Larotrectinib induces durable responses in TRK fusion cancers
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Larotrectinib appeared highly effective for adults and children with tropomyosin receptor kinase fusion cancers, according to study results presented at the virtual American Association for Cancer Research Annual Meeting.
Larotrectinib (Vitrakvi, Bayer) induced durable responses in this patient population.
However, patients with other neurotrophic receptor tyrosine kinase (NTRK) alterations — including point mutations and amplifications — derived limited benefit.
“These data strongly support the clinical importance of testing for NTRK gene fusions in order to identify patients who would benefit from larotrectinib treatment,” David S. Hong, MD, deputy chair of the department of investigational cancer therapeutics in the division of cancer medicine at The University of Texas MD Anderson Cancer Center, said during a presentation.
Larotrectinib — a selective tropomyosin receptor kinase (TRK) inhibitor — is approved in the United States for treatment of adults and children with solid tumors that harbor NTRK gene fusions. The agent inhibits constitutively active TRK signaling resulting from NTRK gene fusions.
A pooled analysis showed the agent induced a 79% objective response rate among adults or children with confirmed NTRK gene fusions.
Several other alterations in NTRK genes — such as rearrangements, amplifications, deletions and splice variants — have been identified in different cancer types.
Hong and colleagues pooled data from three clinical trials of adults and children with cancer to evaluate the efficacy of larotrectinib for patients with nonfusion alterations in NTRK genes. Adults received larotrectinib dosed at 100 mg twice daily. Children received 100 mg/m2 twice daily (maximum 100 mg twice daily).
Key efficacy outcomes included investigator-assessed ORR, duration of response, PFS and OS. Investigators also assessed adverse events.
The analysis included 159 patients with NTRK fusions. This group represented 17 tumor types, including soft tissue sarcoma (23%), infantile fibrosarcoma (18%), thyroid cancer (16%) and salivary gland cancer (13%). The analysis also included 73 patients with nonfusion alterations. This group represented 25 tumor types, including lung cancer (14%), soft tissue sarcoma (12%) and colon cancer (11%).
In the fusion group, most fusions were in NTRK1 (40%) or NTRK3 (55%). NTRK alterations identified in the nonfusion group included point mutations (11%), amplifications (7%), rearrangements (4%) and deletions (1%). Twenty-four patients in the nonfusion group had other oncogenic alterations.
The fusion and nonfusion groups were balanced with regard to sex, but patients in the nonfusion group were older (median age, 58 years vs. 43 years). Most patients had received prior cancer therapy (94% for fusion vs. 97% for nonfusion); a higher percentage of patients in the nonfusion group had received three or more prior therapies (63% vs. 26%).
Median treatment duration was 7.9 months in the fusion group and 1.7 months in the nonfusion group.
Researchers reported an ORR of 79% (95% CI, 72-85) in the fusion group, with 24 patients (16%) achieving complete response, 97 (63%) achieving partial response, 19 (12%) demonstrating stable disease and nine (6%) exhibiting progressive disease.
Median duration of response was 35.2 months (95% CI, 22.8-not estimable).
Only one patient in the nonfusion group responded to larotrectinib. The patient — who had NTRK1 amplification — achieved partial response that lasted 3.7 months.
Seventeen patients (23%) in the nonfusion group had stable disease and 48 (66%) had progressive disease.
At the time of data cutoff, 64% of patients with NTRK fusions remained on larotrectinib treatment, with the longest duration being 47 months. In the nonfusion group, with the exception of one person who remained on treatment for 27 months, patients discontinued after an average of 2.5 months.
Patients in the fusion group achieved longer median duration of response (35.2 months vs. 3.7 months), PFS (28.3 months vs. 1.8 months) and OS (44.4 months vs. 10.7 months).
Most adverse events were grade 1 or grade 2.
Patients in the nonfusion group appeared more likely than those in the fusion group to experience grade 3 or grade 4 adverse events (58% vs. 49%) or to discontinue treatment due to adverse events (25% vs. 6%). – by Mark Leiser
Reference:
Hong DS, et al. Abstract CT062. Presented at: AACR Annual Meeting; April 27-28, 2020 (virtual meeting).
Disclosures: Hong reports research or grant funding from AbbVie, Adaptimmune, Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Daiichi Sankyo, Eisai, Eli Lilly, GlaxoSmithKline, Merck, Pfizer, Seattle Genetics, Takeda and several other pharmaceutical companies. Please see the abstract for all other researchers’ relevant financial disclosures.
Perspective
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Vincent Chung, MD
Larotrectinib is a highly selective TRK inhibitor approved in November 2018 for patients harboring NTRK gene fusions. NTRK gene fusions are genomic rearrangements containing the kinase domain of TRK 1, 2 or 3 and a dimerization domain generating an oncogenic driver. This FDA approval was based upon an initial study that evaluated 55 patients harboring 17 unique TRK-fusion positive tumor types. That study, published in 2018 in The New England Journal of Medicine by Drilon and colleagues, demonstrated an overall response rate of 75%. Regardless of patient age and tumor type, marked and durable tumor responses were seen in patients with TRK fusion tumors treated with larotrectinib.
At AACR this year, Hong and colleagues presented updated results from a pooled analysis of three phase 1/phase 2 clinical trials of larotrectinib for patients with TRK-fusion positive solid tumors. The analysis included 159 patients treated with larotrectinib. The objective response rate was 79%, with 16% having complete responses. The 73 patients with nonfusion TRK alterations, such as point mutations or amplifications, had minimal benefit with larotrectinib.
This is an important study confirming the tumor agnostic activity of larotrectinib and highlights the importance of evaluating patients’ tumors for TRK fusions. Given the favorable safety profile and high response rate, larotrectinib provides our patients with a targeted therapy for an oncogenic driven tumor leading to prolonged survival with good quality of life. The next step will be to study the mechanisms of resistance and to develop therapies to overcome it.
Perspective
Back to TopPatricia Mucci LoRusso, DO
The patients who really benefited from larotrectinib all had TRK fusions. Despite having such robust activity initially, several patients eventually progressed, as you can see from the PFS and OS curves. Why do these patients progress? What are the mechanisms of resistance, and can this resistance be overcome? What is known about acquired resistance?
Drilon and colleagues published data in 2017 on 31 patients they had treated, and they found that about 10% of patients had bypass mechanisms. They could not identify a resistance mechanism for about 25% of patients. In the remaining 65%, they identified mechanisms of acquired resistance that were directly related to TRK fusion alterations, with the greatest mutation for eventual resistance to first-generation inhibitors being solvent front.
The main mechanism of resistance is on target, the TRK fusion having a secondary mutation. Several companies have gone on to develop second-generation TRK inhibitors that have as one of their positive characteristics activity against the NTRK secondary mutations.
So, how should we approach these patients? Obviously we have the front-line TRK inhibitors, but when patients progress, it is important to look at those tumors and identify the mechanism of resistance. If it is off target, we need to treat with drugs — perhaps even combinations — that target those mechanisms. If they’re on target, we need to consider a second-generation TRK inhibitor and, at the time of progression after treatment with a second-generation inhibitor, look at those tumors again to determine how best to subsequently treat those patients.
Reference:
Drilon A, et al. Cancer Discov. 2017;doi:10.1158/2159-8290.CD-17-0507.
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