Palbociclib in combination with an aromatase inhibitor is, among other therapeutic indications, approved for first-line treatment of postmenopausal patients with hormone receptor-positive, HER2-negative, locally advanced or metastatic breast cancer.

After a first early benefit assessment in 2017, the German Institute for Quality and Efficiency in Health Care (IQWiG) has now reassessed whether the combination offers an added benefit in comparison with the appropriate comparator therapy for these patients.

The more recent, comprehensive trial data also show no prolonged overall survival or other benefits in patient-relevant outcomes.

However, under the combination of palbociclib with letrozole, certain severe side effects occurred clearly more often in the studies than under placebo plus letrozole.

In view of the study data that are now available, IQWiG sees proof that affected women have lesser benefit from palbociclib in combination with an aromatase inhibitor than from the appropriate comparator therapy.

On resubmission

As early as since November 2016, palbociclib has been approved for the treatment of women with advanced hormone receptor-positive breast cancer for whom further surgery, radiotherapy or chemotherapy with curative intent is no longer an option.

In its dossier assessment, IQWiG had derived an indication from the data submitted by the manufacturer from two ongoing studies that palbociclib plus letrozole provides less benefit to postmenopausal women in the first-line treatment than placebo plus letrozole.

In particular, no advantage was seen in overall survival, and the so-called progression-free survival referred to by the manufacturer was not a validated surrogate for this patient-relevant outcome.

At the same time, there was an increase of severe side effects, including changes in the blood count.

Due to the preliminary nature of the data from the PALOMA-2 study, the Federal Joint Committee (G-BA) had set a time limit on its decision, thus placing the early benefit assessment on resubmission in a way. After expiry of the decision, the manufacturer has now submitted a new dossier in which it cites - albeit incompletely - results for the final data cut-off of PALOMA-2 and, in addition, results from the PALOMA-4 study, which is still ongoing.

Only negative effects

The course of overall survival of the PALOMA-2 study participants was almost identical in both arms; there was no clear advantage or disadvantage of palbociclib over placebo at any time.

The survival data from the PALOMA-4 study also show no difference.

A different picture emerges with several severe side effects and the related treatment discontinuations: Such events occurred clearly more often with palbociclib than without - to a large extent shortly after the start of treatment, and in some cases even several years later.

Thus, blood and lymphatic system disorders occurred more often, such as neutropenia, i.e. a lack of neutrophil granulocytes, which play an important role in the immune system. This resulted in proof of lesser benefit versus the appropriate comparator therapy.

Scepticism about the surrogate outcome justified

“The situation is rarely so clear”, explains Katrin Nink. "While only a few severe side effects such as neutropenia occurred in the placebo arms of the studies, their number increased rapidly in the palbociclib arms shortly after the start of the study. The two curves diverge rapidly and do not converge later either. However, if we look at the survival curves of the two studies, the palbociclib and placebo arms are almost congruent along their entire length. This confirms our initial scepticism: a positive effect observed early on in the so-called progression-free survival is here, as so often, unfortunately not a good indicator that the affected women will live noticeably longer."

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 (AMNOG) supervised by the Federal Joint Committee (G-BA). After publication of the dossier assessment, the  G-BA conducts a commenting procedure and makes a final decision on the extent of the added benefit. You can find an overview of the results of IQWiG’s benefit assessment in an English extract In addition, the website informedhealth.org published by IQWiG provides easily understandable information on this benefit assessment.

Source: Institute for Quality and Efficiency in Health Care