The other 3 trials with atezolizumab involve adding chemotherapy and bevacizumab (Avastin) to atezolizumab. This regimen is chemotherapy, anti-VEGF therapy, plus a checkpoint inhibitor. We have 3 global indications in ovarian cancer for bevacizumab. The idea with bevacizumab is to add to those 3 opportunities: frontline, platinum-resistant, and platinum-sensitive settings. It is a very exciting time, and very ambitious.
Are there any safety issues with these combinations?
We have seen no safety contraindications; both PARP inhibitors and checkpoint inhibitors can generally be given at full dose. Again, these are in very early stages and need to be confirmed. Similarly, full-dose chemotherapy and checkpoint inhibitors can also be combined, but it is really the efficacy that we need to focus on.
Could an oncolytic vaccine, similar to what we have available in melanoma, have potential in ovarian cancer?
Another option would be to increase the mutational burden through the introduction of neoantigens. One strategy might be to use a vector—perhaps listeria—which could package neoantigens; that is certainly being tried by at least 2 pharmaceutical companies. There are a number of ways to deliver antigens to improve the efficacy of checkpoint inhibitors.
What challenges still exist with immunotherapy in ovarian cancer?
The challenge in ovarian cancer with immuno-oncology has been that the number of tumor-infiltrating lymphocytes is relatively low, at 50%, and the number of cells that express PD-L1 are relatively low, as well. Importantly, the mutational burden or neoantigen levels are low. We haven't had the single-agent activity that we have seen in other tumors, where we have had accelerated approval from a single-arm trial with a high overall response rate, acceptable toxicity, and responses that are durable. We have had to do slow and expensive randomized phase III trials. It is exciting, but it will only be personally satisfying if we can bring these medicines to patients and prove that they are both efficacious and safe.
Although we don't have checkpoint inhibitors that are FDA approved yet, we certainly have 3 PARP inhibitors and, depending on what part of the world you live in, 2 or 3 bevacizumab indications. Therefore, we have immunotherapy, VEGF-targeted therapy, and PARP inhibition. The challenge is, do we combine all 3 together? Or just 2? If so, which 2 and in what sequence? That is going to fill our plate regarding research for the next 5 to 10 years.