Neoadjuvant Chemotherapy Benefit Retains Stronghold for Patients With MIBC, UTUC

Effective treatment paths leveraging neoadjuvant chemotherapy have been well-established for patients with muscle-invasive bladder cancer (MIBC), with mounting retrospective and prospective data continuing to demonstrate overall survival benefit compared with adjuvant chemotherapy. Not only does treatment confer enhanced survival outcomes, but biologic information garnered from treatment provide investigators with prognostic information to further refine treatment regimens, according to Jean Hoffman-Censits, MD.

“Across the board, there is some consistency in terms of the pathological complete response [pCR], somewhere between 20% and 40%, and the ability to safely get to surgery, which has always been a concern with cisplatin-based chemotherapy,” said Hoffman-Censits during a presentation at the 15th Annual Interdisciplinary Prostate Cancer Congress^® and Other Genitourinary Malignancies.¹ Hoffman-Censits is the codirector of the Upper Tract Urothelial Cancer Multidisciplinary Clinic at Johns Hopkins Medicine in Baltimore, Maryland. In her presentation, Hoffman-Censits reviewed the latest data supporting treatment pathways for patients with muscle invasive or upper-tract urothelial cancers.

Neoadjuvant Therapy Preferred for MIBC

Efforts to optimize the benefit of neoadjuvant chemotherapy among patients with muscle-invasive urothelial carcinoma have been undertaken in the phase 3 VESPER trial (NCT01812369). The trial was designed to compare outcomes between 6 cycles of dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (dd-MVAC), or 4 cycles of gemcitabine and cisplatin (GC) as neoadjuvant chemotherapy. The trial also included a cohort of patients who received adjuvant chemotherapy.²

Hoffman-Censits first reviewed the data that supported the conclusion that both regimens of neoadjuvant chemotherapy were better tolerated than adjuvant chemotherapy with 58% of patients (n = 127/218) completing 6 cycles of dd-MVAC and 66% of patients (n = 144/219) completing 4 cycles of GC compared with 37% (n = 11/30) and 46% (n = 12/26) in the adjuvant group, respectively.

“This reinforces what we have seen in the clinic that adjuvant chemotherapy just does not seem to be as well tolerated,” Hoffman-Censits said.

In the neoadjuvant group, pCR (ypT0pN0) was observed in 84 (42%) and 71 (36%) patients who received dd-MVAC and GC, respectively (P = .0221). A non-muscle invasive status (<ypT2pN0) was achieved in 126 (63%) and 98 (49%) patients, respectively (P = .007). An organ-confined status (<ypT3pN0) was obtained in 154 (77%) and 124 (63%) patients, respectively (P = .001).

Most of the grade 3 or higher Common Terminology Criteria for Adverse Events (CTCAEs) concerned hematological toxicities, reported in 129 (52%) patients in the dd-MVAC group and 134 (55%) patients in the GC group. Other reported grade 3 or higher CTCAEs were anemia (22% vs 7.8%; P < .0001), neutropenia (39% vs 46%; P = .14), febrile neutropenia (6.5% vs 2.4%; P = .053), and thrombopenia (20% vs 17%; P = .5), respectively.

Hoffman-Censits noted that findings from a review of clinical trials evaluating immunotherapy treatments including single agents, immune-oncology (IO) combinations, and IO plus chemotherapy combinations in the neoadjuvant setting showed similar efficacy across populations including among cisplatin-eligible and cisplatin-ineligible patients.

“What is striking is that no matter what the study or what the regimen, the pCR across the board is pretty similar,” Hoffman-Censits said. “We are seeing a common theme in terms of neoadjuvant treatment and pCR outcomes. The addition of chemotherapy increases that pCR, but not so significantly.” 

Notably, Hoffman-Censits referenced the phase 2 HCRN GU 16-257 trial (NCT03558087), in which patients with cT2-T4aN0M0 MIBC who were cisplatin eligible received 4 cycles of gemcitabine, cisplatin, and nivolumab (Opdivo) followed by clinical restaging including urine cytology, MRI/CT of the bladder, cystoscopy, and bladder/prostatic urethral biopsies.³

Patients achieving a clinical complete response (cCR), which included a normal cytology, imaging, and cT0/Ta, were eligible to proceed without cystectomy and receive nivolumab twice weekly for 8 weeks followed by surveillance; otherwise, patients underwent cystectomy.

At 1 year, 31 of 64 patients who underwent restaging achieved a cCR and an estimated 81.2% of patients were alive with bladder intact at 1 year (95% CI, 60.4%-95.8%). Among those who did not achieve cCR (n = 33), 11% were alive with bladder intact at 1 year (95% CI, 2.9%-91.7%).

Hoffman-Censits noted that more data is eagerly awaited with neoadjuvant immunotherapy and its role in bladder preservation with preselected trials leveraging markers such as DNA mismatch repair as well as unselected trials evaluating single-agent and combination regimens.

Broadening the scope, she added, “There are various randomized phase 3 trials that are completed, maturing, or ongoing that may impact the standard of care and this discussion maybe a year from now.”

Neoadjuvant Treatment Strikes Benefit in UTUC

Hoffman-Censits noted that up-staging remains a common problem in the diagnosis of bladder cancer. This is particularly evident among patients with upper-tract urothelial cancer (UTUC). “[High-grade] tumors in the upper-tract that are in ureter or in the renal pelvis are excessively difficult to biopsy and the stage,” she said. “The expectation that you would get the same staging as you would in MIBC is not there, it is uncommon that a [bit] of muscle would come out of one of those biopsies.”

In the preoperative setting, approximately 58% of patients may be eligible for cisplatin-based chemotherapy, Hoffman-Censits noted. however, after nephroureterectomy and lymph-node resection, the eligible percentage drops to approximately 15%.¹

Data from preoperative trials demonstrate the benefit of 4 cycles of neoadjuvant chemotherapy resulted in tumor downstaging and complete response rates for patients with high-grade clinically invasive UTUC. In a phase 2 trial ECOG-ACRIN 8141 NAC (NCT02412670), 29 patients with baseline creatinine clearance greater than 50 mL per minute were assigned to 4 neoadjuvant chemotherapy cycles of accelerated methotrexate, vinblastine, doxorubicin, and cisplatin.⁴

Eight percent of patients completed all planned treatments, 10.3% achieved ypT0N0 and 1 achieved ypT0Nx for a recorded pCR in 13.8% (90% CI, 4.9%-28.8%). Tumor downstaging to at least ypT1 was observed in 18 patients (62%).⁴

Outcomes were similar for patients treated with neoadjuvant gemcitabine and cisplatin in the phase 2 trial (NCT01261728). At the 2022 Genitourinary Cancers Symposium, final results were presented and showed that among 57 treated patients, the overall pCR was 19% with 63% of patients experiencing tumor downgrading.⁶ Further, investigators presented progression-free survival (PFS) and overall survival (OS) data for survivors that showed, when stratified by pathologic response those with tumors stage lower than stage ypT2N0 who had a complete or partial response had significantly higher PFS and OS outcomes (P < .001). The 2-year PFS rate for responders (n = 36) was 91% vs 52% for nonresponders (n = 21), and the 2-year OS rate was 100% vs 80%.

“The rate of pCR does correlate with PFS and OS, so this is important information as we are again considering whether or not patients would be eligible for additional treatment in the adjuvant setting,” Hoffman-Censits said.

Adjuvant Treatment Explorations Remain Crucial

Investigators of the phase 3 POUT trial (NCT01993979) evaluated adjuvant chemotherapy, a favored approach in Europe, among patients with UTUC after nephroureterectomy. Patients with disease staged as either pT2-T4 pN0-N3 M0 or pTany N1-3 M0 were randomly assigned surveillance (n = 129) or four 21-day cycles of adjuvant chemotherapy, which was either cisplatin or carboplatin (n = 132).⁵

Results showed that adjuvant chemotherapy significantly improved disease-free survival (DFS) (HR, 0.45; 95% CI, 0.30-0.68; P = .0001) at a median follow-up of 30.3 months (range, 18.0-47.5). Three-year event-free estimates were 71% (95% CI, 61%-78%) and 46% (95% CI, 36%-56%) for chemotherapy and surveillance, respectively.

Noting these outcomes, Hoffman-Censits said that chemotherapy tolerance has an advantage in the neoadjuvant setting, but that these data were not powered for comparison.

In ECOG-ACRIN 8141 NAC (n = 30), 90% of patients completed 4 cycles of cisplatin and 80% completed 4 cycles. In the phase 2 trial of gemcitabine/cisplatin (n = 53), 96% of patients completed 3 cycles of treatment and 83% completed 4 cycles. In the data from POUT, among the 76 patients assigned to gemcitabine/cisplatin, 71 started treatment with 67% of patients completing 3 cycles and 59% completing 4 cycles. OF note, 13% switched from cisplatin to carboplatin on study.

“Just because the data do not necessarily support adjuvant therapy, there is still support to consider adjuvant therapy for these patients, so that should not be forgotten,” Hoffman-Censits concluded.

In MIBC, Hoffman-Censits noted that data from the phase 3 CheckMate 274 trial (NCT02632409), examined the role of checkpoint inhibitors in patients who received cisplatin in the neoadjuvant setting or were ineligible for cisplatin. Patients were randomly assigned 1:1 to nivolumab (n = 353) or placebo (n = 356) every 2 weeks for up to 1 year following radical cysectomy.⁷ Of note, 20% of patients in the trial had UTUC.

The percentage of patients who had DFS at 6 months was 74.9% (95% CI, 69.9%-79.2%) with nivolumab and 60.3% (95% CI, 54.9%-65.3%) with placebo. At 12 months, these rates were 62.8% (95% CI, 57.3%-67.8%) and 46.6% (95% CI, 41.1%-51.9%), respectively (HR, 0.70; 98.22% CI, 0.55-0.90; P < .001).

Among patients with a PD-L1 expression level of 1% or more, the percentage of patients who had DFS at 6 months was 74.5% (95% CI, 66.2%-81.1%) and 55.7% (95% CI, 46.8%-63.6%), respectively. At 12 months, these rates were 67.2% (95% CI, 58.4%-65.3%) and 45.9% (95% CI, 37.1%-54.2%), respectively (HR for disease recurrence or death, 0.55; 98.72% CI, 0.35-0.85; P < .001).

“Based on the intention-to-treat analysis, adjuvant nivolumab for selected patients who meet this high-risk criteria, is now guideline endorsed,” Hoffman-Cistis concluded.

References

1. Hoffman-Censits J. Management of muscle-invasive urothelial cancer. Presented at: 15th Annual Interdisciplinary Prostate Cancer® and other GU Malignancies Congress. March 11-12, 2022. New York, NY.
2. Pfister C, Gravis G, Fléchon A, et al; VESPER Trial Investigators. Randomized phase III trial of dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin, or gemcitabine and cisplatin as perioperative chemotherapy for patients with muscle-invasive bladder cancer. Analysis of the GETUG/AFU V05 VESPER- trial secondary endpoints: chemotherapy toxicity and pathological responses. Eur Urol. 2021;79(2):214-221. doi:10.1016/j.eurouro.2020.08.024
3. Galsky MD. Daneshmand S, Chan KG, et al. Phase 2 trial of gemcitabine, cisplatin, plus nivolumab with selective bladder sparing in patients with muscle-invasive bladder cancer (MIBC): HCRN GU 16-257. J Clin Oncol. 2021;29(15):4503. doi:10.1200/JCO.2021.39.15_suppl.4503
4. Margulis V, Puligandla M, Trabulsi EJ, et al. Phase II trial of neoadjuvant systemic chemotherapy followed by extirpative surgery in patients with high grade upper tract urothelial carcinoma. J Urol. 2020;203(4):690-698. doi:10.1097/JU.0000000000000644
5. Yip W, Coleman J, Wong NC, et al. Final results of a multicenter prospective phase II clinical trial of gemcitabine and cisplatin as neoadjuvant chemotherapy in patients with high-grade upper tract urothelial carcinoma. J Clin Oncol. 2022;40(suppl 6):440. doi:10.1200/JCO.2022.40.6_suppl.440
6. Birtle A, Johnson M, Chester J, et al. Adjuvant chemotherapy in upper tract urothelial carcinoma (the POUT trial): a phase 3, open-label, randomised controlled trial. Lancet. 2020;395(10232):1268-1277. doi:10.1016/S0140-6736(20)30415-3
7. Bajorin DF, Witjes JA, Gschwend JE, et al. Adjuvant nivolumab versus placebo in muscle-invasive urothelial carcinoma. N Engl J Med. 2021;384:2102-2114. doi:10.1056/NEJMoa2034442