Practical Considerations for ADC Selection in HR+/HER2- mBC

Transcript:

Komal Jhaveri, MD, FACP: We have these 2 exciting ADCs [antibody-drug conjugates] now for our patients in clinic, both with survival benefit. We have trastuzumab deruxtecan [T-DXd], and we use that with patients who had at least 1 line of chemotherapy, [with] no more than 2 lines of chemotherapy. And that’s based on HER2-low status. Then we have sacituzumab [govitecan], where we use them for pretreated patients or maybe HER2-zero until we complicate this matter even more without HER2 ultra-low patients. Wait for the DESTINY-[Breast]06 [NCT04494425] data. Then we’re going to complicate that even more with datopotamab from the TROPION-[Breast]01 trial [NCT05104866], which is going to be potentially looking at the same patient population regardless of HER2-low status. It’s similar to the T-DXd population.

How are you thinking about all these drugs? Again, embarrassment of the riches. We’re going to have more. How should we be thinking about T-DXd today? How should we be thinking about patients who progress on T-DXd? Your institution presented some data about ADC after ADC. Could you walk us through about what do we need to do with current uses of ADCs? How do we use them and what do we do in the future to address this more?

Aditya Bardia, MD, MPH: Absolutely. I think you bring up a good point and that’s why the analysis was done. Increasingly, we are going to face numbers of ADCs in terms of which one do we start with and how do we sequence them. So, in our analysis, we just looked at ADC after ADC, and then based on switch in antibody was a switch in payload. A subset looked at if patienst got SG [sacituzumab govitecan] first and then T-DXd or vice versa. And the bottom line is that if you use SG [sacituzumab govitecan] first or T-DXd first, it does work as you would expect. If you use the other agent, it does work for some patients, but there are others who have crossed resistance. The activity of SG [sacituzumab govitecan] after T-DXd might not be the same as what we saw in TROPiCS-02 clinical trial [NCT03901339].

Similarly, if you use SG [sacituzumab govitecan] first and then you use T-DXd, the outcomes are not the same as what we saw in DESTINY-Breast04 [NCT03734029]. Now how do we use [it] in clinic? We need biomarkers because we just don’t know which subgroup of patients will continue to derive benefit versus not. It’s very similar to the CDK4 story where you just need biomarkers to guide who needs continued medication versus not. Hopefully in the future, by either sequencing or additional work, we can identify biomarker to guide ADC sequencing.

Gregory Vidal, MD, PhD: Yes. To just add to that, it’s also identifying what is the resistant mechanism. If the resistant mechanism for T-DXd is down regulation of the HER2 receptor, then you can imagine probably using a Trop target with a similar payload [that] may still be active. We have to figure [that] out. Whereas if it’s resistant to the payload, then they may be cross-resistance across all topoisomerase 1 inhibitors. So again, biomarkers [are] very important.

VK Gadi, MD, PhD: I will just want to add to that. If you stop the drug, because of say pulmonary toxicity, I’d be more than open to switching over to sacituzumab [govitecan] after.

Komal Jhaveri, MD, FACP: What an excellent point.

Gregory Vidal, MD, PhD: What if Dato [datopotamab deruxtecan] is approved? Because the company who has both drugs are competing 2 different drugs in the same space, which is interesting to me. Would you do T-DXd and then Dato, or Dato and T-DXd? Would you even consider doing that?

Komal Jhaveri, MD, FACP: If DBO-06 is positive, and there’s a good chance it could be because if in the second line setting you’re seeing a doubling of PFS [progression-free survival] from 5 to 10 months for our HR-positive patients that are HER2 low, if you use that in the first line, could we still expect to see a good benefit with an ADC-like approach? There’s a good possibility that that’s possibly true.

Then, you have datopotamab that might be active and that might get approved in the second [or] third-line setting. So then you’re thinking about using datopotamab after T-DXd similar payloads but different targets. I think we don’t know the answer to that, but there is an ongoing study that I think is trying to address this question at least a little bit. Maybe tell us about that study and do you think that’s going to potentially help us address this a little bit better?

Aditya Bardia, MD, MPH: Absolutely. It’s a trial called TRADE-DXd. It’s essentially trading the antibody and keeping DXd, or deruxtecan, the same. In that trial, patients start with datopotamab deruxtecan first and then go to T-DXd or vice versa. That’ll give us more information about what’s the optimal sequencing with these ADCs.

Komal Jhaveri, MD, FACP: So essentially [there is] more to come from the sequencing and the biomarker work. Any other exciting ADCs that you are excited about beyond these 3 that we already discussed?

Aditya Bardia, MD, MPH: There are other ADCs targeting, say HER3, and we saw some data at ASCO 2023 [American Society of Clinical Oncology Annual Meeting] that looked pretty promising. There are ADCs that are targeting other antigens. I think we are likely going to see more ADCs in the future with different antibodies, with different payloads. It presented nice results with bispecific ADCs where within the same ADC you have 2 different types of antibodies. We are likely going to see more and more of ADCs in the future.

Komal Jhaveri, MD, FACP: So more work here to be done. More data to be expected.

Transcript edited for clarity.

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