Nichole Tucker

In a recent interview, Joaquim Bellmunt, MD, PhD, associate professor, Medicine, Harvard Medical School and director, Bladder Cancer Program, Beth Israel Deaconess Medical Center, discussed long-term data from the phase 3 JAVELIN Bladder 100 trial of frontline maintenance avelumab (Bavencio) in patients with metastatic urothelial cancer (mUC) who received first-line chemotherapy.

The interview took place earlier this year during the 2022 GU Cancers Symposium, where the updated findings were shared. Bellmunt also previews additional data from the JAVELIN Bladder 100 trial that will be presented at the 2022 ASCO Annual Meeting.

As a recap, what was observed in the primary analysis of the JAVELIN Bladder 100 trial?

: The primary analysis of survival showed that the median overall survival in the patients who receive avelumab maintenance was 21.4. And in the best supportive care arm, it was 14.3 months. That means a 7-month improvement in median overall survival with a hazard ratio of 0.69.

The first analysis was done in October 2019. And the analysis presented at AUA was after at least 2 years of follow-up with a data cutoff of June 2021. So, with that, we see that the long-term follow-up of this trial is confirming the results that were already published in the 

How was the long-term analysis of the JAVELIN Bladder 100 trial carried out?

This trial was designed in patients with metastatic bladder cancer that were receiving treatment with platinum gemcitabine or carboplatin/gemcitabine and if the patients didn't progress, meaning if the patients were able to obtain partial response, stable disease, or complete response, then the patients were randomized to receive maintenance avelumab plus best supportive care.

With this recent analysis, what we have seen is that the median overall survival in the avelumab maintenance is 23.8 months, and in the best supportive care arm it is like 15.0 months, meaning an 8-month difference in the median. The hazard ratio is more or less the same at 0.76, and the benefit has been seen across different subgroup of patients. Independent of patients responding or not responding, all patients benefited from receiving avelumab maintenance.

The benefit was seen in survival and was also seen in progression-free survival. So, in this updated analysis, the PFS in the overall population of patients receiving avelumab was 5.5 months, it was 2.1 months in patients receiving best supportive care. So, a substantial PFS prolongation was seen in these patients receiving avelumab maintenance.

Another analysis being presented during AUA is around subsequent therapy the patients received because obviously, we know that a particular therapy sometimes impacts overall survival. And what we saw in the analysis was that in patients that were assigned receive avelumab maintenance, 11.4% of patients received subsequent therapy with a PD-1 or PD-L1 inhibitor while in the best supportive care 53% of patients received a PD-1/PD-L1 inhibitor. This means that giving maintenance avelumab sooner provides a survival advantage.

What did longer follow-up teach you about frontline maintenance avelumab treatment in this patient population?

We now know that the percentage of patients who are alive in this trial or at years is 49.8% in the avelumab maintenance population versus 38.4% in the best supportive care arm. We haven't seen unexpected adverse events, so it confirms the safety of this type of approach when using switch maintenance to manage patients who do not progress to chemotherapy in the first line.

These results support the recommendation of avelumab first-line maintenance as a standard of care in urothelial cancer, patients with metastatic disease receiving chemotherapy with platinum-based therapy, carboplatin, or cisplatin, and those who are not progressing. So, this is a new standard of care when managing metastatic bladder cancer patients.

So, now the concept of avelumab maintenance as the standard of care has been included in all the guidelines.

What other type of sub analysis will be important from this study?

Upcoming at the ASCO 2022 Annual Meeting, we are going to update additional data on what's the role of second-line therapies if the patient will receive chemotherapy as rescue therapy because this is something that we don't know presently.

What do we do after the patient has received chemotherapy, followed by maintenance avelumab and they progress? Some guidelines say the next step is enfortumab vedotin, and in fact, there is very limited data on that. In the analysis that is going to be presented at ASCO, we are going to see the results of a patient receiving rechallenge with chemotherapy because those patients have already responded to first-line chemotherapy, or at least they have not progressed. The patients have a holiday period where they receive avelumab maintenance and then when they progress, some patients can receive again platinum-based therapy. And this is something that we don't know, all these data need to be collected. So, what's the outcome in these patients, either it's good to receive subsequent chemotherapy, or maybe there is a chance to give a targeted therapy, but we presently don't know.

We know that the blood cancer landscape is changing so quickly, we are waiting for new trials in the first line combining immunotherapy with an antibody-drug conjugate that may be changing the future in the way that we treat first-line metastatic patients. As more data are being analyzed from these trials, we will be able to design the best strategy in terms of how to sequence therapy in patients with bladder cancer in order to provide improved survival while preserving the quality of life. That's a very important thing.

1. Powles T, Park SH, Voog E, et al. Avelumab first-line (1L) maintenance for advanced urothelial carcinoma (UC): long-term follow-up results from the JAVELIN Bladder 100 trial. 

. 2022;40(suppl 6):487. doi:10.1200/JCO.2022.40.6_suppl.487

Articles

“This is a new standard of care when managing metastatic bladder cancer patients,” says Joaquim Bellmunt, MD, PhD.

Expert reviews long-term maintenance avelumab results in urothelial cancer

Darolutamide (Nubeqa) continued to demonstrate benefits in overall survival (OS) and prostate-specific antigen (PSA) outcomes in patients with nonmetastatic castration-resistant prostate cancer (nmCRPC), regardless of whether or not they had received prior local therapy with radiotherapy (RT) or radical prostatectomy (RP).

Findings from a post-hoc analysis of the phase 3 ARAMIS trial (NCT02200614) presented at the 2022 AUA Annual Meeting showed that the safety and tolerability of darolutamide in patients with nmCRPC were also consistent between patients who received prior local therapy compared with those who did not.

Previously, results from the planned primary analysis of the study showed that darolutamide significantly prolonged metastasis-free survival (MFS) compared with placebo in men with nmCRPC with no added toxicity. In a population of 1509 patients, the median MFS was 40.4 months with darolutamide vs 18.4 months with placebo (HR, 0.41; 95% CI, 0.34-0.50; 

< .001), resulting in a 31% reduction in the risk of metastasis or death. Findings also trended in favor of the darolutamide arm across all secondary end points, including overall survival, time to pain progression, time to cytotoxic chemotherapy, and time to a symptomatic skeletal event.

The safety profile of darolutamide has been consistently favorable.1 In the primary analysis, treatment discontinuation occurred in 8.9% of the darolutamide group compared with 8.7% of the placebo arm. Overall, the rates of adverse events (AEs) were similar between the 2 arms, but darolutamide was associated with a higher incidence of seizures, falls, fractures, cognitive disorder, or hypertension vs placebo.

Long-term follow-up in the ARAMIS study lasted for 3 years. Patients with nmCRPC were randomized 2:1 in the study to receive either darolutamide 600 mg twice daily or placebo while continuing androgen-deprivation therapy (ADT). The long-term analysis assessed the secondary study end points of OS, PSA outcomes, and AEs in the patients who received prior local therapy of RP or RT to the primary tumor vs those who received neither therapy.

The 3-year survival and median time to PSA progression were estimated using Cox regression analyses, which were adjusted for age, baseline ECOG performance status, Gleason score, and time to diagnosis. The study investigators defined PSA response as a ≥ 50% decline from baseline (PSA50). AEs were summarized across the subgroups of patients who had prior RP (n = 239), RT (n = 177), either RP or RT (n = 416), neither RP nor RT (n = 538), and all patients treated with darolutamide (n = 954) in ARAMIS.

Overall, 43.6% of darolutamide-treated patients had received prior RP or RT. At baseline, the median age of patients across the subgroups ranged from 72.0 years to 76.0 years. The median PSA level in patients previously treated with RP was 6.2 ng/mL (range, 1.8-132.8), and the median PSA doubling time was 4.1 months (range, 0.7-10.4) in the RP or RT subgroup, 4.7 months (range, 1.0-11) in the neither RP or RT subgroup, and 4.4 months (range, 0.7-11.0) in all darolutamide-treated patients.

The majority of patients in the study had an ECOG performance status of 0 rather than 1 and a Gleason score ≥ 7 rather than < 7. The time from initial diagnosis to treatment in the study ranged from 74.5 months to 107.9 months.

In the darolutamide-treated population, the median OS was not reached across any subgroups or in the overall population. Among patients who received prior RP, the 3-year survival rate was 89.6%. Those treated previously with RT was a 3-year survival rate of 83.3%. Those treated with RP or RT and those who received neither had a 3-year survival rate of 86.9% and 79.0%, respectively. In all darolutamide-treated patients, the 3-year survival rate was 82.6%. In comparison, patients given placebo had a 3-year survival rate of 77.0%.

Results also showed that regardless of prior therapy, the median time to PSA progression was similar across subgroups and showed consistency with the overall ARAMIS patient population. Contrarily, the median time to PSA progression was 7.2 months in the placebo arm.

Specifically, in patients previously treated with RP (n = 239), the median time to PSA progression was 29.6 months. Those previously treated with RT (n = 177) had a 29.5-month median time to PSA progression. Among those who were previously treated with RP or RT (n = 416), the median time to PSA progression was 29.5 months, and those who received neither form of prior therapy (n = 538) had a median time to PSA progression of 26.0 months. In all darolutamide-treated patients (n = 954), the median time to PSA progression was 29.5 months.

In terms of PSA50, response rates were similar for darolutamide-treated patients regardless of their prior therapy subgroup. PSA50 responses across the prior therapy subgroups were also consistent with the overall darolutamide-treated arm in the ARAMIS trial. In the placebo arm, 33.0% achieved PSA50 response.

Patients who were treated with RP before darolutamide had an 85.8% PSA50 response rate compared with 85.3% for those treated with RT, 85.6% for those treated with RP or RT, 83.8% for those who had neither prior therapy, and 84.6% in the all darolutamide-treated patient population.

The safety profile observed with darolutamide in the longer-term analysis was consistent across all prior therapy subgroups. Overall, AEs were observed in 86.6% of the RP subgroup, 89.3% of the RT subgroup, 87.7% of the RP or RT subgroup, 84.2% of the group who receive neither RP or RT, and 85.7% of the all the darolutamide population. More than 20% of patients in each subgroup experienced grade 3 or higher AEs.

Common AEs observed during the study included fatigue, hypertension, bone fracture, falls, rash, and mental impairment. These AEs were determined to be events that are commonly observed with androgen receptor inhibitors. Local AEs that occurred in > 5% of any subgroup included fatigue, constipation, abnormally frequent urination, hematuria, and dysuria.

1. Siemens DR, Fizazi K, Shore ND, et al. Efficacy and safety of darolutamide in nonmetastatic castration-resistant prostate cancer patients with and without prior local therapy with radical prostatectomy or radiotherapy. 

. 2020;207(5):e451. doi:10.1097/JU.0000000000002570.05

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

. 2019;380(13):1235-1246. doi:10.1056/NEJMoa1815671

The benefit with darolutamide was observed, regardless of whether or not patients had prior local therapy. 

Long-term darolutamide data show sustained efficacy in nmCRPC

Findings from the BIONIKK study published in 

 suggest that biomarker-driven treatment selection based on tumor molecular phenotype may be on the horizon in the treatment paradigm for metastatic renal cell carcinoma (RCC).

The study (NCT02960906) specifically examined this precision medicine pathway in the context of treatment selection between nivolumab (Opdivo) with or without ipilimumab (Yervoy) and a VEGFR tyrosine kinase inhibitor (TKI) in the first-line setting for patients with metastatic clear-cell RCC (ccRCC).

Frontline treatment of ccRCC has changed tremendously since 2015, when the immune checkpoint inhibitor (ICI), nivolumab, was granted FDA approval. Since then, ICIs alone and in combinations have entered the space and offer options for patients with RCC subtypes.

Prior research showed that treatment with sunitinib (Sutent) in patients with good response to the agent had molecular and pathological features closest to normal kidney tissue (ccrcc3), investigators hypothesized that immune-high ccrcc4 tumors would respond to nivolumab-based therapy, either with or without ipilimumab (Yervoy), because of the immune-enriched tumor microenvironment. Moreover, ccrcc1 tumors would have a better response to the combination of nivolumab and ipilimumab compared with nivolumab alone because of the need to recruit antitumor cytotoxic T cells.

“To our knowledge, this is the first study to show the feasibility of prospective patient and treatment selection based on tumor gene expression in metastatic renal cell carcinoma. By allocating treatment according to tumor molecular group, we enriched the population who achieved an objective response with nivolumab, nivolumab–ipilimumab, and VEGFR tyrosine kinase inhibitors (VEGFR-TKIs),” wrote the study authors led by Yann-Alexandre Vano, a medical oncologist at the Hôpital Européen Georges-Pompidou.

To conduct the biomarker-driven, open-label, noncomparative, randomized, phase 2 BIONIKK trial (NCT02960906), patients with ccRCC from 15 university hospitals and cancer centers in France were enrolled. Those eligible for the study were patients aged 18 years or older who had newly diagnosed or recurrent stage IV RCC, an ECOG performance status of 0-2, 1 or more measurable lesion per RECIST v1.1, and had not received previous systemic therapy for metastatic disease.

In terms of molecular grouping, the presence of a sarcomatoid component and PD-L1 expression was centrally assessed by an expert uropathologist on selected formalin-fixed paraffin-embedded tumor samples for all patients. Samples were selected by certain criteria, which included tumors with ≥ 60% of viable tumor cells, ≤ 20% of necrosis, of highest grade, and with the highest immune infiltrate. Also, the presence of a sarcomatoid component was identified and PD-L1 expression was assessed using the PD-L1 22C3 antibody. Tumors with TC ≥ 1% were PD-L1 positive.

The patients with ccrcc1 and ccrcc4 disease were assigned to receive either nivolumab 3 mg/kg or nivolumab with ipilimumab 1 mg/kg. Those with ccrcc2 and ccrcc3 groups disease were assigned to receive 1 of 2 VEGFR TKIs (sunitinib 50 mg/day for 4 weeks every 6 weeks or oral pazopanib [Votrient] 800 mg daily continuously).

The primary end point of the study was the objective response rate (ORR) by investigator assessment per RECIST v1.1. Secondary end points of the study included ORR at week 22, progression-free survival (PFS), overall survival, duration of response (DOR), duration of treatment, and safety and tolerability.

Overall, there were 61 patients assigned to receive nivolumab monotherapy, 101 assigned to the combination of nivolumab and ipilimumab, and 40 received a VEGFR TKI.

Among patients with ccrcc1, those treated with nivolumab alone had an ORR of 29% (95% CI, 16%-45%) vs 39% (95% CI, 24%-55%) with nivolumab plus ipilimumab (Odds ratio [OR], 0.63; 95% CI, 0.25-1.56). Patients with ccrcc4 disease had an ORR of 44% (95%, 20%-70%) on nivolumab monotherapy vs 50% (95% CI, 26%-74%) in patients treated with nivolumab/ipilimumab (OR, 0.78; 95% CI, 0.20-3.01).

Responses were higher among patients with ccrcc2 compared with other phenotypes and lower in patients with ccrcc3 disease. Specifically, those with ccrcc2 treated with a VEGFR TKI had an ORR of (50% (95%, 33%-67%) vs 51% (95% CI, 34%-68%) with nivolumab plus ipilimumab (OR, 0.95 (0.38-2.37). Among the patients with ccrcc3, the ORR was 0 with VEGFR TKI therapy compared with 20% (95% CI, 1%-72%; OR, not evaluable [NE]).

DORs were not reached (NR) in any treatment arm, but ranged from 6.0 months to 11.8 months, depending on phenotype and the treatment administered. The shortest time to response was observed in patients with ccrcc4 disease treated with nivolumab monotherapy, with a time to response of 2.2 months (range, 2.2-NR). The longest time to response was among patients with ccrcc2 disease treated with a VEGFR TKI at 4.9 months (range, 2.8-16.5).

PFS was assessed in the ccrcc1, ccrcc2, and ccrcc4 groups. In patients with ccrcc1 disease who received the combination of nivolumab and ipilimumab, the median PFS was 7.7 months (95% CI, 5.0-12.9) compared with 5.2 months (95% CI, 2.4-9.1) among those treated with nivolumab alone (hazard ratio [HR] 1.27 (95% CI, 0.77-2.11).

The median PFS in patients with ccrcc4 treated with the ICI combination was 13.0 months (95%CI, 2.5-NE) vs 7.8 months (95% CI, 2.3-NE) with nivolumab alone (HR, 1.37 (95% CI, 0.57-3.29)

Finally, patients in the ccrcc2 group treated with nivolumab plus ipilimumab had a median PFS of 11.1 months (95% CI, 7.7-23.2) vs 14.4 months (10.6-NE) with VEGFR TKI treatment (HR, 0.75; 95% CI, 0.40-1.39).

Safety was assessed based on treatment with the nivolumab monotherapy, nivolumab plus ipilimumab, and VEGFR TKI therapy, and grade 1/2 adverse events (AEs) were observed in 76%, 54%, and 30% respectively. In the nivolumab-only group, the most common low-grade AEs were fatigue (50%), pruritus (24%), and maculopapular rash (17%). For patients treated with the ICI combination, the most common grade 1/2 AEs were fatigue (50%), pruritus (31%), and diarrhea (32%). Lastly, in the VEGFR TKI arms, the most common grade 1/2 AEs were fatigue (65%), diarrhea (53%), and oral mucositis (43%).

“Our results confirm that the response to nivolumab alone or with ipilimumab and to VEGFR-TKIs is different depending on the characteristics of the tumor and its microenvironment. The feasibility of prospectively selecting patients by their molecular group for treatment choice opens the way to larger biomarker-based trial designs,” wrote Vano et al.

1. Vano Y, Elaidi R, Bennamoun M, et al. Nivolumab, nivolumab–ipilimumab, and VEGFR-tyrosine kinase inhibitors as first-line treatment for metastatic clear-cell renal cell carcinoma (BIONIKK): A biomarker-driven, open-label, non-comparative, randomized, phase 2 trial [Published online ahead of print April 04, 2022].

The study specifically examined this precision medicine pathway in the context of frontline treatment selection between nivolumab with or without ipilimumab and a VEGFR tyrosine kinase inhibitor. 

Study shows feasibility of mRCC treatment selection based on tumor gene expression

An analysis of the phase 2 TITAN-RCC trial shared during the 2022 ASCO Genitourinary Cancers Symposium identified immune-cell related parameters associated with increased efficacy of nivolumab/ipilimumab combination therapy in patients with advanced or metastatic clear cell renal cell carcinoma (RCC).

Study results presented by Marc-Oliver Grimm, MD, Jena University Hospital, revealed that having 4-1BB or LAG-3-expressing T cells at baseline correlated with response to nivolumab induction. Moreover, nivolumab/ipilimumab boosts were associated with a high proportion of PD-L1-expressing myeloid cells and plasmacytoid dendritic cells (pDC) during boost cycles.

Response to immune checkpoint inhibitors in patients with RCC appears to vary from patient to patient. There is a need in the field to identify key predictors of response to immunotherapy. With consideration that a boost of nivolumab plus ipilimumab improved response compared with nivolumab monotherapy in patients with RCC treated in the TITAN-RCC clinical trial,

 investigators assessed characteristics of blood-circulating immune cell subsets within the study population to identify the markers of response.1

TITAN-RCC included 207 patients with ccRCC whose disease was metastatic or locally advanced according to histologically confirmation. Patients were required to have intermediate or high International Metastatic RCC Database Consortium (IMDC) risk, be either untreated or previously treated with 1 prior tyrosine kinase inhibitor, and have measurable disease per RECIST v1.1, and a Karnofsky performance score ≥ 70.

Baseline characteristics of the intention-to-treat (ITT) population of 207 patients showed a median patient age of 65 years (range, 20-87), and the population was predominantly male (71%). Fifty-three percent of patients entered the study while in the first-line treatment setting and the remaining 47% were second line. In terms of IMDC risk factors, 18% of the ITT population had a Karnofsky performance score of < 80%, 65% had an initial RCC diagnosis < 12 months, and laboratory values including hemoglobin, platelet count, neutrophil, and calcium were adequate. Overall, 70% of the ITT population had intermediate-risk disease, 25% had poor-risk disease, and 4.3% had favorable-risk disease.

Among the 137 patients who received an immunotherapeutic boost during the study, the median age was 64 years (range, 20-86), and the cohort was also 71% male. Forty-eight of the patients were the first line and 52% were second line. IMDC risk factors were adequate and similar o the ITT population. Overall, 74% of the boost group had intermediate-risk disease, 21% had poor-risk disease, and 5.1% has favorable-risk disease.

“Patients received nivolumab induction until week 16 and continued with nivolumab maintenance upon remission. Patients who had stable disease or progressive disease or early progressive disease at week 8 continued up to 4 cycles,” explained Grimm during the presentation. The 4 cycles included immunotherapeutic boosts of nivolumab 3 kg/mg with ipilimumab 1 kg/mg in patients who were stable after 4 cycles. Nivolumab maintenance was then continued in these patients at multiple time point during induction and before each boost cycle.

Investigators looked at 198 samples from patients with RCC, 105 of whom were treated in the frontline setting, and 93 of whom were second line. The samples were evaluated using multiparametric flow cytometry for frequency and phenotype of T cell, monocyte, myeloid-derived suppressor cell (MDSC), and dendritic cell (DC) subsets. Further, uni- and multivariable logistic regression modeling was used to look into the association between treatment response and immune parameters.

By flow cytometry, immune response in the Mo, MDSC, CTL, Th, and Treg cells were evaluated. Further, single marker models that were adjusted for age and gender. Data showed that most of the markers investigated had some correlation with immune response except for CD8-positive T cells like TIM-1, VISTA, OX40, CD69, and CD28 compared with PD-1, LAG-3, CTLA-4, and others. In the CD4-positive T-cell category, only VISTA and CD69 were not associated with immune response.

Results for responders to nivolumab induction were split into 3 categories. First, of those with 4-1BB-positive, CD8-positive T cells at baseline, 41 responded to therapy while 106 did not respond (odds ratio [OR] 1.03; 95% CI, 1.01-1.07). Among the patients with 4-1BB-positive, CD4-positive T cells at baseline, there were 43 responders and 106 non-responders (OR, 1.05; 95% CI, 1.02-1.08). In the last category of patients with LAG-3-positive, CD4-positive T cell at baseline, 41 patients had a response to nivolumab induction while 106 did not respond (OR, 1.03; 95% CI, 1.01-1.05).

Looking at CD14-positive monocytes and pDC, at the time of the first boost cycle, patients with CD86-positive cells were most likely to respond to therapy compared with those with CD40-positive cells or PD-L1-positive cells. Also, ICOS positivity did not correlate with response to the nivolumab/ipilimumab boost.

Across the board in CD14-, e-MDSC-, and pDC-expressing cells, PD-L1 expression correlated with non-response to immunotherapy with nivolumab plus ipilimumab boost at cycle 1. Only 4 patients with PD-L1 expression in CD14-positive cells responded compared with 41 nonresponders (OR, 1.22; 95% CI, 1.06-1.58). In patients with PD-L1 expression in e-MDSC, there were 4 responders and 30 nonresponders (OR, 1.44; 95% CI, 1.02-1.41). Finally, in patients who have PD-L1-expressing pDC, there were only 7 responders versus 40 nonresponders (OR, 1.08; 95% CI, 1.01-1.17).

“These immune cell parameters may represent novel predictive biomarkers for the response to nivolumab and or nivolumab/ipilimumab therapy in clear cell RCC,” stated Grimm.

1. Grimm MO, Kesselmeier M, Leucht K, et al. Novel predictive biomarkers of response to immune checkpoint blockade with nivolumab ± ipilimumab in the TITAN-RCC phase 2 trial. J Clin Oncol. 2022;40(6):367-367. doi: 10.1200/JCO.2022.40.6_suppl.367

2. Grimm MO, Esteban E, Barthelemy P, et al. Efficacy of nivolumab/ipilimumab in patients with initial or late progression with nivolumab: Updated analysis of a tailored approach in advanced renal cell carcinoma (TITAN-RCC).J Clin Oncol. 2021;39(suppl 5): 4576-4576. doi: 10.1200/JCO.2021.39.15_suppl.4576

An analysis of the phase 2 TITAN-RCC trial found multiple immune cell factors associated with high rates of response to nivolumab/ipilimumab in advanced renal cell carcinoma.

Nichole Tucker

Articles

Expert reviews long-term maintenance avelumab results in urothelial cancer

Long-term darolutamide data show sustained efficacy in nmCRPC

Study shows feasibility of mRCC treatment selection based on tumor gene expression

Efficacy markers identified for nivolumab/ipilimumab in renal cell carcinoma