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Welcome to the Breast Cancer Sessions with the Video Journal of Oncology (VJOncology.com).

A roundtable discussion filmed in Chicago, IL, during the ASCO 2022 meeting with experts Matteo Lambertini & Evandro de Azambuja who discuss the latest breaking news in breast cancer, including trial updates exploring ADCs and CDK4/6 inhibitors.

 

Welcome to the Breast Cancer Sessions brought to you by the Video Journal of Oncology (VJOncology).

Following an exciting day at the ASCO 2022 meeting, leading breast cancer experts get together to share their highlights. This exclusive roundtable session is chaired by Matteo Lambertini (Institut Jules Bordet, Brussels, Belgium), who is joined by Evandro de Azambuja (Institut Jules Bordet, Brussels, Belgium). The speakers discuss pivotal results from exciting clinical trials in breast cancer, including the Phase III trials DESTINY-Breast04, TROPiCS-02, PALOMA-2 and MAINTAIN.

Transcript

Matteo Lambertini:
Dear colleagues and friends. Hello, my name is Matteo Lambertini. I’m a Medical Oncologist from Geneva, Italy, and we are here at the ASCO conference together with the Evandro de Azambuja from the Institute Jules Bordet to discuss some of the most important breast cancer presentations. Particularly, Evandro would love to discuss two topics with you. One is the use of ADCs in breast cancer. And the second one is some important news on CDK4/6 inhibitors. So we will start with ADCs. We are just back from the plenary session where we had a fantastic and extraordinary presentation on the DESTINY-Breast04 trial that has been simultaneously published in the New England Journal of Medicine. This is a trial in patient with HER2-low breast cancer, meaning hormone receptor positive mostly HER2 1+ or 2+, FISH negative and a few patients also with triple negative disease, but HER2-low. So again, 1+, 2+, FISH negative, the HER2 status. These are patients that were pre-treated with endocrine therapy and at least one line of chemotherapy and were randomized to receive the ADC trastuzumab deruxtecan or chemotherapy of physicians choice. And the results are really extraordinary. A doubling in progression-free survival from 5 to 10 months, median PFS hazard ratio, 0.51, and also significant improvement in overall-survival with more than a six month median gain in overall-survival. Again, statistically significant, highly clinically relevant. So Evandro, my first question, have you ever seen results like that in the breast cancer field?

Evandro de Azambuja:
Yeah. Thank you very much, Matteo, for this question and I think this presidential session was excellent. The plenary session, a standing ovation, we’ve seen results in metastatic breast cancer that you haven’t seen before, the hormone receptor positive population with HER2-low. We have seen with this drug, if it is ADC trastuzumab deruxtecan in HER2-positive and there you have seen fantastic results, with extremely important hazard ratios. But now we move this drug into a population that has not many treatments left to fail into endocrine therapy or some chemotherapies. And this population, really, we account for about 50% of our metastatic breast cancers today, they are considered HER2-low, like you mentioned, HER2 1+ or 2+ with a FISH negative. In this population, we can see an improvement, which is statistically significant, but clinically meaningful in doubling the progression-free survival for these patients. And also the overall-survival that you gain with this drug in this patient population is incredible, we haven’t seen these before. And this trial really shows that in this patient population, this drug is coming to be a new standard of care in this setting.

Matteo Lambertini: 
Yeah, maybe before going into other ADC that have been presented in this setting, just one question, more clinically based question on the toxicity profile of this agent, how we should manage patient in clinical practice. We had also yesterday in the oral session, in the metastatic breast cancer track, the presentation of the DESTINY-03 updated safety data to have some more information and insights on the toxicity profile of this drug. Most important side effects, nausea and vomiting, fatigue, and then rare but important lung toxicity. So what’s your take on the toxicity and what should we do in clinical practice to manage this drug as compared, for example, to T-DM1 where we are now used to these agents for a longer time?

Evandro de Azambuja:
Yeah. Thinking back to this, when they present the first result on the phase one with 184 patients in the HER2 positive disease, there they found quite a high number, about 15% of interstitial lung disease. And it was quite worrisome because there are some Grade 3 toxicity. They didn’t have a Grade 5 at the moment, but it is important, it may impact a lot of the patient’s quality of life. In the Phase III, the Breast-03 in HER2+ they also found some toxicities, ILDs, but mainly Grade 1 and Grade 2. And with these learning curves, I think, you select the patients, we follow the patients, regularly review scans, and this is what was applied in this patient population. They were mono receptor positive HER2-low. So they followed patients with scans on a regular basis. There are clear guidelines when you have the suspicion and you have the diagnosis of interstitial lung disease. So I think that we still see some cases about 15% Grade 1, Grade 2, there was one Grade 5, it’s unfortunate, but we can manage much better today. In terms of nausea and vomiting, we know that they exist and if it is drug fatigue as well, we can manage that. And another thing that raised concern in the beginning, whether this would increase the cardiotoxicity, it did not. So, from the cardiac standpoint it’s safe, for the interstitial lung disease I think you learned much better how to early diagnose, how to treat those patients and how to prevent a fatal or a Grade 3 or higher toxicity.

Matteo Lambertini: 
So we can say that in terms of nausea and vomiting, we should manage this drug as a drug with moderate ematogenic potential, so at least using two agents as prophylaxis for nausea, starting from cycle one. And then from the lung toxicity, maybe it’s important to discuss with the radiologist the imaging, not only from a RECIST perspective, but also to look into this potential toxicity, Grade 1, mostly asymptomatic that we can see with the CT scan. Then it’ll be another issue for the early setting where we have already trials ongoing, but this will be discussed at next conferences. So final question on the ADC, because yesterday we had the presentation of the TROPiCS-02 trial with another ADC, sacituzumab govitecan in the same setting. So patient with hormone receptor positive, HER2-negative disease as the DESTINY-04 trial, but it’s a bit more heavily pre-treated patient population.

Matteo Lambertini: 
So patient receive a median of three chemotherapy lines before entering the trial. It was only one in DESTINY-04, so a bit more pre-treated patient population. Also this ADC demonstrated significant improving in progression-free survival. So the study met its primary end points, a positive trial, however, how to interpret this data after seeing the T-DXd data of DESTINY-04 is a bit more complex. It’s just 1.5 month improvement in median progression-free survival, no overall-survival gain with these agents. So how should we interpret this data? Can we sequence these agents?

Evandro de Azambuja:
Yeah. So this is an interesting question. We’ve seen that sacituzumab govitecan can improve progression-free survival, overall-survival in the triple negative population. But in this TROPiCS-02, the heavily-pre treated hormone receptor positive, HER2-negative, we see a statistically significance, but the question is this clinically meaningful 1.5? We still have to see data on the impact of quality of life on those patients that was not presented, we need to know that. We need to understand which is the impact in costs as well. I think it is… We need to have a little bit more information, we have to wait a little bit longer to say this is a standard of care, and you need to see how we are going to use this agent in clinical practice because you have other chemotherapies, indeed improves progression for survival, but it’s still no overall survival benefits. We do not have information in quality of life in this trial. So might be that it becomes in the future a possibility of treatment for patients, but I think this is too immature, you have to have a longer follow-up on those patients.

Matteo Lambertini:
So now Evandro, switching topic and going to the CD4/6 inhibitor, I think we have two important trials to be discussed. I will start first with the PALOMA-2 trial, just reminder to all colleagues, this is the pivotal study with palbociclib in the endocrine sensitive patient population. So first-line treatment, addition of palbociclib on the top of an aromatase inhibitor first line endocrine-sensitive disease. So we have data from ribociclib trial, as well as abemaciclib data in this same setting where we have a gain in over-survival it is statistically significant for ribociclib, not statistically significant for abemaciclib, but in terms of absolute gain, there are very similar these two trials with a median overall-survival beyond five years for both ribociclib and abemaciclib. So we were waiting for the palbociclib data and what we see is that we don’t have any evidence of an overall-survival improvement in PALOMA-2 with the performance of the endocrine therapy arm that is similar to what we see for the other two trials, but the CDK4/6 inhibitor arm does not exceed the 5-year median OS as we’ve seen with the other two drugs. So how to interpret in clinical practice this data? Can we still say that these are similar drugs? So as a class effect more than single agent effect. Going back also to the PFS data that are exactly the same for these three agents.

Evandro de Azambuja:
Yeah, that’s very interesting. You’ve raised a lot of questions during the presentation, after the presentation. So as you mentioned, the three drugs, they have a similar benefit in progression-free survival. Today, we have in first-line, second-line, we have different trials with ribociclib, abemaciclib and palbociclib. In first-line we have improvement in overall-survival, with ribociclib, in second-line as well. We have three trials with ribociclib showing improvement in overall-survival. We have one trial with abemaciclib showing improvement in overall-survival. And for the moment you don’t have any trial, and I don’t think you’re going to have trials, with palbociclib showing improvement in overall-survival, they are all negative, they didn’t show improvement. In terms of PFS, three drugs, they have a similar benefit. In terms of overall-survival, only two drugs could demonstrate. And the story of palbociclib is also interesting to look for the trials that have been testing this drug in the adjuvant setting in a high-risk patient population, hormonal receptor positive, HER2-negative. In the post-neoadjuvant setting patients are high-risk with residual disease. This drug also did not show improvement in disease-free survival. So this drug can show improvement to progress-free survival, but you cannot translate to overall-survival. So our feeling that the three drugs are not the same, although palbociclib and ribociclib, if you look biochemically, they’re very similar, but I think they are still different. Might be because how they bind to the CDK4 and to the CDK6, that might be a difference that explains those results. But I think today you have to really discuss with your patients, explain the data, and I think you need to give them the drugs that give the most benefits for patient progression-free survival and overall-survival. That would be what they’re going to do today.

Matteo Lambertini: 
And then the final point I wanted to discuss is the MAINTAIN trial, which is a very important clinical question, what to do in patient progressing on CDK4/6 inhibitor. So this trial, the concept of this study, this is a small study, 120 patients randomized, after progressing on first-line endocrine therapy plus CDK4/6 inhibitor randomized to go for endocrine therapy alone. So our current standard of care outside the PIK3CA-mutated population, or to continue CDK4/6 inhibitor beyond progression, like what we have seen with anti-HER2 agents, in the HER2-positive disease. And the CDK4/6 inhibitor was ribociclib in this trial. And the endocrine therapy partner of course, was changed as compared to what the patient received first-line. So if first line was Fulvestrant, then the second line was exemestane. If AI first-line, then was fulvestrant second-line. The trial was positive, it met its primary endpoint of PFS, actually almost a doubling in median PFS with the addition of a CDK4/6  inhibitor beyond progression on endocrine therapy, plus CDK4/6 inhibitor. And the second important message from this trial is that the performance of endocrine therapy, in patient progressing on a CDK4/6 inhibitor is very poor. It’s around 2.5 month median PFS. So what’s your take on this trial, Evandro? And do you think this is something that we should potentially apply in clinical practice based on this trial?

Evandro de Azambuja: 
That’s a very interesting question. When we started treat the patients with CDK4/6 inhibitors and they had excellent response, then they progressed, the question to us was clinically always, should we just change the endocrine therapy and keep the CDK4/6 inhibitors to try to prolong? And this is what the trial did, they gave a ribociclib, they changed the endocrine therapy. This is still a positive trial progress-free survival, it is very impressive, but it’s still very small Phase II randomized trial. So I cannot say for sure that you can change all clinics today based on the trial, but certainly it is hypothesis generation. I think for selected patients, you could consider today giving continued CDK4/6 inhibitors and change endocrine therapy, because as you mentioned, endocrine therapy alone, the progression-free survival is very poor. You see less than three months in those patients. I think you need to give something more to those patients. Of course, for those with PI3K mutation, you go for alpelisib, for those who are BRC1 mutated or BRC2 mutated can go for PARP inhibitors. But for those who do not have this option, I think you may consider in some cases where you don’t have a big burden of progression, you have small progressions, you may consider this to keep CDK4/6 inhibitor and change the endocrine therapy. I think it could be very interesting for practice. This is something that we do with HER2-positive diseases like you mentioned. And I think it’s something you could consider doing for the CDK4/6 inhibitors.

Matteo Lambertini: 
But also on this topic, we are just at the beginning of the story because there are other trials exploring the same strategies. So we will have more data in the upcoming conferences on this topic. So Evandro, thanks a lot for discussing these important studies. I think it’s a great ASCO conference where we had very important presentation that we really improved the way we take care of patients with advanced breast cancer.

Evandro de Azambuja:
Yeah. Thank you very much. I fully agree with you, Matteo.

Disclosures

Recording date: 06-June-2022; Feature publication date: 17-June-2022.

Matteo Lambertini

Dr Lambertini reports the following conflicts of interest:
Consulting/Advisory Boards: Roche, Lilly, Novartis, AstraZeneca, Pfizer, Seagen, Gilead, MSD, Exact Sciences
Speaker honoraria: Roche, Lilly, Novartis, Pfizer, Takeda, Ipsen, Sandoz, Libbs, Knight
Travel support: Gilead

Evandro de Azambuja

No disclosures provided