Pembrolizumab Shows Activity in Select Rare Sarcomas

Pembrolizumab Shows Activity in Select Rare Sarcomas
Sarcomas are rare malignancies, and effective therapies, apart from surgery and radiotherapy, are largely limited to chemotherapy and a handful of targeted agents.

But a few rare sarcoma subtypes may respond to therapy with the immune checkpoint inhibitor pembrolizumab (Keytruda), as French investigators demonstrated in the phase 2 AcSé trial.

Results from the study were presented online during the European Society of Medical Oncology (ESMO) Virtual Congress 2020.

“We all know that there is limited single-agent activity of PD-1 antibodies or PD-L1 antibodies as well as CTLA-4 antibodies in unselected sarcoma populations. But we also know that sarcomas are more than 150 different histotypes or molecular subtypes of disease,” commented led author Jean-Yves Blay, MD, PhD, from Université Claude Bernard in Lyon, France.

Combinations of checkpoint inhibitors and antiangiogenic agents have been associated with prolonged progression-free survival (PFS) in alveolar soft part sarcomas (ASPSs), and single-agent activity of immunotherapeutic agents has been reported in other rare subtypes, including chordoma and rhabdoid tumors, he said.

But given the rarity and heterogeneity of sarcomas, investigators are increasingly “moving from a one-size-fits-all approach to a basket approach, and this was the intent of this clinical trial,” Blay said.

AcSé Study Details

AcSé was a multicenter, open-label study involving patients with metastatic or treatment-refractory rare disease types, including sarcomas.

Patients with histologically confirmed diagnoses of rare sarcomas with metastatic disease or unresectable locally advanced tumors for whom there were no alternative treatment options were eligible.

Although there was no set definition of “rare,” for most sarcoma subtypes included in the study, the incidence was less than 1 per one million population.

The cohort included 81 patients: 24 with chordoma, 14 with alveolar ASPS, five with desmoplastic small round cell tumor (DSRCT), six with SMARCA4-malignant rhabdoid tumor (SMBT), and 32 with diseases of other histotypes, including epitheliod sarcoma, myxoid liposarcoma, chondrosarcoma, angiosarcoma, and other unspecified types.

The median age of the patients was 48 years. Patients had received a median of two prior lines of therapy.

Patients received pembrolizumab 200 mg intravenously every 21 days for up to 2 years or until disease progression or unacceptable toxicity or until the physician or the patient decided to withdraw.

Some Objective Responses Seen

The primary endpoint was the objective response rate by intention to treat at 84 days. Among all patients with sarcoma, there were no complete responses, but five patients (6%) had a partial response. An additional 34 patients had stable disease, for a disease control rate of 48%.

The best responses by histotype were seen in 2 of 6 patients with SMBT, 1 of 5 patients with epitheloid sarcoma, 2 of 24 with chordoma, 5 of 14 with ASPS, and 2 of 22 with other types.

There were no objective responses among patients with myxoid liposarcoma, DSRCT, chondosarcoma, or angiosarcoma.

At a median follow-up of 228 days, the median PFS was 7.9 months. Median overall survival was 19.7 months. In all, 33 patients died during follow-up, after a median of three cycles.

In all, 60% of patients who had had an initial response experienced disease progression or withdrew before 84 days. These patients were counted as nonresponders in the intention-to-treat analysis.

PFS was superior among patients with ASPS, chordoma, and DSCRT compared with patients with diseases of other histologies.

Overall survival was also superior among patients with ASPS and chordoma compared with patients with other sarcoma subtypes.

Toxicities were recorded in 28 patients. Grade 3 events occurred in four patients (one case each of cognitive disorder, bullous pemphigus, febrile aplasia, and erysipelas). There was one case of grade-4 lipasemia.

Blay noted that the four subtypes for which pembrolizumab prolonged PFS ― ASPS, chordoma, SMBT, and DSCRT ― are not consistently associated with either PD-L1 expression, high tumor mutational burden, cell infiltrates, or tertiary lymphoid structures that might make them susceptible to a PD-1/PD-L1 inhibitor.

“Therefore, additional translational research is foreseen to understand the determinants of response in these sarcoma histotypes,” he said.

Anti-PD-1 Recommended for Some Subtypes

Invited discussant Javier Martin-Broto, MD, PhD, from the Instituto de Biomedicina de Sevilla, Sevilla, Spain, commented that compared with other studies of immunotherapy with pembrolizumab (SARC028) or nivolumab (Opdivo; Alliance A091401), “the longer median progression-free survival observed in the current study could be highly related to the subtypes included in the study.”

In other studies with drug combinations, the respective median PFS for chordoma, ASPS, and epithelioid sarcoma was 14 months, 10.9 – 12.4 months, and 5.53 – 6 months, he noted.

“Anti PD-1 agents should be included in the therapeutic arsenal of some subtypes as an example alveolar soft part sarcoma or malignant rhabdoid tumors. Anti-PD-1 immunomodulation deserves further investigations in tumors with misfunctioning SWItch/Sucrose Non-Fermentable complex, such as epithelioid sarcoma, dedifferentiated chordoma, and others,” he said.

Martin-Broto also recommended that clinical research be conducted into regimens for sarcomas that combine chemotherapy with immunomodulators.

The study was supported by Merck Sharp & Dohme. Blay disclosed honoraria, consulting/advising, and research funding from MSD and others. Martin-Broto disclosed consulting/advising, speakers bureau participation, and research funding from several companies, not including MSD.

European Society for Medical Oncology (ESMO) Annual Meeting 2020: Abstract 1691O, presented September 21, 2020.

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