A case report and literature review of a pathologic complete response to alectinib in ALK-positive stage IV non-small cell lung cancer

Abstract

Background

Stage IV non-small cell lung cancer is not a curative stage. However, a novel approach to local treatment of the primary tumor may improve progression-free survival. The choice between radiotherapy or surgery, as well as the optimal timing for these treatments remains to be determined. We report here the first case, to our knowledge, of a multi-metastatic patient treated with consolidative surgery after neoadjuvant alectinib, resulting in a complete pathological response.

Case Description

The patient was, as is typically observed in populations with oncogenic alterations such as anaplastic lymphoma kinase (ALK) rearrangements, a young and non-smoker; however, he was male. Bronchial endoscopy confirmed the diagnosis of bronchopulmonary adenocarcinoma with strong ALK expression demonstrated by immunohistochemistry. We initiated alectinib as first-line treatment for metastatic disease; however, due to the induced oligo-metastatic disease, a local treatment of the primary tumor was discussed during multidisciplinary board. Lobectomy was performed and histological examination confirmed the complete pathological response. Adjuvant alectinib was continued for unspecified duration due to the lack of available data.

Conclusions

This case suggests that local treatment, even in patients with stage IV disease, performed at the time of the best response to systemic therapy, may offer an improvement in progression free survival and perhaps a glimpse of a cure.

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Key findings

• First case of complete pathological response in a multimetastatic non-small cell lung cancer (NSCLC) after anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI).

What is known and what is new?

• TKI have improved survivals in stage IV NSCLC and neoadjuvant TKIs are currently evaluated in ongoing clinical trials.

• Consolidative treatment should be realized at the time of the best response to systemic treatment and these local treatments of the primary tumor may improve survival in metastatic patients; but surgery is more difficult after systemic therapy and we don’t have reliable marker for residual disease.

What is the implication, and what should change now?

• Consolidative local treatment may offer the possibility of a cure in metastatic settings.

• The role of circulating tumor DNA (ctDNA) to monitoring the time of the best response and the duration of adjuvant systemic treatment warrants further exploration.

Introduction

Although relatively rare, anaplastic lymphoma kinase (ALK) translocations are found in approximately five percent of non-squamous non-small cell lung cancer (NSCLC), more frequently in young patients and those who are light or non-smoker. Targeted therapies in NSCLC have considerably improved survival of patients with stage IV lung cancer and molecular alteration (1). Despite this improvement, relapse is inevitable and there is no possibility of a cure. Local treatment of the primary tumor, such as radiotherapy, or less frequently surgery, can be proposed to improve progression-free survival (PFS). Even if they are used in current practice, whether they should be applied upfront, at the time of the best response or at the time of progression, is not well determined.

We present here a case in which surgery was performed as consolidative treatment at the time of the best response following neoadjuvant alectinib in a patient with initially multi-metastatic disease. We present this case in accordance with the CARE reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-254/rc).

Case presentation

In March 2020, a 33-year-old man, non-smoker and without any notable medical history, was admitted to the Emergency Department of University Hospital of Caen due to chest pain. Analgesic treatment was initially prescribed but showed no improvement, so he returned to the Emergency Department four days later. Chest computed tomography (CT) revealed a 5-cm right parahilar mass with mediastinal lymph node enlargement and an ipsilateral moderate pleural effusion (Figure 1). The positron emission tomography (PET)-CT showed bilateral adrenal (Figure 2) and right supra-clavicular lymph node metastases. A bronchial endoscopy was performed and pathological examination confirmed a TTF1+ and p40− lung adenocarcinoma. Immunohistochemical test using the VENTANA anti-ALK D5F3 antibody showed strong expression of ALK protein. No other co-alterations were identified. The final diagnosis was clinical stage IV lung adenocarcinoma [cT3N3M1c according to the 8^th edition of the tumor-node-metastasis (TNM) classification] (2). Treatment with alectinib, 600 mg twice a day, was initiated on April 3, 2020.

Figure 1.

Right parahilar mass syndrome with multiple mediastinal lymphadenopathies, vascular sheathing and ipsilateral moderate pleural effusion observed on the parenchymal sections of the thoracic computed tomography scan from March 2020.

Figure 2.

Initial PET-CT in April 2020 showing bilateral adrenal metastases. CT, computed tomography; PET, positron emission tomography.

The first follow-up CT on May 19, 2020 demonstrated a good partial response in all metastatic sites, along with good tolerance of alectinib. Twenty months later, CT confirmed the persistence of this partial response. A new PET-CT showed a complete metabolic response in lymph node and adrenal glands (Figure 3A), with only residual uptake in the right upper lobar nodule (Figure 3B). In absence of secondary brain lesion on magnetic resonance imaging (MRI) and no respiratory contraindication, after discussion at our multidisciplinary board, right upper lobectomy was proposed and performed on September 12, 2022, 29 months after initiation of alectinib, without complications. Histological examination did not identify any residual tumor cells, thus classifying the tumor as ypT0N0R0, thus confirming the complete pathological response (Figure 4).

Figure 3.

Total regression of adrenal lesions (A) and partial response of the primary tumor (B) after 2 years of alectinib, in March 2022.

Figure 4.

Hematoxylin-eosin staining of the initial biopsy (original magnification, ×20) (A) and of the surgical specimen (original magnification, ×4) (C), as well as immunohistochemical test using anti-ALK antibody on the initial biopsy (original magnification, ×20) (B) and the postoperative tissue (original magnification, ×4) (D) show a pathological complete response in surgical specimen of September 2022. Moreover, histological examination demonstrates extensive stromal fibrosis with associated chronic inflammation and histiocytic reaction with no residual viable adenocarcinoma’s cells.

After multidisciplinary discussion and considering the initial metastatic stage, good treatment tolerance, the patient’s young age and his consent, adjuvant alectinib was proposed. Two years after the surgery, the treatment is still well tolerated, with no suspicious lesion on the brain, thoracic and abdominal CT scans.

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committees, and with the Helsinki Declaration and its subsequent amendments. Written informed consent was obtained from the patient for the 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

To our knowledge, this is the first case of a complete pathological response after neoadjuvant tyrosine kinase inhibitors (TKIs) in a patient with stage IV NSCLC and ALK rearrangement. According to our literature review, available in Table S1, 19 cases of complete pathological response have been reported, but only in patients with locally advanced disease. This strategy is currently being prospectively evaluated in ongoing clinical trials. In the ALNEO study, preliminary results confirmed the good tolerance of neoadjuvant alectinib in patients with surgically resectable stage III ALK-positive NSCLC, administered preoperatively during 8 weeks and during 96 weeks after surgery (3). More recently, Zhao et al.’s study confirms that ALK-targeted therapy is feasible and well tolerated as neoadjuvant treatment in resectable stage IIB to III with ALK fusion and may be the optimal choice for an induction strategy (4).

In patients with stage IV NSCLC, the question remains when the best time is to offer local treatment, and which treatment would be most appropriate. Historically, for patients with stage IV disease, local treatments were performed in cases of oligo-progressive disease, when secondary resistance to TKI develops, which occurs in approximately 95% of cases (5) or upfront when the initial stage of diagnosis indicates oligo-metastatic disease, in combination with systemic treatment. More recently, local treatments have been proposed at the time of the best response to systemic therapy, which corresponds to what might be called consolidative treatments. Serial CT scans during TKI treatment allow the determination of the best response time. Nishino et al.’s study showed that the median time to achieve the best response in patients treated with alectinib as first-line therapy was approximately 21 months (95% confidence interval: 9 to not reached) (6). The BRIGHTSTAR phase II trial evaluated the feasibility and safety of local treatments in 32 multi- or oligo-metastatic patients after 8 weeks of brigatinib treatment. According to this study, performing early surgery and/or radiotherapy improves disease control, which could extend PFS and overall survival (OS), two secondary objectives of the future phase III study (5).

The second point concerns the type of local treatment to offer. Radiotherapy is the preferred option because it can be used without invasive procedure. Nevertheless, only surgery allows for histopathological evaluation of the primary tumor. In our patient, this consolidative treatment was proposed with the hypothesis of persistent cells in the tumor, suggested by the residual uptake of the pulmonary nodule in the right upper lobe (7). Currently, the use of PET-CT to detect residual tumor cells carries the possibility of false positives, as seen in our case, where the anatomopathological examination of the residual metabolic uptake tissues revealed only granuloma. This raises the issue of surgery, particularly lung surgery, which is not without morbidity. Some studies have noted increased surgical time and intraoperative complications, with more difficult tissue dissection and vascular risks, after neoadjuvant TKI (8-10).

The next point to discuss is the duration of postoperative treatment with TKI. Adjuvant treatments aim to reduce the risk of recurrence, in the hypothesis of persistent disease at a micro-metastatic stage, currently undetectable by imaging techniques. The phase III ALINA trial showed a significant improvement in disease-free survival (DFS) and a reduction in brain recurrence for resected NSCLCs positive for ALK rearrangement with adjuvant alectinib for 2 years, compared to four cycles of chemotherapy (11). In ongoing trials for patients with locally advanced disease, alectinib and brigatinib are being tested for 3 years after chemo-radiotherapy, compared to durvalumab for 1 year in the HORIZON-01 (NCT05170204) (12) and BOUNCE (NCT05718297) (13) trial respectively. This suggests that, in our patient with stage IV disease, TKI should be pursued for at least 3 years. The challenge now is to identify a biomarker of disease persistence or recurrence after local ablative treatment to monitoring the duration of adjuvant treatment. According to several studies, circulating tumor DNA (ctDNA) could be an interesting predictive marker in these situations, potentially better than Response Evaluation Criteria in Solid Tumors (RECIST)-based radiological evaluation (14-16). Additionally, for metastatic patients with detectable ctDNA, it can be assumed that TKI should not be stopped as long as ctDNA remains detectable. We did not use ctDNA in our patient’s case as the initial plasma level was not available. However, further research is needed to better characterize patients most likely to achieve complete responses.

Conclusions

To our knowledge, this is the first case of ALK-positive stage IV lung cancer achieving a complete response with ALK TKI. Despite the many questions this raises, particularly regarding the role of complementary local treatments and the duration of systemic therapies, this case gives us a glimpse of the possibility of a cure in situations where, until now, treatments have had only a palliative intent. The challenge is to identify predictive markers in metastatic patients who are likely to achieve complete responses after TKI.

Supplementary

The article’s supplementary files as

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 committees, and with the Helsinki Declaration and its subsequent amendments. Written informed consent was obtained from the patient for the 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.