Impact of BCR::ABL1 single nucleotide variants on asciminib efficacy

Abstract

Asciminib is a potent and selective inhibitor of BCR::ABL1, with potential to avoid toxicity resulting from off-target kinase inhibition. Forty-nine patients treated with asciminib under a managed access program in the UK were evaluated for toxicity and response. Intolerance, rather than resistance (65% vs. 35%), was the most common reason for cessation of the last-line of treatment but asciminib was well tolerated, with most patients (29, 59%) remaining on treatment at a median of 14 months follow-up, and only 6 (12%) stopping for intolerance. Of 44 patients assessable for response, 29 (66%) achieved a complete cytogenetic response (CCyR) or better, with poorer responses seen in those stopping their last-line of therapy for resistance. Fewer patients with a prior history of a non-T315I-BCR::ABL1 single nucleotide variant (BSNV), or a non-T315I-BSNV detectable at baseline achieved CCyR. Serial tracking of BSNV by next generation sequencing demonstrated clonal expansion of BSNV-harbouring populations, which in some settings was associated with resistance (E459K, F317L, F359I), while in others was seen in the context of ongoing response, often with intensified dosing (T315I, I502F). These data suggest that asciminib exerts selective pressure on some BSNV-harbouring populations in vivo, some of which may respond to intensified dosing.

Fig. 1. Clinical outcome and toxicity data.

A Treatment status at time of data collection, B best response achieved on asciminib, C haematological toxicity and D non-haematological toxicity. CCyR: complete cytogenetic response (BCR::ABL1 IS level ≤ 1%), MMR, major molecular response (BCR::ABL1 IS level ≤ 0.1%), MR4, BCR::ABL1 IS level ≤ 0.01% IS, MR4.5, BCR::ABL1 IS level ≤ 0.0032% IS, LFT: liver function tests, DR: dose reduction, IS: international scale.

Fig. 2. Impact of BCR::ABL1 single nucleotide variants (BSNVs) detected in baseline samples on response to asciminib treatment.

A impact of detectable T315I-BSNV in baseline sample on best response achieved, B impact of detectable non-T315I-BSNV in baseline sample on best response achieved, C details of BSNV detected in baseline samples with dose, treatment status, and best response information. BSNV, BCR::ABL1 single nucleotide variants, NGS: next generation sequencing, mg: milligrams, CHR: complete haematological response, CCyR: complete cytogenetic response (BCR::ABL1 IS level ≤ 1%), MMR: major molecular response (BCR::ABL1 IS level ≤ 0.1%), BD: bis in die (twice a day).

Fig. 3. Detection of BCR::ABL1 single nucleotide variants (BSNVs) in final (stopping) and most recent (ongoing) samples.

A schematic of stopping samples analysed, B details of BSNV in baseline sample, asciminib dose, treatment status, best response, BSNV detected in the sample at the time of stopping, BSNV denoted in red are new in the stopping samples, those in blue are no longer detectable in the stopping sample, C schematic of ongoing treatment samples analysed, D details of BSNV in baseline sample, asciminib dose, treatment status, best response, BSNV detected in the most recent sample while on treatment, BSNV denoted in orange are new in the treatment samples, those in blue in the baseline sample are no longer detectable in the treatment sample, those in purple have expanded on treatment. BSNV, BCR::ABL1 single nucleotide variant, CHR: complete haematological response, CCyR: complete cytogenetic response (BCR::ABL1 IS level ≤ 1%), MMR: major molecular response (BCR::ABL1 IS level ≤ 0.1%), BD: bis in die, twice a day, OD: once daily, IS, international scale. ^#stopped treatment for intolerance associated with poor response, *total F317L amino acid substitution from both c.949 T > C (45%) and c.951 C > A (51%).

Fig. 4. BCR::ABL1 single nucleotide variant dynamics over time.

A patient ASC-01, BCR::ABL1 IS level (blue) and E459K-BSNV VAF (purple) over time, starting before (white background), then during treatment with asciminib (pink background), until asciminib cessation, B patient ASC-41, BCR::ABL1 IS level (blue), and G250E- (lavender), Y253H- (black), T315I- (orange), F359I- (green), E459K- (maroon) BSNV VAF over time, before (white background) and during (pink background) asciminib treatment C patient ASC-04, BCR::ABL1 IS level results (blue) and I502F-BSNV VAF (teal) before (white background) and during (pink background) asciminib treatment, D patient ASC-23, BCR::ABL1 IS level (blue) and T315I-BSNV VAF (orange) before (white background) and during (pink background) asciminib treatment. BCR::ABL1 IS level (left y-axis), BSNV expressed as variant allele frequency (right y-axis) over time (months, x-axis), BSNV, BCR::ABL1 single nucleotide variant, VAF, variant allele frequency, BD, bis in die, twice a day, IS, international scale.