ASCO 2021: A Phase 2 Single-Arm Study of Cabozantinib in Patients with Advanced or Unresectable Renal Cell Carcinoma Pretreated with One Immune Checkpoint Inhibitor: The BREAKPOINT Trial (MeetUro Trial 03-NCT03463681)

( While vascular endothelial growth factor (VEGF)-targeted therapy was the standard of care for more than a decade, there have been transformational changes in first-line therapy for patients with advanced renal cell carcinoma (RCC) in the past three years. Foremost among these is the move from monotherapy to combination approaches. While CheckMate 214 first brought combination therapy with dual checkpoint inhibition (nivolumab and ipilimumab) to the forefront, subsequent studies have examined combinations of immune checkpoint inhibitors and tyrosine-kinase inhibitors in the first-line setting. However, the use of combination therapy in the first-line setting has further emphasized the need to identify novel therapeutic targets and further lines of therapy. In the Kidney and Bladder Poster session at the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting, Dr. Giuseppe Procopio presented data examining the role of cabozantinib in patients who had previously received immunotherapy.

To do so, the authors performed an open-label, single-arm, multicenter, phase II study (NCT03463681) among patients with mRCC who received an anti-PD-1/PD-L1-agent in the adjuvant or first-line metastatic space. Patients received cabozantinib 60 mg/daily until progressive disease (PD) or unacceptable toxicity.


The authors examined, as the primary endpoint, progression-free survival (PFS) by Brookmeyer-Crowley test, as well as secondary endpoints including overall survival (OS), objective response rate (ORR), and safety. In addition, the authors performed exploratory analyses of tissue PD-L1 expression, to assess the modulating activity of cabozantinib on local and systemic tumor immunity and to explore bone formation and reabsorption markers.

The authors enrolled 49 patients of whom 48 were included in the analysis. The median age of included patients was 62.5 years (range: 30-78) and 63% of patients were male. At baseline, 26% of patient had IMDC (Heng) good risk disease, 47% had intermediate-risk disease, and 28% had poor-risk disease, while IMDC risk group could not be determined in 2%. Three-quarters (74%) of patients received an IO-IO combo as first-line treatment of metastatic disease, 17% received IO-TKI therapy, and 9% of patients received adjuvant IO monotherapy.

Included patients received a median of 10 cycles of cabozantinib (range 5-17 cycles) with 25 patients (53%) continuing on therapy at the time of data cut-off. Of those that ceased therapy, 1 patient stopped for toxicity, 13 for radiological progressive disease, 6 patients for clinical progressive disease or death, while 2 patients discontinued for reasons other than toxicity or progressive disease.

Among evaluable cases, no patients had a complete response, 17 patients (43%) achieved a partial response, and 15 patients (37%) had stable disease as the best response. At a median follow-up of 8.0 months (4.4-13.5 months), 71% of patients were alive and the median progression-free survival was 9.3 months (95% CI 7.1-29.0 months).

Severe toxicity, defined at grade 3-4 adverse events, occurred in 34% of patients, with common events including serum bilirubin increase, hypertension, calcium, and sodium serum levels alterations, and oral mucositis. Minor adverse events (grade 1-2) were observed in 61% of patients, including diarrhea, nausea, oral mucositis, dysgeusia, hand-foot syndrome, fatigue, and hypothyroidism.


Adverse event-related treatment delays were seen in 53.5% of patients and dose reductions were required for 23 patients (48%).

The authors concluded that cabozantinib after IO-IO or IO-TKI therapy showed promising efficacy and was well tolerated, though longer follow-up is needed for final survival and biomarker analysis.

Presented by: Giuseppe Procopio, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

Written by: Christopher J.D. Wallis, Urologic Oncology Fellow, Vanderbilt University Medical Center Contact: @WallisCJD on Twitter at the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting, Virtual Annual Meeting #ASCO21, June, 4-8, 2021
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