Efforts Continue to Expand Immunotherapy Impact in Sarcoma

Elizabeth Loggers, MD, PhD

Researchers are hoping the immunotherapy revolution occurring across several cancer types will extend to the field of sarcoma.

Results from the phase II SARC028 trial presented at the 2016 Connective Tissue Oncology Society (CTOS) annual meeting showed that the PD-1 inhibitor pembrolizumab (Keytruda) induced a response rate of approximately 20% in the overall cohort of patients with soft tissue and bone sarcomas. In a subgroup of patients with undifferentiated pleomorphic sarcoma, the response rate was 44%.

Also at the CTOS meeting, the Fred Hutchinson Cancer Research Center presented a single institution retrospective analysis of monotherapy with pembrolizumab or the PD-1 inhibitor nivolumab (Opdivo), as well as a combination regimen of nivolumab and the CTLA-4 inhibitor ipilimumab (Yervoy).

OncLive: What have been some of the results that you have seen with these agents in sarcoma?

Are there any new data with these immunotherapy agents that are being presented here at CTOS?

Study author Elizabeth Loggers, MD, PhD, discussed the findings of the study with OncLive in an interview at CTOS. Loggers is an associate member in the clinical research division at Fred Hutch, an assistant clinical professor of Medicine at the University of Washington, and medical director of Supportive and Palliative Care at Seattle Cancer Care Alliance.Loggers: Well, in actual facts, one of the problems is that we are still waiting for the results of many studies that have used these agents. What we do know from some of the early results is that there are some subtypes of sarcoma that really don’t have great treatment options that have seen responses such as epithelioid sarcoma, chondrosarcomas, dedifferentiated leiomyosarcoma, and undifferentiated sarcomas.There have been a number of different abstracts presented that were very interesting, looking at the role of different immune infiltrates into the tumors—tumor infiltrating lymphocytes as well as tumor infiltrating macrophages, which I think will be very exciting as this science develops.

What would you say were the next steps with your research?

Our results were our single institution retrospective study of patients who were receiving either single-agent nivolumab or pembrolizumab or combined therapy with nivolumab and ipilimumab. These patients are of interest because these agents have been very effective in melanoma, lung cancer, renal cancer, and the combined agents have been more effective than the single agent for some conditions. So we were interested in whether that would hold true for sarcoma patients.Well, I think it’s really important to interpret our results with caution because they are just a single institution, non-randomized study. What we were interested in was whether overall survival would be different for individuals who received single-agent, immune-based approaches versus combination.

What our data showed was that people who received single- agent therapy actually lived longer in this small, single institution retrospective analysis. So again, we want to interpret this with caution, but it leads us to interesting questions about which will be better for our patients—single agent or combined agents—especially understanding the toxicities will be greater with combined therapy.

We’ve got the Alliance study results that are going to help us definitively answer this question, but what our study does is underline the importance of understanding really simple things like dose, interval, and the underlying mechanisms by which these agents work, which may be different in sarcoma than in melanoma or in lung cancer.

So there is a lot of hype about immunotherapy in all cancer types, do you think that immunotherapy will play a major role in the treatment of sarcoma in the future?

When we understand that, we’ll know how to optimally use these drugs. What is really critical, which was discussed in many of the sessions here, is that we return to looking at sarcoma specifically. There has not been a lot of phase I style data where we’ve actually confirmed that the dose and the interval for the schedule for these drugs are optimized for mesenchymal tumors, so I think that’s something that were going to hopefully see. In addition, hopefully we’ll see more phase II studies where we actually compare these drugs to each other and to different combinations. We are all very excited for the Alliance study results and the results for the SWOG rare tumors studies, which are starting soon.Absolutely, I think sarcoma will be one of the novel diseases in which immunotherapies are developed. I know at our own institution, we’ll be initiating work with CAR-T cells, we’ll also be doing an early study of pembrolizumab plus doxorubicin, our most active cytotoxic chemotherapy agent.

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

Sarcoma, as Dr. William Tap has said, is a fantastic disease to study immunotherapy in because of the genetic diversity, the known important of immune cells in the disease and its development, and drugs that are used in this environment can be fast-tracked to approval. So I think it’s a perfect disease to improve our understanding of immune-based therapies.There is so much to be learned about our most common sarcoma subtypes, but there are potentially 50 to 100 other subtypes that are very rare that don’t always get included in the approval process for sarcoma drugs. We really need to focus on those patients and families because they deserve attention just like the more common subtypes and they have the potential to advance what we understand about immune-based therapies and the genetics and selection of patients for certain drugs. I’m hopeful that we’ll see a great change in the way we approach these rare subtypes in the next 5 to 10 years.