Larotrectinib Benefits Patients With NTRK Fusions, Regardless of Pretreatment or Performance Status

David S. Hong, MD

Larotrectinib (Vitrakvi) led to high and durable responses in patients with NTRK fusions, irrespective of prior therapy or ECOG performance status (PS), according to David S. Hong, MD, who presented a pooled analysis from 3 clinical trials that evaluated the agent in patients with NTRK alterations during the 2020 AACR Virtual Annual Meeting I.

"Patients with NTRK fusions who have had a significant number of prior therapies can benefit from larotrectinib. In some cases, this has to be looked at on the ground level, but even some patients with an ECOG PS of 3 can benefit from NTRK inhibition," said Hong.

In the first analysis, patients were stratified according to the number of prior lines of therapy they had received (0, 1, 2, or 3 or greater) and baseline ECOG PS (0, 1, 2, or 3). The objective response rate (ORR) was highest in previously untreated patients with an ECOG PS of 0 (91%). However, larotrectinib showed benefit across each group, reaching an ORR of 85% in patients who had received at least 3 lines of prior therapy and 33% in patients with an ECOG PS of 3.¹

However, the benefit of larotrectinib did not extend to patients with other NTRK alterations beyond fusions. In the second analysis, investigators evaluated the efficacy of larotrectinib in patients according to NTRK gene status. Among 159 patients with NTRK fusions and 73 patients with non-fusion alterations, including point mutations, amplifications, rearrangements, and deletions, the ORR was 79% in the fusion group versus 1 partial response (PR) in the non-fusion group. Moreover, the median duration of response was 35.2 months and 3.7 months in the fusion and non-fusion groups, respectively.²

In an interview with OncLive, Hong, deputy chair, Department of investigational Cancer Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, discussed the results of these analyses with larotrectinib in patients with NTRK alterations.

OncLive: What do these long-term data show regarding larotrectinib’s use in patients with NTRK fusions?

Hong: Larotrectinib has been approved for almost 2 years. It's novel in the sense that it is the first targeted therapy that is approved across tumor types and ages. These data reconfirm the incredible efficacy and incredible safety of this drug in patients with NTRK fusions.

According to the post hoc analysis, how do responses to larotrectinib differ in the NTRK fusion versus non NTRK-fusion populations?

In this analysis, we pooled data from 3 studies [that evaluated larotrectinib in patients with NTRK fusions]: the phase 1 trial in adults (NCT02122913), the phase 1/2 SCOUT trial (NCT02637687) in pediatric patients, and the phase 2 NAVIGATE trial (NCT02576431) in adult and pediatric patients. These 3 trials led to the approval of larotrectinib in patients with NTRK fusions. We wanted to understand the differences in [outcomes] between patients with other NTRK alterations versus those with fusions.

When we started the pediatric and the adult phase 1 trial, there was not a whole lot of data regarding the efficacy of larotrectinib in patients with NTRK fusions or other alterations, such as mutations or amplifications. The phase 1 pediatric and adult trial allowed patients with all tumor types [to enroll]. In the dose-escalation, and, to some extent the expansion portions, we tried to determine whether larotrectinib had some efficacy in patients with other alterations.

Patients with NTRK fusions are relatively rare. Patients with fusions, mutations, amplifications, in addition to patients without those alterations were allowed on the trial. When we looked at the data comparing fusions with these other alterations in this kind of retrospective, pooled analysis, we saw marked differences [in outcomes]. There was a total of 159 patients with NTRK gene fusions compared with 73 patients who had non-fusion tumors. The response rates were dramatically different. The response rate in the NTRK fusion population was 79%, which included a 16% complete response rate compared with patients with other alterations in which only 1 patient had a very short-lived PR.

Were these responses durable?

We also saw a marked difference [in the durability of these responses]. Patients with NTRK fusions confirmed over a 35-month duration of response (DOR) and an overall survival reaching almost 44 months. Patients in the non-fusion group had a median DOR of close to 2.5 months. Only 1 patient had a durable response, which was probably related to their disease course.

Were there any new adverse events (AEs) of note?

There were no new AEs in the fusion and non-fusion groups. In the non-fusion group, there was a higher incidence of all-grade treatment-emergent AEs, which was probably related to the rapid progression of their underlying disease and not necessarily related to the drug. We really have not seen a whole lot of new AEs among these patients who have been on larotrectinib for approximately 47 months. It's remarkable how safe this drug has been in the majority of patients.

What are the implications of these data?

This drug works primarily in patients with NTRK fusions. We need to identify these patients with NTRK fusions to get the full bang for our buck with [TRK inhibitors]. These patients are out there, and there are probably more than we realize. Even in patients with advanced cancer, next-generation sequencing (NGS) is not widespread in America or other places. We recognize that it is not financially feasible for all countries, but there are standard operating procedures in the European Union and other places [that can help with access]. Identifying these patients is really key because they do appear to have incredible benefit from TRK inhibitors.

What were the findings regarding larotrectinib's efficacy across varying degrees of pretreatment and performance status?

In the phase 2 NAVIGATE study, we allowed patients with an ECOG PS of 3 to enroll given the significant benefit we saw initially in these patients in the phase 1 trial. It's important to note that, in general, patients with an ECOG PS of 3 are not going to do as well as patients with an ECOG PS of 1. However, in patients with an ECOG PS of 3, we did see benefit in a number of patients with NTRK fusions. I'm not one to [advise against] the judgement of individual physicians in the community, but we did see benefit in patients with an ECOG PS of 3 on the trial.

Patients who had fewer prior therapies tended to have a better response [to larotrectinib]. However, we also saw that these patients still have benefit from larotrectinib regardless of the number of prior therapies they have received. It's not clear whether these patients with NTRK fusions should receive larotrectinib up front or after standard chemotherapy.

Some of these patients can benefit for very long periods of time [with larotrectinib]. Our very first patient in the phase 1 trial still remains on study almost 5.5 years later, even though she was refractory to several lines of standard therapy for sarcoma. This tells you how oncogenically addicted these patients were to this pathway and how incredibly suppressing [larotrectinib] was to the tumor.

Is there any other research with larotrectinib, either planned or ongoing, you would like to highlight?

One of the patients in the phase 1 trial who had [an NTRK] amplification did respond [to larotrectinib], albeit it was a short-lived response. There has been another report of another patient with [NTRK]-amplified esophageal cancer who also responded [to larotrectinib]. That was reported with off-label use of the drug. There may be a possibility of benefit in certain subsets of patients with [NTRK] amplifications. That is a hypothesis we're testing in an investigational trial that I'm running.

How has the approval of entrectinib (Rozlytrek) impacted the use of larotrectinib, if at all?

These approvals are going to help us get the word out on NTRK fusions. The more evidence we have that patients who have NTRK fusions can receive an NTRK inhibitor, whether it’s larotrectinib or entrectinib, will benefit patients.

References

1. Drilon A, Van Tilburg CM, Farago AF, et al. Larotrectinib in TRK fusion cancer patients: outcomes by prior therapy and performance status. Presented at: 2020 AACR Virtual Meeting I; April 27-28, 2020. Abstract CT199. bit.ly/2YNRkmj.
2. Hong D, Dowlati A, Burris H, et al. Efficacy and safety of larotrectinib in patients with cancer and NTRK gene fusions or other alterations. Presented at: 2020 AACR Virtual Meeting I; April 27-28, 2020. Abstract CT062. bit.ly/3cl0Xg9.