Taletrectinib Elicits Encouraging Responses in Crizotinib-Pretreated ROS1+ NSCLC

Caicun Zhou, MD, PhD

The investigational next-generation ROS1/NTRK inhibitor taletrectinib (AB-106) was found to elicit encouraging responses with an acceptable toxicity profile in patients with ROS1-positive non–small cell lung cancer (NSCLC), according to preliminary data from the phase 2 TRUST trial (NCT04395677).¹

Results, which were presented during the Chinese Society of Clinical Oncology (CSCO) 2021 Annual Meeting, showed that as of June 16, 2021, taletrectinib elicited a confirmed objective response rate (ORR) of 90.5% in a subset of 21 patients who were naïve to crizotinib (Xalkori), with a disease control rate (DCR) of 90.5% (n = 19/21). In a subset of patients who received prior crizotinib (n = 16), the confirmed ORR with the agent was 43.8% (n = 7), with a DCR of 75.0% (n = 12).

ROS1 G2032R mutations were detected in 3 of the patients in the crizotinib-pretreated subgroup, and all these patients experienced tumor regression. Specifically, 2 patients experienced a partial response to taletrectinib, and 1 achieved stable disease.

Notably, among 6 patients who had brain metastases prior to enrollment, the intracranial (IC) objective response rate (IC-ORR) was 83.3% (n = 5).

“We are pleased with the interim phase 2 data, which have shown taletrectinib to be safe and tolerable, a very promising novel therapy for patients with ROS1 fusion–positive lung cancer,” Caicun Zhou, PhD, MD, director of the Department of Oncology in Shanghai Pulmonary Hospital, stated in a press release. “Responses appear particularly impressive in crizotinib treatment–naïve patients, and while the number of crizotinib pretreated patients is limited, so far, most patients continue to show benefit from the drug.”

Taletrectinib is a selective, blood–brain barrier penetrant, next-generation ROS1/NTRK inhibitor that was developed to showcase potent activity against the ROS1 fusion, as well as crizotinib-resistant ROS1 mutations, largely G2032R.² Previously, the agent has demonstrated clinical activity in those with advanced ROS1 fusion–positive NSCLC who are either naïve to ROS1 TKIs or who were pretreated with crizotinib. Data from 2 phase 1 trials have showed that taletrectinib has a manageable toxicity profile in this population.³

The ongoing, multicenter, phase 2 trial enrolled patients with histologically or cytologically confirmed locally advanced or metastatic NSCLC who were at least 18 years of age, had an ECOG performance status of 0 or 1, and at least 1 measurable lesion per RECIST v1.1 criteria. ROS1 fusions in tumor tissue were determined via the use of molecular assays and then were confirmed in the central laboratory.

The trial was comprised of 1 parts. The first portion of the research had a lead-in dose titration period where the agent was given at a daily dose of 400 mg (n = 3) and 600 mg (n = 3). In part 2, all patients received taletrectinib at a daily dose of 600 mg. Cohort 1 of patients would be those who were naïve to crizotinib (n = 60), and cohort 2 would include those who received prior crizotinib (n = 40).

The primary end points of the trial were ORR per RECIST v1.1 criteria and independent review committee (IRC) assessment. Key secondary end points comprised ORR, duration of response (DOR), progression-free survival (PFS), IC-ORR, IC-DOR, and IC-PFS per RECIST v1.1 and both IRC and investigator assessment.

Between July 2020 and April 2021, a total of 40 patients received taletrectinib. The median age of study participants was 53.5 years (range, 32-77), 57.5% were female, 77.5% had an ECOG performance status of 1, 60% had stage IVB disease, and 90% had adenocarcinoma. Moreover, 15% of patients had brain metastases.

Twenty-five percent of patients did not receive prior treatment, 27.5% had received chemotherapy only, 17.5% had crizotinib only, and 30% had previously received both chemotherapy and crizotinib.

Among the 6 patients enrolled to the first portion of the trial, 5 were crizotinib naïve and 1 had previously received crizotinib. Of the 34 patients who had been enrolled to part 2, 16 were crizotinib naïve and 18 had prior crizotinib. In all 21 patients who were naïve to crizotinib, ROS1 fusions were confirmed via the central laboratory; this was true for 11 of the 19 patients who were pretreated with crizotinib.

Prior results presented during the 2021 ASCO Annual Meeting showed that the ORR in 15 crizotinib-naïve patients with taletrectinib was 93% (95% CI, 68.1%-99.8%), with a DCR of 93% (95% CI, 68.1%-99.8%). In 5 crizotinib-pretreated patients, the ORR with the agent was 60% (95% CI, 14.7%-94.7%), with a DCR of 100% (95% CI, 47.8%-100%).

Notably, 3 patients who were pretreated with crizotinib were found to have tumors that harbored the ROS1 G2032R mutation and all these patients were noted to have experienced tumor regressions with taletrectinib.

Tmax was approximately 3 to 4 hours following the administration of taletrectinib, and exposure increase of the agent was found to be dose dependent. The steady state for taletrectinib was reached on day 8 after several doses, with accumulation ratios of 2 to 4.

Regarding safety, all-grade treatment-related adverse effects (TRAEs) were experienced by 85.0% of patients; 12.5% experienced grade 3 or higher TRAEs with taletrectinib. The most commonly experienced toxicities included diarrhea (all-grade, 55.0%), nausea (all-grade, 35.0%), vomiting (all-grade, 35.0%), aspartate aminotransferase increase (all-grade, 57.5%; grade 3 or higher, 10%), alanine aminotransferase increase (all-grade, 55%; grade 3 or higher, 7.5%), anemia (all-grade, 17.5%), and neutrophil count decrease (all-grade, 15.0%; grade 3 or higher, 2.5%).

“We are glad to see the interim phase 2 data of taletrectinib presented at the CSCO meeting, one of the most authoritative clinical oncology conferences in China,” Dr Hui Zhou, senior vice president of Innovent Biologics, Inc., stated in a press release. “In China, ROS1-positive patients currently have limited treatment options. Novel therapies are urgently needed, and taletrectinib has good efficacy and safety results, which offers hope to patients with ROS1 fusion–positive patients with NSCLC.”

References

1. Innovent and AnHeart announce interim data from phase 2 trial (TRUST study) of taletrectinib in ROS1-positive NSCLC at the CSCO 2021 Annual Meeting. News release. Innovent Biologics, Inc. September 27, 2021. Accessed September 28, 2021. https://bit.ly/2XW1Ppe
2. Zhou C, Fan H, Wang Y, et al. Taletrectinib (AB-106; DS-6051b) in metastatic non-small cell lung cancer (NSCLC) patients with ROS1 fusion: preliminary results of TRUST. J Clin Oncol. 2021;39(suppl 15):9066. doi:10.1200/JCO.2021.39.15_suppl.9066
3. Ou S-HI, Fujiwara Y, Shaw AT, et al. Efficacy of taletrectinib (AB-106/DS-6051b) in ROS1+ NSCLC: an updated pooled analysis of US and Japan phase 1 studies. JTO Clinical and Research Reports. 2021;2(1):100108. doi:10.1016/j.jtocrr.2020.100108