Pembrolizumab Shows Significant Promise in the Treatment of Sarcoma


Treatment with pembrolizumab led to a reduction of tumor size in 33% of patients with undifferentiated pleomorphic sarcoma and dedifferentiated liposarcoma.

Hussein A. Tawbi, MD, PhD

Hussein A. Tawbi, MD, PhD

Treatment with pembrolizumab (Keytruda) led to a reduction of tumor size in 33% of patients with undifferentiated pleomorphic sarcoma and dedifferentiated liposarcoma, according to interim results from the phase II SARC-028 trial.1The study, presented at the 2016 ASCO Annual Meeting, investigated the PD-1 inhibitor in 7 different subtypes of previously treated sarcoma.

These findings demonstrate significant promise for immunotherapy in sarcoma, said SARC-028 principal investigator Hussein A. Tawbi, MD, PhD, who presented the data.

“Even with the standard of care for first-line treatment in sarcoma, which is doxorubicin, the response rates can be as low as 10%,” Tawbi, associate professor of Melanoma and Medical Oncology at The University of Texas MD Anderson Cancer Center, said in an interview withTargeted Oncology. “If you look at the most recently approved therapy in sarcoma, trabectedin (Yondelis), response rates were less than 10%. Therefore, 33% tumor shrinkage for an agent that has never been used in this setting is really remarkable.”

The study included 40 patients with soft tissue sarcoma and 40 patients with bone sarcomas accrued from 12 different centers across the country.

To be included in the trial, patients had to have advanced disease, an ECOG performance status of 0 or 1, and be amenable to biopsy. Patients in the soft tissue sarcoma cohort were between the ages of 18 and 61, with 18 being the minimum age for inclusion, and had received 1 (n = 8), 2 (n = 14), 3 (n = 14), or another amount (n = 4) of prior therapies.

The soft tissue sarcoma subtypes included in the trial were leiomyosarcoma, liposarcoma, undifferentiated pleomorphic sarcoma, and synovial sarcoma. Arms were intentionally balanced to have 10 patients per subtype.

The bone sarcoma cohort included 21 patients with osteosarcoma, 13 patients with Ewing sarcoma (ES) and 6 patients with high-grade/dedifferentiated chondrosarcoma (CS). Patients included in the trial were between the ages of 16 and 70, with 12 being the minimum age of inclusion, and had also received 1 (n = 7), 2 (n = 16), 3 (n = 14), or another amount (n = 3) of prior therapies.

All patients were treated with pembrolizumab at 200 mg every 3 weeks for 21 days. Tumor biopsies were collected at 0 and 8 weeks and at progression.

The primary endpoint for each arm was objective response rate (ORR) by RECIST 1.1 (target ORR = 25%, 82% power vs 10% ORR, α = 0.042). Secondary objectives included safety and tolerability, response rate, progression-free survival (PFS) overall survival (OS), and correlation of pretreatment PD-L1 with response.

Of the 80 enrolled patients, 76 were evaluable for response by RECIST at the time the data were presented.

The best response rate was seen among patients with undifferentiated pleomorphic sarcoma. Of the 9 evaluable patients in that subgroup, 4 had a partial response (PR) and 3 patients experienced stable disease (SD). Among patients with liposarcoma (n = 9), 2 had a PR, and 4 had SD. In the synovial sarcoma cohort (n = 9), 1 patient had PR and 2 had SD; in leiomyosarcoma (n = 10) no patients experienced a PR and 6 had stable disease.

Three patients from the soft tissue sarcoma cohort have not reached first-scan assessment. In the entire soft tissue sarcoma cohort, the ORR was 19%.

The PFS rate at 8 weeks was 67% in the undifferentiated pleomorphic sarcoma subgroup, 63% in the liposarcoma subgroup, 50% in the leiomyosarcoma subgroup, and 30% in the synovial sarcoma subgroup.

The soft tissue sarcoma cohort results, especially in the undifferentiated pleomorphic sarcoma and liposarcoma subgroups, were “remarkable,” said Tawbi.

“The study was, in some respects, a breakthrough because it really brought this new modality to sarcoma which hasn’t been utilized before,” he said. “Showing that pembrolizumab as a single-agent, which is a very safe drug, can actually have an impact in this disease is, in itself, quite important.”

However, the results in bone sarcomas were not as promising.

In osteosarcoma (n = 19), 1 patient had a PR while 5 had SD. In Ewing sarcoma (n = 13), 0 patients had a PR, 2 had SD, and in high-grade/dedifferentiated chondrosarcoma (n = 6) 1 patient had a PR and 2 had SD. Two patients have not yet reached first-scan assessment.

The ORR for the bone sarcoma cohort was 5% (n = 2).

In the entire study population, including both soft tissue and bone sarcoma cohorts, PFS was 53%. This was a particularly important finding, said Tawbi.

“One of the secondary endpoints that we looked at that is really important and relevant is the 3-month PFS,” he said. “It is a well-validated endpoint in second-line therapy in sarcoma and, typically, if you have anything that has better than a 3-month PFS of 40% or above, it is considered to be an effective therapy.”

Across both cohorts, the toxicity profile was similar to what has been seen with pembrolizumab in other tumor types, said Tawbi.“This is a really safe medicine when used alone and that is very important for patient’s care,” he added.

There were 59 serious adverse events reported in the total study population; however, only 10 were likely to be related to pembrolizumab, according to Tawbi.

Common side effects included immune-related adrenal insufficiency, diarrhea, and acute interstitial nephritis.

Next Steps

Biopsies were collected from 70 out of 80 patients prior to treatment and 62 patients following treatment. These samples will be extremely helpful for research purposes going forward, said Tawbi.

“We are analyzing the samples to be able to tell if, for instance, PD-1 expression matters. We also need to determine whether T-cell infiltrate before and during treatment matters, and if there are changes in the immune system cells in response to treatment that correlate with the clinical response,” said Tawbi.

One goal is to better understand why undifferentiated pleomorphic sarcoma and liposarcoma did better with pembrolizumab than other sarcoma subtypes.

Already, researchers at The University of Texas MD Anderson Cancer Center have found a potential link between PD-1 expression and response in undifferentiated pleomorphic sarcomas, said Tawbi. There was an approximate 30% rate of PD-1 expression in that subgroup, which almost coincides with the response rate to pembrolizumab in the study, he said.

Additional patients will be added to the cohorts who responded to pembrolizumab and the efficacy of the agents will be further investigated in each subtype going forward. Combination treatments may also be considered if pembrolizumab continues to show success in the field of sarcoma.

Overall, immunotherapy has a lot of potential in this space, said Tawbi.

“Immunotherapy has one quality that is very lacking in most other approaches to cancer, which is the fact that responses and clinical benefit tend to be durable and last long,” he said. “In melanoma, we now speak of cure in patients who have metastatic disease. When we started with ipilimumab (Yervoy), the cure rates were 20%. Now, with the combination of ipilimumab and nivolumab (Opdivo) the cure rate is 55%. If we can translate not necessarily just the percentages, but even the word ‘cure’ from melanoma to other cancers such as sarcoma, I think we will have really opened up horizons and truly transform the care of patients with sarcoma.


Tawbi H A, Burgess MA, Crowley J, et al. “Safety and efficacy of PD-1 blockade using pembrolizumab in patients with advanced soft tissue (STS) and bone sarcomas (BS): Results of SARC028—A multicenter phase II study.J Clin Oncol. 2016;34 (suppl; abstr 11006).

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