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For patients with metastatic triple-negative breast cancers who are not candidates for immunotherapy, what is your current approach? Why is this such a clinical challenge in treatment decision-making? Thomas, would you like to start?

Thomas Bachelot, MD, PhD: Yeah. Clearly, those patients are very difficult to take care of because their disease is very severe, and immunotherapy is such an important treatment for estrogen-negative breast cancer. When we cannot use it because we know it will not be useful, it is clearly more difficult. The big problem here, in the first-line, we have to find the treatment that may be the most efficient in terms of disease responses and the duration of response, and most particularly overall survival, that is for sure. Having the most efficient treatment available is really important. Mafalda, what do you see as challenge for those patients?

Mafalda Oliveira, MD, PhD: Yeah, I agree with you, Thomas. I think that these patients are difficult to treat because the prognosis is so bad. I am really glad to see some very nice, better treatment options entering the clinic. I would say the practice evidence is moving faster than implementation because of several reasons. One of them is the approval barrier, at least here in Europe. It does not go as fast as in the US. We do have some approvals in the first-line for these patients, but then you will have to wait for the country-specific approvals. The implementation in the regulatory part of the implementation is one hurdle.

The other one is that usually physicians and all the care team are not used to these new drugs. I think that these with the disease is the key question that we must address when these drugs come to the clinical practice. We have already implemented some protocols regarding patient management to some of these ADCs that are already approved in later line settings. As the indication broadens to the first-line, that will be really important to have supporting infrastructure for patient management that allow doctors to confidently prescribe these drugs in this setting.

Thomas Bachelot, MD, PhD: You are right, but I think that most medical oncologists will easily adapt. They are not that different from standard chemotherapy. We are used to give chemotherapy that is very toxic to a lot of patients already. There is nothing really different from standard chemotherapy. There may be some apprehension because some of the toxicities are quite different from what we have seen before. We may go there like and then have some problem with stomatitis and other toxicities. Once you have managed that two or three times, then I think it should not a big problem in the end.

Can you describe for our listeners what does a patient who is ineligible for immunotherapy look like? How are they currently present in your clinic? Another question that came up was with regards to this emerging agents, can you provide to our listeners with the examples of what those are and where they are in their current approval status in the European Union?

Mafalda Oliveira, MD, PhD: Yes, sure. Patients that is currently present with triple negative breast cancer that are ineligible for immunotherapy in first-line represent about 65% of all patients with triple negative breast cancer. I suspect this number will increase in the future as the neoadjuvant immunotherapy is more and more used. I will suspect that we will have some more patients that have received prior immunotherapy for their early triple-negative breast cancer and then recur thereafter, which currently is a small subset of the patients with metastatic triple-negative breast cancer that we have.

These patients, typically, we know that they will have a short survival. An overall survival time of less than two years. These are patients really in need of better treatment options. It is not infrequent that they have a high burden of disease. They will need treatments that induce a good response and allow to alleviate the symptom burden they experience because of their disease.

Currently, as I was saying before the reimbursement of these new anti-TROP2 ADCs in Europe is not the same for each country. We have some approvals from the European medical agencies. Then each country must provide the criteria for reimbursement. In Spain, for instance, we do not have reimbursement yet for anti-TROP2 ADCs in first-line triple-negative breast cancer ineligible for immunotherapy.

Thomas Bachelot, MD, PhD: That is a big problem. In France, we do not have it either. We are still waiting for datopotamab to be reimbursed. We have the system, but it is only in the second-line metastatic settings. The patients should have received at least two lines of treatment, including the adjuvant. We cannot put it before second-line metastatic setting. If they have been treated in the adjuvant setting, and for patients with metastatic at diagnosis, we have to use the third-line metastatic setting.

Among patients with triple negative that need chemotherapy, there is a small subgroup that may be more important in the years to come than the ones that were ER positive at diagnosis, then when they relapse after hormone treatment, they lose the expression of ER. They are basically secondary triple-negative breast cancer. We tend to see more of those patients right now, and they have quite aggressive disease and difficult to treat. Those are quite resistant to chemotherapy. It is another part of the patients we need to use to treat the new ADC.

Mafalda Oliveira, MD, PhD: We have data now from both ADCs across the treatment spectrum for triple-negative breast cancer. We do have data. The first data came from the ASCENT trial using sacituzumab govitecan in second-line plus metastatic triple-negative breast cancer with improvements in PFS and overall survival in this patient population, irrespective of the PD-L1 status or the use of prior immunotherapy.

Now we have, for the same ADC, data from the ASCENT-03 trial, looking at the patients with triple-negative breast cancer that are PD-L1 negative or PD-1 anti-PD-1 ineligible in the first-line setting. Also a benefit in terms of PFS compared to chemotherapy. Then we have data from the datopotamab deruxtecan in the first-line setting for metastatic triple-negative breast cancer, PD-L1 negative or immunotherapy ineligible, also, with an advantage in PFS and overall survival for this patient population.

We do have now data from anti-TROP2 ADCs for metastatic triple-negative breast cancer, first-line and subsequent lines of therapy. I would love to know what Thomas thinks, but for this patient population that has a very aggressive disease and a very short overall survival time, I would say that, as soon as we use the most effective drugs, the better. If available, I would favor the use of these anti-TROP2 ADCs in first-line setting. If not, so if the patient could not have received it in first-line, then definitely that would be my preferred option in second-line or posterior lines for the patient.

Thomas Bachelot, MD, PhD: Yeah, I totally agree with you. Our strategy right now is to find the one that is commercialized, reimbursed, and we use it the soonest as possible. We look at the approved data, and as soon as the patient can receive it, we will do. Unfortunately, as we just said in France for the TROP2 ADC, we only sacituzumab govitecan right now. Now we have T-DXd for HER2-low.

The patient with triple negative breast cancers that are HER2-low, we could use T-DXd sooner in fact, because we can use it in second-line. So, sometimes we start with T-DXd, if the patient is HER2-low and we can use it before the sacituzumab govitecan, that is a little trick in the reimbursement form. We are just waiting eagerly that those two TROP2 ADC could be used in the first-line setting, which would be much better.

You talked earlier about some of the toxicities associated with this agent. How do you use each agent's toxicity profile to make your informed decision as to what to recommend to your patients? How do you bring in their current comorbidities into this decision-making as well?

Mafalda Oliveira, MD, PhD: Currently, the clinical experience we have here in Spain, it comes mainly from the clinical trials. I think that moving forward, knowing the toxicity profile of both ADCs and knowing how to explain it to the patients will be key to understand which ADC is better for which patients. For instance, with sacituzumab govitecan, we know that the main toxicities are neutropenia and diarrhea. For instance, for a patient that has a prior GI condition that has diarrhea as a side effect, or a patient that has been exposed to several cytotoxic chemotherapies, that has a low bone marrow reserve that should be taken into account when thinking about giving sacituzumab govitecan.

Of course, there are prophylactic measures that can be used and are very effective in mitigating these side effects. This is something that we also must keep in mind.

For the datopotamab deruxtecan, there are mainly two side effects that should be very early managed, and for which we should also give a  prophylactic measures, which are the stomatitis and the ocular surface toxicities. For the stomatitis, it is key to educate the patient to receive prophylactic mouthwashes. Currently, in the label, there is indication to have corticosteroid-based mouthwashes. Together with other mouthwashes like mouthwashes that are used to mitigate these side effects. In the label, there is also the recommendation for the use of ice chips during the infusion that in some patients can also be helpful.

Regarding the ocular surface, toxicity is very important, on one side, to instruct the patients to keep the eye very well hydrated. So, eye drops are very important, also, as a prophylactic measure. If available, and this is something that we can also discuss because it depends on the countries, but if available, the referral to an ophthalmologist to have a closer follow-up on all the eye surface toxicities can also be helpful.

I do not know how it is in France. At least here in Spain, the access to ophthalmologists can be a problem. What I would say is that prophylactic measures, eye drops from the very beginning, and ideally try to get these ophthalmological assessment and follow-up during the first infusions of datopotamab, but not to wait for that to start the treatment because otherwise you can delay the treatment.

In Spain? Is it a referral? Is it a timing issue? If you ever encounter yourself with a patient, who you would like to put on this treatment, but you would like to be proactive, how would you go about interacting with some ophthalmologists, or at least getting that connection in place before the patient goes on treatment, or once they are on treatment?

Mafalda Oliveira, MD, PhD: At least here in Spain, it is a problem of access. Typically, the ophthalmology departments of the hospitals are not prepared to manage all these side effects coming from cytotoxic chemotherapy. They are more focused in other pathology, eye-specific pathology, let us say. Typically, the consultation takes not less than 6 months or something like that, which is of course a too long to wait for the ophthalmologist consultation. This is a problem that many public hospitals, at least because of how the health system is organized in Europe, many hospitals face.

Thomas Bachelot, MD, PhD: It is exactly the same problem in France. I totally agree with what Mafalda said. It is maybe a problem for when the datopotamab will be commercialized to have those consultation very rapidly.

For the moment, when we have used datopotamab it was in clinical trials. For that, we have a specific collaboration with some ophthalmologists. Everything is pre-planned. It is very easy. For the common practice, it could be a problem. The good thing here you were asking the question how we will select patients. I think we can obviously preselect patients depending of their condition. For most patients, the selection will be on treatment. You have some patients that will have eye disorders, some patients will have stomatitis, others that will have diarrhea on datopotamab. The good thing is both are commercialized in the same time. I hope it will be the case. We could jump from one to the other because the main toxicities are quite different. For example, if you have datopotamab and then eye toxicities, you can go to sacituzumab you have, and then you go to the datopotamab and so on.

I think it will be much help us to adapt the treatment to the tolerance of the patients. If it is not been adapted beforehand because of a pre-existing condition.

You mentioned earlier that you sometimes look into HER2 positivity to maybe decide on whether you would like to go for HER2 agent first. I have not heard you mention anything with regards to interstitial lung disease or pneumonitis. How do you monitor for these, and what would trigger for you to look more closely to these patients?

Thomas Bachelot, MD, PhD: If we use T-DXd, we will do the same that for HER2-positive disease. Unfortunately, in the case of triple-negative breast cancer, as the PFS is much shorter than for HER2-positive disease, the problem will not be as important.

In any case, those patients have CT scan every 2 months just to look at the disease evolution. It will be the same exam that we look at ILD. Obviously, it is something that everybody should be aware. In case of ILD, that is grade 1 we have to follow the rules to be sure that it is not getting more severe.

Again, you are right, we look at the patient, if the patient have previous problems with the lungs, you have chronic lung disease, we will be very careful not to use T-DXd. The other one, datopotamab, does have ILD but it is less prominent

Mafalda Oliveira, MD, PhD: I think that in this case, in addition to the very close look at the CT scans, it is very important. Also, the patient education. What I usually tell my patients on T-DXd is that if they start to experience some persistent cough or less tolerance to exercise, they should flag it immediately to the clinical team.

It is very helpful also to have a pulse oximetry to measure the peripheral saturation of oxygen. Of course, it is not the gold standard, but it can give you a hint of whether there is something going on with the lung that will trigger the imaging to look for the ILD.

Frequent CT scans and patient education. That is the key messages for preventing ILD and to manage ILD before it can be a really important problem to patients.

When you are thinking about practice readiness and involving the care team that is going to support whoever physician is implementing these treatments once they become available, what does that look like? What does that workflow look like at your institution? You have identified the patient. You are ready to educate that individual about this next treatment. What does the workflow look like? What is the environment in your clinic? What are the individuals that you work closely to make this a success? Your pharmacies, your nurses, and other important members of the care team that just make sure the patient is safe throughout.

Mafalda Oliveira, MD, PhD: We really need to have and to provide education to the doctors on how to manage the new side effects that are not very similar to the ones that we are used to with chemotherapy. The concern about stomatitis or the concern about ocular surface events that pops up as a major area of concern, of interest. I think that is really important because there is a learning curve for these newer side effects that it does not mean that people cannot deliver the drugs because of these side effects, or the patients cannot receive the drugs because they have these side effects, it just means that we all need to learn how to manage the side effects. These can be tolerable by the patients and may not have an impact on how we treat the patients and on the efficacy of the drug. This is a key message.

That relates to your second question, actually, because I think, at least in my experience here in the hospital, the involvement of nurses that educate the patients about the side effects and give written guidelines on how to manage these side effects to patients. There are also some apps that are being also developed to educate the patients  through some key and very simple measures that they can take at home, and also on when they should contact the hospital to receive more dedicated guidance. If the side effects do not disappear with the first wave of measures. I think all these are very important.  

Also, the involvement of the pharmacists is important because, at least here at our experience in Spain, is that the pharmacists help us to optimize, for instance, a premedication patients receive prior to the infusion, and they work with us to understand how we can optimize the infusion timing for these patients. To have a multidisciplinary team is really important to implement these new drugs in the clinical practice, patient education, and also patient access to information and to adequate management guidelines for all these new side effects.

Thomas Bachelot, MD, PhD: If we take what we have learned already by giving chemotherapy and adapt it to those specific treatment just Mafalda said, I think it should not be a problem in the years to come to adapt and treat our patients correctly with those drugs.

The ILD most particularly for T-DXd, is really a problem, and we discuss it regularly because we regularly have new patients who present ILD. Each time it is a new discussion, and we see the younger fellow, and we make an example, and we go through as a procedure to be sure that everything is done fine and we do not have accident.

I think with datopotamab as a the two main toxicities that we have just discussed as a mucositis and the eye toxicities will be a challenge. Mostly the eye toxicity is quite rare. We have to be really aware of it and try to find a way to have rapid consultation with ophthalmologists, that is for sure. Mucositis is quite frequent, and people have to be aware. The patients have to be aware, and we have to be careful with prescribing mouthwash systematically for the patients to do it with prednisolone and so on. I think that is the most important. I do not see much other toxicities that will be a challenge for the datopotamab.

Mafalda Oliveira, MD, PhD: I think these therapies are a great scientific advance, but they also require us to rethink how we deliver care. I think education is really key in order for us to achieve that goal.