SN-38

Sacituzumab Govitecan-hziy in Refractory Metastatic Triple-Negative Breast Cancer

A. Bardia, I.A. Mayer, L.T. Vahdat, S.M. Tolaney, S.J. Isakoff, J.R. Diamond, J. O’Shaughnessy, R.L. Moroose, A.D. Santin, V.G. Abramson, N.C. Shah, H.S. Rugo, D.M. Goldenberg, A.M. Sweidan, R. Iannone, S. Washkowitz,
R.M. Sharkey, W.A. Wegener, and K. Kalinsky
ABSTR ACT

BACKGROUND
Standard chemotherapy is associated with low response rates and short progression- free survival among patients with pretreated metastatic triple-negative breast cancer. Sacituzumab govitecan-hziy is an antibody–drug conjugate that combines a human- ized monoclonal antibody, which targets the human trophoblast cell-surface anti- gen 2 (Trop-2), with SN-38, which is conjugated to the antibody by a cleavable linker. Sacituzumab govitecan-hziy enables delivery of high concentrations of SN-38 to tumors.
METHODS
We conducted a phase 1/2 single-group, multicenter trial involving patients with advanced epithelial cancers who received sacituzumab govitecan-hziy intravenously on days 1 and 8 of each 21-day cycle until disease progression or unacceptable toxic effects. A total of 108 patients received sacituzumab govitecan-hziy at a dose of 10 mg per kilogram of body weight after receiving at least two previous antican- cer therapies for metastatic triple-negative breast cancer. The end points included safety; the objective response rate (according to Response Evaluation Criteria in Solid Tumors, version 1.1), which was assessed locally; the duration of response; the clini- cal benefit rate (defined as a complete or partial response or stable disease for at least 6 months); progression-free survival; and overall survival. Post hoc analyses deter- mined the response rate and duration, which were assessed by blinded independent central review.
RESULTS
The 108 patients with triple-negative breast cancer had received a median of 3 previ- ous therapies (range, 2 to 10). Four deaths occurred during treatment; 3 patients (2.8%) discontinued treatment because of adverse events. Grade 3 or 4 adverse events (in ≥10% of the patients) included anemia and neutropenia; 10 patients (9.3%) had febrile neutropenia. The response rate (3 complete and 33 partial responses) was 33.3% (95% confidence interval [CI], 24.6 to 43.1), and the median duration of response was 7.7 months (95% CI, 4.9 to 10.8); as assessed by independent central review, these values were 34.3% and 9.1 months, respectively. The clinical benefit rate was 45.4%. Median progression-free survival was 5.5 months (95% CI, 4.1 to 6.3), and overall survival was 13.0 months (95% CI, 11.2 to 13.7).
CONCLUSIONS
Sacituzumab govitecan-hziy was associated with durable objective responses in pa- tients with heavily pretreated metastatic triple-negative breast cancer. Myelotoxic effects were the main adverse reactions. (Funded by Immunomedics; IMMU-132-01 ClinicalTrials.gov number, NCT01631552.)

The authors’ full names, academic degrees, and affiliations are listed in the Appendix. Address reprint requests to Dr. Bardia at the Massachusetts General Hospital Can- cer Center, Harvard Medical School, Law- rence House 304, 10 N. Grove St., Bos- ton, MA 02114, or at bardia.aditya@mgh
.harvard.edu.
N Engl J Med 2019;380:741-51. DOI: 10.1056/NEJMoa1814213
Copyright © 2019 Massachusetts Medical Society.

the tumor microenvironment, thereby allowing for the delivery of therapeutic concentrations of the drug in bystander cells to which the conjugate has not bound. Sacituzumab-bound tumor cells are killed by intracellular uptake of SN-38, and adja- cent tumor cells are killed by the extracellular release of SN-38.24
IMMU-132-01 is a phase 1/2, basket design, open-label, single-group, multicenter trial involv- ing patients with various types of advanced solid cancers who have received at least one previous therapy for metastatic disease. Preliminary results for 69 patients with metastatic triple-negative breast cancer have been reported.25 In 2016, saci- tuzumab govitecan-hziy was assigned a “break- through therapy” designation by the Food and Drug Administration (FDA) for the treatment of patients with metastatic triple-negative breast can- cer who have received at least two previous thera- pies for metastatic disease, and, accordingly, the protocol was amended to require further enroll- ment in a more defined population of patients with metastatic triple-negative breast cancer who had received at least two lines of previous therapy, including previous taxane therapy. Here, we report updated results for all patients who received saci- tuzumab govitecan-hziy as a third-line or higher line of therapy for metastatic triple-negative breast cancer at the clinically selected dose level of 10 mg per kilogram of body weight.

Methods
Trial Design and Oversight
Eligibility criteria that were previously described for patients with metastatic triple-negative breast cancer25 also apply to the overall trial population (see the Methods section in the Supplementary Ap- pendix, available with the full text of this article at NEJM.org). Sacituzumab govitecan-hziy was ad- ministered as an intravenous infusion on days 1 and 8 of 21-day cycles until disease progression or unacceptable adverse events. In case of severe treatment-related adverse events, dose reductions of 25% were allowed for the first occurrence and of 50% for the second occurrence, with treatment discontinuation at the third occurrence. Hemato- poietic growth factors or blood transfusions were allowed at the investigator’s discretion; however, prophylactic treatment before the first dose (cy- cle 1, day 1) was not allowed. All patients with metastatic triple-negative breast cancer in the

Efficacy Evaluations
Staging computed tomography (CT) and magnetic resonance imaging (MRI) were performed at base- line and at 8-week intervals from the start of treat- ment until disease progression requiring discon- tinuation of treatment. Confirmatory CT and MRI were performed no sooner than 4 weeks after an initial partial or complete response. Subsequent imaging was performed at 8-week intervals after the confirmatory imaging.
The primary efficacy end point was the objec- tive response rate. Assessment of response was performed according to Response Evaluation Crite- ria in Solid Tumors, version 1.1. Local assessments were used for treatment decisions and for the pri- mary efficacy analysis. Other efficacy end points were the time to response and the duration of re- sponse in patients who had a response, the clinical benefit rate (defined as a complete or partial response or stable disease for at least 6 months), and progression-free and overall survival.
Blinded independent central review of staging

scans was also obtained for the 56 patients (of the 108 with metastatic triple-negative breast cancer) who had complete or partial remission, or at least a 20% reduction in the baseline sum of the diam- eters of the target lesions, according to local site evaluation. This blinded independent review, which was performed by Intrinsic Imaging, included re- views by two independent radiologists and a third adjudicating radiologist, if needed.

Safety Evaluations
Safety evaluations included assessments of adverse events and serious adverse events, laboratory safety evaluations, vital signs, physical examination, and 12-lead electrocardiography (ECG). A 12-lead ECG was to be performed at baseline, after completion
* Race or ethnic group was reported by the patients.
† Eleven patients did not indicate or declined to indicate their race or ethnic group; four identified as Native American, Dominican, Hispanic, or mixed race.
‡ The Eastern Cooperative Oncology Group (ECOG) performance-status scale ranges from 0 to 5, with 0 indicating that the patient is fully active with no re- strictions, 1 indicating that the patient is ambulatory and able to carry out work of a light or sedentary nature but restricted in physically strenuous activ- ity, and higher numbers indicating increasing degrees of disability.
§ Visceral organs were defined as solid organs, excluding the brain.
of the infusion on day 1 of every even-numbered treatment cycle, at the end of treatment, and at the end of the trial. Adverse events were coded according to the Medical Dictionary for Regulatory Activities, version 20.0, and severity was graded according to Common Terminology Criteria for Adverse Events (CTCAE), version 4.0. For events

Table 2. Summary of Adverse Events in Patients Receiving Sacituzumab Govitecan-hziy.*
Adverse Event Patients (N=108)

Any Grade Grade 3 Grade 4

number of patients with event (percent)
Any adverse event 108 (100) 71 (66) 21 (19)
Gastrointestinal disorders 102 (94) 21 (19) 0
Nausea 72 (67) 7 (6) 0
Diarrhea 67 (62) 9 (8) 0
Vomiting 53 (49) 7 (6) 0
Constipation 37 (34) 1 (1) 0
Abdominal pain† 27 (25) 1 (1) 0
Mucositis‡ 15 (14) 0 0
General disorders and administration-site conditions 82 (76) 10 (9) 0
Fatigue and asthenia 59 (55) 9 (8) 0
Peripheral edema 17 (16) 0 0
Pyrexia 13 (12) 0 0
Blood and lymphatic system disorders 80 (74) 25 (23) 15 (14)
Neutropenia§ 69 (64) 28 (26) 17 (16)
Anemia 54 (50) 12 (11) 0
Metabolism and nutrition disorders 70 (65) 21 (19) 2 (2)
Decreased appetite 32 (30) 0 0
Hyperglycemia 26 (24) 3 (3) 1 (1)
Hypomagnesemia 23 (21) 1 (1) 0
Hypokalemia 19 (18) 2 (2) 0
Hypophosphatemia 16 (15) 10 (9) 0
Dehydration 14 (13) 4 (4) 0
Skin and subcutaneous tissue disorders 66 (61) 5 (5) 0
Alopecia 39 (36) 0 0
Rash¶ 30 (28) 2 (2) 0
Pruritus 17 (16) 0 0
Dry skin 15 (14) 1 (1) 0
Abnormal values 62 (57) 22 (20) 6 (6)
Decreased white-cell count 23 (21) 9 (8) 3 (3)
Prolonged activated partial thromboplastin time 15 (14) 2 (2) 0
Increased aspartate aminotransferase level 15 (14) 1 (1) 0
Increased alanine aminotransferase level 15 (14) 1 (1) 0
Decreased weight 15 (14) 0 0
Increased blood alkaline phosphatase level 12 (11) 2 (2) 0
Increased blood lactate dehydrogenase level 11 (10) 0 0
Nervous system disorders 59 (55) 4 (4) 0
Headache 23 (21) 1 (1) 0
Dizziness 22 (20) 0 0
Neuropathy‖ 20 (19) 0 0
Dysgeusia 12 (11) 0 0

Table 2. (Continued.)
Adverse Event Patients (N=108)

Any Grade Grade 3 Grade 4

number of patients with event (percent)
Infections and infestations 56 (52) 11 (10) 2 (2)
Respiratory infection** 23 (21) 3 (3) 0
Urinary tract infection 22 (20) 3 (3) 0
Musculoskeletal and connective-tissue disorders 56 (52) 0 0
Back pain 24 (22) 0 0
Arthralgia 17 (16) 0 0
Pain in extremity 11 (10) 0 0
Respiratory, thoracic, and mediastinal disorders 55 (51) 4 (4) 1 (1)
Cough and productive cough 21 (19) 0 0
Dyspnea 20 (19) 2 (2) 1 (1)
Psychiatric disorders 27 (25) 1 (1) 0
Insomnia 15 (14) 0 0
* Shown are the adverse events of any grade (according to Common Terminology Criteria for Adverse Events [CTCAE], version 4.0) that occurred in at least 10% of the patients. The Medical Dictionary for Regulatory Activities system organ class and preferred terms are reported whenever possible.
† This category includes abdominal pain, abdominal distention, upper abdominal pain, abdominal discomfort, and ab- dominal tenderness.
‡ This category includes stomatitis and mucosal inflammation.
§ This category includes neutropenia and decreased neutrophil counts. Febrile neutropenia of all grades was observed in 10 patients (9%), and grade 3 and grade 4 febrile neutropenia was observed in 7 patients (6%) and 2 patients (2%), respectively.
¶ This category includes maculopapular rash, generalized rash, dermatitis acneiform, and skin disorder.
‖ This category includes peripheral neuropathy, paresthesia, peripheral sensory neuropathy, and hypoesthesia.
** This category includes upper respiratory tract infection, viral upper respiratory tract infection, lower respiratory tract infection, pneumonia, influenza, bronchitis, and respiratory syncytial virus infection.
with varying severity, the maximum reported grade was used in summaries. The safety evaluation for the cohort of patients with metastatic triple-neg- ative breast cancer was the same as that for the overall trial population.

Statistical Analysis
Details of the statistical analyses have been de- scribed previously.25 When the cohort of patients with metastatic triple-negative breast cancer was evaluated to identify those who received sacituz- umab govitecan-hziy at a dose of 10 mg per kilo- gram and had received at least two previous therapies for metastatic disease, the target group included 108 patients. The response rate and the exact 95% confidence intervals were calculated with the use of the Clopper–Pearson method. Progression-free and overall survival and time- to-event end points were analyzed with the use of Kaplan–Meier methods, with medians and cor- responding 95% confidence intervals determined according to the Brookmeyer and Crowley method
with log–log transformation. Subgroup analyses were used to evaluate the effect of patient factors and previous cancer treatments.
The trial was approved by the institutional review board at each investigational site before initiation of the trial and was performed in ac- cordance with the Declaration of Helsinki, the International Council for Harmonisation guide- lines for Good Clinical Practice, the FDA Code of Federal Regulations, the requirements of national drug and data protection laws, other applicable regulatory requirements, and the standard oper- ating procedures of Immunomedics. All patients provided written informed consent before en- rollment.

Results
Patient Population
A total of 108 patients with metastatic triple-nega- tive breast cancer (median age, 55 years) were en- rolled between June 2013 and February 2017. The
patients had been heavily pretreated (median of 3 previous anticancer regimens [range, 2 to 10]). A total of 106 of these patients (98%) had received taxanes and 93 (86%) had received anthracyclines. The baseline demographic characteristics of the patients are summarized in Table 1. At the time of data cutoff (December 1, 2017), the median duration of follow-up among the 108 patients with metastatic triple-negative breast cancer was 9.7 months (range, 0.3 to 36.5). Eight of these patients were continuing to receive treatment. A total of 100 patients (92.6%) had discontinued treatment, and in 86 of these patients (80%), discontinuation was because of disease progression. Other reasons for discontinuation are listed in Table S1 in the Supplementary Appendix.

Safety
The 108 patients with metastatic triple-negative breast cancer received a mean of 18.7 doses of sacituzumab govitecan-hziy (range, 1 to 102), or 9.6 cycles (range, 1 to 51), with a median duration of exposure of 5.1 months (range, 0.03 to 36.1). A total of 99 patients (92%) received preinfusion medications (acetaminophen, antihistamines, H2 antagonists, glucocorticoids, antiemetics, anxio- lytics, and atropine). The most common adverse events were nausea, diarrhea, fatigue, neutropenia, and anemia, and the most common adverse events of grade 3 or higher (>5% incidence) included neu- tropenia, anemia, and a decreased white-cell count, as outlined in Table 2. Diarrhea (predominantly grade 1) was a common adverse event (in 62% of the patients overall); the incidence of CTCAE grade 2 diarrhea was 14%, and the incidence of at least grade 3 diarrhea was 8%. No peripheral neuropa- thy of grade 3 or higher was reported. Four pa- tients (4%) had adverse events leading to death during treatment (details are provided in the Results section in the Supplementary Appendix). Serious adverse events were reported in 35 pa- tients (32%); the most common (>2% incidence) were febrile neutropenia (in 7% of the patients), vomiting (in 6%), nausea (in 4%), diarrhea (in 3%), and dyspnea (in 3%).
Adverse events leading to interruption of treat- ment occurred in 48 of the 108 patients (44%); the most common reason was neutropenia. Three pa- tients (3%) discontinued treatment because of ad- verse events; 2 patients discontinued because of drug-related events, and 1 patient discontinued because of hypertension, which was thought by

the investigator not to be drug-related. Transient changes in laboratory safety values that occurred during treatment included decreases in blood-cell counts and alterations in biochemical values, which generally recovered by the end of treatment.

Efficacy
In Figure 1A, a waterfall plot shows the breadth and depth of responses according to local assess- ment in 108 patients with metastatic triple-nega- tive breast cancer. The response rate was 33.3% (36 of 108 patients), including complete respons- es in 3 patients (2.8%). The clinical benefit rate (including stable disease for at least 6 months) was 45.4% (49 of 108 patients). In Figure 1B, a swimmer plot shows the onset and durability of response in each of the 36 patients who had an objective response. In these patients, the median time to response was 2.0 months (range, 1.6 to 13.5), and the median duration of response was 7.7 months (95% confidence interval [CI], 4.9 to 10.8). The response rate (34.3% [95% CI, 25.4 to 44.0]) and median duration of response (9.1 months [95% CI, 4.6 to 11.3]) according to blinded inde- pendent review were similar to those determined by local assessment (Table S5 in the Supplemen- tary Appendix). According to local assessment, the estimated probability that a patient would have a response at 6 months was 59.7%, and the esti- mated probability that a patient would have a response at 12 months was 27.0% (Fig. S2 in the Supplementary Appendix). At the database cutoff date, 6 patients had long-term responses with a response for more than 12 months (range, 12.7 to 30.4). Table 3 summarizes the results according to investigator assessment.
We evaluated the response to sacituzumab govitecan-hziy in a variety of patient subgroups (Table S6 in the Supplementary Appendix) and found no meaningful differences in response rates according to patient age, the onset of metastatic disease, the number of previous therapies, or the presence or absence of visceral metastases. The response rate was 44% (8 of 18) among patients who had received previous checkpoint inhibitors; however, these results and those of all the reported subgroups should be interpreted with caution given the small number of patients available, which led to wide confidence intervals.
At the time of data cutoff, 94 patients (87.0%) had disease progression and 77 patients (71.3%) had died. The median progression-free survival

was 5.5 months (95% CI, 4.1 to 6.3); the estimated probability of progression-free survival was 41.9% at 6 months and 15.1% at 12 months (Fig. 1C). The median overall survival was 13.0 months (95% CI, 11.2 to 13.7); the estimated probability of survival was 78.5% at 6 months and 51.3% at 12 months (Fig. S3 in the Supplementary Ap- pendix).
To analyze efficacy in relation to the aggres- siveness of the clinical course and to address concerns regarding relatively indolent tumor bi- ologic characteristics in the trial population, we compared the duration of treatment with sacituz- umab govitecan-hziy with that of previous anti- cancer treatment in the 108 patients with meta- static triple-negative breast cancer for whom data were available. The median duration of treatment with sacituzumab govitecan-hziy (5.1 months) was approximately twice that with the previous anti- cancer treatment (2.5 months); this highlights the clinical activity and lack of cross-resistance with this antibody–drug conjugate (Fig. 2).

Discussion
Among patients with metastatic triple-negative

breast cancer who had received at least two pre- vious therapies for metastatic disease (median, three) and who received treatment with sacitu- zumab govitecan-hziy, the response rate was 33.3%, the median duration of response was 7.7
months, the median progression-free survival was 5.5 months, and the median overall survival was 13.0 months. Efficacy was observed in patients who had received taxanes and anthracyclines, sug- gesting a lack of cross-resistance to previous cyto-

Table 3. Summary of Treatment Efficacy, According to Local Assessment.
Patients
Variable (N=108)
Complete response — no. of patients (%) 3 (2.8)
Partial response — no. of patients (%) 33 (30.6)
Stable disease — no. of patients (%) 40 (37.0)
Progressive disease — no. of patients (%) 28 (25.9)
Not evaluated — no. of patients (%)* 4 (3.7)
Objective response rate†
No. of patients 36
% of patients (95% CI) 33.3 (24.6–43.1)
Clinical benefit rate‡
No. of patients 49
% of patients (95% CI) 45.4 (35.8–55.2)
Median duration of response (95% CI) — mo 7.7 (4.9–10.8)
treatment with cytotoxic agents in this patient population,26 were not observed. Hypersensitivity events of grade 3 or higher that were associated with infusion of monoclonal antibodies were infre- quent (in 3 patients [3%]). Four deaths occurred during treatment (within 30 days after the last dose of sacituzumab govitecan-hziy); all deaths were at- tributed by the investigators to disease progres- sion, and none were considered to be related to sacituzumab govitecan-hziy (see the Results sec- tion in the Supplementary Appendix). The safety profile of sacituzumab govitecan-hziy in the 108 patients with metastatic triple-negative breast can- cer was generally consistent with that in the overall safety population of 420 patients who had a variety of tumor types (Table S3 in the Supplementary Appendix).
The long-term efficacy of the various treat-

* These patients could not be evaluated because of death, transfer to hospice, withdrawal due to clinical progression, or withdrawal due to grade 4 neutrope- nia before any radiologic assessment of response.
† The objective response rate is the percentage of patients with a complete re- sponse or partial response.
‡ The clinical benefit rate is the percentage of patients with a complete re- sponse or partial response or stable disease for at least 6 months.

toxic chemotherapy. The duration of treatment with sacituzumab govitecan-hziy was longer than with the immediate previous antitumor therapy (5.1 months vs. 2.5 months); this provides fur- ther evidence of clinical activity in patients with difficult-to-treat metastatic triple-negative breast cancer. Although a subgroup analysis based on the patients’ age, the onset of metastatic disease, the number of previous therapies, or the presence or absence of visceral metastases showed no meaningful differences in outcomes, the small number of patients led to wide confidence inter- vals, and thus the homogeneity of clinical out- comes observed in these subgroups is weak and should be interpreted with caution.
The most relevant adverse events in patients with metastatic triple-negative breast cancer, as well as in the larger population of patients with multiple tumor types who received sacituzumab govitecan-hziy, included neutropenia and diarrhea, which were managed with routine supportive care according to general practice guidelines (i.e., early intervention with granulocyte colony-stimulating factor and early intervention for diarrhea). Few patients discontinued treatment because of adverse events. Severe drug-related neuropathy or cardiac adverse events, which may limit the duration of
ment options for patients with metastatic triple- negative breast cancer (serial application of single agents) is limited.12-14,16 Poor outcomes seen in pa- tients with metastatic triple-negative breast cancer, as compared with other breast cancer subtypes, are partly explained by the lack of actionable driver mutations or established molecular targets, there- by leaving sequential single-agent chemotherapy as the main treatment approach.7,10 Sacituzumab govitecan-hziy is an antibody–drug conjugate with Trop-2 as the target of recognition; it can deliver cytotoxic chemotherapy to tumors, including ad- jacent cancer cells, in concentrations that are higher than those with standard chemotherapy and may reduce toxic effects in normal tissues that do not express the target.24 High expression of Trop-2 in triple-negative breast cancer and its association with a poor prognosis suggest that it is a rational therapeutic target in this patient population.19,21
The cytotoxic component of sacituzumab gov- itecan-hziy is SN-38, a highly potent topoisomer- ase I inhibitor and metabolite of irinotecan. The cytotoxic activity of SN-38 delivered through sacituzumab govitecan-hziy is 100 to 1000 times as high as that of irinotecan.27 In animal models, the tumor-to-serum area under the curve ratio for SN-38 was 20 to 40 times as high with sacituz- umab govitecan-hziy as it was with irinotecan, whereas concentrations that were 20 to 136 times as high as those with irinotecan were delivered into the tumor.24 Clinically, serum concentrations of glucuronidated SN-38, the molecular species most strongly associated with toxic effects, were
Receipt of last previous therapy Receipt of sacituzumab govitecan-hziy Continuation of treatment

*****

30 24 18 12 6 0 6 12 18 24 30 36 42
Months

Figure 2. Duration of Treatment with Sacituzumab Govitecan-hziy and with the Last Previous Therapy in the 108 Patients with Metastatic Triple-Negative Breast Cancer.
Asterisks indicate patients who received therapy for only 1 day. The vertical dashed lines at 6 months and 12 months show the clinically meaningful end points for patients with metastatic triple-negative breast cancer. When the month and year were available, a missing start date was imputed as the 15th of the month, and a missing end date was imputed as the last day of the month.

substantially lower than those of SN-38 with sacituzumab govitecan-hziy and substantially low- er than glucuronidated SN-38 concentrations re- ported with irinotecan.28 This may explain the considerably lower discontinuation rates and clin- ically relevant lower rates of grade 3 or 4 gastro- intestinal toxic effects in this trial than in trials of irinotecan. Although toxic effects associated with sacituzumab govitecan-hziy are similar to those of irinotecan, these data suggest that saci- tuzumab govitecan-hziy has a better side-effect profile and is less likely to be associated with more severe adverse effects.29 The less severe nature of these adverse events with sacituzumab govitecan- hziy was reflected in the low incidences of adverse events leading to treatment discontinuation (3%) and death during treatment (4%), as well as in the absence of grade 3 or 4 neurotoxicity.
Toxic effects of irinotecan, especially neutrope- nia, have been associated with UGT1A1*28 homo- zygosity30,31 and with other variants of UGT1A1 or DPYD.32-34 The incidence of neutropenia increased numerically with the number of *28 copies, where- as this pattern was not observed for other adverse events of interest such as diarrhea (Table S4 in Supplementary Appendix). However, the results are based on a retrospective, exploratory analysis, and additional validation is needed before they can be used for clinical decision making related to sacituzumab govitecan-hziy.
Among the few studies involving pretreated patients with metastatic breast cancer, one of the largest, EMBRACE (Eisai Metastatic Breast Can- cer Study Assessing Physician’s Choice Versus Eribulin), involved 762 patients who had received a median of four previous chemotherapy regimens,
and 19% had triple-negative breast cancer.26 Ad- verse events leading to discontinuation of treat- ment occurred in 13% of the patients receiving eribulin and 15% receiving treatment of the physician’s choice (any single-agent chemotherapy, hormone, or radiotherapy). In the EMBRACE study, the incidence of neutropenia was 52% with eribu- lin (the incidence of grade 4 neutropenia was 24%) and 30% with the physician’s choice (grade 4 neu- tropenia, 7%) and the response rate was 12% with eribulin (duration of response, 4.2 months) and 5% with the physician’s choice (duration of response, 6.7 months). The response rate of 33% and the duration of response of 7.7 months re- ported with sacituzumab govitecan-hziy compare favorably.26 In addition, topoisomerase inhibition may have advantages over microtubule inhibition in these patients, given that altered DNA repair pathways are common in triple-negative breast cancer.35 Furthermore, confirmed objective re- sponses were noted in patients who had received previous programmed death 1–based therapy or programmed death ligand 1–based therapy, sug- gesting a lack of cross-resistance with immune checkpoint inhibitors and the potential useful- ness of combination therapy.
Direct comparison with other chemotherapy approaches was not possible in this trial because of its noncomparative design. However, we used the response rate as the primary end point, which is less subject to bias than progression-free sur- vival in a single-group trial and has been used for

accelerated approval in other oncology trials,36-38 with only a small portion of indications under the accelerated approval program failing to verify clinical benefit.39 A confirmatory multicenter, ran- domized, phase 3 trial (ASCENT; ClinicalTrials.gov number, NCT02574455) is currently recruiting pa- tients in North America and Europe to compare sacituzumab govitecan-hziy with the physician’s choice of four single-agent types of chemotherapy (capecitabine, gemcitabine, vinorelbine, and er- ibulin) in patients with metastatic triple-negative breast cancer that is refractory or relapsed after at least two previous forms of chemotherapy (in- cluding a taxane).
In conclusion, sacituzumab govitecan-hziy (IMMU-132) had efficacy with a 33% response rate in a heavily pretreated population of patients with metastatic triple-negative breast cancer. Diarrhea and myelosuppression were the primary adverse events, and discontinuation rates were low.
Editor’s note: After this article went to press, the trial sponsor was informed by the FDA that the suffix “-hziy” had not yet been formally approved.
Supported by Immunomedics.
Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.
A data sharing statement provided by the authors is available with the full text of this article at NEJM.org.
We thank the patients and their caregivers, the clinical trial investigators and their team members who participated in this trial, Heather Horne and Dr. Pius Maliakal for trial management, Dr. Sharon K. Wyhopen for critical review of an earlier version of the manuscript and participation in discussions, Veristat for as- sistance with the data analysis, and Dr. Axel Glasmacher of AG Life Science Consulting and Peloton Advantage for editorial and writing support with an earlier version of the manuscript.
Appendix
The authors’ full names and academic degrees are as follows: Aditya Bardia, M.D., Ingrid A. Mayer, M.D., Linda T. Vahdat, M.D., M.B.A., Sara M. Tolaney, M.D., M.P.H., Steven J. Isakoff, M.D., Ph.D., Jennifer R. Diamond, M.D., Joyce O’Shaughnessy, M.D., Re- becca L. Moroose, M.D., Alessandro D. Santin, M.D., Vandana G. Abramson, M.D., Nikita C. Shah, M.D., Hope S. Rugo, M.D., Da- vid M. Goldenberg, Sc.D., M.D., Ala M. Sweidan, M.B.A., M.S., Robert Iannone, M.D., Sarah Washkowitz, J.D., Robert M. Sharkey, Ph.D., William A. Wegener, M.D., Ph.D., and Kevin Kalinsky, M.D.
The authors’ affiliations are as follows: the Massachusetts General Hospital Cancer Center (A.B., S.J.I.) and Dana–Farber Cancer Institute (S.M.T.), Harvard Medical School, Boston; Vanderbilt–Ingram Cancer Center, Nashville (I.A.M., V.G.A.); Weill Cornell Medical College (L.T.V.) and New York–Presbyterian–Columbia University Irving Medical Center (K.K.), New York; University of Colorado Can- cer Center, Aurora (J.R.D.); Texas Oncology, Baylor University Medical Center, US Oncology, Dallas (J.O.); Orlando Health University of Florida Health Cancer Center, Orlando (R.L.M., N.C.S.); Yale University School of Medicine, New Haven, CT (A.D.S.); University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center, San Francisco (H.S.R.); Immunomedics, Morris Plains, NJ (D.M.G., R.I., S.W., R.M.S., W.A.W.); and AIS Consulting, Ann Arbor, MI (A.M.S.).

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Copyright © 2019 Massachusetts Medical Society.

Sacituzumab Govitecan-hziy in Refractory Metastatic Triple-Negative Breast Cancer
A. Bardia, I.A. Mayer, L.T. Vahdat, S.M. Tolaney, S.J. Isakoff, J.R. Diamond, J. O’Shaughnessy, R.L. Moroose, A.D. Santin, V.G. Abramson, N.C. Shah, H.S. Rugo, D.M. Goldenberg, A.M. Sweidan, R. Iannone, S. Washkowitz,R.M. Sharkey, W.A. Wegener, and K. Kalinsky

ABSTR ACT
BACKGROUNDStandard chemotherapy is associated with low response rates and short progression- free survival among patients with pretreated metastatic triple-negative breast cancer. Sacituzumab govitecan-hziy is an antibody–drug conjugate that combines a human- ized monoclonal antibody, which targets the human trophoblast cell-surface anti- gen 2 (Trop-2), with SN-38, which is conjugated to the antibody by a cleavable linker. Sacituzumab govitecan-hziy enables delivery of high concentrations of SN-38 to tumors.METHODSWe conducted a phase 1/2 single-group, multicenter trial involving patients with advanced epithelial cancers who received sacituzumab govitecan-hziy intravenously on days 1 and 8 of each 21-day cycle until disease progression or unacceptable toxic effects. A total of 108 patients received sacituzumab govitecan-hziy at a dose of 10 mg per kilogram of body weight after receiving at least two previous antican- cer therapies for metastatic triple-negative breast cancer. The end points included safety; the objective response rate (according to Response Evaluation Criteria in Solid Tumors, version 1.1), which was assessed locally; the duration of response; the clini- cal benefit rate (defined as a complete or partial response or stable disease for at least 6 months); progression-free survival; and overall survival. Post hoc analyses deter- mined the response rate and duration, which were assessed by blinded independent central review.RESULTSThe 108 patients with triple-negative breast cancer had received a median of 3 previ- ous therapies (range, 2 to 10). Four deaths occurred during treatment; 3 patients (2.8%) discontinued treatment because of adverse events. Grade 3 or 4 adverse events (in ≥10% of the patients) included anemia and neutropenia; 10 patients (9.3%) had febrile neutropenia. The response rate (3 complete and 33 partial responses) was 33.3% (95% confidence interval [CI], 24.6 to 43.1), and the median duration of response was 7.7 months (95% CI, 4.9 to 10.8); as assessed by independent central review, these values were 34.3% and 9.1 months, respectively. The clinical benefit rate was 45.4%. Median progression-free survival was 5.5 months (95% CI, 4.1 to 6.3), and overall survival was 13.0 months (95% CI, 11.2 to 13.7).CONCLUSIONSSacituzumab govitecan-hziy was associated with durable objective responses in pa- tients with heavily pretreated metastatic triple-negative breast cancer. Myelotoxic effects were the main adverse reactions. (Funded by Immunomedics; IMMU-132-01 ClinicalTrials.gov number, NCT01631552.)

The authors’ full names, academic degrees, and affiliations are listed in the Appendix. Address reprint requests to Dr. Bardia at the Massachusetts General Hospital Can- cer Center, Harvard Medical School, Law- rence House 304, 10 N. Grove St., Bos- ton, MA 02114, or at [email protected] Engl J Med 2019;380:741-51. DOI: 10.1056/NEJMoa1814213Copyright © 2019 Massachusetts Medical Society.

riple-negative breast cancer, which is defined by a lack of tumor-cell expres- sion of the estrogen receptor, progesteronereceptor, and human epidermal growth factor receptor 2 (HER2),1,2 accounts for approximately 15% of invasive breast cancers3-5 and is associated with aggressive tumor biology and a poor prog- nosis. Triple-negative breast cancer is more com- mon in younger women than in older women and in black persons than in persons of other races and ethnic groups, and it is often associated with visceral metastases.2,4Although targeted therapies have benefited pa- tients with other subtypes of breast cancer, and several targeted therapies for hormone-receptor– positive and HER2-positive breast cancer have re- cently been approved for use,6-9 sequential single- agent chemotherapy remains the standard of care for patients with metastatic triple-negative breast cancer.7,10 Recently, a progression-free survival of 7.2 months was reported with investigational use of atezolizumab and nab-paclitaxel combination therapy in previously untreated patients with meta- static triple-negative breast cancer.11 However, a majority of patients have disease progression after receiving first-line therapy, and standard therapeu- tic options are limited to chemotherapy. Standard chemotherapy is associated with low response rates (10 to 15%) and short progression-free sur- vival (2 to 3 months) among patients with pre- treated metastatic triple-negative breast cancer.12-16 Overall survival among patients with this form of breast cancer has not changed over the past 20 years6; this highlights the need for advances in therapeutic options for these patients.Sacituzumab govitecan-hziy (IMMU-132; Im- munomedics) is an antibody–drug conjugate in which SN-38 (an active metabolite of irinotecan), a topoisomerase I inhibitor, is coupled to the hu- manized antitrophoblast cell-surface antigen 2 (Trop-2) monoclonal antibody hRS7 IgG1κ through the cleavable CL2A linker.17 Trop-2, a transmem- brane calcium signal transducer, is overexpressed in many epithelial cancers, and it stimulates can- cer-cell growth.18,19 Trop-2 is detected in breast cancer cells, including those in triple-negative breast cancer,19,20 and its expression is reported in more than 85% of tumors.21,22 On binding to Trop-2, hRS7 (in free or conjugated form) is inter- nalized and delivers SN-38 into the tumor cell.23 In addition, because of the cleavable linker, SN-38 is released in tumors both intracellularly and in
the tumor microenvironment, thereby allowing for the delivery of therapeutic concentrations of the drug in bystander cells to which the conjugate has not bound. Sacituzumab-bound tumor cells are killed by intracellular uptake of SN-38, and adja- cent tumor cells are killed by the extracellular release of SN-38.24IMMU-132-01 is a phase 1/2, basket design, open-label, single-group, multicenter trial involv- ing patients with various types of advanced solid cancers who have received at least one previous therapy for metastatic disease. Preliminary results for 69 patients with metastatic triple-negative breast cancer have been reported.25 In 2016, saci- tuzumab govitecan-hziy was assigned a “break- through therapy” designation by the Food and Drug Administration (FDA) for the treatment of patients with metastatic triple-negative breast can- cer who have received at least two previous thera- pies for metastatic disease, and, accordingly, the protocol was amended to require further enroll- ment in a more defined population of patients with metastatic triple-negative breast cancer who had received at least two lines of previous therapy, including previous taxane therapy. Here, we report updated results for all patients who received saci- tuzumab govitecan-hziy as a third-line or higher line of therapy for metastatic triple-negative breast cancer at the clinically selected dose level of 10 mg per kilogram of body weight.
MethodsTrial Design and OversightEligibility criteria that were previously described for patients with metastatic triple-negative breast cancer25 also apply to the overall trial population (see the Methods section in the Supplementary Ap- pendix, available with the full text of this article at NEJM.org). Sacituzumab govitecan-hziy was ad- ministered as an intravenous infusion on days 1 and 8 of 21-day cycles until disease progression or unacceptable adverse events. In case of severe treatment-related adverse events, dose reductions of 25% were allowed for the first occurrence and of 50% for the second occurrence, with treatment discontinuation at the third occurrence. Hemato- poietic growth factors or blood transfusions were allowed at the investigator’s discretion; however, prophylactic treatment before the first dose (cy- cle 1, day 1) was not allowed. All patients with metastatic triple-negative breast cancer in the

efficacy data set received treatment at a starting dose of 10 mg per kilogram.The sponsor, Immunomedics, designed the trial and gathered the data. Data analysis was performed by Veristat and by authors who are employed by Immunomedics. All the authors assume respon- sibility for the accuracy and completeness of the data and vouch for the fidelity of the trial to the protocol, which is available at NEJM.org. The first draft of the manuscript was written by the first author with the sponsor and a medical writer paid by the sponsor. All the authors contributed to the writing, review, and revision of the manuscript.
Efficacy EvaluationsStaging computed tomography (CT) and magnetic resonance imaging (MRI) were performed at base- line and at 8-week intervals from the start of treat- ment until disease progression requiring discon- tinuation of treatment. Confirmatory CT and MRI were performed no sooner than 4 weeks after an initial partial or complete response. Subsequent imaging was performed at 8-week intervals after the confirmatory imaging.The primary efficacy end point was the objec- tive response rate. Assessment of response was performed according to Response Evaluation Crite- ria in Solid Tumors, version 1.1. Local assessments were used for treatment decisions and for the pri- mary efficacy analysis. Other efficacy end points were the time to response and the duration of re- sponse in patients who had a response, the clinical benefit rate (defined as a complete or partial response or stable disease for at least 6 months), and progression-free and overall survival.Blinded independent central review of staging
scans was also obtained for the 56 patients (of the 108 with metastatic triple-negative breast cancer) who had complete or partial remission, or at least a 20% reduction in the baseline sum of the diam- eters of the target lesions, according to local site evaluation. This blinded independent review, which was performed by Intrinsic Imaging, included re- views by two independent radiologists and a third adjudicating radiologist, if needed.
Safety EvaluationsSafety evaluations included assessments of adverse events and serious adverse events, laboratory safety evaluations, vital signs, physical examination, and 12-lead electrocardiography (ECG). A 12-lead ECG was to be performed at baseline, after completion* Race or ethnic group was reported by the patients.† Eleven patients did not indicate or declined to indicate their race or ethnic group; four identified as Native American, Dominican, Hispanic, or mixed race.‡ The Eastern Cooperative Oncology Group (ECOG) performance-status scale ranges from 0 to 5, with 0 indicating that the patient is fully active with no re- strictions, 1 indicating that the patient is ambulatory and able to carry out work of a light or sedentary nature but restricted in physically strenuous activ- ity, and higher numbers indicating increasing degrees of disability.§ Visceral organs were defined as solid organs, excluding the brain.

of the infusion on day 1 of every even-numbered treatment cycle, at the end of treatment, and at the end of the trial. Adverse events were coded according to the Medical Dictionary for Regulatory Activities, version 20.0, and severity was graded according to Common Terminology Criteria for Adverse Events (CTCAE), version 4.0. For events

Table 2. Summary of Adverse Events in Patients Receiving Sacituzumab Govitecan-hziy.*Adverse EventPatients (N=108)
Any GradeGrade 3Grade 4
number of patients with event (percent)Any adverse event108 (100)71 (66)21 (19)Gastrointestinal disorders102 (94)21 (19)0Nausea72 (67)7 (6)0Diarrhea67 (62)9 (8)0Vomiting53 (49)7 (6)0Constipation37 (34)1 (1)0Abdominal pain†27 (25)1 (1)0Mucositis‡15 (14)00General disorders and administration-site conditions82 (76)10 (9)0Fatigue and asthenia59 (55)9 (8)0Peripheral edema17 (16)00Pyrexia13 (12)00Blood and lymphatic system disorders80 (74)25 (23)15 (14)Neutropenia§69 (64)28 (26)17 (16)Anemia54 (50)12 (11)0Metabolism and nutrition disorders70 (65)21 (19)2 (2)Decreased appetite32 (30)00Hyperglycemia26 (24)3 (3)1 (1)Hypomagnesemia23 (21)1 (1)0Hypokalemia19 (18)2 (2)0Hypophosphatemia16 (15)10 (9)0Dehydration14 (13)4 (4)0Skin and subcutaneous tissue disorders66 (61)5 (5)0Alopecia39 (36)00Rash¶30 (28)2 (2)0Pruritus17 (16)00Dry skin15 (14)1 (1)0Abnormal values62 (57)22 (20)6 (6)Decreased white-cell count23 (21)9 (8)3 (3)Prolonged activated partial thromboplastin time15 (14)2 (2)0Increased aspartate aminotransferase level15 (14)1 (1)0Increased alanine aminotransferase level15 (14)1 (1)0Decreased weight15 (14)00Increased blood alkaline phosphatase level12 (11)2 (2)0Increased blood lactate dehydrogenase level11 (10)00Nervous system disorders59 (55)4 (4)0Headache23 (21)1 (1)0Dizziness22 (20)00Neuropathy‖20 (19)00Dysgeusia12 (11)00

Table 2. (Continued.)Adverse EventPatients (N=108)
Any GradeGrade 3Grade 4
number of patients with event (percent)Infections and infestations56 (52)11 (10)2 (2)Respiratory infection**23 (21)3 (3)0Urinary tract infection22 (20)3 (3)0Musculoskeletal and connective-tissue disorders56 (52)00Back pain24 (22)00Arthralgia17 (16)00Pain in extremity11 (10)00Respiratory, thoracic, and mediastinal disorders55 (51)4 (4)1 (1)Cough and productive cough21 (19)00Dyspnea20 (19)2 (2)1 (1)Psychiatric disorders27 (25)1 (1)0Insomnia15 (14)00* Shown are the adverse events of any grade (according to Common Terminology Criteria for Adverse Events [CTCAE], version 4.0) that occurred in at least 10% of the patients. The Medical Dictionary for Regulatory Activities system organ class and preferred terms are reported whenever possible.† This category includes abdominal pain, abdominal distention, upper abdominal pain, abdominal discomfort, and ab- dominal tenderness.‡ This category includes stomatitis and mucosal inflammation.§This category includes neutropenia and decreased neutrophil counts. Febrile neutropenia of all grades was observed in 10 patients (9%), and grade 3 and grade 4 febrile neutropenia was observed in 7 patients (6%) and 2 patients (2%), respectively.¶ This category includes maculopapular rash, generalized rash, dermatitis acneiform, and skin disorder.‖This category includes peripheral neuropathy, paresthesia, peripheral sensory neuropathy, and hypoesthesia.** This category includes upper respiratory tract infection, viral upper respiratory tract infection, lower respiratory tract infection, pneumonia, influenza, bronchitis, and respiratory syncytial virus infection.

with varying severity, the maximum reported grade was used in summaries. The safety evaluation for the cohort of patients with metastatic triple-neg- ative breast cancer was the same as that for the overall trial population.
Statistical AnalysisDetails of the statistical analyses have been de- scribed previously.25 When the cohort of patients with metastatic triple-negative breast cancer was evaluated to identify those who received sacituz- umab govitecan-hziy at a dose of 10 mg per kilo- gram and had received at least two previous therapies for metastatic disease, the target group included 108 patients. The response rate and the exact 95% confidence intervals were calculated with the use of the Clopper–Pearson method. Progression-free and overall survival and time- to-event end points were analyzed with the use of Kaplan–Meier methods, with medians and cor- responding 95% confidence intervals determined according to the Brookmeyer and Crowley methodwith log–log transformation. Subgroup analyses were used to evaluate the effect of patient factors and previous cancer treatments.The trial was approved by the institutional review board at each investigational site before initiation of the trial and was performed in ac- cordance with the Declaration of Helsinki, the International Council for Harmonisation guide- lines for Good Clinical Practice, the FDA Code of Federal Regulations, the requirements of national drug and data protection laws, other applicable regulatory requirements, and the standard oper- ating procedures of Immunomedics. All patients provided written informed consent before en- rollment.
ResultsPatient PopulationA total of 108 patients with metastatic triple-nega- tive breast cancer (median age, 55 years) were en- rolled between June 2013 and February 2017. The

patients had been heavily pretreated (median of 3 previous anticancer regimens [range, 2 to 10]). A total of 106 of these patients (98%) had received taxanes and 93 (86%) had received anthracyclines. The baseline demographic characteristics of the patients are summarized in Table 1. At the time of data cutoff (December 1, 2017), the median duration of follow-up among the 108 patients with metastatic triple-negative breast cancer was 9.7 months (range, 0.3 to 36.5). Eight of these patients were continuing to receive treatment. A total of 100 patients (92.6%) had discontinued treatment, and in 86 of these patients (80%), discontinuation was because of disease progression. Other reasons for discontinuation are listed in Table S1 in the Supplementary Appendix.
SafetyThe 108 patients with metastatic triple-negative breast cancer received a mean of 18.7 doses of sacituzumab govitecan-hziy (range, 1 to 102), or 9.6 cycles (range, 1 to 51), with a median duration of exposure of 5.1 months (range, 0.03 to 36.1). A total of 99 patients (92%) received preinfusion medications (acetaminophen, antihistamines, H2 antagonists, glucocorticoids, antiemetics, anxio- lytics, and atropine). The most common adverse events were nausea, diarrhea, fatigue, neutropenia, and anemia, and the most common adverse events of grade 3 or higher (>5% incidence) included neu- tropenia, anemia, and a decreased white-cell count, as outlined in Table 2. Diarrhea (predominantly grade 1) was a common adverse event (in 62% of the patients overall); the incidence of CTCAE grade 2 diarrhea was 14%, and the incidence of at least grade 3 diarrhea was 8%. No peripheral neuropa- thy of grade 3 or higher was reported. Four pa- tients (4%) had adverse events leading to death during treatment (details are provided in the Results section in the Supplementary Appendix). Serious adverse events were reported in 35 pa- tients (32%); the most common (>2% incidence) were febrile neutropenia (in 7% of the patients), vomiting (in 6%), nausea (in 4%), diarrhea (in 3%), and dyspnea (in 3%).Adverse events leading to interruption of treat- ment occurred in 48 of the 108 patients (44%); the most common reason was neutropenia. Three pa- tients (3%) discontinued treatment because of ad- verse events; 2 patients discontinued because of drug-related events, and 1 patient discontinued because of hypertension, which was thought by
the investigator not to be drug-related. Transient changes in laboratory safety values that occurred during treatment included decreases in blood-cell counts and alterations in biochemical values, which generally recovered by the end of treatment.
EfficacyIn Figure 1A, a waterfall plot shows the breadth and depth of responses according to local assess- ment in 108 patients with metastatic triple-nega- tive breast cancer. The response rate was 33.3% (36 of 108 patients), including complete respons- es in 3 patients (2.8%). The clinical benefit rate (including stable disease for at least 6 months) was 45.4% (49 of 108 patients). In Figure 1B, a swimmer plot shows the onset and durability of response in each of the 36 patients who had an objective response. In these patients, the median time to response was 2.0 months (range, 1.6 to 13.5), and the median duration of response was 7.7 months (95% confidence interval [CI], 4.9 to 10.8). The response rate (34.3% [95% CI, 25.4 to 44.0]) and median duration of response (9.1 months [95% CI, 4.6 to 11.3]) according to blinded inde- pendent review were similar to those determined by local assessment (Table S5 in the Supplemen- tary Appendix). According to local assessment, the estimated probability that a patient would have a response at 6 months was 59.7%, and the esti- mated probability that a patient would have a response at 12 months was 27.0% (Fig. S2 in the Supplementary Appendix). At the database cutoff date, 6 patients had long-term responses with a response for more than 12 months (range, 12.7 to 30.4). Table 3 summarizes the results according to investigator assessment.We evaluated the response to sacituzumab govitecan-hziy in a variety of patient subgroups (Table S6 in the Supplementary Appendix) and found no meaningful differences in response rates according to patient age, the onset of metastatic disease, the number of previous therapies, or the presence or absence of visceral metastases. The response rate was 44% (8 of 18) among patients who had received previous checkpoint inhibitors; however, these results and those of all the reported subgroups should be interpreted with caution given the small number of patients available, which led to wide confidence intervals.At the time of data cutoff, 94 patients (87.0%) had disease progression and 77 patients (71.3%) had died. The median progression-free survival

Figure 1. Response and Survival among 108 Patients with Metastatic Triple-Negative Breast Cancer.Panel A shows a waterfall plot of the best percent change from baseline in the sum of the diameters of the target lesions (longest diameter for non-nodal le- sions and short axis for nodal lesions). In 3 patients (2 with stable disease and 1 with progressive disease) (asterisks), the best percent change was zero. The dashed lines at 20% and -30% indicate progressive disease and partial response, respectively, according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. Additional details are providedin the Results section in the Supplementary Appendix. Panel B shows a swimmer plot of the objective respons- es (according to RECIST, version 1.1) from the start of treatment to disease progression, as determined by lo- cal assessment. At the time of the analysis, 6 patients had a continuing response. The vertical dashed lines show the response at 6 months and 12 months, which are clinically meaningful end points for patients with metastatic triple-negative breast cancer. Panel C shows a Kaplan–Meier analysis of progression-free survival among the 108 patients.
was 5.5 months (95% CI, 4.1 to 6.3); the estimated probability of progression-free survival was 41.9% at 6 months and 15.1% at 12 months (Fig. 1C). The median overall survival was 13.0 months (95% CI, 11.2 to 13.7); the estimated probability of survival was 78.5% at 6 months and 51.3% at 12 months (Fig. S3 in the Supplementary Ap- pendix).To analyze efficacy in relation to the aggres- siveness of the clinical course and to address concerns regarding relatively indolent tumor bi- ologic characteristics in the trial population, we compared the duration of treatment with sacituz- umab govitecan-hziy with that of previous anti- cancer treatment in the 108 patients with meta- static triple-negative breast cancer for whom data were available. The median duration of treatment with sacituzumab govitecan-hziy (5.1 months) was approximately twice that with the previous anti- cancer treatment (2.5 months); this highlights the clinical activity and lack of cross-resistance with this antibody–drug conjugate (Fig. 2).
DiscussionAmong patients with metastatic triple-negative
breast cancer who had received at least two pre- vious therapies for metastatic disease (median, three) and who received treatment with sacitu- zumab govitecan-hziy, the response rate was 33.3%, the median duration of response was 7.7months, the median progression-free survival was 5.5 months, and the median overall survival was 13.0 months. Efficacy was observed in patients who had received taxanes and anthracyclines, sug- gesting a lack of cross-resistance to previous cyto-

treatment with cytotoxic agents in this patient population,26 were not observed. Hypersensitivity events of grade 3 or higher that were associated with infusion of monoclonal antibodies were infre- quent (in 3 patients [3%]). Four deaths occurred during treatment (within 30 days after the last dose of sacituzumab govitecan-hziy); all deaths were at- tributed by the investigators to disease progres- sion, and none were considered to be related to sacituzumab govitecan-hziy (see the Results sec- tion in the Supplementary Appendix). The safety profile of sacituzumab govitecan-hziy in the 108 patients with metastatic triple-negative breast can- cer was generally consistent with that in the overall safety population of 420 patients who had a variety of tumor types (Table S3 in the Supplementary Appendix).The long-term efficacy of the various treat-
* These patients could not be evaluated because of death, transfer to hospice, withdrawal due to clinical progression, or withdrawal due to grade 4 neutrope- nia before any radiologic assessment of response.† The objective response rate is the percentage of patients with a complete re- sponse or partial response.‡ The clinical benefit rate is the percentage of patients with a complete re- sponse or partial response or stable disease for at least 6 months.
toxic chemotherapy. The duration of treatment with sacituzumab govitecan-hziy was longer than with the immediate previous antitumor therapy (5.1 months vs. 2.5 months); this provides fur- ther evidence of clinical activity in patients with difficult-to-treat metastatic triple-negative breast cancer. Although a subgroup analysis based on the patients’ age, the onset of metastatic disease, the number of previous therapies, or the presence or absence of visceral metastases showed no meaningful differences in outcomes, the small number of patients led to wide confidence inter- vals, and thus the homogeneity of clinical out- comes observed in these subgroups is weak and should be interpreted with caution.The most relevant adverse events in patients with metastatic triple-negative breast cancer, as well as in the larger population of patients with multiple tumor types who received sacituzumab govitecan-hziy, included neutropenia and diarrhea, which were managed with routine supportive care according to general practice guidelines (i.e., early intervention with granulocyte colony-stimulating factor and early intervention for diarrhea). Few patients discontinued treatment because of adverse events. Severe drug-related neuropathy or cardiac adverse events, which may limit the duration ofment options for patients with metastatic triple- negative breast cancer (serial application of single agents) is limited.12-14,16 Poor outcomes seen in pa- tients with metastatic triple-negative breast cancer, as compared with other breast cancer subtypes, are partly explained by the lack of actionable driver mutations or established molecular targets, there- by leaving sequential single-agent chemotherapy as the main treatment approach.7,10 Sacituzumab govitecan-hziy is an antibody–drug conjugate with Trop-2 as the target of recognition; it can deliver cytotoxic chemotherapy to tumors, including ad- jacent cancer cells, in concentrations that are higher than those with standard chemotherapy and may reduce toxic effects in normal tissues that do not express the target.24 High expression of Trop-2 in triple-negative breast cancer and its association with a poor prognosis suggest that it is a rational therapeutic target in this patient population.19,21The cytotoxic component of sacituzumab gov- itecan-hziy is SN-38, a highly potent topoisomer- ase I inhibitor and metabolite of irinotecan. The cytotoxic activity of SN-38 delivered through sacituzumab govitecan-hziy is 100 to 1000 times as high as that of irinotecan.27 In animal models, the tumor-to-serum area under the curve ratio for SN-38 was 20 to 40 times as high with sacituz- umab govitecan-hziy as it was with irinotecan, whereas concentrations that were 20 to 136 times as high as those with irinotecan were delivered into the tumor.24 Clinically, serum concentrations of glucuronidated SN-38, the molecular species most strongly associated with toxic effects, were

Receipt of last previous therapyReceipt of sacituzumab govitecan-hziyContinuation of treatment

*****
30241812606121824303642Months
Figure 2. Duration of Treatment with Sacituzumab Govitecan-hziy and with the Last Previous Therapy in the 108 Patients with Metastatic Triple-Negative Breast Cancer.Asterisks indicate patients who received therapy for only 1 day. The vertical dashed lines at 6 months and 12 months show the clinically meaningful end points for patients with metastatic triple-negative breast cancer. When the month and year were available, a missing start date was imputed as the 15th of the month, and a missing end date was imputed as the last day of the month.

and 19% had triple-negative breast cancer.26 Ad- verse events leading to discontinuation of treat- ment occurred in 13% of the patients receiving eribulin and 15% receiving treatment of the physician’s choice (any single-agent chemotherapy, hormone, or radiotherapy). In the EMBRACE study, the incidence of neutropenia was 52% with eribu- lin (the incidence of grade 4 neutropenia was 24%) and 30% with the physician’s choice (grade 4 neu- tropenia, 7%) and the response rate was 12% with eribulin (duration of response, 4.2 months) and 5% with the physician’s choice (duration of response, 6.7 months). The response rate of 33% and the duration of response of 7.7 months re- ported with sacituzumab govitecan-hziy compare favorably.26 In addition, topoisomerase inhibition may have advantages over microtubule inhibition in these patients, given that altered DNA repair pathways are common in triple-negative breast cancer.35 Furthermore, confirmed objective re- sponses were noted in patients who had received previous programmed death 1–based therapy or programmed death ligand 1–based therapy, sug- gesting a lack of cross-resistance with immune checkpoint inhibitors and the potential useful- ness of combination therapy.Direct comparison with other chemotherapy approaches was not possible in this trial because of its noncomparative design. However, we used the response rate as the primary end point, which is less subject to bias than progression-free sur- vival in a single-group trial and has been used for
accelerated approval in other oncology trials,36-38 with only a small portion of indications under the accelerated approval program failing to verify clinical benefit.39 A confirmatory multicenter, ran- domized, phase 3 trial (ASCENT; ClinicalTrials.gov number, NCT02574455) is currently recruiting pa- tients in North America and Europe to compare sacituzumab govitecan-hziy with the physician’s choice of four single-agent types of chemotherapy (capecitabine, gemcitabine, vinorelbine, and er- ibulin) in patients with metastatic triple-negative breast cancer that is refractory or relapsed after at least two previous forms of chemotherapy (in- cluding a taxane).In conclusion, sacituzumab govitecan-hziy (IMMU-132) had efficacy with a 33% response rate in a heavily pretreated population of patients with metastatic triple-negative breast cancer. Diarrhea and myelosuppression were the primary adverse events, and discontinuation rates were low.Editor’s note: After this article went to press, the trial sponsor was informed by the FDA that the suffix “-hziy” had not yet been formally approved.Supported by Immunomedics.Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.A data sharing statement provided by the authors is available with the full text of this article at NEJM.org.We thank the patients and their caregivers, the clinical trial investigators and their team members who participated in this trial, Heather Horne and Dr. Pius Maliakal for trial management, Dr. Sharon K. Wyhopen for critical review of an earlier version of the manuscript and participation in discussions, Veristat for as- sistance with the data analysis, and Dr. Axel Glasmacher of AG Life Science Consulting and Peloton Advantage for editorial and writing support with an earlier version of the manuscript.

AppendixThe authors’ full names and academic degrees are as follows: Aditya Bardia, M.D., Ingrid A. Mayer, M.D., Linda T. Vahdat, M.D., M.B.A., Sara M. Tolaney, M.D., M.P.H., Steven J. Isakoff, M.D., Ph.D., Jennifer R. Diamond, M.D., Joyce O’Shaughnessy, M.D., Re- becca L. Moroose, M.D., Alessandro D. Santin, M.D., Vandana G. Abramson, M.D., Nikita C. Shah, M.D., Hope S. Rugo, M.D., Da- vid M. Goldenberg, Sc.D., M.D., Ala M. Sweidan, M.B.A., M.S., Robert Iannone, M.D., Sarah Washkowitz, J.D., Robert M. Sharkey, Ph.D., William A. Wegener, M.D., Ph.D., and Kevin Kalinsky, M.D.The authors’ affiliations are as follows: the Massachusetts General Hospital Cancer Center (A.B., S.J.I.) and Dana–Farber Cancer Institute (S.M.T.), Harvard Medical School, Boston; Vanderbilt–Ingram Cancer Center, Nashville (I.A.M., V.G.A.); Weill Cornell Medical College (L.T.V.) and New York–Presbyterian–Columbia University Irving Medical Center (K.K.), New York; University of Colorado Can- cer Center, Aurora (J.R.D.); Texas Oncology, Baylor University Medical Center, US Oncology, Dallas (J.O.); Orlando Health University of Florida Health Cancer Center, Orlando (R.L.M., N.C.S.); Yale University School of Medicine, New Haven, CT (A.D.S.); University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center, San Francisco (H.S.R.); Immunomedics, Morris Plains, NJ (D.M.G., R.I., S.W., R.M.S., W.A.W.); and AIS Consulting, Ann Arbor, MI (A.M.S.).
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