Pazopanib Plus Oral Cyclophosphamide Shows Benefit in Platinum-Resistant Epithelial Ovarian Cancer

Pazopanib (Votrient) plus oral cyclophosphamide is a well-tolerated regimen that has clinically relevant benefit in patients with platinum-resistant or -refractory epithelial ovarian cancer, according to results from a retrospective study published in the Journal of Clinical Oncology.¹

Results showed that 45% of patients had a partial response with the combination, 30% achieved stable disease, and 25% experienced disease progression. The median progression-free survival (PFS) was 5.5 months with pazopanib plus cyclophosphamide and the median overall survival was 9.5 months.

“This analysis presents a measure of effectiveness of the pazopanib and cyclophosphamide combination in patients with platinum-resistant or -refractory [epithelial ovarian cancer] in a real- world setting,” Seema Gulia, MD, DM, of Tata Memorial Centre, and her co-investigators wrote. “Our results suggest that this combination is associated with a clinically meaningful objective response, clinical benefit, and PFS benefit in a heavily pretreated patient population.”

The retrospective study recruited women through a database of medical records to find those who had recurrent platinum-resistant or -refractory epithelial ovarian cancer and previously received pazopanib and cyclophosphamide after failure of available standard chemotherapies.

A total of 20 patients with epithelial ovarian cancer were treated with the combination between April 2014 and April 2018; 17 patients had platinum-resistant disease and 3 patients had platinum-refractory disease. Most patients had an ECOG performance score of 2 at the time of treatment initiation. The median age of the participants was 52 years (range, 40-60 years) and 95% of patients had serous histology. Sixty percent of patients had received a median of 4 or more prior lines of chemotherapy (range, 2-8) and 3 patients had previously received bevacizumab (Avastin).

Patients were given oral pazopanib at 600 mg daily in 2 doses (400 mg and 200 mg) and they were given oral cyclophosphamide at 50 mg daily for 21 days every 28 days until disease progression or unacceptable toxicity. Patients received a median of 6 cycles (range, 2-48) of pazopanib and cyclophosphamide, and 6 patients received treatment for >12 months. Additionally, 1 patient with platinum-refractory disease had continued on treatment for 48 months at the time of analysis.

Dose reductions were required in 70% of patients because of toxicity; however, no patient stopped treatment because of adverse reactions, according to the investigators. Common adverse events associated with the regimen included fatigue (55%; 30% grade 1/2 and 25% grade 3/4), diarrhea (45%; 30% grade 1/2 and 15% grade 3/4), elevation in liver enzymes (50%; 45% grade 1/2 and 5% grade 3/4), mucositis (50%; 40% grade 1/2 and 10% grade 3/4), myelosuppression (35%), hand-foot syndrome (45%; 35% grade 1/2 and 10% grade 3/4), hair depigmentation (15%, all grade 1/2), and hypertension (5%).

Of the 12 patients who experienced progressive disease, 8 received another line of chemotherapy with or without bevacizumab. The additional lines of therapy included weekly paclitaxel (n = 5); liposomal doxorubicin (n = 1); irinotecan (n = 1); and gemcitabine plus carboplatin (n = 1). The other 4 patients were provided with supportive care without further disease-directed therapy.

“Despite the small sample size, encouraging responses were seen in difficult-to-treat patients,” the investigators wrote.

Several studies have examined pazopanib in combination with chemotherapies in ovarian cancer as well as other malignancies. For example, in a less heavily treated patient population who had received up to 2 prior lines of chemotherapy, the combination of pazopanib plus paclitaxel resulted in a median PFS of 6.3 months.2 Another similar phase II trial examining pazopanib in combination with weekly paclitaxel showed a PFS of 7.5 months with the combination versus 6.2 months with paclitaxel alone, a difference that was not determined to be statistically significant.3 The median PFS of 5.5 months observed in this analysis in a more heavily treated population compares favorably with these results, according to the investigators.

In addition to its safety and effectiveness, the combination may also serve as a more convenient, less costly option for this patient population.

“Pazopanib and cyclophosphamide combination is less expensive and has the advantage of oral administration compared with other standard treatment options,” the investigators wrote. “The treatment cost of pazopanib and cyclophosphamide is approximately US $285 per cycle, whereas that of bevacizumab-based therapy is approximately US $1,765 per cycle. Therefore, pazopanib plus cyclophosphamide is a more feasible therapeutic option in our patients.”

Investigators of the study concluded that the combination of pazopanib and oral cyclophosphamide may be considered as a treatment option for heavily pretreated patients with epithelial ovarian cancer.

References

1. Gulia S, Ghosh J, Bajpai J, et al. Pazopanib and oral cyclophosphamide in women with platinum-resistant or -refractory epithelial ovarian cancer [published online March 31, 2020]. JCO Global Oncology. doi: 10.1200/JGO.19.00331
2. Pignata S, Lorusso D, Scambia G, et al. Pazopanib plus weekly paclitaxel versus weekly paclitaxel alone for platinum-resistant or platinum-refractory advanced ovarian cancer (MITO 11): a randomised, open-label phase 2 trial. Lancet Oncol. 2015;16(5):561-568. doi: 10.10165/S1470-2045(15)70115-4
3. Richardson DL, Sill MW, Coleman RL, et al. Paclitaxel with and without pazopanib for persistent or recurrent ovarian cancer: a randomized clinical trial. JAMA Oncol. 2018;4(2):196-202. doi: 10.1001/jamaoncol.2017.4218