ABSTRACT
Antibody-drug conjugates (ADCs) are a fast-growing class of cancer drugs designed to selectively deliver cytotoxic payloads through antibody binding to cancer cells with high expression of the target antigen, thus reducing systemic exposure and minimizing off-target effects. However, ADCs are associated with various ocular adverse events (AEs) that may impact treatment administration and patient outcomes. In this review, we provide a summary of ocular AEs associated with approved and investigational ADCs, recommendations for the mitigation and management of ocular AEs, current guidelines and expert opinions, and recommendations for clinical practice. A literature search was performed, using PubMed and Google Scholar, for English-language articles published between January 1985 and January 2023 to identify studies reporting ocular AEs associated with ADC use. Search terms included generic and investigational names of all identified ADCs, and further searches were performed to identify strategies for managing ADC-associated ocular AEs. ADC-associated ocular AEs include symptoms such as blurred vision and foreign-body sensation and signs such as corneal fluorescein staining, corneal pseudomicrocysts, and conjunctivitis. Reported management strategies include ADC dose modification (eg, dose delay or reduction), cool compresses, artificial tears, topical vasoconstrictors, and topical steroids. Although ADC dose modification appears to be beneficial, the preventive and/or therapeutic benefits of the remaining interventions are unclear. Although the exact mechanisms are not fully understood, most ADC-associated ocular AEs are reversible with dose delay or dose reduction. Management of ocular AEs requires a multidisciplinary approach to minimize treatment discontinuation and optimize clinical outcomes.
ABSTRACT
BACKGROUND: Sotorasib 960 mg once daily is approved to treat KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC). Sotorasib exhibits non-dose proportional pharmacokinetics and clinical responses at lower doses; therefore, we evaluated the efficacy and safety of sotorasib 960 mg and 240 mg. METHODS: In this phase 2, randomized, open-label study, adults with KRAS G12C-mutated advanced NSCLC received sotorasib 960 mg or 240 mg once daily. Primary endpoints were objective response rate (ORR) and safety. Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and pharmacokinetics. The study was not powered for formal statistical hypothesis testing. RESULTS: In the 960 mg group (n = 104), ORR was 32.7 % and DCR was 86.5 %. In the 240 mg group (n = 105), ORR was 24.8 % and DCR was 81.9 %. Median PFS was 5.4 months (960 mg) and 5.6 months (240 mg). At a median follow-up of 17.5 months, median OS was 13.0 months (960 mg) and 11.7 months (240 mg). AUC0-24 h and Cmax were 1.3-fold numerically higher with the 960 mg dose. Treatment-emergent adverse events (TEAEs, ≥10 %) for 960 mg and 240 mg doses, respectively, were diarrhea (39.4 %; 31.7 %), nausea (23.1 %; 19.2 %), increased alanine aminotransaminase (14.4 %; 17.3 %), and increased aspartate aminotransferase (13.5 %; 13.5 %). CONCLUSIONS: Patients treated with sotorasib 960 mg once daily had numerically higher ORR and DCR, and longer DOR and OS, than patients treated with 240 mg in this descriptive analysis. TEAEs were manageable with label-directed dose modifications. CLINICAL TRIAL REGISTRATION: NCT03600883.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Mutation , Proto-Oncogene Proteins p21(ras) , Humans , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/pathology , Male , Female , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Middle Aged , Aged , Proto-Oncogene Proteins p21(ras)/genetics , Adult , Aged, 80 and over , Drug Administration Schedule , Pyridines/adverse effects , Pyridines/administration & dosage , Pyridines/pharmacokinetics , Pyridines/therapeutic use , Progression-Free Survival , Piperazines , PyrimidinesABSTRACT
Exosomes are nanosized extracellular vesicles released by cells to transport biomolecules such as proteins and RNAs for intercellular communication. Exosomes play important roles in cancer development and metastasis; therefore, they have emerged as potential liquid biopsy biomarkers for cancer screening, diagnosis, and management. Many exosome cargos, including proteins, RNAs, and lipids, have been extensively investigated as biomarkers for cancer liquid biopsy. However, carbohydrates, an important type of biomolecule, have not yet been explored for this purpose. In this study, we reported a new exosomal carbohydrate biomarker, α-linked Thomsen-Friedenreich glycoantigen (TF-Ag-α; Galß1-3GalNAc-α). To translate our discovery into clinical settings, we developed a surface plasmon resonance-based assay which utilized a unique mAb, JAA-F11, with high specificity to measure the levels of exosomal TF-Ag-α in blood. To the best of our knowledge, we are the first to demonstrate that exosomes carry TF-Ag-α. We detected exosomal TF-Ag-α in as low as 10 µL serum samples from patients with cancer, but in contrast, levels were negligible in those from normal controls. With a total of 233 patients with cancer and normal controls, we showed that exosomal TF-Ag-α detected lung cancer (n = 60) and breast cancer (n = 95) from normal controls (n = 78) with ≥95% and ≥97% accuracy, respectively. These results demonstrated that exosomal TF-Ag-α is a potential liquid biopsy biomarker for cancer diagnosis. SIGNIFICANCE: Exosomes or small extracellular vesicles have emerged as potent biomarkers of cancer liquid biopsy. We discovered a new exosomal carbohydrate marker, TF-Ag-α (Galß1-3GalNAc-α), and showed that exosomal TF-Ag-α detected both lung and breast cancers with >95% accuracy. Our findings demonstrated that exosomal TF-Ag-α is a promising liquid biopsy biomarker for cancer screening and early detection.
Subject(s)
Antigens, Tumor-Associated, Carbohydrate , Biomarkers, Tumor , Breast Neoplasms , Exosomes , Lung Neoplasms , Humans , Exosomes/metabolism , Lung Neoplasms/diagnosis , Lung Neoplasms/blood , Lung Neoplasms/pathology , Female , Biomarkers, Tumor/blood , Breast Neoplasms/diagnosis , Breast Neoplasms/blood , Breast Neoplasms/pathology , Liquid Biopsy/methods , Antigens, Tumor-Associated, Carbohydrate/blood , Middle Aged , Aged , Male , AdultABSTRACT
Introduction: EML4-ALK is an oncogenic driver, seen in around five per cent of advanced non-small-cell lung cancer (NSCLC) patients, which can be targeted with anaplastic lymphoma kinase tyrosine kinase inhibitors with great response rates. Disease flare refers to sudden rapid disease worsening on tyrosine kinase inhibitors (TKI) discontinuation, which is associated with shorter survival and worse outcomes. Here, we review cases previously published in the literature where patients developed disease flares, and contrast this with our patients who had prolonged survival despite TKI discontinuation. Case description: We report three different patients with advanced ALK-positive NSCLC seen at our institute, who had EML4-ALK translocation variant 1 oncogenic driver on next-generation sequencing. They received treatment with several different ALK inhibitors before opting to discontinue TKI. They were able to come off TKI safely without developing disease flare and had prolonged survival. Discussion: Shorter time to progression on TKI, presence of symptoms with disease progression or central nervous system/pleural metastasis have been previously linked with development of flare, although this was not seen in our case series. Tumour response at the time of treatment discontinuation, line of therapy, overall disease burden, fusion variant and co-alteration status can affect the prognosis of these patients after ALK TKI cessation. In particular, variant 1 and wild-type TP53 status may be a suitable patient population for dose optimisation strategies. Intermittent TKI dosing strategies may help to avoid acquiring resistance mutations and prevent long-term treatment toxicities. Conclusion: It is important for clinicians to identify patients at risk for developing disease flare on TKI discontinuation to improve outcomes. Intermittent TKI dosing strategies require further investigation. LEARNING POINTS: Patients who develop disease flare after cessation have poor survival and worse outcomes.Certain phenotypic and molecular characteristics of the tumour may help clinicians identify which patients are likely and which are unlikely to develop disease flare on TKI discontinuation.Advanced ALK-positive NSCLC with variant 1 and wild-type TP53 may be a suitable patient population for intermittent TKI dosing investigations.
ABSTRACT
BACKGROUND: The ADAURA trial confirmed adjuvant Osimertinib's efficacy in EGFR-mutated Non-small-cell lung cancer (NSCLC), yet the limited mature overall survival (OS) data at approval poses a challenge. This study explores patient preferences in the absence of complete OS information, hypothesizing that disease-free survival (DFS) benefit alone may influence adjuvant Osimertinib pursuit. METHODS: At Roswell Park Comprehensive Cancer Center (Jan-Dec 2021), patients assessed for adjuvant therapy received a survey probing OS and DFS preferences. Scenarios were (a) minimum OS justifying Osimertinib, (b) minimum DFS improvement justifying 3-years of adjuvant Osimertinib, (c) minimum 5-year DFS percent change, and (d) minimum OS justifying copay changes. Results were analyzed. RESULTS: Of 524 NSCLC patients, 51 participated. Scenario 1 saw 56% requiring a 12-month OS benefit for Osimertinib justification. In scenario 2, 72% deemed a 12-month DFS benefit sufficient. Scenario 3 revealed 31% opting out despite a 10% OS increase. Scenario 4 showed varied willingness to pay, with 33% unwilling to any shoulder copayment even with a 10-year OS benefit. CONCLUSION: This study explores patient preferences without complete OS data, revealing diverse thresholds. Factors include employment, education, and willingness to pay. Findings underscore shared decision-making importance. Limitations include sample size, potential biases, and regional focus; larger cohorts are needed for validation.
ABSTRACT
Background: Based on preclinical data showing addition of CDK4/6 inhibitors to gemcitabine is synergistic, ribociclib was evaluated in combination with gemcitabine to determine the maximum tolerated dose (MTD) and dose limiting toxicities (DLT). Methods: In this single arm multicohort phase I trial, we evaluated the safety and efficacy of Ribociclib plus Gemcitabine in patients with advanced solid tumors. Patients received Gemcitabine intravenously on days 1 and 8 followed by Ribociclib days 8-14, with treatment repeated every 3 weeks. Results: The study enrolled 43 patients between October 2017 and September 2019. The escalation phase (19 patients) determined the MTD and recommended phase II dose (RP2D) to be ribociclib 800mg daily and gemcitabine 1000mg/m2 for the expansion phase (24 patients). One patient experienced Grade 4 thrombocytopenia. Eleven patients experienced Grade 3 adverse events (AE), the most common being neutropenia, thrombocytopenia, and anemia. No partial or complete responses were observed. 15/22 (68%) of efficacy evaluable patients who received the MTD achieved best response of stable disease. Conclusions: The addition of Ribociclib to Gemcitabine was tolerated well and yielded stability of tumors in both cohorts. Ribociclib and gemcitabine could have synergistic activity in certain tumor types, and our data provides support for the combination. Clinical Trial Registration: NCT03237390.
ABSTRACT
Pembrolizumab, a widely used immune checkpoint inhibitor (ICI), has revolutionized the treatment of non-small cell lung cancer (NSCLC). Identifying unique tumor characteristics in patients likely to respond to pembrolizumab could help the clinical adjudication and development of a personalized therapeutic strategy. In this retrospective study, we reviewed the clinical data and pathological features of 84 NSCLC patients treated with pembrolizumab. We examined the correlation between the clinical and demographic characteristics and the tumor histopathologic features obtained before immunotherapy. The response to pembrolizumab therapy was evaluated via the Response Evaluation Criteria in Solid Tumors (RECIST). The clinical data and cancer tissue characteristics were assessed and compared among three groups according to the following RECIST: the responsive group (RG), the stable disease group (SD), and the progressive disease group (PD), where the RG comprised patients with either a complete response (CR) or a partial response (PR). The overall survival rate of the RG group was significantly higher than the SD and PD groups. In addition, the percentage of pre-treatment viable tumor cell content in the RG and SD groups was significantly higher. At the same time, the extracellular stroma proportion was significantly lower than that of the PD group. The number of tumor-infiltrating lymphocytes (TILs) in the RG group was significantly higher than in the PD group. There were no significant differences in tumor necrosis, the stroma composition, PD-L1 expression level (TPS 1-49% vs. ≥50%), and treatment response. In conclusion, our population of NSCLC patients who experienced positive treatment responses to pembrolizumab therapy had a better prognosis compared to patients with either SD or PD. Moreover, the relative proportions of viable tumor cells to tumor-associated lymphocytes were associated with responsiveness to treatment. It is expected that larger prospective clinical studies will further validate these findings.
ABSTRACT
WHAT IS THIS SUMMARY ABOUT?: This is a plain language summary of a study called CodeBreaK 100. The CodeBreaK 100 study included patients with non-small-cell lung cancer that had spread outside the lung (advanced). Lung cancer is one of the most common forms of cancer. CodeBreaK 100 specifically looked at patients with a particular change(mutation) in the KRAS gene resulting in the mutated protein called KRAS G12C. The KRAS G12C mutation can lead to development and growth of lung cancer. Patients received a treatment called sotorasib, which has accelerated approval or full approval in over 50 countries for patients with non-small-cell lung cancer with the KRAS G12C mutation. The CodeBreaK 100 study looked at whether sotorasib is a safe and effective treatment for advanced non-small-cell lung cancer. Sotorasib is designed to specifically target and lock the mutated KRAS protein in the inactive state to treat non-small-cell lung cancer. WHAT WERE THE RESULTS?: In total, 174 adults were treated with sotorasib. Treatment-related side effects were seen in 70% of patients and were severe in 21% of patients. The most common side effects included diarrhea, increased liver enzymes, nausea and tiredness. 70 (41%) patients responded to sotorasib and 144 (84%) patients had tumors that either remained stable or shrunk in size. 29 (41%) patients who responded to sotorasib responded for over 12 months. After 2 years, 9 patients with a response remained on sotorasib; there were no notable increases in tumor size or development of new tumors over this time. There were 5patients who received sotorasib for more than 2 years and continued to respond. Long-term benefit was seen for some patients. Patients also benefitted from treatment when the tumor expressed different amounts of a protein called PD-L1.In total, 33% of patients were still alive after 2 years. WHAT DO THE RESULTS MEAN?: Results show the long-term benefit of sotorasib therapy for people with advanced KRAS G12C-mutated non-small-cell lung cancer. Clinical Trial Registration: NCT03600883 (CodeBreaK 100) (ClinicalTrials.gov).
Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Piperazines , Pyridines , Pyrimidines , Adult , Humans , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Proto-Oncogene Proteins p21(ras)/genetics , Language , MutationABSTRACT
Programmed cell death ligand (PD-L1) expression by immunohistochemistry (IHC) lacks sensitivity for pembrolizumab immunotherapy selection in non-small cell lung cancer (NSCLC), particularly for tumors with low expression. We retrospectively evaluated transcriptomic PD-L1 by mRNA next-generation sequencing (RNA-seq). In an unselected NSCLC patient cohort (n = 3168) tested during standard care (2017-2021), PD-L1 IHC and RNA-seq demonstrated moderate concordance, with 80% agreement overall. Most discordant cases were either low or negative for PD-L1 expression by IHC but high by RNA-seq. RNA-seq accurately discriminated PD-L1 IHC high from low tumors by receiver operator curve (ROC) analysis but could not distinguish PD-L1 IHC low from negative tumors. In a separate pembrolizumab monotherapy cohort (n = 102), NSCLC tumors classified as PD-L1 high versus not high by RNA-seq had significantly improved response, progression-free survival, and overall survival as an individual measure and in combination with IHC high or low status. PD-L1 IHC status (high or low) trended toward but had no significant associations with improved outcomes. Conventional PD-L1 IHC testing has inherent limitations, making it an imperfect reference standard for evaluating novel testing technologies. RNA-seq offers an objective PD-L1 measure that could represent a complementary method to IHC to improve NSCLC patient selection for immunotherapy.
ABSTRACT
Long interspersed nuclear element-1 (LINE-1 or L1), the most abundant family of autonomous retrotransposons occupying over 17% of human DNA, is epigenetically silenced in normal tissues by the mechanisms involving p53 but is frequently derepressed in cancer, suggesting that L1-encoded proteins may act as tumor-associated antigens recognized by the immune system. In this study, we established an immunoassay to detect circulating autoantibodies against L1 proteins in human blood. Using this assay in >2,800 individuals with or without cancer, we observed significantly higher IgG titers against L1-encoded ORF1p and ORF2p in patients with lung, pancreatic, ovarian, esophageal, and liver cancers than in healthy individuals. Remarkably, elevated levels of anti-ORF1p-reactive IgG were observed in patients with cancer with disease stages 1 and 2, indicating that the immune response to L1 antigens can occur in the early phases of carcinogenesis. We concluded that the antibody response against L1 antigens could contribute to the diagnosis and determination of immunoreactivity of tumors among cancer types that frequently escape early detection. SIGNIFICANCE: The discovery of autoantibodies against antigens encoded by L1 retrotransposons in patients with five poorly curable cancer types has potential implications for the detection of an ongoing carcinogenic process and tumor immunoreactivity.
Subject(s)
Neoplasms , Retroelements , Humans , Long Interspersed Nucleotide Elements/genetics , Neoplasms/genetics , Autoantibodies/genetics , Immunoglobulin G/geneticsABSTRACT
PURPOSE: Durable progression-free survivors (dPFSors) over 2 years have been reported among patients with melanoma or non-small-cell lung cancer (NSCLC) who received PD-(L)1 therapy. However, risk of progression still exists and the optimal imaging surveillance interval is unknown. METHODS: Individual patient data for progression-free survival (PFS) were extracted from PD-1 blockade clinical trials with a follow-up of at least 5 years. Patients with a PFS of at least 2 years were considered as dPFSors. Conditional risks of progression/death (P/D) every 3, 4, 6, and 12 months in each subsequent year were calculated. We prespecified three different levels of risk between scans (10%, 15%, or 20%) to allow clinicians and patients to decide on the scanning interval on the basis of considerations of imaging frequency and risk tolerance. An interval is considered acceptable if the upper bound of the 95% CI of the risk at each scan is lower than a prespecified level. RESULTS: Of 1,495 and 3,752 patients with melanoma and NSCLC, 474 (31.7%) and 586 (15.6%) were dPFSors, respectively. Among them, the PFS probability for an additional 3 years was 76.4% and 48.1%, respectively. Not more than 8% of patients had P/D in any quarter in the 3 years. With a risk threshold of 10%, melanoma dPFSors can be scanned every 6 months during the third year and then every 12 months in years 4 and 5. The interval for NSCLC would be every 3 months in the third year and every 4 months in years 4 and 5. The higher risk tolerance of 15% and 20% would allow for less frequent scans. CONCLUSION: On the basis of their own risk tolerance level, our findings allow clinicians and dPFSors make data-driven decisions regarding the imaging surveillance schedule beyond every 3 months.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Melanoma , Humans , Carcinoma, Non-Small-Cell Lung/drug therapy , Lung Neoplasms/drug therapy , Programmed Cell Death 1 Receptor/therapeutic use , Disease-Free Survival , Melanoma/drug therapyABSTRACT
Introduction: In stage IV NSCLC with solitary or oligometastatic brain metastasis, surgical resection of the primary and definitive management of the brain metastasis is an accepted standard. However, the effect of systemic chemotherapy after surgical resection on overall survival is not well-established. Methods: We used the National Cancer Database to retrospectively identify individuals with NSCLC as the primary tumor along with synchronous brain metastases who underwent thoracic resection with or without adjuvant chemotherapy. Chi-square and Wilcoxon rank sum tests were performed to compare categorical and continuous variables, respectively, across the treatment groups. Kaplan-Meier and Cox proportional modeling were done to determine the survival benefit. Results: A total of 310 (71.9%) of the cohort received perioperative chemotherapy, most of whom (79.4%) received it in the adjuvant setting. Patients receiving chemotherapy were likely to be younger (p = 0.002), privately insured (p = 0.01), and receive radiation (p < 0.001). Perioperative chemotherapy was significantly associated with survival on both univariate (hazard ratio = 0.71[0.52 - 0.99]) and multivariable (hazard ratio = 0.66 [0.47 - 0.92]) in addition to age (p = 0.03), Charlson-Deyo score (p = 0.02), pathologic N stage (p = 0.02), and adenocarcinoma histology (p = 0.02). Kaplan-Meier analysis confirmed this result with a significantly better survival with perioperative chemotherapy (p = 0.02). Further subgroup analysis using pathologic N stage revealed similar effect in pN1 (p = 0.001), but not pN0 (p = 0.2) patients. Conclusions: Perioperative chemotherapy for pN0-1 NSCLC with synchronous brain metastasis is associated with improved OS in this analysis.
ABSTRACT
Background: Immune checkpoint inhibitors (ICIs) such as programmed cell death protein-1 (PD-1) inhibitors or PD-1 ligand-1 (PD-L1) inhibitors have led to remarkable improvement in outcomes of non-small cell lung cancer (NSCLC). Unfortunately, the significant benefits of ICI therapy are frequently limited by resistance to treatment and adverse effects, and the predictive value of pre-treatment tumor tissue PD-L1 expression is limited. Development of less invasive biomarkers that could identify responders and non-responders in early on-treatment could markedly improve the treatment regimen. Accumulating evidence suggests that baseline gut microbiota profile is associated with response to PD-1/PD-L1 blockade therapy. However, change in the gut microbiome composition during PD-1/PD-L1 blockade therapy and its relation to response remain unclear. Methods: Here, we analyzed pre- and on-treatment fecal samples from five NSCLC patients receiving anti-PD-1 immunotherapy, alone or in tandem with chemotherapy, and performed 16S rRNA sequencing. Results: The overall alpha diversity of the baseline gut microbiome was similar between three responders and two non-responders. While the gut microbiome composition remained stable overall during treatment (R2 = 0.145), responders showed significant changes in microbiome diversity between pre- and on-treatment samples during anti-PD-1 therapy compared to non-responders (P = 0.0274). Within the diverse microbiota, responders showed decreases in the abundance of genera Odoribacter, Gordonibacter, Candidatus Stoquefichus, Escherichia-Shigella, and Collinsella, and increase in abundance of Clostridium sensu stricto 1. In contrast, non-responders demonstrated on-treatment increases in genera Prevotella, Porphyromonas, Streptococcus, and Escherichia-Shigella, and decrease in abundance of Akkermansia. Conclusions: This pilot study identified a substantial change in gut microbiome diversity between pre- and on-treatment samples in NSCLC patients responding to anti-PD-1 therapy compared to non-responders. Our findings highlight the potential utility of gut microbiota dynamics as a noninvasive biomarker to predict response to PD-1/PD-L1 blockade therapy for a wide variety of malignancies, which sets a path for future investigation in larger prospective studies.
ABSTRACT
Tumor derived exosomes (TEXs) have emerged as promising biomarkers for cancer liquid biopsy. Conventional methods (such as ELISA and qRT-PCR) and emerging biosensing technologies mainly detect a single type of exosomal biomarker due to the distinct properties of different biomolecules. Sensitive detection of two different types of TEX biomarkers, i.e., protein and microRNA combined biomarkers, may greatly improve cancer diagnostic accuracy. We developed an exosome protein microRNA one-stop (Exo-PROS) biosensor that not only selectively captured TEXs but also enabled in situ, simultaneous detection of TEX protein-microRNA pairs via a surface plasmon resonance mechanism. Exo-PROS assay is a fast, reliable, low sample consumption, and user-friendly test. With a total of 175 cancer patients and normal controls, we demonstrated that TEX protein-microRNA pairs measured by Exo-PROS assay detected lung cancer and breast cancer with 99% and 96% accuracy, respectively. Exo-PROS assay also showed superior diagnostic performance to conventional ELISA and qRT-PCR methods. Our results demonstrated that Exo-PROS assay is a potent liquid biopsy assay for cancer diagnosis.
Subject(s)
Biosensing Techniques , Exosomes , Lung Neoplasms , MicroRNAs , Humans , MicroRNAs/genetics , Exosomes/metabolism , Biomarkers, Tumor/analysis , Neoplasm Proteins/metabolism , Lung Neoplasms/diagnosis , Lung Neoplasms/genetics , Lung Neoplasms/metabolism , Biosensing Techniques/methodsABSTRACT
Lack of reliable predictive biomarkers is a major limitation of combination therapy with chemotherapy and anti-programmed cell death protein 1/programmed death-ligand 1 (anti-PD-1/PD-L1) therapy (chemo-immunotherapy). We previously observed that the increase of peripheral blood CD8+ T cells expressing CX3CR1, a marker of differentiation, correlates with response to anti-PD-1 therapy; however, the predictive and prognostic value of T-cell CX3CR1 expression during chemo-immunotherapy is unknown. Here, we evaluated the utility of circulating CX3CR1+CD8+ T cells as a predictive correlate of response to chemo-immunotherapy in patients with non-small cell lung cancer (NSCLC). At least 10% increase of the CX3CR1+ subset in circulating CD8+ T cells from baseline (CX3CR1 score) was associated with response to chemo-immunotherapy as early as 4 weeks with 85.7% overall accuracy of predicting response at 6 weeks. Furthermore, at least 10% increase of the CX3CR1 score correlated with substantially better progression-free (P = 0.0051) and overall survival (P = 0.0138) on Kaplan-Meier analysis. Combined single-cell RNA/T-cell receptor (TCR) sequencing of circulating T cells from longitudinally obtained blood samples and TCR sequencing of tumor tissue from the same patient who received a long-term benefit from the treatment demonstrated remarkable changes in genomic and transcriptomic signatures of T cells as well as evolution of TCR clonotypes in peripheral blood containing highly frequent tumor-infiltrating lymphocyte repertoires overexpressing CX3CR1 early after initiation of the treatment despite stable findings of the imaging study. Collectively, these findings highlight the potential utility of T-cell CX3CR1 expression as a dynamic blood-based biomarker during the early course of chemo-immunotherapy and a marker to identify frequent circulating tumor-infiltrating lymphocyte repertoires. Significance: Current approaches to combined chemotherapy and anti-PD-1/PD-L1 therapy (chemo-immunotherapy) for patients with NSCLC are limited by the lack of reliable predictive biomarkers. This study shows the utility of T-cell differentiation marker, CX3CR1, as an early on-treatment predictor of response and changes in genomic/transcriptomic signatures of circulating tumor-infiltrating lymphocyte repertoires in patients with NSCLC undergoing chemo-immunotherapy.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Humans , Carcinoma, Non-Small-Cell Lung/drug therapy , Prognosis , Lung Neoplasms/drug therapy , B7-H1 Antigen/analysis , CD8-Positive T-Lymphocytes/chemistry , Immunotherapy/methods , Receptors, Antigen, T-Cell/genetics , CX3C Chemokine Receptor 1/geneticsABSTRACT
Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.In the longest follow-up, to our knowledge, for a KRASG12C inhibitor, we assessed the long-term efficacy, safety, and biomarkers of sotorasib in patients with KRAS G12C-mutated advanced non-small-cell lung cancer (NSCLC) from the CodeBreaK 100 clinical trial (ClinicalTrials.gov identifier: NCT03600883). This multicenter, single-group, open-label phase I/phase II trial enrolled 174 patients with KRAS G12C-mutated, locally advanced or metastatic NSCLC after progression on prior therapies. Patients (N = 174) received sotorasib 960 mg once daily with the primary end points for phase I of safety and tolerability and for phase II of objective response rate (ORR). Sotorasib produced an ORR of 41%, median duration of response of 12.3 months, progression-free survival (PFS) of 6.3 months, overall survival (OS) of 12.5 months, and 2-year OS rate of 33%. Long-term clinical benefit (PFS ≥ 12 months) was observed in 40 (23%) patients across PD-L1 expression levels, in a proportion of patients with somatic STK11 and/or KEAP1 alterations, and was associated with lower baseline circulating tumor DNA levels. Sotorasib was well tolerated, with few late-onset treatment-related toxicities, none of which led to treatment discontinuation. These results demonstrate the long-term benefit of sotorasib, including in subgroups with poor prognosis.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Humans , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Kelch-Like ECH-Associated Protein 1 , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , NF-E2-Related Factor 2 , Proto-Oncogene Proteins p21(ras)/geneticsABSTRACT
The Thomsen-Friedenreich antigen (TF-Ag-α) is found on ~85% of human carcinomas but is cryptic on normal tissue. The humanized highly specific hJAA-F11-H2aL2a and -H3L3 antibodies target TF-Ag-α without binding to TF-Ag-beta (found on surface glycolipids of some normal cells). The relative affinity of H3L3 is 17 times that of H2aL2a, which would seem to favor superior efficacy, however, increased affinity can result in less tumor penetration. To assess the potential therapeutic efficacy of these antibodies, four human cancer- mouse xenograft models were treated with H2aL2a and H3L3. The tumor xenograft models used were human non-small cell lung cancer, H520, and small cell lung cancer, HTB171 in nude mice and human triple negative breast cancer, MDA-MB-231 and HCC1806 in SCID mice. H2aL2a significantly decreased tumor growth in both breast and both lung cancer models. H2aL2a showed statistically equal or better efficacy than H3L3 and has superior production capabilities. These results suggest that H2aL2a may be superior as a naked antibody, as an antibody drug conjugate or as a radiolabeled antibody, however the higher affinity of H3L3 may lead to better efficacy in bi-specific therapies in which the binding is decreased due to the presence of only one TF-Ag-α binding site.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Immunoconjugates , Lung Neoplasms , Humans , Animals , Mice , Lung Neoplasms/therapy , Mice, Nude , Heterografts , Mice, SCID , Antigens, Tumor-Associated, Carbohydrate , Antibodies , GlycolipidsABSTRACT
Background: CIMAvax-EGF is an epidermal growth factor (EGF)-depleting immunotherapy which has shown survival benefit as a switch maintenance treatment after platinum-based chemotherapy in advanced non-small cell lung cancer (NSCLC). The primary objective of this trial is to establish the safety and recommended phase II dose (RP2D) of CIMAvax-EGF in combination with nivolumab as second-line therapy for NSCLC. Methods: Patients with immune checkpoint inhibitor-naive metastatic NSCLC were enrolled using a "3+3" dose-escalation design. Toxicities were graded according to CTCAE V4.03. Thirteen patients (one unevaluable), the majority with PD-L1 0%, were enrolled into two dose levels of CIMAvax-EGF. Findings: The combination was determined to be safe and tolerable. The recommended phase 2 dose of CIMAvax-EGF was 2.4 mg. Humoral response to CIMAvax-EGF was achieved earlier and in a greater number of patients with the combination compared to historical control. Four out of 12 evaluable patients had an objective response.