Second-line trastuzumab deruxtecan for metastatic HER2-positive breast cancer: Interview with Javier Cortés

Prof. Javier Cortés is head of breast cancer and gynaecological cancers, as well as Clinical Investigator in the breast cancer research program, at Vall d’Hebron Institute of Oncology in Barcelona, Spain. He is one of the European leaders in the field of HER2+ breast cancer, and has led fundamental trials that resulted in the approval of pertuzumab, eribulin and everolimus for metastatic breast cancer. Prof. Cortés is on the Scientific Committee of ESMO and is an active member of ASCO and the Spanish Society of Medical Oncology.

Prof. Cortés presented the results of the DESTINY-Breast03 trail in the Presidential Symposium at the European Society of Oncology annual meeting in September 2021. Medicom Medical Publishers interviews him about the impact of those results on breast cancer care today.



 

Medicom: Thank you so much for joining us today, Prof. Cortes, can you comment on the importance of  the DESTINY-Breast03 trial you presented at ESMO 2021?

Thank you very much. The open-label randomised DESTINY-Breast03 trial is the first phase 3 trial comparing trastuzumab deruxtecan (T-DXd), a novel anti-HER2 antibody-drug, with trastuzumab-emtansine (T-DM1) head-to-head. As you know, we have made terrific improvements in the prognosis of HER-2 positive metastatic breast cancer. However, even today the great majority of our patients will die because of the disease. There is obviously still an unmet need.

When we look at the history of metastatic breast cancer, we see that the standard of care in the first line setting has been the combination of trastuzumab, pertuzumab and taxane. This therapy is based on the CLEOPATRA trial (NCT00567190), which demonstrated a median progression-free survival of 18.7 months. The standard-of-care in the second line setting is still based on the fundamental data of the EMILIA trial (NCT00829166), which showed a median progression-free survival of 9.6 months. However, this trial was published many years ago, by Sunil Verma (MD) in 2012. When we look at the more recent clinical trials and real world evidence studies, we can see that with T-DM1, the median progression-free survival now ranges between six to seven months at best. Luckily, novel treatments are coming. We have promising data from the DESTINY-Breast01 trial NCT03248492, a large phase two study investigating the efficacy of trastuzumab deruxtecan (T-DXd), in HER2-positive patients in the third line or beyond. In this heavily treated population, the overall response rate was approximately 61%, with a median progression-free survival rate of 16.4 months.

Following this trial, a head-to-head randomised phase 3 trial was conducted, called DESTINY-Breast03 (NCT03529110). Patients with unresectable or metastatic HER-2 positive breast cancer, previously treated with taxane and trastuzumab were randomised in a one to one fashion to either T-DM1 or T-DXd. Key primary endpoint was the progression-free survival as assessed by blinded independent central review. Key secondary endpoint was overall survival. Other secondary endpoints were the overall response rate, the duration of response, and investigator-assessed progression-free survival. A total of 524 patients were randomised. Baseline characteristics of interest were that approximately 2% of patients had a history of brain metastases and about 70% of patients had B-cell disease. In addition, 89% of patients were categorised as HER-2 3+, according to the central analysis that was mandatory to be enrolled in this study. Also notably, 8-10% of the patients did not receive prior treatment for metastatic disease. At ESMO, we presented the interim analysis of the trial.

 

Medicom: Can you comment on the spectacular efficacy data of this trial?

At a median follow-up of 16 months, the progression-free survival was 6.8 months for T-DM1 receivers. It was not reached for T-DXd. The corresponding hazard ratio was 0.28, with a p-value of 7.8 × 10^^-22. The progression-free survival rate was 34% for T-DM1 users and 76% for TDX-d users. By investigator review, the median progression-free survival was 25.1 months with T-DXd and 7.2 months with T-DM1. Corresponding hazard ratio was 0.26, with a P-value of 6.5 × 10^-24. When you look at the progression-free survival in all key subgroups; prior pertuzumab or not, B-cell or no B-cell disease, prior lines of therapy, and the presence of brain metastasis, we observed that all subgroups benefitted equally. The secondary endpoint, 12 months overall survival, was 94% in patients treated with T-DXd and  86% in patients treated with T-DM1, with a hazard ratio of 0.56 and a p-value of 0.007. This result did not cross the pre-specified boundary for superiority at this interim analysis. Lastly, an overall response rate was observed in about 80% of the patients treated with T-DXd compared to 34% of the patients treated with T-DM1.

 

Medicom: That 80% overall response rate in previously treated patients is quite impressive.

It's not only the 80%, as you point out. It's also the 16% of patients that showed a complete response. And what is much more impressive in my opinion, is that only three patients in the T-DXd arm (1.1%) did have progressive disease as best response, compared with 17.5% in the T-DM1 arm.

 

Medicom: So why is it TDX-d is so much better than TDM-1?

I cannot answer that question just yet. However, there are four differences between the two drug types I would like to highlight. First, the payload is completely different. In T-DM1 the payload is an antibody-conjugatable maytansinoid, whereas in T-DXd  the payload is a topoisomerase-1-inhibitor. Next, T-DXd demonstrates a higher drug-to-antibody ratio, 8:1, compared with T-DM1, 3.5:1. Another point of interest is the cleavable linker. In T-DXd, the linker is stable in plasma and has a short systemic half-life. This decreases the drug’s capacity for toxicity. In addition, T-DXd is selectively cleaved by lysosomal cathepsins. And these lysosomal cathepsins are much more expressed in tumour cells compared to normal cells. Finally, we observe that the payload of T-DXd is membrane-soluble and can affect neighbouring cells, creating a bystander antitumor effect. Something that does not happen with T-DM1.

 

Medicom: Obviously we're all wondering what this does in first-line metastatic disease. But what about early disease? Can we think about this as a potential post neoadjuvant treatment for residual disease?

That's a good question. There are two ongoing clinical trials that are addressing this issue. One of them is targeting metastatic disease in the first-line setting. Basically, it compares the regimen of the CLEOPATRA trial with T-DXd plus pertuzumab. Another trial compares T-DXd head-to-head against T-DM1 in an adjuvant setting after non-pathological complete response, following a neoadjuvant approach. I expect that T-DXd will be superior to T-DM1 in these trials.

Medicom: The data you presented suggests that T-DXd is more suitable as an option in the second line instead of the third line. Do you think we can give T-DM1 to our patients after T-DXd?

What has happened in the history of breast cancer in particular, and in the history of cancer in general: when you have a good drug, this drug moves up a line.  As a consequence, the other drug will come after. I think that we will need to look at the activity of T-DM1 in real-world evidence studies to see what it looks like. I think that I might expect some degree of activity, because the payload is completely different than the payload of T-DXd. However, I don't know if we will have the 34-35% of responses that we have seen in the EMILIA trial and the THERESA trial (NCT03741088).

 

Medicom: At ESMO, there was a highlighted trial called the TULIP trial, investigating trastuzumab duocarmazine.  Can you put the results of this trial into context with the DESTINY-Breast03 data?

Just as we do not know the activity of T-DM1 after T-DXd, we do not know the activity of trastuzumab duocarmazine after T-DXd. When you look at the TULIP data, the progression-free survival endpoint was achieved, with a hazard ratio of 0.64. The overall response rate of trastuzumab duocarmazine (28%) was identical to T-DM1. However, almost 80% of the patients showed toxicity of any grade. Toxicity grade three or higher was reported in 21.2% of the patients. In addition, 2% of the patients had a fatal event. So, I think trastuzumab duocarmazine is a tough drug and we have to learn how to manage it. Therefore, my answer is very clear. T-DM1 is a better option to be explored compared with trastuzumab duocarmazine after T-DXd, at this point in time.

 

Medicom: One thing that puzzled me, although the interstitial lung disease (ILD) numbers were actually quite low on this DESTINY-Breast03 trial, there was a fairly high discontinuation rate. Could you comment on that?

It is true that we observed more discontinuations in the T-DXd arm (12 to 13%) than in the T-DM1 arm (5%). The great majority of this difference could indeed be addressed to cases of ILD pneumonitis. Fortunately, most of these cases were grade 1 or 2. Only two patients, 0.8%, demonstrated grade 3 pneumonitis and no grade 4 or 5 pneumonitis occurred. Nonetheless, we have to learn how to manage this grade 2 pneumonitis ILD issue in the future. All in all I would say that the impressive improvement in activity provided by T-DXd nominates this drug as a potential next standard-of-care in the second-line setting, despite having 13% of discontinuations.

 



Posted on 12 October, 202118 November, 2021