The addition of palbociclib (Ibrance) to endocrine therapy led to a consistent improvement in progression-free survival (PFS), according to a biomarker analysis of a recently reported randomized trial.<sup>1</sup>
Richard S. Finn, MD
The addition of palbociclib (Ibrance) to endocrine therapy led to a consistent improvement in progression-free survival (PFS), according to a biomarker analysis of a recently reported randomized trial.1
The biomarker study failed to identify any subgroup of patients with advanced estrogen receptor (ER)-positive who did not benefit from treatment with the CDK4/6 inhibitor. In particular, variation in levels of the proliferation marker did not serve as a stratifying factor, as reported at 2016 ESMO Congress.
“These exploratory analyses did not identify a subgroup of ER-positive patients who did not benefit from the addition of palbociclib to letrozole,” said Richard S. Finn, MD, assistant professor of medicine at the University of California, Los Angeles. “While the PFS of the control group varied with several of these markers, palbociclib consistently improved PFS.”
The findings came from a prespecified analysis of the PALOMA-2 trial, which compared letrozole with or without palbociclib in postmenopausal patients with untreated advanced ER-positive/HER2-negative breast cancer. Initially reported at the 2016 ASCO Annual Meeting, results showed that the primary finding was a 10-month improvement in median PFS among patients who received the combination (24.8 vs 15 months; HR, 0.58; 95% CI, .46-.72;P<.0001).
Using tissues samples from 568 of 666 patients in the trial, investigators performed immunohistochemistry (IHC) analysis by central review of ER expression and levels of various proteins in the cyclin D/CDK4,6/Rb pathway. Results were expressed as an H-score, taking into account the intensity and number of cells staining at a specific level of intensity, said Finn. The IHC findings were correlated with PFS in the biomarker analysis set.
The results showed that patients benefited from the addition of palbociclib regardless of whether their tumors were ER-positive or ER-negative (but progesterone receptor-positive). Patients with ER-positive disease had a median PFS of 24.9 months with palbociclib and 16.3 months with letrozole alone (P<.0001). Those with ER-negative tumors had a median PFS of 15.6 months with the combination and 5.4 months with letrozole monotherapy (P= .0030). Quantitative analysis by quartile of ER expression also showed an advantage for the combination over letrozole alone.
The combination significantly improved PFS in patients who tested positive for expression of retinoblastoma (Rb) protein (24.2 vs 13.7 months,P<.0001). The jury remained out for Rb-negative tumors, as the median PFS was 18.5 months with letrozole alone and not evaluable with the combination. However, a small sample size (n = 51) limited the analysis.
Examination of PFS by cyclin D1 expression revealed a consistent benefit for the combination therapy. Quartile analysis showed a median PFS of 22 to 25 months with the combination and 10 to 16 months for letrozole alone, differences that were all statistically significant.
The consistency in favor of combination therapy continued in the analysis ofp16status. Patients withp16-positive tumors had a median PFS of 24.8 months with palbociclib and 13.8 months without (P<.0001). Thep16-negative subgroup included only 84 patients, but a 3-month difference in favor of the combination emerged from the analysis.
The analysis of Ki-67 expression was of particular interest because palbociclib preferentially inhibits proliferation of luminal ER-positive human breast cancer cell lines. Using a cutoff of 15% for Ki-67 expression, investigators found that expression below the cutoff was associated with a median PFS of 19.2 months with letrozole alone. However, the median had yet to be reached with the combination (P=.0015). For patients with Ki-67 expression above the cutoff, the median PFS was 19.2 months with palbociclib and 11.0 months without (P= .0006).
Changing the Ki-67 cutoff to 20% did not change the results, as tumor expression ≤20% was associated with a median PFS of 27.6 months with palbociclib and 16.8 months without (P= .0002). In patients with less Ki-67 expression, the median PFS was 17.5 months with the combination and 8.4 months without (P= 0.0007).
Finn R, Jiang Y, Rugo HS, et al. Biomarker analyses from the phase 3 PALOMA-2 trial of palbociclib with letrozole compared with placebo plus letrozole in postmenopausal women with ER+/HER2- advanced breast cancer. Presented at: 2016 ESMO Congress; October 7-11, 2016, Copenhagen, Denmark.