Case: A woman in her late 40s who received treatment for triple-negative breast cancer develops lung metastases 2 years later

DR LOVE: Welcome to Oncology Today: “Integrating Antibody-Drug Conjugates into the Management of Hormone Receptor-Positive and Triple-Negative Metastatic Breast Cancer.” This is medical oncologist Dr Neil Love. I met with Dr Sara Hurvitz from the Fred Hutchinson Cancer Center in Seattle, and to begin, she provided an overview of TROP2-targeting ADCs and presents an example of the integration of these agents into clinical practice.

DR HURVITZ: So we’ll first go through some data relating to targeting TROP2. We have 1 drug that’s approved, an antibody-drug conjugate, sacituzumab govitecan in triple-negative and hormone receptor-positive. And another one that’s hot on the tail of sacituzumab, and that is datopotamab deruxtecan. Not yet approved, but we have seen Phase III data.

Sacituzumab govitecan is an antibody that targets TROP2, which is highly expressed on most breast cancer. And the antibody is very specific for TROP2 and it’s loaded up with a topoisomerase-1 inhibitor, or cytotoxic payload, with a pretty high drug-to-antibody ratio of 7.6 to 1. Now the linker hydrolyzes, so it doesn’t require that the ADC get inside the cell to work. It actually gets into the neighborhood of the cancer cell and this hydrolysable linker breaks up, releasing the chemo. And because of that, we have a little bit more off-target toxicity. Some would call that a bystander effect. It’s 2 different ways of looking at the same feature.

So I want to share a case of mine. This was a 48-year-old woman who was diagnosed with a Stage II, 3 cm, 1 lymph node positive, triple-negative disease. We treated her with the Priyanka Sharma neoadjuvant docetaxel/carboplatin for 6 cycles. She had a pathologic complete response at the time of surgery. But unfortunately, 2 years later, develops a significant cough. And a scan shows a solitary lung nodule as well as a suspicious rib lesion. Her lung lesion was biopsied, and it was triple-negative breast cancer. So she received first-line chemotherapy and had a partial response for over a year, almost a year and a half. And then, she received second-line chemotherapy and had stable disease for 10 months. So the first thing to note about her is her disease isn’t behaving really normally for triple-negative. Triple-negative disease is defined by what it’s not rather than by what it is, and there is a lot of heterogeneity in disease behavior. And hers had pretty nice long-term responses to standard chemo. But ultimately, she had disease progression in her lungs and liver.

DR LOVE: Yeah. Before you go on, just to talk a little bit more about the case. I’m not sure exactly when she was treated, but it seems like it was in the pre-522 days. What was her PD-1 level? Was IO on board by the time she had mets or was that before then too?

DR HURVITZ: It was before then. In fact, it was right around the time of the ASCENT trial and we had the ASCENT study open. She had now had 2 prior lines of chemo. But yes, we didn’t even, I don’t think we even had PARP inhibitors. I think they were still in Phase III testing at the time. Now she wasn’t a BRCA mutation carrier. But this was almost the Dark Ages compared to how we are looking at triple-negative breast cancer now.

DR LOVE: And what happened with her?

DR HURVITZ: So she actually went onto the ASCENT clinical trial, and she received sacituzumab govitecan. I don’t recall the exact specifics because I’m at a new healthcare center, so I can’t look at her record. But she had a very, very long response to sacituzumab and tolerated it well. Complete hair loss, but really didn’t have the diarrhea and problems that I’ve seen other patients experience with sacituzumab, neutropenia. She tolerated it beautifully.

DR LOVE: I didn’t realize you see many patients who don’t have neutropenia with sacituzumab. Is that the case?

DR HURVITZ: Yeah. The majority do, in my experience. In fact, I am using growth factor a lot in my patients up front, especially if they’re coming in heavily pretreated or having problems with neutropenia. So this was interesting. It was early experience. It was one of my first patients I treated with the drug. So I didn’t really know what we were going to see. We only had the Phase I data to inform. But it was, she had a pretty remarkable response and did well. She was, again, pretty healthy and young, very active and wasn’t beat up by chemo. She’d had 2 lines. One of them was capecitabine. And so she wasn’t horribly heavily pretreated. Her bone marrow was in good shape.

DR LOVE: On Tuesday, we did a webinar on myeloma and I showed a video of a patient who’d received the bispecific teclistamab. Had been on it, remission for a year and a half, no problem. The day I interviewed him was the day it was approved.

DR HURVITZ: Wow.

DR LOVE: And I kind of use that case. And here, same thing with this woman, right?

DR HURVITZ: Right.

DR LOVE: She participates in a trial, but it’s not like she benefited. What was her quality-of-life like during that time period? And I don’t know what you might want to share about her in terms of what her life was like or how it affected her life.

DR HURVITZ: Yeah. She was married and had a very active life, was super positive, would bake all the nurses and doctors cookies, bring them into the infusion center. She had such a positive outlook and was so eager to be a part of research for both the altruistic reasons, but also for wanting to have access to a potentially novel therapy that was better than chemo which is really all we had for triple-negative. Her quality of life was good. She came in every week, 2 weeks on, 1 week off as is prescribed. And overall, felt pretty good. I think the complete hair loss affects people in how they feel but she had her wig and really, really trooped along. Now I can’t say that that’s representative of every patient I’ve treated with this drug. I think diarrhea can be quite substantial. I had another patient who needed to come off because the diarrhea and neutropenia was so significant. She’d had a complete response everywhere. And she went back East to spend time with her family and say her goodbyes because she felt, I can’t tolerate this therapy. I’d rather be off all therapy than feel like this and not be with my family. And it was, like, 4 months later, she came back to the clinic. She felt great and her hair was growing back. And she said, I’d like to go back on it. Let’s do a reduced dose. So we scanned her, and she had a maintained complete response being off therapy that long. So we reduced the dose and went again. It’s just interesting though. You can’t predict necessarily who is going to tolerate it really well and who is going to run into trouble and really want to come off therapy completely.

DR LOVE: That’s such an amazing story. Another thing about this case that we were talking about before is this woman did have prior adjuvant therapy, and that whole scenario of having to have gone through adjuvant treatment and yet, having metastatic disease. She sounds like she’s so positive that maybe that wasn’t a huge deal. But I’m just kind of curious the kind of things that come up. Do patients feel frustrated that they went through adjuvant therapy?

DR HURVITZ: Yeah, I think anger is a normal part of grief. And looking for blame, right? So she never went through that process that was visible to me. But I think as oncologists, we sometimes overtreat in the adjuvant and neoadjuvant setting because we’re afraid of that blame and anger if the recurrence happens. And sometimes, we’re not giving the most biologically rational therapy because of that. So I think that’s why we tend to overtreat, because of the fear of it coming back and then feeling responsible for it. Some disease is just bad and we don’t have the right tools to prevent a recurrence. So yes, no one wants to face that. You can feel that tension in the room, sometimes quite overtly, when a person is really unhappy that they went through that. And the why. Why did this happen? What did I do wrong? What did you do wrong, my oncologist? And again, listening I think is an important component. And usually, the patient will pull themselves up by their bootstraps and get on marching on new therapy. But sometimes, this will lead to loss of faith in the standard medical practices and looking elsewhere.

DR LOVE: Before you go on, I am curious what the follow-up was. What happened with this woman?

DR HURVITZ: Well, she ultimately did develop disease progression. She was treated with another line of chemotherapy, did okay. Went on a clinical trial of a PARP inhibitor. She didn’t have a BRCA mutation, but it was a PARP inhibitor study for patients with homologous recombination deficiency. And had some stability of her disease and then went onto the TROPION study that was led by my colleague, and received datopotamab deruxtecan. She’s one of my only patients who sequenced ADCs like this.

DR LOVE: Wow.

DR HURVITZ: And she had disease stabilization for a period of time. She did quite well. I want to say it was, again, I don’t have her chart, but around 6 months, 7 months where her disease really calmed down which was surprising to me since both drugs are targeting TROP2 and both have similar payloads. So she’s one of the ones I think in Ian Krop’s presentation where he said there were patients on TROPION who’d received sacituzumab govitecan who derived benefit. Ultimately, she, I think, had 11 lines of therapy before passing.

DR LOVE: Wow.

DR HURVITZ: She lived, I think, 7 or 8 years with metastatic disease which underscores the heterogeneity of this breast cancer because, of triple-negative, so many patients will not make it past a few years. The median survival is still 1 year. But there is this very broad curve with very different behaving tumors.

DR LOVE: How did she do on the dato? I’ve heard about mucositis. Any eye issues?

DR HURVITZ: No eye issues. I think she contended with the mucositis and was doing mouthwashes during that.

DR LOVE: Also, just curious given she sounds like a very, very proactive person, kind of what the end of her life was like.

DR HURVITZ: So she is one who had palliative care involved from the outset. At my former institution, we instituted an embedded APP model of palliative care where the nurse practitioner was embedded in the clinics and saw metastatic patients with high-risk tumors including breast cancer, GI cancers. This was an initiative to help decrease the amount of patients who were doing their end-of-life hospitalized having not even talked about hospice up until the last month of their lives. So she had palliative care involved very early on. And as her disease became more difficult and more recalcitrant to treatment, she had already expressed her goals of care. She and her husband were on board. And she did not pass away in the hospital. She passed away at home on hospice.

DR LOVE: That APP thing sounds like an awesome idea. They’re still doing it there at UCLA?

DR HURVITZ: Yeah. Yeah, they are. We’ve published on it at a lot of the various symposia. In fact, the APP who started the program with me and a number of other people at UCLA left UCLA to go to medical school. And she is, I told her contact me when you’ve done your residency. I will hire you. It’s an amazing program.

DR LOVE: You tell her to contact me. Tell her to contact me because I want her to help me with education. Alright, let’s get back to the data here.

Clinical trials investigating TROP2-targeting antibody-drug conjugates

DR HURVITZ: Alright. So the ASCENT clinical trial was the study that led to the FDA approval of sacituzumab govitecan compared to treatment of physician’s choice which is single-agent chemo. And the original study required at least 2 prior chemos, one of which could have been in the early-stage setting, but had to be within a 12-month period from their disease recurrence.

And the primary endpoint was progression-free survival. On the left side, you can see the significant improvement in median PFS, 5.6 months with saci, 1.7 months with the chemo, and a 0.41 hazard ratio which was pretty phenomenal. Again though, that PFS of under 6 months is notable just how aggressive this disease is. So although we were all congratulating one another for this great data, the median survival was 12 months with sacituzumab. So we do need to do better.

The clinical benefit was looked at according to TROP2 expression levels. With T-DM1, the HER2-targeting antibody-drug conjugate, you really need high expression of HER2 for there to be benefit. But with sacituzumab targeting TROP2, it doesn’t appear that progression-free survival benefits depend on how much TROP2 expression level there is. So in other words, you don’t need to test your patients’ tumors for TROP2 expression level because regardless of whether they have low expression in the left upper corner, medium in the right upper corner, and left lower quadrant or high expression, you’re seeing benefit compared to treatment of physician’s choice.

Safety, neutropenia and diarrhea are the things we see most. It’s notable that really, over 50% of patients will have Grade 3/4 neutropenia, which is why a lot of clinicians are using upfront prophylaxis with G-CSF. Not as much nausea and vomiting. I think that’s fairly easy to mitigate. But the diarrhea, 10% will have Grade 3. So it needs to be watched really closely and proactively managed.

So this was my patient. She received sacituzumab govitecan. She had a partial response. And she tolerated well for about 2 years with disease control.

DR LOVE: So again, I’m not sure exactly when this happened, but I noticed she was HER2 0. So I’m guessing she might have been in the pre-HER2-low era. So theoretically, if she could have hung on a little bit longer, maybe you could have found a little HER2.

DR HURVITZ: Exactly, especially with the data from DESTINY-Breast06 presented with the ultralow.

DR LOVE: Right.

DR HURVITZ: Where the IHC 0 can be subclassified and you can find patients who may benefit from T-DXd.

Alright. So moving on, we have the TROPiCS-02 study. And this is looking at sacituzumab in hormone receptor-positive, HER2-negative breast cancer that had progressed after endocrine therapy and 2 to 4 prior lines of chemo for metastatic disease. Hormone receptor-positive breast cancer does have expression of TROP2, which is the rationale behind studying this here.

The progression-free survival was significantly improved. Again, 5.5 months with SG, 4.0 months with treatment of physician’s choice. When these data were first presented, there was no significant overall survival benefit, and a lot of us were a little bit dubious about the 5-week improvement in progression-free survival in whether this was going to end up being a practice changer.

However, the overall survival was followed. And Hope Rugo published these results showing a 3.2-month improvement in median overall survival that was statistically significant. Hazard ratio of 0.79, so practice changing data. And now, we have sacituzumab govitecan for all breast cancer except for HER2 amplified or HER2 overexpressing.

If you compare it, again, based on or looking at based on the TROP2 expression level, that left chart there shows you that only 5% of the breast cancers had 0 TROP2 expression. So really, pretty much all patients have some level of TROP2 expression on their tumor. And if you break it down on the right side based on whether their tumor had an H-score, which is an expression level of TROP2, of less than 100 or 100 and greater, you’re seeing benefit with sacituzumab regardless, very similar to what we saw with the ASCENT study.

And then the activity by HER2 IHC score. Why are they looking at it based on HER2 expression level, HER2-low or IHC 0 when this is a TROP2-targeted ADC? Well this drug came out around the time that T-DXd became available for HER2-low breast cancer. So they’re demonstrating that this drug works regardless of level of HER2 expression.

So there are a number of ongoing Phase III trials of sacituzumab in earlier lines including the curative setting. But shown here are 2 studies actively enrolling, ASCENT-03 and ASCENT-04. They are different just based on whether or not a patient has tumor expression of PD-L1. And looking at sacituzumab in the front-line setting previously untreated for PD-L1 negative on the left side and for those that have PD-L1 positive breast cancer in the front-line setting combined with pembrolizumab.

Saci-IO is a Phase II study looking at sacituzumab with pembrolizumab in the first-line setting with or without pembro in PD-L1 negative breast cancer. Again, a number of these studies ongoing.

And then as I mentioned, we have Dato-DXd which is essentially T-DXd, but targeting TROP2 with the datopotamab. It, again, has this very high potency payload. And the drug-to-antibody ratio is around 4.

The TROPION-Breast02 study is looking at Dato-DXd versus single-agent chemo of physician’s choice in metastatic triple-negative breast cancer in the front-line setting for patients who are not candidates for PD-L1 therapy. And they have to have central testing for PD-L1.

TROPION-Breast01 is looking at Dato-DXd in hormone receptor-positive, HER2-negative breast cancer. Similar design, 1-to-1 ratio, randomization ratio.

And these data were actually presented by Aditya Bardia at ESMO this past year showing a significant improvement in progression-free survival, median PFS of 6.9 months versus 4.5 months with a hazard ratio of 0.64. So comparatively looking at TROPiCS-02 versus TROPION-Breast01. Again, different patient populations but that hazard ratio, not totally different.

Adverse events: We are seeing more stomatitis with datopotamab deruxtecan and also some neutropenia, although the rates of neutropenia are quite low. When you’re looking at Grade 3/4, much lower with Dato-DXd than we’ve seen with sacituzumab. And in fact, very low uses of G-CSF. So this may be one of the differentiating features between datopotamab and sacituzumab.

Identifying and targeting HER2 in HER2 low-expressing disease

DR HURVITZ: So moving on to HER2 low-expressing breast cancer. We know that HER2 is expressed on normal tissues throughout the body physiologically. And in fact, there was early evidence when HER2 became a thing in the ’80s. Mike Press did some very nice analyses showing that HER2 expression is on normal tissue as well as all breast cancers. And if you actually use fresh frozen tissue to test for HER2, you can see the expression level of HER2 to a much greater extent. But because we’re testing paraffin-embedded formalin-fixed tissue, there’s a lot of loss of antigen expression impeding our ability to actually tell how much HER2 expression is there.

And that’s becoming important because we now have an ADC available for HER2 low-expressing breast cancer. Traditionally, it was a binary decision. Is it HER2 overexpressing or is it HER2-negative? But now, we have to look at whether there are lower levels of expression of HER2 because we have an ADC with benefit in patients with HER2-low expression.

When this all came out, a number of researchers went back and looked at retrospective analyses to see whether HER2-low breast cancer has a distinct behavior or prognosis. And most of the studies show that there’s no survival difference in HER2-low versus HER2 0 disease, so it’s not a distinct classification. However, we could still use that antigen expression level to get the chemotherapy into the region of the cancer cell.

And that’s what T-DXd does. It is taken up into the HER2-expressing cell, the payload is released. And that payload is membrane permeable, able to leave the cancer cell and kill a neighboring tumor cell that doesn’t have any expression of HER2. So this is the mechanism of bystander effect.

The DESTINY-Breast04 study looked at T-DXd versus single-agent chemotherapy in a Phase III study requiring those patients who had hormone receptor-positive breast cancer to have exhausted endocrine therapy. And patients had to have had at least 1 to 2 lines of chemo in the metastatic setting.

And these are the practice-changing results that led to the immediate approval of T-DXd for HER2-low breast cancer, showing an improved progression-free survival and overall survival that was highly statistically significant.

And you can see here that the patients benefited even in the hormone receptor-negative or triple-negative cohort. Now there were not that many patients who had triple-negative disease in DESTINY-Breast04, but it did lead some to think you could use T-DXd in HER2-low triple-negative disease. Thus, competing with sacituzumab govitecan, which targets TROP2 but has a similar mechanism of action of its cytotoxic payload.

The adverse events: Nausea and vomiting, I would say everyone has some level of nausea. In the trials, all grade nausea was in three quarters of patients. So it’s something that I see as highly emetogenic and I treat really, really aggressively up front my patients for that. There is some diarrhea, but not to the extent that I see with sacituzumab. And hair loss is substantial, but not complete. I’ve never seen anyone completely lose all their hair, but they do have significant hair thinning.

DR LOVE: Actually, I was just flashing when you were mentioning Dr Sharma. We did a program on bladder cancer at the GU Oncology meetings, and one of the things we talked about was HER2. And I couldn’t find any GU people who really knew much about T-DXd, so I did a video with Dr Sharma and we showed it there. And then afterwards, they asked one of the faculty, well what would you do in terms of prevention of nausea and vomiting? And you could see he was just like, had no clue. And he goes, I think I’d do what she just said, which I think is what’s happening everywhere. Everybody’s asking the breast people, what do we do? And speaking of that, I had not heard before about this frozen tissue thing. That sounds interesting. How much of a difference is there? And is there enough that, you know, if you have a situation, I think your next case is maybe a little bit like that, where you just keep finding HER2 0 and you’re trying to find some HER2 and you’ve got a biopsy you’re about to do, would you do it fresh?

DR HURVITZ: You could. Pathologists aren’t though. I think this whole expression level thing is a big mess right now and needs a lot of work. The IHC test was not developed to quantify low levels of expression of HER2. It just wasn’t designed because they were just looking for those who had overexpression. And I think that there are going to be other technologies utilized, MasSpec, mRNA, things like this. But we saw data from DESTINY-Breast06 that indicates this ultralow HER2 may benefit. So we may find ourselves at a point where kind of like with sacituzumab, you don’t need to test for HER2, you just try the drug. So it’d be interesting though to do a study and use fresh tissue like a neoadjuvant study with T-DXd and use fresh tissue and just find if there is any patient where you can’t see HER2. Mike Press indicates you can see HER2, and Dennis Slamon says the same thing, you can see HER2 if you’re using the right antibody and the right tissue in the right conditions, you can find it pretty much on all breast cancer. So it may be that we’re going to use it in everyone.

DR LOVE: Yeah, it’s kind of like you were saying. It’s almost like you’re backing into the sacituzumab TROP2 thing. And there are a lot of ADCs. Enfortumab also, same thing. They use it in bladder cancer. They don’t look at nectin levels or whatever.

Incidentally, one of the things, before you keep going, I was mentioning enfortumab. And I know you’re going to maybe get into this, but we’re seeing such interest, and you mentioned the trial looking at saci plus pembro, in combining ADC with IO. It’s now first-line therapy of metastatic bladder. It beat cisplatin by far. And I guess I was wondering from, I guess, a hypothetical point of view, do you think it would be more effective to combine an IO with an ADC or just regular chemo? Because, of course, they do that also in lung cancer, for example.

DR HURVITZ: Yeah. I think if the ADC is more effective at killing cancer cells and releasing those tumor antigens, there may be some preclinical rationale to combine it, that there will be better efficacy with IO. Some chemotherapies are immunogenic, and I think there is mounting evidence that ADCs can be immunogenic as well. We’ll see from the ASCENT-04 study if that actually bears fruit in metastatic triple-negative breast cancer. I’m certainly interested in seeing that. But I think early evidence indicates, as you said, in other tumor histologies that this may be a thing. It may be better than chemo and IO.

DR LOVE: Alright, please continue.

Case: A woman in her early 50s who received treatment for Stage I breast cancer later develops multiple lesions similar to the original cancer

DR HURVITZ: Okay. So this question of whether or not there’s a threshold of HER2 expression needed for activity of T-DXd. I thought I’d start with a case. And this is a 53-year-old woman who had Stage I ER/PR-positive, HER2 0, low-grade invasive ductal carcinoma. Recurrence score was 9. And she was treated with tamoxifen. She refused radiation. And this is a patient I saw at the Hutch, actually, 18 months later, she developed a fever of unknown origin and she was being worked up by infectious disease. And they found a left breast mass, so contralateral, liver lesions, bone lesions. They biopsied the breast, and it was very similar to the original cancer. It was ER/PR strongly positive and HER2 1+ by IHC. A FISH had never been done. So she received first-line standard CDK4/6 inhibitor endocrine therapy. She was found by a liquid biopsy to have a PIK3CA mutation, so went onto alpelisib. She couldn’t tolerate it really well and after a few cycles, switched to everolimus. She then had progression, went onto capecitabine. And at that point, they biopsied her liver and it was ER-positive, PR-negative and HER2 2+ by IHC, but now this FISH test, the first time they do FISH, they see the copy number is 4.3 and the ratio is 2.1, so kind of this indeterminate-ish range. And it just didn’t smell right. They had done a Tempus and a FoundationOne® test and never found HER2 amplification. They keep seeing the PIK3CA. And she picked up an ESR1 mutation. But she started T-DXd, had a beautiful response for 18 months. And then at progression of disease, went onto T-DM1, and it didn’t hold her for even 2 to 3 cycles. At her first scan, she was progressing. And so currently, we’ve sent the tissue from the original, from all 3 biopsies she’s had in the course of her disease to Mike Press, and he’s analyzing the HER2. So I don’t have a result for you. But what my suspicion is, is that this is HER2-low, not HER2-amplified breast cancer, which is why T-DXd worked so well and why T-DM1 did not. But we’ll have to wait and see.

So the rationale for looking at T-DXd in HER2-low breast cancer from a clinical standpoint came from the Phase II study.

DR LOVE: In general, if you have a patient who is even HER2-positive — well let’s say HER2 low like this or if you think she’s HER2 low, I guess she could be HER2-positive I guess, what do you usually do after T-DXd?

DR HURVITZ: Well, that’s a great question because we don’t know yet the mechanism of resistance to T-DXd or to other ADCs. There’s a lot of hypotheses that loss of the antigen expression can lead to resistance or that there’s efflux pumps leading to resistance to the cytotoxic payload, so we don’t know. And I think there has been some, there have been some retrospective datasets from UCSF and, I think, at Mass General looking at how patients have done by sequencing one ADC after the next. And we don’t see that there’s super great activity, but there are some patients who have tumor responses. This is an unknown area. There are trials ongoing to look at switching ADCs to define if you can sequence. T-DM1 is a drug that really relies on very high levels of HER2 expression. And if T-DXd is killing those cells that have the most HER2 expression preferentially, I’m not going to have a lot of faith that T-DM1 is going to work after T-DXd. So I tend to use chemotherapy or an ADC that is targeting a different antigen on the cell. And I tend to do that in clinical trial rather than sequencing T-DXd by, you know, followed by dato or sacituzumab because I don’t have a lot of faith that that’s going to work.

DR LOVE: Yeah. I was going to say, why not give her sacituzumab?

DR HURVITZ: You could, but I —

DR LOVE: Just because she’s had 2 ADCs?

DR HURVITZ: Yeah, I’m just concerned that the chemo, that there is resistance to the chemo payload because they both are topoisomerase-1 toxins.

DR LOVE: Right.

DR HURVITZ: And so I’d prefer to use something that has a slightly different mechanism of action, eribulin, for example. In fact, there are drugs that are now, you know, these maytansinoid cytotoxic payloads kind of fell out of favor.

DR LOVE: Right, right.

DR HURVITZ: And now that we’re seeing the emergence of novel ADCs using microtubule poisons.

DR LOVE: Alright, please continue.

Thresholds of HER2 expression and the efficacy of trastuzumab deruxtecan (T-DXd)

DR HURVITZ: The Phase II DAISY trial provided the clinical rationale to look at T-DXd in HER2-low breast cancer. And what I’m showing you here are the outcomes based on the cohorts which are based on level of HER2 expression. So on the far left, patients with overexpressing HER2 breast cancer have a really good objective response, the best objective response of 71%. That waterfall plot showing almost everyone had their disease shrink. With 1+ or 2+ in the middle panel there, you see nice benefits but slightly less. You’re not seeing as much benefit as you were with overexpressing. And in the cohort with IHC 0, again, you’re seeing sort of this mixed responses with the best objective response rate of 30%. So making people wonder, does the level of expression really predict benefit from T-DXd? My concern with this data set is I don’t think IHC is a great way to be testing for or quantifying HER2 expression levels.

And actually, if you look at data that was presented by Yael Bar at ASCO last year, she presented the patients who had core biopsy, surgical biopsy and metastatic biopsy samples available, matched samples. There were 35 patients, and there were only 50% of patients who had similar results at all 3 timepoints. There was some change. I don’t know if it was the disease was changing or it was in the ability to detect the level of expression of HER2 from time to time.

And if you actually look at, there was, I believe out of Johns Hopkins, there was this round robin of 18 very experienced pathologists who were asked to decide whether a tumor was HER2 0 or 1+ by IHC for HER2. And only 26% concordance was reported there. And as we mentioned earlier, HER2 0 doesn’t actually mean full absence of HER2. Because by definition, according to ASCO-CAP guidelines, HER2 0 can be absolutely no staining or incomplete membrane staining that’s faint or barely perceptible up to 10% of the tumor cells, and that’s termed ultralow for HER2 expression.

We know that there are these complexities of quantifying HER2 expression level. And so now, I think the way that we determine whether a patient is a candidate for T-DXd is saying that if at any timepoint their disease had a 1+ expression level, then they’re a candidate. Even if the most recent biopsy shows IHC 0, you don’t need to repeat the biopsy if at one point in their disease course, there was a 1+. And the more you biopsy a patient, or test samples, the higher the chance that you’re going to find a 1+ there. In fact, up to 81% in this cohort. And in another cohort presented at ASCO last year, 100% of patients who had their tumors tested 5 times had a 1+ level found at one point.

So alternate methods of detection are being looked at including MasSpec on the left and HER2 mRNA levels on the right side here.

The DESTINY-Breast06 study was just presented at ASCO. This study looked at T-DXd versus chemo in patients who had HER2-low expression level or ultralow expression level. Meaning greater than 0, but less than 1+. And patients had to have, this was all hormone receptor-positive, and they had to have had at least 2 previous endocrine therapies. But it was the first time they were receiving chemotherapy, so front-line chemo.

The PFS was significantly improved by over 5 months, meeting its primary endpoint.

And when you looked at outcomes, the overall survival was not statistically significant yet. However, if you look at patients that are HER2 low, there is a nice trend in the HER2-low and in the intent-to-treat population toward benefit with overall survival.

And looking at the progression-free survival and overall survival in the ultralow patients, again, IHC 0, but a little bit of expression of HER2. You’re seeing somewhat similar benefits with T-DXd in this patient population. Now the FDA has not yet approved T-DXd for HER2 ultralow, but many of us are wondering whether they will approve it based on these PFS data that were seen.

And the objective response rates look better with T-DXd. Interestingly, 56% of patients had a confirmed objective response rate in the HER2 low. And for ultralow, it was over 60% of patients who had an objective response. So really, sort of calling to attention the activity of this drug in this setting.

Case: A woman in her late 50s receiving T-DXd for HER2-low metastatic breast cancer develops asymptomatic ground glass infiltrates in the lung

DR HURVITZ: So we have a third case here. This is a 59-year-old woman who started T-DXd for HER2-low metastatic breast cancer involving the liver and lungs. After 3 cycles, she had a complete response. However, on the scans, we saw ground glass infiltrates in the bilateral upper lung lobes. She was completely asymptomatic. Her O2 sat was normal. Her vital signs were normal. Her lung exam was normal. And so the question becomes, what should we do in this situation?

So we stopped her T-DXd. We tested for COVID and we initiated steroids to be proactive since we saw bilateral ground glass opacities. And repeated her CT scan in 4 weeks and it showed complete resolution of the lung findings and her exam and symptoms remained normal. She restarted T-DXd and we continued to follow her scans, every 8 to 9 weeks, of her lungs because if we saw that happen again, we’d need to be aggressive. And she did achieve control of her disease for another 15 months. So just underscoring that it’s important to stop T-DXd even with Grade 1 asymptomatic pneumonitis.

This is the side-effect profile we see with T-DXd. As I mentioned earlier, nausea is a predominant finding. Fatigue as well. Not full, but notable alopecia. And neutropenia, but not as high as we see with sacituzumab.

And then in terms of interstitial lung disease, anywhere from 10% to 15% of patients will have any grade of pneumonitis. There have been deaths, which is why it’s so important to be proactive. And if a patient develops any level of symptomatic ILD, therapy needs to be permanently discontinued. Now there are studies planned, or maybe even ongoing, to look at whether you can resume after Grade 2 if it resolves, but I wouldn’t do that as standard of care.

DR LOVE: I wanted to ask you in terms of sequencing of drugs in patients who are HER2 low. We actually did a CME program a couple hours after the original data was presented. I’m not sure if you were there or not. And right from the beginning, we were hearing triple-negative, sacituzumab, more data, that goes first. ER-positive, T-DXd. And I kind of am still hearing that. But I sort of wonder whether or not you also factor in the clinical circumstance, given what you just talked about for the potential for ILD. Now granted, if you can screen the patient, the risk of it being really serious is much, much less. But these kind of reflex thoughts about, particularly in ER-positive, to go with T-DXd. If you have a patient who is older or even not but who has not very aggressive disease, how do you think that through? Do you automatically go to T-DXd? Or given the toxicity profile, even quality-of-life-wise, I don’t even know how they would compare. But particularly with the threat of a serious adverse effect, does that affect it or do you just generally go with T-DXd?

DR HURVITZ: I discuss, because we do have both drugs available for both the disease types. And so I think they’re in direct competition. So I present the data to my patients in terms of what we know, explaining we’ve never done a head-to-head comparing the 2 agents. My opinion is the quality of life tends to be better on T-DXd. That’s what I see. If we’re really aggressive with the nausea, using an NK1 inhibitor up front, olanzapine up front, steroids, really aggressive with treating the nausea, I think overall, my experience has been a better quality of life. But I don’t have the data to support that. It’s anecdotal.

The ILD, it’s interesting. I was involved in a lot of the studies with T-DXd, so I have really good experience utilizing it, and this was my first patient who developed ILD. I just haven’t seen it. So I think it’s very important to be super proactive. Presence of lung mets doesn’t appear to be a predictor for development of ILD. Asian patients may have a slightly higher risk. I do look at creatinine levels. There was a pooled analysis showing that if creatinine levels, if patients’ renal function wasn’t so hot, they may be at higher risk. And I look at O2 sats. Because if it’s less than 95%, that’s a predictor for a higher chance of developing ILD. So I am looking at their baseline features. Any evidence of interstitial lung disease, fibrosis or ILD with any other agent in a patient’s history, I would not use T-DXd.

DR LOVE: What about screening? I know breast people are very aggressive, every 8 weeks or whatever. Do you continue that for, like, 2, 3 years?

DR HURVITZ: I do it at least 18 months. I try to stick with the 8 to 10 weeks. Sometimes, with scheduling, it’s hard to get them done. I do pull back on the abdominal imaging. If a patient’s had a beautiful response, I’m not putting them in a whole-body scanner every 8 to 10 weeks. But I am doing non-cons, CTs of the lungs and trying to stick with that because there is some evidence that patients will still have it beyond the first year. I don’t know if it can creep up after, you know, at year 2 or 2 and a half or 3. If T-DXd is approved in the front-line setting for HER2-positive metastatic breast cancer, we may have patients on that drug for 5, 7 years. So we’re going to need to follow that real-world data very carefully to see what is the trajectory. I don’t believe that the risk all of a sudden goes away.

DR LOVE: Speaking of T-DXd first line, are you expecting that’s going to happen?

DR HURVITZ: I expect the study is going to be positive. CLEOPATRA showed a PFS of 18 and a half months in very treatment-naïve patients. And in the DB03 study where patients were more heavily pretreated, the PFS was almost 30 months. So it’s already beat it in a cross-trial comparison in more heavily pretreated disease. So I think it’s right that patients get T-DXd in perpetuity in the front-line setting. I think that’s going to call into question a lot of quality-of-life issues. And I’d rather see a test of it as an induction therapy for 6 to 12 cycles followed by maintenance HP in really exceptional responders. So I think we’re going to have to answer that question when the data is out.

DR LOVE: That’s interesting. That’s not been tested or is that in any of the trials?

DR HURVITZ: It’s not been tested, but I think it’s being planned in a study to see if you could drop the T-DXd. And there is this study of T-DXd ongoing now, I think, that’s looking, or planned, that’s looking at T-DXd in ER-positive breast cancer in the front-line setting. What you do, induction T-DXd followed by CDK4/6 inhibitor plus endocrine therapy versus the CDK4/6 inhibitor endocrine therapy. And that’ll be interesting because that’s a maintenance strategy in HER2-low breast cancer. So why not do something similar in HER2-positive breast cancer if DB09 is positive?

DR LOVE: And this would be HER2 low?

DR HURVITZ: This would be HER2 low, exactly. Exactly.

DR LOVE: HER2 low, first line, ER-positive. Wow.

DR HURVITZ: Yeah. And it may not, it may or may not happen. I’ve just heard through the rumor mill that this sort of concept of looking at whether you can use the T-DXd as induction and then maintain with a better tolerated regimen, oral regimen. That would be a similar approach I’d want to see in HER2-positive breast cancer, right?

DR LOVE: Yeah, absolutely.

DR HURVITZ: Where you do an induction with T-DXd.

DR LOVE: Yeah, sure.

DR HURVITZ: And then maintain with HP.

DR LOVE: Or maybe no maintenance. I don’t know.

DR HURVITZ: Right, right. For those really exceptional responders.

DR LOVE: Speaking of MRD, how’s that coming along with breast?

DR HURVITZ: It’s still controversial. I think we need — the studies are ongoing. We’ll have better answers in the future. But we’re still kind of in the dark ages right now. And I think the problematic part of it is patients can get these tests done as, you know, they’re commercially available. So in the clinical, outside of a clinical trial, in the clinical setting, it’s raising a lot of questions we as clinicians don’t know how to answer for our patients.

Novel ADC strategies under investigation

DR LOVE: Alright. Let’s finish out with some of the novel strategies.

DR HURVITZ: Okay, sounds good. So a number of studies ongoing. The DESTINY-Breast08 clinical trial is a study evaluating T-DXd in combination with a number of novel partners including durvalumab and paclitaxel, capivasertib, endocrine therapy. And dose expansion is built in these studies. So we’ll start seeing more and more data come forth from this study.

The BEGONIA study is looking at Dato-DXd with durvalumab. Dr Schmid reported these results showing some very nice durable responses in 80% of the patients. They’re still on therapy. And seen in both PD-L1 low and high. And an objective response rate of 74%. So that was pretty notable results. Again, a small sample size, 53 patients, but it is very interesting.

We’re seeing some novel conjugates. The trastuzumab duocarmazine presented results from the TULIP study in HER2-positive breast cancer has a lot of ocular issues. So I’m not sure we’re ever going to see that approved in that realm, but it is being tested in HER2 low. Disitamab vedotin is also showing some interesting objective response rates and is in development.

Patritumab is targeting HER3, and is showing results and activity in all types of breast cancer, all different subtypes. And the data, I think, are actually kind of interesting, especially for triple-negative breast cancer where we’re still really looking for benefit. Now the question is going to become if we have patri and dato and T-DXd all available to us, all using the same payload, at some point, isn’t there going to be cross-resistance to the payload because they all have the same payload. But this will, I think, provide us evidence that targeting HER3 with an ADC is beneficial. And maybe we’ll find a group of patients where this would be particularly effective.

And then they have the AdvanTIG-211 study looking at an anti-TIGIT and anti-PD1 in first-line triple-negative breast cancer. Again, very interesting. These are drugs that are already further along in other tumor histologies showing benefit. And this is for triple-negative disease.

Zenocotuzumab is being evaluated in HER2 low. This is a bispecific antibody, we’re going to hear more and more about these, that target both HER2 and HER3 and can lead to immune activation. So this is being looked at in HER2-amplified as well as in HER2-low, ER-positive breast cancer.

DR LOVE: I don’t really know much about this other sacituzumab, how it’s different.

DR HURVITZ: Yeah.

DR LOVE: Do you know anything about it?

DR HURVITZ: Sacituzumab tirumotecan is a novel TOPO1 inhibitor again. It’s targeting TROP2, so it’s the same antibody as in sacituzumab, but just a slightly different payload. Similar drug-to-antibody ratio. This was a Phase III study reported by a Chinese group, I believe, looking at Sac-TMT versus single-agent chemo of physician’s choice. It’s a very similar design to the ASCENT clinical trial.

And the curves look great. The separation of curves looks better than we even saw with the ASCENT study. On the left side, you can see the high TROP2 expression level patients deriving a lot more benefit it seems than the ones with low and median TROP2 expression level on the right side. But both sides look pretty convincing that this is active regardless of TROP2 expression level.

The side-effect profile, it seems like there’s less of the neutropenia that we’re seeing, you know, significant neutropenia. There is stomatitis, however, and other side effects shown here. And there was a patient who had Grade 2 ILD. We don’t tend to see ILD with sacituzumab govitecan. And some ocular toxicity as well.

And then there were updated results from DESTINY-Breast04 presented at ESMO last year, again, looking at progression-free survival on the left side and overall survival on the right. Just more mature data underscoring the activity of T-DXd in HER2-low disease.

DR LOVE: So with yesterday being the deadline to send in to San Antonio, I’m just kind of curious what you’re looking forward to seeing at San Antonio.

DR HURVITZ: Oh gosh. Well, I’d love to see DESTINY-Breast09. I don’t know if, I’m not involved in the study, so I have no knowledge of whether or not that front-line T-DXd study is going to be presented or mature. That’ll be interesting. I think TROPION-Breast02 in triple-negative for datopotamab, hopefully, we’ll see that soon. The ASCENT-03 and 04, I don’t think they’re close to being ready, but maybe in the next year or 2. Yeah, I think there’s going to be a lot more data coming out about ADCs. Maybe we’ll see some data from the combination studies looking at ADC with novel combinations.