Lung Carcinoid Tumors With Potentially Actionable Genomic Alterations and Responses to Targeted Therapies

Abstract

Background: Effective treatments for patients with advanced lung carcinoids remain limited. The prevalence of potentially actionable genomic alterations (AGAs) among lung carcinoids is not well-understood.

Materials and methods: Lung carcinoids submitted for next-generation sequencing (NGS) at a Clinical Laboratory Improvement Amendments (CLIA)-certified genomics laboratory from September 2013 to March 2024 were retrospectively investigated to determine prevalence of AGAs. We evaluated outcomes with genotype-matched targeted therapies in patients with advanced lung carcinoids with AGAs identified across 3 institutions and comprehensive literature search.

Results: Among 321 cases of lung carcinoids profiled by NGS, 8 (2.5%) harbored potential AGAs (4 [1.2%] with commercially available targeted therapies), including KRAS mutations (n = 4, 1.2%: G12C, G12D, G12R, G12V), ALK fusions (n = 2, 0.6%), BRAF D594N (n = 1, 0.3%), and RET fusion (n = 1, 0.3%). None of the 24 typical carcinoids harbored an AGA. Collectively across these database-identified patients, our multi-institutional cohort, and literature review, we identified 36 cases of lung carcinoids with potential AGAs (24 with commercially available targeted therapies), predominantly comprising fusions of ALK (n = 14), RET (n = 5), and NTRK (n = 2). Of 27 with known disease stage, 19 had stage 4 disease, and 13 (68.4%) had outcomes reported following targeted therapies. Median treatment duration was 12.0 months (95% CI: 6.7-16.0). Median progression-free survival (PFS) was 10.6 months (95% CI: 6.7-16.0) across all targeted therapy lines and 14.0 months (95% CI: 1.3-NA) with first-line targeted therapies. Objective response rate with at least one targeted therapy was 61.5%.

Conclusions: Patients with advanced lung carcinoids harboring AGAs can derive meaningful benefit from genotype-matched targeted therapies, highlighting potential role for NGS in patients with advanced carcinoids.

Keywords: Advanced lung carcinoids; Fusion drivers; Genotype-matched therapies; Next-generation sequencing; Targetable alterations.

Figure 1:. Flowchart demonstrating the integrated cohort of carcinoids with potential AGAs.

Of 344 cases of lung carcinoids submitted to a CLIA-certified genomics laboratory (Caris Life Sciences), 321 had NGS results available, with 8 cases identified of carcinoids with potential AGAs (comprising the Molecular Profiling Cohort). A total of 36 cases of carcinoids with potential AGAs were identified across multiple sources. Abbreviations: AGA, actionable genomic alteration; CLIA, Clinical Laboratory Improvement Amendments; seq, sequencing.

Figure 2:. Landscape of actionable genomic alterations (AGAs) among lung carcinoids.

(A) Frequency of potential AGAs (with commercially available targeted therapies or with investigational-only targeted therapies) among 321 carcinoid cases in the Molecular Profiling Cohort that underwent sequencing with Caris Life Sciences NGS Platform. (B) Landscape of AGAs identified in lung carcinoids across the Molecular Profiling Cohort, multi-institutional cohort, and literature case review. Colors indicate AGAs identified in carcinoid: NOS (blue), AC (green), mixed AC and NSCLC (brown), or TC (gold). *Cases in the literature case review cohort were previously published.^–,– Abbreviations: AC, atypical carcinoid; AGA, actionable genomic alterations; NSCLC, non-small cell lung cancer; TC, typical carcinoid.

Figure 2:. Landscape of actionable genomic alterations (AGAs) among lung carcinoids.

(A) Frequency of potential AGAs (with commercially available targeted therapies or with investigational-only targeted therapies) among 321 carcinoid cases in the Molecular Profiling Cohort that underwent sequencing with Caris Life Sciences NGS Platform. (B) Landscape of AGAs identified in lung carcinoids across the Molecular Profiling Cohort, multi-institutional cohort, and literature case review. Colors indicate AGAs identified in carcinoid: NOS (blue), AC (green), mixed AC and NSCLC (brown), or TC (gold). *Cases in the literature case review cohort were previously published.^–,– Abbreviations: AC, atypical carcinoid; AGA, actionable genomic alterations; NSCLC, non-small cell lung cancer; TC, typical carcinoid.

Figure 3:. Representative pathology and radiologic findings in advanced lung carcinoids with AGAs treated with targeted therapy.

Pathology findings (H&E and IHC) in addition to baseline and restaging computed tomography scans and/or brain magnetic resonance imaging scans for Cases 3 (A and B) and 4 (C and D) are shown. Cerebellar resection specimen (A) for Case 3 was consistent with AC, with IHC positive for neuroendocrine markers. Restaging scans (B) demonstrated extracranial SD and intracranial PR ongoing after 12.7 months of osimertinib. Biopsies of the mediastinal mass and AZ recess nodule (C) for Case 4 demonstrated distinct histopathologies with adenosquamous carcinoma in the mediastinal mass and AC in the AZ nodule, with strong ALK immunoreactivity at both sites. Restaging scans (D) demonstrated shrinkage of the mediastinal mass and AZ recess nodule ongoing at 15 months on lorlatinib, with overall PR by RECIST v1.1. Abbreviations: atypical carcinoid, AC; azygoesophageal, AZ; hematoxylin and eosin, H&E; immunohistochemistry, IHC; PR, partial response; SD, stable disease.

Figure 3:. Representative pathology and radiologic findings in advanced lung carcinoids with AGAs treated with targeted therapy.

Pathology findings (H&E and IHC) in addition to baseline and restaging computed tomography scans and/or brain magnetic resonance imaging scans for Cases 3 (A and B) and 4 (C and D) are shown. Cerebellar resection specimen (A) for Case 3 was consistent with AC, with IHC positive for neuroendocrine markers. Restaging scans (B) demonstrated extracranial SD and intracranial PR ongoing after 12.7 months of osimertinib. Biopsies of the mediastinal mass and AZ recess nodule (C) for Case 4 demonstrated distinct histopathologies with adenosquamous carcinoma in the mediastinal mass and AC in the AZ nodule, with strong ALK immunoreactivity at both sites. Restaging scans (D) demonstrated shrinkage of the mediastinal mass and AZ recess nodule ongoing at 15 months on lorlatinib, with overall PR by RECIST v1.1. Abbreviations: atypical carcinoid, AC; azygoesophageal, AZ; hematoxylin and eosin, H&E; immunohistochemistry, IHC; PR, partial response; SD, stable disease.

Figure 4:. Swimmer plot demonstrating progression-free survival for patients with advanced lung carcinoid tumors treated with targeted therapies (n=13).

*Cases in the literature case review cohort were previously published.^,–,– Abbreviations: NE, not evaluable; No, number; PD, progressive disease; PR, partial response; Pt, patient; SD, stable disease; UK, unknown response.