Camonsertib in DNA damage response-deficient advanced solid tumors: phase 1 trial results

Abstract

Predictive biomarkers of response are essential to effectively guide targeted cancer treatment. Ataxia telangiectasia and Rad3-related kinase inhibitors (ATRi) have been shown to be synthetic lethal with loss of function (LOF) of ataxia telangiectasia-mutated (ATM) kinase, and preclinical studies have identified ATRi-sensitizing alterations in other DNA damage response (DDR) genes. Here we report the results from module 1 of an ongoing phase 1 trial of the ATRi camonsertib (RP-3500) in 120 patients with advanced solid tumors harboring LOF alterations in DDR genes, predicted by chemogenomic CRISPR screens to sensitize tumors to ATRi. Primary objectives were to determine safety and propose a recommended phase 2 dose (RP2D). Secondary objectives were to assess preliminary anti-tumor activity, to characterize camonsertib pharmacokinetics and relationship with pharmacodynamic biomarkers and to evaluate methods for detecting ATRi-sensitizing biomarkers. Camonsertib was well tolerated; anemia was the most common drug-related toxicity (32% grade 3). Preliminary RP2D was 160 mg weekly on days 1-3. Overall clinical response, clinical benefit and molecular response rates across tumor and molecular subtypes in patients who received biologically effective doses of camonsertib (>100 mg d^-1) were 13% (13/99), 43% (43/99) and 43% (27/63), respectively. Clinical benefit was highest in ovarian cancer, in tumors with biallelic LOF alterations and in patients with molecular responses. ClinicalTrials.gov registration: NCT04497116 .

Fig. 1. Overview of the TRESR trial: a CRISPR–Cas9 chemogenomic-informed clinical trial.

a, SNIPRx CRISPR–Cas9-enabled chemogenomic screen to identify ATRi-sensitizing and synthetic lethal alterations for patient selection. b, Patient enrollment by gene and tumor type and overview of pre-planned analyses, which included (1) clinical endpoints; (2) PK in plasma and PD in pre-treatment and on-treatment biopsies; (3) hypothesis-generating genomic analyses, such as the assessment of allelic status (that is, biallelic versus non-biallelic alterations) and somatic versus germline status; and (4) analysis of longitudinal ctDNA as an early marker of camonsertib activity. c, CONSORT diagram of TRESR monotherapy patient populations. Patients enrolled in M1c received a single dose on day 3 in the fed state and continued from day 1 (fasted state) on either the 5/2 (n = 3) or 3/4 (n = 9) schedule. 3/4, 3 d on, 4 d off; 5/2, 5 d on, 2 d off; CN, copy number; CRC, colorectal cancer; HomDel, homozygous deletion; M, module; TCGA, The Cancer Genome Atlas; Tx, therapy.

Fig. 2. Clinical outcomes in TRESR.

a, Duration of treatment by genotype. Clinical benefit is defined as a treatment duration of at least 16 weeks (without evidence of progression) and/or a RECIST 1.1 or tumor marker response. The gray dotted line indicates 16 weeks. b, Case report for a patient (n = 1) with gRAD51C LOF ovarian cancer who had complete disappearance of the TLs. c, Case report for a patient (n = 1) with a gATM LOF pancreatic cancer who had a late response to camonsertib. 69F, 69-year-old female; 77F, 77-year-old female; g, genomic; Plt., platinum.

Fig. 3. ctDNA MRs in TRESR.

a, Best ctDNA response by enrollment gene. MR is defined as a 50% decrease from baseline in the mVAF. Kaplan–Meier-estimated PFS (b) and DOT by MR (c). log-rank P = 0.00015 for PFS and P = 0.000027 for DOT in patients with MR versus no MR. CR, complete response.

Extended Data Fig. 1. Pharmacokinetics of camonsertib at pharmacologically active dose levels.

Geometric mean plasma concentration time profiles of camonsertib on cycle 1 day 1 are plotted at specified dose levels of 100 mg QD (n = 8 patients), 120 mg QD (n = 31 patients), 160 mg QD (n = 63 patients), or 200 mg (n = 5 patients). Error bars represent geometric standard deviation. The red dashed line represents the pre-clinical in vivo tumor pCHK1 IC₈₀, which is the target for pharmacological activity (~10–12 hours coverage). Note that not every patient was evaluated at every timepoint. IC₈₀, 80% inhibitory concentration; hr, hours; QD, once daily.

Extended Data Fig. 2. Pharmacodynamic biomarkers of ATR inhibition.

(a) yH2AX (top) and pKAP1 (bottom) changes in H-score with camonsertib treatment from baseline to cycle 2 day 10 in patients treated with camonsertib at the indicated dose and schedules. (b) Representative histology micrographs from pre- and on-treatment biopsies taken 3 days prior to treatment initiation and at 30 days on-treatment from a patient with ER+ breast cancer treated with 160 mg QD camonsertib on the 3/4 continuous schedule. 2/1w, 2 weeks on, 1 week off; 3/4, 3 days on, 4 days off; 5/2, 5 days on, 2 days off; ATR, ataxia telangiectasia and Rad3-related kinase; cont, continuous; ER, estrogen receptor; QD, once daily; Tx, treatment.

Extended Data Fig. 3. Clinical outcomes of ovarian cancer patients treated with camonsertib.

(a) Duration of treatment. (b) Kaplan–Meier estimate for progression-free survival. Median progression-free survival was 35 weeks. RECIST, Response Evaluation Criteria in Solid Tumors.

Extended Data Fig. 4. Analysis of allelic status of the enrollment gene.

(a) Clinical benefit and molecular response rate of tumors stratified by biallelic versus non-biallelic status. (b) Comparison of the enrollment NGS test result for ATM with retrospective ATM IHC and allele-specific copy-number result. Micrographs show images of CRPC tissue from two of 30 patients subjected to IHC analysis with an anti-ATM antibody, illustrating cancers with intact ATM expression (ATM IHC intact) and loss of ATM expression (ATM IHC loss), respectively. CH, CHIP; CHIP, clonal hematopoiesis of indeterminate potential; CRPC, castration-resistant prostate cancer; ctDNA, circulating tumor DNA; IHC, immunohistochemistry; InDel, insertion or deletion; NGS, next-generation sequencing; NL, no loss detected; QNS, quantity not sufficient; SC, subclonal detection.

Extended Data Fig. 5

Kaplan–Meier estimate of (a) progression-free survival and (b) duration of treatment by gene allelic status.

Extended Data Fig. 6. Clinical outcomes in patients harboring reversions of their tumor alterations at study enrollment.

(a) Duration of treatment in the 10 patients in which reversion alterations were identified either by liquid biopsy or tumor sequencing. (b) Case report of a 69-year-old female with triple-negative breast cancer harboring polyclonal BRCA1 reversion alterations in ctDNA. BRCA1 reversion alterations decline with camonsertib treatment and rise prior to progression of non-target lesions. 69F, 69-year-old female; ctDNA, circulating tumor DNA; MR, molecular response; NTL, non-target lesion; PARPi, poly adenosine diphosphate-ribose polymerase inhibitor; Plt, platinum; RECIST, Response Evaluation Criteria in Solid Tumors; TL, target lesion; TNBC, triple-negative breast cancer; VAF, variant allele frequency.