Investigators Lay Groundwork for Exploring TROP-2 as a Therapeutic Target in NSCLC

George R. Simon, MD

Clinicians looking for additional options for the treatment of patients with non–small cell lung cancer (NSCLC) may soon be gaining another actionable biomarker with the emergence of exciting new data concerning targeting the cell-surface glycoprotein (TROP-2).¹

“[TROP-2] is a calcium signal transducer that can activate the MAP kinase pathway, and downstream of MAP kinases are ERK1 and ERK2 which are important mediators of progressions, proliferation, and metastases,” George R. Simon, MD, said during an OncLive^® scientific interchange and workshop. “TROP-2 is also involved in the activation of cyclin E and cyclin D as cell cycle progression proteins. TROP-2 signaling appears to be dependent on beta-catenin and direct interaction between beta-catenin and the intracellular domain of TROP-2 has been associated with stem-like properties for the cancer cell. There are many potential pathways TROP-2 signaling can affect, leading to increased malignant potential.”

Figure. Mechanism of Action for TROP-2–Directed Antibody-Drug Conjugates

Simon is a professor of medicine and department chair of the H. Lee Moffitt Cancer Center as well as the executive medical director of the Moffitt Cancer Center-AdventHealth clinical research unit in Celebration, Florida.

During the interchange, Simon presented findings from a 2016 meta-analysis performed by Zeng et al that evaluated the association between TROP-2 expression and prognosis among 2569 patients with solid tumors. The analysis encompassed 16 studies in Europe and Asia. Investigators extracted and summarized features from each trial including score for TROP-2 assessment, cut-off values to determine TROP-2 overexpression, and number of patients analyzed.²

The primary outcomes of the analysis were overall survival (OS) and disease-free survival (DFS). Findings from the analysis showed that TROP-2 overexpression was associated with worse OS outcomes (pooled HR, 1.896; 95% CI, 1.5992.247, P < .001) and a shorter DFS (pooled HR, 2.336; 95% CI, 1.596-3.419, P < .001). Specifically, among patients with NSCLC (n = 93), OS was also significantly reduced for patients with TROP-2 overexpression (HR, 1.60; 95% CI, 0.15-17.26).

In another retrospective study, Li et al sought to more specifically define the role of TROP-2 overexpression in NSCLC. Investigators examined TROP-2 expression via immunohistochemistry in a population of 68 patients with lung adenocarcinoma.³

Results from the analysis showed that TROP-2 expression was significantly elevated in the tissue from patients with adenocarcinoma compared with normal lung tissue (P < .05). Additionally, among patients with lung adenocarcinoma, TROP-2 overexpression was correlated with worse tumor, node, metastasis stage (P = .012), lymph node metastasis (P = .038), and histologic grade (P = .013). A Kaplan-Meier survival analysis also determined that disease harboring high levels of TROP-2 was associated with a poor prognosis (P = .046).

Investigators concluded that TROP-2 plays a significant role in promoting lung adenocarcinoma and could be a novel prognostic biomarker as well as a therapeutic target in the space.

“We now know from previous studies that TROP-2 expression is associated with poor prognosis,” Simon said. “[This is true] specifically in adenocarcinomas and not so much in squamous or carcinomas and because of its selective expression in tumors vs normal lung and an increased expression in adenocarcinomas. It is thought to be a potentially actionable biomarker in patients with nonsquamous NSCLC.”

TROP-2–Directed Agent Displays Robust Results

TROP-2–targeted therapeutics, specifically antibody-drug conjugates (ADCs), are under investigation in patients with solid tumors. These include the novel agent datopotamab deruxtecan and an agent that has demonstrated strong signals in breast cancer, sacituzumab govitecan-hziy (Trodelvy), which are the focus of several ongoing trials in NSCLC (Table). Datopotamab deruxtecan is an ADC made up of a TROP-2directed monoclonal antibody conjugated to a topoisomerase I inhibitor via a tetrapeptide-based cleavable linker.⁴

Table. Select Ongoing Trials Evaluating TROP-2 ADCs in NSCLC

TROPION-PanTumor01 (NCT03401385) is a phase 1 dose-escalation/dose-expansion study that is evaluating datopotamab deruxtecan in patients with solid tumors who were unselected for TROP-2 expression. Notably, the trial permitted patients with stable or treated brain metastases. The primary end point of the trial is safety and tolerability. Secondary end points consisted of efficacy and pharmacokinetics.

In the NSCLC cohort (n = 180), the median number of prior therapies was 3 (range, 1-9). A little less than half of patients (42%) were aged at least 65 years, 37% had a history of brain metastases, and nearly all had received prior chemotherapy (96%). Patients were treated with datopotamab deruxtecan at a dose of 4 mg/kg (n = 50), 6 mg/kg (n = 50), or 8 mg/kg (n = 80).

At a median follow-up of 11.4 months (range, 3.1-25.9), the overall response rate (ORR) by blinded independent central review was 24%, 26%, and 24% in the low-, middle-, and high-dose groups, respectively. Two patients in both the 4 mg/kg and 6 mg/kg groups were still undergoing treatment with unconfirmed responses as of the January 8, 2021, data cutoff.

In terms of safety, treatment-emergent adverse events (TEAEs) at grade 3 or greater were observed in 47% of patients across dose levels. Common TEAEs of any grade reported across dose levels included nausea (52%), stomatitis (48%), alopecia (39%), and fatigue (32%). Any-grade TEAEs of special interest due to their frequency with another TROP-2 directed ADC were not as frequent with datopotamab deruxtecan treatment: decreased neutrophil count/neutropenia (6%) and diarrhea (16%).

Treatment discontinuation due to TEAEs occurred at a rate of 15% overall, with 14% of the 6 mg/kg group, 10% of the 8 mg/kg group, and 19% of the 8 mg/kg group being forced to stop treatment due to a TEAE. Drug-related interstitial lung disease, a commonly observed TEAE for ADCs, occurred at any grade in 11% of patients across dose levels. Any-grade drug-related interstitial lung disease was more common at the highest dose level (15%) compared with the 4 mg/kg dose (10%) and the 6 mg/kg dose (4%).

“The 4 mg/kg and the 6 mg/kg doses were better tolerated than the 8 mg/kg,” Simon said. “The most common adverse effects were mucosal inflammation, stomatitis, anemia, and fatigue. Importantly, a significant amount of interstitial lung disease [was also] reported.”

Study authors concluded that datopotamab deruxtecan has demonstrated promising efficacy with a manageable safety profile for a heavily pretreated population with advanced/metastatic NSCLC. Six mg/kg was determined to be the recommended dose in the phase 3 TROPIONLUNG01 trial (NCT04656652).

Ongoing Trials Are Charting the Future of TROP-2

On the heels of the exciting findings from TROPION-PanTumor01, TROPION-LUNG01 was initiated to further examine the safety and efficacy of datopotamab deruxtecan compared with docetaxel. The randomized, parallel assignment trial is aiming to enroll approximately 590 patients with advanced or metastatic NSCLC with or without actionable genomic alterations.⁵

Datopotamab deruxtecan 6 mg/kg will be given as an intravenous infusion on day 1 of each 3-week cycle. Similarly, docetaxel 75 mg/ m² will be administered intravenously on day 1 of each 3-week cycle.

Patients with actionable genomic alterations need to have experienced disease progression on or after 1 platinum-containing therapy and 1 to 2 prior lines of approved targeted therapy. Those without actionable genomic alterations must also have received at least 1 platinum-containing regimen, as well as an anti-PD-1/PD-L1 monoclonal antibody.

The primary end points of the trial are progression-free survival (PFS) and OS. Secondary end points include ORR, duration of response (DOR), and safety. The trial is actively recruiting patients and has an estimated completion date of June 27, 2024.

Additionally, the phase 2 TROPION-Lung05 trial (NCT04484142) is also currently evaluating datopotamab deruxtecan monotherapy in patients with NSCLC. The trial will enroll approximately 137 patients whose disease harbors known actionable genomic alterations and who have been treated with 1 prior platinum-containing therapy and at least 1 targeted therapy. Datopotamab deruxtecan will again be given intravenously at a dose of 6 mg/kg once every 3 weeks.⁶

The primary end point is ORR. Secondary end points include PFS, DOR, OS, and safety. The trial is no longer accepting new patients and is estimated to be completed by May 2024.

Finally, investigators of the phase 2 ORCHARD trial (NCT03944772) are seeking to establish the role of TROP-2 inhibition in combination with the EGFR tyrosine kinase inhibitor, osimertinib (Tagrisso) in patients with EGFR-mutant advanced NSCLC with progression following first-line treatment with the osimertinib.⁷

Patients without a biomarker match (ALK, RET, BRAF) will receive oral osimertinib 80 mg once daily plus intravenous datopotamab deruxtecan 4 mg/kg every 3 weeks. If no dose-limiting toxicities occur in the first 3 or 4 patients, enrollment to a 6-mg/kg dose cohort can be initiated. Safety and tolerability data will inform expansion of the 4- or 6-mg/kg cohort to 16 patients. Tumor assessments using RECIST 1.1 criteria will be performed every 6 weeks for the first 24 weeks, then every 9 weeks until disease progression. The primary outcome is investigator-assessed confirmed ORR. Secondary outcomes include safety/tolerability, DOR, and pharmacokinetics.⁷

Sacituzumab Govitecan Undergoes Investigation

The ADC sacituzumab govitecan will be evaluated vs single-agent docetaxel during the phase 3 EVOKE-01 trial (NCT05089734) in patients with metastatic NSCLC who have progressed on or after platinum-based chemotherapy and immune checkpoint inhibitor therapy. According to a trial overview presented in a poster during the International Association for the Study of Lung Cancer (IASLC) 2022 World Conference on Lung Cancer, the primary end point of the open-label, global, multicenter, randomized trial is to determine if sacituzumab govitecan will provide an overall survival (OS) benefit vs docetaxel in this patient population.⁸

Previously reported data from the phase 1/2 IMMU-132-01 basket study (NCT01631552) showed that single-agent sacituzumab govitecan produced a median OS of 9.5 months, an ORR of 16.7%, and a manageable safety profile in patients with metastatic NSCLC, including 59% who received at least 3 prior lines of therapy.

References

1. Mito R, Matsubara E, Komohara Y, et al. Clinical impact of TROP2 in non-small lung cancers and its correlation with abnormal p53 nuclear accumulation. Pathol Int. 2020;70(5):287-294. doi:10.1111/pin.12911
2. Zeng P, Chen MB, Zhou LN, Tang M, Liu CY, Lu PH. Impact of TROP2 expression on prognosis in solid tumors: a systematic review and meta-analysis. Sci Rep. 2016;6:33658. doi:10.1038/srep33658
3. Li Z, Jiang X, Zhang W. TROP2 overexpression promotes proliferation and invasion of lung adenocarcinoma cells. Biochem Biophys Res Commun. 2016;470(1):197-204. doi:10.1016/j.bbrc.2016.01.032
4. Garon E, Johnson M, Lisberg A, et al. MA03.02 TROPION-PanTumor01: updated results from the NSCLC cohort of the phase 1 study of datopotamab deruxtecan in solid tumors. J Thorac Oncol. 2021;16(suppl 10):S892-S893. doi:10.1016/j.jtho.2021.08.118
5. Study of DS-1062a versus docetaxel in previously treated advanced or metastatic non-small cell lung cancer with or without actionable genomic alterations (TROPION-LUNG01). ClinicalTrials.gov. Updated September 16, 2022. Accessed September 22, 2022. https://clinicaltrials.gov/ct2/show/NCT04656652
6. Study of DS-1062a in advanced or metastatic non-small cell lung cancer with actionable genomic alterations (TROPION-Lung05). ClinicalTrials.gov. Updated July 28, 2022. Accessed August 15, 2022. https://clinicaltrials.gov/ct2/show/NCT04484142
7. De Langen J, Cho BC, Piotrowska Z, et al. ORCHARD platform study: osimertinib + datopotamab deruxtecan (Dato-DXd) cohort in patients (pts) with advanced NSCLC (aNSCLC) who have progressed on first-line (1L) osimertinib. Poster presented at: European Society for Medical Oncology Congress 2022; September 9-13, 2022; Paris, France.
8. Reinmuth N, Reznick D, Liu SY, et al. Phase 3 EVOKE-01 study of sacituzumab govitecan vs docetaxel in NSCLC after prior platinum and checkpoint inhibitors. Poster presented at: IASLC 2022 World Conference on Lung Cancer; August 6-9, 2022; Vienna, Austria.

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