The second-line treatment with trastuzumab deruxtecan (T-DXd; Enhertu®; Daiichi Sankyo and AstraZeneca) leeds to significantly longer overall survival compared with trastuzumab emtansine (T-DM1; Kadcyla®; Genentech/Roche) in patients with Human Epidermal Growth Factor Receptor 2 (HER2-) positive metastatic breast cancer.[1][2]
This is the conclusion based on the updated results from the DESTINY-Breast03 phase III clinical trial, supported by Daiichi Sankyo and AstraZeneca and presented at the San Antonio Breast Cancer Symposium, held December 6-10, 2022 in San Antonio, Tx.
Second-line treatment
Trastuzumab emtansine is the current standard treatment for patients diagnosed with HER2-positive metastatic breast cancer whose disease progresses after treatment with a combination of anti-HER2 antibodies and a taxane.[1]
“Almost all patients with HER2-positive metastatic breast cancer experience disease progression on first-line treatment, requiring transition to a second-line treatment,” said Sara Hurvitz, MD, a professor of medicine at the David Geffen School of Medicine at the University of California Los Angeles and Jonsson Comprehensive Cancer Center.
A tale of two ADCs
Two antibody-drug conjugates (ADCs), trastuzumab deruxtecan and trastuzumab emtansine, are approved as second-line treatment for this patient population. Both therapies utilize trastuzumab to seek HER2-expressing cells and deliver a cytotoxic drug.
In the case of trastuzumab deruxtecan, the cytotoxic payload induces cell death by inhibiting topoisomerase; the conjugated drug of trastuzumab emtansine kills cells by disrupting microtubule assembly.
DESTINY-Breast03
The DESTINY-Breast03 trial compared the efficacy and safety of trastuzumab deruxtecan with those of trastuzumab emtansine in patients with HER2-positive metastatic breast cancer that progressed on or after first-line treatment.
Previously published interim results from the trial demonstrated that patients treated with trastuzumab deruxtecan had significantly longer progression-free survival (PFS) compared with patients who received trastuzumab emtansine. These results led to the approval of trastuzumab deruxtecan as a second-line treatment for this patient population.[1]
However, overall survival data had not been reached in the first interim analysis.
“While PFS benefits are important, the gold standard measure of efficacy is overall survival,” said Hurvitz.
Previously unreported
In her presentation, Hurvitz will share previously unreported overall survival data from the trial, as well as updated PFS and safety data. Among the 524 patients enrolled in the trial, 261 received trastuzumab deruxtecan, and 263 received trastuzumab emtansine. The median study follow-up was 28.4 months for the trastuzumab deruxtecan arm and 26.5 months for the trastuzumab emtansine arm.
New data showed that patients treated with trastuzumab deruxtecan had a 36 percent lower risk of death than those treated with trastuzumab emtansine, a statistically significant improvement. In addition, overall survival rates were significantly higher for patients treated with trastuzumab deruxtecan: After 12 months, 94.1 percent of patients in the T-DXd arm were alive, compared with 86 percent of those in the trastuzumab deruxtecan arm. After 24 months, overall survival rates were 77.4 percent and 69.9 percent for patients treated with trastuzumab deruxtecan and trastuzumab emtansine, respectively.
Favoring trastuzumab deruxtecan
Updated PFS data continued to favor trastuzumab deruxtecan, and Hurvitz will report median values for the first time. The median PFS in patients treated with trastuzumab deruxtecan was 28.8 months, compared with 6.8 months for patients treated with T-DM1. Objective responses were observed in 78.5 percent of patients who received trastuzumab deruxtecan and 35 percent of patients treated with trastuzumab emtansine. Furthermore, 21.1 percent of patients treated with trastuzumab deruxtecan had a complete response, as compared with 9.5 percent of patients treated with trastuzumab emtansine.
Grade 3 or higher treatment-related adverse events were observed in 56.4 percent and 51.7 percent of patients in the trastuzumab deruxtecan and trastuzumab emtansine arms, respectively. Drug-related interstitial lung disease/pneumonitis was observed in 15.2 percent and 3.1 percent of patients in the trastuzumab deruxtecan and trastuzumab emtansine arms, respectively. Hurvitz noted that new cases of interstitial lung disease/pneumonitis were mild or moderate in severity.
Statistical significant
“The results of this analysis demonstrated remarkable overall survival and continued PFS benefit with trastuzumab deruxtecan in patients with HER2-positive metastatic breast cancer who progressed on prior therapy, further supporting the use of trastuzumab deruxtecan over trastuzumab emtansine in the second-line setting,” Hurvitz noted.
“With this overall survival analysis, we can confirm that the previously demonstrated benefit from trastuzumab deruxtecan in PFS improvement transforms into a statistically significant improvement in overall survival, a substantial advantage for our patients.
“In addition, trastuzumab deruxtecan continued to demonstrate a manageable and tolerable safety profile, with similar rates of treatment-related adverse events between treatment arms,” she added.
| Summary of efficacy and safety results for trastuzumab deruxtecan and trastuzumab emtansine | ||
| trastuzumab deruxtecan | trastuzumab emtansine | |
| Efficacy | N = 261 | N = 263 |
| OS HR (95% CI); P value | 0.64 (0.47–0.87); 0.0037a | |
| mOS, mo (95% CI) | NR (40.5–NE) | NR (34.0–NE) |
| OS rate, % (95% CI) | ||
| 12 mo | 94.1 (90.4–96.4) | 86.0 (81.1–89.8) |
| 24 mo | 77.4 (71.7–82.1) | 69.9 (63.7–75.2) |
| 36 mo | 69.3 (62.5–75.1) | 55.4 (47.4–62.8) |
| mPFS by BICR, mo (95% CI) | 28.8 (22.4–37.9) | 6.8 (5.6–8.2) |
| HR (95% CI); P value | 0.33 (0.26–0.43); <0.000001a,b | |
| mPFS by investigator, mo (95% CI) | 29.1 (23.7–NE) | 7.2 (6.8–8.3) |
| HR (95% CI); P value | 0.30 (0.24–0.38); <0.000001a,b | |
| Confirmed ORR by BICR, % (95% CI) | 78.5 (73.1–83.4) | 35.0 (29.2–41.1) |
| P value | <0.0001a,b | |
| Complete response | 55 (21.1) | 25 (9.5) |
| Partial response | 150 (57.5) | 67 (25.5) |
| mDoR by BICR, mo (95% CI) | 36.6 (22.4–NE) | 23.8 (12.6–34.7) |
| Safety, n (%) | N = 257 | N = 261 |
| Grade ≥3 TEAEs | 145 (56.4) | 135 (51.7) |
| Serious TEAEs | 65 (25.3) | 58 (22.2) |
| TEAEs associated with: | ||
| Drug interruption | 136 (52.9) | 76 (29.1) |
| Dose reduction | 66 (25.7) | 38 (14.6) |
| Drug discontinuation | 55 (21.4) | 24 (9.2) |
| Death | 6 (2.3) | 6 (2.3) |
| aTwo–sided. bNominal P value. | ||
Study limitation
Future analyses of DESTINY-Breast03 may investigate the efficacy of trastuzumab deruxtecan in patients with brain metastases and explore predictive markers of response, Hurvitz noted. Ongoing studies aim to determine the efficacy and safety of trastuzumab deruxtecan as a first-line treatment for patients with HER2-positive metastatic breast cancer.
A limitation of the study was the disproportionate enrollment of Asian patients as compared with North American and European patients. An additional limitation was that median overall survival was not reached at the time of this analysis.
Clinical trial
DS-8201a Versus T-DM1 for Human Epidermal Growth Factor Receptor 2 (HER2)-Positive, Unresectable and/or Metastatic Breast Cancer Previously Treated With Trastuzumab and Taxane [DESTINY-Breast03] – NCT03529110
Highlight of prescription information
Trastuzumab deruxtecan (T-DXd; Enhertu®; Daiichi Sankyo and AstraZeneca)[Prescribing Information]
Trastuzumab emtansine (T-DM1; Kadcyla®; Genentech/Roche) [Prescription information]
Reference
[1] Cortés J, Kim SB, Chung WP, Im SA, Park YH, Hegg R, Kim MH, Tseng LM, Petry V, Chung CF, Iwata H, Hamilton E, Curigliano G, Xu B, Huang CS, Kim JH, Chiu JWY, Pedrini JL, Lee C, Liu Y, Cathcart J, Bako E, Verma S, Hurvitz SA; DESTINY-Breast03 Trial Investigators. Trastuzumab Deruxtecan versus Trastuzumab Emtansine for Breast Cancer. N Engl J Med. 2022 Mar 24;386(12):1143-1154. doi: 10.1056/NEJMoa2115022. PMID: 35320644.
[2] Hurvitz SA. Trastuzumab deruxtecan versus trastuzumab emtansine in patients with HER2–positive metastatic breast cancer: Updated survival results of the randomized, phase 3 study DESTINY–Breast03. Abstract GS2-02 Presenting during the San Antonio Breast cancer Symposium/SABCS held Dec. 6 – 10, 2022
Featured image: SABCS. Photo courtesy: © 2022 AACR/SABCS / MedMeetingImages/Todd Buchanan. Used with permission.
