Repotrectinib Shows Promising Activity in ROS1+ NSCLC

Jessica J Lin, MD

Repotrectinib (TPX-0005) demonstrated a clinically meaningful and durable benefit across multiple doses in patients with ROS1 fusion—positive non–small cell lung cancer (NSCLC).

Overall response rates (ORRs) were 80% for tyrosine kinase inhibitor (TKI)-naïve patients (95% CI, 44-97) and 18% for TKI-refractory patients (95% CI, 4-44), including 33% for those who received a dose of 160 mg once daily, according to findings from the ongoing phase I/II TRIDENT-1 study. Interim analysis results were presented at the 19th World Conference on Lung Cancer (WCLC).¹

The use of TKIs with activity against ALK, ROS1, or TRKA-C may have a significant benefit for those with tumors harboring ALK, ROS1 or NTRK1-3 rearrangements; however, resistance to these agents consistently develops.

“Crizotonib (Xalkori) at this time remains the only [FDA] approved targeted therapy for patients with advanced ROS1-positive lung cancer. Despite the effectiveness of crizotinib, patients almost invariably acquire resistance. G2032R represents the most common ROS1 resistance mutation that emerges following crizotinib,” explained Jessica J Lin, MD, thoracic oncology, Massachusetts General Hospital.

Repotrectinib, manufactured by TP Therapeutics, is a next-generation, potent kinase inhibitor against wildtype and mutated ALK, ROS1 and TRK family kinases, “especially the clinically significant solvent front mutations, gatekeeper mutations, and emerging compound mutations after multiple line treatments,” according to a TP Therapeutics press release.² “Repotrectinib may provide new opportunities in the clinic to inhibit the abnormal signaling of ALK, ROS1, or TRK family in solid malignancies, and overcome resistance seen in refractory patients.”

Preclinical studies have demonstrated potent activity of repotrectinib against wild-type and mutant ROS1 kinases.

Therefore, in phase I of the TRIDENT-1 study, the investigators aimed to determine the maximum-tolerated dose (MTD) and/or recommended phase II dose (RP2D) of repotrectinib monotherapy in TKI-naïve and TKI-refractory (≥1 TKI) patients with advanced ALK/ROS1/TRK-positive solid tumors. Safety, pharmacokinetics, and preliminary antitumor efficacy served as secondary objectives for the study.

A range of solid tumors were treated, with the most common being NSCLC (83%). Median age was 52 years (range, 30-75). The median number of prior systemic therapies was 2 (range, 1-8), 20 (67%) patients had prior ROS1 TKIs, and 27 (90%) had prior chemotherapy.

During her presentation, Lin discussed the safety analysis of all patients as well as a subgroup efficacy analysis of patients with ROS1-positive NSCLC. As of the July 13, 2018, data cutoff, 72 patients had been treated across a variety of dose levels: 40 mg once daily (n = 13); 80 mg once daily (n = 12); 160 mg once daily (n = 23); 240 mg once daily (n = 10); 160 mg twice daily (n = 12); 160 mg twice daily; and 200 mg twice daily (n = 2).

Repotrectinib appeared to be well tolerated, with most adverse events (AEs) being grade 1 or 2, including dizziness (50%), dysgeusia (45.8%), paresthesias (29.2%), constipation (19.4%), fatigue (18.1%), anemia (12.5%), and nausea (11.1%). Grade 3 anemia (4.2%) and dizziness (2.8%) also occurred, as well as one event each of increased weight, dyspnea/hypoxia, pleural effusion, and hypophosphatemia.

Four dose-limiting toxicities were observed: grade 2 or 3 dizziness (n = 3; 2 at 160 mg twice daily, and 1 at 240 mg once daily) that resolved upon study drug reduction and treatment continued; and grade 3 dyspnea/hypoxia (n=1 at 160 mg twice daily) that resolved after study drug discontinuation. Two deaths occurred during study treatment: 1 due to disease progression and 1 of sudden death, which may have been related to the study drug.

Neither the MTD nor the RP2D has been reached, and therefore, is ongoing.

Antitumor activity in the 27 patients with ROS1-positive NSCLC was observed at each of the dose levels except for 200 mg twice daily. Per independent review, best ORR was 80% (95% CI, 44-97) for TKI-naïve patients and 18% (95% CI, 4-44) for TKI-refractory patients.

Of the 10 TKI-naïve patients, median time to response (TTR) was 1.6 months, and the clinical benefit ratio (CBR) was 100% (95% CI, 69-100). Five of 8 patients remain in confirmed partial response (cPR; 3.7+ to 11.1+ months).

Of the 17 TKI-pretreated patients, TTR was 1.6 months (95% CI, 1.5-1.8) at a dose of 160 mg once daily. In addition, CBR was 76% (95% CI, 56-97) and 1 patient remains in cPR (11.1+ months).

An ongoing blinded independent review identified 7 evaluable patients with target central nervous system (CNS) lesions at baseline. Of the 3 TKI-naïve patients and the 4 TKI-pretreated patients, intracranial ORR was 100% (95% CI, 29-100) and 25%, respectively.

As of July 13, 2018, 15 of 27 patients with ROS1-positive NSCLC (56%) remain on treatment.

In addition, the researchers identified 4 patients with the G2032R mutation who were resistant to treatment with crizotinib, of which all of them experienced tumor regressions on repotrectinib treatment. However, 1 patient experienced cPR at the 160 mg one daily dose, and after a 7.4-month duration of response, the patient remains on treatment at 11+ months.

“The preliminary TRIDENT-1 phase I data warrant further clinical testing of repotrectinib in ROS-1 positive NSCLC and other solid tumors harboring ROS1 fusions,” Lin said.

References

1. Lin J, Kim D, Drilon A, et al. Safety and Preliminary Clinical Activity of Repotrectinib (TPX-0005), a ROS1/TRK/ALK Inhibitor, in Advanced ROS1 Fusion-Positive NSCLC. Presented at: the IASLC 19th World Conference on Lung Cancer; September 23-26; Toronto, Canada. Abstract OA02.02.
2. TP Therapeutics Announces Updated Interim Phase 1 Data with Repotrectinib (TPX-0005) in ROS1 Fusion-positive NSCLC to be Presented at World Conference on Lung Cancer. Business Wire web site. https://www.businesswire.com/news/home/20180905005355/en/TP-Therapeutics-Announces-Updated-Interim-Phase-1. Published Sept. 5, 2018. Accessed Sept. 23, 2018.