Dr Antoine Italiano on Extended Follow-up Findings of Larotrectinib in Patients With TRK Fusion Cancer

Antoine Italiano, MD, PhD, head of Early Phase Trials and Sarcoma Units at Institut Bergonié, Bordeaux, France, addresses findings of an extended follow-up of larotrectinib in patients with TRK fusion cancer that indicated prolonged progression-free survival in those undergoing the NTRK inhibitor.

Findings of an extended follow-up of larotrectinib in patients with TRK fusion cancer indicates that the NTRK inhibitor is more effective than any other treatment for this patient population, said Antoine Italiano, MD, PhD.


Can you speak on the goals of the study assessing longer follow-up of larotrectinib use in patients with TRK fusion cancer?

The main point we have investigated in this study is the specific endpoint called the growth modulation index (GMI), which actually represent the ratio of PFS [progression-free survival] on an investigational treatment, larotrectinib, vs the PFS on a previous line of treatment the patient received.

This endpoint, GMI, is particularly useful in settings where it's very challenging to perform randomized study and therefore to have a control arm. And this is the case, for instance, with NTRK fusion, which is a very rare condition. So, GMI allowed using the patient as its own control, and we consider that a GMI ratio of more than 1.33 indicates a very promising activity.

This is what we observed in this study. We have analyzed the GMI for all the patients having received previous line of therapy, and then larotrectinib, based on the presence of NTRK fusion. So, 122 patients were included in the analysis and we observed the GMI of more than 1.33 in about 74% of patients, meaning that clearly, the most efficient systemic treatment in this specific population is the NTRK inhibitor.

Can you speak on the significance of the observed rise in GMI for those undergoing larotrectinib, and what benefits may come through longer PFS?

This means that since we don't have any randomized study, this intra-patient comparison, in which the patient is used as their own control, clearly indicates that larotrectinib is actually more effective than conventional treatment the patient has received. And for me, this clearly suggests that at least for patients within NTRK fusion, the best systemic treatment is NTRK inhibitor, larotrectinib.

So, we observed the regime of more than 1.33 in about 74% of the patients, so the majority of them. And more importantly, for a significant proportion of patients, GMI was higher than 5, and actually the median GMI was 8.9. So, this clearly indicates that larotrectinib is more effective than any other treatment, using this specific population characterized by NTRK infusion.

There were several patients whose GMI fell below the 1.33 threshold. Were there any notable trends observed in these patient populations, and those who met the threshold as well?

There were some patients in fact with the GMI less than 1.33, but you have also to consider that a significant number of these patients were censored, and so were not progressive at the time of statistical analysis. Importantly, for a majority of these patients, treatment was still ongoing so probably we will do a new update of this analysis in the next few months or few years. Probably, this proportion of patients with a GMI of less than 1.33 will decrease.

So, actually, we did some subgroup analyses. For instance, the age of the patient, pediatric vs adults, the number of metastatic sites, so metastatic disease vs locally advanced disease, and in all these subgroups we observed in the majority of patients a GMI significantly higher than 1.33. So, the benefit of larotrectinib is evident in all the subgroups, and there is no specific subgroup benefiting more than another one.


Hong DS, Italiano A, Briggs A, et al. Intra-patient comparison from larotrectinib clinical trials in TRK fusion cancer: An expanded dataset. J Clin Oncol 39, 2021 (suppl 15; abstr 3114). doi:10.1200/JCO.2021.39.15_suppl.3114