Trodelvy® (sacituzumab govitecan-hziy)

ADC Sequencing in HER2- mBC

This document is in response to your request for information regarding Trodelvy® (sacituzumab govitecan-hziy [SG]) and sequencing with other antibody-drug conjugates (ADCs) in the treatment of human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (mBC).

This document includes content from, or references to, clinical practice guidelines and inclusion should not be interpreted as a treatment recommendation or an endorsement of the guidelines by Gilead Sciences, Inc.

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Summary

Real-World Data on Sequential ADC Use in mBC1-17

This document summarizes efficacy and safety data on the sequential use of ADCs, primarily SG and T-DXd (SGT-DXd vs T-DXdSG), in patients with HER2- mBC. Included are findings from retrospective, real-world analyses of single-center and multicenter studies, as well as EHR databases. Studies of ≤40 patients were excluded.

Results of progression-based endpoints (most commonly PFS2), OS, and response outcomes (ORR, RR, and CBR); analyses by HR status (HR+, HR-, and TNBC), HER2 expression (HER2-, HER2-ultra-low, HER2-low, and HER2-null), LoT, and use of intervening therapy, are presented. Of the 13 studies included, three reported safety outcomes.9,10,16

Clinical Study Data on Sequential ADC Use in mBC18

The phase 1, TROPION-PanTumor01 study, is evaluating the safety and efficacy of Dato-DXd in relapsed/refractory metastatic solid tumors and includes 44 patients with aTNBC. Eleven patients, 2 patients, and 1 patient had previously received SG, T-DXd, and patritumab deruxtecan, respectively. Results for all patients vs TOP1 inhibitor-naïve patients (n=30) for mPFS (95% CI) was 4.4 (3–7.3) mo vs 7.3 (3–18) mo, respectively, and for mOS (95% CI) was 13.5 (10.1–16.3) mo vs 14.3 (10.5–NE) mo, respectively.

NCCN Clinical Practice Guidelines in Oncology for Breast Cancer19

SG and Dato-DXd are listed as Category 1, preferred 1L treatment options for PD-L1- (CPS <10) mTNBC and no germline BRCA1/2 mutation.

SG + pembro is listed as a Category 1, preferred 1L treatment option for PD-L1+ (CPS ≥10) mTNBC regardless of germline BRCA1/2 status. While available data are in the 1L setting, this regimen can be used for 2L+ if PD-(L)1 inhibitor therapy has not been previously used. If there is disease progression while on a PD-(L)1 inhibitor, there are no data to support an additional LoT with another PD-(L)1 inhibitor.

SG is listed as a Category 1 preferred 2L treatment option for patients with recurrent unresectable or metastatic HR+/HER2- breast cancer with visceral crisis or endocrine refractory breast cancer who are not candidates for T-DXd (T-DXd is recommended as a Category 1 preferred treatment option for patients who test HER2 (ERBB2) IHC 1+ or 2+/ISH-). SG may be used in adult patients after prior treatment that includes ET, CDK4/6i, and ≥2 lines of chemotherapy, 1 of which was a taxane, and ≥1 of which was in the metastatic setting. SG may be considered for later line if not used as 2L therapy. T-DXd may be used in those previously treated with ≥1 line of ET in the metastatic setting.

SG is listed as a Category 1 preferred 2L treatment option for patients with recurrent unresectable or mTNBC as 2L therapy. SG may be considered for later line if not used as 2L therapy. T-DXd is listed as a category 2A other recommended 2L treatment option for patients with recurrent unresectable or mTNBC who test HER2 (ERBB2) IHC 1+ or 2+/ISH- and no germline BRCA1/2 pathogenic variant. T-DXd can be considered for later line for HER2 (ERBB2) IHC 1+ or 2+/ISH- if not used in 2L or may be considered 1L therapy when disease has progressed during or within 6 months after completing adjuvant chemotherapy.

Real-World Data on Sequential ADC Use in mBC

Retrospective Study of mBC and HER2 Expression1

An analysis of breast tumor specimens that underwent profiling compared clinical outcomes in patients treated with SG, T-DXd, or in both in sequential order (ie, SGT-DXd [n=360] and T-DXdSG [n=420]). Of the patients treated with both ADCs, the TOT2 was calculated from the beginning of ADC1 treatment to the end of ADC2 treatment. OS data were determined from the time of ADC initiation to the last date or known clinical activity (per insurance claims). See Table 1 for select patient and disease characteristics.

Table 1. Select Baseline Demographics and Disease Characteristics of Patients Treated With Both ADCs1

aHER2-low: IHC 1+ and >10% positive cells or IHC 2+ with >10% positive cells and chromogenic ISH-. HER2-ultra-low: IHC 1+, 2+, or 3+ and ≤10% positive cells. HER2-null: IHC 0+.

Study results

The overall median (95% CI) TOT2 for patients who received both ADCs was similar regardless of sequence: SGT-DXd, 10.8 (10.1–11.7) mo; T-DXdSG, 10.4 (9.74–‍10.9) mo (P=0.356). Within the HER2-null group, the use of SGT-DXd was associated with a longer TOT2 vs T-DXdSG; the sequence of ADC treatment did not impact TOT2 in other HER2 groups (Table 2).

Table 2. TOT2 Outcomes According to ADC Sequence Overall and by HER2 Category1

Note: HRs <1 favor SG before T-DXd, and HRs >1 favor T-DXd before SG.

See Table 3 for outcomes in patients in the HER2-null group according to HR+/- status.

Table 3. Outcomes Among Patients With HER2-Null Tumors According to ADC Sequence and HR+/- Status1

Efficacy analyses according to HR- status, in patients with HR- mBC, SGT-DXd had a significantly longer TOT2 relative to T-DXdSG (HR 0.643; 95% CI 0.504–0.82; P<0.001). Treatment benefit was also observed for OS: HR 0.646; 95% CI 0.471–0.887; P=0.006); this observation was noted in patients with HR-/HER2-null mBC (Table 3).

In patients with HR+/HER2-low mBC, T-DXdSG was associated with significantly longer TOT2 relative to SGT-DXd (HR 1.43; 95% CI 1.01–2.03; P=0.044); however, T-DXdSG did not result in a significantly longer OS (HR 0.957; 95% CI 0.539–1.7; P=0.88).

Retrospective Study in the US2

An observational study, using the Flatiron Health EHR database, evaluated the efficacy of immediate LoT after T-DXd, in patients with mBC (HER2+ [n=419], HR+/HER2- [n=292], and TNBC [n=82]). Median patient age was 58 y, 55.4% (n=439) of patients had a disease-free interval ≥24 mo, and had received a median (range) of 4 (1–14) prior LoT; 76.8% (n=609) experienced progression on prior T-DXd, whereas 23.2% (n=184) discontinued prior T-DXd for other reasons.

In patients with HR+/HER2- mBC and mTNBC, a total of 29.8% (n=87) and 22% (n=18) of patients, respectively, received T-DXdSG. Of 21 patients with HER2+ mBC who received  T-DXdSG, 61.9% (n=13) had converted to HER2- mBC at the time of receipt of SG.

The mPFS of patients with HR+/HER2- mBC and mTNBC that received T-DXdSG was 2.6 mo and 3 mo, respectively (CI were not reported).

Across all mBC patients, after adjustment for prior LoT, SG was associated with shorter mPFS vs other treatments (Table 4). SG was also associated with a significantly shorter mPFS vs chemotherapy in patients with ER+/HER2- mBC (n=142 [Table 4]).

Table 4. mPFS by Post-T-DXd Regimen2

aT-DXd, anti-HER2 regimens, chemotherapy, and other treatments including ET.

bCapecitabine, eribulin, gemcitabine, or vinorelbine.

Retrospective Multicenter Study in Europe3

A European, retrospective study (N=331) is evaluating patients with HER2-low mBC who are receiving SG and T-DXd, either sequentially or not. At this first analysis, a total of 103 and 228 patients had HR- or HR+ mBC respectively. The primary endpoint was PFS2.

SG was ADC1 in 85.4% of patients with HR- mBC and was given as first or second LoT in 58% of these patients; the median (range) treatment duration of SG was 7 cycles (2–24). T-DXd was ADC1 in 77.6% of patients with HR+ mBC and was given as first or second LoT in 20.3% of patients; the median (range) treatment duration of T-DXd was 8 cycles (1–35). For SG-treated patients with HR- mBC, mPFI1 (95% CI) was 5.4 (4.7–6.4) mo vs 6.3 (5.5–8.1) mo for T-DXd-treated patients with HR+ mBC.

A total of 206 (62.2%) patients received intermediate treatment between ADC1 and ADC2. The mPFI (95% CI) following ADC1 was 2.9 (2.7–3.6) mo in the overall population, 2.7 (2.5–3.5) mo with eribulin (n=79) and 4.2 (2.7–5.7) mo with capecitabine (n=30).

At initiation of ADC2, 81.3%, 7.6% and 22.7% of the patients had visceral, bone-only and brain or meningeal metastases, respectively. ADC2 was given after a median (range) of 4 (1–11) LoT. With a median follow-up of 8.6 mo, mPFS2 (95% CI) was 2.6 (2.4–2.8) mo. mPFS2 (95% CI) for ADC2 by subgroup was 2.4 (2.2–2.8) mo for patients with HR+ receiving SG and 2.7 (2.4–3.4) mo for patients with HR- receiving T-DXd. Multivariate analyses showed no difference in PFS2 per number of LoT (continuous variable, P=0.056), however, longer mPFS2 was demonstrated with consecutive use of ADC1-ADC2 treatment (3 mo, HR 0.7; P=0.009) and for T-DXd as ADC2 (2.9 mo, HR 0.44; P<0.001).

Primary resistance, defined as progressive disease as best response, to ADC1 and ADC2 was seen in 25.4% and 65.6% of patients, respectively. Of the 226 evaluable patients who did not show primary resistance to ADC1, 63.3% developed primary resistance to ADC2. Primary resistance to ADC2 was observed in 73.3% and 54.4% of patients treated with SG and T-DXd as ADC2, respectively. mPFS2 (95% CI) for early ADC2 use (≤3L, n=39) was 2.9 (2–4.5) mo, with 60% of patients being primary resistant. Of note, 57 patients were still receiving ADC2 at the time of the first analysis and were not evaluable for ADC2 response.

This study is ongoing and it is expected that approximately 150 further patients will be enrolled.

Retrospective Multicenter Study in France

A study in women with HR+ or HR‑/HER2-low mBC evaluated the efficacy of sequential SG and T-DXd (Table 5) ± intermediary LoT. A total of 75 patients, who received SG or T-DXd as ADC1 (SG for HR-, n=49 and for HR+, n=8; and T-DXd for HR-, n=4 and for HR+, n=14) received intermediary LoT before ADC2. See Table 5 for select patient and treatment characteristics.4

Table 5. Select Baseline Demographics and Disease and Treatment Characteristics4

aData were not available for 13 patients. Other regimens were as follows: paclitaxel, Navelbine, vinorelbine, doxorubicin (each, n=2); PARP inhibitor, cyclophosphamide + methotrexate, Navelbine + thiotepa, other (each, n=1). bHR-, n=100; HR+, n=15. cHR-, n=8; HR+, n=56. dHR-, n=8; HR+, n=56. eHR-, n=100; HR+, n=15.

Preliminary results4

The primary endpoint was mPFS2 in the overall population; other endpoints were mPFS2 by subgroups, mPFI1 (Table 6), and mOS in the whole population and subgroups. The median follow-up duration was 5.3 mo.

Table 6. PFS2 and PFI1 by mBC Subtype and ADC Sequence4

mPFS2 (95% CI) for patients with intermediary LoT (n=75) was 2.6 (2–3.1) mo, vs 3.1 (2.4–3.6) mo for patients with no intermediary LoT (n=104). There was no significant difference in mOS by HR status (P=0.616).

Clinical cross-resistance was defined as primary resistance to ADC2 after secondary resistance to ADC1. The ORR for ADC1 was 35.4% (9 CR and 54 PR) and 19% (1 CR and 27 PR) for ADC2. For ADC1 (n=178), 72 (40.4%) and 106 (59.6%) patients were considered to have PR1 and SR1, respectively. For ADC2 (n=147), 80 (54.4%) and 67 (45.6%) patients were considered to have PR2 and SR2, respectively. PR2 was more frequent than PR1.

Primary and secondary resistance for both ADCs were reported in 40 (27%) and 41 (27.9%) patients, respectively. However, 40 patients (49.4%) with SR1 who were evaluable for ADC2 were considered to have PR2, and 26 patients (39.4%) considered PR1 who were evaluable for ADC2 were considered to have SR2. Treatment duration was, however, short, with a median (range) of 4.1 (0.7–7.7) mo for patients with SR2.

Extended follow-up results

At a later data cutoff date, with a median follow-up of 20.2 mo, 170 patients discontinued ADC2; tumor progression was the cause of death in 140 patients (78.2%).5,6

First intermediary treatment after ADC15

The mPFI1 (95% CI) of the 62 patients for whom the type of intermediate treatment was available was 2.6 (2.3–3.3) mo; of the 23 patients who received eribulin as the first intermediate treatment after ADC1, the mPFI1 (95% CI) was 3.5 (2.5–4.1) mo.

Additional subgroup analyses

The overall mPFS2 (95% CI) was 2.7 (2.3–3.1) mo.6 mPFS2 (95% CI) in patients with HR+ mBC who received SG and in patients with HR- mBC who received T-DXd was 2.1 (1.8–2.7) mo and 3.1 (2.6–3.7) mo, respectively. In a multivariate analysis of SG vs T‑DXd as ADC2 that adjusted for ECOG PS, HR+/- status, sequential ADC use, histologic subtype, and number of LoTs in the metastatic setting, PFS2 was improved with T-DXd (HR 0.53; 95% CI 0.32–0.89; P=0.015).5

The overall mOS was 7.3 (95% CI 6.3–8.9) mo. Among those with HR+ and HR- mBC, mOS was 8 (95% CI 6.3–9.5) mo and 7.3 (95% CI 5.3–10.2) mo, respectively. The PR1 rate was 40.4%, and PR2 rate was 59.4%.5

An additional analysis of ADC2 use as ≤3L treatment (n=35) included 31 patients with HR- mBC, including 29 who received SGT-DXd and 2 who received T‑DXdSG, and 4 patients with HR+ mBC, each of whom received T‑DXdSG. ADC2 as ≤3L vs >3L (n=144) resulted in a longer mPFS2 (95% CI): 3.1 (2–5.4) mo vs 2.6 (2.1–‍3) mo, respectively. Within the subgroup of patients who received early ADC2, the PR1 rate was 37.1%, and the PR2 rate was 55.9%.5

Retrospective US Study at MD Anderson Cancer Center7

A study of patients with HER2-low mBC in the US evaluated survival outcomes with sequential SG and T-DXd given in either order. Overall, 98% of patients were female, and the median age was 52 y. See Table 7 for select patient and treatment characteristics.

Table 7. Select Baseline Demographics and Disease Characteristics Overall and by ADC Sequence7

Study results

After an overall median follow-up of 14.5 mo, there were marginally greater improvements in PFS1 and PFS2 with SGT-DXd relative to the opposite sequence; there was no difference in OS between ADC sequences (Table 8). In a subgroup analysis of patients with HR+ mBC, there were no significant differences in PFS or OS between ADC sequences.

Table 8. Univariate Analysis: Survival Outcomes Overall and by ADC Sequence7

aDefined as survival from first ADC to death or last follow-up.

Retrospective Cohort Study in the US (N=472)8 

A single center study included patients with mTNBC (n=354) and HR+/HER2- mBC (n=118). The median patient age was 51 y. A total of 62% and 38% of patients had HER2-low and HER2-IHC 0, respectively, and 84% and 34% of patients had received ≥1 and ≥3 prior LoT, respectively. Table 9 shows the number of patients who were treated sequentially with SG and T-DXd.

Table 9. ADC by Sequence and mBC Subtype8

Median follow-up duration was 9.1 mo. Table 10 shows OS results by ADC sequence.

Table 10. Multivariable Analysis: OS by ADC Sequence8

Retrospective Cohort Study in the US (N=100)9

A single center study included patients with HR+/HER2-low and HR-/HER2-low mBC who were treated sequentially with T-DXdSG (n=70) or SGT-DXd (n=30). The primary study objective was to estimate the median combined time to progression per treatment sequence to determine if PFS2 significantly declined based on sequence.

The median patient age was 56.3 y and all patients had received ≥1 prior LoT in the metastatic setting. The majority of patients that were ER+ received T-DXdSG (65.7%) vs SGT-DXd (26.7%); HER2 IHC status was similar between groups with most patients being HER2 IHC 1+ (figures not provided).

Study results showed that PFS1+PFS2 and mOS were comparable between the sequences (log-rank P=0.7 for both), however, PFS and RR were reduced with SG and T-DXd when used in the second sequence (Table 11).  

Table 11. Efficacy Outcomes by ADC Sequence9

More patients had ≥1 Grade ≥3 AEs in the T-DXdSG group vs the SGT-DXd group, 62.9% vs 39%, respectively, but this was not statistically significant (P=0.23).

Retrospective, Multicenter Cohort Study in the US10

A study that included mostly female patients with HER2-low and HR+ or HR- mBC from 5 academic centers evaluated the efficacy and safety of sequential SG and T-DXd monotherapy (in either order ± intervening LoT). See Table 12 for select baseline demographics, disease characteristics, and treatment history.

Table 12. Select Baseline Demographics, Disease Characteristics, and Treatment History by mBC Subtype10

Efficacy results

Results for patients who received SG and T-DXd as ADC1 or ADC2, intervening therapies between ADCs, and outcomes by mBC subtype are shown in Table 13. TTFs were generally longer with ADC1 than with ADC2 (77.4%; n=65), but 19 patients (22.6%) had longer TTF with ADC2 than with ADC1. In these 19 patients, TTF was 6.9 mo with ADC2 and 2.5 mo with ADC1; 13 patients discontinued ADC1 due to disease progression and 6 due to toxicity, including ILD during T-DXd treatment (n=3).

Table 13. Prior and Intervening Therapies, Efficacy, and Survival Status by mBC Subtype and ADC Sequence10

aIntervening therapies were: eribulin (n=13), liposomal doxorubicin (n=10), gemcitabine + carbo (n=9), cape (n=6), paclitaxel (n=6), vinorelbine (n=4), olaparib (n=3), and fulvestrant (n=3).

bAssessed by investigator. Defined as the proportion of patients with responding disease at the first provider‑ordered scan.

cResponses were not available for all patients, as several patients discontinued treatment prior to the first scan; thus, the denominators are different.

dDefined as the time from the start of ADC to the time of discontinuation due to any reason (eg, disease progression, toxicity due to treatment, or death).

eNot determined due to the small size of the subgroup.

fDefined as the date from the start of the ADC to the date of death or the last follow-up.

Among patients with HR+/HER2-low mBC and either ADC sequence, there was no difference in the mTTF between ADC1 and ADC2 in prespecified subgroups (eg, age ≤65 y/>65 y, visceral metastasis pre-ADC1, CNS metastases pre-ADC1, and
de novo/non‑de novo mBC). In this mBC subset, for mOS, there were no differences between ADC1 and ADC2 by subgroup, except according to age among those who received SGT-DXd: ≤65 y, 26 mo; >65 y, 15.7 mo (P=0.05).

Among patients with HR-/HER2-low mBC treated with SGT-DXd, there was no difference in the mTTF between ADC1 and ADC2 in age, de novo/non‑de novo mBC, or visceral metastases pre-ADC1 subgroups. Patients without CNS disease (n=19) vs with CNS disease (n=6) pre-ADC1 had a significantly longer mTTF (7.9 vs 5.2 mo, respectively; P=0.047) and a longer mOS (19.3 vs 11.6 mo; P<0.0001). No comparisons could be made for patients with HR-/HER2-low mBC treated with T‑DXdSG due to the small sample size.

No significant difference in the TTF of ADC2 was observed between patients who received an intervening therapy and those who did not (HR 1.497; 95% CI 0.921–2.434; P=0.104). The time on treatment with ADC1 vs ADC2 was not significantly different in those who did not receive an intervening therapy (HR 0.978; 95% CI 0.618–1.547; P=0.923).

Several factors were associated with a significantly longer OS from the start of ADC1 in a multivariate analysis: use of SGT-DXd vs T-DXdSG (HR 0.461; 95% CI 0.246–0.864; P=0.016); age at ADC1 (HR 0.864; 95% CI 0.746–1; P=0.05); and time from diagnosis of mBC to the start of ADC1 (HR 0.985; 95% CI 0.974–0.997; P=0.012).

Safety results

With SG treatment, there was no significant difference in the proportion of patients who required dose reduction according to HR+/HR- status, regardless of SG as ADC1 or ADC2, presence or absence of visceral metastases, or age ≤65 y/>65 y. Seven patients with HR+/HER2-low mBC and 1 patient with HR-/HER2-low mBC discontinued treatment due to toxicity (overall, n=8 [9.5%]); 41 patients (48.8%) required dose reduction. Similar rates of patients with HR+/HER2-low and HR-/HER2-low mBC received growth factor support (62.5% [35/56] vs 64.3% [18/28]). Overall, 16 SG-treated patients (19%) had delays in ADC treatment due to neutropenia. See Table 14 for further details.

With T-DXd treatment, no significant difference was seen in rates of dose reduction according to HR+/HR- status or according to treatment as ADC1 vs ADC2; 10 patients (11.9%) discontinued treatment due to toxicities, and 15 (17.9%) required dose reductions. Additional safety outcomes for T-DXd are shown in Table 14.

ILD was reported in 14 patients (16.7%) in the T-DXd group; 7 received T-DXd as ADC1 and 7 as ADC2, and 9 and 5 patients were in the HR+/HER2-low mBC and HR‑/HER2-low mBC groups, respectively. The median (range) time to ILD onset was 3.8 (0.3–22.9) mo. Steroids were used to manage ILD in all patients, and 9 patients required hospitalization. Two patients with Grade 1 ILD were rechallenged with T-DXd after ground glass opacities resolved on imaging; neither patient had a recurrence of ILD. Three patients (3.6%) died due to ILD-related complications.

Table 14. Dose Reductions, Discontinuations, Growth Factor Support, and ILD/Pneumonitis by mBC Status and ADC Sequence10

aTreatment as ADC1. bTreatment as ADC2. cGrade 3–4, 4.2%; Grade 5, 4.2%. dGrade 1–2, 21.9%. eGrade 3–‍4, 12%; Grade 5, 8%.

Retrospective Single-Center Study in the US

A study reported real-world effectiveness with sequential SG and T‑DXd (given in either order ± intermediary LoT) in patients with mBC.11 ADC1 sequencing for patients with HR+ mBC (n=54) was: SG, n=14; T-DXd, n=40; of the 31 patients with mTNBC, 19 received SG as ADC1, and 12 received T‑DXd.11,12 See Table 15 for additional patient characteristics.

Table 15. Select Patient Demographics and Disease Characteristics by ADC111

Study results11

The mPFS (95% CI) with ADC2 was 3.5 (2.67–7.7) mo when SG was given first and 2.83 (2.57–‍3.73) mo when T-DXd was given first (HR 1.69; 95% CI 0.98–2.94; P=0.06). See Table 16 for PFS by ADC sequence and Table 17 for results of a multivariable analysis.

Table 16. mPFS of SG and T-DXd as ADC1 or ADC211

Table 17. Multivariable Analysis of ADC2 PFS11

Across the entire cohort, regardless of ADC1, mPFS with ADC2 was shorter than with ADC1 in 75% of patients; 14 patients remained on treatment at the data cutoff. Fourteen patients had a PFS2 >6 mo, which was longer than PFS1 in 9 patients. In this subgroup of patients, 2 patients who received T-DXd as ADC1 had a loss in HER2 expression from before T-DXd treatment (HER2 IHC 1–2+ and 1+) to after T-DXd treatment (HER2-IHC 0).

A3 Retrospective Multicenter Study in the US

A study across three academic medical centers evaluated efficacy and cross‑resistance with the sequential use of ADCs.13,14 Patients (N=68) with mBC received ≥2 ADCs; of those, 30 (44.1%) had HR+/HER2- mBC, 38 (55.9%) had TNBC, and 50 (73.5%) had HER2-low. ADC2 was received at a median (range) age of 59.6 (29.9–‍88.6) y, and the median number of prior LoTs in the metastatic setting before ADC2 was 4. Sixty patients received 2 ADCs, and 8 received 3 ADCs.13

Study results13

In the overall population, mPFS (95% CI) with ADC1 was 161 (131–224) d and with ADC2 was 77 d (51–112; P<0.01). See Table 18 for mPFS by mBC subtype and ADC sequence.

Table 18. A3 Study: mPFS by mBC Subtype and ADC Sequence13

Cross-resistance, defined as progressive disease on ADC2 at the time of first restaging or <60 d of treatment on ADC2, was present in 36 patients and absent in 38 patients. When the payload of ADC2 was changed, cross-resistance was seen in 57.1% of patients (8/14); when both the antibody target and payload were changed, cross-resistance was seen in 48.9% of patients (23/47). When ADC2 had the same payload but a different antibody target, cross-resistance was seen in 30% of patients (3/10). In 3 patients, neither the antibody target nor the payload was changed in ADC2, and 66.7% of patients (2/3) showed cross-resistance.

EHR Retrospective Study in the US17

A study (N=1490) using the Flatiron Health EHR database evaluated the efficacy of T-DXd in patients with mBC. A total of 83 patients, most of whom had TNBC, had been exposed to SG prior to treatment with T-DXd. An adjusted analysis was conducted to correct for the confounding of prior LoT on outcomes (Table 19).

Table 19. T-DXd Outcomes by Prior Use of SG17

Retrospective Multicenter Study in China15

A study (N=79) across three hospitals evaluated female patients with locally advanced or mBC who received ≥2 different types of ADC (T-DM1, T‑DXd, RC48, and SG). A total of 64 (81%), 35 (44.3%), and 8 (10.1%) patients had HER2+, HR+, or TNBC, respectively. SG was received as ADC1 (n=6) or ADC2 (n=1) in patients with HER2-low.

mPFS was numerically longer with SG than with HER2 ADCs (9.1 vs 6.35 mo; HR 0.5; 95% CI 0.15–1.6; P=0.207). Among those who progressed after SG, no significant difference in mPFS was seen between patients treated with RC48 or T-DXd. Progression after HER2 ADC was not reported because only 1 patient was treated with RC48 prior to SG.

Retrospective Multicenter Study in the US16

A study (N=115), across four academic centers in the US, included SG-treated female patients with mTNBC. The median (range) age at SG initiation was 60 (31–85) y. The median (range) number of previous therapies in the metastatic setting was two (0-8). A total of 61 patients (56%) had primary refractory disease.

A subgroup of patients with HER2-low BC received SGT-DXd (n=26); of these, four patients had HER2 IHC 0 at the time of biopsy of the metastatic site but were observed to have HER2-low BC at the initial BC diagnosis. The median (95% CI) follow-up time for patients who had SGT-DXd was 17.5 (15.6–17.6) mo, ORR was 34.8% (n=8) and CBR was 65% (n=15). mPFS (95% CI) was 7 (4.6–10.1) mo.

Of the patients who received T-DXd after experiencing a clinical benefit with SG, five patients (33.3%) experienced clinical benefit on T-DXd while 10 patients (67.7%) did not (P=0.12); in this group, the PFS (95% CI) was 9.5 (6.1–18.6) mo and the OS was not reached, with a lower limit of 13.6 mo. Of the patients who received T-DXd after not experiencing a clinical benefit with SG (n=8), none of the patients experienced a clinical benefit; in this group, the PFS (95% CI) and OS (95% CI) were 3.4 (1.3–4.7) mo and 8.9 (4–9.6) mo, respectively.

A total of three patients received T-DXd after discontinuing SG due to Grade 3 fatigue, anemia, and diarrhea. None of these side effects recurred after initiation of T-DXd.

Clinical Study Data on Sequential ADC Use in mBC

TROPION-PanTumor01 Study in aTNBC18

A phase 1, multicenter, open-label study is evaluating the safety and efficacy of Dato-DXd in relapsed/refractory metastatic solid tumors, including in 44 patients with aTNBC. The median (range) number of prior therapies in the metastatic setting was 3 (1–10). Eleven patients, 2 patients, and 1 patient had previously received SG, T-DXd, and patritumab deruxtecan, respectively.

Study results

Survival rates and ORRs were reported for all patients and among patients who were naive to treatment with TOP1 inhibitors (Table 20). Safety outcomes by prior ADC use and outcomes specific to sequencing with SG were not reported.

Table 20. TROPION-PanTumor01: Survival and RRs18

Ongoing Prospective Sequencing ADC Studies

Phase 2, Multicenter Cohort Study: STORM

A phase 2, randomized study (NCT07368543) will evaluate the efficacy of sequential treatment with SG and T-DXd in HER2-low (IHC 1+)/Trop-2-high mBC; SG will be prioritized for patients with high Trop-2 expression. The correlation between changes in tumor-associated protein expression levels and ADC efficacy will investigate mechanisms of ADC resistance. It is estimated that 216 patients will be enrolled.

Multicenter Registry Study: ENCORE

A multicohort real-world study (NCT06774027) is evaluating the safety and efficacy of sequential ADCs. Cohorts 1 and 2 will evaluate sequential ADCs per SoC in ~35 patients with HR+/HER2- mBC and ~25 patients with mTNBC, respectively, prior to ADC1. Cohorts 3 and 4 will evaluate sequential ADCs per SoC in ~25 patients with HR+/HER2- mBC and ~15 patients with mTNBC, respectively, prior to ADC2. Intervening therapies between ADC1 and ADC2 are permitted. It is estimated that 100 patients will be enrolled.

Phase 2, Multicenter Study: SERIES

A phase 2, single-arm, multicenter, open-label study (NCT06263543) is evaluating the efficacy and safety of SG in patients with HR+/HER2-low mBC who progressed on T-DXd. It is estimated that 75 patients will be enrolled.

Phase 4, Cohort Study

A phase 4 study (NCT07162259) will evaluate the efficacy, safety, and potential resistance mechanisms of molecular biomarker-guided sequential ADC therapy (SGT-DXd vs T-DXdSG) following CDK4/6i progression in patients with HR+/HER2- aBC. It is estimated that 40 patients will be enrolled.

References

1. Sledge GW, Xiu J, Solzak JP, et al. Comparing clinical benefit of trastuzumab deruxtecan and sacituzumab govitecan in a large cohort of HER2-negative metastatic breast cancer  [Poster 1076]. Presented at: American Society of Clinical Oncology (ASCO) Annual Meeting; May 30-June 3, 2025; Chicago, IL.

2. Tarantino P, Lee D, Foldi J, et al. Outcomes of subsequent treatment regimens after trastuzumab deruxtecan in patients with metastatic breast cancer. J Natl Cancer Inst. 2025;117(11):2327-2335.

3. Poumeaud F, Morisseau M, Cavaillon S, et al. Evidence accumulates against sequencing Topo1-ADCs in HER2-low metastatic breast cancers: results from International, retrospective, real-world ADC-Low-Europe cohort. Presented at: San Antonio Breast Cancer Symposium; December 9-12, 2025; San Antonio, TX.

4. Poumeaud F, Morisseau M, Cabel L, et al. Efficacy of administration sequence: sacituzumab govitecan and trastuzumab deruxtecan in HER2-low metastatic breast cancer. Br J Cancer. 2024;131(4):702-708.

5. Pomeaud F, Morisseau M, Reich M, et al. Efficacy of sequential antibody-drug conjugates targeting topoisomerase-1 in HER2-low metastatic breast cancer: updated results and additional analyses from the French Multicenter Retrospective ADC-Low Cohort [Poster 312P]. Presented at: European Society for Medical Oncology (ESMO) Congress; May 14-17, 2025; Munich, Germany.

6. Pomeaud F, Morisseau M, Reich M, et al. Efficacy of sequential antibody-drug conjugates targeting topoisomerase-1 in HER2-low metastatic breast cancer: updated results and additional analyses from the French Multicenter Retrospective ADC-Low Cohort [Astract 312P]. Presented at: European Society for Medical Oncology (ESMO) Congress; May 14-17, 2025; Munich, Germany.

7. Valero V, Wang Z, Damodaran S, Bassett Jr R, Tripathy D, Raghavendra A. Outcomes of subsequent antibody drug conjugate regimen in ADC-resistant HER2 low metastatic breast cancer [Poster 605P]. Presented at: European Society for Medical Oncology (ESMO) Congress; October 17-21, 2025; Berlin, Germany.

8. Raghavendra AS, Wang Z, Bassett R, et al. Real-world outcomes of sacituzumab govitecan in hormone receptor-positive and triple-negative breast cancer: Impact of prior therapy [Poster]. Presented at: San Antonio Breast Cancer Symposium; December 9-12, 2025; San Antonio, TX.

9. Kordic A, Ruel N, Kethireddy N. Single institution retrospective analysis of antibody-drug conjugate sequencing in HR+/HER2-low and HR-/HER2-low metastatic breast cancer [Poster]. Presented at: San Antonio Breast Cancer Symposium; December 9-12, 2025; San Antonio, TX.

10. Huppert LA, Mahtani R, Fisch S, et al. Multicenter retrospective cohort study of the sequential use of the antibody-drug conjugates trastuzumab deruxtecan and sacituzumab govitecan in patients with HER2-low metastatis breast cancer. NPJ Breast Cancer. 2025;11(1):34.

11. Mai N, Klar Lieberman MM, Ferraro E, et al. Sequential antibody-drug conjugate therapy in patients with metastatic breast cancer treated with sacituzumab govitecan and trastuzumab deruxtecan. JCO Precis Oncol. 2025;9:e2400898.

12. Mai N, Klar M, Ferraro E, et al. Real world outcomes of sequential ADC therapy in metastatic breast cancer: Patients treated with sacituzumab govitecan and trastuzumab deruxtecan [Abstract]. Presented at: American Society of Clinical Oncology (ASCO) Annual Meeting; May 31-June 4, 2024; Chicago, IL.

13. Abelman RO, Spring LM, Fell G, et al. Sequencing antibody-drug conjugate after antibody-drug conjugate in metastatic breast cancer (A3 study): multi-institution experience and biomariker analysis [Poster]. Presented at: San Antonio Breast Cancer Symposium; December 5-9, 2023; San Antonio, TX.

14. Abelman RO, Spring LM, Fell G, et al. Sequencing antibody-drug conjugate after antibody-drug conjugate in metastatic breast cancer (A3 study): multi-institution experience and biomariker analysis [Abstract]. Presented at: San Antonio Breast Cancer Symposium; December 5-9, 2023; San Antonio, TX.

15. Chen M, Huang R, Chen R, et al. Optimal sequential strategies for antibody-drug conjugate in metastatic breast cancer: evaluating efficacy and cross-resistance. Oncologist. 2024;5;29(8):e957-e966.

16. Alaklabi S, Roy AM, Zagami P, et al. Real-world clinical outcomes with sacituzumab govitecan in metastatic triple-negative breast cancer. JCO Oncol Pract. 2025;21(5):620-628.

17. Tarantino P, Lee D, Foldi J, et al. Outcomes with trastuzumab deruxtecan by biomarker status, line of treatment and prior receipt of sacituzumab govitecan in a large real-world database of patients with metastatic breast cancer. ESMO Open. 2025;10(7):105330.

18. Bardia A, Krop IE, Kogawa T, et al. Datopotamab deruxtecan in advanced or metastatic HR+/HER2- and triple-negative breast cancer: results from the phase I TROPION-PanTumor01 study. J Clin Oncol. 2024:Jco2301909.

19. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) Breast Cancer Version 4.2026. May, 2026.

2L/3L=second/third-line
ADC=antibody-drug conjugate
ADC1/ADC2=first/second antibody-drug conjugate
aTNBC=advanced triple-negative breast cancer
cape=capecitabine
carbo=carboplatin
CBR=
CDK4/6i=cyclin-dependent kinase 4/6 inhibitor
CNS=central nervous system
CPS=combined positive score
CR=complete response
Dato‑DXd=datopotamab deruxtecan
ECOG PS=Eastern Cooperative Oncology Group Performance Status
EHR=electronic health record
ER=estrogen receptor
ERBB2= Erb-B2 Receptor Tyrosine Kinase 2
ET=endocrine therapy
HER2=human epidermal growth factor receptor 2
HR=hazard ratio
HR+/-=hormone receptor‑positive/negative
IHC=immunohistochemistry
ILD=interstitial lung disease
ISH=in situ hybridization
LoT=line(s) of therapy
mBC=metastatic breast cancer
(m)PFI1=(median) progression-free interval with first antibody‑drug conjugate
(m)PFS=(median) progression‑free survival
mPFS1/mPFS2=median progression-free survival with first/second antibody-drug conjugate
(m)PFS2=(median) progression-free survival with second antibody‑drug conjugate
mOS=median overall survival
mTNBC=metastatic triple‑negative breast cancer
NCCN=National Comprehensive Cancer Network
NE=not evaluable
ORR=objective response rate
(m)OS= (median) overall survival
pembro=pembrolizumab
PFS1+PFS2=combined time to progression
PR=partial response
PR1/PR2=primary resistance with antibody‑drug conjugate 1/2
RC48=disitamab vedotin
RR=response rate
SG=sacituzumab govitecan
SoC=standard of care
SR1/SR2=secondary resistance with antibody‑drug conjugate 1/2
T-DM1=trastuzumab emtansine
T-DXd=trastuzumab deruxtecan
TNBC=triple-negative breast cancer
TOP1=topoisomerase I
TOT2=time on treatment from the start of ADC1 to the last of ADC2 among those treated with 2 ADCs
(m)TTF= (median) time to treatment failure

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