Trophoblast cell-surface antigen-2 (Trop-2) is expressed in epithelial cancers, including hormone receptor-positive (HR+) metastatic breast cancer (mBC). Sacituzumab govitecan (SG; Trodelvy®) is an ...antibody–drug conjugate composed of a humanized anti-Trop-2 monoclonal antibody coupled to SN-38 at a high drug-to-antibody ratio via a unique hydrolyzable linker that delivers SN-38 intracellularly and in the tumor microenvironment. SG was granted accelerated FDA approval for metastatic triple-negative BC treatment in April 2020.
We analyzed a prespecified subpopulation of patients with HR+/human epidermal growth factor receptor 2-negative (HER2−) HR+/HER2− mBC from the phase I/II, single-arm trial (NCT01631552), who received intravenous SG (10 mg/kg) and whose disease progressed on endocrine-based therapy and at least one prior chemotherapy for mBC. End points included objective response rate (ORR; RECIST version 1.1) assessed locally, duration of response (DOR), clinical benefit rate, progression-free survival (PFS), overall survival (OS), and safety.
Fifty-four women were enrolled between 13 February 2015 and 1 June 2017. Median (range) age was 54 (33-79) years and all received at least two prior lines of therapy for mBC. At data cut-off (1 March 2019), 12 patients were still alive. Key grade ≥3 treatment-related toxicities included neutropenia (50.0%), anemia (11.1%), and diarrhea (7.4%). Two patients discontinued treatment due to treatment-related adverse events. No treatment-related deaths occurred. At a median follow-up of 11.5 months, the ORR was 31.5% 95% confidence interval (CI), 19.5%–45.6%; 17 partial responses; median DOR was 8.7 months (95% CI 3.7–12.7), median PFS was 5.5 months (95% CI 3.6–7.6), and median OS was 12 months (95% CI 9.0–18.2).
SG shows encouraging activity in patients with pretreated HR+/HER2− mBC and a predictable, manageable safety profile. Further evaluation in a randomized phase III trial (TROPiCS-02) is ongoing (NCT03901339).
ClinicalTrials.gov NCT01631552; https://clinicaltrials.gov/ct2/show/NCT01631552
•Safety and efficacy of sacituzumab govitecan (SG), a Trop-2–directed antibody–drug conjugate, were evaluated in patients with hormone receptor-positive/epidermal growth factor receptor 2-negative metastatic breast cancer (mBC).•Key grade ≥3 treatment-related toxicities included neutropenia (50.0%), anemia (11.1%), and diarrhea (7.4%).•In 54 patients who received SG (10 mg/kg) and at least two prior lines of therapy for mBC, the objective response rate was 31.5%.•Responses achieved with SG were durable, with a median duration of response of 8.7 months and a median progression-free survival of 5.5 months.•Clinical activity seen is encouraging in relation to current standard-of-care chemotherapies in this setting.
The pivotal phase III ASCENT trial demonstrated improved survival outcomes associated with sacituzumab govitecan (SG), an anti-trophoblast cell-surface antigen 2 (anti-Trop-2) antibody-drug conjugate ...linked with the topoisomerase-inhibitor SN-38, over single-agent chemotherapy treatment of physician’s choice (TPC) in previously treated metastatic triple-negative breast cancer (mTNBC). This prespecified, exploratory biomarker analysis from the ASCENT trial evaluates the association between tumor Trop-2 expression and germline BRCA1/2 mutation status with clinical outcomes.
Patients with mTNBC refractory to or progressing after two or more prior chemotherapies, with one or more in the metastatic setting, were randomized to receive SG (10 mg/kg intravenously days 1 and 8, every 21 days) or TPC (capecitabine, eribulin, vinorelbine, or gemcitabine) until disease progression/unacceptable toxicity. Biopsy or surgical specimens were collected at study entry to determine Trop-2 expression level using a validated immunohistochemistry assay and histochemical scoring. Germline BRCA1/2 mutation status was collected at baseline.
Of 468 assessable patients, 290 had Trop-2 expression data 64% (n = 151 SG) versus 60% (n = 139 TPC) and 292 had known BRCA1/2 mutation status 63% (n = 149 SG) versus 61% (n = 143 TPC). Median progression-free survival in SG- versus TPC-treated patients was 6.9, 5.6, and 2.7 months versus 2.5, 2.2, and 1.6 months for high, medium, and low Trop-2 expression, respectively. Median overall survival (14.2, 14.9, and 9.3 months versus 6.9, 6.9, and 7.6 months) and objective response rates (44%, 38%, and 22% versus 1%, 11%, and 6%) were numerically higher with SG versus TPC in patients with high, medium, and low Trop-2 expression, respectively. Efficacy outcomes were numerically higher with SG versus TPC in patients with and without germline BRCA1/2 mutations.
SG benefits patients with previously treated mTNBC expressing high/medium Trop-2 compared with standard-of-care chemotherapy and regardless of germline BRCA1/2 mutation status. The small number of patients with low Trop-2 expression precludes definitive conclusions on the benefit of SG in this subgroup.
•The majority of patients (80%) with mTNBC in the ASCENT study with available data had high/medium tumor Trop-2 expression.•Survival outcomes and ORRs were numerically higher in SG- versus TPC-treated patients with high/medium Trop-2 expression.•Benefit of SG in patients with high/medium Trop-2 expression was similar to that of overall primary efficacy population.•The small number of patients with low Trop-2 expression prevents definitive conclusions on benefit of SG in this subgroup.•Benefit of SG over TPC was also similar regardless of germline BRCA1/2 mutation status.
Sacituzumab govitecan (SG), a trophoblast cell surface antigen-2 (Trop-2)-directed antibody-drug conjugate, has demonstrated antitumor efficacy and acceptable tolerability in a phase I/II multicenter ...trial (NCT01631552) in patients with advanced epithelial cancers. This report summarizes the safety data from the overall safety population (OSP) and efficacy data, including additional disease cohorts not published previously.
Patients with refractory metastatic epithelial cancers received intravenous SG (8, 10, 12, or 18 mg/kg) on days 1 and 8 of 21-day cycles until disease progression or unacceptable toxicity. Endpoints for the OSP included safety and pharmacokinetic parameters with investigator-evaluated objective response rate (ORR per RECIST 1.1), duration of response, clinical benefit rate, progression-free survival, and overall survival evaluated for cohorts (n > 10 patients) of small-cell lung, colorectal, esophageal, endometrial, pancreatic ductal adenocarcinoma, and castrate-resistant prostate cancer.
In the OSP (n = 495, median age 61 years, 68% female; UGT1A1∗28 homozygous, n = 46; 9.3%), 41 (8.3%) permanently discontinued treatment due to adverse events (AEs). Most common treatment-related AEs were nausea (62.6%), diarrhea (56.2%), fatigue (48.3%), alopecia (40.4%), and neutropenia (57.8%). Most common treatment-related serious AEs (n = 75; 15.2%) were febrile neutropenia (4.0%) and diarrhea (2.8%). Grade ≥3 neutropenia and febrile neutropenia occurred in 42.4% and 5.3% of patients, respectively. Neutropenia (all grades) was numerically more frequent in UGT1A1∗28 homozygotes (28/46; 60.9%) than heterozygotes (69/180; 38.3%) or UGT1A1∗1 wild type (59/177; 33.3%). There was one treatment-related death due to an AE of aspiration pneumonia. Partial responses were seen in endometrial cancer (4/18, 22.2% ORR) and small-cell lung cancer (11/62, 17.7% ORR), and one castrate-resistant prostate cancer patient had a complete response (n = 1/11; 9.1% ORR).
SG demonstrated a toxicity profile consistent with previous published reports. Efficacy was seen in several cancer cohorts, which validates Trop-2 as a broad target in solid tumors.
•Sacituzumab govitecan (SG) is a Trop-2-directed antibody-drug conjugate with a hydrolyzable linker and an SN-38 payload.•The most frequent treatment-related adverse events (TRAEs) were nausea, diarrhea, neutropenia, alopecia, and fatigue.•Grade ≥3 TRAEs were infrequent except for treatment-related grade ≥3 neutropenia; discontinuation due to AEs was 8.3%.•AEs with SG parallel those of chemotherapy and can be managed with proactive intervention per established guidelines.•Objective response rates, coupled with disease control, are apparent across small disease cohorts, warranting further study.
The landscape of clinical trials testing risk-adapted modulations of cancer treatments is complex. Multiple trial designs, endpoints, and thresholds for non-inferiority have been used; however, no ...consensus or convention has ever been agreed to categorise biomarkers useful to inform the treatment intensity modulation of cancer treatments.
An expert subgroup under the European Society for Medical Oncology (ESMO) Precision Medicine Working Group shaped an international collaborative project to develop a classification system for biomarkers used in the cancer treatment de-intensification, based on a tiered approach. A group of disease-oriented clinical, translational, methodology and public health experts, and patients’ representatives provided an analysis of the status quo, and scanned the horizon of ongoing clinical trials. The classification was developed through multiple rounds of expert revisions and inputs.
The working group agreed on a univocal definition of treatment de-intensification. Evidence of reduction in the dose-density, intensity, or cumulative dose, including intermittent schedules or shorter treatment duration or deletion of segment(s) of the standard regimens, compound(s), or treatment modality must be demonstrated, to define a treatment de-intensification. De-intensified regimens must also portend a positive impact on toxicity, quality of life, health system burden, or financial toxicity. ESMO classification categorises the biomarkers for treatment modulation in three tiers, based on the level of evidence. Tier A includes biomarkers validated in prospective, randomised, non-inferiority clinical trials. The working group agreed that in non-inferiority clinical trials, boundaries are highly dependent upon the disease scenario and endpoint being studied and that the absolute differences in the outcomes are the most relevant measures, rather than relative differences. Biomarkers tested in single-arm studies with a threshold of non-inferiority are classified as Tier B. Tier C is when the validation occurs in prospective-retrospective quality cohort investigations.
ESMO classification for the risk-guided intensity modulation of cancer treatments provides a set of evidence-based criteria to categorise biomarkers deemed to inform de-intensification of cancer treatments, in risk-defined patients. The classification aims at harmonising definitions on this matter, therefore offering a common language for all the relevant stakeholders, including clinicians, patients, decision-makers, and for clinical trials.
•The landscape of clinical trials testing risk-adapted modulations of cancer treatments is complex.•Several trial designs and endpoints are used to evaluate de-intensified cancer therapies.•ESMO has developed a classification to categorise biomarkers to inform risk-guided intensity modulation of cancer treatments.•The classification includes three tiers, based on the clinical trial methodology and results.•The ESMO classification will help harmonise definitions, thereby facilitating communication with all relevant stakeholders.
For women with breast cancer who undergo mastectomy, immediate breast reconstruction (IR) offers a cosmetic and psychological advantage. We evaluated the association between demographic, hospital, ...surgeon and insurance factors and receipt of IR. We conducted a retrospective hospital-based analysis with the Perspective database. Women who underwent a mastectomy for invasive breast cancer (IBC) and ductal carcinoma in situ (DCIS) from 2000 to 2010 were included. Logistic regression analysis was used to determine factors predictive of IR. Analyses were stratified by age (<50 vs. ≥50) and IBC versus DCIS. Of the 108,992 women with IBC who underwent mastectomy, 30,859 (28.3 %) underwent IR, as compared to 6,501 (44.2 %) of the 14,710 women with DCIS who underwent mastectomy underwent IR. In a multivariable model for IBC, increasing age, black race, being married, rural location, and increased comorbidities were associated with decreased IR. Odds ratios (OR) of IR increased with commercial insurance (OR 3.38) and Medicare (OR 1.66) insurance (vs. self-pay), high surgeon-volume (OR 1.19), high hospital-volume (OR 2.24), and large hospital size (OR 1.20). The results were identical for DCIS, and by age category. The absolute difference between the proportion of patients who received IR with commercial insurance compared to other insurance, increased over time. Immediate in-hospital complication rates were higher for flap reconstruction compared to implant or no reconstruction (15.2, 4.0, and 6.1 %, respectively,
P
< .0001). IR has increased significantly over time; however, modifiable factors such as insurance status, hospital size, hospital location, and physician volume strongly predict IR. Public policy should ensure that access to reconstructive surgery is universally available.
Purpose
Estrogen receptor (ER) and progesterone receptor (PR) status is prognostic and predictive in breast cancer. Because metastatic breast tumor biopsies are not routinely feasible, circulating ...tumor cells (CTCs) offer an alternative source of determining ER/PR tumor status.
Methods/patients
Peripheral blood was collected prospectively from 36 patients with metastatic breast cancer. CTCs were isolated using the microfluidic OncoCEE™ platform. Detection was accomplished with an expanded anti-cytokeratin (CK) cocktail mixture and anti-CD45. ER/PR protein expression was assessed by immunocytochemistry (ICC) on the CK+ cells and compared to the primary and/or metastatic tumor by immunohistochemistry (IHC).
Results
Among the 24 CK + CTC cases, a concordance of 68 % (15/22) in ER/PR status between primary breast tumor and CTCs and 83 % (10/12) between metastatic tumor and CTCs was observed. An overall concordance of 79 % (19/24) was achieved when assessing CTC and metastatic tumor (primary tumor substituted if metastatic breast biopsy not available). A test sensitivity of 72 % and specificity of 100 % was identified when comparing CTCs to tumor tissue. Of the 7 discordant cases between CTCs and primary tumor tissue, 2 were concordant with the metastatic biopsy.
Conclusions
CTC ER/PR status using the OncoCEE™ platform is feasible, with high concordance in ER/PR status between tumor tissue (IHC) and CTCs (ICC). The prognostic and predictive significance of CTC ER/PR protein expression needs further evaluation in larger trials.
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