Utilizing Immunotherapy to Combat Lung Cancer in Understudied Patient Populations

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Suchita Anigol

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ABSTRACT

Lung cancer is the cause of the most cancer-related deaths in adults worldwide, and past treatments, although innovative, have not been able to reduce these exorbitant death rates. Recently, a new form of treatment called immunotherapy has emerged. Immunotherapy allows the body’s immune system to fight off the tumor. However, while many clinical studies have shown that immunotherapy is effective in fighting advanced stage non-small cell lung cancer (NSCLC), the strict eligibility requirements of these trials have excluded many important and pertinent groups of patients, thus minimizing these studies’ applicability. This literature review examines current studies which have evaluated the correlation between the efficacy of immunotherapy and different important understudied patient groups such as those with poor Eastern Cooperative Oncology Group Performance Status (ECOG PS), never smokers, Epidermal Growth Factor Receptor (EGFR) mutation/Anaplastic Lymphoma Kinase rearrangements (ALK-R), galectin-3 expression, and immune-related adverse events (irAEs) outside of clinical trials. All these studies reveal that more research needs to be conducted in order to both verify the results of these studies in the broader patient population and further elucidate the efficacy of immunotherapy between more understudied groups. This would allow for a better selection of candidates for this treatment and lower costs, trouble, or harm for patients.

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INTRODUCTION

Lung cancer is the deadliest form of cancer, claiming the most lives of cancer patients world-wide. In 2020, it is estimated that 135,720 people will die of lung cancer in the US alone [1]. Only 25% of patients with lung cancer are diagnosed at an early stage and less than two thirds of those are able to find an effective treatment [2]. Chemotherapy, radiation therapy, and targeted therapy after surgery have all previously been the main treatment utilized for advanced stage non-small cell lung cancer (NSCLC), which accounts for approximately 80% of lung cancers [2]. While these treatments can greatly benefit patients with limited nodal disease and locally advanced tumors, microscopic resection followed by chemotherapy only improves the survival rate of patients with locally resectable tumors by 5%, indicating that new research on treatment options for later stages is extremely crucial and needed [2]. For this reason, immunotherapy, a form of treatment that was previously only used for metastatic melanoma is now also becoming a more common treatment for patients suffering from advanced NSCLC.

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Immunotherapy was first discovered by Dr. William B. Coley in 1891 when he used streptococcal vaccines to treat different cancers in patients [3]. He observed that the streptococcal organisms stimulated the patients’ immune systems through erysipelas, allowing for the immune system to attack the tumor cells [4]. Despite Coley’s success, doctors criticized his results as other innovative treatments such as chemotherapy arose, leading to immunotherapy being forgotten until recently [4]. While immunotherapy was previously only approved for a few types of tumors, recent scientific studies caused the U.S. Food and Drug Administration to approve two immunotherapy drugs for treatment of advanced NSCLC in 2015 [5]. In one such study by Brahmer et al. [6], 272 patients with advanced NSCLC received either nivolumab every 2 weeks or docetaxel every 3 weeks. Results showed that the overall survival (OS) for nivolumab, an immunotherapy treatment, was 9.2 months while the OS with docetaxel, a chemotherapy medication, was only 6.0 months [6].

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While this study proved the benefits of immunotherapy to treat advanced NSCLC, only patients with an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0-1 were eligible to be tested [6]. This strict criterion for the clinical trial excluded patients with greater disabilities and symptoms such as systemic immunosuppression, active CNS metastases, autoimmune diseases, and those who had received prior docetaxel, checkpoint-targeted, or systemic therapy [6]. As a result, the outcomes of this study are not representative of the broader patient population outside of clinical trials [7]. For this very reason, current studies have focused on testing the efficacy of immunotherapy on various understudied groups excluded from these original clinical trials. This literature review will first discuss the definition of immunotherapy and then analyze the efficacy of this treatment on those with poor Eastern Cooperative Oncology Group Performance Status (ECOG PS), never smokers, Epidermal Growth Factor Receptor (EGFR) mutation/Anaplastic Lymphoma Kinase rearrangements (ALK-R), galectin-3 expression groups, all who were typically excluded during older clinical trials. This will then be followed by an emphasis on an important and common yet understudied phenomena, immune-related adverse events (irAEs), and its effect on immunotherapy.  

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WHAT IS IMMUNOTHERAPY

As Coley discovered through his experiments, cancer is not only determined by characteristics of the tumor cells, but also dependent on the state of the immune system. In a process called immunotherapy, certain drugs are administered to the patient to help boost the immune response against the cancer cell [2]. Specifically, most immunotherapy research has been focused on regulatory immune-inhibitory pathways including programmed cell death protein-1 (PD1), the receptor found on activated T-cells, and programmed cell death protein-1 ligand (PD-L1), the ligand typically expressed on dendritic cells and macrophages [2]. These immune checkpoint proteins are co-inhibitory factors that regulate the activity of T cells to avoid harmful immune system responses [2]. However, PD-L1 is overexpressed on tumor cells and binds to PD-1 receptors on T cells to deactivate them [2]. Recent studies have been testing the efficacy of immune checkpoint inhibitors (ICIs) such as pembrolizumab or nivolumab that can block the ligation of PD1/PD-L1 in NSCLC patients with high PD-L1 expression [2]. Although monoclonal antibodies to PD1 and PD-L1 have been approved for clinical use, little is known regarding the performance of this treatment on other NSCLC groups such as poor ECOG PS, never smokers, EGFR mutation/ALK-R, galectin-3 expression, and irAEs patients that are not included in these clinical trials.

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EFFICACY OF IMMUNOTHERAPY ON UNDERSTUDIED GROUPS 

Current studies have been analyzing the efficacy and safety of immunotherapy for NSCLC in a non-clinical trial setting to better determine which patient populations are eligible for this treatment. A study by Dudnika et al. [8] treated 260 random patients suffering from advanced NSCLC with nivolumab and evaluated them for OS in order to study the efficacy and safety of nivolumab outside of clinical trials. Results showed that while most factors showed no relationship with OS, ECOG PS was the only variable which significantly correlated with changes in survival rates [8]. Patients with ECOG PS of 0-1 had a median OS of 9.5 months while patients with ECOG PS ≥2 had a median OS of 3.5 months [8]. According to Dudnika et al. [8], patients with poor prognosis, such as ECOG PS ≥2, are commonly underrepresented in clinical trials; however, they typically make up to 30-50% of the oncological patient population. Furthermore, patients with poor ECOG PS are prone to toxic treatment effects during systemic therapies, yet little data exists regarding the safety and efficacy of ICIs on these patients [8]. The discrepancy within these results indicates that the efficacy of immunotherapy is not as high as stated in the controlled clinical trials and varies widely depending on ECOG PS.

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A similar study used 613 patients previously treated for NSCLC and treated them with nivolumab every other week to provide efficacy and safety data outside of clinical trials [7]. Unlike the previous study, they included more understudied categories such as never smokers, EGFR mutations, and ALK-R, along with poor ECOG PS, in order to evaluate their correlation with the treatment [7]. These categories were specifically chosen for representation due to their typical exclusion from older clinical trials. The results from this study showed that the overall response rate (ORRs) of patients with never smoking status was 8%, mutated EGFR was 7%, ALK-R was 17%, ECOG PS 0–1 was 24%, ECOG PS 2 was 11%, and ECOG PS 3–4 was 4% [7]. These numbers reveal that never smokers, poor ECOG PS, and EGFR mutation/ALK-R were actually independent negative predictors of progression free survival (PFS) with nivolumab treatment, indicating thus again that the outcomes of the older clinical trials are not representative of all patients [7].

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Both of these newer studies reveal that clinical trials were inaccurate regarding the efficacy of immunotherapy due to their lack of representation of various understudied groups. The study by Dudnika et al. [8] showed that the clinical trials did not account for poor ECOG PS when testing for the efficacy of immunotherapy. Furthermore, the study by Fujimoto et al. [7] discovered that more understudied groups such as never smokers, EGFR mutations, ALK-R, and poor ECOG PS correlated with lower efficacy, suggesting again that the difference in results may have been due to the clinical trials excluding these patients. Future studies could further research the correlation between immunotherapy and more understudied categories to help better understand the efficacy of treatment on different patients.

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Additionally, patients with galectin-3 expression also have low immunotherapy efficacy. High galectin-3 expression is normally found in NSCLC tumor cells and can block apoptosis, increase cell proliferation, induce T cell apoptosis when shed, and allow for immune escape of the tumor [9]. A study by Capalbo et al. [9] sought to identify reliable predictive markers of tumor responsiveness in order to better select patients as candidates for immunotherapy. Researchers treated 34 patients expressing PD-L1 positive NSCLC with pembrolizumab and followed up with a retrospective immune-phenotypic analysis on the tumor biopsies to identify the galectin signature and its correlation with the success of the anti-PD1 immunotherapy [9]. The study revealed that 62% of these patients had high galectin-3-expressing tumors while 38% showed low galectin-3-expressing tumors [9]. 90% of patients with high expression of galectin showed a dramatic progression of NSCLC despite being treating with pembrolizumab [9].

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This novel study was the first to test the correlation between the expression of galectin-3 and immunotherapy, offering evidence that the efficacy of immunotherapy on understudied categories and markers, such as galectin-3 expression, should be further scrutinized to help make immunotherapy treatment more successful. To help solve this concern, the study also discovered an inexpensive immunohistochemical method, which could be used to evaluate the expression of galectin-3 in tumor cells before selecting the most responsive tumors or patients as candidates for immunotherapy [9]. This way, patients who are incompatible with pembrolizumab can avoid unnecessary exposure and treatment costs. However, the study only considered a small pool of the population. In order to confirm the result of the study, this research would need to include a bigger pool of patients of different categories before implementing the results into current treatment practices.

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IMMUNE-RELATED ADVERSE EFFECTS 

IrAEs, such as thyroid dysfunction and gastrointestinal toxicity, are common inflammatory side effects caused by nonspecific immune activation from ICIs [10]. While irAEs have been associated with increased efficacy of immunotherapy treatment in melanoma patients, the correlation between irAEs and ICIs in NSCLC has scarcely been investigated [10]. To further explore this, Sato et al. [10] treated 38 advanced NSCLC patients with nivolumab every 2 weeks for a duration of 102 days in a recent study. 28.9% of patients experienced an irAE; however, these patients had a favorable ORR (63.3%) compared to those without an irAE (7.4%) [10]. Those with an irAE also had PFS that lasted the entire study while those without only had a PFS of 49 days [10]. A similar study by Fujimoto et al. [11] assessed the effect of a specific and common irAE, pneumonitis, on the efficacy of immunotherapy. In this study, only six NSCLC patients with mild idiopathic interstitial pneumonia (IIP) were tested with 3 mg of nivolumab every other week [11]. Of these patients, 50% continued to have normal disease with a PFS of 3.0-3.8 months while 50% experienced partial response with a PFS of 6.5-9.1 months [11]. The study concluded that patients with IIP have a higher risk of the irAE pneumonitis when treated with immunotherapy; however even with these risks, the benefits of the immunotherapy for advanced NSCLC was still found to outweigh the risks of pneumonitis [11].

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Once again, these informative studies were some of the first to evaluate how immunotherapy affected patients who experienced an irAE. Through discovering vital information regarding the connection between irAEs and immunotherapy that can be utilized before administering treatment, researchers demonstrated the importance of understanding the efficacy of immunotherapy on understudied groups. However, as a pilot study, Fujimoto et al. [11] was not able to directly conclude anything regarding the correlation between the treatment and pneumonitis due to the extremely small sample size. Similarly, the study by Sato et al. [10] also only assessed a small cohort that was not necessarily representative of the general population. Both studies would need to be repeated with a much larger pool of patients and compared again to confirm these findings.

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CONCLUSION

Lung cancer is the most fatal type of cancer in adults, claiming thousands of lives every year. However, despite sophisticated treatment options, technological advancements, and innovative surgery techniques, death rates are still exorbitant. This has caused scientists to explore new forms of treatment such as immunotherapy, which allows for the body’s immune system to fight off the cancer cells on its own. While past clinical trials have approved the use of immunotherapy for NSCLC, new studies have revealed that these trials excluded many categories of patients; therefore, the results of these trials aren’t representative of all NSCLC patients. For this reason, newer research studies have been focusing on the efficacy of the treatment on understudied groups with NSCLC and have already found that never smokers, poor ECOG PS, EGFR mutation/ALK-R, and galectin-3 expression may lead to lower survival rates with immunotherapy while irAEs could lead to higher survival rates of patients. Future research should focus on verifying the results of these studies and further understanding the correlation between more understudied groups in clinical trials and the effectiveness of immunotherapy. This is critical because it would allow for a better selection of candidates for immunotherapy and lower costs, trouble, or harm for patients suffering from lung cancer.

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Conflicts of Interest: The author of this review has no conflicts of interest to disclose. 

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References: 

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