Expert Point of View: Prithviraj Bose, MD

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Prithviraj Bose, MD, Professor in the Department of Leukemia at The University of Texas MD Anderson Cancer Center, Houston, shared his thoughts on MANIFEST-2 and TRANSFORM-1 with The ASCO Post. While both were international phase III trials that showed similar benefits with two different agents—pelabresib and navitoclax, respectively, added to ruxolitinib—Dr. Bose emphasized some important differences.

MANIFEST-2 was a larger trial—430 patients vs 252 for TRANSFORM-1—but it also enrolled a generally lower-risk population: Dynamic International Prognostic Scoring System (DIPSS) intermediate-1 risk patients comprised 60% of the MANIFEST-2 population, whereas in TRANSFORM-1 more than 80% were DIPSS intermediate-2 risk. In both studies, the addition of a second drug essentially doubled the proportion of patients achieving ≥ 35% spleen volume reduction (SVR35) at week 24, the primary endpoint; yet in MANIFEST-2, pelabresib provided more relief of symptoms, he pointed out.

“SVR35 was similar in the trials, but with pelabresib and ruxolitinib, the TSS [total symptom score] was numerically better with the combination, whereas with navitoclax and ruxolitinib it was not; in fact, it was a little worse. And when you look at the > 90% of patients in MANIFEST-2 who had intermediate-risk disease (intermediate-1 or intermediate-2), symptom scores were statistically significantly better with the combination,” he observed.

“So, for more than 90% of the patients in MANIFEST-2, the combination had a benefit for symptoms. And for 40% receiving the combination vs only 18% receiving ruxolitinib, both spleen and symptom endpoints were met—which is a powerful statement. Finally, tolerability seems better with pelabresib than navitoclax, so, overall, I think from the findings in MANIFEST-2, there is more to be encouraged about,” Dr. Bose concluded.

The lack of TSS benefit might partially be explained by the high single-agent activity of ruxolitinib, “which sets a high bar that is difficult to improve upon,” he acknowledged. “But whenever a second drug is added, you’re likely to also see some toxicity from it, and navitoclax does have a reasonable side-effect burden. This could adversely affect those symptom and quality-of-life metrics.”

Dr. Bose added that myelofibrosis regulatory approval of new agents typically requires that benefit be demonstrated in both spleen volume and symptom score. Applying this standard, based on the present results, he said he is hopeful that pelabresib/ruxolitinib could be approved but is less optimistic about navitoclax/ruxolitinib.

DISCLOSURE: Dr. Bose reported financial relationships with Incyte, BMS, CTI, MorphoSys, Blueprint, Cogent, Sumitomo, Ionis, GSK, Novartis, Karyopharm, AbbVie, Pharma Essentia, Jubilant, and Morphic.

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