- 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%Trusted Source 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 receptorTrusted Source,
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 nucleotideTrusted
Source (small unit of DNATrusted Source) is altered.
The exon 20
insertion mutationTrusted Source 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 chemotherapyTrusted Source,
there were no effective treatments for exon 20 available in the United Kingdom,
as the tyrosine kinase inhibitorsTrusted Source (TKIs)
used to treat other EGFR+ mutations do not work against exon 20.
However, in 2021, a new
TKI, mobocertinib
(Exkivity), received accelerated
approvalTrusted Source 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
MobocertinibTrusted Source 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 effectsTrusted
Source, 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.
“AmivantamabTrusted
Source 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.
