BERLIN, 17 Jan (APM) - Single-arm and basket studies provided by Bayer for its tumour-agnostic drug Vitrakvi (larotrectinib) were insufficient to conclude on its added benefit, said Germany's lower health technology assessment (HTA) body IQWiG.
"There are many indications that [Vitrakvi] has great potential. But even for an 'early benefit assessment' it can sometimes be too early - namely when the data presented do not allow meaningful comparisons," IQWiG's deputy director Stefan Lange said in a late Wednesday statement on its recommendation for a "no added benefit" rating on Vitrakvi (APMHE 65486).
"In the future, we will need reliable comparative data for benefit assessments of therapies that cover all tumour types".
Single-arm studies are generally problematic for HTA as "by definition, an added benefit can only be proven compared to another therapy", IQWiG said.
IQWiG does not rule out taking into account data from basket studies in an assessment as "in principle [they would] allow comparisons".
"Basket studies can also be carried out with control groups that have received the best treatment currently available - and this may well be best supportive care" which was the comparative therapy designated for Vitrakvi's assessment.
However, in the case of Vitrakvi, "none of the three ongoing Phase I and Phase II studies has a comparative arm", IQWiG said.
"Studies without comparative data may, exceptionally, be sufficient for an approval" when they can prove that "the substance has an effect on the tumour. However, if the question is whether such an effect is associated with a patient-relevant benefit, explicit comparative data are needed," IQWiG said.
Based on IQWiG's recommendation and after a consultation phase including comments from medical experts and Bayer, higher HTA body G-BA will rule on Vitrakvi's level of added benefit in early April.
Vitrakvi was approved in Europe in September 2019 for adult and paediatric patients with solid tumours that display a neurotrophic tyrosine receptor kinase (NTRK) gene fusion, who have a disease that is locally advanced, metastatic or where surgical resection is likely to result in severe morbidity and who have no satisfactory treatment options (APMHE 64453).
It is the first tumour-agnostic drug - also called histology independent cancer drug - approved in the EU while the U.S. Food and Drug Administration (FDA) has approved three histology independent drugs since 2017: Merck & Co's Keytruda (pembrolizumab) in one extension of indication (APMHE 53211), Vitrakvi (APMHE 60771) and Roche's Rozlytrek (entrectinib) (APMHE 64070).
Lange pointed out that HTA bodies in other countries also see "the lack of suitable data as the main obstacle to an appropriate assessment" of histology independent cancer drugs.
On Friday - after the publication of IQWiG's statement -, the UK's NICE rejected Vitrakvi for NHS England use in a draft decision because of its cost, but pushed for more data to be collected (APMHE 65882).
Lange mentioned the "no reimbursement" recommendation taken by the Canadian Agency for Drugs and Technologies in November 2019 and issues raised by members of NICE and NHS England in an article published in the British Medical Journal on 2 January.
IQWiG reckoned that patient populations targeted by Vitrakvi are made of several small groups, which is one reason why the approval studies are small.
But IQWiG pointed out that Bayer said in its dossier that Vitrakvi would deserve an "unquantifiable added benefit" rating based on the provided studies despite the fact that "it does not contain comparative data from patients treated with best supportive care".
Bayer referred to "several effects that it classifies as so large ("dramatic") that they should allow a conclusion despite the lack of comparisons", IQWiG said.
The company mentioned a median overall survival of the severely ill patients on Vitrakvi in the last data section (44.4 months), a time to progression "at least five times longer in about one third of them than under their previous systemic therapy" and "about one sixth of the patients having achieved complete remission".
Moreover, in many children, amputation of the affected limbs could be avoided, symptoms and quality of life have also improved significantly in many patients" and Vitrakvi "has hardly any serious side effects".
As IQWiG needed comparative data, it carried out these additional analyses on 15 cancers using data from studies on other drugs that Bayer "has partly listed in the dossier but has not used".
No sufficiently strong effect could be seen in overall survival and "no suitable data were available" in morbidity, quality of life and adverse events endpoints, IQWiG said.
IQWiG also criticised "deficiencies" in the cross-tumour type evaluations submitted by Bayer.
"For example, analyses were not pre-specified and results were presented selectively. Unfortunately, this also meant that it was not possible to verify the data on the avoidance of amputations in children," IQWiG said.
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