TROP2 Offers Attractive Therapeutic Target in Breast Cancer and Other Solid Tumors

Ian Krop, MD, PhD

New data with TROP2-targeted therapy showing reduced rates of myelosuppression have fueled enthusiasm for TROP2-directed antibody-drug conjugates (ADCs) for patients with breast cancer and other solid tumors, strengthening the evidence in support of the class’s safety and efficacy.

The first indication for a TROP2-directed ADC came in 2020 when the FDA granted accelerated approval to sacituzumab govitecan-hziy (Trodelvy) for patients with metastatic triple-negative breast cancer (mTNBC).¹ TROP2 is highly expressed in multiple epithelial cancers and is involved in intracellular signaling via multiple pathways, including MAPK, PI3K/AKT, ERK, and JNK. These pathways are often associated with the proliferation, spread, and invasion of cancer cells.^2,3

“TROP2 is a cell surface transmembrane protein that is seen in normal tissues, but overexpressed in cancers,” Ian Krop, MD, PhD, explained in an interview with OncologyLive. “In cancers, it’s been shown functionally to lead to higher proliferation rates and less apoptosis, meaning better survival of the [cancer] cells. Overexpression [of TROP2] in cancer has been associated with poor prognosis. All those [factors] make it an attractive target for anticancer therapies.”

Krop is the director of the Clinical Trials Office, chief clinical research officer and associate director of clinical sciences at Yale Cancer Center, and a professor of internal medicine (medical oncology) at Yale School of Medicine in New Haven, Connecticut.

Sacituzumab govitecan is currently the only TROP2-directed ADC approved by the FDA. Following the 2020 accelerated approval of the agent for the treatment of patients with mTNBC who received at least 2 prior therapies for metastatic disease, the indication was converted to a regular approval in April 2021 for the treatment of patients with mTNBC who underwent 2 or more prior systemic therapies, with at least 1 of them for metastatic disease. Also in April 2021, the FDA granted accelerated approval to the ADC for the treatment of patients with locally advanced or metastatic urothelial cancer who previously received platinum-containing chemotherapy and a PD-L1 inhibitor. Finaly, in February 2023, the FDA approved sacituzumab govitecan in hormone receptor–positive, HER2-negative breast cancer following endocrine-based therapy and at least 2 other systemic treatments in the metastatic setting.^1,4,5

Aditya Bardia, MD, MPH, FASCO

“[These indications for sacituzumab govitecan] highlight that these are cancers where TROP2 is overexpressed and thus a TROP2-[directed] ADC…could have a therapeutic role,” Aditya Bardia, MD, MPH, FASCO, director of translational research integration and a professor in the Department of Medicine, Division of Hematology/Oncology at UCLA Health Jonsson Comprehensive Cancer Center in Los Angeles, California, noted in a separate interview with OncologyLive. “There are [also] a number of additional drugs in development.”

Dato-DXd Stirs Excitement for TROP2-Directed Therapy in Breast and Lung Cancer

Beyond sacituzumab govitecan, the TROP2-targeted ADC that is furthest along in the development pipeline is datopotamab deruxtecan (Dato-DXd). “Dato-DXd is a TROP2-directed ADC with a more stable linker that more selectively delivers deruxtecan to tumor cells. It has a bystander effect and can [also] affect other cells that do not express TROP2,” Bardia explained (Figure).²

Figure. Mechanism of Action of Anti-TROP2

Antibody-Drug Conjugate Datopotamab Deruxtecan²

The ongoing phase 1 TROPION-PanTumor01 study (NCT03401385) is the first in-human trial of Dato-DXd. The study is enrolling patients with previously treated advanced solid tumors, including hormone receptor–positive, HER2-negative breast cancer and TNBC. Updated findings from the study showed that treatment with Dato-DXd led to overall response rates (ORRs) of 26.8% (95% CI, 14.2%-42.9%) and 31.8% (95% CI, 18.6%-47.6%) in patients with hormone receptor–positive, HER2-negative breast cancer (n = 41) and TNBC (n = 44), respectively. The median progression-free survival (PFS) was 8.3 months (95% CI, 5.5-11.1) and 4.4 months (95% CI, 3.0-7.3), respectively.⁶

“The evidence of clinical activity was encouraging, and there are ongoing phase 3 trials,” Bardia noted. “In terms of safety profile, the rate of myelosuppression was low with Dato-DXd, which is in contrast to the other TROP2-[directed] ADCs, such as sacituzumab govitecan, [which has] high rates of myelosuppression.”

The positive data from TROPION-PanTumor01 led to the initiation of the phase 3 TROPION-Breast01 study (NCT05104866), which is investigating Dato-DXd in patients with inoperable or metastatic hormone receptor–positive, HER2-negative breast cancer who experienced disease progression with endocrine therapy and have received 1 or 2 prior lines of chemotherapy. Findings from the primary analysis of the study, presented during the 2023 European Society for Medical Oncology Congress, demonstrated that patients who received Dato-DXd (n = 365) achieved a significant PFS benefit compared with those who received investigator’s choice of chemotherapy (HR, 0.63; 95% CI, 0.52-0.76; P < .0001).⁷

“The [safety] profile [of Dato-DXd] is manageable; it’s interesting [because] it’s quite different than that of sacituzumab govitecan,” Krop added. “Sacituzumab govitecan’s toxicity most notably [consists of] neutropenia, as well as some gastrointestinal toxicities. With Dato-DXd, even though it has the same target and the same class of payload [as sacituzumab govitecan], we see little clinically meaningful toxicity in [terms of] hematologic values. Stomatitis [was reported in approximately] 50% of patients [who received Dato-DXd but] it’s almost all grade 1 or 2. Although there was a small percentage of patients with grade 3 or higher stomatitis, it didn’t lead to a significant number of patients discontinuing the drug.”

Findings from TROPION-Breast01 led to the FDA accepting the biologics license application (BLA) for Dato-DXd in April 2024 for the treatment of adult patients with unresectable or metastatic hormone receptor–positive, HER2-negative breast cancer who have received prior systemic treatment for unresectable or metastatic disease. The Prescription Drug User Fee Act (PDUFA) action date is January 29, 2025.⁸

Dato-DXd is also being evaluated in a phase 3 study for the treatment of patients with non–small cell lung cancer (NSCLC). During the 2024 International Association for the Study of Lung Cancer World Conference on Lung Cancer (WCLC 2024), investigators shared updated findings from the phase 3 TROPION-Lung01 study (NCT04656652). TROPION-Lung01 is examining Dato-DXd vs docetaxel in patients with previously treated metastatic NSCLC with or without actionable genomic alterations.⁹

Prior data from TROPION-Lung01 met the study’s coprimary end point of PFS, showing a significant improvement with Dato-DXd vs docetaxel (HR, 0.75; 95% CI, 0.62-0.91; P = .004). These findings supported the FDA’s acceptance of the BLA for Dato-DXd for the treatment of adult patients with previously treated, locally advanced or metastatic nonsquamous NSCLC in February 2024, with a PDUFA date decision expected in the fourth quarter of 2024.¹⁰

Data from the final overall survival (OS) analysis of the study presented during WCLC 2024 showed that patients who received Dato-DXd (n = 299) experienced a median OS of 12.9 months (95% CI, 11.0-13.9) compared with 11.8 months (95% CI, 10.0-12.8) among patients treated with docetaxel (n = 305; HR, 0.94; 0.78-1.14; P = .530), missing the study’s second coprimary end point. However, Dato-DXd did provide a non–statistically significant OS benefit vs docetaxel in the subgroup of patients with nonsquamous histology, reducing the risk of death by 16% (HR, 0.84; 95% CI, 0.68-1.05); investigators concluded that the agent could be a new therapeutic option for this patient population.⁹

Additionally, investigators presented an analysis of TROPION-Lung01 during WCLC 2024 that examined the predictive value in terms of clinical outcomes of TROP2 expression by normalized membrane ratio (NMR) per quantitative continuous scoring (QCS). Data from the analysis showed that patients positive for TROP2 expression by QCS-NMR who received Dato-DXd (n = 107) achieved a median PFS of 6.9 months compared with 4.1 months among patients in this group who received docetaxel (n = 107; HR, 0.57; 95% CI, 0.41-0.79). Comparatively, patients who were negative for TROP2 per QCS-NMR experienced a median PFS of 2.9 months vs 4.0 months in the respective arms (HR, 1.16; 95% CI, 0.79-1.70).¹¹

Study authors concluded that evaluation of TROP2 expression by QCS-NMR could represent the first TROP2 biomarker and the first computational pathology biomarker for predicting response to Dato-DXd in patients with NSCLC. They also noted that the biomarker is being further investigated in frontline advanced NSCLC in the phase 3 AVANZAR (NCT05687266) and TROPION-Lung10 (NCT06357533) studies, in which Dato-DXd is being examined in combination with durvalumab (Imfinzi) plus carboplatin and rilvegostomig, respectively.

Next Wave of TROP2-Targeted Agents Aims to Build on Previous Gains

Beyond Dato-DXd are multiple TROP2-directed ADCs progressing through the development pipeline. The novel TROP2-targeted ADC sacituzumab tirumotecan, which also employs the bystander effect, is being investigated in patients with previously treated recurrent TNBC or mTNBC who experienced disease progression following treatment with at least 2 chemotherapy regimens in the phase 3 OptiTROP-Breast01 trial (NCT05347134). The primary end point of the study is PFS by blinded independent central review (BICR); OS is the key secondary end point.¹²

Findings from the final analysis of OptiTROP-Breast01 presented during the 2024 American Society of Clinical Oncology Annual Meeting showed that patients who received sacituzumab tirumotecan (n = 130) achieved a median PFS by BICR of 6.7 months (95% CI, 5.5-8.0) compared with 2.5 months (95% CI, 1.7-2.7) among those treated with investigator’s choice of chemotherapy (n = 133; HR, 0.32; 95% CI, 0.22-0.44; P < .00001). Findings from the interim OS analysis showed that median OS was not yet reached with sacituzumab tirumotecan (95% CI, 11.2-not estimable) vs 9.4 months (95% CI, 8.5-11.7) with chemotherapy.

Sacituzumab tirumotecan monotherapy is being investigated for the frontline treatment of patients with PD-L1–negative TNBC in a phase 3 study (NCT06279364) and in combination with pembrolizumab (Keytruda) for the treatment of patients with early-stage TNBC in the adjuvant setting in the phase 3 MK-2870-012 trial (NCT06393374).

Another novel TROP2-directed ADC, BNT325/DB-1305, received fast track designation from the FDA in January 2024 for the treatment of patients with platinum-resistant ovarian epithelial, fallopian tube, or primary peritoneal cancer following 1 to 3 prior lines of systemic therapy. Preliminary findings from a phase 1/2 study (NCT05438329) supported the decision, demonstrating that patients with advanced solid tumors (n = 23), including NSCLC and TNBC, achieved an ORR of 30.4% and a disease control rate of 87.0%. The 1 patient with fallopian tube cancer experienced an unconfirmed partial response.^13,14

“[TROP2-directed ADCs] are moving into first-line metastatic breast cancer [treatment], as well as early[-stage] breast cancer,” Bardia said in conclusion. “There are a number of pivotal studies looking at these drugs, both in the neoadjuvant and adjuvant settings, predominantly for TNBC, and there is also interest in combining these drugs with other agents, particularly immunotherapy. TROP2-directed ADCs appear to be [superior] vs standard chemotherapy, and they’ve changed how we treat [patients with] metastatic breast cancer. In the future, as they move into early[-stage] breast cancer, the question will be [a matter of weighing] the efficacy and the toxicity profile [of these agents] in a curative setting.”

References

1. FDA grants regular approval to sacituzumab govitecan for triple-negative breast cancer. FDA. Updated April 8, 2021. Accessed September 6, 2024. bit.ly/4d2gIrc
2. Okajima D, Yasuda S, Maejima T, et al. Datopotamab deruxtecan, a novel TROP2-directed antibody-drug conjugate, demonstrates potent antitumor activity by efficient drug delivery to tumor cells. Mol Cancer Ther. 2021;20(12):2329-2340. doi:10.1158/1535-7163.MCT-21-0206
3. Zaman S, Jadid H, Denson AC, Gray JE. Targeting Trop-2 in solid tumors: future prospects. Onco Targets Ther. 2019;12:1781-1790. doi:10.2147/OTT.S162447
4. FDA grants accelerated approval to sacituzumab govitecan for advanced urothelial cancer. FDA. April 13, 2021. Accessed September 6, 2024. bit.ly/4cYgP72
5. FDA approves sacituzumab govitecan-hziy for HR-positive breast cancer. FDA. February 3, 2023. Accessed September 6, 2024. bit.ly/4d9l5R8
6. 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;42(19):2281-2294. doi:10.1200/JCO.23.01909
7. Bardia A, Jhaveri K, Im SA, et al. Datopotamab deruxtecan (Dato-DXd) vs chemotherapy in previously-treated inoperable or metastatic hormone receptor-positive, HER2-negative (HR+/HER2–) breast cancer (BC): primary results from the randomised phase III TROPION-Breast01 trial. Ann Oncol. 2023;34(suppl 2):S1264-S1265. doi:10.1016/j.annonc.2023.10.015
8. Datopotamab deruxtecan biologics license application accepted in the U.S. for patients with previously treated metastatic HR positive, HER2 negative breast cancer. News release. Daiichi Sankyo. April 2, 2024. Accessed September 11, 2024. https://www.daiichisankyo.com/files/news/pressrelease/pdf/202404/20240402_E.pdf
9. Sands J, Lisberg A, Okamoto I, et al. Datopotamab deruxtecan vs docetaxel in patients with non-small cell lung cancer: final overall survival from TROPIONLung01. Abstract presented at: International Association for the Study of Lung Cancer 2024 World Conference on Lung Cancer; September 7-10, 2024; San Diego, CA. Abstract 2640.
10. Datopotamab deruxtecan biologics license application accepted in the US for patients with previously treated advanced nonsquamous non-small cell lung cancer. News release. AstraZeneca. February 19, 2024. Accessed September 11, 2024. bit.ly/4e5Clbh
11. Garassino MC, Sands J, Paz-Ares L, et al. Normalized membrane ratio of TROP2 by quantitative continuous scoring is predictive of clinical outcomes in TROPION-Lung01. Abstract presented at: International Association for the Study of Lung Cancer 2024 World Conference on Lung Cancer; September 7-10, 2024; San Diego, CA. Abstract 4037.
12. Xu B, Yin Y, Fan Y, et al. Sacituzumab tirumotecan (SKB264/MK-2870) in patients (pts) with previously treated locally recurrent or metastatic triple-negative breast cancer (TNBC): results from the phase III OptiTROP-Breast01 study. J Clin Oncol. 2024;42(suppl 16):104. doi:10.1200/JCO.2024.42.16_suppl.104
13. BioNTech and DualityBio receive FDA fast track designation for next-generation antibody-drug conjugate candidate BNT325/DB-1305. News release. BioNTech SE. January 31, 2024. Accessed September 11, 2024. bit.ly/3XHuDOE
14. Marathe O, Cheng Y, Spira AI, et al. DB-1305 (a Trop-2 targeted antibody-drug-conjugate [ADC]) in patients (pts) with advanced solid tumors: preliminary clinical results from the phase (Ph) I/IIa study. Ann Oncol. 2023;34(suppl 2):S480. doi:10.1016/j.annonc.2023.09.1875