Emerging landscape and treatment options in breast cancer

Breast cancer (BC) is the most common malignancy and the leading cause of cancer death worldwide in women; in 2020, almost 2.3 million people were diagnosed, and more than half a million died from BC [1]. Triple-negative breast cancer (TNBC), a subtype of BC lacking the expression of two hormone receptors (HR) (estrogen receptor [ER], progesterone receptor [PR]), and human epidermal growth factor receptor type 2 [HER2], affects approximately every sixth BC patient and is associated with a poor prognosis, an early relapse, and a high frequency of lung, liver and brain metastases [2].

Final analysis of KEYNOTE-355

Pembrolizumab, a humanized anti-PD-1 monoclonal antibody, showed ­encouraging antitumor activity across different tumor entities, including metastatic TNBC (mTNBC) [3-6]. The KEYNOTE-355 trial (NCT02819518) was the first phase III study evaluating an anti-PD-1 immunotherapy against mTNBC that showed a significant and ­clinically meaningful improvement in progression-free survival (PFS) among patients with PD-L1-positive (CPS ≥ 10) disease [6]. Based on these results, the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) approved pembrolizumab in November 2020 and in October 2021, respectively, for the first-line treatment of patients with locally recurrent unresectable or mTNBC whose ­tumors express PD‑L1 with a CPS ≥ 10 [7, 8]. The final results from the KEYNOTE-355 clinical trial were presented at ESMO 2021 [9].

Patients were randomized (2:1) to ­either pembrolizumab plus chemotherapy (taxane or gemcitabine-carboplatin) or placebo plus chemotherapy. Exclusion criteria were administration of systemic steroids, active central nervous system (CNS) metastases, and active autoimmune disease. Patients’ characteristics were well-balanced between the pembrolizumab group (n = 566) and the control arm (n = 281), in terms of age, ECOG PS 1, CPS status, and use of taxane chemotherapy. The co-primary endpoints were PFS and OS in patients with PD-L1-positive tumors.

A benefit of the addition of pembrolizumab to the chemotherapy backbone was particularly observed for the PD-L1 CPS ≥ 10 group, in whom PFS and OS were both significantly improved. After a median follow-up of 44.1 months, the combined therapy resulted in a median PFS (mPFS) of 9.7 months and a mOS of 23.0 months in the pembrolizumab arm versus 5.6 and 16.1 months in the control arm, respectively (Figure 1). Pembrolizumab plus chemotherapy reduced the risk of death by 27 % (HR, 0.73; 95 % CI, 0.55-0.95; p = 0.0093) as compared to chemotherapy alone. The objective response rate (ORR) reached 52.7 % in the pembrolizumab arm versus 40.8 % in the control arm; disease control rate (DCR) was 65.0 % versus 54.4 %, respectively.

Although for patients with PD-L1 CPS ≥ 1 a significant benefit was observed for PFS (mPFS, 7.6 vs 5.6 months), only a trend was observed for OS (mOS, 17.6 vs 16.0 months; p = 0.0563). ORR reached 44.9 versus 38.9 % and DCR 58.6 versus 53.6 %, respectively. A similar trend was observed in the overall population (ITT), where mPFS was 7.5 versus 5.6 months, and mOS reached 17.2 versus 15.5 months. In the ITT, the ORR was 40.8 versus 37.0 %, and DCR was 56.0 % versus 51.2 %. Duration of response (DoR) was higher in the PD-L1 CPS ≥ 10 subset (PD-L1 CPS ≥ 10, 12.8 vs 7.3 months; PD-L1 CPS ≥ 1, 10.1 vs 6.8 months; ITT, 10.1 vs 6.5 months).

No new safety signals were identified. The most common treatment-related adverse events (TRAEs) were anemia (49.1 % in the pembrolizumab + chemotherapy group vs 45.9 % in the placebo + chemotherapy group), neutropenia (41.1 % vs 38.1 %), and nausea (39.3 % vs 41.3 %). TRAEs of grade 3 to 5 occurred in 68 % of patients in the investigational arm and 67 % of those in the control arm.

The KEYNOTE-355 study has met both co-primary endpoints. The authors concluded that these results support the use of pembrolizumab in combination with chemotherapy as a new standard of care for patients with locally recurrent unresectable or metastatic TNBC whose tumors express PD L1 (CPS ≥ 10).

Figure 1: Median OS in the PD-L1 CPS ≥ 10 patient population of the KEYNOTE-355 trial

Figure 1: Median OS in the PD-L1 CPS ≥ 10 patient population of the KEYNOTE-355 trial

Dual immune checkpoint blockade in TNBC

Preclinical studies showed synergistic antitumor effects when combining PD-1 and LAG-3 inhibition [10, 11], as well as an enhancement of treatment efficacy when using chemotherapy plus immunotherapy in patients with advanced TNBC [12, 13]. A phase II study (NCT03499899) presented at this year’s ESMO meeting examined the efficacy and safety of the anti-PD-1 antibody spartalizumab combined with the LAG-3 inhibitor LAG525 in addition to chemotherapy [14].

A total of 88 checkpoint inhibitor (CPI) naïve female patients with advanced TNBC and ≤1 prior line of systemic treatment were randomized (1:1:1) into three arms: LAG525 (400 mg IV, Q3W) + spartalizumab (300 mg IV, Q3W); LAG525 + spartalizumab + carboplatin (AUC6 IV Q3W); or LAG525 + carboplatin. Following the premature closure of the LAG525 + spartalizumab arm due to increased progressive disease, subsequent enrolled patients were randomized (1:1) into both other arms. The primary endpoint was ORR per RECIST v1.1.

In the LAG525 + spartalizumab, LAG525 + spartalizumab + carboplatin, or LAG525 + carboplatin group, the median age was 57.0/50.0/53.5 years and 50.0/23.5/41.2 % presented with an ECOG PS ≥ 1. Almost all patients had a metastatic disease, whereas more than half of the enrolled subjects were first-line patients. After a median follow-up of 12.5 months, no treatment arm met the primary endpoint (ORR per RECIST v1.1 analyzed when all pts had ≥24 weeks follow-up or discontinued tumor assessments for any reason. Proof of preliminary efficacy required both a posterior mean ORR ≥35 % and a posterior probability of (ORR ≥25 %) ≥90 %. Further efficacy outcomes and safety were secondary endpoints). In the triplet combination arm (n=34), the ORR reached 32.4 % with five patients achieving a complete response (CR); the ORR in the LAG252 + carboplatin group (n=34) was 17.6 %. Tumor shrinkage was observed in 20/69/61 % of the LAG525 + spartalizumab, LAG525 + spartalizumab + carboplatin, and LAG525 + carboplatin group, respectively, (Figure 2). A high ORR (47.4 %) was seen in patients receiving the triplet regimen in the first-line setting (n=19). Although data should be interpreted with caution due to the small number of patients, an exploratory subgroup analysis revealed higher ORRs in PD-L1-positive, LAG3-positive, and CD8-positive patients treated with the triplet combination compared to each duplet therapy. Median PFS resulted in 1.4/4.3/3.0 months and mOS in 6.1/11.6/8.0 months in the LAG525 + spartalizumab, LAG525 + spartalizumab + carboplatin, and LAG525 + carboplatin group, respectively.

The most common grade ≥ 3 AEs (in %) were anemia (0/26.5/20.6), platelet count decreased (5.3/20.6/5.9), thrombocytopenia (0/23.5/11.8) and neutrophil count decreased (0/23.5/5.9) in the LAG525 + spartalizumab arm, LAG525 + spartalizumab + carboplatin and LAG525 + carboplatin arm, respectively. The study of LAG525 in combination with spartalizumab and/or carboplatin in patients with an advanced TNBC did not meet its primary endpoint, thus no further clinical investigation is planned.

Figure 2: Best percentage change of the targeted lesions from baseline per RECIST v1.1 in each study arm.

Figure 2: Best percentage change of the targeted lesions from baseline per RECIST v1.1 in each study arm.

DESTINY-Breast03: antibody-drug conjugates in HER2+ mBC

HER2 positive breast cancer (HER2+ BC) accounts for 14 % of all female breast cancer cases [15]. Traditionally associated with a poor prognosis [16], patients with HER2+ BC benefitted from the development of HER2-targeted therapy [17]. The monoclonal antibodies trastuzumab and pertuzumab, in combination with taxane and the antibody-drug conjugate (ADC) trastuzumab emtansine (T-DM1), are well established systemic treatment strategies in the first- and second-line therapy of HER2+ mBC [18]. Recent studies evaluating oral tyrosine kinase inhibitors (TKIs), such as tucatinib and neratinib, as well as ADCs like trastuzumab deruxtecan (T-DXd) showed further improvements in this patient population [18].

The phase II DESTINY-Breast01 trial (NCT02564900) already showed a robust antitumor activity of T-DXd in the third-line treatment of HER2+ mBC (mPFS, 19.4 months; ORR, 61.4 %; ­estimated 12-months OS, 85 %) [19, 20]. Based on these results, T-DXd received U.S. FDA and EMA approval for its use in patients with unresectable or ­metastatic HER2+ BC following two or more prior anti-HER2-based regimens [21, 22].

The head-to-head, randomized, phase III DESTINY-Breast03 (NCT03529110) study evaluated T-DXd versus T-DM1 in patients with HER2+ mBC previously treated with trastuzumab and a taxane; the results were presented at ESMO 2021 [23]. The global trial randomized (1:1) 524 females with unresectable or metastatic HER2-positive breast cancer to either receive T-DXd (5.4 mg/kg, Q3W) or T-DM1 (3.6 mg/kg, Q3W). Patients who had progressed within six months after the end of (neo)adjuvant treatment ­including trastuzumab and a ­taxane were allowed. The median age was 54 years; more than half of the patients were Asian, about one fifth of ­patients had a history of brain metastases and 70 % had visceral disease at enrollment.

The interim analysis with data cutoff of May 21, 2021, showed that T-DXd significantly improved the progression-free survival (PFS) – the primary endpoint assessed by blind independent central review (BIRC) – compared with T-DM1 (not yet reached vs 6.8 months; HR, 0.28; 95 % CI, 0.22-0.37; p = 7.8 x 10-22); the 12-month PFS rate was 75.8 % for T-DXd versus 34.1 % for T-DM1 (Figure 3). Improved efficacy with T-DXd was shown across all prespecified subgroups including hormone receptor status, prior pertuzumab treatment, presence of visceral disease, number of prior therapy-lines, and presence/absence of brain metastases.

The median OS was not estimated (NE) in both arms (HR, 0.56; 95 % CI, 0.36-0.86; p = 0.007172) and the 12-month OS rates were 94.1 % in the T-DXd arm versus 85.9 % in the T-DM1 arm. Confirmed ORR was 79.7 % for T-DXd (16.1 % with a complete response [CR], 63.6 % with a partial response [PR]) versus 34.2 % for T-DM1 (8.7 % with a CR, 25.5 % with a PR). Median follow-up was 16.2 months for T-DXd and 15.3 months for T-DM1. At the time of this interim analysis, more than 50 % of patients remained on T-DM1 (n = 132) compared with 18 % on T-DM1 (n = 47).

In terms of safety, grade ≥ 3 TRAEs occurred in 45.1 % of patients treated with T-DXd versus 39.8 % of those in T-DM1 arm. As AE of special interest, interstitial lung disease (ILD) was reported with grades 1 to 3 in 10.5 % of patients in T-DXd arm and 1.9 % in those in T-DM1 arm; moreover, no grade 4 or 5 adjudicated drug related ILD/pneumonitis events were observed in either arm. The most frequent TEAEs leading to treatment discontinuation were (ILD)/pneumonitis (8.2 %) with T-DXd and thrombocytopenia (2.7 %) with T-DM1.

These data demonstrated a significant superiority of T-DXd over T-DM1 and thus support T-DXd becoming the standard of care (SOC) for the second-line treatment of HER2+ mBC.

Figure 3: PFS as assessed by blind independent central review (BIRC) in the DESTINY-Breast03 study

Figure 3: PFS as assessed by blind independent central review (BIRC) in the DESTINY-Breast03 study

DESTINY-Breast09: 1L T-DXd in HER2+ mBC

In patients with HER2+ mBC, taxane plus trastuzumab plus pertuzumab – the standard first-line triple therapy – demonstrated high mPFS and mOS [24]; however, following this treatment, resistance was emerging. Therefore, new therapeutic options are needed to delay the development of resistance and thus extend the overall survival of patients in 1L setting.

DESTINY-Breast09 (NCT04784715) is a global, randomized, phase III ongoing study aiming to evaluate the safety and efficacy of T-DXd (5.4 mg/kg) with or without pertuzumab compared with SOC (taxane [docetaxel or paclitaxel], trastuzumab and pertuzumab) as first-line treatment in patients with HER2+ (IHC 3+ or ISH+) mBC; the study design was presented at ESMO 2021 (Figure 4) [25]. Randomization is 1:1:1 to receive either T-DXd as a monotherapy with a pertuzumab‑matching placebo, T-DXd in combination with pertuzumab or SOC. Randomization will be stratified by prior treatment (de novo versus recurrent), HR status and PIK3CA mutation status (detected versus not detected).

The primary endpoint of DESTINY-Breast09 is PFS by BIRC, while secondary endpoints include OS, ORR, DoR, pharmacokinetics, health-related quality of life (HR-QoL) and safety. The study plans to recruit more than 1,100 patients; enrollment started in April 2021 and recruitment is currently ­ongoing in 298 study locations worldwide.

Figure 4: Study design of DESTINY-Breast09 in HER2+ (IHC 3+ or ISH+) mBC

Figure 4: Study design of DESTINY-Breast09 in HER2+ (IHC 3+ or ISH+) mBC

Neo-LaTH (JBCRG-16) study: long-term follow-up

Dual HER2 blockade with trastuzumab has been shown to produce a greater survival benefit compared with trastuzumab alone; several studies in the neoadjuvant setting for HER2+ BC reported improved efficacy by adding dual HER2 blockade to chemotherapy [26]. Both NeoSphere (trastuzumab plus pertuzumab) and NeoALTTO (TKI lapatinib plus trastuzumab) studies reported a significantly increased pathological complete response (pCR) rate [26]. The phase II Neo-LaTH study (JBCRG-16) (UMIN000007576) randomized Japanese patients with HER2+ primary BC (T1c-3 N0-1 M0; target lesion ≤7 cm), aged 20 – 70 years with no prior therapy for breast cancer evaluate the efficacy and safety of lapatinib and trastuzumab (6 w) followed by lapatinib and trastuzumab plus weekly paclitaxel (12 w) with/without prolonged anti-HER2 therapy prior to chemotherapy (18 vs. 6 w), and in ER positive (ER+) patients, with/without endocrine therapy, for the treatment of HER2+ primary breast cancer [27]. As reported previously, comprehensive pCR rate (CpCR, ie. no residual tumor or residual ductal carcinoma in situ) – the ­primary endpoint – was achieved in 101 patients (47.9 %) and was significantly higher in ER-negative (ER-) than in ER+ patients (ER-, 63.0 %; ER+, 36.1 %; p = 0.0034). Overall, pCR with pN0 was achieved in 42.2 % of patients (ER-, 57.6 %; ER+, 30.3 %) [27]. At this year’s ESMO meeting, long-term 5-year follow-up data, after successful surgery, of the Neo-LaTH study were reported [28].

The disease-free survival (DFS) rate was 87.8 % and higher in patients who achieved CpCRypN0 (i.e., comprehensive pathological complete response with a pathologically negative axilla) after neoadjuvant treatment. Among non-pCR patients, G2b (defined as only focal invasive tumor residues confirmed in the removed breast tissue; near pCR) was confirmed in nine of 35 ER- patients and in eleven of 78 ER+ patients. Adjuvant anthracycline therapy was given in 48.6 %. In the ER+ cohort, the 5-year distant DFS rate ranged between 90 to 93 % in patients who did not achieve CpCRypN0, regardless of use of adjuvant A. Moreover, it should be taken into account that brain metastases did occur in some cases, even in patients who achieved CpCRypN0.

Neoadjuvant induction of dual HER2 blockade therapy with trastuzumab and lapatinib combined with paclitaxel resulted in a higher 5-year DFS rate in patients who achieved CpCRypN0 after neoadjuvant treatment compared with those who did not. Omission of adjuvant anthracycline therapy may thus be considered in patients who achieved CpCRypN0 after neoadjuvant treatment.

KATE3: ADC combined with PD-L1 inhibition

An exploratory analysis of the KATE2 study – the first randomized phase II trial investigating the use of T-DM1 plus atezolizumab in HER2+ advanced BC – suggested a survival benefit for patients with PD-L1-positive tumors treated with the dual therapy; however, the magnitude of the effect remained unclear because of small sample sizes and imbalances in baseline prognostic factors [29]. At ESMO 2021, the study design of KATE3 (NCT04740918), an ongoing phase III study to evaluate the efficacy and safety of T-DM1 with atezolizumab or placebo in patients with centrally-determined HER2-positive and PD-L1 positive unresectable locally advanced BC (laBC) or mBC patients who received prior trastuzumab (± pertuzumab) and taxane-based therapy, was presented [30].

Study participants must have progressed either during or after prior trastuzumab (+/- pertuzumab) and taxane-based therapy for laBC or mBC, or during (or within 6 months after completing) trastuzumab (+/- pertuzumab) and taxane-based therapy in the neoadjuvant and/or adjuvant setting. Eligible patients are randomized (1:1) to 3-weekly cycles of T-DM1 (3.6 mg/kg) and atezolizumab (1200 mg) or T-DM1 (3.6 mg/kg) and placebo. Approximately 350 patients will be enrolled at approximately 175 sites worldwide and stratified by hormone receptor status, disease status, and world region. PFS (investigator assessed) and OS constitute the co-primary endpoints, while secondary endpoints include ORR, DoR, as well as OS and PFS in patients with baseline brain metastases, central nervous system PFS, patient-reported outcomes, and safety.

coopERA Breast Cancer: next generation SERD in ER+/HER2- BC

HR+/HER2- is the most common subtype of breast cancer, with an age-adjusted rate of 88.1 new cases per 100,000 women [15]. Endocrine therapy (ET) – including selective estrogen receptor modulators (SERMs), aromatase inhibitors (AIs), or selective estrogen receptor degraders (SERDs) – is the backbone to treat advanced ER+ BC [31]; however, drug resistance remains a challenge [31]. The only approved SERD, fulvestrant, has to be administered through an intramuscular injection and presents poor pharmacokinetics [32]. Giredestrant, a next generation investigational SERD, already showed a promising antitumor activity in mBC, either as monotherapy or in combination with the CDK4/6 inhibitor palbociclib [33].

The neoadjuvant phase II study CoopERA Breast Cancer (NCT04436744) evaluated giredestrant versus anastrozole in ER+/HER2- untreated BC (locally assessed). Results from a pre-planned interim analysis were presented at ESMO 2021 [33]. At the data cut-off of April 9, 2021, this trial enrolled 202 untreated ER+/HER2- BC postmenopausal women whose tumor was at least 1.5 cm at the time of presentation and who had a baseline Ki67 score of 5 % or greater. A total of 109 patients were already randomized (1:1) to receive a daily oral dose of either giredestrant (30 mg) or anastrozole (1 mg) during a 2-week window of opportunity phase. Patients then received 16 cycles (days 1-28, 28 days each) of either giredestrant or anastrozole at the same dose, combined with oral palbociclib at a daily dose of 125 mg (days 1-21) pre-surgery.

Patients’ characteristics were well balanced with a median age of 65 years in the giredestrant arm and 62 years in the anastrozole arm; in both arms, most patients had a stage IIA disease (45 % versus 38 %), a nodal status of N0 (56 % versus 49 %), and a tumor status of T2 (65 % vs 62 %) at diagnosis, respectively. Among the 83 patients assessed in the interim analysis, giredestrant showed a mean Ki67 reduction – the primary endpoint – of 80 % versus 67 % for anastrozole during the window of opportunity phase (1-14 days) (Figure 5). In total, 25 % of tumors exhibited a ­complete cell cycle arrest rate (CCCA) with giredestrant versus 5 % with anastrozole. Consistent Ki67 suppression was observed in patients with baseline Ki67 ≥ 20 % (83 % reduction with giredestrant vs 71 % with anastrozole) or baseline Ki67 < 20 % (65 % vs 24 %, respectively).

Safety results were consistent with the known safety profile of giredestrant, with fewer patients experiencing AEs related to giredestrant (28 %) versus anastrozole (38 %); the most common AEs were arthralgia (5.7 % versus 10.9 %), decreased blood cell count (3.8 % versus 9.1 %), bradycardia (5.7 % versus none), and vomiting (5.7 % versus none). No grade ≥ 3 AEs or serious AEs (SAEs) were associated with giredestrant.

This is the first randomized study showing a superior antiproliferative ­activity of an oral SERD over an ­aromatase inhibitor and with a favorable safety profile in HR+/HER2- BC. Giredestrant is currently being investigated in further phase III studies evaluating its efficacy in ER+/HER2- la/mBC patients versus letrozole (persevERA Breast Cancer, NCT04546009) and in the ad­juvant ­setting versus ET of physician’s choice (lidERA Breast Cancer, NCT04961996).

Figure 5: coopERA Breast Cancer trial: relative reduction in Ki67 with giredestrant and anastrozole at Week 2

Figure 5: coopERA Breast Cancer trial: relative reduction in Ki67 with giredestrant and anastrozole at Week 2

MONARCH 2: CDK4/6 inhibition in HR+/HER2- BC

In the global, double-blind, phase III study MONARCH 2 (NCT02107703), abemaciclib – a selective CDK4/6 inhibitor – plus fulvestrant significantly extended PFS and OS versus fulvestrant alone (mPFS 16.4 vs 9.3 months; mOS 46.7 vs 37.3 months) in patients with HR+/HER2- advanced BC [34, 35]. A pooled analysis of the endocrine therapy naïve (EN) participants of the MONARCH 2 study was presented at ESMO 2021 [36] .

In the EN cohort – consisting of EN patients with measurable disease excluded from the ITT population of MONARCH 2 (n=20) as well as additional participants enrolled under EN addendum (n=90) –, patients had a mean age of 54 years (range, 31 - 86), 43.6 % had an ECOG of 1 and 60.9 % were postmenopausal (natural or surgical). The participants received abemaciclib (200 mg or 150 mg twice daily [BD]) and fulvestrant (500 mg intramuscularly on day 1 and 15 of cycle 1, then day 1 of cycle 2 and subsequent cycles)). Most of the patients had ductal breast carcinoma (75.5 %), stage IV disease (69.1 %), at least three organs involved (68.2 %) and had ER+/PR+ (78.2 %) breast cancer at diagnosis.

After a median follow-up of 9.8 months, ORR assessed by investigator, which was the primary endpoint, was 59.1 %. One patient achieved a CR, 64 subjects experienced a PR, 20 patients had a stable disease (SD) lasting for at least six months, whereas one patient had progressive disease (PD). The clinical benefit rate (CBR) reached 77.3 % (Figure 6), while PFS and DOR were not yet mature.

The safety profile was consistent with that previously reported in the MONARCH 2 main study. TEAEs of grade ≥ 3 occurred in 55.6 % of patients, the most common ones being neutropenia (23.1 %), diarrhea (13.9 %), and anemia (6.5 %).

These pooled data of the EN cohort confirmed the favorable ORR and the good safety profile previously reported for fulvestrant monotherapy in participants with a similar disease state.

Figure 6: Waterfall plot outlining the investigator’s assessed best overall response of the EN cohort in the MONARCH 2 study.

Figure 6: Waterfall plot outlining the investigator’s assessed best overall response of the EN cohort in the MONARCH 2 study.

SASCIA trial: a novel ADC in HER2- BC patients

Sacituzumab govitecan (SG), which has been approved by the U.S. FDA in April 2021 for the treatment of unresectable la/mTNBC patients with at least two prior therapies, is a novel Trop-2-directed antibody conjugated to a topoisomerase I inhibitor [37]. A prior phase I/II trial showed an ORR of 31 % and a CBR of 48 % for SG in heavily pre-treated HR+/HER2- mBC patients [38].

At ESMO 2021, the study design of the ongoing phase III prospective, multi-center, randomized, open label, parallel group study, SASCIA trial (NCT04595565), was presented; this trial investigates SG in patients with HER2-negative BC with high relapse risk after standard neoadjuvant treatment [39]. Eligible patients (1,200 planned) have to be HER2- (centrally confirmed) and either HR+ (≥1 %) or HR- (<1 %) as assessed on tissues from post-neoadjuvant residuals of the breast or residual nodal invasion defined as follows: for HR- disease, any residual invasive disease > ypT1mi; for HR+ disease, a CPS+EG score ≥ 3, or CPS+EG score 2 and ypN+ using local ER and grade assessed on core biopsies taken before the start of the neoadjuvant treatment. Subjects must have received a taxane-based neoadjuvant chemotherapy (NACT) for 16 weeks, including six weeks of a taxane. For patients with a progressive disease that occurred after at least six weeks of taxane-containing NACT, a total treatment period of less than 16 weeks is eligible. CPI therapy during NACT is allowed, while radiotherapy should be delivered before the begin of the study treatment. Patients are randomized (1:1) to receive either SG (10 mg/kg; days 1 and 8, Q3W, 8 cycles) or treatment of physician’s choice (capecitabine, carboplatin, observation, endocrine-based therapy will be administered according to local guidelines). Primary study endpoint is invasive disease-free survival (iDFS); secondary endpoints include OS, safety, compliance, patient-reported outcome, quality of life, biomarker analysis and ctDNA dynamics.

The study, which is currently running in 32 German centers, is conducted in collaboration with the AGO-B Breast Study Group. Recruitment has started in December 2020 and will take an estimated 36 months.


  1. Sung H et al., Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin 2021; 71(3): 209-249
  2. Siddharth S et al., Racial Disparity and Triple-Negative Breast Cancer in African-American Women: A Multifaceted Affair between Obesity, Biology, and Socioeconomic Determinants. Cancers 2018; 10(12): 514
  3. Schmid P et al., Pembrolizumab plus chemotherapy as neoadjuvant treatment of high-risk, early-stage triple-negative breast cancer: results from the phase 1b open-label, multicohort KEYNOTE-173 study. Ann Oncol 2020; 31(5): 569-581
  4. Nanda R et al., Effect of Pembrolizumab Plus Neoadjuvant Chemotherapy on Pathologic Complete Response in Women With Early-Stage Breast Cancer: An Analysis of the Ongoing Phase 2 Adaptively Randomized I-SPY2 Trial. JAMA oncology 2020; 6(5): 676-684
  5. Schmid P et al., Pembrolizumab for Early Triple-Negative Breast Cancer. N Engl J Med 2020; 382(9): 810-821
  6. Cortes J et al., Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer (KEYNOTE-355): a randomised, placebo-controlled, double-blind, phase 3 clinical trial. Lancet 2020; 396(10265): 1817-1828
  7. EMA approval of pembrolizumab. https://ec.europa.eu/health/documents/community-register/html/h1024.htm. Last accessed November 2021
  8. FDA approval of pembrolizumab. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-pembrolizumab-locally-recurrent-unresectable-or-metastatic-triple. Last accessed November 2021
  9. Rugo HS et al., KEYNOTE 355: Final Results from a Randomized, Double blind, Phase 3 Study of First line Pembrolizumab + Chemotherapy versus Placebo + Chemotherapy for Metastatic Triple Negative Breast Cancer. ESMO 2021, LBA1
  10. Woo SR et al., Immune inhibitory molecules LAG-3 and PD-1 synergistically regulate T-cell function to promote tumoral immune escape. Cancer Res 2012; 72(4): 917-927
  11. Ghosh S et al., TSR-033, a Novel Therapeutic Antibody Targeting LAG-3, Enhances T-Cell Function and the Activity of PD-1 Blockade In Vitro and In Vivo. Mol Cancer Ther 2019; 18(3): 632-641
  12. Zitvogel L et al., Mechanism of action of conventional and targeted anticancer therapies: reinstating immunosurveillance. Immunity 2013; 39(1): 74-88
  13. Emens LA et al., The interplay of immunotherapy and chemotherapy: harnessing potential synergies. Cancer Immunol Res 2015; 3(5): 436-443
  14. Carey LA et al., A phase II study of LAG525 in combination with spartalizumab (PDR001), PDR001 and carboplatin (Carbo), or Carbo, as first- or second-line therapy in patients (Pts) with advanced (Adv) triple-negative breast cancer (tnbc). ESMO 2021, 275 P
  15. National Cancer Institute, Surveillance, Epidemiology, and End Results Program. Cancer Stat Facts: Female Breast Cancer Subtypes. https://seer.cancer.gov/statfacts/html/breast-subtypes.html. Last accessed November 2021
  16. Hynes NE et al., The biology of erbB-2/neu/HER-2 and its role in cancer. Biochim Biophys Acta 1994; 1198(2-3): 165-184
  17. Ferretti G et al., Improved prognosis by trastuzumab of women with HER2-positive breast cancer compared with those with HER2-negative disease. J Clin Oncol 2010; 28(20): e337; author reply e338-9
  18. Bredin P et al., Systemic therapy for metastatic HER2-positive breast cancer. Semin Oncol 2020; 47(5): 259-269
  19. Modi S et al., Abstract PD3-06: Updated results from DESTINY-breast01, a phase 2 trial of trastuzumab deruxtecan (T-DXd ) in HER2 positive metastatic breast cancer. Cancer Research 2021; 81(4 Supplement): PD3-06
  20. Perez J et al., Trastuzumab deruxtecan in HER2-positive metastatic breast cancer and beyond. Expert Opin Biol Ther 2021; 21(7): 811-824
  21. Enhertu SmPC. https://www.ema.europa.eu/en/documents/product-information/enhertu-epar-product-information_en.pdf. Last accessed November 2021
  22. FDA approval Enhertu. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-fam-trastuzumab-deruxtecan-nxki-unresectable-or-metastatic-her2-positive-breast-cancer; . Last accessed November 2021
  23. Cortes J et al., Trastuzumab Deruxtecan (TDXd) vs Trastuzumab Emtansine (T DM1) in Patients With HER2+ Metastatic Breast Cancer: Results of the Randomized, Phase 3 Study DESTINY Breast03. ESMO 2021, LBA1
  24. Swain SM et al., Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med 2015; 372(8): 724-734
  25. Tolaney S et al., Phase III study of trastuzumab deruxtecan (T-DXd) with or without pertuzumab vs a taxane, trastuzumab and pertuzumab in first-line (1L), human epidermal growth factor receptor 2–positive (HER2+) metastatic breast cancer (mBC): DESTINY-Breast09. ESMO 2021, 328TiP
  26. Yu L et al., Dual HER2 Blockade versus a Single Agent in Trastuzumab-Containing Regimens for HER2-Positive Early Breast Cancer: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. J Oncol 2020; 2020: 5169278
  27. Masuda N et al., Efficacy and safety of trastuzumab, lapatinib, and paclitaxel neoadjuvant treatment with or without prolonged exposure to anti-HER2 therapy, and with or without hormone therapy for HER2-positive primary breast cancer: a randomised, five-arm, multicentre, open-label phase II trial. Breast Cancer 2018; 25(4): 407-415
  28. Fujisawa T et al., Long-term follow-up of neoadjuvant dual anti-HER2 therapy with trastuzumab and lapatinib plus paclitaxel, with or without endocrine therapy for HER2-positive primary breast cancer: Neo-LaTH (JBCRG-16) study. ESMO 2021, 142P
  29. Emens LA et al., Trastuzumab emtansine plus atezolizumab versus trastuzumab emtansine plus placebo in previously treated, HER2-positive ­advanced breast cancer (KATE2): a phase 2, multicentre, randomised, double-blind trial. Lancet Oncol 2020; 21(10): 1283-1295
  30. Loi S et al., KATE3: A phase III study of trastuzumab emtansine (T-DM1) in combination with atezolizumab or placebo in patients with previously treated HER2-positive and PD-L1–positive locally advanced or metastatic breast cancer. ESMO 2021, 329TiP
  31. Lu Y et al., Selective Estrogen Receptor Degraders (SERDs): A Promising Strategy for Estrogen Receptor Positive Endocrine-Resistant Breast Cancer. J Med Chem 2020; 63(24): 15094-15114
  32. Blackburn SA et al., Fulvestrant for the treatment of advanced breast cancer. Expert Rev Anticancer Ther 2018; 18(7): 619-628
  33. Hurvitz SA et al., Neoadjuvant giredestrant (GDC 9545) + palbociclib palbo ) vs anastrozole (A) + palbo in post menopausal women with ­oestrogen receptor positive, HER2 negative, ­untreated early breast cancer (ER+/HER2 eBC ): Interim analysis of the randomised, open label, phase 2 coopERA BC study. ESMO 2021, LBA14
  34. Sledge GW et al., The Effect of Abemaciclib Plus Fulvestrant on Overall Survival in Hormone Receptor–Positive, ERBB2-Negative Breast Cancer That Progressed on Endocrine Therapy—MONARCH 2: A Randomized Clinical Trial. JAMA Oncology 2020; 6(1): 116-124
  35. Sledge GW et al., MONARCH 2: Abemaciclib in Combination With Fulvestrant in Women With HR+/HER2− Advanced Breast Cancer Who Had Progressed While Receiving Endocrine Therapy. Journal of Clinical Oncology 2017; 35(25): 2875-2884
  36. Trujillo J-LG et al., Abemaciclib plus fulvestrant in participants with HR+/HER2- advanced breast cancer: A pooled analysis of the endocrine therapy naïve (EN) participants in MONARCH 2. ESMO 2021, 241P
  37. FDA approval of sacituzumab govitecan. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-regular-approval-sacituzumab-govitecan-triple-negative-breast-cancer. Last accessed November 2021
  38. Bardia A et al., Efficacy of sacituzumab govitecan (anti-Trop-2-SN-38 antibody-drug conjugate) for treatment-refractory hormone-receptor positive (HR+)/HER2- metastatic breast cancer (mBC). Journal of Clinical Oncology 2018; 36(15_suppl): 1004
  39. Marme F et al., Phase III post-neoadjuvant study evaluating sacituzumab govitecan (SG), an antibody drug conjugate in primary HER2-negative breast cancer patients with high relapse risk after standard neoadjuvant treatment: SASCIA. ESMO 2021, 199TiP

© 2021 Springer-Verlag GmbH, Impressum