For the treatment of breast cancer, antibody-drug conjugates are emerging as effective players that could impact all subtypes of this disease, according to Kevin Kalinsky, MD, MS, Director of the Glenn Family Breast Cancer at the Winship Cancer Institute of Emory University, Atlanta.
In the metastatic setting, ado-trastuzumab emtansine (T-DM1) was approved more than 5 years ago in HER2-positive metastatic breast cancer. More recently, fam-trastuzumab deruxtecan-nxki (T-DXd) became available also for patients with HER2-positive metastatic breast cancer, and sacituzumab govitecan-hziy was approved for patients with metastatic triple-negative breast cancer. These agents are but the first of an exciting class of therapeutics being evaluated as single agents and in combination with inhibitors of poly (ADP-ribose) polymerase (PARP) and immune checkpoint inhibitors.
Kevin Kalinsky, MD, MS
“Keep your eyes on antibody-drug conjugate development,” Dr. Kalinsky said during a presentation at PER’s Miami Breast Cancer Conference, held virtually this year.1 “In my opinion, antibody-drug conjugates have the potential to change how we are treating patients with metastatic disease and hopefully will impact patients in the operable setting as well.”
Antibody-drug conjugates offer selective delivery of a toxic payload. They bind to an antigen and internalize to the early endosome; they are then degraded in the lysosome, triggering the release of the payload and ultimately cell death.
Sacituzumab Govitecan in Triple-Negative Disease
Sacituzumab govitecan is a humanized antibody that targets trophoblast cell-surface antigen-2 (Trop-2). Trop-2 is an epithelial antigen expressed on many solid cancers, including 88% of metastatic triple-negative breast tumors. Its SN-38 payload is more potent than the parent compound irinotecan, delivering up to 136 times more of irinotecan’s active metabolite.
Sacituzumab govitecan was approved based on findings from a single-arm open-label study (part of a basket trial). In this study, 33.3% of previously treated patients with metastatic triple-negative breast cancer responded, and stable disease was observed in 45.4%.2,3
The confirmatory trial, the phase III ASCENT study of 529 patients, was halted early due to “compelling evidence of efficacy per unanimous recommendation of the data safety and monitoring committee,” Dr. Kalinsky said. Median progression-free survival was 5.6 months with sacituzumab govitecan vs 1.7 months with standard therapy (hazard ratio [HR] = 0.41; P < .0001).
“What’s really telling the story is the doubling in overall survival for patients receiving sacituzumab govitecan [median, 12.1 vs 6.7 months; HR = 0.48; P < .0001],” noted Dr. Kalinsky. “It’s not infrequent that you see a nice response rate in a phase II study that is not always seen in phase III, but here the response rate was recapitulated (35%; P < .0001) in the phase III confirmatory trial.”
Sacituzumab Govitecan by Trop-2 Expression
At the 2020 San Antonio Breast Cancer Symposium, Hurvitz et al reported findings by Trop-2 expression.4 Although higher response rates were seen in patients with high (44%) and medium (38%) expression, low expressors of Trop-2 still responded (22%). Similarly, the drug also worked well in patients with both germline BRCA1/2-positive tumors or wild-type BRCA tumors, the investigators further showed. The main message is the benefit seen with sacituzumab govitecan is broad, and patients should not be selected based on Trop-2 or BRCA status, according to Dr. Kalinsky.
Toxicities related to sacituzumab govitecan tend to be neutropenia, gastrointestinal issues, fatigue, and alopecia. Although 46% of patients in the ASCENT trial had any grade of alopecia, in Dr. Kalinsky’s experience, essentially all patients lose their hair.
Sacituzumab Govitecan in Other Subtypes
What about sacituzumab govitecan in other subtypes of breast cancer? The same basket study evaluated the drug in patients with metastatic hormone receptor–positive/HER2-negative breast cancer; response rates (31.5%) were similar to those in triple-negative disease.2 Median progression-free survival was 5.5 months, and median overall survival was 12 months.
These data led to the phase III TROPICS-02 trial of 400 patients who experienced disease progression on at least one endocrine therapy, a taxane, and an inhibitor of cyclin-dependent kinases 4/6 (CDK4/6) as well as at least two prior lines of chemotherapy. Sacituzumab govitecan will be compared with physician’s choice (capecitabine, vinorelbine, gemcitabine, eribulin). The study has been completed, but the data have not yet been reported.
Sacituzumab govitecan is also being evaluated in the early disease setting and in combination with checkpoint inhibitors and PARP inhibitors. “There’s lots to look forward to with this agent,” Dr. Kalinsky predicted.
Ladiratuzumab Vedotin in Triple-Negative Disease
Ladiratuzumab vedotin (also known as SGN-LIV1A) targets the LIV-1 zinc transporter, a transmembrane cell-adhesion molecule that is highly expressed in metastatic breast cancer. The payload is the microtubule-disrupting agent monomethyl auristatin E.
A phase I study included 60 patients with metastatic triple-negative breast cancer, most with LIV-1 expression and at least two prior lines of cytotoxic chemotherapy.5 The confirmed response rate was 25%, rising to 35% among patients receiving the recommended phase II dose.
In another study, the I-SPY trial, however, ladiratuzumab vedotin did not “graduate” to further evaluation; the response rate among patients receiving the antibody-drug conjugate followed by doxorubicin/cyclophosphamide (AC) was actually lower than with a taxane followed by AC.6 The population included patients with hormone receptor–negative/HER2-negative, and hormone receptor–positive/HER2-negative disease.
Ladiratuzumab vedotin is being evaluated in a weekly dosing schedule and in combination with pembrolizumab in the first-line setting in metastatic triple-negative breast cancer. Toxicities reported with this agent include alopecia, neutropenia, nausea, transaminitis, and neuropathy.
T-DXd in HER2-Low Expressors
T-DXd, which targets HER2 and has a topoisomerase inhibitor payload, proved efficacious in patients with metastatic HER2-positive breast cancer in the phase II DESTINY-Breast01 trial, leading to its approval.7 However, about half of all patients with breast cancer have tumors with low HER2 expression, and these women are largely considered to be HER2-negative—and not candidates for anti-HER2 therapies.
A first-in-human study has investigated T-DXd in 54 patients with advanced or unresectable or metastatic HER2-low–expressing tumors refractory to standard treatment.8 HER2-low was defined as immunohistochemistry (IHC) 1+ or 2+ or negative by in situ hybridization. The overall response rate was 37%, and the median duration of response was 10.4 months.
“We saw a nice response rate in both IHC 2+ and IHC 1+ patients,” Dr. Kalinsky noted. “Given these interesting and notable responses in HER2-low disease, a phase III trial, DESTINY-Breast04, is under way in unresectable HER2-low breast cancer (disease progression on endocrine therapy), evaluating T-DXd vs physician’s choice. We are eagerly awaiting data to see whether there is a role for this molecule in the HER2-low setting.”
The most common toxicities with this agent are nausea, anorexia, and alopecia, but the most concerning ones are interstitial lung disease and pneumonitis. Five such fatal cases have occurred, but none after detailed monitoring and early intervention. Dr. Kalinsky urged clinicians to “be mindful of this toxicity.”
Trastuzumab Duocarmazine
Trastuzumab duocarmazine (also known as SYD-985) has a protease cleavable linker with a DNA alkylating toxin. A phase I study of 99 patients demonstrated a 33% response rate in HER2-positive disease, 40% in HER2-low/estrogen receptor–negative disease, and 27% in HER2-low/estrogen receptor–positive disease.9 “In this HER2-low population, we saw some nice responses, albeit the population was small,” commented Dr. Kalinsky.
Ocular toxicity and fatigue are the most commonly reported side effects with this agent. Trastuzumab duocarmazine is currently being evaluated in I-SPY 2.
Patritumab Deruxtecan
Lastly, patritumab deruxtecan (also known as U3-1402) uses the same payload as T-DXd and targets HER3, which is expressed on a number of solid tumors. It was evaluated in a phase I/II study of 42 heavily pretreated patients with metastatic HER3-positive breast cancer, including those with HER2-positive, hormone receptor–positive, and triple-negative disease.10 The objective response rate was 43%, and the median progression-free survival was 8.3 months.
“We saw nice responses, despite patients having a median of six prior lines of therapy,” Dr. Kalinsky commented. “This was in HER3-expressing tumors, but the population included the classic subtypes.”
DISCLOSURE: Dr. Kalinsky has an immediate family member who holds stock or other ownership interests in Array BioPharma, GRAIL, and Pfizer; has served as a consultant or advisor to AstraZeneca, BioTheranostics, Cyclocel, Eisai, Genentech/Roche, Immunomedics, Ipsen, Lilly, Merck, Novartis, Pfizer, and Seattle Genetics; has participated in a speakers bureau for Lilly; has received institutional research funding from Acetylon, Amgen, Calithera Biosciences, CytomX Therapeutics, Genentech/Roche, Immunomedics, Incyte, Lilly, Novartis, Pfizer, Seattle Genetics, and Zeno Pharmaceuticals; has been reimbursed for travel, accommodations, or other expenses by AstraZeneca, Lilly, and Pfizer; and has held other relationships with Genentech and Immunomedics.
REFERENCES
1. Kalinsky K: Antibody-drug conjugates for HER2-negative breast cancer. 2021 Miami Breast Cancer Conference. Presented March 6, 2021.
2. Kalinsky K, Diamond JR, Vahdat LT, et al: Sacituzumab govitecan in previously treated hormone receptor-positive/HER2-negative metastatic breast cancer: Final results from a phase I/II, single-arm, basket trial. Ann Oncol 31:1709-1718, 2020.
3. Bardia A, Mayer IA, Vahdat LT, et al: Sacituzumab govitecan-hziy in refractory metastatic triple-negative breast cancer. N Engl J Med 380;741-751, 2019.
4. Hurvitz SA, Tolaney SM, Punie K, et al: Biomarker evaluation in the phase 3 ASCENT study of sacituzumab govitecan versus chemotherapy in patients with metastatic triple-negative breast cancer. 2020 San Antonio Breast Cancer Symposium. Abstract GS3-06. Presented December 10, 2020.
5. Modi S, Pusztai L, Forero A, et al: Phase I study of the antibody-drug conjugate SGN-LIV1A in patients with heavily pretreated triple-negative metastatic breast cancer. 2017 San Antonio Breast Cancer Symposium. Abstract PD3-14. Presented December 7, 2017.
6. Beckwith H, Schwab R, Yau C, et al: Evaluation of SGN-LIV1a followed by AC in high-risk HER2-negative stage II/III breast cancer: Results from the I-SPY 2 trial. 2020 San Antonio Breast Cancer Symposium. Abstract PD1-10. Presented December 9, 2020.
7. Modi S, Saura C, Yamashita T, et al: Trastuzumab deruxtecan in previously treated HER2-positive breast cancer. N Engl J Med 382;610-621, 2020.
8. Modi S, Park H, Murthy RK, et al: Antitumor activity and safety of trastuzumab deruxtecan in patients with HER2-low–expressing advanced breast cancer: Results from a phase Ib study. J Clin Oncol 38:1887-1896, 2020.
9. Saura C, Thistlethwaite F, Banerji U, et al: A phase I expansion cohorts study of SYD985 in heavily pretreated patients with HER2-positive or HER2-low metastatic breast cancer. 2018 ASCO Annual Meeting. Abstract 1014. Presented June 2, 2018.
10. Yonemori K, Masuda N, Takahashi S, et al: Single agent activity of U3-1402, a HER3-targeting antibody-drug conjugate, in HER3-overexpressing metastatic breast cancer: Updated results from a phase I/II trial. 2019 ESMO Breast Cancer Conference. Abstract 291. Presented May 2, 2019.
