T-DXd: ‘Remarkable’ Survival Gains in Advanced Breast Cancer

SAN ANTONIO —Trastuzumab deruxtecan (T-DXd, Enhertu) has yielded significant and clinically meaningful improvements in progression-free survival (PFS) and overall survival for patients with advanced HER2+ breast cancer when used as second-line and in later lines of therapy, new data confirm.

However, the reports also highlighted the potential problem of interstitial lung disease (ILD) as an adverse event associated with T-DXd, which requires close monitoring.

The findings come from the DESTINY-Breast03 and the DESTINY-Breast-02 trials and were presented here at the San Antonio Breast Cancer Symposium (SABCS) 2022.

DESTINY-Breast03 involved over 520 patients with previously treated unresectable or metastatic HER2+ breast cancer. The patients were randomly assigned to receive either T-DXd or the earlier-generation antibody-drug conjugate trastuzumab emtasine (T-DM1, Kadcyla).

The results, which were presented at the meeting and were simultaneously published in The Lancet, are an update of a previous interim analysis.

They showed that PFS increased by 77% and that overall survival improved by 36% with T-DXd when compared to T-DM1.

This represents a “clinically meaningful and statistically significant improvement in overall survival” as well as a “continued PFS benefit” for previously treated patients, said study presenter Sara Hurvitz, MD, Jonsson Comprehensive Cancer Center, University of California, Los Angeles.

With a “manageable and tolerable” safety profile, she believes these latest results demonstrate a “remarkable” PFS and overall survival benefit and that they further support the use of T-DXd as a “preferred second-line treatment” for patients with HER2+ metastatic breast cancer.

T-DXd is already approved by the US Food and Drug Aministration (FDA) for second-line use for patients with unresectable or metastatic HER2+ breast cancer who have received one prior anti-HER2 therapy. The approval was based on results from a prior interim analysis of DESTINY-Breast03.

These updated results are “amazing,” commented Álvaro Rodríguez-Lescure, MD, PhD, a medical oncologist at Elche General University Hospital, Elche, Alicante, Spain. “We are not used to seeing these PFS curves in metastatic breast cancer,” he said.

He was reacting to the presentation on Twitter. He said that the “bar is now high and the challenge will be to improve it,” although doing so will always be worth it, as patients “deserve more.”

Used in Later Lines of Therapy

The DESTINY-Breast02 trial was conducted in 600 patients who had already received multiple lines of therapy, including prior treatment with T-DM1.

Compared with a physician’s choice of two standard-of-care regimens, T-DXd was associated with a 64% improvement in median PFS and a 34% increased in median overall survival.

Study presenter Ian Krop, MD, PhD, chief clinical research officer at the Yale Cancer Center, New Haven, Connecticut, said this trial “definitely shows that T-DXd is active in the post-T-DM1 third-line setting,” although he added that “in oncology, we tend to use our best therapies earlier. We don’t hold them back.

“The main reason for that is, unfortunately, there’s significant attrition of patients from one line to another, meaning that a patient is not able to receive a next line of therapy after they progress because they either die of their disease or they develop some significant complication…that makes them unable to receive another line,” he explained.

This attrition rate, he explained, ranges from 10% to 30% with each line of therapy, and indeed, in the control arm of the current study, 30% of patients “were not able to receive a next line of therapy when they left the trial.”

Krop said that given the “unprecedented efficacy” of T-DXd in the second line (as shown in the DESTINY-Breast03 trial), “it would really be a shame for patients not to receive that drug just because you’re waiting to use it in a later line, which they may never get because of an unexpected event.”

Consequently, his results, although “confirmatory,” do “not change clinical practice,” he said. “T-DXd should still be used in virtually all patients [in second line] based on the DESTINY-Breast03 trial,” he added.

Improving on Past Results

Commenting on both trials, Rachel Abelman, MD, a senior fellow in the breast oncology group at Massachusetts General Hospital, Boston, told Medscape Medical News, “We’re all really excited about antibody-drug conjugates and expanding the space.

“Ever since the clinical use of T-DM1, we’ve seen that they can provide patients with clinical effectiveness and hopefully decreased toxicity” in comparison with previous treatment options.

She said that with T-DXd, the “goal” is to use it as second-line treatment in patients with advanced HER2+ breast cancer. Ongoing work includes seeing how T-DXd can be used “most effectively” and identifying patients “who qualify for multiple antibody-drug conjugates.”

Interstitial Lung Disease as Adverse Event

Both trials also highlighted a problem with T-DX therapy ― the occurrence of ILD as an adverse event, although the vast majority of cases were grade 1 or 2.

Hurvitz commented that it was “interesting” that rates of all-grade ILD increased over time, although “what’s notable…is the lack of deaths,” potentially as a result of clinicians “becoming better at catching it early when it’s asymptomatic.”

In cases in which ILD is asymptomatic and were observed only on scans, T-DXd is withheld and treatment with it is not resumed until ILD resolves, she explained. With grade 2 events, “we completely stop therapy and should not resume it ever.”

That, Hurvitz, is a “hard stop,” although her team is investigating whether treatment can be safely resumed in those patients. She cautioned that that should be undertaken only “in the context of a clinical trail.

“Moreover, we should as clinicians continue to follow CT scans of the lungs closely in our patients being treated with T-DXd, because this is an event that can occur even up to a year or longer of a patient being on therapy.”

Abelman agreed that ILD is “something that we are very mindful of” and is of paramount importance “as we consider what’s clinically best for a patient.

“Fortunately, the updated data showed that there were no grade 4 or 5 events,” which is “reassuring. “As we see more patients on these effective therapies, we’ll have more data to guide our decisions.”

Details of Results for T-DXd Used in Third Line

Krop reminded the meeting audience that T-DXd was shown in DESTINY-Breast01 (a phase 2 single-arm study) to have strong antitumor activity in the third line, including after treatment with T-DM1. The results lead to FDA approval of the drug for the treatment of unresectable or metastatic HER2+ breast cancer for patients who have received two or more prior anti-HER2-based regimens in the metastatic setting.

He explained that DESTINY-Breast02 was a randomized, multicenter, open-label, phase 3 trial that was launched as a confirmatory trial for DESTINY-Breast01.

Women with HER2+ resectable or metastatic breast cancer who have experienced documented radiographic progression after their most recent treatment and who had previously received T-DM1 were included and were randomly assigned to receive T-DXd or physician’s choice of trastuzumab plus capecitabine or lapatinib or capecitabine.

Overall, 406 patients were assigned to T-DXd and 202 to physician’s choice.

The median age of the patients was approximately 54 years. Just over half of tumors were hormone receptor (HR) positive, and just under a fifth of patients had brain metastases at baseline. Over three quarters had received two or three prior lines of therapy.

The median duration of follow-up was 21.5 months for patients treated with T-DXd and 18.6 months for patients in the physician’s choice arm. The median duration of treatment was 11.3 months with T-DXd, vs approximately 4.5 months with physician’s choice.

The primary endpoint of centrally adjudicated PFS was met, at a median of 17.8 months with T-DXd vs 6.9 months with physician’s choice (hazard ratio [HR], 0.36; P < .000001).

At 24.4 months, 42.2% of T-DXd patients were progression free. In the comparator arm, 13.9% were progression free.

These findings were seen in all key subgroups, including when patients were stratified patients by age, HR status, prior pertuzumab therapy, baseline brain metastases, and prior lines of therapy.

On the key secondary endpoint of overall survival, there was a significant improvement with T-DXd, at a median of 39.2 months vs 26.5 months with physician’s choice (HR, 0.66; P = .0021). At 24 months, 65.9% of T-DXd patients and 54.3% of physician’s choice patients were still alive.

In terms of safety, 41.3% of T-DXd patients experienced a drug-related grade ≥3 treatment-emergent adverse event (TEAE), vs 30.8% in the comparator arm.

Drug-related TEAEs that led to drug discontinuations were seen in 14.4% of T-DXd patietns and in 5.1% of physician’s choice patients. The most common such events with T-DXd were pneumonitis, in 6.2%, and ILD, in 3.2%. The most common event in the physician’s choice arm was palmar-plantar erythrodysesthesia, in 1.5%.

Specifically regarding drug-related ILD, Krop showed that with T-DXd, the median time to onset was 209.5 days and that the vast majority of the 42 cases were of grade 1 or grade 2, although there were three cases of grade 3 and two cases of grade 5 ILD.

Overall, the most all-grade common TEAEs were nausea (72.5%), vomiting (37.6%), alopecia (37.1%), and fatigue (36.4%) among patients assigned to T-DXd and diarrhea (53.8%), palmar-plantar erythrodysesthesia (51.3%), nausea (37.4%), and fatigue (26.7%) among those given physician’s choice.

Details of Results for T-DXd in Second Line

Hurvitz noted that DESTINY-Breast03 involved 524 women with HER2+ breast cancer who had been previously treated with trastuzumab and a taxane in the metastatic or (neo)adjuvant setting and who had experienced recurrence within 6 months of therapy.

The median age of the patients ws 54 years, and most came from Asia. They were randomly assigned to receive T-DXd or T-DM1. Approximately 15% had baseline brain metastases. Around 40% had received one prior line of therapy; just under 25% had received two.

The median follow-up was 28.4 months in the T-DXd arm and 26.5 months in the T-DM1 arm. the median duration of treatment was 18.2 months and 6.9 months, respectively.

The updated results showed that the median centrally adjudicated PFS was approximately four times longer for T-DXd than for T-DM1, at 28.8 months and 6.8 months, respectively (HR, 0.33; P < .000001).

At 24 months, 53.7% of T-DXd were progression free, vs 26.4% of those who received T-DMI1.

Overall survival was also significantly longer with T-DXd (HR vs T-DM1, 0.64; P = .00037). In neither arm was the median overall survival reached, but at 24 months, 77.4% of T-DXd patients and 69.9% of those receiving T-DM1 were still alive.

The overall response rate was 78.5% with T-DXd, including 21.1% of patients who had a complete response. This was significantly higher than the response rate of 35.0% with T-DM1 (P < .0001), which included 9.5% of patients with a complete response.

The rate of grade ≥3 TEAEs was similar in the two treatment arms, at 47.1% with T-DXd and 42.1% with T-DM1. Drug-related TEAEs associated with drug discontinuation occurred in 19.8% of patients given T-DXd and 6.5% in the T-DM1 arm.

The most common events associated with drug discontinuation in T-DXd patients were pneumonitis, in 5.8%; ILD, in 5.1%; and pneumonia, in 1.9%. The most common adverse events linked to T-DM1 were decreased platelet count, in 1.5%; pneumonitis, in 1.1%; and thrombocytopenia, in 1.1%.

As in DESTINY-Breast02, pneumonitis and ILD TEAEs were largely of grade 1 or 2, although there were two cases of grade 3 events. Hurvitz noted that between the interim analysis and the current analysis, the overall rate of ILD increased from 10.5% to 15.2%.

The most common TEAEs of any grade in T-DXd-treated patients were nausea (77.0%), vomiting (51.8%), constipation (37.4%), and anemia (37.0%). In the T-DM1 arm, the most common events were decreased platelet count (43.7%), increased aspartate aminotransferase level (41.4%), increased alanine aminotransferase level (31.8%), and nausea (30.3%).

In the post-presentation discussion, Hurvitz was asked about the relatively low rate of crossover from T-DM1 to T-DXd after patients experienced progression compared with that from T-DXd to T-DM1

In the T-DXd arm, 71.4% of patients who experienced progression were given a post-study anticancer treatment, including T-DM1 (35.2%), trastuzumab (23.6%), and an anti-HER2 tyrosine kinase inhibitor (TKI) (20.9%).

Among patients treated with T-DM1, 78.6% went on to have another anticancer treatment, including trastuzumab (37.0%), an anti-HER2 TKI (35.8%), and T-DXd (17.3%).

She said this is likely due to the large proportion of Asian patients in the study, for whom T-DXd is “not available as standard of care.”

Hurvitz added that this a “very important” consideration and one they will “pay attention to as we continue to follow these data.”

The study was supported by Daiichi Sankyo and AstraZeneca. Hurvitz reports relationships with Ideal Implant and Daiichi Sankyo and institutional funding from Ambrx, Amgen, AstraZeneca, Arvinas, Bayer, Daiichi Sankyo, CytomX Therapeutics, Dantari, Dignitana, G1 Therapeutics, Genentech/Roche, Gilead Sciences, GSK, Immunomedics, Eli Lilly and Company, MacroGenics, Novartis, Pfizer, OBI Pharma, Phoenix Molecular Designs, Orinoco Pharmaceuticals, Pieris Pharmaceuticals, Puma Biotechnology, Radius Health, Samumed, Sanofi, Seattle Genetics, and Zymeworks.Krop reports relationships with AstraZeneca, Daiichi Sankyo, Genentech/Roche, Macrogenics, Pfizer, Bristol-Myers Squibb, Seattle Genetics, Taiho Oncology, Merck, Novartis, and PureTech Health.

San Antonio Breast Cancer Symposium (SABCS) 2022: Abstracts GS2-01 and GS2-02. Presented December 7, 2022.

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