Collecting duct carcinoma: new biological inroads in this rarest of rare cancers

A key to developing novel treatment approaches for rare cancers is unraveling elements of their biology. In this issue of ESMO Open, Rametta et al.¹ do just that, highlighting the expression of two antigens (nectin-4 and trop-2) in patients with collecting duct carcinoma (Figure 1). It is important to recognize that collecting duct carcinoma represents a diagnosis of exclusion, with the differential diagnosis including other renal medulla-derived cancer types such as upper tract urothelial carcinoma and renal medullary carcinoma.² The genomic underpinnings of the disease are poorly understood—in a series of 19 patients, the most commonly observed molecular alterations occurred in NF2 (neurofibromin 2, a tumor-suppressor gene encoding merlin), SETD2 (SET domain containing 2, a histone methyltransferase and tumor-suppressor gene), and CDKN2A (cyclin-dependent kinase inhibitor 2A, a tumor-suppressor gene involved in cell-cycle regulation).³ However, sparse literature exists to link these alterations to meaningful responses to existing targeted therapies.

Figure 1.

Outline of pathways salient to the current and possible future treatment options for collecting duct carcinoma.

AXL, AXL receptor tyrosine kinase; MET, mesenchymal-epithelial transition factor; MHC, major histocompatibility complex; PD-1, programmed cell death protein 1; PD-(L)1, programmed death-ligand 1; TCR, T-cell receptor; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor.

Impressively, three prospective studies have been completed to guide management of patients with advanced collecting duct carcinoma. In 2007, Oudard et al.⁴ reported results from a phase II study assessing the combination of either cisplatin or carboplatin with gemcitabine in 23 patients, yielding one complete and five partial responses [objective response rate (ORR) 26%]. Median progression-free survival (PFS) was 7.1 months and median overall survival (OS) was 10.5 months. Several of the investigators affiliated with this study later reported a small series of five patients treated with platinum–gemcitabine in conjunction with bevacizumab. In this experience, three responses (60%) were observed and the median PFS and OS were an impressive 15.1 months, respectively.⁵ Unfortunately, this success was not replicated in a prospective phase II study evaluating the same regimen in patients with both collecting duct carcinoma and renal medullary cancer.⁶ The study was terminated after an interim analysis due to a lack of additional benefit with bevacizumab and an increase in toxicity. Most recently, Procopio et al.⁷ reported results from the phase II BONSAI study (caBozantinib in cOllectiNg ductS Renal Cell cArcInoma, a phase 2 trial evaluating first-line cabozantinib in metastatic collecting duct carcinoma), evaluating cabozantinib in patients with advanced collecting duct carcinoma. Among 23 assessable patients, one complete response and seven partial responses were observed (ORR 35%). Although the response rate is indeed impressive, median PFS was a modest 4 months and median OS was just 7 months. In a follow-up experience termed BONSAI-2, patients received nivolumab after failure of cabozantinib.⁸ Among four assessable patients, one partial response and two stable disease events were observed. However, with these limited numbers, it is hard to draw definitive conclusions about the role of immunotherapy in this setting.

The investigators leading the aforementioned studies deserve hearty congratulations for enrolling patients in this exquisitely rare setting. However, it is fair to say that no regimen has produced durable responses in a large proportion of patients. Testing the noted chemotherapy regimens in collecting duct carcinoma lends itself to the presumed similarity between this entity and urothelial cancer. In this regard, it is worthwhile exploring whether newer agents for urothelial cancer may bear relevance. The study from Rametta et al.¹ provides insight into this approach. The expression of nectin-4 and trop-2 in 41% and 89% of cases examined, respectively, suggests that drugs targeting these entities may be relevant in this setting. Enfortumab vedotin, an antibody–drug conjugate (ADC) linking a nectin-4 antibody to a monomethyl auristatin E payload, has shown activity in the neoadjuvant and metastatic settings of urothelial cancer.⁹ The role of sacituzumab govitecan (an ADC of a trop-2 antibody linked to an SN-38 [7-ethyl-10-hydroxycamptothecin, the active topoisomerase I-inhibiting metabolite of irinotecan and the cytotoxic payload of sacituzumab govitecan] payload) is more controversial in urothelial cancer, with a phase III study suggesting no benefit in PFS and OS versus conventional chemotherapy in patients who had previously progressed on platinum-based regimens and a checkpoint inhibitor.¹⁰ Still, sacituzumab govitecan remains approved for use in specific settings in advanced breast cancer and (in the opinion of the authors) warrants further investigation in collecting duct carcinoma in the advanced setting.¹¹ It is encouraging to see that investigators associated with the biomarker study that is the subject of this editorial have forged ahead with a prospective phase II study of enfortumab vedotin with pembrolizumab in collecting duct carcinoma (NCT06302569). Their work published in this journal serves as sound justification for further clinical exploration and represents the path toward breakthroughs in this rare disease.