Locally advanced/metastatic non-small-cell lung cancer in Lebanon: focus on ALK tyrosine kinase inhibitors

ABSTRACT

Treatment of non-small-cell lung cancers (NSCLC) has evolved over the last decade. According to studies, the use of targeted therapies has significantly increased the life expectancy of patients. Moreover, ALK-tyrosine kinase inhibitors (ALK-TKIs) have improved clinical outcomes. In Lebanon, translating recommendations into clinical practice remains challenging. A Lebanese expert panel of oncologists was convened to describe the management paradigm and the clinical evidence supporting the optimal use of next-generation TKIs in patients with ALK-rearranged NSCLC and to provide an expert overview of local challenges and recommendations for optimizing the management of advanced NSCLC in Lebanese patients. The experts agreed that these recommendations should be part of a healthcare strategy to be implemented at the national level.

Plain language summary

Article highlights.

ALK-TKIs: ALK-tyrosine kinase inhibitors

NSCLC:

Overview of NSCLC management

• Over the last decade, non-small-cell lung cancers (NSCLC) management has evolved and is now based on genetic alterations, including ALK rearrangements. The use of ALK-tyrosine kinase inhibitors (ALK-TKIs) has changed the management paradigm for advanced NSCLC.

Recommendations of NSCLC management in Lebanon

• Diagnosis:

  • ○
    NGS testing should be preferred over sequential testing to identify several actionable targets, especially in young patients, light smokers, or non-smokers with squamous or mixed histology.
• Treatment:

  • ○
    Due to limitations or unavailability of certain treatments, patients can either be encouraged to enroll in clinical trials or receive a first-generation ALK inhibitor that is always available, instead of a third-generation drug that is extremely potent but may pose a high risk of relapse if given intermittently.
  • ○
    Panel experts agreed that lorlatinib would be the treatment of choice in patients with brain metastases. In other patients, clinicians would opt for any ALK-TKI. Patients with advanced NSCLC should have a systematic follow-up every 4–6 months, including brain magnetic resonance imaging (MRI).
  • ○
    Patients who develop drug resistance following ALK-TKI treatment should be offered a rebiopsy or a liquid biopsy.
  • ○
    MDT-based multimodal approach should be implemented for the management of NSCLC.
• Managing toxicity:

  • ○
    Most adverse events resolve without any intervention. For grade I adverse events (AEs), neither dose reduction nor withholding treatment is necessary. However, for grade II or above AEs, the dose should be reduced and in cases where a severe AE re-occurs, treatment must be stopped and the patient monitored for recovery. For cognitive dysfunction, physicians should rule out any potential causes of Central nervous system (CNS) impairment before attributing it to lorlatinib treatment.

Limitations in the Lebanese practice

• Several challenges are currently affecting Lebanese practice, including a deteriorating healthcare system, limited access to biomarker testing, high costs associated with diagnosis and treatment and shortages in medication and equipment.

1. Introduction

This review aims to describe the management paradigm and the clinical evidence supporting the optimal use of next-generation tyrosine kinase inhibitors (TKIs) in patients with ALK rearrangement-driven non-small-cell lung cancers (NSCLC) and to provide an expert overview of local challenges and recommendations for optimizing the treatment of advanced NSCLC in Lebanese patients. The discussion was based on current guidelines and the experience of the expert panelists in the actual treatment of patients with NSCLC in Lebanon.

2. Background

Lung cancer remains the leading cause of cancer-related death worldwide, accounting for 18% of all cancer deaths according to the Globocan 2020 [1]. Nevertheless, studies have shown that NSCLC patients have had significant improvement in life expectancy, specifically related to the use of appropriately targeted drugs [2,3]. Recent advances in diagnostic techniques and a better understanding of oncogenic driver alterations have significantly changed the therapeutic landscape in NSCLC management [2,4–6]. Current guidelines emphasize the importance of tissue and/or blood biomarker identification to define patient subgroups and help guide treatment decisions. Thus, identifying the ALK gene rearrangement in NSCLC allows the use of a targeted approach. ALK receptor tyrosine kinase gene rearrangements occur in 2–8% of NSCLC and has become an important target in this cancer subtype [2,4,5,7]. ALK-driven NSCLC is now recognized as an entity that carries distinct epidemiology, molecular biology and prognosis [5]. ALK-tyrosine kinase inhibitors (TKIs) have shown superior clinical outcomes compared with traditional cytotoxic chemotherapy (increased overall survival OS rates and progression-free survival (PFS) rates, with improved patient quality of life) [8–11]. Some studies have even reported an exceptional median OS time of nearly 7 years (6.8 years) from the diagnosis of stage IV disease in patients treated by ALK inhibitors [12]. Thus, these agents have been integrated into current guidelines to treat advanced NSCLC [13,14]. In Lebanon, translating recommendations into clinical practice remains overly challenging due to an ineffective healthcare system as a result of serious socio-economic and health crises, with inequity in access to healthcare and problematic access to therapy (challenges related to biomarker testing in Lebanese laboratories, cost of diagnosis/treatment and shortages of medications and equipment) [15–17].

3. Local epidemiology, prevalence & burden of the disease

3.1. Prevalence of NSCLC

In 2020, lung cancer accounted for 2,206,771 new cases worldwide (11.4% of all new cases) [18], with around 85% being NSCLC [14]. As per GLOBOCAN Lebanon data 2020, lung cancer ranked second in both males (890 new cases; 15.4%) [19] and females (507 new cases; 8.7%) [20]. Regarding the estimated number of deaths, it ranked first in males (789 deaths; 22.8%) [21] and second in females (455 deaths; 15.3%) [22]. Data from the Lebanese National Cancer Registry from 2005 to 2015 show that lung cancer accounted for 9.2% of all newly diagnosed cancers, ranking as the second most common cancer in Lebanon [23]. When compared with other countries from the Middle East and North Africa (MENA) region, Lebanon is reported among the highest age-standardized rates (ASR) for incidence and mortality related to lung cancer per 100,000 population in the region, with respective values of 18.7 and 16.6 [23,24]. The burden of the disease seems to affect older patients more than younger ones [23].

Studies exploring the histological type of lung cancer among Lebanese patients are scarce. A study about the trends of lung cancer incidence by gender and histological type from 2005 to 2008 identified adenocarcinoma as the predominant subtype among both males and females, a pattern different from those seen in most Arab countries (where squamous cell carcinoma is more prevalent) [25]. Another study exploring the most common carcinoma types from 2009 to 2014 (n = 665) [26] showed similar results, with adenocarcinoma being identified in 48% of patients with malignant lung tumors, whereas the other subtypes consisted of squamous cell carcinoma (23.0%) and small cell carcinoma (13.3%) [26].

3.2. ALK rearrangement incidence

Regarding the prevalence of ALK rearrangements, studies from around the world reported numbers ranging from five to eight percent, depending on the studied populations [2,7]; these rearrangements were more frequently identified in young female patients, never or light-smokers and patients with adenocarcinoma histology [4,5]. As for the local data, a study among 152 patients with NSCLC from Lebanon (2014–2016) identified 18 patients with ALK gene rearrangements (using the immunochemistry, IHC), six being confirmed by the fluorescence in situ hybridization (FISH) technique [27]. In this study, the ALK gene rearrangement was significantly associated with the female gender and non-smoking status [27]. In another prospective study conducted in 2017 in the Levant region, only three out of the 157 patients tested for the EML4-ALK translocation (the only one studied in the research) were positive (two female and two non-smokers), with an estimated ALK rearrangement of 1.9% [28]. A more recent study comparing the ALK rearrangement prevalence in the MENA region highlighted the lowest overall ALK positivity in Lebanon (2.2% of the 137 Lebanese patients) compared with all other studied countries (overall prevalence of 8.7%) [29]. Interestingly, samples from Lebanon had a lower proportion of males and a higher mean age than other MENA countries, although none of the studied characteristics (sex, ethnicity, smoking history, or histologic subtype) were significantly associated with ALK-positive NSCLC in the entire sample [29].

4. Biomarker testing: who, when, how & where?

4.1. Who? When?

The latest guidelines of the National Comprehensive Cancer Network (NCCN Guidelines^®; Version 3.2022, March 16, 2022) for NSCLC highlight that the determination of the histologic subtype and molecular testing is required to define the best treatment options in patients diagnosed with advanced/metastatic non-squamous NSCLC. Molecular testing includes the identification of several biomarkers, in other words, EGFR, KRAS and BRAF mutations, ALK, ROS1, RET and NTRK1/2/3 rearrangements, MET exon 14 (METex14) skipping and PD-L1 profiling (for a potential immunotherapy regimen) [13].

4.2. How?

Several techniques have been suggested in routine for the identification of ALK gene rearrangements, including FISH, IHC and molecular biology approaches [2,4,5,14,30]. FISH has long been considered the gold standard for detecting ALK rearrangements. It uses fluorochrome-labeled probes that bind with complementarity to specific regions of the chromosome, allowing the detection of several rearrangements [4,5]. IHC uses a primary antibody that binds to the antigen in the sample, yielding a specific signal (coloration). It allows the detection of the ALK protein as compared with normal tissues [4,5]. The use of FISH in clinical routine raised some concerns since it was associated with false-negative results, high costs and specific requirements for equipment and the quality of the specimen [2,29,31,32]. Studies have also shown that IHC-positive ALK protein expression correlates with tumor response to ALK inhibitors, even in ALK FISH-negative cases [2,14,33]. Therefore, the latest American Society of Clinical Oncology (ASCO, 2018) endorsed the guidelines of the College of American Pathologists, the International Association for the Study of Lung Cancer and the Association for Molecular Pathology, stating that IHC could be an acceptable standard alternative to FISH for ALK testing [30,32]. Molecular biology approaches, particularly the reverse transcriptase-polymerase chain reaction (RT-PCR) or next generation sequencing (NGS), might be useful in detecting ALK-fusion partner/variant and secondary ALK mutations that emerge during the treatment. Indeed, NGS is a specific technology allowing for the process of multiple DNA sequences, thus yielding large amounts of data stream related to mutations and molecular mechanisms of cancer [5]. Recent reports have indicated that RNA NGS or combined DNA/RNA NGS are now considered the preferred method for detecting gene fusions, as they have demonstrated greater sensitivity compared with DNA-based NGS [34].

However, NGS is very expensive and requires highly specialized equipment and qualified personnel to be used in clinical routine.

In Lebanon, many laboratories adopt the sequential approach consisting of performing several tests for the detection of several mutations/rearrangements. IHC is used in routine and in some laboratories the FISH technique is adopted for confirmation of the results. However, guidelines highlight that multiplexed genetic sequencing panels (when available and accessible) are preferred over multiple single-gene tests to identify multiple actionable targets in lung cancer or novel ALK mutations but require the use of new tissue and/or cell samples [2,30,32].

4.3. Where?

Testing is available in several academic institutions and laboratories in Lebanon and more awareness has been raised in the past decades to improve the testing rates for metastatic NSCLC, especially non-squamous histology.

5. Overview of treatment guidelines

According to 2022 NCCN guidelines Version 1 [13], in ALK rearrangement NSCLC discovered prior to first-line systemic therapy, three ALK inhibitors are the preferred first-line therapies, in other words, alectinib, brigatinib and lorlatinib. Two other agents, ceritinib and crizotinib, are considered other recommended options and could also be recommended under certain circumstances. The latest 2023 European Society for Medical Oncology (ESMO) guidelines recommend five agents as first-line therapies for the treatment of stage IV metastatic NSCLC with ALK translocation: first-generation crizotinib (level of evidence I-B), second-generation ALK inhibitors (ceritinib I-B, alectinib I-A and brigatinib I-A) and lorlatinib (I-A) [35].

6. Data on different ALK TKIs

6.1. Crizotinib background

Crizotinib was the first drug to be approved as an ALK inhibitor [36,37]. It was initially developed as a MET- and ROS1- inhibitor, but its activity toward ALK kinase turned out to be clinically active ALK-rearranged NSCLC [2]. The PROFILE 1014 study has reported that crizotinib is superior to standard chemotherapy regimens in patients with previously untreated advance ALK-positive NSCLC (higher PFS rates of 10.9 months, hazard ratio [HR] = 0.45; p < 0.001 and a considerable improvement in quality of life [38,39].

However, resistance to crizotinib is quite frequent and its activity is limited by poor penetration of the blood brain barrier resulting in a high incidence of brain metastases. Therefore, second-generation ALK-inhibitors have been developed to overcome the resistance to crizotinib and improve the binding capacity and central nervous system (CNS) penetration [2,5].

6.2. Next-generation ALK inhibitors

Second- and third-generation ALK-inhibitors include several agents as presented in Table 1. In clinical trials, ceritinib was compared with standard chemotherapy while all other agents were compared with crizotinib [14].

Table 1.

Summary of next-generation ALK inhibitors.

	ALK-inhibitor	HRa	Trial	Cross-over allowed (Y/N)	Ref.
2nd generation	Ceritinib	–	ASCEND-4	–	[40]
	Alectinib	0.43	ALEX	N	[8]
	Brigatinib	0.48	ALTA1L	Y	[9]
	Ensartinib	0.51	Exalt3	N	[10]
3rd generation	Lorlatinib	0.28	CROWN	N	[11]

^aHR for PFS as compared with crizotinib.

HR: Hazard ratio; N: No; Y: Yes.

According to the results of all these studies, all agents showed similarities when considering PFS as the primary end point, with similar HR [8–10], the lowest being for lorlatinib (HR = 0.28) [11]. The latter also showed impressive results in preventing the development of brain metastases, with a significant longer time to CNS progression with lorlatinib as compared with crizotinib (HR = 0.07) and an intracranial complete response rate of 71% for the CROWN study, which makes it a good option for ALK-positive brain metastases patients [11]. Finally, lorlatinib showed to be active against most of the known ALK resistance mutations, including the highly resistant G1202R mutation (frequent in tumors carrying the EML4-ALK variant 3 gene fusion) [11,41]. In light of all these considerations, lorlatinib emerged as the preferred first-line treatment option for patients with ALK-positive metastatic NSCLC [42–44].

7. Expert opinion methodology for identification of key challenges/opportunities

The expert opinion methodology was developed by a steering committee of experts over several steps. Initially, an exhaustive literature review was performed to identify current guidelines and practices related to the diagnosis (including molecular testing for ALK rearrangements) and treatment options to develop a guided discussion that would trigger the experts' opinion regarding challenges, recommendations and future directions in the management of patients with advanced NSCLC, particularly those exhibiting ALK rearrangements. Subsequently, a pre-meeting questionnaire was distributed to eight NSCLC experts to identify key questions for discussion at the meeting. Finally, the expert panel of oncologists then gathered to have an interactive group session about the use of ALK TKI in advanced NSCLC in Lebanon. This discussion was led by two scientific coordinators chosen for their extensive experience and distinguished record in NSCLC treatment.

This manuscript was written based on the group discussion; it was reviewed by all experts to incorporate the Lebanese experience in the treatment expert opinion.

8. Key challenges & opportunities

8.1. Challenges

Several challenges can be identified when treating patients with ALK-driven advanced NSCLC:

• The complexity of diagnosis and lack of multidisciplinary teams [24]:

  • ○
    Inappropriate procedures to provide adequate material for diagnosis: lack of expert bronchoscopists or interventional radiologists in remote centers [45];
  • ○
    Poor sample handling: incorrect fixation, poor storage, insufficient tissue for testing (although the required quantity for IHC is much lower than that for FISH testing, insufficient tissue can be a challenge if additional tests are required, e.g., NGS, etc.) [24,45].
• Molecular testing:

  • ○
    Shortage in material for molecular testing due to cost constraints and the economic hardship faced by the laboratories and Lebanese healthcare system [17,46];
  • ○
    Lack of expertise in remote centers, outside the large hospital centers (university medical centers): lack in reading the tests, false-negative/positive tests, lack of knowledge/understanding of the clinical implication of molecular testing, small centers might not process sufficient numbers of samples annually to guarantee the technical proficiency of a laboratory;
  • ○
    Sequential testing: to minimize expenses for patients, physicians may opt for individual gene testing rather than conducting panel testing;
  • ○
    Lack of RNA NGS testing in Lebanon;
  • ○
    Outsourcing molecular testing to international centers might be correlated to time and cost concerns since time is crucial for patients with advanced-stage diseases.
• Access to medications and molecular diagnosis:

  • ○
    Drug shortages and costs: the main issue with ALK inhibitors is their availability, accessibility and affordability, especially in a country like Lebanon [15]. As of October 2019, Lebanon has been facing one of the most severe economic crises [16]. The economic decline and the local currency depreciation have led to a sharp decrease in the purchasing power of the Lebanese, who were no longer able to afford the actual cost of healthcare, including diagnosis (particularly costly novel molecular testing) and treatment costs (particularly innovative targeted therapies) [15,47,48]. The Ministry of Public Health (MOPH) and third-party payers were also unable to cover the management costs, which led to inequity in cancer care since only people with a high income could afford advanced, expensive treatments [15]. In an attempt to contain the situation, the Central Bank issued an interim measure to subsidize the importation of medications in part. However, added to other factors, the currently adopted subsidization mechanism has led to frequent stock ruptures, delays in drug import and suboptimal patient care [15,46].
  • ○
    Lack of health governance and clear strategy: in the absence of good governance for health and a clear exit strategy (lack of political will and stability, steep economic crisis), cancer patients had to suffer most from drug shortages and stock outs [17,46]. Some were forced to have intermittent treatments, delays in treatment sessions and consequently suffer from relapse (clinical cases of rapid or hyper progression of the disease), resistance to treatment and even death [48]. Some patients tried to order their medications through people traveling abroad (Europe, Turkey, etc.) or online (from Bangladesh/India for cheaper options), which raised the issue of quality (questionable storage and transport conditions, lack of quality control, etc.) [47,48].

• Workforce burnout and shortage and absence of multidisciplinary teams:

  Since the last quarter of 2019, many Lebanese healthcare workers have fled the country and many are planning to leave. The remaining others are working in highly stressful conditions under the detrimental impact of a combined mental and social burnout added to financial stress [17,49]. Moreover, although cancer patients have been exhibiting high levels of fear and anxiety due to the current situation in Lebanon, they are rarely evaluated by a psychiatrist or psychologist for their mental health and overall health-related quality of life [50,51].

• Resistance to ALK TKI [52]

  The clinical benefits of targeting ALK using TKIs are often limited due to the emergence of drug resistance. Patients with ALK rearrangements invariably develop resistance to treatment that requires a reevaluation by re-biopsy (tissue and blood for cfDNA) and retesting for molecular alterations to adapt treatment options [41].

8.2. Opportunities

Several studies exploring the efficacy of second and third-generation ALK inhibitors in advanced ALK-positive NSCLC have demonstrated better outcomes in patients: increased survival rates and progression-free survival rates and improved quality of life. Lorlatinib, the reversible third-generation ALK inhibitor, has a particular place in therapy since it can overcome multiple ALK resistance mutations (such as L1196M and G1269A) and penetrate better the blood-brain barrier [41].

9. Recommendations & future directions

• Recommendations for diagnosis

  • ○
    Molecular testing: Expert panelists agreed that NGS or RNA NGS for targeted panels, when available and accessible, should be preferred over sequential testing because it helps identify several actionable targets, especially in young patients, light smokers, or non-smokers with squamous or mixed histology [32]; however, NGS is not always performed in Lebanon because it is expensive and not covered by any third-party payer;
  • ○
    Quality control: Quality of the results should be guaranteed regardless of the method used to detect ALK rearrangements; laboratories are urged to have an effective external and internal quality assurance system/auditing for each biomarker (e.g., positive and negative controls in IHC to avoid false results). Tests should also be accredited based on the norms of the country where these tests are performed [4];
  • ○
    Reimbursement of tests: Experts agreed that given the combined economic and health crises in Lebanon, constructive cooperation and coordination are required across all stakeholders, particularly pharmaceutical companies, to put in place actions that would help patients with NSCLC access and cover molecular testing (cover part or total cost for genetic/NGS testing, for example). Experts suggested that only tests performed in controlled laboratories (such as in university hospitals) should be sponsored; positive data should also be confirmed to guarantee that the right patient, with the right molecular profiling, is being treated with the right medication.
• Recommendations for drug shortages and cost constraints:

  • ○
    Need for national coordination/collaboration: Panelists agreed that stakeholders, particularly pharmaceutical companies, should be involved in a strategic plan to help patients with NSCLC access and cover their treatment (e.g., negotiating prices of targeted treatments with the local management of pharmaceutical companies, especially for patients with no health coverage). Such actions would be beneficial for both patients and physicians;
  • ○
    Clinical trials and compassionate use of medications: Another solution would be to encourage patients to enroll in clinical trials in Lebanese institutions or to benefit from the compassionate access to innovative medications prior to market authorization, especially for patients with no other available treatment option (relapse or resistance to treatment) [15,53];
  • ○
    If none of the previously mentioned suggestions is available, panel experts recommend opting for a first-generation ALK inhibitor that would be available all the time rather than treating with a super potent third-generation drug that might lead to high odds of relapse if taken intermittently;
  • ○
    Oncologists are also calling on the Lebanese diaspora and international organizations to help provide essential medications for cancer patients and sustain the healthcare system, particularly oncology [17].
• Recommendations for treatment options:

  • ○
    Panel experts highlighted that their treatment goals include checking for international and local data related to efficacy, PFS, safety profile and quality of life while taking into account the available treatment options in Lebanon.
    Recommendations for treatment options- Efficacy:
  • ○
    Panel experts agreed that any second or third-generation ALK-TKI could be used in patients with advanced NSCLC; all agents are potent, with high response rates and acceptable side effects profiles;
  • ○
    Panel experts agreed that lorlatinib would be the drug of choice in patients diagnosed with brain metastases. In other patients, clinicians would opt for any ALK-TKI, knowing that lorlatinib seems to protect against brain metastases. In all cases, clinicians stated that they might choose any available option due to drug shortages and cost constraints. If only first-generation crizotinib is available, patients should benefit from a closer follow-up to check for relapse and the possible emergence of brain metastases (as evaluated clinically and radiologically);
  • ○
    Experts agreed that opting for first-line treatment should take into account concomitant medications, comorbidities, hepatic (with alectinib), renal and pulmonary (with brigatinib) functions, especially in elderly patients with several comorbidities and co-medications;
  • ○
    Although it is not clearly stated in guidelines, experts agreed that patients with advanced NSCLC should benefit from a systematic follow-up every four to six months, including brain checkups using magnetic resonance imaging (MRI).
    Recommendations for treatment options- Managing toxicity:
  • ○
    Panel experts agreed that most side effects related to ALK-TKI are minor toxicities (grades I-II) [54] and neurological toxicity with lorlatinib is more frequently reported in patients receiving whole brain radiotherapy;
  • ○
    Panel experts agreed that according to the data presented in publications and international congresses, most adverse events (AEs) resolve without any intervention. Dose reduction or withholding treatment are not required for grade I AEs; however, the dose must be reduced for grade II or above and if a severe AE re-occurs, the treatment must be stopped and the patient monitored for recovery;
  • ○
    Cognitive impairments are among the reported side effects. These include memory impairment, confusion and processing speed disorders and are mainly from grade I, while the occurrence of grade III or IV cognitive AEs is very low;
    Strategy to manage cognitive dysfunction: experts agreed that physicians should rule out any potential causes of CNS impairment before linking it to lorlatinib treatment (e.g., cerebrovascular accident).
    Recommendations for treatment options- Resistance to ALK inhibitors
  • ○
    A better understanding of the acquired resistance is essential for clinical decisions. In that context, patients with drug resistance after ALK-TKI treatment should be offered a rebiopsy or a liquid biopsy (cell-free DNA or cfDNA) [32]. Studies have demonstrated that plasma NGS testing significantly increases the detection of therapeutically targetable mutations (including secondary drug-resistant mutations) and provides the optimal molecularly guided therapy in patients with advanced NSCLC (stage IV) [40,41,55];
  • ○
    Panel expert agreed that lorlatinib seem to have promising results in this regard; however, more data are still needed to implement its use into clinical guidelines as the new standard of care [11,41].
    Recommendations for treatment sequencing
  • ○
    Given the lack of data on sequencing and the caveat of inter-trial comparisons related to differences in design methodologies (crossover allowed or not, ALK TKI compared with standard chemotherapy or first-generation medications), selecting the best treatment and optimal sequencing approach remains one of the main challenges when treating a patient with specific genetic alterations [43,44]. Hence, while some studies advocate for the sequencing of lorlatinib upfront due to its excellent intracranial activity, particularly in patients with ALK-positive brain metastases [11,43], other reports suggest that it should be restricted to clinical situations when the patient needs it [44]. Further data from clinical trials are warranted to shape the best sequencing regimen.
• Recommendations for multidisciplinary teams (MDT) management:

  • ○
    As recommended by the oncology societies and suggested by recent expert panel recommendations for the MENA region [24,56], an MDT-based multimodal approach should be implemented for the treatment of NSCLC. Such an approach, combining the expertise of several team members (including medical and radiation oncologists, pulmonologists, surgeons, pathologists, molecular biologists, pharmacists, psychiatrists, clinical nurses and other healthcare professionals) might be helpful since it allows for a more personalized and effective care plan for patients with advanced NSCLC. It should be emphasized that pulmonologists and interventional radiologists have a prominent role in securing adequate and sufficient tissue samples from each patient (even with minimally invasive techniques) to allow for molecular testing and guide the final therapeutic decision [13]. Multidisciplinary conferences are essential not only at the time of diagnosis but also throughout the progression of the disease, where rebiopsies are discussed.
• Recommendations for research

  • ○
    Research and participation in clinical trials in oncology are essential components that would improve the standard of care and help patients benefit from innovative treatment, especially in patients with advanced stages such as patients with advanced metastatic NSCLC. Hence, local real-world data would allow the establishment of national registries for a better understanding of the patients' outcomes in Lebanese settings. Research is also expected to bridge gaps related to understanding the impact of local practices, including the presence/absence of a multidisciplinary team in NSCLC management, on treatment outcomes and the overall patient functioning and quality of life [57].
• Long-term recommendations for the Lebanese healthcare system

  • ○
    Lebanon has consistently been recognized as one of the most developed healthcare systems in the MENA region through world-renowned physicians and healthcare professionals, an excellent hospital infrastructure and the availability of innovative treatments and novel equipment [15]. Before the current crisis, the Healthcare Access and Quality Collaborators ranked Lebanon first in the MENA region and 33rd worldwide (Global Burden of Disease Study 2016 [58]). Therefore, implementing a comprehensive and sustainable national pharmaceutical and healthcare strategy is urgently needed in Lebanon to regain healthcare quality. Such a strategy would involve all stakeholders who will strive to build a somehow “resilient” healthcare system that would resist and overcome any economic, political, or health turmoil [15,17,46].

10. Conclusion

Over the last decade, the treatment of advanced NSCLC patients has become extremely reliant on the identification of oncogenic driver alterations, including ALK rearrangements. Hence, the use of ALK-TKIs has considerably changed the paradigm of management of this disease with better outcomes in patients. However, the optimal use of the next-generation TKIs faces several challenges related to economic hardship, drug/material shortages and political instability in Lebanon, thus compromising the quality of care. This review summarizes several recommendations that could optimize the management of patients with the available options and resources. Experts agreed that these recommendations should be part of a larger comprehensive healthcare strategy involving all stakeholders and urgently implemented at the national level.

11. Future perspective

More data is needed regarding the acquired resistance and the role of plasma NGS testing in the detection of therapeutically targetable mutation to determine the best treatment and optimal sequencing approach when treating patients with specific genetic alterations. Several challenges limit Lebanese practice, including the economic crisis, drug accessibility and the lack of updated national guidelines. According to experts, establishing national registries is essential for providing real-world data to better understand patient outcomes in the Lebanese setting and supporting the development and implementation of a comprehensive and sustainable strategy to regain quality, build a resilient healthcare system and encourage MDT-based multimodal approaches for the management of NSCLC.

Funding Statement

Medical writing support was provided by Carla Abou Selwan from Science PRO s.a.r.l, Lebanon and was funded by Pfizer.

Author contributions

Concept and design of study: all authors. Drafting the article and revising it critically for important intellectual content: all authors. Final approval of the version to be published: all authors.

Financial disclosure

Medical writing support was provided by Carla Abou Selwan from Science PRO s.a.r.l, Lebanon and was funded by Pfizer.

Competing interests disclosure

All authors have completed the ICMJE uniform disclosure form.

A Tfayli: received honoraria from Pfizer Inc. as advisory board member. No additional disclosures.

H Ghanem: received honoraria from Pfizer Inc. as advisory board member and has participated as a speaker and consultancy for BMS, Astellas, Takeda, Pfizer, Lilly, Bayer, Janssen, BMS.

F Nasr: received honoraria from Pfizer Inc. as advisory board member and has participated as a speaker in symposiums with Pfizer, Lilly, Servier, Janssen, MSD, BMS.

HR Kourie: received honoraria from Pfizer Inc. as advisory board member and has participated as a speaker with Pfizer, Astrazeneca, Roche, Amgen, Merck, MSD, BMS, Eli Lilly, New Bridge, Astellas, Janssen and Novartis.

G El Hachem: received honoraria from Pfizer Inc. as advisory board member and has participated in advisory boards for Janssen, Merck, Astrazeneca and Amgen.

J Debs: Pfizer employment.

S Masri: Pfizer employment.

HI Assi: received honoraria from Pfizer Inc. as advisory board member. No additional disclosures.

RG Campelo: Received honoraria from Pfizer Inc. as advisory board speaker.

Advisory boards: MSD, Bristol-Myers, Roche, Boehringer Ingelheim, Pfizer, Novartis, AstraZeneca, Lilly, Takeda.

Consultancy: MSD, Bristol-Myers, Roche, Boehringer Ingelheim, Pfizer, Novartis, AstraZeneca, Lilly, Takeda.

Speaker honoraria: MSD, Bristol-Myers, Roche, Boehringer Ingelheim, Pfizer, Novartis, AstraZeneca, Lilly, Takeda.

J Kattan: received honoraria from Pfizer Inc. as advisory board member and has participated in advisory boards for Amgen, MSD, Merck, Roche. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Writing disclosure

Medical writing support was provided by C Abou Selwan from Science PRO s.a.r.l, Lebanon and was funded by Pfizer.