This podcast provides observations and commentary on the JCO article "Randomized, Double-Blind, Phase II Study of Regorafenib in Patients with Metastatic Osteosarcoma" by Davis et al. My name is Brian Van Tine, and I am an Associate Professor of Medicine in the Division of Oncology at Washington University School of Medicine. My oncologic specialty is sarcoma.

Osteosarcoma (OS) is the most common type of primary malignant bone cancer, frequently occurring in children and adolescents. It can also be found in older adults around the age of 70, but unfortunately, though rare, can be found in patients of any age. Thus, Osteosarcoma is a disease that not only do pediatric oncologists need to know about, but also adult oncologists. Osteosarcoma occurs primarily at the metaphysis of the bone, in regions of rapid bone growth, in bone-forming cells called osteoblasts. Various risk factors for the development of osteosarcoma include underlying bone pathologies, such as Paget’s Disease, prior radiation treatment, and genetic predisposition due to mutations, such as Li-Fraumeni Syndrome, caused by mutations to TP53, or in retinoblastoma mutation patients.

Currently, in the curative setting, OS is treated with chemotherapy with cisplatin, doxorubicin, and high-dose methotrexate (HD-MTX), followed by surgical resection of the tumor. Patients who relapse with metastatic disease have limited options, regiments such as ifosfamide with etoposide and gemcitabine with docetaxel are used with an expected 4-month PFS of only 12%, but the standard of care for osteosarcoma has not changed in 30 years.

This is where the Sarcoma Alliance for Research and Collaboration, or SARC for short, comes in. SARC is a non-profit organization dedicated to the development and support of research for the prevention, treatment and cure of sarcoma. It is a collaborative group comprised of leading sarcoma physicians dedicated to performing clinical trials in rare diseases. It is their 24th trial and is the subject of the JCO article that accompanies this podcast, where Dr. Lara Davis and colleagues report their findings of a Randomized, Double-Blind, Phase II Study of Regorafenib in Patients with Metastatic Osteosarcoma.

This trial took place across 12 US centers between 2014 and 2018 and enrolled 42 patients between the ages of 18 and 76. Once again, the age distribution highlights that osteosarcoma is not just a pediatric disease, and that there is a dedication to rare disease researchers to accrue to rare disease clinical trials at SARC. In this trial, patients were randomized one to one to either Regorafenib or placebo on a 28-day cycle and responses were assessed using RECIST version 1.1 every 8 weeks. At the time of progression on placebo, patients were allowed to crossover to Regorafenib.

Following the release of the European REGOBONE trial, a study of similar design that showed a significant benefit of regorafenib in osteosarcoma patients, an independent Data Safety and Monitoring Committee (DSMC) was convened by SARC due to concerns regarding continuing to enroll on a placebo-controlled study. The committee recommended closing the study after enrollment of 42 or the 48 planned patients.

Here is what they found. At the time of analysis, they found a progression free survival of 3.6 months for Regorafenib and 1.7 months for placebo with a hazard ratio of = 0.42; a 95% confidence interval of 0.21-0.85, and a p=0.017. Given the crossover design, there was no overall survival seen with a p-value of 0.62. In addition, no new safety concerns with regorafenib treatment were identified during SARC024 and adverse events were generally manageable with dose reductions. Notably, the median dose at the end of blind treatment was 120 mg. Taken together, this makes this the second trial to clearly show benefit for the use of single agent Regorafenib for the treatment of Osteosarcoma

Highlighting the issues with using RECIST to evaluate tumors that make bone in their matrix, only 3 patients on Regorafenib achieved a partial response. Whether this is a cytostatic response to Regorafenib or part of the bone biology of osteosarcoma will need to be determined in future work.

There are a number of meaningful observations that come from this trial. First, and most obviously, Regorafenib is active for the treatment of osteosarcoma and it is oral. While at this time, it is not listed in the NCCN guidelines, this publication makes the second randomized trial supporting its use. I would hope the guidelines change to reflect these publications soon.

Next, there was a very important paper published in JCO in 2016 by senior author Katy Janeway. It was a summary of seven negative phase II trials from the Children’s Oncology Group (COG) that established the natural history of unresectable osteosarcoma to have an event free survival (EFS) of 12% at 4 months. They concluded that, “This evaluation provides a baseline for disease progression in a population of children and young adults with recurrent/refractory osteosarcoma that can be used as comparison for the design of future phase II trials in osteosarcoma.” In the current trial and the REGOBONE trial, the placebo arms of this trial and the REGOBONE study demonstrate similar rapid progression: 10% in 16-week PFS in SARC024 and 0% in 12-week PFS in REGOBONE. These become the 8th and 9th trials with a placebo arm that supports the data of the 2016 JCO publication that stated that the progression free survival of placebo for the treatment of osteosarcoma is well established. To be fair to the authors and to be clear, SARC24 was started two years before the Janeway publication, but are supportive of stopping placebo controls in phase II trials of osteosarcoma in future trial designs.

Once again, the authors are to be congratulated on their findings, which I find practice changing. Their dedication to rare cancer research is benefitting patients that agree to participate in clinical trials. Working together they have identified an active agent for the treatment of osteosarcoma. It will be interesting to see what the next steps are for the SARC team, as they have proposed combination studies based on Regorafenib in their discussion.

Finally, rare disease research and clinical trials in sarcoma are desperately needed to improve the outcomes of our patients. Thank you to JCO for highlighting the work from Lara Davis and colleges and the Sarcoma Alliance for Research and Collaboration. This national organization has sites across the country where sarcoma patients can enroll on clinical trials. A list of adult and pediatric sarcoma referral centers and the clinical trials that are available in sarctrials.org.

This concludes this JCO podcast. Thank you for listening.

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An Advance for the Treatment of Osteosarcoma