G TKIs supports a new standard of care for pts with CML-CP for whom ≥2 prior TKIs have failed. This study is sponsored by Novartis. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

ASC4FIRST: A Phase III Study of Asciminib vs Investigator-Selected Tyrosine Kinase Inhibitor in Patients with Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase (CML-CP)

Background: The main treatment goal for patients (pts) with newly diagnosed Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia in chronic phase (CML-CP) is disease control. Standard therapy is with any of the tyrosine kinase inhibitors (TKIs) approved for 1st-line (1L) use: the 1st-generation TKI imatinib (IMA) or one of the 2nd-generation (2G) TKIs bosutinib (BOS), dasatinib (DAS), and nilotinib (NILO). However, in 1L CML-CP, >50% of pts treated with IMA develop resistance to or intolerance of therapy, and 30% to 40% of pts treated with a 2G TKI need to switch therapy by 5 years. In addition, only 30% to 55% of pts achieve a deep molecular response (DMR); needed criterion for attempting treatment-free remission. While 2G TKIs yield a higher major molecular response (MMR) than IMA, they are associated with more adverse events (AEs), including arterio-occlusive events. Therefore, treatment options with improved efficacy and tolerability are needed for pts in 1L CML-CP. Asciminib is the first BCR::ABL1 inhibitor that works by Specifically Targeting the ABL Myristoyl Pocket (STAMP) and has been recently approved by the FDA for Ph+ CML-CP patients treated with ≥2 prior TKIs. In the pivotal phase III ASCEMBL trial in pts treated with ≥2 prior TKIs, after over 2 years of follow-up, asciminib demonstrated sustained superior efficacy, safety and tolerability compared with bosutinib. Here we present a phase III trial evaluating asciminib vs an investigator-selected approved TKI in adult pts with newly diagnosed Ph+ CML-CP. Methods: ASC4FIRST (NCT04971226) is a multicenter, open-label, randomized, phase III study of asciminib 80 mg once daily (QD) monotherapy compared with an approved, investigator-selected TKI (~50% IMA; ~50% either BOS, or DAS, or NILO) for adult pts with newly diagnosed Ph+ CML-CP (expected N=402). Eligible pts must not have received prior TKI therapy for CML except for ≤2 weeks of either IMA, NILO, DAS, or BOS and must have Eastern Cooperative Oncology Group performance status of 0 or. Pts could have received prior hydroxyurea (HU) and/or anagrelide treatment. Pts will be randomized 1:1 to asciminib or investigator-selected TKI using 2 strata: European Treatment and Outcome Study Long-Term Survival (ELTS) score and the control arm TKI selected by the investigator before randomization (Figure). Pts randomized to the investigator selected TKI arm will receive their selected TKIs at approved doses: IMA 400 mg QD, BOS 400 mg QD, DAS 100 mg QD, or NILO 300 mg twice daily. Dose recommendations as per local label should be followed for participants with hepatic and renal impairment. The primary objectives are to compare the efficacy of asciminib vs investigator-selected TKIs and to compare the efficacy of asciminib vs IMA in the stratum of investigator-selected IMA. The primary endpoint is MMR at week 48. The study will be positive if either of these objectives is met. The key secondary endpoint is MMR at week 96. Additional secondary endpoints include time to discontinuation of study treatment due to an AE (TTDAE); MMR, MR4, MR4.5, complete hematological response (CHR) and BCR::ABL1 ≤1% at and by all scheduled data collection time points; duration of and time to first MMR, MR4 and MR4.5; time to treatment failure; event-free survival, failure-free survival, progression-free survival, and overall survival. Pts will remain on treatment for 5 years after the last pt.'s first treatment has been administered, unless they have discontinued early due to treatment failure, disease progression, intolerance, or investigator/pt. decision. All pts including those who discontinue early will continue to be followed up for survival and disease progression until the end of the study. Current Status: As of 18th July 2022, 203 participants have been randomized and are receiving treatment. This Novartis-sponsored study is ongoing. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

ASC2ESCALATE: A Phase 2, Single-Arm, Dose-Escalation Study of Asciminib Monotherapy in Patients (Pts) with Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Previously Treated with 1 Prior Tyrosine Kinase Inhibitor (TKI)

BACKGROUND: The discovery of adenosine triphosphate (ATP)-competitive TKIs has extended life expectancy in CML; despite these advances, 28% to 40% of newly diagnosed pts with CML-CP discontinue treatment by 5 years, prompting a switch to second-line (2L) therapy. Discontinuation rates increase in 2L; up to 86% of pts discontinue therapy, with 20% to 30% discontinuing 2L therapy due to disease progression. Dose-escalation studies show that some pts experiencing resistance to therapy can achieve responses with higher doses of their TKI, while use of another second-generation (2G) TKI has shown limited clinical benefit in pts experiencing resistance to a 2G TKI. Asciminib is the 1st BCR::ABL1 inhibitor that Specifically Targets the ABL Myristoyl Pocket (STAMP), allowing asciminib to have activity against most BCR::ABL1 mutations that impart resistance to ATP-competitive TKIs. Asciminib was 1st approved in the United States for pts with CML-CP after ≥2 TKIs at 80 mg once daily (QD) and 40 mg twice daily (BID) and CML-CP with the T315I mutation at 200 mg BID. In the phase 3 ASCEMBL study, asciminib 40 mg BID showed superior efficacy vs bosutinib 500 mg QD in pts with CML-CP after ≥2 prior TKIs at weeks 24 (major molecular response [MMR], 25.5% vs 13.2%) and 96 (MMR, 37.6% vs 15.8%) and favorable tolerability with >2 years’ follow-up. In a large phase 1 dose-finding trial, asciminib demonstrated safety across doses of 80 to 200 mg QD and 10 to 200 mg BID in pts with CML-CP/accelerated phase without and with the T315I mutation previously treated with ≥2 and ≥1 TKIs, respectively (maximum tolerated dose was not reached in this study). Here, we describe the phase 2 ASC2ESCALATE trial investigating the efficacy and safety of 2L asciminib with dose escalation in pts with CML-CP (NCT05384587). STUDY DESIGN AND METHODS: This is a phase 2, open-label, multicenter, single-arm, dose-escalation study in the United States (Figure). Adult pts (aged ≥18 years) with CML-CP without the T315I mutation who experienced resistance (BCR::ABL1IS >1% with 6-12 months of first-line [1L] treatment or >10% with >12 months of 1L treatment) or intolerance (BCR::ABL1IS >0.1%) with ≥6 months of treatment with 1 prior ATP-competitive TKI are eligible (Table). All pts will initiate treatment with asciminib 80 mg QD. For pts not achieving BCR::ABL1IS <1% at 6 months, dose will be escalated to 200 mg QD if pts do not have grade ≥3 toxicity or persistent grade 2 toxicity refractory to optimal management. In pts not achieving MMR at 12 months, either dose escalation from 80 to 200 mg QD or from 200 mg QD to 200 mg BID will occur or the pts will discontinue study treatment. Pts who achieve MMR at 12 months will continue asciminib at their current dose. Pts deriving clinical benefit from asciminib per investigator assessment may receive post-trial access. Pts may discontinue at any time due to unacceptable toxicity or progression or at investigator/pt discretion. The primary endpoint is the proportion of pts achieving MMR at 12 months. Secondary endpoints include MMR rates by 3, 6, 18, and 24 months; MR4.5 (BCR::ABL1IS ≤0.0032%) at 24 months; time to and duration of MMR; time to treatment failure; and safety/tolerability. To investigate progression-free and overall survival, time from the first dose to progression or death due to any cause during the study, respectively, will be measured. CONCLUSIONS: ASC2ESCALATE is the 1st clinical trial designed to assess asciminib in pts with CML-CP requiring 2L therapy and seeks to provide information on the efficacy and safety of dose escalation for pts not meeting certain response milestones. Treatment using a dose escalation strategy with asciminib in 2L could enable a greater proportion of pts with CML-CP not meeting milestones to achieve molecular responses and provide another option for those experiencing intolerance of or resistance to ATP-competitive TKIs. Recruitment for this study is planned to begin August 2022 with an approximate enrollment of 92 pts with CML-CP across ≈40 sites. This study is sponsored by Novartis. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

ASC4START: A Phase IIIb, Open-Label, Randomized Study of Tolerability and Efficacy of Asciminib Versus Nilotinib in Patients with Newly Diagnosed Philadelphia Chromosome-Positive Chronic Myelogenous Leukemia in Chronic Phase

Objectives: Tyrosine kinase inhibitors (TKIs) have greatly improved treatment outcomes for patients with newly diagnosed chronic myelogenous leukemia in chronic phase (CML-CP), transforming it into a chronic disease requiring long-term treatment. This emphasizes the need for treatments that combine high efficacy with a favorable safety profile, improving over currently available options. Asciminib is a first-in-class BCR::ABL1 inhibitor specifically targeting the ABL myristoyl pocket (STAMP) which has been approved by the FDA with subsequent approvals worldwide for patients with Philadelphia chromosome-positive (Ph+) CML-CP, previously treated with ≥2 prior TKIs based on the results of the ASCEMBL (NCT03106779) trial. The ABL specificity of asciminib compared with the selectivity of second-generation (2G) TKIs can reduce off-target effects and improve tolerability while maintaining efficacy and reducing the probability of developing resistance. The ongoing ASC4FIRST (NCT04971226) study will evaluate the efficacy and safety of asciminib vs investigator-selected TKI in patients with newly diagnosed Ph+ CML-CP. Additional data on asciminib in newly diagnosed Ph+ CML-CP may help to address patient-centric objectives, in particular the ability of patients to remain on treatment without having to permanently discontinue due to adverse events (AEs). The ASC4START study (NCT05456191) will primarily evaluate the tolerability of asciminib vs the 2G TKI nilotinib in adult patients with newly diagnosed Ph+ CML-CP, as measured by the time to study treatment discontinuation due to adverse event (TTDAE). The study will also report on further safety, efficacy and quality of life (QoL) outcomes. Methods: This is a phase IIIb, multi-center, open-label, randomized study in patients ≥18 years of age with newly diagnosed Ph+ CML-CP. The trial will enroll approximately 541 patients with CML-CP diagnosed within 3 months of study entry and an Eastern Cooperative Oncology Group (ECOG) performance status ≤1. Patients cannot be included if they have received previous treatment for CML with any other anticancer agents (except hydroxyurea and/or anagrelide), have confirmed central nervous system infiltration, or present impaired cardiac function or abnormalities in cardiac repolarization. Patients will be randomized 1:1 to receive asciminib 80 mg once daily or nilotinib 300 mg twice daily, both administered orally under fasting conditions; randomization will be stratified based on European Treatment Outcome Study long-term survival (ELTS) score at diagnosis (high vs intermediate vs low) to help achieve balance between the treatment arms (Figure). The primary endpoint is TTDAE, defined as the time from the date of the first dose of study treatment to the date of discontinuation of study treatment due to an AE. Secondary endpoints include type, frequency and severity of AEs; dose modifications due to AE; changes in laboratory values that fall outside pre-determined ranges; clinically notable ECG changes; time to discontinuation due to selected reasons (lack of efficacy/treatment failure/disease progression/suboptimal response/death); major molecular response (MMR), MR4, MR4.5, complete hematological response (CHR), and BCR::ABL1 ≤1% at and by all scheduled data collection time points; duration of and time to first MMR, MR4 and MR4.5; time to treatment failure; event-free survival, progression-free survival and overall survival. Secondary endpoints related to QoL include change from baseline in overall scores and individual scales of the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaires QLQ-C30 and QLQ-CML24. Participants will be treated in the study until approximately 64 discontinuations due to AEs are met; treatment duration for an individual patient is expected to be 2‒4.5 years. Current status: The study is recruiting as of October 2022. This study was sponsored by Novartis Pharmaceuticals. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Permanent Discontinuation of Tyrosine Kinase Inhibitor Frontline Therapy in Patients with Chronic Phase Chronic Myeloid Leukemia Patients during the First 36 Months of Treatment: A "Campus CML" Study

Background Tyrosine kinase inhibitors (TKIs) have changed prognosis and treatment results of chronic myeloid leukemia (CML). However, the first years of therapy are crucial to achieve optimal response, defined as the achievement of deep molecular response: in this early phase, however, different toxicities or suboptimal response/resistance may occur, leading to permanent frontline TKI discontinuation and need for a second-line switch. Methods To evaluate in a large real-life cohort of CML patients the incidence and the different pattern of events leading to a permanent frontline TKI discontinuation during the first 3 years of therapy, 1168 CP-CML patients diagnosed from 1/2012 and 12/2019 at 21 Hematology Centres and treated with frontline imatinib (IM) or second-generation (2G) TKIs dasatinib or nilotinib were retrospectively analysed. Results Frontline TKI was IM in 737 (63.1%) and 2G-TKIs in 431 (36.9%) cases: the main clinical features at diagnosis of the entire cohort and according to frontline treatment are reported in the Table 1. Commonest comorbidities were arterial hypertension (37.4%), previous neoplasm (14.1%), diabetes (10.9%), peripheral vascular diseases (8.4%), ischemic heart disease (6.9%) and COPD (6.7%). IM-treated patients were older (p<0.001) and had more comorbidities (p=0.002 for COPD and p<0.001 for all other diseases). Total number of patients who had discontinued frontline TKI at the 36th month of observation was 391/1168 (33.5%), being higher with IM (294/737, 39.8%) than with 2G-TKIs (96/431, 22.3%) (p<0.001). Cumulative incidence of permanent TKI discontinuation was 19.6% [95% confidence interval (CI) 17.3-21.9] at 12 months, 29.7% (95%CI 27.0-32.4) at 24 months and 34.2% (95%CI 31.5-36.9) at 36 months, respectively: cumulative incidence of discontinuation according to frontline TKI is shown in the Figure (p<0.001 at any time-point). Among the 391 patients who discontinued frontline TKI, the main causes were hematologic toxicity in 27 (6.9%), extra-hematologic toxicity in 106 (27.1%), primary resistance in 166 (42.4%), secondary resistance in 18 (4.6%), evolution in blastic phase in 17 (4.3%), unrelated deaths in 36 (9.2%) and other causes in 21 (5.4%). At univariate analysis, in addition to IM as frontline TKI, baseline factors predictive for an higher rate of TKI discontinuation were age > 65 years (p=0.001), WBC ≥ 100 x 109/l (p<0.001), Hb < 10 g/dl (p<0.001), spleen enlargement ≥ 5 cm below costal margin (p<0.001) and high Sokal score (p<0.001). At multivariate regression logistic analysis, frontline IM (HR 3.22; 95%CI 2.34 - 4.42, p<0.001), WBC ≥ 100 x 109/l (HR 2.18; 95%CI 1.57 - 3.02, p<0.001), spleen enlargement ≥ 5 cm (HR 1.91; 95%CI 1.22 - 3.00, p=0.005) and Sokal high risk (HR 1.78; 95%CI 1.16 - 2.72, p=0.007) retained an independent predictive role on TKI discontinuation. Conclusions This real-world study on over 1100 CML patients reveals that about one third of newly diagnosed CML patients discontinued frontline TKI during the first 3 years of therapy, mostly for primary resistance or toxicity. Discontinuation rates were higher with IM compared to 2G-TKIs at any time-point: however, the impact of older age, higher risks and heavier burden of comorbidities in IM patients should be considered. Other factors seemed to affect the risk of frontline TKI discontinuation but their role needs further refined investigations. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

CML-423 Trial in Progress: A Phase III Study of Asciminib vs an Investigator-Selected Tyrosine Kinase Inhibitor (TKI) in Patients With Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase (CML-CP)

Four TKIs are approved for first-line (1L) use in CML-CP: the first-generation TKI imatinib and the second-generation (2G) TKIs bosutinib, dasatinib, and nilotinib. However, in 1L CML-CP, >50% of patients treated with imatinib develop resistance/intolerance to therapy, and 30%-40% of patients treated with a 2G TKI need to change therapy by 5 years. While 2G TKIs yield a higher major molecular response (MMR) than imatinib, they are associated with more adverse events (AEs). Asciminib is a recently approved BCR::ABL1 inhibitor that targets the ABL1 myristoyl pocket. In the phase III ASCEMBL trial in patients with CML-CP treated with ≥2 prior TKIs, asciminib resulted in improved MMR (25.5% vs 13.2%) at week 24 and fewer treatment discontinuations due to AEs (5.8% vs 21.1%) vs bosutinib. We present a phase III trial evaluating asciminib vs an investigator-selected approved TKI in 1L CML-CP. As of March 28, 2022, 69 patients were randomized and receiving treatment. To assess the efficacy of asciminib vs investigator-selected TKI and asciminib vs imatinib within the stratum of patients who selected imatinib as the prerandomization TKI, via the primary endpoint of MMR at week 48. The study will be positive if either of these objectives is met. This is a multicenter, open-label, randomized, phase III study (NCT04971226). Newly diagnosed adults with CML-CP who have not received prior TKI therapy for CML, except for ≤2 weeks of imatinib, bosutinib, dasatinib, or nilotinib therapy, are eligible. Prior to randomization, patients and investigators will select a prerandomization TKI; 50% of patients who select imatinib and 50% who select a 2G TKI as their prerandomization TKI will be randomized to the investigator-selected TKI arm; the remaining 50% from each group will be randomized to receive asciminib. End of Study (EOS) is 5 years from the last patient first treatment. Asciminib 80mg once daily (QD), or an investigator-selected TKI (imatinib, bosutinib, dasatinib, or nilotinib at their approved doses) until EOS or premature discontinuation. MMR at week 48 is the primary endpoint, with MMR at week 96, safety, and deep molecular responses as secondary endpoints.

CML-231 Long-Term Results of Tyrosine Kinase Inhibitors Discontinuation in Patients With Chronic Myeloid Leukemia

Evaluation of long-term follow-up results of treatment-free remission (TFR) in chronic myeloid leukemia (CML) patients is relevant for the introduction of this approach into routine clinical practice. To analyze the outcomes in a long-term follow-up of a Russian cohort of CML patients who discontinued tyrosine kinase inhibitors (TKI) therapy. TKI treatment was discontinued in 185 CML patients with deep molecular response (DMR, at least MR4, BCR::ABL1≤0.01% IS, duration ≥1 year), including 113 patients in the prospective RU-SKI trial and 72 patients in the retrospective group out of the trial. Molecular relapse and TKIs restart was in the case of major MR (MMR, BCR::ABL1>0.1%) loss. In pregnant patients, TKIs were restarted in case of MR2 (BCR::ABL1>1%) loss. Baseline Characteristics: Male 39%, the median age was 43 (21-86) years. Imatinib and second-generation TKIs (2G TKIs) were in 124(67%) and 61(63%) patients accordingly. The median duration of TKI therapy was 83 (6-218) months. The second discontinuation was in 8 patients. Median time of follow-up without therapy was 6 years. Therapy was resumed in 96 (52%) patients with MMR loss and in 6 (3.2%) patients without MMR loss (DMR loss, withdrawal syndrome). Seven (3.8%) patients have died (not related to CML). In total, 80 (43%) patients remained in TFR. Survival without therapy at 2 and 5 years after TKI discontinuation was 48% (CI 41-55%) and 42% (CI 34-49%) respectively. In patients with first and second discontinuation survival without therapy was 43% versus 12.5% (p=0.036). The cumulative incidence of MMR loss 5 years after TKI discontinuation was 53% (95% CI 47-59%). Loss of MMR between 1 and 3 years after TKI stop was in 9 patients, between 3 and 5 years - in 6 patients. There was no MMR loss after 57 months of follow-up. After 5 years of follow-up BCR::ABL1 level fluctuations 0.01-0.1% were in 4 (5%) patients. The probability of MMR loss after 5 years of follow-up was 53%. Molecular relapses were rare after 2 years without TKI therapy. However, molecular monitoring with a frequency of 2-3 times a year during long-term observation in TFR is mandatory for patients' safety, especially in those with detectable MRD.

Trial in Progress: A Multicenter, Open Label, Randomized, Phase III Study of Asciminib (80 mg Once Daily) Vs Investigator-Selected TKI in Newly Diagnosed Adult Patients with Chronic Myeloid Leukemia in Chronic Phase

BACKGROUND: Patients (pts) with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP) may be treated with 1 of the 4 tyrosine kinase inhibitors (TKIs) approved for first-line (1L) use: the first-generation TKI imatinib and the second-generation (2G) TKIs bosutinib, dasatinib, and nilotinib. Deep molecular responses (DMRs) are important criteria for attempting treatment-free remission, an important goal for pts in 1L. However, in 1L, only about 30% of pts treated with imatinib and 30%-55% of pts treated with a 2G TKI achieve MR 4.5 (BCR-ABL1levels on the International Scale≤0.0032%). More than 50% of pts with CML-CP treated with imatinib develop resistance or intolerance to therapy. Among pts treated with a 2G TKI in 1L, 30%-40% need to change therapy by 5 years. Therefore, new treatment options are needed to help pts achieve their treatment goals in 1L.The main treatment goal for all pts is achievement of disease control, which potentially requires lifelong treatment. Therefore, highly potent, safe treatment options are needed for newly diagnosed pts with CML-CP. Asciminib is an investigational drug that inhibits the BCR-ABL1 oncoprotein through a novel mechanism of action: specifically targeting the ABL myristoyl pocket (STAMP). Due to asciminib's specifically targeting the ABL kinase family (ABL1, ABL2, BCR-ABL1), asciminib monotherapy offers the potential to improve safety and tolerability vs TKIs that target the adenosine triphosphate binding site of BCR-ABL1 and thus have varying degrees of selectivity toward ABL kinases. Asciminib has shown promising efficacy and safety in heavily pretreated adult pts with CML in phase I and III trials. In a phase III trial for pts with CML-CP treated with ≥2 prior TKIs, major molecular response (MMR) was achieved by 25.5% of pts on asciminib (40 mg twice daily [BID]) vs 13.2% on bosutinib at week 24. In the phase I trial of asciminib monotherapy at doses of 10-200 mg BID and 80-200 mg once daily (QD), 48% of pts with CML-CP treated with ≥2 prior TKIs without T315I mutations achieved or maintained MMR by 12 months. Here we present the upcoming phase III trial evaluating asciminib 80 mg QD monotherapy vs an investigator-selected approved TKI in newly diagnosed adult pts with CML-CP.OBJECTIVE: The primary objectives of this study are to assess the efficacy of asciminib vs an investigator-selected TKI (either imatinib, bosutinib, dasatinib, or nilotinib) in 1L and to compare the efficacy of asciminib within the stratum receiving investigator-selected imatinib in 1L through the primary end point of MMR rates at week 48. DMRs and; other long-term outcomes are also of interest.DESIGN: This is a multicenter, open-label, randomized, phase III study of asciminib at 80 mg QD compared with an approved, investigator-selected TKI (either imatinib, bosutinib, dasatinib, or nilotinib) for adult pts with newly diagnosed CML-CP in 1L (expected N=402; NCT04971226). Pts may not have received prior TKI therapy for CML, with the exception of ≤2 weeks of imatinib therapy and must have Eastern Cooperative Oncology Group performance status (ECOG PS) scores of 0 or 1. Pts who have previously received hydroxyurea or anagrelide may be included. Pts will be randomized 1:1 to the asciminib and investigator-selected TKI arms using 2 strata: European Treatment and Outcome Study (EUTOS) long-term survival (ELTS) risk score and the control arm TKI selected by the investigator prior to randomization (Figure 1). Pts randomized to the investigator-selected TKI arm will receive their selected TKIs at approved doses: imatinib, 400 mg QD; bosutinib, 400 mg QD; dasatinib, 100 mg QD; or nilotinib, 300 mg BID.Pts will remain on study for 5 years after the last pt first treatment has occurred, unless they have discontinued early due to treatment failure, disease progression, intolerance, or investigator or pt decision. Pts who discontinue early will continue to be followed up for survival and disease progression until the end of the study.MAIN OUTCOMES: The primary end point is MMR at week 48. Key secondary end points include MMR at week 96; exploratory end points include biomarker assessments.CONCLUSIONS: This study will assess the efficacy of asciminib 80 mg QD in adult pts with newly diagnosed CML-CP vs currently approved TKIs in 1L.This study is sponsored by Novartis. [Display omitted] DisclosuresCortes: Bristol Myers Squibb, Daiichi Sankyo, Jazz Pharmaceuticals, Astellas, Novartis, Pfizer, Takeda, BioPath Holdings, Incyte: Consultancy, Research Funding; Sun Pharma: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Bio-Path Holdings, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Hochhaus: Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Research Funding; Pfizer: Research Funding; Incyte: Research Funding. Takahashi: Kyowahakko-Kirin: Research Funding; Ono: Research Funding; Asahikasei: Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Eizai: Research Funding; Toyamakagaku: Research Funding; Chugai: Research Funding; Otsuka Pharmaceutical: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Larson: CVS/Caremark: Consultancy; Gilead: Research Funding; Astellas: Consultancy, Research Funding; Rafael Pharmaceuticals: Research Funding; Epizyme: Consultancy; Takeda: Research Funding; Novartis: Research Funding; Cellectis: Research Funding. Issa: Syndax Pharmaceuticals: Research Funding; Kura Oncology: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Bombaci: CML Advocates Network: Consultancy, Current Employment, Membership on an entity's Board of Directors or advisory committees, Other: Organizational Grant Funding; MPN Advocates Network: Membership on an entity's Board of Directors or advisory committees, Other: Organizational Grant Funding; AIL - Associazione Italiana contro le Leucemie, i Linfomi e il Mieloma ONLUS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Organizational Grant Funding; CLL Advocate Network: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Organizational Grant Funding; Novartis: Consultancy, Other: Organizational Grant Funding; Jazz: Consultancy, Other: Organizational Grant Funding; Ceogene: Consultancy, Other: Organizational Grant Funding; Incyte: Consultancy, Other: Organizational Grant Funding; Takeda: Consultancy, Other: Organizational Grant Funding. Ramscar: Novartis: Current Employment. Kapoor: Novartis: Current Employment, Current equity holder in publicly-traded company. Ifrah: Novartis: Current Employment. Hughes: Novartis: Honoraria, Research Funding; BMS: Research Funding; Takeda: Honoraria.

Analysis of Early Events during the First Year of Tyrosine Kinase Inhibitor Therapy in Patients with Chronic Phase - Chronic Myeloid Leukemia: A “Campus CML” Study

Background Tyrosine kinase inhibitors (TKIs) revolutionized treatment of chronic myeloid leukemia (CML). However, the first months of therapy are crucial, as optimal response is defined as the achievement of molecular milestones at 3, 6 and 12 months (mo.) and as many toxicities, also causing a TKI switch, are more frequent in the 1st year.Methods To evaluate achievement of early molecular response (MR) and incidence of events leading to a TKI change during the 1st year of therapy, we retrospectively studied 1650 CP-CML patients diagnosed from 2012 and 2019 at 31 Hematology Centres and treated with frontline imatinib (IM) or second-generation (2G) TKIs dasatinib or nilotinib. Optimal MR at 3, 6 and 12 mo. were assessed according to 2020 ELN recommendations.Results Frontline TKI was IM in 926 (56.1%) and 2G-TKIs in 724 (43.9%) cases: the main clinical features at diagnosis of the entire cohort and according to frontline treatment is reported in the Table 1. Commonest comorbidities were arterial hypertension (38.7%), previous neoplasm (13.6%), diabetes (11.3%), peripheral vascular diseases (7.8%), COPD (7.5%) and ischemic heart disease (6.8%). IM-treated patients were older (p<0.001), with higher ELTS score (int/high 47.6% vs 35.6%, p<0.001) and more comorbidities (p<0.005 for all diseases).Optimal MR was achieved at 3 mo. by 1186/1430 (82.9%), at 6 mo. by 1025/1352 (75.8%) and at 12 mo. by 826/1264 patients (65.3%), respectively.Total number of patients discontinuing TKI in the 1st year was 321/1650 (19.4%), being higher with IM (237/926, 25.5%) than 2G-TKIs (84/724, 11.6%) (p<0.001). Main causes were primary resistance (8.7%, 12.3% IM vs 4.2% 2G-TKIs, p<0.001), extra-hematologic toxicity (6.4%, 8.2% IM vs 4.2% 2G-TKIs, p>0.001), hematologic toxicity (1.7%, 2.0% IM vs 1.4% 2G-TKIs, p=0.25) and progression (1.0%, 1.2% IM vs 0.8% 2G-TKIs, p=0.56). Cumulative incidence of discontinuation at 3, 6 and 12 mo. were 5.6%, 10.7% and 19.3%, respectively; values for IM and 2G-TKIs at the three timepoints were 8.1%, 15.0%, 25.5% and 2.5%, 5.3%, 11.5% (p<0.001) (Fig. 1).Conclusions This real-world study on over 1600 CML patients shows that almost 20% discontinue frontline TKI during the 1st year, mostly for primary resistance or toxicity. Discontinuation rates are higher with IM compared to 2G-TKIs, mostly at 3 mo. and are probably due to a lower attainment of early MR. The impact of older age, higher risks and heavier burden of comorbidities in IM patients should be considered and need deeper investigation. [Display omitted] DisclosuresElena: GILEAD: Membership on an entity's Board of Directors or advisory committees; NOVARTIS: Membership on an entity's Board of Directors or advisory committees; PFIZER: Membership on an entity's Board of Directors or advisory committees; CELGENE: Other: funding for meeting participation. Sportoletti: AstraZeneca: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Stagno: InCyte: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Other: Support for attending meetings and/or travel; Novartis: Consultancy, Honoraria, Other: Support for attending meetings and/or travel, Research Funding. Iurlo: Pfizer: Speakers Bureau; Incyte: Speakers Bureau; Novartis: Speakers Bureau; Bristol Myers Squibb: Speakers Bureau. Bonifacio: Novartis: Honoraria; Pfizer: Honoraria; Amgen: Honoraria; Bristol Myers Squibb: Honoraria. Breccia: Pfizer: Honoraria; Incyte: Honoraria; Abbvie: Honoraria; Bristol Myers Squibb/Celgene: Honoraria; Novartis: Honoraria. Latagliata: Novartis: Honoraria; Pfizer: Honoraria; BMS Cellgene: Honoraria.

Will the clinical development of 4th-generation “double mutant active” ALK TKIs (TPX-0131 and NVL-655) change the future treatment paradigm of ALK+ NSCLC?

Our current treatment paradigm of advanced anaplastic lymphoma kinase fusion (ALK+) non-small cell lung cancer (NSCLC) classifies the six currently approved ALK tyrosine kinase inhibitors (TKIs) into three generations. The 2nd-generation (2G) and 3rd-generation (3G) ALK TKIs are all “single mutant active” with varying potencies across a wide spectrum of acquired single ALK resistance mutations. There is a vigorous debate among clinicians which is the best upfront ALK TKI is for the first-line (1L) treatment of ALK+ NSCLC and the subsequent sequencing strategies whether it should be based on the presence of specific on-target ALK resistance mutations or not. Regardless, sequential use of “single mutant active” ALK TKIs will eventually lead to double ALK resistance mutations in cis. This has led to the creation of fourth generation (4G) “double mutant active” ALK TKIs such as TPX-0131 and NVL-655. We discuss the critical properties 4G ALK TKIs must possess to be clinically successful. We proposed conceptual first-line, second-line, and molecularly-based third-line registrational randomized clinical trials designed for these 4G ALK TKIs. How these 4G ALK TKIs would be used in the future will depend on which line of treatment the clinical trial design(s) is adopted provided the trial is positive. If approved, 4G ALK TKIs may usher in a new treatment paradigm for advanced ALK+ NSCLC that is based on classifying ALK TKIs based on the intrinsic functional capabilities (“singe mutant active” versus “double mutant active”) rather than the loosely-defined “generational” (first-, second-,third-,fourth-) classification and avoid the current clinical approaches of seemingly random sequential use of 2G and 3G ALK TKIs.

Cytogenetic and Molecular Responses after 2 Years of Tyrosine Kinase Inhibitor (TKI) Treatment in Simplicity, an Observational Study of Chronic-Phase Chronic Myeloid Leukemia (CP-CML) Patients (Pts) in Routine Clinical Practice

Introduction: Data on clinical response and factors associated with response in CP-CML outside clinical trials are limited.SIMPLICITY (NCT01244750) is an ongoing observational study of CP-CML pts in routine clinical practice receiving first-line (1L) imatinib (IM), dasatinib (DAS) or nilotinib (NIL) in the US and Europe. This analysis aims to describe the factors associated with achievement of complete CyR (CCyR) and major MR (MMR).Methods: Clinical response after start of 1L TKI was assessed by CyR (karyotype or FISH) and MR (only tests by PCR on the international scale were included) as determined by the treating physician. Proportions of patients achieving CCyR and MMR between 30 days and either 12 or 24 months (mos) are presented; data at specified time points will be provided at presentation. Logistic regression models were used to identify factors associated with CCyR and MMR by 12 and 24 mos after 1L TKI initiation.Results: By March 03 2017, 1242 pts were enrolled prospectively in SIMPLICITY, receiving IM (n=416), DAS (n=418) or NIL (n=408); 55% were male. The median (interquartile range; min-max) age of pts at initiation of 1L TKI was 57 (46-68; 18-91) years; 35% of pts were treated in Europe, 65% in the US; 53% at academic centers and 47% at community practices.Numbers of pts followed by 3, 6, 12 and 24 months were 1233, 1224, 1195 and 1121, respectively. Of pts followed 12% (n=151), 31% (n=384), 44% (n=522) and 51% (n=567) had documented CyR testing by 3, 6, 12 and 24 mos; 23% (n=285), 55% (n=672), 72% (n=857) and 84% (n=937) of pts had documented MR testing by 3, 6, 12 and 24 mos; and 7% (n=82), 19% (n=231), 32% (n=379) and 42% (n=475) of pts had documented testing by both CyR and MR by 3, 6, 12 and 24 mos.Proportions of pts remaining on their 1L TKI declined with duration of follow-up. Of pts with documented CyR testing, 93% (n=141), 93% (n=356), 89% (n=464) and 85% (n=484) had remained on their 1L TKI by 3, 6, 12 and 24 mos, respectively. Of pts with documented MR testing, 93% (n=266), 91% (n=610), 85% (n=728) and 78% (n=730) had remained on their 1L TKI by 3, 6, 12 and 24 mos, respectively.In this non-controlled study, proportions of pts achieving CCyR were similar for pts tested by 12 and by 24 mos. For both periods, the proportion of pts achieving CCyR was highest for pts on 1L DAS, lower for 1L NIL, and lowest for 1L IM. Proportions of pts achieving MMR were higher for pts tested by 24 mos than by 12 mos. For both periods, the proportion of pts achieving MMR was highest for pts on 1L NIL, lower for 1L DAS, and lowest for 1L IM. Proportions were lower when calculated among pts followed through the period but not necessarily tested (intention-to-treat).Multivariate logistic regression analysis identified factors associated with MMR or CCyR by 12 and 24 mos after 1L TKI initiation. Receiving a second-generation (2G) TKI (i.e. DAS or NIL) as 1L therapy was associated with CCyR by 12 mos (odds ratio [OR]=2.6; p<0.001) and by 24 mos (OR=1.8; p=0.024), but not with MMR in either timeframe. BCR-ABL<10% by 3 mos was associated with MMR by 12 mos (OR=3.2, p<0.001) and by 24 mos (OR=2.4, p=0.002). Compared with switching in 3-12 mos, switching to a second-line (2L) TKI in 30 days-3 mos was associated with CCyR (OR=6.2; p=0.004) and MMR (OR=3.3; p=0.001) by 12 mos. Also, compared with switching in 3-12 mos, not switching within 12 mos was associated with CCyR (OR=4.5; p<0.001) and MMR (OR=2.2; p<0.001) by 12 mos. Compared with switching in 6-24 mos, switching to a 2L TKI in 30 days-6 mos was associated with MMR (OR=2.1; p=0.012) by 24 mos. Compared with switching in 6-24 mos, not switching within 24 mos was associated with MMR (OR=3.1, P<0.001) or CCyR (OR=4.4, P<0.001) by 24 mos.Conclusions: Response monitoring observed in clinical practice is not aligned with ELN/NCCN guidelines, so outcomes for the full SIMPLICITY cohort may differ from presented data on monitored patients. The lack of correlation between a 2G TKI as 1L therapy and achievement of MMR is unexpected, but may result from switches to 2L TKI in IM suboptimal responders or from differences in testing patterns in the individual cohorts; the uncontrolled nature of this study may have also contributed. Early switching of TKI treatment (previously found to be driven by toxicity, not response, and often from IM to 2G TKI) was associated with achieving MMR or CCyR by 12 mos. Not switching TKI, potentially a marker of better tolerance and adherence, was associated with achieving MMR or CCyR by 12 mos and 24 mos. [Display omitted] DisclosuresCortes:Teva: Research Funding; ARIAD: Consultancy, Research Funding; Sun Pharma: Research Funding; ImmunoGen: Consultancy, Research Funding; Novartis Pharmaceuticals Corporation: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Goldberg:Bristol Myers Squibb: Research Funding, Speakers Bureau; Pfizer: Honoraria; Novartis: Honoraria, Research Funding, Speakers Bureau; Jazz: Speakers Bureau; Ariad: Speakers Bureau; Celgene: Speakers Bureau; COTA: Employment, Equity Ownership. Hehlmann:Novartis: Research Funding; BMS: Consultancy. Mauro:Bristol-Myers Squibb: Consultancy. Zyczynski:Bristol-Myers Squibb: Employment. Sen:ICON Clinical Research: Employment. Foreman:ICON Clinical Research: Employment. Gajavelli:Bristol-Myers Squibb: Employment. Gambacorti-Passerini:BMS: Consultancy; Pfizer: Consultancy, Honoraria, Research Funding.

Effectiveness of Second-Line (2L) Tyrosine Kinase Inhibitor (TKI) Therapy after Resistance or Intolerance to a Prior TKI in Patients with Philadelphia Chromosome-Positive Chronic Myeloid Leukemia in Chronic Phase (Ph+ CML-CP)

Introduction: Second-generation (2G) TKIs have shown better efficacy than first-generation (1G) TKI in patients (pts) with Ph+ CML-CP. However, real-world evidence for 2G TKIs as 2L therapy following resistance or intolerance to prior therapy is limited. BCR-ABL1 mutations have different sensitivities to TKIs, highlighting the need to consider the mutational status of pts when selecting the next best TKI in pts who are resistant to prior CML therapy. This study reports real-world treatment effectiveness of 2G TKIs as 2L therapy in the US among pts with Ph+ CML-CP following resistance, intolerance, or other reasons for termination of 1L TKI. Methods: From 6/21/2019-8/30/2019, data were retrospectively collected from pt clinical charts via an online case report form completed by US oncologists/hematologists from an existing panel of physicians. Eligible charts were those of adult pts diagnosed with Ph+ CML-CP who were initiated on a 2G TKI (dasatinib, nilotinib, or bosutinib) as 2L therapy between 01/2013-06/2017 outside of a clinical trial. Molecular response (MR; MR2 = BCR-ABL ≤ 1%/2-log reduction, MMR/MR3 = BCR-ABL ≤ 0.1%/3-log reduction, MR4 = BCR-ABL ≤ 0.01%/4-log reduction) achieved during the course of 2L therapy was assessed using Kaplan-Meier (KM) analyses and reported for the overall cohort and for the following subgroups: (1) 1G TKI as 1L therapy, (2) 2G TKI as 1L therapy, (3) treatment with a 2L TKI that is not recommended based on the mutation profile (per National Comprehensive Cancer Network [NCCN] practice guidelines), (4) 1L TKI termination due to intolerance/management of adverse events (AEs), and (5) 1L TKI termination due to resistance/lack of efficacy. Results: A total of 111 physicians (academic-based practices: 45%; community: 55%) abstracted data for 539 pts. Approximately half of physicians had access to qPCR test with a sensitivity of detection of at least MR4.5 (53%); 27% had access to a level of detection of MR4 and 20% of MR3. For the overall cohort, the mean age was 56 years and 56% were male. At the time of diagnosis, 60% of pts had an intermediate and 10% had a high Sokal risk score. A total of 61% of pts were treated with 1G TKI and 39% were treated with 2G TKI in 1L therapy; pts treated with dasatinib in 1L were observed to be older with a higher comorbidity burden than those using 1G TKI. The most common reasons for terminating 1L TKI therapy were lack of efficacy (46%), resistance (28%), intolerance/management of AEs (22%), and pt preference (15%; not mutually exclusive). At 2L TKI therapy initiation, 15% of pts did not undergo a mutation test, 34% had no mutations, and the most prevalent BCR-ABL1 mutation was T315I (16%); 26% received a TKI as 2L therapy that was not recommended based on their mutation profile. In 2L TKI therapy, 41% of pts received nilotinib, 19% dasatinib, and 40% bosutinib; median 2L TKI duration was 37 months. KM response rates on 2L TKI for MR2 at 12 months, MR3 at 12 months and MR4 at 24 months (time points influencing treatment decision in clinical practice based on NCCN and European LeukemiaNet [ELN] guideline recommendations) were 71%, 55%, and 46%, respectively. The lowest MR rates at these key time points were observed in the subgroup of pts for whom the TKI is not recommended based on the mutation profile (rates of MR2 at 12 months of 59%, MR3 at 12 months of 40%, and MR4 at 24 months of 22%) and those with 1L TKI termination due to resistance/lack of efficacy (rate of MR4 at 24 months of 43%; stratifications by subgroup are shown in Figures 1A-C). Conclusions: This study highlights the treatment challenges for 2L TKI therapy in Ph+ CML-CP and provides insights into the opportunities to refine 2L treatment options to improve outcomes for many pts. Although 2G TKIs have higher efficacy and lower progression rates in 1L vs 1G TKI, a substantial proportion of pts still do not achieve the important treatment response milestones; almost 50% did not achieve MMR within 12 months of 2L TKI therapy. This study also suggests that TKI switching from 1L to 2L uninformed by mutational testing adversely impacts treatment response. There appears to be a need for more effective communication to highlight the relevance and timing of mutation testing, access to adequate sensitive tools mandated by practice guidelines (e.g., NCCN, ELN) to monitor MR, and new effective treatment options for pts with CML-CP resistant or intolerant to prior therapy, particularly among pts presenting with mutations. Disclosures Mukherjee: EUSA Pharma: Consultancy; Aplastic Anemia and MDS International Foundation: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Bristol Myers Squib: Honoraria; Celgene/Acceleron: Membership on an entity's Board of Directors or advisory committees; Partnership for Health Analytic Research, LLC (PHAR, LLC): Honoraria; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Cao:Novartis: Current Employment, Current equity holder in publicly-traded company. Sadek:Novartis: Current Employment, Current equity holder in publicly-traded company. Maegawa:Novartis Pharmaceutical Corporation: Current Employment, Current equity holder in publicly-traded company. Latremouille-Viau:Novartis Pharmaceutical Corporation: Consultancy, Other: Dominique Latremouille-Viau is an employee of Analysis Group, Inc. which received consultancy fees from Novartis.; Sanofi Genzyme: Consultancy, Other: Dominique Latremouille-Viau is an employee of Analysis Group, Inc. which received consultancy fees from Sanofi Genzyme.. Pivneva:Novartis: Consultancy, Other: Irina Pivneva is an employee of Analysis Group, Inc which received consultancy fees from Novartis.. Guérin:Novartis: Consultancy, Other: Annie Guérin is an employee of Analysis Group, Inc which received consultancy fees from Novartis.. Smith:Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Efficacy and Safety of Ponatinib (PON) in Patients with Chronic-Phase Chronic Myeloid Leukemia (CP-CML) Who Failed One or More Second-Generation (2G) Tyrosine Kinase Inhibitors (TKIs): Analyses Based on PACE and Optic

Introduction: The use of 2G TKIs in patients with CP-CML who have failed ≥1 2G TKIs is not associated with durable responses; there is limited clinical evidence to support that switching to alternate 2G TKI therapy improves long-term clinical outcomes for these patients. Patients with resistant and intolerant CP-CML with substantial prior 2G treatment demonstrated deep, lasting responses to PON in the pivotal PACE trial. A post hoc modeling analysis of the data from PACE suggested a relationship between dose and safety events (including arterial occlusive events [AOEs]). The OPTIC trial was designed to prospectively evaluate response-based PON dosing regimens with the aim of optimizing its efficacy and safety in patients with CP-CML; the interim analysis (IA) demonstrated clinically manageable safety and AOE profiles with response-based PON dosing regimens. The combined PACE and OPTIC trials comprise the largest patient population in a post-2G TKI setting. We present the efficacy and safety outcomes of these patients over time. Methods: PACE (NCT01207440) evaluated PON in patients with refractory CML or Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). OPTIC (NCT02467270) is a multicenter, randomized Phase 2 trial characterizing the safety and efficacy of PON over a range of 3 starting doses (45, 30, or 15 mg/day); patients with CP-CML receiving 45 or 30 mg/day reduced their doses to 15 mg/day upon achieving ≤1% BCR-ABL1IS. Data from patients with CP-CML in PACE (n=254) and the 45-mg starting dose cohort (45 mg→15 mg) in OPTIC (n=92) who have been treated with ≥1 2G TKI are presented; OPTIC data are from the IA. Efficacy data includes molecular responses (measured using polymerase chain reaction and performed at the same central lab for both studies) and survival outcomes over time. Safety data, including treatment-emergent AOE rates following adjudication, are also presented. Results: A combined 350 PON-treated patients from the PACE and OPTIC trials who have received ≥1 prior 2G TKI were analyzed; efficacy results are summarized in Table 1. The ≤1% BCR-ABL1IS response rates increased over time and ranged from 42% to 52% in the OPTIC IA 45-mg starting dose cohort and in PACE. Progression-free survival and overall survival were 52% and 73%, respectively, in PACE (up to 5 years) and 81% and 93%, respectively, at the OPTIC IA (up to 2 years) (Table 1). Serious treatment-emergent adverse event (AE) and AOE rates (including exposure-adjusted AOE rates) were lower in OPTIC IA with a response-adjusted dosing regimen compared with PACE (Table 2). Propensity score analyses comparing AOE incidence among all patients in OPTIC vs PACE demonstrate that the relative risk for adjudicated AOEs is 64% lower in OPTIC when compared with PACE after adjusting for baseline differences, duration of exposure, and total PON dose received. Analyses on responses by mutation status also will be presented. Conclusions: In this analysis, comprising the largest patient population of CP-CML patients in a post-2G TKI setting, ponatinib shows high response rates and robust survival outcomes in patients who have failed 2G TKIs. With the response-adjusted dosing regimen in OPTIC (starting at 45 mg and reducing to 15 mg upon response), efficacy outcomes were consistent with that of PACE, while the overall incidences of AOEs and serious treatment emergent-AEs were lower; exposure-adjusted AOEs during the first 2 years were also lower. The ongoing OPTIC study is also evaluating lower starting doses of ponatinib (30 and 15 mg) and primary analysis of this study will provide a refined understanding of the benefit:risk profile of the 3 starting doses of ponatinib in CP-CML patients. Disclosures Kantarjian: Adaptive biotechnologies: Honoraria; Ascentage: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; Pfizer: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Sanofi: Research Funding; Immunogen: Research Funding; BMS: Research Funding; Daiichi-Sankyo: Honoraria, Research Funding; Aptitute Health: Honoraria; BioAscend: Honoraria; Delta Fly: Honoraria; Amgen: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Oxford Biomedical: Honoraria; Jazz: Research Funding. Deininger:Fusion Pharma: Consultancy; Blueprint Medicines Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: part of a study management committee, Research Funding; SPARC: Research Funding; DisperSol: Consultancy; Leukemia &amp; Lymphoma Society: Research Funding; Novartis: Consultancy, Other, Research Funding; Medscape: Consultancy; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Other, Research Funding; Galena: Consultancy, Honoraria, Other; Pfizer: Honoraria, Other, Research Funding; Ariad: Consultancy, Honoraria, Other; Celgene: Research Funding; Gilead Sciences: Research Funding; Sangamo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Honoraria, Other, Research Funding. Abruzzese:Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bms: Honoraria. Apperley:Pfizer: Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Incyte: Honoraria, Research Funding, Speakers Bureau; Bristol Myers Squibb: Honoraria, Speakers Bureau. Cortes:Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Sun Pharma: Research Funding; BiolineRx: Consultancy, Research Funding; Amphivena Therapeutics: Research Funding; Telios: Research Funding; BioPath Holdings: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Research Funding; Astellas: Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Merus: Research Funding; Immunogen: Research Funding; Arog: Research Funding. Chuah:Pfizer: Other: Travel, Research Funding; Korea Otsuka Pharmaceutical: Honoraria; Bristol-Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria. DeAngelo:Jazz: Consultancy; Autolos: Consultancy; Novartis: Consultancy, Research Funding; Abbvie: Research Funding; Forty-Seven: Consultancy; Amgen: Consultancy; Agios: Consultancy; Blueprint Medicines Corporation: Consultancy, Research Funding; Takeda: Consultancy; Glycomimetics: Research Funding; Pfizer: Consultancy; Shire: Consultancy; Incyte Corporation: Consultancy. DiPersio:Magenta Therapeutics: Membership on an entity's Board of Directors or advisory committees. Hochhaus:Bristol-Myers Squibb: Honoraria, Research Funding; Incyte: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Takeda: Honoraria; MSD: Research Funding. Lipton:Takeda: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Bristol-Myers Squibb: Honoraria; BMS: Consultancy, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding. Nicolini:Sun Pharma Ltd: Consultancy; Incyte: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau. Pinilla Ibarz:Takeda: Consultancy, Speakers Bureau; Sanofi: Consultancy; TG Therapeutics: Consultancy; Sunesis Pharmaceuticals: Consultancy; Abbvie: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Novartis: Consultancy; Pharmacyclics: Consultancy, Speakers Bureau; AstraZeneca: Consultancy, Speakers Bureau. Rea:BMS: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees. Rosti:Pfizer: Research Funding, Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; Incyte: Speakers Bureau; Novartis: Speakers Bureau. Rousselot:Pfizer: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Takeda: Consultancy; Bristol-Myers Squibb: Consultancy; Novartis: Consultancy. Shah:Bristol-Myers Squibb: Research Funding. Talpaz:IMAGO: Consultancy; BMS: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Novartis: Research Funding; Constellation Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Srivastava:Takeda: Current Employment. Lu:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Current Employment. Mauro:Bristol-Myers Squibb: Consultancy, Honoraria, Other: Travel, Accommodation, Expenses, Research Funding; Pfizer: Consultancy, Honoraria, Other: Travel, Accommodation, Expenses, Research Funding; Sun Pharma/SPARC: Research Funding; Takeda: Consultancy, Honoraria, Other: Travel, Accommodation, Expenses, Research Funding; Novartis: Consultancy, Honoraria, Other: Travel, Accommodation, Expenses, Research Funding.

Determinants of Choice of Front-Line Tyrosine Kinase Inhibitor for Chronic Phase CML: A Study from the “Registro Italiano LMC & Campus CML”

Introduction : therapy of chronic phase (CP) chronic myeloid leukemia (CML) is based on tyrosine kinase inhibitors (TKIs) in virtually all patients. Three TKIs are approved for first-line therapy in Italy: imatinib and two second-generation (2G) TKIs, dasatinib and nilotinib. Choice of the front-line TKI is based on a combined evaluation of patient's and disease characteristics, age, risk, comorbidities and concomitant medications. Treating physician's preference and, in some cases, economic considerations, particularly after the advent of generic imatinib, may play a role in TKI selection. However, to date, few data are available on TKI use in a whole nation and on the possible drivers of treatment choice. Aim of the present work was to analyse the use of front-line TKI therapy in a large, unselected cohort of Italian CP-CML patients, correlating patient's features to drug choice. Methods: in the framework of the national Campus CML program, we retrospectively evaluated 1422 patients with CP-CML diagnosed from 2012 and 2019 in 21 haematologic Centres, mostly in academic and/or tertiary hospitals, widespread through the entire Italian territory and treated frontline with imatinib, dasatinib or nilotinib. Results: median age at diagnosis was 59.9 years [interquartile range (IQR) 47.1 - 71.7], with 317 (22.3%) patients under 45 years, 552 (38.8%) between 45 and 65 years and 553 (38.9%) older than 65 years; 821 (57.7%) patients were males. Among 1364 evaluable patients, CML risk according to Sokal score was low in 540 (39.6%), intermediate in 610 (44.7%) and high in 214 (15.7%) patients respectively; the number at low, intermediate or high risk according to the novel ELTS score among 1325 evaluable patients was 759 (57.3%), 402 (30.3%) and 164 (12.4%) respectively. Considering comorbidities, 1003 (70.6%) patients had at least one active disease at the time of CML diagnosis, the most common being hypertension (n=547, 38.5%), previous neoplasms (n=185, 13.0%), diabetes (n=150, 10.6%), chronic bronchopulmonary diseases (n=114, 8.0%), acute myocardial infarction (n=95, 6.7%), previous stroke (n=36, 2.5%) and other vascular diseases (n=98, 6.9%). Among 1335 evaluable patients, 813 (60.9%) were taking at least one concomitant medication, with 280 (21.0%) taking 3-5 drugs and 140 (10.5%) taking 6+ drugs at time of TKI start. As to the frontline therapy, 794 (55.8%) received imatinib and 628 (44.2%) were treated with 2G-TKIs, (226 dasatinib and 402 nilotinib) respectively. According to age, 2G-TKIs were chosen for majority of patients aged &amp;lt;45 (69.1%) while imatinib was used in 76.9% of patients over 65 (p&amp;lt;0.001). There was a predominance of imatinib use across all Sokal (51.1% in low, 61.3% in intermediate and 51.4% in high) and ELTS (50.3% in low, 60.4% in intermediate and 66.5%) risk categories. We observed a prevalent use of 2G-TKIs in patients presenting with higher WBC counts (55.1% if WBC &amp;gt;100,000/mm3 vs 38.2% if WBC &amp;lt;100,000/mm3; p&amp;lt;0.001), lower Hb (53.8% if Hb &amp;lt;10 g/dl vs 41.9 if Hb &amp;gt;10 g/dl; p=0.001) and bigger spleen (65.1% if spleen &amp;gt;5 cm vs 44.8% if spleen 1-5 cm vs 37.3% if spleen not palpable; p&amp;lt;0.001). There was a decreasing use of 2G-TKIs with higher number of concomitant drugs: 64.4% for 0, 47.7% for 1-2, 27.0% for 3-5 and 13.6% for &amp;gt;5 drugs, respectively (p&amp;lt;0.001). Concordantly, there was a significant higher use of imatinib in patients with hypertension (69.8%), diabetes (70.0%), COPD (73.7%), previous neoplasms (73.0%), AMI (86.3%) or stroke (97.2%) history (p&amp;lt;0.001 for all conditions). Lastly, we observed a wider use of imatinib (61.1%) in patients diagnosed in years 2018-19, compared to those of the period 2012-17 (53.7%; p=0.01). In multivariable analysis, factors correlated with imatinib use were age &amp;gt; 45 years, intermediate or high Sokal risk, presence of some comorbidities (2nd neoplasia and stroke) and number of concomitant medications. Conclusions: preliminary results of this observational study on almost 1500 patients show that around 55% of newly diagnosed Italian CP-CML patients receive imatinib as front-line therapy, and that the use of 2G-TKI is prevalent in the younger patients and in those with no concomitant clinical conditions. The counterintuitive finding of imatinib prevalence as frontline treatment in high risk patients might be explained by the older age of these patients. Introduction of the generic formulation in 2018 seems to have fostered the use of imatinib. Figure Disclosures Breccia: Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Abbvie: Consultancy; Bristol-Myers Squibb/Celgene: Consultancy, Honoraria. Cavazzini:Pfize: Honoraria; Incyte: Honoraria; Novartis: Honoraria. Saglio:Bristol-Myers Squibb: Research Funding; Pfizer: Research Funding; Incyte: Research Funding; Novartis: Research Funding; Ariad: Research Funding; Roche: Research Funding.