Taletrectinib Shows Promising ORR and Tolerability in ROS1+ NSCLC

Misako Nagasaka, MD, PhD

Taletrectinib (AB-106/DS-6051b) has demonstrated encouraging response rates and a favorable safety profile in patients with ROS1-positive non–small cell lung cancer (NSCLC), regardless of crizotinib (Xalkori) pretreatment status, according to Misako Nagasaka, MD, PhD.

On August 3, 2022, the FDA granted a breakthrough therapy designation to taletrectinib for the treatment of adult patients with advanced or metastatic ROS1-positive NSCLC who are naïve to ROS1 inhibitors or who previously received crizotinib. This designation was based on findings from the ongoing phase 2 TRUST trial (NCT04395677), which evaluated a primary end point of overall response rate (ORR) and secondary end points including disease control rate (DCR), progression-free survival (PFS), and safety.

In TRUST, the ORR among the crizotinib-naïve patients was 92.5%, and the DCR was 95.5%. The ORR among the crizotinib-pretreated patients was 50.0%, with a DCR of 78.9%. Additionally, of the 5 patients with ROS1 G2032R mutations, the ORR was 80%, with 4 achieving a partial response and 1 achieving stable disease. Of the patients with measurable brain lesions, the intracranial ORR was 91.7% and the intracranial DCR was 100%. The median PFS has not yet been reached for either cohort.¹

“Taletrectinib is potentially the best-in-class ROS1 TKI,” Nagasaka said. “It has good activity in the treatment-naïve population as well as the crizotinib-treated patient population. It has good central nervous system (CNS) penetration, and it has activity against the resistant ROS1 G2032R mutation. The lower rates of TrkB-related adverse effects [AEs] are promising and will help many patients.”

In an interview with OncLive^®, Nagasaka discussed the various needs taletrectinib meets in the ROS1-positive population, initial efficacy data with the agent, and its impressive safety profile.

Nagasaka is an associate clinical professor of medicine in the Division of Hematology/Oncology at the University of California, Irvine School of Medicine in Orange.

OncLive^®: What is the significance of this FDA breakthrough therapy designation?

Nagasaka: Taletrectinib is a potent and selective next-generation ROS1 inhibitor. [This designation] provides hope to patients, both in the frontline and post-crizotinib settings, with NSCLC harboring ROS1 fusions.

How might taletrectinib support some unmet needs for this patient population?

ROS1 can occur in different tumor types, but in NSCLC, it occurs in about 1% to 2% [of patients]. We are looking at taletrectinib for both the newly diagnosed patient population as well as for the post-crizotinib or post-entrectinib [Rozlytrek] populations.

Some of the unmet needs [in this population are for] those with brain metastases, either ones that are de novo, or [ones that have developed] through resistance, for example, to crizotinib. Patients who are primarily resistant to crizotinib [also have unmet needs]. An additional unmet need is in patients who have developed a resistant G2032R mutation. Taletrectinib is promising in all these settings.

What is the mechanism of action of taletrectinib?

Taletrectinib is an oral, potent, selective, next-generation ROS1 inhibitor, and it is also a pan–NTRK fusion inhibitor. [A benefit of] taletrectinib is that its ROS1 inhibition is much stronger than its inhibition of TrkB.

What key efficacy data stood out to you from the TRUST trial?

The TRUST trial enrolled patients in China and looked at the efficacy and safety of taletrectinib in both ROS1 TKI-naïve patients as well as crizotinib-pretreated patients. Impressive clinical activity was seen in patients with ROS1 TKI–naïve NSCLC, in particular, with the ORR in this population being 92.5% and the DCR being 95.5%. The ORR in the crizotinib-pretreated patient population was 50.0%, and the DCR was 78.9%. Additionally, all 3 patients with G2032R mutations had tumor regression.

[These data were not too] surprising. It’s good to see initial activity from taletrectinib, although the [sample sizes] that were reported were a bit low. For the TKI-naïve patients, the ORR of 92.5% [came from an arm of 67 patients], and for the crizotinib-pretreated patients, the response rate of 50.0% [came from an arm of 38 patients].

What AEs with the agent are important to note?

The safety profile is an important differentiating factor to consider when you’re comparing treatment options. From the TRUST study, taletrectinib was found to be well tolerated. In the safety cohort, the most common any-grade TRAEs were diarrhea, nausea, and vomiting, and common lab-related AEs included increases in aspartate aminotransferase and alanine aminotransferase, but these were mostly reversible.

Strikingly, there was a low frequency of neurological AEs compared with entrectinib and repotrectinib [TPX-0005], and that is because we think that taletrectinib does not inhibit TrkB much compared with other agents.

What might the future hold for taletrectinib in ROS1-positive NSCLC? Where might this agent fit into the treatment paradigm?

The goal of any cancer treatment is better efficacy with better tolerability. Taletrectinib has a good start, with efficacy observed in patients in the treatment-naïve population, as well as in the resistant-disease population. It also has great CNS penetration, and the [incidence of] TrkB-related AEs appears to be less compared with other agents, which is also an important factor to consider. Hopefully, the ongoing [phase 2] TRUST-II study [NCT04919811], which is a global version of the TRUST study, will help us bring this drug to many patients around the world.

What ongoing and upcoming lung cancer research at UC Irvine are you excited about?

At UC Irvine, we have multiple studies on targeted treatment. Targets include ROS1, which we’ve been talking about, as well as other targets such as EGFR, ALK, MET, RET, and KRAS G12C. We are also opening multiple antibody-drug conjugate [ADC] studies. We have the [phase 1b] DESTINY-Lung03 [NCT04686305] and [phase 3] DESTINY-Lung04 [NCT05048797] trials, which [are investigating treatments with] HER2-directed ADCs. This is an exciting area.

Reference

1. Li W, Yang N, Ma HW, et al. The efficacy and safety of taletrectinib in patients with TKI-naïve or crizotinib-pretreated ROS1-positive non–small cell lung cancer (NSCLC). J Clin Oncol. 2022;40(suppl 16):8572-8572. doi:10.1200/JCO.2022.40.16_suppl.8572