PALOMA-1/TRIO-18 Phase II Results Support CDK4/6 Inhibition in Advanced Breast Cancer

Palbociclib plus letrozole boosts progression free survival in first-line treatment of patients with ER-positive, HER2-negative breast cancer

medwireNews: Addition of palbociclib, an inhibitor of the cyclin-dependent kinases (CDKs) 4 and 6, to letrozole significantly prolongs progression-free survival in women with advanced oestrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer, a phase II study suggests.

“These results provide the first clinical data to show a role for CDK4/6 inhibition in breast cancer”, writes the team led by Dennis Slamon, from University of California Los Angeles in the USA, in The Lancet Oncology.

Participants in the multicentre PALOMA-1/TRIO-18 trial were initially recruited in two cohorts, one that included women with ER-positive, HER2-negative status only and a second including women with additional genetic changes, specifically amplification of cyclin D1 (CCND1), loss of p16 or both. However, based on the results of an interim analysis that showed CCND1 amplification or p16 loss was unlikely to further improve patient outcome over the use of ER and HER2 status alone, the investigators combined the cohorts for endpoint analysis.

Median progression-free survival was significantly longer for the 84 patients who were randomly assigned to receive open-label, oral palbociclib (125 mg once daily for 3 weeks followed by a week off treatment) plus letrozole (2.5 mg once daily) compared with the 81 who were given letrozole alone, at 20.2 months and 10.2 months, respectively.

The team also reports that a greater proportion of patients achieved an objective response and clinical benefit in the combination group than the letrozole alone group.

The grade 3 or 4 adverse events that were more common with palbociclib plus letrozole than with letrozole alone were neutropenia (54 vs 1%), leukopenia (19 vs 0%) and fatigue (4 vs 1%). Serious adverse events that occurred in more than one patient in the combined treatment arm were pulmonary embolism, back pain and diarrhoea.

Dennis Slamon and colleagues conclude: “Overall, our results suggest that palbociclib in combination with letrozole could become an important treatment option, substantially improving upon letrozole alone for the treatment of postmenopausal women with [ER]-positive, HER2-negative, advanced breast cancer.”

In an accompanying comment, Michael Gnant, from the Medical University of Vienna in Austria, and co-authors commend the researchers on their “well-designed” trial and add that “doubling progression-free survival matters to our patients and is something that physicians have long been waiting to see.”

And “[t]herefore, and with all due caution, based on sound preclinical evidence and these new clinical results, we believe that CDK4/6 inhibitors are here to stay”, they conclude.


Finn RS, Crown JP, Lang I, et al. The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study. Lancet Oncol; Advance online publication 16 December 2014. doi: 10.1016/S1470-2045(14)71159-3

Gnant M, Steger GG, Bartsch R. CDK4/6 inhibitors in luminal breast cancer. Lancet Oncol; Advance online publication 16 December 2014. doi: 10.1016/S1470-2045(14)71188-X

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