Potential Seen for Entrectinib for Specific Patients With Sarcoma Harboring Genetic Rearrangements

sarcomatreated with entrectinib in the STARTRK-2 basket trial, according to the results of a case study presented at the 2017 Connective Tissue Oncology Society Annual Meeting that took place in Maui, Hawaii.¹Each of the 3 patients experienced a confirmed clinical response of 30% tumor reduction or more from treatment with entrectinib.

Entrectinib is a potent and selective inhibitor ofTRK,ROS1, and ALK that also demonstrates activity in the central nervous system. In phase I studies, the multikinase inhibitor showed an objective response rate of 79% across multiple tumor types, and in a safety analysis of 203 patients treated with the recommended phase II dose of entrectinib across 3 clinical studies, a mild toxicity profile was demonstrated with mostly grade 1/2 adverse events (AEs). No grade 4 AEs occurred in more than 1% of patients, and no grade 5 treatment-related AEs were observed.²

“This is a very active drug in a select number of patients who have these mutations. The prospect so far is great because I don’t see any significant side effects,” Kumar Sankhala, MD, said in an interview with Targeted Therapies in Oncology™. Previously working at Sarcoma Oncology Center, in Santa Monica, California, Sankhala is now the co-director of sarcoma medical oncology and director of clinical research at Cedars- Sinai Medical Center in Los Angeles, California.

STARTRK-2 is an ongoing multicenter phase II basket study of patients withNTRK, ROS1, or ALK gene fusions across multiple solid tumor types, excluding those with ALK-positive non—small cell lung cancer (NCT02568267) and patients previously treated with a tyrosine kinase inhibitor. Patients were tested for NTRK1/2/3, ROS1, and ALK gene fusions before being enrolled in the trial and treated with daily entrectinib, starting at a dose of 600 mg.¹

One subgroup of interest in the STARTRK-2 trial comprises patients with soft tissue sarcomas harboring these genetic rearrangements. “You cannot treat all sarcomas the same way with similar drugs. We have to understand their molecular biology individually and how to target that,” Sankhala said. “I think this drug, entrectinib, is a big leap in that process [of treating specific genetic alterations in individual types of sarcomas].”

In a previous study, Sankhala and his coauthors investigated the detection of NTRK, ROS1, and ALK gene rearrangements in patients with sarcoma. The authors suggested that although the frequency of these gene fusions across tumor types might be on the order of 3% or less, patients with sarcoma may have a higher prevalence.³

The authors tested patients with immunohistochemistry screening and a next-generation sequencing assay to identify patients with these rearrangements, who would in turn be eligible for the STARTRK-2 basket trial. In the study, Sankhala et al observed a prevalence of ALK rearrangements in 5% of patients with leiomyosarcoma, ROS1 fusions were identified in 4% of patients with ovarian/uterine sarcomas, and NTRK1/2/3 fusions were found in 8% of patients with breast sarcomas, 5% withfibrosarcomas, and 5% with stomach or small intestine sarcomas (TABLE).³

Sankhala noted that it is more challenging to test for genetic rearrangements in patients with bone sarcomas because samples from patients with bone sarcomas are usually not compatible with newer genomic testing technologies. That is why these patients were not included in the study, although he hopes that this capability will change in the future. In a case study of patients treated at the Sarcoma Oncology Center, 3 patients with sarcoma, each of whom harbored an NTRK or ALK gene fusion, were treated with entrectinib in the STARTRK-2 trial.¹

The first patient was a 49-year-old woman withendometrial stromal sarcoma, which had metastasized to the lung and right kidney, with a fusion in the TPM3-NTRK1 gene. She had previously undergone a total abdominal hysterectomy with bilateral salpingo-oophorectomy and had been treated with gemcitabine, doxorubicin, and docetaxel (Taxotere). While on entrectinib, she achieved an early response of 30.2% reduction in her tumor burden, which later increased to a 79% reduction from baseline.

Sankhala said that he could never forget this patient’s case because she had a great deal of tumor burden, pain, and discomfort but experienced an unexpected response from treatment with entrectinib while on the clinical trial. “When we saw her, she was quite miserable, and when we started her on the treatment I thought, there are no side effects from this treatment, we aren’t doing any harm, and it’s worth trying [entrectinib].... When I saw her later her life had totally changed. The tumor had almost gone, the pain had gone, the discomfort had gone, and all that misery had gone away. She was quite symptomatic and we saw a dramatic response,” he said.

The second patient, a 60-year-old woman with leiomyosarcoma metastatic to the abdomen, pelvis, liver, and left retroperitoneum, had an NPHP3-ALK gene fusion. After prior treatment of debulking surgery, tamoxifen, aldoxorubicin, and ifosfamide, she was treated with entrectinib and achieved a complete response by her eighth cycle and is still on the study after 7 months.

A 72-year-old female patient with uterine leiomyosarcoma and an IGFBP5-ALK gene fusion is still on the study at 13 months. She had previously received debulking surgery, radiotherapy with gemcitabine and cisplatin, aldoxorubicin and gemcitabine, nivolumab (Opdivo), and trabectedin (Yondelis). On entrectinib, she had a partial response of 32% reduction from baseline by cycle 8.

In their poster, the study authors noted that further work is needed to better characterize subtypes of patients with sarcoma, including those with NTRK1/2/3, ROS1, and ALK gene fusions; however, the results of the case study suggested that it was important to identify patients with these alterations who could respond to treatment with entrectinib. “The frequency for patients being tested for these mutations are still low,” Sankhala commented. “We should take more advantage of these [types of] agents [like entrectinib].”

References:

1. Multani P, Manavel EC, Hornby Z, et al. Preliminary evidence of clinical response to entrectinib in three sarcoma patients. Presented at: 2017 Connective Tissue Oncology Society Annual Meeting; November 8-11, 2017; Maui, Hawaii. Poster 080. ctos.org/Portals/0/PDF/2017%20CTOS%20Final%20Program.pdf.
2. Ahn M-J, Cho BC, Siena S, et al. Entrectinib in patients with locally advanced or metastatic ROS1 fusion-positive non-small cell lung cancer (NSCLC). Presented at: IASLC 18th World Conference on Lung Cancer; October 15-18, 2017; Yokohama, Japan. Abstract 8564. ignyta.com/wp-content/uploads/2017/10/ WCLC2017-Entrectinib-final-slides_v2.pdf.
3. Sankhala KK, Potts SJ, Christiansen J, et al. Immunohistochemistry screening to increase the efficiency of next generation sequencing for detection of NTRK, ROS1, and ALK gene rearrangements (fusions) in sarcoma patients. Presented at: 2016 Connective Tissue Oncology Society Annual Meeting; November 9-12, 2016; Lisbon, Portugal. Poster 033. ignyta.com/wp-content/uploads/2016/09/CTOS- 2016-Sarcoma-NTRK-ROS1-ALK-Ignyta-Potts.pdf.