Targeted Therapy and Immunotherapy in the Treatment of Non–Small Cell Lung Cancer

Shroff, Girish S.; Groot, Patricia M. de; Papadimitrakopoulou, Vassiliki A.; Truong, Mylene T.; Carter, Brett W.

doi:10.1016/j.rcl.2018.01.012

Cited by 65 publications

(86 citation statements)

References 56 publications

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“…EGFR-associated signaling pathways can be deregulated through different mechanisms, the most important of which is EGFR mutation (32). The most common EGFR mutations are 19Del and L858R, which are known as activating EGFR mutations in NSCLC (33). Activating EGFR mutations may result in constitutive activation of the receptor and diverse downstream signaling pathways, independent of ligand binding (34,35).…”

Section: Discussionmentioning

confidence: 99%

Significance of the epidermal growth factor receptor mutation status and differences among molecular subgroups in surgically resected lung microinvasive adenocarcinoma

et al. 2018

Oncol Lett

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Lung microinvasive adenocarcinoma (MIA) is a newly-defined subtype of early stage non-small cell lung cancer (NSCLC). However, its epidermal growth factor receptor (EGFR) mutation status and clinical significance remain unclear. The present study aimed to determine EGFR mutation characteristics and identify their significance in patients with resected lung MIA. The present study also analyzed clinicopathological differences between EGFR molecular subgroups defined as 19Del and L858R. The present study examined EGFR mutations in 79 consecutive lung MIA resection specimens and compared the differences in clinicopathological features between the EGFR wild-type and mutation groups, as well as between the 19Del and L858R subgroups. EGFR mutations were detected in 60 (75.95%) tumors. The most common mutations were 19Del (28 cases; 35.44%) and L858R (30 cases; 37.97%). Two patients harbored rare mutations and one of them had a concomitant double mutation. EGFR mutations were significantly associated with microinvasion component, thyroid transcription factor 1 (TTF-1) expression, intratumoral fibrosis and inflammatory cell infiltration. Subgroup evaluation indicated that there was a significant association between 19Del and tumor size, maximum diameter of microinvasion, presence of intratumoral fibrosis and inflammatory cell infiltration. Similar associations were observed for the L858R subgroup, and L858R was associated with TTF-1 expression. In particular, 19Del occurred more frequently in MIA with a smaller size, with a smaller microinvasive area, without TTF-1 expression, and lacking intratumoral fibrosis and inflammatory cell infiltration. By contrast, L858R was detected more frequently in MIA with entirely different tumor features. In conclusion, the results of the present study indicated that surgically resected MIA cases harboring different EGFR gene statuses exhibit distinct clinicopathological features. Significant differences in pathological features associated with the tumor microenvironment were identified in MIA with 19Del or L858R mutations. Therefore, the present study proposed that MIA should be classified into molecular subgroups based on EGFR mutation subtypes. The molecular sub-classification should be taken into account for prognostic evaluation and clinical management of MIA.

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Section: Discussionmentioning

confidence: 99%

Significance of the epidermal growth factor receptor mutation status and differences among molecular subgroups in surgically resected lung microinvasive adenocarcinoma

et al. 2018

Oncol Lett

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“…Treatment for non‐small cell lung cancer (NSCLC) has evolved significantly over the last decade with the approval of several targeted and immune checkpoint therapies for specific patient subpopulations. For patients with advanced NSCLC harboring an activating mutation in the tyrosine kinase (TK) domain of the epidermal growth factor receptor ( EGFR ) or who have activating rearrangements in anaplastic lymphoma kinase ( ALK ) or ROS‐1 , targeted treatment is available in the form of small molecule TK inhibitors (TKIs) . Despite clinical benefit from TKIs, nearly all patients develop disease progression through various acquired resistance mechanisms.…”

Section: Introductionmentioning

confidence: 99%

Randomized Phase II Trial of Seribantumab in Combination with Erlotinib in Patients with EGFR Wild-Type Non-Small Cell Lung Cancer

et al. 2019

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Background Seribantumab (MM‐121) is a fully human IgG2 monoclonal antibody that binds to human epidermal growth factor receptor 3 (HER3/ErbB3) to block heregulin (HRG/NRG)‐mediated ErbB3 signaling and induce receptor downregulation. This open‐label, randomized phase 1/2 study evaluated safety and efficacy of seribantumab plus erlotinib in advanced non‐small cell lung cancer (NSCLC). Here, we report the activity of seribantumab plus erlotinib, versus erlotinib alone, in patients with EGFR wild‐type tumors and describe the potential predictive power of HRG. Materials and Methods Patients with EGFR wild‐type NSCLC were assigned randomly to receive seribantumab + erlotinib or erlotinib alone. Patients underwent pretreatment core needle biopsy and archived tumor samples were collected to support prespecified biomarker analyses. Results One hundred twenty‐nine patients received seribantumab + erlotinib (n = 85) or erlotinib alone (n = 44). Median estimated progression‐free survival (PFS) in the unselected intent‐to‐treat (ITT) population was 8.1 and 7.7 weeks in the experimental and control arm, respectively (hazard ratio [HR], 0.822; 95% confidence interval [CI], 0.37–1.828; p = 0.63), and median estimated overall survival was 27.3 and 40.3 weeks in the experimental and control arm, respectively (HR, 1.395; 95% CI, 0.846 to 2.301; p = .1898) In patients whose tumors had detectable HRG mRNA expression, treatment benefit was observed in the seribantumab + erlotinib combination (HR, 0.35; 95% CI, 0.16–0.76; p = .008). In contrast, in patients whose tumors were HRG negative, the HR was 2.15 (95% CI, 0.97–4.76; p = .059, HRG‐by‐treatment interaction, p value = .0016). Conclusion The addition of seribantumab to erlotinib did not result in improved PFS in unselected patients. However, predefined retrospective exploratory analyses suggest that detectable HRG mRNA levels identified patients who might benefit from seribantumab. An ongoing clinical trial of seribantumab, in combination with docetaxel, is underway in patients with advanced NSCLC and high HRG mRNA expression (NCT02387216). Implications for Practice The poor prognosis of patients with non‐small cell lung cancer (NSCLC) underscores the need for more effective treatment options, highlighting the unmet medical need in this patient population. The results of this study show that a novel biomarker, heregulin, may help to identify patients with advanced NSCLC who could benefit from treatment with seribantumab. On the basis of the observed safety profile and promising clinical efficacy, a prospective, randomized, open‐label, international, multicenter phase II trial (SHERLOC, NCT02387216) is under way to investigate the efficacy and safety of seribantumab in combination with docetaxel in patients with heregulin‐positive advanced adenocarcinoma.

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“…1 In recent years, the therapeutic strategies for non-small cell lung cancer (NSCLC) have been enriched with small molecular targeted therapy and immunotherapy. 2 For targeted therapy, several positive and practical indicators of their efficacy have been identified by accumulating clinical and laboratory evidence, such as epidermal growth factor receptor (EGFR) mutation. 3 After failure of previous treatments, immunotherapy still shows favorable clinical benefits.…”

Section: Introductionmentioning

confidence: 99%

A reliable and feasible way to predict the benefits of Nivolumab in patients with non-small cell lung cancer: a pooled analysis of 14 retrospective studies

Cao

et al. 2018

OncoImmunology

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Objective: Nivolumab has been used for treating non-small cell lung cancer (NSCLC) worldwide. Whether neutrophil-lymphocyte ratio (NLR) can predict the prognosis of NSCLC treated with Nivolumab is still under debate. This meta-analysis was to assess the significance of NLR as a predictive factor in NSCLC patients receiving Nivolumab.Methods: Databases including PubMed, Embase, and the Cochrane library were searched to identify eligible studies evaluating the role of NLR in predicting prognosis of NSCLC treated with Nivolumab until March 2018 without language restrictions. The meta-analysis was performed using hazard ratio (HR) of progression free survival (PFS) and overall survival (OS) in NSCLC patients with various NLR.Results: A total of 14 retrospective studies consisting of 1225 NSCLC patients were included. The combined results showed that relatively higher baseline NLR was associated with poor PFS (HR = 1.44; 95% confidence interval (CI):1.18–1.77; p < 0.05) and OS (HR = 1.75; 95% CI: 1.33–2.30; p < 0.05) after treatment of Nivolumab. Subgroup analysis suggested that NLR ≥ 5 was more reliable for PFS (HR = 1.73; 95%CI: 1.14, 2.62; p < 0.05) and OS (HR = 1.76; 95%CI: 1.47, 2.10; p < 0.05). In addition, post-treatment NLR also had predictive roles for PFS (HR = 3.17; 95%CI: 1.48, 6.82; p < 0.05) and OS (HR = 2.26; 95%CI: 1.05, 4.86; p < 0.05).Conclusion: Our findings suggest that NLR can be used as a prognostic biomarker for NSCLC treating with Nivolumab, and the recommended cutoff value of NLR is 5.

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Targeted Therapy and Immunotherapy in the Treatment of Non–Small Cell Lung Cancer

Cited by 65 publications

References 56 publications

Significance of the epidermal growth factor receptor mutation status and differences among molecular subgroups in surgically resected lung microinvasive adenocarcinoma

Significance of the epidermal growth factor receptor mutation status and differences among molecular subgroups in surgically resected lung microinvasive adenocarcinoma

Randomized Phase II Trial of Seribantumab in Combination with Erlotinib in Patients with EGFR Wild-Type Non-Small Cell Lung Cancer

A reliable and feasible way to predict the benefits of Nivolumab in patients with non-small cell lung cancer: a pooled analysis of 14 retrospective studies

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