Greetings from Chicago, where once again, immunotherapy remains the highlight of most ASCO presentations. This year was particularly exciting, as we finally got to see the preliminary results of the first clinical trials of checkpoint inhibitors for sarcomas. So, I will update all of you on the most recent data, explain how we still have more questions than answers, and try to consolidate future directions.
SARC 028 – Investigator Dr. Tawbi – Pembrolizumab (Keytruda) for Sarcomas
This study enrolled 40 patients with high grade, metastatic soft tissue sarcoma resistant to at least one line of chemotherapy (leiomyosarcoma, undifferentiated pleomorphic sarcoma, dedifferentiated liposarcoma, and synovial sarcoma) and 40 patients with bone sarcomas (osteosarcoma, Ewings sarcoma, and dedifferentiated chondrosarcoma). Patients received pembrolizumab alone every three weeks until scans showed progression. Overall 11 of the 40 patients with soft tissue sarcomas had their tumors shrink while only 3 patients with bone sarcomas had tumor shrinkage. Patients with tumor shrinkage in the soft tissue sarcoma arm included 4 patients with undifferentiated pleomorphic sarcoma (UPS), 5 patients with dedifferentiated liposarcoma (dLPS), and 1 patient each with synovial sarcoma and 1 with leiomyosarcoma. The patient with synovial sarcoma worsened soon after showing the shrinkage, while the patients with UPS and dLPS have ongoing responses. The patients with response in bone tumors included one patient with Ewings sarcoma, one with osteosarcoma, and one with dedifferentiated chondrosarcoma. Most patients with Ewings sarcoma, synovial sarcoma, and leiomyosarcoma rapidly progressed.
In Dr. George’s study from Dana Farber, 12 women were treated with nivolumab for uterine leiomyosarcoma – there were no tumor responses and all patients had progressive disease by their first three month scan. However, she is running another trial for uterine leiomyosarcoma with pembrolizumab that has 37 patients – although the official data is not available, the unofficial report is that only 1 woman responded to pembrolizumab, although her response was spectacular.
This suggests that at least for some sarcoma patients, pembrolizumab may be an active drug -there is about a 19% overall chance that you will have shrinkage, and it may be higher if you have UPS or dedifferentiated LPS. This is similar to the reported response rates in other types of cancer including lung cancer, bladder cancer, and gastric cancer, and about 10% less than melanoma.
What this also means though is that if you have synovial sarcoma, leiomyosarcoma, or Ewing’s sarcoma, you have a very low chance of having benefit from single agent PD-1 inhibitors – so I would NOT recommend using these drugs off-label by themselves. Instead, we should make sure to enroll patients like this on clinical trials of combination treatments, at least until we figure out a better biomarker to predict and find those few patients who will respond in these types of histologies.
There are a couple of other poster presentations again reporting sporadic responders in similar histologies.
How do we identify responders?
Dr. Sandra D’Angelo from Memorial Sloan Kettering gave a fantastic talk on the overview of checkpoint inhibitors and what we know so far about how to use them. She described her theories on how some sarcomas are HOT tumors – meaning that the tumors are full of immune cells already, and some are COLD, with almost no immune cells. It seems like the tumors that had the best responses are likely to be the hot tumors, although we’ll have to wait for the analysis of the responders in the SARC 028 trial to be sure about this.
The next question is how can we transform cold tumors into hot tumors? there are lots of ideas – like using chemotherapy, radiation, or blood-vessel blasting drugs to allow immune cells to get into the tumors better. Overall, there are tons of potential new trial ideas to explore combinations of immunotherapy treatments. Lots of work to do!
For some additional reading material, although these may be a bit medical, see the attached slides and transcript of my discussion of the significance of these studies, and Dr. D’Angelo’s excellent educational article summarizing the current role of checkpoint inhibitors.
more updates soon!
Since some of the data belongs to the researchers, please do not repost or distribute the slides without express permission.