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ESMO East 2023: Updates in Kidney and Bladder Cancer with Dr Pedro Barata

Presentation by Dr Pedro Barata, MD MSc, University Hospitals Seidman Cancer Center



At the 2023 ESMO East review conference presented by Total Health in Fort Lauderdale, Florida, Dr Pedro Barata from University Hospitals Seidman Cancer Center presented updates in renal cell (kidney) cancer and urothelial (bladder) cancer, as reported at this year’s European Society for Medical Oncology (ESMO) Congress held in Madrid, Spain.  The abstracts selected focused on the use of novel targeted therapies in these cancers, as well as the use of immunotherapy, which helps the body’s immune system to more efficiently recognize and kill cancer cells.

 

Renal Cell Carcinoma (RCC)

 

LITESPARK-005

 

For RCC, Dr Barata reviewed results from the LITESPARK-005 Trial, a randomized open-Label phase III study of belzutifan versus everolimus treatment in patients with previously treated (refractory) advanced clear cell RCC (ccRCC).  Belzutifan is an agent which targets the hypoxia-inducible factor (HIF) pathway, which plays a major role in ccRCC, and in earlier studies this agent was shown to have clinical activity in previously treated ccRCC.  In the study, patients with inoperable, advanced/refractory ccRCC were randomized to either belzutifan or everolimus, the current standard of care.  Dr Barata noted the heavily pretreated patient population, with nearly half having received 3 prior lines of therapy.  For the primary endpoint of progression-free survival (PFS), there was a relative reduction of 25% with belzutifan versus everolimus (hazard ratio [HR]=0.75; P<0.001), with the difference in PFS becoming most evident after about 9 months. For the key secondary endpoint of overall response rate (ORR), the difference was 21.9% versus 3.5% for belzutifan versus everolimus (P<0.00001).  Dr Barata also noted the results for time to response (TTR) and duration of response (DoR), and he suggested that unlike some other anti-cancer agents, responses with belzutifan tended to occur slowly, over time.  In addition, he noted some of the patient reported outcomes in the trial, which also favored belzutifan over everolimus, with less clinical deterioration for these late stage ccRCC patients.  Summarizing, Dr Barata noted that the results from the study establish HIF inhibition as a new therapeutic pathway to target in advanced ccRCC, with a statistically significant improvement in both PFS and ORR with belzutifan over everolimus, and the agent was well tolerated.

 

LITESPARK-003

 

In light of the findings from LITESPARK-005, Dr Barata noted results from LITESPARK-003, also presented at ESMO 2023, examining the combination of belzutifan with tyrosine kinase inhibitor (TKI) agent, cabozantinib, in advanced/refractory ccRCC patients who had either not received a prior treatment (treatment naïve), or who had received prior therapy with immunotherapy or another targeted treatment, with the primary endpoint of ORR.  Results from the trial for Cohort 1 (treatment naïve group) and Cohort 2 (pretreated group) are summarized in BOX 1.  As expected, ORR for the treatment naïve patients was better than for the pretreated cohort, and the TTR was also shorter (BOX 1).  Dr Barata also noted the results for DoR of 28 to 31 months in either cohort, as “quite remarkable”, with PFS results of well over 1 year, even for pretreated patients.

 

Box 1.  Efficacy Results for LITESPARK-003 (Belzutifan + Cabozantinib Combination) in ccRCC

Cohort 1 (treatment naïve) ccRCC

Cohort 2 (pretreated) ccRCC

ORR: 70%

ORR: 31%

TTR: 1.9 months

TTR: 3.2 months

DoR: 28.6 months

DoR: 31.5 months

PFS: 30.3 months

PFS: 13.8 months

Urothelial Carcinoma (Bladder Cancer)

 

Reviewing the results for urothelial carcinoma (UC) from ESMO 2023, Dr Barata briefly reviewed the previously reported results for enfortumab vedotin (EV), and antibody-drug conjugate (ADC), used in combination with pembrolizumab (Pembro), an immunotherapy, for patients with UC who are unable to tolerate cisplatin-based chemotherapy.  Results from the EV-103 study had shown and ORR of 64.5%, with complete responses (CR) observed in 10.5% of patients, and less than 8% of patients with progressive disease with this combination, a finding which led to accelerated approval of the EV+Pembro regimen.

 

EV-302/KEYNOTE A39

 

With this background, Dr Barata highlighted results from the EV-302/KEYNOTE-A39 trial presented at ESMO 2023; this was an open-Label, randomized, phase III study which examined the efficacy of EV + Pembro as compared with chemotherapy (Chemo) for patients with previously untreated locally advanced or metastatic UC (irrespective of their ability to tolerate cisplatin based chemotherapy).  The results for the primary end point of PFS showed a significant benefit of the combination regimen over chemotherapy, with a median PFS of 12.5 versus 6.3 months in the respective groups, corresponding to a relative reduction of 55% in the risk for progression or death with the combination (HR=0.45; P<0.00001).  Dr Barata noted this was the first clinical trial to show that any therapy was superior to platinum-based chemotherapy in a first line setting.  He further noted the overall survival (OS) results from the trial which also showed a significant benefit of the EV + Pembro combination therapy over Chemo, with a 53% improvement with the combination (median OS = 31.5 vs. 16.1 months; HR=0.47; P<0.00001).  Importantly, the benefit in OS was observed regardless of whether the patients were, or were not eligible for cisplatin-based chemotherapy, and there was a benefit of the combination seen across all subgroups of patients.  The results for ORR (BOX 2) also strongly favored the combination regimen, and there were no new safety concerns.  The principle adverse events were mostly low grade, and included skin reactions, peripheral neuropathy, sensory and motor events, and ocular disorders.  Dr Barata noted that results from the trial suggest that EV + Pembro is a potential new standard of care for first line treatment of locally advanced/metastatic UC.

 

Box 2.  ORR Results from EV-302/KEYNOTE-A39

 

EV + Pembro

Chemo

ORR

67.7%

44.4%*

Complete Response

29.1%

12.5%

Partial Response

38.7%

32.0%

Stable Disease

18.8%

33.8%

*(P<0.00001)

 


CheckMate 901

 

Dr Barata noted that there has been an ongoing effort to incorporate the use of immunotherapy earlier in advanced UC by combining immune checkpoint inhibitors (ICI) with chemotherapy, but thus far results had been underwhelming.  In this regard, he noted results from the CheckMate 901 trial, also presented at the ESMO 2023 Presidential Session.  This was a phase III trial comparing the use of the ICI nivolumab (Nivo), in combination with gemcitabine/cisplatin (G/C), versus G/C alone as first line treatment for advanced UC, and Dr Barata noted that the trial only enrolled those patients who were cisplatin eligible.  Results for the primary endpoint of OS showed a significant benefit of Nivo+G/C over G/C alone, with a median OS of 21.7 vs. 18.9 months in the respective group, corresponding to a 22% relative reduction in risk for death (HR=0.78; P=0.0171).  Results for ORR also showed a benefit of the combination and TTR was short with both regimens (BOX 3).  Dr Barata reviewed the adverse event profile, which was consistent with that previously seen for ICI and chemotherapy combinations, with grade 3 or higher events occurring in 62% and 52% of patients in the respective groups, and leading to discontinuation in 11% and 8%.  Lastly, he noted that these potentially practice changing results for advanced UC from CheckMate 901 were also recently published in the New England Journal of Medicine.

Box 3.  Secondary Endpoints from CheckMate 901

 

Nivo+G/G

G/C

ORR

57.6%

43.1%

Complete Response

21.7%

11.8%

Partial Response

35.9%

31.3%

Stable Disease

25.3%

28.3%

Median TTR

2.1 months

2.1 months

Median DoR

9.5 months

7.3 months

 

Speaker Disclosure Information: Dr Barata listed the following disclosures for this presentation:

Consultant: Astellas; AstraZeneca; Eisai; Exelixis; Janssen, EMD Serono; Dendreon; Pfizer, Seattle Genetics, BMS, Bayer, Guardant Health; Caris Life Sciences; Contracted Research: AstraZeneca, Merck, Caris Life Sciences, ESSA Pharma; Research Grant: BlueEarth Diagnostics, Merck, Exelixis, Merus; Speaker’s Bureau (Unbranded): Bayer, Caris Life Sciences, Pfizer, AstraZeneca

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