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Soft Tissue Sarcoma Case Studies

Clincial Trial and Overall Survival Data with Olaratumab

Published Online:Oct 25, 2016
Mark Agulnik, MD, reviews the goals of therapy and treatment options in advanced soft tissue sarcoma, and discusses dosing strategies and treatment options using case-based scenarios.

Advanced Soft Tissue Sarcoma with Mark Agulnik, MD Case 1

Mark Agulnik, MD: For the data pertaining to the clinical trial, the phase Ib/II of olaratumab and doxorubicin, we could then look at some of the subgroup analyses and subset analysis to see whether or not there was a certain patient population that would derive more benefit than others. We see right across the board, if we’re looking at PDGFR-α, it did not predict a response to therapy versus having no expression of PDGFR-α. When we look at the subtype analysis in the different histologies, we see a benefit throughout all histologies. When we look at patients, who had been previously treated with one line of therapy or two lines of therapy, but had no prior exposure to doxorubicin, we see that they themselves derive therapy from this. We certainly know that after progression, a number of patients will receive other lines of therapies, as well.

The impressive part of the data, when we look at the clinical trial of olaratumab and doxorubicin, is to specifically look at the progression-free survival and the overall survival outcomes. And, overall survival in this trial was statistically significant and was very impressive versus the group that got doxorubicin by itself. If we start looking at the numbers, we see in the overall survival group that the combination therapy derived a benefit of 25.6 months versus just over 14 months for the group that received single agent. Therefore, we have almost a 1-year advantage for a combination therapy. Then, when we look at progression-free survival, we see that there is a slight advantage of 6.6 months versus just over four months for the single agent. The question always becomes, why do you only have a little bit of a progression-free survival advantage, but then a prolonged overall survival advantage? This really goes to the question of, is the addition of olaratumab to doxorubicin somehow changing the biology of the tumor, so that perhaps the tumor becomes less aggressive? And, in being less aggressive, perhaps the patient is able to live longer.

When we look at toxicity profiles for the combination therapy of olaratumab and doxorubicin, we see that they’re very similar to the toxicity profile of doxorubicin. And, so, what we would anticipate seeing, and what we did see in the trial, was neutropenia or myelosuppression. We also saw diarrhea, mucositis, nausea, and these were all things that we would anticipate, the alopecia that we would anticipate, as well. The values or the numbers of the patients that were affected were slightly higher than in the single-agent group, but there was nothing uncharacteristic or different than wasn’t to be expected. Now, in the clinical trial, we used 8 cycles of adriamycin or doxorubicin with olaratumab.

Traditionally, in most practices and in most prior clinical trials, we utilize about 6 cycles of adriamycin or doxorubicin, and, therefore, one has to look would people feel comfortable using 8 cycles, and is there anything we could do to protect the patient against the side effects of the drugs. The side effect that we’re concerned about is the cardiomyopathy that could develop from the 8 cycles of adriamycin. In this trial in particular, after 4 cycles of treatment, starting at cycle number 5, patients were treated with Zinecard every time they received adriamycin for cycle 5 through 8 as a cardioprotectant.

Given the impressive data that were achieved with the combination therapy of olaratumab and adriamycin, it will become the first-line therapy in the standard of care for patients with metastatic or unresectable disease. The question then becomes, if you have an overall survival of 25.6, which is much higher than what would have been anticipated with single-agent adriamycin, do you then use this regimen as a first-line therapy or do you still challenge it against other clinical trials? So, I think what needs to happen amongst the community of academic sarcoma specialists is for us to really look at whatever’s coming through in the pipeline for a first-line agent. Do we anticipate this will improve upon what we now have as a first-line therapy? If we do feel it would improve upon that, then I do think as a group it is important to use a clinical trial and try to push the envelope further. If we don’t feel that there is a likelihood of that happening, as we have seen 2 very large first-line trials that were negative trials, does it make more sense to start to pursue more second-line therapies, third-line therapies, and novel therapeutics?


Case 1:

  • The patient is a 36 year-old Caucasian man, referred to a center of excellence after diagnosis of a high-grade undifferentiated pleomorphic sarcoma located in the retroperitoneum.
  • The tumor is large (8 cm), deeply seated, and unresectable because of its location and invasion of major vascular structures.
  • His performance status is 0.
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