Impact of PD-L1 expression on the efficacy of first-line crizotinib in advanced ROS1-rearranged NSCLC.

BACKGROUND: The predictive value of programmed death-ligand 1 (PD-L1) expression for the efficacy of tyrosine kinase inhibitors (TKIs) in patients with advanced ROS1-rearranged non-small cell lung cancer (NSCLC) remains underexplored. This study analyzed patients with advanced NSCLC harboring ROS1 rearrangements who received first-line crizotinib to evaluate the correlation between baseline PD-L1 expression and crizotinib efficacy. METHODS: In this study, the clinical data from 371 patients diagnosed with ROS1-rearranged NSCLC at Shanghai Chest Hospital between November 2017 and December 2022 were reviewed. The patients were categorized into three groups according to the baseline PD-L1 expression: tumor proportion score (TPS) <1%, TPS 1 %-49 %, and TPS≥50 %. The objective response rate (ORR), disease control rate (DCR), and progression-free survival (PFS) following first-line crizotinib treatment were measured. RESULTS: A total of 64 patients were included in the analysis, with 16 patients in the TPS<1% group, 22 in the TPS 1 %-49 % group, and 26 in the TPS≥50 % group. The overall DCR was 100 %, and the overall ORR was 76.5 %. The ORRs were 81.2 % (13/16) in the TPS<1% group, 63.6 % (14/22) in the TPS 1 %-49 % group, and 84.6 % (22/26) in the TPS≥50 % group (p = 0.218). The median PFS across all patients was 20.21 months (95 % CI: 15.71-24.71), with a median PFS of 28.96 months (95 % CI: 19.87-38.04) in the TPS<1% group, 17.56 months (95 % CI: 12.25-22.86) in the TPS 1 %-49 % group, and 25.85 months (95 % CI: 18.52-33.17) in the TPS≥50 % group (p = 0.100). The median PFS for patients with CD74 fusion was 18.23 months (95 % CI: 15.24-21.22), while those with non-CD74 fusion exhibited a PFS of 16.49 months (95 % CI: 9.75-23.23) (p = 0.359). CONCLUSION: Patients with advanced ROS1-rearranged NSCLC were found to benefit from first-line crizotinib treatment, irrespective of baseline PD-L1 expression.

Multicenter evaluation of an automated, multiplex, RNA-based molecular assay for detection of ALK, ROS1, RET fusions and MET exon 14 skipping in NSCLC.

The current study assessed the performance of the fully automated RT-PCR-based Idylla™ GeneFusion Assay, which simultaneously covers the advanced non-small cell lung carcinoma (aNSCLC) actionable ALK, ROS1, RET, and MET exon 14 rearrangements, in a routine clinical setting involving 12 European clinical centers. The Idylla™ GeneFusion Assay detects fusions using fusion-specific as well as expression imbalance detection, the latter enabling detection of uncommon fusions not covered by fusion-specific assays. In total, 326 archival aNSCLC formalin-fixed paraffin-embedded (FFPE) samples were included of which 44% were resected specimen, 46% tissue biopsies, and 9% cytological specimen. With a total of 179 biomarker-positive cases (i.e., 85 ALK, 33 ROS1, 20 RET fusions and 41 MET exon 14 skipping), this is one of the largest fusion-positive datasets ever tested. The results of the Idylla™ GeneFusion Assay were compared with earlier results of routine reference technologies including fluorescence in situ hybridization, immunohistochemistry, reverse-transcription polymerase chain reaction, and next-generation sequencing, establishing a high sensitivity/specificity of 96.1%/99.6% for ALK, 96.7%/99.0% for ROS1, 100%/99.3% for RET fusion, and 92.5%/99.6% for MET exon 14 skipping, and a low failure rate (0.9%). The Idylla™ GeneFusion Assay was found to be a reliable, sensitive, and specific tool for routine detection of ALK, ROS1, RET fusions and MET exon 14 skipping. Given its short turnaround time of about 3 h, it is a time-efficient upfront screening tool in FFPE samples, supporting rapid clinical decision making. Moreover, expression-imbalance-based detection of potentially novel fusions may be easily verified with other routine technologies without delaying treatment initiation.

Individualized targeted treatment in a case of a rare TFG::ROS1 fusion positive inflammatory myofibroblastic tumor (IMT).

BACKGROUND: Inflammatory myofibroblastic tumor (IMTs) are rare mesenchymal neoplasms with slow growth. Resection is considered as therapeutic standard, with chemotherapy being insufficiently effective in advanced disease. ALK translocations are present in 50% of cases, ROS1 fusions (YWHAE::ROS1, TFG::ROS1) are extremely rare. Here, we present a case with TFG::ROS1 fusion and highlight the significance of molecular tumor boards (MTBs) in clinical precision oncology for post-last-line therapy. CASE PRESENTATION: A 32-year-old woman presented with IMT diagnosed at age 27 for biopsy and treatment evaluation. Previous treatments included multiple resections and systemic therapy with vinblastine, cyclophosphamide, and methotrexate. A computed tomography scan showed extensive tumor infiltration of the psoas muscles and the posterior abdomen. Next generation sequencing revealed an actionable ROS1 fusion (TFG::ROS1) with breakpoints at exon 4/35 including the kinase domain and activating the RAS-pathway. TFG, the Trk-fused gene, exerts functions such as intracellular trafficking and exhibits high sequence homology between species. Based on single reports about efficacy of ROS1-targeting in ROS1 translocation positive IMTs the patient was started on crizotinib, an ATP-competitive small molecule c-MET, ALK and ROS1-inhibitor. With a follow-up of more than 9 months, the patient continues to show a profound response with major tumor regression, improved quality of life and no evidence for severe adverse events. CONCLUSION: This case underscores the importance of the availability of modern molecular diagnostics and interdisciplinarity in precision oncology to identify rare, disease-defining genotypes that make an otherwise difficult-to-treat disease targetable.

Refractory response to entrectinib for ROS-1 rearranged NSCLC with concurrent de novo TP53 mutation showing good response to CNS lesion, but poor duration of response: A case report.

Entrectinib, a ROS-1 inhibitor, has been shown to be effective for patients with ROS-1 fused NSCLC, and has been established as the standard of care for this population. Entrectinib has been shown to achieve a better response to brain metastasis due to the characteristic of the drug having a weak interaction with P-glycoprotein and, even in prospective studies, the intracranial response is higher. Patients have been known to acquire resistance to molecularly targeted drugs such as EGF-TKIs or ALK-TKIs during targeted therapy. Similarly, the mechanisms of resistance to entrectinib have been reported, but information about the effects of TP53 mutation with entrectinib are still limited. Here, we experienced a case of a patient with ROS-1 fusion and concurrent TP53 mutation who was treated with entrectinib, resulting in a response to brain metastasis but rapid resistance to entrectinib. Our case demonstrates both the intracranial activity of entrectinib and the potential for resistance to entrectinib due to TP53 mutation.

ROS1 Alterations as a Potential Driver of Gliomas in Infant, Pediatric, and Adult Patients.

Gliomas harboring oncogenic ROS1 alterations are uncommon and primarily described in infants. Our goal was to characterize the clinicopathological features and molecular signatures of the full spectrum of ROS1 fusion-positive gliomas across all age groups. Through a retrospective multi-institutional collaboration, we report a collection of unpublished ROS1 fusion gliomas along with the characterization and meta-analysis of new and published cases. A cohort of 32 new and 58 published cases was divided into the following 3 age groups: 19 infants, 40 pediatric patients, and 31 adults with gliomas. Tumors in infants and adults showed uniformly high-grade morphology; however, tumors in pediatric patients exhibited diverse histologic features. The GOPC::ROS1 fusion was prevalent (61/79, 77%) across all age groups, and 10 other partner genes were identified. Adult tumors showed recurrent genomic alterations characteristic of IDH wild-type glioblastoma, including the +7/-10/CDKN2A deletion; amplification of CDK4, MDM2, and PDGFRA genes; and mutations involving TERTp, TP53, PIK3R1, PIK3CA, PTEN, and NF1 genes. Infant tumors showed few genomic alterations, whereas pediatric tumors showed moderate genomic complexity. The outcomes were significantly poorer in adult patients. Although not statistically significant, tumors in infant and pediatric patients with high-grade histology and in hemispheric locations appeared more aggressive than tumors with lower grade histology or those in nonhemispheric locations. In conclusion, this study is the largest to date to characterize the clinicopathological and molecular signatures of ROS1 fusion-positive gliomas from infant, pediatric, and adult patients. We conclude that ROS1 likely acts as a driver in infant and pediatric gliomas and as a driver or codriver in adult gliomas. Integrated comprehensive clinical testing might be helpful in identifying such patients for possible targeted therapy.

The Additional Exclusions of ROS1 Fusions (In Addition to EGFR Mutation and ALK Fusions) in the Cemiplimab NSCLC FDA Indication (EMPOWER-Lung 1 and -Lung 3). Catching Up with Current Scientific View of Immunotherapy in Never-Smoker Predominant Actionable Driver Mutation Positive NSCLC?

Cemiplimab is one of seven immune checkpoint inhibitors (ICIs) approved for the first-line (1L) treatment of advanced NSCLC in the US based on EMPOWER-Lung 1 and -Lung 3 trials. In addition to exclusion of NSCLC patients harboring EGFR mutations and ALK fusion from 1L treatment with ICIs, exclusion of ROS1 fusion is an additional unique exclusion the use of criterion for cemiplimab in the US FDA indication based on the design of the EMPOWER lung trials. We review the effectiveness of ICIs in never-smoker predominant NSCLC with driver mutations (EGFR, ALK, ROS1, RET, HER2) and question whether exclusion of ROS1 fusion would put cemiplimab at a competitive disadvantage given the requirement for insurance to prove ROS1 fusion negativity. We further discuss whether the US FDA as a regulatory authority has the right and responsibility to harmonize the use of ICIs in these actionable driver mutations to standardize community practice for the benefit of patients and to advance the development of next-generation treatment for these driver mutations.

Case Report: Response to crizotinib treatment in a patient with advanced non-small cell lung cancer with LDLR-ROS1 fusion.

C-ros oncogene 1 (ROS1) fusion is a pathogenic driver gene in non-small cell lung cancer (NSCLC). Currently, clinical guidelines from the National Comprehensive Cancer Network (NCCN) have recommended molecular pathologic tests for patients with NSCLC, including the detection of the ROS1 gene. Crizotinib is a small molecule tyrosine kinase inhibitor of anaplastic lymphoma kinase (ALK), ROS1, and mesenchymal-epithelial transition (MET). In recent years, the efficacy of crizotinib in NSCLC patients with ROS1 fusion has been reported. Here, a 77-year-old woman was diagnosed with stage IVA lung adenocarcinoma harboring a novel low-density lipoprotein receptor (LDLR)-ROS1 fusion variant. This novel LDLR-ROS1 fusion was identified by targeted DNA next-generation sequencing (NGS) panel and then verified by RNA fusion panel based on amplicon sequencing. This patient benefited from subsequent crizotinib therapy and achieved progression-free survival of 15 months without significant toxic symptoms. Our case report recommended a promising targeted therapeutic option for patients with metastatic NSCLC with LDLR-ROS1 fusion and highlighted the importance of genetic testing for accurate treatment.

Overcoming CEP85L-ROS1, MKRN1-BRAF and MET amplification as rare, acquired resistance mutations to Osimertinib.

Lung cancer is the most common cancer-related cause of death worldwide, most of which are non-small cell lung cancers (NSCLC). Epidermal growth factor receptor (EGFR) mutations are common drivers of NSCLC. Treatment plans for NSCLC, specifically adenocarcinomas, rely heavily on the presence or absence of specific actionable driver mutations. Liquid biopsy can guide the treatment protocol to detect the presence of various mechanisms of resistance to treatment. We report three NSCLC EGFR mutated cases, each treated with Osimertinib in a combination therapy regimen to combat resistance mechanisms. The first patient presented with EGFR L858R/L833V compound mutation with MET amplification alongside CEP85L-ROS1 fusion gene, the second with EGFR exon 19del and MKRN1-BRAF fusion, and the last EGFR L858R/V834L compound mutation with MET amplification. Each regimen utilized a tyrosine kinase inhibitor or monoclonal antibody in addition to osimertinib and allowed for a prompt and relatively durable treatment response.

KLC1-ROS1 Fusion Exerts Oncogenic Properties of Glioma Cells via Specific Activation of JAK-STAT Pathway.

Here, we investigated the detailed molecular oncogenic mechanisms of a novel receptor tyrosine kinase (RTK) fusion, KLC1-ROS1, with an adapter molecule, KLC1, and an RTK, ROS1, discovered in pediatric glioma, and we explored a novel therapeutic target for glioma that possesses oncogenic RTK fusion. When wild-type ROS1 and KLC1-ROS1 fusions were stably expressed in the human glioma cell lines A172 and U343MG, immunoblotting revealed that KLC1-ROS1 fusion specifically activated the JAK2-STAT3 pathway, a major RTK downstream signaling pathway, when compared with wild-type ROS1. Immunoprecipitation of the fractionated cell lysates revealed a more abundant association of the KLC1-ROS1 fusion with JAK2 than that observed for wild-type ROS1 in the cytosolic fraction. A mutagenesis study of the KLC1-ROS1 fusion protein demonstrated the fundamental roles of both the KLC1 and ROS1 domains in the constitutive activation of KLC1-ROS1 fusion. Additionally, in vitro assays demonstrated that KLC1-ROS1 fusion upregulated cell proliferation, invasion, and chemoresistance when compared to wild-type ROS1. Combination treatment with the chemotherapeutic agent temozolomide and an inhibitor of ROS1, JAK2, or a downstream target of STAT3, demonstrated antitumor effects against KLC1-ROS1 fusion-expressing glioma cells. Our results demonstrate that KLC1-ROS1 fusion exerts oncogenic activity through serum-independent constitutive activation, resulting in specific activation of the JAK-STAT pathway. Our data suggested that molecules other than RTKs may serve as novel therapeutic targets for RTK fusion in gliomas.

ADK-VR2, a cell line derived from a treatment-naïve patient with SDC4-ROS1 fusion-positive primarily crizotinib-resistant NSCLC: a novel preclinical model for new drug development of ROS1-rearranged NSCLC.

Background: ROS1 fusions are driver molecular alterations in 1-2% of non-small cell lung cancers (NSCLCs). Several tyrosine kinase inhibitors (TKIs) have shown high efficacy in patients whose tumors harbour a ROS1 fusion. However, the limited availability of preclinical models of ROS1-positive NSCLC hinders the discovery of new drugs and the understanding of the mechanisms underlying drug resistance and strategies to overcome it. Methods: The ADK-VR2 cell line was derived from the pleural effusion of a treatment-naïve NSCLC patient bearing SDC4-ROS1 gene fusion. The sensitivity of ADK-VR2 and its crizotinib-resistant clone ADK-VR2 AG143 (selected in 3D culture in the presence of crizotinib) to different TKIs was tested in vitro, in both 2D and 3D conditions. Tumorigenic and metastatic ability was assessed in highly immunodeficient mice. In addition, crizotinib efficacy on ADK-VR2 was evaluated in vivo. Results: 2D-growth of ADK-VR2 cells was partially inhibited by crizotinib. On the contrary, the treatment with other TKIs, such as lorlatinib, entrectinib and DS-6051b, did not result in cell growth inhibition. TKIs showed dramatically different efficacy on ADK-VR2 cells, depending on the cell culture conditions. In 3D culture, ADK-VR2 growth was indeed almost totally inhibited by lorlatinib and DS-6051b. The clone ADK-VR2 AG143 showed higher resistance to crizotinib treatment in vitro, compared to its parental cell line, in both 2D and 3D cultures. Similarly to ADK-VR2, ADK-VR2 AG143 growth was strongly inhibited by lorlatinib in 3D conditions. Nevertheless, ADK-VR2 AG143 sphere formation was less affected by TKIs treatment, compared to the parental cell line. In vivo experiments highlighted the high tumorigenic and metastatic ability of ADK-VR2 cell line, which, once injected in immunodeficient mice, gave rise to both spontaneous and experimental lung metastases while the crizotinib-resistant clone ADK-VR2 AG143 showed a slower growth in vivo. In addition, ADK-VR2 tumor growth was significantly reduced but not eradicated by crizotinib treatment. Conclusions: The ADK-VR2 cell line is a promising NSCLC preclinical model for the study of novel targeted therapies against ROS1 fusions and the mechanisms of resistance to TKI therapies.

Crizotinib-Resistant ROS1 G2101A Mutation Associated With Sensitivity to Lorlatinib in ROS1-Rearranged NSCLC: Case Report.

gene rearrangements occur in 1% to 2% of NSCLC. Acquired "on-target" mutations within the ROS1 kinase domain are a known resistance mechanism to the first-line ROS1 inhibitor crizotinib. Here, we report the first case of a patient with an acquired ROS1 G2101A resistance mutation after first-line crizotinib, who responded to lorlatinib. The response was dramatic but short in duration.

Identification of a Rare BAIAP2-ROS1 Fusion and Clinical Benefit of Crizotinib in the Treatment of Advanced Lung Adenocarcinoma: A Case Report.

Objective: Previous studies have shown that fusion partners have a potential role in influencing different tumorigenic abilities of ROS1 fusion variants, as well as potential differential responses to crizotinib. Therefore, it is important to accurately identify the type of ROS1 rearrangement in NSCLC for clinical treatment selection. Materials and Methods: Deep-coverage targeting solid tumor 31 cancer-related genes panel was used to capture DNA-based NGS information to detect gene fusion. RNA fusion panel based on hybrid capture sequencing was performed to verify gene fusions from total RNA which isolated from formalin fixed paraffin-embedded (FFPE) tissue blocks. Results: Using DNA-targeted NGS method, we identified a novel BAIAP2-ROS1 fusion in a 71-year-old non-smoking female patient with stage IVB lung adenocarcinoma. Rearrangement consisted of BAIAP2 in exon1-exon13 of chr17: q23 and ROS1 in exon35-exon43 of chr6: q22, which were further confirmed by RNA-based NGS methodology. A complete kinase domain in ROS1 fusion was preserved. The patient subsequently received crizotinib and showed significant tumor reduction until 17 months, who got benefit from targeted therapy. Conclusion: This study discovered a novel BAIAP2-ROS1 rearrangement; it provides more knowledge of ROS1 fusion in clinical personalized treatment. The good response to crizotinib therapy emphasizes the importance of DNA-based and RNA-based NGS in rare fusion identification in clinical practice.

The potential and limitation of targeted chromosomal breakpoint sequencing for the ROS1 fusion gene identification in lung cancer.

ROS1 fusion genes are rare but important driver genes in lung cancer. Owing to their rarity, many clinicopathological features and treatment responses for each ROS1 fusion variant are still largely unknown and require further investigation. RNA is the preferable template for the ROS1 fusion gene screening, but deterioration of RNA in FFPE often makes the detection challenging. To resolve the difficulty, a targeted chromosomal breakpoint sequencing method was developed for searching the ROS1 fusion gene, and was compared with fluorescence in situ hybridization, immunohistochemistry, RT-qPCR using 260 lung cancer samples of Southern Taiwan. The results showed that ROS1-altered cases were present at low frequencies, did not share distinct clinicopathological features, and often carried other driver mutations. The performance of the targeted sequencing assay was superior to the RT-qPCR in ROS1 fusion gene identification when the cDNAs were from FFPE samples, but long-read DNA sequencing and fresh-frozen samples would be better to revolve all fusion genes. Precise determination of all ROS1 fusion variants and concomitant driver mutations using both genomic DNA and RNA would be required to help improve the treatment of patients with ROS1 alterations.

Complete and durable response to crizotinib in a patient with malignant pleural mesothelioma harboring CD74-ROS1 fusion.

Malignant pleural mesothelioma (MPM) is a rare and deadly malignancy with an extremely poor prognosis. The median overall survival (OS) of this disease is 12-18 months. However, the oncogenic driver mutations of MPM are rarely understood, and the targeted therapy for it is still under investigation. In this report, we describe a case of MPM with CD74-ROS1 fusion who obtains complete and durable response after receiving crizotinib. By the time of submission, the progression-free survival (PFS) with crizotinib has been 6.0 years, and the patient has survived for 7.6 years. Currently, he is still in complete remission (CR). To the best of our knowledge, this case represents the first report of CD74-ROS1 fusion identified in MPM. Meanwhile, it is also the first report of complete and long-term response to crizotinib in a patient with MPM positive for CD74-ROS1 fusion. This case report might contribute to the tumorigenesis and targeted therapy of this deadly disease.

Rare MYH9-ROS1 Fusion Gene-Positive Lung Adenocarcinoma Showing Response to Entrectinib Treatment: A Case Study.

The c-ros oncogene 1 (ROS1) fusion gene is a rare genomic alteration detected in nearly 1-2% of lung adenocarcinomas. The major partner genes of ROS1 include CD74, SDC4, and EZR. Here, we report a case of MYH9-ROS1 fusion gene-positive lung adenocarcinoma, a rare ROS1 fusion gene. The patient was a woman in her 40s who was diagnosed with advanced primary lung adenocarcinoma after a thorough examination. Initial genetic testing conducted using mediastinal lymph node biopsy specimens collected by endobronchial ultrasound-guided transbronchial needle aspiration revealed no driver gene mutations, including the ROS1 fusion gene. The patient was treated with four courses of immunochemotherapy. As the disease worsened, another genetic test was conducted using FoundationOne® CDx, and the MYH9-ROS1 fusion gene was detected. Multiple lung metastases disappeared after the administration of entrectinib; the response persisted up to a year. Adverse events of rash, dysgeusia, and peripheral edema were observed, and the patient required temporary drug interruption; however, we were able to continue entrectinib following a short-term drug interruption. This is the first report on the effectiveness of entrectinib against lung adenocarcinoma with the rare MYH9-ROS1 fusion gene.

Case Report: Adjuvant Crizotinib Therapy Exerted Favorable Survival Benefit in a Resectable Stage IIIA NSCLC Patient With Novel LDLR-ROS1 Fusion.

Novel adjuvant strategies are needed to optimize outcomes after complete surgical resection in patients with early-stage non-small-cell lung cancer (NSCLC). The adjuvant treatment of ROS Proto-Oncogene 1 (ROS1) fusion-positive resected NSCLC is challenging because there is no curative confirmed randomized controlled trial. Next-generation sequencing (NGS) and immunohistochemistry (IHC) staining were performed on the biopsy sample. In this case, we identified a novel LDLR-ROS1 fusion in a resectable stage IIIA NSCLC patient. The patient received crizotinib as adjuvant treatment and achieved recurrence-free survival (RFS) for 29 months, without significant symptoms of toxicity. In this case, we report a novel LDLR-ROS1 fusion responding to crizotinib in a patient with lung adenocarcinoma, supporting the use of adjuvant treatment with the ROS1 inhibitor exerting clinical survival benefit in ROS1 fusion-positive resected NSCLC.

EZR-ROS1 fusion renal cell carcinoma mimicking urothelial carcinoma: report of a previously undescribed gene fusion in renal cell carcinoma.

A subset of renal cell carcinomas harbor gene fusions, and we report the first case of an EZR-ROS1 fusion in renal cell carcinoma. A 47-year-old female presented with hematuria and a mass involving the renal pelvis. Renal biopsy revealed a tumor with solid and tubular architecture that was diffusely positive for PAX8, CK7, and vimentin; retained expression of INI1; focally positive for P504S; and negative for GATA3 and TFE3. Partial nephrectomy was performed, and histologically, the tumor had solid and tubular architecture with mucin-like content within tubules. The nuclei corresponded to WHO/ISUP grade 2 and 3. The morphology was neither specific nor diagnostic, and a final diagnosis of unclassified renal cell carcinoma with solid and tubular architecture was rendered. Molecular sequencing revealed an EZR-ROS1 fusion: a fusion that has never been reported in renal cell carcinoma. Recognition of this fusion is of significance if the tumor becomes metastatic as treatment with crizotinib may be considered.

Case Report: Detection of Double ROS1 Translocations, SDC4-ROS1 and ROS1-GK, in a Lung Adenocarcinoma Patient and Response to Crizotinib.

ROS1 rearrangement, identified in ~2% of non-small cell lung cancer (NSCLC), has defined a distinctive molecular subtype. Patients with ROS1 fusion have been shown to be highly sensitive to treatment with crizotinib. However, the efficacy of crizotinib in NSCLC patients with double ROS1 fusions remains to be elucidated. Here, we report a 40-year-old male diagnosed with stage IIIA lung adenocarcinoma. Two ROS1 fusions [SDC4-ROS1 (EX2:EX32) and ROS1-GK (EX31:EX13)] were detected simultaneously in tumor tissue of this patient by next-generation sequencing. Crizotinib was administered, and the patient showed a partial response in lung lesions. Nevertheless, a brain lesion was found at 8 months after treatment. The slightly short duration of response may be related to the presence of ROS1-GK rearrangement. This case proved that patients with SDC4-ROS1 and ROS1-GK fusions may be sensitive to crizotinib, but short progression-free survival of this case showed that the presence of ROS1-GK rearrangement may affect the efficacy of crizotinib. A large-scale investigation on the efficacy of ROS1 inhibitors in patients with complex ROS1 fusions should be conducted in the future.

Response to Immune Checkpoint Inhibition as Monotherapy or in Combination With Chemotherapy in Metastatic ROS1-Rearranged Lung Cancers.

INTRODUCTION: ROS1 fusions are oncogenic drivers in 1% to 3% of NSCLCs. The activity of immune checkpoint inhibitor (ICI) monotherapy or in combination with chemotherapy (chemotherapy with ICI [chemo-ICI]) in these tumors and their immunophenotype have not been systematically described. METHODS: In this multi-institutional retrospective study, tumor programmed death-ligand 1 (PD-L1) expression and tumor mutational burden (TMB) were evaluated in patients with ROS1-rearranged NSCLC. Time-to-treatment discontinuation (TTD) and objective response rate (ORR) (Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1) were calculated for patients treated with ICI or chemo-ICI in the metastatic setting. RESULTS: A total of 184 patients were identified. Among 146 assessable cases, PD-L1 expression was less than 1% in 60 (41%), 1% to 49% in 35 (24%), and greater than or equal to 50% in 51 tumors (35%). Of 100 (92%) TMB-assessable tumors, 92 had less than 10 mutations per megabase. TMB was significantly lower for ROS1-rearranged tumors (n = 97) compared with tumors with EGFR (n = 1250) or KRAS alterations (n = 1653) and all other NSCLC tumors (n = 2753) evaluated with Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (median TMB = 2.6 versus 3.5, 7.0, and 6.1 mutations per megabase, p < 0.001). Among patients treated with ICI, median TTD was 2.1 months (95% confidence interval [CI]: 1.0-4.2 mo; n = 28) and ORR 13% (2 of 16 RECIST-assessable; 95% CI: 2%-38%). Among patients treated with chemo-ICI, median TTD was 10 months (95% CI: 4.7-14.1 mo; n = 11) and ORR 83% (5 of 6 RECIST-assessable; 95% CI: 36%-100%). There was no difference in PD-L1 expression (p = 0.91) or TMB (p = 0.83) between responders and nonresponders. CONCLUSIONS: Most ROS1-rearranged NSCLCs have low PD-L1 expression and TMB. The activity of ICI in these tumors is modest. In contrast, chemo-ICI can achieve meaningful activity.