O'Malley Discusses the Role of Bevacizumab Maintenance in an Ovarian Cancer Case Study

David OMalley, MD

David OMalley, MD

During aTargeted Oncologylive case-based peer perspectives presentation, David O’Malley, reviewed the treatment considerations and decisions he makes when treating patients with ovarian cancer. O’Malley, a professor in the Department of Gynecology, and the director of Gynecologic Oncology Clinical Research at the James Cancer Center, Ohio State University, explained to the group the factors that go into treatment decision making during the meeting based on a case scenario of a patient with high-grade serous carcinoma.

Case

January 2017

A 69-year-old Caucasian woman presented to the emergency department with shortness of breath. Her past medical history indicated mild hypertension and diabetes mellitus, medically managed, and morbid obesity. A physical exam showed large-volume ascites.

A CT angiography of the chest showed large bilateral pulmonary effusions, but no pulmonary thromboembolism. A CT of the abdomen and pelvis demonstrated peritoneal carcinomatosis and bilateral masses. Laboratory findings were remarkable for CA 125, 525 U/mL. A thoracentesis (1500 cc); cytology showed high-grade adenocarcinoma and a paracentesis (4500 cc); cytology showed high-grade adenocarcinoma. A core biopsy of omentum showed high-grade serous carcinoma. Markers for p53, PAX 8, WTI, and CX7 were all positive, and the patient wasBRCA1/2wild type.

When do you typically test forBRCA 1/2mutation status, and do you test for somatic mutations in the tumor?

Interestingly, they sentBRCAmutation testing right away for this patient with ovarian cancer. I was not doing that until just recently. The National Comprehensive Cancer Network (NCCN) recommendations say to test for germline [BRCAmutations] at diagnosis, but the somatic is at recurrence. We haven’t changed it yet, but I’m sure that subject is going to come up. I have not been doing germline at diagnosis; I’ve been doing it after the patient has completed her chemotherapy. However, I think we need to be checking it right away. We know that 10% to 20% of cases are going to be germline, but we also know that 10% to 15% of patients will haveBRCAsomatic mutations. We have another group that is going to have homologous recombination deficiency (HRD), which is up to almost 40%. Forty percent of patients are going to have some HRD, or it will not be intact.

There are some platforms in which you can send the somatic and the germline together as 1 bill. So the question of double billing is normally: Is Medicare going to cover both of them? That is resolved with this method.

Are you doing circulating tumor DNA testing?

We are going to see more and more of this. The ARIEL2 and ARIEL3 data show that we can see the reversion mutations in the tumor that predict when the patient will become resistant.^1,2There is a paper coming out that will show this. I think in 5 to 10 years, this is all we are going to be doing. However, the way I read the data right now is that we are not there yet.

Do you use bevacizumab (Avastin) in the up-front setting now that it is approved for ovarian cancer?

I don’t use it unless it is on clinical trial, or I give them 1 or 2 cycles [of chemotherapy], especially with neoadjuvant therapy, and their ascites aren’t drying up. I will perform surgery on them, and sometimes they develop ascites in the postoperative setting. Or their CA 125 is not really going down. I will add bevacizumab to those patients. Now that we have the FDA indication, I can give it. Before, I had to argue [with insurance] about how they are becoming resistant.

If there is 1 way to treat these patients, it is with platinum doublet with bevacizumab up front and then, at recurrence, platinum doublet plus or minus bevacizumab followed by PARP inhibitor maintenance. It is the cleanest way to treat. We have statistically significant progression-free survival in the up-front setting with bevacizumab, and you could argue both ways. You could say it doesn’t make that much difference because you’re giving them 14 months of therapy for a 6-month improvement. But I think we should be looking at this more, particularly with what we have available. We know that we will have more data on bevacizumab [maintenance] and that it continues to show benefit.

The problem with this drug is the hypertension and the renal [effects]. For this particular patient, and looking at this subpopulation of patients, the ICON7 data showed that if you have a suboptimal debulking or if you had large ascites, those curves seemed to be much more divergent than when we include all-comers.³When we looked at the subanalysis of the GOG data, we didn’t quite see that divergence.^4,5However, in my own practice, that is when I’m using bevacizumab up front: suboptimal debulking, very high-risk disease, and resistant ascites. I’m not doing it in all stage IV patients, but I think it would make sense [to do it].

Neoadjuvant treatment makes my surgery a lot easier. But when you look at the data, if we use neoadjuvant on everyone, they do not seem to do as well. The FDA indication said after surgery—it didn’t say attempted cytoreduction; it didn’t say how do you define your surgery. If you send them to international radiology, and they give them sedation and they stick a needle in the tumor, is that considered surgery? I’m not sure how you define it. It is a lot easier when the patient is sitting right in front of you when you try to make these decisions. The other problem is that as we start doing more neoadjuvant therapy with bevacizumab, which it is currently not indicated for, we have to worry about the bowel proliferation. If you start treating these heavily bowel-involved patients, you will start seeing this adverse event (AE) reaching 2% to 4%. It is real. If you are going to give bevacizumab up front, and you are working with a surgical oncologist, you need to make sure that you know when they are planning on doing surgery, to omit that final cycle of bevacizumab. I don’t start it the first cycle afterward either, for that same reason, particularly with bowel resection.

The patient underwent debulking surgery with incomplete cytoreduction. She was treated as part of a clinical trial with carboplatin/paclitaxel plus bevacizumab followed by continuous bevacizumab maintenance.

April 2018

Fifteen months later, the patient complained of severe abdominal bloating and fatigue. Imagining showed multifocal recurrence within the abdominal cavity. Her CA 125 was elevated to 322 U/mL and she had an ECOG performance status of 1.

She was started on carboplatin/docetaxel (Taxotere) and after 6 cycles of therapy she had a partial response to therapy with bulky residual disease. She was then initiated on rucaparib (Rubraca) maintenance therapy, 600 mg twice a day (BID). Her hemoglobin fell to 7.2 g/dL; managed with treatment interruption, and then dose reduction to rucaparib 500 mg.

What are the choices for second-line therapy?

The patient has recurred 15 months later. Her ECOG performance status is 1, and she has multifocal disease. Her CA 125 is not quite as high as it was, but it is still 10-fold [too high]. She started a platinum-doublet chemotherapy after. Now, you may say, How are we going to define platinum sensitivity with the use of bevacizumab? We still define it the same way. It is 6 months.

We have changed our definition of platinum sensitivity, but we don’t have great data on this yet. Classically, it was 6 months from the completion of chemotherapy. If you recurred within that time frame, you didn’t show platinum. We are [learning] more and more that we should show that those patients are resistant and refractory to platinum, particularly if they had a good response. This patient had a suboptimal debulking, had chemotherapy, got a complete response, and then didn’t recur for 15 months. I would argue that this patient is still platinum sensitive. With the bevacizumab, you could argue that it made [the disease] worse.

I don’t use a lot of docetaxel in the second-line setting, but a lot of people do. It is nice for neuropathy, but I think the fatigue is a challenge. My No. 1 [choice for second-line therapy] would be platinum with gemcitabine. We’ve published a phase II trial dosing both of the drugs on day 1 and day 15.⁶It was nice, and then you can give the pegfilgrastim (Neulasta) on both. You still have thrombocytopenia, but you don’t have the neutropenia. It was well tolerated. We have only the single-arm, phase II trial at Ohio State University, but it is a nice way to give it.

If they are healthy, I start platinum/gemcitabine on day 1 and day 15 at 1000 mg. If they are not healthy or if they’ve had trouble with their bone marrow before, I’ll do 800 mg. I do 300 mg only on the carboplatin. When you add the bevacizumab, you also add it on day 1 and day 15. You get bevacizumab twice too. The bone marrow support is such a challenge with day 1 and day 8. If I do it on a clinical trial, I will dose day 1 and day 8, but outside a clinical trial, I dose them on day 1 and day 15.

Carboplatin/paclitaxel is nice to do, but these patients are on their second haircut at 15 months, and they’re thinking, Really, I’m going to lose my hair again? It is tough. I love weekly paclitaxel for recurrence, especially with bevacizumab. So I’d rather hold that and keep the neuropathy down. We don’t have a randomized prospective trial with all 3 doublets. I presented 1 at the GOG 7 years ago, and it wasn’t enough, so we still have no idea what we should be doing.

At the European Society for Medical Oncology annual meeting, the Europeans did look at bevacizumab with carboplatin plus gemcitabine on day 1 and day 8 versus bevacizumab with carboplatin/pegylated liposomal doxorubicin (PLD).⁷PLD outperformed, and it was statistically and clinically significant. That is not yet in publication, but it was very surprising to me. When you look at the neutropenia on day 1 and day 8, the dose intensity is so diluted with the day 1 and day 8 treatment. I suspect that is why the carboplatin/PLD did so much better. I think carboplatin/PLD is now higher in my practice [in terms of treatment preference].

Now, this person had frontline bevacizumab. And as we just discussed, we are not doing that much frontline bevacizumab yet. If you look at the market data, 30% to 40% of patients were using up-front bevacizumab before it was approved. We suspect that that will go up to about 50% to 60%. More people are using it now than aren’t in the frontline setting.

Would you go back to bevacizumab if you used it in the first line?

As I said before, we are going to have published data soon that show that it continues to show benefit. We published this 8 years ago in a retrospective fashion that shows you continue to benefit. Again, this is just retrospective in our practice. We now have prospective data to support that. I would absolutely go to bevacizumab again.

What is the rationale for using maintenance therapy, and what are the options?

This patient had a partial response. In the past, I would have just treated [with] cytotoxic doublet plus or minus bevacizumab and kept going until she begged me to stop. She still has measurable disease, and her CA 125 is still elevated. If the patient starts to get beat up, you have to give her a holiday at some point. These people, hopefully, have 3 to 5 years to live depending on how good of a population we have.

We have data from the bevacizumab and PARP inhibitor trials that [show that] even if you have persistent disease and only a partial response, [patients] clearly benefit from maintenance therapy. I use all 3 agents approved for ovarian cancer: niraparib (Zejula), olaparib (Lynparza), and rucaparib. The most underdiscussed impact of the indication for rucaparib is that it was the first time we had a somatic indication for a drug in ovarian cancer. I went from sending no tissue for next-generation sequencing to 100%, at least for HRD. Pazopanib (Votrient) is also in the NCCN guidelines because of a positive trial in Europe. There were a couple of US sites that participated, but it is category 3 [in the NCCN guidelines], and it is very hard to get paid for in the United States. It is not an easy drug to get in and very rarely used.

I try to base my decisions on what data are available to guide me. If you were to say bulky disease, the only drug that tested this was rucaparib. For all the other agents, patients were not allowed to have anything more than 2 cm on the clinical trial. I think the more interesting question now is: What are we going to do with maintenance in a platinum-sensitive recurrence? There are 3 drugs in 1 class and a fourth in a completely different class. How do we decide? I don’t know the answer.

Which patients are eligible for PARP inhibition?

We know the addition of bevacizumab with the cytotoxic improves our complete response rate by about 30% if you look at the OCEAN trial.⁸The problem with that is that there are no data to support switching the maintenance drug. I think we will [start to look at this] because of the way the current randomized prospective trials are in maintenance.

InBRCAwild-type patients, I do use PARP inhibition. I think it is the only time I can give a patient with a nongermline mutation a PARP inhibitor. There are definitely patients who benefit with wild-typeBRCAon PARP inhibition as well.

What toxicity concerns do you consider with PARP inhibition?

I’m just figuring it out with my patients right now. More than half of the patients on the trial need a dose reduction. However, you will still have benefit. One thing I’ve learned is that you have to send them home with antimedics. They can call in, but save yourself a phone call. Many of them already have them because they’ve been on cytotoxic therapy, so educate them to take them. I tend to use the antimedics before dose reduction.

The problem is they are taking ondansetron (Zofran) every day or at twice-a-day dosing. They get constipated, and then you’re chasing after that. So I think the dose reductions are really interesting.

Most of the toxicities are grade 2, and we’ll see some grade 3. When they are saying that it is well tolerated, you don’t see a lot of grade 3 toxicities, but you seea lotof grade 2 AEs. My main reason for dose reduction before [gastrointestinal events] is fatigue. [Patients] can have really profound fatigue. I have a patient who was really active and couldn’t get out of bed to go to church. I think it is important to educate them to call us and to not stay at home for the month and not be able to get off the couch. I start the education right away.

The hematologic AEs are real, particularly with niraparib. The thrombocytopenia with niraparib is profound and real. If you see the platelets drop on niraparib, don’t wait that next week. Hold therapy and repeat it. The problem is our nurses aren’t trained. They see greater than 100 and think they are OK. If they go from 190 to 105, they are going to tank. The next one, they’ll be 10.

How would you have managed this patient’s anemia?

My third reason for dose reduction is anemia. I will transfuse. I used to treat through those, and I’ve learned the hard way that most of them require dose reduction. In this case, she is reduced to 500 mg.

References:

1. Swisher EM, Lin KK, Oza AM, et al. Rucaparib in relapsed, platinum-sensitive high-grade ovarian cancer (ARIEL2 part 1): an international, multicentre, open-label, phase 2 trial.Lancet Oncol. 2017;18(1):75-87. doi: 10.1016/S1470-2045(16)30559-9.
2. Coleman RL, Oza AM, Lorusso D, et al; ARIEL3 Investigators. Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial.Lancet. 2017;390(10106):1949-1961. doi: 10.1016/S0140-6736(17)32440-6.
3. Perren TJ, Swart AM, Pfisterer J, et al; ICON7 Investigators. A phase 3 trial of bevacizumab in ovarian cancer.N Engl J Med. 2011;365(26):2484-2496. doi: 10.1056/NEJMoa1103799.
4. Coleman RL, Brady MF, Herzog TJ, et al. Bevacizumab and paclitaxel-carboplatin chemotherapy and secondary cytoreduction in recurrent, platinum-sensitive ovarian cancer (NRG Oncology/Gynecologic Oncology Group study GOG-0213): a multicentre, open-label, randomised, phase 3 trial.Lancet Oncol. 2017;18(6):766-791. doi: 10.1016/S1470-2045(17)30279-6.
5. Rossi L, Verrico M, Zaccarelli E, et al. Bevacizumab in ovarian cancer: a critical review of phase III studies.Oncotarget.2017;8(7):12389-1240 doi: 10.18632/oncotarget.13310.
6. Eisenhauer EL, Zanagnolo V, Cohn DE, et al. A phase II study of gemcitabine, carboplatin and bevacizumab for the treatment of platinum-sensitive recurrent ovarian cancer.Gynecol Oncol. 2014;134(2):262-26 doi: 10.1016/j.ygyno.2014.05.030.
7. Pfisterer J, Dean AP, Baumann K, et al. Carboplatin/pegylated liposomal doxorubicin/bevacizumab (CD-BEV) vs. carboplatin/gemcitabine/bevacizumab (CG-BEV) in patients with recurrent ovarian cancer. A prospective randomized phase III ENGOT/GCIG-Intergroup study (AGO Study Group, AGO-Austria, ANZGOG, GINECO, SGCTG). In: Proceedings from the 2018 European Society for Medical Oncology Congress; October 19-23, 2018; Munich, Germany. Abstract 933O.
8. Aghajanian C, Blank SV, Goff BA, et al. OCEANS: a randomized, double-blind, placebo-controlled phase III trial of chemotherapy with or without bevacizumab in patients with platinum-sensitive recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer.J Clin Oncol. 2012;30(17):2039-2045. doi: 10.1200/JCO.2012.42.0505.