Hayley Virgil

An analysis across 5 clinical trials in advanced renal cell carcinoma (RCC) showed a survival benefit with frontline immunotherapy versus sunitinib (Sutent) in the total patient population; however, when stratifying patients by risk status, it remained inconclusive whether upfront immunotherapy was optimal in patients with favorable-risk disease.

Investigators reported at the 2021 ESMO Congress that all clinical trials included in the analysis reported an advantage to overall survival (OS) and progression-free survival (PFS) with an immunotherapy regimen compared with sunitinib (HR for OS, 0.71; 95% CI, 0.61-0.84; HR for PFS, 0.64; 95% CI, 0.51-0.82). Notably, the favorable-risk subgroup analysis indicated that no difference was observed in terms of OS between the treatment cohorts (HR, 1.07; 95% CI, 0.81-1.41) with a trend toward an advantage of immunotherapy for PFS (HR, 0.74; 95% CI, 0.46-1.19).

Due to recent evidence indicating that this patient population may experience an improved prognosis after being treated with immunotherapy, investigators launched the meta-analysis to evaluate the safety and efficacy of first-line immunotherapy compared with sunitinib in those with favorable-risk advanced RCC.

Investigators underwent a systemic search of PubMed, Ovid MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials, and the evidence was assessed for quality. Survival hazard ratios were extracted for both the overall patient population and the favorable-risk subgroup.

Investigators used findings from 5 clinical trials, including the phase 3 CheckMate 9ER trial (NCT03141177), which examined nivolumab (Opdivo) plus cabozantinib (Cabometyx) versus sunitinib in previously untreated RCC; the phase 3 CheckMate214 trial (NCT02231749) which examined nivolumab plus ipilimumab (Yervoy); the phase 3 JAVELIN Renal 101 study (NCT02684006), which examined avelumab (Bavencio) plus axitinib (Inlyta); the phase 3 KEYNOTE-426 study (NCT02853331), which examined pembrolizumab (Keytruda) plus axitinib; and the phase 3 CLEAR trial (NCT02811861), which examined lenvatinib (Lenvima) plus pembrolizumab. The meta-analysis included a total of 1088 patients.

For the favorable-risk population in the CheckMate 9ER trial, investigators reported a hazard ratio (HR) of 0.84 for OS (95% CI, 0.35-1.97) and an HR of 0.62 (95% CI, 0.38-1.01) for PFS. Additionally, in the CheckMate214 trial, investigators reported HRs of 1.19 (95% CI, 0.77-1.85) and 1.65 (95% CI, 1.16-2.35) for OS and PFS, respectively, within the same patient population. The JAVELIN Renal 101 trial reported an HR of 0.81 (95% CI, 0.34-1.96) for OS and 0.63 for PFS (95% CI, 0.40-0.99) in the favorable-risk population. Moreover, the KEYNOTE-426 study reported HRs of 1.06 (95% CI, 0.60-1.86) and 0.79 (95% CI, 0.57-1.09) for OS and PFS, respectively. Lastly, the CLEAR trial reported HRs of 1.15 (95% CI, 0.55-2.40) and 0.41 (95% CI, 0.28-0.62) for OS and PFS, respectively, in this patient population.

Moreover, investigators noted that the safety profile appeared to be consistent with previously reported findings.

As the survival advantage garnered from an immunotherapy regimen has not yet been confirmed among those with favorable-risk advanced RCC, additional prospective trials containing a larger sample size and longer follow up are needed in order to confirm the benefit.

1. Manneh R, Lema M, Ibatá L, et al. Immunotherapy vs sunitinib as first-line treatment for advanced renal cell carcinoma in favourable risk patients. A meta-analysis of randomized clinical trials. Poster presented at 2021 European Society of Medical Oncology Annual Congress; September 16-21, 2021; virtual. Accessed September 16, 2021. Abstract 677P.

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Additional prospective trials containing a larger sample size and longer follow up are needed to determine the optimal treatment sequence in favorable-risk advanced renal cell carcinoma. 

Frontline immunotherapy benefit in favorable-risk advanced RCC remains inconclusive

The FDA has officially released its finalized recommendation for the use of metastases-free survival (MFS) as an end point in clinical trials evaluating treatments for patients with nonmetastatic castration-resistant prostate cancer (nmCRPC).

In addition to including editorial changes for clarity, the guidance also has recommendations for sponsors on aspects such as general trial design, imaging, and considerations for interpreting data from the trial and MFS analyses.

A prolonged assessment period and low death rate means that the utility of overall survival (OS) can be impractical as a primary end point to support drug approvals for patients with prostate cancer. These issues were explored during the 2011 Oncologic Drugs Advisory Committee meeting wherein members recommended that other end points be explored that can be measured earlier in the disease course, such as MFS which could prove to be useful in evaluating the impact of treatment in this patient population.

The guidance highlighted several general considerations for clinical trial designs that utilize MFS as an end point. For example, the FDA recommends defining MFS prior to starting the trial—which should exclude local progression events such as progression in pelvic lymph nodes below the aortic bifurcation—as well as considering stratification of randomization by prior local definitive therapy or lack of prior definitive therapy. Prostate-specific antigen (PSA) doubling time should also be considered, according to the guidance.

Other recommendations include utilizing a superiority trial design and excluding patients who are likely to benefit from local therapy. This population of patients could be enrolled following local therapy provided that their PSA continues to rise and other enrollment criteria for CRPC and minimum PSA value are met.

In terms of imaging consideration, the guidance states that sponsors ought to prespecify acceptable imaging modalities and how often assessments should be completed. Additionally, it is important to prespecify and justify the radiographic definition of nonmetastatic disease. Radiographic definition of local disease and progression, as well as metastatic disease, should also be prespecified. In order to interpreted results with MFS, the significance of MFS improvement should be notably greater than frequency of imaging.

“FDA recommends a blinded independent central review of imaging studies to assess any potential assessment bias. Sponsors may also consider using an audit where a random sample of scans are sent for independent review. Sponsors should seek advice from the Agency about the design of an audit for MFS,” the guidance stated.

When it comes to interpreting the results of trials utilizing MFS as an end point, interim efficacy analyses of MFS are discouraged to avoid over overestimating and underestimating MFS benefit. Moreover, the magnitude of MFS improvement that is required to support drug approval will be based on trial design, safety, patient population, and overall risk/benefit assessment. Additionally, although demonstration of OS benefit is not required, a formal interim OS analysis should be conducted at the time of final MFS analysis.

Lastly, the guidance highlighted several final considerations for MFS analyses. As missing data may complicate MFS analyses, it is imperative to put procedures in place that minimize missing data.

“The statistical analysis plan should specify the primary analysis and one or more sensitivity analyses to evaluate the effect of missing observations on the results,” the guidance read. “Sponsors can consider additional analyses of progression-free survival (including both local and metastatic progression) to support the primary MFS analysis.”

Before the draft guidance was released, the FDA had approved the use of apalutamide (Erleada) in February 2018 for patients with nmCRPC, marking it as the first drug approved on the basis of a clinical trial with an MFS primary end point.

 The phase 3 SPARTAN trial (NCT01946204) enrolled 1207 patients with nmCRPC who were treated with either apalutamide or placebo. Results indicated that apalutamide yielded a median MFS of 40.5 months vs 16.2 months in those who received placebo (HR, 0.28; 95% CI, 0.23-0.35; 

Similarly, enzalutamide (Xtandi) received approval in July 2018 for the treatment of nmCRPC with MFS, which was defined as the time from randomization to loco-regional and/or distant radiographic progression or death up to 112 days following treatment discontinuation with no radiographic progression, as the primary end point of the supporting trial.

 Findings from the supporting phase 3 PROSPER trial (NCT020032924) indicated that enzalutamide yielded a median MFS of 36.6 months vs 14.7 months in the control arm (HR, 0.29; 95% CI, 95% CI, 0.24-0.35; 

Lastly, the FDA approval of darolutamide (Nubeqa) on July 30, 2019, was based on the results of the phase 3 ARAMIS (NCT02200614) trial, in which 1509 patients with nmCRPC achieved a significant improvement in MFS, the primary end point of the study.

 For this trial, MFS was defined as the time from randomization to first signs of distant metastases or death from any cause within 33 weeks of the patient’s last evaluable scan. Those who received the experimental agent experienced a median MFS of 40.4 months vs 18.4 months among those in the placebo arm (HR, 0.41; 95% CI, 0.34-.050; 

 <.0001). Notably, the OS data were not mature.

FDA. Nonmetastatic Castration-Resistant Prostate Cancer: Considerations for Metastasis-Free Survival Endpoint in Clinical Trials, version 8.21. Accessed August 9, 2021. https://bit.ly/3s0o4FG

FDA approves new treatment for a certain type of prostate cancer using novel clinical trial endpoint. News release. FDA. February 14, 2018. Accessed August 6, 2021. 

Smith MR, Saad F, Chowdhury S, et al. Apalutamide treatment and metastasis-free survival in prostate cancer. 

. 2018;378(15):1408-1418. doi:10.1056/NEJMoa1715546

FDA approves enzalutamide for castration-resistant prostate cancer. News release. July 13, 2018. Accessed August 9, 2021. 

Hussain M, Fizazi K, Saad F, et al. Enzalutamide in men with nonmetastatic, castration-resistant prostate cancer

. 2018;378:2465-2474. doi:10.1056/NEJMoa1800536

FDA approves darolutamide for non-metastatic castration-resistant prostate cancer. News release. FDA. July 30, 2019. Accessed August 9, 2021. 

Fizazi K, Shore N, Tammela TL, et al. Darolutamide in nonmetastatic, castration-resistant prostate cancer. 

. 2019;380:1235-1246. doi:10.1056/NEJMoa1815671

The FDA has officially released its finalized recommendation for the use of metastases-free survival as an end point in clinical trials evaluating treatments for patients with nonmetastatic castration-resistant prostate cancer.

Final FDA blueprint available for MFS end point in nonmetastatic CRPC trials

A study of patients treated through the Veteran’s Health Administration (VHA) found that Black men with prostate cancer were less likely to choose or be offered the most beneficial treatment options, according to results published in 

The findings showed that within the VHA overall, race does not appear to influence the receipt of definitive treatment; however, Black men with prostate cancer were reported as receiving less definitive treatment in high-benefit situations than non-Black patients.

Findings from the study indicated that Black veterans with prostate cancer were 5% more likely to receive radiation therapy or surgery than non-Black patients (

Additionally, veterans of all races who were likely to derive benefit from definitive therapy were 40% more likely to receive treatment than those who did not require it (

 <.001). Despite the advantages of advanced care that are currently available to this population of patients, Black men who were highly likely to derive benefit from treatment were 11% less likely to undergo treatment than non-Black patients of a similar age and disease severity (odds ratio, 0.89; 

“Our study suggests, for reasons that remain unclear, that Black men who need treatment may be choosing against the most beneficial prostate cancer therapies (which are often more invasive), or that such 'high-benefit' treatments, are not being offered to them as aggressively as they are to non-Black patients,” co-investigator Joseph Ravenell, MD, associate dean for diversity affairs and inclusion at New York University (NYU) Langone, associate professor at NYU Grossman School of Medicine, and co-leader of community outreach and engagement at the Perlmutter Cancer Center, stated in a press release.

Previous findings have indicated that Black patients trend toward undergoing definitive prostate cancer treatments less than men of other races. However, it has yet to be seen as to whether this is due to avoidance of overtreatment in those with low-risk disease and avoid life-changing adverse effects such as erectile dysfunction and incontinence. Another reason for these disparities could be a reduction in appropriate care. This inspired the study’s investigators to examine the role of race in prostate cancer treatment benefit.

Investigators behind the retrospective cohort study identified 35,427 men through the VHA Corporate Warehouse who had been diagnosed with low- to intermediate-risk disease from 2011 to 2017. The majority who were included in the study were over the age of 60, were married, and had no notable comorbidities.

Men were characterized based on life expectancy and disease severity. For example, while a man in his 50s with aggressive disease who had undergone surgery or radiotherapy would be considered a high-benefit patient, older men with non-aggressive prostate cancer would be categorized as low benefit.

Additional findings from the study indicated that Black patients are more commonly diagnosed with prostate cancer 2 years earlier than patients of other racial groups of all ages. However, this population is more likely to be diagnosed with more aggressive disease. Additional research must be conducted to identify the forces that are responsible these racial disparities.

“Despite great strides in prostate cancer care over the past few decades, racial disparities in care persist, and there remains a lot to be done to better understand why this is happening and what we can do to finally close the gap. At the end of day, our goal is to offer patients the most appropriate cancer care they need, using a culturally sensitive approach,” Danil Makarov, MD, MHS, an associate professor in the Departments of Urology and Population Health at NYU Grossman School of Medicine, concluded.

1. Study sheds light on persistent racial disparities in prostate cancer care in the United States. News Release. NYU Langone Health. June 29, 2021. https://bit.ly/2VAt4V7

2. Rude T, Walter D, Ciprut S, et a. Interaction between race and prostate cancer treatment benefit in the Veterans Health Administration. Cancer. Published online June 29, 2021. doi: 10.1002/cncr.33643

Among patients treated through the Veteran’s Health Administration, Black men with prostate cancer were less likely to choose or be offered the most beneficial treatment options.

Study shows racial disparities in prostate cancer treatment selection

 showed that female, Black, and Hispanic patients with renal cell carcinoma (RCC) have a higher likelihood of receiving non–guideline-based treatment.

Findings from the retrospective cohort study identified that in the overall study population, female patients were treated more aggressively vs their male counterparts, with statistically significantly lower adjusted odds of undertreatment (odds ratio [OR], 0.82; 

 <.001) and higher adjusted odds of overtreatment (OR, 1.27; 

 <.001). Moreover, Black race was also associated with a statistically significantly higher adjusted odds of both undertreatment (OR, 1.42; 

 <.001) vs White race. An association with undertreatment (OR, 1.20; P = .004) and overtreatment (OR, 1.06; 

 = .01) was also identified in patients with Hispanic ethnicity.

“To our knowledge, this study represents the first attempt to assess the associations between demographic factors and receipt of non–guideline-based treatment among patients with kidney cancer,” the authors of the study wrote. “We found that female patients with kidney cancer had higher odds of receiving more aggressive treatment than men, which was associated with increased rates of overtreatment for small kidney masses and potentially increased risk for unjustified complications.”

A trend towards downstaging for patients with kidney cancer has been observed, due in part to the fact that smaller tumors of 4 cm or less have a lower potential for metastases and are associated with a higher likelihood of death from competing causes.

 As such, a number of guidelines have been implemented advocating for nephron-sparing approaches or active surveillance in those with smaller tumors.

However, while the overtreatment of indolent tumors needs to be recognized, attention also needs to be paid to aggressive disease that is being undertreated, particularly in underserved racial and ethnic groups and those who are uninsured.

 As the association between patient demographics and clinical decision making are not yet understood, investigators set out to assess the link between certain demographic factors and receipt of non–guideline-based treatment for RCC.

The study pulled data from the National Cancer Database, which featured 339,641 patients with a primary diagnosis of RCC from January 1, 2010, to December 31, 2017. After exclusions, investigators had a final population of 158,445 patients with cT1-2, N0, M0 RCC.

The population included in the study was notably young and healthy, among whom age and comorbidities were unlikely to be associated with treatment decisions. The median age was 58 years (interquartile range [IQR], 50-64) with 75.7% of all patients being white, 62.8% being male, 57.6% having private insurance. Additionally, 23.2% of the population had a Charlson-Deyo Comorbidity Index score of 0 and 76.8% had a score of 1.

Guideline-based treatment was administered to 69.4% of the population whereas 30.6% were given a non-guideline treatment. Among those who were given a non-guideline treatment, 2.5% were undertreated and 28.2% were overtreated.

“The total number of patients increased over time, and the proportion of patients receiving guideline-based treatment increased over the study period, from 11,206 of 16,934 (66.2%) in 2010 to 15,055 of 21,126 patients (71.3%) in 2017 (

A subgroup analysis revealed that the association between female sex and overtreatment was preserved for both small cT1a kidney tumors of less than 2 cm (OR, 1.15; 

 = .001) and large cT1a tumors of 2 to 4 cm (OR, 1.13; 

 <.001). Moreover, women were found to have statistically significantly lower adjusted odds of undertreatment for cT1b tumors (OR, 0.79; 

 <.001), although no association was identified for cT2 tumors.

Additionally, a statistically significant association was identified between Black race and undertreatment of cT1b and cT2 kidney tumors. Those with smaller tumors had significantly lower adjusted odds of overtreatment (OR, 0.72; 

 < .001) and those with larger tumors (OR, 1.20; 

 = .003) had statistically significant higher adjusted odds for overtreatment.

Investigators also identified a significant association between uninsured status and less aggressive treatment vs those with private insurance. Those who had an uninsured status were found to have a statistically significant higher adjusted odds ratio of undertreatment (OR, 2.63; 

< .001) and lower odds of overtreatment (OR, 0.72; 

<.001). A subgroup analysis found that the association for overtreatment of small cT1a tumors were significant (OR, 0.40; 

< .001), as well as for undertreatment of cT1b (OR, 2.49; 

< .001). However, similar findings were not identified for the overtreatment of large cT1a lesions (OR, 1.01; 

Moreover, those with Medicare had a statistically significant association with higher adjusted odds of undertreatment (OR, 1.67; 

 <.001), as well as overtreatment (OR, 1.21; 

The investigators of the study concluded that it is important to keep these disparities in mind when selecting a treatment strategy for individual patients and should be further considered by health care policy makers.

Howard JM, Nandy K, Woldu SL, et al. Demographic factors associated with non-guideline–based treatment of kidney cancer in the United States. 

. 2021;4(6):e2112813. doi:10.1001/jamanetworkopen.2021.12813

Smaldone MC, Kutikov A, Egleston BL, et al. Small renal masses progressing to metastases under active surveillance: a systematic review and pooled analysis. 

. 2012;118(4):997-1006. doi:10.1002/cncr.26369

Kutikov A, Egleston BL, Canter D, et al. Competing risks of death in patients with localized renal cell carcinoma: a comorbidity based model. 

. 2012;188(6):2077-2083. doi:10.1016/j.juro.2012.07.100

Finelli A, Ismaila N, Bro B, et al. Management of small renal masses: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol. 2017;35(6):668-680. doi:10.1200/JCO.2016.69.9645

Campbell S, Uzzo RG, Allaf ME, et al. Renal mass and localized renal cancer: AUA Guideline. 

. 2017;198(3):520-529. doi:10.1016/j.juro.2017.04.100

NCCN. NCCN Clinical Practice Guidelines in Oncology. Kidney Cancer, version 4.2021. Accessed June 29, 2021. https://bit.ly/3w5lLl8

Schwartz K, Ruterbusch JJ, Colt JS, et al. Racial disparities in overall survival among renal cell carcinoma patients with young age and small tumors. 

. 2016;5(2):200-208. doi:10.1002/cam4.578.

Tan, HJ, Chuang RJ, Shirk JD, et al. Health insurance status and disparities in kidney cancer care. 

. 2016;3(1):18-24. doi:10.1016/j.urpr.2015.05.009

Batai K, la Rosa AH, Zeng J, et al. Racial/ethnic disparities in renal cell carcinoma: Increased risk of early-onset and variation in histologic subtypes. 

. 2019;8(15):6780-6788. doi:10.1002/cam4.2552

“To our knowledge, this study represents the first attempt to assess the associations between demographic factors and receipt of non–guideline-based treatment among patients with kidney cancer,” the authors of the study wrote. 

Hayley Virgil

Articles

Frontline immunotherapy benefit in favorable-risk advanced RCC remains inconclusive

Final FDA blueprint available for MFS end point in nonmetastatic CRPC trials

Study shows racial disparities in prostate cancer treatment selection

Study highlights gender and racial disparities in receiving optimal treatment for kidney cancer