A Q&A with MSK’s Dr. Jonathan Coleman
MSK’s comprehensive program for patients with upper tract urothelial carcinoma (UTUC) offers kidney-sparing treatment options whenever possible.
“Traditionally, radical nephroueterectomy has been the gold standard for managing high-risk UTUC,” said urologic surgeon Jonathan Coleman, MD. “But the knee-jerk reaction to take out every kidney with a high-grade cancer doesn’t always apply. MSK offers treatment options not available at other centers that are helping more patients with UTUC achieve better outcomes, including avoiding kidney removal and the worry about potentially needing dialysis.”
In this Q&A with Dr. Coleman, we discuss MSK’s renal preservation options for patients with complicated UTUC and discover MSK’s multidisciplinary program that extends from the lab to clinical care to trials in progress.
How does UTUC differ from bladder cancer, and what does the patient population look like?
UTUC is a tumor type that is similar to bladder cancer, but the tumor is located in the renal pelvis, arising from the cells lining the kidneys and the ureters. It has similar causes as bladder cancer but is increasingly recognized as a genomically distinct disease. UTUC is rare, occurring in about 7,000 cases annually in the United States. It tends to affect older patients who often have other significant medical conditions, including reduced kidney function.
UTUC has a five-year mortality rate higher than 50%, compared to less than 25% for bladder cancer.
What is MSK’s approach to managing complex UTUC cases?
One of the things MSK does very well is treating complicated cancer cases such as UTUC with multidisciplinary expertise. For example, I have a patient with UTUC and lung cancer – both caused by smoking and with a high metastatic potential. He essentially has only one functioning kidney, and it is the one affected by UTUC. He was told by other centers his only option was kidney removal and dialysis.
The patient came to MSK after learning there’s no other program, even within New York City, where patients with UTUC can receive the latest treatment options. Our multidisciplinary team of medical oncologists and surgeons are collaborating to develop an individualized treatment strategy to provide him with a combination of organ-sparing surgery and effective drug therapies to target both tumor types based on genetic markers with the hope of achieving the best possible outcome.
What advances have made renal preservation possible for a growing number of patients?
Recently, MSK led a groundbreaking clinical trial of dostarlimab, a first-line immune checkpoint inhibitor, for patients with locally advanced rectal tumors with mismatch repair deficiency (MMRd). The strategy was incredibly effective — all 18 patients achieved a complete clinical response with no evidence of tumor within at least six months of follow-up. The study participants avoided standard surgery, chemoradiation, and chemotherapy, which can result in life-altering bowel and bladder dysfunction, incontinence, and sexual dysfunction.
The trial was led by MSK medical oncologist Andrea Cercek, MD, Section Head of Colorectal Cancer, and physician-scientist Luis Diaz Jr., MD, Head of the Division of Solid Tumor Oncology. The impressive results were published in the New England Journal of Medicine.
Last year, we reported the results of a retrospective study of our clinical experience at MSK supporting immune checkpoint inhibition as a neoadjuvant therapy or as an organ-sparing option for patients with Lynch syndrome. We identified 10 patients with Lynch syndrome-associated UTUC who were treated with immune checkpoint inhibitors. Seven patients had solitary kidneys resulting from prior nephroureterectomy. Of the four patients with localized disease, 75% had a complete response, and of the six patients with metastatic disease, 67% were progression-free at 24 months.
Dr. Cercek is now investigating whether the same approach will help a broader group of patients with locally advanced MMRd solid tumors avoid surgery in a Phase 2 study of dostarlimab (NCT04165772). The study includes patients with UTUC caused by Lynch syndrome, which is defined by inherited mismatch-repair mutations in the MLH1, MSH2, MSH6, PMS2, or EPCAM genes.
Lynch syndrome is typically associated with an elevated risk of developing colon cancer, rectal cancer, and ovarian cancer. However, many clinicians are unaware it is found in a sizeable proportion of UTUC cases. When we screen for Lynch in this patient population, we find it in about 9 to 12% of patients.
Does MSK screen all patients with UTUC for Lynch syndrome?
Yes. At MSK, we recommend all patients with UTUC undergo both genetic and germline genomic testing using MSK-IMPACT® (Integrated Mutational Profiling of Actionable Cancer Targets), our targeted tumor-sequencing test.
I recently led the team of experts who published the first American Urologic Association/Society of Urologic Oncology guidelines for diagnosing and managing non-metastatic UTUC. The guidelines recommend universal screening for Lynch syndrome.
We are trying to get the word out that all patients with UTUC should be screened for Lynch syndrome, not only to inform treatment options but also because it is an inherited syndrome associated with a higher risk of several other cancers, including the main three but also gastric, small bowel, pancreatic, prostate, bile duct, and brain cancers, and sarcomas.
People with a first-degree relative with Lynch syndrome have a 50% chance of inheriting it. Identifying Lynch predisposition in patients means we can also screen their family members and hopefully identify tumors earlier or, in some cases, take preventive steps to avoid the risks of these cancers developing.
Does MSK-IMPACT® reveal other actionable mutations relevant to UTUC?
Yes. Genomic testing with MSK-IMPACT® may reveal FGFR3 (fibroblast growth factor receptor 3) mutations, which affect about 60% of patients with UTUC. Knowing a tumor has this mutation may open the door for treatment with the targeted therapy erdafitinib. By contrast, FGFR3 mutations are less prevalent in bladder cancer, affecting about 10 to 15% of patients.
You recently reported the results of a clinical trial investigating a split-dose neoadjuvant regimen. What were the highlights?
We recently led a multisite Phase 2 trial of neoadjuvant gemcitabine and split-dose cisplatin for patients with high-risk UTUC before kidney removal surgery. The split-dose approach was well tolerated and effective, with higher survival outcomes compared to historical series.
Specifically, of the 57 patients evaluated, 36, or 63%, had a pathologic response, with a complete pathologic response found in 11 patients (19%). At a median follow-up of 3.1 years, the two- and five-year progression-free survival rates were 89% and 72%, and overall survival rates were 93% and 79%, respectively. These results were published in the Journal of Clinical Oncology. This approach is now recommended for our patients with high-grade cancers before surgery.
How does your lab research factor into finding new treatment options for patients with UTUC?
My research lab is one of very few dedicated to studying UTUC. Our work is fully funded by grants from the National Institutes of Health and the Department of Defense, and philanthropic donations.
Our focus is on understanding the mechanisms of disease progression and recurrence and responses to therapies. We employ genomics, transcriptomics, metabolomics, and tumor immune microenvironment profiling of patient samples, as well as patient-derived organoids and xenograft models.
Our lab has also been leading the development of novel photodynamic therapies for local tumor ablation, using preclinical models to support translational studies for ongoing clinical trials. One active area of investigation is studying combinations of photoablation with immunotherapies.
In a nutshell, what sets MSK’s program for patients with UTUC apart from other centers?
At MSK, our focus is on helping patients avoid losing a kidney whenever possible. We have the specialized expertise required to manage complex UTUC cases and leverage all existing technologies and treatment options. We also invest in translational research to discover new ways to improve patients’ survival and quality of life.
