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79 Early and Deep Molecular Responses Achieved with Frontline Asciminib in Chronic Phase CML – Interim Results from ALLG CML13 Ascend-CMLClinically Relevant Abstract

Program: Oral and Poster Abstracts
Type: Oral
Session: 632. Chronic Myeloid Leukemia: Clinical and Epidemiological: Novel Agents
Hematology Disease Topics & Pathways:
Non-Biological therapies, Therapies
Saturday, December 10, 2022: 9:30 AM

David T Yeung, MBBS, PhD, BSc, FRACP, FRCPA1,2,3, Naranie Shanmuganathan, MBBS, FRACP, FRCPA4,5,6, John Reynolds, PhD7*, Susan Branford, PhD8, Mannu Walia, Msc PhD9*, Agnes S. M. Yong, MD, PhD10, Jake Shortt, FRACP, FRCPA, PhD11,12, Kate Burbury, MBBS, FRACP, FRCPA, DPhil13*, Nicholas Viiala, MBBS FRACP FRCPA14,15*, Ilona Cunningham, MBBS, FRACP, FRCPA16, David M. Ross, MBBS, PhD, FRACP, FRCPA17*, Rosemary Harrup, MBBS FRACP FRCPA18*, Matthew Wright, MBBS, FRCPA, FRACP19*, Cecily Forsyth, MBBS, FRACP, FRCPA20, Alwyn Bernard D'Souza, MBBS, FRACP, FRCPA21*, Robin J Filshie, MBChB, PhD, FRACP, FRCPA22, Peter J. Browett23,24, Steven W Lane, MD, PhD25,26, Carolyn Grove, MBBS, PhD27*, Andrew Grigg, MBBS, MD, FRACP, FRCPA28* and Timothy Hughes, MD, MBBS, FRACP, FRCPA2,3,29

1Precision Cancer Medicine Theme, South Australian Health and Medical Research Institute, Adelaide, SA, Australia
2Department of Haematology, Royal Adelaide Hospital and SA Pathology, Adelaide, SA, Australia
3Adelaide Medical School, The University of Adelaide, Adelaide, Australia
4Department of Haematology, Royal Adelaide Hospital and SA Pathology, Adelaide, Australia
5Department of Genetics and Molecular Pathology, SA Pathology, Adelaide, Australia
6School of Pharmacy and Medical Science, University of South Australia, Adelaide, SA, Australia
7The Alfred Hospital and Monash University, Melbourne, VIC, Australia
8Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, Australia
9Australasian Leukaemia and Lymphoma Group, Richmond, Australia
10Haematology, Royal Perth Hospital and University of Western Australia, Perth, Australia
11Monash Haematology, Monash Health, Clayton, VIC, Australia
12School of Clinical Sciences at Monash Health, Monash University, Melbourne, VIC, Australia
13Peter MacCallum Cancer Centre, Melbourne, Australia
14University of NSW, Sydney, Australia
15Liverpool Hospital, Sydney, Australia
16Haematology Department, Concord Repatriation General Hospital, University of Sydney, Sydney, Australia
17Haematology, Flinders Medical Centre and Flinders University, Bedford Park, SA, Australia
18Royal Hobart Hospital, University of Tasmania, Tasmania, Australia
19Department of Haematology, Fiona Stanley Hospital, Perth, Australia
20Gosford Hospital and Newcastle University, Gosford, NSW, Australia
21Capital Coast Health and Otago University, Wellington, New Zealand
22Department of Hematology, St. Vincent's Hospital Melbourne, Melbourne, VIC, Australia
23Department of Molecular Medicine and Pathology, University of Auckland School of Medicine, Auckland, New Zealand
24Auckland City Hospital, Grafton, New Zealand
25Cancer Care Services, Royal Brisbane and Women's Hospital, Brisbane, Australia
26Cancer Program, Queensland Institute of Medical Research, Brisbane, Australia
27Department of Haematology, Sir Charles Gairdner Hospital & PathWest, Nedlands, Australia
28Department of Clinical Haematology, Austin Health, Heidelberg, VIC, Australia
29South Australian Health and Medical Research Institute SAHMRI, Adelaide, SA, Australia

ATP-competitive BCR::ABL1 inhibitors are effective as frontline treatment for many Chronic Phase (CP) CML patients. However, a significant minority of patients experience treatment failure with currently available drugs, due to resistance or toxicities. Asciminib, a first-in-class drug that inhibits BCR::ABL1 by binding to its myristoyl site, is efficacious in patients who have failed 2 or more lines of treatment (Rea et al, Blood 2021). The Australasian Leukaemia Lymphoma Group (ALLG) CML13 ASCEND-CML trial aims to assess its tolerability and efficacy in the frontline setting.

ALLG CML13 is a prospective open-label phase II study, enrolling 100 patients over 15 Australian and New Zealand sites. Patients commence treatment with asciminib 40mg twice a day (BID), and are assessed thereafter according to optimal 2020 ELN targets (BCR::ABL1 ≤10%, ≤1% & ≤0.1% at 3, 6, 12 months respectively); and ≤0.01% at 18 months. Patients with treatment failure (BCR::ABL1 >10% at 3 or 6 months; BCR::ABL1 >1% at 12 or 18 months) continue asciminib and add either imatinib, dasatinib or nilotinib, according to physician preference. Patients who have not failed, but have not achieved optimal response at 6, 12, or 18 months, have their asciminib dose doubled to 80mg BID. Co-primary end points are achievement of early molecular response (EMR, BCR::ABL1 ≤10% at 3 months) and major molecular response (BCR::ABL1 ≤0.1%) by 12 months. We report a protocol-specified interim analysis of EMR that allows for reporting of repeated confidence intervals. This trial received funding support from Novartis.

By data cut-off at July 15, 2022, the trial remains open to recruitment with 79/100 patients registered, with a median follow-up of 10 (0-19) months. The most commonly reported grade 3/4 adverse events thus far were neutropenia, and thrombocytopenia (n=5 and 4, 5.5% and 5.2%, respectively); as well as increased lipase and amylase without clinical pancreatitis (n=6 & 2; 7.8% & 2.6%, respectively). Grade 3 increased AST/ALT, anaemia, back pain, abdominal pain and infection were each reported once. Nine patients have discontinued asciminib: 1 with persistent grade 4 cytopenia requiring HSCT, 4 with recurrent asymptomatic lipase elevations (including 1 patient who registered but had not started therapy), 1 withdrawn consent and 1 lost to follow-up. Two patients had resistance: 1 had confirmed loss of MMR at 9 months after reaching a nadir of 0.067% at 6 months, without evidence of a kinase domain or myristoyl site mutation; 1 transformed to lymphoid blast crisis at 6 months with myristoyl site mutations A337T (40%), A337V (10%) and P465S (10%), having previously achieved BCR::ABL1 of 0.37% at 3 months.

The molecular analysis for EMR includes all registered patients with at least 3 months of follow-up (n=63); 1 patient missed this assessment, and 3/63 patients had withdrawn by this timepoint (all 4 scored as non-responders). EMR was achieved by 59/63 (93.7%; 99.1% CI 81.1-98.9%). By 3 months, 11 patients have already achieved MR4 or better; 29/63 patients achieved MMR (Fig 1 & 2). Three patients had asciminib dose escalation on protocol: 1 patient with BCR::ABL1 of 1.1% at 6 months, and 2 with BCR::ABL1 of 0.34% and 0.43% at 12 months; subsequent molecular results are pending.

Trial interim analysis suggest asciminib to have favorable tolerability and efficacy as frontline treatment for CP-CML. The EMR rate is particularly encouraging, and is likely to translate to improved long term outcomes, with higher achievement of deep molecular responses and potentially treatment-free survival. Equally encouraging is the safety profile and early discontinuation rate. Cytopenia and lipase elevations were the most common adverse events, and appear to be ABL1 inhibitor class effects, though clinically relevant pancreatitis has not occurred.

Disclosures: Yeung: Amgen: Honoraria; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Research Funding. Shanmuganathan: Amgen: Other: Meeting sponsorship; Novartis: Honoraria. Reynolds: Novartis: Current equity holder in publicly-traded company; Abbvie: Research Funding; Alcon: Current equity holder in publicly-traded company. Branford: Cepheid: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Qiagen: Honoraria; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Yong: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Research Funding; Celgene: Honoraria. Shortt: Ostuka: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Astellas: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Mundipharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astex: Research Funding. Viiala: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Forsyth: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other. Browett: BeiGene: Research Funding; Abbvie: Honoraria; Arrowhead: Honoraria; Roche: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Eysa Pharma: Membership on an entity's Board of Directors or advisory committees; MSD: Honoraria. Grove: Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: chairperson at local Abbvie Education Event for which my institution received hororaria., Speakers Bureau; Australian advisory boards as below: Consultancy; Otsuka: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees. Grigg: Novartis: Membership on an entity's Board of Directors or advisory committees. Hughes: BMS: Consultancy, Research Funding; Enliven: Consultancy, Research Funding; Novartis: Consultancy, Research Funding.

OffLabel Disclosure: Asciminib is only currently registered for CML in the 3rd line setting, and is not licensed for use in newly diagnosed patients.

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