The current standard-of-care for patients with metastatic soft-tissue sarcoma isn’t very effective, but few, if any, novel treatments have been able to improve on the poor outcomes. Olaratumab is a human antibody that can block a cell signaling process also involved in cancer. A combination treatment with doxorubicin resulted in a significant increase in progression free and overall survival, suggesting a potential shift in the treatment of soft-tissue sarcomas.
The context
Soft-tissue sarcoma is very rare as it only accounts for 1% of adult cancers. It is also a very diverse disease as 50 different subtypes exist. This complicates treatment, as each of these types can respond differently to a therapy. Nevertheless, the medical need is high as with the current treatment options, survival for patients with metastatic disease is only 12 – 16 months. Despite extensive research efforts, no treatments have yet been able to improve this outcome. At best, some trials have succeeded in postponing disease progression slightly, but often at the expense of more side-effects.
A new human monoclonal antibody, olaratumab, was discovered that interferes with the so-called Platelet-derived growth factor (PDGF) signalling system. Its natural function is to help the body regenerate by growing and evolving stem cells or by stimulating the formation of new blood vessels. However, it is also associated with cancer as disturbances can facilitate metastasis. Blocking this system by binding an antibody to the receptor has shown antitumor activity on human tumors grown in mice. This study wanted to expand on those results by testing the human safety and efficacy of the compound in a clinical setting.
The nuts and bolts
This study combines a phase Ib (15 patients) and phase II study (133 patients) on patients with a histologically confirmed diagnosis of locally advanced or metastatic soft-tissue sarcoma. A number of exclusion criteria were used, for example no previous treatment with anthracycline. In the phase II study, patients were randomly assigned doxorubicin alone as a control, or in combination with olaratumab. The tumor response was assessed every 6 weeks. The final endpoints were safety, progression-free and overall survival.
In this trial, the efficacy of adding olaratumab to the current standard-of-care treatment doxorubicin was tested. This way, the median time to disease progression could be increased from 4.1 to 6.6 months. The median overall survival went from 14.7 to 26.5 months. These benefits were independent of factors such as tumor type, number of previous treatments or how much PDGF receptor the patient expressed. The greater effect on overall survival compared to disease progression suggests that the effect persists beyond the treatment period.
As in all trials, side-effects are monitored and measures are taken to protect the patient. For example, the dose is reduced or the treatment is stopped when necessary. Adverse effects often associated with a doxorubicin treatment were more frequent in patients that received the combination treatment. However, this did not result in an increased number of hospital admissions, treatment discontinuations or deaths.
How will this help me?
Adding olaratumab to the standard treatment for metastatic soft-tissue sarcoma leads to a significant increase in overall survival, along with an acceptable safety profile. While the unmet medical need for sarcoma patients remains huge, this is the first time the standard treatment can be improved so drastically, leading to a potential shift in the treatment of soft-tissue sarcoma. Further clinical studies will be performed before it will become clinically available.
Source
Olaratumab and doxorubicin versus doxorubicin alone for treatment of soft-tissue sarcoma: an open-label phase 1b and randomised phase 2 trial – The Lancet (2016)