Clinical Trials In Non-small Cell Lung Cancer Research Articles

Women are Underrepresented in Non-small Cell Lung Cancer Clinical Trials: A Systematic Review.

To perform a systematic review of clinical trials examining non-small cell lung cancer (NSCLC) to better understand the equity afforded to women in the study of lung cancer. An electronic search was conducted for all NSCLC clinical trials published between 2010 and 2020 with included words "carcinoma, non-small cell, lung" and "non-small cell lung cancer." Studies from PubMed, Cochrane, and SCOPUS were included and were uploaded into Covidence to assist with systematic review. All articles were screened by two separate individuals and reviewed for location, study type, cancer stage, field of study of the research team, and percentage of females included. Student's t-test was used to compare the means of males and females. Across the 269 studies that met inclusion criteria, fewer females than males were enrolled (38.7% vs. 61.1%; p < 0.0001). Compared with studies from 2010 to 2015, those from 2016 to 2020 had greater representation of females (36.7% vs. 41.4%, p = 0.0091, respectively). Both nonsurgical and surgical studies enrolled fewer female than male patients (38.1% vs. 61.7%, p < 0.0001; 43.1% vs. 57.2%, p = 0.0002, respectively). Clinical trials from the USA had the least difference between sexes with an average of 46.7% females enrolled. Less females compared with males were enrolled in early-stage NSCLC (37.6% female vs. 62.6% male, p < 0.0001) and late-stage NSCLC trials (37.6% female vs. 62.0% male, p < 0.0001). Despite recent improvement, there continues to be significant underrepresentation of females compared with males in NSCLC clinical trials.

Women are Underrepresented in Non-small Cell Lung Cancer Clinical Trials: A Systematic Review.

To perform a systematic review of clinical trials examining non-small cell lung cancer (NSCLC) to better understand the equity afforded to women in the study of lung cancer. An electronic search was conducted for all NSCLC clinical trials published between 2010 and 2020 with included words "carcinoma, non-small cell, lung" and "non-small cell lung cancer." Studies from PubMed, Cochrane, and SCOPUS were included and were uploaded into Covidence to assist with systematic review. All articles were screened by two separate individuals and reviewed for location, study type, cancer stage, field of study of the research team, and percentage of females included. Student's t-test was used to compare the means of males and females. Across the 269 studies that met inclusion criteria, fewer females than males were enrolled (38.7% vs. 61.1%; p < 0.0001). Compared with studies from 2010 to 2015, those from 2016 to 2020 had greater representation of females (36.7% vs. 41.4%, p = 0.0091, respectively). Both nonsurgical and surgical studies enrolled fewer female than male patients (38.1% vs. 61.7%, p < 0.0001; 43.1% vs. 57.2%, p = 0.0002, respectively). Clinical trials from the USA had the least difference between sexes with an average of 46.7% females enrolled. Less females compared with males were enrolled in early-stage NSCLC (37.6% female vs. 62.6% male, p < 0.0001) and late-stage NSCLC trials (37.6% female vs. 62.0% male, p < 0.0001). Despite recent improvement, there continues to be significant underrepresentation of females compared with males in NSCLC clinical trials.

Development and preliminary validation of a platform for systematic, unbiased pre-screening of non-small cell lung cancer (NSCLC) across three community oncology practices.

e23230 Background: With a rapidly increasing number of candidate drugs and clinical trials in oncology, efficiency in clinical trial execution has become a primary focus area for innovation. Currently, fewer than 5% of oncology patients enroll in clinical trials, and data suggests a lack of diversity in clinical trial patient populations compared to the broader patient demographic. To address these issues, we developed a systematic unbiased pre-screening platform for all patients. This approach holds the promise of hastening clinical trials by enhancing the identification of eligible patients and concurrently promoting diversity among those invited to participate in these trials. Methods: A framework for use of EMR ingested data and standardized abstraction of select 160 variables was developed for patients with NSCLC. An algorithm based on 7 key eligibility criteria was developed to generate an automated assessment of eligibility for a presumed trial. Abstracted data was compared to a medical oncologist’s assessment (gold standard) and the automated tool was validated by comparing eligibility assessment before each visit with that of a medical oncologist. Results: Three community oncology practices in the US participated. Source data-verified values for histology, ECOG PS, treatment history, line of therapy, and current metastatic status were available for &gt; 90% of patients in real-time. Tumor NGS testing rates for actionable alterations exceeded 75%. From Oct 23, 2023 to Jan 14, 2024, 786 NSCLC pts had MD visits. Preliminary validation of the automated tool in 79 patients revealed concordant classification in 76/79 pts (96.2%). Sensitivity, specificity, PPV and NPV were &gt; 90%. Concordance for all variables was 98% between the abstractor and medical oncologist. Conclusions: A platform for systematic, unbiased pre-screening of patients for clinical trials in NSCLC has been developed to support and facilitate oncology sites without imposing financial or resource burdens or affecting routine clinical workflow. Preliminary validation supports high performance. Updated validation data will be presented in the meeting. The high levels of data completeness and quality, including NGS testing rates that are substantially higher than what has previously been reported in community centers, underscore their suitability as clinical trial sites.

Comparison of survival outcomes between clinical trial participants and non-participants of patients with advanced non-small cell lung cancer: A retrospective cohort study

BackgroundClinical trials for advanced non-small cell lung cancer (NSCLC) have been conducted extensively. However, the effect of participation in clinical trials on survival outcomes remains unclear. This study aimed to assess whether participation in clinical trials was an independent prognostic factor for survival in patients with advanced NSCLC. MethodsWe analyzed the medical records of patients aged ≥18 years who were newly diagnosed with stage IIIB or IV NSCLC and received chemotherapy or immunotherapy from September 2016 to June 2020 in this retrospective cohort study. To reduce the impact of confounding factors, propensity score matching (PSM) was performed. The Kaplan-Meier method and log-rank test were used to calculate and compare the overall survival (OS) and progression-free survival (PFS) of the patients. Finally, Cox proportional hazards regression was employed to examine the correlation between clinical trial participation and survival outcomes. ResultsThe study enrolled 155 patients in total, of which 62 (40.0 %) patients participated in NSCLC clinical trials. PSM identified 50 pairs of patients in total. The median PFS and OS of clinical trial participants and non-participants were 17.2 vs. 13.9 months (p = 0.554) and 32.4 vs. 36.5 months (p = 0.968), respectively. According to the results of multivariate Cox proportional hazards regression analysis, clinical trial participation was not an independent prognostic factor for advanced NSCLC patients (HR: 0.89, 95 % CI: 0.50–1.61; p = 0.701). ConclusionsThe clinical trial participants with advanced NSCLC displayed similar survival outcomes compared with the non-participating patients in this cohort.

Prevention of chemotherapy-induced neutropenia (CIN) with plinabulin (Plin) vs placebo (Plac) in patients (pts) with non-small cell lung cancer (NSCLC) treated with docetaxel (Doc): A pooled analysis from 3 randomized trials.

e21163 Background: CIN can lead to increased patient/healthcare burden, resource utilization, hospitalizations, and poorer quality of life (QoL). G-CSF has a high incidence of bone pain and mild thrombopenia and is given the day after chemo. Plin, a novel non-G-CSF small molecule, protects the bone marrow stem cell, has minimal bone pain, and protects platelet precursors. Plin is given on the same day as chemo and has NSCLC anticancer efficacy (ESMO 2021, Feinstein). The CIN effects of Doc plus Plin vs Doc with Plac were pooled from 3 NSCLC clinical trials. Methods: Data from randomized trials, phase (Ph) 3 trial 103 (NCT02504489), Ph2/3 trial 105 ( NCT03102606 ), and Ph2 trial 101 (NCT00630110) were pooled. Pts were randomized to either Doc (75mg/m2) plus Plin (20mg/m2 or its pharmacokinetic equivalent) (n = 146) or Doc plus Plac (n = 296). Doc was administered on day 1 of each 21-day cycle x 4 cycles, and Plin or Plac was administered ~30 minutes after Doc. Neutrophil counts were taken at predose and day (D) 8 of each cycle in studies 101 &amp; 103, and on predose, D1, 2, 6, 7, 8, 9, 10, 15, and 21 in study 105. Pts given G-CSF in D1-D3 were excluded. Duration of severe neutropenia (DSN) was calculated by methods previously reported (ASH 2022, Blayney). All Grade (Gr) and Gr4 neutropenia (N) rates, Absolute N count (ANC), febrile N (FN) rate, and ANC on D8 (‘nadir’) were obtained. QoL scores were obtained in studies 103 and 105 by EORTC QLQ-C30. Patient-reported adverse events (AEs) were collected. Results: Pt demographics were comparable. Plin was statistically and clinically significantly superior to Plac for All Gr and Gr4 N frequencies, Day 8 ANC (‘nadir’), and DSN (all had p &lt; 0.0001). Febrile Neutropenia (FN) and infection rates were numerically lower (see table). Fewer pts were treated with antibiotics among pts treated with Plin. Platelet count was unaffected with Plin; grade (gr) 3/4 thrombocytopenia was &lt; 1% with either Plin or Plac. The total frequency of treatment-emergent AEs for Plin vs Plac were 71% vs 80%. QoL scores were similar for Plin and Plac. Conclusions: In 3 independent randomized studies (101, 103, and 105), Plin demonstrated a superior benefit for CIN and showed clinical benefit for infection rate versus Plac. Additionally, Plin has the added benefits of pt convenience (same-day dosing and no additional visits or wearable device), a favorable safety and tolerability profile, anticancer efficacy, and QoL maintenance, which represents a distinct advantage over G-CSF. Clinical trial information: NCT02504489 ; NCT03102606 ; NCT00630110 . [Table: see text]

Abstract 6429: A surrogate to the anti-IL1RAP antibody nadunolimab induces tumor microenvironment changes to the metastatic lung and reduces metastatic lesions in mouse models of metastatic cancer

Abstract Interleukin-1 Receptor Accessory Protein (IL1RAP) is a coreceptor for the IL-1 receptor (IL1R1) and is required for IL-1α and IL-1β signaling. IL1RAP is expressed in the tumor microenvironment (TME); on cancer cells, stromal cells and on infiltrating immune cells in several types of cancers, including non-small cell lung cancer (NSCLC), pancreatic cancer (PDAC), triple-negative breast cancer (TNBC) and in metastatic lesions. Nadunolimab (CAN04) is a fully humanized ADCC-enhanced IgG1 antibody targeting IL1RAP and blocking both IL-1α and IL-1β signaling, currently evaluated in combination with chemotherapy in phase I/II clinical trials in NSCLC and PDAC (NCT03267316) and in TNBC (NCT05181462). Interim efficacy data are available for PDAC and NSCLC and are stronger than expected from chemotherapy alone based on historical controls; in a total of 73 PDAC patients, median iPFS is 7.2 months and median OS 12.7 months, while in a total of 30 NSCLC patients, a response rate of 53% is achieved, resulting in median PFS of 6.8 months. Microenvironmental IL1RAP-dependent IL-1 signaling contributes to tumorigenesis, tumor invasiveness and an immune-suppressive TME, partly driven by infiltration and induction of myeloid-derived suppressor cells (MDSCs). We have thus used the MDSC-rich 4T1 murine mammary tumor TNBC model to study metastatic lesions and TME modulation in 4T1 metastatic lungs upon treatment with a mouse surrogate antibody to nadunolimab. Infiltration of gMDSC/Ly6G+ cells was very prominent in metastatic lungs from mice with orthotopically implanted 4T1 breast cancer cells compared to lungs from naive mice. Interestingly, infiltrating Ly6G+ cells from metastatic lungs had a distinctly upregulated IL1RAP expression compared to Ly6G+ cells from naïve lungs. Treatment with the nadunolimab surrogate antibody significantly reduced the number of lung metastases and induced prominent changes in the lung microenvironment where nanostring analysis showed global changes in adhesion and migration-related genes, as well as genes associated with cell activation. The effect on metastasis was not confined to the 4T1 model since a reduction of metastatic tumor cells after treatment with the mouse surrogate antibody was also observed in the murine B16-F10-luc i.v. model. Together these data indicate that targeting IL1RAP is an effective way to modulate the TME and counteract the suppressive environment in metastatic tissue, and ultimately may reduce the potential for metastatic tumors in cancer patients. Citation Format: Elin Jaensson Gyllenbäck, Camilla Rydberg Millrud, Petter Skoog, Caitríona Grönberg, David Liberg. A surrogate to the anti-IL1RAP antibody nadunolimab induces tumor microenvironment changes to the metastatic lung and reduces metastatic lesions in mouse models of metastatic cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6429.

Effectiveness of immunological agents in non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) continues to claim millions of lives worldwide. Although its poor prognosis is largely attributed to the lack of adequate and precise detection technologies, cancer cells' suppression of the immune system adds on to the difficulty of identifying abnormal NSCLC tumors in their early stages. Therefore, cancer immunotherapy, which activates the immune system and helps it fight tumors, has recently become the most sought-after technique, especially in the advanced stages of NSCLC, where surgery or chemotherapy may or may not bring about the desired survival benefits in patients. This review focuses on the various immunotherapeutic interventions and their efficacy in advanced NSCLC clinical trials. Monoclonal antibodies like anti-PD-1/PD-L1 agents and anti-CTLA-4 antibodies, cancer vaccines, oncolytic viruses and adoptive T cell therapy have been discussed in brief. Furthermore, the effects of gender, age, and race on the efficacy of immune checkpoint inhibitors and suggest plausible future approaches in the realm of immuno-oncology. Immunotherapy is used alone or in combination either with other immunological agents or with chemotherapy. However, the efficacy of these strategies depends extensively on various demographic variables, as some patients respond perfectly well to immunotherapy, while others do not benefit at all or experience disease progression. By targeting a "hallmark" of cancer (immune evasion), immunotherapy has transformed NSCLC management, though several barriers prevent its complete effectiveness. All these immunological strategies should be interpreted in the current setting of synergistic treatment, in which these agents can be combined with chemotherapy, radiotherapy, and, or surgery following patient and tumor characteristics to proportionate the best-individualized treatment and achieve superior results. To better pursue this goal, further investigations on cost-effectiveness and sex-gender, race, and age differences in immunotherapy are needed.

Health-related quality of life is underestimated and underreported in phase III clinical trials in NSCLC

Major associations of medical oncologists remark that novel anticancer treatments should guarantee improvement of survival outcomes as well as of patients’ quality of life (QoL). Herein, we investigated QoL assessment and reporting in phase III randomized controlled trials (RCTs) testing new drugs in metastatic non-small cell lung cancer (NSCLC), published between 2010 and 2021. We selected 172 RCTs for further analysis. Only 2/172 (1.2%) trial included QoL among primary study endpoints. Of note, 40/172 (23.3%) trials did not include QoL assessment among endpoints. The majority of RCTs (102/172, 59.3%) did not report QoL results in primary publications. Particularly, RCTs testing immunotherapy, target therapy and chemotherapy did not disclose QoL data in primary publications in 97.0%, 51.5% and 46.5% of cases, respectively. Next, we found that only 43/95 (45.3%) positive studies reported QoL results in primary articles. Of the 102 trials missing QoL data in primary manuscripts, only 21 (20.6%) disclosed QoL results in a secondary publication. Finally, we found a common fail in adherence to CONSORT-PROs items in publications reporting QoL results. In summary, our study reveals a relevant inadequate assessment and under-reporting of QoL in RCTs of novel systemic treatments for patients with metastatic NSCLC.

Association of community cancer centers key quality care recommendations for stage IB to IIIA non–small cell lung cancer.

30 Background: Early-stage diagnosis of non-small cell lung cancer (NSCLC) provides patients the best opportunity for long-term survival. There are documented deficiencies, however, in the quality of care many receive. Optimal care for persons with early-stage NSCLC requires a well-coordinated, multifaceted approach. The Association of Community Cancer Centers (ACCC) assembled a group of experts to create a quality document to guide care for persons with early-stage NSCLC. Methods: We convened an expert panel of lung cancer specialists with expertise in medical oncology, thoracic surgery, radiation oncology, oncology nursing, and epidemiology. The panel developed a document with 30 key quality recommendations for care of persons with stage IB to IIIA NSCLC. Evidence-based recommendations were incorporated from American Society of Clinical Oncology, International Association for the Study of Lung Cancer, American Society for Radiation Oncology, Commission on Cancer, and National Comprehensive Cancer Network guidelines and recommendations. A consensus decision-making model was utilized and recommendations were compiled in tabular format. Results: The key areas identified by the committee were: Care Coordination and Patient Education, Diagnosis and Biomarker Testing, Staging and Treatment Planning, and Post-Treatment Survivorship Care. Highlights of Care Coordination and Patient Education included shared decision-making, access to a care navigator, psychosocial support and patient education on NSCLC management, clinical trials, smoking cessation and tobacco dependence interventions, and community resources. Diagnosis and Biomarker Testing recommendations include multidisciplinary evaluation and care coordination, biomarker testing (eg, EGFR) in patients with stage IB to IIIA NSCLC who may be eligible for targeted therapy, PD-L1 testing in patients with resected stage II to IIIA NSCLC, and discussing post-resection targeted therapy. Staging and Treatment Planning recommendations include invasive staging, multimodality staging as appropriate, multidisciplinary treatment planning, and post-resection initiation of adjuvant therapy within 60 days when given. Recommendations for Post-Treatment Survivorship Care include implementation of standard surveillance, survivorship care plans, access to palliative care services, and sustained assessment of distress and referral to psychosocial support services. Conclusions: Well-coordinated, evidence-based care delivery is paramount to achieving the best outcome for individuals with early-stage NSCLC. The ACCC quality care document is an expert designed tool, combining evidence-based recommendations from multiple sources, to help achieve this goal.

In This Issue

In This Issue

Neoadjuvant and Adjuvant Immunotherapy in Non-Small Cell Lung Cancer-Clinical Trials Experience.

Across all tumor types, we observe that the role of immunotherapy has increased rapidly. Due to a number of potential advantages, it is considered in neoadjuvant treatment of localized tumors. In neoadjuvant settings, immunotherapy addresses micrometastatic diseases at the moment of their formation. However, some issues concerning neoadjuvant and adjuvant immunotherapy still has to be covered. The choice of drug and use of monotherapy or combination regimens remains unclear. The timing of surgery and preoperative evaluation of neoadjuvant immunotherapy efficacy is challenging. Although there is currently limited confirmed clinical data to support the use of immune checkpoint blockade in the neoadjuvant and adjuvant settings, there are many studies exploring this strategy in NSCLC patients.

Improvements in access to cancer clinical trials facilitated by comprehensive genomic profiling in non-small cell lung cancer.

59 Background: The use of comprehensive genomic profiling (CGP) in cancer patients could lead to additional enrollment in clinical trials that study novel genetic biomarkers, potentially reducing treatment costs for payers and improving health outcomes for patients. Our objective was to estimate the number of additional clinical trials in which patients with non-small cell lung cancer (NSCLC) could potentially enroll due to the use of CGP vs. a comparator panel of 50 genes or less. Methods: Clinical trials in NSCLC that started between 2015 - 2020 were identified from the Aggregate Analysis of ClinicalTrials.gov (AACT) database. Trials with unknown status or study sites outside the United States only were excluded. We abstracted information on required genetic alterations based on the study eligibility criteria. We calculated the incremental number of trials available to patients due to results generated by CGP (FoundationOne CDx, 324 genes) vs. a commercially available comparator panel that was 50 genes or less (Oncomine Dx Target Test, 23 genes) by phase and calendar year. The additional trials were characterized by disease severity, type of therapy, and setting. Results: Enrollment eligibility was dependent on genetic variant status in 35% (250/709) of all identified NSCLC trials. There were 29 (248 vs. 219) additional clinical trials available to patients through the use of CGP, 12% of all gene-specific trials for NSCLC. We identified 45 uses of genetic markers in the 29 additional clinical trials. The most frequent genetic marker in the incremental trials was microsatellite instability, accounting for 44% of all identified markers (20/45). The incremental number of trials available to patients due to the use of CGP did not vary significantly over time but varied by phase – most of the additional clinical trials were in phase 1 or 2 (28/29, 97%). Most of the incremental trials were in metastatic disease (22/29, 76%) and were conducted in academic or advanced community settings (18/29, 62%). The most frequently studied type of intervention in these studies was targeted monotherapy (8/29, 28%), followed by immuno-monotherapy (7/29, 24%). Conclusions: Clinical trials in NSCLC initiated over the past 5 years have consistently included CGP-specific genes or markers in eligibility criteria. Patients with NSCLC have the potential to benefit from the use of CGP as compared to smaller gene panels through improved access to clinical trials.[Table: see text]

P16.06 Comparison of Clinical Outcomes of Patients With Advanced NSCLC In Clinical Trials and in the Real World Received PD-1/PD-L1 Inhibitor

Although PD-1/PD-L1 inhibitors have become the standard treatment for patients with advanced non-small cell lung cancer (NSCLC), data from clinical trials are difficult to be verified in the real world. This study aims to compare the differences in population characteristics, treatment modes and clinical outcomes of advanced NSCLC patients received PD-1/PD-L1 inhibitors between the real-world (RWS) and the clinical study (RCT).

Abstract 953: Efficacy of amivantamab, a bispecific EGFR/MET antibody, correlates with EGFR expression and signaling in NSCLC models with wild-type EGFR

Abstract Small molecule EGFR inhibitors have proven effective in treatment of Non-Small Cell Lung Cancer (NSCLC) with activating EGFR mutations, however there is minimal to no efficacy in wild-type EGFR NSCLC. Amivantamab, an EGFR/MET bispecific antibody, has demonstrated clinical activity across a diverse range of EGFR activating mutations in an ongoing Phase I trial and differentiates from anti-EGFR antibodies tested previously in NSCLC clinical trials due to dual targeting and enhanced interaction with Fc receptors on immune cells. As candidate biomarkers to predict response in wt EGFR disease, EGFR and MET expression (immunohistochemistry (IHC)) and signaling (proximity ligation assays (PLA)), as well as tumor associated macrophage (TAM) content, were assessed in 39 NSCLC wt EGFR patient-derived xenograft (PDX) models. A strong correlation (EGFR r=0.63; p&amp;lt;0.0001; MET r=0.83; p&amp;lt;0.0001) between the IHC and PLA scores for both EGFR and MET confirmed the expected link between signaling level and receptor expression. Based on these data, 14 models with different levels of EGFR and MET expression and TAM infiltration were selected for amivantamab efficacy assessment. While no correlation was found between MET IHC H-score and efficacy, positive correlations were identified between EGFR H-score and PLA-score to amivantamab efficacy. Exclusion of models with known oncogenic driver mutations downstream of EGFR and MET, such as KRAS and PI3K, led to strong correlations to both EGFR expression and signaling (IHC - r=0.90; p=0.002; PLA - r=0.92; p=0.001). Indeed, models with EGFR H-score ≥170 and no alternative driver mutations achieved prolonged tumor stasis or complete tumor regressions with amivantamab treatment. No correlation between TAM content and amivantamab efficacy was observed. Previous studies have demonstrated superior amivantamab efficacy in models driven by either mutant EGFR or amplification of MET, compared to a version lacking Fc interaction; however, both antibodies demonstrated similar efficacy in 13 out of 14 NSCLC wt EGFR PDX models. This suggests that while amivantamab efficacy requires Fc-interaction in models driven by EGFR mutation or MET amplification (ligand-independent), the Fc-interaction is not required for efficacy in wt EGFR driven NSCLC models. We hypothesize that NSCLC PDX models with higher levels of wt EGFR are more growth dependent on EGFR ligands, and thus inhibited by the ligand blocking activity of amivantamab. The lack of species cross-reactivity with the MET ligand HGF, likely underestimates MET signaling dependencies in these mouse models, although this may play a role in patient tumors. These findings suggest NSCLC patients with elevated wt EGFR expression and lacking driver mutations may achieve therapeutic benefit from amivantamab treatment. Citation Format: Benjamin Henley, Kristen Chevalier, Matthew Smith, Smruthi Vijayaraghaven, Barbara Bushey, Gerald Chu, Joshua Curtin, Nataša Obermajer, Kathryn Packman, Sylvie Laquerre, Matthew Lorenzi, Eric Haura, Sheri Moores. Efficacy of amivantamab, a bispecific EGFR/MET antibody, correlates with EGFR expression and signaling in NSCLC models with wild-type EGFR [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 953.

Modern Challenges for Early-Phase Clinical Trial Design and Biomarker Discovery in Metastatic Non-Small-Cell Lung Cancer

Oncology research has changed extensively due to the possibility to categorize each cancer type into smaller subgroups based on histology and particularly on different genetic alterations due to their heterogeneity. The consequences of this heterogeneity are particularly evident in the management of metastatic non-small-cell lung cancer (NSCLC). This review will discuss the benefits and challenges of incorporating precision medicine into early- through late-phase metastatic NSCLC clinical trials, discussing examples of drug development programs in oncogene- and non-oncogene-addicted NSCLC. The experiences of clinical development of crizotinib, gefitinib and osimertinib are depicted showing that when a targeted drug is administrated in a study population not selected by any biomarker, trials could produce negative results. However, the early detection of biomarker-driven biology helps to obtain a greater benefit for a selected population and can reduce the required time for drug approval. Early clinical development programs involving nivolumab, pembrolizumab and avelumab, immune checkpoint inhibitors, taught us that, beyond safety and activity, the optimal selection of patients should be based on pre-specified biomarkers. Overall, the identification of predictive biomarkers is one of the greatest challenges of NSCLC research that should be optimized with solid methodological trial designs to maximize the clinical outcomes.

P25.10 Computational Simulations on Safety of Tumor Treating Fields Delivered to the Lungs in Mesothelioma and NSCLC

Tumor Treating Fields (TTFields) inhibit cancer cell division by utilizing low intensity alternating electric fields in the intermediate frequency. TTFields are FDA-approved for glioblastoma and malignant pleural mesothelioma (MPM). The phase 2 trial STELLAR trial (Ceresoli et al, Lancet Onc 2019; NCT02397928) demonstrated promising results with a median overall survival of 18.2 months (95% CI 12.1‍–‍25.8) in patients with MPM treated with TTFields plus standard of care chemotherapy. The efficacy of TTFields therapy depends on the frequency of the electric field: 150 kHz is the optimal frequency for MPM and Non-Small-Cell lung cancer (NSCLC). Preclinical studies suggest that treatment efficacy increases with the intensity of the electric field. The higher the field intensity, the larger the therapeutic effect, with a therapeutic threshold of 0.7 V/cm above which TTFields exert a significant anti-mitotic effect. However, Delivery of an electric field to the body unavoidably leads to deposition of heat in the tissue, and it is important to insure that TTFields are delivered in an optimal manner so as not to lead to thermal damage of the patient’s tissues. Here we performed numerical simulations to determine the thermal safety of TTFields at therapeutic levels delivered to the upper torso. Delivery of TTFields to the thorax of computational models using the Optune Lua device was simulated. Male, female, and obese models (Virtual Population, IT’IS foundation) were used. Numerical simulations were performed using Sim4life (v3.0, ZMT Zurich). The field intensities within the lungs of the models were evaluated. Thermal safety was analyzed using specific absorption rate (SAR), which is a metric for assessing heating due to electromagnetic absorption. The simulations showed that for all 3 models, the Optune Lua device delivers TTFields at therapeutic intensities greater than 0.7 V/cm RMS to cover at least 76% of the lungs. SAR values within the internal organs were generally below the levels at which thermal damage occurs (10 W/kg) as set out in the ICNIRP guidelines for occupational exposure (Health Phys 1998;74:494–522) with maximum SAR levels not exceeding 20 W/kg. In the superficial body layers higher SAR values were observed. However, the Optune Lua device incorporates temperature control that prevents the skin from heating to levels at which thermal damage can occur. The results of this study support the observations that Optune Lua delivers TTFields to the lungs at therapeutic levels in a manner that is unlikely to cause thermal damage in patients. Optune Lua is safe for use in MPM and NSCLC. These data will help in ongoing and planned NSCLC clinical trials, such as the phase 3 LUNAR trial [NCT02973789] that is currently investigating the efficacy of TTFields therapy combined with immune checkpoint inhibitors or docetaxel.

Canagliflozin Mediates Effective Blockade of the mTORC1 - HIF-1a Pathway, Inhibits Growth and Enhances Non-Small Cell Lung Cancer (NSCLC) Response to Radiotherapy (RT)

Alterations in NSCLC cell metabolism contribute to rapid tumor growth, resistance to RT and poor prognosis. The mammalian Target of Rapamycin Complex 1 (mTORC1) - Hypoxia-Inducible Factor-1α (HIF-1α) pathway mediates expression of the Warburg glycolytic phenotype in NSCLC and induces RT resistance. Earlier, we showed that the new diabetes agent Canagliflozin (CANA), developed to control hyperglycemia through inhibition of the renal Na+-glucose co-transporter 2 (SGLT2), also inhibits mitochondrial complex I respiration and blocks mTORC1 signaling. In this study, we analyzed CANA’s transcriptional and post-translational effects and its regulation on RT response in preclinical models of NSCLC. Cell proliferation and clonogenic survival assays were used to assess the efficacy of CANA (0–30 μM) and RT (0–8 Gy) in adenocarcinoma (A549, H1299, H1975) and squamous cell carcinoma (SK-MES-1) NSCLC cells. Protein immunoblotting, RT-qPCR and RNAseq of A549 NSCLC cells were performed to study regulation of pathway activation and gene expression in response to CANA and RT. In-vivo effects of the two agents were examined with ectopic A549 xenografts grown in immunodeficient nude mice treated with CANA (100 mg/kg/day in chow diet) and/or RT (5 Gy). RNAseq showed that clinically achievable CANA doses (10 μM) mediate profound regulation of NSCLC cell transcriptional activity with over 100 upregulated and 80 downregulated genes. CANA significantly downregulates HIF-1α pathway-related genes that mediate HIF-1α stability and nuclear transfer, glycolysis and lipogenesis, tyrosine kinase receptor signaling and inhibition of apoptosis. CANA treatment led to activation of AMP-activated protein kinase (AMPK) and blockade of the mammalian target of rapamycin complex 1 (mTORC1) pathway. It abolished phosphorylation of the mitosis marker, histone H3. This was consistent with long-term induction of the G1/S cyclin-dependent kinase inhibitor p27kip1. Clinically relevant doses of CANA suppressed proliferation and clonogenic survival in all NSCLC cell lines but this was enhanced in the K-Ras mutant/LKB1null A549 cells. Combination index analysis indicated additivity and sensitization interaction between the CANA and RT anti-proliferative effects. In the A549 xenograft model, CANA enhanced the cytotoxic effects of RT in an additive manner. CANA mediates effective suppression of the mTORC1-HIF-1α pathway, regulates gene expression and mediates potent anti-tumor activity in NSCLC models in-vitro and in-vivo. Given that CANA is a widely-used, well-tolerated and economical agent, this work indicates strong potential for this agent to be investigated rapidly in NSCLC clinical trials in combination with RT.

Phenotyping clinical trial treatment regimens in cancer: An integrative ontology, artificial intelligence and knowledge engineering approach.

e14054 Background: Matching clinical attributes (i.e. indications, lab tests, treatment regimens) of clinical trial eligibility criteria with real world patient data is extremely challenging. Attribute phenotyping is one of the key components of Trial2Patient, a customized system developed by Sema4 to find patients for clinical trials. Transforming treatment regimens to a standard ontology and encoding drugs with standard nomenclatures will facilitate the semantic retrieval of treatments mentioned in clinical trial criteria. This will also enable the interoperation between different data sources that is often required for fast-learning and scalable healthcare information system. Methods: Free text containing treatment regimen/medication terms were extracted and preprocessed from three sources: 1) clinical trials listed in a commercial database citeline.com, 2) clinical trials listed in clinicaltrials.gov, and 3) National Comprehensive Cancer Network (NCCN) Guidelines. The regimen terms such as neoadjuvant therapy for non-small cell lung cancer, checkpoint inhibitor, EGFR inhibitor, androgen deprivation therapy (ADT), among many others, were profiled by AI methods (i.e. pattern reorganization and rule-based) and knowledge engineering via Sema4’s in-house knowledge base (CAV), Pharmaprojects in citline.com and NCCN Guidelines. The drugs related to each regimen were identified and mapped to RxCUI via RxNorm ontology. Results: We identified 76 regimen terms for non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC) and prostate cancer (e.g. PD-L1 ≥1% nonsquamous NSCLC, bone antiresorptive therapy for M1 castration resistant prostate cancer), and 14,476 drug-category pair (e.g. pembrolizumab is a PD-1 inhibitor, pembrolizumab is used as the third line and beyond systemic therapy for M1 CRPC). All drugs identified were mapped to RxCUI for real world patient matching. Conclusions: This approach systematically extracted and normalized regimens and medications mentioned in clinical trials in NSCLC, SCLC and prostate cancer to standard codes. These standardized data can be used in mapping treatment histories of a patient to the eligibility criteria for clinical studies or for identifying studies relevant to a patient. The outcome of profiling cancer treatment regimens through standard ontology RxNorm may be particularly valuable in cancer studies based on real-world evidence.

CM082, a novel angiogenesis inhibitor, enhances the antitumor activity of gefitinib on epidermal growth factor receptor mutant non-small cell lung cancer in vitro and in vivo.

BackgroundCM082 is a novel angiogenesis inhibitor targeting vascular endothelial growth factor receptor (VEGFR) and platelet‐derived growth factor receptor (PDGFR). The purpose of this research was to evaluate the antitumor activity of CM082 combined with gefitinib on epidermal growth factor receptor (EGFR) mutant non‐small cell lung cancer (NSCLC) in vitro and in vivo.MethodsThe effect of CM082 on human umbilical vein endothelial cells (HUVECs) was assessed. In vitro and in vivo efficacy of CM082 combined with gefitinib on EGFR NSCLC cell lines (HCC827 harboring E746_A750 deletion and H3255 harboring L858R) and a xenograft model was evaluated.ResultsCM082 inhibited VEGF‐induced cell growth, phosphorylation of VEGFR and downstream signaling molecules, tube formation, and cell migration of HUVECs. Furthermore, CM082 combined with gefitinib was more effective in inhibiting growth and colony formation and inducing apoptosis of H3255 and HCC827 cells in vitro than monotherapy. Moreover, tumor growth inhibition by the combination in a H3255 xenograft model was 107.7% more than that by gefitinib (93.6%) (P < 0.0001) and CM082 (51.4%) (P < 0.0001) alone. In addition, coadministration had a better effect on inhibiting cell proliferation, inducing apoptosis, and inhibiting the expression of CD31 and VEGF‐A. The combination therapy had a stronger inhibition effect on STAT3 phosphorylation than monotherapy.ConclusionsCM082, a novel angiogenesis inhibitor, enhances the antitumor activity of gefitinib on EGFR mutant NSCLC by inhibiting proliferation and angiogenesis and promoting apoptosis of tumor cells.Key points Significant findings of the study CM082, a novel angiogenesis inhibitor, enhances the antitumor activity of gefitinib on EGFR mutant NSCLC by inhibiting proliferation and angiogenesis and promoting apoptosis of tumor cells. What this study adds These findings justify evaluation of the efficacy of CM082 combined with gefitinib in patients with EGFR mutant advanced NSCLC in clinical trials.

Effectivity and safety of PD-1/PD-L1 inhibitors for different level of PD-L1-positive, advanced NSCLC: A meta-analysis of 4939 patients from randomized controlled trials

BackgroundEffective improvement for the programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) inhibitors had been shown in advanced non-small cell lung cancer (NSCLC) patients compared with traditional therapy. However, we do not have ample evidences to demonstrate the safety and effectivity in the treatment of PD-L1-positive, advanced NSCLC. The relation was controversial about the expression of PD-L1 and survival outcomes of PD-1/PD-L1 inhibitors. Materials and methodsElectronic databases (PubMed, EMBASE, and the Cochrane library) and major conference proceedings were systematically searched for all clinical trials in NSCLC using PD-1/PD-L1 inhibitors. Randomized controlled trials (RCTs) were included to compare PD-1/PD-L1 inhibitors with chemotherapy in advanced NSCLC patients reporting adverse events (AEs) and immune-related AEs (irAEs). The incidence, Hazard Ratio (HR), Odds Ratio (OR), and corresponding 95% confidence interval (CI) of outcomes were calculated. ResultsA total of 4939 patients from 10RCTs were included. In the group of PD-L1 ≥ 1%, PD-L1 ≥ 5%, PD-L1 ≥ 10%, PD-L1 ≥ 50%, the HR of OS is 0.31(95%CI 0.38–0.23; p < 0.0001), 0.47(95%CI 0.82–0.12; p = 0.008), 0.85(95%CI 1.17–0.53; p < 0.0001), 0.47(95%CI 0.59–0.36; p < 0.0001) respectively. The HR of PFS is 0.13(95%CI 0.01–0.24; p = 0.027), 0.31(95%CI 0.00–0.62; p < 0.0001), 0.62(95%CI 0.30–0.93; p < 0.0001), 0.40(95% CI 0.20–0.59; p < 0.0001) respectively. In terms of summary adverse events, PD-1/PD-L1 inhibitors groups had a significant lower risks in any treat-realated AEs than chemotherapy. About irAEs, PD-1/PD-L1 inhibitors groups had a significant higher risks in irAEs than chemotherapy. ConclusionPD-1/PD-L1 inhibitors are generally effected and safer than chemotherapy for patients with PD-L1-positive, advanced NSCLC. However, PD-1/PD-L1 inhibitors can generate a unique spectrum of irAEs, and even life-threatening.