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Improvement in progression-free
survival with ribociclib + letrozole
may represent a paradigm shift in
advanced breast cancer
Adding the CDK4/6 inhibitor ribociclib to letrozole therapy
significantly improved progression-free survival in postmenopausal
women with hormone receptor-positive advanced breast cancer,
finds the first interim analysis of data from the randomised, placebo-
controlled, double-blind MONALEESA2.
A
s reported by Gabriel Hortobagyi, MD, of the University of Texas MD Anderson Cancer
Center, the combination of ribociclib + letrozole Houston led to a 44% improvement in
progression-free survival when used as a first-line treatment combination.
He noted, “This was the definitive study to demonstrate the superiority of the combination of
ribociclib + letrozole over letrozole alone.”
A total of 668 postmenopausal women with hormone receptor-positive, HER2-negative advanced
breast cancer, who had not undergone prior systemic treatment, were randomised to ribociclib
(600 mg daily, 3 weeks on/1 week off) + letrozole (2.5 mg daily, continuous), or letrozole + placebo.
A 44% improvement was observed in the primary objective of progression-free survival versus
placebo in patients taking ribociclib (hazard ratio 0.556, P = 0.00000329). Median progression-
free survival was 14.7 months in patients taking placebo but was not reached in those taking
ribociclib at data cutoff.
“The results represent compelling proof of principle,” saidDr Hortobagyi, “and suggest a paradigm shift
in metastatic, hormone receptor-positive breast cancer. They also suggest that testing combinations
of ribociclib with other inhibitors of various signalling pathways might lead to additional progress in
the management of several subtypes of breast cancer.”
Patients who demonstrated measurable disease at baseline exhibited a significantly higher objective
response rate to ribociclib + letrozole than to letrozole alone (53% vs 37%; P = 0.00028), as well
as a better rate of clinical benefit rate (80% vs 72%, P = 0.02).
Serious adverse events were reported by fewer than 5% of patients in both groups. Other adverse
events were significantly more common in patients taking ribociclib. Fifty-nine percent of patients
in the ribociclib arm suffered from neutropenia versus 1% in the placebo arm. Leukopenia occurred
in 21% versus 1%, lymphopenia in 7% versus 1%, respectively. Patients who received ribociclib
exhibited higher incidences of elevated alanine aminotransferase and aspartate aminotransferase.
Too few patients in the study died to enable a reliable analysis of the impact of ribociclib therapy
on overall survival.
Dr Hortobagyi concluded that the combination of ribociclib and letrozole prolonged progression-
free survival significantly and was well tolerated versus letrozole alone in postmenopausal women
with hormone receptor-positive, HER2-negative advanced breast cancer who had received no
prior therapy for advanced breast cancer.
Giuseppe Curigliano, MD, of the European Institute of Oncology, Milan, Italy, commented, “I
believe the results of this study are significant because now we have a new CDK4/6 inhibitor for
patients with oestrogen receptor-positive metastatic breast cancer, in addition to palbociclib (already
FDA approved) and abemaciclib (under development).”
He added, “The addition of ribociclib to letrozole raises the rate of toxicity, but overall, if we
evaluate the magnitude of clinical benefit, adding ribociclib is clearly beneficial.”
Dr Curigliano said, “Further studies of ribociclib should examine biomarkers to better identify
patients who would respond to the addition of the drug to letrozole.”
etoposide carboplatin. So, it’s certainly
possible that etoposide carboplatin
isn’t enough to engender benefit in
the neoadjuvant setting for small-cell
tumours of the bladder, and perhaps
with more patients treated with a more
aggressive regimen, maybe they would
have seen a different result.
Dr Pal:
I’ve seen phenomenal
responses with this regimen of
Adriamycin ifosfamide followed by
cisplatin etoposide, concurrent with
what you’ve just outlined. With all the
buzz around immuno-oncology, the
question that frequently comes up
in our clinic is whether or not these
agents are applicable to patients with
rare histologies. So if I see a patient
with a mix of transitional cell and
small-cell, a mix of transitional cell
and adenocarcinoma, is it reasonable
to potentially apply I-O in that setting?
Dr Siefker-Radtke:
Well, the way
we’re thinking about bladder cancer
is definitely changing. In the past,
all of our trials would exclude
patients with a predominant non-
urothelial component. So if we saw
predominantly small-cell tumours,
predominantly adenocarcinomas,
microcapillary, or sarcomatoid,
we would typically exclude those
patients from the trial, but as we
start understanding more about the
biology, I think this is going to have to
change, and I would argue we should
start including these patients because
the biology might actually predict the
benefit with specific agents.
For instance, when we look at
microcapillary tumours, we see
enrichment for perhaps HER2
signatures in that group of patients.
And even when Bogdan Czerniak and
Charles Guo in our group did some
subtyping work in microcapillary,
where they would isolate the
microcapillary component, and then
an adjacent urothelial component that
did not have microcapillary features
and what they found is that by gene
expression profiling they essentially
overlap. They appear biologically
to be the same tumour, so even if
there’s a less than 50% component
of microcapillary those tumours may
behave in a microcapillary fashion, and
if we exclude them from our clinical
trials, then we might actually miss
groups of patients who would benefit
from a specific targeted treatment.
ESMO 2016
27
DECEMBER 2016