Xaluritamig: a first step towards a new target, new mechanism for metastatic prostate cancer

Introduction

T cells have long been known to possess potent anti-neoplastic properties, but only recently has this realization led to a revolution in cancer treatment (1). Pharmacologic manipulation of T cells by immune checkpoint blockade transformed the treatment landscape of solid tumor oncology, leading to durable remissions across a number of previously incurable malignancies (2). Unfortunately, immune checkpoint inhibitors (ICIs) have had modest activity, at best, in treating advanced prostate cancer. Despite several phase 3 randomized trials, both alone and in combination with other agents, thus far no ICI has been shown a statistically significant benefit on primary survival analysis (3,4).

The lack of efficacy of ICIs in prostate cancer is often attributed to the low tumor mutational burden (TMB), low expression of PD-(L)1, and the immunologically ‘cold’ or ‘uninflamed’ tumor microenvironment (TME) of castrate-resistant and primary prostate cancer (5). Thus leveraging approaches aimed at increasing immunogenicity and inducing immune infiltrates in the prostate cancer TME is an active area of clinical investigation. Indeed, new classes of drugs aimed at increasing T cell infiltration [e.g., bispecific T cell engagers (TCEs)] represent an attractive approach for tumor types that have historically not responded robustly to ICIs alone (6).

With a few exceptions, ICI therapy has been similarly unsuccessful in the treatment of most hematologic malignancies (7). Instead, chimeric antigen receptor (CAR) T cells and TCEs, which redirect autologous T cells toward tumor antigens, have shown promising results and transformed the treatment landscape (8). CAR-T cell therapies involve the ex-vivo manipulation of T cells to express a CAR against a tumor antigen. This “living therapy” has led to dramatic responses and cures in treatment-refractory acute lymphoblastic leukemia and diffuse large B-cell lymphoma (9,10). TCEs are antibody-based constructs designed to possess dual specificity for T cells (e.g., often via CD3 binding) and a tumor-associated antigen. These agents drive T cells into the TME and in turn, lead to cytokine production and T cell-mediated cytotoxicity (11). While these strategies have been touted as a means to bring immunotherapy to prostate cancer, T-cell redirection therapies have not to date shown meaningful clinical efficacy in this malignancy.

STEAP1 targeted TCE: rationale and clinical data for Xaluritamig

With this context, we read with great interest the clinical report by Kelly et al. of the first-in-human study of a TCE Xaluritamig (AMG509), targeting six-transmembrane epithelial antigen of the prostate (STEAP1), in patients with metastatic castration-resistant prostate cancer (mCRPC) (NCT04221542), as well as the detailed pre-clinical description of the molecule (12,13). STEAP1 is a prostate tumor antigen expressed on most prostate cancers with limited expression in normal tissues, and is a highly promising target for this malignancy. Xaluritamig is a humanized bi-specific antibody consisting of two STEAP1 binding domains, a CD3e binding fragment variable domain and an Fc domain to prevent effector function. To mitigate on-target, off-tumor toxicity, the molecule was designed to target cells with only high expression of STEAP1. In an in vitro system, Xaluritamig-mediated lysis was minimal in cells with low levels of STEAP1 expression, as seen in normal human bronchial smooth muscle cells and aortic endothelial cells. In a mouse model, complete tumor stasis was observed at 0.01 mg/kg, and tumor regression of 61.6% and 66.2% was seen at of 0.01 and 0.1 mg/kg respectively. An evaluation of the molecule in cynomolgus monkeys, which have a similar expression pattern of STEAP1, indicated minimal on-target off-tumor toxicity.

Based on this encouraging pre-clinical data, a phase 1, open-label dose-escalation study with multiple cohorts was opened in March 2020. Ninety-seven patients were enrolled in the dose-exploration monotherapy cohort. Patients were required to have mCRPC, an Eastern Cooperative Oncology Group performance status of 0 or 1, and disease refractory to an androgen-receptor pathway inhibitor (ARPI) and 1–2 prior lines of taxane chemotherapy. STEAP1 expression was not mandated. Due to the risk of cytokine release syndrome (CRS), hospitalization was required for the first cycle of therapy. Thirty-three percent of patients were Asian, reflecting the geographical diversity of sites involved in the study. Of the enrolled subjects, the median prostate-specific antigen (PSA) was 113, the median number of prior lines of therapy was 4, and 37% of patients had liver metastases, indicating a high-risk, unmet-need study population.

After establishing 0.1 mg as the highest tolerable priming dose, a target dose of 1.5 mg weekly was achieved using a step-up dosing schedule. Fifty-five percent of patients experienced grade ≥3 toxicities, and 19% discontinued therapy due to treatment-related adverse events. The most common toxicity was CRS, which occurred in 72% (70/97) of patients. Most CRS events were low grade (as graded per Lee 2014 criteria); although 27% of patients received tocilizumab (14). Two patients experienced grade 3 CRS, one of which occurred at a higher priming dose than was ultimately recommended, and the other prior to initiation of prophylactic pre-C1 and step-up doses of dexamethasone. Other treatment-related toxicities include fatigue (45% overall, 11%≥ grade 3) and myalgias (34% overall, 12%≥ grade 3). The etiology of these musculoskeletal adverse events is not currently clear, as the authors highlight that STEAP1 is not highly expressed in muscle and creatine kinase levels were not elevated in patients who experience these adverse events. Going forward, muscle biopsies may be helpful in clarifying the mechanism of this unexpected toxicity and lead to potential mitigation strategies.

In addition to the reasonable safety profile observed, the study demonstrated very encouraging signs of efficacy in this heavily pre-treated cohort. In the PSA-evaluable cohort, PSA₅₀ and PSA₉₀ responses were observed in 49% and 28% of patients respectively. Responses were numerically higher among patients in the high-dose cohort, with 59% and 36% of these patients achieving PSA₅₀ and PSA₉₀ responses. In patients with measurable disease, 24% of patients achieved a confirmed partial response. Radiographic responses were also more common in the high-dose cohort, with 41% of these patients achieving a confirmed response compared to 3% in the low-dose cohort. Notably, both PSA and radiographic responses occurred quickly (most occurred at first evaluation) and preliminary data suggests a relatively long duration of response, with a median duration of RECIST response of 9.2 months, with 25% of patients remaining on treatment at the time of the report.

One key limitation that may preclude broader uptake is the need for hospitalization. We therefore look forward to the results from the remaining study cohorts, which will assess the safety and tolerability of this agent when administered in outpatient infusion centers, either IV or as a subcutaneous formulation and in combination with standard-of-care therapies for prostate cancer (i.e., abiraterone and enzalutamide). This challenge emphasizes the need, as a field, to work on strategies to minimize CRS moving forward. The pre-medications implemented during the trial were successful, however there may be room for even further optimization. Methods to identify patients who are most likely to develop CRS could lead to a risk-adapted approach, where some are able to be managed as outpatients while others receive more intensive prophylactic immunomodulation with tocilizumab, an approach that is gaining traction in upcoming CAR-T cell trials (15). Additionally, it is worth exploring variations in the cadence of dosing. Rather than adhering strictly to weekly infusions, future research could investigate transitioning to the less intensive maintenance schedule, or treatment hiatuses followed by restarting at the time of disease progression.

We must also learn more about how Xaluritamig fits best within the existing armamentarium of therapies for mCRPC. As chemotherapy can negatively impact T cell function, it is conceivable that the optimal use of this agent is in an earlier line setting, and we look forward to the ongoing study arm assessing its use in a less pre-treated cohort. Another potential factor that may affect the real-world efficacy of Xaluritamig is the increasing utilization of ¹⁷⁷Lu-PSMA-617 radioligand therapy (LuPSMA). Lymphocytes are highly sensitive to radiation, and LuPSMA is well known to induce lymphocytopenia. Only 4% of patients enrolled in this trial had received LuPSMA prior to Xaluritamig, and it is possible its success would be compromised in patients who had received prior LuPSMA therapy.

Alternative STEAP-1 targeted therapeutics

While larger confirmatory studies are needed, STEAP1 targeting TCE clearly appears to be an effective strategy. But are bi-specifics the end-all means of targeting STEAP-1 or might antibody drug conjugates (ADCs) or CAR-T cells be a superior strategy?

One prior attempt at targeting STEAP1 with an ADC incorporating a monomethyl auristatin E payload, vandortuzumab vedotin (DSTP3086S), demonstrated marginal efficacy—and carried significant dose-limiting toxicity (16). Despite mandating STEAP1 expression by immunohistochemistry (IHC), PSA₅₀ responses were only observed in 14% of patients, and among the 46 patients with RECIST evaluable disease, only one had a confirmed radiographic response. Demonstrably, a compelling target, while necessary, is not sufficient. T-cell redirection, with a “cellular payload” may have benefits compared to ADCs, due to the potential for fewer off-target off-tumor toxicity, the ability to target both mitotically active as well as dormant cells, and as observed with hematologic malignancies, deep and lasting remissions (17). However, we must also be cautious in completely discounting anti-STEAP1 ADCs based on a single trial. ADCs are relatively inexpensive, typically have a more predictable toxicity profile without risk of CRS, and have an established performance record across a number of solid malignancies. ADCs are relatively modular constructs, and there is significant potential for optimization of a STEAP-1 ADC. Improvement upon antibody internalization, the drug-antibody ratio, and/or the cytotoxic payload may be needed before the benefits of this therapeutic modality can be realized.

A recent study highlights the potential of CAR-T cell therapy as another means of targeting STEAP1 (18). In their report, Bhatia et al. engineered a CAR-T cell with a 4-1BB co-stimulatory domain and with a defined CD4:CD8 composition directed against STEAP1. The construct demonstrated anti-tumor efficacy, and a survival benefit (97 vs. 31 days) was shown in a mouse model. Importantly, the STEAP1 CAR-T cell therapy did not induce on-target off-tumor toxicities at sites of non-malignant STEAP1 expression. Based on these compelling pre-clinical findings, a phase 1/2 clinical trial testing STEAP1 CAR-T cells in combination with enzalutamide is planned, with an estimated start date of May 2024 (NCT06236139).

Debates regarding the relative merits and drawbacks of TCEs as compared to CAR-T cell therapy abound in the malignant hematology literature and may presage upcoming debates in prostate cancer (19,20). CAR-T cells do have the capacity to engraft long-term responses and provide ongoing immune surveillance, which may theoretically lead to more durable responses compared to TCEs, which have a relatively short half-life, often requiring weekly dosing. Unfortunately, lack of persistence has been an issue broadly for CAR-T cells for solid malignancies, and unless strategies to circumvent this are developed, the ability to provide repeat dosing may in fact be a benefit for TCEs. The tumor immune microenvironment and significant toxicities are additional barriers to the use of CAR-T cells in mCRPC, as demonstrated in a recent trial of PSMA CAR-T therapy (21).

CAR-T cells are also not susceptible to the development of anti-drug antibodies (ADAs). ADAs were observed in 54% of patients receiving Xaluritamig. However, only about half of these impacted Xaluritamig exposure, and preliminary analysis did not show an impact of ADA on clinical response, indicating that the development of ADAs may not be a critical barrier to this therapy as it has been for other TCEs.

A key finding from the STEAP1 CAR-T preclinical study was the identification of recurrent tumor antigen escape (i.e., loss of STEAP1) as a mechanism of resistance to STEAP1 targeting. If multiple STEAP-1 targeting therapeutics ultimately show efficacy in randomized trials, this implies that clinicians may have to choose between these agents rather than having the option to use them in sequence. This same logic potentially applies to the multitude of constructs in development targeting other cell surface markers as well. Other resistance mechanisms, such as loss of major histocompatibility complex (MHC) class I and T cell exhaustion may further limit the use of multiple lines of TCE therapies (22). Ultimately, in the absence of head-to-head comparisons, personalized, pragmatic approaches may be needed to determine which option is best for an individual patient.

Challenges and further directions

Identification of antigens that are homogenously expressed on tumors, while maintaining restricted expression in normal tissues has been a major barrier to the development of targeted therapies in prostate cancer. In addition to STEAP1, a number of other candidate prostate cancer cell surface targets have been identified in recent years, including prostate-specific membrane antigen (PSMA), prostatic acid phosphatase (PAP), and prostate stem cell antigen (PSCA), among others (23). However, a major hurdle to the use of these targets is the remarkable inter- and intra-patient heterogeneity of the prostate cancer cell surfaceome. Treatment pressure, such as from the manipulation of the androgen axis, cytotoxic chemotherapy, or targeted therapy, also impacts the expression of cell surface antigens, further complicating efforts.

The relevance of antigen heterogeneity and expression is best exemplified by efforts to target PSMA, owing to the ability of PSMA positron emission tomography (PET) to non-invasively provide a longitudinal and whole-body view of PSMA. PSMA expression was mandated in all the major trials studying LuPSMA, and subsequent analyses of enrolled patients found high PSMA expression to strongly correlate with response (24,25). Tissue-based studies have corroborated these findings. In a recent cohort of patients with mCRPC who underwent rapid autopsy, 25% of patients had no detectable PSMA expression and 63% of cases harbored at least 1 PSMA-negative site (26).

In contrast to studies of PSMA-targeted therapies, this trial of Xaluritamig did not require an assessment of STEAP1 expression. STEAP1 PET imaging is being explored, however, there is currently no standard way to ascertain global STEAP1 expression (27). IHC-based analysis is simple and feasible, but as we have seen with PSMA, assessment of a single tissue site might not be representative. However, a recent autopsy study revealed that STEAP1 may benefit from more homogenous expression compared to PSMA. In this cohort of patients with mCRPC, 87.7% of evaluable tissues demonstrated staining for STEAP1, with 28% of tissues showing STEAP1 but not PSMA staining (18). Conversely, only 0.9% of tissues showed PSMA expression without STEAP1. Furthermore, most patients (68%) had uniform STEAP1 expression, contrasting with the more heterogenous expression pattern observed with PSMA. Still, STEAP1 is far from a universal prostate antigen, and so research into how STEAP1 expression correlates with response to Xaluritamig should be performed to understand how to optimally select patients for this treatment. Approaches combining Xaluritamig with therapies targeting other cell surface antigens may ultimately be necessary to overcome the heterogeneity of prostate cancer.

Better understanding of the biology and regulation of STEAP1 may also yield insights into combinations and treatment sequences that may maximize outcomes with Xaluritamig. A recent study found STEAP1 to be epigenetically regulated, and that STEAP1 over-expression could be driven by DNA methyltransferase inhibitors and histone deacetylase inhibitors, suggesting that pharmacologic epigenetic modulation could potentiate the effects of anti-STEAP1 therapies (28). Preliminary in vitro evidence shows androgen receptor inhibition may also lead to increased STEAP1 expression, and therefore combination therapy with an ARPI such as enzalutamide could be synergistic (29).

In addition to strategies to modulate target antigen expression, approaches to increase T cell activation with TCEs represent another active area of investigation. Enhancement of T-cell anti-tumor responses may be achieved by activation of the key co-stimulatory domain CD28 (with the use of a CD28 specific TCE in combination with or instead of a CD3 targeted TCE), or by interference of the programmed death pathway (e.g., in combination with ICIs) (30). Indeed, these strategies are currently being tested clinically in several mCRPC trials (NCT03972657, NCT06085664, NCT06095089, and NCT05585034) (31). However, whether these novel TCE molecules lead to improved efficacy without additional toxicity remains to be seen.

Conclusions

Xaluritamig appears to be a highly promising new therapeutic option for patients with mCRPC. While a larger phase 3 trial is needed, this study offers by far the most compelling evidence to date that STEAP1 can be safely used as a target for prostate cancer and that T cell re-direction is a viable strategy in prostate cancer. Work to mitigate toxicity and improve patient selection will be important in determining the success of this therapy. We are highly encouraged by the work done by Kelly and colleagues and are appreciative of the patients who took part in this landmark study. This trial represents real progress and ushers in a new era for the use of targeted immunotherapy for prostate cancer. We look forward to further advancements in this field.

Acknowledgments

Funding: This work was supported by the National Institute of Health (T32 CA009515-38) and the Northwest Prostate Cancer SPORE (CA097186).

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-24-28/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-24-28/coif). M.T.S. is a paid consultant and/or received Honoria from Sanofi, AstraZeneca, Janssen and Pfizer. He receives research funding to his institution from Novartis, Zenith Epigenetics, Bristol Myers Squibb, Merck, Immunomedics, Janssen, AstraZeneca, Pfizer, Hoffman-La Roche, Tmunity, SignalOne Bio, Epigenetix, Xencor, Incyte and Ambrx, Inc., and was on the Data Safety Monitoring Board or Advisory Board of Sanofi, Fibrogen, AstraZeneca, Janssen, Pfizer. J.E.H. serves as a paid consultant to Seagen, Daiichi Sankyo, and ImmunityBio. She receives sponsored research funding to her institution from Astra Zeneca, Bristol Meyers Squibb, Crescendo Biologics, Macrogenics, Johnson & Johnson Innovative Medicine, PromiCell, Amgen and Vaccitech; and research funding paid to institution from DOD, NIH, PCF. L.F. discloses research funding to the institution from Abbvie, Amgen, Bavarian Nordic, BMS, Janssen, Merck, Roche/Genentech; consulting fees from Abbvie, Amgen, BMS, Daiichi Sankyo, Merck, Roche/Genentech; ownership interests in Actym, Atreca, Bioatla, Bolt, Immunogenesis, NGMBio, Nutcracker, RAPT, Senti, Sutro, unrelated to the work here; and served on the Data Safety Monitoring Board or Advisory Board of Actym, Atreca, Bioatla, Bolt, Immunogenesis, NGMBio, Nutcracker, RAPT, Senti, Sutro. E.Y.Y. discloses research funding to institution from Dendreon, Merck, SeaGen, Blue Earth, Bayer, Lantheus, Tyra, Oncternal; consulting fees from Jansen, Merck, AAA Novartis, Bayer, Aadi Bioscience, Oncternal, BMS, Loxo, Lantheus. The other author has no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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