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Diagnostic Challenges and Clinical Updates in Soft Tissue Sarcomas

Gary K. Schwartz, MD, a professor of medicine, chief of the Division of Hematology​/Oncology, and deputy director of Herbert Irving Comprehensive Cancer Center at Columbia University Medical Center, discusses the benefit of dose reducing ipilimumab (Yervoy) plus nivolumab (Opdivo) in metastatic sarcomas.

Although there was no increase in responses in the ALLIANCE A091401 trial, there was a suggestion of improvement in overall survival (OS) and progression-free survival (PFS). This indicates that some patients with gastrointestinal stromal tumor experienced stabilization of disease that was not reflected by RECIST criteria, says Schwartz. There are subtypes of sarcomas that are sensitive to immunotherapy, such as dedifferentiated liposarcoma (DDLS) and undifferentiated pleomorphic (UPS) sarcoma, though the numbers are low. For example, in a SARC study, investigators gave single-agent pembrolizumab (Keytruda) to patients with sarcoma and did not see an overwhelming number of responses, adds Schwartz.

It has been suggested that the combination of ipilimumab plus nivolumab is superior to nivolumab alone. Before this study, relatively low treatment-related adverse effects (AEs) had been observed with the regimen, explains Schwartz. The study design used a lower dose of ipilimumab, also known as the “sarcoma dosing,” with patients being given a full dose of nivolumab at 3 mg/kg and 1 mg/kg of ipilimumab. With that dose reduction of ipilimumab, a drop in immune-related AEs was observed in the DDLS and UPS subgroups, providing a safer option for patients.

These results weigh ipilimumab's benefit against its risk of increased immune-related toxicities. In melanoma, this remains a concern because studies now suggest that it does not matter what dose of ipilimumab is used. However, inthe ALLIANCE A091401 study's lower dose of ipilimumab yielded a reduced toxicity, while still suggesting an improved benefit with regard to response rate, OS, and PFS, concludes Schwartz.

Gary K. Schwartz, MD, discusses the benefit of dose reducing ipilimumab plus nivolumab in metastatic sarcomas.

Dr. Schwartz on the Benefit of Dose Reduced Nivolumab/Ipilimumab in Metastatic Sarcomas

Gary K. Schwartz, MD, a professor of medicine, chief of the Division of Hematology​/Oncology, and deputy director of Herbert Irving Comprehensive Cancer Center at Columbia University Medical Center, discusses future research efforts in the field of sarcoma.

The phase 2 Alliance A091401 trial has validated and verified what was learned from the original study published in the 

: there are subsets of sarcoma that are sensitive to immunotherapy, says Schwartz. Combination therapy may provide a slight advantage for some patients, but this needs to be validated in larger studies, according to Schwartz. The data available from small, randomized studies are comprised of about 24 patients; they are not powered to look at progression-free survival and overall survival differences, Schwartz adds. However, trends suggest that there could be some benefit with a combination therapy versus a single-agent.

Efforts are needed to identify novel drugs and the patients who may benefit the most from these approaches, Schwartz adds. More work needs to be done to identify new targets, as well. Attempts are also being made to combine immunotherapy with chemotherapy; however, it is unclear if that approach will have a large impact. In other tumor types, such as lung cancer, chemoimmunotherapy combinations are being used and are now leading the way in drug development. 

New targets are under exploration in sarcoma. Some of these targets include T cells, as well as CD40 and STING. The field will be hearing more about these targets and the potential role they play with regard to immunotherapy, concludes Schwartz.

Gary K. Schwartz, MD, discusses future research efforts in the field of sarcoma.

Dr. Schwartz on Future Research Efforts in Sarcoma

Gary K. Schwartz, MD, professor of medicine, chief, Division of Hematology​/Oncology, ​deputy director, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, discusses the results from the gastrointestinal stromal tumor (GIST) cohort of the phase 2 Alliance A091401 trial.

In the Alliance A091401 trial, patients with advanced sarcoma were randomized to receive nivolumab (Opdivo) alone or in combination with ipilimumab (Yervoy).

In the United States, GIST is a common sarcoma ​subtype, ​and finding new therapies is of critical importance​, says Schwartz.

Until the GIST cohort was added to the trial, it was unknown whether patients with GIST could benefit from immunotherapy, Schwartz explains.

However, no patients in the GIST cohort achieved a partial or complete response with either the single agent or combination regimen, and the trial was stopped ​early due to increased treatment-related adverse effects, Schwartz concludes.

Gary K. Schwartz, MD,  discusses the results from the gastrointestinal stromal tumor cohort of the phase 2 Alliance A091401 trial.

Dr. Schwartz on Results From the GIST Cohort in the Alliance A091401 Trial 

Gary K. Schwartz, MD, professor of medicine; chief, Division of Hematology​/Oncology; and ​deputy director of the Columbia University Herbert Irving Comprehensive Cancer Center, discusses the updated design of the phase 2 Alliance A091401 trial for metastatic sarcomas.

The Alliance A091401 trial is a phase 2 randomized study comparing nivolumab (Opdivo) alone versus nivolumab plus ipilimumab (Yervoy) in patients with advanced sarcomas. The original paper showed that the combination of nivolumab plus ipilimumab resulted in higher response rates than nivolumab alone, says Schwartz.

In the original study design, it appeared that there were several subtypes of sarcoma—particularly undifferentiated pleomorphic sarcoma (UPS) and liposarcoma—in which an increased response rate relative to other subtypes was observed.

In the original study design, no particular sarcoma subtype was included because, at that time, no data indicated that one subtype would have a superior outcome with the treatment over another. As such, patients with all subtypes of sarcoma were included; this is complicated because sarcoma is a disease with numerous different subtypes, all of which are biologically different and have different outcomes, explains Schwartz.

When the study was originally conducted in 2017, investigators were curious to know whether 1 subtype would have a superior outcome over another with the approach. Data from the first study published in 2018 in the 

 suggested that UPS and dedifferentiated liposarcoma subtypes would both fare better with the combination, concludes Schwartz.

Gary K. Schwartz, MD, discusses the updated design of the phase 2 Alliance A091401 trial for metastatic sarcomas.

Dr. Schwartz on the Updated Design of the Alliance A091401 Trial in Metastatic Sarcomas

Gary K. Schwartz, MD, professor of medicine, chief, Division of Hematology​/Oncology, ​deputy director, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, discusses results of the Alliance A091401 trial (NCT02500797) in patients with metastatic sarcoma.

Findings from the phase 2 study suggested that the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) is superior when compared with nivolumab alone in this patient population, says Schwartz. ​Notably, at least 2 responses were confirmed with the combination in patients with undifferentiated pleomorphic sarcoma and leiomyosarcoma. No responses were seen with nivolumab alone or the combination in patients with gastrointestinal stromal tumor.

The objective response rates were 5% and 16% in the nivolumab (n = 38) and nivolumab/ipilimumab arms (n = 38), respectively. Additionally, trends toward improved overall survival and progression-free survival were ​observed with the combination, Schwartz concludes.

Gary K. Schwartz, MD, discusses results of the Alliance A091401 trial (NCT02500797) in patients with metastatic sarcoma.

Dr. Schwartz on ​the Results of the Alliance A091401 Study in Metastatic Sarcoma

Gary Schwartz, MD, Baylor Scott & White Center for Thoracic Surgery, discusses the potential of single-agent durvalumab (Imfinzi) for the treatment of patients with stage III, locally advanced, unresectable non—small cell lung cancer (NSCLC).

The trial, which was published in November in 

, showed an incredible increase in disease-free survival and progression-free survival. It more than doubled in patients with stage III lung cancer who could not undergo surgery for a variety of reasons. Overall survival data are not yet mature.

Patients in the trial received either chemotherapy and radiation, which was considered definitive in that they were not going to have surgery afterwards, or chemotherapy and radiation followed by immunotherapy. Schwartz says there was an incredible survival benefit seen in those patients. He notes that patients did experience pneumonitis, which is somewhat concerning overall, but it is still too early to comment on.

Gary Schwartz, MD, Baylor Scott & White Center for Thoracic Surgery, discusses the potential of single-agent durvalumab (Imfinzi) for the treatment of patients with stage III, locally advanced, unresectable non–small cell lung cancer (NSCLC).

Dr. Schwartz on the Results of the PACIFIC Trial

	Gary Schwartz, MD, a medical oncologist and chief of the Hematology and Oncology Division at Columbia University Medical Center, discusses a randomized phase III trial investigating eribulin (Halaven) versus dacarbazine in patients with leiomyosarcoma and adipocytic sarcomas.

Eribulin lengthened survival by eight weeks compared to dacarbazine, which is significant in sarcoma, a disease that has never had a survival benefit from a novel therapy, says Schwartz.

Median overall survival for eribulin and dacarbazine was 13.5 and 11.5 months, respectively (HR = 0.768, 95% CI 0.618—0.954; P= 0.017). Progression-free survival was 2.6 months in both arms (HR = 0.877, 95% CI 0.710–1.085; P= 0.229).

Eribulin is approved to treat metastatic breast cancer. This study represents one of the first times it has been investigated in sarcoma.

Gary Schwartz, MD, a medical oncologist and chief of the Hematology and Oncology Division at Columbia University Medical Center, discusses a randomized phase III trial investigating eribulin (Halaven) versus dacarbazine in patients with leiomyosarcoma and adipocytic sarcomas.


Dr. Gary Schwartz on the Survival Benefit of Eribulin In Sarcoma

	Chief, Melanoma and Sarcoma Service Memorial Sloan-Kettering Cancer Center

The first and largest national clinical study to evaluate the safety and efficacy of an IGF-1R antibody (cixutumumab) and an mTOR inhibitor (temsirolimus) in combination therapy for a range of sarcomas has achieved its primary endpoint of improvement in progression-free survival at 12 weeks in patients with bone and soft-tissue sarcomas. The drug combination demonstrated clinical activity that merits the need for future trials.

The evidence of stable disease for more than 1 year in patients with solitary fibrous tumor and of partial response in patients diagnosed with Ewing sarcoma, osteosarcoma, or chondrosarcoma indicates that these drugs offer significant clinical benefit to subsets of patients. Toxicities were consistent with what has been reported previously for this drug combination.

Approximately 13,000 cases of soft-tissue and bone sarcoma are diagnosed annually in the United States. The median survival time from diagnosis for patients with metastatic disease is about 10 to 18 months.

Researchers at Memorial Sloan-Kettering Cancer Center undertook the multicenter, open-label, phase II study in 19 cancer centers nationwide. The findings were published in 

Nationwide, 388 patients aged ≥16 years who progressed after one (and up to four) prior chemo regimens, with a confirmed diagnosis of bone or soft-tissue sarcoma were allocated on the basis of IGF-1R expression by immunohistochemistry to one of three treatment groups: IGF-1R-positive soft-tissue sarcoma, IGF-1R-positive bone sarcomas, or IGF-1R-negative bone and soft-tissue sarcoma.

Of the 54 assigned to each group, the following were progression-free at 12 weeks by intentionto- treat analysis:

		17 in the IGF-1R-positive soft-tissue sarcoma group

		19 in the IGF-1R-positive bone sarcoma group

Although patients are still being treated, this trial has completed enrollment.

Median progression-free survival, overall survival, and response according to histological subtype and IGF-1R status were analyzed.

The median progression-free survival for the most common histological subtypes were 7.5 weeks for Ewing sarcoma, 6.0 weeks for osteosarcoma, 21.4 weeks for chondrosarcoma, 11.4 weeks for leiomyosarcoma, and 12.9 weeks for undifferentiated pleomorphic sarcoma.

For patients with osteosarcoma and leiomyosarcoma, IGF-1R status did not affect median progression- free survival. However, for Ewing sarcoma and chondrosarcoma, IGF-1R immunohistochemistry expression had a statistically significant effect on median progression-free survival.

For patients with Ewing sarcoma, the median progression- free survival was 5.7 weeks for those with IGF-1R-positive disease and 17.7 weeks for those with IGF-1R-negative disease. For patients with chondrosarcoma, the median progressionfree survival was 23.0 weeks for those with IGF-1R-positive disease and 8.1 weeks for those with IGF-1R-negative disease.

The primary endpoint of progression-free survival at 12 weeks ranged from 31% in patients with IGF-1R-positive, soft-tissue sarcomas to 39% in patients with IGF-1R-negative sarcoma.

Median overall survival was 16.2 months for Ewing sarcoma, 14.6 months for leiomyosarcoma, not reached for osteosarcoma, 13.6 months for chondrosarcoma, 15.5 months for undifferentiated pleomorphic sarcoma, and 18.9 months for others. Patients with IGF-1R-negative Ewing sarcoma also had a numerical improvement in median overall survival when compared with those who were IGF-1R-positive.

Articles

The first and largest national clinical study to evaluate the safety and efficacy of an IGF-1R antibody and an mTOR inhibitor in combination therapy for a range of sarcomas has achieved its primary endpoint of improvement in progression-free survival at 12 weeks in patients with bone and soft-tissue sarcomas. 

Gary Schwartz, MD

Articles

Diagnostic Challenges and Clinical Updates in Soft Tissue Sarcomas

Dr. Schwartz on the Benefit of Dose Reduced Nivolumab/Ipilimumab in Metastatic Sarcomas

Dr. Schwartz on Future Research Efforts in Sarcoma

Dr. Schwartz on Results From the GIST Cohort in the Alliance A091401 Trial

Dr. Schwartz on the Updated Design of the Alliance A091401 Trial in Metastatic Sarcomas

Dr. Schwartz on the Results of the Alliance A091401 Study in Metastatic Sarcoma

Dr. Schwartz on the Results of the PACIFIC Trial

Dr. Gary Schwartz on the Survival Benefit of Eribulin In Sarcoma

Combination of Cixutumumab and Temsirolimus Demonstrates Improved Progression-Free and Encouraging Overall Survival for Bone and Soft Tissue Sarcoma

Gary Schwartz, MD

Articles

Diagnostic Challenges and Clinical Updates in Soft Tissue Sarcomas

Dr. Schwartz on the Benefit of Dose Reduced Nivolumab/Ipilimumab in Metastatic Sarcomas

Dr. Schwartz on Future Research Efforts in Sarcoma

Dr. Schwartz on Results From the GIST Cohort in the Alliance A091401 Trial

Dr. Schwartz on the Updated Design of the Alliance A091401 Trial in Metastatic Sarcomas

Dr. Schwartz on ​the Results of the Alliance A091401 Study in Metastatic Sarcoma

Dr. Schwartz on the Results of the PACIFIC Trial

Dr. Gary Schwartz on the Survival Benefit of Eribulin In Sarcoma

Combination of Cixutumumab and Temsirolimus Demonstrates Improved Progression-Free and Encouraging Overall Survival for Bone and Soft Tissue Sarcoma

Dr. Schwartz on the Results of the Alliance A091401 Study in Metastatic Sarcoma