Mobocertinib: UK to withdraw in EGFR+ exon 20 lung cancers…let’s EXCLAIM the results…

Mobocertinib: UK to withdraw in EGFR+ exon 20 lung cancers…let’s EXCLAIM the results…

Patients with lung cancer who have EGFR exon 20 mutations typically have a poor prognosis. Other than chemotherapy, no other treatment options exist because other tyrosine kinase inhibitors (TKIs) against EGFR do not work against this particular alteration. But in 2021, the horizon looked more optimistic. The FDA granted accelerated approval for mobocertinib. This approval for patients with locally advanced or metastatic lung cancer who harboured the EGFR exon 20 insertion mutation, which occurs in about 10% of cases, was based on results from an early clinical trial showing mobocertinib was fairly well tolerated. The same therapy was later approved in the UK in November 2022. However, despite the early promising data, in October 2023, Takeda voluntarily withdrew the drug from the US market because the phase III ECLAIM-2 trial showed no improvement in progression-free survival (PFS), the primary endpoint of the study. In the trial, almost 20% of patients stopped treatment, half of patients took a treatment break owing to toxicity and 25% of recipients needed a dose reduction.

In the UK, mobocertinib will be withdrawn in March 2024. For patients with EGFR exon 20 mutant lung cancer, this withdrawal is disappointing as those currently receiving mobocertinib will no longer have access to this drug and (unlike the USA) no other treatment options are approved on the NHS. Although no new safety concerns were noted, this withdrawal decision is based on the failure of the phase III trial to meet its primary endpoint. Encouragingly, patients receiving mobocertinib before its withdrawal will still be able to obtain the drug free of charge as part of a compassionate use programme, provided that they derive clinical benefit. But for patients who may benefit after failure to respond to chemotherapy, the possibility of not having access to any other treatment options are concerning. It is rare for a drug company to withdraw a product when a confirmatory trial shows non-inferiority to standard of care. Some critics have suggested that the phase III trial should have included a separate arm of mobocertinib plus chemotherapy rather than testing if mobocertinib was more efficacious than standard chemotherapy in the first-line setting.

The lessons learned from this accelerated approval and withdrawal scenario are that trial designs and meeting full clinical trial criteria are crucial to determine the true benefits of a therapy, and that moving a therapy from second or later line to first line does not always translate to an expected superior outcome compared with standard options!


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