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Prognostic Factors in De Novo Metastatic Renal Cell Carcinoma: A Report From the Latin American Renal Cancer Group

LARCG

Abstract

Purpose

To assess the effect of clinical and pathological variables on cancer-specific and overall survival (OS) in de novo metastatic patients from a collaborative of primarily Latin American countries.

Patients and methods

Of 4,060 patients with renal cell carcinoma diagnosed between 1990 and 2015, a total of 530 (14.5%) had metastasis at clinical presentation. Relationships between clinical and pathological parameters and treatment-related outcomes were analyzed by Cox regression and the log-rank method.

Results

Of 530 patients, 184 (90.6%) had died of renal cell carcinoma. The median OS of the entire cohort was 24 months. American Society of Anesthesiology classification 3-4 (hazard ratio [HR]: 1.64), perirenal fat invasion (HR: 2.02), and ≥ 2 metastatic organ sites (HR: 2.19) were independent prognostic factors for 5-year OS in multivariable analyses. We created a risk group stratification with these variables: no adverse risk factors (favorable group), median OS not reached; one adverse factor (intermediate group), median OS 33 months (HR: 2.04); and two or three adverse factors (poor risk group), median OS 14 months (HR: 3.58).

Conclusions

Our study defines novel prognostic factors that are relevant to a Latin American cohort. With external validation, these easily discerned clinical variables can be used to offer prognostic information across low- and middle-income countries.

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We create a new arm “LARCG images”

Clinical Case (Hospital Britanico, Buenos Aires, Argentina).

1. Valoración multimétodo de una lesión renal mesorrenal izquierda, posterior, con un crecimiento predominante exofítico. La lesión es hipointensa en T2, sin un componente graso macro o microscópico y con marcada restricción en secuencia de difusión, sugestivo de hipercelularidad. Tras la administración de contraste ev., su realce es tenue y progresivo. En tomografía se objetiva hipodensa y cont tenue realce. Se realizaron reconstrucciones 3D e impresión 3D como parte de la valoración pre-quirúrgica. La lesión correspondía a un carcinoma papilar tipo II. Hospital Británico de Buenos Aires, Argentina.

2. Lesión quística en el polo superior del riñón derecho, con dos engrosamientos parietales, de morfología nodular, que muestran realce post-contraste ev. Se realizaron reconstrucciones 3D como parte de la valoración prequirúrgica. Hospital Británico de Buenos Aires, Argentina.

3. Recurrencia local de carcinoma renal de células claras en el sitio quirúrgico de nefrectomía parcial. Se observa un lesión sólida mesorrenal. Se realiza reconstrucción 3D como parte de la valoración pre-quirúrgica y su correlación con la pieza de nefrectomía. Hospital Británico de Buenos Aires, Argentina.

Summary of Kidney Cancer Take-Home Messages from ASCO 2021

As a result of the COVID-19 pandemic, this year’s American Society of Clinical Oncology (ASCO) Meeting was again held virtually from 4-8 June 2021. The virtual presentations are available to view on the ASCO website. The International Kidney Cancer Coalition (IKCC) attended the virtual scientific programme to keep abreast of the latest advances in the care and treatment of people with kidney cancer.

Please note: The following summary was prepared by patient advocates for the benefit of patient organisations around the world who focus on kidney cancer. While this summary has been medically reviewed, the information contained herein is based upon public data shared at this meeting and is not intended to be exhaustive or act as medical advice. Patients should speak to their doctor about their own care and treatment.

Pembrolizumab as an adjuvant therapy

Adjuvant therapy is medication that is given in addition to surgery to try to prevent the cancer from coming back. Adjuvant therapy can be used to kill any remaining microscopic cancer cells, or it can control the growth of any remaining cancer.

Nephrectomy is the standard of care for renal cell carcinoma; however, in between 20-80% of patients the cancer comes back after nephrectomy (recurrence). Adjuvant therapy would help to prevent recurrence of the disease after nephrectomy in patients with locally advanced renal cell carcinoma. Vascular endothelial growth factor (VEGF) inhibitors and cytokines have been tested as adjuvant therapies for renal cell carcinoma, but the benefit for patients has been inconsistent.

The phase 3 KEYNOTE-564 trial looked at the use of pembrolizumab as an adjuvant therapy for patients with clear cell renal cell carcinoma after having a nephrectomy. Patients had good performance status and intermediate or high-risk disease, including those with lymph node spread of their cancer. Some patients had very limited metastatic disease (e.g., single small lung metastasis) which was removed with surgery, and they could be included in this trial as well. Patients were not able to enter the trial if they had been treated with radiotherapy for their cancer, or if the cancer had spread to their brain or bones. Patients were randomly allocated to two separate groups with similar features and given either pembrolizumab or placebo for about one year.

Pembrolizumab significantly reduced the relative risk of the cancer returning by about one third (32%). After one year of treatment, 85.7% of patients on pembrolizumab remained free from disease, while 76.2% remained disease-free on placebo. This 10% difference remained at 2 years, were 77.3% of pembrolizumab patients remained disease-free compared to 68.1% on placebo. The trial remains ongoing to collect more information on overall survival times; however, the data shows an early trend that pembrolizumab may reduce the risk of death. More follow up is required to make any definitive conclusions about overall survival.

Side effects were reported from most patients in the study (96.3% of patients on pembrolizumab and 91.1% on placebo). There were no new side effects reported with pembrolizumab compared with previous trials. The most common immune-related side effects on pembrolizumab affected the thyroid gland (hypo- or hyperthyroidism) and were manageable. Only 7% of patients needed to be treated with high dose corticosteroids to treat immune-related side effects.

Pembrolizumab is currently approved by several health authorities around the world for use in combination with axitinib as a first medication for patients with advanced renal cell carcinoma. In this adjuvant setting, pembrolizumab is not yet approved. More mature overall survival data will be important for reimbursement in many jurisdictions.

Combination therapies continue to dominate treatment regimens

Advanced renal cell carcinoma is best treated today with a combination of either two drugs that unleash the immune system (immune checkpoint inhibitors; nivolumab and ipilimumab) or an immune checkpoint inhibitor drug (pembrolizumab, avelumab or nivolumab) plus a tablet that blocks the blood supply to cancers (VEGF inhibitor; axitinib, lenvatinib, cabozantinib). Combination therapies continue to be of great interest, with the presentation of updated results from some ongoing studies and results from some new combinations.

CheckMate 9ER: nivolumab plus cabozantinib

Ongoing results from the phase 3 CheckMate-9ER clinical trial with nivolumab (immune checkpoint inhibitor) plus cabozantinib (VEGF inhibitor) were presented. Earlier data from the CheckMate 9ER study showed that the nivolumab/cabozantinib combination doubled the average time to when the treatment stopped working and the cancer started growing again (progression-free survival) compared to sunitinib and nearly twice as many patients responded to the combination.

In this poster session, a deeper understanding of how baseline disease characteristics may affect the clinical outcomes of patients and may help with clinical decision-making was presented. Patients were followed for nearly 2 years. Time to when the treatment stopped working and the cancer started growing again, overall survival time and a reduction in the size of the cancer were assessed. Patients were grouped according to baseline risk status (favourable, intermediate, or poor), organ site of metastases, number of organs with any tumours, or size of the original tumour.

Nivolumab plus cabozantinib showed survival benefits compared with sunitinib regardless of risk status, organ site of metastases, or the size or number of tumours at baseline. These results support this combination as a new first-line treatment option for patients with advanced renal cell carcinoma.

CLEAR: lenvatinib plus pembrolizumab

Results from the phase 3 CLEAR study have shown that lenvatinib (VEGF inhibitor) used together with pembrolizumab (immune checkpoint inhibitor) resulted in better survival and a reduction in the size of the cancer compared to sunitinib when used for patients with advanced renal cell carcinoma who had not been treated with medication before. In this oral presentation, the health-related quality of life of these patients was reported.

There were 1069 patients in this study, who were put into 3 groups: one group were treated with lenvatinib plus pembrolizumab, another group with lenvatinib plus everolimus, and the third group with sunitinib. Health-related quality of life was assess using three questionnaires, (FKSI-DRS, EORTC QLQ-C30, and EuroQoL EQ-5D-3L), at baseline, on day 1 of each cycle of treatment and when the patient came off treatment. Only quality of life information from patients who had been treated with at least one dose of study medication was analysed.

Patients treated with the lenvatinib plus pembrolizumab combination had better physical function and cancer symptoms, such as tiredness (fatigue), shortness of breath (dyspnoea), and constipation. Overall quality of life on the questionnaires was at least like sunitinib.

KEYNOTE-426: pembrolizumab plus axitinib

The KEYNOTE-426 study of the immune checkpoint inhibitor, pembrolizumab plus the VEGF inhibitor, axitinib for advanced renal cell carcinoma continues to show survival benefits compared with sunitinib as a first treatment after surgery. The combination significantly improved survival time, time to when the drug stopped working and the cancer started growing again (progression-free survival) and reduced the size of the cancer compared to sunitinib (59.3% patients versus 35.7%). The combination had manageable side effects as a first medication for metastatic renal cell carcinoma.

In this oral presentation, further follow-up data from KEYNOTE-426 over more than 42 months were presented to see how the pembrolizumab/axitinib combination helps patients survive.

Overall, 861 patients were randomly put into two groups to be given the pembrolizumab plus axitinib combination (432) or sunitinib (429). Patients were followed for an average of 42 months, during which time 418 patients had unfortunately died. Pembrolizumab/axitinib continues to improve average overall survival time (45.7 versus 40.1 months) and time to when the drug stopped working and the cancer started growing again (15.7 versus 11.1 months). Over the 42-month follow-up period overall survival rate was 57.5% with the combination compared to 48.5% with sunitinib, and progression-free survival rate was 25.1% compared to 10.6% with sunitinib. The cancer got smaller in 60.4% of patients on pembrolizumab/axitinib compared to 39.6% of patients on sunitinib. 10% of patients had a complete response with pembrolizumab/axitinib compared to 3.5% with sunitinib. Nearly half (47.2%) of the combination group received further anti-cancer medication, while nearly two thirds of the sunitinib group were given further treatment.

There were 105 patients with sarcomatoid renal cell carcinoma in the study. Pembrolizumab/axitinib improved the 12-month overall survival rate (83.4% versus 79.5%), time to when the drug stopped working and the cancer started growing again, and a reduction in the size of the cancer (58.8% versus 31.5%) compared to sunitinib in patients with sarcomatoid renal cell carcinoma. There were complete responses to treatment in 11.8% of patients with no complete responses in the sunitinib group.

In summary, this is the longest follow-up of an immune checkpoint inhibitor combined with a VEGF inhibitor for the first treatment after surgery for advanced renal cell carcinoma. Although patients in the favourable risk group still do not show a statistically significant improvement in survival, it is important to remember that this trial was not designed to look at that. Additionally, we do not yet see a ‘tail of the curve’ in this trial: in immunotherapy treatments, we look for long term durable treatment responses where patients remain progression free and alive for a prolonged period. Nevertheless, these results show that pembrolizumab/axitinib continues to show improved survival and with no new side effects.

First-in-class glutaminase inhibitor in combination with cabozantinib

Cell metabolism in renal cell carcinoma tumours is disrupted, and renal cell carcinoma tumour cells tend to have high levels of an enzyme called glutaminase, a key enzyme in the metabolism of glutamine, which is important for tumour growth and survival. Glutamine is an amino acid that is found in most proteins. Renal cell carcinoma cells have increased dependence on glutamine for cell growth. Telaglenastat is a glutaminase inhibitor that blocks the use of glutamine by renal cell carcinoma cells as a vital source of energy for cell growth. In a phase 1 study, telaglenastat showed encouraging safety and effectiveness when used in combination with cabozantinib as a second- or third-line treatment for metastatic renal cell carcinoma.

In this oral presentation the phase 2 CANTATA study compared telaglenastat plus cabozantinib with placebo plus cabozantinib in previously treated patients with clear-cell metastatic renal cell carcinoma. There were 444 patients randomly put into two groups to be treated with telaglenastat/cabozantinib or placebo/cabozantinib. Patients were followed for an average of around 1 year. There was no benefit of telaglenastat/cabozantinib in terms of time to when the drug stopped working and the cancer started growing again (9.2 versus 9.3 months), or a reduction in the size of the cancer (31% versus 28%) compared to placebo/cabozantinib. Rates of side effects were similar between the two treatment groups and included high blood pressure and diarrhoea.

In summary, the addition of telaglenastat did not improve the efficacy of cabozantinib as a second or third-line treatment for metastatic renal cell carcinoma. However, the combination of telaglenastat plus cabozantinib was well tolerated with side effects expected from each treatment.

Addressing an unmet need for non-clear cell kidney cancer

HCRN GU16-260: nivolumab monotherapy with nivolumab/ipilimumab salvage therapy

The HCRN GU16-260 study reported on the effectiveness and side effects of nivolumab for untreated patients with the most common form of renal cell carcinoma called clear cell renal cell carcinoma. For the people who didn’t respond to nivolumab alone, they were given up to four doses of ipilimumab in addition to nivolumab treatment. However, there is limited information on this treatment schedule in people with non-clear cell renal cell carcinoma. This poster presentation reports on the effectiveness of this treatment regimen in patients with non-clear cell renal cell carcinoma.

Untreated patients with advanced non-clear cell renal cell carcinoma were given nivolumab after surgery until their cancer started growing again, they could not tolerate the side effects, or they completed 96 weeks of treatment. People whose cancer started growing again or those who had stable disease at 48 weeks were given 4 doses of ipilimumab in addition to the nivolumab treatment (this is called salvage therapy).

Thirty-five people with non-clear cell renal cell carcinoma entered the study, and of these 54% had papillary renal cell carcinoma, 17% had chromophobe renal cell carcinoma and the subtype of renal cell carcinoma was unclassified in 29% of people. 26% of patients also had sarcomatoid features.

Nivolumab alone has limited effectiveness in untreated non-clear cell renal cell carcinoma patients with 14.3% responding to treatment. Most responses (4 of 5) were seen in patients with sarcomatoid and/or unclassified tumours. Time to when the drug stopped working and the cancer started growing again was 4 months, and the side effects were like previous nivolumab studies. More than half of the patients (57%) went on to have treatment with nivolumab plus ipilimumab with only one response to treatment. Thus, nivolumab should not be routinely used alone in the first-line metastatic setting and it should continue to be used with ipilimumab upfront. Better treatments for these patients need to be investigated.

Cabozantinib plus nivolumab combination therapy

The cabozantinib/nivolumab combination has been shown to be effective at improving survival in patients with metastatic clear cell renal cell carcinoma in a phase 3 trial. This poster presentation reports the results of a phase 2 trial of cabozantinib/nivolumab in patients with non-clear cell renal cell carcinoma.

A total of 47 patients with advanced non-clear cell renal cell carcinoma and who had received 0 or 1 prior medications (excluding prior immune checkpoint inhibitors) were included in the study in two groups. Group 1 were patients with papillary, unclassified, or translocation associated renal cell carcinoma, and group 2 were patients with chromophobe renal cell carcinoma. All patients were treated with the cabozantinib plus nivolumab combination and followed for just over a year. Most patients (65%) were previously untreated after surgery, and the remaining patients had one prior treatment with either a VEGF inhibitor or mTOR inhibitor. The cancer got smaller in 48% of patients in group 1. Time to when the treatment stopped working and the cancer started growing again was 12.5 months and the average overall survival time was 28 months. There were no responses to treatment in the patients with chromophobe renal cell carcinoma (group 2). Side effects were consistent with those reported in the phase 3 trial. These results compare favourably to previous work in these rare kidney cancers and merit further evaluation in a randomised fashion to confirm this approach as the optimum first line therapy.

The cabozantinib/nivolumab combination treatment had an acceptable safety profile and showed promising survival benefits in metastatic non-clear cell renal cell carcinoma patients with papillary, unclassified, or translocation renal cell carcinoma, but activity in patients with chromophobe renal cell carcinoma was limited.

Savolitinib plus durvalumab combination therapy

A protein called MET (also called hepatocyte growth factor receptor) has been found to stimulate the growth and development of tumours, especially papillary renal cell carcinoma. Savolitinib is a MET inhibitor, which has been shown to have some effectiveness against patients with papillary renal cell carcinoma and alterations in the MET gene (called MET-driven papillary renal cell carcinoma). Durvalumab is an immune checkpoint inhibitor called a PD-L1 inhibitor that has been tested in combination with savolitinib in metastatic papillary renal cell carcinoma with response rates (cancer shrinkage on scans) of 29%. This poster presentation reports on the effectiveness of savolitinib in combination with durvalumab in patients with MET-driven metastatic papillary renal cell carcinoma.

A total of 41 papillary renal cell carcinoma patients were treated with a combination of savolitinib plus durvalumab after surgery and followed for a little over 2 years. Twenty-nine percent of patients responded to treatment and the average time to when the treatment stopped working and the cancer started growing again was 4.9 months. Of the 41 patients in the study, 34% had MET-driven papillary renal cell carcinoma and 71% were previously untreated. Average time to when treatment stopped working and overall survival time in these patients were 10.5 months and 27.4 months, respectively. 57% percent of MET-driven papillary renal cell carcinoma patients responded to treatment. No new side effects were reported.

This study showed that the combination of savolitinib and durvalumab is effective in patients with MET-driven papillary renal cell carcinoma. A randomised phase III study to confirm these findings is planned.

The gut microbiome boosts immune checkpoint inhibitor activity

Recent evidence suggests that the bacteria in the gut (the gut microbiome) interacts with immune checkpoint inhibitors in metastatic renal cell carcinoma. Both specific bacterial species and the diversity of the microorganisms in the gut drive the interaction. In this poster presentation the bacterium Clostridium butyricum, which produces butyrate, was investigated to see if it could modulate the gut microbiome in patients with metastatic renal cell carcinoma being treated with the nivolumab/ipilimumab combination and improve clinical outcomes. This bacterium is the key constituent of CBM-588.

Thirty patients with clear cell and/or sarcomatoid metastatic renal cell carcinoma were randomised 2:1 to be treated with nivolumab/ipilimumab plus CBM-588 or nivolumab/ipilimumab. Patient had intermediate or poor risk disease and were previously untreated with medication. Stool samples were collected to analyse the bacterial content at baseline and 12 weeks. The researchers looked at the effect of the CBM-588 treatment on the Bifidobacterium species of bacteria in the gut as the primary end point of the study, in addition to patient survival and response to treatment.

There was an 8-fold increase in Bifidobacterium bifidum and a 6-fold increase in Bifidobacterium adolescentis from baseline to week 12 in the patients who were treated with nivolumab/ipilimumab plus CBM-588. Clostridium butyricum was detected only in patients receiving CBM-588. There were more microorganisms that cause disease (pathogens) detected in the stools of patients not receiving CBM-588. Response to treatment was significantly higher in patients receiving nivolumab/ipilimumab plus CBM-588 compared to nivolumab/ipilimumab alone, the control group (59% versus 11%). Time to when treatment stopped working and the cancer started growing again was also improved with the addition of CBM-588. There were no serious or life-threatening side effects in both treatment groups. The particularly poor performance of the control group is unexplained.

This is the first randomised, prospective study to that shows enhancement of immune checkpoint inhibitor response with a live bacterial product. This was a very small study so future trials are warranted.

Treatment for renal cell carcinoma brain metastases

Brain metastases resulting from the spread of renal cell carcinoma are especially difficult to treat because drugs are stopped from getting to the brain by a membrane called the blood-brain barrier. Most patients with brain metastases have, therefore, been excluded from phase 3 clinical trials. In the phase 3/4 CheckMate 920 study, the combination of nivolumab/ipilimumab was assessed in patients with advanced renal cell carcinoma for the treatment of brain metastases.

This study looked at 28 previously untreated patients with brain metastases from renal cell carcinoma that were not causing symptoms (asymptomatic). These patients had not received medication for their cancer but could have had local treatment (radiation or surgery). Of these patients, 14.3% had sarcomatoid renal cell carcinoma. Patients were treated with the nivolumab/ipilimumab combination for up to 2 years. In 31% of patients the brain metastases reduced in size, there were no complete responses, 8 partial responses and 10 patients had stable disease. The average time to response was 2.8 months and the average duration of response was two years. A quarter of patients had progression of their brain metastases. The average time to when the treatment stopped working and the cancer started growing again was 9 months. The trial remains ongoing to collect more information on overall survival times.

There were a few serious or life-threatening side effects to treatment, such as diarrhoea/colitis (7.1%), inflammation of the pituitary gland (3.6%), rash (3.6%), hepatitis (3.6%), and diabetes (3.6%).

This study showed that patients with previously untreated metastatic renal cell carcinoma and brain metastases could have responses to nivolumab/ipilimumab. Practically, immunotherapy appears to be active in brain metastases but localised therapy, such as stereotactic radiation or surgery to the brain metastases, remain important treatments.

Small renal masses in Latin-American population: characteristics and prognostic factors for survival, recurrence and metastasis – a multi-institutional study from LARCG database

Abstract

Background

To evaluate demographic, clinical and pathological characteristics of small renal masses (SRM) (≤ 4 cm) in a Latin-American population provided by LARCG (Latin-American Renal Cancer Group) and analyze predictors of survival, recurrence and metastasis.

Methods

A multi-institutional retrospective cohort study of 1523 patients submitted to surgical treatment for nonmetastatic SRM from 1979 to 2016. Comparisons between radical (RN) or partial nephrectomy (PN) and young or elderly patients were performed. Kaplan-Meier curves and log-rank tests estimated 10-year overall survival. Predictors of local recurrence or metastasis were analyzed by a multivariable logistic regression model.

Results

PN and RN were performed in 897 (66%) and 461 (34%) patients. A proportional increase of PN cases from 48.5% (1979–2009) to 75% (after 2009) was evidenced. Stratifying by age, elderly patients (≥ 65 years) had better 10-year OS rates when submitted to PN (83.5%), than RN (54.5%), p = 0.044. This disparity was not evidenced in younger patients. On multivariable model, bilaterality, extracapsular extension and ASA (American Society of Anesthesiologists) classification ≥3 were predictors of local recurrence. We did not identify significant predictors for distant metastasis in our series.

Conclusions

PN is performed in Latin-America in a similar proportion to developed areas and it has been increasing in the last years. Even in elderly individuals, if good functional status, sufficiently fit to surgery, and favorable tumor characteristics, they should be encouraged to perform PN. Intending to an earlier diagnosis of recurrence or distant metastasis, SRM cases with unfavorable characteristics should have a more rigorous follow-up routine.

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Consideration in the management of renal cell carcinoma during the Covid-19 pandemic

Stênio de Cássio Zequi, Diego Abreu

Abstract

Introduction

Recently the COVID-19 pandemic became the main global priority; main efforts and health infrastructures have been prioritized in favor of COVID-19 battle and the treatment of benign diseases has been postponed. Renal cell cancer (RCC) patients configure a heterogenous populations: some of them present indolent cases which can safely have postponed their treatments, others present aggressive tumors, deserving immediate care. These scenarios must be properly identified before a tailored therapeutic choice.

Objectives

We propose a risk- based approach for patients with RCC, to be used during this unprecedented viral infection time.

Materials and Methods

After a literature review focused in COVID-19 and current RCC treatments, we suggest therapeutic strategies of RCC in two sections: surgical approach and systemic therapy, in all stages of this malignance.

Results

Patients with cT1a tumors (and complex cysts, Bosniak III/IV), must be put under active surveillance and delayed intervention. cT1b-T2a/b cases must be managed by partial or radical nephrectomy, some selected T1b-T2a (≤7cm) cases can have the surgery postponed by 60-90 days). Locally advanced tumors (≥cT3 and or N+) must be promptly resected. As possible, minimally invasive surgery and early hospital discharge are encouraged. Upfront cytoreduction, is not recommendable for low risk oligometastatic patients, which must start systemic treatment or even could be put under surveillance and delayed therapy. Intermediate and poor risk metastatic patients must start target therapy and/or immunotherapy (few good responder intermediate cases can have postponed cytoreduction). The recommendation about hereditary RCC syndromes are lacking, thus we recommend its usual care. Local or loco regional recurrence must have individualized approaches. For all cases, we suggest the application of a specific informed consent and a shared therapeutic choice.

Conclusions

In the pandemic COVID -19 times, a tailored risk-based approach must be used for a safe management of RCC, aiming to not compromise the oncological outcomes of the patients.

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New LARCG Paper: “Characteristics and Surgical Outcomes in Very Elderly Patients (≥75 years) with Renal Cell Carcinoma: Data from the Latin American Renal Cancer Group”

ABSTRACT

Background: The incidence of renal cell carcinoma (RCC) is increasing globally due to an aging population and widespread use of imaging studies. Objective: The aim of this study was to describe the characteristics and perioperative outcomes of RCC surgery in very elderly patients (VEP), ≥ 75 years of age. Methods: This is a retrospective comparative study of 3656 patients who underwent the treatment for RCC from 1990 to 2015 in 28 centers from eight Latin American countries. We compared baseline characteristics as well as clinical and perioperative outcomes according to age groups (<75 vs. ≥75 years). Surgical complications were classified with the Clavien-Dindo score. We performed logistic regression analysis to identify factors associated with perioperative complications. Results: There were 410 VEP patients (11.2%). On bivariate analysis, VEP had a lower body mass index (p < 0.01) and higher ASA score (ASA >2 in 26.3% vs. 12.4%, p < 0.01). There was no difference in performance status and clinical stage between the study groups. There were no differences in surgical margins, estimated blood loss (EBL), complication, and mortality rates (1.3% vs. 0.4%, p = 0.17). On multivariate regression analysis, age ≥75 years (odds ratio [OR] 2.33, p < 0.01), EBL ≥ 500 cc (OR 3.34, p < 0.01), and > pT2 stage (OR 1.63, p = 0.04) were independently associated with perioperative complications. Conclusions: Surgical resection of RCC was safe and successful in VEP. Age ≥75 years was independently associated with 30-day perioperative complications. However, the vast majority were low-grade complications. Age alone should not guide decision-making in these patients, and treatment must be tailored according to performance status and severity of comorbidities.

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Kidney Cancer Take-Home Messages from ASCO GU 2020

New kid on the block: sitravatinib

Dr Pavlos Msaouel from the University of Texas MD Anderson Cancer Center, USA talked about the results from one of the first clinical trials of a combination of a new drug, sitravatinib, with nivolumab in people with advanced kidney cancer that had already been treated.

Sitravatinib is a type of drug called a tyrosine kinase inhibitor (TKI), which works by limiting the growth of blood vessels to the tumour. Sitravatinib may also work by making the tissue around the tumour less attractive to cancer cells. Nivolumab is an immune checkpoint inhibitor that has been shown to work in kidney cancer. Nivolumab releases the ‘brakes’ on the immune system allowing the immune cells to kill the cancer cells more effectively. Since a combination of these two drugs seems to work well in a few other cancers, like bladder cancer, the researchers thought it might work in kidney cancer as well.

“The way sitravatinib works led us to explore whether the inhibition of these pathways by sitravatinib can induce, enhance or restore responses to immunotherapy in patients with locally advanced or metastatic kidney cancer who had previously progressed on immunotherapy,” Dr Msaouel said. “We used nivolumab as the immunotherapy backbone and tested whether ist combination with sitravatinib would produce good responses in immunotherapy-resistant renal cell carcinoma.”

The main purpose of this study was to see if patients could manage to take the two drugs together. There were 40 kidney cancer patients in this study. The side effects of the combination of sitravatinib and nivolumab appeared manageable. The most common side effect was diarrhoea, but it was not very bad. Four patients stopped treatment because of problems with side effects (only 10% of all patients). Researchers also wanted to find the best dose of sitravatinib for kidney cancer patients, and they found that a pill of 120 mg once a day gave the best results when combined with nivolumab. The researchers are planning a larger follow-up study with this dose of sitravatinib and nivolumab.

Although the results are still very early, the combination of these two drugs showed encouraging benefits for patients with advanced kidney cancer who had already been treated with a TKI (like sunitinib and pazopanib), without too many severe side effects.

Should the original kidney tumour be removed from people with advanced kidney cancer who are taking immunotherapy?

Surgery to remove the kidney tumour is often the preferred treatment for people with kidney cancer that has not spread. Recently, doctors have been questioning whether it is beneficial to operate to remove the kidney tumour in patients with kidney cancer that has already spread beyond the kidney. In most other cancers that have spread, performing this kind of surgery is not recommended. It carries all the risks and downsides of invasive surgery, but generally does not improve survival. Instead, cancer medicines (e.g. tablets, chemotherapy or immunotherapy) have proven more beneficial.

Historically, kidney cancer has been considered an exception. Clinical trials of cytokines, such as interleukin-2 and interferon- alpha, in the late 1990s showed that people with advanced kidney cancer treated with cytokines lived longer if they had surgery to remove the kidney tumour, compared to those who did not.

In the 2000’s, cytokines were largely replaced by targeted therapy for the treatment of advanced kidney cancer. Clinical trials of surgery before and during treatment with targeted therapy clearly showed no benefit of removing the kidney tumour.

A new family of immunotherapies for advanced kidney cancer include drugs such as nivolumab, ipilimumab, avelumab and pembrolizumab. These drugs work by releasing the ‘brakes’ on the immune system allowing the immune system to kill the cancer cells. These immune checkpoint inhibitor drugs are sometimes given in combination with targeted therapies that block the blood supply to the tumour. Many researchers and oncologists have questioned whether the old studies of kidney surgery for people with advanced cancer apply to today’s patients who have access to These new, and sometimes more effective medicines.

At the ASCO GU Cancers Symposium 2020, researchers from a large international research team known as the IMDC used data from people across the world to see whether surgery to remove the kidney tumour improved the lives of people taking immune checkpoint inhibitors.

They found that surgery was associated with improved survival in patients who took immune checkpoint inhibitors. However, the team stressed that these results do not apply to all patients with advanced kidney cancer. People taking immune treatment and surgery together are likely to be younger and have less medical problems. Because this was not a controlled study, these findings should be interpreted as preliminary only. Patients should decide very carefully if they are offered surgery, and in general, cancer medicines should be prioritised.

Radiation is safe, but does not improve immunotherapy in kidney cancer

New medicines for patients with advanced kidney cancer have improved rapidly in recent years, but many people need better outcomes, so research and clinical trials are more important than ever. Immunotherapy is one of these treatments.

Radiation has been used to treat cancer for over a century. Computers now enable radiotherapy to be focused so precisely, that it delivers a very high dose of radiation to a tumour, killing cancer cells but causing less damage to surrounding healthy tissues. Research in the laboratory has suggested that radiation might help immunotherapy by killing Cancer cells and making them more visible to the immune system.

Two clinical trials were presented at the ASCO GU meeting. First was the Phase II NIVES trial. In this trial, advanced kidney cancer patients who had been treated with targeted therapy were treated with the immunotherapy drug nivolumab and focused radiation. Radiation appeared safe with the immunotherapy, but people in the trial did not seem to benefit more than past studies of immunotherapy alone.

The second trial was the RADVAX RCC trial, which combined two immunotherapy drugs (nivolumab and ipilimumab) with focused radiation in patients with advanced kidney cancer. The benefit of adding focused radiation to the two immunotherapy drugs seemed at least equal to past studies of taking the two immunotherapy drugs alone and appeared safe.

Both these clinical trials enrolled small numbers of patients. In both trials, radiation was given to only 1-2 spots of cancer. These trials do not support immediate use of radiation with immunotherapy in people with kidney cancer, but they show that if radiation is needed, it is safe when taking immunotherapy. One situation where this might be useful is if one tumour starts to grow, while other spots of the cancer are shrinking due to immunotherapy treatment; “hunting down tumours that escape” seems like an attractive and sensible idea. Future trials will tell us if there are better ways of improving the benefit of immunotherapy in combination with radiation.

Moving up the chain to HIF-2α to block blood vessels in kidney cancer

Advanced kidney cancer is best treated today with the combination of either two drugs that unleash the immune system (immunotherapy; nivolumab and ipilimumab) or an immunotherapy drug (pembrolizumab or avelumab) plus a tablet that blocks blood supply to cancers (TKI; axitinib). These combinations of treatments help some people, but unfortunately the majority of people do not experience complete disappearance of their cancer. These people need further treatment, and most of the current options are of limited effectiveness.

Many kidney cancers (the clear cell type) grow many extra blood vessels. This is often because the machinery that controls blood vessel growth is broken. For the last decade or more we’ve had tablets that work at the end of this chain; tablets that end in -nib like sunitinib and pazopanib.

A new clinical trial was reported at ASCO GU using a new tablet that works further up the chain, closer to the breakdown. This link in the chain is called hypoxia-inducible factor, HIF-2α. A new tablet called MK-6482 blocks the action of HIF-2α. MK-6482 was tested in 55 patients who had taken several previous treatments for kidney cancer; most had taken at least three prior drugs.

In about one-quarter of people, their tumour significantly shrank in size, and in 80% of patients their cancer was controlled and didn’t grow while on treatment. People taking MK-6482 seemed to manage to tolerate the drug; only two people had to stop the treatment because of side effects. This result is promising enough that MK-6482 is being studied in a randomised trial compared against another drug used for kidney cancer; everolimus. If this bigger study is positive, MK-6482 could be a new treatment option for advanced kidney cancer patients who have tried other drug treatments but not been successful. As it seems to be well tolerated, it might also be able to be combined with other treatments like immunotherapy in the future.

POSTERS

Poster 767: Researchers are testing whether adding cabozantinib, a TKI for advanced kidney cancer patients, makes the nivolumab plus ipilimumab combination treatment work better in an ongoing clinical trial called COSMIC-313.

The COSMIC-313 trial was presented in a poster by Professor Toni Choueiri from the Dana-Farber Cancer Institute in Boston, USA. This study is looking for 676 people with advanced kidney cancer who are in poor health or whose cancer is growing fast (those at either intermediate or poor risk on the IMDC scale). The trial is looking for people who have not been treated with anything else before. Patients will be treated with nivolumab and ipilimumab together and then randomly allocated to take either a placebo tablet or cabozantinib. Neither the patient nor the doctor will know if they are receiving placebo or cabozantinib.

For each patient, the researchers will be assessing the time from starting treatment in the trial to when the cancer gets worse (progression-free survival) to determine the success of the trial. Researchers will also record all the side effects in this study to see which treatment is tolerated the best (nivolumab, ipilimumab, cabozantinib or nivolumab, ipilimumab, placebo). The trial is looking for patients now in North America, Europe, the Asia-Pacific region, and Latin America (https://clinicaltrials.gov/ct2/show/NCT03937219).

A scan shows a mass on your kidney – is it cancer? Or something less aggressive? Poster 623 looked at the use of a biopsy; removal of a small piece of the kidney mass with a needle to look at the cells under a microscope to see if they are cancer. The question being asked was whether taking a biopsy reduced over treatment in people found to have a benign, less aggressive mass called an oncocytoma. The researchers followed 170 people with proven oncocytoma. Seventy percent (70%) had been diagnosed using a biopsy and after biopsy almost all people (93.4%) chose to take active surveillance; no surgery, just watch the lump with scans and doctor’s appointments. On average, these oncocytoma grew only 1mm per year, though a quarter of people had growth at a rate >5mm per year. Less than 10% of people chose to have an operation after starting surveillance, and no-one had spread of their cancer. Biopsy reduces the use of unnecessary surgery and its side-effects for benign renal masses, such as oncocytoma. The information from this study gave us further information about oncocytoma and supports the use of active surveillance as a safe Management option, which can reduce the harm caused by over treatment.

Poster 637 reported on a group of patients facing one of the toughest situations; their kidney cancer had spread into the brain. This was a real-world report of 17 patients with advanced kidney cancer in the brain. The patients were treated with ipilimumab and nivolumab combination immunotherapy. For a lot of people, the treatment wasn’t successful. However, some people benefited from combination immunotherapy treatment. Forty-two percent (42%) of people had shrinkage of their tumour (though no-one saw cancers disappear completely) and another 29% had stable disease where their cancer stopped growing. Only about 20% of people did not respond to treatment and their cancer continued to grow. The amount of treatment, and the amount of side-effects was similar to that seen in other clincial trials with the combination immunotherapy treatment. Of note, 50% (3/6) patients treated with this combination after failing to respond to another treatment had tumour shrinkage.

In relation to this, Poster 687 looked at another trial of two drugs called avelumab and axitinib (JAVELIN Renal 101 trial; an immunotherapy and TKI). Some people on this trial had kidney cancer that had spread to the brain, and the combination of drugs might have helped People more than taking a TKI tablet (sunitinib) alone. People with kidney cancer that has spread to the brain still face a very tough path, but these very small reports give some hope that new Treatments might even help in this very difficult situation.

Poster 642 presented data from the International Metastatic RCC Database Consortium (IMDC) looking at the question of what happens to people if their kidney cancer spreads to specific parts of the body. If a cancer spreads to brain, liver or bones, that is generally a worrying situation in most cancers. Spread of the cancer (metastases) to organs that make hormones (endocrine organs like the pancreas, thyroid, adrenal) are infrequent but this study showed that people with this pattern of spread had the longest median overall survival. The study confirmed what is seen in most cancers; bone, liver and brain metastases were associated with a shorter survival. Understanding these patterns is useful for patient counselling about treatment options and for designing new clinical trials.

Poster 655 used a different database called REMARCC (Registry of MetAstatic RCC) that follows people with advanced kidney cancer. Four hundred and forty seven (447) patients with or without bone metastases were included in the analysis. The authors concluded that presence of bone metastases does not independently predict survival or outcomes in advanced kidney cancer. This is at odds with the IMDC poster above; this is an important area of ongoing study.

Poster 686 reported on a very rare group of people with metastatic fumarate hydratase (FH) deficient renal cell carcinoma (RCC), a rare metabolic variant of RCC. The authors reported on the experiences of 32 patients with FH-RCC showing a distinct pattern of disease course with immediate spread around the kidney into the space between organs inside the abdomen (the peritoneal space). People with FH-RCC had a high chance of response to targeted therapy combinations (e.g. VEGFR/mTOR Inhibitor combinations; lenvantinib + everolimus), but there were limited responses to immune checkpoint inhibitiors, at least when given as a single drug like nivolumab or pembrolizumab.

Finally, Poster 707 reported on a question we would have thought incredible only a few years ago; if you have kidney cancer that has spread from the outset, you take combination immunotherapy and all the cancer spots on your scans completely disappear, and all that remains is the original spot in the kidney… should you then have an operation to remove the primary kidney cancer? Is it worth the risk of an operation to be able to say that the scans are all clear?

This poster reported the challenges of nephrectomy after complete response to immune checkpoint inhibitors for metastatic renal cell carcinoma. Eleven patients who had not had surgery at diagnosis were included in the study. The operations were perhaps more difficult, and one patient died of post-operative complications, but live cancer was still found in most patients. The authors concluded that surgery to remove the primary kidney cancer following combination immunotherapy could allow people to have a “complete response” in selected patients. Due to technical complexity and complication rates, this surgery should be performed in centers with extensive experience. Although only a small number of patients were investigated, this study looked at a new treatment pattern, and more data on surgical safety are needed.

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