Enhertu Nabs A First With UK Standalone Approval

The UK conditional approval of Daiichi Sankyo/AstraZeneca’s advanced breast cancer drug Enhertu was issued in accordance with “transitional provisions” that apply to drugs that received a positive opinion from the European Medicines Agency before the end of the Brexit transition period.

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There is significant unmet clinical need for patients with HER2 positive metastatic breast cancer

Daiichi Sankyo/AstraZeneca’s Enhertu (trastuzumab deruxtecan) has become the first new cancer medicine to be authorized by the UK’s Medicines and Healthcare products Regulatory Agency since it became an independent regulator in January following the end of the Brexit transition period.

Enhertu has been granted conditional authorization in the UK as a monotherapy for the treatment of adult patients with unresectable or metastatic HER2 positive breast cancer who have received two or more prior anti-HER2 based regimens.

The UK decision mirrors the recent approval of the drug by the European Commission for the same indication. Enhertu was granted EU-wide approval on 18 January following an accelerated review by the European Medicines Agency’s human drugs evaluation committee, the CHMP. (Also see "Early EU Approval Wins In Line For Daiichi/AZ & Lilly" - Pink Sheet, 11 Dec, 2020.)

There has been some confusion about the drug's approval pathway in the UK. A spokesperson for Daiichi Sankyo/AZ initially told the Pink Sheet that Enhertu’s UK approval, issued on 12 February, followed the MHRA’s new “reliance route” based on the CHMP positive opinion and the marketing authorization approval decision issued by the commission.*

The MHRA, however, said the drug was not approved via the so-called reliance route. Instead, the drug was approved in accordance with the “transitional provisions” set out in the Human Medicines Regulations that apply to applications that were the subject of a positive opinion from the CHMP before the end of the Brexit transition period, the MHRA told the Pink Sheet.

Under this, the MHRA grants a Great Britain (England, Scotland and Wales) marketing authorization in line with the CHMP's opinion unless the UK had recorded a divergent opinion, the MHRA said.

The companies involved have since admitted that they “made an error” as post Brexit transition “there has been some confusion with the terminology used” regarding UK approval pathways. “The submission route changed during the engagement as timelines changed,” the spokesperson said. The companies explained that they had initially anticipated taking the reliance route, but this decision was changed in the end. "We have since re-clarified this internally."

Patient Access

“This is the first new cancer medicine to be authorised by the MHRA in 2021 and our focus now is on securing access for NHS patients as quickly as possible,” said Arun Krishna, head of oncology at AstraZeneca UK. The drug is currently being evaluated by NICE (the health technology assessment bodies for England and Wales) and the Scottish Medicines Consortium.

NHS access decisions are expected later in 2021. Specifically, NICE expects to publish its technology appraisal guidance for Enhertu on 19 May.

“We will now work closely in partnership with the MHRA to fulfil all regulatory requirements before stock can be available in the UK,” said Haran Maheson, commercial director for oncology at Daiichi Sankyo UK. These are the same standard processes that would need to be fulfilled following an EMA approval for any medicine, such as finalizing licence information on the packaging and patient information leaflets, the spokesperson explained.

Unmet Need

There remain significant unmet clinical needs for patients with HER2 positive metastatic breast cancer, since the disease remains incurable with patients eventually progressing after currently available treatment options.

Although significant advances have been made in treating breast cancer, there is “no clear standard of care for patients with metastatic HER2 positive disease following progression on first and second-line treatment,” said Rebecca Roylance, consultant medical oncologist at University College London Hospitals.

Also, many patients do not have a durable response to other available later-line treatment options, Roylance noted. “The authorization of trastuzumab deruxtecan by the MHRA and EMA brings a new treatment option to patients and their doctors in the UK.”

The UK’s conditional authorization of the drug is based on the results of a single arm, Phase II DESTINY-Breast01 trial of trastuzumab deruxtecan (5.4 mg/kg) in 184 patients with HER2 positive metastatic breast cancer.

The trial “showed a duration of response not previously seen in patients after progression on 1st and 2nd line treatment” and the drug’s approval “will shift clinical discussions towards a focus on targeted treatment,” said AZ UK’s Krishna. 

* This article was updated on 17 February 2021 to include corrections from the MHRA and the companies involved about the drug's approval pathway via the transitional provisions.