Dana Chase, MD, expands on the pivotal clinical trials, managing toxicities, and the questions researchers still need to answer regarding bevacizumab for patients with ovarian cancer.
Dana Chase, MD
Three pivotal clinical trials have shown the significance of the angiogenesis inhibitor bevacizumab (Avastin) as treatment for patients with recurrent ovarian cancer. However, asks Dana Chase, MD, what else can be accomplished with this agent to provide a greater benefit to patients?
The randomized phase III GOG-02131 and OCEANS trials2 were the basis for the FDA’s December 2016 expanded approval of bevacizumab in ovarian cancer to include patients with platinum-sensitive recurrent disease as part of a combination regimen with chemotherapy followed by continued use of the angiogenesis inhibitor.
In GOG-0213, results demonstrated that the addition of bevacizumab to chemotherapy led to a nonstatistically significant median overall survival (OS) difference of 5 months versus chemotherapy alone of 42.6 months versus 37.3 months, respectively (HR, 0.84). The median progression-free survival (PFS) with bevacizumab was 13.8 months compared with 10.4 months with chemotherapy alone (HR, 0.61; 95% CI, 0.51-0.72).
The OCEANS study showed a median PFS improvement of 4 months for bevacizumab with chemotherapy (12.4 months) versus placebo plus chemotherapy (8.4 months; HR, 0.46; 95% CI, 0.37-0.58; P <.0001). However, the secondary endpoint of OS also did not show statistically significant improvement (HR, 0.95).
Moreover, the phase III AURELIA trial3 led to the November 2014 FDA approval of bevacizumab in combination with chemotherapy for patients with platinum-resistant recurrent ovarian cancer. The decision was based on a 62% improvement in PFS with bevacizumab demonstrated in the trial.
During the 2017 OncLive® State of the Science Summit on Advanced Ovarian Cancer, Chase, an associate professor at Creighton University, University of Arizona College of Medicine, and gynecologist oncologist with Arizona Oncology, lectured on the use of bevacizumab in patients with recurrent disease. In an interview, she expanded on the pivotal clinical trials, managing toxicities with these regimens, and the questions researchers still need to answer regarding bevacizumab.Chase: Talking about recurrent ovarian cancer is one of the most challenging parts of being a gynecologic oncologist. These women had treatment before, they have had surgery, and now they’re suffering a recurrence. The approach to treatment for them can be very difficult. You are not only trying to manage a tumor that’s not resectable, but you’re also trying to manage toxicities. These women, at this point, know that they are not going to be cured. They have things they want to do in their life, and they don’t want to feel too sick. They are sick of feeling sick. You have to really manage disease control with toxicity, which is really important to consider in this patient population.
I talked about 3 trials: GOG-213, OCEANS, and AURELIA. Those 3 studies specifically led to the approval for bevacizumab, an antiangiogenesis therapy in recurrent ovarian cancer.
AURELIA is a study that looked at platinum-resistant patients with a doublet treatment, which includes a chemotherapy backbone with bevacizumab added to it. That study did show an improvement in PFS, and was very noteworthy for the improvement in quality of life and the reduction of abdominal symptoms. And, bevacizumab is a relatively easy-to-tolerate medication, so these patients really did not have much more toxicity.
GOG-0213 and OCEANS are both studies that led to the approval of bevacizumab in recurrent platinum-sensitive ovarian cancer. GOG-0213 used carboplatin with paclitaxel and bevacizumab, and the OCEANS study used carboplatin with gemcitabine and bevacizumab. GOG-0213 had an impressive improvement in OS and the OCEANS study had an improvement in PFS. Therefore, we are now allowed to treat platinum-sensitive patients with chemotherapy plus bevacizumab followed by bevacizumab maintenance. Again, the toxicity of bevacizumab maintenance is very easy to address in these patients; they are essentially able to get back to their normal lives. That is one of the most challenging parts of my job—managing these side effects. For example, with paclitaxel—one of the most commonly used drugs for ovarian cancer—I always tell my patients that the number 1 side effect that patients complain about is hair loss. Paclitaxel causes alopecia.
Second to that, paclitaxel in combination with carboplatin causes fatigue and the paclitaxel especially causes neuropathy. Neuropathy sounds like a benign side effect, but the reality is that these women can’t feel their fingertips or toes. If they are elderly, they slip and fall in the supermarket, they can’t button their shirts, they can’t play the piano, and they can’t turn a page of a book. Neuropathy sounds benign but we don’t have a good medication for it. It can be semipermanent, and there is really nothing that we have that is good to offer to manage it.
Nausea and vomiting can also be a side effect of the chemotherapy drugs, both carboplatin/paclitaxel and carboplatin/gemcitabine. Gemcitabine tends to cause more hematologic toxicities, as well as some pretty noteworthy fatigue. Again, just like neuropathy, fatigue is something we don’t have a good treatment for. It’s very hard to have a platinum-sensitive or platinum-resistant patient who feels intense fatigue.
For bevacizumab, on the other hand, it is really worth pointing out that it’s a very well-tolerated drug. Most of the toxicities related to it are manageable. We have medications to manage hypertension; most patients don’t come off the drug for hypertension, as we are able to control it with medications. Overall, bevacizumab is a pretty well-tolerated drug that patients can stay on for long term.
You do have to talk to patients about the risk of bowel perforation and fistula, but those are rare toxicities. You have to caution a patient about it, but it’s not something you deal with very often. That is a good question. With new therapies coming onboard, how you sequence your treatment is going to be the big question. Do you give bevacizumab upfront, the second-line setting, or wait to give it in the third- or fourth-line setting?
Also, can you give it a second time? Is it less effective if you give it as regimen 2, 3, 4? Does it matter when you've given it regimen 1? The 2 questions that are most important are sequencing and whether you can repeat it if you’ve already given it once before.
Potentially, down the road, we might see bevacizumab combined with other targeted agents, which might be exciting to see if we can knock off some of these cytotoxics all together and just give targeted agents together. That might be down the road at some point. We are all going to start giving a lot more PARP inhibitors. Really, I have had less than a handful of patients on a PARP inhibitor. But now, with recent FDA approvals, we are going to start using them more and getting a better feel for how they’re tolerated. I worry a little bit about the toxicity and the side effect profile, so I am excited to get more experience with it.
Moreover, I am super excited about the improvements they have shown in germline BRCA patients, as well as the somatic patients. That is going to be exciting and, if immunotherapy can break through some of the difficulty we have had in curing ovarian cancer, that would be really exciting—especially upfront. Those are the 2 areas that I am the most excited about.