Kidney Cancer Journal | Volume 8, January – December 2024

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.

Over the past several years, four regimens incorporating immune checkpoint inhibitors have become widely used in the front-line setting to treat metastatic clear cell renal cell carcinoma: nivolumab with ipilimumab, axitinib with pembrolizumab, cabozantinib with nivolumab, and lenvatinib with pembrolizumab. These regimens all demonstrated favorable response rates and survival outcomes compared to sunitinib in phase III trials. As these data have matured, nivolumab with ipilimumab has been most clearly associated with durable long-term disease response and stable survival benefit. Moreover, responses obtained using nivolumab with ipilimumab are more likely to persist after treatment discontinuation compared to regimens containing a VEGFR-TKI. These outcomes underline the value of using nivolumab with ipilimumab to pursue durable response in patients with advanced clear cell renal cell carcinoma.

Background:

Kidney cancer is amongst the deadliest genitourinary malignancies. Neoadjuvant systemic therapy has the potential to improve survival and overall outcomes in select patients. Enrolling patients in trials of neoadjuvant treatment for kidney cancer is challenging, which limits neoadjuvant treatment development.

Objective:

This study aims to develop a better understanding of the barriers patients face in kidney cancer clinical trial participation, with a particular focus on neoadjuvant trials for renal cell carcinoma.

Methods:

From 2022–2023, we recruited participants with a history of kidney cancer through a Qualtrics survey that was sent to the Kidney Cancer Association (KCA) and Kidney Cancer Cure (KCCure) mailing lists and social media pages. Patient responses on demographics, clinical information, and perspectives were evaluated.

Results:

Ninety-four individuals completed the survey. Eighty-one percent of respondents reported not participating in clinical trials due to not being informed about potential applicable trials. Importantly, many (76%) respondents reported that prevention of cancer return was a highly important reason to participate in clinical trials. Most respondents reported a willingness to undergo a kidney biopsy (59%), and/or additional appointments (58%) and surgery delays.

Conclusions:

Increased patient awareness about clinical trials with the potential to delay cancer recurrence may increase patient participation in clinical trials. Clinical trial design, including additional appointments or interventions and/or minor surgery delays are not major barriers to trial participation.

Background:

Cabozantinib, a tyrosine kinase inhibitor (TKI), is a prevalent second-line (2 L) therapy and was approved for use after progression on TKIs. However, the 1 L treatment setting has changed since the approval of cabozantinib monotherapy in salvage therapy settings.

Objective:

To assess the differential effectiveness of cabozantinib after prior progression on 1 L ipilimumab with nivolumab (IPI + NIVO) compared to programmed death receptor-1 (PD-1) or PD-1 ligand (PD-L1) inhibitors (PD1/L1i) with TKIs.

Methods:

Utilizing a nationwide electronic health record (EHR)-derived de-identified database, we included patients with metastatic clear cell renal cell carcinoma (mccRCC) who received 1 L treatment with an immune checkpoint inhibitor (ICI)-based combination and 2 L treatment with cabozantinib monotherapy. These patients were categorized based on the type of 1 L ICI-based combination received: IPI + NIVO vs. PD1/L1i with TKI. Real-world time to next therapy (rwTTNT) and real-world overall survival (rwOS) were summarized using Kaplan-Meier curves and compared using Cox-proportional hazard models adjusted for International mRCC Database Consortium (IMDC) risk groups.

Results:

Among 12,285 patients with metastatic renal cell carcinoma, 237 were eligible and included. Median rwTTNT was 8 months for the IPI + NIVO subgroup and 7.5 months for the PD1/L1i + TKI subgroup (HR 1.05, 95% CI: 0.74–1.49, p = 0.8). Median rwOS was 17 months for IPI + NIVO and 16 months for PD1/L1i + TKI subgroup (HR 0.79, 95% CI: 0.52–1.20, p = 0.3).

Conclusions:

Cabozantinib remains effective as a 2 L therapy for mccRCC independent of the type of prior 1 L ICI-based combination. Further research is needed to validate these findings and explore the ideal sequencing of therapies.

The rise of immune-based combination therapies has revolutionized the treatment landscape for metastatic renal cell carcinoma (mRCC), offering significant improvements in response rates and survival. However, along with these advancements come challenges in managing treatment-related adverse events, particularly renal toxicities. Kidney biopsies represent the gold standard in diagnosing and managing these complications, providing insights into histopathological patterns and guiding therapeutic strategies. It is important to emphasize that in most of the cases expertise in onco-nephrology can enable accurate diagnosis and management of nephrotoxicities, and that in clinical practice, renal biopsy is often not easily feasible. Research efforts are underway to identify biomarkers and imaging techniques that can accurately detect renal damage characteristics without the need for invasive procedures. Promising candidates have been identified; however, validation studies are essential to enhance their effectiveness and integrate them into standard clinical practice. This paper underscores the importance of individualized approaches in managing renal adverse events and calls for further research to improve diagnostic capabilities for acute kidney injury in the context of immune-based combination therapies.

The therapeutic landscape of clear cell renal cell carcinoma (ccRCC) has dramatically evolved in the last decade. Immuno-oncology (IO) and/or tyrosine kinase inhibitor (TKI) based doublet therapies have become standard in the frontline setting for most patients with advanced ccRCC. For previously-treated advanced ccRCC, multiple agents are available including belzutifan, a hypoxia inducible factor 2 alpha (HIF2-α) inhibitor. However, the challenging goal of developing therapies with a unique mechanism of action remains. Many such promising agents are currently in development such as novel TKIs, inhibitors targeting alternative checkpoints, cellular therapies, radioligands, antibody-drug conjugates, and agents targeting fatty acid metabolism. Further, the role of microbiome is being actively investigated in advanced ccRCC, with ongoing studies evaluating its effect when combined with standard therapies. Mature data from trials with these agents is eagerly awaited.

Background:

Renal cell carcinoma (RCC) accounts for approximately 90% of kidney cancers, with a significant percentage of patients presenting with metastatic disease. Recent evidence suggests a notable role of the human microbiome in the onset, progression, and therapeutic outcomes of RCC.

Objective:

This systematic review aims to synthesise current knowledge on the association between the microbiome and RCC, focusing on pathogenesis, progression, and response to therapy.

Methods:

Complying with PRISMA guidelines, databases including PubMed, Embase, and Web of Science were searched for relevant studies up to December 7, 2023. The inclusion criterion was English-language articles that discussed RCC in relation to the microbiome of any body region. Screening was performed in a two-phase manner by three authors.

Results:

From 570 articles, 65 met the inclusion criteria. The gut microbiome (GM) emerged as a potential RCC pathogenesis driver, with certain bacteria associated with increased or decreased risk. Studies have also demonstrated that antibiotics and other medications can influence RCC therapeutic outcomes, reducing the effectiveness of immune-modulating therapies.

Conclusions:

While multiple bacterial species and antibiotics have been implicated in influencing RCC, further research is necessary to elucidate these relationships and investigate the efficacy of microbiome modulation on therapy effectiveness. Findings underscore the significant impact of the microbiome on RCC, suggesting the potential for microbiota-targeted therapeutics.