Study underway to evaluate immunotherapy plus radiation for newly diagnosed sarcoma

Vincent Y. Ng

A clinical trial is underway to assess use of two immunotherapy agents, durvalumab and tremelimumab, plus radiation therapy for the treatment of newly diagnosed high-risk sarcoma.

The goal of the Neoadjuvant XRT Immunotherapy and Surgery for Soft Tissue Sarcoma (NEXIS) trial is to stimulate the immune system with the combined treatment regimen to destroy a patient’s initial tumor and any remaining microscopic cancer cells that may spore other tumors.

“Immunotherapy is revolutionizing how we treat other types of cancer, and we want to find out whether this treatment — combined with radiation — can also transform how we treat soft tissue sarcomas,” Vincent Y. Ng, MD, assistant professor of orthopedics at University of Maryland School of Medicine, said in a press release.

HemOnc Today spoke with Ng about the treatment landscape for soft tissue sarcoma, how this trial will be conducted, and the rationale for why immunotherapy in combination with radiation may be beneficial.

 

Question: Can you describe the treatment landscape for soft tissue sarcoma?

Answer: For large, high-grade nonmetastatic soft tissue sarcomas, the standard of care is radiation plus wide surgical resection. Some centers do cytotoxic chemotherapy — including doxorubicin and ifosfamide, as well — but it is relatively toxic to the patient, and its effectiveness is limited and controversial. About 50% of patients are cured with current regimens. Unfortunately, although most patients do not present with detectable metastases, about half of patients will develop metastatic disease. Once soft tissue sarcoma has metastasized, it generally is not considered curable, and very few patients achieve long-term survival.

 

Q: What are the goals of your research?

A: The goals of our research are to develop a systemic agent or agents that will outperform current regimens and reduce the appearance of metastatic disease. Soft tissue sarcomas are more common than bone sarcomas, and many patients unfortunately succumb to this disease. Very few significant breakthroughs have been achieved in drug therapy for soft tissue sarcoma in the past several decades.

 

Q: What is the rationale for why immunotherapy in combination with radiation may be beneficial?

A: This is one of the most interesting aspects of the NEXIS trial. Radiation has been shown — in some instances in humans and in some animal models — to have a beneficial effect not only for killing the primary tumor, but also for reducing tumor deposits elsewhere. This is called the abscopal effect. It is thought that this is mediated through the immune system. Radiation can ‘unmask’ certain tumor antigens such that the patient’s immune system then can recognize the tumor as an enemy and attack it throughout the body. The body’s immune system is trained to recognize abnormal cells. Aggressive tumors, however, are able to suppress the immune system in its immediate vicinity, and this allows the tumor to grow relatively unchecked by the immune system. The new immune therapy agents reverse this process and actually put the immune system into overdrive. Our hope is that radiation will help the immune system recognize the tumor, and that the immune therapy will help stimulate the white blood cells to seek and destroy any metastatic cells that have disseminated throughout the body. We are combining the two immune therapy agents — durvalumab (Imfinzi, AstraZeneca) and tremelimumab (MedImmune/AstraZeneca) — together to amplify their effect. They work in different yet synergistic manners. Further, patients are eligible to receive GRID radiotherapy or proton beam radiation. These modes of delivering radiation to the tumor may be more advantageous in some aspects than traditional photon beam radiation. They allow a higher dose of radiation with limited side effects to normal tissue. Immune therapy is generally better tolerated by patients than cytotoxic chemotherapy. Further, with this trial design, patients will receive the standard of care — radiation plus surgery — and the immune therapy is simply added. There is no planned change in the radiation or surgery timing on account of this trial. If patients require cytotoxic chemotherapy in the future, they can still receive those drugs.

Q: Why have immunotherapy approaches not been explored previously in sarcoma given the success observed in other tumor types?

A: Immune therapy has revolutionized the treatment of certain other types of cancer. Many patients are surviving longer and achieving more durable results compared with prior treatment regimens. In sarcoma, there have been trials performed to assess immune therapy for patients with advanced disease. Many of these patients have a high tumor burden and may have already failed traditional chemotherapy. In the NEXIS trial, we are using immunotherapy paired with radiation as a front-line weapon against newly diagnosed soft tissue sarcoma. The rationale is that, rather than waiting until the immune system is already exhausted late in the disease process by a heavy tumor burden and by chemotherapy, the immune system may be able to more effectively combat the sarcoma early in treatment. Also, rather than waiting until there are substantial metastases, the immune system may be able to clear microscopic amounts of tumor and prevent the appearance of metastatic disease.

 

Q: How will this trial be conducted?

A: This is a prospective, single-arm clinical trial. All patients who elect to join the trial will receive the therapeutic agents. Adults who have resectable, extremity-based intermediate- or high-grade soft tissue sarcomas at least 5 cm in size and no significant metastatic disease are eligible.

 

Q: What is your hypothesis?

A: We hypothesize that patients will have reduced incidence of metastatic disease and signs of treatment efficacy either radiographically or histologically. We also hypothesize that the regimen will be well tolerated, with limited toxicity or side effects.

 

Q: What is the timeline for data availability?

A: We are enrolling for the trial. We hope to accrue patients over the next 2 to 3 years.

 

Q: Is there anything else that you would like to mention?

A: Soft tissue sarcoma is very dangerous and should be treated at a high-level institution that has experience treating this set of cancerous tumors. We are able to successfully eradicate the tumor at the original site in the vast majority of cases using carefully planned radiation and limb-preserving surgery. However, the more substantial long-term risk for patients is the appearance of incurable metastases elsewhere in the body, even after the primary tumor is removed. We want to develop a regimen to increase patients’ chances for cure by harnessing and augmenting the immune system to fight sarcoma throughout the body early in the disease process. This regimen is added to what we already know works well for the primary tumor. – by Jennifer Southall

 

For more information:

Vincent Y. Ng, MD, can be reached at University of Maryland Greenebaum Comprehensive Cancer Center, 110 S. Paca St., 6th Floor, Suite 300, Baltimore, MD 21201; email: vng@umoa.umm.edu.

Disclosure: Ng reports no relevant financial disclosures.

Vincent Y. Ng

A clinical trial is underway to assess use of two immunotherapy agents, durvalumab and tremelimumab, plus radiation therapy for the treatment of newly diagnosed high-risk sarcoma.

The goal of the Neoadjuvant XRT Immunotherapy and Surgery for Soft Tissue Sarcoma (NEXIS) trial is to stimulate the immune system with the combined treatment regimen to destroy a patient’s initial tumor and any remaining microscopic cancer cells that may spore other tumors.

“Immunotherapy is revolutionizing how we treat other types of cancer, and we want to find out whether this treatment — combined with radiation — can also transform how we treat soft tissue sarcomas,” Vincent Y. Ng, MD, assistant professor of orthopedics at University of Maryland School of Medicine, said in a press release.

HemOnc Today spoke with Ng about the treatment landscape for soft tissue sarcoma, how this trial will be conducted, and the rationale for why immunotherapy in combination with radiation may be beneficial.

 

Question: Can you describe the treatment landscape for soft tissue sarcoma?

Answer: For large, high-grade nonmetastatic soft tissue sarcomas, the standard of care is radiation plus wide surgical resection. Some centers do cytotoxic chemotherapy — including doxorubicin and ifosfamide, as well — but it is relatively toxic to the patient, and its effectiveness is limited and controversial. About 50% of patients are cured with current regimens. Unfortunately, although most patients do not present with detectable metastases, about half of patients will develop metastatic disease. Once soft tissue sarcoma has metastasized, it generally is not considered curable, and very few patients achieve long-term survival.

 

Q: What are the goals of your research?

A: The goals of our research are to develop a systemic agent or agents that will outperform current regimens and reduce the appearance of metastatic disease. Soft tissue sarcomas are more common than bone sarcomas, and many patients unfortunately succumb to this disease. Very few significant breakthroughs have been achieved in drug therapy for soft tissue sarcoma in the past several decades.

 

Q: What is the rationale for why immunotherapy in combination with radiation may be beneficial?

A: This is one of the most interesting aspects of the NEXIS trial. Radiation has been shown — in some instances in humans and in some animal models — to have a beneficial effect not only for killing the primary tumor, but also for reducing tumor deposits elsewhere. This is called the abscopal effect. It is thought that this is mediated through the immune system. Radiation can ‘unmask’ certain tumor antigens such that the patient’s immune system then can recognize the tumor as an enemy and attack it throughout the body. The body’s immune system is trained to recognize abnormal cells. Aggressive tumors, however, are able to suppress the immune system in its immediate vicinity, and this allows the tumor to grow relatively unchecked by the immune system. The new immune therapy agents reverse this process and actually put the immune system into overdrive. Our hope is that radiation will help the immune system recognize the tumor, and that the immune therapy will help stimulate the white blood cells to seek and destroy any metastatic cells that have disseminated throughout the body. We are combining the two immune therapy agents — durvalumab (Imfinzi, AstraZeneca) and tremelimumab (MedImmune/AstraZeneca) — together to amplify their effect. They work in different yet synergistic manners. Further, patients are eligible to receive GRID radiotherapy or proton beam radiation. These modes of delivering radiation to the tumor may be more advantageous in some aspects than traditional photon beam radiation. They allow a higher dose of radiation with limited side effects to normal tissue. Immune therapy is generally better tolerated by patients than cytotoxic chemotherapy. Further, with this trial design, patients will receive the standard of care — radiation plus surgery — and the immune therapy is simply added. There is no planned change in the radiation or surgery timing on account of this trial. If patients require cytotoxic chemotherapy in the future, they can still receive those drugs.

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Q: Why have immunotherapy approaches not been explored previously in sarcoma given the success observed in other tumor types?

A: Immune therapy has revolutionized the treatment of certain other types of cancer. Many patients are surviving longer and achieving more durable results compared with prior treatment regimens. In sarcoma, there have been trials performed to assess immune therapy for patients with advanced disease. Many of these patients have a high tumor burden and may have already failed traditional chemotherapy. In the NEXIS trial, we are using immunotherapy paired with radiation as a front-line weapon against newly diagnosed soft tissue sarcoma. The rationale is that, rather than waiting until the immune system is already exhausted late in the disease process by a heavy tumor burden and by chemotherapy, the immune system may be able to more effectively combat the sarcoma early in treatment. Also, rather than waiting until there are substantial metastases, the immune system may be able to clear microscopic amounts of tumor and prevent the appearance of metastatic disease.

 

Q: How will this trial be conducted?

A: This is a prospective, single-arm clinical trial. All patients who elect to join the trial will receive the therapeutic agents. Adults who have resectable, extremity-based intermediate- or high-grade soft tissue sarcomas at least 5 cm in size and no significant metastatic disease are eligible.

 

Q: What is your hypothesis?

A: We hypothesize that patients will have reduced incidence of metastatic disease and signs of treatment efficacy either radiographically or histologically. We also hypothesize that the regimen will be well tolerated, with limited toxicity or side effects.

 

Q: What is the timeline for data availability?

A: We are enrolling for the trial. We hope to accrue patients over the next 2 to 3 years.

 

Q: Is there anything else that you would like to mention?

A: Soft tissue sarcoma is very dangerous and should be treated at a high-level institution that has experience treating this set of cancerous tumors. We are able to successfully eradicate the tumor at the original site in the vast majority of cases using carefully planned radiation and limb-preserving surgery. However, the more substantial long-term risk for patients is the appearance of incurable metastases elsewhere in the body, even after the primary tumor is removed. We want to develop a regimen to increase patients’ chances for cure by harnessing and augmenting the immune system to fight sarcoma throughout the body early in the disease process. This regimen is added to what we already know works well for the primary tumor. – by Jennifer Southall

 

For more information:

Vincent Y. Ng, MD, can be reached at University of Maryland Greenebaum Comprehensive Cancer Center, 110 S. Paca St., 6th Floor, Suite 300, Baltimore, MD 21201; email: vng@umoa.umm.edu.

Disclosure: Ng reports no relevant financial disclosures.

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