Removal of drug may impact care

By Staff 9 Min Read

  • EGFR+ lung cancer is a type of lung cancer, not linked to smoking, that is caused by one of a number of nonhereditary gene mutations.
  • One mutation, exon 20, had no effective treatments beyond chemotherapy until a tyrosine kinase inhibitor called Mobocertinib (marketed as Exkivity) was licensed in 2021.
  • However, the manufacturers withdrew it from use in the United States late last year, and health authorities in the United Kingdom plan to follow suit next month.
  • EGFR+ campaigners are concerned that people in the United Kingdom with this mutation will now have no treatment options to extend life after chemotherapy.

Even though, according to the Centers of Disease Control and Prevention (CDC), 80–90% of lung cancer cases are linked to smoking, a significant number of lung cancers are not smoking-related.

Most of these are non-small cell lung cancers (NSCLC), caused by mutations of the epidermal growth factor receptor, termed EGFR+ lung cancers.

These cancers often present in younger people and have atypical symptoms, such as shoulder pain, or other musculoskeletal symptoms, rather than the coughing, breathlessness and recurrent chest infections that are usually seen in smoking-related lung cancers.

Several different nonhereditary mutations can lead to EGFR+ lung cancer. The most common are EGFR 19 deletion — where part of the gene is missing — and EGFR L858R point mutation, in which one nucleotide (small unit of DNA) is altered.

The exon 20 insertion mutation is the third most common cause of EGFR+ lung cancer, being responsible for up to 10% of cases. People with this mutation generally have a poorer prognosis than people with different mutations.

Apart from platinum-based chemotherapy, there were no effective treatments for exon 20 available in the United Kingdom, as the tyrosine kinase inhibitors (TKIs) used to treat other EGFR+ mutations do not work against exon 20.

However, in 2021, a new TKI, mobocertinib (Exkivity), received accelerated approval from the Food and Drug Administration (FDA) for the treatment of locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations. The oral therapy was approved for use in the U.K. in November 2022.

Prof. Siow Ming Lee, professor of medical oncology at University College London, and consultant medical oncologist at University College London Hospitals (UCLH) told Medical News Today:

“NSCLC patients with the uncommon EGFR+ exon 20 insertion mutations have an unmet need. […] Mobocertinib is a first-in-class, oral tyrosine kinase inhibitor (TKI) specifically designed to selectively target the uncommon epidermal growth factor receptor (EGFR) Exon20 insertion mutations.”

Dr. Gini Harrison, psychologist and research trustee at EGFR+ UK, and EGFR+ survivor, also emphasized how withdrawing mobocertinib from use would severely impact people who rely on it the most.

She explained:

“Mobocertinib is currently the only drug in the U.K. that is licensed for use with this patient group in an NHS [National Health Service] setting. Removing this drug from the market will mean that these patients have no treatment options beyond chemotherapy, which will certainly reduce lifespans and increase mortality rates.”

In early clinical trials, mobocertinib was well tolerated by patients, stopped their cancer from worsening, and increased their survival time, leading to optimism about its potential for people with the exon 20 mutation.

However, in October 2023, the manufacturer, Takeda, voluntarily withdrew Mobocertinib from use in the United States.

In phase 3 clinical trials, the drug failed to show a significant effect on progression-free survival (PFS). During the trial, 17% of participants stopped the treatment, half of the patients had to take a break in treatment, and 25% needed the dose reduced because of side effects, although there were no significant safety concerns.

Takeda said in a press release that it was withdrawing the drug because “the Phase 3 EXCLAIM-2 confirmatory trial, […] did not meet its primary endpoint and thus did not fulfil the confirmatory data requirements of the Accelerated Approval granted by the U.S. FDA nor the conditional marketing approvals granted in other countries.”

However, Prof. Lee explained that the trial had its own shortcomings.

“It is unfortunate that when Takeda designed the first-line trial, the investigator did not include a separate trial arm combining Mobocertinib with chemotherapy,“ he told us.

“Instead, they tested a mobocertinib monotherapy arm against standard chemotherapy, despite knowing that the best ORR [tumor objective response rate] achieved as a second line was approximately 30% in pre-treated NSCLC patients,” Prof. Lee noted.

And if health authorities do withdraw this drug from use in the U.K.? Prof. Lee warned:

“Patients relapsing after first-line platinum chemotherapy will no longer be able to access the drug after the official withdrawal of the conditional marketing authorization for mobocertinib, which will occur in March 2024.”

Dr. Harrison also expressed her frustration to MNT, saying that “[t]he withdrawal of Mobocertinib is purely based on the fact that the drug failed to meet its clinical endpoint in a recent clinical trial.“

It is not being withdrawn due to safety concerns, and indeed, no new safety concerns have arisen since the drug received its initial licence,” she emphasized.

“Instead,” Dr. Harrison explained, “the drug is being withdrawn because it was licensed on the proviso that a positive result was achieved in an RCT [randomised control trial], showing it to be more efficacious than chemotherapy in a first line setting.”

”The recent RCT (EXCLAIM-2) [trial] showed this was not achieved; however, [the drug] was shown to be as effective as chemotherapy in this setting. Given the effectiveness is on par with a licensed, effective treatment, withdrawing the drug entirely seems both unnecessary and harmful to patients,” she added.

Although mobocertinib will not be available for new patients going forward, Prof. Lee gave some reassurance to those already taking the medication.

“Patients initiated on treatment with mobocertinib before its withdrawal will still be able to access the drug through a compassionate use programme free of charge as long as they are deriving clinical benefit from the medication,” he said.

There are alternatives to Mobocertinib in the U.S., but it is the only treatment funded by the National Health Service (NHS) for exon 20 patients in the U.K.

One other drug licensed for use in the U.K. that has shown potential for exon 20 — aminvantamab — is available only privately, so cannot be accessed by those without private insurance or other means of funding, as Dr. Harrison explained.

Amivantamab is an efficacious drug that is used in standard practice for exon 20 patients in Europe and the USA. It is actually approved for private use by the MHRA in the U.K., but is not currently licensed by NICE. While NICE recognises Amivantamab is likely to be efficacious for exon 20, they deem it too expensive to offer it on the NHS.”

– Dr. Gini Harrison

She called for the drug to be made available to NHS patients: “[r]ecent randomised controlled trials have shown that amivantamab is likely to be a very efficacious alternative to mobocertinib.”

“Given that this drug is already available privately in the U.K., we suggest that there should be a way to expedite NICE approval processes in situations where the withdrawal of a drug from the market leaves a treatment gap and an unmet need for patients,” she added.

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