(UroToday.com) The 2024 Southern California Genitourinary Cancer Research Forum featured a bladder cancer session and a presentation by Dr. Alexandra Drakaki discussing key updates in bladder cancer. Dr. Drakaki started her presentation by emphasizing that from neoadjuvant to adjuvant to metastatic disease, there is still a chance for a cure in bladder cancer. A key basic principle in urothelial cancer is to treat based on cisplatin eligibility for neoadjuvant, adjuvant, and first-line metastatic disease. The key criteria for assessing cisplatin eligibility are as follows:
- Creatinine clearance > 60
- Neuropathy grade <2
- Ototoxicity grade <2 (subjective need vs use of hearing aids)
- NYHA class <3
- ECOG 0-1
In the neoadjuvant disease space, the current standard of care in cisplatin eligible patients is gemcitabine + cisplatin or dose dense MVAC. The GETUG-AFU V05 VESPER trial is a randomized phase III trial of 500 patients with cT2-4aN0M0 urothelial carcinoma of the bladder receiving neoadjuvant chemotherapy or pT3-4 or pTanyN+Many receiving adjuvant chemotherapy. Included patients were randomized to either six cycles of dose-dense MVAC once every two weeks or four cycles of gemcitabine and cisplatin once every three weeks before surgery (neoadjuvant group) or after surgery (adjuvant group). Results of the primary endpoint outcome of three-year progression-free survival subsequently published in The Journal of Clinical Oncology in 2022.1 Of the 493 patients in the intent-to-treat population, 88.6% received chemotherapy in the neoadjuvant setting, with the remaining 11.4% receiving adjuvant chemotherapy. Median patient age was 63.0 years. Three-year progression-free survival in patients receiving neoadjuvant chemotherapy was significantly higher in the dose dense MVAC arm (66% versus 56%; HR: 0.70, 95% CI: 0.51 to 0.96, p=0.025):
Overall survival among patients receiving neoadjuvant chemotherapy was in favor of dose dense MVAC (HR: 0.71, 95% CI: 0.52 to 0.97):
An ongoing study in the neoadjuvant disease space for cisplatin eligible patients is the KEYNOTE-B15 trial, which is a phase III study of gemcitabine + cisplatin versus perioperative enfortumab vedotin + pembrolizumab. The trial design is as follows:
Among patients who are cisplatin ineligible, what is the standard of care? For those who desire bladder sparing, chemotherapy + radiotherapy is an option, and for those who are surgical candidates, upfront radical cystectomy + lymph node dissection followed by adjuvant treatment may be an option. However, Dr. Drakaki emphasized that if neoadjuvant therapy is the standard of care in muscle invasive bladder and this holds true for cisplatin eligible patients, then it is probably also true for cisplatin ineligible patients if we can give effective drugs safely.
One such study is the EV-103 cohort H trial that assesses neoadjuvant enfortumab vedotin in cisplatin ineligible patients with MIBC. Patients received 3 cycles of neoadjuvant enfortumab vedotin (1.25 mg/kg) on Days 1 and 8 of every 3-week cycle prior to radical cystectomy and pelvic lymph node dissection. The primary endpoint of the study was pathological complete response rate (ypT0N0) by central review. Key secondary endpoints included pathological downstaging rate (yp T0,Tis,Ta,T1,N0) and safety. The trial design for EV-103 cohort H is as follows:
There were 22 patients treated, with the following clinical stage: cT2 (68.2%), cT3 (27.3%), and cT4 (4.5%) tumors. There were 19 patients that completed all three cycles of enfortumab vedotin and 21 underwent radical cystectomy and pelvic lymph node dissection, with one patient having a partial cystectomy. The median time from the end of neoadjuvant enfortumab vedotin to cystectomy was 1.8 months (range: 1.0-2.7). Overall, 36.4% (95% CI 17.2-59.3) of patients had a pathological complete response, and pathological downstaging was seen in 50.0% (95% CI 28.2-71.8) of patients.
In a study assessing enfortumab vedotin +/- pembrolizumab in cisplatin ineligible patients with previously untreated locally advanced or metastatic urothelial cancer2 (EV-103 Cohort K), the confirmed objective response rate was 64.5% (95% CI, 52.7 to 75.1) and 45.2% (95% CI, 33.5 to 57.3) for patients treated with enfortumab vedotin + pembrolizumab (n = 76) and enfortumab vedotin monotherapy (n = 73), respectively. The median duration of response was not reached for the combination and was 13.2 months for monotherapy, and 65.4% and 56.3% of patients who responded to the combination and monotherapy, respectively, maintained a response at 12 months.
Dr. Drakaki notes that it is important to build upon past knowledge as we move forward:
- We know that durvalumab + tremelimumab is safe and effective in cisplatin ineligible patients
- EV 103 cohort H confirms enfortumab vedotin is also safe and effective in this population
- Durvalumab adds to tremelimumab
- Enfortumab vedotin adds to PD-1 therapy
Thus, based on the aforementioned, Dr. Drakaki suggests that we should study a triple combination of durvalumab + tremelimumab + enfortumab vedotin in the adjuvant setting, which is the hypothesis behind the VOLGA trial:
Moving to the adjuvant disease space, Dr. Drakaki notes that adjuvant chemotherapy after nephroureterectomy is standard of care for upper tract urothelial carcinoma based on the POUT trial. Earlier in 2024, the final results of the POUT trial were published in Journal of Clinical Oncology.3 In the extended follow-up, the 5-year DFS was 62% versus 45%, univariable HR 0.55 (95% CI, 0.38 to 0.80, p = 0.001) benefiting adjuvant chemotherapy vs surveillance. Additionally, the restricted mean survival time was 18 months longer (95% CI, 6 to 30) in the chemotherapy arm. The 5-year OS was 66% versus 57%, with univariable HR 0.68 (95% CI, 0.46 to 1.00, P = .049) and the restricted mean survival time difference was 11 months (95% CI, 1 to 21):
With regards to standard of care for adjuvant therapy for muscle-invasive urothelial carcinoma, Dr. Drakaki discussed the CheckMate 274 trial4 which is a phase 3, randomized, double-blind, multicenter study of adjuvant nivolumab versus placebo. This was a positive trial, with a DFS benefit in both the intention to treat analysis and the PD-L1 > 1% analysis:
Presented at ASCO GU 2024, the AMBASSADOR trial is a phase 3 randomized adjuvant study of pembrolizumab in muscle-invasive and locally advanced urothelial carcinoma versus observation. Patients underwent stratified 1:1 randomization to pembrolizumab 200 mg IV every 3 weeks for 1 year (18 cycles) versus observation. The dual primary endpoints were disease-free and overall survival. The trial design for AMBASSADOR is as follows:
At a median follow-up of 22 months, pembrolizumab improved disease-free survival in the intent-to-treat population from 14 to 29 months (HR: 0.69, 95% CI: 0.54 to 0.87, p=0.001):
PD-L1 status was prognostic, but not predictive of treatment response, for DFS outcomes, as summarized below:
To date, the interim overall survival analyses do not demonstrate a benefit for adjuvant pembrolizumab (HR: 0.98, 95% CI: 0.76 – 1.26, p=0.88):
The IMvigor010 trial5 randomized patients with muscle invasive urothelial carcinoma to adjuvant atezolizumab versus observation, with the following trial design:
Unfortunately, this was a negative trial, with no DFS benefit in the intention to treat population (HR 0.89, 95% CI 0.74-1.08). However, the IMvigor010 trial showed us that circulating tumor DNA (ctDNA) is prognostic and predictive after adjuvant atezolizumab.6 Among 581 patients, ctDNA testing at the start of therapy (cycle 1 day 1) identified 214 (37%) patients who were positive for ctDNA and who had poor prognosis (observation arm HR 6.3, 95% CI 4.45-8.92). Notably, patients who were positive for ctDNA had improved disease-free survival and overall survival in the atezolizumab arm versus the observation arm (disease-free survival HR 0.58, 95% CI 0.43-0.79, OS HR 0.59, 95% CI 0.41-0.86):
Based on these ctDNA results, two trials are now using ctDNA as a randomization factor, including IMvigor011 and MODERN:
Dr. Drakaki notes that with regard to metastatic bladder cancer, it has been a 10 year journey:
Moving to the first line metastatic disease space, there have been several very exciting trials that have recently presented data. CheckMate 901 was presented at ESMO 2023 assessing 1:1 randomization of first-line nivolumab + gemcitabine-cisplatin versus gemcitabine-cisplatin alone. The study met its primary endpoint of OS, with a median improvement of nearly 3 months (21.7 versus 18.9 months; HR: 0.78, 95% CI: 0.63 – 0.96, p=0.017):
The other co-primary endpoint of PFS per BICR was also significant with improvement in median PFS from 7.6 to 7.9 months (HR: 0.72, 95% CI: 0.59 – 0.88, p=0.0012):
A big step forward was the ESMO 2023 presentation of EV-302, a phase III study of enfortumab vedotin and pembrolizumab versus gemcitabine + cisplatin/carboplatin. Patients in this trial were randomized 1:1 to either enfortumab vedotin + pembrolizumab (n=442) or gemcitabine + cisplatin/carboplatin (n=444) for a maximum of 6 cycles. Notably, there were no maximum treatment cycles for enfortumab vedotin (i.e., continued until clinical/disease progression or unacceptable toxicity), whereas pembrolizumab was administered for a maximum of 35 cycles. The dual primary endpoints were progression-free survival, assessed via blinded independent central review (BICR), and OS. The study design is as follows:
A complete response was observed in 29% of patients in the enfortumab vedotin + pembrolizumab arm, compared to 12.5% for platinum-based chemotherapy. The objective response rates were 68% and 44%, respectively:
OS was nearly doubled in the enfortumab vedotin + pembrolizumab arm, with median survivals of 31.5 and 16.1 months, respectively (HR: 0.47, 95% CI: 0.38 – 0.58, p<0.00001). These survival benefits were observed despite a higher proportion of patients in the chemotherapy arm receiving a subsequent systemic therapy (66.2% versus 28.9%):
Dr. Drakaki concluded with highlighting several upcoming and ongoing trials. First, DV-001 is in progress, which is a phase 3 open-label, randomized, controlled study of disitamab vedotin with pembrolizumab versus chemotherapy in untreated locally advanced or metastatic urothelial carcinoma that express HER2:
An ongoing trial is a study of ADRX-0706 in selected advanced solid tumors, with a dose escalation part A in patients with histologically confirmed select solid tumors, and a dose expansion part B in three disease-specific cohorts, including urothelial carcinoma:
A final ongoing trial highlighted by Dr. Drakaki is the LOXO-FG3-22001 trial, an open label, multicenter study of LOXO-435 (LY3866288) in advanced solid tumor malignancies with FGFR3 alterations:
Dr. Drakaki concluded her presentation by discussing key updates in bladder cancer by stating that sometimes there is only one chance for cure, so let’s make a change together.
Presented by: Alexandra Drakaki, MD, University of California Los Angeles, Los Angeles, CA
Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Associate Professor of Urology, Georgia Cancer Center, Wellstar MCG Health, @zklaassen_md on Twitter during the 2024 Southern California Genitourinary Cancer Research Forum, Costa Mesa, CA, Fri, Mar 1, 2024.
References:
- Pfister C, Gravis G, Flechon A, et al. Dose-Dense Methotrexate, Vinblastine, Doxorubicin, and Cisplatin or Gemcitabine and Cisplatin as Perioperative Chemotherapy for Patients With Nonmetastatic Muscle-Invasive Bladder Cancer: Results of the GETUG-AFU V05 VESPER Trial. J Clin Oncol 2022;40(18):2013-22.
- O’Donnell PH, Milowsky MI, Petrylak DP, et al. Enfortumab vedotin with or without pembrolizumab in cisplatin ineligible patients with previously untreated locally advanced or metastatic urothelial cancer. J Clin Oncol. 2023 Sep 1;41(25):4107-4117.
- Birtle AJ, Jones R, Chester J, et al. Improved disease-free survival with adjuvant chemotherapy after nephroureterectomy for upper tract urothelial cancer: Final results of the POUT trial. J Clin Oncol. 2024 Feb 13 [Epub ahead of print].
- Bajorin DF, Witjes JA, Gschwend JE, et al. Adjuvant nivolumab versus placebo in muscle-invasive urothelial carcinoma. N Engl J Med. 2021 Jun 3;384(22):2102-2114.
- Bellmunt J, Hussain M, Gschwend JE, et al. Adjuvant atezolizumab versus observation in muscle-invasive urothelial carcinoma (IMvigor010): A multicentre, open-label, randomized, phase 3 trial. Lancet Oncol. 2021 Apr;22(4):525-537.
- Powles T, Assaf ZJ, Davarpanah N, et al. ctDNA guiding adjuvant immunotherapy in urothelial carcinoma. Nature. 2021 Jl;595(7867):432-437.