Neoadjuvant Immunotherapy Plus Radiation Shows Promise in Soft Tissue Sarcoma

Vincent Y. Ng, MD

The use of neoadjuvant durvalumab (Imfinzi) and tremelimumab plus radiation appears to show an improved radiologic and histologic response for patients with high-risk soft tissue sarcoma, according to preliminary results of the phase I/II NEXIS trial (NCT03116529), said Vincent Y. Ng, MD. 

"Immunotherapy research in sarcoma is several years behind research in other types of cancer due to its rarity," said Ng. "There have been relatively few breakthroughs in soft tissue sarcoma research, and we are optimistic that this may be one. We are combining the very best standard of care, proton-beam radiation therapy, and wide surgical resection with immunotherapy." 

In the trial, patients are given concurrent radiation with 3 intravenous doses of durvalumab at 1500 mg and 75 mg of tremelimumab once every 4 weeks prior to surgery.

Surgical resection is performed 5 to 8 weeks after stopping radiation and 4 weeks after stopping immunotherapy. If patients have no evidence of disease progression following surgery, they are administered 9 doses of durvalumab once every 4 weeks or until disease progression. 

Initial data, based on RECIST criteria, from 7 patients who received the complete NEXIS protocol demonstrated that 5 patients had stable disease (SD), 1 had a partial response (PR), and 1 had disease progression. Conversely, based on PERCIST criteria, 2 patients had SD, there were 2 PRs, 2 complete responses, and 1 patient had disease progression. 

“[This may be] one of the most exciting developments in cancer research for a long time,” Ng explained. “Early results showed that more than half of patients had good responses based on metabolic imaging and pathologic evaluation, and currently do not have evidence of disease. The immunotherapy was well tolerated with only grade 1 and 2 adverse events.” 

In an interview with  OncLive  during the 2019 Musculoskeletal Tumor Society Annual Meeting, Ng, an assistant professor of orthopedics at the University of Maryland Medical Center, discussed what implications the NEXIS study could have in soft tissue sarcoma treatment and the next steps going forward.

OncLive: What are the next steps of the NEXIS trial?

Ng: This is one of the first neoadjuvant immunotherapy radiation trials for soft tissue sarcoma in the United States. Patients and physicians are excited about possibilities with immunotherapy, particularly since traditional chemotherapy and even targeted therapy have had limited results.

Going forward, we are hoping to enroll more patients with primary soft tissue sarcoma who have high-risk disease and who, at least according to historical measures, have a high risk of relapse with metastatic disease.

Endpoints such as radiologic and pathologic outcomes are not always indicative of success with soft tissue sarcoma, and there are limited numbers of patients with this disease. That makes it difficult to do randomized, controlled trials.

We will know if it is making a meaningful difference if we see a significant difference in survival compared with historical rates, or to have multiple anecdotal success stories that otherwise would be highly improbable with other treatment modalities. 

What role does immunotherapy currently have in this patient population?

Most patients with high-risk soft tissue sarcoma present with early-stage disease. With the best of radiation and surgery, we know that we can solve the primary tumor in the vast majority of cases.

The main issue we face is how to address micrometastatic disease. Prior attempts with chemotherapy and targeted therapy have not provided dramatic improvement. Neoadjuvant immunotherapy and what we have seen with other cancer types and at least preliminarily here, may be a possibility. 

What factors do you consider in determining whether patients are eligible for combination immunotherapy and radiation?

Basically, any patient with high-risk soft tissue sarcoma can be considered for this clinical trial. There are basic science data to show that using immunotherapy in the neoadjuvant setting before the tumor is actually removed may be able to teach the immune system how to find and destroy metastatic disease. It seems that if we wait until patients have late-stage disease, it may be less effective to employ immunotherapy at that point. 

What is the key takeaway for this study for physicians?

Immunotherapy is a relatively new phenomenon, and although it is now widely used for other cancer types, I hope patients and physicians realize that immunotherapy is a promising clinical trial option for soft tissue sarcoma—not only as a second- or third-line option for metastatic disease, but as a neoadjuvant option in the primary setting. 

Ng VY, Sausville S, Miller K, et al. Neoadjuvant combination immunotherapy/radiation for high-risk soft tissue sarcoma (NEXIS): preliminary results from an integrated phase I/II, single-arm, prospective clinical trial. Presented at: 2019 Musculoskeletal Tumor Society Annual Meeting; October 2 to 4, 2019; Portland, OR. Abstract 9.