Phase I Trial of First-in-Class ATR Inhibitor M6620 (VX-970) as Monotherapy or in Combination With Carboplatin in Patients With Advanced Solid Tumors

Abstract

PURPOSE Preclinical studies demonstrated that ATR inhibition can exploit synthetic lethality (eg, in cancer cells with impaired compensatory DNA damage responses through ATM loss) as monotherapy and combined with DNA-damaging drugs such as carboplatin. PATIENTS AND METHODS This phase I trial assessed the ATR inhibitor M6620 (VX-970) as monotherapy (once or twice weekly) and combined with carboplatin (carboplatin on day 1 and M6620 on days 2 and 9 in 21-day cycles). Primary objectives were safety, tolerability, and maximum tolerated dose; secondary objectives included pharmacokinetics and antitumor activity; exploratory objectives included pharmacodynamics in timed paired tumor biopsies. RESULTS Forty patients were enrolled; 17 received M6620 monotherapy, which was safe and well tolerated. The recommended phase II dose (RP2D) for once- or twice-weekly administration was 240 mg/m2. A patient with metastatic colorectal cancer harboring molecular aberrations, including ATM loss and an ARID1A mutation, achieved RECISTv1.1 complete response and maintained this response, with a progression-free survival of 29 months at last assessment. Twenty-three patients received M6620 with carboplatin, with mechanism-based hematologic toxicities at higher doses, requiring dose delays and reductions. The RP2D for combination therapy was M6620 90 mg/m2 with carboplatin AUC5. A patient with advanced germline BRCA1 ovarian cancer achieved RECISTv1.1 partial response and Gynecologic Cancer Intergroup CA125 response despite being platinum refractory and PARP inhibitor resistant. An additional 15 patients had RECISTv1.1 stable disease as best response. Pharmacokinetics were dose proportional and exceeded preclinical efficacious levels. Pharmacodynamic studies demonstrated substantial inhibition of phosphorylation of CHK1, the downstream ATR substrate. CONCLUSION To our knowledge, this report is the first of an ATR inhibitor as monotherapy and combined with carboplatin. M6620 was well tolerated, with target engagement and preliminary antitumor responses observed.

First-in-Human Trial of the Oral Ataxia Telangiectasia and RAD3-Related (ATR) Inhibitor BAY 1895344 in Patients with Advanced Solid Tumors

“…This study of BAY 1895344 provides proof-of-concept clinical evidence in line with these preclinical investigations. A previous study of the intravenous ATR inhibitor M6620 demonstrated a durable response in a patient with advanced colorectal cancer harboring molecular aberrations, including ATM protein loss, 2 heterozygous truncating mutations in ARID1A, and ARID1A protein loss, as well as heterozygous truncating mutations in CHEK1, FANCM, RAD50, POLD1, and FANCP (SLX4)(14). In our study, single-agent ATR inhibition with oral BAY 1895344 resulted in a manageable safety profile and multiple durable RECIST partial responses in patients with a range of different tumor types.BAY 1895344 was dosed intermittently in a 3 days on/4 days off regimen to achieve tumor targeting while allowing for recovery of normal tissues during the 4 days off-treatment period(11).…”

<p>Up-and-Coming Experimental Drug Options for Metastatic Colorectal Cancer</p>

“…52 Fifteen patients in the combination therapy group had SD. 52 Approximately 7% of patients with colorectal cancer have ATM mutations, so this represents an exciting new target and also introduces a novel means to overcome platinum resistance. 54 Onvansertib (NMS-P937, NMS-1,286,937, PCM-075)…”

“…Berzosertib is a first-in-class ataxia–telangiectasia and Rad3 related (ATR) inhibitor. 52 ATR, along with ataxia-telangiectasia mutated (ATM), are members of the phosphatidylinositol-3 kinase-related kinase (PIKK) family of protein kinases, which regulate the DNA damage response (DDR). 53 ATR is recruited to damaged single-stranded DNA, whereas ATM is recruited to damaged double-stranded DNA.…”

“… 53 Loss of ATM places higher reliance on ATR for DNA repair and cell survival. 52 This led to the hypothesis that ATR inhibition in ATM -deplete tumors may sensitize those tumors to conventional chemotherapy. 52 A phase I trial included 40 patients with advanced solid tumors and examined berzosertib monotherapy (17 patients) and berzosertib in combination with carboplatin (23 patients).…”

“… 52 A phase I trial included 40 patients with advanced solid tumors and examined berzosertib monotherapy (17 patients) and berzosertib in combination with carboplatin (23 patients). 52 All 17 patients were evaluable in the monotherapy arm. 52 One patient with mCRC and ATM loss achieved CR with berzosertib monotherapy and maintained this response for 29 months.…”