Antibody-Drug Conjugates in Treating TNBC

Transcript:

Joyce A. O’Shaughnessy, MD: Tell us about new ways of giving chemotherapy. You’ve really been a pioneer in this, Aditya, and you had some really interesting data at San Antonio. So, update us on the antibody-drug conjugates.

Aditya Bardia, MD, MPH: Yes. I think the general philosophy of antibody-drug conjugates is that you have an antibody that would bind to an antigen that is overexpressed in cancer cells but not so much in normal cells and then use that as a way of delivering high doses of chemotherapy to the cancer cells while sparing the normal cells. Because we know that chemotherapy works, particularly for triple-negative disease, but it’s an issue of the toxicity. So, this is a way of giving high doses of chemotherapy to the cancer cells.

So, the data we presented at San Antonio were related to an antibody-drug conjugate called sacituzumab govitecan, or IMMU-132. And it’s a TROP-2 antibody that binds to TROP-2—positive cells, has a hydrolyzable linker, and is then linked with SN38, which is the active metabolite of irinotecan and is a topoisomerase inhibitor.

And this was a trial where it was a basket trial. It started in radio-solid tumors, including breast cancer. In the dose escalation portion of the trial, responses were seen in metastatic triple-negative breast cancer, so that arm was expanded. And we saw evidence of clinical activity in those expansions as well. So, we then designed a trial specifically looking at sacituzumab govitecan as a third-line agent and beyond in patients with metastatic triple-negative breast cancer. And that is what was presented at San Antonio—looking at activity of this agent as a third-line option and beyond. About 110 patients were enrolled, and patients had received at least 2 prior lines of chemotherapy agents in the metastatic setting. And in this heavily pretreated population, an objective response rate of 34% was seen, and the responses were durable as per central review. The duration of response was about 9 months. And there were some patients who also had complete responses. So, coming back to what you were saying earlier, we are looking at those patients who potentially would have complete response or if there were even cures in the metastatic setting. So, some evidence of that activity was also seen with this agent.

Then we did a subset analysis. Can we identify biomarkers? Can we predict that this is a patient population that’ll benefit from this agent versus not? We looked at age, looked at visceral match, looked at TROP-2 expression. And really, there was no difference as far as response to sacituzumab govitecan was concerned. We couldn’t identify our biomarker based on these classic clinical pathologic features.

But there was a signal with use of prior immunotherapy. So, patients who had received prior PD-1 inhibitors tended to have a higher objective response rate. There were only 19 patients in this study. The objective response rate in that patient population was 45%. So, whether use of prior immunotherapy somehow primes the tumor and makes it more sensitive to chemotherapy agents in general or ADCs in general, we just don’t know. But I think it’s hypothesis-generating and something that needs to be followed up on.

And the next step as far as this agent is concerned is a global confirmatory phase III trial called the ASCEND trial. And the design is very similar to the EMBRACA or the OlympiAD trial standard: study agent versus chemotherapy. So, it’s a trial where patients with metastatic triple-negative breast cancer, third-line or more, would be randomized to receive this agent versus standard chemotherapy, which would be eribulin or could be capecitabine or Navelbine (vinorelbine tartrate).

Joyce A. O’Shaughnessy, MD: A very promising non-class-resistant agent to the old FM38. There’s a couple of other ADCs; triple-negative disease seems to be a real area of focus for ADCs. Could you update us a little on those?

Aditya Bardia, MD, MPH: I think there are at least 2 that are fairly advanced in terms of development. One is an agent called glembatumumab, which is an ADC against GPNMB (glycoprotein non-metastatic B). It has a different payload. The payload is MMAE (monomethyl auristatin E), which is a microtubule inhibitor. And in the randomized phase II trial of looking at this agent was ischemia therapy.

They saw a benefit with glembatumumab in triple-negative breast cancers that had overexpression on GPNMB, which is about one-third of triple-negative breast cancers. So, the confirmatory phase III trial called the METRIC trial is ongoing, and we’re anxiously waiting for the results. And if that’s positive, this would be an agent that we could use, particularly in GPNMB-positive triple-negative breast cancer.

And the other agent is an agent that targets LIV-1, which signals to the STAT pathway. So, there’s an ADC by Seattle Genetics that targets LIV-1, and the results, which were presented at San Antonio, showed that in patients who had metastatic triple-negative breast cancer, you could see decent activity with this ADC. The response rate was 32%. And, again, it was a patient population that had received a number of prior therapies.

The linker and the payload in this ADC is MMAE. So, they did notice peripheral neuropathy, which is a side effect of microtubule inhibitors in general, which is not seen with sacituzumab govitecan, because that’s more of a DNA-damaging agent. So, in terms of toxicities, it all depends on what the payload is. The other toxicities were alopecia and some hematologic toxicities. But I think the ADCs would probably add another option in terms of the use of chemotherapy for patients with metastatic disease.

Joyce A. O’Shaughnessy, MD: Yes, really interesting. And it would be nice to finally have something approved with the triple-1 inhibitors, with the sacituzumab govitecan, eventually. And then I know they’re moving up. They’re moving into the neoadjuvant setting that could be combined with checkpoint inhibitors to see if we could get even more leverage from them.

Transcript Edited for Clarity