The PD-1 inhibitor pembrolizumab (Keytruda) displayed activity with a manageable safety profile in patients with certain rare and ultra-raresarcoma histotypes, according to findings from the phase 2 AcSé Pembrolizumab trial (NCT03012620) published in the Lancet Oncology.

Efficacy results from the French basket trial showed that a combined population of patients with sarcomas that have an incidence rate of less than 1 case per 1 million people per year (n = 97) achieved a 12-week objective response rate (ORR) of 6.2% (95% CI, 2.3%-13.0%), with no patients experiencing a complete response (CR). The median follow-up was 13.1 months (range, 0.1-52.8) and the data cutoff was April 11, 2022.

In terms of best overall response, 2 patients achieved a CR and 15 experienced a partial response (PR). The stable and progressive disease rates were 36% and 46%, respectively. Patients experienced a median duration of response (DOR) of 11.3 months (95% CI, 8.3-not reached [NR]) and the median time to response was 5.7 weeks (IQR, 2.9-16.6). The median overall survival (OS) was 19.7 months (95% CI, 11.6-NR) and the median progression-free survival (PFS) was 2.8 months (95% CI, 2.5-5.0).

The AcSé Pembrolizumab trial was a single-arm 7-cohort basket study that enrolled patients with unresectable locally advanced or metastatic rare cancers. Patients needed to have disease that was resistant or refractory to standard therapy, or for which standard therapy did not exist or was not considered appropriate, and no other experimental treatment options were available.

The report published in Lancet Oncology included findings from a substudy of patients with sarcomas from 24 sites in France. Histologic subtypes consisted of: chordoma (n = 34); alveolar soft part sarcoma (n = 14); SMARCA4-deficient sarcoma or malignant rhabdoid tumor (n = 12); desmoplastic small round cell tumor (n = 8); epithelioid sarcoma (n = 6); dendritic cell sarcoma (n = 4); clear cell sarcoma (n = 3); myxoid liposarcoma (n = 3); solitary fibrous tumor (n = 2); leiomyosarcoma (n = 1); perivascular epithelioid cell tumor (n = 1); intimal sarcoma MDM2 (n = 1); granular cell tumor (n = 1); soft part chondrosarcoma (n = 1); low grade fibromyxoid sarcoma (n = 1); unclassified small round cell sarcoma (n = 1); angiosarcoma (n = 1); and fibrosarcoma (n = 1). All patients included in the substudy were at least 15 years old, had an ECOG performance status of 1 or less, and had an estimated life expectancy of at least 90 days.

Findings revealed that patients with chordoma experienced a PR rate of 12% with a median DOR of 7.9 months (95% CI, 5.5-14.2). The stable and progressive disease rates were 71% and 18%, respectively. The median OS was NR (95% CI, 14.9-NR) and median PFS was 6.1 months (95% CI, 4.6-11.5).

One patient with alveolar soft part sarcoma achieved a CR, with a DOR of 11.3 months. Seven more patients in this subgroup experienced a PR for a PR rate of 50%, with a median DOR of 4.9 months (95% CI, 0.3-23.8). The stable and progressive disease rates were both 21%. The median OS was NR (95% CI, NR-NR) and the median PFS was 6.6 months (95% CI, 5.5-NR).

The other CR occurred in a patient with epithelioid sarcoma who experienced a DOR of 8.4 months. The median OS was 2.5 months (range, 1.6-NR) and the median PFS was 2.3 months (range, 0.9-NR).

Patients in the SMARCA4-deficient sarcoma or malignant rhabdoid tumor subgroup experienced a PR rate of 25%, with a median DOR of 13.3 months (95% CI, 8.3-33.5). The stable and progressive disease rates were 25% and 50%, respectively. The median OS was 2.8 months (range, 1.6-NR) and the median PFS was 2.0 months (range, 0.7-NR).

One patient with a desmoplastic small cell round tumor experienced a PR for a PR rate of 13%, with the response lasting 4.4 months. The progressive disease rate in this subgroup was 88%. The median OS was 7.4 months (range, 4.3-NR) and the median PFS was 2.0 months (range, 2.0-NR).

All patients with dendritic cell sarcoma, myxoid liposarcoma, clear cell sarcoma, solitary fibrous tumor, leiomyosarcoma, intimal sarcoma MDM2, granular cell tumor, soft part chondrosarcoma, unclassified small round cell sarcoma, angiosarcoma, or fibrosarcoma experienced disease progression. Conversely, all patients with perivascular epithelioid cell tumor or low grade fibromyxoid sarcoma achieved stable disease.

Overall, the median number of cycles of pembrolizumab was 6 (IQR, 4-17) at data cutoff and 2 patients remained on treatments. Reasons for discontinuation included disease progression (75%), adverse events (AEs; 7%), protocol ended (9%), death (6%), and patient decision (2%). Dose interruptions were reported in 16 patients and 47 patients had died at the data cutoff.

The median age in the intention-to-treat population was 51 years (IQR, 35-65). Most patients were male (55%) and had an ECOG performance status of 1 (67%). The median number of prior lines of therapy was 2 (range, 1-3); patients underwent 0 (20%), 1 (27%), 2 (25%), or 2 or more (29%) prior lines.

All patients received pembrolizumab at a dose of 200 mg intravenously on the first day of each 21-day cycles for up to 24 months or until disease progression. Those who were under the age of 18 received 2 mg/kg of pembrolizumab up to a maximum dose of 200 mg. Dose reduction was not permitted and treatment could be discontinued due to unacceptable toxicity, intercurrent illness, or changes in the patient’s condition preventing further therapy.

The primary end point was ORR and secondary end points included best overall response, time to response, DOR, OS, PFS, and safety.

In terms of safety, the most common grade 1 or 2 AEs included anemia (38%), lymphopenia (30%), diarrhea (23%), nausea (23%), dyspnea (22%), cough (22%), and pruritus (20%). Common grade 3 AEs included anemia (7%), abdominal pain (5%), and increased alanine aminotransferase (5%). Grade 4 AEs included increased aspartate aminotransferase (2%), thromboembolic event (1%), and anemia (1%), among others. One instance each of grade 5 biological inflammatory syndrome, dyspnea, general physical health deterioration, esophageal ulcer, and pulmonary pleural metastasis were reported.

In their conclusion, study authors noted that once the basket trial is complete a central review will commence to further explore their findings. They also stated that “…the clinical activity of pembrolizumab needs to be further confirmed in expanded cohorts and prospective studies with a careful monitoring of real-world data.”