Sir,
Hormonal manipulation constitutes the backbone of management of advanced hormone-receptor-positive
(HR+) breast cancer. The availability of cyclin-dependant kinase (CDK) 4/6 inhibitors
has led to significant improvements in the outcome of this population. Palbociclib,
ribociclib, and abemaciclib are now approved as first-line therapy for HR+ advanced
breast cancer in combination with aromatase inhibitors (AIs) in postmenopausal women.
Randomized Phase 3 trials have shown a significant increase in progression-free survival
(PFS) of around 9–10 months when compared with anti-estrogen therapy alone when used
in endocrine-naive patients [Table 1 ].[1 ]
[2 ]
[3 ]
[4 ] When used in the second-line setting, the PFS gain is in the range of 6–7 months.
The overall survival (OS) gain of 7 months (statistically nonsignificant) in the PALOMA
3 study could not answer the question of optimal sequencing of CDK 4/6 inhibitors,
as 18% of patients received subsequent CDK 4/6 inhibitors in placebo arm.[5 ] Thus, we have a situation of an effective drug that can be sequenced in both the
frontline and second-line settings, with no definitive evidence to suggest that a
particular strategy of sequencing produces a definite survival benefit. To add to
the clinician's dilemma, there are data from the FALCON trial which bring out single-agent
fulvestrant as another treatment option in the endocrine-naive setting.[6 ] In addition, a recent publication highlights improved PFS and OS with a combination
of fulvestrant plus anastrozole.[7 ] The subsequent lines could never be evidence based after that as there is no data
on how AI + CDK4/6 inhibition will work after exposure to fulvestrant. Thus, it is
likely that the recommendations of use in first line will remain the same in future.
Table 1
Summary of Phase 3 trials of cyclin-dependant kinase 4/6 inhibitors in metastatic
hormone-positive breast cancer
Trial
n (randomization)
Sequence of treatment
Treatment
Median PFS (months)
HR
P
PFS - Progression-free survival; HR - Hazard ratio; AI - Aromatase inhibitor; NR -
Not reported
PALOMA 2 (postmenopausal only)
666 2:1
First line
Palbociclib + letrazole versus letrazole
24.8 versus 14.5
0.58 (0.46-0.72)
<0.001
PALOMA 3 (premenopausal - 21%)
521 2:1
Second line
Fulvestrant + palbociclib versus fulvestrant + placebo
11.2 versus 4.6
0.46 (0.36-0.59)
<0.000
MONALESSA 7 (premenopausal only)
672 1:1
First line
Ribociclib versus tamoxifen/letrazole + goserelin
23.8 versus 13
0.55 (0.44-0.69)
<0.0001
MONALESSA 3 (postmenopausal)
484 2:1
First and second (48.8%)
Ribociclib + fulvestrant versus fulvestrant
20.5 versus 12.8
0.59 (0.48-0.73)
<0.001
MONALESSA 2 (postmenopausal)
668 2:1
First
Ribociclib + letrazole versus letrazole
25.3 versus 16
0.58 (0.45-0.70)
Log rank P=9.63x10-8
MONARCH 3 (postmenopausal)
493
First
Abemaciclib + AI versus anastrozole/letrazole
Median NR versus 14.7
0.54 (0.41-0.72)
0.004
MONARCH 2 (postmenopausal)
669 2:1
First
Abemaciclib + fulvestrant versus fulvestrant
16.4 versus 9.3
0.55 (0.44-0.68)
<0.001
In this scenario, comparison of treatment costs can guide us to assess the optimal
strategy in developing countries with resource limitations. In India, majority of
the health-care expense is borne out of pocket by the patient, and further, the proportion
of patients who present with metastatic disease is significantly higher than that
in the Western population. Abemaciclib is not yet available in this region. In India,
the monthly cost of ribociclib is INR ₹51,600 (USD 739) and palbociclib is INR ₹67,857
(USD 971) as on December 31, 2018. The direct cost comparison of palbociclib and ribociclib
with median PFS benefit in months is depicted in [Figure 1a ] and [b ]. The costs of hospital visits, investigations, and hospitalizations are excluded.
Per-day cost of these drugs is depicted in [Figure 2 ]. As per companies' compassionate access program after compulsory 10 cycles of palbociclib
and 12 cycles of ribociclib consumption, these medicines are supplied at free of cost
till disease progression or unacceptable toxicity. Presuming that the two molecules
are equi-efficacious and equi-toxic and the reduction of dose/interruption of therapy
due to toxicity is similar, for 10 and 12 cycles of palbociclib and ribociclib, the
expenditures are ₹678,570 and ₹619,200, respectively.
Figure 1: (a) Cyclin-dependent kinase 4/6 inhibitors in postmenopausal metastatic
breast cancer: Comparison of cost and median progression-free survival. (b) Cyclin-dependent
kinase 4/6 inhibitors in premenopausal metastatic breast cancer: comparison of cost
and median progression-free survival
Figure 2: Cyclin-dependent kinase 4/6 inhibitors – per-day expenditure
In palliative setting, treatment is continued indefinitely till progression. Thus,
if two ways of sequencing therapies generate equivalent overall outcomes, a strategy
which uses any expensive drug for a shorter duration should be the clear winner. While
the first-line use of CDK antagonists leads to an unprecedented PFS of 2 years with
apparent better quality of life and psychological benefit to the patients, it involves
the use of an expensive drug for a median duration of around 2 years, which significantly
escalates the total cost of therapy. The National Institute for Health and Care Excellence
has approved the first-line use of palbociclib and ribociclib with a caveat of cost
agreement.[8 ]
[9 ] On the other hand, second-line use has a major advantage in terms of reduced costs
[Figure 1a ] and [b ]. Further, endocrine resistance was present in 21.3% (111/521) of cases in the PALOMA
3 study, a subgroup where CDK inhibitor use was found to be ineffective in terms of
improving survival. These patients may also be considered for fulvestrant alone or
in a combination of exemestane and everolimus as the second-line regimen. Although
it may be wise to choose exemestane + everolimus in this difficult set of patients,
using this regimen indiscriminately as a cheaper option in the hormone-naive population
may be counterproductive and may jeopardize survival, as there is some evidence to
suggest that CDK 4/6 inhibition works poorly after mammalian target of rapamycin (mTOR)
inhibitors, not to mention the increased toxicity concerns with mTOR inhibitors.[10 ]
The scientific evidence pertaining to CDK 4/6 inhibitors has created a challenging
situation for health-care providers for optimizing the sequence of CDK 4/6 inhibitors.
The financial aspects are important for any health-care system. When the treatment
is out of pocket, placing CDK 4/6 inhibitors in the second line will definitely reduce
the financial toxicity across the world, especially in resource-limited countries.
