(UroToday.com) The ANZUP 2021 annual scientific meeting included a presentation by Dr. Matthew Galsky discussing the evolving treatment landscape for metastatic urothelial cancer. Dr. Galsky started by highlighting that urothelial carcinoma is not an uncommon malignancy, accounting for 82,000 new diagnoses/year in the United States and ~429,000 new diagnoses/year worldwide. However, until recently, the FDA approvals for new therapeutics in urothelial cancer over the last 30 years has been dismal:
Since 2016-2017 the resurgence of approvals in urothelial carcinoma have been fueled by the advent of immune checkpoint inhibitors for locally advanced and metastatic urothelial carcinoma, including atezolizumab, nivolumab, durvalumab, avelumab, and pembrolizumab:
However, the accelerated FDA approval pathway has had challenges, with FDA approval being revoked for atezolizumab and durvalumab in the post-platinum setting. Based on the age and comorbidities of urothelial carcinoma patients, approximately 50% of patients are “cisplatin-ineligible” secondary to: (i) ECOG performance status = 2, (ii) creatinine clearance < 60 mL/min, (iii) Grade >= 2 hearing loss, (iv) Grade >= 2 neuropathy, and (v) New York Heart Association Class III congestive heart failure. Atezolizumab and pembrolizumab were initially approved via the accelerated FDA approval pathway for front-line treatment of cisplatin-ineligible patients, however based on recent data and additional FDA review, pembrolizumab has full approval only in platinum-ineligible patients, whereas the approval for atezolizumab is still under review:
Subsequently, a series of randomized clinical trials have recently refined first-line treatment for metastatic urothelial carcinoma, aiming to answer several questions:
- DANUBE : is there a role for chemotherapy + immunotherapy?
- KEYNOTE 361 : is there a role for immunotherapy alone upfront?
- IMvigor 130 : is there a role for biomarker selection for immunotherapy?
- JAVELIN-100 : is there a role for “switch maintenance” immunotherapy?
- CheckMate 901: is there a role for immunotherapy doublet therapy?
In the phase 3 JAVELIN Bladder 100 trial, avelumab first-line maintenance + best supportive care significantly prolonged overall survival versus best supportive care alone in patients with advanced urothelial carcinoma that had not progressed on first-line platinum-based chemotherapy (HR 0.69, 95% CI 0.56 to 0.86; 1-sided p = 0.0005):
Based on the IMvigor 130 and KEYNOTE 361 trials, platinum-based chemotherapy + anti-PD-1/PD-L1 leads to minor improvements in progression free survival in the intention to treat cohorts. However, neither of these studies have led to significant improvements in overall survival. Dr. Galsky emphasized that this was a combination of therapeutics that most oncologists thought would be more beneficial for advanced urothelial carcinoma patients, specifically based on previous results of similar combination regimens in other solid organ malignancies such as lung cancer. One of the potential clues to these differences may be the immunomodulatory effects underlying durable responses with cisplatin in urothelial cancer. In work presented by Dr. Galsky at ESMO 2021, exploratory data from the randomized phase III IMvigor130 study suggest improved OS with the addition of atezolizumab to cisplatin but not carboplatin-based chemotherapy. Together, these findings raise the hypothesis that cisplatin may be associated with specific favorable immunomodulatory effects. Furthermore, the effects of cisplatin +/- atezolizumab on overall survival are most prominent in patients with PD-L1 IC-high tumors as depicted in the following table:
Subsequently, single-cell RNA sequencing was performed on peripheral blood mononuclear cells (PMBCs) obtained at Cycle 1 Day 1 and Cycle 3 Day 1 from 70 IMvigor130 patients receiving atezolizumab + platinum and gemcitabine (platinum [cisplatin or carboplatin]/gemcitabine; Arm A) or placebo + platinum/gemcitabine (Arm C):
Gene expression profiling of paired pre-/post- neoadjuvant gemcitabine + cisplatin samples was used to study cisplatin-related changes in the tumour microenvironment (tumor microenvironment; n=113).
In IMvigor130 Arm C cisplatin- vs carboplatin-treated patients, on-treatment enrichment of Hallmark TNFα signaling via NFkB and inflammatory response gene sets was observed across all immune cell clusters, with trends even more pronounced in Arm A. Among top-ranked genes enriched in PBMCs post-cisplatin versus post-carboplatin was NINJ1, which mediates plasma membrane rupture during lytic cell death, releasing damage-associated molecular patterns (eg, HMGB1). In a separate cohort in the neoadjuvant setting, TNFα signaling via NFkB was also enriched in paired tumour samples post- versus pre-gemcitabine + cisplatin chemotherapy:
Dr. Galsky notes that the above study may suggest that perhaps the type of chemotherapy does matter and why there was less of an efficacious therapeutic benefit seen in these clinical trials. Certainly, the utility of PD-L1 testing is not particularly clear, likely secondary to different scoring systems (tumor cell, immune cell) as highlighted in the following table:
When looking at platinum-based chemotherapy versus anti-PD-1/PD-L1 in the upfront setting in the DANUBE, KEYNOTE 361, and IMvigor 130 trials, there was minimal difference between chemotherapy and immunotherapy. However, when limited to the PDL1+ populations, a benefit from immunotherapy emerges, albeit with different assays identifying different subsets of patients:
Unfortunately, based on the DANUBE trial, a combination of anti-CTlA4 (tremelimumab) + anti-PD-L1 (durvalumab) versus chemotherapy did not reach its primary endpoint of overall survival benefit. Of note, this is also the trial design of the yet to report results CheckMate 901 trial testing nivolumab + ipilimumab versus chemotherapy, albeit with the primary analysis being restricted to patients with high PD-L1 expression.
Dr. Galsky notes that the landscape of metastatic urothelial carcinoma in 2021 is as follows:
Dr. Galsky emphasized that there are three main areas of interest with regards to future directions: (i) moving treatment earlier, (ii) combination regimens, and (iii) biomarkers. For the remainder of the discussion, Dr. Galsky focused on several upcoming combination regimens that are showing promise, including PD-1/PD-L1 + CTLA4 blockade, ADC-based combinations, VEGFR TKI-based combinations, FGFR3-based combinations, and sEphB4-BSA combinations. With regards to ADCs + PD-1/PD-L1 blockade, two particular trials have shown response benefit. The combination of the anti-nectin-4 agent enfortumab vedotin + pembrolizumab demonstrated an objective response rate of 73%. Similarly, the anti-HER2 agent RC48 + toripalimab showed an objective response rate of 94%. Albeit small, single-arms studies, Dr. Galsky highlighted that these are quite unprecedented response rates in this disease space. As such, the combination of enfortumab vedotin + pembrolizumab has been moved forward to the phase 3 trial setting (EV-302), testing the combination regimen versus platinum-based chemotherapy in patients with chemotherapy naïve metastatic urothelial carcinoma. The primary endpoints for this trial are overall survival and progression free survival.
FGFR3 mutations are somewhat common in metastatic advanced urothelial carcinoma, particularly on Exon 7 (R248C – 9.7%; S249c – 66.6%) and Exon 10 (G372C – 4.3%; Y375C – 15.1%). Of note, genetic silencing of FGFR3 leads to upregulation of immune related gene sets. Several trials have shown a response signal combining FGFR3 inhibition with PD-1/PD-L1 blockade. This includes erdafitinib + cetrelimab with an objective response rate of 55% (as well as the phase 2 NORSE trial at ESMO showing an objective response rate of 68%), and the combination of rogaratinib + atezolizumab showing an objective response rate of 58%.
The last combination discussed by Dr. Galsky was pembrolizumab + the tyrosine kinase sEphB4-HSA. Presented at ESMO 2021, over a median follow up of 23.0 months, in the entire cohort of 70 patients, the median duration of response was not reached (95% CI 13.3 to not reached), with a 21.4% partial response rate and 15.7% complete response rate. In patients that were EphrinB2+ (n=46), the median duration of response was also not reached (95% CI 11.9 to not reached), with a 28.3% partial response rate and a 23.9% complete response rate:
Dr. Galsky concluded his presentation of the evolving treatment landscape for metastatic urothelial carcinoma with the following summary points:
- Immunotherapy has changed the metastatic urothelial carcinoma treatment landscape
- Platinum-based chemotherapy followed by immunotherapy maintenance is now standard of care
- Moving immunotherapy earlier in the disease landscape will impact metastatic urothelial carcinoma treatment
- There are multiple exciting combination regimens in late stage development
Presented by: Matthew Galsky, MD, Director of Genitourinary Medical Oncology, Tisch Cancer Institute, Professor of Medicine, Mount Sinai
Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, @zklaassen_md on Twitter during the 2021 Australian and New Zealand Urogenital and Prostate (ANZUP) Cancer Trials Group Annual Scientific Meeting (ASM), Sunday, Oct 17 – Monday, Oct 18, 2021.
- Powles T, van der Heijden MS, Castellano D, et al. Durvalumab alone and durvalumab plus tremelimumab versus chemotherapy in previously untreated patients with unresectable, locally advanced urothelial carcinoma (DANUBE): A randomized, open-label, multicentre, phase 3 trial. Lancet Oncol. 2020;21(12):1574-1588.
- Powles T, Csoszi T, Ozguroglu M, et al. Pembrolizumab alone or combined with chemotherapy versus chemotherapy as first-line therapy for advanced urothelial carcinoma (KEYNOTE-361): A randomized, open-label, phase 3 trial. Lancet Oncol. 2021 May 26;S1470-2045(21)00152-2.
- Galsky MD, Arranz Arija JA, Bamias A, et al. Atezolizumab with or without chemotherapy in metastatic urothelial cancer (IMvigor130): A multicentre, randomized, placebo-controlled phase 3 trial. Lancet. 2020 May 16;395(10236):1547-1557.
- Powles T, Park SH, Voog E, et al. Avelumab Maintenance Therapy for Advanced or Metastatic Urothelial Carcinoma. N Engl J Med 2020 Sept 24;383(13):1218-1230.