CME
Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™
Released: March 17, 2023
Expiration: March 16, 2024
Joyce O’Shaughnessy, MD:
Krop and colleagues presented the results of the DESTINY-Breast02 trial for the first time. This phase III trial enrolled HER2-positive patients with metastatic breast cancer who had previous treatment with T-DM1.36 The enrolled patients were randomized 2:1 to receive T-DXd or physician’s choice of trastuzumab/capecitabine or lapatinib/capecitabine. The primary endpoint was centrally assessed PFS.
Joyce O’Shaughnessy, MD:
In this trial, approximately 40% and 60% of the patients had HR-negative and HR-positive disease, respectively. Nearly 80% in each treatment arm had visceral disease.
Joyce O’Shaughnessy, MD:
Nearly all of the patients had at least 2 previous lines of therapy for their metastatic breast cancer, with the majority having received 2 or 3 previous lines. By study design, 100% had previous T-DM1, and nearly 80% in each treatment arm had previous pertuzumab.
Joyce O’Shaughnessy, MD:
The primary endpoint of PFS was significantly better with T-DXd, with a median PFS of 17.8 months vs 6.9 months with treatment of physician’s choice. OS was also significantly improved with T-DXd, with a median OS of 39.2 months with T-DXd vs 26.5 months with treatment of physician’s choice. The hazard ratios were striking: 0.36 for PFS and 0.66 for OS. This is yet another study showing a significant improvement in OS with T-DXd compared with other standard HER2-targeted therapies—in this case, T-DM1.
Joyce O’Shaughnessy, MD:
Among the secondary endpoints, the ORR and clinical benefit rate were also dramatically higher with the T-DXd compared with the physician’s choice treatment: 69.7% vs 29.2% and 82.3% vs 46.0%, respectively.
Joyce O’Shaughnessy, MD:
No new safety signals emerged in this study. There were a few discontinuations of T-DXd because of pneumonitis (6.2%) and ILD (3.2%), but I think we are improving at understanding who needs to permanently discontinue T-DXd and initiate steroid treatment. Overall, there were 4 deaths on T-DXd.
Joyce O’Shaughnessy, MD:
The TEAEs show an expected toxicity profile, with no other new safety issues identified.
Joyce O’Shaughnessy, MD:
ILD and LV dysfunction are both AEs of special interest with T-DXd. Especially when using T-DXd as a later-line therapy, we do see a small number of ILD-related deaths. On this trial, there were 2 drug-associated deaths on T-DXd from ILD.
Joyce O’Shaughnessy, MD:
The DESTINY-Breast02 data add to the evidence that T-DXd offers very substantial improvement in PFS and OS as a later-line treatment in HER2-positive metastatic patients. We are still awaiting data on T-DXd in the first-line setting (DESTINY-Breast09, NCT04784715). With T-DXd as the standard of care in the second-line setting, as we will discuss next, I do not think these data have much clinical relevance because we will be more likely to use T-DXd before T-DM1 rather than after. However, I do think this trial shows us that we can expect to see more cases of ILD the later in treatment we use T-DXd.
Sara A. Hurvitz, MD:
I agree. I think these data are very important. They confirm the findings from the very first single-arm study, DESTINY-Breast01, where patients were more heavily pretreated.
The only place I would use these data in the clinical setting are for my patients who have been doing well on their second- or third-line therapy and have already received T-DM1. DESTINY-Breast02 gives us reassurance that using T-DXd after T-DM1 will still improve PFS and OS compared with another strategy such as lapatinib- or capecitabine-based therapy.
Sara A. Hurvitz, MD:
I do agree with your point that most of our patients are now going to get T-DXd in an earlier setting based on the results of DESTINYBreast-03. This phase III clinical trial randomized patients with HER2-positive metastatic breast cancer who had previously received trastuzumab and a taxane to receive T-DXd or T-DM1. These data were first presented at the European Society for Medical Oncology Congress in 2021, where PFS was shown to be significantly longer with T-DXd vs T-DM1.37 At that time, the median PFS was not yet reached with T-DXd and the OS data were not mature, so these data were updated at SABCS 2022.38,39
Sara A. Hurvitz, MD:
Approximately 40% of patients in this study had received 1 previous line of therapy, but approximately 60% had received ≥2 previous lines of therapy for metastatic disease. In a way, this study complements the data from DESTINY-Breast02 because some patients in this trial had received more lines of therapy. Approximately 60% of patients here had previously received pertuzumab.
Sara A. Hurvitz, MD:
In this updated analysis at a median follow-up of 28.4 months, the median PFS for T-DXd has now been met and was 28.8 months, which I believe is the longest PFS noted to date for metastatic HER2-positive breast cancer, and, of note, in a more heavily pretreated setting. This compared favorably with T-DM1, for which the median PFS was 6.8 months. This improvement was highly statistically significant, with a hazard ratio of 0.33.
Sara A. Hurvitz, MD:
At this second OS interim analysis, neither arm had reached the median OS, but there was a statistically significant improvement with T-DXd compared with T-DM1, with a hazard ratio of 0.64.
Sara A. Hurvitz, MD:
All of the analyzed subgroups appeared to have an OS benefit from the use of T-DXd. This includes HR status, visceral disease, and previous pertuzumab.
Sara A. Hurvitz, MD:
The ORR with T-DXd was nearly 80%, which was more than double that seen with T-DM1 (35.0%). With T-DXd, 21% of patients had a CR vs 10% of patients with T-DM1. For those who had a response with T-DXd, the median duration of response was slightly more than 3 years (36.6 months).
Sara A. Hurvitz, MD:
The safety summary appeared similar to the previous report. With the longer treatment duration, rates of treatment-related discontinuations and AEs related to longer exposure have increased as well. At this longer follow-up time point, however, there were no ILD-related deaths, as adjudicated by a committee. There were no grade 4 ILD events nor any additional grade 3 events since the previous analysis.40 There were a few additional grade 1 and 2 ILD events since the interim analysis, bringing the total incidence of ILD to 15%. As Dr. O’Shaughnessy mentioned earlier, I think we are getting better at looking for ILD on imaging in asymptomatic patients and stopping therapy immediately when needed, allowing us to mitigate the risk of serious ILD-related toxicities and deaths.
The analysis of treatment-emergent AEs also does not show any new safety concerns.
Sara A. Hurvitz, MD:
In summary, I think these data support the practice-changing data that we saw in the initial PFS presentation in 2021. The OS analysis now firmly indicates that T-DXd should be the gold standard therapy in the second-line setting for HER2-positive metastatic breast cancer. I am now looking forward to seeing the results from the ongoing phase III trial comparing T-DXd head to head with our standard first-line therapy of docetaxel/trastuzumab/pertuzumab.
Joyce O’Shaughnessy, MD:
I completely agree—these data are amazing, and T-DXd is our standard of care here.
One question for you, Dr. Hurvitz. Do you get regular surveillance CT scans on patients receiving T-DXd, even if you do not need to image the chest for cancer?
Sara A. Hurvitz, MD:
Yes, I use an every 6-8 week lung imaging regimen in patients on T-DXd, even for those who have had great clinical responses. ILD can occur even after patients have been receiving therapy for 1 year or longer. It can sneak up and show up as ground-glass opacities or infiltrates in the lung in an asymptomatic patient. If you see that, you want to take the opportunity to hold therapy and allow the patient to recover, at which point you can resume. But if a patient becomes symptomatic, T-DXd must be permanently discontinued.
Joyce O’Shaughnessy, MD:
The final study we will discuss is addressing our need for more treatment options for our HER2-positive patients with brain metastases. Currently, we may use the tucatinib triplet with capecitabine and trastuzumab, or T-DXd. The TBCRC 022 trial used a combination of neratinib plus T-DM1; neratinib is usually coupled with capecitabine, so it is interesting to see if this combination may benefit patients with brain metastases.
The trial enrolled several cohorts of patients with HER2-positive metastatic breast cancer with measurable brain metastases. This analysis focused on cohort 4: Cohort 4A included patients with previously untreated brain metastases; cohort 4B included progressive brain metastases after previous local CNS-directed therapy and T-DM1 naive; and cohort 4C included progressive brain metastases after previous local CNS-directed therapy with previous T-DM1.41 No previous neratinib was allowed. The primary endpoint in each cohort was the Response Assessment in Neuro-Oncology-Brain Metastases (RANO-BM).
Joyce O’Shaughnessy, MD:
These patients had received a median of 2 previous lines of chemotherapy in the metastatic setting, and none had received tucatinib. Of those with progressive brain metastases, approximately 50% to 70% had previously been treated with whole-brain radiation therapy and stereotactic radiosurgery.
Joyce O’Shaughnessy, MD:
The CNS response analysis shows that the neratinib plus T-DM1 doublet is active in HER2-positive brain metastases. In cohort 4C—the patients with progressive brain metastases and previous T-DM1—the CNS ORR was 28.6%. Among patients with progressive brain metastases and no T-DM1, it was 29.4%, and was 33.3% in those with untreated brain metastases.
Joyce O’Shaughnessy, MD:
This was a very small trial, but even so, we can see a potential OS benefit with the combination of neratinib and T-DM1. This combination may be an option in patients with brain metastases.
Joyce O’Shaughnessy, MD:
The treatment was associated with some diarrhea (32%), including grade 3 events (23%), but the overall safety appears to be acceptable. I did not notice any overlapping toxicity, so this seems to be a reasonable option.
Joyce O’Shaughnessy, MD:
To summarize, in HER2-positive patients, we saw from the DESTINY-Breast02 trial that T-DXd significantly improves PFS and OS compared with capecitabine/trastuzumab or capecitabine/lapatinib in T-DM1–pretreated patients. This may be useful for our patients who receive T-DM1 in the adjuvant setting.
Even more exciting are the updated results of DESTINY-Breast03, showing a significant improvement in OS and an incredibly long median PFS of 28.8 months with T-DXd in patients previously treated with trastuzumab and a taxane. Those who respond have a median duration of response of 3 years. These are incredible data in the second-line setting, and T-DXd is going to supplant T-DM1 as the preferred second-line therapy. By using T-DXd earlier in the treatment course and for a longer period of time, we must be aware that the percentage of patients who get ILD will also go up. There were no ILD-related deaths on this trial, however, and we can better manage this risk through chest CT surveillance to look for ILD in asymptomatic patients. That will allow us to interrupt T-DXd when needed, treat the ILD, and then resume T-DXd at a lower dose.
As shown in the TBCRC 022 trial, combining neratinib with T-DM1 is a clever strategy that may provide a relatively safe additional treatment option for our patients with brain metastases. Although there were small numbers of patients, approximately one third benefited with an objective response in the CNS, which is quite interesting. These patients had not previously had tucatinib, so this is an innovative way to use neratinib for the treatment of brain metastases without combining it with capecitabine.
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