Ribociclib
Dose Reductions Produce Consistent Survival Outcomes in HR+/HER2- Advanced
Breast Cancer
According to findings from the phase 3 MONALEESA-2 trial,
dose adjustments of ribociclib (Kisqali) compared to the normal dose resulted
in identical overall survival (OS) outcomes in patients with hormone
receptor-positive, HER2-negative advanced breast cancer (NCT01958021).
During the 2022 American Society of Clinical Oncology
Annual Meeting, data from the study's final protocol-specified OS analysis were
presented.
According to a landmark analysis, those who had at least
one reduction 3 months into treatment had a median OS of 63.1 months, compared
to 65.7 months for those who had no reductions during that time period (HR,
0.96; 95 per cent CI, 0.68-1.36). Furthermore, in a time-varying Cox regression
analysis of OS by dosage decrease, the median OS in the modification group was
66.0 months (95 per cent CI, 57.6-75.7) and 60.6 months (95 per cent CI,
42.5-79.2), while in the conventional group it was 60.6 months (95 per cent CI,
42.5-79.2). (HR, 0.87; 95 percent CI, 0.65-1.18).
In a presentation of the findings, Lowell Hart, MD, FACP,
scientific director of clinical research at Florida Cancer Specialists and
Research Institute, explained, "The ribociclib starting dose is 600 mg per
day." "To control treatment-related adverse events, the MONALEESA-2
[trial] protocol allowed decreases to 400 mg or 200 mg per day." [These]
decreases may be necessary to assist a patient stay on medication if they have
encountered AEs."
The OS results were consistent with previous findings
from the MONALEESA-3 (NCT02422615) and MONALEESA-7 (NCT02278120) studies,
implying that deviating from the prescribed dose of 600 mg daily on a 3 week
on/1 week off cycle in combination with endocrine therapy will result in a
similar OS advantage. Notably, neither the length of therapy nor the timing of
dose reduction had any effect on the results.
The MONALEESA-2 trial enrolled postmenopausal women with
hormone receptor–positive HER2-negative advanced breast cancer who had not
previously received treatment for the disease. Participants were randomly
assigned to receive either a normal regimen of ribociclib (600 mg) on a 3-week
on/1-week off schedule with 2.5 mg/day of letrozole continuously or a placebo
plus letrozole.
The time from the first dosage reduction or interruption
to the last dose date, referred to as relative dose intensity 2 (RDI2), was
also used to evaluate the results. The total mg of the dose delivered was
divided into three categories: low (64.27 per cent), medium (64.27 per cent
-95.86 per cent), and high (> 95.86 per cent).
Low RDI2 had a median OS of 62.6 months (95 per cent CI:
50.0-80.7), medium RDI2 had a median OS of 63.9 months (95 per cent CI:
48.8-not achieved [NR]), and high RDI2 had a median OS of 65.3 months (95 per
cent CI; 50.5-NR). The hazard ratio was 0.99 when comparing low RDI2 to high
RDI2 (0.59-1.42; 95 per cent CI). Between medium and high RDI2, the hazard
ratio was 0.97. (95 per cent CI, 0.68-1.38).
The researchers performed landmark analyses to assess the
link between dosage decreases and overall survival. The analysis attempted to
address the potential for guarantee-time bias by dividing patients into two
groups ("yes" or "no" in terms of dose reduction). Patients
whose exposure to the chemical above the thresholds were also excluded from the
trial. The "yes" and "no" options showed if a dosage
reduction occurred before the milestone time.
Among the 334 evaluable patients, 125 did not require a
dose decrease (37.3%), 124 required one (37.1%), 76 required two (22.9%), and 9
required three or more (37.3%). (2.7 per cent). AEs (58.1%), dosage errors
(3.3%), lack of efficacy (0.3%), physician decision (3.0%), and
patient/guardian decision (3.0%) were all reasons for more than three-dose
reductions (3.3 percent ). For three patients, the reduction explanation was
lacking (0.9 per cent ).
The median time to first dose decrease was 3 months, and
baseline characteristics of individuals who needed changes and those who didn't
were comparable. The median age of individuals who needed a reduction and those
who did not was 62.0 years at the start. The majority of the patients had an
ECOG performance level of 1 or 2. (63.6 per cent vs 56.8 per cent).
In patients who needed at least one adjustment, the
median duration of ribociclib exposure was 19.1 months, compared to 10.8 months
in those who did not.
The median follow-up time between randomization and data
cutoff was 79.7 months, with a median follow-up time of 49.35 months between
randomization and date of last contact or death (range, 1-86.7 months). By the
data cutoff date, 209 of 334 patients (62.6 per cent) needed dose reductions,
while 275 needed dose interruptions (82.3 per cent).
Neutropenia was the most common all-grade adverse effect
(AE) among individuals who required and did not require a dose decrease,
according to a safety review. It was also due to the AE that dose reductions
were induced (42.1 per cent).
Hart wrapped up his talk by summarising the findings from
the three MONALEESA trials that were completed.
"Taken together, the findings from MONALEESA-2,
MONALEESA-3, and MONALEESA-7 imply that patients receiving ribociclib plus
endocrine therapy who require dose adjustments from the recommended starting
dose due to AES or other factors can do so without jeopardising overall
survival," he said.