Reference Detail

Ref Type

abstract

PMID

Authors

B.A. Carneiro, E. Rosen, E. Fontana, E.K. Lee, N.B. Mettu, S. Lheureux, R. Plummer, I.M. Silverman, J.D. Schonhoft, J. Yang, G. Gomez, K. Fei, D. Ulanet, P.A. Basciano, T.A. Yap, M. Hoejgaard

Title

619MO Camonsertib (cam) monotherapy in patients (pts) with advanced cancers harboring ATM loss-of-function (LoF)

Journal	Vol	Issue	Date	Pages	Journal Short Title
Annals of Oncology	35	Supplement 2	September 2024

URL

https://www.annalsofoncology.org/article/S0923-7534(24)02205-1/fulltext

Abstract Text

Background Ataxia telangiectasia and Rad3-related kinase inhibitors (ATRi) are synthetic lethal with ataxia telangiectasia-mutated (ATM) kinase LoF. Safety and dose optimization of cam (ATRi) monotherapy in TRESR (NCT04497116) was previously reported. Here we characterize the efficacy of cam monotherapy in the subset of pts with tumor ATM LoF. Methods TRESR enrolled 55 pts with advanced cancers and A) pathogenic ATM alterations based on NGS (tumor [n=27], germline testing [n=16], ctDNA [n=10]) or B) ATM IHC loss <10% (n=2). Central genomic and ATM IHC analysis were performed post-enrollment. Efficacy assessments included overall response (RECIST or tumor marker response), clinical benefit rate ([CBR]; response or on-treatment ≥16 wks), and progression free survival (PFS) in pts (n=46/55) treated with efficacious cam doses (>100 mg/day) with ≥1 post-baseline tumor assessment. Safety was also assessed (6 Mar 24 data cut). Results In the 55pts, ATM enrollment alterations were of germline (n=32) or somatic (n=19) origin and centrally confirmed in 48 pts. ATM biallelic LoF and ATM IHC loss were detected in 54% (21/39) and 63% (22/35) of tumors, respectively. In tumors with known IHC and allelic status (n=30), biallelic ATM LoF was significantly enriched for ATM protein loss (87%; 13/15) compared to non-biallelic LoF (40% [6/15], P = 0.02). The efficacy population comprised 9 pancreatic, 8 prostate, 6 colorectal, and other cancers (n=23; <5 pts/tumor type); median 3 lines prior therapy. 22% of pts were treated >12 mos, 4 pts ongoing (18-39+ mos). Overall response was 15% (7/46); 21% (7/33) excluding pts with confirmed non-biallelic LoF. Responses occurred late (median 8.3 mos) and were durable (3.1-20.8+ mos). In tumors harboring germline or somatic ATM LoF overall response was 18% (5/28) and 13% (2/15), respectively. CBR was 48% (22/46) with benefit observed in pts with NSCLC (2/2), bile duct (3/4), colorectal (3/6), and prostate (4/8) cancers. PFS at 6 mos was 46%. At the optimized dosing regimen, Gr3 anemia rate was 11% overall, 0/8 in the ATM subgroup. Conclusions Cam monotherapy resulted in durable responses and stable disease in multiple ATM-altered advanced cancers. Enrichment for biallelic ATM LoF may be a promising approach for ATRi monotherapy.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
ATM inact mut	Advanced Solid Tumor	predicted - sensitive	RP-3500	Phase Ib/II	Actionable	In a Phase I/II trial (TRESR), RP-3500 treatment resulted in an overall response rate (ORR) of 15% (7/46) and clinical benefit rate of 48% (22/46) in advanced solid tumor patients with ATM inactivation, an ORR of 18% (5/28) with germline ATM loss of function (LOF) mutations, and an ORR of 13% (2/15) with somatic ATM LOF mutations, with benefit in patients with non-small cell lung (n=2), bile duct (3/4), colorectal (3/6), and prostate (4/8) cancers (Ann Oncol (2024) 35 (Suppl_2): S496; NCT04497116).	detail...