Larotrectinib Elicits Clinically Meaningful PFS Improvement Through GMI in TRK Fusion+ Cancers

Antoine Italiano, MD

Larotrectinib (Vitrakvi) demonstrated a clinically meaningful improvement in progression-free survival (PFS) compared with time to progression (TTP) on prior treatment in patients with TRK fusion—positive cancers using a measure known as the growth modulation index (GMI), according to results of an analysis presented at the 2019 ESMO Congress.

In the analysis, which included patients enrolled in 1 of 3 clinical trials, two-thirds of evaluable patients with TRK fusion—positive cancer on larotrectinib as their most recent therapy had a GMI ≥1.33, which was the threshold set for meaningful clinical benefit of the treatment. GMI is the ratio of PFS with the current therapy to TTP on the patient’s most recent prior line of therapy on which the patient experienced progression.

"GMI is a measure that incorporates patients as their own control," lead investigator of the analysis, Antoine Italiano, MD, professor of medical oncology, Institut Bergonie, Bordeaux, France, stated in a presentation during the meeting. "A GMI of more than 1.33 represents a 33% improvement with the current treatment over the prior treatment, and has been proposed as a threshold of clinically meaningful benefit. This intra-patient comparative analysis suggests that TRK-specific inhibition with larotrectinib improves outcome in patients with TRK fusion cancer compared with nontargeted therapies.”

GMI was used to evaluate the clinical activity of larotrectinib compared with the most recent prior treatment in 53 patients (42 adults, 11 pediatric) with metastatic TRK fusion—positive cancer. Eligible patients were analyzed from across 3 clinical trials in which they had been on treatment for at least 6 months (or discontinued early) and had at least 1 prior line of systemic therapy in the metastatic setting. Patients with 13 different tumor types were included.

"Randomized controlled trials are challenging for the cancer population, particularly when the investigated drug targets a molecular alteration shared by several tumor types with different natural histories and standards of care," he said. "In addition to low numbers of eligible patients for enrollment, the choice of the comparator arm challenges the feasibility of randomized trials in patients harboring rare oncogenic drivers."

TRK fusions occur in a wide range of adult and pediatric cancers and are identified far more often in rare tumor types than in more common cancers. The most common tissue types in Italiano’s analysis were soft tissue sarcoma (n = 12), lung cancer (n = 7), thyroid cancer (n = 6), and colon cancer (n = 6).

A total of 29 patients had NTRK1 gene fusions, 22 had NTRK3 fusions, and 2 had NTRK2 fusions. Of the 53 patients, 16 (30.2%) had received 2 prior lines of therapy and 24 (45.3%) received ≥3 prior lines.

The median GMI per independent committee assessment was 2.87 (range, 0.01-48.75). Some 71.7% of patients had a GMI of ≥1.00, 5.7% had a GMI between 1.0 and 1.33, and 66% had a GMI >1.33. Fifteen patients (28.3%) had a GMI <1.0 and 60.4% had a GMI ≥2.0.

Of the 18 patients with a GMI <1.3, 9 are still on treatment. “Subgroup analysis of GMI demonstrated that patients had clinically meaningful responses to larotrectinib irrespective of age, tumor type, ECOG performance status, TRK gene fusion, and number of prior lines of therapy,” said Italiano.

A high proportion of patients with GMI >1.33 had either a complete or partial response compared with ≤1.33. “However, 35% of nonresponders derived clinically meaningful benefit from larotrectinib, with a GMI of more than 1.33,” he said.

More than three-fourths (78.8%) of patients with a best overall response of complete or partial response had a GMI >1.33. Still, 45.0% of nonresponders derived clinically meaningful benefit from larotrectinib. Fifty-eight percent of patients with stable disease as best response had a GMI >1.33.

Caveats to the data, according to the authors, are that: 1) GMI underestimates the clinical benefit in patients on treatment who have not progressed at the time of analysis, 2) patients with the poorest prognosis may have been excluded as patients had to have received at least 1 prior line of therapy for inclusion, and 3) TTP data on the most recent prior treatment were provided by physicians.

Italinao A, Nanda S, Keating K, et al. Growth modulation index (GMI) as a comparative measure of clinical activity of larotrectinib versus prior systemic treatments in adult and pediatric TRK fusion cancer patients. Presented at 2019 ESMO Congress; September 27-October 2, 2019; Barcelona, Spain. Abstract 485P.Nat Med. doi:10.1038/nm.4118.

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