Advanced Breast Cancer - Episode 12

Key Trials in R/R Metastatic TNBC


Debu Tripathy, MD: I want to stay on the theme of metastatic triple-negative breast cancer. We’ll come back to some of the neoadjuvant data. But this field has also moved along quite a bit in terms of other drugs. First and foremost among them has been the antibody-drug conjugate sacituzumab govitecan, which is generating data and hopefully will be available soon. Adam, do you want to provide an update on that?

Adam M. Brufsky, MD, PhD: Ian can probably talk about...better than I can on this agent, but the bottom line is that sacituzumab govitecan is antibody that’s TROP2, which is present in 96% of metastatic breast cancer. I think it’s linked to an exatecan derivative also. Again, we’re talking third-line metastatic triple-negative disease. That’s probably even worse than the third-line in terms of prognosis than in triple-negative HER2 [human epidermal growth factor receptor 2]—positive disease. The median survivals are less than a year. The median PFS [progression-free survival] to most agents is probably in the 2- to 3-month range. Then we have this phase I/II trial, which has really expanded to phase II of around 110 patients, 120 patients, that Aditya Bardia presented and published last year, where basically the response rate was 34%. I think the PFS was around 6 months or 7 months—a little over 5 months or 6 months. The overall survival clearly looked to be better than historical controls. I think that it did get priority review by the FDA. What happened during that priority review was that there were some issues with antibody production. Interestingly enough, the issues were not severe enough to put a clinical hold on the trial, which is an interesting…

Hope S. Rugo, MD: Manufacturing, yeah.

Adam M. Brufsky, MD, PhD: Yeah, it was some manufacturing issue that I think has now been resolved. Before and during this time, there’s a phase III trial that actually has finished accrual, called ASCENT. In this trial, women in third-line triple-negative metastatic breast cancer were randomized to sacituzumab govitecan or the standard of physician’s choice of 4 different drugs. That trial has finished accrual, and the hope is within a year we may see something if there are enough events and that will answer the question. The real question is if the FDA will give the priority accelerated approval now or if they will wait for the phase III. That’s the big question that everybody has in mind.

Hope S. Rugo, MD: It would be great to see ASCENT next year. What’s interesting about this particular drug is that they all are in the same class, these TOPO1 inhibitors. But sacituzumab govitecan has an SN-38, which is the active metabolite of irinotecan. You don’t get that much diarrhea from it, which is intriguing.

Adam M. Brufsky, MD, PhD: You do get the hair loss, though, which was surprising.

Hope S. Rugo, MD: Also, with T-DXd [trastuzumab deruxtecan], you get some hair loss. Where the linker can be metabolized, you probably see more free drug, and you can have more hair loss, although I have to say it’s nothing like taxanes.

Adam M. Brufsky, MD, PhD: This is 1 where there’s a bystander effect as well, correct?

Ian E. Krop, MD, PhD: Well, it’s got a...linker. I’m not sure how well they’ve established.

Hope S. Rugo, MD: There’s no bystander.

Joyce A. O’Shaughnessy, MD: It does have a bystander effect.

Hope S. Rugo, MD: But there’s no bystander part because you’re targeting TROP2, and so ER [estrogen receptor]—positive disease has TROP2 also. So it’s a little different…

Adam M. Brufsky, MD, PhD: We’re talking about bystander of…

Hope S. Rugo, MD: HER2 is a little different.

Debu Tripathy, MD: Let me also ask you all about another related area for triple-negative, for advanced triple-negative. Of course, now the other drug in this area, at least for germline BRCA, but a lot of the triple-negative case obviously is PARP inhibitors with olaparib. This is one of the dilemmas we face as first-line therapy in someone who is a germline BRCA mutation carrier, so I’d like your thoughts on not a very common group. How are you approaching that?

Joyce A. O’Shaughnessy, MD: The MEDIOLA trial is one that has put together a phase I/II. It was put together for germline BRCA patients, olaparib with durvalumab, and it looks very safe. It’s not randomized, so you really can’t tell to what extent the checkpoint has added, plus the fact they’re pretreated patients. But we’re going in that direction that safety is a start. Makes biologic sense to combine the 2 because of the homologous recombination deficiency inherent in the BRCA1/2, so they may be more sensitive to checkpoint inhibitors.

One of the trials that is really interesting is the DORA trial, which is being conducted in triple-negative breast cancer patients, so not just for germline BRCA first-line metastatic disease. They get a platinum-based regimen. If they’ve got a response or stable disease, then they get randomized to maintenance therapy with olaparib versus olaparib plus durvalumab. So that will be really nice. Right now we don’t have enough data to combine that first-line PARP inhibitor with the checkpoint inhibitor. If a patient is germline BRCA and her cancer is PD-L1 [programmed death-ligand 1] positive, I will go where I know there’s a survival advantage in a phase III trial. I will go with the IMpassion130 trial data for her. Should she fatigue of the chemotherapy, it wouldn’t be unreasonable to bring in a PARP inhibitor at that point because we have some safety data. But we could also just sequence it as well.

Speaking of which, we saw some very interesting data at ESMO [European Society for Medical Oncology 2019 Congress] on the BROCADE trial in patients who had first-line and second-line metastatic germline BRCA who received paclitaxel-carboplatin with or without veliparib. Basically, then they were allowed to stop the paclitaxel, stop the carboplatin, stop them both, and continue. It was placebo-controlled, continued on maintenance, and 36% of the patients continued on monotherapy maintenance. There was a large improvement in progression-free survival in favor of a maintenance strategy, which we had not really heretofore…

Adam M. Brufsky, MD, PhD: But the curves actually in that BROCADE separated when you started the maintenance.

Joyce A. O’Shaughnessy, MD: Yes, yes.

Adam M. Brufsky, MD, PhD: They didn’t separate until you started the maintenance.

Hope S. Rugo, MD: OK, great, we should take the ovarian cancer approach.

Adam M. Brufsky, MD, PhD: Correct.

Hope S. Rugo, MD: We’re just way behind compared with ovarian cancer. But there’s the DORA study, and now KEYLYNK-009 is opening, which is GEM [gemcitabine]—CARBO [carboplatin]–PEMBRO [pembrolizumab] without PD-L1 requirement and then randomizing to either continuing the triplet or dropping to PEMBRO with olaparib as a maintenance approach. It’s going to be fascinating because we don’t know we’re going to measure HRD [homologous recombination deficiency] to see if that makes a difference as well.

Adam M. Brufsky, MD, PhD: I have to ask a question, though, about the backbone. I know it’s not as exciting of a question as some of those we’ve asked about. But remember we...this randomized phase II tnAcity with CARBO—taxane, CARBO–GEM, and GEM–CARBO. The CARBO–taxane was the best of the 3, significantly better in terms of PFS. So why are we still using GEM –CARBO in the control arms in trials?

Hope S. Rugo, MD: I think the issue is most of the patients…

Adam M. Brufsky, MD, PhD: Are BRCA associated. Is that what you’re going to say?

Hope S. Rugo, MD: No, the issue is that a lot of patients relapse at 6 months or greater. In fact, the patients with the worst outcome where her hands are just that we don’t know what to do relapse in the first 6 months. At 6 months, that as our guideline isn’t quite right. It’s longer than we would have liked to have enrolled in IMpassion130 because of that.

Adam M. Brufsky, MD, PhD: That’s a good point.

Ian E. Krop, MD, PhD: But do you even need both? Do you need to do a doublet of chemotherapy?

Adam M. Brufsky, MD, PhD: I don’t know. It’s a great question. That’s an excellent. Isn’t there a trial now with CARBO alone as the control arm?

Hope S. Rugo, MD: You know, my bias is that the combination works really well. I’ve had so many patients with triple-negative disease. That’s all they ever responded to. They responded for 8 months, and then they don’t respond to anything more. I do think it’s a very active combination. I know you’ve oriented toward that, but I’ve had a lot…

Adam M. Brufsky, MD, PhD: I mean, this is not as sexy for our audience…

Ian E. Krop, MD, PhD: It’s a practical question…

Hope S. Rugo, MD: The iniparib trial looked really good—Joyce’s trial.

Ian E. Krop, MD, PhD: Right. Clearly, it’s active. The question is, would you get the same activity by sequencing 1 after another.

Hope S. Rugo, MD: Well, GEM alone is not very phenomenal.

Transcript Edited for Clarity