Case 4: Recurrent Ovarian Cancer, Platinum-Resistant, BRCA WT

EXPERT PERSPECTIVE VIRTUAL TUMOR BOARD

Robert L. Coleman, MD:Let’s go on to a case of platinum-resistant disease. Dave, why don’t you go ahead and introduce the patient to us, and we’ll go through it.

David O’Malley, MD:This is a great case because she had intraperitoneal chemotherapy [IP] up front.

Robert L. Coleman, MD:Of course, probably from your institution, with a 7-month PFS [progression-free survival].

David O’Malley, MD:So she gets a clinical remission. Her CA 125 [cancer antigen 125 level] is 30.5 [U/mL]. Seven months later, she presents with abdominal distention. We ended up having imaging and also getting a biopsy, which confirms widely metastatic disease. I think this is an interesting question because she’s at 7 months. Is she really platinum-resistant? You know, what’s looking interesting in these patients as we approach them and we move forward is really redefining what we call platinum-resistant disease. We’ve started to define it as those who are not eligible for platinum, and that may be somebody who’s had a hypersensitive reaction. It could be somebody who you think has already had their maximum benefit from platinum. Interestingly, for this patient, our clinical trials have not caught up. And so, she would not be eligible. She recurred more than 7 months, even though she was having symptoms before then. But if you didn’t get that CA 125 before 6 months, she may not be eligible.

Robert L. Coleman, MD:Yeah, I think I’m really impressed by this, and we see these cases a lot. They say, “Well, it’s more than 6. Therefore, they’re platinum sensitive.” But if you think about this case, she must have had a decent surgery because they considered her a candidate for IP therapy. Her starting volume of disease is already small. She got good treatment, and she had an assessment at the end of that, which basically said that there was nothing visible and her CA 125 level was in the 30s [U/mL]. And then at 7 months she had a measurable tumor? To me, that is basically the continuum of growth that just was subclinical. I think that it probably was growing on treatment. To me, I think these patients really define, and as you pointed out, we’ve started to get away from this 6-month thing because, in reality, we kind of made that number up, right? If you go back to the original studies, they did the 3 to 12 months, and 12-plus months, or they segmented differently. They were looking at the opportunity or the observed responses to re-treat with a platinum when there were few choices.

But when we at the GOG [Gynecologic Oncology Group] set up the GOG 146Q and 126Q studies, we used 6 months as the line, 1 prior treatment. Six months less, you get 126Q drugs; 6 months more, you get 146Q drugs. And after doing 2 decades of that kind of work, it kind of got into people’s minds. Obviously, all the drugs in the platinum-sensitive space, even the nonplatinums, were better. They have higher response rates in patients who are less... But you said she’s 7 months, and you said it’s a good question. So what would you have done?

David O’Malley, MD:I’m not sure what the right thing to do on these patients is. First of all, get them on a clinical trial. We can no longer just try to make this stuff up. We have to improve the treatment of these patients. First of all, get them on a clinical trial. But what happens if she wasn’t eligible? I didn’t have a platinum-sensitive disease open. FORWARD II is really interesting right now as kind of a platinum agnostic. We consider somebody who you don’t think is eligible for platinum-based therapy. FORWARD II is mirvetuximab, and we have an expansion cohort with bevacizumab. She would be eligible for this clinical trial. Now, if she recurred within 6 months, she has a plethora of other NRG [Oncology] and collaborative group trials, as well as pharma-sponsored trials that she would be eligible for. In this patient, I may reintroduce platinum with potentially a doublet. We often use gemcitabine, and that may be a patient population for which I would use and particularly bring bevacizumab in.

Robert L. Coleman, MD:Shannon, what do you think about that? Seven months…

Shannon N. Westin, MD:I think everything Dave said is wrong.

Robert L. Coleman, MD:I am so glad I have you here, because then it’s always me.

Shannon N. Westin, MD:No, I think he did a great job. Of course, the priority is clinical trials in this population. Depending on where you are, you may have a plethora of different options. I think different trials combining the drugs we know, like bevacizumab and PARP [poly (ADP ribose) polymerase] inhibitors, and trying to figure out which way to give those to get the most benefit. But this patient I would not probably re-treat with platinum. I might consider gemcitabine and cisplatin, because there are some data around that—overcoming platinum resistance. And so for a patient who is not able to go on a trial and has pretty reasonable kidney function, I would consider that. But really, where I would be looking toward are the AURELIA combinations: bevacizumab plus chemotherapy.

Robert L. Coleman, MD:I’m glad you brought up AURELIA because I want to get to that. I want Dave to go through that. But if you think about OCEANS, which was gemcitabine-carboplatin, plus or minus bevacizumab; and GOG-0213, which is paclitaxel-carboplatin, plus or minus bevacizumab; and now you think about liposomal doxorubicin-carboplatin with bevacizumab versus gemcitabine-carboplatin-bevacizumab, in each of those trials, they used a 6-month cutoff. But they also stratified 6 to 12, 12-plus. And it’s interesting that in every 1 of these trials we still see the same magnitude of benefit in the 6 to 12 as we do in 12-plus. And even in the trabectedin trials, we see that there still is some modicum of benefit there. Now, they may not be this kind of patient: Complete clinical response, and then at 7 months they have measurable disease. That may be different than the patient who actually had bulky disease, responded, and was disease-free for 7 months. You know what I’m saying?

David O’Malley, MD:I’ve translated that to say I’m going to treat these patients with platinum doublets until they’re refractory. And when we really look at the outcomes in the most recent trials, we’ve always quoted 15% to 20% for platinum-resistant disease. In our current treatment paradigm, it’s probably 5% plus or minus…

Robert L. Coleman, MD:Yeah, so many are optimally cytoreduced, and you get complete responses after frontline treatment.

David O’Malley, MD:When we look at these patient populations, we’re not doing nearly as well as we thought we were.

Susana M. Campos, MD, MPH:I would go back and treat with a platinum because she’s either platinum sensitive or platinum resistant at this point in time. You’re going to have to figure this out somewhere along the line. I do exactly what you described. I go back to cisplatin and gemcitabine at somewhat attenuated dosages because of the thrombocytopenia and myelosuppression. And I have to say, at 6 months I still buy a response, and I’m often surprised at that. And so she’ll become platinum-resistant at 1 point in time, but if you define her as platinum resistant now, you’ve basically negated the possibility of giving her a platinum in the future, just by the logic that you’ve used. So it will declare and speak to you at that point in time.

David O’Malley, MD:And then we look at the AURELIA data: 1:1—cytotoxic versus cytotoxic bevacizumab. In the 3 arms, in the standard of care it was physician and patient choice. It was paclitaxel-topotecan, and pegylated liposomal doxorubicin, or PLD. The topotecan could have been given daily or weekly in this patient population. So if they fall into that group, if we utilize the platinum-Gemzar, for example, and you could argue that we should use a different doublet, what we showed was a statistically significant and clinically significant improvement with a doubling of the progression-free survival. The hazard ratio was about 0.5. So when you look at the entire population, you see those benefits. But then when you break it down in a subpopulation—and this is not a planned analysis, this was only a letter to the editor—we have a really impactful difference between the use. And paclitaxel plus bevacizumab: 53% overall response rate versus weekly paclitaxel, by itself, which was only a 30% response rate. Topotecan was a 0% response rate. If you added bevacizumab, it was 17%. And then, in the PLD, we have about an 8% response. If you added bevacizumab, it went up to about 14%.

And 1 thing they did really, really well in the AURELIA data was look at the abdominal symptoms. Those patients who we all know are going to benefit for bevacizumab present with ascites.

Robert L. Coleman, MD:Ascites, yeah.

David O’Malley, MD:And they showed, in those populations, again, the greatest benefit was in those treated with paclitaxel and bevacizumab.

Robert L. Coleman, MD:I often say the same thing. Here you have a drug combination that the patients are on for longer periods of time. They have more toxicity because there are 2 drugs versus 1. Yet there’s an improvement in the quality of life. So you have more toxicity but an improvement in quality of life. I think it goes right to your point. Interestingly, that primary endpoint for that QOL [quality-of-life] assessment was at the 9-week time point, so it was very early on that they saw the benefit. It was initial benefit, right away.

Transcript edited for clarity.