PALOMA-2 Final Update: Is This the End of Palbociclib?
In January 2024, Slamon et al. published the final overall survival (OS) analysis for the PALMOA-2 trial of first-line non-steroidal aromatase inhibitor (NSAI) and palbociclib. The results confirm what had been reported for a few years: palbociclib does not confer a statistically significant OS benefit over placebo. This raises interesting questions regarding the pitfalls of cross-trial comparisons and how to draw meaningful clinical conclusions from large trials.
First: a little background.
PALOMA-2 was a study examinig the addition of palbociclib to the NSAI letrozole. Patients were randomised 2:1 to receive palbociclib 125mg daily from day 1 to day 21, followed by a 7-day break, or matching placebo. Key inclusion criteria were:
Age ≥ 18 years
Postmenopausal status
Oestrogen-receptor positive/HER2-negative (ER+/HER2-) advanced breast cancer
No prior systemic therapy for advanced disease
ECOG PS 0-2
Measurable disease per RECIST v.1.1
Adequate organ function
Image courtesy Journal of Clinical Oncology, 2024
In total, 666 patients were recruited. 444 patients received palbociclib, while 222 received placebo. Characteristics were well balanced across the two groups, but a few numerical differences should be noted:
More patients in the palbociclib arm (40.8%) were ≥65 years old (cf. 36.5%)
More patients in the palbociclib arm (57.9%) had an ECOG PS of 0 (cf. 45.9%)
Fewer patients in the palbociclib arm (42.6%) had ≥3 sites of disease (cf. 46.8%)
Previously, data demonstrated a statistically and clinically significant progression-free survival (PFS) benefit with palbociclib vs placebo (24.8 vs. 14.5 months, HR 0.58, p<0.001), but no overall survival benefit has been established. The above publication comes roughly eighteen months after initial publication of this data, with a few additions.
The final intention-to-treat (ITT) OS analysis confirmed that palbociclib did not provide a significant overall survival benefit over placebo for patients with untreated ER+ metastatic breast cancer. The median OS was 53.9 months for the combination compared with 51.2 months for placebo (HR 0.96, p=0.34). No subgroup demonstrated a significant OS benefit with palbociclib compared to placebo.
A pre-planned pooled analysis of patients in both the phase 2 PALOMA-1 trial and PALOMA-2 reinforced this finding: the median OS was 51.8 months in the combination group compared to 46.8 months in the control arm (stratified HR 0.92, 95% CI 0.78-1.12).
The time to subsequent chemotherapy was significantly higher in the experimental arm (median TTC 38.1 months vs 29.8 months, HR 0.73), which is likely related to the superior PFS of the combination. At data cutoff, 50 patients were still receiving active treatment with the trial regimen, with 45 of those receiving palbociclib + letrozole.
As previously reported, there was a significant rate of data loss due to withdrawal of consent or loss of follow-up. This proportionally affected the control arm (21.2%) more than the experimental arm (13.3%). In the updated publication, the authors attempted to retrieve survival data for these patients, reducing this imbalance: 9.2% vs 11.7% of patients were lost in the experimental and control arms, respectively.
The vast majority of patients in both arms received ≥1 post-study systemic therapy: 80.7% in the combination arm and 87.6% in the control arm. Most significantly, 26.7% of patients in the placebo arm received subsequent CDK4/6 inhibitor (89.7% received palbociclib), compared to 11.8% in the combination arm.
So, what does this mean for prescribing practices? Given the disappointing results of PALOMA-2, is palbociclib effectively dead as a first-line treatment?
An interesting review of this subject comes from Drs. Grinshpun, Tolaney, Jeselsohn and two Oncology for the Inquisitive Mind alumni: Harold Burstein and Erica Myaer. Published in March 2023, the review examines the existing evidence for palbociclib, ribociclib and abemaciclib, and attempts to contextualise these often confliting data.
To begin, it is important to be aware of the pharmacokinetic and pharmacodynamic differences between the three available CDK4/6 inhibitors. Palbociclib and ribociclib are given intermittently, while abemaciclib is given continuously. Palbociclib has a higher affinity for CDK6, while ribociclib and abemaciclib had a higher affinity for CDK4 (CDK4:CDK6 inhibition ratio: 1, 4 and between 5-9, for palbociclib, ribociclib and abemaciclib, respectively). Abemaciclib also has a proven ability to penetrate the blood-brain barrier.
The below table summarises the pertinent findings of each of the five major trials in this space.
Table courtesy of npj Breast Cancer
Of note, the PFS across the studies is remarkably similar, with MONALEESA-3 the only significant outlier (33.6 months). This could be explained by that trial’s use of fulvestrant instead of an NSAI. The OS is also fairly similar across both control (average ~51 months) and investigation arms; PALOMA-2 is the only trial with a mOS of <55 months.
So why the difference, given it is common for this family of drugs to be lumped together and described as “equivalent” or “interchangeable”?
The authors of the npj Breast Cancer article have several hypotheses. First was the issue of timing: palbociclib received regulatory approval during the recruitment phase of many of these studies, none of which allowed crossover or early unblinding. As a result, the rate of consent withdrawal was relatively high, as noted by the PALOMA-2 data above. The true rate of crossover was, therefore, unknown, and its impact on results cannot be assessed.
There are also differences in the various accrued populations, a common refrain in warnings against cross-trial comparisons. For example, in PALOMA-2, 14.3% of patients came from Asia, roughly double the proportion found in MONALEESA-2 (7.6%). Grinshupan et al. suggest the potential for greater toxicity amongst an Asian population due to slower drug clearance. Differences in drug metabolism between ethnicities are a known entity; capecitabine, for example, is known to be metabolised more efficiently in patients from parts of Asia. However, the impact on the overall survival results in the two studies is hypothetical, and likely will remain so forever.
So, we have different results for similar but distinct therapies that, for myriad reasons, cannot be directly compared with any accuracy. So, what is an oncologist to do?
The Bottom Line:
While it may seem obvious, Grinshupan et al. emphasise that there is no need to change therapy for patients who are established on - and receiving benefit from - palbociclib. There is conflicting evidence about switching CDK4/6 after progression and no evidence for changing prior, so any benefit is likely to be small.
However, it is difficult not to compare trials in of different treatment options, at least subconsciously. For newly diagnosed patients, it is becoming standard of care to use ribociclib or abemaciclib, given their established overall survival benefit. However, if there is a contraindication for either agent - such as cardiac disease or arrhythmias for ribociclib - palbociclib should be considered. It carries a definite PFS benefit, will likely delay progression to chemotherapy, and may extend overall survival on an individual basis.
Sources:
Slamon DJ, Diéras V, Rugo HS et al. Overall Survival With Palbociclib Plus Letrozole in Advanced Breast Cancer. Journal of Clinical Oncology. 2024; 42:9 https://doi.org/10.1200/JCO.23.00137
Grinshpun A, Tolaney SM, Burstein HJ et al. The dilemma of selecting a first line CDK4/6 inhibitor for hormone receptor-positive/HER2-negative metastatic breast cancer. NPJ Breast Cancer. 2023 9: 15. https://doi.org/10.1038%2Fs41523-023-00520-7
