The investigators in this study hypothesized that axi would be tolerable in combination with pembro, and that this combination would have a measurable effect in the first-line treatment setting for mRCC. The primary endpoints were related to dose-finding, and secondary endpoints were related to dose-expansion.
After the first phase was completed, which studied dose-limiting toxicity, the maximum tolerated dose was estimated to be 5mg axi BID (continuous) + pembro 2mg/kg q3w. 52 treatment-naïve mRCC patients were then accrued for the second phase of the study. 46% of patients had favorable IMDC risk, which made this cohort somewhat more favorable-risk than other comparable studies.
At the time of data cutoff, 27 patients had to discontinue treatment due to treatment-related adverse events (AEs), disease progression, or both. The median duration of treatment was 14.5 months. 65% of patients had Grade >=3 AEs, mostly related to axitinib. Very few immune-related toxicities.
7.7% had a complete response, 65% had a partial response, 15% had stable disease, 6% had progressive disease, and a calculated ORR% was 73%. Overall, these are impressive statistics with promisingly durable treatment responses. The waterfall plot below shows the distribution of responses, with most exhibiting some effect.
The median time to response was 2.8 months, so responses tended to occur early. 19/38 responders continued to respond at the time of follow-up cutoff, and 14 responders exhibited progression. Median response duration was 18.6 mo. Interestingly, of 10 responders who stopped due to toxicity, 5 are still responding to treatment. Analyzing the survival curves, the median PFS was 21 months, and median OS was not reached with 90% of patients alive at 18 months.
In conclusion, the combination of axi + pembro is a promising new front-line therapy combination for mRCC. Importantly, it is a combination with good tolerability that is able to take advantage of combining mechanisms of VEGF inhibition and immunomodulation. The combination therapy was better than either axi or pembro monotherapy, so there is a clear synergy that is being exploited. Yet to be answered is whether this response requires co-administration of axi + pembro, or if sequential administration may also lead to similar response rates. A phase III trial of axi + pembro vs. sunitinib will give us more information about how effective this treatment combination is compared to the current standard-of-care.
This is an exciting time for combination therapy in front-line mRCC treatment. Exploiting VEGF inhibition and IO therapy is now possible with tolerable drug combinations such as axi + pembro; and this will result in continued improvement in therapies for patients with this aggressive disease.
Presented by: Michael B. Atkins, MD, Georgetown University
Written by: Shreyas Joshi, MD, Fox Chase Cancer Center, Philadelphia, PA at the 2018 American Society of Clinical Oncology Genitourinary (ASCO GU) Cancers Symposium, February 8-10, 2018 - San Francisco, CA