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.

FIG 1.

Patient flow diagram. AUC, area under the curve; RP2D, recommended phase II dose. (*) Part B started with a dose-escalation design, but dose reductions were required because of toxicities.

FIG 2.

Pharmacodynamic profile of M6620. (A) Ataxia telangiectasia and Rad3-related protein (ATR) pathway schematic. (B) Biopsy schematic. (C) Patient characteristics for biopsy study. (D) Spaghetti plot. (E) Phosphorylated checkpoint kinase 1 (pCHK1) immunohistochemistry (IHC) image from patient 23; predose biopsy (top) and postdose biopsy (bottom), with negative immunoglobulin G (IgG) controls on the right. Approx, approximately; AUC, area under the curve.

FIG 3.

Patient with colorectal cancer who achieved a RECISTv1.1 complete response (CR) to M6620 monotherapy. (A, B) At last assessment, the patient remained in RECISTv1.1 CR with an ongoing progression-free survival of 29 months. At trial baseline, the patient had disease progression in his left common iliac lymph nodes, the largest of which measured 30 mm along the long axis and 18 mm along the short axis (B, top panel). There was also disease progression with worsening peritoneal disease in his anterior abdomen and asymmetric thickening of his transverse colon lateral to surgical clips, in keeping with a local tumor recurrence with transmural infiltration (B, bottom panel). (A) Immunohistochemistry of archived tumor sample showed ataxia-telangiectasia mutated (ATM) loss (left) and AT-rich interaction domain 1A (ARID1A) loss (right). Patient also had other relevant aberrations (see Results section). (B) Computed tomography scans before treatment (left) and 29 months after treatment (right) demonstrated response of left common iliac lymph node and other lesions to single-agent M6620. Top panel shows left common iliac node. Bottom panel shows local recurrence in transverse colon with peritoneal malignant infiltration and left para-aortic nodes. (C, D) Patient with ovarian cancer achieved a RECISTv1.1 partial response to M6620 plus carboplatin combination therapy. (C) Computed tomography scans before (left) and 5 months after therapy (right) showed partial response of left peritoneal disease. (D) There was a corresponding decrease in cancer antigen 125 (CA125) levels, which was a Gynecologic Cancer Intergroup response.

FIG 4.

Maximum change from baseline in the sum of target tumor lesion diameters with combination therapy. AUC, area under the curve; PD, progressive disease; PR, partial response; SD, stable disease.