Trials In Non-small Cell Lung Cancer Research Articles

Augmenting external control arms using Bayesian borrowing: a case study in first-line non-smallcell lung cancer.

Aim: This study aimed to improve comparative effectiveness estimates and discuss challenges encountered through the application of Bayesian borrowing (BB) methods to augment an external control arm (ECA) constructed from real-world data (RWD) using historical clinical trial data in first-line non-small-cell lung cancer (NSCLC). Materials & methods: An ECA for a randomized controlled trial (RCT) in first-line NSCLC was constructed using ConcertAI Patient360™ to assess chemotherapy with or without cetuximab, in the bevacizumab-inappropriate subpopulation. Cardinality matching was used to match patient characteristics between the treatment arm (cetuximab+chemotherapy) and ECA. Overall survival (OS) was assessed as the primary outcome using Cox proportional hazards (PH). BB was conducted using a static power prior under a Weibull PH parameterization with borrowing weights from 0.0 to1.0 and augmentation of the ECA from a historical control trial. Results: The constructed ECA yielded a higher overall survival (OS) hazard ratio (HR) (HR=1.53; 95% CI: 1.21-1.93) than observed in the matched population of the RCT (HR=0.91; 95% CI: 0.73-1.13). The OS HR decreased through the incorporation of BB (HR=1.30; 95% CI: 1.08-1.54, borrowing weight=1.0). BB was applied to augment the RCT control arm via a historical control which improved the precision of the observed HR estimate (1.03; 95% CI: 0.86-1.22, borrowing weight=1.0), in comparison to the matched population of the RCT alone. Conclusion: In this study, the RWD ECA was unable to successfully replicate the OS estimates from the matched population of the selected RCT. The inability to replicate could be due to unmeasured confounding and variations in time-periods, follow-up and subsequent therapy. Despite these findings, we demonstrate how BB can improve precision of comparative effectiveness estimates, potentially aid as a bias assessment tool and mitigate challenges of traditional methods when appropriate external data sources are available.

Abstract 6187: Multimodal characterization of tertiary lymphoid structures identified via deep learning on digitized H&E images in NSCLC

Abstract Background: Tertiary lymphoid structures (TLS) have recently shown association with improved outcomes for patients treated with immunotherapy across several cancer types. But pathologist-led identification of TLS on routine hematoxylin and eosin (H&E) stained images is time-consuming & lacks standardization. We developed a deep learning (DL) approach to identify TLS on digitized H&E whole slide images (WSI) of non-small cell lung cancer (NSCLC). We also elucidate underlying identified TLS biology by investigating corresponding transcriptomic profiles & multiplex immunofluorescence (mIF) images. Methods: DL model was trained using mature TLS (mTLS) annotated by 5 board-certified pathologists following standardized definitions across WSI of NSCLC, breast & bladder cancers. Model was validated using blinded, exhaustive annotations on 60 WSI by the same pathologists in consensus. To identify underlying biology associated with model-identified TLS presence, phase 3 clinical trial of advanced NSCLC with H&E and corresponding bulk RNA-Seq was analyzed using differentially expressed genes(DEG). Cellular phenotypes of model-identified TLS were elucidated in procured NSCLC WSI labeled with mIF panel & then H&E stained. Results: DL model achieved a validation F1-score of 0.56 (precision=0.52). DEG analyses resulted in significant association of TLS related gene signatures with model-identified TLS presence (q<0.05). Immuno-histopathological evaluation of model-identified mTLS revealed concordance with central clusters of CD20+ B cells surrounded by a mix of CD20+ B & CD3+ T cells. Conclusions: We developed a DL model to detect TLS in H&E WSI & demonstrated their concordance in transcriptomics and mIF. With further validation, DL identified TLS could potentially serve as an imaging-based biomarker in clinical outcome datasets. Table 1. Data distribution for instance-based deep learning model training, validation and independent deployment A. Model development Cancer type Training Validation Digitized H&E Slides with mTLS by Pathologists mTLS countby Pathologists Digitized H&E Slides tested mTLS count by Pathologists (in consensus) True positive mTLS count(Model identified) NSCLC 98 283 20 99 57 Breast 107 315 20 48 35 Bladder 103 262 20 65 48 B. Model deployment in independent cohorts NSCLC Dataset H&E images Other corresponding modality Samples Total Digitized Slides Digitized H&E Slides with mTLS by Pathologists Digitized H&E Slides with model identified TLS OAK (clinical trial, NCT02008227) 320 68 55 Matched patients with RNA seq 282 Procured 23 6 4 Matched slides with mIF panel (pan-cytokeratin, CD3, CD8, CD163/68, CD20, CD138, BCMA, DC-LAMP) 23 Citation Format: Niha Beig, Evan Liu, Geoffrey Schau, Assaf Amitai, Barzin Nabet, Rajiv Jesudason, Eloisa Fuentes, Hartmut Koeppen, Sertan Kaya, Namrata S. Patil, Minu K. Srivastava, Robert Johnston, Cleopatra Kozlowski, Jennifer Giltnane, Daniel Ruderman. Multimodal characterization of tertiary lymphoid structures identified via deep learning on digitized H&E images in NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6187.

Exploratory Assessment of Galectin-1, -3, and -9 in Non-Small Cell Lung Cancer.

Galectins play a pivotal role in lung cancer oncogenic pathways, influencing apoptosis, angiogenesis, and tumor metastasis. Biomarkers that diagnose, prognose, and guide cancer treatment are crucial, with galectins having the biomarker potential for non-small cell lung cancer (NSCLC). Using enzyme-linked immunosorbent assay (ELISA), we assessed serum galectin-1, -3, and -9 levels in NSCLC patients. A retrospective chart review was performed to examine patient demographics, cancer stage, tumor biology, cancer treatment, and patient outcomes. Galectin levels were then compared across these factors. In this exploratory analysis, galectin-3 levels were significantly lower in patients with squamous cell lung cancer (p = 0.0019) and in patients exposed to chemotherapy (p = 0.0375). Galectin-1 levels were significantly lower in patients with previous metastasis but had no correlation with future metastasis. Abnormal galectin-1 levels were significantly correlated with decreased overall survival (OS) in NSCLC (p = 0.0357) and specifically in patients with surgically resectable NSCLC (p = 0.0112). However, abnormal galectin-1 levels were not found to correlate with decreased OS in multivariable analysis (p = 0.0513). These findings may have clinical implications as galectin-3 inhibitors are in trials for NSCLC. Additionally, they suggest that galectin-1 has potential as a prognostic marker for surgically resectable NSCLC.

Examining crossover and postprotocol therapies in first-line immunotherapy trials in non-small cell lung cancer (NSCLC).

Immune checkpoint inhibitor (ICI) therapy has led to significant improvement in outcomes for patients with nononcogene-driven advanced non-small cell lung cancer (NSCLC). The rate of crossover and receipt of postprotocol ICI in frontline trials for advanced NSCLC has not been systematically evaluated. ClinicalTrials.gov was used to identify phase 3 studies evaluating the use of immunotherapy or combination chemoimmunotherapy against chemotherapy alone in the frontline management of advanced NSCLC. Data on outcomes, rate of crossover and/or subsequent post-protocol receipt of immunotherapy, and the start dates of these clinical trials were then extracted. Twenty-three frontline trials in nononcogene-driven advanced NSCLC were identified. Six trials with ICI monotherapy/dual ICI therapy and 17 trials evaluating chemotherapy/ICI in first-line advanced NSCLC were included in the analysis. The crossover rate ranged 0% to 54% in ICI monotherapy/dual ICI trials and 0% to 52% in chemotherapy/ICI trials. Nineteen of 23 trials provided information on subsequent postprotocol therapies. Among the trials not allowing crossover, postprotocol ICI was administered to 17% to 45.8% of patients. Information regarding the eventual receipt of ICI therapy was available for 22 of 23 trials. Of 6631 patients, 2507 (37.8%) randomized to the control arm eventually received ICI therapy. The rate of crossover and postprotocol ICI use was low in frontline trials for first-line NSCLC incorporating ICI. Given the proven survival overall survival of ICI in a broad population, there is a need to ensure availability of this life-prolonging therapy in future trials, either by crossover treatment or postprotocol administration.

Development of clinical trials for non-small cell lung cancer drugs in China from 2005 to 2023.

Over the past few decades, the development of anti-cancer drugs in China has made outstanding achievements based on the support of national policies. To assess the progress of non-small cell lung cancer (NSCLC) drugs, we conducted a statistical analysis of clinical trials of drugs targeting NSCLC in China from 2005 to 2023. We downloaded, screened and analysed the data from three official websites, the Centre for Drug Evaluation of China National Medical Products Administration website (NMPA), ClinicalTrials.gov and the Chinese Clinical Trial Registry (ChiCTR). From January 1, 2005 to April 15, 2023, a total of 1,357 drug clinical trials that met the standards were included, and the number of registered drug clinical trials has been increasing year by year, reaching the maximum of 199 in 2021. Among them, the maximum of 462 items (34.05%) in phase II clinical trials, followed by 333 (24.54%) in phase III clinical trials, and 139 (10.24%) in phase IV clinical trials. In all drug clinical trials, industry sponsored trials (ISTs) have 722 items (53.21%), which are higher than investigator-initiated trials (IITs). The clinical trials of chemical drugs have a maximum of 723 items (53.28%), while biopharmaceuticals have grown rapidly in the past 10 years, with a total of 374 (27.56%), and 48.19% of the drug clinical trials of combined medication. In addition, the geographical distribution of the leading units and participating units of Chinese drug clinical trials are uneven, and economic regions such as Beijing, Shanghai, Jiangsu are obviously ahead of other regions. From 2005 to 2023, the clinical trials of registered drugs for the treatment of NSCLC increased rapidly. Among them, due to the development of immunotherapy, the clinical trials of biopharmaceuticals and drugs for combined medication are growing most rapidly, while the exploration of the original drugs is a little far from enough. Our research provides a direction for the future drug clinical trials of NSCLC, laying foundation for further extending the survival rate of patients with NSCLC.

THU374 Fulminant Type 1 Diabetes Mellitus And DKA Secondary To Pembrolizumab

Abstract Disclosure: I. Iqbal: None. M. Khan: None. M. Ahmad: None. R. Mehreen: None. Introduction: Pembrolizumab is a programmed cell death receptor (PD-1) binder on T cells, which promotes their activation against cancer cells. It can also cause unwanted T cell activation against the body’s own cells, leading to type 1 diabetes mellitus (DM1), among other autoimmune phenomena. We are reporting a case of a new onset pembrolizumab-induced fulminant DM1 who presented with diabetic ketoacidosis (DKA). Despite the emerging data on immune checkpoint inhibitors (ICPI), fulminant DM1 with DKA in a previously nondiabetic patient is still uncommon. Case Presentation: A 66-year-old female with a history of recurrent metastatic non-small cell lung cancer (NSCLC) presented to the emergency room (ER) with an extensive itchy rash. She was enrolled in a clinical trial for NSCLC, where she received immunotherapy with pembrolizumab for five months. Rash was treated outpatient for scabies, with no improvement. She was then started on prednisone 40mg daily and betamethasone 0.05% cream. She applied the cream daily but took prednisone orally for only one day, after which she could not tolerate it due to anxiety and restlessness. She ran out of betamethasone three days before coming to ER. On admission, vitals were: Heart rate 90 beats per minute, blood pressure 119/95 mmHg, respirations 20/minute. The exam showed flushed cheeks, red and dry macules on the skin with excoriations, and dry mucus membranes. Random blood glucose levels (BSL) were 660mg/dl. Labs were; HCO3 16mmol/L, Beta-hydroxy butyrate 20mmol/L, anion gap 17mmol/L, Hemoglobin A1c: 5.6%. For DKA, we started an insulin drip. Workup revealed very low C-peptide levels of 0.2ng/ml, with a concomitant BSL of 500mg/dL. Anti-islet cell and anti-glutamic acid decarboxylase antibodies (anti-GAD) were positive with levels of 0.04 nmol/L and 0.07 nmol/L, respectively. Once she stabilized and the anion gap closed, she was transitioned to subcutaneous insulin and discharged on 42 units of Lantus, along with 12 units of premeal Lispro and sliding-scale insulin. She was removed from the clinical trial due to complications. Unfortunately, she got readmitted with influenza A, Staphylococcus aureus bacteremia, and another episode of DKA, complicated with respiratory failure, and she decided on hospice. The patient passed away after two days. Conclusion: Immune-related adverse event of new-onset fulminant DM1, leading to DKA, is a serious and potentially fatal complication of pembrolizumab. For patients receiving pembrolizumab, who have uncontrolled BSL, we suggest checking the anti-islet cell and anti-GAD antibody levels and DKA risk stratification to allow the timely initiation of insulin and prevent further complications. Presentation: Thursday, June 15, 2023

Tackling the immunotherapy conundrum: advances and challenges for operable non-small-cell lung cancer treatment.

Lung cancer is the most common cause of cancer-related deaths worldwide. Non-small-cell lung cancer (NSCLC) represents the majority of lung cancer cases, and its standard treatment is primarily surgery. Nonetheless, this type of cancer exhibits an important rate of tumor recurrence. Immune checkpoint inhibitors (ICIs) have demonstrated significant survival benefits in many cancers, especially in early-stage NSCLC. This review considers the latest CheckMate816, IMpower010 and KEYNOTE-091 trials that led to US FDA approvals. The new wave of resectable NSCLC trial results are also summarized. Finally, the latest challenges for these treatment modalities, such as the choice between neoadjuvant and adjuvant use, the accurate identification of biomarkers and the presence of driver mutations such as EGFR, are discussed.

Representativeness of Patients Enrolled in the Lung Cancer Master Protocol (Lung-MAP).

Lung Cancer Master Protocol (Lung-MAP), a public-private partnership, established infrastructure for conducting a biomarker-driven master protocol in molecularly targeted therapies. We compared characteristics of patients enrolled in Lung-MAP with those of patients in advanced non-small-cell lung cancer (NSCLC) trials to examine if master protocols improve trial access. We examined patients enrolled in Lung-MAP (2014-2020) according to sociodemographic characteristics. Proportions for characteristics were compared with those for a set of advanced NSCLC trials (2001-2020) and the US advanced NSCLC population using SEER registry data (2014-2018). Characteristics of patients enrolled in Lung-MAP treatment substudies were examined in subgroup analysis. Two-sided tests of proportions at an alpha of .01 were used for all comparisons. A total of 3,556 patients enrolled in Lung-MAP were compared with 2,215 patients enrolled in other NSCLC studies. Patients enrolled in Lung-MAP were more likely to be 65 years and older (57.2% v 46.3%; P < .0001), from rural areas (17.3% v 14.4%; P = .004), and from socioeconomically deprived neighborhoods (42.2% v 36.7%, P < .0001), but less likely to be female (38.6% v 47.2%; P < .0001), Asian (2.8% v 5.1%; P < .0001), or Hispanic (2.4% v 3.8%; P = .003). Among patients younger than 65 years, Lung-MAP enrolled more patients using Medicaid/no insurance (27.6% v 17.8%; P < .0001). Compared with the US advanced NSCLC population, Lung-MAP under represented patients 65 years and older (57.2% v 69.8%; P < .0001), females (38.6% v 46.0%; P < .0001), and racial or ethnic minorities (14.8% v 21.5%; P < .0001). Master protocols may improve access to trials using novel therapeutics for older patients and socioeconomically vulnerable patients compared with conventional trials, but specific patient exclusion criteria influenced demographic composition. Further research examining participation barriers for under represented racial or ethnic minorities in precision medicine clinical trials is warranted.

Analysis of phase III clinical trials in metastatic NSCLC to assess the correlation between QoL results and survival outcomes

BackgroundIn addition to improving survival outcomes, new oncology treatments should lead to amelioration of patients’ quality of life (QoL). Herein, we examined whether QoL results correlated with PFS and OS outcomes in phase III randomized controlled trials (RCTs) investigating new systemic treatments in metastatic non-small cell lung cancer (NSCLC).MethodsThe systematic search of PubMed was conducted in October 2022. We identified 81 RCTs testing novel drugs in metastatic NSCLC and published in the English language in a PubMed-indexed journal between 2012 and 2021. Only trials reporting QoL results and at least one survival outcome between OS and PFS were selected. For each RCT, we assessed whether global QoL was “superior,” “inferior,” or with “non-statistically significant difference” in the experimental arm compared to the control arm.ResultsExperimental treatments led to superior QoL in 30 (37.0%) RCTs and inferior QoL in 3 (3.7%) RCTs. In the remaining 48 (59.3%) RCTs, a statistically significant difference between the experimental and control arms was not found. Of note, we found a statistically significant association between QoL and PFS improvements (X2 = 3.93, p = 0.0473). In more detail, this association was not significant in trials testing immunotherapy or chemotherapy. On the contrary, in RCTs testing target therapies, QoL results positively correlated with PFS outcomes (p = 0.0196). This association was even stronger in the 32 trials testing EGFR or ALK inhibitors (p = 0.0077). On the other hand, QoL results did not positively correlate with OS outcomes (X2 = 0.81, p = 0.368). Furthermore, we found that experimental treatments led to superior QoL in 27/57 (47.4%) trials with positive results and in 3/24 (12.5%) RCTs with negative results (p = 0.0028). Finally, we analyzed how QoL data were described in publications of RCTs in which QoL outcomes were not improved (n = 51). We found that a favorable description of QoL results was associated with sponsorship by industries (p = 0.0232).ConclusionsOur study reveals a positive association of QoL results with PFS outcomes in RCTs testing novel treatments in metastatic NSCLC. This association is particularly evident for target therapies. These findings further emphasize the relevance of an accurate assessment of QoL in RCTs in NSCLC.

Outcome differences by sex in oncology clinical trials.

e18808 Background: NIH guidance advises clinical trials to analyze participants by sex to improve inclusivity. We performed a systematic analysis of reported differences in outcomes between males and females in a registry of oncology clinical trials to characterize treatment response differences more broadly by sex for future trials. Methods: We analyzed Trialtrove ( https://citeline.informa.com/trials/results ), a trial repository using over 58,000 sources, to search for oncology trials that compared outcomes in male and female participants. We implemented algorithms using Python3 programs to search for all trials that contained terms regarding sex in the context of terms suggesting comparison or outcome and considered these as candidate comparison trials. Candidate trials were manually curated to record comparisons by sex across cancer type, treatment, outcome measure, “similar” or “different” by sex and evidence. Outcomes were classified as either “survival / response / other outcome” (SRO) or side effects (E). Evidence for each comparison was labeled as statistically significant (multivariate or univariate), having non-significant numerical evidence, or having no numerical evidence. We counted only those trials in which all comparisons by sex were consistent. Results: 472 of 89,221 oncology trials in Trialtrove (data freeze 12/23/22) (0.5%) performed 532 post-treatment comparisons by sex. Among 288 trials that did statistical SRO comparisons, 47 (16%) trials reported that males showed better, statistically significant treatment responses, while 122 (42%) trials reported better results for females. We observed the strongest differences by sex for two disease-treatment pairs: EGFR inhibitors (EGFRi) in non-small cell lung cancer (NSCLC) and rituximab in non-Hodgkin’s lymphoma (NHL). In 82 trials with SRO comparisons in NSCLC, 35 (43%) showed better treatment responses in females, and 13 (16%) showed better treatment responses in males. Among the 36 NSCLC trials using EGFRi, 21 (58%) showed better treatment responses in females, versus only 1 (3%) in males. In contrast, among all 46 other NSCLC trials with SRO comparisons, 14 (30%) favored females and 12 (26%) favored males. These results suggest that EGFRi may have treatment-specific benefits in females with NSCLC. Among 33 trials with SRO comparisons in NHL, 20 (61%) showed better treatment response in females, versus only 4 (12%) in males. 13 of these trials used rituximab, among which 10 (77%) favor females and only 1 (8%) favors males. Better response in females to rituximab has been reported in single trials but not characterized in aggregate. Conclusions: Our search identified two clinically important disease-treatment pairs that showed markedly improved outcomes in females versus males. Better understanding of differences in treatment response by sex across clinical trials is needed, both to improve inclusivity and as a basis for potential future combination treatments.

Analytical and clinical validation of oncomine Dx target (ODxT) test and local testing for identifying patients with HER2 (ERBB2)-mutant (HER2m) non–small-cell lung cancer (NSCLC) for treatment with trastuzumab deruxtecan (T-DXd) in DESTINY-Lung01/02 (DL-01/02).

9033 Background: Based on the international DL-01 trial, the US Food and Drug Administration (FDA) approved the ODxT Test as a companion diagnostic (CDx) to identify patients (pts) with NSCLC harboring activating HER2 mutations who may benefit from T-DXd. The ODxT Test uses next-generation sequencing (NGS) to detect genomic alterations in formalin-fixed, paraffin-embedded tumor tissue. The accuracy of the ODxT Test by central testing and its agreement with clinical trial assays (CTAs; NGS, polymerase chain reaction, etc.) by local testing was evaluated using analytical and clinical validation data from DL-01 cohort 2 and DL-02 arm 1. Methods: ODxT Test and Illumina TruSight Tumor170 NGS assay results were compared for analytical accuracy in NSCLC samples from DL-01 and commercial vendors. Diagnostic agreement was assessed for DL-01/02 by concordance between the ODxT Test and CTAs. Clinical accuracy per objective response rate (ORR) and duration of response (DoR) to T-DXd were evaluated in all pts with HER2m NSCLC identified by ODxT Test vs CTA. Activating HER2 mutations included single nucleotide variants and exon 20 insertions. Pts received T-DXd 6.4 mg/kg in DL-01 or 5.4 mg/kg (FDA-approved dose) in DL-02 every 3 weeks. Results: NSCLC samples from DL-01 (n = 91), DL-02 (n = 102), and commercial vendors (n = 129) were individually assessed. The ODxT Test met requirements for analytical accuracy (≥90% agreement when excluding unknown results), with a positive percent agreement (PPA) of 100% and negative percent agreement (NPA) of 99.1% for detecting HER2 mutations. Clinical accuracy of the ODxT Test also met FDA requirements (excluding unknowns) for NPA (≥98%) and PPA (95% CI lower bound ≥85%). DL-01 PPA (95% CI) was 98.0% (89.2%-100%) and NPA was 100.0% (96.6%-100%); for DL-02, PPA was 96.7% (88.7%-99.6%) and NPA was 100% (96.6%-100%). In DL-01, confirmed ORR (95% CI) for pts with HER2m NSCLC identified by central ODxT Test was 58.3% (43.2%-72.4%) vs 54.9% (44.2%-65.4%) of pts identified by local CTA; median DoR (95% CI) was 12.0 mo (5.5 mo-18.2 mo) per the ODxT Test vs 9.3 mo (5.7 mo-14.7 mo) per CTA. In DL-02 (prespecified interim analysis early cohort), ORR (95% CI) was 53.6% (33.9%-72.5%) per ODxT Test vs 53.8% (39.5%-67.8%) per CTA; median DoR (95% CI) was not estimable (NE [NE-NE]) per the ODxT Test and NE (4.2 mo-NE) per CTA. Conclusions: This study demonstrates the analytical and clinical accuracy of the ODxT Test as a CDx for detecting activating HER2 mutations in NSCLC to identify pts who may benefit from T-DXd. A high level of agreement was also shown between the ODxT Test and CTAs. Clinical trials for HER2m NSCLC may successfully use a central testing assay as a CDx while allowing adequately validated local testing assays to expedite patient enrollment. Clinical trial information: NCT03505710 , NCT04644237 .

Peripheral myeloid cells as prognostic markers in patients (pts) with non-small cell lung cancer (NSCLC) treated with cemiplimab: Pooled analysis of EMPOWER-Lung 1 and EMPOWER-Lung 3 phase 3 trials.

9028 Background: Circulating innate and adaptive immune cells can modulate clinical responses to immune checkpoint inhibition in pts with cancer; however, there are no clear validated baseline clinical tests to guide clinicians, outside of programmed cell death-ligand 1 (PD-L1) IHC tests on limited biopsy specimens. High neutrophil/lymphocyte ratio (NLR) is associated with poor prognosis in NSCLC, but data are limited on the potential contribution of other immune cells such as monocytes and eosinophils in modulating systemic immune response. Further, previous correlative studies have not established clinically actionable immune cell cut-off values. Methods: We used multiple quantitative analytic methods including multivariable Cox regression and conditional decision trees to assess the prognostic importance of NLR and peripheral myeloid cells, including monocytes and eosinophils, in pts with NSCLC treated with cemiplimab in Phase 3 trials EMPOWER-Lung 1 (NCT03088540) and EMPOWER-Lung 3 (NCT03409614). In EMPOWER-Lung 1, pts with PD-L1 ≥50% were randomized 1:1 to cemiplimab 350 mg every 3 weeks (Q3W) or platinum-based chemotherapy (chemo). EMPOWER-Lung 3 was a 2-part study. In Part 1, pts with PD-L1 &lt; 50% were randomized 1:1:1 to chemo, cemiplimab 350 mg Q3W + chemo, or cemiplimab 350 mg Q3W + ipilimumab 50 mg Q6W + chemo. In Part 2, pts were randomized 2:1 to receive cemiplimab 350 mg or placebo Q3W + chemo. Results: Overall, 691 pts in EMPOWER-Lung 1 and 769 pts in EMPOWER-Lung 3 were included in this analysis. The results showed significant association between multiple factors including NLR and overall survival (OS) and progression-free survival (PFS). For pts with NLR &gt; 3.98 vs ≤3.98, median OS (95% CI) was 10 (9–13) vs 20 (17–24) months (HR: 2.04; 95% CI: 1.60–2.61; P&lt; 0.001) and median PFS (95% CI) was 4 (4–6) vs 6 (6–7) months (HR: 1.80; 95% CI: 1.50–2.18; P&lt; 0.001), respectively, accounting for known prognostic factors. In multivariable analyses, monocytes (OS HR: 1.72; 95% CI: 1.29–2.30; P&lt; 0.001; PFS HR: 1.37; 95% CI: 1.08–1.75; P= 0.010) and log eosinophils (OS HR: 0.90; 95% CI: 0.85–0.97; P= 0.003; PFS HR: 0.93; 95% CI: 0.88–0.98; P= 0.004) were significantly associated with OS and PFS in both studies. (Neutrophil + monocyte)/lymphocyte ratio was the top predictor of both OS and PFS in decision tree analysis. Peripheral blood cell count correlations were not affected by tumor PD-L1 levels (ρ &lt; 0.15 for all markers). Conclusions: This is a large and comprehensive prognostic analysis of data from two prospective Phase 3 clinical trials in advanced NSCLC. Clinically actionable peripheral blood cell count parameters, incorporating putative immunosuppressive myeloid cells (neutrophils and monocytes) and protective lymphocytes and eosinophils, may help predict response to anti–PD-1 therapy in advanced NSCLC. Clinical trial information: NCT03088540 , NCT03409614 .

CAN-2409 plus prodrug with standard of care immune checkpoint inhibitor for patients with stage III/IV NSCLC.

TPS9162 Background: Immune checkpoint inhibitors (ICI) are a standard of care (SOC) treatment that have improved outcomes for patients (pts) with non-small cell lung cancer (NSCLC). However, most pts progress, signaling a need for combination approaches to further improve outcomes. CAN-2409 is a replication-defective adenoviral construct encoding the herpes simplex virus thymidine kinase (HSV-tk) gene that is injected intratumorally followed by 2 weeks of prodrug (valacyclovir or acyclovir). HSV-tk converts the prodrug in the tumor microenvironment into a toxic metabolite, resulting in immunogenic cell death, while the adenoviral proteins provide a strong pro-inflammatory signal. Together, this leads to in situ vaccination against the patient’s own tumor. As a result, CD8+ cytotoxic T cells are educated on how to recognize and kill tumor cells in both the injected tumor and the uninjected metastases. A completed neoadjuvant phase I trial in resectable NSCLC demonstrated safety and immune stimulation (Predina et al 2021), warranting further investigation of CAN-2409 + prodrug as a therapy that can lead to improved long-term outcomes for pts with NSCLC who have a suboptimal response to ICI. Methods: LuTK02 (NCT04495153) is an open-label, multi-arm, phase II clinical trial to evaluate CAN-2409 + prodrug added to SOC ICI (anti-PD-(L)1) therapy in pts with stage III/IV NSCLC presenting with inadequate response (as defined below) to ICI. Cohort 1 includes pts with nonresponding but stable disease ≥18 weeks after starting ICI; cohort 2 includes pts with progressive disease ≥18 weeks after starting ICI. Key eligibility criteria include RECIST-evaluable disease; an injectable lesion (via bronchoscopy or US/IR guidance); ability to continue ICI for the treatment period; no change of ICI or prior interruptions of &gt; 4 weeks within 6 months of enrollment; and no focal therapy at &gt; 3 sites of disease within 12 months prior to enrollment. Key exclusion criteria include a history of ICI immune-related adverse events and known alterations in EGFR, ALK, or ROS1. Eligible patients receive 2 injections of CAN-2409 approximately 6 weeks apart followed by prodrug for 14 days. After treatment of ~40 evaluable pts in cohort 2 with two injections of CAN-2409, the protocol has been amended to include a new cohort (n~20) of pts treated with three injections of CAN-2409 approximately 4 weeks apart, each followed by prodrug for 14 days, to further define the optimal therapeutic regimen. Primary endpoints are overall response and/or disease control rate per RECIST 1.1 criteria and safety of CAN-2409 + prodrug. Secondary endpoints include duration of response, PFS, OS, and biomarker studies. Exploratory endpoints include evaluation of effects in non-injected lesions, changes in non-target (per RECIST) lesions, tumor growth trajectory, and viral shedding. Clinical trial information: NCT04495153 .

Phase 3 trial of durvalumab combined with domvanalimab following concurrent chemoradiotherapy (cCRT) in patients with unresectable stage III NSCLC (PACIFIC-8).

TPS8609 Background: The PACIFIC trial (NCT02125461) established up to 12 months of consolidation therapy with durvalumab as standard of care (SoC) for patients with unresectable stage III non-small-cell lung cancer (NSCLC) and no disease progression after platinum-based cCRT. To improve outcomes further in this population, novel immunotherapy combinations that build on the backbone of PD-L1 inhibition with durvalumab are being explored. Domvanalimab (AB154) is a Fc-silent humanized IgG1 monoclonal antibody that blocks interaction of the T cell immunoreceptor with Ig and ITIM domains (TIGIT; upregulated by immune cells) with CD112 and CD155 (expressed by tumor and antigen-presenting cells), reducing inhibition of T cells and natural killer cells and, thereby, promoting antitumor activity. The combination of TIGIT inhibition with PD-(L)1 inhibition has shown encouraging activity in phase 1 and 2 trials in metastatic NSCLC, with enriched benefit observed among patients with PD-L1 positive tumors (Rodriguez-Abreu, et al. 2020; Niu, et al. 2020). In ARC-7 (NCT04262856), a randomized, phase 2 trial, the combination of domvanalimab and PD-1 inhibition was associated with improvement in progression-free survival (PFS) versus PD-1 inhibition alone (HR, 0.55; 95% CI, 0.31–1.0) in treatment-naïve patients with metastatic NSCLC and high PD-L1 expression (tumor proportion score ≥50%) (Johnson, et al. 2022). PACIFIC-8 (NCT05211895) is assessing the efficacy and safety of durvalumab combined with domvanalimab as consolidation therapy in patients with PD-L1 positive, unresectable stage III NSCLC and no disease progression after platinum-based cCRT. Methods: PACIFIC-8 is a phase 3, double-blind, placebo-controlled, randomized, global trial. Eligible patients (aged ≥18 years) must have PD-L1 positive, unresectable stage III NSCLC (tumor cell [TC] expression ≥1% by central lab; VENTANA SP263 IHC assay), WHO performance status 0/1, documented EGFR/ALK wild-type tumor status, and not have progressed following definitive, platinum-based cCRT (≥2 cycles). Approximately 860 patients will be randomized (1:1) to receive SoC durvalumab (1500 mg IV) combined with either domvanalimab (20 mg/kg IV) or placebo, every 4 weeks for up to 12 months. The primary endpoint is PFS (RECIST v1.1) by blinded independent central review (BICR) in patients with PD-L1 TC ≥50%. Secondary endpoints include PFS (RECIST v1.1; BICR) in patients with PD-L1 TC ≥1%, overall survival, objective response rate and duration of response (RECIST v1.1; BICR), safety/tolerability, and patient-reported outcomes. Trial enrollment is ongoing. Previously presented at the European Society for Medical Oncology (ESMO) Congress 2022, FPN (Final Publication Number): 971TiP, Mustafa Özgüroğlu et al. – Reused with permission. Clinical trial information: NCT05211895 .

Abstract 5705: Digital pathology based prognostic &amp; predictive biomarkers in metastatic non-small cell lung cancer

Abstract Background: In recent years, a relationship between the tumor microenvironment (TME) and patient response to targeted cancer immunotherapy has been suggested. We applied machine-learning algorithms on H&amp;E stained tissue to study the TME in metastatic non-small cell lung cancer (NSCLC) patients. Our goal was to identify digital pathology (DP) features associated with outcome under combination treatment or monotherapy with atezolizumab (atezo), an anti-PD-L1 therapy, and relate those features to other data modalities. We analyzed patient data from two phase 3 clinical trials, OAK (docetaxel versus atezo in 2L+ NSCLC) and IMpower150 (bevacizumab, carboplatin, and paclitaxel (BCP) versus BCP+atezo (ABCP) in advanced 1L non-squamous NSCLC). Methods: As part of our effort to build a DP-based tumor-immune microenvironment atlas, digitized H&amp;E images were registered onto the PathAI research platform. Over 200K annotations from 90 pathologists were used to train convolutional neural networks (CNNs) that classify slide-level human-interpretable features (HIFs) of cells and tissue structures from images and deployed on images from OAK and IMpower150. HIFs and PD-L1 status were associated with outcome in all samples in each arm in OAK and results were validated in IMpower150, using Cox proportional hazard models. Bulk RNAseq was run using samples extracted from the same area as the H&amp;E slide. Results: We identified a composite feature capturing the ratio of immune cells to fibroblasts in the stroma predictive of both overall survival (OS) (HR=0.74 p=0.0046) and progression-free survival (PFS) (HR=0.87 p=0.14). While patients primarily benefit from atezo if they are PD-L1 high, we found that even PD-L1 negative patients benefited from atezo when enriched for this feature (22C3 PD-L1 assay: OS HR=0.59 p=0.015, PFS HR=0.8 p=0.25; SP142 PD-L1 assay: OS HR=0.74 p=0.12, PFS HR=0.88 p=0.45). We thus recognized a DP feature that was predictive for positive outcome with atezo treatment, independent of PD-L1 levels. This association was then validated in IMpower150 comparing ABCP to BCP, both overall (OS HR=0.69 p=0.012) and in PD-L1 negative patients (SP263 assay OS HR=0.56 p=0.034). Integrating with RNAseq, patients enriched for this DP feature showed similar enrichment for B and T gene signatures and depletion in CAF-related gene signatures, thus showing the harmonization of TME between different data modalities. Conclusions: Using a deep learning-based assay for quantifying pathology features of the TME from H&amp;E images in two NSCLC trials, we identified a novel biomarker predictive of outcome to PD-L1 targeting therapy, even in PD-L1 low &amp; negative patients. Importantly, our work shows how different data modalities (DP, gene expression) can be integrated to further our understanding of the TME. Citation Format: Aditi Qamra, Minu K. Srivastava, Eloisa Fuentes, Ben Trotter, Raymond Biju, Guillaume Chhor, James Cowan, Steven Gendreau, Webster Lincoln, Lisa McGinnis, Luciana Molinero, Namrata S. Patil, Amber Schedlbauer, Katja Schulze, Adam Stanford-Moore, Laura Chambre, Ilan Wapinski, David S. Shames, Hartmut Koeppen, Stephanie Hennek, Jane Fridlyand, Jennifer M. Giltnane, Assaf Amitai. Digital pathology based prognostic &amp; predictive biomarkers in metastatic non-small cell lung 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 5705.

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.

Abstract 3375: Ultrasensitive ctDNA minimal residual disease monitoring in early NSCLC with PhasED-Seq

Abstract Background: Circulating tumor DNA (ctDNA) minimal residual disease (MRD) detection is a promising approach for personalization of adjuvant therapy in non-small cell lung cancer (NSCLC). First generation ctDNA MRD assays that employ tumor-informed approaches to track single nucleotide variants (SNVs) have limits of detection (LOD95) of ~1E-4 and have high positive predictive values for recurrence. However, they have suboptimal clinical sensitivity, with false negative results at the completion of therapy in most patients who will ultimately recur. PhasED-Seq is a novel ctDNA MRD method that tracks multiple “phased” variants (PVs) within individual DNA fragments with a LOD95 ~100-fold better than first generation assays. Here we report PhasED-Seq ctDNA MRD results for the first prospective cohort of early stage NSCLC patients. Methods: Tumor tissues (n=46), PBMCs (n=46) and plasma samples (n=169) from 46 Stage I-III NSCLC patients treated with curative intent were prospectively collected at Memorial Sloan Kettering Cancer Center. All patients underwent resection and received neoadjuvant +/- adjuvant therapy (n=14), adjuvant therapy only (n=17), or neither (n=15). Samples were analyzed in Foresight Diagnostics' CLIA laboratory (Aurora, CO) using personalized PhasED-Seq. Briefly, PVs were identified via whole genome sequencing of tumors and matched blood germline DNA. Custom capture panels targeting PVs were synthesized and used to assess MRD status in pre-, on- and post-treatment plasma samples. Detection of ctDNA MRD was assessed at a post-treatment landmark, defined as the first post-therapy sample or when not available the last post-surgical sample taken during therapy. To enable comparisons, the same plasma samples were analyzed using an SNV-based ctDNA MRD approach. Results: PVs were identified in tumor tissue from all 46 patients. Across all plasma samples PhasED-Seq achieved a median LOD95 of 1.3E-6 and as low as 2.5E-7. Of 74 plasma samples with detectable ctDNA, 38 (51%) contained concentrations below 1E-4 and the lowest level of ctDNA MRD detected was 1.7E-7. For post-treatment landmark samples (n=45), the median time from end of therapy was 2 months. Cancer recurred in all patients (n=10) with detectable MRD at the landmark. Furthermore, PhasED-Seq better stratified freedom from recurrence (log-rank p=3E-8, Cox HR=10.8) than the SNV-based approach (log-rank p=0.08, Cox HR=2.5) and detected MRD at the landmark in more patients who ultimately recurred (56% vs 28%). PhasED-Seq also achieved longer lead times, including detecting MRD in 66% of samples collected 12 to 24 months prior to recurrence versus only 33% using SNV-based monitoring. Conclusion: PhasED-Seq achieves ctDNA detection below 1 part per million and appears to be significantly more sensitive than SNV-based MRD monitoring. These results suggest that PhasED-Seq is a promising approach for use in risk adapted trials in early stage NSCLC. Citation Format: James M. Isbell, Bob T. Li, Pedram Razavi, Jorge Reis-Filo, Si-Yang Liu, Pier Selenica, Prasad Adusumilli, Matthew Bott, David R. Jones, Valerie W. Rusch, Smita Sihag, Darren J. Buonocore, Justin Jee, Emily Lebow, Daniel Gomez, Andreas Rimner, Fernando C. Santini, Charles M. Rudin, Jordan E. Eichholz, Andres Martinez, Daphne Alerte, Gregory J. Hogan, Andre Schultz, Ronald P. Schuyler, Alanna Roff, Dustin Hite, Jacob J. Chabon, David M. Kurtz, Ash A. Alizadeh, Maximilian Diehn. Ultrasensitive ctDNA minimal residual disease monitoring in early NSCLC with PhasED-Seq [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 3375.

Assessing the impact of open-label designs in patient-reported outcomes: investigation in oncology clinical trials.

Knowledge of treatment assignment may affect patient-reported outcomes (PROs), which is of concern in oncology, where open-label trials are common. This study measured the magnitude of open-label bias by comparing PROs for similar patient groups in oncology trials with different degrees of concealment. Individual patient data from ipilimumab arms of 2 melanoma and docetaxel arms of 2 non-small cell lung cancer (NSCLC) trials were adjusted for differences using propensity score weighting. Patients were aware of treatment assignment in CA184-022 and CheckMate 057 (open-label) but not in MDX010-20 and VITAL (blinded). Overall survival (OS) and mean changes from baseline to week 12 in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (melanoma) and Lung Cancer Symptom Scale (NSCLC) scores were compared between open-label and blinded groups. After adjustment, baseline characteristics were balanced between blinded (melanoma, n = 125; NSCLC, n = 424) and open-label (melanoma, n = 69; NSCLC, n = 205) groups. Study discontinuation and PRO completion rates at week 12 and OS were similar. There was no clear direction in differences in change scores between groups. In the melanoma trials, role functioning (mean = -5.2, 95% confidence interval [CI] = -15.4 to 5.0), global health status (mean = -1.3, 95% CI = -8.7 to 6.1), and pain (mean = 6.2 , 95% CI = -1.8 to 14.2) favored the blinded, whereas emotional functioning (mean = 2.2, 95% CI = -5.8 to 10.2) and diarrhea (mean = -8.3, 95% CI = -17.3 to 0.7) favored the open-label group. In the NSCLC trials, changes in dyspnea (mean = 5.4, 95% CI = -0.7 to 11.5) favored the blinded and changes in appetite (mean = -1.2, 95% CI = -8.1 to 5.7) favored the open-label group. None were clinically or statistically significant. This study adds to the growing evidence demonstrating that concerns regarding open-label bias should not prohibit the interpretation of large and meaningful treatment effects on PROs.

Tumor Response, Disease Control, and Progression-Free Survival as Surrogate Endpoints in Trials Evaluating Immune Checkpoint Inhibitors in Advanced Non-Small Cell Lung Cancer: Study- and Patient-Level Analyses.

Background: To assess the usefulness of tumor response and progression-free survival (PFS) as surrogates for overall survival (OS) in non-small cell lung cancer (NSCLC) trials with immune checkpoint inhibitors (ICI), which have not been confirmed. Methods: Patient- and trial-level analyses were performed. The Response Evaluation Criteria in Solid Tumors was preferred for image assessment. For trial-level analysis, surrogacy was assessed using the weighted rank correlation coefficient (r) following "reciprocal duplication." This method duplicates all plots as if the experimental and the reference arms were switched. Monte Carlo simulations were performed for evaluating this method. Results: A total of 3312 cases were included in the patient-level analysis. Patients without response (first line (1L): hazard ratio (HR) 1.95, 95% confidence interval (CI) 1.71-2.23; second or later line (2L-): HR 4.22, 95% CI 3.22-5.53), without disease control (1L: HR 4.34, 95% CI 3.82-4.94; 2L-: HR 3.36, 95% CI 2.96-3.81), or with progression during the first year (1L: HR 3.42, 95% CI 2.60-4.50; 2L-: HR 3.33, 95% CI 2.64-4.20), had a higher risk of death. Systematic searches identified 38 RCTs including 17,515 patients for the study-level analysis. Odds ratio in the objective response rate (N = 38 × 2, r = -0.87) and HR in PFS (N = 38 × 2, r = 0.85) showed an excellent association with HR in overall survival, while this effect was not observed in the disease control rate (N = 26 × 2, r = -0.03). Conclusions: Objective response rate and PFS are reasonable surrogates for OS in NSCLC trials with ICI.

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.