ASCO 2018: Prospective Phase II Multi-Center Study of Individualized Axitinib Titration for Metastatic Renal Cell Carcinoma After Treatment with PD-1 / PD-L1 Inhibitors

Chicago, IL ( Currently the standard of care treatment for patients with metastatic renal cell carcinoma (MRCC), after being treated with immune checkpoint inhibitors (CPI) therapy, includes VEGF receptor Tyrosine Kinase Inhibitors (TKIs). However, to date, there is no prospective data published on this specific topic.

Axitinib is a VEGF- receptor inhibitor and has been shown in the past to have increased efficacy with dose titration. [1] The currently used titration schema increases the dosage from 5mg BID to 7mg BID to 10mg BID every 4 weeks. Unfortunately, this has been shown to lead to toxicity due to the significant dosage increase. Therefore, the authors conducted a prospective, multi-center phase II trial of Axitinib given on an individualized dosing algorithm, instead of the standard used titration schema, in patients with mRCC after being treated with CPI.

In this study (NCT02579811), only patients with clear cell mRCC, with adequate organ function, and measurable disease, who were recently treated with anti PD-1 / PD-L1 therapy were included. According to the trial protocol, patients were treated with Axitinib 5mg BID starting dose with upward dose titration of 1mg BID increments up to a maximum dose of 10mg BID, every 14 days. The dosage was increased as long as there were no grade 2 Axitinib-related adverse events, which included mucositis, diarrhea, hand-foot-syndrome, or fatigue. If grade 2 adverse events occurred, patients had to take a 3-day break and then resume the same dose. In any case of recurrent grade 2 adverse events, despite repeating treatment breaks, or in cases where grade 3 or 4 adverse events had occurred, the dose was reduced in 1mg BID increments.

According to the trial protocol, the primary outcome of this phase 2 trial was progression free survival (PFS) with 38 patients needed to improve PFS from 6.5 months to 9.5 months (a = 0.10; power 80%). The trial schema can be seen in figure 1.

image 19

The authors stated that they have completed accrual and had recruited 38 patients, of which 74% were male and 26% were female. The median age was 64, and almost 90% of the patients had a Kranofsky performance status of over 80%. The International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk groups among the patients were 16% favorable, 66% intermediate, and 19% poor risk. Almost all of the patients (94%) had not undergone nephrectomy at trial accrual. However, more than 70% of the patients had received at least 2 prior therapies, with most patients receiving anti PD-1(89%), where 65% had received nivolumab as a single therapy, 15% received both ipilimumab and nivolumab; and 13% received other therapies (Table 1).

image 19b

The results demonstrated that the median PFS was 9.2 months, with 54% of patients still being on Axitinb. The overall response rate (ORR) was 39.5%. When specifically assessing the dose of Axitinib that patients received, the median highest dose per patient was 6mg BID (with a range of 5-9 mg) and 44% of patients required dose reduction to less than 5mg BID. The 6-month event free survival rate was 65% and the 1-year event free survival rate was 31%. The Axitinib related toxicities are demonstrated in table 2.

image 19c

The authors concluded that Axitinib is a highly active post checkpoint inhibitor therapy in heavily pretreated MRCC patients. A more granular titration schema leads to clinical activity of Axitinib across a wide dose range. There were low rates of grade 3 adverse events in this trial, emphasizing smaller dose titration increments and increased treatment breaks. These data support the use of Axitinib in MRCC patients post checkpoint inhibitor therapy.

Presented by: Moshe Chaim Ornstein, MD, MA, Cleveland Clinic Taussig Cancer Institute

Written by: Hanan Goldberg, MD, Urologic Oncology Fellow (SUO), University of Toronto, Princess Margaret Cancer Centre, Twitter:@GoldbergHanan at the 2018 ASCO Annual Meeting - June 1-5, 2018 – Chicago, IL USA

[1] Rini BI1, Melichar B, Ueda T, et al. Axitinib with or without dose titration for first-line metastatic renal-cell carcinoma: a randomised double-blind phase 2 trial. Lancet Oncol. 2013 Nov;14(12):1233-42. doi: 10.1016/S1470-2045(13)70464-9. Epub 2013 Oct 18.