Pembrolizumab/Lenvatinib Combo Under Investigation in Classic Kaposi Sarcoma


Alice Indini, MD, discusses the ongoing PULSAR trial examining pembrolizumab plus lenvatinib as a novel therapeutic option for patients with classic Kaposi sarcoma.

Alice Indini, MD

Alice Indini, MD

For patients with classic Kaposi sarcoma who relapse following their first or second line of chemotherapy, treatment options are extremely limited, according to Alice Indini, MD. In an effort to expand options available to this population, the phase 2 PULSAR study (EudraCT 2020-004426-36) is examining a novel combination comprised of pembrolizumab (Keytruda) and lenvatinib (Lenvima).1

Classic Kaposi sarcoma is a rare, cutaneous neoplasm of endothelial origin that is caused by chronic human herpesvirus-8 (HHV-8) infection and impaired immune function status. Currently, chemotherapy represents the standard treatment for this population, yielding response rates that range only from 30% to 50%. As such, there is a strong clinical need for more novel therapeutic approaches.

Previous studies have shown promising results with the utilization of anti–PD-1 antibodies in these patients. Additionally, HHV-8 viral genes have been shown to contribute to tumorigenesis through VEGF signaling pathways, and the combination of pembrolizumab and lenvatinib has shown promising activity spanning several tumor types.2

The phase 2 trial will enroll patients with a histologically confirmed diagnosis of classic Kaposi sarcoma who had progressed on, or experienced an inadequate response to, 1 or more prior lines of chemotherapy. The primary end point of the trial is objective response rate, and key secondary end points include duration of response, progression-free survival, overall survival, tolerability, and safety. Investigators will also examine HHV8 DNA plasma levels, PD-L1 expression and tumor-infiltrating lymphocytes in tumor specimens at baseline and at the time of treatment discontinuation.

“The most important thing is that we are moving to novel treatment strategies for patients with classic Kaposi sarcoma, and this will hopefully lead to a reduction in cytotoxic [chemotherapy], especially for those who experience relapse [or] recurrence,” Indini said. “Hopefully, with reduced toxicity…we can [also] induce longer [responses] than [what has been seen with] chemotherapy, and this will lead to better disease control and better quality of life for our patients.”

In an interview with OncLive®, Indini, a medical oncologist in the Medical Oncology Unit, Department of Internal Medicine, at Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico in Milan, Italy, further discussed the ongoing PULSAR trial examining pembrolizumab plus lenvatinib as a novel therapeutic option for patients with classic Kaposi sarcoma.

OncLive®: What was the rationale for the phase 2 PULSAR trial?

Indini: The phase 2 PULSAR trial is evaluating the [combination] of pembrolizumab, an anti–PD-1 antibody, with lenvatinib, which is an antibody targeting the VEGF receptor. Classic Kaposi sarcoma is an endothelial neoplasm that originates from chronic HHV-88 infection.

There is a strong rationale for the use of immunotherapy in this neoplasm, both due to its viral origin and to preliminary evidence of response to anti–PD-1 as a monotherapy and the combination of anti–PD-1 and anti–CTLA-4 antibodies. VEGF is highly expressed among Kaposi sarcoma tumor cells and in the tumor microenvironment. Plenty of clinical trials are currently underway [to explore] the combination of pembrolizumab and lenvatinib, [the latter of] which seems to enhance the activity of immunotherapy.

Could you expand on the trial design and the methods utilized?

The single-arm trial will include patients with classic Kaposi sarcoma who have no possibility of treatment, which means most of the patients [will receive this combination] after their first or second line of chemotherapy. Classic Kaposi sarcoma is an orphan disease for which there is no standard treatment; it is also a rare disease, which lacks [official] guidelines.

[The trial] will include patients who have received at least 1 previous [line of] chemotherapy, with good performance status, good organ function, and without a known human immunodeficiency virus infection. Patients need to have measurable lesions, and this is usually common because [classic Kaposi sarcoma] is a cutaneous and mucosal neoplasm.

We will administer pembrolizumab in association with lenvatinib at the standard dose, and patients will have clinical follow-up with our dermatologist. There will be the option to have biopsies [done] on cutaneous lesions to assess which changes happen in the tumor microenvironment and in PD-L1 expression [over the course of treatment compared with baseline]. Then, we will assess disease response, not only clinically, but also with PET/CT scans.

In the case of disease recurrence, patients will be able to receive a second course of treatment, [if they had experienced] good disease response and they did not experience treatment-related toxicity. Study treatment will [be administered for] up to 2 years, and [patients] will [have] the [option] to continue 1 of the treatments in case a single treatment required interruption per investigator discretion.

What is your hope for this trial?

I hope that accrual will be fast enough, because we have had some difficulties [in the past]. These patients are older, and sometimes it can be difficult to propose treatment [to this population]. We also want to let our colleagues know that [about this trial]. Since [classic Kaposi sarcoma] is a rare disease, [we must] refer these patients to centers where [our patients can be] offered [options beyond] classic chemotherapy.

I hope that preliminary results from tissue and blood sample analyses will provide us with information regarding the connection between the immune system and this neoplasm, as this is a very fascinating [area that begs for further exploration].


  1. Indini A, Tourlaki A, Barbin F, et al. A phase II single-arm study of pembrolizumab plus lenvatinib in previously treated classic Kaposi sarcoma (CKS): The PULSAR trial. Ann Oncol. 2021;32(5):S1111-S1128. doi:10.1016/annonc/annonc712
  2. Makker V, Colombo N, Casado Herraez A, et al. Randomized phase 3 study of lenvatinib plus pembrolizumab for advanced endometrial cancer: subgroup analysis of patients with DNA mismatch repair-deficient tumors. Presented at: 2021 IGCS Annual Global Meeting; August 30-September 2, 2021; virtual.
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