Nanoparticle-drug conjugate regimen for kidney cancer has no benefit over standard treatments

Despite promising efficacy results in earlier trials, an investigational regimen of CRLX101, a nanoparticle-drug conjugate (NDC) containing camptothecin plus bevacizumab did not demonstrate any advantage over standard of care (SOC) treatments in patients with metastatic renal cell carcinoma (mRCC). The results of the study were published in Annals of Oncology.

Currently, there is no defined standard treatment for patients with mRCC. A previous phase 1/2 study of CRLX101 plus bevacizumab showed a manageable safety profile as well as encouraging efficacy in RCC with prior lines of therapy. This led researchers to develop a randomized phase 2 trial targeting the third-/fourth-line setting.

This randomized phase 2 trial, led by Martin H. Voss, MD, at the Memorial Sloan Kettering Cancer Center in New York, NY, compared CRLX101 plus bevacizumab to the best SOC treatment in refractory mRCC.

Ideally, NDCs improve drug delivery to tumors and improve antitumor activity while reducing toxicity by gradually releasing their payload after they enter the cell. CRLX101 is an investigational NDC composed of a polymer backbone linked to camptothecin, a topoisomerase-1 inhibitor. In preclinical models, antiangiogenic effects were shown across various solid tumor malignancies.

Patients were recruited across 34 centers in the United States and Korea. Eligible patients were at least 18 years of age, had an ECOG performance status of 0 to 1, and a life expectancy of greater than three months. In addition, they had mRCC of any histologic subtype and had received two to three prior lines of targeted therapy, including one vascular endothelial growth factor (VEGF)-inhibiting regimen.

Participants were randomized to either CRLX101 plus bevacizumab or any regimen considered SOC, defined as an approved regimen of the investigator’s choice. Options for SOC included approved tyrosine kinase inhibitors (TKIs)—such as axitinib, sorafenib, and sunitinib—or rapalogs (inhibitors of the mammalian target of rapamycin [mTOR]) including everolimus and temsirolimus, provided the drug had not previously been received.

Patients in the investigational arm (n=55) received 15 mg/m² CRLX101 plus bevacizumab 10 mg/kg IV on days 1 and 15 of a 28-day cycle. To decrease the risk of CRLX101-induced cystitis, patients received pre- and post-IV hydration. Premedication included a systemic corticosteroid and histamine blockers. Guidance for dose delays and dose modification of CRLX101 was provided.

Patients randomized to SOC (n=56) were treated according to the manufacturer’s label and institutional standards. Regimens included axitinib (n=18), bevacizumab monotherapy (n=19), everolimus (n=7), pazopanib (n=4), sorafenib (n=4), sunitinib (n=2), and temsirolimus (n=2).

Disease extent was assessed every eight weeks with independent radiological review (IRR). Treatment was continued until disease progression or intolerance to treatment; cross-over was not permitted.

The primary endpoint was progression-free survival (PFS) in patients with clear cell mRCC by blinded IRR. Secondary endpoints included overall survival (OS), objective response rate (ORR), and safety.

Most participants had clear-cell RCC (88.7%), and most patients were in the favorable (30.4%) and intermediate (46.1%) Memorial Sloan Kettering Cancer Center risk categories. More than half (60.9%) had received two prior lines of therapy. Patients were evenly distributed across the two treatment arms, although those in the investigational group tended to be older.

The primary endpoint analysis of PFS based on blinded IRR assessment included 102 clear cell RCC (ccRCC) patients. A PFS event (progression, death, or censoring) was noted in 70.0% of the CRLX101 plus bevacizumab group and 73.1% in the SOC group.

The median PFS was 3.7 months vs 3.9 months for patients receiving CRLX101 plus bevacizumab and SOC, respectively. Investigator assessment noted median PFS of 3.9 months and 5.2 months for CRLX101 plus bevacizumab and SOC, respectively.

The ORR among ccRCC, per blinded IRR assessment, was 4.8% for CRLX101 plus bevacizumab and 14.0% for SOC.

At the time of data cutoff, 56 patients were in survival follow-up. The median OS was 16.1 months and 16.4 months for CRLX101 plus bevacizumab and SOC, respectively.

Several subgroup analyses evaluated outcomes for patients with non-clear cell variants. The outcomes were comparable in both treatment groups.

Treatment with CRLX101 plus bevacizumab was generally well tolerated, and no new safety signal was identified. The most common adverse events (AEs) for CRLX101 plus bevacizumab included fatigue, nausea and constipation, decreased appetite, and headache. In the SOC group, fatigue, diarrhea, nausea, and hypertension were the most commonly reported AEs.

"Despite promising efficacy data on the earlier phase 1b/2 trial of mRCC, this randomized trial did not demonstrate improvement in PFS for the CRLX101 plus bevacizumab combination when compared with approved agents in patients with heavily pretreated clear cell mRCC,” the authors concluded.

The investigators noted that further development in this disease is not planned. However, the study design using a ‘SOC’ comparator arm when there is no defined standard lends itself readily for comparison and can be an example for future studies.

To read more about this study, click here.