Kidney Cancer Journal | Volume 8, Issue 1

A Phase 1b/2 Study of Combination 177Lu Girentuximab Plus Cabozantinib and Nivolumab in Treatment naïve Patients with Advanced Clear Cell RCC

Status: Recruiting
Clinicaltrials.gov identifier: NCT05663710
Sponsor: M.D. Anderson Cancer Center
Enrollment: 100

Rationale: Girentuximab, a monoclonal antibody that targets carbonic anhydrase IX (CAIX), an enzyme highly expressed in clear cell RCC, has been evaluated in a radiolabeled fashion in localized RCC. A Phase 3 ZIRCON study of 89Zr-DFO-girentuximab (TLX250-CDx) showed that TLX250-CDx was well tolerated and could accurately and noninvasively identify clear cell RCC. Extrapolating the trajectory of the advent of PSMA PET imaging followed by 177LuPSMA treatment options for patients with metastatic prostate cancer, it is provocative to consider the possibility of a similar theranostic approach to improve the effect of current front-line treatments in metastatic RCC. This is especially compelling if, by conjugating radioisotopes to receptor binding analogs targeting CAIX, a radioligand treatment could activate the immune microenvironment to lead to a greater complete response (CR) rate.

Study Design: This open label, Phase 1b/2 single-center study enrolls patients with locally advanced or metastatic predominantly clear cell RCC, with at least one measurable lesion as defined by RECIST v1.1. Patients with ECOG performance status of 0-1 with adequate hematologic and organ function who have not previously received any frontline systemic therapy for metastatic RCC will be enrolled. All patients enrolled to treatment will undergo a pre-treatment PET scan and biopsy. Patients will be treated with 177Lu-girentixuimab every 12 weeks for up to 3 treatments. After the first cycle (12 weeks) of treatment, nivolumab and cabozantinib will be added. The first five patients will be enrolled for the purposes of safety lead-in to evaluate myelosuppression. Patients will be treated for a maximum of 3 treatments of 177Lu-girentuximab and will continue on nivolumab plus cabozantinib until progression or unacceptable toxicity.

Endpoints: The co-primary endpoints of this study are to determine safety of the combination of 177Lu-girentuximab with nivolumab plus cabozantinib and to evaluate the CR rate with the combination in patients with previously untreated clear cell RCC. Secondary objectives include objective response rate (ORR) and progression free survival (PFS) of the combination. The study will also evaluate the effects of the combination on inducing activated T cell infiltration as exploratory endpoints.

Neoadjuvant pembrolizumab and axitinib in renal cell carcinoma with associated inferior vena cava tumor thrombus (NEOPAX)

Status: Recruiting
Clinicaltrials.gov identifier: NCT05969496
Sponsor: University of Colorado, Denver
Enrollment: 17

Rationale: Surgical resection is often indicated for a patient with RCC who also has findings of an inferior vena cava (IVC) tumor thrombus. However, in this setting, surgery is not without risk, with significant perioperative mortality as well as elevated recurrence rates. As a result, neoadjuvant approaches to treatment of patients with RCC with IVC tumor thrombus are of interest, especially as systemic therapy approaches have evolved to include the combination of vascular endothelial growth factor tyrosine kinase inhibitors (VEGF TKIs) and immune checkpoint inhibitors (ICIs).

Study Design: This open label, Phase 2 study enrolls patients with histologically proven RCC with a clear cell component, who are deemed upfront surgical candidates suitable to undergo nephrectomy per the treating urologist. Patients may have cT3b, cT3c, or cT4, cN0 or cN1, and cM0 or cM1 disease (participants could be suitable for nephrectomy for cytoreductive or curative intent), and must have an IVC tumor thrombus. In terms of other key eligibility criteria, participants cannot have received prior systemic therapy for RCC, cannot have active autoimmune disease requiring immunosuppressive therapy with the exception of vitiligo, Sjogren’s syndrome, Type 1 diabetes, hypothyroidism or adrenal/pituitary insufficiency on stable replacement therapy. They also cannot have had active CNS metastases. All participants enrolled to the study will be treated with pembrolizumab and axitinib for a total of 12 weeks, after which they will undergo imaging to assess response and for staging. Patients can then undergo definitive surgery within 2 weeks (+/- 7 days) after end of treatment scan.

Endpoints: The primary endpoint of the study is to evaluate the change in IVC tumor thrombus extent based on Mayo classification, based on MRI imaging obtained at baseline and at 12 weeks of therapy. A co-primary endpoint is to evaluate the change in IVC tumor thrombus size from baseline using anteroposterior and transverse diameter. Secondary endpoints include evaluating surgical complications after neoadjuvant therapy, based on the Clavien-Dindo classification and using a 30-day post-operative timepoint, as well as examining the safety profile of axitinib with pembrolizumab in these patients, and 1 year progression free survival (1-yr-PFS) and overall survival (1-yr-OS).

RCC has witnessed a significant increase in its incidence over the last five decades, ranking as the ninth most common cancer globally. Although survival rates have improved substantially, RCC remains one of the deadliest urological cancers. Traditionally, RCC subtypes were classified based on histopathological features. However, in recent years, there has been a paradigm shift towards molecular and genomic characterization of RCC, leading to the recognition of distinct molecular subtypes.

The 2022 World Health Organization (WHO) classification introduced a new category called “molecularly defined renal carcinomas,” encompassing various subtypes, including SMARCB1-deficient medullary carcinoma, ALK-rearranged RCC, FH-deficient RCC, SDH-deficient RCC, ELOC-mutated RCC, TFEB-altered RCC, and TFE3-rearranged RCC.

These molecular subgroups have significant consequences for diagnosis, prognosis, and treatment. Molecularly defined RCCs are frequently underrepresented in clinical trials, encouraging additional research to identify beneficial therapeutics. Immune checkpoint inhibitors and tyrosine- kinase inhibitors have shown promising results in some subtypes, while others may benefit from specific inhibitors targeting their molecular drivers. Additionally, these classifications have important prognostic implications, guiding treatment decisions and genetic counseling.

Over the past decade, innovations in radiation technology and technique have led to the increasing use of stereotactic body radiotherapy (SBRT) for the treatment of renal cell carcinoma. We provide an overview of SBRT and review the role of SBRT for treatment of localized and oligometastatic RCC. We also provide a brief overview of the current state of knowledge with regards to the combination of SBRT and novel systemic agents commonly used in the treatment of RCC. As outcomes from trials investigating SBRT mature, showing excellent efficacy and tolerability, it is likely that SBRT use will continue to increase in future years.

BACKGROUND:
It remains unclear which patients with cT1b renal cell carcinoma (RCC) benefit most from partial nephrectomy (PN) versus radical nephrectomy (RN) considering oncological outcomes and renal function.

OBJECTIVE:
To compare oncological and functional outcomes of RN with PN for cT1b RCC.

METHODS:
This is a retrospective analysis of patients who underwent RN or PN for cT1b between 2010 and 2022 (n = 241). Patients were grouped by RN or PN and matched by age, sex, Charlson Comorbidity Index, BMI, PADUA score, RENAL score, ASA score, and preoperative kidney function (eGFR) using propensity score matching. The 10-year overall survival (OS), 10-year cancer-specific survival (CSS), and 10-year recurrence-free survival (RFS) were compared. Change in eGFR from baseline to 5-year follow-up was assessed.

RESULTS:
After matching, 100 patients remained in each group for analysis. The 10-year OS, CSS, and RFS rates were similar between groups. For patients classified as low risk, the PN group displayed a higher recurrence rate compared to RN (7 vs. 0, p = 0.01). Patients who underwent RN had worse 1-year postoperative eGFR than PN (RN: 57 [44–65], PN: 73 [60–87], p < 0.001). RN was more likely to induce new-onset chronic kidney disease (CKD) stage ≥3b compared to PN (p < 0.001). Complication rate after PN was significantly higher (p = 0.003).

CONCLUSION:
10-year survival rates were similar, despite more recurrences in the PN group. Our data shows that post-surgical renal function is superior for PN. Nevertheless, RN is a reliable treatment option when preservation of renal function is not a priority.

Papillary renal cell carcinoma (pRCC) comprises 15-20% of all patients with renal cell carcinoma (RCC). Although in the localized setting where pRCC appears to have better outcomes than clear cell RCC (ccRCC), patients with metastatic pRCC have significantly worse outcomes than patients with metastatic ccRCC. Because of the overall rarity of pRCC, there have been less research and clinical trials devoted to this subtype. Therefore, treatment of pRCC has generally been extrapolated from approved therapies for ccRCC. Recent data shows promise with newer tyrosine kinase inhibitors, and there is emerging evidence on their combination with immune checkpoint inhibitors. However, more dedicated clinical trials to pRCC are urgently needed, as response rates and outcomes still lag behind ccRCC. This review summarizes the pathophysiology, genetic features, the evolution of treatment approaches since the systemic cytokine era, and current challenges of managing pRCC.

BACKGROUND:
The role of active surveillance (AS) has been recognized as a management strategy for localized small renal masses (SRMs). The EAU guidelines suggest AS can be offered to frail and/or comorbid patients diagnosed with SRM due to the low cancer-specific-mortality (CSM) and higher competing-cause mortality. As specific cut-offs defining the characteristics of frail and comorbid patients who may benefit from AS remain less clear, our objective is to conduct a systematic review aiming to identify potential characteristics that could assist physicians in shared decision-making.

METHODS:
The systematic literature review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. Two authors independently screened the literature according to the PICOs criteria previously outlined in our registered review protocol (via Pubmed, Embase, and the Cochrane Central Register of Controlled Trials), extracted data, and assessed the risk of bias, using Newcastle-Ottawa Scale. Studies that analyzed differences in patient’s tumor-related and molecular characteristics associated with any differences in growth rate (GR), overall survival (OS), cancer-specific survival (CSS), and metastasis-free survival (MFS), were considered eligible.

RESULTS:
Nineteen studies comprising a total of 5105 patients were analyzed. Patient-specific factors such as age and cardiovascular index, which demonstrated a predominant impact on OS, exhibited a high degree of consistency across the analyzed studies. Less concordance was found when exploring GR, with the main predictors being ethnicity, age, sex, comorbidity, symptoms, and eGFR. The analysis of tumor-related characteristics, such as tumor size, nephrometry score, and mass histology, among others, yielded contradictory outcomes concerning their impact on GR and CSS.

CONCLUSION:
Age, cardiovascular index, and chronic kidney disease have shown to be reliable predictors of OS. Nonetheless, significant debates persist regarding tumor characteristics or molecular markers that may influence survival and GR.

Further research is awaited to shed light on the potential to identify prognostic factors. This would aid in pinpointing the subgroup of patients who could experience additional benefits from AS, potentially leading to a reduced risk of progression.

It is imperative to standardize approaches to AS and reporting of results, as this will be pivotal for future quantitative analyses.