LASER: A Phase 2 Trial of ¹⁷⁷Lu-PSMA-617 as Systemic Therapy for RCC

Abstract

Renal cell carcinoma is one of the most common malignancies in the United States, with clear cell renal cell carcinoma (ccRCC) comprising approximately 70% of all cases. ccRCC remains therapeutically challenging, particularly in patients whose disease progresses after therapy with immune checkpoint inhibitors and tyrosine kinase inhibitors. Prostate-specific membrane antigen (PSMA), expressed in the tumor neovasculature of ccRCC, offers a potential therapeutic target for radiopharmaceutical therapy with ¹⁷⁷Lu-PSMA-617, a well-established therapy in the management of prostate cancer. Methods: This is a single-center, open-label, single-arm, phase 2 clinical trial designed to evaluate the safety and efficacy of ¹⁷⁷Lu-PSMA-617 in patients with advanced PSMA-positive ccRCC. Eligible participants must have measurable disease, have received at least 1 immune checkpoint inhibitor and 1 tyrosine kinase inhibitor, and demonstrate PSMA-avid disease in the majority of lesions on baseline ⁶⁸Ga-PSMA-11 PET/CT. Patients will receive up to 6 cycles of ¹⁷⁷Lu-PSMA-617 every 6 wk. A 2-stage design is used: 9 patients will be enrolled in stage 1, with trial continuation dependent on at least 1 objective response. If criteria are met, 15 additional patients will be enrolled, for a total of 24. The primary endpoint is the objective response rate in accordance with RECIST 1.1. Secondary endpoints include safety, progression-free survival, and overall survival. Exploratory objectives include the correlation of imaging biomarkers, circulating cell-free DNA, and genomic alterations with clinical outcomes. Conclusion: This prospective trial aims to evaluate the safety and preliminary efficacy of ¹⁷⁷Lu-PSMA-617 in patients with advanced PSMA-positive ccRCC. The results of this study may support the clinical development of PSMA-targeted radiopharmaceutical therapy as a novel treatment option for patients whose disease has progressed after standard systemic therapies.

Renal cell carcinoma (RCC) is among the most common malignancies in the United States, with over 80,000 new cases projected in 2025 (1). Although most patients present with localized disease, up to one third have locally advanced or metastatic disease at diagnosis, and approximately 40% of those initially treated for localized tumors will ultimately experience disease recurrence (2). The prognosis for metastatic RCC remains poor, with a 5-y survival rate of approximately 15% (1). Clear cell RCC (ccRCC) accounts for about 70% of all RCC cases and is characterized by loss of the Von Hippel-Lindau tumor suppressor gene in most tumors (3).

First-line systemic therapies for advanced ccRCC typically include combinations of immune checkpoint inhibitors (ICIs) and tyrosine kinase inhibitors (TKIs), which have demonstrated survival benefits over sunitinib alone in randomized trials (4–7). Treatment options for ccRCC are limited in the second-line setting and beyond. Available therapies include alternative TKIs (8–10), lenvatinib plus everolimus (11), and belzutifan (12), a hypoxia-inducible factor-2α inhibitor recently approved on the basis of a progression-free survival (PFS) benefit in refractory disease. However, recent phase 3 trials have shown no additional benefit from ICI rechallenge compared with TKI monotherapy (13,14), limiting sequencing strategies in later lines of therapy.

Approximately 40%–50% of patients do not have a radiographic response to first-line ICI–TKI combinations, and approximately 10% of patients experience primary progression (5). The increasing use of combination therapies in early lines of treatment, along with the adoption of adjuvant pembrolizumab in high-risk localized disease, further narrows treatment options after disease progression. These challenges highlight the need for novel therapies in ccRCC, particularly those evaluating a new mechanism of action.

Prostate-specific membrane antigen (PSMA) is a transmembrane protein highly expressed in prostate cancer and a target that has been exploited for the imaging and treatment of prostate cancer (15–21). ¹⁷⁷Lu-PSMA-617 is a PSMA-targeting β-emitting radiopharmaceutical that delivers targeted radiation to PSMA-positive tissue, inducing DNA damage and tumor cell death (19). The drug has proven benefit in metastatic castration-resistant prostate cancer before and after chemotherapy (20,21) and is generally well-tolerated, with common adverse effects including mild hematologic toxicity, xerostomia, and fatigue (19).

Despite its name, PSMA is not prostate-specific and is expressed in the neovasculature of many solid tumors, including ccRCC, where it may be detected in approximately 80% of cases and imaged via PSMA PET/CT (22,23). Given the limited systemic therapy options in ccRCC, the known expression of PSMA in ccRCC, and the proven activity of ¹⁷⁷Lu-PSMA-617 in PSMA-positive advanced prostate cancer, we developed a clinical trial to evaluate the activity and safety of ¹⁷⁷Lu-PSMA-617 in advanced PSMA-positive ccRCC.

MATERIALS AND METHODS

Study Design

This is a single-center, open-label, single-arm, phase 2 clinical trial conducted at Dana-Farber Cancer Institute in collaboration with Brigham and Women’s Hospital in Boston, Massachusetts, designed to evaluate the safety and efficacy of ¹⁷⁷Lu-PSMA-617 in patients with advanced PSMA-positive ccRCC previously treated with at least 1 ICI and TKI. The study will enroll up to 24 patients across 2 sequential stages. ⁶⁸Ga-PSMA-11 PET/CT will be performed at baseline for eligibility and after 2 treatment cycles to confirm persistent PSMA-avid disease before continuation of therapy. Optional biopsies at baseline and during treatment are planned for correlative analyses.

The primary objective is to evaluate the efficacy of ¹⁷⁷Lu-PSMA-617 in patients with advanced ccRCC. Secondary objectives are to evaluate safety of ¹⁷⁷Lu-PSMA-617, PFS, and overall survival (OS) in patients with advanced ccRCC. Exploratory objectives include evaluating associations between baseline PSMA PET/CT parameters (including SUV_max, SUV_mean, and total tumor volume) and treatment response, as well as assessing correlations between baseline genomic alterations and clinical outcomes. Additional analyses will explore changes in circulating cell-free DNA during therapy and the emergence of genomic alterations associated with resistance.

Ethics approval has been obtained from the local institutional review board, and written informed consent will be obtained from all participants by study investigators or trained research staff before enrollment (DF/HCC 25-216). The study is registered at ClinicalTrials.gov (NCT06964958), with conduct monitored per institutional procedures. The trial design is depicted in Figure 1.

FIGURE 1.

Design of LASER trial. PR/CR = partial response/complete response.

Study Population

Eligible participants must have pathologically confirmed advanced or metastatic RCC with a clear cell component, including patients with sarcomatoid features. Patients will be identified and recruited through oncology and nuclear medicine clinics. All patients must have received at least 1 prior ICI and TKI in the adjuvant, neoadjuvant, or metastatic setting. Patients must have PSMA-avid disease on baseline ⁶⁸Ga-PSMA-11 PET/CT, defined as at least 1 lesion with uptake greater than liver background and no or limited (i.e., ≤25% of lesions not meeting the uptake criteria) PSMA-negative lesions. The study team reviews the entire tumor burden on PET/CT to determine this proportion and ensure accurate classification. In addition, patients must have measurable disease in accordance with RECIST 1.1, defined as at least 1 lesion with a diameter of 10 mm or greater on CT, MRI, or clinical examination or of 20 mm or greater on chest radiograph (24). Additional eligibility criteria include age of at least 18 y, Eastern Cooperative Oncology Group performance status of 0–2, and adequate organ and marrow function. Patients of reproductive potential must use effective contraception, and all participants must be able to provide written informed consent. Patients will be excluded if they have received prior PSMA-targeted therapy, recent radiotherapy, or investigational treatments or have active malignancies likely to interfere with study outcomes. The full inclusion and exclusion criteria are outlined in Table 1.

TABLE 1.

 Inclusion and Exclusion Criteria

Inclusion criteria	Exclusion criteria
Age ≥ 18 y	Prior PSMA-targeted therapy
Confirmed advanced or metastatic ccRCC (sarcomatoid allowed)	Radiotherapy within 4 wk or antineoplastic therapy (approved or experimental) within 14 d before cycle 1 day 1 of study therapy
Prior therapy with at least 1 ICI and TKI in any setting	Concurrent treatment with investigational agents
Measurable disease in accordance with RECIST 1.1	Active/untreated brain metastases (eligible if stable ≥ 4 wk and not using corticosteroids)
Presence of at least 1 PSMA-avid lesion (uptake greater than in liver) on baseline PET/CT, with absence (≤25%) of PSMA-negative lesions	Unresolved toxicities from prior therapy (except alopecia; neuropathy ≤ grade 2 allowed)
Eastern Cooperative Oncology Group performance status of 0–2	Symptomatic or impending cord compression
Adequate organ and marrow function*	Concurrent active malignancy (except low-risk malignancy or malignancy in remission)
Agreement to use effective contraception	Presence of serious or uncontrolled medical illness
Ability to provide informed consent	Pregnancy or lactation

^*Absolute neutrophil count ≥ 1.5 × 10⁹/L, platelets ≥ 100 × 10⁹/L, hemoglobin ≥ 9 g/dL, total bilirubin ≤ 1.5 times the upper limit of normal (ULN) (≤2 times ULN in patients with known or suspected Gilbert syndrome), alanine transaminase and aspartate transaminase ≤ 3 times ULN (or ≤ 5 times ULN if liver metastases), and estimated glomerular filtration rate ≥ 40 mL/min/1.73 m² .

Screening procedures include retrieval of informed consent, physical examination, laboratory testing, and ⁶⁸Ga-PSMA-11 PET/CT. TKI, mammalian target of rapamycin, and hypoxia-inducible factor inhibitors will be held for at least 7 d or 3 half-lives (whichever is shorter) before baseline PET/CT. All imaging will be reviewed in a multidisciplinary setting to confirm eligibility. Patients meeting all criteria and demonstrating PSMA-positive disease will proceed to treatment; those with PSMA-negative disease (defined as >25% non–PSMA-avid lesions) will be ineligible for study therapy.

Treatment Plan

Participants will receive ¹⁷⁷Lu-PSMA-617 at a fixed dose of 7.4 GBq (200 mCi) ± 10% intravenously every 6 wk (1 cycle = 42 d), for up to 6 cycles. For cycle 1, participants must meet all laboratory and clinical parameters outlined in the eligibility criteria. For subsequent cycles, laboratory values and toxicities will be reviewed before dosing, with appropriate dose delays or modifications implemented as necessary. Continuation beyond cycle 2 requires confirmation of persistent PSMA-avid disease post–cycle 2 PET/CT.

Administration of ¹⁷⁷Lu-PSMA-617 will adhere to local policies for radiopharmaceutical therapy administration as well as national radiation safety standards. Supportive care is allowed and may include analgesics, antiemetics, antidiarrheals, antiallergic drugs, corticosteroids, anticoagulants, bisphosphonates, and nonlive vaccines. Packed red blood cell transfusions are permitted as needed. Concurrent metformin is allowed. The prophylactic use of growth factors is not permitted unless clinically required.

Other systemic therapies for ccRCC are not permitted. Local treatments (e.g., radiotherapy, ablation, surgery) may be allowed if clinically indicated, but lesions treated locally will not be evaluable for response. Coadministration of ¹⁷⁷Lu-PSMA-617 with radiotherapy requires prior sponsor approval because of limited safety data. Live vaccines and prophylactic myeloid growth factors are not permitted.

Endpoints

The primary endpoint is the objective response rate (ORR), as defined in RECIST 1.1 (24). Secondary endpoints include safety, as assessed by the incidence and severity of treatment-related adverse events (graded per Common Terminology Criteria for Adverse Events [CTCAE] version 5.0), PFS (i.e., time from treatment initiation to disease progression or death from any cause), and OS (i.e., time from treatment initiation to death from any cause).

Exploratory endpoints will assess associations between quantitative PSMA PET/CT parameters (SUV_max, SUV_mean, and total tumor volume) and clinical outcomes. Dynamic changes in imaging biomarkers after 2 cycles of ¹⁷⁷Lu-PSMA-617 will be evaluated in relation to therapeutic response. In a subset of patients undergoing optional pretreatment and on-treatment biopsies, molecular correlates of response or resistance will be investigated through immunohistochemistry, targeted DNA/RNA sequencing, and epigenomic profiling. Circulating cell-free DNA changes will also be explored for associations with radiographic response and resistance patterns. Study results will be made publicly available via ClinicalTrials.gov and scientific dissemination.

Assessment

Baseline evaluations will be conducted within 4 wk before the initiation of protocol therapy. Baseline imaging will include ⁶⁸Ga-PSMA-11 PET/CT to confirm PSMA positivity and define the extent of metastatic disease and must be completed no more than 6 wk before initiation. ⁶⁸Ga-PSMA-11 PET/CT will be performed in accordance with the detailed protocols described in the joint guidelines for prostate cancer imaging issued by the European Association of Nuclear Medicine and the Society of Nuclear Medicine and Molecular Imaging (25). Baseline clinical characteristics, including history of nephrectomy, will be documented and presented.

Participants will undergo regular clinical and laboratory assessments, including physical examination and Eastern Cooperative Oncology Group performance status, on days 1 and 22 of each treatment cycle. Laboratory tests will be conducted on days 1, 8, 15, 22, 29, and 36 of cycle 1 and on days 1 and 22 of cycles 2–6.

Radiographic tumor assessments will be performed every 2 cycles (12 wk) using CT scans of the chest, abdomen, and pelvis. Brain imaging may be included at baseline or as clinically indicated. Disease response will be evaluated according to RECIST 1.1. A repeat ⁶⁸Ga-PSMA-11 PET/CT is required before day 1 of cycle 3 to confirm continued PSMA expression and appropriateness for ongoing ¹⁷⁷Lu-PSMA-617 therapy (cycles 3–6).

Archival tumor tissue is required for histologic confirmation, and optional tumor biopsies will be collected before day 1 of cycles 1 and 3, when feasible. PSMA expression will be evaluated by immunohistochemistry on archival tumor tissue, when available. Blood samples for germline DNA analysis and exploratory biomarkers will be obtained at baseline and protocol-defined time points.

Adverse events will be monitored continuously and graded according to CTCAE version 5.0. End-of-treatment evaluation will occur within 30–42 d after the final dose. Long-term follow-up will be conducted approximately every 6 mo for up to 5 y to assess survival and disease status or until radiographic progression or initiation of subsequent anticancer therapy.

Treatment Discontinuation

Treatment with ¹⁷⁷Lu-PSMA-617 will continue for up to 6 cycles unless 1 of the following occurs: disease progression, unacceptable toxicity, development of a new medical condition that precludes further treatment, or health changes that, in the investigator’s judgment, make continued treatment inappropriate. Treatment will also be discontinued for noncompliance with study procedures or withdrawal of consent.

Follow-up

Participants whose therapy is discontinued because of unacceptable adverse events will be followed until resolution or stabilization of the event. All participants who discontinue treatment before the protocol-defined endpoint will continue protocol-specified follow-up, including periodic assessment of disease and survival status. For those who discontinue before disease progression, radiographic assessment will be performed at least every 12 wk, per routine practice in advanced RCC, until documented progression or initiation of subsequent anticancer therapy. After progression, survival follow-up will continue every 6 mo for up to 5 y.

Dose Modifications

Dose delays and modifications will follow predefined criteria established in CTCAE version 5.0. Toxicities may necessitate temporary treatment holds and, when persistent or severe, a 20% dose reduction. Treatment may be delayed for up to 42 d to allow for recovery. The management of specific toxicities, including hematologic suppression, renal impairment, salivary gland toxicity, and elevated liver enzymes, is outlined in protocol-defined guidelines. In general, grade 3–4 toxicities will require dose reduction or discontinuation. Continued therapy after treatment-related organ dysfunction will be reviewed by the study investigators.

Statistical Plan

This single-center, phase 2 trial will use Simon optimal 2-stage design to evaluate the efficacy of ¹⁷⁷Lu-PSMA-617 in patients with advanced ccRCC. The design allows for early termination if no objective responses are observed among the first 9 patients. If at least 1 response is seen, the trial will proceed to enroll an additional 15 patients, for a total of 24. The treatment will be considered effective if at least 3 responses are observed among all evaluable patients. On the basis of prior data from the LITESPARK-005 trial showing a 22% ORR with belzutifan (12), this design assumes a 5% ORR as unacceptably low and a 25% ORR as clinically meaningful. It provides 90% power to detect an ORR of 25%, with a 1-sided α of 0.10 and a 63% probability of early trial discontinuation if the true ORR is 5%.

The primary endpoint, ORR, defined as the proportion of evaluable patients achieving a confirmed complete or partial response per RECIST 1.1 by central radiologic review, will be reported with an 80% exact binomial CI adjusted for the 2-stage design. Time-to-event outcomes, including PFS and OS, will be estimated using the Kaplan–Meier method, with median values and event-free rates reported as well as 95% CIs. Adverse events will be graded per CTCAE version 5 and summarized by type, severity, attribution, and worst grade; events leading to treatment modification or delay, as well as laboratory abnormalities, will also be reported.

DISCUSSION

Patients with advanced ccRCC face limited treatment options after disease progression on ICIs and TKIs, highlighting a critical unmet need for novel therapeutic strategies. PSMA-targeted radiopharmaceuticals have shown significant success in clinical settings for both imaging and radiopharmaceutical therapy in prostate cancer (16–21). This approach has fundamentally changed the way prostate cancer is managed, enhancing diagnoses, refining disease evaluation, and offering a targeted treatment option for metastatic disease, leading to approval by the Food and Drug Administration and widespread integration into clinical practice (20). PSMA is expressed in the neovasculature of several solid tumors, including ccRCC (22). Translational evidence from human metastatic ccRCC samples has demonstrated PSMA expression in tumor neovasculature (26), and preclinical radiopharmaceutical therapy studies in ccRCC models further support the feasibility of PSMA-targeted therapy (27). Recent gene expression analyses in metastatic ccRCC showed that higher PSMA expression correlates with angiogenic signaling and a better response to vascular endothelial growth factor–targeted therapy (28). As vascular endothelial growth factor–targeted therapies remain a mainstay of metastatic RCC treatment, these findings further support the rationale for PSMA-targeted therapy.

Although the application of ¹⁷⁷Lu-PSMA-617 in nonprostatic malignancies is still emerging, several cases have been documented across various tumor types. Cancers of the salivary glands were most often targeted, followed by brain tumors and osteosarcoma, in which PSMA expression has been identified (29).

Several studies have demonstrated the utility of PSMA PET imaging for staging and detecting recurrence in patients with RCC (23,30); however, clinical data on ¹⁷⁷Lu-PSMA-617 radiopharmaceutical therapy in this setting remain scarce, with only a single case report published to date (31). The present study is the first clinical trial in the United States and is currently the only ongoing clinical investigation evaluating the safety and efficacy of ¹⁷⁷Lu-PSMA-617 in patients with advanced ccRCC. A prospective trial in Europe, PRadR (NCT06059014) (32), was initiated to investigate ¹⁷⁷Lu-PSMA-617 in a similar patient population but has since been suspended because of low patient accrual, according to the ClinicalTrials.gov registry. Similar to PRadR, LASER investigates ¹⁷⁷Lu-PSMA-617 in advanced RCC but allows administration of up to 6 treatment cycles, compared with 4 in PRadR, permitting evaluation of extended treatment duration and cumulative activity.

Patients will be selected on the basis of PSMA PET avidity, with uptake exceeding liver background and limited PSMA-negative disease, to selectively include patients who are most likely to benefit from therapy. Given the primarily renal excretion of ¹⁷⁷Lu-PSMA-617, history of nephrectomy is documented, as patients with prior nephrectomy may have reduced renal reserve, and renal function is closely monitored throughout the trial as part of the study protocol. The 2-stage phase 2 design enables early discontinuation for futility and efficient assessment of preliminary antitumor activity in this novel setting. Inclusion criteria require prior treatment with both an ICI and a TKI, reflecting the current treatment landscape and addressing the unmet need in later lines of therapy. Unlike prostate cancer, where PSMA is expressed directly on tumor cells, PSMA in ccRCC is restricted to the tumor neovasculature (22,33), which may influence therapeutic uptake and distribution. Despite this difference, retrospective and preclinical studies have shown promising PSMA PET uptake patterns in RCC (23,30), supporting the therapeutic rationale.

By incorporating optional biopsies and correlative imaging and molecular endpoints, this trial is positioned to explore response biomarkers and resistance mechanisms in the ccRCC setting. Although the current study does not include a comparator arm or directly compare ¹⁷⁷Lu-PSMA-617 with other standard therapies, it will provide foundational data on the safety, ORR, PFS, and OS in this population. Should promising activity be observed, future trials may explore ¹⁷⁷Lu-PSMA-617 in combination with immunotherapies or other systemic therapies for RCC, as well as in non–clear cell histologies.

CONCLUSION

This single-center, phase 2 clinical trial will be one of the first to investigate radiopharmaceutical therapy in RCC, a therapeutic approach with a novel mechanism of action in this disease. The study is actively enrolling and has the potential to generate pivotal prospective data on the safety and efficacy of this targeted approach, paving the way for new treatment strategies in a population with limited options.

DISCLOSURE

This study was supported by Novartis. Wanling Xie reports advisory board/consulting fees from the Prostate Cancer Clinical Trials Consortium. Stephanie Berg reports advisory board/consulting fees from Eisai, Natera, Guardant, Exelixis, Xencor, and Johnson & Johnson. Wenxin Xu reports research funding, paid to the Dana-Farber Cancer Institute, from OncoHost, Arsenal Biosciences, and Merck; advisory board fees from Eisai, Exelixis, Xencor, and Jazz Pharmaceuticals; and consulting fees from Aveo Oncology, Merck, Celdara Medical, and Deciphera. Srinivas Viswanathan reports funding from National Institutes of Health grants 5U01CA269505 and 5R01CA286652; past research support from Bayer; and involvement in institutional patent applications on the detection of molecular alterations in ctDNA and therapeutic targeting of cancer vulnerabilities (outside the submitted work). Xiao Wei reports research funding, paid to the Dana-Farber Cancer Institute, from Amgen, Bristol Myers Squibb, MacroGenics, Novartis, and Poseida Therapeutics; and advisory board fees from AstraZeneca, Dendreon, and Novartis. Toni Choueiri reports relationships with Alkermes, Arcus Bio, AstraZeneca, Aravive, Aveo, Bayer, Bristol Myers-Squibb, Bicycle Therapeutics, Calithera, Caris, Circle Pharma, Deciphera Pharmaceuticals, Eisai, EMD Serono, Exelixis, GlaxoSmithKline, Gilead, HiberCell, IQVA, Infinity, Institut Servier, Ipsen, Jansen, Kanaph, Lilly, Merck, Nikang, Neomorph, Nuscan/PrecedeBio, Novartis, Oncohost, Pfizer, Roche, Sanofi/Aventis, Scholar Rock, Surface Oncology, Takeda, Tempest, Up-To-Date, CME and non-CME events (Mashup Media, Elite Elements, Peerview, OncLive, MJH, CCO and others), Xencor, outside the submitted work; has institutional patents filed on molecular alterations and immunotherapy response/toxicity, rare genitourinary cancers, and ctDNA/liquids biopsies; has equity in Tempest, Pionyr, Osel, Precede Bio, CureResponse, InnDura Therapeutics, Primium, Abalytics, Faron Pharma; serves on committees for NCCN, GU Steering Committee, ASCO (BOD 6/2024-), ESMO, ACCRU, KidneyCan; has received medical writing and editorial assistance support that may have been funded by Communications companies in part; has mentored several non-U.S. citizens on research projects with potential funding (in part) from non-U.S. sources/Foreign Components. The institution (Dana-Farber Cancer Institute) may have received additional independent funding of drug companies or/and royalties potentially involved in research around the subject matter. He is supported in part by the Dana-Farber/Harvard Cancer Center Kidney SPORE (2P50CA101942-16) and Program 5P30CA006516-56, the Kohlberg Chair at Harvard Medical School and the Trust Family, Michael Brigham, Pan Mass Challenge, Hinda and Arthur Marcus Fund, Roger and Kathy Marino Fund for Research Acceleration, Frank Shaughnessy Kidney Cancer Research Fund, and Loker Pinard Funds for Kidney Cancer Research at DFCI. Heather Jacene reports funding from National Institutes of Health grants R01CA251803, R01CA235589; research funding, paid to Dana-Farber Cancer Institute, from Blue Earth Diagnostics Ltd. and Lantheus; honoraria from Elsevier; scientific advisory board fees from Luminance Biosciences; and royalties from Cambridge Publishing. Praful Ravi reports research funding, paid to Dana-Farber Cancer Institute, from Blue Earth Diagnostics Ltd., Lantheus, Novartis, Convergent, and AstraZeneca; and consulting fees from Bayer and Curium. No other potential conflict of interest relevant to this article was reported.