FormalPara Key Summary Points

Platinum-based chemotherapy continues to be an important first-line treatment option for patients with advanced urothelial carcinoma, particularly where use of enfortumab vedotin plus pembrolizumab is limited by considerations related to toxicity or cost.

Approximately half of patients with advanced urothelial carcinoma are eligible for cisplatin, and most cisplatin-ineligible patients can receive carboplatin; eligibility for cisplatin or carboplatin can be determined using criteria that consider renal function, performance status, and specific comorbidities.

In patients who have a response or stable disease with cisplatin- or carboplatin-based chemotherapy, avelumab first-line maintenance has been shown to prolong overall survival and is standard of care in international treatment guidelines.

The long-term safety profile of avelumab first-line maintenance has been demonstrated, including in patients who received first-line cisplatin- or carboplatin-based treatment and in older patients.

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Podcast Transcript

Podcast Discussion (MP4 5,63,697 KB))

Podcast Attendees: Jun Gong (JG) and Melissa A. Reimers (MAR)

JG: Hello, everyone. My name is Jun Gong, and I am a medical oncologist here at Cedars-Sinai Medical Center in Los Angeles, California, and it's my pleasure to be joined by Dr. Melissa Reimers.

MAR: Hi, everyone. I'm Melissa Reimers. I'm also a medical oncologist, specializing in genitourinary cancers at Washington University in St. Louis.

JG: Today, we're going to be talking about an important topic called, “Practical considerations in patients with advanced urothelial cancer receiving first-line cisplatin- or carboplatin-based chemotherapy followed by avelumab maintenance.”

MAR: The key topics we'll be covering today include the evolving role of platinum-based chemotherapy in this disease setting in the context of recent trial results, practical considerations when considering first-line cisplatin- or carboplatin-based chemotherapy, and avelumab first-line maintenance treatment. Now, it is important to note that treatment options vary in different countries, so the points we discuss may be affected by local considerations.

So, Jun, why don't you start us off by sharing some key information about advanced urothelial carcinoma?

JG: That would be my pleasure, Melissa. In the US, bladder cancer is the 6th most common cancer site, with more than 82,000 new cases and more than 16,000 deaths estimated in 2023 [1]. Bladder cancer is primarily a disease of older age, with an average age of diagnosis of 73 years in the US [2, 3]. Other key risk factors include tobacco smoke, exposure to occupational chemicals such as aromatic amines, and male sex [2]. Urothelial carcinoma (or UC) is the most frequent type of bladder cancer, accounting for 90% of cases. It also arises outside of the bladder in an additional 10% of patients, including the urethra, ureter, and renal pelvis [4, 5].

Patients with unresectable locally advanced or metastatic urothelial carcinoma, which is collectively termed as advanced or stage IV disease, have a poor prognosis [6]. Typically, the stages [are classified] by TNM staging, and advanced urothelial carcinoma includes T4b, any N, M0; or any T, any N, M1a or M1b [7]. Approximately 5% of patients have metastatic or M1 disease at the time of diagnosis [4, 8], and, additionally, of the 20% of those diagnosed with muscle-invasive disease (meaning stage II or III disease) who undergo surgical resection, approximately half subsequently relapse with stage IV disease [4, 9].

In the US, patients diagnosed with metastatic bladder cancer have a 5-year overall survival rate of around 8% [8]. Factors that predict a worse prognosis include visceral metastases and poor performance status [10,11,12,13]. Real-world studies have shown that many patients with advanced urothelial carcinoma do not receive any systemic treatment. For example, across various US studies, 14–60% of patients did not receive any systemic anticancer treatment [14]. Increasing the use of available treatments is therefore an important objective for improving outcomes in this disease.

Melissa, could you summarize recent developments in the treatment landscape for advanced urothelial carcinoma?

MAR: Absolutely, Jun; thanks. Platinum-based chemotherapy has been the cornerstone of first-line treatment for urothelial carcinoma following studies showing clinical activity reported several decades ago [15,16,17], and it is an established treatment option in international treatment guidelines [4, 18,19,20]. In patients who are progression-free after platinum-based chemotherapy, avelumab maintenance treatment is recommended [4, 19, 20]. However, recent results from phase 3 clinical trials have provided new treatment options, and this has really been groundbreaking for the field.

Importantly, the EV-302 phase 3 trial compared first-line treatment with enfortumab vedotin (or EV) plus pembrolizumab versus platinum-based chemotherapy in patients with previously untreated advanced urothelial carcinoma. In the EV plus pembrolizumab arm, EV treatment was administered continuously until disease progression or unacceptable toxicity on days 1 and 8 of a 21-day cycle, and pembrolizumab was administered on day 1 for up to 35 cycles. In the chemotherapy arm, patients received a maximum of 6 cycles of cisplatin or carboplatin in combination with gemcitabine, and approximately 30% of patients also received avelumab maintenance therapy. Use of avelumab maintenance, importantly, was permitted after a late amendment in the study protocol [21].

Overall survival and progression-free survival were significantly longer with EV plus pembrolizumab versus platinum-based chemotherapy alone. The median overall survival was 31.5 versus 16.5 months, and median progression-free survival was 12.5 versus 6.3 months, respectively. It’s important to note that the toxicity profiles were markedly different between the treatment arms. In the EV plus pembrolizumab arm, common treatment-related adverse events of special interest included skin reactions, peripheral neuropathy, hyperglycemia, and pneumonitis. Skin reactions occurred in 66.8% of patients overall and reached grade 3 or above in 15.5%, and peripheral neuropathy occurred in 63.2% and was grade 3 or above in 6.8%. Hyperglycemia occurred in 13% and was grade 3 or above in 6.1%, and pneumonitis occurred in 9.5% and was grade 3 or above in 3.6%. As we would expect, and are all well familiar with, in the platinum-based chemotherapy arm the most common treatment-related adverse events were related to myelosuppression. Anemia occurred in 56.6% of patients overall and was grade 3 or above in 31.4%, neutropenia occurred in 41.6% and was grade 3 or above in 30.0%, and thrombocytopenia occurred in 34.2% and was grade 3 or above in 19.4%. Other common chemotherapy-related adverse events included nausea, which occurred in 38.8% and was grade 3 or above in 2.8%, and fatigue, which occurred in 36.0% and was grade 3 or above in 4.2%. Serious treatment-related adverse events occurred in 27.7% of the patients with the EV plus pembrolizumab group and in 19.6% of patients with chemotherapy [21].

Based on these data, in the US, EV plus pembrolizumab was approved in December of 2023 for first-line treatment of patients with advanced urothelial carcinoma, irrespective of cisplatin eligibility, and represents a new standard of care in the setting [4, 19, 22].

It’s important to note that another recent phase 3 trial, the CheckMate 901 trial, has reported longer overall survival with nivolumab plus cisplatin and gemcitabine followed by nivolumab monotherapy compared with cisplatin and gemcitabine alone. The median overall survival was 21.7 months compared with 18.9 months, respectively [23], and, based on this trial, nivolumab plus cisplatin and gemcitabine was approved in the US in March 2024 and is an important additional option for cisplatin-eligible patients [4, 19, 24].

We will now move on to the role of platinum-based chemotherapy in advanced urothelial carcinoma, considering these recent developments. Jun, would you like to discuss what these developments mean for the role of platinum-based chemotherapy in the treatment of advanced urothelial carcinoma?

JG: Sure thing, Melissa. In updated guidelines for patients with advanced urothelial carcinoma, platinum-based chemotherapy followed by avelumab maintenance remains a recommended treatment option for cisplatin-eligible or -ineligible patients [4, 19]. For cisplatin-eligible patients, cisplatin-gemcitabine in combination with nivolumab is also recommended. Although EV plus pembrolizumab is the preferred regimen and has been approved in the US, availability in other countries will depend on health technology assessments, pricing, reimbursement negotiations, and local approvals [25,26,27].

Furthermore, the toxicity profile of EV plus pembrolizumab may make this combination less suitable for some patients. EV plus pembrolizumab is administered continuously and is also associated with cumulative toxicity, particularly neuropathy [21, 26,27,28]. Across several clinical trials, 87.0% of patients who developed neuropathy with EV had residual neuropathy at last evaluation, which was a grade greater than or equal to 2 in 45.0% [22]. Patients with pre-existing neuropathy of grade 2 or higher were excluded from clinical trials of EV [21, 29, 30]. Additionally, because of the risk of hyperglycemia, patients with uncontrolled diabetes were also excluded from trials of EV [21, 29, 30], and these patients may also be less suitable for EV plus pembrolizumab. It has been reported that patients with a high body mass index have an increased risk of hyperglycemia and skin toxicities with EV [29, 31, 32]. The prescribing information states that EV should be avoided in patients with moderate or severe hepatic impairment, defined as Child–Pugh B or C, based on an increased risk of grade 3 or above adverse reactions and death [22]. However, these patients may also be more challenging to treat with chemotherapy—in particular, gemcitabine. The potential impact of toxicity on quality of life may have greater relevance when discussing treatment options with patients who are predicted to have longer survival or longer treatment durations and where subsequent treatment options are an important consideration. This may, for example, include patients with a low tumor burden, such as those with lymph node-only or nonvisceral disease [10,11,12,13, 33, 34].

We'll now discuss criteria to identify eligibility for platinum-based chemotherapy. Melissa, could you summarize how we can identify patients who are eligible for platinum-based chemotherapy?

MAR: Certainly, Jun. In the treatment guideline, regimens recommended for patients with advanced urothelial carcinoma are cisplatin-containing regimens, specifically cisplatin plus gemcitabine or dose-dense MVAC, which is methotrexate, vinblastine, doxorubicin, and cisplatin, while carboplatin plus gemcitabine is also an option [4, 19, 20]. However, cisplatin-based chemotherapy is preferred to carboplatin-based chemotherapy in eligible patients [4, 18, 20]. Eligibility or ineligibility for cisplatin-based chemotherapy in patients with advanced urothelial carcinoma is well established and is based on the Galsky criteria [35, 36]. Patients are considered ineligible for cisplatin if they have any of the following: an ECOG performance status of 2 or greater, creatinine clearance of less than 60 mL per minute, hearing loss of grade 2 or greater, peripheral neuropathy of grade 2 or above, or New York Heart Association class 3 or 4 heart failure. It's important to know that about 50% of patients with advanced urothelial carcinoma are eligible for cisplatin-based treatment [20, 36]. Criteria have also been proposed by a working group to identify patients ineligible for any platinum-containing chemotherapy, and these are: an ECOG performance status of 3 or more, creatinine clearance of less than 30 mL per minute, an ECOG performance status of 2 in combination with a creatinine clearance of less than 30 mL per minute, peripheral neuropathy of grade 2 or above, or New York Heart Association class 3 or 4 heart failure [37].

Most patients can be treated with carboplatin-based chemotherapy. For example, in a study that assessed platinum eligibility in patients receiving first-line treatment in 5 European countries, among patients who were categorized as cisplatin ineligible, 70% were still eligible to receive carboplatin therapy and 30% were ineligible for any platinum-based treatment [38]. In addition, split-dose cisplatin plus gemcitabine is an alternative to standard single-day cisplatin dosing in cisplatin-ineligible patients with borderline renal impairment, although data in advanced urothelial carcinoma are limited for this approach [39,40,41]. However, irrespective of the regimen, up to 6 cycles of platinum-based chemotherapy are recommended, with fewer cycles acceptable in patients with cumulative toxicity [4, 18, 19].

JG: Thanks, Melissa. Let’s explore the criteria for cisplatin or platinum chemotherapy eligibility by considering a hypothetical patient case. For example, which platinum agent would be most suitable for a patient aged 80 years who presents with de novo metastatic urothelial carcinoma, who has borderline renal impairment (creatinine clearance of 55–60 mL per minute) but who is fully active (ECOG performance score of 0) and has no relevant comorbidities?

MAR: Based on this description, this patient could be considered for cisplatin treatment. As we discussed earlier, the key factors to consider regarding cisplatin eligibility are renal function, performance status, and the presence or absence of neuropathy. It is important to note that age alone should not be a concern with regard to eligibility for cisplatin treatment.

JG: Great points there, Melissa. What about a patient aged 60 years with a good performance status who has had disease progression 18 months after undergoing nephroureterectomy for upper-tract urothelial carcinoma, and who has labile renal function, meaning that their creatinine clearance is not consistently above the range of 55–60 mL per minute?

MAR: Because of the risks associated with cisplatin-related nephrotoxicity, carboplatin could be considered in this patient, and that recommendation is consistent with the criteria proposed by the Platinum Ineligibility in Bladder Cancer Working Group [37].

Now we'll transition to discussing clinical benefits associated with the avelumab maintenance treatment in patients with advanced urothelial carcinoma. As we have mentioned earlier, treatment guidelines recommend avelumab maintenance in patients who are progression-free after platinum-based chemotherapy [4, 19, 20]. Jun, could you discuss why avelumab maintenance is recommended and summarize the data to show its clinical benefits?

JG: My pleasure, Melissa. Phase 3 trials have shown that 72–79% of patients with advanced urothelial carcinoma have a response or stable disease with platinum-based chemotherapy; however, durations of response and progression-free survival without maintenance treatment are limited [21, 42,43,44]. In the JAVELIN Bladder 100 phase 3 trial, avelumab first-line maintenance treatment was shown to extend the benefits of platinum-based chemotherapy [45, 46]. In the trial, 700 patients with advanced urothelial carcinoma who were progression-free (i.e., with ongoing complete response, partial response, or stable disease) after receiving 4–6 cycles of first-line chemotherapy with either cisplatin or carboplatin plus gemcitabine were randomized to receive avelumab plus best supportive care or best supportive care alone. Patients had a treatment-free interval of 4–10 weeks from end of chemotherapy until start of study treatment, allowing for the resolution of any chemotherapy-related toxicities [45,46,47].

After 2 years of follow-up in all patients, median overall survival was 23.8 months with avelumab plus best supportive care versus 15.0 months with best supportive care alone [46]. Median progression-free survival was 5.5 versus 2.1 months, respectively. In an exploratory post hoc analysis, median overall survival measured from the start of first-line chemotherapy in the avelumab arm was 29.7 months [48]. However, it should be noted that the trial population only included patients without disease progression following first-line chemotherapy. Thus, median survival in an overall first-line population would be shorter. Efficacy benefits were observed across a range of subgroups, including those defined by patient and chemotherapy characteristics [46, 47, 49]. The efficacy and safety of avelumab first-line maintenance were also consistent in older patients, including those aged more than 65 or 75 years [50], and in patients with a high body mass index [51]. Based on JAVELIN Bladder 100 data, avelumab first-line maintenance was approved in the US in June 2020 [52, 53]. In treatment guidelines, avelumab first-line maintenance is a recommended treatment option for patients with advanced urothelial carcinoma that has not progressed with first-line platinum-based chemotherapy [4, 18, 20].

The effectiveness of the JAVELIN Bladder regimen has also been confirmed in several real-world studies [54,55,56]. For example, in an Italian compassionate use program for avelumab first-line maintenance in 464 patients, median overall survival was 26.2 months and median progression-free survival was 7.6 months [54]. In the AVENANCE study of avelumab first-line maintenance in 595 patients in France, median overall survival in the overall population was 21.3 months. Furthermore, in the subgroup of patients from AVENANCE who received second-line antibody–drug conjugate treatment after avelumab, median overall survival was 31.3 months when measured from the start of avelumab and 40.8 months when measured from the start of first-line chemotherapy in this selected population without disease progression following first-line chemotherapy [55].

It is also important to discuss the safety profile of avelumab maintenance treatment. Melissa, would you like to highlight the key information?

MAR: Absolutely, Jun, thanks. Adverse events with avelumab are generally consistent with those seen in other immune checkpoint inhibitors and mostly do not overlap with those of platinum-based chemotherapy, which we discussed earlier. In long-term safety analyses in avelumab-treated patients from JAVELIN Bladder 100, grade 3 or above treatment-related adverse events occurred in 19.5% of patients [46]. The most common treatment-related adverse events of any grade were pruritis in 14.8% of patients, hypothyroidism in 11.0%, fatigue in 10.8%, diarrhea in 10.5%, and asthenia in 10.5%. The most common treatment-related adverse events of grade 3 or above were increased lipase in 3.5% and increased amylase in 2.3% [57].

Grade 3 or above immune-related adverse events occurred in 7.6% of patients, and the most common were rash and hepatitis, which occurred in 1.5% each [58]. Patients receiving avelumab should undergo appropriate monitoring to enable early identification and management of immune-mediated adverse events, including monitoring of liver enzymes, creatinine, and thyroid function [52]. If an immune-mediated event occurs, avelumab should be withheld or discontinued, depending on the severity and type of adverse event. In the JAVELIN Bladder 100 trial, 21.8% of avelumab-treated patients had an infusion-related reaction of any grade [46]. Before the first 4 infusions of avelumab, patients should receive premedication with antihistamine and acetaminophen, and should be monitored for signs and symptoms of infusion-related reactions [52].

The safety profile of avelumab maintenance treatment is also supported by patient-reported outcome data from the JAVELIN Bladder 100 trial. These data show that the quality of life was maintained during avelumab first-line maintenance, and that the extent to which patients were bothered by side effects did not correspond to a decline in overall quality of life [59]. Quality of life was also maintained in the subgroup of patients who received at least 12 months of avelumab maintenance treatment [60].

JG: Those were great points, Melissa. One question that often comes up is: How long should avelumab maintenance treatment be continued? Can you speak to this?

MAR: Yes, of course. The prescribing information for avelumab states that treatment should be continued until disease progression or unacceptable toxicity, which is consistent with the design of the JAVELIN Bladder 100 trial [45, 46, 52]. Within the trial population, 34% of avelumab-treated patients received at least 1 year of treatment, and 19% received at least 2 years of treatment; importantly, no new safety concerns were identified with longer treatment durations [46]. It’s also important to note that no data are available to evaluate whether avelumab can be discontinued after a specific duration in patients with long-term response or stable disease. I know this question also comes up frequently in other disease types, where patients may receive shorter durations of immunotherapy.

Jun, what do we know about outcomes with avelumab maintenance therapy depending on whether patients received carboplatin- or cisplatin-based chemotherapy?

JG: Within the avelumab arm of the JAVELIN Bladder 100 trial, 52% of patients had received prior cisplatin-based chemotherapy, 42% had received prior carboplatin-based chemotherapy, and 6% had switched between cisplatin and carboplatin [45]. Compared with patients who received cisplatin, the subgroup of patients who received carboplatin included a higher proportion of patients aged 65 years or older, a higher proportion with an Eastern Cooperative Oncology Group performance status of 1 or higher, [and] a lower proportion with creatinine clearance less than 60 mL per minute. These characteristics are consistent with criteria for cisplatin ineligibility [49].

In both the cisplatin and carboplatin subgroups, overall survival and progression-free survival were longer in patients who received avelumab first-line maintenance plus best supportive care compared with patients who received best supportive care alone [48, 49]. Hazard ratios for overall survival were 0.79 in the cisplatin subgroup and 0.69 in the carboplatin subgroup. Longer median overall survival with avelumab was observed in patients who had received first-line cisplatin versus carboplatin: 25.1 versus 20.8 months from the start of avelumab maintenance. This may reflect differences in patient characteristics between the 2 subgroups. The long-term safety profile with avelumab first-line maintenance was generally similar after cisplatin- versus carboplatin-based chemotherapy regimens. The cisplatin subgroup had lower rates of grade 3 or above avelumab treatment-related adverse events than the carboplatin subgroup (16.5% vs. 22.5%), in addition to lower rates of treatment-related adverse events leading to discontinuation (8.8% vs. 14.8%) [48].

MAR: Great, thanks so much, Jun. Let's now discuss another hypothetical case study to illustrate practical considerations about switching between platinum-based chemotherapy and avelumab. This patient was diagnosed with de novo metastatic urothelial carcinoma, had started first-line treatment with carboplatin and gemcitabine, and had a partial response after 2 cycles of treatment. Carboplatin and gemcitabine were continued, and the patient had mild neutropenia and anemia, which were grade 1 after 3 cycles, but which became severe (up to grade 3) at cycle 4, and were associated with grade 2 fatigue. A small additional tumor reduction was observed after cycle 4, but the best response remained a partial response. So, in your opinion, should this patient undergo further cycles of chemotherapy, or should they move on to avelumab treatment at this point?

JG: Well, Melissa, given the similar overall survival and progression-free survival benefits seen with avelumab in the JAVELIN Bladder 100 trial in patients who had received 4 or 6 cycles of platinum-based chemotherapy [45, 46], the suggested approach would be to stop chemotherapy and start avelumab. Avelumab would be started after a treatment-free interval of 4 weeks, assuming that the patient had recovered from chemotherapy-related toxicities. The patient would also undergo a further tumor scan to confirm that no disease progression had occurred. Before starting avelumab, the potential for immune-related toxicities and infusion-related reactions would be discussed with the patient, including an explanation of potential signs and symptoms. The patient would receive routine premedication with acetaminophen and an antihistamine immediately prior to the first 4 doses of avelumab as prophylaxis for infusion-related reactions.

So, Melissa, to conclude this discussion, are there any take-home messages you’d like to provide the audience?

MAR: Yes, Jun. Based on our discussion today, I think the most important points to highlight are the fact that platinum-based chemotherapy has proven efficacy in the treatment of advanced urothelial carcinoma and has a well-characterized and manageable safety profile. While EV plus pembrolizumab has certainly shown superior efficacy compared with platinum-based chemotherapy, its toxicity profile may make it less preferable for some patients. Another key consideration is the fact that availability of EV plus pembrolizumab in countries outside the US may be limited by financial considerations and local approval processes. Therefore, platinum-based chemotherapy does remain an important treatment for many patients. Eligibility for cisplatin or any platinum-based chemotherapy can be determined by assessing renal function, performance status, and the presence or absence of specific comorbidities. We’ve also reviewed today the fact that avelumab first-line maintenance is a recommended treatment option for patients without disease progression after cisplatin- or carboplatin-based chemotherapy, and it has been shown to extend survival and preserve quality of life. Use of avelumab maintenance is supported by an increasing range of clinical evidence, including phase 3 data, subgroup analyses, and various real-world studies.

JG: I’d like to thank you, Dr Melissa Reimers, for providing such high-level clinical expertise [and] allowing us to review the data in the landscape together. Although there are a lot of considerations and nuances to selecting different regimens, I think you and I would both agree that we are in a lucky space right now for our patients, where we have so many options to consider, and we look forward to improving outcomes in bladder cancer together into the future.

MAR: Thank you, Jun, for such a fantastic discussion.