Immunotherapy Meets the Frontline in Bladder Cancer, Leaving Gaps in Later Lines

Thomas Flaig, MD

Vice Chancellor for Research

University of Colorado Denver

Denver, CO

University of Colorado Anschutz

Medical Campus

Aurora, CO

Emerging data from recent trials, regulatory approvals, and presentations during the 2024 American Urological Association Annual Meeting paint a positive treatment landscape for patients with metastatic and non–muscle-invasive bladder cancer. “Just looking back 10 years, we had almost no standard second-line therapies in advanced bladder cancer,” Thomas Flaig, MD, told Targeted Therapies in Oncology during an interview. “And in the first line, our options were gemcitabine- cisplatin or dose-dense MVAC [methotrexate, vinblastine sulfate, doxorubicin hydrocholoride, and cisplatin].” Flaig, vice chancellor for research at the University of Colorado Anschutz Medical Campus in Aurora and the University of Colorado Denver, added that immunotherapy is now making inroads in the first-line setting.

CheckMate901

In the first part of the 2-part phase 3 CheckMate901 trial (NCT03036098), a total of 608 patients with previously untreated, unresectable or metastatic urothelial carcinoma were randomly assigned to receive nivolumab (Opdivo) plus gemcitabine-cisplatin followed by nivolumab or to receive gemcitabine-cisplatin alone.¹

After a median follow-up of 33.6 months, overall survival (OS) for patients in the treatment arm was 21.7 months (95% CI, 18.6-26.4) compared with 18.9 months (95% CI, 14.7-22.4) for patients in the control arm (HR, 0.78; 94% CI, 0.63-0.96; P = .02).

Patients who received the combination also had favorable progression-free survival (PFS) vs gemcitabine-cisplatin alone (HR, 0.72; 95% CI, 0.59-0.88; P = .001). Median PFS was 7.9 months and 7.6 months, respectively. At 12 months, the PFS rate was 34.2% and 21.8%, respectively.¹

Investigators also reported positive and durable responses for the combination arm. The objective response rate (ORR) was 57.6%, with a complete response (CR) rate of 21.7%, in the combination arm vs a 43.1% ORR, with a CR rate of 11.8%, for patients receiving gemcitabine-cisplatin alone. The duration of CR for the treatment arm was 37.1 months vs 13.2 months in the control arm.¹

Historically, no new agent led to improved survival when added to first-line cisplatin-based chemotherapy. “The treatment in the comparator arm, gemcitabine-cisplatin, has been used for decades in this space,” Flaig said. “But suddenly, this was displaced by these positive data.”

Ultimately, this triplet therapy was approved by the FDA based on these findings for first-line treatment in patients with unresectable or metastatic urothelial carcinoma.² “This is a notable addition to our armamentarium, and it fits a general theme of integrating immune checkpoint inhibitors into first-line regimens,” Flaig said.

Couple this with the approval at the end of 2023³ of the antibody-drug conjugate and immunotherapy combination of enfortumab vedotin-ejfv (Padcev) plus pembrolizumab (Keytruda) for patients with locally advanced or metastatic urothelial cancer, and it becomes apparent that immune checkpoint inhibitors will have a presence in first-line regimens, Flaig said.

This approval for this combination was based on efficacy findings from the EV-302 trial (NCT04223856), an open-label, randomized study evaluating 886 patients with locally advanced or metastatic urothelial carcinoma who had no prior systemic therapy for advanced disease. Patients were randomly assigned to receive either enfortumab vedotin plus pembrolizumab (EVP; n = 442) or chemotherapy (n = 444).⁴

Investigators reported a statistically significant improvement in OS for the treatment arm vs the control arm. Further, the combination reduced the risk of death by 53% compared with chemotherapy.⁴

The median OS was 31.5 months (95% CI, 25.4not reached) in the EVP arm compared with 16.1 months (95% CI, 13.9-18.3) in the chemotherapy arm (HR, 0.47; 95% CI, 0.38-0.58; P < .00001).

The OS benefit was seen regardless of the patient’s PD-L1 status or the presence of visceral metastases, and the findings were consistent regardless of whether the patient was treated with cisplatin or carboplatin.⁴

Treatment with the combination also led to a significant improvement in PFS vs chemotherapy. The median PFS was 12.5 months (95% CI, 10.4-16.6) with EVP compared with 6.3 months (95% CI, 6.2-6.5) with chemotherapy. This resulted in a 55% reduction in the risk of disease progression or death (HR, 0.45; 95% CI, 0.38-0.54; P < .00001). The PFS benefit was sustained across all prespecified subgroups, such as those defined by cisplatin eligibility, PD-L1 status, and visceral metastases.⁴

Response rates also favored the treatment arm. The confirmed ORR was 67.7% in the EVP arm compared with 44.4% in the chemotherapy arm. The ORR in the EVP arm consisted of a CR rate of 29.1% and a partial response rate of 38.7%. The stable disease rate was 18.8% and the progressive disease rate was 8.7% in the EVP arm. In the chemotherapy arm, the ORR consisted of a CR rate of 12.5% and a partial response rate of 32%; the stable disease rate was 33.8%, and the progressive disease rate was 13.6%.⁴

“The enfortumab vedotin and pembrolizumab combination will become a very active therapy,” Flaig said. “The combination had a greater than 50% reduction in risk of disease progression or death, which is something you don’t see in oncology these days.”

“Now the interesting part of this is that patients with degraded kidney function or patients who aren’t candidates for cisplatin could receive enfortumab vedotin and pembrolizumab,” he continued. “You’ve now opened up this very active regimen to a broader group of patients.”

Taking it a step further, he asked, “The next challenge is, what do you do next if the patient progresses after these 2 regimens?”

American Urological Association Meeting

Multiple presentations at the recent 2024 American Urological Association Annual Meeting focused on novel gene therapies and immunotherapy combinations.

For example, an open-label, phase 3 trial (NCT02773849) evaluated the recombinant adenovirus vector-based gene therapy nadofaragene firadenovec-vncg (Adstiladrin) in patients with BCG-unresponsive non–muscle- invasive bladder in 2 cohorts: carcinoma in situ (CIS) with or without Ta/ T1 (n = 107) and Ta/T1 without CIS (papillary disease [PD]; n= 50). Bladder preservation and safety profile were examined.⁵

Patients received nadofaragene firadenovec intravesically once every 3 months with cystoscopy and cytology assessments. Mandatory biopsies were taken at 12 months, after which patients entered a 4-year follow-up; those who remained high-grade recurrence free (HGRF) were offered continued treatment at their physician’s discretion.⁵

Investigators reported that for all treated patients, the median follow-up was 50.8 months (IQR, 39.1-60.0), with 26.8% of patients receiving 5 or more instillations and 7.6% of patients receiving treatment for at least 57 months. In terms of efficacy, at 57 months, 5.8% of patients with CIS and 14.6% of patients with PD were HGRF and the HGRF survival rate was 13.2% (95% CI, 6.9%-21.5%) and 32.7% (95% CI, 19.5-46.6) in the CIS and PD cohorts, respectively.⁵

Within 5 years after the first dose of nadofaragene firadenovec, 40.8% and 29.2% of patients in the CIS and PD cohorts underwent radical cystectomy, respectively.⁵

At 5 years, the OS rate was 76.3% (95% CI, 64.6%-84.5%) in the CIS group and 85.9% (95% CI, 70.9%-93.5%) in the PD group. In total, 5 patients had progressed to muscle- invasive disease (4 patients with CIS and 1 patient with PD), which was determined by transurethral resection of bladder tumor at the time of high-grade recurrence. No new safety signals were identified on long-term follow-up.⁵

Investigators concluded that the agent provided nearly half of patients with bladder preservation at 60 months and that it was a safe intravesical treatment option for patients with BCG-unresponsive CIS whether with or without Ta/T1, as well as for those with Ta/T1 without CIS.⁵

Looking Ahead

Flaig noted that the muscle-invasive space is going to be moving quickly.

“I think urologists are going to drive a lot of treatments, especially when it comes to local, focused therapies,” Flaig said. “It will be interesting to see how this all gets sorted out.”

Muscle-Invasive Bladder Cancer

In muscle-invasive bladder cancer, results from the phase 2 NURE-Combo trial (NCT04876313)6 evaluated the chemotherapy-immunotherapy combination of nivolumab plus nab-paclitaxel (Abraxane). Safety and efficacy end points were measured to determine the potential value of expanding chemotherapy combinations with immune checkpoint inhibitors. Findings were presented during the 2024 American Urological Association Annual Meeting by Chiara Mercinelli, MD, of IRCCS San Raffaele Hospital in Milan, Italy.

To be enrolled in the trial, patients were cisplatin ineligible or declined cisplatin- based treatment, had previously untreated muscle-invasive bladder cancer with adequate hematologic counts and function, and had an ECOG performance status of 1 or 0. The primary end point was pathologic complete response (ypT0N0). Secondary end points included event-free survival, OS, medical safety, and surgical safety.⁶

Thirty-nine patients were screened for the study, of which 7 were excluded due to either patient refusal or evidence of either N2, N3, or M1 disease. One patient was excluded due to a diagnosis of a nonmuscle-invasive tumor following centralized pathological review.

Thirty-one patients remained; from a histological perspective, 17 patients (54.8%) had stage cT3 or cT4 stage cancer, 14 (45.2%) had cT2, 2 (6.5%) had N1, and 15 (48.4%) had a variant histology component. The entire cohort completed neoadjuvant treatment and were thus evaluable for the primary end point.⁶

Patients received 4 cycles of nivolumab at 360 mg every 3 weeks plus nab-paclitaxel at 125 mg/m2 on day 1 and 8 once every 3 weeks. This was followed by radical cystectomy and by 13 administrations of adjuvant nivolumab at 360 mg once every 3 weeks.6 Median follow-up was 12 months (IQR, 9-17.5). The median time from treatment initiation to surgery was 4 months (IQR, 3-4). A total of 12 patients (38.7%; 95% CI, 21.8%-57.8%) achieved a ypT0N0 response, and 22 patients (71.0%; 95% CI, 51.9%85.8%) achieved a major pathological response (FIGURE).⁶

Three patients refused radical cystectomy and were offered transurethral resection of the bladder tumor. This occurred “prior to maintenance nivolumab after evidence of ctDNA [circulating tumor DNA] negative assay and MRI complete response,” according to the investigators. Overall, the investigators observed a 12-month event-free survival rate of 96.4% (95% CI, 89.9%-100%).⁶

The most common hematological adverse events (AEs) of any grade were anemia in 20 (64.5%) patients and neutropenia in 6 (19.4%) patients. Grade 3 or 4 anemia was observed in 1 (3.2%) patient, and grade 3 or 4 neutropenia was seen in 3 patients (9.7%).⁶

The most common any-grade nonhematological AEs included gastrointestinal disorder in 14 (45.2%) patients, asthenia in 12 (38.7%) patients, cutaneous toxicity in 11 (35.5%) patients, and increased aspartate aminotransferase/alanine aminotransferase in 7 (22.6%) patients.⁶

Serious treatment-related AEs (TRAEs) occurred in 3 (9.7%) patients, and serious surgery-related AEs were observed in 8 (25.8%) patients. Five patients (16.1%) received less than 4 cycles of neoadjuvant treatment due to TRAEs. Grade 3 TRAEs were observed in 8 patients and there were no grade 4 or higher TRAEs observed. Clavien-Dindo classification was used to assess postcystectomy complications within 90 days of radical cystectomy; grade IIIa or higher complications were seen in 8 (25.8%) patients.⁶

“[The] NURE-Combo trial provided insights into the potential value of expanding chemotherapy combinations with immune checkpoint [inhibitors] in muscle- invasive disease,” Mercinelli said during her concluding remarks.⁶

"This approach was effective and safe, suggesting the possible role of nab-paclitaxel in replacing cisplatin as a backbone therapy for a population with [an] unmet clinical need. [The] results also strengthen the role of clinical complete response to envision organ-sparing approaches.”

REFERENCES:
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2. FDA approves nivolumab in combination with cisplatin and gemcitabine for unresectable or metastatic urothelial carcinoma. FDA. Updated March 7, 2024. Accessed May 21, 2024. https://tinyurl.com/3hup8nza
3. FDA approves enfortumab vedotin-ejfv with pembrolizumab for locally advanced or metastatic urothelial cancer. FDA. Updated December 15, 2023. Accessed May 22, 2024. https://tinyurl.com/h76k3k7y
4. Powles TB, Perez Valderrama B, Gupta S, et al. LBA6 EV-302/KEYNOTE-A39: open-label, randomized phase III study of enfortumab vedotin in combination with pembrolizumab (EV+P) vs chemotherapy (Chemo) in previously untreated locally advanced metastatic urothelial carcinoma
(la/mUC). Ann Oncol. 2023;34(suppl 2):S1340. doi:10.1016/j.annonc.2023.10.106
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6. Necchi A, Mercinelli C, Basile G, et al. PD34-10 first results of NURE-Combo: a phase 2 study of neoadjuvant nivolumab (NIVO) and nab-paclitaxel (ABX) followed by postsurgical adjuvant NIVO
in patients (PTS) with muscle-invasive bladder cancer (MIBC). J Urol. 2024;211(5S):e722. doi:10.1097/01.JU.0001008768.36634.79.10