A multi-institutional team of researchers led by Duke Cancer Institute (DCI) radiation oncologist David Kirsch, MD, PhD, has been awarded an eight-year, $2.5 million grant from Stand Up to Cancer. The funds support a clinical trial to investigate the efficacy of treatment of patients with high-risk soft-tissue sarcoma with radiotherapy and immunotherapy.
This “Phase II Randomized Controlled Trial of Neoadjuvant Pembrolizumab With Radiotherapy and Adjuvant Pembrolizumab,” also known as the Stand Up To Cancer SARC 032 trial (SU2C-SARC032) is being sponsored by the Sarcoma Alliance for Research through Collaboration (SARC), and hosted at 12 U.S. and potentially several overseas sites including in Canada, Italy and Australia. (A $1-million-dollar grant from Merck Sharp & Dohme Corp. will help support the international trial patient accrual component).
The target population is patients with high-risk soft tissue sarcomas of the extremity — for example in the arm, leg, hip or shoulder — that hasn’t metastasized. High risk, in this case, is defined as intermediate or high grade tumor(s) that are greater than five centimeters in size, look aggressive under the microscope and have particular histologies identified by the pathologist.
“This is the first trial utilizing immune checkpoint inhibitors in sarcoma patients that don’t have metastatic disease,” said Kirsch, the overall principal investigator (PI) of the trial. “Pembrolizumab and radiation haven’t been combined before in any systematic way for treating cancer of the extremity. This trial will test the combination of pembrolizumab, radiation therapy, and surgery in patients with high risk sarcoma to try to prevent metastatic disease.”
Pembrolizumab is what’s known as an anti-PD1 immune checkpoint inhibitor. The immunotherapeutic drug doesn’t aim to kill cancer cells directly, but to remove the breaks on the part of the immune system that is poised to fight cancer. First approved by the FDA in December 2015 for the treatment of metastatic melanoma, the drug has since been approved in the treatment of several cancers, including metastatic non-small cell lung cancer, recurrent or metastatic head and neck squamous cell carcinoma, refractory or relapsed classical Hodgkin lymphoma, advanced stomach or gastroesophageal junction cancers, and advanced urothelial carcinoma.
Since the trial opened in July, four of an anticipated 110 adult patients have been enrolled and started treatment, including one from Duke. (Kirsch anticipates the eventual participation of 10 to 15 Duke patients.)
Half of the total patients enrolled will get the standard-of-care five weeks of radiation, followed by surgery. The other half, over the course of one year, will get one dose of pembrolizumab; followed by five weeks of radiation, including a second dose of pembrolizumab; then a third dose before surgery; surgery; then another 14 doses of pembrolizumab. All patients will have scans every three months after surgery for several years.
“The trial seeks to discover, whether two years out from treatment, the cancer has come back in any way,” said Kirsch. “Combining radiation and immunotherapy has the potential to be a game-changer for sarcoma patients, but we have to do the trial to find out.”
He’s hoping this combination will not only cause a response in the irradiated tumor, but that it will stimulate the immune system to fight cancer at distant sites.
The trial team will simultaneously be looking at immune cells in the lab. Once a patient’s tumor is resected, pieces of it will be sent to the Duke lab of Kent Weinhold, PhD — the Duke Immune Profiling Core — for analysis. Blood samples taken from the patients before, during and after treatment will also be analyzed.
“We’ll also look for circulating tumor DNA,” said Kirsch. “I think that these correlative endpoints may be really informative, regardless of the outcome of the trial, for planning future studies with immunotherapy and radiation.”
The SU2C-SARC032 trial builds on the work of the four-year SARC 028 trial, begun in March 2015, which is testing pembrolizumab alone (without radiation) in patients with metastatic sarcoma, and has shown promising preliminary results.
Duke Cancer Institute’s Richard Riedel, MD, is the Duke site lead investigator on that trial, in addition to being the overall medical oncology PI on SU2C-SARC032.
Yvonne Mowery, MD, PhD, also from Duke, is the overall radiation oncology PI for SU2C-SARC032 and young investigator on the Stand Up to Cancer grant, and Brian Brigman, MD, PhD is the overall surgical oncology PI.
“While there are over 70 different types of sarcomas, we know from SARC 028 that patients whose tumors exhibited two of the more common histologies showed responses (to pembrolizumab) when their tumors were metastatic,” said Kirsch, who didn’t participate in that trial. “These are the types of sarcomas we’ll be studying with this SU2C-SARC032 protocol.”
Cost-Benefit of Radiation
At Duke for the past decade, Kirsch is the Barbara Levine University Professor in the Departments of Radiation Oncology and Pharmacology & Cancer Biology. He is also the vice chair for basic and translational research in the Department of Radiation Oncology at Duke School of Medicine. He runs a research lab with numerous ongoing projects studying sarcoma and radiation biology, and also treats adult sarcoma patients.
“I’ve always been interested in taking care of cancer patients and fascinated by cancer biology and how cancers develop,” said Kirsch, who likes to “problem solve” and “come up with the best solution for each patient.”
While radiation oncologists caution that all cancer patients can be at greater risk of getting cancer after receiving radiation treatments, the risk is generally small.
“We always have to weigh up the potential benefits of radiation,” explained Kirsch. “The benefit of adding in radiation is that it improves the chances that the cancer won’t come back. We know that if sarcoma patients, for example, just have surgery, the cancer comes back at least one-third of the time. If they have surgery plus radiation, then the sarcoma only comes back at that site in one out of ten patients.”
There have already been a number of preclinical studies from around the world, said Kirsch, suggesting that treating other cancers with radiation in combination with pembrolizumab, improves outcomes. And, there are now a number of ongoing clinical trials in other cancers testing radiation and pembrolizumab, but mostly in metastatic settings. (At Duke, radiation oncologist Manisha Palta, MD, is currently the PI on a Duke-based study — the PROCEED trial — testing a combination of radiation, chemotherapy, and pembrolizumab before surgery in the treatment of locally advanced esophageal and gastric cancers.)
Kirsch anticipates that at some point before the end of the SU2C-SARC032 trial, the team may be able to discern whether there are any short-term side effects from the combination of radiation and pembrolizumab; a secondary outcome of the trial. (Since pembrolizumab is so new, there’s no data on the drug’s long-term side-effects or outcomes or even a protocol for how long to take it — for the treatment of any cancer.)
In related research, Kirsch’s lab is performing preclinical studies of the combination of radiation therapy and immunotherapy, which is funded in part by the Sarcoma Alliance for Research through Collaboration (SARC). Kirsch and Weinhold are co-PI’s of a full project in the SARC SPORE competitive renewal that is currently being reviewed at the National Cancer Institute for funding. If funded, this would provide further support for mechanistic preclinical studies that can be paired with the SU2C-SARC032 human clinical trial.
*The SARC 032 trial team has submitted an amendment to the FDA asking to lower the age of eligibility for the trial from 18 to 12 years old. Pembrolizumab has recently been approved for use in patients 12 years old and up in other cancers, and in other trials.