Exceptional long term response to crizotinib in ROS 1‐postive advanced non small cell lung cancer

Abstract

Non‐small‐cell lung cancer (NSCLC) accounts for the majority of lung cancer cases worldwide, with a significant proportion of patients harbouring actionable oncogenic alterations. Among these alterations, the ROS1 rearrangement represents a distinct subset with therapeutic implications. Here, we present the case of a 52‐year‐old man diagnosed with advanced NSCLC harbouring the ROS1 fusion gene. Despite the initial poor response to conventional chemotherapy, the patient exhibited an exceptional and sustained response to crizotinib, with a progression‐free survival of 94 months and complete metabolic response on PET scan. This case underscores the importance of molecular profiling in guiding treatment decisions and highlights the efficacy of targeted therapies for ROS1‐positive NSCLC.

Here, we present the case of a 52‐year‐old man diagnosed with advanced NSCLC harbouring the ROS1 fusion gene. Despite the initial poor response to conventional chemotherapy, the patient exhibited an exceptional and sustained response to crizotinib, with a progression‐free survival of 94 months and complete metabolic response on PET scan. This case underscores the importance of molecular profiling in guiding treatment decisions and highlights the efficacy of targeted therapies for ROS1‐positive NSCLC.

INTRODUCTION

Non‐small cell lung cancer (NSCLC) is a heterogeneous disease with diverse molecular subtypes that necessitate personalized treatment approaches. ¹ Approximately 85% of lung cancers are NSCLC and 50% harbour oncogenic alterations that can be targeted by therapy. Among these alterations, ROS1 rearrangements have emerged as a distinct subset, occurring in approximately 2.8%–4% of NSCLC cases in India. ² ROS1 fusion genes are frequently observed in young individuals, non‐smokers, and light smokers. ROS1‐positive tumours are usually diagnosed at an advanced stage (III–IV) with brain metastases and lymph node involvement. They are also associated with major thromboembolic risks, including thrombotic microangiopathy and disseminated intravascular coagulation (DIC). ³ , ⁴

CASE REPORT

A 52‐year‐old man presented with a three‐month history of cough, appetite loss, and shortness of breath in 2015. His performance status was 2 and vital signs were stable. CT revealed an ill‐defined soft tissue dense hilar lesion in the right hilum encasing the right main bronchus, right upper lobe bronchus, and middle lobe bronchus. There was collapse of the right middle lobe and encasement of the right descending pulmonary artery. Mediastinal lymph nodes were noted in right upper paratracheal, right lower paratracheal (1 cm in short axis), left lower paratracheal, subcarinal (1.1 cm in short axis) and paraesophageal. Bronchoscopy revealed a tumour in the distal right middle lobe measuring 0.5–1 cm from the origin. Histopathological examination (HPE) confirmed adenocarcinoma with a signet ring cell morphology. Immunohistochemistry (IHC) showed positivity for CK 7 and TTF‐1, while synaptophysin was negative.

A whole‐body PET‐CT scan demonstrated FDG‐avid soft tissue lesions with areas of cavitation in the hilum extending into the right middle lobe, causing cutoff of the right middle lobe bronchus and encasement of the right superior pulmonary vein. FDG‐avid lymph nodes were observed in the right hilar, right upper paratracheal, and subcarinal regions. Staging revealed cT4b N2M0–STAGE IIIB disease (Figure 1). The Multidisciplinary Tumour Board (MDTB) recommended induction chemotherapy followed by chemoradiation due to the bulky disease burden. PET‐CT performed in January 2016 after three courses of pemetrexed carboplatin showed poor response. Subsequently, the patient received second‐line chemotherapy with cisplatin and docetaxel for four cycles. PET‐CT scan in April 2016, after completion of four cycles of cisplatin and docetaxel, revealed progressive disease with pleural effusion, new FDG‐avid collapse‐consolidation of the right basal segments, and bone metastasis involving the right 5th rib (Figure 2). Repeat biopsy and molecular testing showed EGFR and ALK negativity, FISH for Ros 1 rearrangement was positive.

FIGURE 1.

Pre‐chemotherapy ¹⁸FDG‐PET computed tomography image indicates a stage IIIB tumour (cT4b N2M0).

FIGURE 2.

Whole‐body ¹⁸FDG‐PET‐CT and chest x‐ray images demonstrate disease progression, manifested by the presence of a bone lesion in right 5th rib and right sided pleural effusion.

In July 2016, the patient was administered crizotinib (250 mg twice daily). PET/CT after 15 months of crizotinib therapy showed a complete response, which was sustained during the subsequent follow‐up visits (Figure 3, 4 and 5). The most recent PET/CT scan in November 2023 demonstrated a complete metabolic response. The patient remained asymptomatic and was still doing well. He exhibited an exceptionally good response to crizotinib, achieving a progression‐free survival of 94 months with no significant adverse effects observed).

FIGURE 3.

A comparison of whole‐body ¹⁸FDG PET‐CT scans before and after 15 months of initiation of treatment with crizotinib.

FIGURE 4.

A comparison of chest x rays before and after 15 months of initiation of treatment with crizotinib.

FIGURE 5.

WB ¹⁸FDG PET‐CT conducted 88 months after crizotinib treatment.

DISCUSSION

Lung cancer is a major cause of cancer‐related deaths worldwide. ⁵ NSCLC accounts for approximately 84% of lung cancer cases and encompasses various distinct types based on molecular characteristics and targetable oncogenic drivers. ROS1, a tyrosine kinase receptor, falls within this spectrum. ⁶ ROS1 rearrangements result in fusion genes, such as CD74–ROS1, activating vital signalling pathways for cell survival and growth. ⁷ ROS1 rearrangement detection is crucial for all metastatic lung cancers and employs techniques such as immunohistochemistry (IHC), fluorescence in situ hybridisation (FISH), reverse‐transcriptase‐polymerase chain reaction (RT‐PCR), and next‐generation sequencing (NGS). ⁸ Although IHC is cost‐effective and sensitive, FISH remains the gold standard owing to its specificity, whereas RT‐PCR and NGS offer alternatives (Figure 5).

Various tyrosine kinase inhibitors (TKIs), particularly crizotinib, show promise. Crizotinib, a tyrosine kinase inhibitor targeting ROS1, gained FDA approval as a first‐line treatment based on the PROFILE 1001 study, a single‐arm study of 50 patients that demonstrated an overall response rate (ORR) of 72% and a median progression‐free survival (PFS) of 19.2 months. ⁹ Subsequent studies, such as those by EUCROSS ¹⁰ and METROS, ¹¹ further support the efficacy of crizotinib, albeit with some variations possibly attributed to patient selection.

Tian et al. reported a case of a 58‐year‐old man with advanced lung adenocarcinoma with ROS1 rearrangement. The patient exhibited persistent malignant pleural and peritoneal effusion and underwent a combination therapy consisting of crizotinib and anlotinib. Remarkably, the patient experienced a progression‐free survival (PFS) period of 4 years. ¹²

Despite the efficacy of crizotinib, resistance can arise, either de novo or acquired, through various mechanisms. Primary resistance may stem from factors such as KRAS mutations or limited central nervous system (CNS) penetration. ¹³ Acquired resistance mechanisms may be ROS1‐dependent or‐independent, necessitating the development of new‐generation TKIs targeting specific resistance mechanisms. ¹⁴

Newer drugs for ROS1‐positive NSCLC are being developed to address the challenges of drug resistance that arise during treatment. Repotrectinib is a next‐generation ROS1 inhibitor particularly effective against resistance mutations like ROS1F2004C, which often develop after treatment with entrectinib. ¹⁵ Lorlatinib is a brain‐penetrant third‐generation ATP competitive reversible TKI of ALK and ROS1 retaining activity in vitro on several crizotinib‐resistant ROS1 mutations. ¹⁶ Taletrectinib (DS‐6051b), an investigational drug, targets both ROS1 and NTRK fusions and is designed to overcome resistance to first‐generation inhibitors. ¹⁷ Although Cabozantinib is primarily a MET inhibitor, it also shows activity against ROS1 rearrangements, offering potential in patients resistant to ROS1‐targeted therapies. ¹⁸ Ensartinib, initially developed as an ALK inhibitor, is now being tested for efficacy in ROS1‐positive NSCLC, particularly in cases involving brain metastases. ¹⁹

Key ROS1 resistance mutations include G2032R, a common mutation that is resistant to first‐generation TKIs. Newer drugs such as repotrectinib and taletrectinib are effective against this mutation. Repetition of F2004C/V mutations in the ATP pocket is known to cause resistance to type II inhibitors but remains sensitive to type I inhibitors such as lorlatinib and repotrectinib. D2033N is another mutation that can lead to decreased efficacy of certain TKIs, whereas L1951R is a less common mutation that is still under investigation for its impact on resistance. ²⁰

Off‐target resistance mechanisms also play significant roles in the efficacy of ROS1 inhibitors. MET amplification is one such mechanism that drives resistance by activating alternative signalling pathways. To address this issue, combination therapies involving MET and ROS1 inhibitors have been explored. Additionally, tumours may develop secondary bypass tracks that reduce the efficacy of ROS1 inhibitors, necessitating the use of combination or multi‐targeted therapies to overcome this challenge. ²¹ , ²²

The case presented here underscores the remarkable efficacy of crizotinib in the treatment of ROS1‐positive advanced NSCLC with an exceptional long‐term response. Despite initially exhibiting a poor response to conventional chemotherapy, this patient achieved a sustained and remarkable response to crizotinib, with a progression‐free survival (PFS) of 94 months and a complete metabolic response on PET/CT imaging.

This emphasizes the importance of molecular profiling in guiding treatment decisions for NSCLC. The absence of significant adverse effects observed in this case further supports the safety and tolerability profile of crizotinib in the treatment of ROS1‐positive NSCLC. This is crucial to ensure the quality of life of patients undergoing long‐term treatment.

This case prompts further research to understand the mechanisms underlying the exceptional responses to targeted therapies such as crizotinib. Additionally, it underscores the need for continued efforts to optimize treatment strategies and develop new‐generation TKIs to address potential resistance mechanisms.

The remarkable and sustained response observed in this case emphasizes the importance of targeted therapies, particularly crizotinib, for ROS1‐positive NSCLC. Further studies are warranted to elucidate the factors contributing to exceptional responses and optimize treatment strategies for patients with similar molecular profiles. This case adds to the growing body of evidence supporting the efficacy and favourable outcomes of targeted therapies for advanced NSCLC.

AUTHOR CONTRIBUTIONS

Keechilat Pavithran: Visualization; design; supervision; validation; writing—critical review and editing; final approval. Anjali Murali: Conceptualization; acquisition; writing—original draft preparation. Anju Farsana A: Conceptualization; acquisition; writing—original draft preparation. Sobha Subramaniam: Conceptualization; resources and materials. Indu R. Nair: Conceptualization; resources and materials. Malini Eapen: Conceptualization; resources and materials.

CONFLICT OF INTEREST STATEMENT

None declared.

ETHICS STATEMENT

The authors declare that appropriate written informed consent was obtained for the publication of this manuscript and accompanying images.

Murali A, Farsana A A, Subramaniam S, Eapen M, Nair IR, Pavithran K. Exceptional long term response to crizotinib in ROS 1‐postive advanced non small cell lung cancer. Respirology Case Reports. 2024;12(9):e70033. 10.1002/rcr2.70033

DATA AVAILABILITY STATEMENT

No data available.