Aditya Bardia, MD, MPH: The sacituzumab govitecan is an antibody drug conjugate that targets Trop2. Trop2 is EpCAM2, which is an epithelial antigen that’s overexpressed in more than 95% of triple-negative breast cancer, so it’s an antigen that’s universally expressed in triple-negative breast cancer. So, the idea with an antibody-drug conjugate is, you deliver higher doses of chemotherapy to the cancer cells while relatively sparing the normal cells. So sacituzumab govitecan, the antibodies against Trop2, it has a linker, and the toxic payload is SN-38, which is the active metabolite of irinotecan. And the way it works is that it delivers the SN-38 to tumor cells but also has a bystander effect. So, even if cells are Trop2 negative because of the bystander effect, those could be affected by SN-38.

In a phase I/phase II basket trial, we looked at the activity of this agent in multiple solid tumors, including triple negative. We saw activity in triple-negative breast cancers, had discussion with the FDA, got breakthrough designation status. And then after discussion with the FDA, the trial got modified to only look at the activity of this agent in the third-line and beyond setting. And we looked at 110 patients. This was presented at the San Antonio Breast Cancer Symposium last year, where the overall response rate was approximately 30% in patients who had received a number of prior therapies. And the responses were deep as well as durable, and the progression-free survival was in the range of 6 months. And with standard chemotherapy, it’s usually in the range of 2 to 3 months. So, although it was a nonrandomized trial, the outcomes appear to be almost double as compared with what one would anticipate with standard chemotherapy. So there’s the confirmatory ASCENT trial ongoing, which is comparing this agent versus chemotherapy of physician’s choice, specifically for third-line and beyond, metastatic, triple-negative breast cancer.

Joyce O’Shaughnessy, MD: It is enrolling really well, I understand, too. It’s really moving along. How about safety?

Aditya Bardia, MD, MPH: The 3 main adverse effects we’ve seen with this agent are all adverse effects that have been described with SN-38 or irinotecan, which include diarrhea. The incidence of grade 3 diarrhea is lower than irinotecan, but diarrhea is an adverse effect that you see with this agent. Neutropenia is, again, an adverse effect of SN-38. And the third adverse effect, which I think is a bit problematic and concerning for patients, is alopecia.

Adam M. Brufsky, MD, PhD: Yes. That’s what I can tell you. I have a patient who is on ASCENT…We forgot to tell her, and she got very mad.

Tiffany A. Traina, MD: They do allow scalp cooling on ASCENT.

Adam M. Brufsky, MD, PhD: You allow scalp cooling—oh, really?

Joyce O’Shaughnessy, MD: Scalp cooling is good. So when are we going to have this agent, Aditya?

Aditya Bardia, MD, MPH: The company filed for approval in May and, as per FDA regulations, the FDA has to give an answer, I think, by 14th of January, so anytime before that.

Joyce O’Shaughnessy, MD: Yes, so maybe we’ll get a Christmas present—a Christmas present for me. I want one.

Adam M. Brufsky, MD, PhD: It could be a New Year’s present.

Joyce O’Shaughnessy, MD: I’m hoping for Christmas.

Heather L. McArthur, MD, MPH: But aren’t there plans to look at this in the hormone receptor—positive disease, as well?

Aditya Bardia, MD, MPH: That’s right. So, the company had an announcement today actually that there would be a phase III trial looking at this agent versus standard chemotherapy for ER [estrogen receptor]—positive metastatic breast cancer. In the phase I/phase II study, one of the baskets was also ER-positive metastatic breast cancer. In that setting also, a response rate of approximately 30% was seen, which is much higher than what we see with chemotherapy in general. Usually we see that ER-positive disease does not respond to chemotherapy. The response rate is usually 10%, 15%, but at least with this agent, we saw a much higher response rate.

Heather L. McArthur, MD, MPH: And is the Trop2 prevalence in ER-positive disease…as high as what we’re seeing in triple-negative disease?

Aditya Bardia, MD, MPH: So, we looked at the RNA expression profile of Trop2 in luminal A, B, basal tumors, and there’s really no difference. So it’s Pan expressed.

Joyce O’Shaughnessy, MD: And it’s very high. We don’t even have to select, right? We don’t even have to select for it, right? That’s a beautiful thing.

Adam M. Brufsky, MD, PhD: In the patients in that basket that you did, were any of them prior treated with CDK4/6?

Aditya Bardia, MD, MPH: In the ER-positive patients, yes.

Adam M. Brufsky, MD, PhD: In ER positive, they were. So patients were treated with CDK4/6.

Aditya Bardia, MD, MPH: Correct.

Adam M. Brufsky, MD, PhD: OK, good.

Joyce O’Shaughnessy, MD: The topoisomerase inhibitors, the SN-38, is highly non—cross-resistant. We’ve seen that in other trials, but we just never had a way to really give it to our patients, so this is really a very key thing. Now, I’m personally hoping that we’re going to be able to use it sooner than later in triple-negative breast cancer because of the durability of the responses. But, initially, it will be third line and later, but hopefully we’ll be able to get it up sooner.

Aditya Bardia, MD, MPH: Absolutely—first, second line, or even in early breast cancer. I think this agent could potentially move into those settings. And you brought up a good point about topoisomerase inhibitors because, if you look at antibody-drug conjugates traditionally, all the toxic payloads have targeted microtubules, T-DM1.

Adam M. Brufsky, MD, PhD: MMAE [monomethyl auristatin E.

Aditya Bardia, MD, MPH: MMAE. But the other antibody drug conjugate that has a topoisomerase inhibitor is the Daiichi-Sankyo compound, the DS-8201, and that also has shown good level of activity.

Joyce O’Shaughnessy, MD: Remarkable.

Adam M. Brufsky, MD, PhD: It does in the HER2-positive group, very much so, yes.

Joyce O’Shaughnessy, MD: So good work with that, Aditya. Very, very good, because that’s hard to get accelerated approval based on a phase II data—fingers crossed.

Heather L. McArthur, MD, MPH: And it’s so exciting to have so many promising options.

Joyce O’Shaughnessy, MD: Yes, it’s so exciting.

Heather L. McArthur, MD, MPH: Yes, it’s so hopeful.

Joyce O’Shaughnessy, MD: Thank goodness, yes. So, real progress, real progress. Well, thank you so much. It’s been really fun visiting with everybody and getting all the new data out there for everybody. So thank you so much for a great conversation. This has really been extremely informative. And, before we end this discussion, I would just like to say thank you once again to everybody, and we will be back after the next meeting. And thank you very much for your attention.

Transcript edited for clarity.