Sara Tolaney, MD, MPH, discusses the recent FDA approval of T-DXd and pertuzumab for HER2-positive breast cancer and its supporting data.
Fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) combined with pertuzumab (Perjeta) was approved by the
Patients in the trial had advanced or metastatic HER2-positive breast cancer and received either T-DXd plus pertuzumab (n = 383), T-DXd plus placebo (n = 387), or THP (n = 387).2 Regarding efficacy, patients in the T-DXd plus pertuzumab arm experienced a median progression-free survival (PFS) by blinded independent central review (BICR) of 40.7 months (95% CI, 36.5-not estimable [NE]) compared with 26.9 months (95% CI, 21.8-NE) for the THP arm, resulting in a 44% reduction in the risk of disease progression or death (HR, 0.56; 95% CI, 0.44-0.71; P < .0001).1
Additionally, objective response rates (ORRs) among patients in the trial favored the T-DXd plus pertuzumab arm, at 87% (95% CI, 83%-90%) vs 81% (95% CI, 77%-85%) in the THP arm. Tolaney added that overall survival (OS) data from the trial still need more time to mature but show numerical trends in favor of the T-DXd plus pertuzumab arm.
“There are patients who do have excellent long-term outcomes with the [THP] approach, but the data with T-DXd and pertuzumab, which in essence show doubled PFS [rates], I think make [the combination] a new SOC,” Tolaney, chief of the Division of Breast Oncology and associate director for the Susan F. Smith Center for Women’s Cancers, and an associate professor of medicine at Harvard Medical School in Boston, Massachusetts, said in an interview with OncLive®.
In the interview, Tolaney not only underscored and expanded on the significance of the approval but outlined how this approval could affect the space in coming years.
Tolaney: I was excited to see the approval for T-DXd and pertuzumab in the first-line metastatic HER2-positive [breast cancer] setting. There was a profound impact on PFS where T-DXd and pertuzumab in essence, almost doubled PFS compared with the historic CLEOPATRA [THP] regimen. This [approval] does mark an important step forward as a new treatment option for our patients and will have impact on their long-term outcomes.
The DESTINY-Breast09 trial was a randomized phase 3 study that looked at T-DXd with or without pertuzumab compared with THP [also known as] the CLEOPATRA regimen. In essence, what was observed at an interim analysis was that the T-DXd and pertuzumab arm was superior to the THP arm. Median PFS for the T-DXd arm was 40.7 months compared with 26.9 months for the THP arm. This [improvement] was statistically significant and very clinically meaningful when you see the PFS in essence almost double with a hazard ratio [HR] of 0.56. The T-DXd monotherapy arm remains blinded, [because] the arm did not meet the stringent criteria that were set for superiority at the time of this interim analysis; [thus] we will have to wait for the [final] PFS analysis to see those data.
The combination of T-DXd and pertuzumab does [seem] to be a big improvement compared with the THP standard that we have had as a SOC for over a decade. It is nice to be able to see a new change [in the SOC] for patients.
What we saw with T-DXd and pertuzumab was that the combination did have a numerical increase in ORR compared with THP. Additionally, [we saw] an improvement in complete response [CR] rates, almost a doubling in CRs with T-DXd and pertuzumab compared with THP. [These data] are intriguing because we have always wondered if there may be a subset of patients that we could potentially cure in the metastatic setting. Seeing a higher CR rate at least is provocative [of this idea] and we will have to see how it pans out with longer follow-up.
OS data remain highly immature. There was a numerical trend favoring T-DXd and pertuzumab compared with THP, but again, these data do need longer follow-up.
We have been used to using THP in the frontline setting for over 10 years and it has remained a standard. However, the first-line metastatic HER2-positive breast cancer space has been dynamic. Several other trials also read out over the last year including the phase 3 PATINA trial [NCT02947685] which looked at adding palbociclib [Ibrance] to trastuzumab, pertuzumab, and endocrine therapy for patients with hormone receptor–positive, HER2-positive disease who completed taxane-based induction treatment. We also saw data recently at the
Both trials were positive studies, showing that maintenance strategies can improve PFS. I think [these data] do leave [the space] in a conundrum at this time about how to approach individual patients with metastatic HER2-positive disease when there are several different approaches one can take. We are still awaiting [FDA] approval of palbociclib based on data from the PATINA trial as well as tucatinib based on the HER2CLIMB-05 trial. [The treatment regimen from these trials] are not the SOC yet, but I assume [the data from these trials] will lead to FDA approvals, at which point the space will be faced with a challenge on how to personalize treatments.
It is nice to have options for patients, but for now T-DXd plus pertuzumab has yielded the longest PFS that we have seen in an unselected group of patients with HER2-positive disease who were not restricted based on estrogen receptor [ER] status or getting through induction therapy.2 [T-DXd plus pertuzumab] can work for the vast majority of patients upfront. This is important since [T-DXd plus pertuzumab also proved beneficial] irrespective of PI3K mutation status. [To reiterate,] benefits [for T-DXd plus pertuzumab] were seen across all subgroups of patients and I think that makes the combination a nice new SOC.
What we saw from DESTINY-Breast09 was that the combination of T-DXd and pertuzumab was better than THP in all subgroups of patients irrespective of hormone receptor status, PI3K status, and whether patients were de novo or recurrent. Considering this, with these new maintenance strategies there may be physicians who want to choose an optimal maintenance regimen if patients are ER-positive or HER2-positive. There may be physicians who prefer using THP induction followed by endocrine [therapy plus] HP and palbociclib.
The question is, how do you choose which patients receive which regimen? Obviously, we do not have great data [to answer this question] since the subsets in DESTINY-Breast09 suggested superiority across the board but were not tested head-to-head against these maintenance strategies. [Right now] we do not know the answer to this question, but what we do know is that patients with more aggressive disease like [those with] recurrent, PI3K-mutated or extensive visceral disease typically have shorter PFS to first-line therapy and may be at risk for not getting through induction therapy with a taxane-based regimen. This would make me nervous to approach these kinds of patients with an induction maintenance strategy rather than starting off with T-DXd plus pertuzumab in the first line. Using optimal therapies in frontline settings is critical.
Another situation where there may be pushes towards using T-DXd plus pertuzumab in the first-line setting is in patients with brain metastasis. We know that T-DXd has very robust efficacy in the central nervous system. We saw this in the results of the
T-DXd and pertuzumab works across all subsets but it is critical that physicians think about T-DXd and pertuzumab for patients who have more aggressive disease.2
We have seen that T-DXd and pertuzumab moved up in the metastatic setting over time, going from DESTINY-Breast01 [NCT03248492] with T-DXd having a later indication to DESTINY-Breast03 [NCT03529110] which moved T-DXd into the second line of therapy and now DESTINY-Breast09 which has moved T-DXd into the first line of therapy. What we are seeing is an evolution where T-DXd is now moving into the early-stage setting, with data from DESTINY-Breast11 [NCT05113251] showing that T-DXd administered sequentially with THP yields high pathologic CR rates of around 70%. Moreover, in DESTINY-Breast05 [NCT04622319] T-DXd reduced rates of recurrence by half compared with ado-trastuzumab emtansine [T-DM1; Kadcyla] in the residual disease setting. We are seeing benefits across all stages of HER2-positive disease, but what we are trying to understand is: can T-DXd also have efficacy in early-stage HER2-negative disease such as HER2-low tumors? We still have more to learn, but it is impressive that this agent has had such a profound effect on patient outcomes.
