Prevalence of Molecular Mutations in Non–Small Cell Lung Cancer and Current Treatment Approaches in the MENA Region: Systematic Review and Expert Opinion

Abstract

Over the past decade, the discovery of immunotherapy and targeted therapy has set new standards for the management of advanced non–small cell lung cancer (NSCLC). This study aims to investigate the prevalence of ALK, EGFR, KRAS, ROS1, MET, BRAF, and HER2 mutations in patients with NSCLC within the Middle East and North Africa (MENA) region and to assess the current state of molecular testing and targeted treatments in the Gulf Cooperation Council (GCC) region. The systematic literature review was performed using PubMed, Google Scholar, and Google searches to identify studies on the prevalence of ALK, EGFR, KRAS, ROS1, MET, BRAF, and HER2 mutations in patients with NSCLC in the MENA region. Additionally, 10 experts from the GCC region were interviewed to provide insights into molecular mutation testing, the challenges faced, and the current approaches to targeted therapies. The prevalence of ALK, EGFR, KRAS, ROS1, MET, and BRAF mutations was 7.9% (95% CI, 6.69–9.03%), 24% (95% CI, 22.05–25.41%), 19.7% (95% CI, 15.29–24.07%), 2.2% (95% CI, 0.77–3.57%), 4.7% (95% CI, 2.29–7.07%) and 3.7% (95% CI, 1.54–5.80%), respectively. HER2 mutation data were unavailable. Treatment generally adhered to international guidelines, with therapy selection based on tumor stage, molecular profile, and drug availability. Expert opinions highlighted significant advancements in molecular diagnostics and targeted therapies but also pointed out the challenges in standardizing and implementing these techniques across the GCC region. This review underscores the importance of personalized and region-specific approaches to NSCLC treatment, given the significant differences in mutation patterns in the MENA region. Further research is needed to gain a more comprehensive understanding of the prevalence and effect of driver mutations across broader MENA countries to inform future treatment strategies.

INTRODUCTION

In 2022, lung cancer was the most commonly diagnosed cancer, with nearly 2.5 million new cases constituting 12.4% of all cancers globally. Lung cancer is the leading cause of cancer death with an estimated 1.8 million deaths accounting for 18.7% of cancer fatalities.[1] It is also the leading cause of cancer-related mortality in men and the second leading cause after breast cancer among women.[1] In the Gulf Cooperation Council (GCC) countries (Bahrain, Kuwait, Oman, Qatar, Saudi Arabia, and the United Arab Emirates [UAE]), lung cancer is the seventh most diagnosed cancer, with an incidence of 4.7% of all cancers.[2] Management of lung cancer imposes a substantial financial burden. Global economic cost of lung cancer from 2020 to 2050 is projected to be about 3.9 trillion international dollars.[3] In Saudi Arabia, the annual expenditure due to lung cancer was estimated at US $2.49 billion in 2015, which is projected to be US $50.17 billion in the period 2015–2030.[4]

Non–small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) are the two major types of lung cancer, of which NSCLC accounts for 85% of newly diagnosed cases.[5,6] Adenocarcinoma, squamous cell carcinoma, and large cell carcinoma are the three histological subtypes of NSCLC.[5] Treatment and prognosis of patients with NSCLC depends on the tumor stage and molecular profile. For early-stage patients, surgery is the mainstay of curative intent treatment; however, the majority of cases present with advanced-stage disease.[7] Over the past decade, discovery of immunotherapy and targeted therapy has set new standards for the management of advanced NSCLC.[7] Anaplastic lymphoma kinase (ALK), epidermal growth factor receptor (EGFR), Kirsten rat sarcoma (KRAS), c-ROS oncogene 1 (ROS1), mesenchymal-epithelial transition (MET), v-raf murine sarcoma viral oncogene homolog B (BRAF), and human epidermal growth factor 2 (HER2) are the widely targeted genetic alterations.[7] Currently, approximately 60% of patients with NSCLC harbor driver mutations.[8] These advancements in NSCLC suggest that identification of histopathological subtypes and molecular mutations profiles is crucial in selecting suitable treatment regimens.[9]

The distribution of ALK, EGFR, KRAS, ROS1, MET, BRAF, and HER2 mutations varies across populations. In western populations, the prevalence of these mutations are reported as follows: ALK, 2–7%; EGFR, 10–16%; KRAS, 22–33%; ROS1, 1–2%; MET, 2–5%; BRAF, 1–3%; and HER2, 2–3%.[7,10] In the Middle East and North Africa (MENA), ALK and EGFR are reported at 5% and 17%, respectively.[5,11] However, data on prevalence of molecular mutations in the GCC countries remain limited. Furthermore, there is a paucity of data on how available therapies are translated into real-world clinical practice across the GCC.

This literature review aimed to determine the frequency of ALK, EGFR, KRAS, ROS1, MET, BRAF, and HER2 mutations in patients with NSCLC in the GCC. Given the limited data available, the scope was expanded to include the broader MENA region to provide a comprehensive analysis. To address current challenges in clinical practice, expert opinions were obtained from key opinion leaders in the GCC countries, focusing specifically on molecular testing and targeted treatments for NSCLC.

METHODS

The systematic literature review was performed using PubMed, Embase, and Google Scholar databases to identify studies on the prevalence of driver mutations in patients with NSCLC in the GCC region. Due to the limited availability of data, the initial search scope, which focused on the Gulf region, was expanded to encompass the broader MENA region to provide a comprehensive analysis. English language records published in peer-reviewed journals between July 2013 and January 2025 were included. Search strings included different combinations of the following terms: NSCLC, non–small-cell lung carcinoma, lung adenocarcinoma, lung cancer, incidence, epidemiology, prevalence, frequency, molecular mutations, clinicopathological, oncogene mutations, driver mutations, genetic alterations, ALK, EGFR, KRAS, ROS1, MET, BRAF, and HER2. The search was conducted using specific country or region names such as Bahrain, Kuwait, Oman, Qatar, UAE, Arab, Middle East, Arabic, Arabian, Saudi Arabia, and Gulf. Cross-references of the included articles, systematic reviews, and review articles were manually searched to identify additional publications. Abstracts published as a conference proceeding of the European Society for Medical Oncology (ESMO) and the American Society of Clinical Oncology (ASCO) were also considered to identify unpublished records.

Both observational cohort and clinical human studies were included. If populations among published records were duplicative or identical, the most recently published study was included. Data regarding study characteristics (first author’s name, year of publication, location, sample size) and clinicopathological characteristics (smoking status, screening method, frequency of mutations and treatment regimens) were extracted from each publication. This systematic review adheres to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.[12]

The fixed effect pooled prevalence was calculated by summing the number of cases and sample sizes from all included studies, then dividing the total number of cases by the total sample size.[13] The 95% CI was calculated using Microsoft Excel (Microsoft Office 365, version 2501).[14]

To understand how NSCLC is treated in the Gulf region, we interviewed experts from the Gulf region by phone or in person. Medical oncologists with NSCLC expertise shared their views on molecular mutation testing, the challenges faced, and the current approach in targeted therapies for driver mutations in the region.

RESULTS

ALK Mutation

The initial search in the mentioned databases yielded 39 publications, of which 2 were conference proceedings. Thirty-two records were screened for eligibility after excluding seven duplicate publications or publications with overlapping populations. Fourteen studies containing relevant ALK mutation incidence data were included for this review. The articles provided data from Saudi Arabia, Kuwait, Bahrain, Oman, UAE, and Lebanon. Multicenter studies from the Levant, MENA regions were also identified (Fig. 1).

Figure 1.

Flow chart of publications identified and included for anaplastic lymphoma kinase (ALK) mutation prevalence.

A total of 2470 patients with NSCLC were enrolled in the selected studies. The median age was 64 years, with a range of 25–93 years. The studies by Al Dayel et al and Mohieldin et al did not contain information on age and male to female ratio.[15,16] NSCLC was more prevalent in men in all the included studies, accounting for 68.6% of cases (1364 of 1987). Smoking history was reported in 11 of 14 analyzed studies. About 58.5% of patients (1078 of 1844) were either active or past smokers. Six studies tested for ALK mutations using fluorescence in situ hybridization (FISH), two studies using next-generation sequencing (NGS), two studies using immunohistochemistry (IHC), and four studies did not report information regarding screening methods. Baseline demographics of the included studies have been summarized in Supplemental Table 1, available online. ALK mutations were tested in 2035 of 2470 cases. ALK mutation prevalence was 7.9% (95% CI, 6.69–9.03%) in the MENA region, with 8% in Saudi Arabia and 9.4% in UAE. Data on prevalence of ALK mutations are described in Table 1.

Table 1.

Frequency of ALK mutation in patients with NSCLC by country or region

Country/Region	Study	Samples Analyzed (N)	Frequency of ALK Mutation, n (%)
Overall [95% CI]		2035	160 (7.9) [6.69–9.03]
Saudi Arabia	Alanazi et al[18]	32	4 (13)
	Al Dayel et al[16]	97	3 (3)
	Alamri et al[21]	92	15 (10.7)
	Katib et al[47]	65	1 (1.5)
United Arab Emirates	Azribi et al[22]	180	27 (15)
	Shafiq et al[19]	192	8 (4.2)
Kuwait, Saudi Arabia	Mohieldin et al[15]	386	38 (9.8)
Bahrain	Mubarak et al[17]	57	6 (10.5)
Oman	Furrukh et al[48]	14	1 (7.1)
Lebanon	El Naderi et al[49]	152	6 (4)
Middle East and North Africa	Jazieh et al[11]	448	39 (8.7)
Levant region	Tfayli et al[50]	157	3 (2)
Middle East	Khoueiry et al[20]	53	1 (1.2)
Kuwait	Shafik et al[51]	110	8 (7.3)

ALK: Anaplastic lymphoma kinase; NSCLC: non–small cell lung cancer.

EGFR Mutation

The initial search in the databases mentioned yielded 52 publications, of which one abstract was from conference proceedings. Forty-one records were screened for eligibility after excluding nine duplicate publications or publications with overlapping populations. Eighteen studies containing relevant EGFR mutation incidence data were included for this review. The articles provided data from Saudi Arabia, Kuwait, Bahrain, Oman, UAE, Egypt and Lebanon. Multicenter studies from the Gulf, Levant, MENA regions were also identified (Fig. 2).

Figure 2.

Flow chart of publications identified and included for epidermal growth factor receptor (EGFR) mutation prevalence.

A total of 3517 patients with NSCLC were enrolled in the selected studies. The median age was 63 years, with a range of 25–93 years. NSCLC was more prevalent in men in all the included studies, accounting for 70.3% of cases (2473 of 3517). The study by Mubarak et al did not contain information on smoking history.[17] About 50.2% (1767 of 3517) of the patients were either active or past smokers. Quantitative polymerase chain reaction (qPCR)–based assays and NGS were used to screen for mutations in the EGFR gene; nine studies did not report information regarding screening method. Baseline demographics of the included studies have been summarized in Supplemental Table 2. EGFR mutations were tested in 2444 of 3517 cases. EGFR mutation prevalence was 24% (95% CI, 22.05–25.41%) in the MENA region, with 11.9% in Lebanon and 37% in Kuwait. Data on prevalence of EGFR mutations are described in Table 2.

Table 2.

Frequency of EGFR mutation in patients with NSCLC by country or region

Country/Region	Study	Samples Analyzed (N)	Frequency of EGFR Mutation, n (%)
Overall [95% CI]		2444	580 (24) [22.05–25.41]
Saudi Arabia	Alanazi et al[18]	49	17 (35)
	AlQahtani et al[52]	71	18 (25.4)
	Alamri et al[21]	98	15 (10.7)
	Katib and Mulla[47]	17	5 (29.4)
United Arab Emirates	Azribi et al[22]	188	64 (34)
	Shafiq et al[19]	192	29 (15)
Bahrain	Mubarak et al[17]	65	14 (21.5)
Oman	Furrukh et al[48]	43	12 (28)
Kuwait	Shafik et al[53]	81	30 (37)
Gulf region	Jazieh et al[54]	230	66 (28.7)
Middle East and North Africa	Jazieh et al[11]	209	61 (13.6)
Levant region	Tfayli et al[50]	205	32 (15.6)
Middle East	Khoueiry et al[20]	85	8 (9.4)
Middle East and North Africa	Jazieh et al[55]	103	26 (25.2)
Middle East and North Africa	Jazieh et al[56]	164	42 (25.6)
Lebanon	Naderi et al[57]	201	24 (11.9)
Kuwait	Shafik et al[51]	110	36 (32.7)
Egypt	Helal et al[58]	333	81 (24)

EGFR: epidermal growth factor receptor; NSCLC: non–small cell lung cancer.

KRAS Mutation

The initial search in the databases mentioned yielded 85 publications. Four studies containing relevant KRAS mutation incidence data were included for analysis.[11,18-20] A total of 783 patients with NSCLC were enrolled in the selected studies, and KRAS mutations were tested in 315 samples. KRAS mutations were found in 19.7% (95% CI, 15.29–24.07%) of cases (62 of 315) in the MENA region, with 39% in Saudi Arabia and 8% in the UAE (Supplemental Table 3).

ROS1 Mutation

The initial search in the databases mentioned yielded 83 publications. Four studies containing relevant ROS1 mutation incidence data were included for analysis.[18,19,21,22] A total of 670 patients with NSCLC were enrolled in the selected studies, and ROS1 mutations were tested in 414 samples. The overall frequency of ROS1 mutations in the MENA region was 2.2% (95% CI, 0.77–3.57%), with 2.4% in Saudi Arabia and 1.6% in UAE (Supplemental Table 4).

MET, BRAF, and HER2 Mutations

The initial search in the databases mentioned yielded 89 and 82 publications for MET and BRAF mutations respectively. Three studies from UAE, Saudi Arabia, and the Middle East region containing relevant MET and BRAF mutations incidence data were included for analysis.[18-20] A total of 335 patients with NSCLC were enrolled in the selected studies, and MET mutations were tested in 299 samples. The frequency of MET mutations was 4.7% (95% CI, 2.29–7.07%) and the frequency of BRAF mutations was 3.7% (95% CI, 1.54–5.80%) in 300 tested samples. Data regarding the frequency of HER2 mutations in the MENA region are not available (Supplemental Tables 5 and 6).

Expert Opinion on Molecular Testing and Targeted Treatment for NSCLC

Ten medical oncologists, including two from Qatar, three from the UAE, one from Oman, two from Kuwait, one from Iraq, and one from Saudi Arabia, shared their insights on molecular testing and targeted treatment for NSCLC in the GCC region. According to the specialists, government-affiliated cancer centers across the region primarily conduct in-house molecular profiling testing using NGS platforms, particularly the Oncomine Comprehensive Assay (Thermo Fisher Scientific),[23] funded by the government. Some local centers also offer NGS liquid biopsy techniques, enhancing diagnostic capabilities. Private-sector oncology centers mainly use commercially available NGS tests, although practices can vary based on insurance coverage and test availability. In Qatar, the government covers the cost for Qatari patients, and charity organizations support expatriates and uninsured individuals with their diagnostics and treatment. In Oman, insurance companies cover NGS costs only for residents. Experts further explained that within GCC countries, medical oncologists typically initiate the pathology review process, which triggers comprehensive molecular profiling, including NGS and PD-L1 assays, for all patients with biopsy-proven lung adenocarcinoma, regardless of disease stage.

Experts note that as most patients are above 65 years old with comorbidities, follow-up tissue biopsy is often not feasible. Moreover, some patients refuse to undergo follow-up biopsy, which makes obtaining sufficient tissue sample challenging. Therefore, according to experts, liquid biopsy can be an alternative to detect changes in actionable mutations and inform treatment choices. Liquid biopsy uses circulating DNA (ctDNA) from plasma, which can reflect metastatic tumors better than tissue biopsy. A key challenge of liquid biopsy is that in patients with low tumor burden, sensitivity and specificity can be affected. Previous studies have demonstrated the effectiveness of liquid biopsy in identifying actionable genetic alterations, diagnosing, and predicting treatment response. Moreover, it can markedly shorten the time needed for laboratory results, leading to earlier treatment and improved survival outcomes in patients with lung cancer.[24,25]

Key actionable mutations such as EGFR (exons 18, 19, 20 and 21) and ALK have been adapted into clinical practice in Qatar for monitoring disease progression and guiding treatment choices. BRAF testing for lung cancer was introduced in Kuwait less than 5 years ago, so the actual incidence of BRAF V600E mutation is still unknown. In the absence of these actionable mutations, tissue or liquid biopsy is not repeated. Patients harboring KRAS G12C mutations, which until recently lacked targeted treatment options, would typically receive chemotherapy, with some also receiving immunotherapy depending on PD-L1 expression and clinical context. Expert opinion on the status of molecular testing in the Gulf region is depicted in Table 3.

Table 3.

Expert opinion on the status of molecular testing in Gulf region

Country	Molecular Tests	Turnaround Time	In-House or Outsourced	Sponsor	Comments
Qatar	NGS PCR IHC	3 wk 4–5 d Immediate	In-house	Covered by hospital; NGS and liquid biopsy are sponsored by pharmaceutical companies in some cases	In case of adenocarcinoma PCR and NGS are done regardless of stage If a young nonsmoker patient has squamous cell carcinoma, NGS is performed
UAE	IHC NGS	Immediate 2–3 wk	In-house Outsourced	Sponsored by pharmaceutical companies (NGS up to 5–10 mutations)	NGS testing (beyond 10 mutations) is self-paid
Oman	NGS	3 wk	In-house	NGS panels (Astra 22 gene NGS Lab 21) are sponsored by pharmaceutical companies	Molecular testing is done following the diagnosis, again upon progression, or in case of unexpected response
Kuwait	NGS	10–14 d	In-house	Sponsored by the government through Ministry of Health	Molecular testing (tissue or liquid) is conducted on a national level upon diagnosis

IHC: immunohistochemistry; NGS: next-generation sequencing; PCR: polymerase chain reaction; UAE: United Arab Emirates.

In GCC countries, the first-line targeted therapies for oncogene-driven lung adenocarcinomas align with the latest recommendations from the National Comprehensive Cancer Network (NCCN), ESMO, and ASCO. Table 4 gives more details about the current practice for treating NSCLC in this region. Most of the systemic treatments approved by the US Food and Drug Administration (FDA) are funded through governmental healthcare systems, ensuring that patients have access to up-to-date therapies.

Table 4.

Expert opinion on the current practice in the treatment of NSCLC in the Gulf region

Country	Treatment of early- and late-stage NSCLC	Targeted therapy
Qatar	Early-stage NSCLC is treated with neoadjuvant chemotherapy and immunotherapy before surgery Surgery is followed by adjuvant chemotherapy and immunotherapy to prevent recurrence and improve survival Immunotherapy agents include atezolizumab, nivolumab, and pembrolizumab Late-stage treatment is based on the molecular profile of the tumor and the presence of actionable mutations The treatment selection does not depend on the site of the metastasis, but for patients with CNS metastasis, the treatment for ALK and EGFR mutation should be able to penetrate the blood-brain barrier, which eliminates the need for radiotherapy and surgery	Patients with EGFR mutation are treated with osimertinib, whereas those with ALK mutation receive either alectinib or lorlatinib as first-line therapy For patients with BRAF mutation, trametinib + dabrafenib are given, whereas patients with HER2 or KRAS mutation are given chemotherapy and immunotherapy
UAE	For early-stage (stage 1 and 2) resectable cancer, surgery is the main treatment option, followed by adjuvant immunotherapy. If the tumor has an actionable mutation, such as EGFR, ALK, or BRAF, targeted therapy is also given after surgery to prevent recurrence For stage 3 cancer, chemotherapy and radiation therapy are given, followed by adjuvant immunotherapy to improve survival and reduce the risk of metastasis For stage 4 cancer, the treatment is based on the presence or absence of actionable mutations in the tumor. If the tumor does not have any actionable mutation, chemotherapy and immunotherapy or immunotherapy alone is given Stereotactic radiosurgery is an option for small size metastasis. For symptomatic and large brain metastasis, whole-brain radiotherapy followed by targeted therapy is used	If the patient has an EGFR mutation, osimertinib and erlotinib are the preferred drugs Alectinib or lorlatinib are the options for ALK mutation, but lorlatinib is usually reserved as a second-line option. However, there is a shift towards using lorlatinib as a first-line treatment For patients with brain metastasis, treatments such as alectinib and lorlatinib that can cross the blood-brain barrier are given for ALK mutation
Oman	Chemotherapy and immunotherapy are the treatment options for stage 4 patients who do not have actionable mutations in their tumors, which represent around 30% of all patients Older patients with poor performance status (2 or beyond) or comorbidities may be given monoimmunotherapy	Crizotinib and alectinib used to be the main treatments for ALK, but now brigatinib and lorlatinib have become more widely used The patient profile influences the choice of medication, as well as the presence of CNS metastasis
Kuwait	Surgery is the main treatment for stage 1 NSCLC, but radiation therapy is an option for older patients with comorbidities Patients may also receive neoadjuvant or adjuvant or perioperative systemic therapy, based on the updated guidelines For unresectable locally advanced (stage 3) NSCLC, concurrent chemotherapy and radiation therapy are given, followed by adjuvant immunotherapy. Patients with stage 4 disease are offered targeted therapy when actionable mutations are identified. In the absence of such alterations, treatment typically involves a combination of chemotherapy and immunotherapy, or immunotherapy alone in cases of high PD-L1 expression.	Crizotinib is no longer the first-line treatment for ALK mutated NSCLC in Kuwait. Alectinib and brigatinib are preferred alternatives; however, Lorlatinib has recently emerged as one of the preferred first-line treatments, particularly for patients who present with CNS metastases. It is also used in second line setting for patients with G1202R acquired resistance mutation. For EGFR mutations, osimertinib is the preferred first-line treatment for exon 19 deletions and exon 21 L858R substitutions. It may also be combined with chemotherapy in selected patients (FLAURA-2 protocol). Osimertinib is also effective against certain rare EGFR mutations, including exon 18 G719X and exon 21 L861Q. For other uncommon EGFR alterations, such as exon 20, the current options include chemotherapy alone or in combination with immunotherapy, pending the availability of Amivantamab. For ROS1 mutations, crizotinib remains a commonly used agent, although lorlatinib is sometimes used. In cases with BRAF v600E mutation, the combination of dabrafenib and trametinib has demonstrated clinical efficacy. Additionally, encorafenib combined with binimetinib has recently shown promising data as a potential first-line treatment option.

ALK: anaplastic lymphoma kinase; BRAF: v-raf murine sarcoma viral oncogene homolog B; CNS: central nervous system; EGFR: epidermal growth factor receptor; HER2: human epidermal growth factor 2; KRAS: Kirsten rat sarcoma; NSCLC: non–small cell lung cancer; PD-L1: programmed cell death 1 ligand 1; ROS1: c-ROS oncogene 1; UAE: United Arab Emirates.

DISCUSSION

Previous studies have demonstrated that the frequency of oncogenic driver mutations differs according to ethnicity and geographic region.[7,26] However, data on the prevalence of these mutations in the GCC countries remain limited. Therefore, this systematic review aimed to determine the frequency of oncogenic driver mutations in patients with NSCLC in the MENA region, with a specific focus on the GCC region. The GCC countries, representing a key subset of the MENA, have a combined population of approximately 63 million, accounting for 12% of the total regional population.[27] Unlike the other MENA countries, which differ significantly in socioeconomic factors and disease patterns, the GCC countries exhibit homogeneity in health systems and disease patterns, making them a unique subset.[28] These countries share similar health regulations, health systems, and health challenges, yet disparities in healthcare resources exist across the MENA countries.[28] As approved targeted therapies for these mutations are available in the GCC, mutation testing plays a crucial role in the management of NSCLC. Therefore, expert opinions were sought from the GCC region on molecular mutation testing, the associated challenges, and the current approach to targeted therapies for driver mutations.

ALK

ALK protein, encoded by the ALK gene, is a tyrosine kinase that consists of transmembrane segment and an extracellular domain.[7] Translocation fusion of the ALK gene with the echinoderm microtubule-associated protein-like 4 (EML4) gene leads to the EML4-ALK fusion oncogene.[7] EML4-ALK fusion is the most commonly observed ALK rearrangement in NSCLC, which was first discovered in 2007.[7] As per the previously published reports, the frequency of ALK mutations varies between 1% and 19% depending on ethnicity.[29,30] A recent systematic review and meta-analysis conducted by Parra-Medina et al[26] found that the frequency of ALK mutations is 5% in the Hispanic or Latino population. A meta-analysis evaluating the prevalence of driver mutations in Black populations reported that the frequency of ALK mutation was 1%, 2%, 6%, and 7% in Black, White, Asian, and Hispanic populations, respectively.[30] Two different studies found a relatively high ALK mutation incidence of 19% and 15% in Asian patients.[11,29] In this study, overall frequency of ALK mutation was 7.9% among 2035 patients with NSCLC in the MENA region. In our analysis, ALK mutation rates in the MENA region appear higher than those reported in White and Black populations, and comparable to rates in Hispanic cohorts, but lower than that in the Asian populations. The treatment landscape for ALK-positive NSCLC has evolved rapidly in the past decade, with the development and approval of several ALK inhibitors.[31] Crizotinib was the first ALK inhibitor, followed by second-generation inhibitors like ceritinib, alectinib, and brigatinib and third-generation lorlatinib, each showing improved efficacy and safety.[32-34] The CROWN trial highlighted the significant efficacy of lorlatinib, establishing it as a new standard of care for patients with advanced ALK-positive NSCLC.[34]

EGFR

The EGFR gene codes for a transmembrane protein and an extracellular domain that act as a ligand binding site. The EGFR protein is a part of the receptor tyrosine kinase family that has intrinsic tyrosine kinase activity. Ligand binding triggers receptor dimerization and tyrosine residue autophosphorylation. This activates downstream pathways that regulate proliferation, survival, angiogenesis, and metastasis of the cell. Mutations in EGFR deregulate the autoinhibition of the receptor, resulting in prolonged activation of the receptor, promoting pro-oncogenic effects.[5,7] EGFR mutations are highly prevalent in patients with NSCLC, with the incidence ranging between 10% and 50%.[7] In the study by Parra-Medina et al,[26] the frequency of EGFR mutation was 22% (n = 22,130) in Hispanic patients with NSCLC; this meta-analysis found that the frequency of EGFR mutation was 6%, 12%, 46%, and 35% in Black, White, Asian, and Hispanic populations respectively.[26] Boustany et al[5] evaluated the prevalence of EGFR mutations in the MENA region and reported a frequency of 17.2% (n = 6122). Another systematic review by Benbrahim et al included 1215 patients from the MENA region and found that 21.2% carried EGFR mutations.[35] In the study by Nassar et al,[36] 15.7% (n = 1775) of patients with Arab descent had EGFR mutations. In this study, overall frequency of EGFR mutation was 24% among 2444 patients analyzed with NSCLC in the MENA region. The frequency of EGFR mutations in the MENA region is comparatively higher than in the White and Black populations, whereas it is lower than in the Asian and Hispanic populations. The current landscape of targeted therapy for EGFR mutations in NSCLC includes four approved tyrosine kinase inhibitors (TKIs): gefitinib, erlotinib, afatinib, and osimertinib.[37] Osimertinib is a third-generation EGFR TKI that can inhibit both the common sensitizing mutations (exon 19 deletions and L858R) and the most prevalent resistance mutation (T790M).[38]

KRAS

KRAS gene encodes for the proteins that are part of multiple signaling pathways. These proteins transmit signals that instruct the cells to proliferate, differentiate, and survive.[39] KRAS was considered an undruggable target; however, adagrasib and sotorasib, which target the KRAS G12C mutation, were recently approved for use by the FDA.[39] KRAS is the most frequent mutation observed in NSCLC, accounting for about one-third of cases. Prevalence of KRAS mutation is higher in White (33.38%) and Black (27.33%) compared with Asian (11.75%) and Hispanic populations (14%).[30] In the MENA region, only four studies with small sample sizes were found that reported the frequency of KRAS mutation.[11,18-20] In this study, the overall frequency of KRAS mutation was 19.7% among 315 patients.

ROS1

The ROS1 gene encodes for the ROS1 protein, which shares structural similarities with ALK protein. ROS1 is a transmembrane protein that contains an extracellular domain, a hydrophobic segment, and an intracellular domain with a carboxyl terminal. Its function is not clearly understood, but it is thought to activate multiple signaling pathways that regulate proliferation, differentiation, and survival. ROS1 gene rearrangement causes fusion with another gene, which leads to deregulation of kinase activity, which in turn results in abnormal activation of downstream pathways.[40] The prevalence of ROS1 alteration does not vary significantly based on ethnicity. The overall prevalence has been reported to be between 0.9 and 2.6% worldwide.[40] The distribution of ROS1 rearrangements ranges between 1.54 and 2.59% in the Asian population and between 1.7% and 2.5% in the White population.[41] Although data on ROS1 rearrangements in the MENA region are limited, our study found that the overall frequency of ROS1 mutations was 2.2% (9 of 414), with a frequency of 2.4% in Saudi Arabia and 1.6% in the UAE. These findings suggest that the frequency in the MENA region is comparable to that in other regions, despite the scarcity of studies conducted in this area. It is important to identify the ROS1 mutations as patients can benefit from targeted therapy such as crizotinib and entrectinib.[40]

MET, BRAF, and HER2

The BRAF gene codes for BRAF kinase, and mutations in BRAF lead to uncontrolled cell proliferation and survival.[42] Dabrafenib plus trametinib is a combination therapy for patients with BRAF V600E–mutant NSCLC, which is a rare but aggressive subtype.[43] The BRAF mutations have been reported to occur in about 1–4% of patients with advanced NSCLC.[30] The prevalence of BRAF mutations was 1, 3, 4, and 2% in Black, White, Hispanic, and Asian populations in a study by Costa et al.[30] The MET proto-oncogene encodes for receptor tyrosine kinase that binds to hepatocyte growth factor (HGF).[44] Aberrations in exon 14 region of the MET gene result in prolonged activation of receptor tyrosine kinase and downstream pathways.[44] Capmatinib and tepotinib are MET inhibitors that have been approved for patients with advanced NSCLC and MET exon 14 skipping mutations, which confer resistance to other therapies.[45] MET mutation occurs in about 1–10% of NSCLC cases, ranging from 3–4% in White populations to 0.9% in Asian populations.[7,26] HER2 belongs to the receptor tyrosine kinase family, and three types of HER2 alterations have been identified in patients with NSCLC: mutation, amplification, and HER2 overexpression.[46] For HER2 mutations, trastuzumab deruxtecan is a novel antibody-drug conjugate that has shown promising activity.[37] The reported incidence of mutation and amplification is 2–4%, and the incidence of protein overexpression varies between 2.5 and 34%.[46] Only three studies[18-20] from the MENA region have analyzed the frequency of BRAF (3.7%, N = 300) and MET (4.7%, N = 299) mutations, and no studies have reported the frequency of HER2 mutations in the MENA region. More studies with larger sample sizes are warranted to establish the prevalence of KRAS, ROS1, MET, BRAF, and HER2 mutations in the MENA region.

Limitations

This study has several limitations. First, the studies included lacked uniformity in the types of samples and genotyping methods used, with some studies not providing information on these methods. Additionally, not all patients in some studies were genotyped, which could introduce a disproportion in the analysis. The demographic diversity of the populations in the region also contributed to the heterogeneity of the study. Furthermore, a random-effects meta-analysis was not conducted to account for this heterogeneity; we relied instead on fixed-effect pooled prevalence, which assumes homogeneity across studies and provides a weighted average of the prevalence.[13] Therefore, the results should be interpreted with caution.

That this study focuses on the GCC region is a potential limitation. Future research should aim to include expert opinions from the broader MENA region to capture a more comprehensive view of the diverse perspectives and practices within the region.

CONCLUSION

This systematic review and expert opinion provide significant insights into the molecular profile and clinical management of NSCLC in the MENA and GCC region and highlights considerable variation in the prevalence of ALK, EGFR, KRAS, ROS1, MET, BRAF, and HER2 mutations, differing notably from other global populations. It also details the current state of molecular testing and treatment approaches for these driver mutations in the GCC countries. Further research is warranted to establish a more comprehensive understanding of the prevalence and effect of driver mutations across the broader MENA region to guide more personalized NSCLC management strategies in the future.

Supplemental Material

Supplemental materials are available online with the article.