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.
Dr Daniel Y C Heng (CA)
Dr Vishal Navani (UK)
Dr Rachel Giles (NL)
Dr Michael Jewett (CA)
Dr Eric Jonasch (USA)
Dr Sharon Deveson Kell (UK)