Pembrolizumab Becomes First Anti-PD-1 Therapy to Show Activity in Kaposi’s Sarcoma

Promising anti-tumor activity has been demonstrated with pembrolizumab (Keytruda) along with an acceptable safety profile in patients with classic and endemic Kaposi’s sarcoma, signaling that anti-PD-1 therapy may be a new therapeutic option for this patient population, according to results from a phase 2 study published in the Lancet Oncology.

The objective response rate observed with pembrolizumab was 71% (95% CI, 44%-90%), meeting the study’s primary end point. The investigator-initiated, single-arm, proof-of-concept, phase 2 multicenter study is the first known study to evaluate the role of PD-1 blockade in patients with classic and endemic Kaposi’s sarcoma.

“Although studies of classic and endemic Kaposi’s sarcoma are scarce, the response rate of classic Kaposi’s sarcoma to pegylated liposomal doxorubicin is approximately 70%, with 12% of patients experiencing grade 3-4 adverse events, and a median duration of response of 25 months, and the duration of response with paclitaxel was 13 months with a rate of grade 3-4 adverse events ranging from 5% to 20%,” wrote the study authors, led by Julie Delyon, MD, of the Lausanne University Hospital in France.

The small study included 26 patients, 17 of whom had classic Kaposi’s sarcoma and 9 of whom had endemic disease. All patients enrolled were adults aged 18 or older with histologically proven disease who required systemic therapy. Patients were required to have at least 4 measurable active cutaneous lesions of at least 5 mm, along with adequate hematological, renal, hepatic function, and an ECOG performance score of 0 or 1.

According to the Simon’s 2-stage optimal plan, the study was 90% powered to detect a 30% or higher ORR to achieve a significant result. With a response rate less than 5%, pembrolizumab would have been deemed inactive in patients with classic and endemic Kaposi’s sarcoma, according to the study’s protocol.

Treated with pembrolizumab 200 mg via intravenous infusion every 3 weeks for 6 months, patients in the study were followed for a median of 20.4 months (interquartile range [IQR], 18.1-24.1). The primary end point assessed in the study was objective response rate (ORR) determined by the number of complete responses (CRs) or partial responses (PRs) achieved from the start of treatment until the 6-month timepoint. Secondary end points of the study included best ORR, response rates at 3 and 6 months, response rate according to the number of lesions and size, and tumor infiltration of target lesion at month 3 and 6, the response rate on lymphoedema scale from 0 to 3 at months 3 and 6, time to response (TTR), duration of response (DOR) and time to progression (TTP).

The population was 88%, and largely of Sub-Saharan African and Caribbean descent (53%). Fifty-nine percent of patients had 10 to 50 cutaneous lesions while only 6% had more than 100.

Mild Kaposi’s sarcoma-associated oedema was identified at baseline in 59% of patients while 18% had moderate symptoms, and 24% had none. No patients in the study had severe Kaposi’s sarcoma-associated oedema. In terms of Kaposi’s sarcoma extracutaneous extension, 65% of patients had no lymph node and no visceral extension, while 24% had lymph node extension only, and 13% had both lymph node and bone extension. The majority of patients (71%) had an ECOG performance score of 0 compared with 1 (29%).

Most patients (65%) were previously treated with chemotherapy. Also, 29% of the study population had prior radiotherapy, and 18% had interferon therapy. HHV8 viral load in whole blood at baseline was positive in 53% of patients, undetectable in 47%, and date were unavailable for 12%.

Responses to pembrolizumab treatment in patients with classic and endemic Kaposi’s sarcoma leading to the 71% ORR including CRs in 12% of patients, PRs in 59%, and stable disease (SD) in 29% within 6 months of initiating therapy.

The median TTR among responders was 4.8 months (IQR, 3.4-12.0), and the median DOR was 23.4 months (95% CI, 21.2 to not evaluable [NE]). The median TTP on pembrolizumab was 24 months (95% CI, 15-NE).

At 3 months, CRs were observed in 6% of patients, PRs in 47%, SD in 41%, and progressive disease (PD) in 6%). At the 6-month mark, CRs were achieved in 13%, PRs in 59%, SD in 12%, and PD in 18%.

In terms of safety, treatment-related adverse events (TRAEs) occurred in 76% of patients. The TRAEs observed included acute cardiac decompensations and granulomatous reaction, each occurring in 6% of patients. The most common any-grade TRAEs observed with pembrolizumab in the study were diarrhea (18%), pruritis (18%), creatine phosphokinase test evaluation (12%), and hypophysitis with hypercortisolism (12%).

“This work might form the basis of larger prospective studies. If these results are confirmed, treatment with anti-PD-1 could become part of the standard armamentarium for patients with classic or endemic Kaposi’s sarcoma requiring a systemic treatment, which could have a positive impact on the prognosis of patients with classic and endemic Kaposi’s sarcoma, wrote Deylon, et al.

_REFERENCE:

_{Delyon J, Biard L, Renaud M, et al. PD-1 blockade with pembrolizumab in classic or endemic Kaposi's sarcoma: a multicentre, single-arm, phase 2 study. Lancet Oncol. 2022;23(4):491-500. doi: 10.1016/S1470-2045(22)00097-3.}