BERLIN, Dec 15 (APM) - Germany's lower health technology assessment (HTA) body said on Friday it recommends a 'less benefit' rating for Novartis's Kisqali (ribociclib) in advanced breast cancer because of increased side effects.
In its recommendation
, IQWiG rejected Novartis's key argument that progression-free survival (PFS) is a valid surrogate for the overall survival (OS) primary endpoint to support positive added benefit for Kisqali.
CDK4/6 inhibitor Kisqali was approved in the EU in combination with an aromatase inhibitor in first line for advanced breast cancer in August, five months after U.S. approval (APMHE 54395
), and launched in Germany in mid-September (APMHE 54700
The IQWiG recommendation will feed into the evaluation of higher HTA body G-BA, which will be published by mid-March 2018 after a consultation phase including comments from medical experts and Novartis.
G-BA's rating will form the basis of reimbursement price negotiations with umbrella payer group GKV-Spitzenverband (GKV-SV).
IQWiG's recommendation was based on the results of the Phase III MONALEESA-2 trial, which compared a combination of Kisqali and letrozole to placebo+letrozole. Letrozole was one of the comparators designated for the German assessment.
IQWiG said that no differences were seen between the two regimens in terms of overall survival (OS). IQWiG disagreed with Novartis over whether added benefit was shown for the subgroup of patients without liver and/or lung metastases.
IQWiG rejected analysis provided by Novartis to validate PFS as a surrogate endpoint for OS, saying it was not suitable.
The determination of disease progression was based on radiological photographic methods using the response evaluation criteria in solid tumours (RECIST) criteria, IQWiG said.
This "is based exclusively on imaging techniques and not on symptoms that the patient perceives" and therefore cannot be considered as "patient-relevant per se", IQWiG said.
Novartis provided its own surrogate validation, the surrogate validation provided by Pfizer for the assessment of its CDK4/6 inhibitor Ibrance (palbociclib) and data from the "Mammakarzinoma" tumour register.
IQWiG also pointed out that a surrogate endpoint can be validated in the benefit assessment if the analysis used "appropriate statistical methods", the patient population is sufficiently limited, interventions are comparable (for instance drugs with a comparable mechanism of action) and high correlation is shown between the effects of the treatment on the surrogate endpoint and those on the primary endpoint.
"These criteria are not sufficiently met by any of the procedures submitted by the pharmaceutical company," IQWiG said.
More severe side effects and a higher level of treatment discontinuation because of side effects were reported in the Kisqali treatment arm, IQWiG said. This supported the conclusion that Kisqali showed less benefit that its comparator.
On other endpoints, no difference between the treatment arms was shown in symptoms, health status or quality of life.
Discussion on PFS
Whether or not PFS should be taken into account in the German HTA procedure is a hot topic, as a growing number of cancer drugs were approved on the basis of PFS only.
Kisqali's U.S. and EU approvals were both based on the MONALEESA-2 trial, where PFS was defined as a primary endpoint. The study was stopped early after interim data analysis showed the drug met the criteria of "clinically meaningful improvement in PFS" (APMHE 47888
In anticipation of Kisqali's assessment, Novartis Germany commissioned a report, published in November, to support recognition of PFS (APMHE 55570
Discussions in Germany on the value of PFS in HTA were sparked off after Ibrance was rated as having no added benefit.
Pfizer (APMHE 53145
), AbbVie, AstraZeneca (APMHE 53627
), Bayer (APMHE 53495
), Novartis (APMHE 55570
), Bristol-Myers Squibb and the German pharma lobby vfa (APMHE 54497
, APMHE 54964
) in turn made their positions known and asked the G-BA for changes because of negative HTA ratings that were followed in some cases by market withdrawals.
In an interview with APM, G-BA chair Josef Hecken said he was "completely comfortable" with criticisms of oncology assessment methods (APMHE 55737