medwireNews: The randomized FIRSTMAPPP study supports the use of sunitinib for the treatment of patients with metastatic progressive pheochromocytomas and paragangliomas.
The rate of progression-free survival (PFS) at 12 months, the primary endpoint, was 36% among the 39 participants who were assigned to receive the multitargeted receptor tyrosine kinase inhibitor and 19% among the 39 who instead received placebo.
As the 90% confidence interval for the placebo rate included 20%, “the hypotheses of our design were validated and sunitinib was considered effective,” write Eric Baudin (Gustave Roussy, Villejuif, France) and co-researchers in The Lancet.
They continue: “Our study has immediate impact for the treatment of patients with progressive metastatic phaeochromocytomas and paragangliomas, as we show for the first time in a randomised controlled trial that sunitinib is effective in this difficult-to-treat disease.”
In a comment related to the study, Mitsuhide Naruse (Ijinkai Takeda General Hospital, Kyoto, Japan) and William Young Jr (Mayo Clinic College of Medicine and Science, Rochester, Minnesota, USA) highlight that the FIRSTMAPPP trial “took 7 years to enrol 78 patients with this rare endocrine malignancy.”
They believe that it “is a major step forward, but further progress is needed on comprehensive treatment strategies that prioritise and combine treatment options […] based on clinical findings, such as assessment of the rate of tumour progression, biochemical phenotypes, nuclear imaging findings, and germline genetic testing-based molecular clusters.”
The double-blind, phase 2 trial included 78 patients with sporadic or inherited metastatic pheochromocytomas and paragangliomas who had progressed within 18 months of diagnosis. Participants were aged a median of 54 years, 59% were men, and 69% had received prior treatment. Just under a third (32%) harbored SDHB germline mutations and 40% had hypertension at baseline.
At a median follow-up of 29.7 months, the median PFS duration was 8.9 months for patients who received sunitinib 37.5 mg/day and 3.6 months for those given placebo, and the objective response rates were 36.1% and 8.3%, respectively.
The median overall survival duration was numerically shorter in the sunitinib than placebo group, at 26.1 versus 49.5 months, but the investigators point out the groups did not differ significantly. They suggest that this endpoint “is likely to be affected by the crossover achieved in 69% of patients in the placebo group, the prolonged median overall survival of patients with metastatic phaeochromocytomas and paragangliomas allowing numerous lines of treatments, and the low number of patients studied.”
As for the safety, adverse events (AEs) of grade 3 or worse occurred in 72% of sunitinib-treated patients and 62% of those given placebo. The most common events of this severity in the sunitinib arm were asthenia (18 vs 3%) and hypertension (13 vs 10%).
There were three fatal AEs in the sunitinib group, one case each of respiratory insufficiency, amyotrophic lateral sclerosis, and rectal bleeding, but only the latter was considered related to treatment. There were two deaths in the placebo group, one due to aspiration pneumonia and the other due to septic shock.
Baudin and colleagues say that tyrosine kinase inhibitors “with the highest rate of cardiovascular adverse events should be used with extreme caution in patients with metastatic phaeochromocytomas and paragangliomas.”
They add, however, that “no drug withdrawal was related to hypertension and hypertension-related grade 3–4 adverse events were comparable in the sunitinib and placebo groups, which suggests that sunitinib 37.5 mg per day is a good compromise.”
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Lancet 2024; doi:10.1016/S0140-6736(23)02554-0
Lancet 2024; doi:10.1016/S0140-6736(23)02828-3