Redefining Frontline Therapy in Undifferentiated Pleomorphic Sarcoma

For clinicians treating undifferentiated pleomorphic sarcoma (UPS), the integration of immune checkpoint inhibitors remains one of the most debated paths in sarcoma. While the high mutational burden and inflammatory profiles of these tumors make them prime candidates for immunotherapy, the clinical community is currently split: some practitioners adopt pembrolizumab early based on anecdotal success, while others reserve it strictly for the refractory setting due to a lack of randomized data.

In this interview, Seth M. Pollack, MD, Chair of the phase 3 ECOG-ACRIN EA7222 trial (NCT06422806), addressed this evidence gap. He explained how the combination of doxorubicin (Andriamycin) and pembrolizumab (Keytruda) aims to move immunotherapy from an "experimental" frontline addition to a validated standard of care. By evaluating progression-free survival (PFS) and overall survival (OS), the EA7222 trial seeks to provide the definitive evidence needed to shift the treatment paradigm away from doxorubicin monotherapy.

Pollack is the Steven T. Rosen, MD, Professor of Cancer Biology and Director of the Sarcoma Program at Northwestern University, and co-leader of the Cancer Immunology and Immunotherapy Initiative at the Robert H. Lurie Comprehensive Cancer Center.

Transcript:

Right now, nobody knows what the right way to use a checkpoint inhibitor for UPS is. There are some people who are doing it up front even though our typical philosophy is that for a front-line therapy, you should have good evidence, and we don’t have good evidence for frontline checkpoint inhibitors in UPS. Some people out there are saying, ‘Well, this is a nontoxic treatment, and sometimes when it works, it can be amazing, so let’s move it into the front line.’ Other people are saying, ‘Well, this treatment doesn’t have any randomized evidence. All of the evidence is in small studies. I'm going to use it way in the refractory setting, not until we after we've used all our standard agents.’ While the ECOG-ACRIN 7222, trial is not a frontline study, meaning that some patients could have had other treatments, [like] votrient [Pazopanib] and/or GemTax [gemcitabine/paclitaxel] is their frontline treatment. For most people and for most treating physicians, doxorubicin is the frontline agent.

If [the trial is] positive, it’ll say you should use doxorubicin with pembrolizumab, like you use doxorubicin. For most people, that would be frontline. There’s some people out there who maybe you think votrient is right for them as front line or a different chemotherapy agent, but for most people, it’ll move chemotherapy plus immunotherapy into the frontline, and then the primary end point of that trial is progression-free survival, but a key secondary end point is overall survival. That is going to be one thing that I’m interested [in seeing], because if the overall survival is positive, that will be one of the first times we’ve seen a benefit in a combination treatment, beating doxorubicin alone.