ASCO GU 2020: Adjuvant Options in High-Risk Muscle Invasive Bladder Cancer After Primary Intervention

The landscape of adjuvant treatment for high-risk muscle-invasive bladder cancer (MIBC) after a primary intervention has a long history but is still unclear. At the bladder cancer session at GU ASCO 2020, Dr. Matthew Galsky discussed adjuvant treatment options for these high-risk patients. There are several states and state transitions in the adjuvant setting after local therapy (either cystectomy or radiation). Patients are either cured or not cured and then the decision is whether the patient should receive systemic therapy. These states are summarized as follows:

asco gu 2020 treatment options for these high risk patients

asco gu 2020 treatment options for these high risk patients

Dr. Galsky summarized the landscape of adjuvant cisplatin-based combination chemotherapy in bladder urothelial carcinoma as follows:

9 trials
949 patients
HR for OS: 77 (95%CI 0.65-0.91)

But what happens to cisplatin ineligible patients and patients with residual disease after neoadjuvant chemotherapy? In the upper tract urothelial carcinoma literature, Dr. Galsky notes that we have the POUT trial that showed among 260 patients the HR for disease-free survival was 0.49 (95%CI 0.31-0.76).

According to Dr. Galsky, there are several “provocative questions” in the adjuvant setting:

Dose adjuvant chemotherapy cure patients?
Can we identify patients who need treatment?
Can we identify patients who benefit from treatment?
Are we paying attention to the biology?
What are the right endpoints?

Looking at the colorectal cancer literature to assess whether adjuvant chemotherapy can cure patients, Dr. Galsky notes that DFS outcomes after 2- or 3-year median follow-up are excellent predictors of 5-year OS. But who needs adjuvant therapy is difficult and may be assessed with tissue-based or blood-based parameters. Considering the neoadjuvant chemotherapy literature for MIBC, a study of 1,553 patients showed that 314 had a pathological complete response at the time of cystectomy and 1,239 patients had pathologic residual disease.¹ Over a median follow-up 2.65 years (range 0.01-9.97), median survival was 2.5 years (95% CI 2.2-2.9) for those with residual disease and not reached for those with complete response. Dr. Galsky argues that pathologic response to neoadjuvant chemotherapy could act as a surrogate endpoint: this is good at the individual level but poor as surrogate endpoint at the trial-level. Dr. Galsky notes that residual disease at cystectomy after neoadjuvant chemotherapy could serve as a drug development paradigm.

For assessing who may benefit from treatment, Dr. Galsky highlights that DDR alterations may be able to identify patients who should receive adjuvant chemotherapy. In preliminary work, DSS was improved for patients with mutations in ATM, RB1 or FANCC. The PROOF 302 study will randomize mFGFR3 UTUC or MIBC patients that had prior neoadjuvant chemotherapy (≥ pT2 and/or yN+) or cisplatin-ineligible UTUC (≥ pT2 pN0-2 M0, ≥ pT3 or pN+) to infigratinib monotherapy x 12 months (125 mg daily for 21 of 28 days) vs placebo with a primary endpoint of DFS. If biomarkers are predictive and prognostic, we will know who is cured by local therapy and who is not cured with local therapy setting up appropriate adjuvant chemotherapy.

Whether we are paying attention to the relevant biology is debatable. Our tendency is that when a drug shows safety and activity in the metastatic setting, the drug is then moved to the perioperative setting. Dr. Galsky notes that looking at long-term follow-up after radical cystectomy, there are a number of recurrences at 6 months, a few more at 3 years and then the survival curves typically stabilize. What is the genesis for these recurrences? Seeding? Dormancy? Colonization? At this point, we do not know. There are several trials (CheckMate 274, IMvigor010, and AMBASSADOR) that are assessing PD-1/PD-L1 blockade vs placebo or observation among patients with ≥pT3 or pN+ disease or ≥pT2 or pN+ if the patient received prior neoadjuvant chemotherapy. Dr. Galsky notes that as of a news release on January 24, 2020, IMvigor010 adjuvant atezolizumab did not meet its primary endpoint of DFS compared to observation.

Dr. Galsky highlighted several take-home messages from his adjuvant chemotherapy talk:

Adjuvant trials in urothelial bladder carcinoma have faced challenges
ypResidual disease may be the appropriate development path
ctDNA is poised to change the adjuvant paradigm
Clinical design and endpoint harmonization is critical

Presented by: Matthew Galsky, MD, Medical Oncologist, Professor of Medicine, Director of Genitourinary Medical Oncology, Director of the Novel Therapeutics Unit, and Co-Director of the Center of Excellence for Bladder Cancer, Tisch Cancer Institute and the Icahn School of Medicine, Mount Sinai, New York, New York

Written By: Zachary Klaassen, MD, MSc – Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, Twitter: @zklaassen_md at the 2020 Genitourinary Cancers Symposium, ASCO GU #GU20, February 13-15, 2020, San Francisco, California

References:
1. Waingankar N, Jia R, Marqueen KE, et al. The impact of pathological response to neoadjuvant chemotherapy on conditional survival among patients with muscle-invasive bladder cancer. Urol Oncol 2019 Sep;37(9):572.e21-572.

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