Tofacitinib Bests Methotrexate Monotherapy in Phase 3 RA Trial

June 23, 2014

The latest of numerous tofacitinib trials in rheumatoid arthritis, this one (head-to-head against methotrexate monotherapy) has results in line with previous research. Like others, it is unable to resolve a major question about risk.

Lee EB, Fleischmann R, Hall S, et al. for the ORAL Start Investigators. Tofacitinib versus Methotrexate in Rheumatoid ArthritisN Engl J Med (2014) 370:2377-2386 June 19. doi: 10.1056/NEJMoa1310476

Fazio S. Tofacitinib versus Methotrexate in Rheumatoid Arthritis. Now@NEJM June 20th, 2014

The latest of many studies of tofacitinib (Xeljanz) in rheumatoid arthritis (RA), this one gives about the same results as others. The big open question is the risk for cancer, and this study is not powered to answer it. The prevalence of cancer is so low with this drug that it is detected only rarely in any randomized trial of a reasonable size.

In this phase 3 study, tofacitinib (either 5 mg or 10 mg given twice daily) was superior to methotrexate as initial monotherapy in patients with moderate to severe rheumatoid arthritis. Superiority was based on the co-primary end points of American College of Rheumatology 70 (ACR70) response and modified total Sharp score at six months. Adverse events, consistent with earlier studies, continue to be a concern.

Thirty-eight percent of patients reached ACR 70 on the highest dose of tofacitinib, but only 12% on methotrexate.

The differences in Sharp scores were not clinically significant. The minimum clinically significant difference in the Sharp score is 4.6 points, and none of the groups reached that, although tofacitinib did make a statistically significant difference in preserving joint structure. In 24 months, the Sharp score in methotrexate patients progressed 2.1 points, while the tofacitinib patients progressed only 0.3 points in the highest-dose group.

In the tofacitinib group, 4% developed herpes zoster, the most common adverse effect, compared to 1.1% in the methotrexate group.

There were five cancers a mong the 770 patients in the tofacitinib group:  one non-Hodgkin’s lymphoma [NHL] judged related, one NHL judged possibly related, and three judged not related. Of the 186 patients in the methotrexate group, one developed stomach cancer, judged possibly related.

Overall, patients discontinued methotrexate about as often as tofacitinib.

Pfizer sponsored the study and analyzed the data.

 6 months24 months
 MTX (N=373)5 mg T (n=397)10 mg T (n=186)MTX (N=373)5 mg T (n=397)10 mg T (n=186)
Sharp (change)0.80.2<0.12.10.60.3
ACR 70 (%)12.025.537.715.234.437.6