What do we know about the role of neoadjuvant targeted therapy in early-stage EGFR-mutant and ALK-fused non-small cell lung cancer?—a narrative review of the current literature

Introduction

Rationale and background

Non-small cell lung cancer (NSCLC) is a tumour that often recurs, even after complete resection and either neoadjuvant or adjuvant chemotherapy. As a result, it remains the leading cause of cancer-related mortality worldwide (1). To reduce the risk of recurrence and to improve long-term survival in early-stage NSCLC, many studies have investigated neoadjuvant, adjuvant and perioperative approaches including chemotherapy, immunotherapy and targeted therapies.

For years, adjuvant or neoadjuvant platinum-based chemotherapy was the only approved treatment option for resectable NSCLC (2). In the immune-checkpoint-inhibitor (ICI) era, phase III trials such as IMpower010 and KEYNOTE-091 demonstrated a survival benefit of adding adjuvant immunotherapy after platinum-based chemotherapy in early-stage disease (3,4). More recently, phase III trials such as CheckMate816 (5), KEYNOTE-671 (6), CheckMate77T (7) and AEGEAN (8) also demonstrated the efficacy and survival benefit of neoadjuvant and/or perioperative chemoimmunotherapy regimens in resectable NSCLC. Thus, the therapeutic landscape for early-stage resectable NSCLC has become much more diverse.

However, there is a paucity of such data for early-stage tumours harbouring actionable genetic alterations (AGAs) in the genes for epidermal growth factor receptor (EGFR), v-Raf murine sarcoma viral oncogene homolog B (BRAF), anaplastic lymphoma kinase (ALK), tyrosine protein kinase ROS proto-oncogene (ROS) or RET proto-oncogene (RET). In advanced tumours harbouring driver mutations, first-line targeted therapy is the current standard of care and is superior to standard chemotherapy in terms of survival and quality of life (9). Among these driver mutations, EGFR-mutations are the most common in NSCLC and are found in approximately 16% of lung adenocarcinomas (9). Second most common alterations (approximately 4%) are fusions of the ALK gene with other genomic partners, such as the echinoderm microtubule-associated protein-like 4 (EML4) gene, resulting in the EML4-ALK oncogene and subsequent aberrant ALK kinase activity (9). EGFR-mutant and ALK-fused tumours can be specifically inhibited with tyrosine kinase inhibitors (TKIs) such as third-generation EGFR TKI osimertinib, second-generation ALK TKIs alectinib and brigatinib or the third-generation ALK TKI lorlatinib, respectively (10-13). Efficacy data for alectinib with a 5-year overall survival (OS) of 62.5% in advanced-stage NSCLC is promising even regarding the application of TKI in earlier tumour stages (14). Apart from adjuvant treatment with EGFR TKI osimertinib, which is approved by both the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for adjuvant therapy after resection in EGFR-mutated NSCLC based on the results of the ADAURA trial (15), recently published data from the phase III ALINA trial (16) led to the approval of alectinib as adjuvant treatment after tumour resection in ALK-fused NSCLC by both the FDA and the EMA. However, so far there is only little evidence for a neoadjuvant or perioperative treatment approach in EGFR-mutated and ALK-fused NSCLC. Although there are a few case reports and ongoing trials, there is still a lack of sufficient and reliable data. Moreover, it remains unclear whether (neo-)adjuvant TKI therapy alone is sufficient to eliminate residual tumour cells, or whether additional chemotherapy is required.

Objectives

In this narrative review, we aim to summarize the landscape of perioperative treatment regimens and their relevance for resectable NSCLC harbouring EGFR-mutations and ALK-fusions. We will continue to review the current evidence for neoadjuvant targeted therapy, focusing on pathological treatment effects, survival outcomes and safety data. We present this article in accordance with the Narrative Review reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-359/rc).

Methods

The authors conducted an electronic literature search to identify the relevant literature that was published in PubMed and ClinicalTrials.gov (last search phase June 2024) (Table 1). The search was restricted to English language. Apart from peer-reviewed manuscripts, also conference abstracts have been included in this review, even though they have not yet been published following peer review. The titles and abstracts of the search results were screened and irrelevant publications were excluded by authors’ choice. Only the relevant manuscripts were further examined for their full text to extract the relevant information. However, as this is meant to be a narrative review, we did not perform a systematic literature search and the included literature is based on authors’ choice. The literature selected for this manuscript covers a period from 2008 to 2024.

Case report

In 09/2021, a 70-year-old female non-smoker presented at the University Hospital Muenster (Germany) with a lung lesion in the right upper lobe that was incidentally detected on an external cardiac magnetic resonance imaging (MRI) scan. The MRI was performed to evaluate for progression of underlying coronary artery disease after percutaneous coronary intervention in 07/2016. At the time of presentation, the patient was in good physical condition [Eastern Cooperative Oncology Group (ECOG) 1] and did not suffer from relevant symptoms. She had worked as an occupational health physician in a hospital until 2017. Her medical history included coronary artery disease, pulmonary tuberculosis in 1975 (treated), cerebral ischaemia and a history of hepatitis B. Her cardiovascular risk was increased by elevation of lipoprotein (a), dyslipoproteinemia, arterial hypertension and obesity (body mass index 29.6 kg/m²).

Imaging by ¹⁸F-fluorodeoxyglucose positron emission tomography (FDG PET), computed tomography (CT) and MRI of the brain revealed a pulmonary tumour in the right upper lobe (Figure 1) with suspected infiltration of the visceral pleura and ipsilateral lymphogenic metastases (right hilum, mediastinal level 4R, infracarinal level 7), but no evidence of contralateral or distant organ/brain metastases.

Figure 1 CT and PET/CT scan at baseline and after 2 and 4 months of neoadjuvant brigatinib. (A) Axial CT images, lung window. (B) Axial CT images, chest window. (C) Axial fused PET/CT images. CT, computed tomography; PET, positron emission tomography.

A biopsy was then taken using endobronchial ultrasound, transbronchial needle aspiration and cryobiopsy. Pathological examination of the tissue revealed a thyroid transcription factor 1 (TTF1)-positive lung adenocarcinoma (Figure 2A,2B) with intermediate programmed cell death ligand 1 (PD-L1) expression (tumour proportion score 30%, combined positivity score 40%) as determined by immunohistochemistry. Fluorescence in situ hybridization (FISH) and next-generation sequencing (NGS) by RNA sequencing revealed an EML4-ALK fusion variant 1 (exon 13/exon 20) (Figure 2C). Neither FISH analysis, nor NGS revealed other genetic alterations (including ROS, RET, MET, EGFR, BRAF and KRAS genes).

Figure 2 Histopathological tissue analysis from endobronchial cryobiopsy. Histopathological analysis of the primary tumour in the right upper lobe from endobronchial cryobiopsy showing a lung adenocarcinoma (A, hematoxylin and eosin staining) which was found positive for TTF1 (B, TTF1 staining). FISH analysis detected an ALK-fusion (C, ZytoLight^® SPEC ALK/EML4 TriCheckTM Probe, 600× magnification), which was later confirmed via RNA-sequencing. After 4 months of neoadjuvant ALK inhibition the patient subsequently received R0 tumour resection via lobectomy and post-treatment pathological analysis documented a complete pathological tumour regression (D, hematoxylin and eosin staining). TTF1, thyroid transcription factor 1; FISH, fluorescence in situ hybridization; ALK, anaplastic lymphoma kinase.

In summary, we diagnosed an advanced staged ALK-fused NSCLC [Union for International Cancer Control (UICC) 8^th edition stage IIIA; cT1b cN2 cM0]. The tumour was initially regarded as resectable via lobectomy and radical lymphadenectomy. Due to the multi-level lymphonodular advanced tumour stage we decided to perform neoadjuvant treatment with ALK inhibition prior to surgery, similar to current neoadjuvant trials in resectable NSCLC. ALK inhibition was initiated with the second-generation TKI brigatinib (180 mg/day). This approach was in accordance with current EMA approval of brigatinib as first-line treatment in advanced ALK-fused NSCLC. Treatment was well-tolerated by the patient without evidence of side effects. Response was assessed by PET/CT after 2 months showing a radiologic stable disease but metabolic partial remission of the primary tumour (Figure 2). After 2 more months of ALK inhibition, a further PET/CT showed a complete metabolic response of the morphologically identical tumour mass (Figure 1; ycT1b ycN2 ycM0). The patient was therefore assessed for subsequent tumour resection in our thoracic surgery department. In 02/2022, a right upper lobe lobectomy combined with a radical lymphadenectomy was performed. TKI therapy was stopped perioperatively to limit side effects on surgical morbidity.

Post-treatment pathological examination confirmed a pathological complete response (pCR) of the primary tumour to neoadjuvant brigatinib (Figure 1D). Immunohistochemical staining revealed a highly regressive adenocarcinoma in one hilar lymph node without evidence of vital tumour cells. After neoadjuvant treatment and histopathological examination, the tumour was downstaged to IIA (UICC 8^th edition). Following the discussion in our molecular tumour board, adjuvant platinum-based chemotherapy was recommended, followed by continuation of brigatinib due to a high risk of relapse. However, the patient refused chemotherapy and only started adjuvant brigatinib. Based on the patient’s decision brigatinib was stopped in 12/2022. To date (03/2024), remission monitoring has shown durable complete remission of the tumour (Figure 3).

Figure 3 Treatment timeline of the patient in this case report receiving perioperative ALK inhibition. Remission status was evaluated via PET/CT after 2 and 4 months. Adjuvant brigatinib was stopped in 12/2022 based on the patient’s decision (image created in BioRender. Kemper M, 2024. BioRender.com/l12h184). CT, computed tomography; PET, positron emission tomography; ALK, anaplastic lymphoma kinase; UICC, Union for International Cancer Control.

All procedures performed in this study were in accordance with the ethical standards of the institutional and national research committees and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patient for publication of this article and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Discussion

To reduce the risk of disease recurrence in early-stage NSCLC several different perioperative treatment strategies have recently been investigated. Here we will discuss the most recent and current evidence.

Adjuvant and perioperative immunotherapy in non-oncogenic NSCLC

In patients with stage II–III NSCLC, adjuvant and neoadjuvant platinum-based chemotherapy after R0 tumour resection has been shown to improve OS by approximately 5% (2,17,18). Although this benefit is small, it has long been the only approved additional treatment option in this patient population. In 2021 and 2023, additional data from the IMpower010 trial demonstrated a significant benefit in disease-free survival (DFS) and OS for atezolizumab compared to best supportive care after adjuvant chemotherapy in resected stage II–IIIA NSCLC (3,19); this regimen is currently approved by the EMA for patients at high risk of relapse whose tumours are EGFR/ALK wild-type and have a PD-L1 expression (tumour cells score) ≥50% and by the FDA for tumours that have a PD-L1 expression (tumour cells score) ≥1%, respectively. Similarly, the interim analysis of the phase III KEYNOTE-091 trial in 2022 showed improved DFS for pembrolizumab after adjuvant chemotherapy in resected stage IB–IIIA NSCLC regardless of PD-L1 status (4). Thus, pembrolizumab is approved by FDA and EMA for the adjuvant treatment of NSCLC patients who are at high risk of recurrence following complete resection and platinum-based chemotherapy.

Similar to adjuvant strategies, neoadjuvant chemotherapy can improve survival and reduce the risk of disease recurrence in early-stage NSCLC (18). Neoadjuvant and/or perioperative regimens may also be the best choice for stage IIIA–N2 NSCLC in terms of OS (20). As these regimens aim to reduce primary tumour volume, this has the potential not only to reduce the invasiveness of tumour resection, but also to control the response to neoadjuvant chemo-immunotherapy according to pathological remission status. In the phase III CheckMate816 trial, three cycles of nivolumab in combination with platinum-based chemotherapy resulted in a significantly longer median event-free survival (EFS) [31.6 versus 20.8 months; hazard ratio (HR) =0.63, 97.38% confidence interval (CI): 0.43–0.91] and achieved higher pCR rates (24.0% versus 2.2%) compared to chemotherapy alone in stage IB–IIIA resectable NSCLC (5). As a result, the CheckMate816 protocol was the first neoadjuvant immunotherapy regimen approved by the EMA for patients with resectable NSCLC and PD-L1 expression ≥1%. KEYNOTE-671 was another phase III study that evaluated four cycles of perioperative pembrolizumab versus placebo plus cisplatin-based chemotherapy followed by surgery and adjuvant pembrolizumab for up to 13 cycles versus placebo in patients with stage II–IIIB (N2) resectable NSCLC. The addition of perioperative pembrolizumab significantly improved EFS, major pathological response (MPR) and pCR (6), leading to approval by both the FDA and EMA. Other recently published phase III trials further support the efficacy of perioperative nivolumab [CheckMate77T (7)] or durvalumab [AEGEAN (8)] regarding pathological outcome (pCR and MPR rates) and EFS in early-stage resectable NSCLC. The ongoing NeoCOAST trial (NCT03794544) is evaluating the potential of neoadjuvant durvalumab alone or in combination with novel agents in resectable NSCLC (21). In summary, these studies confirm the efficacy and safety of neoadjuvant/perioperative chemo-immunotherapy in early-stage NSCLC.

Adjuvant therapy in EGFR-mutant and ALK-fused NSCLC

In contrast to these promising data on (neo-)adjuvant and perioperative chemo-immunotherapy in non-oncogenic NSCLC, there are few such data in early-stage oncogenic NSCLC, as immunotherapy is known to be less effective and associated with a higher risk of toxicities in EGFR-mutant or ALK-fused NSCLC (22-27). Both the IMpower010 and the KEYNOTE-091 trials included patients with known EGFR-mutations and ALK-fusions, but neither trial required initial testing, so the exact number of patients in these subgroups is unknown. On the one hand, for the small number of patients with known EGFR-mutation or ALK-fusion in Impower010, there was no survival benefit for adjuvant atezolizumab (3,19). On the other hand, in the KEYNOTE-091 trial there was a significant benefit for adjuvant pembrolizumab in patients harbouring an EGFR-mutation (HR =0.44; 95% CI: 0.23–0.84) (4). These conflicting data reflect the so far unknown relevance of adjuvant immunotherapy in oncogenic NSCLC and must be interpreted with caution due to small patient numbers.

Regarding the use of adjuvant targeted therapy, results from early phase II studies suggested beneficial effects of adjuvant EGFR inhibition in resected EGFR-mutant NSCLC. In the SELECT trial, 100 patients with resected stage IA to IIIA EGFR-mutant NSCLC and 2 years of adjuvant erlotinib (after adjuvant chemotherapy with or without radiotherapy) had an improved 2-year DFS compared to historic genotype-matched controls (88% versus 76%), while no changes in OS were observed (28). In a Chinese trial, 2 years of adjuvant erlotinib as compared to four cycles of chemotherapy prolonged 2-year DFS (81.4% versus 44.6%) in patients with stage IIIA EGFR-positive NSCLC, but mature OS data is still missing (29). Data from the phase III CTONG1104 trial further supported the evidence for adjuvant targeted therapy in EGFR-mutant NSCLC. Here, adjuvant gefitinib for 24 months resulted in a significantly longer median DFS compared to four cycles of adjuvant chemotherapy (28.7 versus 18 months; HR =0.60; 95% CI: 0.42–0.87), but with no difference in OS (30,31). In contrast, data from the Japanese phase III IMPACT trial could not confirm this beneficial effect of adjuvant gefitinib on DFS (32). Although these trials demonstrate the efficacy of first-generation EGFR TKIs as adjuvant treatment in EGFR-positive NSCLC, their application is limited due to development of resistance mutations, that might explain the missing translation to OS benefits in these trials. Therefore, the development of osimertinib, a third-generation EGFR TKI that covers a wide range of resistance mutations, has shed new light on the role of adjuvant targeted therapy in resected EGFR-mutant NSCLC. Subsequently, the randomized controlled phase III ADAURA trial demonstrated the efficacy and safety of 3 years of adjuvant osimertinib in resected stage IB–IIIA NSCLC harbouring common EGFR mutations (15). The updated 2023 data showed a significant OS benefit for adjuvant osimertinib versus placebo (88% versus 78%; HR =0.49; 95.03% CI: 0.34–0.70) (33). Therefore, adjuvant osimertinib is the current standard of care (34) for resected early-stage EGFR-mutant NSCLC. Of note, 60% of patients in both the osimertinib and in the placebo arms received adjuvant platinum-based chemotherapy prior to initiation of adjuvant osimertinib or placebo. Therefore, this study cannot answer the question of whether adjuvant TKI treatment is sufficient to eliminate residual tumour cells or whether synergistic effects resulting from the addition of chemotherapy may also be relevant. More recently, data from the phase III LAURA trial demonstrated efficacy of adjuvant osimertinib in unresectable EGFR-mutated stage III NSCLC after chemoradiotherapy resulting in a significantly longer median PFS compared to placebo (39.1 versus 5.6 months; HR =0.16, 95% CI: 0.10–0.24) (35).

Based on the results from the phase III ALINA trial (NCT03456076), alectinib has recently been approved both by FDA and EMA as adjuvant treatment after tumour resection in ALK-fused NSCLC. Alectinib was shown to be the first ALK inhibitor to significantly improve DFS compared to standard chemotherapy after a median follow-up of 27.8 months (88.7% versus 54%; HR =0.24; 95% CI: 0.13–0.43) in patients with resected ALK-positive NSCLC (16). Although this trial has defined a new standard of care, it remains unclear whether adjuvant alectinib is sufficient to eliminate residual tumour cells as patients were not allowed to receive prior adjuvant platinum-based chemotherapy. With this in mind, OS data are still immature and missing from the ALINA trial. The randomized controlled phase III ALCHEMIST trial (NCT02194738) is another study investigating the role of adjuvant targeted therapy. Completely resected stage IB–IIIA NSCLC patients with EGFR mutations will be randomized to either adjuvant erlotinib or observation, while those with ALK-fusions will be randomized to adjuvant crizotinib or observation. The trial will hopefully provide further evidence to support the role of adjuvant targeted therapy. Finally, the second-generation ALK TKI ensartinib is currently being tested in a single-arm phase II trial (NCT05241028) as adjuvant therapy for 3 years in stage IB–IIIA ALK-fused NSCLC.

Perioperative immunotherapy in EGFR-mutated and ALK-fused NSCLC

As mentioned above, neoadjuvant and/or perioperative regimens have the potential to monitor pathological response and reduce tumour burden prior to resection. Here, immunotherapy can induce pCR rates between 17.2% to 25.3% and MPR rates between 30.2 to 36.9%, respectively (5-8). However, patients with oncogenic drivers have typically been excluded from immunotherapy trials such as CheckMate816, AEGEAN and CheckMate77T (5,7,8). Only the KEYNOTE-671 trial included patients with EGFR- or ALK-alterations as molecular testing was not mandatory. Subgroup analysis found evidence of a survival benefit for perioperative pembrolizumab in patients with EGFR-mutations (6). However, as the subgroup numbers are very small, the current evidence is insufficient to clarify the role of perioperative immunotherapy in patients with EGFR-mutations and ALK-fusions.

Neoadjuvant EGFR inhibition

Previously, neoadjuvant erlotinib and gefitinib, both first-generation EGFR TKIs, have shown activity in stage II–IIIA EGFR-mutant NSCLC (36-38). The randomized phase II EMERGING-CTONG 1103 trial randomly assigned 72 patients with stage IIIA (N2) NSCLC harbouring EGFR exon 19 or 21 mutations, to receive erlotinib 150 mg daily (neoadjuvant for 42 days, adjuvant for up to 12 months) or gemcitabine and cisplatin (neoadjuvant for two cycles, adjuvant for up to two cycles). Although the objective response rate (ORR) was better for erlotinib versus chemotherapy (54.1% versus 34.3%), this difference was not significant. Regarding the pathological outcome after surgery, no pCR was detected in either arm and the MPR rate in the erlotinib arm was only 9.7% (3/31) compared to 0% (0/23) in the chemotherapy arm. Nevertheless, perioperative erlotinib resulted in an improved progression-free survival (PFS) compared to chemotherapy in stage IIIA (N2) EGFR-mutant NSCLC (21.5 versus 11.4 months; HR =0.39; 95% CI: 0.23–0.67), but with no difference in OS (36,39). In a phase II study from China, 19 patients with stage IIIA (N2) EGFR-positive NSCLC received erlotinib 150 mg daily for 56 days as neoadjuvant therapy prior to surgery and primary endpoint was the radical resection rate. Here, the radical resection rate was 68.4% (13/19) and pathological downstaging was achieved in 21.1% (4/19) of the patients (38). The authors conclude that neoadjuvant erlotinib might improve the radical resection rate, however, this message is limited as only 14/19 patients underwent surgery. Similar to erlotinib, preoperative gefitinib 250 mg was administered for 42 days to 33 patients with stage II–IIIA NSCLC with common EGFR exon 19 and 21 mutations prior to surgical tumour resection in a phase II trial from Shanghai. Here, the MPR rate was 24.2% and was associated with improved survival (37). The safety and efficacy of afatinib (40 mg daily), a second-generation EGFR TKI, for 2 months in combination with concurrent chemoradiotherapy (cCRT) with or without surgery in stage III EGFR-mutated NSCLC was evaluated in the phase II ASCENT trial. Recently published data showed an ORR of 63% (12/19) to induction afatinib. Twenty-two percent (2/9) of previously unresectable patients became resectable after afatinib induction. Sixty percent (6/10) of the patients that underwent surgery had a major or complete pathological response. With a median follow-up of 5 years, median PFS and OS were 2.6 and 5.8 months, respectively (40). However, the relevance of these studies remains questionable as first- and second-generation EGFR TKIs have been replaced by the third-generation EGFR TKI osimertinib in the treatment of newly diagnosed EGFR-mutant NSCLC patients according to the results of the FLAURA trial (33). For osimertinib, the single-arm phase IIb NEOS trial showed an ORR of 71.1% (27/38) after 6 weeks of neoadjuvant EGFR inhibition with osimertinib 80 mg daily in patients with stage IIA–IIIB (T3–4, N2) lung adenocarcinoma harbouring EGFR exon 19 and/or 21 mutations, followed by surgical resection. Although osimertinib appeared to be safe in this trial (7.5% treatment-related grade 3 adverse events) and 93.8% of patients underwent a successful R0 resection, only 10.7% achieved a MPR (41). Similar data was generated in a multi-institutional phase II trial (NCT03433469), in which a total of 27 patients with resectable stage I–IIIA EGFR-mutated (L858R or exon 19 deletion) NSCLC received osimertinib 80 mg daily for a median of 56 days prior to surgical resection. Eighty-nine percent (24/27) of the patients subsequently underwent surgery, whereas 11% (3/27) converted to definitive chemoradiotherapy. The MPR rate was only 15% and no pCR was observed, thus the primary endpoint was not met in this study (42) (conference abstract, not peer-reviewed yet). Compared to the impressive pathological response rates after neoadjuvant immunotherapy in non-oncogenic NSCLC, these data demonstrate the limited efficacy of neoadjuvant EGFR inhibition to induce pathological response. Retrospective real-word data (43-45) further support these findings and suggest that neoadjuvant EGFR inhibition might not be sufficient to induce a relevant pathological tumour regression (46). Recent data from the FLAURA2 trial in patients with advanced EGFR-mutant NSCLC provide evidence for the efficacy of a combination of a TKI and chemotherapy (47), which can be further supported by recent findings from the LAURA trial (35). A similar strategy is currently being investigated in the PACE-LUNG trial, in which a biomarker-driven strategy using circulating tumour DNA (ctDNA) is being used to decide whether to escalate treatment by adding chemotherapy to osimertinib in advanced EGFR-mutant NSCLC (48). However, these studies lack data on pathological outcome, as they are performed in advanced unresectable NSCLC. Therefore, in patients with resectable stage II–IIIB N2 EGFR-mutated NSCLC, the ongoing phase III NeoADAURA trial (NCT04351555) is evaluating the role of neoadjuvant osimertinib with or without chemotherapy versus chemotherapy alone before surgery (49). As it remains unknown, whether TKIs have the potential to eliminate tumour cells rather than just inhibiting their proliferation, this and other ongoing trials (50) will hopefully provide further information on this unanswered question (Table 2).

Neoadjuvant ALK inhibition

In addition to targeting EGFR-mutations in early-stage NSCLC with EGFR TKIs, the question arises as to whether ALK inhibition may also be a therapeutic option in resectable NSCLC, as ALK-fusions are the second most common driver mutations in NSCLC. However, there is a lack of evidence on the use of ALK TKIs as neoadjuvant treatment in resectable early-stage ALK-positive NSCLC. To date, there are only a few case reports with small patient numbers using predominantly neoadjuvant alectinib (51,52), but also crizotinib (53) or ceritinib (conference abstract, not yet fully published) (54). These reports may show that neoadjuvant ALK inhibition appears to be reasonable in early-stage NSCLC (55). For example, a case series of 9 patients found high rates of MPR (33.3%) and pCR (44.4%) after neoadjuvant ALK inhibition (52). In line with these findings, the above-mentioned patient received the second-generation ALK TKI brigatinib for approximately 4 months prior to surgery, resulting in a pCR, which is consistent with previous reports for neoadjuvant alectinib and demonstrates its efficacy as an alternative neoadjuvant treatment strategy. A recently published real-world head-to-head comparison of first-line alectinib and brigatinib showed similar clinical benefits as well as similar rates of adverse events (56). In addition, the ALTA-3 trial found that brigatinib was not superior to alectinib for PFS in crizotinib-pretreated advanced ALK-fused NSCLC (57), providing further evidence that the two drugs can be used similarly. However, phase II and III trials are still required to confirm the safety and efficacy of neoadjuvant ALK inhibition in early-stage NSCLC (Table 3). A number of phase II trials such as RTOG 1306 (NCT01822496), SAKULA (UMIN00017906) and ARM (NCT03088930) had to be stopped due to recruitment problems as ALK-fusions are very rare and not (yet) routinely tested in early-stage NSCLC (34,55,58). The ongoing ALNEO trial (NCT05015010) is currently evaluating the safety and efficacy of neoadjuvant alectinib for 8 weeks followed by surgery and adjuvant alectinib for up to 96 weeks (34). The NAUTIKA1 trial (NCT04302025) is another phase II trial investigating the role of perioperative targeted therapy in biomarker-selected stage IB–III NSCLC patients (58). In line with the results of the recently presented ALINA trial, it seems conceivable that neoadjuvant ALK inhibition has the potential to downstage tumours and induce pathological remission in early-stage ALK-driven NSCLC prior to tumour resection. There is also similar evidence for locally advanced tumours (59). However, it remains unclear which patients are best suited for these approaches and for how long they should be treated with ALK TKIs prior to surgery, as there is also a risk of tumour progression with ALK inhibition, which in turn reduces the likelihood of complete tumour resection. Furthermore, the value of additional adjuvant TKI therapy and the value of perioperative chemotherapy in this setting is not known.

Surgical outcomes after neoadjuvant treatment

Neoadjuvant immunotherapy regimens have been shown to achieve high MPR and pCR rates with a positive impact on surgical outcome and survival (60,61). For example, the CheckMate816 trial found a shorter median duration of surgery (185.0 versus 213.5 min), less pneumonectomies (16.8% versus 25.2%) and more minimally invasive approaches (29.5% versus 21.5%) for neoadjuvant addition of nivolumab compared to chemotherapy alone. R0 resection rates were also higher for the nivolumab combination (83.2% versus 77.8%). These findings were particularly true for patients with stage IIIA NSCLC (5). However, it needs to be shown whether this correlation between MPR/pCR rates and surgical and survival outcomes can also be assumed after neoadjuvant targeted therapy (46,62). In a case series of five patients with stage IIA to IIIA NSCLC from McGill University Health Centre (Canada), two ALK-positive patients were treated with alectinib 1–2 months prior to surgery, and three EGFR-mutated (exon 19) patients were treated with gefitinib or osimertinib 1–2 months prior to surgery. Two of these patients achieved a MPR, but none achieved a pCR. The initially assessed surgical approach before neoadjuvant TKI therapy would have been a thoracotomy-guided lobectomy in four patients and a video-assisted thoracoscopic surgery (VATS)-guided bilobectomy in the other patient. After neoadjuvant TKI therapy, all five patients underwent VATS-guided (bi-)lobectomy. The authors conclude that despite the unconvincing rates of MPR and pCR after neoadjuvant ALK/EGFR inhibition, this approach has simplified the surgical procedure for these patients (63). Whether this “simplification” of the surgical procedure translates into a long-term survival benefit remains unproven. Therefore, standardized surgical endpoints should be included in future neoadjuvant trials for resectable NSCLC (64).

Safety data on perioperative targeted therapy

Despite the promising effects of perioperative targeted therapy on tumour shrinkage and survival, potential safety issues and toxicities should be carefully considered. Adverse side effects of targeted therapies may delay the timing of surgery (62) and increase the perioperative risk (65). Severe toxicities associated with osimertinib include cardiomyopathy and heart failure (66,67) as well as QT interval prolongation, neutropenia and thrombocytopenia (68,69). With alectinib, bradycardia is a common side effect but reversible by dose reduction or discontinuation (70,71). In addition, the choice of neoadjuvant therapy may affect the side effects of subsequent lines of treatment, as sequential immunotherapy and targeted therapy are known to be associated with a significantly increased risk of severe immune-related adverse events, such as hepatotoxicity (22,72,73).

Summary

Taken together, current data underline the need for molecular testing for driver mutations even in early-stage NSCLC in order to carefully select the right treatment regimen for these patients (62). In addition to EGFR- and ALK-alterations, neoadjuvant strategies are also being tested for other AGAs. For example, the LEADER trial (NCT04712877) is evaluating the feasibility of using comprehensive genomic profiling (CGP) to detect AGAs to guide neoadjuvant therapy selection (74) (conference abstract, not yet fully published). In summary, despite conflicting results, neoadjuvant targeted therapy has the potential to reduce tumour burden through tumour shrinkage and pathological response. To this end, neoadjuvant treatment seems to be safe and may improve surgical procedures and thus morbidity and mortality. It also aims to reduce the risk of disease recurrence in patients with resectable NSCLC. Early molecular testing should be included in current guidelines and novel biomarkers, such as ctDNA, may help to distinguish responders from non-responders to neoadjuvant treatment. Most importantly, in the era of perioperative strategies, a multidisciplinary approach among involved specialists is needed. There is a high unmet need to further investigate the role of neoadjuvant and/or perioperative targeted therapy in early-stage NSCLC.

Conclusions

Results from ongoing clinical trials suggest that neoadjuvant targeted therapies might be effective and improve outcomes in patients with EGFR-mutant and ALK-positive resectable NSCLC. Ongoing trials will provide further evidence on the safety and efficacy of the perioperative use of TKIs in patients with resectable NSCLC. To date, it remains unclear, which treatment regimen (adjuvant, neoadjuvant and/or perioperative) is the best to reduce the risk of tumour recurrence. To improve treatment strategies, patient survival and outcomes, molecular testing should be routinely incorporated in non-metastatic NSCLC.

Acknowledgments

Funding: None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-359/rc

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Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-359/coif). M.K. received support for attending meetings and/or travel as well as research grants from Deutsche Forschungsgemeinschaft (DFG), Pierre Fabre, Amgen, AstraZeneca, Daiichi Sankyo, Janssen-Cilag, Novartis, Roche Pharma, Takeda Pharma. G.L. received grants or contracts from Roche, Gilead, Janssen, Bayer, Celgene, Novartis, AstraZeneca, MorphoSys; received consulting fees from Roche, Gilead, Janssen, Bayer, Celgene, Novartis, AstraZeneca, Takeda, BMS, NanoString, AbbVie, Incyte, MorphoSys, Genmab, Karyopharm, Constellation, ADC, Miltenyi, PentixaPharm, Sobi, Immagene, Genase,Hexal/Sandoz, Lilly, BeiGene, MSD GmbH, Pierre Fabre Pharma GmbH; received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Roche, Janssen, Bayer, Celgene, Takeda, BMS, AbbVie, Incyte, MorphoSys, Sobi, Hexal/Sandoz; payment for expert testimony from Roche; support for attending meetings and/or travel from Janssen, AbbVie, BMS, and Roche; participated on a Data Safety Monitoring Board or Advisory Board from Roche, Gilead, Janssen, Bayer, Celgene, Novartis, AstraZeneca, Takeda, BMS, NanoString, AbbVie, Incyte, MorphoSys, Genmab, Karyopharm, Constellation, ADC, Miltenyi, PentixaPharm, Sobi, BMS Safety Monitoring Board; the author is the president of German Lymphoma Alliance and also in the board of directors GLA. A.B. received honoraria or travel grants not related to this manuscript from Bayer, BMS, Takeda, Onkowissen TV, MSD, Boehringer, AstraZeneca, Sanofi, Pfizer, Streamedup, Lilly, Art Tempi, Amgen, RG GmbH, Roche, Novartis, Digimed Verlag, Janssen, DGHO Juniorakademie, Ärztekammer, Pius Hospital Onsabrück, St. Johannes Hospital DO, WTZ, Daiichi, FOMF, Knappschaft-krankenhaus Bochum; participated on a Data Safety Monitoring Board or Advisory Board from Bayer, BMS, Takeda, Onkowissen TV, MSD, Boehringer, AstraZeneca, Sanofi, Pfizer, Streamedup, Lilly, Art Tempi, Amgen, RG GmbH, Roche, Novartis, Digimed Verlag, Janssen, Daiichi. G.E. received honoraria or travel grants not related to this manuscript from BMS, MSD, Pfizer, Bayer, AstraZeneca, Boehringer, Roche, Merck, Takeda, Novocure, Pierre Fabre, Janssen-Cilag, Lilly, Servier, Roche, Celgene, Actelion, CLS Behring, Fresenius, AOP Health, AMGEN, Daiichi-Sankyo. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and national research committees and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patient for publication of this article and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

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References

1. Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin 2021;71:209-49. [Crossref] [PubMed]
2. Douillard JY, Tribodet H, Aubert D, et al. Adjuvant cisplatin and vinorelbine for completely resected non-small cell lung cancer: subgroup analysis of the Lung Adjuvant Cisplatin Evaluation. J Thorac Oncol 2010;5:220-8. [Crossref] [PubMed]
3. Felip E, Altorki N, Zhou C, et al. Adjuvant atezolizumab after adjuvant chemotherapy in resected stage IB-IIIA non-small-cell lung cancer (IMpower010): a randomised, multicentre, open-label, phase 3 trial. Lancet 2021;398:1344-57. [Crossref] [PubMed]
4. O'Brien M, Paz-Ares L, Marreaud S, et al. Pembrolizumab versus placebo as adjuvant therapy for completely resected stage IB-IIIA non-small-cell lung cancer (PEARLS/KEYNOTE-091): an interim analysis of a randomised, triple-blind, phase 3 trial. Lancet Oncol 2022;23:1274-86. [Crossref] [PubMed]
5. Forde PM, Spicer J, Lu S, et al. Neoadjuvant Nivolumab plus Chemotherapy in Resectable Lung Cancer. N Engl J Med 2022;386:1973-85. [Crossref] [PubMed]
6. Wakelee H, Liberman M, Kato T, et al. Perioperative Pembrolizumab for Early-Stage Non-Small-Cell Lung Cancer. N Engl J Med 2023;389:491-503. [Crossref] [PubMed]
7. Cascone T, Awad MM, Spicer JD, et al. Perioperative Nivolumab in Resectable Lung Cancer. N Engl J Med 2024;390:1756-69. [Crossref] [PubMed]
8. Heymach JV, Harpole D, Mitsudomi T, et al. Perioperative Durvalumab for Resectable Non-Small-Cell Lung Cancer. N Engl J Med 2023;389:1672-84. [Crossref] [PubMed]
9. Tan AC, Tan DSW. Targeted Therapies for Lung Cancer Patients With Oncogenic Driver Molecular Alterations. J Clin Oncol 2022;40:611-25. [Crossref] [PubMed]
10. Peters S, Camidge DR, Shaw AT, et al. Alectinib versus Crizotinib in Untreated ALK-Positive Non-Small-Cell Lung Cancer. N Engl J Med 2017;377:829-38. [Crossref] [PubMed]
11. Camidge DR, Kim HR, Ahn MJ, et al. Brigatinib Versus Crizotinib in ALK Inhibitor-Naive Advanced ALK-Positive NSCLC: Final Results of Phase 3 ALTA-1L Trial. J Thorac Oncol 2021;16:2091-108. [Crossref] [PubMed]
12. Shaw AT, Bauer TM, de Marinis F, et al. First-Line Lorlatinib or Crizotinib in Advanced ALK-Positive Lung Cancer. N Engl J Med 2020;383:2018-29. [Crossref] [PubMed]
13. Ramalingam SS, Gray JE, Ohe Y, Cho BC, Vansteenkiste J, Zhou C, et al. Osimertinib vs comparator EGFR-TKI as first-line treatment for EGFRm advanced NSCLC (FLAURA): Final overall survival analysis. Ann Oncol 2019;30:v914-5.
14. Mok T, Camidge DR, Gadgeel SM, et al. Updated overall survival and final progression-free survival data for patients with treatment-naive advanced ALK-positive non-small-cell lung cancer in the ALEX study. Ann Oncol 2020;31:1056-64. [Crossref] [PubMed]
15. Wu YL, Tsuboi M, He J, et al. Osimertinib in Resected EGFR-Mutated Non-Small-Cell Lung Cancer. N Engl J Med 2020;383:1711-23. [Crossref] [PubMed]
16. Wu YL, Dziadziuszko R, Ahn JS, et al. Alectinib in Resected ALK-Positive Non-Small-Cell Lung Cancer. N Engl J Med 2024;390:1265-76. [Crossref] [PubMed]
17. Pignon JP, Tribodet H, Scagliotti GV, et al. Lung adjuvant cisplatin evaluation: a pooled analysis by the LACE Collaborative Group. J Clin Oncol 2008;26:3552-9. [Crossref] [PubMed]
18. NSCLC Meta-analysis Collaborative Group. Preoperative chemotherapy for non-small-cell lung cancer: a systematic review and meta-analysis of individual participant data. Lancet 2014;383:1561-71. [Crossref] [PubMed]
19. Felip E, Altorki N, Zhou C, et al. Overall survival with adjuvant atezolizumab after chemotherapy in resected stage II-IIIA non-small-cell lung cancer (IMpower010): a randomised, multicentre, open-label, phase III trial. Ann Oncol 2023;34:907-19. [Crossref] [PubMed]
20. Zhao Y, Wang W, Liang H, et al. The Optimal Treatment for Stage IIIA-N2 Non-Small Cell Lung Cancer: A Network Meta-Analysis. Ann Thorac Surg 2019;107:1866-75. [Crossref] [PubMed]
21. Cascone T, Kar G, Spicer JD, et al. Neoadjuvant Durvalumab Alone or Combined with Novel Immuno-Oncology Agents in Resectable Lung Cancer: The Phase II NeoCOAST Platform Trial. Cancer Discov 2023;13:2394-411. [Crossref] [PubMed]
22. Lisberg A, Cummings A, Goldman JW, et al. A Phase II Study of Pembrolizumab in EGFR-Mutant, PD-L1+, Tyrosine Kinase Inhibitor Naïve Patients With Advanced NSCLC. J Thorac Oncol 2018;13:1138-45. [Crossref] [PubMed]
23. Hastings K, Yu HA, Wei W, et al. EGFR mutation subtypes and response to immune checkpoint blockade treatment in non-small-cell lung cancer. Ann Oncol 2019;30:1311-20. [Crossref] [PubMed]
24. Mazieres J, Drilon A, Lusque A, et al. Immune checkpoint inhibitors for patients with advanced lung cancer and oncogenic driver alterations: results from the IMMUNOTARGET registry. Ann Oncol 2019;30:1321-8. [Crossref] [PubMed]
25. Garassino MC, Cho BC, Kim JH, et al. Durvalumab as third-line or later treatment for advanced non-small-cell lung cancer (ATLANTIC): an open-label, single-arm, phase 2 study. Lancet Oncol 2018;19:521-36. [Crossref] [PubMed]
26. Gainor JF, Shaw AT, Sequist LV, et al. EGFR Mutations and ALK Rearrangements Are Associated with Low Response Rates to PD-1 Pathway Blockade in Non-Small Cell Lung Cancer: A Retrospective Analysis. Clin Cancer Res 2016;22:4585-93. [Crossref] [PubMed]
27. Lee CK, Man J, Lord S, et al. Clinical and Molecular Characteristics Associated With Survival Among Patients Treated With Checkpoint Inhibitors for Advanced Non-Small Cell Lung Carcinoma: A Systematic Review and Meta-analysis. JAMA Oncol 2018;4:210-6. [Crossref] [PubMed]
28. Pennell NA, Neal JW, Chaft JE, et al. SELECT: A Phase II Trial of Adjuvant Erlotinib in Patients With Resected Epidermal Growth Factor Receptor-Mutant Non-Small-Cell Lung Cancer. J Clin Oncol 2019;37:97-104. [Crossref] [PubMed]
29. Yue D, Xu S, Wang Q, et al. Erlotinib versus vinorelbine plus cisplatin as adjuvant therapy in Chinese patients with stage IIIA EGFR mutation-positive non-small-cell lung cancer (EVAN): a randomised, open-label, phase 2 trial. Lancet Respir Med 2018;6:863-73. [Crossref] [PubMed]
30. Zhong WZ, Wang Q, Mao WM, et al. Gefitinib Versus Vinorelbine Plus Cisplatin as Adjuvant Treatment for Stage II-IIIA (N1-N2) EGFR-Mutant NSCLC: Final Overall Survival Analysis of CTONG1104 Phase III Trial. J Clin Oncol 2021;39:713-22. [Crossref] [PubMed]
31. Zhong WZ, Wang Q, Mao WM, et al. Gefitinib versus vinorelbine plus cisplatin as adjuvant treatment for stage II-IIIA (N1-N2) EGFR-mutant NSCLC (ADJUVANT/CTONG1104): a randomised, open-label, phase 3 study. Lancet Oncol 2018;19:139-48. [Crossref] [PubMed]
32. Tada H, Mitsudomi T, Misumi T, et al. Randomized Phase III Study of Gefitinib Versus Cisplatin Plus Vinorelbine for Patients With Resected Stage II-IIIA Non-Small-Cell Lung Cancer With EGFR Mutation (IMPACT). J Clin Oncol 2022;40:231-41. [Crossref] [PubMed]
33. Ramalingam SS, Vansteenkiste J, Planchard D, et al. Overall Survival with Osimertinib in Untreated, EGFR-Mutated Advanced NSCLC. N Engl J Med 2020;382:41-50. [Crossref] [PubMed]
34. Liu J, Amini A, Govindarajan A, et al. Targeted Therapies in Early-Stage Resectable Non-Small-Cell Lung Cancer: New Kids on the Block. JCO Precis Oncol 2023;7:e2200445. [Crossref] [PubMed]
35. Lu S, Kato T, Dong X, et al. Osimertinib after Chemoradiotherapy in Stage III EGFR-Mutated NSCLC. N Engl J Med 2024;391:585-97. [Crossref] [PubMed]
36. Zhong WZ, Chen KN, Chen C, et al. Erlotinib Versus Gemcitabine Plus Cisplatin as Neoadjuvant Treatment of Stage IIIA-N2 EGFR-Mutant Non-Small-Cell Lung Cancer (EMERGING-CTONG 1103): A Randomized Phase II Study. J Clin Oncol 2019;37:2235-45. [Crossref] [PubMed]
37. Zhang Y, Fu F, Hu H, et al. Gefitinib as neoadjuvant therapy for resectable stage II-IIIA non-small cell lung cancer: A phase II study. J Thorac Cardiovasc Surg 2021;161:434-442.e2. [Crossref] [PubMed]
38. Xiong L, Li R, Sun J, et al. Erlotinib as Neoadjuvant Therapy in Stage IIIA (N2) EGFR Mutation-Positive Non-Small Cell Lung Cancer: A Prospective, Single-Arm, Phase II Study. Oncologist 2019;24:157-e64. [Crossref] [PubMed]
39. Zhong WZ, Yan HH, Chen KN, et al. Erlotinib versus gemcitabine plus cisplatin as neoadjuvant treatment of stage IIIA-N2 EGFR-mutant non-small-cell lung cancer: final overall survival analysis of the EMERGING-CTONG 1103 randomised phase II trial. Signal Transduct Target Ther 2023;8:76. [Crossref] [PubMed]
40. Chang AEB, Piper-Vallillo AJ, Mak RH, et al. The ASCENT Trial: a phase 2 study of induction and consolidation afatinib and chemoradiation with or without surgery in stage III EGFR-mutant NSCLC. Oncologist 2024;29:609-18. [Crossref] [PubMed]
41. Lv C, Fang W, Wu N, et al. Osimertinib as neoadjuvant therapy in patients with EGFR-mutant resectable stage II-IIIB lung adenocarcinoma (NEOS): A multicenter, single-arm, open-label phase 2b trial. Lung Cancer 2023;178:151-6. [Crossref] [PubMed]
42. Aredo JV, Urisman A, Gubens MA, et al. Phase II trial of neoadjuvant osimertinib for surgically resectable EGFR-mutated non-small cell lung cancer. J Clin Oncol 2023;41:8508.
43. Leng X, Tang J, Wang S, et al. P03.02 Osimertinib as Neoadjuvant Therapy for Resectable EGFR Mutant Non-small Cell Lung Cancer: A Real-World Multicenter Retrospective Study. J Thorac Oncol 2021;16:S979.
44. Hu Y, Ren S, Yang L, et al. Osimertinib as Neoadjuvant Therapy for Resectable Non-Small Cell Lung Cancer: A Case Series. Front Pharmacol 2022;13:912153. [Crossref] [PubMed]
45. Liu W, Ren S, Xiao Y, et al. Neoadjuvant targeted therapy for resectable EGFR-mutant non-small cell lung cancer: Current status and future considerations. Front Pharmacol 2022;13:1036334. [Crossref] [PubMed]
46. Remon J, Saw SPL, Cortiula F, et al. Perioperative Treatment Strategies in EGFR-Mutant Early-Stage NSCLC: Current Evidence and Future Challenges. J Thorac Oncol 2024;19:199-215. [Crossref] [PubMed]
47. Planchard D, Jänne PA, Cheng Y, et al. Osimertinib with or without Chemotherapy in EGFR-Mutated Advanced NSCLC. N Engl J Med 2023;389:1935-48. [Crossref] [PubMed]
48. Acker F, Aguinarte L, Althoff F, et al. Study Design and Rationale for the PACE-LUNG Trial: A Multicenter, Single-Arm, Phase II Clinical Trial Evaluating the Efficacy of Additional Chemotherapy for Patients with EGFRm NSCLC with the Continued Presence of Plasma ctDNA EGFRm at Week 3 After Start of Osimertinib First-Line Treatment. Clin Lung Cancer 2022;23:e473-7. [Crossref] [PubMed]
49. Tsuboi M, Weder W, Escriu C, et al. Neoadjuvant osimertinib with/without chemotherapy versus chemotherapy alone for EGFR-mutated resectable non-small-cell lung cancer: NeoADAURA. Future Oncol 2021;17:4045-55. [Crossref] [PubMed]
50. Grant C, Nagasaka M. Neoadjuvant EGFR-TKI therapy in Non-Small cell lung cancer. Cancer Treat Rev 2024;126:102724. [Crossref] [PubMed]
51. Zhang C, Yan LX, Jiang BY, et al. Feasibility and Safety of Neoadjuvant Alectinib in a Patient With ALK-Positive Locally Advanced NSCLC. J Thorac Oncol 2020;15:e95-9. [Crossref] [PubMed]
52. Shi L, Gao S, Tong L, et al. Pathological complete response to long-course neoadjuvant alectinib in lung adenocarcinoma with EML4-ALK rearrangement: report of two cases and systematic review of case reports. Front Oncol 2023;13:1120511. [Crossref] [PubMed]
53. Zhang C, Li SL, Nie Q, et al. Neoadjuvant Crizotinib in Resectable Locally Advanced Non-Small Cell Lung Cancer with ALK Rearrangement. J Thorac Oncol 2019;14:726-31. [Crossref] [PubMed]
54. Zenke Y, Yoh K, Sakakibara-Konishi J, et al. P1.18-04 Neoadjuvant Ceritinib for Locally Advanced Non-Small Cell Lung Cancer with ALK Rearrangement: SAKULA Trial. J Thorac Oncol 2019;14:S626-7.
55. Chen MF, Chaft JE. Early-stage anaplastic lymphoma kinase (ALK)-positive lung cancer: a narrative review. Transl Lung Cancer Res 2023;12:337-45. [Crossref] [PubMed]
56. Jeon Y, Park S, Jung HA, et al. First-Line Alectinib vs. Brigatinib in Advanced Non-Small Cell Lung Cancer with ALK Rearrangement: Real-World Data. Cancer Res Treat 2024;56:61-9. [Crossref] [PubMed]
57. Yang JC, Liu G, Lu S, et al. Brigatinib Versus Alectinib in ALK-Positive NSCLC After Disease Progression on Crizotinib: Results of Phase 3 ALTA-3 Trial. J Thorac Oncol 2023;18:1743-55. [Crossref] [PubMed]
58. de Scordilli M, Michelotti A, Bertoli E, et al. Targeted Therapy and Immunotherapy in Early-Stage Non-Small Cell Lung Cancer: Current Evidence and Ongoing Trials. Int J Mol Sci 2022;23:7222. [Crossref] [PubMed]
59. Parikh AB, Hammons L, Gomez JE. Neoadjuvant Tyrosine Kinase Inhibition in Locally-advanced Non-small Cell Lung Cancer: Two Cases and a Brief Literature Review. Anticancer Res 2019;39:897-902. [Crossref] [PubMed]
60. Wu Y, Verma V, Gay CM, et al. Neoadjuvant immunotherapy for advanced, resectable non-small cell lung cancer: A systematic review and meta-analysis. Cancer 2023;129:1969-85. [Crossref] [PubMed]
61. Marinelli D, Gallina FT, Pannunzio S, et al. Surgical and survival outcomes with perioperative or neoadjuvant immune-checkpoint inhibitors combined with platinum-based chemotherapy in resectable NSCLC: A systematic review and meta-analysis of randomised clinical trials. Crit Rev Oncol Hematol 2023;192:104190. [Crossref] [PubMed]
62. Lee JM, McNamee CJ, Toloza E, et al. Neoadjuvant Targeted Therapy in Resectable NSCLC: Current and Future Perspectives. J Thorac Oncol 2023;18:1458-77. [Crossref] [PubMed]
63. Sorin M, Huynh C, Rokah M, et al. Neoadjuvant Targeted Therapy in Non–Small Cell Lung Cancer and Its Impact on Surgical Outcomes. Ann Thorac Surg Short Rep 2023;1:102-6.
64. Lee JM, Kim AW, Marjanski T, et al. Important Surgical and Clinical End Points in Neoadjuvant Immunotherapy Trials in Resectable NSCLC. JTO Clin Res Rep 2021;2:100221. [Crossref] [PubMed]
65. Marjanski T, Dziedzic R, Kowalczyk A, et al. Safety of Surgery after Neoadjuvant Targeted Therapies in Non-Small Cell Lung Cancer: A Narrative Review. Int J Mol Sci 2021;22:12244. [Crossref] [PubMed]
66. Ewer MS, Tekumalla SH, Walding A, et al. Cardiac Safety of Osimertinib: A Review of Data. J Clin Oncol 2021;39:328-37. [Crossref] [PubMed]
67. Patel SR, Brown SN, Kubusek JE, et al. Osimertinib-Induced Cardiomyopathy. JACC Case Rep 2020;2:641-5. [Crossref] [PubMed]
68. Yi L, Fan J, Qian R, et al. Efficacy and safety of osimertinib in treating EGFR-mutated advanced NSCLC: A meta-analysis. Int J Cancer 2019;145:284-94. [Crossref] [PubMed]
69. Di Marino P, Chiapperino C, Primavera FC, et al. Pancytopenia During Osimertinib Treatment in a Patient with EGFR-Mutated Non-Small Cell Lung Cancer. Onco Targets Ther 2022;15:407-10. [Crossref] [PubMed]
70. Yuan D, Zhu F, Zuo R, et al. High incidence and reversible bradycardia events following alectinib initiation. Thorac Cancer 2023;14:479-88. [Crossref] [PubMed]
71. Pruis MA, Veerman GDM, Hassing HC, et al. Cardiac Toxicity of Alectinib in Patients With ALK+ Lung Cancer: Outcomes of Cardio-Oncology Follow-Up. JACC CardioOncol 2023;5:102-13. [Crossref] [PubMed]
72. Schoenfeld AJ, Arbour KC, Rizvi H, et al. Severe immune-related adverse events are common with sequential PD-(L)1 blockade and osimertinib. Ann Oncol 2019;30:839-44. [Crossref] [PubMed]
73. Lin JJ, Chin E, Yeap BY, et al. Increased Hepatotoxicity Associated with Sequential Immune Checkpoint Inhibitor and Crizotinib Therapy in Patients with Non-Small Cell Lung Cancer. J Thorac Oncol 2019;14:135-40. [Crossref] [PubMed]
74. Sepesi B, Jones DR, Meyers BF, et al. LCMC LEADER neoadjuvant screening trial: LCMC4 evaluation of actionable drivers in early-stage lung cancers. J Clin Oncol 2022;40:TPS8596.