Safety and pharmacokinetics of DS-6051b in Japanese patients with non-small cell lung cancer harboring ROS1 fusions: a phase I study

Abstract

Oncogenic ROS1 and NTRK fusions were reported in solid tumors, including non-small cell lung cancer (NSCLC). DS-6051b is an oral, potent selective small molecule tyrosine kinase inhibitor. We report the safety, tolerability, efficacy, and pharmacokinetics of DS-6051b in 15 Japanese patients with NSCLC harboring ROS1 fusions. Patients received DS-6051b once daily (400 mg n = 6; 600 mg n = 6; or 800 mg n = 3) for cycles of 3 weeks. Safety, tolerability, maximum-tolerated dose, pharmacokinetics, and recommended dose for phase II were determined. Common treatment-related adverse events were increased: aspartate aminotransferase and alanine aminotransferase (80.0% each), diarrhea (53.3%), and nausea (46.7%). Dose-limiting toxicities (two grade-3 alanine aminotransferase increases) were seen in the 800 mg cohort. The maximum-tolerated dose and recommended phase II dose was 600 mg once daily. Plasma concentrations of free DS-6051b and DS-6051a increased with dose. Compared with a US phase I study, AUC0–24 h on day 15 was higher but narrowed after body weight correction. Objective response rate was 58.3% in patients with target lesions (n = 12) and 66.7% in crizotinib-naïve patients (n = 9). Disease control rate was 100%. DS-6051b is well tolerated and effective in Japanese patients with NSCLC harboring ROS1 fusions and might be a targeted therapy for advanced NSCLC.

U.S. Phase I First-in-human Study of Taletrectinib (DS-6051b/AB-106), a ROS1/TRK Inhibitor, in Patients with Advanced Solid Tumors

“…A smaller phase I study in Japan that enrolled 15 patients with ROS1 þ NSCLC concluded that the MTD and recommended phase II dose for taletrectinib was 600 mg once daily (17). Two grade 3 ALT elevations were observed at the 800-mg once-daily dose and were considered as DLTs.…”

“…Among the total of 15 patients with ROS1 þ NSCLC enrolled, ORR was 66.7% for the nine evaluable patients who were crizotinib-na€ ve and 33.3% for the three patients with evaluable crizotinib-refractory ROS1 þ . Activity against CNS metastasis was also observed (17). There was no patient with NTRK fusion-positive tumors or NET enrolled in the Japanese phase I trial (17).…”

Targeting ROS1 rearrangements in non-small cell lung cancer with crizotinib and other kinase inhibitors

“…Amongst the cohort of 12 patients with ROS1 -rearranged tumors and including seven crizotinib pretreated patients, an objective response was achieved by 6 (50%) (14). Clinical activity seen with other TKIs in ROS1 -rearranged NSCLC has also been described (Tables 1,2), (15,16). …”

<p>Profile of entrectinib and its potential in the treatment of ROS1-positive NSCLC: evidence to date</p>

“…12 Responses to cabozantinib, lorlatinib, DS-6051b and repotrectinib were indeed observed, with a special mention to the last drug, retaining significant activity against brain disease and, even more remarkably, against the recalcitrant ROS1 G2032R mutation. 11,12,14,15,17,19 The evidence concerning the activity of each mentioned ROS1-TKI against specific ROS1 mutants will be likely extended, given the current documentation of resistance mutations from ctDNA in ROS1-positive NSCLC patients, 39,40 similar to EGFR-mutated and ALK-rearranged ones. 41,42 The largescale availability of such analyses, bypassing the practical issues of tumor biopsies, would allow the systemic capture of resistance mechanisms to ROS1 inhibitors and pave the way for the following correlations with drug activity.…”

“…Besides crizotinib (the only drug approved by both FDA and EMA for ROS1-driven NSCLC), additional TKI have shown activity and efficacy in ROS1-rearranged lung cancer: ceritinib, cabozantinib, entrectinib, lorlatinib, brigatinib, DS-6051b and repotrectinib ( Figure 1). [10][11][12][13][14][15][16][17][18][19] According to NCCN guidelines, lorlatinib is the only ROS1-TKI approved after crizotinib failure, 20 based on available clinical trial data. 14,15 Similarly to what observed in EGFR-and ALK-positive diseases, the novel TKI can contribute to the prolongation of disease control (turning out to be a surrogate of OS) in two alternative ways.…”