A new drug, called Palbociclib (trade name: Ibrance), is approved for women with advanced breast cancer whose
cancer cells carry receptors for hormones such as estrogen or
progesterone (HR-positive), and who are not eligible for chemotherapy, radiotherapy or
In these patients, hormones such as estrogen or progesterone accelerate the growth of the cancer cells.
‘An early benefit assessment of whether Palbociclib offers advantages for advanced breast cancer patients over appropriate comparator therapies showed no such added benefit.’
Palbociclib is used either in combination with an aromatase inhibitor or
with the drug fulvestrant. Palbociclib is not approved for the
treatment of tumors carrying the human epidermal growth factor receptor
In an early benefit assessment, the German Institute
for Quality and Efficiency in Health Care (IQWiG) investigated whether
this drug offers advantages for patients over the appropriate comparator
According to the findings, such an added benefit is not proven: The
dossier contained no data or no suitable data on several groups of
patients. Where data were available, i.e. in the first-line treatment
after menopause, severe side effects were more frequent under
palbociclib in combination with letrozole than under letrozole alone,
which resulted in an indication of lesser benefit.
G-BA distinguished between four treatment situations
For the current assessment, the Federal Joint Committee (G-BA)
distinguished between four treatment situations and specified a
different appropriate comparator therapy for each of them. One criterion
was whether the patients have already completed menopause, another one
the line of treatment, i.e. whether and how many treatments have already
been (unsuccessfully) conducted.
No relevant differences in several outcomes
The drug manufacturer presented data from two randomized controlled
trials (RCTs) for one of the four treatment situations, i.e. the
first-line treatment in postmenopausal women. Both RCTs tested
palbociclib in combination with the drug letrozole against letrozole
These data showed no relevant differences between the two study arms
in several outcomes. This was the case for health status (morbidity),
health-related quality of life and treatment discontinuation due to side
Manufacturer used results on progression-free survival
The differences were not statistically significant also in the
outcome "survival" (overall survival). However, the manufacturer used
results on progression-free survival (PFS), which were in favour of
palbociclib. It wanted PFS to be understood as a surrogate for survival.
Since it sometimes takes years before it is shown whether new
treatments actually prolong life, cancer drugs in particular are often
approved on the basis of such surrogates. It is a good sign when the
tumour does not continue to grow or even shrinks under a new treatment.
It is not certain, however, that patients actually survive longer.
PFS would have to be "validated" as a surrogate for survival to be
able to derive an added benefit. There is validity when a change in the
surrogate outcome reliably predicts a change in the same direction of a
Method principally suitable for validation
In its dossier, the manufacturer tried to validate PFS as a
surrogate. It chose a suitable scientific method to estimate the
reliability of PFS (surrogate threshold effect analysis, STE).
The study pool used by the manufacturer did not adequately represent
the research question, however: On the one hand, the manufacturer used
studies that compared two monotherapies. According to the approval,
however, palbociclib can only be used as combination therapy. On the
other, it precisely did not include studies on palbociclib in its
IQWiG therefore conducted its own analysis, which included the
palbociclib studies, but not the monotherapy studies. It was shown that
PFS cannot be considered to be a valid surrogate parameter for survival
in this treatment situation. Hence an added benefit cannot be derived
from the better results for PFS.
Disadvantage of palbociclib in severe side effects
Relevant group differences were shown in severe side effects,
however: These were notably more common under the combination therapy
with palbociclib, from which an indication of greater harm can be
derived. Since this disadvantage was not accompanied by advantages in
other outcomes, IQWiG sees an indication of a lesser benefit of
palbociclib in the overall consideration.
The dossier contained no data for the first-line treatment in women
before or during menopause. Regarding the second and subsequent line of
treatment before, during or after menopause, the study presented was
unsuitable for the assessment because palbociclib was not tested against
the appropriate comparator therapy specified. An added benefit is
therefore not proven.
G-BA decides on the extent of added benefit
The dossier assessment is part of the early benefit assessment
according to the Act on the Reform of the Market for Medicinal Products.