Cabozantinib Active Across Non-Clear Cell Kidney Cancers

Cabozantinib (Cabometyx) yielded clinical activity in heavily pretreated patients with a type of kidney cancer that is notoriously difficult to treat, a retrospective study found.

Among 112 non-clear cell renal cell carcinoma (RCC) patients treated with cabozantinib, 27% achieved an objective response, which included one complete response, reported Lauren Harshman, MD, of the Dana-Farber Cancer Institute in Boston, and colleagues.

Among evaluable patients, the clinical benefit rate was 74%, defined as those who achieved an objective response or stable disease on treatment. At a median 11 months follow-up, progression-free and overall survival were 7 and 12 months, respectively.

“In the absence of available prospective data, our study provides additional evidence for the safety and potential activity of cabozantinib in patients across the metastatic non-clear cell renal cell carcinoma spectrum,” the authors wrote in Lancet Oncology. “Our study cohort consisted of heavily pretreated patients, with 24% having had three or more previous systemic therapies and 89% having poor-risk or intermediate-risk disease.”

Objective responses were seen across all histologic subtypes:

• Papillary: 18 of 66 patients (27%)

• Xp11.2 translocation: 5 of 17 patients (29%)

• Unclassified: 2 of 15 patients (13%)

• Chromophobe: 3 of 10 patients (30%)

• Collecting duct: 2 of 4 patients (50%)

Among 54 patients whose tumors were sequenced, the most common somatic mutations were CDKN2A (22%) and MET (20%), but responses were seen regardless of patients’ mutational status.

“Despite the shortcomings of a retrospective cohort study, absence of central pathology and radiology review, and the complex mixture of non-clear cell tumor histology, this study provides clinicians with credible information that can guide treatment of these notoriously difficult tumors,” said Paul Russo, MD, of Memorial Sloan Kettering Cancer Center in New York City, in a comment that accompanied the study. “Because of the rarity of these tumors, large-scale prospective trials that are successful in metastatic clear cell renal cell carcinoma will be difficult, if not impossible, to do.”

He called the oncologists’ determination to provide real-world care while obtaining and analyzing the data “truly remarkable,” and urged them to reproduce these efforts.

“Awaiting the arrival of more effective systemic agents, and fine-tuning drug selection based on genomics and other biomarkers might allow these investigators the opportunity for future and increasingly effective attempts to tackle these particularly lethal forms of kidney cancer,” said Russo.

For their study, Harshman’s group found 112 metastatic non-clear cell RCC patients across 21 centers in the U.S. and one in Belgium who were treated with daily 60-mg cabozantinib, a tyrosine kinase inhibitor that targets the VEGF, MET, and AXL receptors. Most patients had papillary histology (59%), followed by translocation (15%), unclassified histology (13%), chromophobe (9%), and collecting duct (4%). The one complete response was in a patient with papillary RCC who had previously received radical nephrectomy 3 years prior to metastatic relapse, then achieved stable disease with first-line pazopanib.

Most patients (n=90) received cabozantinib as second- or later-line therapy, though some were treated in first-line (n=22). Rates of response were similar, at 28% and 23%, respectively. Responses were seen in patients with (20%) and without (25%) sarcomatoid features.

At the time of the study analysis, 38 patients remained on cabozantinib while 74 had discontinued therapy. Among those who discontinued, 85% did so due to disease progression (median time to treatment failure was 6.7 months), 7% for toxicity, and 8% for physician or patient preference or other reasons.

Fatigue (52%) and diarrhea (34%) were the most common adverse events of any grade. Grade 3 skin toxicity and hypertension occurred in five and four patients each, respectively. No treatment-related deaths were observed.