T-DXd Effective in Multiple HER2-Expressing Solid Tumors

According to the findings of the international, phase II DESTINY-PanTumor02 study, trastuzumab deruxtecan (T-DXd; Enhertu) was an effective treatment option for people with difficult-to-treat, HER2-expressing solid tumors.

MedPage Today brought together three expert leaders in the field for a virtual roundtable discussion. Moderator Susana Campos, MD, MPH, from the Dana-Farber Cancer Institute in Boston, is joined by Richard Penson, MBBS, of Mass General Cancer Center in Boston, and Elizabeth K. Lee, MD, also of the Dana-Farber Cancer Institute. This final of four exclusive episodes focuses on the updated findings presented at the American Society of Clinical Oncology (ASCO) annual meeting.

Following is a transcript of their remarks:

Campos: Staying on the topic of ADCs [antibody-drug conjugates] — and I actually think this is one of my favorite presentations at the American Society Clinical Oncology meeting — is the DESTINY PanTumor trial. Dr. Lee, I send all my patients to you for this drug. So can you take us down a road of this very, very, very, very interesting drug, trastuzumab deruxtecan and the DESTINY PanTumor trial.

Lee: Yes, absolutely. The DESTINY-PanTumor02 study reported interim efficacy results at ASCO. These were very highly anticipated results, and so this utilized trastuzumab deruxtecan — also known as T-DXd — which is a HER2-targeting antibody drug conjugate. It uses a protease-cleavable linker, and the payload that it carries is an exatecan derivative as an inhibitor of topoisomerase I.

This is a very potent drug. It’s already well used within the oncology armamentarium, albeit not standard of care for gynecologic cancers. It is most used within the breast cancer space, in which there are two FDA approvals for both HER2-positive and HER2-low breast cancer, as well as the gastric cancer space, as well as more recently the non-small cell lung cancer space for ERBB2-mutant non-small cell lung cancer.

And so this DESTINY-PanTumor02 study was meant to look at all these other types of cancer, most notably with cervical, endometrial and ovarian cancers of particular interest to us, in addition to biliary pancreatic and some other tumor types. But so the DESTINY-PanTumor02 study was really based on earlier, early-phase trials suggesting that there was benefit outside of breast, gastric, and lung cancers.

The study enrolled patients based on their tumor type. They were primarily enrolling HER2 expression levels of IHC [immunohistochemistry] 3+ as well as 2+. And I think important to note, this was by the ASCO gastric cancer HER2 IHC scoring, knowing that there’s both the gastric as well as breast cancer scoring guidelines. And this did allow prior HER2 therapy. This was most commonly previous use of HER2-based antibody therapy.

I think there were some very interesting results, before we get to the efficacy and going more towards the baseline demographics. So patients were allowed to enroll based on local IHC testing, but there was certainly central confirmation of IHC scoring. And within that, there was quite a significant increase in the number of patients who were found by central confirmation to have IHC 1+ or IHC 0 for HER2 expression. This was up to about 20% of patients with 0 or 1+ in comparison to local testing at the time of enrollment. It was only about 2% of patients were felt to be HER2-low. So there was quite a jump in those who were HER2-low on central testing.

And I think that is something worthwhile to think about as we go through the efficacy results. So within the cervical, endometrial, and ovarian cancer groups, there was quite a high response rate by investigator assessment; that was the primary endpoint. Within the cervical cancer group it was 50% of patients who achieved a response, and that included 5% of patients achieving a complete response. And again, this is the T-DXd monotherapy. The endometrial cancer group was actually more impressive with almost 58% of patients achieving a response. And within this group, there was almost 18% of patients achieving a complete response. The ovarian cancer group was also impressive with 45% of patients achieving a response.

And in thinking about how the HER2 expression levels really impact the response, the trend was overall very clear that the higher the expression of HER2, the greater the response rate. And so IHC 3+ — I would start with the endometrial cancer group since it was really the most impressive. IHC 3+ expressors within endometrial cancer had an 84.6% response, and 47.1% of the 2+ expressors achieved a response in the endometrial cancer group. The cervical cancer group was also very impressive with 3+ expressors, 75% of them achieved a response compared to 40% in the 2+ cervical cancer patients.

And so I would say that the trend overall — really across all of the tumor types — but most notably within the gynecologic cancer groups, that higher expression did seem to correlate with better response.

Campos: Yeah, I think it’s very exciting, now the question is, are we measuring HER2/neu on everyone? You know what I mean? And especially I think there’s some previous data with abstracts in our patients with carcinosarcoma, this may be a very advantageous agent to continue to investigate. Absolutely. Dr. Penson, your take on the DESTINY PanTumor trial?

Penson: Yes, I completely agree with Dr. Lee. This is really exciting, and exciting enough that we use this drug off-label when people have amplified or HER2 3+ expressing tumors.

And I think that the only thing I would add is that the duration of benefit was really impressive. So I forget exactly, but I think it was 15% of the ovarian cancer patients were still on treatment. And for people who had 3+ tumors, it was approaching 2 years of disease control. The duration of response was 22 months in 3+ expressing tumors. And as we said earlier on, our better understanding really sort of unlocks more of this, because there was generally 40 people in each cohort, but the pancreatic cohort was stopped early at 25 participants because it just didn’t work in pancreatic cancer. Dr. Lee, do you have any thoughts about why?

Lee: So I think we’ve always thought about antibody drug conjugates in terms of the target, but we always have to say in the context of the tumor type and understanding that there are different molecular and biological drivers of each type of cancer. So it could be that that explains the unfortunately … very poor response rate in pancreatic cancer compared to our gynecologic cancers.

Penson: Protecting some patients from ineffective or toxic treatment is sort of part of the sort of sad reality of oncology. But that’s exactly what these studies do. They teach us how to really deliver on the latest and greatest data from ASCO.

Campos: It’s true. And just to add, the payload in this particular case is a topoisomerase inhibitor. And so one has to ask the question, is this the best payload for a pancreatic cancer? I know there are other trials that are looking at ADCs and combining it with gemcitabine (Gemzar), for example. So we have to all be cognizant of what the actual payload is and whether or not that particular payload may have activity in the management of certain disciplines, like you mentioned pancreatic cancer.

Penson: Yeah, I think there’s two things that are sort of important about that. So one is, yeah, absolutely different payloads might be better. Some totally lethal ricin might be the right thing, but that hasn’t really panned out in ADC development. But the second thing is that TOP1 [topoisomerase I] inhibitors have as a class been hard to deliver in terms of benefit and not too much toxicity in clinic. And so to have a class that’s saved by an ADC that really transforms delivery of that, this is a great drug and DESTINY PanTumor02, it’s a great study.

Campos: It really was. It was actually one of the most exciting — and I can remember when trastuzumab was, and granted this is trastuzumab deruxtecan, but I can remember when trastuzumab was only in breast way, way, way back 20 years ago. So it’s really gone quite far.

Well, this has actually been an excellent discussion. I want to thank both of my colleagues, Dr. Richard Penson and Dr. Elizabeth Lee for joining us this morning in a very brief review of gyn malignancies presented at ASCO and plus. So thank you very much for tuning in.

Click here to watch the other videos from this ASCO roundtable series on gynecologic cancers.