Lorlatinib – Csn Chem

Upfront Management of ALK-Rearranged Metastatic Non-small Cell Lung Cancer: One Inhibitor Fits All?

Fabrizio Tabbò1 • Francesco Passiglia1 • Silvia Novello 1

Abstract

Purpose of Review Anaplastic lymphoma kinase (ALK) rearrangements represent a seldom event in non-small cell lung cancer (NSCLC). Given the oncogene alteration, ALK targeting represents the main therapeutic strategy. Here, we review evidence regarding ALK inhibitors (ALKi): clinical activity, safety profiles, financial costs, and biomarkers of efficacy.
Recent Findings During the past 10 years, multiple ALKi have been developed, and four different compounds are currently available as upfront options for ALK+ NSCLC patients: crizotinib, ceritinib, alectinib, and brigatinib. Second-generation (2G) ALKi demonstrated superior clinical activity in terms of median progression-free survival (mPFS), objective response rate (ORR), intracranial disease control, and duration of response (DOR) when compared with crizotinib.
Summary 2G ALKi represent the current gold-standard first-line treatment for ALK-rearranged metastatic NSCLC. Among all available options, in our opinion, alectinib has likely the best profile of clinical activity and safety, thus emerging as the best upfront therapy. More insights will come from ongoing trials and analysis of biomarkers.

Keywords ALK . Rearrangements . First-line . NSCLC . TKI . New-generation . Crizotinib . Ceritinib . Alectinib . Brigatinib . Lorlatinib

Introduction

The discovery of oncogenes driving neoplastic transformation and their role in clinical targeting profoundly revolutionized the management of NSCLC [1, 2]. After the overwhelming history of epidermal growth factor receptor (EGFR)–activat- ing mutations as causes of dramatic responses observed in patients receiving the EGFR–tyrosine kinase inhibitor (TKI) gefitinib, ALK translocations were first reported in NSCLC specimens in 2007, and their oncogenic properties were con- firmed [3–5]. After 10 years of intense investigation, the biological model of “single-gene-dependent oncogene addic- tion” has become less stringent, and the recent demonstration of co-occurring genomic alterations in the same tumor highlighted an intra-driver molecular complexity, thus explaining the wide spectrum of different therapeutic re- sponses and clinical behaviors among equally treated NSCLC patients [6–8]. However, the proper targeting of disrupted tyrosine kinase activity with specific small mole- cules prevailed over classical chemotherapeutic regimens, both in terms of efficacy and tolerability profiles, demonstrat- ing how relevant molecular stratification is at the time of di- agnosis, to define personalized treatment strategies [9, 10].
Oncogene targeting has experienced a rapid improvement during the past few years, with high-throughput technologies recently introduced into clinical practice and new-generation inhibitors approved for clinical use [11, 12]. Particularly, highly selective and brain-penetrating small molecules have been developed for the therapeutic management of advanced ALK+ NSCLC [13•, 14•]. Since the introduction of the first- generation (1G) TKI, crizotinib, multiple efforts have been made to improve efficacy and reduce toxicities associated with these agents. Consequently, there is a crowded field with multiple drugs which have either already completed or are still under clinical development. This poses challenges for clini- cians regarding which is the best ALK inhibitor and when it should be administered [15].

ALK Inhibitors: Clinical Performance Upfront

Based on clinical data and guideline recommendations, the ac- cepted gold-standard, first-line treatment for stage IV ALK+ NSCLC is represented by 2G TKIs: ceritinib which outperformed chemotherapy (ChT), while alectinib outperformed both ChT and crizotinib [16, 17] (Table 1). The ASCEND-4 trial compared ceritinib (at dosage of 750 mg daily) and standard ChT, with a reported mPFS of 16.6 months for ceritinib, compared with 8.1 months of ChT arm. No significant OS differences have been observed between the two treatment arms (HR 0.73, 95% IC 0.50–1.08, p = 0.056), likely because of the high rate of crossover to ALKi at chemotherapy progression. Although no head-to-head comparisons exist, an indirect analysis reported mPFS doubled for ceritinib versus (vs) crizotinib (mPFS of 25.2 vs 10.8 months) [21, 25].
The superiority of alectinib (600 mg twice per day) over crizotinib (250 mg twice daily) has been reported in three different phase III trials: J-ALEX, conducted in pre- or un- treated Japanese patients; ALESIA, limited to untreated pa- tients of Asiatic ethnicity; and ALEX, including previously untreated NSCLC patients. All three studies reported a prolonged mPFS and a deeper objective response, with longer duration in favor of alectinib [13•, 23, 24] (Table 1). The most updated mPFS came from the ALEX trial, reaching 34.8 months for alectinib compared with 10.9 months for crizotinib. Although no definitive overall survival (OS) data are available yet, the 5-year OS is 62.5% for alectinib com- pared with 45.5% for crizotinib [22••]. In the ALTA-1 L trial, brigatinib has been shown to be superior over crizotinib as a first-line treatment for naive patients, with a mPFS 29.4 months for brigatinib compared with 9.2 months for cri- zotinib (HR 0.43, 95% CI 0.31–0.61). Therefore, brigatinib represents an additional valuable option for upfront treatment of ALK+ tumors. [14•] (Table 1).
The first-generation ALKi crizotinib represented the first- line standard of care for a long time and, in certain countries, is still considered to be the main or the only reimbursed option in this setting. Crizotinib approval was based on the results of the phase III PROFILE 1014 trial, where ALK+ patients receiv- ing TKI therapy reported a mPFS of 10.9 vs 7 months for the ChT arm, paving the way for ALK-targeting inhibition in NSCLC [18]. The most recent update of the PROFILE 1014 trial, at a median follow-up of 46 months, revealed a median OS not reached for crizotinib vs 47.5 months for the ChT arm, with the longest OS observed for 57 patients who received crizotinib followed by 2G ALKi. The 4-year OS was reported to be 56.6% for crizotinib. Although approximately 84% of patients in the ChT arm received crizotinib at the time of disease pro- gression, the superiority of crizotinib over ChT in terms of OS was confirmed after crossover adjustment (HR 0.346, 95% CI bootstrap 0.08–0.71), thus supporting the upfront use of this agent [19]. The superiority of crizotinib over ChT was recently confirmed by the results of the phase III randomized PROFILE 1029 study, which included treatment-naive patients of Asian ethnicity who had ALK+ advanced NSCLC [20] (Table 1). Nevertheless, crizotinib is no longer considered to be the standard of care because of inferior activity compared to other drugs in this class and progression in sanctuary sites, such as the central nervous system (CNS) [18, 26••].
Other ALKi (lorlatinib, ensartinib, and entrectinib) are un- der evaluation in ongoing clinical trials and will potentially revolutionize our approach to treatment-naive ALK+ NSCLC patients. The phase III CROWN trial (NCT03052608), which has recently completed the accrual, compared lorlatinib and crizotinib as first-line therapy, and the results are expected by the end of 2020. Activity of the third-generation (3G) TKI, lorlatinib, has been investigated in a large phase II trial, in- cluding untreated or pretreated (with crizotinib or 2G TKI with or without ChT) patients. Lorlatinib was shown to be effective in the post-ALK-TKI setting (ORR 39%, median PFS 6.9 months), with the majority of patients receiving at least one prior second-generation TKI (ORR: 43%), thus lead- ing to the regulatory approval after progression on prior ALKi [27, 28]. Preliminary data suggested better disease control in treatment of naive patients or those solely exposed to crizotin- ib ± ChT, implying that multiple lines of TKI curtail lorlatinib efficacy [27]. The results of the CROWN trial could provide the needed evidence to support the upfront use of this agent. Recently, during the IASLC presidential symposium in August 2020, an interim analysis of the eXalt3 phase III trial (NCT02767804) has been presented. Ensartinib excelled against crizotinib in TKI-naive ALK+ patients treated with up to one line of ChT. Median PFS was not reached for the ensartinib arm compared with 12.7 for the crizotinib arm (HR 0.49, 95% CI 0.30–0.66; P < 0.0001) and DOR at 36 months was of 58.7% for ensartinib vs 26.7 for crizotinib. Final results of this trial are expected at the end of the year and will clarify whether ensartinib will ameliorate overall survival. Activity of this 2G TKI was tested in phase I/II studies, where ensartinib in the TKI-naive cohort showed a promising response rate of 80% and mPFS 26.2 months compared with a response rate of 69% and mPFS 9 months in pretreated patients [29]. Entrectinib, now FDA-approved for the treatment of NTRK- and ROS-1-rearranged NSCLC, reported preliminary activity against ALK in two phase I clinical trials and is currently under investigation in the phase II STARTRK-2 basket trial (NCT02568267). Notably, no prospective, randomized data support sequen- tial crizotinib followed by next-generation ALKi vs next- generation ALKi upfront. Furthermore, no direct comparisons are available between different 2G ALKi, or 2G vs 3G ALKi, thus creating a wide range of choices regarding which TKI should be administered upfront. CNS Disease and ALKi Efficacy Among solid tumors, lung cancer is known to be a disease with a peculiar tropism for CNS as the site of metastases, with brain lesions developing in approximately 30% of patients during the disease course [30]. More than 60% of cancer patients who present with neurological symptoms of brain metastases (BM) as clinical exordium will have a diagnosis of advanced lung cancer [31]. Among all NSCLC patients, those with ALK trans- locations reported the highest incidence of BM at baseline (40%) and a cumulative risk overtime higher than 50% [32, 33]. CNS disease control varies among different TKI genera- tions, with crizotinib having the lowest concentration in cere- brospinal fluid (CSF) (CSF/plasma ratio of 0.0026), because this agent is a substrate of the ATP-binding cassette (ABC) drug efflux transporters [34]. Consequently, CNS represents a common site of progression for ALK+ patients, either with or without BM at diagnosis, who are undergoing treatment with crizotinib. In the PROFILE 1014 trial, patients with docu- mented treated or untreated BM had CNS progression in 70% of cases, while 20% without BM at the time of diagnosis developed them during the course of treatment [33, 35]. Conversely, 2G ALKi (ceritinib, alectinib, and brigatinib) penetrate the blood-brain barrier (BBB), achieving higher concentrations in the CSF and offer a better control of BM. Even more relevant is the performance of these molecules upfront because they are able to prolong patients’ survival without CNS progression [13•, 14•, 21]. Particularly, alectinib showed more profound intracranial responses and was able to prolong the time to BM occurrence compared with crizotinib in the ALEX trial, with an average CNS overall response rate of 80% compared with crizotinib (71% for patients pretreated and 40% for untreated with radiotherapy) [36] (Table 1). Of note, the PFS benefit of alectinib over crizotinib was consis- tent in patients with (HR 0.37, 95% CI 0.23–0.58) and without (HR 0.46, 95% CI 0.31–0.68) CNS metastases at baseline. Similarly, both ceritinib and brigatinib demonstrated a prom- ising intracranial activity with an ORR of 73% and 78% in the ASCEND-4 and ALTA-1L trials, respectively [14•, 21] (Table 1). However, the preliminary results of the phase 2 ASCEND-7 study, specifically devoted to ALK+ NSCLC pa- tients with BM, have recently shown a lower intracranial ORR of ceritinib both in the ALKi-naive cohorts, ranging from 29% (prior brain RT) to 52% (no prior brain RT), and in the ALKi pretreated cohorts, ranging from 28% (no prior brain RT) to 39% (prior brain RT) [37]. Overall, the promising results ob- served with new-generation ALKi are revolutionizing the standard therapeutic approach to CNS disease, confining radiotherapeutic strategies (e.g., WBRT or SBRT) to isolated cases. These approaches were largely necessary during treatment with 1G TKI. Lastly, lorlatinib demonstrated the ability to induce intra- cranial responses in 45% of patients progressing on crizotinib and in 55% of patients progressing on at least one prior ALKi, with the best ORR near 67% achieved in the small cohort of patients receiving only one prior ALKi [28, 38]. Being devel- oped to overcome the limited penetrance of 1G TKI into CSF, lorlatinib is expected to show better CNS disease control in the CROWN trial [39]. Ensartinib, which initially showed an ORR of 69% and a disease control rate of 100% on brain lesions in the phase I/II trial [40], reported relevant prelimi- nary results in patients with intracranial disease in the ongoing phase III study: ORR was 64% (in 11 patients receiving ensartinib) vs 21% (for 19 patients under crizotinib) and de- layed the emergence of new central lesions in patients without baseline brain metastases (23.9 vs 4.2 months; HR 0.32, 95% CI 0.15–0.64; P = 0.0011). Ultimately, these considerations will determine which TKI should be used first in patients with ALK+ tumors. Due to the higher CNS activity, we believe that second- or third- generation ALKi should be used upfront. Toxicity Profile: It Does Matter Better disease control results ran in parallel to improvements in treatment-related adverse events (AE) going from 1G to new-generation ALKi. Crizotinib treatment is encumbered by a large spectrum of frequent toxicities. Among others, vi- sual disorders (diplopia, photopsia, blurred vision) are pecu- liar to crizotinib, as well as bradycardia and QTc enlargement, occurring in approximately 70% of cases, with no events be- ing higher than grade 1–2 [19]. Peripheral edema occurs in 49% of crizotinib- and 25% of alectinib-treated patients [13•]. Also, dysgeusia has been reported for 11% of patients receiv- ing crizotinib versus 52% receiving alectinib. Gastrointestinal toxicities, such as nausea, vomiting, constipation, and diarrhea were associated with different ALKi, with the highest inci- dence of vomiting associated with ceritinib (66% any grade and 5% grade 3–4). Similarly, diarrhea has been observed up to 85% for ceritinib-treated patients [21]. While crizotinib and ceritinib reported an intermediate-risk profile for both symp- toms, alectinib was the best-tolerated agent (diarrhea 12% and vomiting 7%) [13•]. Regarding hepatic toxicities, the most relevant phenomenon is the elevation of serum alanine ami- notransferase and aspartate transaminase (ALT/AST). This appeared to be worse for crizotinib and ceritinib and, to a lesser extent, with brigatinib and alectinib. Ceritinib adminis- tration was associated with an increase in serum AST in 60% of patients, with grade 3–4 toxicities in 50% of them, thus leading to frequent treatment interruptions and drug discontin- uations [13•, 18, 19, 21]. Due to such a high incidence of gastrointestinal and biochemical AEs, the phase Ib trial ASCEND-8 compared the classical schedule of ceritinib at 750 mg daily while fasting vs a reduced dose of 450 mg daily taken with food, reporting similar ORR and sharply reduced incidence of AEs [41]. Myalgia and an increase of creatinphospokinases (CK) have been more frequently described with alectinib (patients reporting musculoskeletal pain, incidence of 23%) and brigatinib (incidence of CPK increase of 40%, with 16% of patients having a grade higher than 3) than other ALKi [18]. On the other hand, brigatinib was characterized by a peculiar and more worrisome adverse event: interstitial lung toxicity, usually with early onset right after therapy was started. Dyspnea and pneumonitis, with a wide range of presentation but at rapid emergence, have been observed in 7% of patients receiving brigatinib, imposing a clear and fast differentiation between drug-induced and disease-related symptoms [42–44]. This reported event, occurring mostly within the first week of treatment, led to brigatinib being administered at a 7-day lead- in dose of 80 mg daily. Other unique, but less relevant, brigatinib-restricted AE is arterial hypertension, with 6% of cases of grade 3–4, imposing drug-dose reduction, and eleva- tion of lipase concentration [42]. The most relevant AEs induced by lorlatinib administration were hypercholesterolemia (81%) and hypertriglyceridemia (60%), with cases of grade 3–4 toxicities occurring in 16% of patients, leading to dose reductions. CNS alterations also have been observed, both in phase I and phase II studies, with 39% experiencing mood alteration and/or change in cognitive functions and speech, all of low-moderate intensity and re- versible after drug interruption. Other neurological symptoms that may occur are peripheral neuropathy, which have been reported in 43% of cases [27, 38]. A large portion of lorlatinib- treated patients undergoes treatment with a lipid-lowering agent, which can cause weight gain. Generally, drug-dose reductions along with medical supportive care make lorlatinib-induced AEs manageable. Lastly, a previously unknown toxicity profile has been ob- served for ensartinib; in the phase I/II study, 56% of patients report rash and pruritus, with 23% being grade 3–4, some- times requiring dose reduction and treatment discontinuation. This phenomenon seems to be related to the elevated concen- tration of the drug into the skin, even hours after its adminis- tration [29]. These data have been confirmed in the interim analysis of the phase III study, where more serious AE has been reported for ensartinib compared to crizotinib (8 vs 6%), and these required more likely dose reduction (24 vs 20%) and treatment discontinuation (9 vs 7%). Although different TKIs share the majority of AEs, such as gastrointestinal effects and biochemical changes, they differ from each other in terms of unique toxicities, which should be taken into account by physicians in order to identify the right drug for the right patient and also improving compliance with treatment. PROs (Patient-Reported Outcomes) and CONs (Financial Toxicities) The advent of TKI inevitably improved quality of life (QOL) and treatment tolerability compared with chemotherapy. Crizotinib administration resulted in an improvement from baseline of general physical condition and disease-specific symptoms, such as cough, dyspnea, fatigue, and pain com- pared with classical ChT (pemetrexed or docetaxel). Nevertheless, TKI (i.e., crizotinib) are encumbered by a spe- cific toxicity, like worsening diarrhea [45]. The favorable pro- file of 1G ALKi has been confirmed in the frontline setting, with a general reduction in symptom burden and significant improvement in QOL [19]. 2G TKIs performed even better with QOL improvements in terms of disease-related symp- toms, particularly in the CNS, and treatment tolerability. In the phase II ASCEND-2 trial, ceritinib improved lung-related symptoms, but its benefit was curtailed by relevant AEs, such as diarrhea, which lasted for the entire treatment period, nau- sea, and vomiting, which dissipated after multiple cycles of therapy [46]. Brigatinib resulted in improved mean QOL, with a small group of patients having worsening symptoms, confirming benefits gained with objective response [47]. Similarly, alectinib, when compared to crizotinib, resulted in a consistent amelioration of health-related QOL and more du- rable reduction of lung-related symptoms. For both of these 2G TKIs, patient-reported outcomes highlight the optimal tol- erability profile [47, 48]. Lorlatinib administration induced improvements in the emotional and social function of patients and reduced meaningfully symptoms such as fatigue and ap- petite loss (in 49% and 42% of patients, respectively); the drug-related AE that had the worst impact remains peripheral neuropathy, as mentioned previously [49]. Improvements in disease control and QOL with the advent of new-generation ALKi posed the central question of health- related costs. This is one of the reasons why broad availability and widespread prescription of these drugs across different countries is impinged. For crizotinib, regulatory agencies faced economic issues. The NICE initially considered the in- cremental cost-effectiveness ratio (ICER) per quality-adjusted life years (QALY) as unfavorable, approving crizotinib in untreated patients only after price re-negotiation [50]. Attempts, based on randomized phase III trials, have been made to evaluate cost-effectiveness of next-generation TKI. Ceritinib treatment was associated with an ICER per QUALY of 66.000$ vs crizotinib and 81.000$ vs chemotherapy, thus overcoming both treatments and conferring higher health ben- efits at reduced costs [51]. In a Chinese analysis, ICER of ceritinib and alectinib per QUALY were more than 60.00$ and 100.000$, respectively. Considering a gain of QALY of 1.32 for ceritinib and 3.30 for alectinib compared with crizo- tinib, the authors conclude that alectinib, which is more effec- tive but also more costly, appeared to be less cost-effective when compared with ceritinib at a dose of 450 mg daily [52, 53]. In another study, conducted on US perspective, brigatinib and alectinib were superior to crizotinib in terms of PFS and reached comparable results of quality-adjusted life years (PFSQALY). However, brigatinib was associated with higher cost compared to alectinib (522.000$ vs 251.000$, respective- ly), thus showing that alectinib is the most cost-effective treat- ment [54]. Always under-appreciated, the financial toxicity of drugs should be taken into account along with drug-related toxicities in the treatment of ALK+ NSCLC. Molecular Landscape of ALK+ NSCLC: One or More Diseases? ALK-driven NSCLC is a disease characterized by the bedrock of ALK translocation as a driving molecular event, where the tyrosine kinase domain of ALK is fused with a 5′ partner (mainly EML4), generating a chimera with constitutive enzy- matic activity [4••]. Regardless of whether the ALK breakpoint always occurs at exon 20, the EML4 region of fragmentation is variable, generating multiple fusion protein variants [4••, 55]. Among several identified EML4-ALK- fused proteins, three (V1, V2, and V3a/b) have been reported as the most frequent: variant 1 (breakpoint in exon 13: 43%), variant 2 (breakpoint in exon 20: 6%), and variant 3a/b (breakpoint in the exon 6a/b: 40%) [4••, 56, 57•]. Diverse attempts have been made, within retrospective studies, to identify a potential prognostic/predictive value for specific EML4-ALK fusion variants. Patients treated with crizotinib seem to obtain a longer mPFS if harboring variant 1. Lin JJ et al. reported that patients with variant 3a/b generally had a reduced PFS when treated with 2G ALKi at crizotinib pro- gression and were more frequently associated with an intra- ALK resistance mutation, as G1202R [57•, 58]. Moreover, in the same study, a deeper response in terms of prolonged PFS was reported for V3 patients when treated with lorlatinib in a second- or third-line setting [57•]. There has been evidence regarding the prognostic role of V3 being associated with higher-risk patients who have worse clinical behaviors. Different studies described a more aggressive phenotype as- sociated with this specific ALK fusion variant, with enhanced metastatic spreading at baseline that consistently worsened with the co-occurrence of TP53 mutations [59–61]. Christopoulos P. et al., in a retrospective series, described the role of TP53 alterations (20% of the cases) and V3 expres- sion (45%) as independent indicators of a more aggressive disease, associated with less TKI responsiveness and higher risk of death [61]. Undoubtedly, these data highlight the mo- lecular complexity of ALK+ disease, explaining the wide spectrum of clinical presentations and evolution with TKI treatment. However, their retrospective nature limits any di- rect application in the clinical setting and spurs subsequent confirmations within randomized trials. Interestingly, in the updated analysis of the ALEX trial, after 10 months of fol- low-up, no clinical differences have been observed regarding PFS and ORR between EML4-ALK V1 and V3 patients when treated with alectinib as a first-line therapy [22••]. Similarly, another element that continues to be poorly un- derstood when a TKI treatment is proposed is the fusion part- ner of ALK, rather than the variant detected. A large number (> 30) 5′ partners of ALK are known, with different distribu- tion among cancers [56] and their biological implications only partly explained [62]. In 2018, Childress MA et al. investigat- ed how specific ALK partners (e.g., FN1, KIF5B, RANBP2, TFG, PRKAR1A, EML4 V1, and V3b) can influence protein stability, its localization, kinase activity, and response to TKI [63•]. Different factors may influence the response of chimeric proteins to the pharmacological inhibition: oligomerization, protein stability and folding, localization, and protein-protein interactions. Thus, authors identified different profiles of re- sponse to TKI based on the 5′ partner; for example, KIF5B- ALK was less sensitive to crizotinib and lorlatinib. This is similar to the limited response observed with RET inhibitors in KIF5B-RET-positive NSCLC [63•, 64].
Certainly, what remains clear and guides physicians’ deci- sions is the presence of ALK intra-kinase domain mutations acquired upon TKI treatment, which are covered differently by different ALKi. Of note, no baseline ALK mutations have been detected in the analyses of the ALEX trial, denoting the absence of biological factors potentially influencing a re- sponse to alectinib or crizotinib [22••]. Secondary ALK mu- tations are acquired after ALKi treatment, with frequency ranging from 20% with 1G up to 71% with 2G TKIs. Of note, each inhibitor is associated with a specific spectrum of muta- tions; G1202R is the most represented after 2G ALKi [26••]. An article by Shaw et al. has recently demonstrated how lorlatinib activity in the post-2G-TKI setting may be strictly dependent on secondary ALK mutation occurrence, with ORR reported to be 69% in ALK mutation-positive compared to 27% in ALK mutation-negative cohorts [65]. Therefore, the evaluation, through tissue re-biopsy or analysis of circulating cell-free DNA, of the presence of secondary-acquired muta- tions and the decision of which inhibitors are suitable for that patient remains prerogative of second- or further-line treat- ment [66, 67]. The molecular alterations underlying the oc- currence of acquired resistance to upfront 3G TKI are still a matter of investigation. However, preliminary reports suggest that sequential therapy with different-generation ALKi may favor the development of specific mutations that predict high resistance to the targeted compounds currently available for clinical use [68].
Therefore, it is relevant to highlight that the choice of the upfront TKI will inevitably influence the molecular evolution of patients’ tumor and, consequently, therapeutic options at disease progression. Sequential strategies of ALKi adminis- tration, the discussion of which is beyond the scope of this review, are somehow predictable based on the upfront ALKi. Understanding the spectrum of activity of each ALKi is of paramount relevance to guide current clinical decision- making because each inhibitor could control specific molecular-defined ALK+ NSCLC [26••, 69].

Conclusion

Since the discovery of ALK translocations in NSCLC in 2007, multiple small molecules have been developed and approved for clinical use. For a restricted fraction (3–8%) of NSCLC patients harboring ALK rearrangements, at least six different ALKi are already available and others are forthcoming. The approval journey of these molecules by regulatory authorities has not always been easy and, undeniably, not equal across different countries. For example, crizotinib, a multi-targeted drug initially developed as anti-MET in 2005, was approved by the FDA in 2011 with the Vysis ALK Break Apart FISH Probe Kit as a companion diagnostic assay [70]. However, in other countries (e.g., Italy), such a compound was only made available in 2015, denoting complex, slow, and articulated approval procedures. Since the advent of crizotinib, multiple other ALKi have been developed, but discrepancies in reim- bursement processes among different agencies and countries still exist and inevitably condition ALKi selection in the real- world practice.
Assuming all TKIs are available in the clinical arena at the same cost, the physician’s choice should be inevitably based on the following: drug activity (in terms of PFS and ORR), intracranial disease control, and safety profile, taking into ac- count patient comorbidities and treatment compliance. The therapeutic decision for ALK-driven disease is to obtain the best disease control at the lowest toxic profile, trying to delay as much as possible both intracranial and extracranial disease progression. Considering the biological relevance of ALK translocations as the oncogenic driver in NSCLC and the cur- rent availability of several ALKi in clinical practice, their cor- rect management is crucial in obtaining the longest survival outcomes and the best quality of life in this subgroup of pa- tients. While waiting for the CROWN trial which is investi- gating lorlatinib in the first-line setting, current evidence sup- ports the use of alectinib as the best upfront option in ALK+ metastatic disease in our view. However, not all countries or centers have equal access to costly treatments, even when they represent the gold standard for the patients.
Lastly, it is relevant to keep in mind that although ALK+ NSCLC is an emblematic example of oncogene addiction, when we have to decide the best ALKi for our patients, we are facing a composite population of diseases with peculiar biological tracts. Not only is the molecular landscape prone to change over time and under drug pressure, but already at baseline we should consider additional markers capable of identifying patients who are harboring aggressive disease, thus differentiating candidates receiving aggressive therapeutic strategies from patients who have indolent disease. Of course, we need to understand more at the individual pa- tient level to precisely tailor ALKi therapy and ultimately be able to select the right drug for the right patient.

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