Chemo-ICI Combo Promising in Soft Tissue Sarcoma

A combination of eribulin (Halaven) and pembrolizumab (Keytruda) offered promising results in patients with metastatic soft tissue sarcomas that were sensitive to immune checkpoint inhibition (ICI), a researcher reported.

In a phase II study, the chemotherapy/ICI combination achieved a progression-free survival (PFS) rate of 69% at 12 weeks in liposarcoma patients and meet the study’s primary endpoint, according to Suzanne George, MD, of the Dana Farber Cancer Institute in Boston.

In addition, patients with cutaneous and visceral angiosarcoma, as well as some with undifferentiated pleomorphic sarcoma (UPS) and SMARCA4-deficient thoracic sarcoma, showed significant responses, she reported at the Connective Tissue Oncology Society (CTOS) virtual meeting.

ICI therapy has a demonstrated “modest but consistent” benefit in certain subtypes of soft tissue sarcoma, particularly UPS and dedifferentiated liposarcomas, while eribulin has also demonstrated activity in sarcoma, most notable in liposarcoma, according to George.

George also noted that combinations of cytotoxic chemotherapies and ICIs are used widely in several malignancies. For instance, the phase Ib/II ENHANCE-1 study showed that eribulin-pembrolizumab had a favorable safety profile in triple-negative breast cancer.

The cohort for the current trial was divided into three: leiomyosarcoma, liposarcoma, and other sarcomas/UPS. The current analysis focused on the liposarcoma and the other sarcomas/UPS cohorts.

Patients were treated with standard doses of eribulin and pembrolizumab every 21 days, with restaging performed every two cycles. Treatment continued for 2 years, or until disease progression, unacceptable toxicity, or patient or physician choice.

The primary objective of the study was PFS at 12 weeks, with a PFS rate of 60% at 12 weeks considered a positive result.

The liposarcoma cohort included 20 patients, 17 of them with dedifferentiated liposarcoma, while the UPS/other cohort had 19 patients, most of who had UPS (n=8) and angiosarcoma (n=3). Median number of prior therapies in each cohort was one.

George’s group reported that the median PFS in the liposarcoma cohort group was 27 weeks, with three partial responses (15% objective response rate).

In the UPS/other cohort, 56% of patients were progression free at 12 weeks, with a median PFS of 12 weeks, and six partial responses (33% ORR).

“It is important to note that all patients with stable disease or response had progressive disease by imaging at study entry,” George stated.

In the liposarcoma cohort, two of the three partial responses (PRs) occurred in patients with de-differentiated liposarcoma, while the third occurred in a patient with pleomorphic liposarcoma. In the UPS/other cohort, three of the six PRs occurred in patients with angiosarcoma, while PRs were also seen in UPS and SMARCA4-deficient thoracic sarcomas.

“Across all subtypes, patients who achieved tumor reduction and partial response, as well as stable disease, had relatively long disease control, while there was a subgroup of patients who had rapid progression,” George reported. “Future studies are needed to understand the rapid progressors, as well as the durable responders in order to optimize patient selection.”

Adverse events were consistent with toxicities seen with these two agents, George said, with neutropenia being the most common grade ≥3 toxicity.

CTOS session chair Breelyn A. Wilky, MD, of the University of Colorado Medicine in Aurora, noted that for “immune-cold” sarcomas, one of the most interesting areas of investigation is the use of chemotherapy, with the idea that chemotherapy may boost antigen presentation and immune infiltration, and enhance ICI activity.

“This study shows exciting results in liposarcoma, UPS, and angiosarcoma,” Wilky stated. “However, these can all be ‘immune-hot’ sarcomas, and can respond to pembrolizumab monotherapy. Thus, randomized clinical trials of chemotherapy combinations are really critical to determine whether outcomes are additive or truly synergistic.”