T-DXd HER2-Positive Breast Cancer: DESTINY-Breast03

T-DXd HER2-Positive Breast Cancer: DESTINY-Breast03

DESTINY-Breast03 Phase 3 clinical trial Study Design for HER2-Positive Breast Cancer

This was a safety update from the DESTINY-Breast03 Phase 3 clinical trial, and as everyone is aware, trastuzumab deruxtecan, which is a medicinal conjugate consisting of an antibody, was approved for patients with HER2-positive metastatic breast cancer. This medication was included in the earlier line setting because of the DESTINY-Breast01 and DESTINY-Breast03 studies. Patients in the second-line scenario who have previously been treated with trastuzumab and/or taxane in a metastatic disease setting or who have experienced a rapid relapse within six months of completing neoadjuvant or adjuvant therapy are candidates for this medication. In addition, the purpose of this study was to revisit and examine a number of other safety factors.

What About the Efficacy From The DESTINY-Breast03 Trail?

Given that we have now completed a more in-depth follow-up. To be more specific, patients participating in the trial who were given trastuzumab deruxtecan have now completed more than 16 months of treatment, during which time we analyzed a number of important and serious side events.

Therefore, when we compare trastuzumab deruxtecan and T-DM1 with regard to treatment-related adverse events of grade three or higher, we find that they are extremely comparable to one another. Side effects that led to treatment discontinuations were a bit higher with trastuzumab deruxtecan in the control arm (for prolonged disease control and the primary endpoint in a single arm phase), about 14.8%, as compared to 7.3% with T-DM1, and in essence, it was 8% of patients with ILD pneumonitis that had to discontinue drug on trastuzumab drug Tocan that was driving that difference between the arms (single arm phase).

We also saw that nausea, vomiting, and alopecia, which is another name for hair loss, were more common with trastuzumab deruxtecan, but fatigue was rather comparable between trastuzumab deruxtecan and T-DM1.

 

We know that the worst episodes of nausea and vomiting occur during the first few cycles of pregnancy, but that they eventually subside and become more manageable. This highlights the importance of anti-medic preventive drugs for our patients at the beginning of the trial, and they have to be continued throughout the course of the study. Exposure-adjusted incident rates for EAIRs are a standardized measure of risk per patient ear, which is one of the unique things that we looked at as part of the safety update. This was one of the more interesting things that we looked at.

 

In clinical studies with long-term follow-up, where the level of follow-up between the two arms may vary, this is a technique that is frequently utilized to examine patient safety. The exposure-adjusted incidence rates appeared pretty advantageous for trastuzumab deruxtecan compared to T-DM1, with one exception. This was something that we noticed across the board, and it was fairly surprising. These were the occurrences that prompted the patient to stop receiving treatment.

 

In addition to this, once more, it was the 8% of people who had ILD pneumonitis. Regarding the ILD pneumonitis, conducting follow-up examinations was an essential step for us. And what we found is that this occurs in approximately 10.9% of people who are being treated with trastuzumab deruxtecan, but it is predominantly a moderate grade 1 or grade 2 occurrence. For example, there have been no grade 4 or grade 5 cases of ILD pneumonitis, which is a significant departure from the results of our first trial, which was called DESTINY-Breast01. And in fact, even grade 3 events are 0.8%. That comes to less than 1%. And because of this, we now have a significant amount of assurance that the trust we are extending is warranted.

Patients who are being treated for ILD pneumonitis with trastuzumab deruxtecan

Patients who are being treated for ILD pneumonitis with trastuzumab deruxtecan, which is an antibody drug conjugate, in the early aligned settings and with increased recommendations about acknowledging holding medicine are doing fairly well. People have a lot of questions, but one of the most prevalent ones is regarding feeling sick and throwing up. I believe that this will be the most noticeable adverse impact that patients will experience as a result of this treatment. When patients were being enrolled in the destiny Bristo three study, there were no mandatory prophylactic anti-medics. This meant that people did not necessarily start nausea medications before they started drug. However, given that we now know that trastuzumab deruxtecan is moderately a mitogenic agent, it is recommended to have a multi-drug anti-medic regimen upfront.

 

In addition to this, the information is really mentioned on the label for trastuzumab deruxtecan. As a result, we often administer an NK-1 in conjunction with either 5-HT3 dexamethasone or a steroid at my medical practice as well as in a number of other locations around the United States. In all honesty, it’s a three-drug treatment plan for nausea. And I believe that now that we are doing that, we are actually able to get a handle on nausea really early on, and our patients will not have to fight as much with this particular side effect.

 

ILD pneumonitis is the topic of another query that we hear rather frequently. This is due to the fact that in the preliminary DESTINY-Breast01 research (human breast cancer, HER2-positive breast cancer), there were multiple occurrences of ILD pneumonitis that were either fatal or grade 5. When the medicine was still in its very early stages of cancer research, it wasn’t fully understood that this may potentially be a very dangerous adverse effect in the field of medical oncology.

 

Now that more people are aware of this issue, there have been more recommendations made for monitoring. We have truly been able to eradicate this problem by holding the medicine, determining when to restart treatment, and figuring out how to manage ILD pneumonitis. There are no cases of grade 4 or grade 5, and the percentage of grade 3 cases has remained below 1%. Therefore, I believe that we have reached a point where we are considerably more at ease when discussing ILD pneumonitis. It is unquestionably something that we need to be on the lookout for, and it is something about which we warn our patients; nevertheless, we are now in a position in DESTINY-Breast03 to be able to control it very successfully (breast cancer).

Will this aid with progression-free survival?

The question that needs to be answered is whether or not this will aid with progression-free survival. In the field of clinical oncology, how exactly would this aid to halt the progression of breast malignancies, namely advanced breast cancer, in this particular patient population? And will this aid physicians and their patient population in clinical oncology, in patients suffering from metastatic breast cancer?

 

This material is most certainly relevant in the present day. Therefore, we have had approval for trastuzumab deruxtecan for these two patients for a considerable amount of time. Now, only very recently, in May of 2022, we got the expanded indication in the second line therapy for patients with HER2-positive metastatic breast cancer, and as a result, more knowledge about the drug’s safety.

 

What Was The Supporting Efficacy Clinical Data?

Tolerability, which helps progression-free survival, and how to manage side effects including nausea and vomiting, as well as how to monitor for inflammatory liver disease (ILD), are immediately useful to doctors.

When compared to T-DM1, trastuzumab deruxtecan was demonstrated to have a 72% lower risk of disease progression, which resulted in an enlarged indication.

Additionally, in the (metastatic) breast cancer trial DESTINY-Breast03, trastuzumab deruxtecan showed a 72% reduction in the risk of death from the disease. The trastuzumab deruxtecan DESTINY-Breast04 (breast cancer) plenary presentation was given at ASCO, and all of us are aware of it. Patients who have a low HER2 level are recommended to use it.

What is the Next Stage For The DESTINY-Breast04 Phase 3 Trial?

In patients who are dealing with HER2-positive metastatic breast cancer, there are now many trials that are looking into the possibility of bringing trastuzumab deruxtecan up into even earlier treatment lines. Therefore, there are currently first-line trials being conducted.

Neoadjuvant trials with trastuzumab deruxtecan are now being conducted for patients with HER2-positive (cancer cells) illness. Will this have an effect on the clinical benefit rate in this patient population when looking at progression-free survival?

In addition, adjuvant trials are being conducted for patients with metastatic breast cancer who may not have a pathologic full response and who are still at a high risk for recurrence.

Therefore, I do not believe that we have heard the last of trastuzumab deruxtecan. I believe that we will continue to see this being used in a variety of contexts for our patients who have HER2-positive metastatic breast cancer, HER2-positive early breast cancer, and other types of disease.

Five Stats About the DESTINY-Breast03 Phase 3 Trail In Patients with Breast Cancer

1. Among 524 randomly assigned patients, the percentage of those who were alive without progression of the disease (for progression free survival) at 12 months was 75.8% (95% confidence interval [CI], 69.8 to 80.7) with trastuzumab deruxtecan and 34.1% (95% CI, 27.7 to 40.5) with trastuzumab emtansine (hazard ratio for progression or death from any cause, 0.28; 95% CI, 0.22 to 0.37; P<0.001).

2. An overall response (a complete or partial response) occurred in 79.7% (95% CI, 74.3 to 84.4) of the patients who received trastuzumab deruxtecan and in 34.2% (95% CI, 28.5 to 40.3) of those who received trastuzumab emtansine.

3. The incidence of drug-related adverse toxicities of any grade was 98.1% with trastuzumab deruxtecan and 86.6% with trastuzumab emtansine, and the incidence of drug-related adverse toxicities of grade 3 or 4 was 45.1% and 39.8%, respectively. Adjudicated drug-related interstitial lung disease or pneumonitis occurred in 10.5% of the patients in the trastuzumab deruxtecan group and in 1.9% of those in the trastuzumab emtansine group; none of these events were of grade 4 or 5.

4. The approval by the Food and Drug Administration (FDA) was based on positive results from the DESTINY-Breast03 Phase III trial that showed Enhertu reduced the risk of disease progression or death by 72% versus trastuzumab emtansine (T-DM1) (hazard ratio [HR] 0.28; 95% confidence interval [CI]: 0.22-0.37; p<0.0001) in patients with HER2-positive unresectable and/or metastatic breast cancer previously treated with trastuzumab and a taxane.

5. Based on ground-breaking DESTINY-Breast03 results showing Enhertu reduced the risk of disease progression or death by 72% versus trastuzumab emtansine (T-DM1)Approval broadens indication for AstraZeneca and Daiichi Sankyo’s Enhertu to earlier use in metastatic breast cancer

Recruitment Details In Patients With Breast Cancer

A total of 524 participants were enrolled in the trial and received systemic treatment at locations spanning 14 nations. The major outcomes that are shown here are from the very first participant who was randomly assigned to the study all the way up to the data cut-off date of May 21, 2021. The presented findings are derived from primary cancer research that was conducted over a period of 33 months. The collection of data is now under progress, and after the conclusion of the study, additional findings will be made public.

Trastuzumab Deruxtecan (T-DXd) Arm

T-DXd was administered as a sterile intravenous (IV) solution at a dose of 5.4 mg/kg every three weeks to participants with HER2-positive, unresectable, or metastatic breast cancer who had previously received trastuzumab and taxane (Q3W).

Ado-trastuzumab Emtansine (T-DM1) Arm

Participants with HER2-positive, unresectable, or metastatic breast cancer who had previously been treated with trastuzumab and taxane and who were then given T-DM1 in accordance with the authorized label were included in the study.

Erika Hamilton, MD – About The Author, Credentials, and Affiliations

Principal Investigator of the Breast Cancer and Gynecologic Cancer Research Programs and a Clinical Oncologist by Profession

In 2013, Dr. Hamilton first started collaborating with Sarah Cannon. Patients suffering from breast cancer and gynecologic cancer are among those whom Dr. Hamilton treats. As the director of the breast cancer and gynecologic cancer research program at Sarah Cannon, she is in charge of managing both the program and the clinical trial menu for these types of cancer across the whole Sarah Cannon network.

Dr. Hamilton attended Washington and Lee University in Virginia for her undergraduate studies before moving on to the University of North Carolina in Chapel Hill for her medical schooling and residency. Dr. Hamilton is a board-certified internal medicine physician. She finished her training in hematology and oncology at Duke University in Durham, North Carolina. While there, she was recognized as one of the Top 5 Finalists for Duke’s Annual House Staff Fellow Teaching Award. Internal medicine and medical oncology are both areas in which she has earned board certifications (breast cancer). Additionally, she holds a partnership position at Tennessee Oncology, PLLC.

AstraZeneca and Daiichi Sankyo DESTINY-Breast Cancer Trials

Daiichi Sankyo and AstraZeneca entered into a global agreement in March 2019 to jointly develop and commercialize Enhertu (a HER2-directed ADC) and datopotamab deruxtecan. The deal does not apply in Japan, where Daiichi Sankyo has exclusive rights, but does apply everywhere else (DS-1062; a TROP2-directed ADC). Daiichi Sankyo is the company that manufactures and distributes both enhertu and datopotamab deruxtecan.

Reference

1. The New England Journal of Medicine – Trastuzumab Deruxtecan versus Trastuzumab Emtansine for Breast Cancer. The New England Journal of Medicine Article, 2022

2. Clinical Trials .Gov – DS-8201a Versus T-DM1 for Human Epidermal Growth Factor Receptor 2 (HER2)-Positive, Unresectable and/or Metastatic Breast Cancer Previously Treated With Trastuzumab and Taxane [DESTINY-Breast03]. NCT03529110, April 29, 2022