Dasatinib activity varies by sarcoma subtype

Dasatinib monotherapy did not control sarcoma growth for at least 6 months in most patients with rare sarcomas, according to the results of a phase 2 study.

However, more than 10% of patients with alveolar soft part sarcoma, chondrosarcoma or chordoma achieved objective tumor responses and protracted stable disease, results showed.

“A number of distinct histological subtypes of sarcoma share the unusual behavior of a low cell proliferation rate but a high risk for local recurrence and systemic spread, which may occur years after definitive treatment of the primary cancer,” Scott M. Schuetze, MD, PhD, professor of medical oncology at University of Michigan Health System, and colleagues wrote. “With few notable exceptions, these sarcomas are resistant to chemotherapy, and patients afflicted with one of these sarcomas are in great need of more effective drug treatment when the disease cannot be excised and is refractory to radiation, or is widely metastatic.”

Dasatinib (Sprycel; Bristol-Myers Squibb, Otsuka) is a small-molecule inhibitor currently approved for the treatment of chronic myelogenous leukemia.

Schuetze and colleagues sought to observe the antitumor activity of dasatinib in 109 patients (median age at study entry, 54 years; range, 22-87) with a range of rare sarcoma subtypes, including alveolar soft part sarcoma (n = 12), chondrosarcoma (n = 33), chordoma (n = 32), solitary fibrous tumor (n = 25) and epithelioid sarcoma (n = 7).

The researchers randomly assigned patients to 100 mg oral dasatinib twice daily, over the course of a 28-day cycle. The study dose was reduced to 70 mg due to toxicity data from other trials investigating dasatinib. The researchers also permitted dose reductions (50 mg twice daily or 100 mg once daily) based on toxicity.

Therapy continued until disease progression, unacceptable toxicity or patient withdrawal.

Patients received initial MRI or CT imaging within 2 weeks of treatment to establish extent of disease, then every 2 months for the first 6 months of treatment. Imaging then continued every 3 months until disease progression.

All patients had discontinued treatment at the time of reporting, with a median of four treatment cycles (range, 1-87). Median number of cycles varied by sarcoma subtype (alveolar soft part sarcoma, n = 7.5; chordoma, n = 6; chondrosarcoma, n = 4; epithelioid sarcoma, n = 9; solitary fibrous tumor, n = 2).

The overall cohort had a 6-month PFS rate of 48%, with a median PFS of 5.8 months and median OS of 21.6 months.

Patients with alveolar soft part sarcoma had the highest 6-month PFS rate by subtype (62%), whereas patients with soft fibrous tumor had the lowest (30%).

Median PFS by subtype ranged from 2 months for solitary fibrous tumor to 11 months for alveolar soft part sarcoma.

Objective tumor responses by Choi criteria occurred in six patients with chondrosarcoma, six patients with chordoma, five patients with solitary fibrous tumor, two patients with epithelioid sarcoma and one patient with alveolar soft part sarcoma.

A post-hoc analysis found that one patient with chordoma achieved an objective response by RECIST criteria.

Seven patients remained on therapy for more than 2 years (alveolar soft part sarcoma, n = 1; chordoma, n = 3; chondrosarcoma, n = 3).

The overall cohort had a 2-year OS rate of 44% and a 5-year OS rate of 13%. Thirty percent of patients with alveolar soft part sarcomas remained alive at 5 years; in contrast, all patients with epithelioid sarcoma died.

Disease progression served as the most common reason for treatment cessation. Grade 3 or grade 4 adverse events seen in greater than 5% of the study population included pain (17%), dyspnea (11%), pleural effusion (6%) and diarrhea (5%).

Six patients died on study, due to disease progression (n = 2), pulmonary complications from sarcoma (n = 3), and reasons unrelated to disease or treatment (n = 1).

“Dasatinib should not be used as a standard treatment for soft fibrous sarcoma, but a comparative study with cediranib [AZD2171, AstraZeneca] or sunitinib [Sutent, Pfizer] may be worthwhile; this will depend on results from the ongoing alveolar soft part sarcoma trial,” Schuetze and colleagues wrote. “The low rate of OS for patients with epithelioid sarcoma highlights the urgent need to identify active drugs to treat patients with metastatic epithelioid sarcoma. Because of a lack of defined drug therapy for the treatment of patients with locally advanced, unresectable or metastatic chondrosarcoma of the bone or chordoma and the results discussed previously, a further evaluation of dasatinib for chondrosarcoma and chordoma should be considered in future clinical trials.”

The study design may be responsible for its disappointing results; however, the findings highlight advances in certain sarcoma subtypes, Victor M. Villalobos, MD, PhD, Brianna Hoffner, NP, and Anthony D. Elias, MD, all of the division of medical oncology at University of Colorado Denver School of Medicine, wrote in a related editorial.

“[H]ad the trial met its primary endpoint, this would have necessitated the assumption that dasatinib is considered active in all five of these sarcoma subtypes when, in reality, the activity was heterogeneous and based on the tumor subtype,” Villalobos and colleagues wrote. “Perhaps the biggest strength of this article is the demonstration that we can indeed perform high-quality clinical trials in the setting of ultrarare cancers.”

Villalobos and colleagues acknowledged the challenge in studying ultrarare sarcomas.

“This opens up more opportunities for developing more selectively designed cohort studies, which may lead us to better data on whether certain therapies are more clearly active,” they wrote. “The ability of the [researchers] to enroll patients with relative rapidity into a trial for extremely rare cancers shows that these types of trials are, in fact, possible and feasible.” – by Cameron Kelsall

Disclosure: The Sarcoma Alliance Through Research and Collaboration and Bristol-Myers Squibb funded this study, and Bristol-Myers Squibb provided dasatinib. Schuetze reports grants and/or personal fees from Amgen, Janssen R&D and Lilly outside of the submitted work. Please see the full study for a list of all other researchers’ relevant financial disclosures. Villalobos, Hoffner and Elias report no relevant financial disclosures.