In an updated analysis of the phase 2 DESTINY-Breast01 study, women with HER2-positive metastatic breast cancer taking antibody-drug conjugate trastuzumab deruxtecan continued to demonstrate favorable efficacy data, durable responses, overall survival rates, and a tolerable safety profile. Physician’s Weekly interviews lead study author Shanu Modi, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center, who presented these results during the 2020 San Antonio Breast Cancer Symposium [1].

View Phase 2 DESTINY-Breast-1 Study Poster Presentation:
Updated Results From DESTINY-Breast01, a Phase 2 Trial of Trastuzumab Deruxtecan (T-DXd) in HER2-Positive Metastatic Breast Cancer

Trastuzumab deruxtecan is an antibody-drug conjugate composed of an anti-HER2 (human epidermal growth factor receptor 2) antibody, a cleavable tetrapeptide-based linker, and a cytotoxic topoisomerase I inhibitor. The FDA granted accelerated approval to trastuzumab deruxtecan in December 2019 for the treatment of unresectable/metastatic HER2-positive breast cancer already treated with at least 2 prior anti–HER2 regimens, based on initial results from the DESTINY-Breast01 study (NCT03248492), presented at the 2019 San Antonio Breast Cancer Symposium, and published in the New England Journal of Medicine [2,3].

At this year’s meeting, the investigators had gathered an additional 9.4 months of follow-up data from the cohort of heavily pretreated patients (n=134) previously exposed to ado-trastuzumab emtansine (T-DM1), receiving a daily dose of trastuzumab deruxtecan of 5.4 mg/kg. The primary endpoint was overall response rate (ORR) by independent review; key secondary endpoints included DCR, DOR, and PFS. Although patients with stable brain metastases were allowed, patients with interstitial lung disease (ILD) were excluded. The median age the women was 55 years (range, 28-96 years). Hormone receptor (HR)–positive tumors were in 53% of subjects; 45% were HR-negative. The median number of prior treatment lines was 6 (range: 2-27), including trastuzumab (100%), T-DM1 (100%), pertuzumab (65.8%), other anti-HER2 antibodies or ADCs (6.0%), other HER2-targeted TKIs (50.5%), hormonal therapy (48.9%), and other prior systemic therapy (99.5%).

With a median follow-up of 20.5 months (range: 0.7-31.4), 20.1% of patients remained on therapy.

The confirmed ORR was 61.4% (95% CI 54.0%-68.5%). Complete response climbed slightly to 6.5%, partial response was observed in 54.9%. Disease remained stable in 35.9%, and progressed in 1.1%. The time to response was the same as reported last year, at 1.6 months (95% CI 1.4-2.6), yet the new data set the current median duration of response at 20.8 months. The estimated 12- and 18-month overall survival (OS) rates were 85% (95% CI 79%-90%) and 74% (95% CI 67%-80%), respectively. The median OS, although still preliminary, was 24.6 months (95% CI 23.1– not estimable). Longer follow-up is needed to acquire mature survival data, which was calculated here at 35% maturity. The median progression-free survival (PFS) based on current data was 19.4 months (95% CI 14.1 months–not estimable).

The safety profile of trastuzumab deruxtecan was consistent with prior reports. A total of 18.5% of patients discontinued treatment. Treatment-emergent adverse events (TEAEs) of at least grade 3 in severityoccurred in 61.4% of patients. TEAEs that led to death occurred in 10 patients (5.4%), 3 of which were deemed treatment-related.

With this longer follow-up period, 3 additional cases of ILD were reported. However, after an estimated 1 year on treatment, the risk of developing ILD decreased, countering the worry that the risk of ILD is related to a cumulative trastuzumab deruxtecan exposure. The etiology and the nature of pulmonary risk with this treatment requires further research.

The ongoing, controlled, phase 3 DESTINY-Breast02 study (NCT03523585) will compare trastuzumab deruxtecan with the investigator’s choice of treatment in patients with HER2-positive breast cancer that has metastasized or is unresectable, and who have received prior treatment with T-DM1.

Lead study author of DESTINY-Breast01 Trial, Shanu Modi, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center

Physician’s Weekly asked Dr. Modi for her perspectives:

What were your take-home messages from your presentation?

“We presented an update on our study, with more confirmatory, good results. Trastuzumab deruxtecan continues to demonstrate clinically meaningful and durable efficacy with an unprecedented median duration of response of 20.8 months and an 18-month landmark OS [rate] of 74%. The data represents over 9 months of extra follow-up data. The primary endpoint of the trial was overall response rate by independent review, and it is basically consistent with a longer follow-up. There was one additional patient who achieved a complete response in this period. The most notable change we observed with the longer follow-up was the durability of benefit; the duration of response rate improved to nearly  21 months, and the progression-free survival improved to just over 19 months. We were pleased to see this continued benefit for our patients. We don’t typically see numbers like that in such heavily pretreated patients, who have already had the best drugs for their type of breast cancer. Clearly, some people on this drug can do well for a very, very long time.”

How does the response rate and durability compare with other HER2-directed regimens?

“This was a straight phase 2 study, with no comparator arm. Sometimes phase 2 data look really promising but turn out to be less promising when tested in randomized studies. Having said that, the findings here were not typical for such a heavily pretreated population. They are actually more reminiscent of what you see in untreated populations, like the CLEOPATRA trial [NCT00567190, 4], for example, which was a first-line study in metastatic patients.

Of course, cross-trial comparisons must be interpreted with caution. Nevertheless, if you look at some of the recent studies in the same refractory space in HER2-positive breast cancer, like HER2CLIMB [NCT02614794, 5], or the SOPHIA trial [NCT02492711, 6], the response rate and overall efficacy observed with trastuzumab deruxtecan in this study appear to substantially exceed those other HER2-directed regimens. The bottom line is we are very excited to see what the randomized studies are actually going to show. ”

Can you comment on the distinct pharmaceutical aspects of this drug?

“Although this is a novel agent we are testing, the backbone is trastuzumab. The linker is different: it is a cleavable linker which preclinical data showed to be very stable. The notable difference is that there are twice as many chemotherapy molecules per antibody than other antibody drug conjugates. It is novel because the payload is a topoisomerase 1 inhibitor;  topoisomerase 1 chemotherapy agents are not used to treat breast cancer routinely.”

The interstitial lung disease developing in some patients: what should physicians watch out for?

“To be honest, there really are no official guidelines except to be vigilant for respiratory symptoms, either new symptoms or worsening of baseline symptoms, and that should prompt intervention on the physician’s part. Such an important part of using this drug is understanding the lung toxicity. There is a lot of work going on pre-clinically to try and understand the pathogenesis. We see pneumonitis with a lot of our therapies, but we do not see grade 5 events with these other therapies. This is new for all of us in breast cancer; education is key. The physician should investigate any symptoms to rule out pneumonitis. If you cannot rule out pneumonitis, and this is possibly drug-induced pneumonitis, those patients need to have a proper referral to your pulmonary colleagues. Good CT scans and pulmonary function tests should probably be done as part of the workup.”

“For people who have any symptoms and x-ray findings, that should be a hard stop with this drug. We do not have enough data to suggest that patients should restart, so no one will recommend restarting in symptomatic patients. You will want to just watch those patients, keep them on steroids until those symptoms and radiograph resolve completely, and then move on to different therapy.

Asymptomatic patients with scan irregularities in their lungs should be considered for early steroid therapy, to resolve those findings. After 4-6 weeks, you can resume treatment in those patients; we did that in the trial, and they responded well to that approach.”

“In general, it is a really exciting time to be treating HER2-positive breast cancer. Despite the underlying lung toxicity risk, which we need to understand even better, there are signals of potential activity with consequent clinical benefit in CNS lesions. That is something being actively investigated at the moment, with high impact potential.”

Poster Presentation: Updated Results From DESTINY-Breast01, a Phase 2 Trial of Trastuzumab Deruxtecan (T-DXd) in HER2-Positive Metastatic Breast Cancer

References

  1. Modi S, et al. Updated results from DESTINY-Breast01, a phase 2 trial of trastuzumab deruxtecan (T-DXd) in HER2-positive metastatic breast cancer. Presented at: 2020 San Antonio Breast Cancer Symposium; December 8-11; 2020; Virtual. Poster Spotlight PD3-06.
  2. Krop IE, et al. [Fam-] trastuzumab deruxtecan (T-DXd; DS-8201a) in subjects with HER2-positive metastatic breast cancer previouslytreated with T-DM1: A phase 2, multicenter, open-label study (DESTINY-Breast01). Presented at: 2019 San Antonio Breast Cancer Symposium; December 10-14, 2019; San Antonio, Texas. Abstract GS1-03.
  3. Modi S, et al. Trastuzumab deruxtecan in previously treated HER2-positive breast cancer. N Eng J Med. 2020;382(7):601-621.
  4. Swain SM et al. Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med. 2015 Feb 19;372(8):724-34.
  5. Murthy RK, et al. Tucatinib, Trastuzumab, and Capecitabine for HER2-Positive Metastatic Breast Cancer. N Engl J Med. 2020 Feb 13;382(7):597-609.
  6. Hugo HS, et al. SOPHIA primary analysis: a phase 3 study of margetuximab + chemotherapy versus trastuzumab + chemotherapy in patients with HER2+ metastatic breast cancer after prior anti-HER2 therapies. J Clin Oncol 2019;37:Suppl:1000-1000.