To the Editor,
Since the new cyclin-dependent kinase 4/6 (CDK4/6) inhibitor drug class has steadily
entered into the clinical practice following the PALOMA, MONALEESA, and MONARCH seminal
trials [1], the therapeutic panorama of metastatic breast cancer (mBC) has been further
enriched and complicated. While these trials have provided solid and reliable data
that support the entry of these drugs into clinical practice, some issues remain.
Many of the current international guidelines, such as those from the National Comprehensive
Cancer Network (NCCN) [2] and European Society for Medical Oncology (ESMO) [3], suggest
the use of CDK4/6 inhibitors for first-line treatment in postmenopausal patients with
luminal mBC, except in case of visceral crisis. However, when CDK4/6 inhibitors are
introduced after progression on endocrine therapy (ET) as monotherapy, it is not yet
well established whether it is possible to maintain the same ET in conjunction with
CDK4/6 inhibitors. Preliminary evidence suggests that CDK4/6 inhibition therapy may
have the potential to reverse endocrine resistance [4], and this combination regimen
would take advantage of this feature.
Some preclinical evidence suggests that there is no cross-resistance among CDK4/6
inhibitors [5]. Therefore, maintaining CDK4/6 inhibition beyond progression by modifying
the ET backbone may represent a future approach, but to date there are no clinical
data. This issue may be addressed once results are known from the MAINTAIN (NCT02632045)
[6] and TRINITI-1 (NCT02732119) [7] trials, which involve patients whose disease progressed
on CDK4/6 therapy. MAINTAIN trial mandates a switch to a new ET (fulvestrant) for
all patients and either additional ribociclib or placebo. The primary endpoint is
progression-free survival (PFS) at 24 weeks from study entry, with a secondary endpoint
of overall response rate in patients who continue CDK4/6 therapy. TRINITI-1 is a phase
I/II, single-arm study of ribociclib in combination with everolimus and exemestane
in patients after previous progression on a CDK4/6 inhibitor therapy. The phase II
portion of this study will evaluate the clinical benefit rate at 24 weeks as a primary
endpoint, and PFS as a secondary endpoint. Notably, TRINITI-1 has included men as
a part of its eligible study population, thus contributing invaluable data for this
particular group in whom CDK4/6 inhibitor efficacy is not well understood.
One feature related to long-term exposure to CDK4/6 inhibitor treatment is activation
of the Akt/mammalian target of rapamycin (mTOR) pathway [8]. As such, the combination
of mTOR inhibitors, such as everolimus, and CDK4/6 inhibitors is of some interest
in order to overcome potential resistance. However, this approach may be limited by
toxicity caused by such combinations. Should the results of the TRINITI-1 trial [7]
indicate efficacy of this combination in the context of patients at high risk of rapid
progression, this treatment could be adopted as first-line treatment and potentially
be trialled against upfront induction chemotherapy.
International guidelines issued by the NCCN [2] and ESMO [3] currently recommend ET
plus a CDK4/6 inhibitor as the preferred first-line treatment option in postmenopausal
women with hormone receptor-positive/human epidermal growth factor receptor 2-negative
(HER2−) mBC, excluding those patients in whom it is necessary to induce rapid disease
control. However, a direct comparison between ET plus CDK4/6 inhibitors and chemotherapy
has never been performed. This comparison is of considerable importance, particularly
in patients with poor prognostic factors (such as an absence of progesterone receptor,
aggressive disease, and so forth) and those with a short interval between the end
of adjuvant ET and subsequent relapse. In postmenopausal women with luminal HER2−
mBC who had not previously received systemic treatment for advanced disease, expanded
analysis emerging from the PALOMA-1 trial demonstrated the achievement of good clinical
benefit rate (over 75%) and a reduction in the risk of progression by 45% in those
patients classified as having the worst prognosis according to clinical factors [9].
This group may be regarded as a surrogate for the clinical group in whom upfront chemotherapy
is recommended. Furthermore, if combined ET plus CDK4/6 inhibition enters the adjuvant
setting over time, a direct comparison between chemotherapy and ET plus CDK4/6 inhibitors
will become increasingly critical.
The recent BOLERO-4 trial [10] demonstrated that ET (letrozole) plus everolimus is
an effective regimen in first-line management of luminal HER2− mBC, with the investigators
concluding that retaining everolimus beyond first-line progression, while switching
the ET to exemestane in the second line, can be an effective option, although these
conclusions are limited because of the small patient subpopulation. These findings
have further enriched and complicated the therapeutic landscape of luminal HER2− mBC,
and future trials should focus on head-to-head comparisons between the two approaches
(mTOR inhibitors and CDK4/6 inhibitors) in the early-line setting.
In order to better understand the place of CDK4/6 inhibitors in the complex therapeutic
landscape of luminal/HER2− mBC, it is increasingly necessary to differentiate patients
who would benefit from this treatment from those who would be exposed to only greater
toxicity without deriving significant advantages. For this identification a contribution
from translational research is necessary, but although preclinical evidence suggests
CCND1 amplification or CDK2N2A loss as predictive markers of response [11], to date
no specific biomarker has yet been identified from exploratory analysis of the PALOMA
trials. Perhaps rather than searching for a single biomarker, increased understanding
of the complex molecular network that underlies neoplastic progression will help us
to instead identify a panel of biomarkers useful to tailor treatment. This could also
help us to understand the correct place for CDK4/6 inhibitors in the increasingly
complex therapeutic algorithm of this breast cancer subgroup. While waiting for these
data, it would probably be wise to reserve these drugs for patients with the highest
risk of progression, administering ET alone in the most indolent clinical situations.
The observation that overexpression of cyclin D1 could be used to promote resistance
to anti-HER2 agents has encourencouraged the use of CDK4/6 inhibitors in estrogen
receptor-positive/HER2-positive mBC in order to resensitize tumor cells [12]. This
has also driven the design of some clinical studies, such as the NA-PHER2 and PATRICIA
trials, that aim to evaluate this innovative approach. The preclinical background
is very encouraging, and CDK4/6 inhibitors represent a promising approach in this
setting, but further data are required.
CDK4/6 inhibitors are the most promising drugs in the last 10 years of breast cancer
therapy, but the journey is still long and we still have a lot to discover about their
potential and limitations.