Pathologic complete response to pralsetinib in stage IV RET-positive non-small cell lung cancer: A case report

Abstract

Neoadjuvant therapy with tyrosine kinase inhibitors has been proposed as a feasible approach for downstaging potential resectable non-small cell lung cancer (NSCLC). Pralsetinib is a paradigm of precision medicine for cancers driven by mutant RET (rearranged during transfection). In this case, we reported dramatic response to Pralsetinib in a stage IV NSCLC patient with RET rearrangement. Strikingly, treatment with 10 months of Pralsetinib impended downstaging of the N2 lymph node and metastatic pleural disease. Histological examination of the surgically resected specimen indicated a pathologic complete response (pCR). The patient was recommended to continue Pralsetinib as an adjuvant therapy. This case highlighted potential application of Pralsetinib in locally advanced RET-positive NSCLC to prime surgical resection. Postoperative Pralsetinib adjuvant therapy should also be considered.

1. Introduction

Pralsetinib is a selective RET inhibitor that showed substantial tumor suppressive potency in RET-positive non-small cell lung cancer (NSCLC) [1]. Herein, we reported a dramatic response to Pralsetinib in a stage IV patient with RET-positive NSCLC. Downstaging of locally metastatic disease was achieved after 10 months of Pralsetinib treatment. The patient underwent surgical resection and histological analysis showed a pathologic compete response (pCR) of the tumor. We discussed the treatment and reviewed relevant literatures.

2. Case presentation

A 66-year-old female, never smoker, without remarkable past medical history, admitted to our institution with complains of shortness of breath in October 2022. The patient also reported productive cough without fever and chill. At admission, the patient had an Eastern Cooperative Oncology Group (ECOG) performance status of 1. On physical examination, her saturation was 88 % on ambient air and percussion on the left chest revealed dullness in the lower lung fields. The contrast enhanced chest computed tomography (CT) revealed a 35 × 30 mm mass located in the left upper lung with enlarged mediastinal and hilar lymph nodes. Massive pleural fluid was found on the left side and thoracocentesis was performed to drain the fluid (Fig. 1A). Cytological examination revealed malignant cells, indicating tumor progression involving pleura (Fig. 1B). Positron emission tomography CT (PET-CT) examination demonstrated increased 18F-FDG uptake of the left upper lung mass with a SUVmax of 15.49. The PET-CT scan also indicated intensive 18F-FDG hypermetabolism in the left pleura nodules (SUVmax = 12.03) and left mediastinal and hilar lymph nodes (SUVmax = 9.66) (Fig. 2A). The biopsy was taken from the lung mass to confirm poorly differentiated adenocarcinoma with a strong positive staining for CK7 (3+), TTF-1 (3+) and Ki67 (70 %) (Fig. 1C). The tumor cells were negative for programmed death ligand-1 (PD-L1). The lung biopsy tissue and pleural effusion were analyzed for genetic alterations by dual DNA- and RNA-based next-generation sequencing (NGS) consisting of 654 cancer related genes (Berry Oncology Inc., Supplementary Table S1), and result showed the presence of KIF5B-RET rearrangement in both samples. Concurrent genetic aberrance was a missense mutation in TP53 (Supplementary Table S2). The NGS testing also revealed a tumor mutation burden (TMB) of 1.25 Muts/Mb. Based on these findings, the patient was diagnosed stage IV (T2aN2M1a) lung adenocarcinoma with a RET rearrangement. The patient started on Pralsetinib treatment with the recommended dosage of 400 mg once daily.

Fig. 1.

The clinicopathologic features of the patient. (A) Contrast enhanced chest CT scan showed a solid mass with pleura traction in the left upper lung. Massive pleural fluid and collapse of left lower lung were noticed. (B) Cytological examination of the pleural effusion revealed malignant cells. (C) Representative HE and IHC images of CK7, TTF-1 and Ki67 ( × 200 magnification). Scale bar = 100 μm.

Fig. 2.

Representative images of PET-CT and chest CT examination. (A) Baseline PET-CT scan showed significant 18F-FDG uptake of the left upper lung mass (SUVmax = 15.49), pleura nodules (SUVmax = 12.03) and left mediastinal and hilar lymph nodes (SUVmax = 9.66). After 10 months of Pralsetinib treatment, a repeated PET-CT revealed a slight increase in 18F-FDG uptake of the primary tumor (SUVmax = 1.37). The 18F-FDG metabolic activity was not detected in the pleura and lymph node. (B) Chest CT examination of the tumor after Pralsetinib targeted therapy. The red circle indicated metastatic pleural disease.

After 2 months of indicated treatment, the patient experienced decreased exercise tolerance and blood testing showed grade 2 leukopenia. Chest CT imaging revealed a reduction in tumor volume to 17 × 12 mm and her pleural effusion disappeared. The metastatic pleural nodules were comparable to the initial findings (Fig. 2B). Thus, a partial response (PR) was achieved according to the Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1) criteria. Since the patient experienced treatment-related adverse events, the dosage of Pralsetinib was gradually reduced to 200 mg once daily since December 2022.

The patient continued to benefit from Pralsetinib therapy in our subsequent follow-ups (Fig. 2B). Surprisingly, the metastatic nodules in the pleura were not visible in chest CT after 7 months of targeted therapy. We thought to anticipate that Pralsetinib treatment not only reduced the size of primary tumor, it also led to disease remission of pleural nodules and metastatic N2 lymph nodes. If this is true, downstaging of the stage IV NSCLC may be achieved and surgical resection could be considered. To confirm this hypothesis, a PET-CT examination was performed in August 2023, and it showed a significant reduction in SUVmax value of the primary tumor (SUVmax = 1.37). Intriguingly, 18F-FDG uptake was not detected in the left pleura and N2 lymph nodes (Fig. 2A). The multi-disciplinary broad involving pulmonologist, oncologist, radiologist and thoracic surgeon held a comprehensive discussion and yielded a conclusion that the downstaging of locally advanced disease was achieved by Pralsetinib, thus, radical resection of the primary tumor could be considered. In September 2023, the patient underwent surgical resection of the left upper apical and posterior (LS1+2) segments (Fig. 3A), together with dissection of pleural nodules and lymph nodes. Severe adhesions were noted intraoperatively (Fig. 3B). The postoperative pathologic results showed no residual and viable tumor cells in the primary tumor site and in the resected pleural nodules. Instead, fibrosclerotic manifestation and lymphocytes infiltration were noticed (Fig. 3C). Four lymph nodes in levels 5–6, and three lymph nodes in levels 10–14 were all negative for tumor cells. The complete pathologic response (pCR), defined as no residual viable tumor cells in resected lung specimen, sampled lymph nodes and pleural nodules after surgery, was gained. The patient continued Pralsetinib 200 mg once daily as postoperative adjuvant therapy.

Fig. 3.

Surgical resection of the tumor and metastatic pleura nodules and lymph nodes. (A) The gross specimen of resected lung. Carbon deposition in the lung surface was noted. The red circle indicated the primary lesion site. (B) Severe adhesions were observed intraoperatively. The red circle indicated a white nodule in the left pleura, which has also been resected for pathologic analysis. (C) Pathologic assessment of resected specimen showed substantial fibrosclerotic manifestation and lymphocytes and neutrophils infiltration. No viable tumor cells were detected. Scale bar = 100 μm.

3. Discussion

We reported an impressive tumor shrinkage after Pralsetinib treatment in the present case. The dosage of Pralsetinib was reduced to 200 mg once daily due to adverse events, however, the patient continued to benefit from low dosage Pralsetinib targeted therapy. In fact, we intended to continue Pralsetinib treatment till disease progression, however, downstaging of locally advanced pleural nodules and N2 lymph nodes was found after 10 months of treatment. The patient underwent radical resection of the primary tumor, as such, Pralsetinib functioned as “neoadjuvant” therapy in our case. Although there are a number of attempts of using targeted therapy in neoadjuvant setting, the present case is different from previous reports. First, most patients enrolled in neoadjuvant trials were potentially resectable stage III NSCLC, downstaging of locally advanced disease to prime surgical resection is one of the primary endpoints of these studies. Our patient was diagnosed stage IV NSCLC. The primary aim of therapy was to prolong patient survival and surgical resection was never considered at the time of diagnosis. Second, the duration of neoadjuvant targeted therapy in most clinical trials was usually within 2 months [2], but we did not confirm downstaging of clinical stage after 2 months of Pralsetinib treatment. With treatment time extending, the pleural nodules gradually became invisible and PET-CT examination after 10 months of treatment indicated a resolution of metastatic disease. The duration of neoadjuvant treatment that reached this goal for downstaging in our case is quite different from other studies, and 10 months treatment with Pralsetinib to downstage the tumor may not be optimal to other RET-positive patients. Finally, the postoperative pathologic results showed pCR. To the best of our knowledge, this is the first case study reporting a therapeutic outcome of pCR to Pralsetinib in a patient with stage IV RET-positive NSCLC.

While it is unclear whether adjuvant therapy needed after pCR? Unfortunately, there are no definitive answers to this question at the moment, but a number of case studies impended disease recurrence after discontinuation of targeted therapy [3]. Thus, sequential management following surgical resection remains challenging and continuous adjuvant therapy is necessary even in patients who have achieved pCR. Tumor flare after discontinuation of adjuvant therapy may occurred, and future clinical trials designed to address the duration of perioperative treatment are urgently needed.

4. Conclusions

In patients with RET-positive NSCLC, treatment with Pralsetinib is a highly efficient strategy to suppress tumor outgrowth. Clinical attempts to use Pralsetinib for disease downstaging in locally metastatic RET-positive NSCLC may be considered.

CRediT authorship contribution statement

Xinxin Chen: Writing – original draft, Resources, Methodology, Formal analysis, Data curation. Guoxin Wang: Writing – original draft, Methodology, Formal analysis, Data curation. Jianfeng Zhang: Visualization, Methodology, Formal analysis, Data curation. Wei Bao: Visualization, Methodology. Jun Cai: Visualization, Methodology. Jing Guo: Visualization, Methodology. Tangfeng Lv: Writing – review & editing, Validation, Methodology, Investigation, Conceptualization. Mingxiang Ye: Writing – review & editing, Validation, Supervision, Project administration, Methodology, Investigation, Funding acquisition, Conceptualization.

Ethics approval and consent to participate

This study was reviewed and approved by Ethics Committee of Jinling Hospital, Nanjing University School of Medicine. Written informed consent was obtained from the patient.

Written consent for publication

Written informed consent for the publication of all data and images in this case report was obtained from the patient.

Funding

This work was funded by the Science and Technology Innovation Research Program of Jinling Hospital (#2023LCYYXH006).

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Handling Editor: DR AC Amit Chopra

Appendix A. Supplementary data

The following is the Supplementary data to this article: