Larotrectinib Trial Yields Promising Real-World Findings in TRK Fusion–Positive Disease

Treatment with larotrectinib (Vitrakvi) resulted in an improvement in overall survival (OS) compared with standard-of-care (SOC) among patients with TRK fusion–positive solid malignancies, according to data from a real-world matching-adjusted indirect comparison (MAIC) trial that were presented at the 2022 American Society of Clinical Oncology Annual Meeting.¹

MAIC is a common methodology that balances patient population characteristics allowing for cross-study comparisons in the absence of individual patient data, explained Carsten Bokemeyer, MD, in a presentation of these data at ASCO. The need for MAIC to assess the efficacy of larotrectinib in this patient population is because neurotrophic-TRK (NTRK) fusions are rare in patients, meaning that single-arm trials conducted to evaluate larotrectinib are limited in comparing its effectiveness against SOC regimens.

In their MAIC OS analysis, researchers found a 78% lower risk of death for patients treated with larotrectinib (n= 85) compared with SOC (n = 28), with a hazard ratio (HR) of 0.09 before weighting, but after adjusting it was 0.22 (95% CI, 0.09-0.52; P = .001). Moreover, after weighting, the median OS of patients on larotrectinib was 39.7 months compared with 10.2 months for patients on SOC treatment.

“We would need further data to confirm this, but this is 1 of the several analyses now performed in recent years that helps to add some information on how much the benefit of using NTRK fusion inhibition in this specific patient population really is,” said Bokemeyer, director of the Division of Oncology, Hematology, and Bone Marrow Transplantation at the University Hospital Hamburg-Eppendorf in Hamburg, Germany, in his ASCO presentation.

Researchers created the 2 study cohorts by looking at a previous analysis from the European Society of Medical Oncology that identified NTRK fusion–positive patients who did not receive TRK inhibitors and used this as the SOC cohort by using data from the Flatiron Health/Foundation Medicine clinico-genomic database.² Then, researchers employed MAIC to compare larotrectinib with SOC by balancing various population characteristics among several studies. Patient-level data was collected from clinical trials with the TRK inhibitor: a phase 1 trial (NCT02122913), the SCOUT trial (NCT02637687), and NAVIGATE trial (NCT02576431). They then aggregated SOC data by matching individual data on common baseline characteristics.¹

A log-rank test of equality, to assess if the 2 groups were similar before the initiation of larotrectinib, found no difference between them (P = .31). After this, an estimation of the treatment effect of larotrectinib vs SOC on OS was conducted.

In order to assess the OS results with more certainty, researchers also conducted 2 sensitivity analyses as excessive matching variables in MAIC can reduce the effective sample size (ESS) and the larotrectinib follow-up was longer than the SOC follow-up.

To address the high uncertainty in the analysis of base cases, they conducted several analyses relaxing missing data assumption and removing variables that had minimal overlap between the studies. In comparison to the base case, with an ESS of 13.1 and an HR of 0.22, when looking at the missing values in prior lines of therapy and patients’ ECOG performance score, the ESS was 23.6 with an HR of 0.10 (95% CI, 0.04-0.22). Then removing patients with cancer of unknown primary (CUP) tumor and breast cancer, the ESS was 26.4 (HR, 0.10; 95% CI, 0.05-0.21), removing patients with colorectal cancer (CRC) showed the ESS at 37.9 (HR, 0.12; 95% CI, 0.05-0.26), and removing patients with salivary cancer, the ESS ended at 38.6 (HR, 0.12; 95% CI, 0.05-0.25).

A restricted mean survival time analysis was also conducted up to 30.5 months, which was the minimum of the largest observed event time within the SOC arm. The researchers found an estimated 10.8-month mean survival advantage with larotrectinib when compared with SOC (95% CI, 7-14.6; P < .01). On average, this meant that potential patients treated with larotrectinib at 30.5 months of follow-up would survive an additional 10.8 months, compared with SOC. However, the researchers wrote in their poster that the analysis presented at ASCO was conservative and that the mean benefit would likely continue to increase with a longer follow-up of patients.

“TRK fusion has become quite famous over the last few years, and we know this is a chromosomal rearrangement that drives oncogenesis in pediatric and adult cancers,” explained Bokemeyer. “And there are specific inhibitors, such as larotrectinib, that selectively and potently block the activity from this fusion protein and have a high activity in patients with cancer.”

Eighty-two percent of patients were positive for NTRK1 fusion in both arms after adjustments, and 39.3% were either 65 years old or older on the trial. In both arms there was an even split between patients with an ECOG performance score of 0-1 and 2-4; whereas before matching, 87.1% of patients on larotrectinib had a performance score of 0-1.

Several tumor types were observed in the SOC arm, including uterine (4%), biliary (4%), stomach (4%), endometrial (4%), CUP (4%), breast (4%), salivary gland (7%), non–small cell lung cancer (18%), soft tissue sarcoma (21%), and CRC (32%). In the larotrectinib arm­, there were no cases of uterine, biliary, stomach, or endometrial cancer. When matching the number of lines of therapy since the patients’ diagnosis, 71.4% of patients had 0-2 lines of therapy and 28.6% had 3 or more lines of therapy since the time of their diagnosis. Most patients (64.3%) had stage III or IV disease at their initial diagnosis, with 17.9% of patients initially diagnosed with stage 0 to II disease. A majority of patients also had no or unknown brain metastases.

Researchers noted some study limitations, including that MAIC assumes that all effect modifiers are considered, and this analysis was limited to data reported from 2021. However, Bokemeyer concluded there is a clear OS advantage for using larotrectinib in NTRK-positive patients.

References

1. Bokemeyer C, Paracha N, Lassen U, et al. Overall survival (OS) of patients with TRK fusion–positive cancer receiving larotrectinib versus standard of care (SoC): A matching-adjusted indirect comparison (MAIC) using real-world data (RWD). J Clin Oncol. 2022;40(suppl 16):6579. doi:10.1200/JCO.2022.40.16_suppl.6579
2. Demetri G, Peters S, Davies J, et al. Characteristics and outcomes of patients (pts) with NTRK fusion-positive (NTRK+) metastatic / locally advanced (LA) solid tumours receiving non-TRK inhibitor (TRKi) standard of care (SoC), and prognostic value of NTRK fusions in clinical practice. Ann Oncol. 2021;32(suppl_5):S382-S406. doi:10.1016/annonc/annonc686