1. Nalley, Catlin

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Two years of adjuvant palbociclib with endocrine therapy did not improve invasive disease-free survival (IDFS) in early HR-positive, HER2-negative breast cancer compared to endocrine therapy alone, according to findings from the phase III PALLAS trial presented at the ESMO Virtual Congress 2020 (Abstract LBA12).

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"Loss of control of the cell cycle is a hallmark of HR-positive breast cancer. CDK4 and 6 inhibitors allow hypo-phosphorylation of the retinoblastoma protein and can reestablish cell cycle control through G1 arrest," noted study author Erica Mayer, MD, MPH, of the Dana-Farber Cancer Institute. "Multiple studies have demonstrated that the combination of a CDK4/6 inhibitor with endocrine therapy prolongs progression-free and overall survival in the first-line and pretreated settings in metastatic HR-positive/HER2-negative breast cancer.


"Based on the activity of CDK4/6 inhibitors in metastatic disease," she continued, "the phase III PALbociclib CoLlaborative Adjuvant Study (PALLAS) was designed to determine if the addition of palbociclib to adjuvant endocrine therapy improves outcomes over endocrine therapy alone in patients with HR-positive, HER2-negative early breast cancer."


Study Details

PALLAS, a phase III open-label trial, randomized patients with stage II-III HR-positive/HER2-negative breast cancer to receive either 2 years of palbociclib with adjuvant endocrine therapy or endocrine therapy alone.


Eligible patients included those who were within 12 months of diagnosis and 6 months of initiating adjuvant endocrine therapy. The primary objective was IDFS. Secondary objectives included IDFS excluding second cancers of non-breast origins, distant recurrence-free survival, locoregional recurrence-free survival, overall survival and safety, as well as quality of life, adherence, and translational science.


Between September 2015 and November 2018, 5,760 patients (median age 52 years) were randomized at 406 sites in 21 countries, according to Mayer. Most patients had stage IIB or III tumors (82.1%) and received prior chemotherapy (82.5%).


Approximately 60 percent of patients had high clinical risk disease, which is defined as at least four axillary lymph nodes involved, or 1-3 nodes involved with either a T3/T4 tumor and/or grade 3 disease.


"Within the safety population, treatment-emergent adverse events occurred in 99.4 percent of patients receiving palbociclib and endocrine therapy versus 88.6 percent receiving endocrine therapy alone," Mayer noted. "Importantly, no new safety signals were observed with palbociclib and endocrine therapy and no treatment-related deaths were observed."


The researchers observed that grade 3 or 4 neutropenia was more common among patients treated with palbociclib (61.3% vs. 0.4%). Febrile neutropenia was uncommon in these patients (1.0%). Other all-grade toxicities that occurred more frequently with palbociclib included leukopenia, fatigue, thrombocytopenia, anemia, upper respiratory tract infection, and alopecia.


"At the time of the interim analysis two read-out with 351 IDFS events, the futility boundary for IDFS was crossed," Mayer reported. "The independent data monitoring committee subsequently reviewed this result and recommended discontinuation of palbociclib in the remaining arm A patients. At this point in time, all PALLAS patients have now moved to long-term follow-up.


"The median follow-up at the time of analysis is 23.7 months. There was no significant difference seen in 3-year IDFS between the arms with a rate of 88.2 percent with palbociclib and endocrine therapy versus 88.5 percent with endocrine therapy alone (HR 0.93, 95% CI 0.76-1.15)," she continued. "Similarly, there was no significant difference seen in 3-year distant recurrence-free survival with a rate of 89.3 percent with palbociclib and endocrine therapy versus 90.7 percent with endocrine therapy alone."


The researchers observed no benefit from palbociclib within clinicopathologic subgroups.


"The rates of palbociclib discontinuation were closely monitored throughout the trial and active efforts, including patient and provider outreach and education, were ongoing to reduce non-protocol-related discontinuations," Mayer explained during her presentation. "At the time of data cutoff, 25.5 percent of patients were still receiving palbociclib, 32.3 percent had completed the planned 2 years of protocol therapy, and 42.2 percent had discontinued prematurely."


Of the patients who discontinued palbociclib prematurely, the majority (64.2%) was due to adverse events. "Protocol-defined adverse events included, for example, persistent grade 3/4 neutropenia despite maximum protocol-defined dose reduction," Mayer said. "Other less frequent reasons included non-compliance, recurrent disease, or withdrawal of consent.


"The rate of early discontinuation of adjuvant endocrine therapy at 24 months with palbociclib and endocrine therapy was 6.9 percent, with no significant difference seen between the arms," she continued.


Approximately half of all patients required at least one palbociclib dose reduction and about one-third required two dose reductions, according to Mayer. "The majority of first reductions from 125 mg to 100 mg occurred within the first 3 months of study therapy."



This initial analysis of the PALLAS trial-at 67 percent of expected events-showed that the addition of palbociclib to adjuvant endocrine therapy did not prolong IDFS compared to endocrine therapy alone in patients with stage II or III HR-positive, HER2-negative breast cancer, Mayer summarized.


"Analysis of clinical pathologic subgroups, including a high clinical risk cohort, did not identify a population of patients receiving benefit from adjuvant palbociclib although these analyses are limited by small numbers of events," she noted, emphasizing that no new toxicities were observed in patients receiving adjuvant palbociclib compared with the metastatic breast cancer setting.


"I want to stress that the PALLAS story does not end here. PALLAS represents an important and unique global collaboration between academia, community practice, and industry, rapidly achieving its desired target accrual to answer an important question in breast cancer management," she said. "And, we hope the collaborative structure pioneered by PALLAS will serve as a model of trial management in the years to come."


Acknowledging that, in this study, the benefits observed in the metastatic setting with palbociclib did not translate into the earlier adjuvant setting, Mayer noted that multiple potential possibilities are being actively explored.


"There is a very long natural history to HR-positive breast cancer," she stated. "Long-term follow-up, which is essential in comprehensively understanding outcomes in luminal disease, will continue for the PALLAS patient population, at least for the next decade.


"Ongoing analysis in the TRANS-PALLAS program, which contains an incredible 6,000 tumor blocks and tens of thousands of patient blood samples, will generate rich translational discovery related to CDK4/6 inhibition, as well as improve our understanding of contemporary management of HR-positive/HER2-negative breast cancer," Mayer concluded.


Catlin Nalley is a contributing writer.