medwireNews: A phase 2 trial has demonstrated promising antitumor activity and manageable toxicity of abemaciclib in previously treated patients with p16ink4A-negative malignant mesothelioma.
“Our results support further investigation of CDK4 and CDK6 inhibition in the context of a molecularly stratified, randomised clinical trial” in this patient population, write the UK researchers in The Lancet Oncology.
Outlining the justification for the current study, they explain that “[m]esotheliomas frequently harbour loss of the chromosome 9p21.3 locus (CDKN2A–MTAP), which is associated with shorter overall survival due to loss of the tumour suppressor p16ink4A, an endogenous suppressor of [CDK4/6].”
The team continues: “Genetic restoration of p16ink4A suppresses mesothelioma in preclinical models, underpinning the rationale for targeting CDK4 and CDK6 in p16ink4A-negative mesothelioma.”
MiST2 included 26 patients aged a median of 67.5 years who had a diagnosis of malignant mesothelioma and tested negative for p16ink4A expression by immunohistochemistry. All had disease of pleural origin and had received at least one prior line of systemic therapy, including standard first-line pemetrexed plus either cisplatin or carboplatin.
Treatment with abemaciclib 200 mg twice a day resulted in disease control at 12 weeks in 14 (54%) patients; three had a partial response and the remaining 11 had stable disease.
As more than 11 of the study participants achieved disease control at this timepoint, the study was considered to have met its primary endpoint, say Dean Fennell, from the University of Leicester, and co-investigators.
A post-hoc exploratory analysis gave the median progression-free survival as 128 days and median overall survival as 217 days.
“This level of disease control compares favourably with other reported positive studies of monotherapy in the relapsed mesothelioma setting,” such as the CONFIRM trial of nivolumab, and also “with results for ipilimumab and nivolumab, as reported in the MAPS2 trial,” note the study authors.
Adverse events (AEs) of any grade occurred in 92% of participants, most commonly fatigue (62%) and diarrhea (50%), while the rate of AEs of grade 3 or worse was 31%. Serious AEs were experienced by 23% of patients and led to treatment discontinuation in one case. There was one death due to an AE (neutropenic sepsis).
Fennell and colleagues conclude: “Further genomic analysis of the trial cohort will be required to uncover molecular correlates that underpin the observed responses and to refine molecular stratification.”
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