ASCO 2019: Classification and Management of Infrequent Genitourinary Malignancies

Chicago, IL (UroToday.com) Samuel A. Funt, MD, provided a summary and analysis of 3 abstracts at ASCO 2019. In this presentation, he focused on filling in the knowledge gaps for patients with metastatic urothelial cancer.

Abstract 4518: Phase II study of nivolumab and ipilimumab for advanced bladder cancer of variant histologies (BCVH)

McGregor et al. assess, in a phase II trial, whether immune checkpoint inhibition (ICIs) are effective in bladder cancers of variant histologies (BCVH), which is increasingly gaining attention. Despite being found in up to 30% of advanced bladder cancers and having a poor prognosis, they are routinely excluded from clinical trials. In this multicenter study, these patients were treated with Nivo/Ipi and then put on nivo maintenance. Objective response ate (ORR) was 37%, and 47% of patients remained on therapy. One complete response (CR) was noted in a patient with plasmacytoid histology. A summary of the responses by histology is seen below:

ASCO2019 RESIST

Median progression free survival (PFS) was 3.8 months and 6-month overall survival (OS) was 81%.

The knowledge gaps that this study filled are as follows:

Addressed:

  • Nivo/Ipi is active in BCVH
Remaining questions:

  • Would Nivo 1/Ipi 3 have been a better regimen?
  • Nivo 1/Ipi 3 (CheckMate-032): ORR was 38% (vs. 27% for Nivo3/Ipi1)
  • There is an ongoing trial of Durvalumab/Tremililumab that may add more data in this space.
  • Correlate studies are needed.
Abstract 4519: Clinical outcomes according to PD-L1 status and age in the prospective international SAUL study of atezolizumab (atezo) for locally advanced or metastatic urothelial carcinoma (UC) or non-UC of the urinary tract 

Sternberg et al. reported on clinical outcomes according to PD-L1 status and age from the results of the prospective international SAUL study of atezolizumab (atezo) for locally advanced or metastatic urothelial carcinoma (UC) or non-UC of the urinary tract. The SAUL study was a real-world study of atezolizumab not limited to patients who met the original IMvigor211 criteria.

The main results of this study are collated into this nice table that Dr. Funt made:

ASCO2019_IMvigor211.png

His main points:

  • In the entire cohort of 997 patients, median OS was 8.6 months and ORR was 13%, similar to the actual IMvigor211 study
  • In the ~2/3 of patients who met IMvigor inclusion criteria, ORR was 14% and the median OS was 10 months – actually better than the original trial!
  • Patients with ECOG status 2 do poorly – median OS 2.3 months, 5% ORR
  • Patients with CNS mets do poorly – median OS 3.7 months, ORR 0%
  • Patients with renal impairment (excluded in the original study) actually did well, ORR 13% and median OS 5.7 months
  • Patients with some (not severe) autoimmune diseases (excluded in the original study) actually did well, ORR 11% and median OS 8.2 months
  • Patients with non-urothelial BCVH did well, ORR 9% and median OS 7.3 months – though clearly not as well as the prior abstract combo of ipi/nivo:
ASCO2019 IMvigor211

Knowledge Gaps that this study filled are as follows:

Addressed:

  • SAUL “real-world” results replicated the IMvigor211 trial results
  • Older patients do as well as younger patients
  • Patients with brain metastases and poor ECOG status do poorly
  • Atezo is safe in patients with renal impairment and autoimmune disease
Remaining questions:

  • Immune checkpoint blockade in BCVH and HIV patients remains understudied
  • Additional studies in real-world challenging patient populations should continue!
Abstract 4581: Comprehensive genomic profiling (CGP) of upper-tract (UTUC) and bladder (BUC) urothelial carcinoma reveals opportunities for therapeutic and biomarker development 

Necchi et al. completed a comprehensive genomic profiling (CGP) of upper-tract (UTUC) and bladder (BUC) urothelial carcinoma, which revealed important opportunities for therapeutic and biomarker development. They analyzed 2463 cases, by far the largest study to address this question. Of these, 479 were UTUC and 1984 were from UCB. Some key findings are (compared to the results by Audenet CCR 2018 of ~600 patients):

  • TP53, RB1 and ERBB2 alterations are more common in UCB
  • HRAS and FGFR3 are more common in UTUC
  • TMB is lower or similar in UTUC than in UCB
  • %MSI-H is higher in UTUC than UCB
  • 39% of UC had tier 1-2 actionable mutations (treatable with approved medications or investigational targeted therapies)
  • A further 29% had tier 3 actionable mutations (provides a strong rationale for clinical trial consideration)
  • Concordance between tissue and liquid biopsies decreases with time – concordance was highest if done within 180 days of each other (67% vs. 50%, respectively)
What knowledge gaps were filled by this study?

Addressed:

  • Everyone with mUC should be sequenced
  • FGFR3 mutations and MSI-H are more frequent events in UTUC
Remaining questions:

  • What are the clinical outcomes of UTUC and UCB patients with genomic variants?
  • What is the genomic landscape of the variant histologies?
  • Can ctDNA results be used to guide therapy? Is it better than tumor DNA?

Presented by: Samuel A. Funt, MD, Medical Oncologist, Memorial Sloan Kettering Center, New York, New York, United States

Written by: Thenappan Chandrasekar, MD, Clinical Instructor, Thomas Jefferson University, @tchandra_uromd, @JEFFUrology, at the 2019 ASCO Annual Meeting #ASCO19, May 31- June 4, 2019, Chicago, IL USA
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