Entrectinib induces durable, intracranial responses in NTRK fusion-positive solid tumors
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Entrectinib demonstrated durable systemic and intracranial responses in patients with NTRK fusion-positive solid tumors, according to study results published in Clinical Cancer Research.
The agent also appeared tolerable and exhibited a safety profile consistent with previous reports.
Rationale and methods
“NTRK fusion-positive solid tumors represent a small but clinically relevant subgroup of patients who might derive significant benefit from targeted therapies. Recently, two inhibitors, entrectinib [Rozlytrek, Genentech] and larotrectinib [Vitrakvi, Bayer], received FDA approval. However, due to the rarity of these molecular events, safety data on these agents were limited to small patient cohorts enrolled into early clinical trials,” Christian Rolfo, MD, PhD, MBA, Drhc, professor and associate director for clinical research at Center for Thoracic Oncology at Mount Sinai’s Tisch Cancer Institute, told Healio.
In addition, data on specific patient subgroups of high clinical relevance, such as brain metastases, remained largely unknown, Rolfo added.
“In this manuscript, we presented updated efficacy and safety data of an integrated analysis of three phase 1/2 studies with entrectinib with a larger number of patients and longer follow-up than previously reported. This is the largest study on safety and efficacy results of entrectinib in NTRK fusion-positive solid tumors,” Rolfo said.
The updated integrated analysis included 121 adults with 14 tumor types and at least 30 histologies. Primary endpoints included objective response rate and duration of response by blinded independent central review. Secondary endpoints included PFS, intracranial efficacy and safety. Researchers included patients who received at least one dose of entrectinib in the safety-evaluable population.
The study had median follow-up of 25.8 months.
Key findings
Results showed an ORR among evaluable patients of 61.2%, including 19 patients with a complete response and 55 with a partial response. Researchers reported a median duration of response of 20 months (95% CI, 13-38.2) and median PFS of 13.8 months (95% CI, 10.1-19.9).
Moreover, they observed an intracranial ORR of 63.6% (95% CI, 30.8-89.1) and median intracranial duration of response of 22.1 months (95% CI, 7.4-not estimable) among 11 patients with blinded independent central review-assessed measurable central nervous system disease.
Researchers found no new safety concerns and grade 1 and grade 2 treatment-associated adverse events to be manageable/reversible with dose modifications. However, 8.3% of patients discontinued treatment due to adverse events.
“The present study confirms the promising efficacy of entrectinib in NTRK fusion-positive solid tumors seen in earlier reports, including a sustained intracranial activity. This is of particular interest, as 21% of patients had CNS metastases at baseline,” Rolfo said. “Furthermore, the favorable safety profile of the drug was confirmed with a high median dose intensity, suggesting that the majority of patients received most of the full planned dose.”
Implications
The results should encourage broader screening for NTRK fusions in patients with solid tumors who may benefit from entrectinib, Rolfo said. The next challenge would be to increase the testing rates for these rare, but clinically relevant, genomic events in clinical practice, he added.
“A broader use of next-generation sequencing techniques, even in liquid biopsy, is recommended for monitoring and identification of resistance mechanisms,” Rolfo said. “In addition, a deeper knowledge of the mechanisms of acquired resistance to first-generation TRK inhibitors might prompt the development of novel therapeutic strategies after failure of these currently approved targeted therapies.”
For more information:
Christian Rolfo, MD, PhD, MBA, Drhc, can be reached at Mount Sinai, One Gustave Levy Place, Box 1079, New York, NY 10029; email: christian.rolfo@mssm.edu.
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