Case report: Sturdy response of ensartinib focusing on EML4-ALK fusion in osimertinib-resistant non-small cell lung most cancers

Non-small cell lung most cancers (NSCLC) accounts for 80%–85% of lung most cancers and is the main explanation for cancer-related dying worldwide (Alexander et al., 2020). Mutations within the epidermal progress issue receptor (EGFR) gene are important targets in NSCLC, affecting practically 50% of East-Asian carriers. Three generations of EGFR tyrosine kinase inhibitors (TKIs) have been developed to focus on completely different delicate mutant websites. The primary-generation reversible EGFR-TKIs, resembling gefitinib, erlotinib, and icotinib, are the first decisions of first-line remedy, providing important survival advantages and good drug security (Gazdar, 2009; Huang et al., 2020). As a result of their excessive incidence of hostile results, the medical software of second-generation EGFR-TKIs, together with afatinib and dacomitinib, is comparatively restricted (Huang et al., 2020). Osimertinib, a third-generation EGFR-TKI, reveals favorable security and wonderful central nervous system (CNS) penetration and is really useful as the brand new first-line remedy of superior NSCLC sufferers in routine observe (Leonetti et al., 2019; Huang et al., 2020).

Nonetheless, improvement of resistance is an inevitable problem in TKI remedy. The acquired resistance mechanisms to osimertinib could be categorized into two main sorts: EGFR-dependent mechanisms, resembling EGFR T790M mutation, and EGFR-independent mechanisms, predominately characterised by MET/HER2 amplification and different bypass activated mutations (Leonetti et al., 2019). In a comparatively small proportion of osimertinib-resistant sufferers, acquired EML4-ALK fusion has been detected (Ho et al., 2017; Minari et al., 2018; Offin et al., 2018). This resistance mechanism has additionally been recognized in sufferers handled with first- and second-generation TKIs. In an early-stage NSCLC affected person with remedy historical past of adjuvant chemotherapy plus gefitinib, twin mutations of ALK-R3HDM1 (A19: R21) and EML4-ALK (E6: A20, variant 3) rearrangement had been detected in his metastatic lymph node. A case that obtained second-line erlotinib and chemotherapy developed acquired EML4-ALK fusion and EGFR 19del mutations (Zeng et al., 2022). EML4-ALK fusion has additionally been reported to function the resistant mechanism to afatinib in an 80-year-old male (Xu et al., 2019). A assessment enrolling 24 NSCLC circumstances reported that three of seven afatinib-relapsed sufferers harbored constructive EML4-ALK fusion (Schrock et al., 2018). For third technology EGFR-TKIs, along with osimertinib, acquired EML4-ALK fusion was additionally recognized in an almonertinib-relapsed NSCLC (Ren et al., 2022). Whether or not influenced by the intensive software in medical observe or TKI generations, sufferers growing acquired EML4-ALK fusion represent a good portion of osimertinib-replased inhabitants (Passaro et al., 2021; Zeng et al., 2022).

The EML4-ALK rearrangement is one other oncogenic driver mutation that happens in 3%–5% of NSCLC and could be focused by ALK-TKIs (McCusker et al., 2019). Crizotinib, a first-generation ALK-TKI, reveals superiority over chemotherapy for ALK-rearranged NSCLC however has restricted results in sufferers with CNS involvement. This limitation has been considerably improved by the second-generation ALK-TKIs, together with ceritinib, alectinib, brigatinib, and ensartinib. Moreover, lorlatinib, a third-generation ALK-TKI, has been developed to beat the first and bought resistance to earlier-generation ALK inhibitors (Wu et al., 2016). Previous to the demonstration of the protection and superior efficacy of second- and third-generation ALK-TKIs in medical trials, crizotinib was the first first-line therapeutic technique for treatment-naive sufferers. Consequently, in beforehand reported circumstances of osimertinib-resistant sufferers growing novel EML4-ALK fusion, crizotinib was administered orally. Regrettably, these circumstances didn’t obtain sturdy drug responses. As an illustration, following osimertinib failure and the detection of EML4-ALK variant 1 (V1), crizotinib was administrated as a posterior line remedy for a smoker affected person, leading to solely a 4-month profit, adopted by brigatinib (Yan et al., 2020). Likewise, a transient response of crizotinib plus osimertinib was noticed in a progressed lung adenocarcinoma affected person beforehand handled with first-line gefitinib and second-line osimertinib (Hou et al., 2021).

Just lately, the first-line remedy choices for major tumors with ALK rearrangement have expanded to incorporate second- and third-generation ALK-TKIs (Peters et al., 2017; Camidge et al., 2018; Horn et al., 2021; Solomon et al., 2023). Consequently, the therapeutic strategy for osimertinib-resistant sufferers with acquired EML4-ALK fusion is not restricted to crizotinib. Amongst these options, alectinib has been administrated to a number of sufferers; nevertheless, it exhibited medical actions for lower than 5 months (von Buttlar et al., 2021; Wang et al., 2023). Regardless of the low frequency of acquired EML4-ALK fusion in osimertinib-resistant circumstances, the numerous variety of sufferers with EGFR mutations bear osimertinib remedy, together with the unfavorable medical outcomes related to subsequent crizotinib or alectinib remedy, underscores the need for additional exploration of simpler remedy methods to enhance medical outcomes.

Right here, we report a case of resectable NSCLC harboring advanced EGFR L858R/G719S, and BRAF V600E mutations. Throughout adjuvant remedy, the affected person skilled long-term advantages from the sequential monotherapy with erlotinib, osimertinib, and ensartinib. Notably, the third-line ensartinib demonstrated considerably improved efficacy and security on this affected person, who developed EML4-ALK fusion following resistance to osimertinib, offering precious steering for medical choices in sufferers administration.

On 5 June 2018, a 71-year-old Chinese language feminine with no smoking historical past was admitted to our hospital presenting power cough and chest misery. Her medical historical past included hepatitis B, which had been in remission for 30 years, and a secure benign meningioma, with no remedy historical past. One month earlier than admission, a fluorine 18 (18F)-labeled fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) recognized a major space-occupying lesion with irregular margins (1.7*1.8 cm) in her left decrease lobe close to the pleura. Moreover, three lymph nodes in mediastinum and left hilum confirmed indicators of metastasis, with no distant metastases noticed. Based mostly on PET-CT scans, this affected person was identified with stage IIIA peripheral lung most cancers with lymph node metastasis. A contrast-enhanced CT (CECT) scan additional confirmed the presence of a nodule within the left decrease lobe (Determine 1B). Small nodules in the proper higher lung and adrenal glands weren’t detected by PET-CT, requiring additional remark. Serum biochemistry exams revealed elevated carcinoembryonic antigen (CEA) and cytokeratin fragment 21–1 (Cyfra21-1), exceeding regular ranges.

On 11 June 2018, with knowledgeable consent, this affected person underwent a left lung lobotomy and full mediastinal lymphadenectomy (Determine 2). Hematoxylin and eosin staining of the excised tumor mass confirmed a stage IIIA infiltrating lung adenocarcinoma of the stable predominant subtype (Determine 1A), with carcinoma metastasis in regional lymph nodes. Panel-based genomic DNA sequencing of tissue samples revealed compound somatic delicate mutations (Repugene Expertise, Hangzhou, Folks’s Republic of China), together with EGFR L858R/G719S and BRAF V600E (Desk 1). Given the excessive recurrence threat, she obtained adjuvant remedy with erlotinib. 4 months after initiating focused remedy, imaging confirmed no tumor lesions in situ, confirmed by the detrimental outcomes of non-invasive liquid biopsy sequencing performed 2 months later (Determine 1C; Desk 1).

Determine 2. Timeline of occasions and detected mutations of this case report.

Desk 1. Genomic alterations and molecular check of this case throughout remedy.

After 13-month remedy of erlotinib, the PET-CT indicated intense FDG exercise in nodules situated within the inferior lobe of the left lung close to the hilar, suggesting intrapulmonary lymph node metastases (Determine 1D). A subsequent plasma genotyping detected a recurring L858R mutation (Desk 1). Osimertinib was tentatively employed as second-line remedy in September 2019, with important tumor discount noticed 7 months later (Determine 1E). Ten months after initiating osimertinib, magnetic resonance imaging of the thoracolumbar vertebrae and routine CT scans revealed slight enlargement of pulmonary nodules, mildly elevated bilateral pleural effusions, and potential bone metastases. Along with continued osimertinib, pleural bevacizumab injections had been began in August 2020 (10-month after initiating osimertinib) to manage pleural effusions, administered month-to-month. After 19 months of osimertinib remedy, the affected person developed new nodules and exhibited clearly elevated bilateral pleural effusions, suggesting potential illness recurrence (Determine 1F). To find out the genetic alternations and subsequent therapeutic methods, pleural effusion was sampled, and the supernatant was subjected to focused panel sequencing in April 2021, which detected an acquired EML4-ALK variant 3 (E6:A20) mutation. In consequence, ensartinib was administered in Might 2021. One month later, a CECT evaluation confirmed alleviated tumor lesion, decreased pleural effusions, and lowered nodules sizes (Determine 1G). Six months after initiating ensartinib, CT scan indicated additional lowered pleural effusions and cleared nodules. At subsequent follow-up visits at 9- and 12-month post-ensartinib remedy, pleural effusions had been persistently decreased. On the final follow-up in July 2022, CT scans confirmed resolved pleural effusions (Determine 1H), and serum marker ranges remained inside regular vary. Along with tolerable rash and minor abnormalities in liver and kidney perform, no different unwanted side effects had been noticed over ensartinib remedy, indicating a positive drug security.

The detection of coexisting mutations of EGFR L858R/G719S and BRAF V600E on this affected person posed a problem in selecting the suitable TKI for adjuvant remedy. BRAF, a key molecule within the EGFR/RAS downstream signaling pathway, is mutated in roughly 1.5%–5.5% NSCLC circumstances, with the predominant genotype being BRAF V600E (Jordan et al., 2017; Lin et al., 2019). Promising efficacy and security have been demonstrated with BRAF inhibitors, resembling dabrafenib (Planchard Okay. et al., 2016), vemurafenib (Subbiah et al., 2019), and the mix of dabrafenib plus trametinib (Planchard B. et al., 2016; Planchard et al., 2017; Ettinger et al., 2021), in medical trials involving superior BRAF V600E mutant NSCLC. The event of acquired BRAF V600E has been reported to render tumor insensitivity to EGFR-TKIs remedy (Ohashi et al., 2012; Ricordel et al., 2018; Westover et al., 2018), indicating potential medical advantages of EGFR and BARF co-inhibition in circumstances with twin mutations. Certainly, an growing variety of circumstances have reported that superior EGFR-mutant NSCLC sufferers that developed concomitant BRAF mutations following acquired resistance to EGFR-TKI remedy exhibit sturdy responses and good tolerance to mixed EGFR and BRAF inhibitors remedy (Aboubakar Nana and Ocak, 2021; Ribeiro et al., 2021; Schaufler et al., 2021). As an illustration, a male affected person with lung adenocarcinoma underwent genetic testing after osimertinib remedy failure, which revealed co-mutations of EGFR T790M/19del and BRAF V600E. Consequently, he switched to a mix remedy of debrafenib, trametinib, and osimertinib, that resulted in an entire remission (Meng et al., 2020). One other feminine affected person who developed resistance to osimertinib was discovered to hold EGFR 19del plus BRAF V600E mutations, obtained debrafenib, trametinib, and osimertinib, and achieved a secure illness inside 6-month of remedy (Zeng et al., 2021). These findings point out that, in our case, introducing BRAF inhibitors may assist enhance survival advantages when mixed with erlotinib. Nonetheless, there’s a lack of complete medical trials on this mixture remedy, and the obtainable medical knowledge are restricted, significantly in circumstances with major BRAF and EGFR mutations. Provided that the resistance mechanisms of debrafenib, trametinib, and EGFR-TKI remained unclear which can restrict subsequent therapeutic choices, this affected person opted for erlotinib monotherapy. A medical response of 14 months confirmed that erlotinib is an efficient remedy.

On the finish of erlotinib remedy, plasma genotyping was performed to information the change in therapeutic technique because of the lack of tumor tissues, and this testing confirmed the presence of EGFR L858R mutation. Based on a diagnostic evaluation of 216 superior NSCLC circumstances, liquid biopsies have proven a 96.5% specificity in detecting L858R (Schrock et al., 2018), suggesting the reliability of this consequence for our affected person. Osimertinib has demonstrated superior efficacy over first- and second-generation EGFR-TKIs in medical trials of superior NSCLC with L858R mutations. The FLAURA examine, which targeted on treatment-naive sufferers with L858R, discovered that these handled with osimertinib had a protracted PFS than these receiving normal EGFR-TKI (gefitinib or erlotinib) (14.4 months vs. 9.5 months) (Soria et al., 2018). One other meta-analysis additionally reported the longest PFS in osimertinib-treated group amongst 12 remedy methods (Zhao Y. et al., 2019). These findings recommend that osimertinib may present a sturdy and protected response for this affected person and we began osimertinib remedy with affected person’s consent. In the course of the course of remedy, regardless of minor radiographic indicators of development, we continued osimertinib as no driver mutations had been detectable within the plasma genetic testing. Nonetheless, 19 months after initiating osimertinib, an EML4-ALK fusion emerged, indicating a change within the tumor’s genetic panorama.

The resistance mechanisms of second-line osimertinib have been systematically documented, reporting that numerous oncogene fusion occasions, together with ALK fusions, happen in lower than 10% of circumstances (Fu et al., 2022). In situations the place sufferers developed acquired EML4-ALK fusion after osimertinib, these sometimes co-occurred with EGFR mutations resembling T790M, L858R, and 19del. Consequently, a mix of osimertinib plus ALK inhibitors is employed. Nonetheless, most sufferers skilled tumor development inside 6 months when osimertinib is mixed with crizotinib or alectinib (Batra et al., 2020; Hou et al., 2021; von Buttlar et al., 2021; Wang et al., 2023; Yan et al., 2020). For instance, one affected person confirmed illness development on CT scans simply 1 month after beginning second-line remedy with osimertinib and crizotinib, and switching to brigatinib solely maintained a secure illness response for 4 months (Yan et al., 2020). Ensartinib, a newly-marketed second-generation ALK inhibitor, has proven superior efficacy to crizotinib in first-line remedy for each systemic and intracranial illness. It has additionally confirmed efficient in circumstances immune to crizotinib or in overcoming alectinib-induced hostile occasions (Batra et al., 2020; Yang et al., 2020; Horn et al., 2021). In mild of this, our affected person obtained ensartinib and maintained high quality of life over a 14-month follow-up, displaying higher outcomes in comparison with prior circumstances handled with crizotinib or brigatinib after osimertinib resistance. It has been reported that one other NSCLC affected person, who developed EML4-ALK fusion after turning into resistant to a different third-generation EGFR-TKI almonertinib, obtained crizotinib mixed with almonertinib however solely had a secure illness standing for 1 month (Ren et al., 2022). It is a far much less efficient case, although you will need to acknowledge that the various effectiveness between ensartinib and different ALK inhibitors is likely to be influenced by the presence of concurrent EGFR mutations, in addition to patient-specific elements. The efficacy of ensartinib in osimertinib-resistant sufferers with co-existing EGFR and ALK mutations requires additional exploration.

In the course of the medical analysis and administration of this case, a number of limitations should be addressed. First, the preoperative medical analysis of this affected person was solely based mostly on CT scans with out histopathological affirmation by way of tissue biopsy, which may have offered a extra definitive analysis. Second, the clinically important mutations recognized by next-generation sequencing weren’t validated utilizing different strategies resembling Sanger sequencing and quantitative polymerase chain response, which may have strengthened the reliability of the outcomes. Lastly, the genotyping performed utilizing blood or pleural effusion samples weren’t additional confirmed in tumor tissues, elevating the potential for false-negative outcomes.