EAU 2021: State-of-the-Art Lecture: Does Every Metastatic Patient Need Immunotherapy in a First-Line Setting?

(UroToday.com) Dr. Enrique Grande from Madrid, Spain provided a state-of-the-art lecture at the European Association of Urology (EAU) 2021 annual meeting’s advanced bladder cancer session discussing immunotherapy in the first-line setting for metastatic bladder cancer. Dr. Grande notes that over the last several years, it seems that immunotherapy covers the entire spectrum of first-line treatment of metastatic bladder cancer. In cisplatin eligible patients, avelumab maintenance therapy is standard of care for those that respond to first-line cisplatin-based chemotherapy. For cisplatin ineligible patients, those that respond to first-line carboplatin-based chemotherapy should also receive avelumab maintenance therapy. Additionally, for PD-L1+ cisplatin ineligible patients, they can also receive first-line single-agent atezolizumab or pembrolizumab therapy:

The key question is “does every metastatic patient need immunotherapy in the first-line setting?” Given the interpatient heterogeneity, intratumoral heterogeneity, and temporal heterogeneity, it is not an easy question to answer. Dr. Grande notes that there are key gaps that still need to be filled for immunotherapy in metastatic urothelial cancer:

Only a minority of patients with otherwise terminal cancer experience life-altering durable survival
There is a lack of reliable biomarkers
Even in those patients who respond to immune checkpoint inhibitors, we do not know the drivers of the primary versus secondary immune landscape
There is a need for a deeper knowledge of the impact of steroids and antibiotics on immune checkpoint inhibitor outcomes and autoimmune toxicities

Dr. Grande questions if response to treatment is secondary to cisplatin-sensitivity or just tumor biology. Assessing the survival curves of the original neoadjuvant chemotherapy clinical trials, it is evident that ~10-20% of cisplatin-eligible patients are long-term survivors (>84 months). Perhaps we are able to clinically identify those patients early that may be cisplatin long-term survivors. Dr. Grande notes that patients without visceral metastases and those with good Karnofsky performance scores are more likely to be cisplatin responders and long-term survivors:

For patients that respond to first-line chemotherapy, do all need maintenance avelumab based on the JAVELIN Bladder 100 trial?¹ Looking at the Kaplan-Meier survival curves from JAVELIN Bladder 100, approximately 25% of patients in the best supportive care arm had durable survival without receiving maintenance avelumab:

Looking closer at this trial, specifically, those that achieved a complete response with first-line chemotherapy, the data is even more striking: for those randomized to best supportive care, more than 50% of patients were long-term survivors without any additional therapy:

Dr. Grande notes that perhaps molecular biology can help us identify those that may not need immunotherapy. A recent consensus on the molecular classification of MIBC showed that among 1,750 MIBC transcriptome profiles there were six molecular classes: luminal papillary (24%), luminal nonspecified (8%), luminal unstable (15%), stroma-rich (15%), basal/squamous (35%), and neuroendocrine-like (3%).² These subtypes are able to prognosticate overall survival:

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Dr. Powles recently presented subgroup analyses of the JAVELIN Bladder 100 trial at ASCO 2021 stratified by molecular subtype, highlighting that the OS benefit for avelumab + best supportive care was apparent across TCGA subtypes except for the luminal subtype:

However, Dr. Grande cautions that there is a lack of clear consistency in response to immunotherapy by molecular subgroup. For example, in the IMVIGOR-210 trial assessing atezolizumab, the basal 1 cluster III subtype had poor complete response rates with the majority of patients having progressive disease, whereas the same subtype in the nivolumab CheckMate-275 trial had the highest complete response rate of any subtype:

Dr. Grande suggests that maybe we should be asking ourselves in what patients does immunotherapy not work? For example, among F-TBRS_high patients, atezolizumab monotherapy had poor overall survival, with a median OS of only 7.7 months. Furthermore, in the DUTRENO trial assessing neoadjuvant durvalumab + tremelimumab, patients with the combination immunotherapy regimen that were PD-L1 low had the worst pT0 rates at only 14.3%.

Dr. Grande concluded his presentation emphasizing that not every metastatic patient needs immunotherapy in the first-line setting, but we still may not be able to identify those patients that can wait to use immunotherapy at the time of disease progression. With the help of molecular subtypes, the following figure highlights the potential future landscape of sequencing therapy for metastatic urothelial carcinoma:

Presented by: Enrique Grande, MD, MD Anderson Cancer Center, Madrid, Spain

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 European Association of Urology, EAU 2021- Virtual Meeting, July 8-12, 2021.

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