The majority of lung cancers are non-small-cell lung cancer (NSCLC). Depending on several factors, including the subtype of lung cancer, and the stage of disease, the 5 years survival of patients diagnosed with NSCLC is 25%, compared to 7% for small cell lung cancer.
Research has shown the involvement of epidermal growth factor receptor (EGFR) oncogene mutations in patients diagnosed with NSCLC. The most common and the ‘classical mutations’, exon 19 deletions and the point mutation L858R at exon 21, predict response to EGFR tyrosine kinase inhibitors (TKIs). The ‘uncommon’ EGFR mutations account for 10-18% of all EGFR mutations and primarily consist of exon 20 insertions (EGFRex20ins). These mutations are the third most common EGFR mutations seen in NSCLC. More than 50 variants of EGFRex20ins mutations have been identified with A767_V769dupASV being the most common variant across multiple surveys.
However, the treatment response of patients with NSCLC with the EGFRex20ins mutation to the currently available EGFR tyrosine kinase inhibitors (TKIs), including osimertinib (Tagrisso®; AstraZeneca), is negligible. In contrast, mobocertinib (Exkivity®; Takeda), previously known as TAK-788, is the first oral treatment that has been approved by the United States Food and Drug Administration (FDA) to treat NSCLC with the EGFRex20ins mutation.
Approval in the United Kingdom
Earlier this month, the United Kingdom’s Medicines and Healthcare products Regulatory Agency (MHRA) has granted conditional marketing authorization to mobocertinib (Exkivity®; Takeda) as a monotherapy treatment for adult patients with epidermal growth factor receptor (EGFR) Exon 20 insertion mutation-positive (Exon20ins+) locally advanced or metastatic non-small cell lung cancer (NSCLC), who have received prior platinum-based chemotherapy. 
This approval marks a significant milestone for patients with this rare and aggressive disease, as there have previously been no targeted treatments NHS reimbursed for this specific type of lung cancer.
The approval of mobocertinib also marks the first anti-cancer drug developed by Takeda to be approved via Project Orbis, which was launched in May 2019 by the US Food and Drug Administration (FDA) Oncology Center of Excellence (OCE) to provide a framework for concurrent submission and review of oncology products among international regulatory agencies. The program aims to deliver faster patient access to innovative cancer treatments with potential benefits over existing therapies.
EGFR Exon20ins+ Mutation
EGFR Exon20ins+ NSCLC mainly affects younger people and non-smokers and carries a worse prognosis than other EGFR mutations. This is because of the aggressive nature of the disease and there are no targeted treatments in the UK’s National Health Service (NHS) reimbursed that specifically target the EGFR Exon20ins mutation. Current treatment options for other EGFR mutations, including tyrosine kinase inhibitors (TKIs) and chemotherapy, only provide limited benefit for Exon20ins+ NSCLC patients .
NSCLC is the most common form of lung cancer, accounting for approximately 85 percent of the estimated 1.8 million new cases of lung cancer diagnosed each year worldwide. EGFR Exon20ins mutations account for five to 10% of all EGFR NSCLC cases and approximately two percent of all NSCLC cases. 
Each year, approximately 30,000 patients are diagnosed with the disease worldwide.
The EGFR Exon20ins+ mutation is a specific mutation that changes the shape of the EGFR protein in a way that makes it difficult for traditional EGFR TKIs to effectively target and treat this type of cancer mutation, and chemotherapy only has limited efficacy.
Due to the rarity of the disease and the typical patient profile, it can often go undiagnosed for some time meaning most patients are diagnosed at Stage IV.
“Patients with EGFR Exon20 insertion+ NSCLC have historically faced a unique set of challenges living with a very rare lung cancer that is not only underdiagnosed but also lacking targeted treatment options that can improve response rates,” explained Marcia Horn, executive director, Exon 20 Group at the International Cancer Advocacy Network (ICAN).
“As a patient advocate working with EGFR Exon20 insertion+ NSCLC patients and their families every day for nearly five years, I am thrilled to witness continued progress in the fight against this devastating disease and am grateful for the patients, families, healthcare professionals, and scientists across the globe who contributed to the approval of this promising targeted therapy,” Horn further noted.
Using an iterative, structure-guided strategy, similar to that employed in the development of other targeted TKIs, mobocertinib was designed to potently inhibit oncogenic variants containing activating mutations in Exon 20.[13
“The impact of a cancer diagnosis is devastating enough, but to then understand that there are no treatments routinely available for your specific type of disease can often make patients feel frustrated and alone,” noted Angela Terry, Chair of EGFR Positive UK.
“So, it is fantastic news that EGFR Exon20 insertion NSCLC patients will now have the opportunity to benefit from an oral, targeted treatment that offers the hope of potentially improved outcomes. We also hope that having targeted treatments available will mean that patients are tested more effectively at diagnosis for this specific mutation – something that has historically been quite variable across the country,” Terry added.
Mobocertinib is a first-in-class, oral TKI that was granted an Innovation Passport by the MHRA, satisfying the entry point for Project Orbis. This is due to the significant unmet need in this rare and aggressive cancer and the ability of mobocertinib to provide patients with an oral targeted treatment that has demonstrated clinically meaningful outcomes, alongside a manageable safety profile.
“The accelerated approval of mobocertinib is testament to the difference this treatment could make to patients that are in critical need of a targeted treatment option,” said Professor Sanjay Popat, Consultant Medical Oncologist, The Royal Marsden NHS Foundation Trust.
“The clinically meaningful benefits and generally manageable side effect profile that mobocertinib can offer to patients marks a step-change in the treatment of this disease and provides hope to patients and their families. The oral administration also adds further value to this treatment option, not only from a patient experience perspective but also in reducing the number of hospital visits for patients whilst we still navigate the Global pandemic,” Popat concluded.
The conditional marketing authorization of mobocertinib for EGFR Exon20ins+ NSCLC in the platinum pre-treated setting is based on phase I/II multicentre, single-arm, open-label study. Eligible patients (N=86) with EGFR Exon20ins+ NSCLC who had previously been treated with platinum-based chemotherapy received mobocertinib at a dose of 160 mg once daily until disease progression or intolerable toxicity. 
In the clinical study, mobocertinib met the primary endpoint by demonstrating a confirmed objective response rate (cORR) of 26%, as assessed by an independent review committee (IRC) and, in addition, achieved a cORR of 34% as per investigator-assessment.  Additional data in 28 platinum pre-treated patients receiving mobocertinib at 160 mg once daily from a phase I/II dose-finding and expansion study demonstrated a 36% cORR, as assessed by an IRC, and 39% as per investigator.
A pooled analysis of platinum pre-treated patients receiving mobocertinib 160 mg (n=114) demonstrated a cORR of 28% (35% per investigator assessment), the median duration of response of 17.5 months, a median progression-free survival of 7.3 months, and a median overall survival of 24 months, all assessed by an IRC. This pooled analysis was presented at the 2021 annual meeting of the American Society of Clinical Oncology (ASCO). 
The safety profile observed with mobocertinib was generally manageable and was considered consistent with that of other TKIs.
The most common adverse reactions (>20%) were diarrhea, rash, nausea, stomatitis, vomiting, decreased appetite, paronychia, fatigue, dry skin, and musculoskeletal pain. Nineteen patients (17%) discontinued due to AEs, most commonly diarrhea (4%) and nausea (4%). 
“Patients in England will be the first in Europe to have access to mobocertinib, a breakthrough drug which will be a lifeline for those with this rare form of the illness,” said UK Health and Social Care Secretary Sajid Javid.
“The treatment will, on a budget-neutral basis to around 100 eligible patients a year with the rare form of cancer. and our early access agreement through Project Orbis has allowed us to make this drug available on an accelerated timescale – a fantastic example of post-Brexit global collaboration ensuring UK patients receive the best possible care and treatment for cancer,” he added.
Mobocertinib will be assessed by UK health technology assessment bodies, starting with the National Institute for Health and Care Excellence (NICE) which aims to publish its recommendation towards the end of 2022.
“[We’re] extremely pleased that the promise of mobocertinib has been recognized by the MHRA via Project Orbis, and that approval has been expedited for patients in dire need of targeted treatment options,” said Emma Roffe, Takeda’s Oncology Country Head for the – UK and Ireland.
“We have worked in close partnership with the clinical community, the regulatory authority and NHS England to demonstrate the value of this innovative treatment and continue to have patients front of mind in our decision making by ensuring that mobocertinib is made available to patients prior to potential NHS reimbursement later in the year,” Roffe concluded.
“I’m delighted we have been able to work with Takeda, the MHRA, and NHS England to reach an agreement to make mobocertinib available for people with this type of lung cancer while we complete our evaluation,” noted Helen Knight, program director in the Centre for Health Technology Evaluation at NICE.
“Collaboration is critical to our role in bringing innovative treatments to patients as rapidly as possible,” she added.
“This is the fourth drug that has been made available by the NHS in England through an early national access agreement following a Project Orbis license, and similar NHS agreements for Osimertinib, Atezolizumab, and cutting-edge therapy Sotorasib which targets the so-called “death star” mutation,” Knight concluded.
The FDA approved mobocertinib on September 15, 2021. At the same time, the FDA approved Thermo Fisher Scientific’s Oncomine Dx Target Test as an NGS companion diagnostic for mobocertinib to identify NSCLC patients with EGFR Exon20 insertions. NGS testing is critical for these patients, as it can enable more accurate diagnoses compared to polymerase chain reaction (PCR) testing, which detects less than 50% of EGFR Exon20 insertions.
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