Pembrolizumab Plus Cyclophosphamide Shows Limited Benefit in Diverse Types of Sarcoma


Pembrolizumab plus low dose metronomic cyclophosphamide demonstrated limited patient benefit in adult patients with diverse types of unresectable locally advanced or metastatic sarcoma.<br /> &nbsp;

One patient with other solitary fibrous tumor, showed an objective partial response and 16 patients attained stable disease (SD) following 6 months of combined pembrolizumab and cyclophosphamide. SD was attained by 6 patients with leiomyosarcoma, 4 patients with undifferentiated pleomorphic sarcoma (UPS), 3 patients with gastrointestinal stromal tumor (GIST), and by 3 patients with low grade endometrial stromal sarcoma.

&ldquo;PD-1 inhibition with pembrolizumab has a very limited activity in sarcomas,&rdquo; said lead author Antoine Italiano MD, PhD, of the Institut Bergoni&eacute;, in Bordeaux, France.

The trial evaluated pembrolizumab in 5 arms of subtypes of soft tissue and bone sarcoma. Preliminary findings revealed that the response in 3 arms of the trial was insufficient to meet the endpoints, leading the investigators to halt accrual in these arms. Two arms of the trial continue to accrue patients; in these arms, 7 patients (12%) remain on treatment.

Italiano presented findings during a poster discussion session on behalf of colleagues in the French Sarcoma Group of a phase II, open-label multicenter two-stage Simon&rsquo;s design study.

In the study, all patients received pembrolizumab at 200mg IV on day 8 of a 21-day cycle plus cyclophosphamide at 50 mg daily on an alternating one week on, one week off metronomic schedule during the study, which comprised 5 independent cohorts of patients with leiomyosarcoma (Arm A), undifferentiated pleomorphic sarcoma (Arm B), GIST (Arm C), osteosarcomas (Arm D), and other sarcomas (Arm E).

The co-primary endpoints for Arms A, B, D, and E were non-progression and objective response rate (ORR) at 6 months; the study planned to accrue more patients if &ge;3 patients had objective response or &ge;7 were progression-free at 6 months. The primary efficacy endpoint for Arm C was non-progression at 6 months; accrual was to continue if 4 or more of the first 10 enrolled patients were progression-free at 6 months

The pre-specified endpoint to justify continuing accrual was not met, leading to discontinuation of accrual in Arms A, C, and E; accrual is ongoing in Arms B and D.

The study enrolled 33 males and 24 female patients between June 2015 and June 2016. The patients had a median age of 53.5 years (range, 43.5-80.3) and the ECOG performance status was 0, 1, 2, 3, or not available for 19, 20, 5, and 1 patients, respectively. The majority (84%) of patients had metastatic disease and the remaining patients had locally advanced disease. Just 2 patients (3.5%) were treatment na&iuml;ve and 35.1% of patients had received 2 or more prior treatments.

All 57 patients were included in the safety analysis and 49 patients were evaluable for efficacy. Response was evaluated according to RECIST 1.1; radiologic tumor assessment was done at baseline and every 8 weeks. Biopsies were done at baseline and tumor plus immune cell samples were collected for translational analysis.

&ldquo;Limited intra-tumoral T-cell infiltration, lack of PD-L1 expression, infiltration by immunosuppressive cells, and the induction of alternative immunosuppressive pathways, such as indoleamine 2,3 —dioxygenase, may play a primary role in the resistance to PD-1 inhibition in sarcomas,&rdquo; explained Italiano.

The translational part of the study evaluated patient samples by immunohistochemistry, which showed little PL-L1 expression on the tumor or immune cells.

In addition, the kynurenine/tryptophan ratio was seen to increase from treatment cycles 1 to 3. Tryptophan is catabolized into kynurenine and several other immunologically active metabolites that suppress T-cell proliferation by indoleamine 2,3—dioxygenase, and an increased serum kynurenine/tryptophan ratio has been shown to associate with disease progression in several types of cancer.

Overall, pembrolizumab was well tolerated with toxicities that were consistent with published data. Treatment discontinuation due to an adverse event occurred in 4 patients (7%), and by investigators decision for 1 patient (2%). Treatment was halted due to progressive disease in 41 patients (84%) and 4 patients (7%) died on study.

&ldquo;These results suggest that combination strategies are needed to improve outcomes of immunotherapy in sarcomas,&rdquo; the authors concluded.

Italiano A; Penel N; Chevreau C; et al. Combination of pembrolizumab and metro- nomic cyclophosphamide in patients with advanced sarcomas: a french sarcoma group study. Presented at: Connective Tissue Oncology Society Annual Meeting; Lisbon, Portugal; November 9-12, 2016. Poster #2570261.

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