Timothy A. Yap, MD from MD Anderson discusses an abstract from Journal of Clinical Oncology entitled 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
Intent
Preclinical studies have shown that ATR inhibition as monotherapy and combined with DNA-damaging drugs such as carboplatin can manipulate synthetic lethality (e.g. in cancer cells with compromised compensatory DNA damage responses due to ATM loss).
PATIENTS AND METHODSÂ
The ATR inhibitor M6620 (VX-970) was tested in this phase I trial as monotherapy (once or twice weekly) and combined with carboplatin (carboplatin on day 1 and M6620 on days 2 and 9 in periods of 21 days). Primary objectives included protection, tolerability, and maximum tolerated dose; secondary objectives included pharmacokinetics and antitumor activity; exploratory objectives included pharmacodynamics in timed paired tumor biopsies.
OUTCOMES
There were forty patients enrolled; 17 received monotherapy with M6620, which was safe and well tolerated. The recommended phase II dose (RP2D) was 240 mg / m2 for once- or twice-weekly administration. A patient with metastatic colorectal cancer with molecular aberrations, including loss of ATM and ARID1A mutation, achieved complete response to RECISTv1.1 and sustained the response, with a progression-free survival of 29 months at the final assessment. Twenty-three patients received M6620 with carboplatin, with hematologic toxicity dependent on the mechanism at higher doses, requiring delays in dosage and reductions. The M6620 90 mg / m2 RP2D with carboplatin AUC5 was used for combination therapy. Despite being platinum refractory and PARP inhibitor-resistant, a patient with advanced germline BRCA1 ovarian cancer obtained RECISTv1.1 partial response and Gynecologic Cancer Intergroup CA125 response. A further 15 patients had stable RECISTv1.1 disease as the best response. The pharmacokinetics is proportional to the dose and exceeded successful preclinical standards. Pharmacodynamic studies have shown a significant inhibition of CHK1, the downstream ATR substrate, in phosphorylation.
FINDINGS
This study is, to our knowledge, the first of a monotherapy ATR inhibitor and combined with carboplatine. With target engagement and tentative antitumor responses observed, M6620 was well tolerated.