SAGA—a phase Ib/II single-arm, multicenter study of sacituzumab govitecan for patients with metastatic esophagogastric adenocarcinoma

Abstract

Background

Treatment of metastatic and locally advanced unresectable esophagogastric adenocarcinoma (EGA) after first-line therapy has limited efficacy. Sacituzumab govitecan (SG) is an antibody-drug conjugate (ADC) linking a TROP-2-directed antibody to the topoisomerase-I inhibitor SN-38. EGA has a high TROP-2 positivity rate and is sensitive to topoisomerase inhibition. Thus far, limited data on the efficacy and safety of SG in this patient population are available.

Aim

To evaluate the safety and efficacy of SG in patients with metastatic EGA who progressed under previous treatment. Objective response rate (ORR) is the primary endpoint.

Trial design

SAGA is a single-arm, non-randomized, open-label multicenter phase Ib/II study. Patients after prior treatment with a fluoropyrimidine-platinum-containing chemotherapy with or without targeted therapy or immunotherapy will be treated with SG intravenously at a dose of 10 mg/kg body weight on days 1 and 8 of a 21-day treatment cycle. After a run-in phase of 20 patients, safety and efficacy will be evaluated and the trial will proceed to a recruitment goal of 56 patients when at least two tumor responses are documented in the run-in phase. A hypothesis of an ORR of 16% is tested against a null hypothesis of an ORR of 5%.

Trial identifiers

EU CT 2023-505257-40-00, NCT06123468, AIO-STO-0123/ass., IKF-t065

Graphical abstract

Specifications table

Subject area	Medicine and Dentistry
More specific subject area	Treatment of metastatic esophagogastric adenocarcinoma
Name of your trial in progress	SAGA trial: A phase Ib/II single-arm, multicenter study of sacituzumab govitecan, a TROP-2-targeting antibody linked with SN-38, for patients with metastatic esophagogastric adenocarcinoma (EGA)
Reagents/tools	Sacituzumab govitecan is given intravenously at a dose of 10 mg/kg body weight on days 1 and 8 of a 21-day treatment cycle.
Trial design	SAGA is a multicenter, binational single-arm phase Ib/II trial evaluating the safety and efficacy of sacituzumab govitecan in patients with metastatic or locally advanced irresectable EGA. The primary endpoint is objective response rate (ORR). A Simon’s two-stage design is used with 20 patients treated in the run-in phase. Only if two or more responses and no worrisome adverse events are observed, the trial will proceed to the second phase with an additional 36 patients. A hypothesis of an ORR of 16% is tested against a null hypothesis of an ORR of 5%.
Trial registration	EU CT 2023-505257-40-00, NCT06123468, AIO-STO-0123/ass., IKF-t065
Ethics	The trial will be conducted according to the principles of the Declaration of Helsinki, the ICH Harmonized Tripartite Guidelines for Good Clinical Practice and the European Union Regulation 536/2014. Informed consent of all participants is required before any activities associated with the clinical trial will be carried out. Participants can withdraw consent to trial procedures at any timepoint without having to give any reason for their decision. The trial was approved by the German Paul Ehrlich Institute and has been reviewed and approved by the ethics committee of the University of Leipzig.
Value of the trial in progress	•Survival of patients with metastatic esophagogastric adenocarcinoma after first-line treatment is short. •SAGA is the first trial to evaluate the safety and efficacy of sacituzumab govitecan in the second line or later. •Translational research will evaluate the relationship between TROP-2 expression in tumor and liquid samples and response to treatment.

Highlights

• •SAGA is a phase Ib/II trial of sacituzumab govitecan in advanced esophagogastric adenocarcinoma.
• •SAGA is the first trial of SG in esophagogastric adenocarcinoma.
• •SG can be given in the second line or later but not after prior treatment with irinotecan.
• •Prior research has shown a high TROP-2 expression rate in esophagogastric carcinoma.
• •Objective response rate (ORR) is the primary endpoint of this study.

Description of protocol

Background

Treatment of metastatic or locally advanced unresectable adenocarcinoma of the gastroesophageal junction (GEJ) and the stomach, summarized in this paper as esophagogastric adenocarcinoma (EGA), has limited efficacy following first-line therapy.¹ Twenty-eight percent of objective responses of mostly short duration were reported in response to treatment with ramucirumab and paclitaxel which is the currently recommended standard of care.² Survival in this setting is short. Thus, there is a huge clinical need for new and more effective therapeutic options.

Sacituzumab govitecan (SG) is an antibody–drug conjugate (ADC) linking the TROP-2-directed antibody hRS7 to the topoisomerase-I inhibitor SN-38 by the hydrolysable linker CL2A (Figure 1).^3,4 ADCs can deliver cytotoxic agents more selectively compared to conventional intravenous chemotherapy, increasing chemotherapy delivery to tumor tissue while reducing off-target adverse effects. EGA has shown a substantial TROP-2 positivity rate (Figure 2)⁵ as well as a sensitivity to topoisomerase inhibitors.^6,7 These observations render SG a promising therapeutic option to evaluate further. To date, limited data on the efficacy of SG in this population are available.⁸

Figure 1.

Structure of sacituzumab govitecan. The chemotherapeutic topoisomerase inhibitor SN-38 is linked to the TROP-2 antibody hRS7 with a high payload-to-antibody ratio of 7.6 by the hydrolysable linker CL2A (visualization based on two articles).^3,4

Figure 2.

TROP-2 expression in a cohort of 361 patients with gastric adenocarcinoma and 75 patients with esophageal adenocarcinoma (own visualization of selected data).⁵

Objective

The SAGA study aims to investigate the safety and the tumor response to treatment with SG after prior systemic treatment of advanced EGA. Objective response rate (ORR) is the primary endpoint, encompassing both partial response (PR) and complete response (CR).

ORR was chosen as the primary endpoint allowing for an evaluation of antitumor activity, requiring a stronger response (PR or CR) than stable disease only.⁹ On the other hand, results can be assessed earlier than overall survival results. Therefore, ORR is frequently used as the endpoint in phase II oncological trials.

Secondary endpoints are the safety and tolerability of SG in the trial population of patients with advanced EGA, the clinical benefit rate [encompassing PR, CR and stable disease (SD)], progression-free survival and overall survival as well as an analysis of survival results in patients with TROP-2 positive tumors only.

Study design and statistical considerations

SAGA is a phase Ib/II study using a Simon’s two-stage design (Figure 3). The hypothesis of an ORR of 16% is tested against a null hypothesis with a response rate of 5%. A one-sided type I error of 5% and a power of 80% yielding a total study population of 56 patients are applied.

Figure 3.

Simon’s two-stage design of the SAGA trial.

In the run-in phase, 20 patients will be treated and monitored closely by the safety monitoring board (SMB). After 20 patients have completed the second cycle of study treatment, recruitment will be halted and the SMB will evaluate safety and efficacy. The study will continue if two or more responses in the run-in phase and no unexpected toxicities occur. In the second phase, six responses in the study population of 56 patients are needed to reject the null hypothesis.

The trial will be conducted in 10-15 treatment centers in Germany and Austria. The estimated study duration is 36 months.

Patient population

Patients with advanced EGA are eligible if their disease has progressed after at least one prior systemic line of treatment. Prior treatment must comprise a combination of a fluoropyrimidine and a platinum compound such as cis- or oxaliplatin. Prior treatment with targeted or immunotherapy is acceptable if clinically indicated [e.g. an anti-human epidermal growth factor 2 (HER2)-directed antibody like trastuzumab in HER2-positive disease and/or a programmed cell death protein 1/programmed cell death ligand 1 (PD-1/PD-L1) antibody according to local regulations].

Patients with microsatellite instable (MSI-high)/deficient mismatch repair (dMMR) tumors have to be treated with a PD-1/PD-L1 inhibitor before enrollment into the SAGA trial. Perioperative therapy is regarded as the first-line treatment when progression has occurred within six months after treatment completion.

Relevant inclusion criteria (full list in Supplementary Table S1, available at https://doi.org/10.1016/j.esmogo.2024.100051) comprise the following:

• •Eastern Cooperative Oncology Group performance status ≤ 1
• •Estimated life expectancy of at least 12 weeks
• •At least one measurable lesion on radiographic imaging as defined by RECIST v1.1
• •Adequate hematological, hepatic and renal function

Patients can be treated in the second line setting or in later lines but are not eligible if they have previously received a topoisomerase inhibitor, e.g. irinotecan or nal-irinotecan. Exclusion criteria are shown in Supplementary Table S2, available at https://doi.org/10.1016/j.esmogo.2024.100051.

Patients can be included into the trial regardless of tumor TROP-2 expression even though 20% of EGA tumor samples were negative in a prior analysis⁵ (Figure 2). An analysis of patients with triple-negative breast cancer has shown responses to SG regardless of the TROP-2 expression score.¹⁰ Heterogeneity of biomarker expression in samples from different metastatic samples has been shown in other biomarker analyses in EGA, e.g. HER2.¹¹ This heterogeneity may be a hypothetical explanation while one single tumor biopsy cannot predict response to an ADC with a specific cellular target. Exploratory analysis will be used to evaluate whether there is a relationship between antitumor activity and TROP-2 expression in our patient population.

It is mandatory to provide blood samples for the translational research program and grant access to archival tissue (see below), but no new biopsies are requested for enrollment into the study.

Study trial treatment

Patients will receive SG intravenously at a dose of 10 mg/kg body weight on days 1 and 8 of a 21-day treatment cycle (Graphical Abstract). Premedication against infusion reactions, nausea and vomiting consisting of histamine receptor antagonists (H1 and H2) as well as steroids and a 5-hydroxytryptamine-3 (5-HT3) antagonist are given before infusion.

No prophylactic use of granulocyte colony-stimulating factor (G-CSF) is recommended. G-CSF should be added in case of severe or prolonged neutropenia only. In case of repeated and relevant neutropenia, dose modifications are recommended, as well as in case of severe non-hematologic adverse events.

Patients homozygous for the UGT1A1∗28 allele are at a higher risk of adverse events when treated with topoisomerase inhibitors like irinotecan or SN-38. Drug glucuronidation and excretion is reduced in patients carrying this genetic alteration. Genetic testing is not mandatory for study participation but drugs altering the UGT1A1 activity have to be avoided while on study treatment.

Treatment will continue until disease progression, withdrawal of consent, occurrence of unacceptable toxicities or a treatment period of 12 months.

Safety monitoring and response evaluation

Adverse events (AEs) will be graded according to the NCI CTCAE v5.0 and will be recorded in an electronic case report form per usual standards. The AE reporting period starts after the patient has received the first dose of SG and continues until 30 days after the last dose has been administered. Serious AEs have to be reported within 24 h.

Treatment response will be assessed by computed tomography or magnetic resonance imaging at baseline and every 8 weeks (+/− 7 days) while on treatment. RECIST v1.1 criteria will be evaluated locally. If patients have discontinued study treatment for any reason other than disease progression, they will be followed with regular visits and imaging every 12 weeks (+/− 14 days) until disease progression. All patients will be followed for survival for up to 12 months after the treatment period of the trial has ended.

Translational research

Archived tissue samples will be analyzed for TROP-2 expression by immunohistochemistry. The most recent biopsy should be provided and will be analyzed. No new biopsies are necessary in order to minimize risk and facilitate participation.

Liquid samples to analyze TROP-2 shedding and circulating tumor DNA (ctDNA) will be collected before the first cycle, before the third cycle and at the time of disease progression. TROP-2 in liquid samples will be analyzed by enzyme-linked immunosorbent assay while ctDNA from blood samples will be analyzed by next-generation sequencing-based panel diagnostics.