Pembrolizumab Antitumor Activity Promises Potential for Sarcoma Subtypes

Melissa Burgess, MD

Pembrolizumab (Keytruda) reduced the size of tumors in patients with a subtype of soft tissue sarcoma, according to updated interim results from the phase II SARC028, multicenter clinical trial, which were reported at the most recent meeting of the Connective Tissue Oncology Society (CTOS) in Lisbon, Portugal.

Although the response rate was approximately 20% in the overall cohort of patients with soft tissue and bone sarcomas, a response of 44% was shown in a subgroup of patients with undifferentiated pleomorphic sarcoma, who also experienced a reduction in tumor size.

"I think that the results from the correlative analysis of SARC028 will help to move the field forward, and they’ve laid out a nice foundation," said Melissa Burgess, MD.

Pembrolizumab has been approved to treat patients with melanoma, lung, and head and neck cancer, and continues to be explored in several other cancer types.

OncLive: Could you provide an overview of SARC028?

In an interview with OncLive, Burgess, medical oncologist, assistant professor of Medicine, University of Pittsburgh Cancer Institute, discusses the significant findings from SARC028 and sheds light on the importance that clinical trials and immunotherapeutic agents will have in the future treatment of patients with sarcoma.Burgess: SARC028 was a multi-institutional study, supported and sponsored by SARC, in which we had 12 different sites in the U.S. looking at single-agent pembrolizumab, an anti-PD1 inhibitor, in 2 cohorts of patients. We looked at soft tissue sarcomas, as well as bone sarcomas. In each of these cohorts, our goal was to look at 40 patients each, and, intentionally, in the soft tissue sarcoma arm, we specifically balanced our cohort among 4 different types of soft tissue sarcoma, including the 3 most common soft tissue sarcomas: undifferentiated pleomorphic sarcoma, leiomyosarcoma, as well as dedifferentiated, or high-grade, liposarcoma, and synovial sarcoma. In the bone sarcoma cohort, we looked at 3 different subtypes, including osteosarcoma, high-grade or dedifferentiated chondrasarcoma, as well as Ewing sarcoma.

Each of these patients received pembrolizumab as a single agent, at 200 mg through IV every 3 weeks. We examined them with the radiologic assessment first at 8 weeks, then every 12 weeks thereafter. These patients were also mandated to have biopsies done, so each patient had to have a biopsy done during screening, as well as at the 8-week mark. We also took samples of peripheral blood at multiple time points throughout the study.

What did the safety profile of pembrolizumab look like in this study?

What are the next steps following these results?

Do you think pembrolizumab could be used to treat other subtypes of sarcoma?

What are some of the other agents that pembrolizumab could potentially be combined with?

Do you see immunotherapy as playing a major role in the future treatment landscape of this disease?

What would you like to see in the next 5 to 10 years in this treatment landscape?

The primary endpoint was to look at objective response rate by the RECIST 1.1 criteria. In the soft tissue cohort, we saw that 4 out of 9 evaluable patients achieved partial responses in the undifferentiated pleomorphic sarcoma cohort. We also saw that 2 out of 9 evaluable patients in the dedifferentiated liposarcoma cohort had partial responses, which was quite significant. We did not see any responses in the leiomyosarcoma cohort, and there was a short-lived response in the synovial sarcoma cohort. In the bone arm, we did see 2 partial responses: 1 in osteosarcoma, and 1 in chondrasarcoma.Pembrolizumab was very well-tolerated in this population. We saw a very limited number of adverse events in these patients. Only about 10% of them were felt to be serious adverse events related to the drug.What’s really important at this point is to analyze all of the tumor samples that we collected, as well as all of the peripheral blood samples. We’re going to do this, and we’re really going to look at the entire immune system to see what’s going on, and tell the whole story of what’s happening. Essentially, we were able to do quality control on our baseline samples, and we found that basically only 7 samples out of the 90 or so we collected are going to be good to use, which is wonderful.I certainly do. Today we saw some really exciting evidence, possibly supporting its use in alveolar soft part sarcoma, as well as a couple lines of evidence for limited activity of responses in epithelioid sarcoma. I think we still have a lot of work to do, but I think it’s really important that we continue to explore this option, probably in combinations. I think that the results from the correlative analysis of SARC028 will help to move the field forward, and they’ve laid out a nice foundation. Based on this clinical activity that we’re seeing now, although small, I think it’s worthy of expansion, and the scientific data that we collect will be helpful moving forward, as it’s laid a nice groundwork for the future.I think right now, there are multiple studies that are ongoing, and these are using other checkpoint inhibitors, vaccines, cytotoxic chemotherapy, the list goes on and on. At this point, I don’t think we quite know exactly what the right combination is. It’s great to see that all these studies are happening. I think the key is going to be working in collaboration internationally to try to move forward with the best combination. Again, I really think the correlative studies are going to really lead the way to the right combination.I still have a lot of hope for immunotherapy in sarcoma. I know there’s a lot of varied evidence out there, but I think we still have a lot of work to be done. We’re just at the beginning. There’s a lot of historical evidence to suggest that immunotherapy works. Immunotherapy is not just checkpoint inhibitors, but there’s a whole host of ways to activate the immune system and decrease the negative inhibition of the immune system. I think there’s definitely going to be a future; we just have to find it.I would like to find the right population of patients, select the right ones who will benefit from immunotherapy. To do this, we just need to keep running the trials and evaluating the correlative evidence that will get us there.