Pathological complete response to neoadjuvant lorlatinib in a patient with stage IIIA ALK-positive non-small cell lung cancer: a case report

Introduction

Lung cancer is the leading cause of cancer-related deaths globally. According to GLOBOCAN projections for 2022, the global incidence of lung cancer is approximately 2.5 million, representing 12.4% of all cancer cases, with an estimated 1.8 million deaths, representing 18.7% of all cancer-related deaths. The 5-year survival rate for lung cancer tends to be below 20% in most countries, and non-small cell lung cancer (NSCLC) is the most common type of lung cancer, accounting for approximately 85% of all lung cancers (1). Surgery is conventionally considered the primary therapeutic option for resectable NSCLC. Unfortunately, delayed diagnosis can sometimes preclude timely surgical intervention.

Neoadjuvant therapy offers an avenue for tumor downstaging and widening the scope for surgical resection by providing systemic treatment before definitive resection. Neoadjuvant chemotherapy has improved 5-year recurrence-free survival rate in patients with surgically locally advanced NSCLC by 5%. Thus, there is a need for additional treatments that reduce disease recurrence, prolong survival, and increase cure rates in patients with resectable NSCLC. The utilization of neoadjuvant treatment for resectable NSCLC offers several potential advantages, including the following: neoadjuvant therapy is generally better tolerated compared to adjuvant therapy; it allows for earlier management of micrometastatic disease; it may lead to less extensive surgical resection (lung-sparing surgery) and higher rates of complete resection (R0). Additionally, an expected advantage is the improved adherence to neoadjuvant treatment as opposed to adjuvant treatment. Given the promising results of targeted therapies in advanced NSCLC patients harboring oncogenic drivers, the question arises as to whether the well-established findings of targeted therapies in advanced NSCLC can be applied to neoadjuvant therapies.

The anaplastic lymphoma kinase (ALK) gene fusion is present in approximately 4–6% of lung adenocarcinomas, making these tumors susceptible to ALK tyrosine kinase inhibitors (TKIs) (2). Neoadjuvant use of ALK-TKIs in resectable ALK-positive NSCLC has not received Food and Drug Administration (FDA) approval, and data from large, randomized trial results are currently unavailable. Investigating the use of ALK-TKIs, such as lorlatinib, in the perioperative management of ALK fusion NSCLC is compelling. Lorlatinib, a third-generation ALK-TKI, exhibits strong efficacy and brain penetration, especially against a range of resistance mutations observed during crizotinib and second-generation ALK-TKI treatments. However, there have been limited reports regarding lorlatinib as neoadjuvant treatment. Here, we present the case of stage IIIA ALK-positive adenocarcinoma harboring ALK rearrangements showing a pathological complete response (pCR) after neoadjuvant lorlatinib treatment. We present this case in accordance with the CARE reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-112/rc).

Case presentation

A 35-year-old man without any symptoms was found to have pulmonary nodules during routine health assessment 2 years ago, and pulmonary nodules were enlarged progressively with follow-up. The patient had smoked about 1 pack of cigarettes per day for 15 years and had no family history of hereditary disease or cancer. A computed tomography (CT) scan (on February 15, 2023) revealed a 4.6 cm × 2.8 cm soft tissue mass in the left inferior lobe with obstructive changes (Figure 1A). Positron emission tomography-CT (PET-CT) scan indicated high 18-fluorodeoxyglucose (FDG) uptake in left inferior lobe mass [4.94 cm × 3.47 cm; standardized uptake value (SUV), 13.8] (Figure 1A), left hilar (stations 4L), and mediastinal lymph nodes (stations 7 and 8) (Figure 1B), strongly suggesting malignant disease and lymph nodes (stations 4L, 7, and 8) metastasis with no signs of distant metastasis.

Figure 1 Imaging evaluation during neoadjuvant treatments. (A) CT and PET-CT at baseline showed a mass located in the left inferior lobe. The tumor continuously shrunk during lorlatinib treatment. (B) Imaging evaluation of lymph nodes during neoadjuvant treatments. PET-CT at baseline was highly indicative of malignant disease and lymph nodes (stations 4L, 7, and 8) metastasis. CT showed that the lymph nodes shrunk obviously after 12-week neoadjuvant targeted therapy with lorlatinib. LN, lymph node; CT, computed tomography; PET, positron emission tomography.

An endobronchial ultrasound-guided transbronchial lung biopsy (EBUS-TBLB) of the left lung mass was performed. Pathological analysis showed adenocarcinoma (Figure 2A). Immunohistochemistry revealed positive staining for Napsin A, cytokeratin (CK), thyroid transcription factor-1 (TTF-1), and ALK (Figure 2B-2E). A panel of 68 lung cancer-related genes was performed using next-generation sequencing on a NextSeg 500 (Illumina, Inc., Madison, WI, USA) and showed echinoderm microtubule-associated protein-like 4 (EML4)-ALK gene fusion (Figure 2F). The patient was diagnosed with clinical stage IIIA [8^th American Joint Committee on Cancer (AJCC): cT2bN2M0] and pulmonary adenocarcinoma with left hilar and mediastinal lymph nodes metastasis.

Figure 2 Pathologic findings of this patient. (A) EBUS-TBLB biopsy of the mass before treatment showed pulmonary adenocarcinoma (HE, ×100). (B-E) Immunohistochemical testing results confirmed positivity of Napsin A, CK, TTF-1, and ALK (HE, ×100). (F) Next-generation sequencing test revealed EML4-ALK fusion. (G) No tumor cells remain in the tumor bed after treatment (HE, ×4). (H) The tumor bed is adjacent to the hilar or parabronchial area, with accompanying large blood vessels and nerve bundles (HE, ×40). (I,J) Fibrotic hyperplasia and chronic inflammatory cell infiltration in the tumor bed (HE, ×100). (K) Foam-like histiocytes and multinucleated giant cell reaction are seen in the tumor bed (HE, ×100). HE, hematoxylin and eosin; CK, cytokeratin; TTF-1, thyroid transcription factor-1; ALK, anaplastic lymphoma kinase; EML4, echinoderm microtubule-associated protein-like 4; EBUS-TBLB, endobronchial ultrasound-guided transbronchial lung biopsy.

Following the multi-disciplinary team (MDT), the tumor was deemed potentially resectable. Neoadjuvant therapy with lorlatinib (100 mg daily) was administered from March 7, 2023, to June 28, 2023, to induce tumor downstaging and prepare for surgery. The patient did not experience any adverse reactions to lorlatinib prior to surgery. Post-treatment contrast-enhanced CT scans on April 6, 2023 (after 4 weeks of lorlatinib treatment), and May 29, 2023 (after 12 weeks of lorlatinib treatment), showed significant reductions in the left inferior lobe lesion to 2.8 cm × 1.5 cm and 1.8 cm × 1.0 cm, respectively, indicating a partial response (PR) (Figure 1A).

The patient underwent left inferior lobectomy with mediastinal lymph node dissection (MLD) and mediastinal cyst resection in video-assisted thoracoscopic surgery (VATS) (on July 13, 2023) after neoadjuvant targeted therapy. The resected residual lesion measured 2 cm × 1 cm × 1 cm with lymph nodes (stations 5, 6, 7, 9, 10, and 11 lymph nodes) involvement. Notably, no tumor cells were found in the entire tumor bed examined and in all resected lymph nodes in the postoperative pathological examination, according to the International Association for the Study of Lung Cancer (IASLC) criteria which suggest a pCR (Figure 2G-2K). After surgery, this patient continued to receive lorlatinib (100 mg daily) and remained disease free at his 10-month follow-up. Based on the dosing duration from the ADAURA trial (3) of the epidermal growth factor receptor (EGFR) TKI osimertinib, we plan to keep the patient on lorlatinib (100 mg daily) as adjuvant therapy for 3 years after surgery. The timeline therapy administration from the episode of care is shown in Figure 3.

Figure 3 Timeline of diagnosis and treatment. ALK, anaplastic lymphoma kinase; NSCLC, non-small cell lung cancer; CT, computed tomography; PR, partial response; MLD, mediastinal lymph node dissection; pCR, pathological complete response.

Patient began experiencing adverse effects of lorlatinib treatment therapy in August 2023 (about 6 months postdose). Weight gain grade 3 and hyperlipidemia grade 3, which was reduced to grade 2 after lipid-lowering therapy with ezetimibe (10 mg, daily), fenofibrate (200 mg, daily) treatment. Sinus tachycardia, which has normalized after treatment with metoprolol (47.5 mg, daily). Depending on the adverse effects of the drug, the patient may continue adjuvant therapy with lorlatinib. We will again advise the patient to take care of dietary control and increase physical activity.

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

Discussion

Most NSCLC patients diagnosed with stage III disease have lost the opportunity for radical resection at the time of initial diagnosis. However, neoadjuvant therapy creates the possibility of radical tumor resection in patients with locally advanced NSCLC and offers a “window of opportunity” for the treatment of malignant tumors. CheckMate 816 (4) demonstrates that neoadjuvant treatment with immunotherapy and chemotherapy significantly improves outcomes in NSCLC. The median event-free survival was 31.6 months with nivolumab plus chemotherapy and 20.8 months with chemotherapy alone. The percentage of patients with a pCR was 24.0% and 2.2%, respectively. Moreover, in stage IIIA patients, PCR rates were 23% and 0.9%, respectively. However, EGFR mutation-positive cases and ALK fusion-positive cases were excluded from this trial. Neoadjuvant targeted therapy is a novel emerging therapy that can target oncogenic mutations and rearrangements. The presented case highlights the significant potential of third-generation ALK-TKI, lorlatinib, in the neoadjuvant setting to achieve a pathologic complete response.

Most research on neoadjuvant-targeted therapies has focused on patients with EGFR-positive NSCLC. There is limited data on the efficacy of ALK-TKIs in ALK-positive NSCLC (5). To date, these limited cases suggest the potential value of achieving either PR or pCR with neoadjuvant ALK-TKIs therapy, but most have focused on first- and second-generation ALK-TKIs (alectinib, crizotinib, or ceritinib). At the World Lung Cancer Congress (WCLC) in 2023, data from the neoadjuvant alectinib cohort of ALK-positive NSCLC in the NAUTIKA1 trial (6) were presented, in which nine eligible patients completed neoadjuvant alectinib treatment, six patients achieved major PR (MPR), and three patients achieved pCR. Zhao et al. (7) reported 11 patients with clinical stage IIB–IIIB NSCLC and ALK fusion mutation who received neoadjuvant therapy with crizotinib. Pre-operative radiologic evaluation showed that 9 patients (72.7%) achieved partial regression, while two patients remained stable disease (SD). All patients underwent successful surgery. According to pathological assessment, one patient achieved pCR and two patients achieved MPR. Yan et al. (8) also highlighted the efficacy of neoadjuvant ALK-TKIs in stage IIA–IIIB ALK-positive NSCLC, 23 (of 24) patients had R0 resections and one patient had R1 resection.

Lorlatinib has a unique structure as a macrocyclic compound designed to effectively penetrate the blood-brain barrier. It exhibits higher potency against wild-type ALK and broader coverage of ALK resistance mutations compared to first- and second-generation ALK inhibitors (9). Moreover, moving the most potent ALK inhibitor to first line may suppress or delay the emergence of on-target resistance and prolong the duration of response (2). Lorlatinib’s potent antitumor activity has prompted us to consider its application for neoadjuvant therapy. In the case study presented, the patient’s initial diagnosis was stage IIIA locally advanced NSCLC, which complicated the prospect of a radical resection. Through neoadjuvant therapy with third-generation ALK-TKI lorlatinib for 3 months, the patient could achieve partial regression before surgery, and achieved pCR through postoperative evaluation. Based on this patient’s very excellent response to lorlatinib and the safety and convenience of adjuvant targeted therapy over adjuvant chemotherapy, we plan to use lorlatinib (100 mg daily) for 3 years of adjuvant therapy. The present case is a meaningful attempt of a third generation ALK-TKI lorlatinib as neoadjuvant therapy in ALK-positive NSCLC patients, and provides a new path for preoperative neoadjuvant therapy for patients harboring ALK mutation.

Surgical resection in patients with oncogenic drivers advanced NSCLC may be more viable after neoadjuvant targeted therapy compared to chemotherapy or radiotherapy. However, identifying patients who would benefit from neoadjuvant target therapy, and determining optimal dosages and durations remain a challenge. However, as the number of cases treated with neoadjuvant ALK-TKIs is currently limited, additional research is needed to further develop these treatment modalities and improve patient prognosis.

Conclusions

This is the case report of a patient with stage IIIA ALK-positive NSCLC who achieved pCR after neoadjuvant lorlatinib therapy. It highlights the feasibility of lorlatinib as neoadjuvant treatment for resectable ALK-positive NSCLC. Further clinical trials focused on neoadjuvant targeted therapies in locally advanced NSCLC are expected to provide further evidence and clarify the optimal regimens.

Acknowledgments

Funding: This work was supported by the National Natural Science Foundation of China (No. 82072564), the Program of Shanghai Academic Research Leader (No. 22XD142280), and the Shanghai Municipal Health Commission (No. 2022XD029).

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-112/rc

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-112/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-112/coif). Z.L. serves as an unpaid editorial board member of Translational Lung Cancer Research from January 2024 to December 2025. 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/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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