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SAN ANTONIO -- Results from two randomized phase III trials supported the use of trastuzumab deruxtecan (T-DXd; Enhertu) as a second- or third-line standard of care in patients with metastatic HER2-positive breast cancer.

In the DESTINY-Breast02 study, treatment with T-DXd led to significant improvements in progression-free survival (PFS) and overall survival (OS) compared with a capecitabine-based regimen among patients previously treated with trastuzumab emtansine (T-DM1; Kadcyla).

In DESTINY-Breast03, T-DXd demonstrated a clinically meaningful and significant improvement in OS, as well as continuation of a PFS benefit that was seen in a previous analysis, compared with T-DM1 in patients previously treated with trastuzumab (Herceptin) and a taxane.

The studies were presented at the San Antonio Breast Cancer Symposium.

T-DXd was already considered the preferred option in the second-line setting for metastatic HER2-positive breast cancer based on the strength of an interim analysis of DESTINY-Breast03, which compared T-DXd to T-DM1, and in the third-line setting on the basis of DESTINY-Breast01, a single-arm phase II study that demonstrated robust activity of T-DXd in a post-T-DM1 setting.

Better in Third-Line vs Capecitabine-Based Regimens

DESTINY-Breast02 was designed as a confirmatory trial to DESTINY-Breast01, said Ian Krop, MD, PhD, of Yale Cancer Center in New Haven, Connecticut.

Among 608 patients with centrally confirmed metastatic HER2-positive breast cancer who were previously treated with T-DM1, median PFS was 17.8 months in the T-DXd arm versus 6.9 months in the arm that received treatment of physician's choice (TPC), corresponding to a 64% reduction in the risk of progression or death (HR 0.3589, 95% CI 0.2840-0.4535, P<0.000001).

At the 2-year landmark analysis, 42% of patients in the T-DXd arm were progression free compared with 13.9% of the TPC arm.

Because the PFS endpoint was statistically significant, OS was evaluated in a formal analysis. Median OS was 39.2 months versus 26.5 months in the T-DXd and TPC arms, respectively (HR 0.6575, 95% CI 0.5023-0.8605, P=0.0021).

The survival curves separated early, Krop noted. "Even at the 12-month time point, there was a substantial difference in survival: 89.4% of patients in the T-DXd arm were alive at the 1-year time point compared with 74.7% of patients on TPC."

The confirmed objective response rate also favored T-DXd over TPC (69.7% vs 29.2%, P<0.0001). Complete responses were observed in 14.0% and 5.0% of patients, respectively.

For this study, patients were randomized 2:1 to T-DXd or TPC, which consisted of either trastuzumab plus capecitabine or lapatinib (Tykerb) plus capecitabine.

"This was largely a third- and fourth-line patient population," Krop said. "All had prior trastuzumab and T-DM1 by design, and 78% had prior pertuzumab [Perjeta] ... all had essentially all of the targeted HER2 therapies that were available at the time the trial was being run."

The proportion of patients with serious treatment-emergent adverse events (TEAEs) was similar in the two arms (25.5% in the T-DXd arm vs 23.6% in the TPC arm). Drug discontinuation related to TEAEs occurred in 14.4% versus 5.1%, respectively, with pneumonitis (6.2%) and interstitial lung disease (ILD; 3.2%) being the most common reasons for discontinuation in the T-DXd arm. The overall rate of ILD with T-DXd was 10.4%, with two patients in this arm having grade 5 ILD.

Although this study assessed T-DXd in the third line, physicians should not wait until the third line to start T-DXd, "given the unprecedented efficacy of T-DXd in this trial and in previous trials," said Krop. "It would really be a shame for patients not to receive it just because you're waiting to use it in a later line, which they may never get to because of some unexpected event."

"That's why I think this study, while confirmatory, does not change our practice," he added. "T-DXd should still be used in the second-line setting in virtually all patients."

OS Superiority Over T-DM1

Updated results from DESTINY-Breast03 demonstrated continued superiority of T-DXd over T-DM1 for PFS, as well as significantly longer OS, reported Sara A. Hurvitz, MD, of the University of California Los Angeles.

The median PFS was 28.8 months in patients treated with T-DXd compared with 6.8 months for patients treated with T-DM1 (HR 0.33, 95% CI 0.26-0.43, P<0.000001). In the interim analysis, median PFS was not reached with T-DXd versus 6.8 months with T-DM1, and the risk of death or progression was reduced by 72% with T-DXd.

Median OS was not reached in either arm, but patients treated with T-DXd had a 36% lower risk of death than those treated with T-DM1 (HR 0.64, 95% CI 0.47-0.87, P=0.0037). At 12 months, 94.1% of patients in the T-DXd arm were alive, compared with 86% in the T-DM1 arm. After 24 months, OS rates were 77.4% and 69.9% for patients treated with T-DXd and T-DM1, respectively.

"In the T-DXd arm, it's notable that 35% of patients who came off treatment were able to go on and receive standard-of-care T-DM1," said Hurvitz. "In the T-DM1 arm, 17% of patients went on to receive standard-of-care T-DXd."

There were no grade 4/5 adjudicated drug-related ILD/pneumonitis events in the T-DXd arm. The rates of any-grade ILD/pneumonitis were 15.2% in the T-DXd arm and 3.1% in the T-DM1 arm. Median treatment exposure was much longer in the T-DXd arm than in the T-DM1 arm (18.2 vs 6.9 months), Hurvitz noted.

DESTINY-Breast03 included 524 patients previously treated with trastuzumab and a taxane in the metastatic or (neo)adjuvant setting with recurrences within 6 months of therapy. They were randomized 1:1 to T-DXd or T-DM1. Median follow-up was 28.4 months in the T-DXd arm and 26.5 months in the T-DM1 arm.

ILD a Concern, but Can Be Caught Early

Press conference moderator Carlos Arteaga, MD, of the Simmons Comprehensive Cancer Center in Dallas, asked Hurvitz if the risk of ILD would change her thinking about T-DXd's place in the treatment armamentarium for metastatic HER2-positive breast cancer and whether therapy with T-DXd could be re-initiated in patients who develop ILD and recover.

"It is interesting" that the rate of all-grade ILD increased with longer follow-up, Hurvitz responded.

"Most of the studies that have reported on T-DXd have reported, across histologies, rates around 15% of all-grade ILD," she said. "What's notable about this trial is the lack of deaths, the lack of grade 4 events. If you look at the time course and our use of T-DXd since it's become widely available in the last 2 to 3 years, I think we're becoming better at catching it early when it's asymptomatic."

She said that she holds therapy even with asymptomatic grade 1 ILD and doesn't resume it until resolution. "With grade 2, we completely stop therapy and should not resume therapy ever," she added. "There are investigations looking at whether or not we can safely retreat patients who had grade 2 that then resolved, but that should only be done in the context of a clinical trial."