Targeted Treatments Showing Early Efficacy in Sarcoma Subtypes

Robin L. Jones, BSc, MB, MRCP, MD

Following in the footsteps of pazopanib (Votrient) and olaratumab (Lartruvo), many targeted therapies are being studied in patients with soft tissue sarcomas (STS), capitalizing on the benefits of targeted therapies in sarcomas. Although chemotherapy-driven approaches remain the standard for treatment of sarcomas, there is a wide range of sensitivities to chemotherapies across the sarcoma subtypes, Robin L. Jones, BSc, MB, MRCP, MD (Res) highlighted. Thus, patients with chemo-resistant histological subtypes may especially benefit from targeted therapy approaches.

During the 2018 ESMO Sarcoma and GIST Symposium, Jones, team leader in sarcoma clinical trials at The Institute of Cancer Research and a consultant medical oncologist at The Royal Marsden, both in London, discussed several targeted therapies in development in specific histological subtypes of sarcoma that have demonstrated early ef cacy signals.

Tazemetostat, an EZH2 inhibitor, demonstrated promising antitumor activity as a single agent in adult patients with epi- thelioid sarcoma who harbored evidence of INI1 loss in a phase II open-label, single-arm study._¹This loss impairs SWI/SNF function, which causes aberrant PRC2 activity and a resulting dependence on EZH2 activity, Jones explained, which “opens up the possibility of treatment with an EZH2 inhibitor.” Epithelioid sarcomas, which are a rare subtype of STS, have recently been characterized byINI1loss.

Of the 31 patients in the study, most had been previously treated, with the mean number of prior lines of therapy being 2; 87% of the patients had metastatic disease at baseline. Four patients (13%) achieved a partial response and 18 (58%) had stable disease, which lasted ≥32 weeks in 6 patients. At the study cutoff, 6 patients (19%) were still receiving treatment with tazemetostat. The median progression-free survival (PFS) was 5.7 months.

The most frequent adverse events (AEs) were grade 1/2 fatigue (39%), nausea (26%), and vomiting (19%). Given the promising activity and the tolerability of the agent, enrollment in the trial was subsequently expanded.

Endoglin, which is upregulated on tumor endothelial cells following inhibition of the VEGF pathway, is being targeted for use in combination with the multikinase inhibitor pazopanib in patients with sarcoma. TRC105, an endoglin antibody, plus pazopanib induced complete responses in 3 of 81 patients (4%) with sarcoma in a phase Ib/IIa study. In the overall study, the median PFS with the combination was 4.14 months.²In patients with angiosarcoma, which is known to densely express endoglin, the median PFS was longer than 11.1 months. AEs commonly observed from treatment with TRC105 included grade ≤2 telangiectasia, grade ≤2 head- ache, and grade ≤3 anemia; no grade 4 or 5 events were observed related to TRC105. This led to the development of the ongoing phase III TAPPAS study of the combination versus pazopanib alone in 124 patients with angiosarcoma (NCT02979899).

The early clinical activity of selinexor, an oral inhibitor of XPO-1, in patients with sarcoma in a phase Ib trial led to the development of the ongoing phase II/III SEAL study of selinexor versus placebo in patients with advanced unresectable dedif- ferentiated liposarcoma (NCT02606461). Of 52 evaluable patients in the phase Ib study of patients with advanced refractory bone sarcoma or STS, 30 (58%) experienced stable disease, which lasted ≥4 months in 17 patients (33%).3 In patients with dedifferentiated liposarcoma, 7 of 15 patients (47%) had stable disease for ≥4 months. A at dose of 60 mg of selinexor was better tolerated in the study, which will be utilized in the phase II/III trial.

CDK4 and MDM2 inhibitors have also been investigated in dedifferentiated liposarcomas; however, Jones noted that this approach has not been as promising as others. “The results of CDK4 and MDM2 inhibitors in dedifferentiated liposarcoma have, to a certain degree, been disappointing. Plus the toxicity of these agents, in terms of hematological and gastrointestinal [adverse events, has also been disappointing],” he commented.

As more than 90% of patients with well-differentiated or dedif- ferentiated liposarcomas have CDK4 ampli cation, targeting CDK4 with CDK4/6 inhibitors seemed like a promising potential target in this patient population.⁴

A phase II trial of the CDK4 inhibitor palbociclib (Ibrance) in 60 patients with well-differentiated or dedifferentiated liposar- coma demonstrated occasional tumor responses and only 1 com- plete response, which lasted ≥2 years.4 Thirty-five patients (58%) in the study were tested and had CDK4 ampli cation. Patients were treated with 125 mg of palbociclib once daily for 21 days of a 28-day cycle.

The PFS rate at 12 weeks, the primary endpoint of the study, was 57.2% and the median PFS was 17.9 weeks. A PFS at 12 weeks of more than 60% would have been found promising.

Most AEs were hematologic toxicities, including neutropenia (grade 3, 33%; grade 4, 3%), anemia (grade 3, 22%), and throm- bocytopenia (grade 3, 5%; grade 4, 2%). This safety pro le was found to be better than the 200-mg dosage of palbociclib. None- theless, studies of CDK4/6 inhibitors continue in patients with dedifferentiated liposarcoma, including a phase II study of abe- maciclib (Verzenio) in this patient population (NCT02846987).

Such studies have led the way for further studies of targeted agents in histology-speci c and molecularly-driven sarcomas.

References:

1. Gounder MM, Stacchiotti S, Schö ski P, et al. Phase 2 multicenter study of the EZH2 inhibi- tor tazemetostat in adults with INI1 negative epithelioid sarcoma (NCT02601950). J Clin Oncol. 2017;35(suppl; abstr 11058). meetinglibrary.asco.org/record/153327/abstract.
2. Attia S, Sankhala KK, Riedel RF, et al. A phase 1B/ phase 2A study of TRC105 (Endoglin Antibody) in combination with pazopanib (P) in patients (pts) with advanced soft tissue sarcoma (STS). J Clin Oncol. 2016;34(suppl; abstr 11016). meetinglibrary.asco.org/record/123125/abstract.
3. Gounder MM, Zer A, Tap WD, et al. Phase IB study of selinexor, a rst-in-class inhibitor of nu- clear export, in patients with advanced refractory bone or soft tissue sarcoma. J Clin Oncol. 2016;34(26):3166-3174. doi: 10.1200/JCO.2016.67.6346.
4. Dickson MA, Schwartz GK, Keohan ML, et al. Progression-free survival among patients with well-di erentiated or dedi erentiated liposarcoma treated with CDK4 inhibitor palbociclib: a phase 2 clinical trial. JAMA Oncol. 2016;2(7):937-940. doi: 10.1001/jamaoncol.2016.0264.