Targeting Trop-2 Overexpression in Breast Cancer and Non-Small Cell Lung Cancer

The transmembrane glycoprotein Trop-2 is involved in cancer progression and metastasis due to its role as a key regulator of the hallmarks of cancer, including cell growth, proliferation, migration, invasion, and survival.^1,2 A variety of human epithelial cancers (eg, malignancies of the breast, lung, bladder, stomach, colon, rectum, pancreas, prostate, cervix, head and neck, and ovary) are characterized by Trop-2 overexpression.^1,2 The overexpression of Trop-2 has been associated with more aggressive disease and worse overall survival (OS) and progression-free survival (PFS) in patients with solid tumors.^1,2

In breast cancer (BC), increased Trop-2 mRNA has been demonstrated to be a strong predictor of lymph node involvement, distant metastasis, and poor OS.³ Although Trop-2 is expressed across all BC subtypes, overexpression is more commonly observed in certain disease subtypes, including hormone receptor­–positive/HER2 (also known as ERBB2)-negative (HR+/HER2-) BC, and triple-negative breast cancer (TNBC).⁴

For lung cancer, the correlation of Trop-2 overexpression with prognosis can vary with lung cancer subtype.⁵ More specifically, high Trop-2 expression is associated with a worse prognosis, higher patient mortality, and shorter OS in patients with lung cancer having an adenocarcinoma histology.^5-7 Interrogation of human samples has also demonstrated high levels of Trop-2 expression to correlate with a high tumor, node, and metastasis stage and a worse disease course in adenocarcinoma.⁷ Additionally, lower rates of survival have been observed in patients with high-grade neuroendocrine tumors, including small cell carcinoma.⁷ Conversely, high Trop-2 expression does not appear to be associated with mortality in squamous cell carcinoma.^5,7

Favorable safety and efficacy study data leading to the FDA approval of sacituzumab govitecan-hziy—an antibody-drug conjugate (ADC) that targets Trop-2—in metastatic TNBC and urothelial cancer established the use of Trop-2–targeting therapeutics as a viable strategy for treating solid tumors.⁸ Moreover, drug modalities targeting Trop-2 offer a novel approach for treating TNBC, estrogen receptor–positive (ER+)/HER2- BC, and NSCLC, which may help to fill existing gaps in the current treatment landscape.^9,10

Breast Cancer

Unmet Needs in TNBC and ER+/HER2- Metastatic BC

Approximately 10% to 15% of all BC cases, and a disproportionate number of BC-related deaths, are related to TNBC, an aggressive form of invasive BC.^11,12 Its prevalence is particularly high in premenopausal women and Black and Hispanic populations.^13,14 TNBC is characterized by a lack of estrogen and progesterone receptors and low expression of HER2. Therefore, TNBC cannot be effectively treated with standard hormone-based therapies and HER2-targeted agents.^12,15 Chemotherapy has produced promising results in early TNBC; however, the majority of patients relapse within the first 3 to 5 years after initial treatment.¹¹ Management of metastatic TNBC remains a clinical challenge, so participation in clinical trials of new treatments often is a good option for patients, regardless of their disease stage.¹⁶ Consequently, there is an urgent unmet need for effective treatment options in patients with metastatic TNBC.¹¹

The most common metastatic BC (MBC) subtype is ER+/HER2-, which has a median PFS of 11 to 24.8 months.^17,18 The 2022 National Comprehensive Cancer Network (NCCN) guidelines indicate that endocrine therapy (ET) using aromatase inhibitors, selective ER modulators, or selective ER down regulators is the preferred first-line treatment for patients with ER+ MBC.^19,20 Despite demonstrated efficacy of ET as first-line treatment for such advanced disease, only an estimated 40% of patients initially respond to ET, and all responders ultimately develop resistance with time.^19,21 Furthermore, notable decreases in efficacy between first- and second-line ETs have been observed.¹⁹ Many patients with ER+/HER- MBC eventually require treatment with chemotherapeutic agents, and a loss of efficacy with subsequent lines of chemotherapy has been demonstrated.¹⁹ Thus, there is a pressing need for additional biomarkers and correlating targeted therapies to help improve survival outcomes for this patient population.

Breast Cancer: FDA-Approved and Investigational ADCs targeting Trop-2

Several ongoing clinical trials for Trop-2–targeting therapies are showing signs of efficacy in patients with TNBC and HR+/HER2- BC.^22-29 Datopotamab deruxtecan (Dato-DXd) is an investigational anti–Trop-2 ADC containing DXd, a potent topoisomerase I inhibitor, coupled to a Trop-2–directed monoclonal antibody via a tetrapeptide-based cleavable linker.²⁵ Sacituzumab govitecan is an anti–Trop-2 ADC that contains SN-38, a water insoluble active metabolite of irinotecan.³⁰ Encouraging efficacy and safety trial data investigating sacituzumab govitecan in the treatment of TNBC have demonstrated meaningful clinical activity and a manageable safety profile.^31-33

Dato-DXd

TROPION-PanTumor01: BC Cohort

In this ongoing phase 1, multicenter, open-label, 2-part study, investigators are assessing the preliminary safety and efficacy of using Dato-DXd in patients with previously treated solid malignancies.²² TROPION-PanTumor01 (NCT03401385) includes patients with advanced/metastatic TNBC as well as those with HR+/HER2- BC that has relapsed or progressed on other standard-of-care treatments. Preliminary data on overall response rate (ORR) according to the RECIST guideline, version 1.1, by blinded independent central review (BICR) were presented in December 2021 at the 2021 San Antonio Breast Cancer Symposium.²²

At the data cutoff point (April 2021), 43 patients with TNBC were treated with at least 1 dose of Dato-DXd. Of these, 95% were treated with at least 2 prior lines of therapy, 44% were given immunotherapy, and 16% were previously treated with sacituzumab govitecan. With a median follow-up of 3.9 months (range, 0.3-9.2 months), the median treatment duration was 2.8 months (range, 0.7-6.9 months).²² In all, 38 patients were evaluable for response; the disease was controlled in 84%, and ORR by BICR was noted in 39% showing evidence of a PR (12 confirmed, 3 pending confirmation). In the 12 patients having a confirmed PR, the median time to response (TTR) was 1.35 months (range, 1.2-3.2 months).²²

Preliminary safety data showed that all-cause treatment-emergent adverse events (TEAEs) of any grade occurred in 95% of patients, and 35% of patients experienced those of grade 3 or higher. None of the patients discontinued treatment due to AEs. Any-grade TEAEs most commonly reported included nausea (58%), stomatitis (53%), alopecia or vomiting (35% each), and fatigue (33%). The TEAEs occurring at grade 3 or higher included stomatitis (9%), fatigue (7%), and vomiting (2%); information on alopecia of at least grade 3 was not available. No diarrhea of grade 3 or higher was reported, and 1 patient experienced a decreased neutrophil count of grade 3.²² Additionally, there were no reported instances of treatment-related interstitial lung disease (ILD) as adjudicated by an independent committee. Serious TEAEs occurred in 12% of patients, and there were no TEAEs associated with death. Dose reductions due to stomatitis, fatigue, mucosal inflammation, dry eye, retinal exudates, and blurred vision occurred in 9 patients, with each TEAE being reported multiple times. Further, 3 patients experienced dose interruptions as a result of stomatitis, mucosal inflammation, bronchitis, and musculoskeletal chest pain.²²

Sacituzumab Govitecan

SASCIA Trial

The phase 3 SASCIA trial (NCT04595565) is a prospective, international, multicenter, randomized, open-label, parallel group study investigating the ADC sacituzumab govitecan given to patients with centrally confirmed HER2- BC. The patients’ tumors also were either HR-negative (HR-) with any residual invasive disease measuring greater than 0.1 cm or HR+ with a clinical and pathologic stage (CPS) and ER status and histologic grade (EG) (CPS + EG score) of at least 3 or a CPS + EG score of 2 and lymph-node metastases. To be eligible for enrollment, patients had received prior taxane-based neoadjuvant chemotherapy for 16 weeks, which needed to include 6 weeks of a taxane.³⁴

The study is evaluating 1200 patients. Patients will be randomly assigned 1:1 to receive 10 mg/kg of sacituzumab govitecan on days 1 and 8 every 3 weeks for 8 cycles or a treatment of physicians choice (eg, capecitabine or platinum-based chemotherapy); ET will be given to patients with HR+ BC per appropriate guidelines.³⁴

Trial enrollment started in December 2020; as of June 2021, 57 patients were enrolled in Germany, and these patients were randomly assigned to one of the treatment arms. The primary end point is invasive disease–free survival, and the key secondary end point is OS. Additional secondary end points include safety, compliance, distant disease–free survival, locoregional recurrence–free interval, and patient-reported outcomes and quality of life.³⁴

IMMU-132-01 Multicenter Basket Trial

The safety and efficacy of sacituzumab govitecan was also studied in IMMU-132-01 (NCT01631552), a phase 1/2, single-arm, open-label, multicenter basket trial. To be eligible for enrollment in the study, adult patients had received a diagnosis of advanced epithelial cancer that was relapsed or refractory to at least 1 standard treatment regimen.³⁵ Patients were given sacituzumab govitecan on days 1 and 8 of each 21-day cycle at a dose of 8, 10, 12, or 18 mg/kg until disease progression, unacceptable toxicity, or death occurred. Prophylactic growth factor support was not permitted before the first day of cycle 1; otherwise, preinfusion medications could be given at the investigator’s discretion.³⁵

Patients were assessed for treatment duration, total number of doses received, and all treatment cycles completed to determine exposure to sacituzumab govitecan. Treatment interruptions and discontinuations were also included in the analysis, as were treatment delays of greater than 3 weeks (> 28 days between dose 1 and 2 in a single cycle or > 35 days between dose 2 in a given cycle and dose 1 of the next cycle).³⁵ End points for treatment efficacy included PFS, duration of response (DOR), OS (per Kaplan-Meier analysis), ORR (ie, confirmed PR and complete response [CR] per RECIST, version 1.1), and clinical benefit rate (CBR; defined as CR, PR, or stable disease for ≥ 6 months).³⁵

TNBC

The IMMU-132-01 basket trial of sacituzumab govitecan included patients with metastatic TNBC who received the drug at the clinically selected dose of 10 mg/kg in the third or later lines of therapy and were selected for analysis of updated results.²⁸ Eligible patients needed to meet enrollment criteria for the full basket trial.²⁸ The 108 patients enrolled were heavily pretreated with a median of 3 prior cancer regimens (range, 2-10 regimens); previous treatment in 106 participants included taxanes (98%) and anthracyclines (86%).²⁸

The objective response rate was 33.3% (PR, 30.6%; CR, 2.8%), with a median TTR of 2.0 months (range, 1.6-13.5 months) and a median DOR of 7.7 months (95% CI, 4.9-10.8). Additionally, the CBR (including stable disease for 6 months) was 45.4%.²⁸ At the time of data cutoff, the median PFS was 5.5 months (95% CI, 4.1-6.3) with an estimated PFS probability of 41.9% at 6 months and of 15.1% at 12 months. Median OS was 13.0 months (95% CI, 11.2-13.7), with estimated 6- and 12-month PFS probabilities of 78.5% and 51.3%, respectively.²⁸

Safety analysis showed that the mean number of doses received was 18.7 (range, 1-102 doses) across an average of 9.6 cycles (range, 1-51 cycles); the median duration of exposure was 5.1 months (range, 0.03-36.1 months).²⁸ Common AEs of any grade included nausea (67%), diarrhea (62%), fatigue and asthenia (55%), neutropenia (64%), and anemia (50%), while those of higher grade included neutropenia (grade 3, 26%; grade 4, 16%), anemia (grade 3, 11%; grade 4, 0%), and decreased white blood cell count (grade 3, 8%; grade 4, 3%). Serious AEs were seen in 32% of patients, with febrile neutropenia (7%), vomiting (6%), nausea (4%), and diarrhea and dyspnea (3% each) reported; AEs leading to death were noted in 4% of patients.²⁸ In all, 44% of patients experienced dose interruptions due to AEs (most often, neutropenia). In total, 3 patients discontinued treatment due to AEs (related to treatment, 2 patients; not related to treatment, 1 patient.²⁸

HR+/HER2- MBC

As part of the IMMU-132-01 basket trial, patients with HR+/HER2- MBC were selected for a prespecified subpopulation analysis to assess the safety and clinical activity of 10 mg/kg of sacituzumab govitecan. Adult patients with HR+/HER2- MBC were eligible if they demonstrated disease progression following at least 2 systemic regimens, including 1 or more ETs and 1 chemotherapy, for metastatic disease.²⁹

In this subpopulation analysis, the primary efficacy end point was objective response rate per RECIST, version 1.1; other efficacy end points included TTR, DOR, and CBR. Median OS and PFS were also included in the efficacy assessment.²⁹ With a median duration of follow-up of 11.5 months (range, 0.7-38.4 months) at the data cutoff, a median of 13.5 doses (range, 1.0-84.0 doses) were received; the median relative dose intensity was 99.8% (range, 47.4%-107.3%).²⁹ An objective response was achieved in 31.5% of patients (PR, 17 patients; 95% CI, 19.5%-45.6%). In these patients, the median TTR was 2.1 months (95% CI, 1.4-7.8), and the median DOR was 8.7 months (95% CI, 3.7-12.7). Stable disease was the best response achieved in 33.3% of patients; therefore, the CBR for this subpopulation was 44.4% (95% CI, 30.9%-58.6%).²⁹ The efficacy results also showed that the median OS and PFS, respectively, were 12.0 months (95% CI, 9.0-18.2) and 5.5 months (95% CI, 3.6-7.6).²⁹

The most common all-grade, treatment-related hematologic AEs included neutropenia (72.2%), anemia (37.0%), and decreased white blood cell count (14.8%); these were of grade 3 or higher in 50.0%, 11.1%, and 9.3% of patients, respectively. All-grade gastrointestinal (GI) AEs related to treatment were nausea (66.7%), diarrhea and vomiting (both 46.3%), and constipation (25.9%). The GI AEs of at least grade 3 were diarrhea (7.4%), vomiting (3.7%), and nausea (1.9%). Other AEs of any grade included fatigue (50.0%), alopecia (44.4%), decreased appetite (31.5%), and headache (18.5%); the only other AE of at least grade 3 noted was fatigue (1.9%).²⁹ Overall, 24.1% of patients required dose reductions, and 7% of patients discontinued therapy due to AEs (only 2 patients discontinued therapy due to treatment-related AEs).²⁹

SKB264

A264 Trial

A Trop-2–directed ADC, SKB264, is being investigated in an open-label, global, first-in-human study of patients with locally advanced or metastatic solid malignancies. The dose escalation study is ongoing. As of March of 2021, 18 adult patients with unresectable solid tumors that relapsed or are refractory to standard treatment have been enrolled. For study inclusion, patients must also show measurable disease according to RECIST, version 1.1.²³

Initial safety results demonstrated that all-cause TEAEs occurred in all 18 patients. The most common were of grades 1 and 2 in severity (nausea [72.2%], alopecia [66.7%]). The most common TEAEs of at least grade 3 in severity included decreases in neutrophil count (27.8%) and white blood cell counts (22.2%) and anemia (16.7%). Patients who experienced TEAEs of grade 3 or higher recovered after receiving treatment; no TEAE led to death.²³

Pharmacokinetic results showed no drug accumulation after multiple doses were given, and exposure to SKB264 increased in proportion to the dose. The dose schedule of every 2 weeks is supported by the half-lives of SKB264 (36 hours) and the free payload (49 hours). In the first cycle, the serum-free payload of total SKB264 peak serum concentration and area under the curve (AUC) were 6% and 5%, respectively, suggesting that the novel linker is stable in the serum.²³

A preliminary efficacy evaluation was performed for the 17 patients having at least 1 tumor assessment. Efficacy was noted at doses from 2 to 6 mg/kg (ORR, 35.5%; disease control rate, 70.6%). A PR according to RECIST, version 1.1, was achieved in 6 patients, which including 2 of 5 participants with TNBC, 2 of 4 with ovarian cancer, 1 with HER2+ BC, and 1 with gastric adenocarcinoma.²³

Lung Cancer

Unmet Needs in NSCLC and SCLC

Lung cancer remains the leading cause of cancer-related death in the United States, accounting for approximately 22% of all cancer deaths among men and women.³⁶ Lung cancer can be classified according to 4 subgroups, including adenocarcinoma, squamous cell carcinoma, small cell carcinoma, and large cell carcinoma, with adenocarcinoma being the most common histology observed.^6,37 NSCLC accounts for the majority of lung cancer diagnoses (80% to 85%) and is responsible for an estimated 85% of lung cancer-associated deaths.³⁷ At the time of diagnosis, approximately 4 in 5 US patients with NSCLC will have metastases upon presentation or during the course of their disease.³⁸ Diagnosis of NSCLC at advanced stages can often lead to greater treatment challenges and an increased risk for disease recurrence and treatment failure.^6,37 For patients with metastatic NSCLC, median survival following standard treatment with platinum-based chemotherapy is 8 to 10 months.³⁸ Despite advanced therapeutic approaches for NSCLC, newer treatments often are effective only for patients with nonsquamous subtypes (5-year relative survival rate, 21.7%), indicating an unmet need within the current treatment landscape.^38,39

Approximately 15% of lung cancer diagnoses involve SCLC, which is associated with one of the lowest 5-year survival rates (6%).²⁷ Due to the aggressive nature of this cancer, roughly two-thirds of patients present with metastatic disease at the time of diagnosis.²⁷ Despite high initial response rates of 60% to 75% among patients with stage IV metastatic SCLC, associated outcomes are poor (PFS, 5.5 months; median OS, < 10 months), and most patients experience relapse within a year after treatment with a platinum-based chemotherapy^.27 Moreover, with no new therapeutics for SCLC approved since 1998, there is an urgent need for additional treatment options and targeted therapies that may help improve outcomes in this patient population.²⁷

Lung Cancer: Investigational ADCs Targeting Trop-2

Dato-DXd

TROPION-PanTumor01 Trial: Dose Analysis in Overall NSCLC Cohort

As part of the TROPION-PanTumor01 trial, data from patients with advanced NSCLC were analyzed.^22,24 To inform dose selection, population pharmacokinetics and exposure-response modeling were performed across doses in 175 patients.²⁴

As of the September 2020 data cutoff, all-grade TEAEs were higher among the 80 patients receiving 8 mg/kg of Dato-DXd than among the 45 participants receiving 6 mg/kg or 50 patients receiving 4 mg/kg of the drug.²⁴ Rates of drug-related TEAEs of at least grade 3 also were higher among patients given the 8-mg/kg dose (34%) than among those given 6- or 4-mg/kg doses (16% and 10%, respectively). Serious TEAEs occurred at higher rates among those given 8 mg/kg of Dato-DxD (20%) than among those given the lower doses (6 mg/kg, 9%; 4 mg/kg, 8%). Drug-related ILD was more frequently seen in patients in the 8-mg/kg cohort (15%) than among the cohorts receiving 6 mg/kg (2%) and 4 mg/kg (2%), as confirmed by an independent adjudication committee. Grade 5 ILD was observed in 3 patients in the 8-mg/kg group.²⁴ Across the 8-, 6-, and 4-mg/kg cohorts, all-grade TEAEs included vomiting (34% vs 18% vs 12%, respectively), anemia (28% vs 16% vs 4%), diarrhea (20% vs 11% vs 6%), and mucositis (29% vs 13% vs 6%).²⁴ Patients given the 8-mg/kg dose were more likely than were those in the 6- and 4-mg/kg cohorts to experience dose interruptions (20% vs 20% vs 4%, respectively) and dose reductions (31% vs 9% vs 2%) due to TEAEs. Treatment discontinuation due to AEs also occurred more frequently in the 8-mg/kg group than in patients receiving 6- or 4-mg/kg doses (15% vs 7% vs 4%).²⁴

Preliminary efficacy data for patients with NSCLC showed an ORR of 25% in the 8-mg/kg cohort, of 21% in the 6-mg/kg cohort, and of 23% in the 4-mg/kg cohort, as determined by BICR. Across the 3 groups, preliminary mean PFS was 5.4 months (95% CI, 4.1-7.1), 8.2 months (95% CI, 1.5-11.8), and 4.3 months (95% CI, 2.0-not estimable), respectively, although data were limited by an immature duration of follow-up of 3 months or less in each cohort (46%, 67%, and 66%, respectively).²⁴

Pharmacometric analysis showed a positive correlation between exposure to Dato-DXd (AUC) with probability of CR or PR and change in tumor size from baseline. A positive correlation was also observed between Dato-DXd exposure and both stomatitis or mucositis of at least grade 2 and incidences of dose reduction. Trends derived from these projected probabilities were confirmed in a virtual population bootstrapped from population pharmacokinetic data of patients with NSCLC.²⁴

TROPION-PanTumor01 Trial: NSCLC Cohort With Actionable Genomic Alterations

An analysis of Dato-DXd use in patients with NSCLC with actionable genomic alterations (AGAs) was conducted as part of the ongoing TROPION-PanTumor01 trial population.²⁵ In all, 34 patients were included in this analysis; investigator-reported AGAs involved EGFR in 29 patients, ALK in 3 patients, and ROS1 and RET in 1 patient each. Overall, 82% of these patients were treated with at least 3 prior regimens, and 85% had prior exposure to tyrosine kinase inhibitor therapy. Notably, osimertinib had been used in 69% of patients with EGFR mutations.²⁵

Patients remained on study for a median duration of 13 months, and the median DOR was 8.5 months (95% CI, 3.3-not estimable). The BICR-confirmed ORR was 35% across treatment doses (95% CI, 19.7-53.5). Nausea (62%) and stomatitis (56%) were the most commonly reported any-grade AEs, and hematologic toxicities were noted infrequently. Grade 5 treatment-related ILD occurred in 1 patient with NSCLC associated with AGAs who was in the 8-mg/kg cohort.²⁵

Sacituzumab Govitecan

IMMU-132-01 Multicenter Basket Trial

NSCLC

An analysis was conducted of patients within the IMMU-132-01 basket trial to assess the safety and antitumor activity of sacituzumab govitecan in patients with metastatic NSCLC with measurable disease that had progressed following 1 or more lines of treatment for stage 4 disease.²⁶ In addition to meeting enrollment criteria for the phase 1 basket trial, eligible patients also needed an ECOG performance status of 0 or 1 and adequate bone marrow, hepatic, and renal function. Patients also were required to have completed systemic therapy 4 or more weeks before enrollment.²⁶ Patients had a median of 3 prior lines of therapy (range, 2-7 lines), and all patients were treated previously with at least 1 platinum-containing regimen; 74% received prior treatment with platinum-based chemotherapy and a taxane, and the remaining 26% of patients also had prior exposure to pemetrexed and/or gemcitabine.²⁶ Additionally, 33% of patients had received immunotherapy (PD-1 or PD-L1 inhibitor), and 32% had been treated with an EGFR inhibitor.²⁶

Among 54 patients with metastatic NSCLC enrolled, 8 patients received the 8-mg/kg dose offered in the full basket trial, and 46 participants received the offered 10-mg/kg dose.²⁶ Of 47 patients evaluable for response, 19% showed a confirmed PR. In the intent-to-treat (ITT) population, the ORR was 17%, with a median TTR of 3.8 months (range, 1.8-11.6 months) and a median DOR of 6.0 months (95% CI, 4.8-8.3).²⁶ Stable disease was observed in 49% of patients, and the CBR was 32%.²⁶ Median PFS in the ITT population was 5.2 months (95% CI, 3.2-7.1), and the median OS was 9.5 months (95% CI, 5.9-16.7), both based on Kaplan-Meier estimates.²⁶

Serious AEs of grade 3 or higher that occurred in at least 5% of patients included neutropenia (28%), leukopenia and pneumonia (9% each), diarrhea and nausea (7% each), and fatigue (6%). Two patients (4%) experienced febrile neutropenia. Grade 3 or 4 neutropenia was more common with use of the 10-mg/kg dose (30%) than the 8-mg/kg dose (13%), although only 8 patients in this study received the lower dose.²⁶ Dose reductions due to neutropenia occurred in 43% of patients, and AEs led to premature discontinuation of treatment in 2 patients.²⁶

SCLC

Another part of the IMMU-132-01 basket trial analysis evaluated the activity of sacituzumab govitecan in patients with metastatic SCLC who had measurable tumors by CT scan and were relapsed or refractory to 1 or more lines of standard therapy for metastatic disease.²⁷ Patients needed to meet full enrollment criteria for the phase 1 basket trial at-large. Further eligibility criteria included an ECOG performance status of 0 or 1; adequate renal, hepatic, and bone marrow function; and completion of prior therapy 2 or more weeks before trial enrollment.²⁷ A majority of patients had extensive disease that included multiple-organ metastases. The median number of prior lines of therapy was 2 (range, 1-7 lines). All patients on trial had received cisplatin or carboplatin plus etoposide and were considered chemoresistant or chemosensitive to their first-line treatment.²⁷

A total of 53 patients with metastatic SCLC were included, with 38 participants receiving the 10-mg/kg dose and 15 receiving the 8-mg/kg dose.²⁷ In the ITT population of 50 patients, PR was achieved in 6 of 36 patients (17%) in the 10-mg/kg group and 1 of 14 patients (7%) in the 8-mg/kg group, resulting in an overall ORR of 14%.²⁷ The median DOR by Kaplan-Meier estimate was 5.7 months (95% CI, 3.6-19.9). Stable disease was achieved as the best response in 42% of patients, with a median duration of 5.6 months (95% CI, 5.2-9.7). The median PFS in the ITT population was 3.7 months (95% CI, 2.1-4.3), and the median OS was 7.5 months (95% CI, 6.2-8.8).²⁷

In total, the most frequently observed all-grade AEs included diarrhea (53%), nausea (51%), fatigue (47%), neutropenia (43%), vomiting (34%), abdominal pain (30%), anorexia (28%), anemia (26%), alopecia (23%), and constipation (21%). Grade 3 or 4 AEs were neutropenia (34%), fatigue (13%), diarrhea (9%), anemia (6%), hypoxia (4%), and febrile neutropenia (2%). No treatment-related deaths were reported.²⁷ Neutropenia was the primary indication for dose reductions needed by 3 patients at the 8-mg/kg dose and 15 patients at the 10-mg/kg dose.²⁷

Future Directions

Emerging data from studies of novel ADCs that target Trop-2 show encouraging antitumor activity and safety data in patients with advanced or metastatic solid tumors, including heavily pretreated populations diagnosed with TNBC, HR+/HER- BC, NSCLC, and SCLC.^{22,23,25-27,29} Preliminary safety data appear to be promising, with these agents showing a manageable AE profile. The unique drug-release mechanism (hydrolysable linker) associated with sacituzumab govitecan elicits a dual mechanism of cytotoxicity following internalization via a significant bystander effect, which may be advantageous in treating tumors exhibiting heterogenous expression of target antigens.^29,40 Further details regarding Dato-DXd need to be elucidated, but the results of previous studies demonstrated an association between DXd payload and a potent bystander effect due to its high degree of membrane permeability.⁴¹ Moreover, preliminary data evaluating the use of these agents warrant further investigation in treating advanced or metastatic NSCLC, SCLC, TNBC, and HR+/HER2- BC.^22,26,27

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