Prof. Dr. med. Christoph von Klot

 

Renal cell carcinoma

 

CheckMate 9ER

Following a primary analysis of this phase III trial in untreated, advanced renal cell carcinoma and a median follow-up of 18.1 months, the data after a follow-up of 55.6 months were now presented at this year's ASCO GU. In the study, 323 patients received nivolumab 240 mg every 2 weeks in combination with cabozantinib 40 mg once daily, while 328 patients received Sutent 50 mg once daily (4 weeks of a 6-week cycle). The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR) and safety. The median PFS in the respective arms was 16.4 vs. 8.4 months (hazard ratio 0.58, 95% confidence interval [95% CI] 0.49-0.70), and the median OS was 46.5 vs. 36.0 months (HR 0.77, 95% CI 0.63-0.95). The ORR was 55.7% (95% CI 50.1-61.2) vs. 27.7% (95% CI 23.0-32.9). Overall, 13.6 % vs. 4.6 % of patients achieved a complete remission. The median duration of response (DOR) was 22.0 (95% CI 18.0-25.2) vs. 15.2 (95% CI 10.9-19.3) months. With a median follow-up of 55.6 months, the combination of nivolumab and cabozantinib continues to show long-term efficacy advantages over Sutent. No new safety concerns were identified.

 

KEYNOTE-564

The KEYNOTE-564 Phase III trial has already shown an improvement in disease-free survival (DFS) with adjuvant pembrolizumab compared to placebo after nephrectomy in patients with clear cell renal cell carcinoma (sarcomatoid components were allowed) and an increased risk of recurrence. In this study, 994 patients were randomized in a 1:1 ratio (pembrolizumab (n=496) to placebo (n=498)). Pembrolizumab was administered at a dose of 200 mg every 3 weeks for 1 year. The results of the continued analysis after a median follow-up of 57.2 months (47.9-74.5 months) have now been published.

The DFS benefit with pembrolizumab over placebo in the current analysis was consistent with previous interim analyses (HR 0.72; 95%CI 0.59-0.87). No new safety signals were observed. In this study, 994 patients were randomized in a 1:1 ratio (pembrolizumab (n=496) to placebo (n=498)). In this study, 994 patients were randomized in a 1:1 ratio (pembrolizumab (n=496) to placebo (n=498)). For the first time, a statistically significant improvement in the secondary endpoint of overall survival (OS) has now been demonstrated with the administration of pembrolizumab (HR 0.62, 95%CI 0.44-0.87; p=0.0024). A total of 55 OS events were observed in the pembrolizumab arm and 86 in the placebo arm. The estimated OS at 48 months was 91.2% with pembrolizumab and 86.0% in the placebo arm. The OS benefit was shown for several significant subgroups:

• M0 disease (HR 0.63, 95%CI 0.44-0.90),
• M1 NED (HR 0.51, 95%CI 0.15-1.75),
• CPS (combined positive score) <1 (HR 0.65, 95%CI 0.31-1.38),
• CPS ≥1 (HR 0.62, 95%CI 0.42-0.91),
• Presence of sarcomatoid components (HR 0.69, 95%CI 0.28-1.70),
• Absence of sarcomatoid components (HR 0.57, 95%CI 0.39-0.84)

Thus, KEYNOTE-564 is the first phase III study to show a clinically meaningful improvement in OS compared to placebo in adjuvant therapy in patients with RCC and an increased risk of recurrence after surgery. The results confirm the adjuvant administration of pembrolizumab as standard therapy.

 

Urothelial cell carcinoma

 

Subgroup analysis of the EV-302/KEYNOTE-A39 study

The EV-302/KEYNOTE-A39 trial (highlight of our ESMO 2023 abstract) had shown breakthrough response and survival data in the first-line treatment of metastatic urothelial cell carcinoma. These results were achieved with a combination therapy of the antibody-drug conjugate enfortumab vedotin and the checkpoint inhibitor pembrolizumab. The advantage was seen both in progression-free survival (PFS) at 12.5 months compared to 6.3 months (hazard ratio 0.45, 95% CI: 0.38 - 0.54; p<0.00001) and in overall survival (OS) at 31.5 months compared to 16.1 months (hazard ratio 0.47, 95% CI: 0.38-0.58; p<0.00001). The risk of death was reduced by 53% with the new combination compared to standard therapy. The overall response rate was 68% (95% CI: 63.1-72.1, p<0.00001) and was thus significantly higher than in the comparative arm with chemotherapy, where it was 44% (95% CI: 39.7%-49.2%). An analysis of the subgroups was carried out at this year's ASCO-GU . This showed for subgroups: Age, performance status, gender, tumor location (upper urinary tract vs. urinary bladder), PD-L1 status, cisplatin eligibility, among others) a clear superiority of the new combination compared to the previous standard therapy with gemcitabine/cisplatin. The advantage in terms of response rate and overall survival was equally demonstrable in the subgroups mentioned. The results continue to clearly support the use of the new combination therapy in metastatic urothelial cell carcinoma.

 

NURE-Combo study

The phase II NURE-Combo study investigated the neoadjuvant administration of nab-paclitaxel + nivolumab followed by radical cystectomy and adjuvant administration of nivolumab. Patients who were unsuitable for cisplatin treatment were included in the study, although patients who refused chemotherapy could also be included. The study is interesting overall as there is currently no neoadjuvant option before cystectomy available for this patient population. A total of only 31 patients were included in the study. Patients received 4 cycles of nivolumab 360 mg every 3 weeks + paclitaxel 125 mg/m2 on days 1 and 8 every 3 weeks, followed by cystectomy and then 13 doses of nivolumab 360 mg every 3 weeks adjuvantly. The primary endpoint was defined as the pathologic complete response rate. The secondary endpoints were pathologic response, tolerability and event-free survival (EFS). At the end of data collection, 29 of the 31 patients included had a pathologic response. Overall, 11 patients (38%) showed a complete response (≤ypT0N0) and 21 (72%) a reduction in tumor stage (≤ypT1N0). There was no progression of the tumor disease during neoadjuvant treatment. After a median follow-up of 10.6 months (IQR: 8-16), one patient showed progression. The 12-month EFS was 96.4% (95%CI: 89.9-100). Overall, the above-mentioned combined neoadjuvant and adjuvant therapy could represent an important new clinical option, especially for platinum-ineligible patients.

 

AMBASSADOR

In this phase III trial, patients with muscle-invasive urothelial cell carcinoma (MIBC) were enrolled and received either pembrolizumab 200 mg every 3 weeks adjuvant or no adjuvant therapy after cystectomy in a 1:1 ratio. Patients were stratified according to PD-L1 status, neoadjuvant chemotherapy and pathologic stage. A total of 702 patients were randomized. Recruitment was terminated early following FDA admission for nivolumab in the same indication. However, 96% of the calculated number of cases was reached. In terms of disease-free survival (DFS), the pembrolizumab arm showed an advantage of 15 months (29 vs. 14 months, HR 0.69, 95% CI 0.55 - 0.87, p=0.001). However, there was no significant difference in overall survival (OS, 50.9 vs. 55.8 months, HR 0.98, 95% CI 0.76 - 1.26, p=0.884). It is noteworthy here that, in contrast to the already approved neoadjuvant therapy with nivolumab (CheckMate-274), no statistically significant dependence on PD-L1 expression could be demonstrated. Grade 3+ adverse events occurred in 48.4% and 31.8% of patients receiving pembrolizumab and observation, respectively.

 

 

Prostate carcinoma

 

Contact-02

In this phase III study, the combination therapy of cabozantinib (a tyrosine kinase inhibitor) and atezolizumab (a PD-L1 inhibitor) was compared with a new anti-hormonal therapy (NHT) in patients with metastatic castration-resistant prostate cancer who showed progression during ongoing NHT therapy. Patients had to be metastatic outside the pelvis. Prior docetaxel therapy in hormone-sensitive status was allowed. The combination of cabozantinib/atezolizumab significantly improved progression-free survival (PFS) and thus met one of the two primary endpoints of the study (median PFS: 6.3 vs. 4.2 months; hazard ratio (HR) 0.65, 95% confidence interval (CI) 0.50-0.84; p = 0.0007). Overall, more toxicities occurred with combination therapy than with NHT alone (grade 3-4: 33% vs. 8%). The data on overall survival (OS) are currently insufficient for a conclusive assessment. A critical point to note is the comparatively weak comparator arm, which consisted of a change of NHT and thus represents a notoriously weak option in this constellation.

PD Dr. med. Christoph-A. J. von Klot

The annual congress of the European Society for Medical Oncology took place in Madrid from 20-24.10.2023. The relevant highlights of the congress are summarized below.

 

Renal cell carcinoma

 

LITESPARK-005 Phase III study

Belzutifan versus everolimus was investigated for patients with previously treated renal cell carcinoma. Patients in this study received up to 3 prior therapies, including PDL1 and TKI lines of therapy. A total of 374 patients were treated with belzutifan and 372 with everolimus. The response rate (ORR) for belzutifan and everolimus was 22.7 vs. 3.5%. The progression-free survival (PFS) was 22.5% vs. 9% (hazard ratio: 0.74; 95% CI: 0.63 - 0.88). In terms of survival (OS), this amounted to 55.2% for belzutifan and 50.6% for everolimus after 18 months of observation. This difference was not significant, at least up to this point. Grade ≥3 side effects were comparable and occurred in just under 2/3 of patients in both arms.

LITESPARK-003 Phase II study

The study investigated belzutifan (120mg) in combination with cabozantinib (60mg) in the first-line setting in patients with metastatic clear cell renal cell carcinoma (ccRCC). The response rate (ORR), which served as the primary endpoint here, was 70%. Patients with a low risk (according to IMDC criteria) even achieved a response rate of 79% (versus 59% for patients with a high risk according to IMDC). Overall, the cohort was comparatively small with 50 patients. In a second cohort, 52 previously treated patients were treated with the above-mentioned combination. The response rate in this group was significantly lower at 31% and no difference was observed with regard to the risk classification according to IMDC. The most common adverse events (AEs) were fatique, anemia and diarrhea.

 

Urothelial cell carcinoma

 

[HIGHLIGHT] Results of the EV-302/KEYNOTE-A39 study

In EV-302/KEYNOTE-A39, patients with locally advanced or metastatic urothelial cell carcinoma were treated with either enfortumab vedotin + pembrolizumab or the standard therapy gemcitabine/cisplatin. For the first time in the first-line situation, there was a clear advantage for the new combination over the established standard of platinum-based chemotherapy. The advantage was shown both for progression-free survival (PFS) with 12.5 months vs. 6.3 months (hazard ratio 0.45, 95% CI: 0.38 - 0.54; p<0.00001), as well as for overall survival (OS) with 31.5 months vs. 16.1 months (hazard ratio 0.47, 95%CI: 0.38-0.58; p<0.00001). The risk of death was thus reduced by 53% with the new combination compared to standard therapy. The overall response rate was 68% (95% CI: 63.1-72.1, P<0.00001) and thus significantly higher than in the comparative arm of chemotherapy at 44% (95%CI: 39.7%-49.2%). The superiority of EV/pembrolizumab across all subgroups was remarkable. This included in particular the PDL status as well as the localization: urinary bladder versus upper urinary tract. Major adverse events of the new treatment combination included maculo-papular rash, hyperglycemia, neutropenia, anemia, diarrhea and sensory neuropathy. The results are most likely to lead to a new first-line standard of care for metastatic urothelial carcinoma and raise questions about the sequence of subsequent therapies and the cost of therapy.

SunRISe-1 Phase IIb study

TAR-200 is a drug delivery system for intravesical drug release. The study included high-risk patients who had not previously responded to instillation therapy with BCG. Without further therapy, these patients are at high risk of disease progression. In the SunRISEe-1 study, the aim was to achieve continuous release of gemcitabine within the urinary bladder via TAR-200. The results of cohort 2 of this study were presented at this year's ESMO 2023 in Madrid. A response rate of 77% was observed for the 30 patients included. The median response time had not been reached at the time the data was presented. The most common treatment-related side effects (similar to those of BCG therapy) were pollakiuria, dysuria and urge to urinate (urge). However, treatment only had to be discontinued in 4% of patients due to side effects. Overall, the results are promising and may represent a treatment option for patients who refuse or are unable to receive a cystectomy if BCG treatment fails.

THOR-2 study

The THOR-2 (Cohort 1) study investigated the effect of oral therapy with erdafitinib (6mg) for patients with non-muscle invasive bladder cancer who had a recurrence in terms of high-risk carcinoma (pTa high grade/ pT1) and FGFR alteration after previous BCG instillation therapy. The comparator to erdafitinib in this study was intravesical instillation with gemcitabine or mitomycin C. The median follow-up was 13.4 months, with a total of 49 and 24 patients receiving erdafitinib and the comparator respectively. For patients with gemcitabine or mitomycin C instillation, relapse-free survival was 11.6 months. For erdafitinib, recurrence-free survival has not yet been achieved during the observation period to date. The calculated risk reduction was 72% (hazard ratio 0.28, 95%CI 0.10 - 0.60). Higher grade adverse events were significantly more common in the erdafitinib arm at 31% vs. 4%. Overall, the study was stopped prematurely due to poor recruitment. However, the results to date indicate a positive effect in terms of relapse-free survival for patients with FGFR alteration. The study is interesting insofar as radical cystectomy is often the only remaining option for the group of patients studied after BCG instillation has failed. The comparatively high toxicity in this setting and the need for prior testing for FGFR alterations are certainly disadvantageous.

THOR phase III study (cohort 2)

Data were shown from pre-treated patients with metastatic or locally advanced urothelial cell carcinoma who had received either erdafitinib (pan-FGFR tyrosine kinase inhibitor, 8mg daily (possibly increased to 9mg)) or pembrolizumab (PD1 receptor inhibitor, 200mg every 3 weeks). Patients had to have an alteration in the fibroblast growth factor receptor (FGFRalt) and must not have received a checkpoint inhibitor beforehand. Patients were randomized in a 1:1 ratio. The primary endpoint was overall survival (OS). The secondary endpoints were progression-free survival (PFS), response rate (ORR) and tolerability. With regard to median overall survival (OS), no significant advantage was shown for erdafitinib (10.9 vs. 11.1 months, hazard ratio of 1.18, 95%CI 0.90 - 1.50; p=0.19). The response rate (ORR, 40.0% vs. 21.6%; p<0.001) and also the duration of progression-free survival (PFS) were longer with erdafitinib. However, the duration of response was significantly longer with pembrolizumab at 14.4 vs. 4.3 months, which could explain the numerically worse overall survival performance for erdafitinib. Higher grade treatment-related adverse events (grade 3 - 4) occurred in 43.4% of cases with erdafitinib and in 13.3% of cases with pembrolizumab. There were no treatment-related deaths with erdafitinib and 3 patients with pembrolizumab (3%). Remarkably and comparatively frequently, central serous retinopathy occurred in 22.5% of patients on erdafitinib.

 

Prostate carcinoma

 

PSMAfore

Patients with metastatic castration-resistant prostate cancer (mCRPC) with progression under androgen receptor-targeted therapy (ARTA) who had not yet received taxane-based chemotherapy were examined. Patients had to have one or more positive findings on PSMA imaging, could not have tumor-specific, PSMA-negative findings and could not be candidates for therapy with a PARP inhibitor. Crossover to the ligand therapy arm was possible after treatment failure under new antiandrogenic therapy (enzalutamide or abiraterone acetate + prednisolone). In the preceding VISION study, 177Lu-PSMA-617 had already demonstrated efficacy in patients following new-generation antiandrogen therapy and taxane-based chemotherapy. In the PSMAfore study, patients received a total of 6 cycles of 177Lu-PSMA-617, with a switch to antiandrogen therapy serving as the comparator arm. The primary endpoint of the study was radiographic progression-free survival (rPFS). A total of 486 patients were included. A comparison of the radioligand therapy with the antiandrogen showed a clear advantage in terms of rPFS for 177Lu-PSMA-617 with 12.02 versus 5.59 months, hazard ratio 0.43, 95%CI 0.33-0.54) The objective response rate (ORR) was also significantly higher for 177Lu-PSMA-617 at 50.7% versus 14.9%. The median duration of response was also higher for 177Lu-PSMA-617 at 13.63 months (95%CI 11.56 - NE) versus 10.05 months (95%CI 4.63 - NE). With 177Lu-PSMA-617, a complete response was achieved in approximately 1 in 5 (21.1%) patients, significantly less than the 2.7% in the comparator arm. In the intention to treat analysis, overall survival (OS) was comparable in both arms (19, vs. 19, hazard ratio 1.16, 95%CI 0.83-1.64). The incidence of ≥3 adverse events was 33.9% in the radioligand therapy arm and 43.1% in the comparator arm. The most common side effects of radioligand therapy were dry mouth and anemia. Overall, the study confirms the good efficacy of 177Lu-PSMA-617 in comparison with a switch to anti-hormonal therapy. Although there is currently no significant advantage in terms of an OS benefit, the interpretation of the data is challenging against the background of a crossover rate of over 84% in this study.

ENZA-p (ANZUP 1901)

This is a Phase 2 study on the simultaneous administration of enzalutamide and 177Lu-PSMA-617, i.e. a next-generation antiandrogen (NHT) and nuclear medicine therapy with a radioligand. Both substances have already been shown to improve overall survival (OS) in metastatic castration-resistant prostate cancer (mCRPC) in the past. Patients with metastatic castration-resistant prostate cancer (mCRPC) were treated in the first line. In other words, patients were included who had not previously received chemotherapy or an androgen receptor pathway inhibitor (prior use of abiraterone and/or docetaxel in the hormone-sensitive stage was permitted). In addition, patients had to have at least two risk factors (elevation of lactate dehydrogenase or alkaline phosphatase, albumin <35 g/L, de novo metastasis at first diagnosis, 3 years since primary diagnosis, >5 bone metastases, visceral metastases, PSA doubling time <84 days, previous therapy with abiraterone acetate). Patients were randomized in a 1:1 ratio to receive either enzalutamide (160mg per day) or enzalutamide combined with 177Lu-PSMA-617. A total of 162 patients with the above criteria were included. The primary endpoint was defined as PSA progression-free survival (PSA-PFS). After a median follow-up period of 20 months, a significantly longer PSA-PFS was shown for the combination therapy compared to monotherapy with enzalutamide (13 vs. 7.8 months, hazard ratio 0.43, 95%CI 0.29-0.63; p<0.001). Serious adverse events were comparable for enzalutamide and the combination therapy at 35% vs. 33%. The study shows an improvement in PSA progression-free survival with combination therapy compared to enzalutamide alone.

MAGNITUDE study

The final results of the MAGNITUDE study were shown. In this phase III study, the combination of niraparib and abiraterone + prednisone vs. placebo and abiraterone + prednisolone was investigated for patients with homologous recombination deficiency (HRR). The prerequisite was the presence of metastatic castration-resistant prostate cancer (mCRPC). A total of 423 patients were included in the study. Of these, 212 patients received the combination therapy and 211 patients only abiraterone acetate + prednisolone. Finally, the analysis focused on BRCA positive patients (n=225). In this subgroup, n=113 patients had received combination therapy and n=112 patients abiraterone acetate + prednisolone. The median follow-up time was 35.9 months. Overall survival (OS) showed an advantage for combination therapy over monotherapy (30.4 vs. 28.6 months, hazard ratio 0.788, 95%CI 0.55-1.120; p=0.1828). A pre-specified multivariable analysis taking into account the baseline imbalances between the patient groups confirmed the survival benefit for the combination therapy more clearly (hazard ratio 0.663, 95%CI 0.464-0.947). The time to symptomatic progression and the time to cytotoxic follow-up therapy were also more favorable with combination therapy. The transfusion rate in the niraparib arm was 27.3%. The results shown support the use of a combination therapy of niraparib and abiraterone acetate + prednisolone in first-line treatment for patients with positive BRCA status and mCRPC.

KEYNOTE-641

This phase III study was aimed at patients with metastatic castration-resistant prostate cancer (mCRPC) who had already been treated with next-generation anti-hormonal therapy (NHT). Many of these patients initially receive docetaxel-based chemotherapy after progression under NHT. In this study, the combination of pembrolizumab, a PD1 inhibitor, with the antiandrogen enzalutamide versus placebo + enzalutamide was investigated for chemonaive patients. A total of 1,244 patients were included. The primary endpoint was defined as overall survival (OS) and radiographic progression-free survival (rPFS). The study was stopped prematurely after the first interim analysis due to a lack of proof of efficacy. The rPFS for the combination therapy was a median of 10.4 months versus 9.0 months (hazard ratio 0.98, 95%CI 0.84-1.14) and for the OS 24.7 months versus 27.3 months (hazard ratio 1.04, 95%CI 0.88-1.22). In addition, the therapy-associated side effects were higher with the addition of pembrolizumab than in the comparator arm. The hopes for a synergistic effect of the above-mentioned combination based on earlier studies were therefore not fulfilled here. This negative study is one of a series of negative study results on immunotherapy for metastatic carcinoma of the prostate.

RADICALS-RT

Results from the RADICALS-RT study together with results from the GETUG-AFU 17 and RAVES studies have already relativized the value of adjuvant radiotherapy compared to salvage radiotherapy after prostatectomy.
The final results of the RADICALS-RT study have now been presented. In the RADICALS-RT study, adjuvant radiotherapy (aRT) was compared with a strategy of surveillance with possible downstream salvage radiotherapy (sRT) for PSA failure. Patients with a postoperative PSA value ≤0.2ng/ml and ≥1 risk factor (Gleason 7-10, pT3/4, positive R status or initial PSA value ≥10ng/ml) were selected for this purpose. A total of 1,396 patients were randomized. 697 patients received aRT and 699 received surveillance and salvage radiotherapy if necessary. The median follow-up was 8 years. The median PSA value at the start of sRT was 0.2ng/ml. The absence of distant metastases after 10 years was 92.7% for aRT and 89.6% for sRT (hazard ratio 0.68, 95%CI 0.43-1.07; p=0.095). The use of hormone deprivation also did not differ significantly between the two arms. The overall survival (OS) for aRT and sRT after 10 years was 87.6 % vs. 87.4 % (hazard ratio 0.98, 95%CI 0.67-1.44; p=0.92). Radiation-associated side effects were significantly more frequent in the aRT group (p<0.001). The results of this study indicate no significant benefit for aRT compared to surveillance with possible subsequent sRT, with a significantly higher risk of urinary and rectal-associated side effects.