Platinum-based Doublet Chemotherapy Research Articles

Improved Prediction of Chemoradiation and Immune Checkpoint Blockade Efficacy with Dynamic bTMB Combined with ctDNA in Unresectable Locally Advanced NSCLC

Consolidation durvalumab after definitive chemoradiation therapy (CRT) has become the new standard of care for patients with unresectable locally advanced non-small-cell lung cancer (LA-NSCLC). However, only a fraction of patients can benefit from it, and current decision-making procedures have limited accuracy. Blood-based tumor mutational burden (bTMB) is a promising biomarker, but whether bTMB alone or combined with circulating tumor DNA (ctDNA) can predict the efficacy of definitive CRT and immune checkpoint inhibitors (ICIs) in patients with LA-NSCLC remains unclear. This cohort study enrolled patients diagnosed with unresectable LA-NSCLC from 2018 to 2022. Patients were assigned to the cohort A receiving definitive CRT alone (intensity modulated radiation therapy or volumetric modulated arc therapy with the prescribed dose of 60 Gy, concurrently or sequentially with two or more cycles of platinum-based doublet chemotherapy), or cohort B undergoing definitive CRT and immunotherapy. Peripheral blood specimens were collected before and after CRT and subjected to next-generation sequencing panel to analyze ctDNA and bTMB. The dynamic change in bTMB (∆bTMB) was calculated as the bTMB level after CRT minus the baseline bTMB level. Potential correlations were identified by Spearman's correlation tests and expressed as R coefficients. Time-dependent receiver operating characteristic curves and areas under the curve (AUCs) were employed to evaluate the predictive power of different models on survival. A total of 73 LA-NSCLC patients were included, with 70 (95.9%) at stage III and 3 at stage II (4.1%). Thirty-six patients (49.3%) assigned to the cohort A were treated with CRT alone and 37 (50.7%) in the cohort B receiving CRT and ICIs. Patients with CRT + ICIs in the cohort B showed significantly improved overall survival (OS; P < 0.01) and progression-free survival (PFS; P = 0.02) than those with CRT alone. Baseline bTMB at cutoff values of 4 to 22 did not predict outcomes (all P > 0.10), while patients with increased bTMB (∆bTMB > 0) after CRT had significantly worse OS and PFS (both P < 0.01) than those with decreased or stable bTMB (∆bTMB ≤ 0). ∆bTMB was independent of the ctDNA level after CRT (P = 0.76, R = -0.04). Patients were further divided into 3 groups based on ∆bTMB and post-CRT ctDNA (∆bTMB > 0/detectable ctDNA vs. ∆bTMB ≤ 0/detectable ctDNA vs. ∆bTMB ≤ 0/undetectable ctDNA), and significant survival differences were observed in the pairwise comparisons of 3 groups (all P < 0.05). The model of ∆bTMB combined with post-CRT ctDNA status exhibited the optimal predictive power on both OS (AUC = 0.80) and PFS (AUC = 0.75) and outperformed each factor, which had been respectively validated in the cohort A and B as well. Dynamic bTMB (∆bTMB) combined with post-CRT ctDNA status is a novel and effective biomarker model of predicting survival outcomes in LA-NSCLC patients treated with CRT ± ICIs, and outperforms each individual feature.

Avelumab Versus Platinum-Based Doublet Chemotherapy as First-Line Treatment for Patients With High-Expression Programmed Death-Ligand 1–Positive Metastatic NSCLC: Primary Analysis From the Phase 3 JAVELIN Lung 100 Trial

IntroductionWe report the primary analysis from JAVELIN Lung 100, a phase 3 trial comparing avelumab (anti⁠–programmed death-ligand 1 [PD-L1]) versus platinum-based doublet chemotherapy as first-line treatment for PD-L1–positive (+) advanced NSCLC. MethodsAdults with PD-L1+ (≥1% of tumor cells; PD-L1 immunohistochemistry 73-10 pharmDx), EGFR and ALK wild-type, previously untreated, stage IV NSCLC were randomized to avelumab 10 mg/kg every 2 weeks (Q2W), avelumab 10 mg/kg once weekly (QW) for 12 weeks and Q2W thereafter, or platinum-based doublet chemotherapy every 3 weeks. Primary end points were overall survival (OS) and progression-free survival (PFS) per independent review committee. The primary analysis population was patients with high-expression PD-L1+ tumors (≥80% of tumor cells). ResultsA total of 1214 patients were randomized to avelumab Q2W (n = 366), avelumab QW (n = 322), or chemotherapy (n = 526). In the primary analysis population, hazard ratios (HRs) for OS and PFS with avelumab Q2W (n = 151) versus chemotherapy (n = 216) were 0.85 (95% confidence interval [CI]: 0.67–1.09; one-sided p = 0.1032; median OS, 20.1 versus 14.9 mo) and 0.71 (95% CI: 0.54–0.93; one-sided p = 0.0070; median PFS, 8.4 versus 5.6 mo), respectively. With avelumab QW (n = 130) versus chemotherapy (n = 129), HRs were 0.79 (95% CI: 0.59–1.07; one-sided p = 0.0630; median OS, 19.3 versus 15.3 mo) and 0.72 (95% CI: 0.52–0.98; one-sided p = 0.0196; median PFS, 7.5 versus 5.6 mo), respectively. No new safety signals were observed. ConclusionsLonger median OS and PFS were observed with avelumab versus platinum-based doublet chemotherapy in advanced NSCLC, but differences in OS and PFS were not statistically significant, and the trial did not meet its primary objective. ClinicalTrials.gov Identifier: NCT02576574.

Genotyping, in silico screening and molecular dynamics simulation of SNPs of MGMT and ERCC1 gene in lung cancer patients treated with platinum-based doublet chemotherapy

Lung cancer, the leading cause of death worldwide, arises from an intricate combination of genetic and environmental factors. Genetic variations can influence the chemotherapeutic response of lung cancer patients in DNA repair genes. This study examines the response to platinum-based drugs among lung cancer patients of North Indian descent who possess genetic variations in the MGMT and ERCC1 genes. P CR-RFLP method was used for genotypic analysis. MedCalc statistical software was used to calculate odds ratios and Median Survival Time (MST). GROMACS software was used to perform Molecular dynamic simulation. ADCC Patients revealed a significant association with MGMT in the heterozygous genotype (HR= 1.56, p=0.02) and also with ERCC1 in both mutant and combined variants (HR= 1.25, p=0.01; HR=0.78, p=0.03). SQCC subjects harbouring ERCC1 polymorphism also reported a 2-fold increase in hazard ratio and a corresponding decrease in survival time for heterozygous and combined variants (HR= 2.55, p=0.02; HR 2.33, p=0.01, respectively). MD simulation results demonstrate a lower RMSD, stable radius of gyration, and lower RMSF, indicating the mutated MGMT protein is more stable than the wild. Further, the docking score for DNA-Wild and DNA-L84F mutants are -201.6 and -131.8, respectively. MD Simulation of the complexes further validated the results. Our study concludes that MGMT and ERCC1 polymorphisms are associated with decreased overall survival. Further, computational analysis of MGMT (rs12917) polymorphism revealed that mutated MGMT cannot bind properly to the DNA and hence cannot properly repair DNA, resulting in lower overall survival. Communicated by Ramaswamy H. Sarma

A multicenter, open-label phase Ib/II study of cadonilimab (anti PD-1 and CTLA-4 bispecific antibody) monotherapy in previously treated advanced non–small-cell lung cancer (AK104-202 study)

PurposeThis study aimed to evaluate the efficacy and safety of cadonilimab (anti PD-1 and CTLA-4 bispecific antibody) in patients with previously treated metastatic non-small-cell lung cancer (NSCLC). MethodsIn this multicenter, open-label, phase Ib/II study, patients with previously treated NSCLC were enrolled in three different cohorts: Cohort A, patients who had failed previous platinum-based doublet chemotherapy and were immunotherapy naïve; Cohort B, patients who had failed previous platinum-based doublet chemotherapy and had primary resistance to immunotherapy (IO); Cohort C, patients who had failed previous platinum-based doublet chemotherapy and had acquired resistance to IO. Eligible patients were given cadonilimab 6 mg/kg intravenously every 2 weeks. The primary endpoint was the objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors version 1.1. ResultsA total of 53 patients were enrolled: including 30 patients in cohort A, 7 in cohort B, and 16 in cohort C. ORR was 10% in cohort A, and there were no responder in cohort B and cohort C. Median overall survival was 19.61 (95% CI 11.30-NE) months, 4.93 (95% CI 1.97-NE) months and 13.16 (95% CI 6.18-NE) months in cohort A, B and C, respectively. Grade 3–4 treatment-related adverse events were reported in 6 (11.3 %) patients, including alanine aminotransferase increased (1.9%), rash (1.9%), chest discomfort (1.9%), hypercalcaemia (1.9%), anaemia (1.9%) and infusion related reaction (1.9%). ConclusionThe study did not meet its primary endpoint. Cadonilimab demonstrated limited efficacy in patients with IO failure, especially in cases of primary resistance. However, cadonilimab might play a role as a second-line immune monotherapy after platinum-based doublet chemotherapy failure and IO naïve, as its efficacy is similar to other immune checkpoint inhibitors after first-line chemotherapy. Cadonilimab was well-tolerated with mild toxicity, making it a potential candidate for the combination strategy.Clinical trial number NCT 04172454.

Real-World Data About Treatment Outcomes for Patients with EGFR-Mutated NSCLC Resistance to Osimertinib and Platinum-Based Chemotherapy.

Docetaxel is an established standard therapy after osimertinib and platinum-based doublet chemotherapy (Pt-doublet) for locally advanced or metastatic non-small cell lung cancer (NSCLC) with an epidermal growth factor receptor gene (EGFR) mutation. To facilitate future therapeutic developments in these patients after treatment with osimertinib and Pt-doublet, we estimated the outcomes of currently used post-treatment therapies. Data of patients with NSCLC who received at least one medication after osimertinib and Pt-doublet between April 2008 and August 2021 were extracted from the Medical Data Vision claims database. The duration of treatment (DoT) (first treatment after osimertinib and Pt-doublet) and overall survival (OS) were estimated. The index date was the first day on which the medication was prescribed. In total, 731 patients (mean age 64years) were screened. The most frequent post-treatments were docetaxel-based chemotherapy (30.2%), immune checkpoint inhibitor (ICI) alone or in combination (17.2%), first-/second-generation EGFR-tyrosine kinase inhibitors (16.7%), osimertinib (16.3%), and Pt-doublet (5.2%). The median DoT and OS (95% confidence interval) of all post-treatments were 3.5 (3.27, 3.77) and 10.3 (9.3, 12.1) months, respectively, reflecting the median DoT (3.8months) and OS (10.0months) of docetaxel-based chemotherapy. Among all post-treatment regimens, ICIs resulted numerically the shortest [2.77 (2.33, 3.00) months] and osimertinib the longest [4.40 (3.47, 5.67) months] median DoT. The median OS was shortest in patients post-treated with ICIs [7.07 (5.40, 9.90) months] and longest in patients rechallenged with Pt-doublet (12.27months), followed by patients post-treated with osimertinib (11.70months). In a subset analysis of patients who received first-line osimertinib and second-line Pt-doublet as well as Pt-doublet immediately after osimertinib, those post-treated with ICIs had the shortest median DoT. Given the limited real-world efficacy on EGFR-mutant NSCLC resistant to osimertinib and platinum-based chemotherapy, the development of more highly potent post-treatment therapies is warranted.

Treatment of Stage IV Non-Small Cell Lung Cancer with Pembrolizumab in Combination with Platinum-Based Doublet Chemotherapy in Vietnam.

Lung cancer has been one of the most prevalent cancers worldwide in recent decades. According to the findings of the KEYNOTE-407 (2018) study on patients with stage IV squamous cell lung cancer, the combination of pembrolizumab and chemotherapy in the first-line treatment prolongs overall survival compared with chemotherapy alone. This study aimed to evaluate the efficacy and side effects of treating patients with stage IV non-small cell lung cancer with pembrolizumab in combination with platinum-based doublet chemotherapy. A retrospective multicenter study on 46 patients at four hospitals in Vietnam between June 2018 and August 2022. Patients received first-line treatment with a protocol of pembrolizumab in combination with platinum-based doublet chemotherapy (pemetrexed plus carboplatin or paclitaxel plus carboplatin). The study's primary endpoints were progression-free survival and safety. The secondary endpoint was overall survival. The median progression-free survival was 11.0 months (95% CI, 7.4-14.7 months). The median overall survival was 23.1 months (95% CI, 18.4-27.8 months). The survival rate of patients after 1 and 2 years was 82.3% and 43.3%, respectively. The most common side effects were anemia and elevated liver enzymes, but they were primarily mild or moderate severity. Progression-free survival did not depend on cancer type based on histology (p = 0.13). The progression-free survival was independent of programmed death ligand-1 expression levels < 50% or ≥ 50% (p = 0.68). Treatment of stage IV non-small cell lung cancer without EGFR and ALK gene mutations with the immunotherapy protocol of pembrolizumab in combination with platinum-based doublet chemotherapy resulted in favorable outcomes without any new safety concerns. A larger sample size and longer follow-up in the future are necessary to yield more complete results.

Early Clearance of Plasma Epidermal Growth Factor Receptor Mutations as a Predictor of Outcome on Osimertinib in Advanced Non-Small Cell Lung Cancer; Exploratory Analysis from AURA3 and FLAURA.

Plasma circulating tumor DNA (ctDNA) analysis is used for genotyping advanced non-small cell lung cancer (NSCLC); monitoring dynamic ctDNA changes may be used to predict outcomes. This was a retrospective, exploratory analysis of two phase III trials [AURA3 (NCT02151981), FLAURA (NCT02296125)]. All patients had EGFR mutation-positive (EGFRm; ex19del or L858R) advanced NSCLC; AURA3 also included T790M-positive NSCLC. Osimertinib (FLAURA, AURA3), or comparator EGFR-tyrosine kinase inhibitor (EGFR-TKI; gefitinib/erlotinib; FLAURA), or platinum-based doublet chemotherapy (AURA3) was given. Plasma EGFRm was analyzed at baseline and Weeks 3/6 by droplet digital PCR. Outcomes were assessed by detectable/non-detectable baseline plasma EGFRm and plasma EGFRm clearance (non-detection) at Weeks 3/6. In AURA3 (n = 291), non-detectable versus detectable baseline plasma EGFRm had longer median progression-free survival [mPFS; HR, 0.48; 95% confidence interval (CI), 0.33-0.68; P < 0.0001]. In patients with Week 3 clearance versus non-clearance (n = 184), respectively, mPFS (months; 95% CI) was 10.9 (8.3-12.6) versus 5.7 (4.1-9.7) with osimertinib and 6.2 (4.0-9.7) versus 4.2 (4.0-5.1) with platinum-pemetrexed. In FLAURA (n = 499), mPFS was longer with non-detectable versus detectable baseline plasma EGFRm (HR, 0.54; 95% CI, 0.41-0.70; P < 0.0001). For Week 3 clearance versus non-clearance (n = 334), respectively, mPFS was 19.8 (15.1 to not calculable) versus 11.3 (9.5-16.5) with osimertinib and 10.8 (9.7-11.1) versus 7.0 (5.6-8.3) with comparator EGFR-TKI. Similar outcomes were observed by Week 6 clearance/non-clearance. Plasma EGFRm analysis as early as 3 weeks on-treatment has the potential to predict outcomes in EGFRm advanced NSCLC.

Design and Rationale for a Phase II/III, Randomized, Double-Blind, Placebo-Controlled Study of Sugemalimab as Consolidation Therapy in Patients With Limited-Stage Small-Cell Lung Cancer Who Have Not Progressed Following Concurrent or Sequential Chemoradiotherapy: The SURPASS Study

BackgroundThere is still a substantial need of more treatment options for patients with limited-stage small cell lung cancer (LS-SCLC). The standard therapy for LS-SCLC is platinum-based doublet chemotherapy administered concurrently with thoracic radiotherapy (cCRT). In China, sequential chemoradiotherapy (sCRT) is also a common practice. However, the disease inevitably progresses in most patients despite the curative intent and initial response. Materials and MethodsSugemalimab is an anti-programmed death ligand-1 (PD-L1) antibody that improved clinical outcomes for patients with stage III non-small cell lung cancer after cCRT or sCRT. The SUPPASS study is a phase II/III, randomized, double-blind, placebo-controlled, multicenter study (NCT05623267) that aims to investigate the efficacy and tolerability of sugemalimab as consolidation therapy in patients with LS-SCLC who have no progression following cCRT or sCRT. Approximately 346 patients will be randomized in a 1:1 ratio to receive sugemalimab 1200 mg or placebo every 3 weeks for up to 12 months. The primary endpoint is progression-free survival (PFS). Key secondary endpoints include overall survival (OS), landmark PFS rate, landmark OS rate, objective response rate and safety. Longitudinal molecular residual disease (MRD) testing will be performed as preplanned exploratory analysis. ConclusionStudy results will help demonstrate the efficacy and tolerability of anti-PD-L1 antibody consolidation therapy in LS-SCLC patients who have not progressed following cCRT or sCRT, and help determine the clinical implications of MRD in LS-SCLC.

Stereotactic body radiation therapy with sequential immunochemotherapy as neoadjuvant therapy in resectable non-small cell lung cancer (SACTION-01 study).

8540 Background: Neoadjuvant PD-1 inhibitor plus chemotherapy increases pathological response for resectable non-small cell lung cancer (NSCLC) compared with chemotherapy alone. Previous phase II trial indicated that stereotactic body radiation therapy (SBRT) served as an immunomodulator and enhanced the effect of preoperative immuno-monotherapy. However, whether SBRT would further increase the efficacy of immunochemotherapy for NSCLC remains unknown. Methods: In this phase II trial, patients with resectable EGFR wild-type stage IIA to IIIB NSCLC were recruited to receive SBRT (24 Gy in 3 daily fractions) to the primary tumor followed by two cycles of PD-1 inhibitor tislelizumab (200 mg) plus platinum-based doublet chemotherapy (Q3W) before surgical resection. The primary endpoint was major pathological response (MPR) defined as no more than 10% of viable tumor cells in the specimen. Simon’s optimal two-stage design was used for conducting the trial. The null hypothesis was that the MPR rate is 0.30, and the alternative hypothesis was that the true MPR rate was 0.50. More than 4 MPRs were needed in stage 1 (n=15) to continue, and if there were 19 or more MPRs in 46 patients by the end of stage 2, the null hypothesis can be rejected. The design controls the type I error rate at 0.05 and yields the power of 0.80. (NCT05319574). Results: Between May 2022 and Jan 2023, 32 patients were enrolled with 31 (96.9%) male and 19 (59.4%) having squamous cell lung cancer. Twenty-six (81.3%) patients had stage IIIA/B disease. All patients received at least one cycle of immunochemotherapy; 23 of the 25 patients (92.0%) who completed treatment had undergone R0 resections, except for one patient who had disease progression and the other one that unable to tolerate surgery because of grade 4 neutropenia. Twenty-two patients underwent minimally invasive approaches and 3 of them (13.6%) converted to thoracotomy. The median percentage of the viable tumor was 0 (interquartile range: 0-4.0%). Twenty patients achieved MPR, which surpassed the prespecified required number to reject the null hypothesis, resulting in the MPR rate of 80.0% (20/25) in the intention-to-treat population, and 87.0% (20/23) in the per-protocol population. Pathological complete response (pCR) was found in 14 patients (56.0% in the intention-to-treat population and 60.9% in the per-protocol population). Nodal clearance status (pN0) was found in 20 of 23 cN1/2 cases (87.0%). Grade 3-4 adverse events related to neoadjuvant treatment included neutropenia (13.0%), anemia (4.3%), and pneumonia (4.3%). No 30-day or 90-day mortality was observed. Conclusions: Neoadjuvant SBRT followed by immunochemotherapy yields unprecedently high MPR and pCR rates in NSCLC without EGFR mutation. The trial will continue to recruit 14 more patients to reach a final sample size of 46 participants. Clinical trial information: NCT05319574 .

MSH3 and MSH6 gene polymorphisms: Association with lung cancer susceptibility and prognostic value in patients with NSCLC undergoing platinum-based chemotherapy.

9031 Background: DNA mismatch repair (MMR) pathway is responsible for recognizing and repairing errors (insertion, deletion and misincorporation of bases) occurring during DNA replication and recombination. Single nucleotide polymorphisms (SNPs) in MSH3 and MSH6 genes are related to development of various cancers. SNPs of particular interest include rs26279 G &gt; A polymorphism for MSH3 and rs3136228 557G &gt; T polymorphism for MSH6. In this cohort study, we evaluated the association of MSH3 (rs26279) and MSH6 (rs3136228) SNPs with occurrence of lung cancer (LC), baseline demographic and clinical characteristics and with overall survival (OS) amongst LC patients undergoing platinum-based doublet chemotherapy. Methods: 500 LC patients and 500 healthy controls were enrolled. Genomic DNA was isolated from 4ml of peripheral blood using a phenol-chloroform extraction procedure and genotyping of patients and controls was performed using PCR-RFLP. All enrolled patients had pathologically confirmed LC. Written informed consent was obtained from all enrolled subjects and the study was approved by institutional ethics committee. Odds ratio (OR) and 95% confidence intervals (CIs) were calculated using logistic regression analysis. Kaplan-Meier method was used for OS analysis and (multivariate) Cox regression models to obtain (adjusted) hazards ratios (HRs). Results: Mean age (61 years) was similar for cases and controls. Compared to controls, LC cohort had higher prevalence of non-smokers (20% vs. 10%), female sex (20% vs. 9%) and smoking pack-years (mean 20.8 vs. 13.8). Majority of LC patients had metastatic disease (54%) and ECOG performance status of 0-1 (45%) or 2 (40%). Adenocarcinoma and squamous were equi-prevalent (41% each). Mutant genotype (TT) for MSH6 polymorphism was more frequent in LC patients (OR = 1.43; 95% CI = 1.01 – 2.03; p = 0.03) with the association more marked in adenocarcinoma histology (OR = 1.74; 95% CI = 1.05 – 2.93; p = 0.03). For non-smokers, mutant genotype (TT) for MSH6 polymorphism was associated with a 3-fold increased risk of LC (OR = 3.22; 95% CI = 1.26 – 8.18; p = 0.01). Amongst females, heterozygous genotype (GA) for MSH3 polymorphism was more frequent amongst LC cases (24%) than controls (16%) (OR = 2.35, 95% CI = 0.85 – 6.52, p = 0.04). Patients treated with docetaxel-platinum chemotherapy and carrying heterozygous (GT) genotype for MSH6 polymorphism had worse OS (median 4.9 vs 9.1 months; adjusted HR = 2.3; p = 0.03). No association was observed between MSH3 (rs26279) and MSH6 (rs3136228) polymorphisms and other baseline clinical/demographic characteristics. Conclusions: The results of this cohort study suggest that MSH3 and MSH6 polymorphisms are involved in modulating the risk towards LC occurence. MSH6 polymorphism is also associated with higher mortality amongst patients treated with docetaxel-platinum chemotherapy.

Long-term outcome for patients with advanced non‒small-cell lung cancer treated by autologous cytokine-induced killer (CIK) cell immunotherapy in combination with sintilimab plus chemotherapy: NSCLC-CCICC-002.

9096 Background: Autologous cytokine-induced killer (CIK) cell immunotherapy in combination with Sintilimab demonstrated robust antitumor activity and safety in the phase Ib CCICC-002 study (NCT03987867) of Non‒Small-Cell Lung Cancer. Long-term outcomes in patients are reported herein. Methods: Systemic therapy naïve patients received platinum-based doublet chemotherapy, Sintilimab (PD1 inhibiter), and CIK cells every 3 weeks for 4 cycles, then maintenance treatment with Sintilimab in squamous and with Sintilimab plus pemetrexed in non-squamous NSCLC until disease progression or unacceptable toxicity or two years. Kaplan-Meier estimates of overall survival (OS) and progression-free survival (PFS) were calculated. OS and PFS were based on immune-related response criteria by investigator assessment (data cut-off, January 31, 2023). Results: From May 2019 to Jan 2021, CCICC-002 enrolled 33 patients（19 squamous, 14 non-squamous NCSLC; 1 patient was excluded because the second biopsy revealed EGFR mutation) aged 46-73 years with median follow-up was 31.4 months (range, 7.6-44.4 months). Estimated 3-year OS was 51.8% in all patients; median OS was not reached (95% CI, 26.6 months-not reached) in all patients. In subgroups, median OS was 27.6 months (95% CI, 13.4 months-not reached) in squamous NCSLC and not reached (95% CI, 29.9 months-not reached) in non-squamous NCSLC, respectively. Median OS was not reached (95% CI, 27.6 months-not reached) in PD-L1 positive patients and 28.3 months (95% CI, 15.6 months-not reached) in PD-L1 negative patients, respectively. Estimated 3-year PFS rate was 27.5% and median PFS was 17.9 months (95% CI, 8.2-26.5 months) in all patients. Median PFS was 17.3 months (95% CI, 5.0-24.0 months) in squamous NCSLC and 22.4 months (95% CI, 5.7 months-not reached) in non-squamous NCSLC, respectively. Median response duration was 18.7 months (95% CI, 10.1-27.6 months). 30.3% of patients were ongoing at data cut-off, and the longest response was ongoing at 41.3 months. 1 of the 5 CMR (complete metabolic response by PET-CT) patients experienced disease progression during observation. Treatment-related AEs (TRAEs) occurred in 94.0% of patients and resulted in study discontinuation in 7.8%, and 15.2% experienced grade 3/4 TRAE. Conclusions: This long-term analysis of CCICC-002 represents the longest follow-up for CIK to date and confirms the durable antitumor activity and tolerability of CIK cells therapy in combination with Sintilimab plus chemotherapy in advanced NCSLC. Further studies are warranted to confirm these preliminary results. Clinical trial information: NCT03987867 .

Reconsidering the cutoff between sensitive and refractory relapses in extensive-stage small cell lung cancer in the era of immunotherapy.

8576 Background: The use of platinum-based doublet chemotherapy combined with immune checkpoint inhibitors (ICIs) has demonstrated promising outcomes in the first-line treatment of extensive-stage small cell lung cancer (ES-SCLC). Relapsed SCLC has been classified into "sensitive" or "refractory" relapse types according to cutoff values (60 or 90 days) of duration from the last chemotherapy administration to disease progression. However, it is unclear whether these cutoff values can be applied to ICI combination therapy. Methods: We retrospectively analyzed a multicenter database of ES-SCLC patients who received second-line therapy after the platinum-etoposide plus ICI (atezolizumab or durvalumab). An optimal cutoff value for the platinum-free interval (PFI) was selected, which minimized the two-sided p-value and maximized hazard ratio (HR) regarding relapse type (sensitive or refractory according to a cutoff value) calculated from a multivariable Cox regression model for overall survival (OS) including performance status (PS) and sex as covariates. The internal validity of the selected cutoff value was assessed via two-fold cross-validation (CV) manner. Results: A total of 101 patients (61 deaths) from 10 hospitals were included in the study. The median follow-up period was 21.1 months. The optimal cutoff value was 75 days (p=0.0002), and when applying this cutoff value, median OS was 15.9 and 5.0 months of sensitive- (n=51) and refractory- (n=50) relapsed patients, and the HR calculated from a two-fold CV was 3.13 (95% confidence interval [CI], 1.66 to 5.90). Additionally, traditional cutoff values of 60 and 90 days also predicted prognosis better, but cutoff values of 110 days or longer did not (Table). Conclusions: Even in the era of combined immunotherapy in ES-SCLC patients, the threshold days for classifying as sensitive- or refractory- relapse did not exhibit a significant change compared to the pre-immunotherapy era. Although further validation studies with a larger sample size would be needed, relapse type classification using the selected cutoff value of 75 days is worth considering as a new prognostic factor for relapsed ES-SCLC patients. [Table: see text]

Phase II trial of safety and efficacy of tislelizumab plus chemotherapy in stage II-IV non small cell lung cancer (LungMark).

8564 Background: The current study aimed to investigate the safety and efficacy of chemotherapy with PD-1 inhibitor, tislelizumab, for stage II-IV NSCLC. Meanwhile to explore the potential biomarkers for safety and efficacy of tislelizumab plus chemotherapy in NSCLC. Methods: This was an open-label, multicenter, phase 2 trial conducted at 3 hospitals in China. Patients with treatment-naïve, stage II-IV NSCLC without EGFR/ALK driver mutations were enrolled. This study consisted of two cohorts, one cohort is potentially resectable disease (PRD) and the other is unresectable disease (URD). The PRD patients received 3-4 cycles of tislelizumab (200 mg Q3w) plus carboplatin-based chemotherapy. Candidates eligible for surgery underwent surgery, followed by adjuvant tislelizumab monotherapy for 1 year. The URD patients received platinum-based doublet chemotherapy plus tislelizumab for 4-6 cycles, followed by tislelizumab for squamous and tislelizumab in combination with pemetrexed for non-squamous, until disease progression or intolerable toxicity. Primary endpoint was safety. Secondary endpoints were efficacy, such as MPR/pCR(PRD cohort), ORR, PFS and OS, etc. Multi-omics analysis of baseline and post-treatment samples were conducted to explore the safety and efficacy for chemoimmunotherapy. (NCT05244837). Results: Between December 2020 and November 2022, a total of 100 eligible patients were enrolled and received at least one cycle of immunochemotherapy. 58 patients were with PRD, of whom 40 (68.9%) were squamous cell lung cancer. 50 (86.2%) patients were stage III disease. During neoadjuvant treatment period, 52 patients (91.2%) experienced neoadjuvant TRAEs. Most of the TRAEs were grade 1or 2. No grade 4 or 5 TRAEs was observed. The most common grade 1 or 2 TRAEs were alopecia (n = 29;50.9%), anemia (n = 25;43.9%), rash (n = 29; 50.9%). Four patients (7.0%) experienced severe TRAE of grade 3 increased ALT/AST.39 patients received surgical resection, R0 resection was performed for 38 (97.4%) patients. 29 (74.4%) achieved MPR (major pathological response), including 19 (48.7%) with a complete pathological response (pCR). 42 patients with URD were enrolled, 26 (61.9%) patients were stage IV disease. 37 patients (88.1%) experienced TRAEs. The most common grade 1 or 2 TRAEs TRAEs were anemia (n = 27; 64.3%), rash (n = 12; 57.0%). Severe TRAEs occurred in 8 (2.0%) cases, including increased ALT/AST, decreased white blood cell count etc. 29 genes were identified as differentially expressed in pre-treatment tumors from patients with pCR compared to non-pCR. Conclusions: Neoadjuvant tislelizumab plus chemotherapy was safe and effective with high MPR and manageable TRAEs in patients with PRD. For patients with URD, tislelizumab plus chemotherapy was generally well tolerated. We have identified a differential immune landscape between pCR and non-pCR tumors. Clinical trial information: NCT05244837 .

Potential biomarkers for immunotherapy in non-small-cell lung cancer.

For individuals with advanced or metastatic non-small cell lung cancer (NSCLC), the primary treatment is platinum-based doublet chemotherapy. Immune checkpoint inhibitors (ICIs), primarily PD-1/PD-L1 and CTLA-4, have been found to be effective in patients with NSCLC who have no EGFR/ALK mutations. Furthermore, ICIs are considered a standard therapy. The quantity of fresh immunogenic antigens discovered by cytotoxic T cells was measured by PD-L1 expression and tumor mutational burden (TMB), which were the first biomarkers assessed in clinical trials. However, immunotherapy did not have response efficacy markers similar to targeted therapy, highlighting the significance of newly developed biomarkers. This investigation aims to review the research on immunotherapy for NSCLC, focusing primarily on the impact of biomarkers on efficacy prediction to determine whether biomarkers may be utilized to evaluate the effectiveness of immunotherapy.

MYC drives platinum resistant SCLC that is overcome by the dual PI3K-HDAC inhibitor fimepinostat

BackgroundSmall cell lung cancer (SCLC) is an aggressive neuroendocrine cancer with an appalling overall survival of less than 5% (Zimmerman et al. J Thor Oncol 14:768-83, 2019). Patients typically respond to front line platinum-based doublet chemotherapy, but almost universally relapse with drug resistant disease. Elevated MYC expression is common in SCLC and has been associated with platinum resistance. This study evaluates the capacity of MYC to drive platinum resistance and through screening identifies a drug capable of reducing MYC expression and overcoming resistance.MethodsElevated MYC expression following the acquisition of platinum resistance in vitro and in vivo was assessed. Moreover, the capacity of enforced MYC expression to drive platinum resistance was defined in SCLC cell lines and in a genetically engineered mouse model that expresses MYC specifically in lung tumors. High throughput drug screening was used to identify drugs able to kill MYC-expressing, platinum resistant cell lines. The capacity of this drug to treat SCLC was defined in vivo in both transplant models using cell lines and patient derived xenografts and in combination with platinum and etoposide chemotherapy in an autochthonous mouse model of platinum resistant SCLC.ResultsMYC expression is elevated following the acquisition of platinum resistance and constitutively high MYC expression drives platinum resistance in vitro and in vivo. We show that fimepinostat decreases MYC expression and that it is an effective single agent treatment for SCLC in vitro and in vivo. Indeed, fimepinostat is as effective as platinum-etoposide treatment in vivo. Importantly, when combined with platinum and etoposide, fimepinostat achieves a significant increase in survival.ConclusionsMYC is a potent driver of platinum resistance in SCLC that is effectively treated with fimepinostat.

Abstract 4535: Clinical outcomes and molecular features of different histopathologic patterns in patients with stage IB non-squamous non-small-cell lung cancer

Abstract Background: About 15% to 20% of patients with stage IB non-small-cell lung cancer (NSCLC) may develop recurrence within 5 years. However, the use of adjuvant therapy for resected stage IB patients remains controversial. This study investigated the differences in prognosis and molecular features between different histopathologic patterns of stage IB non-squamous NSCLC (nsNSCLC) and tried to identify patients who most in need of adjuvant therapy. Methods: A total of 215 patients with completely resected pathologic stage IB (tumor size 3-4 cm) nsNSCLC from Tianjin Medical University Cancer Institute &amp; Hospital between 2014 and 2018 were included in the study. For 130 patients, genomic profiling of tumor tissues was sequenced by a panel of 9 driver genes (OncoScreen® Focus CDx Tissue Kit, Burning Rock Biotech) and the molecular risk stratification was assessed by 14-gene quantitative PCR (qPCR) assay (DetermaRxTM, Burning Rock Biotech). Results: Among the 215 patients, 67.9% were solid/micropapillary-predominant pattern (S/MP), 40.5% had received platinum-based doublet adjuvant chemotherapy, and 5.1% had received adjuvant targeted therapy with or without chemotherapy. Patients with S/MP pattern had significantly worse DFS than those with lepidic/acinar/papillary-predominant (L/A/P) pattern (hazard ratio [HR]: 2.16, 95% confidence interval (CI): 1.28 to 3.67; P = 0.013). However, neither pattern could benefit from adjuvant therapy. EGFR mutation was successfully detected in 75 out of 126 patients (59.5%), and the positive rate in S/MP pattern was significantly lower than that in L/A/P pattern (50.6% vs 79.5%, P = 0.002). However, EGFR mutation status was not a prognostic factor for DFS in neither overall population nor different histopathologic patterns. EGFR-mutant patients showed the trend to benefit from adjuvant targeted-based therapy in the limited samples. Molecular risk stratification was successfully assessed in 99 patients, of which 37.4%, 26.3%, and 36.4% were predicted as molecularly high-risk, intermediate-risk, and low-risk patients, respectively. There were significant differences in the proportion of high- and low-risk patients between S/MP and L/A/P patterns (for high-risk: 46.2% vs 20.6%; for low-risk: 26.2% vs 55.9%; P = 0.009). The high-risk patients had significantly shorter DFS than the low-risk patients (HR, 2.93, 95% CI: 1.31-6.54; P = 0.012), especially those in S/MP pattern (HR, 3.45, 95% CI: 1.46-8.15; P = 0.017). Conclusion: Our study confirms that S/MP pattern is a significantly worse prognostic factor for DFS in nsNSCLC and that there are significant differences in molecular features between these two different histopathologic patterns. qPCR-based assay could reliably identify patients with a worse prognosis in S/MP pattern, suggesting that such patients are most likely to benefit from personalized adjuvant therapy. Citation Format: Dongsheng Yue, Bin Zhang, Chen Chen, Qiang Zhang, Xinyi Wu, Jiping Xie, Changli Wang, Zhenfa Zhang. Clinical outcomes and molecular features of different histopathologic patterns in patients with stage IB non-squamous 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 4535.

Real-world treatment patterns and outcomes of patients with metastatic nonsquamous non-small cell lung cancer after progression on standard-of-care therapy in the United States

ObjectivesData to guide treatment selection in metastatic nonsquamous (mNSq) non-small cell lung cancer (NSCLC) after progression on current standard-of-care (SoC) treatment are limited. We investigated patterns of treatment and clinical outcomes following one or more disease progressions on SoC. Materials and methodsElectronic medical records in the ConcertAI Patient360 NSCLC database were analyzed for US adults with mNSq NSCLC who initiated treatment between 2016 and 2021. Analyses were conducted separately for patients who had ≥1 prior lines of therapy and progression(s) without (Cohort 1) or with (Cohort 2) evidence of targetable genetic alterations (EGFR, ALK, or ROS1). Outcomes included real-world progression-free survival (rwPFS) and overall survival (rwOS). ResultsCohorts 1 and 2 included 281 and 109 patients, respectively. In Cohort 1, subsequent treatment was most often with docetaxel monotherapy (18.5%) or docetaxel + ramucirumab (32.4%). Most patients in Cohort 2 received platinum-based doublet chemotherapy with (22.9%) or without (34.9%) immunotherapy. Median rwPFS and rwOS were 2.9 and 7.2 months, respectively, in Cohort 1, and 3.2 and 10.4 months in Cohort 2. Neither the addition of ramucirumab to docetaxel in Cohort 1 nor the addition of immunotherapy to chemotherapy in Cohort 2 was associated with a marked improvement in additional survival. ConclusionPatients with progressive mNSq NSCLC most commonly received later-line docetaxel for cancer without driver mutations, or platinum-based chemotherapy (following one or more lines of tyrosine kinase inhibitor therapy) for cancer with driver mutations, consistent with guideline recommendations. Median survival was poor regardless of subsequent treatment, highlighting the need for more effective options.

Single-nucleotide polymorphisms of nucleotide excision repair genes and their association with overall survival in North Indian lung cancer patients treated with platinum-based doublet chemotherapy.

The aim of the study is to understand the association of Nucleotide excision repair (NER) inter-genetic polymorphic combinations with overall survival (OS) in lung cancer as well as its histological subtypes in the North Indian population. Genotyping was performed using polymerase chain reaction-restriction fragment length polymorphism. For survival analysis, the univariate Kaplan-Meier and multivariate Cox regression model were applied. Recursive partitioning method, survival analysis tree was applied to study unfavorable genotypic combinations in NER single-nucleotide polymorphisms. Combinatorial studies suggested no association between polymorphic combinations of NER genes and OS in lung cancer patients. When stratified as per lung cancer histological subtypes, adenocarcinomas patients with XPG 670 and XPC 499 polymorphism a significant increase in OS in combined heterozygous and mutant genotype with a lower hazardous ratio (Hazard Ratio1 (HR) = 0.20; P = 0.004). Small-cell lung carcinoma (SCLC) patients with XPF 11985A>G and XPD Arg156Arg polymorphism showed a 4-fold hazard ratio among heterozygous genotype (HR1 = 4.84; P = 0.007) where no significant results are obtained in patients suffering from squamous cell carcinoma histological subtypes. STREE showed XPG Asp1104His (W), XPD Lys751Gln (H + M), XPF Arg415Gln (H + M) genotype was associated with a lower hazard ratio (P = 0.0007) showing survival of 11.6 months when compared with the reference (median survival time = 3.52). It can be concluded that SCLC patients with polymorphic combinations of the NER pathway were associated with a higher risk of mortality. STREE depicted the association of NER polymorphic combinations with a lower hazard ratio predicting them to be a good prognostic factor for lung cancer.

Comparison of Chemotherapy Plus Pembrolizumab vs. Chemotherapy Alone in EGFR-Mutant Non–small-Cell Lung Cancer Patients

IntroductionPlatinum doublet chemotherapy is the standard of care in patients with non–small-cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutation who had disease progression after tyrosine kinase inhibitor (TKI). We aimed to assess immune checkpoint inhibitors efficacy in EGFR-mutant advanced NSCLC. Materials and MethodsWe retrospectively reviewed the data of sensitive EGFR-mutant NSCLC patients who progressed after EGFR-TKIs and received platinum doublet chemotherapy plus immunotherapy between 2015 and 2021. Efficacy outcomes, including overall response rate, progression-free survival, and overall survival, were assessed and compared with those of patients who had received platinum-based doublet chemotherapy. ResultsOf the total 869 patients, 82 treated with pembrolizumab and chemotherapy and 82 with only chemotherapy were selected. The median progression-free survival in patients administered pembrolizumab was significantly longer than those not administered pembrolizumab (6.7 months; 95% confidence interval [CI] 5.0-8.5 vs. 4.2 months; 95% CI 3.3-5.0, hazard ratio [HR] 0.64, 95% CI 0.46-0.89, P = .0076). Improved median overall survival was also observed in patients receiving pembrolizumab plus chemotherapy (26.7 [95% CI 22.6-30.8] vs. 13.4 months [95% CI 10.4-16.4], HR, 0.49 [95% CI 0.31-0.75], P = .0052). In addition, the overall response rate was higher in patients treated with than patients treated without pembrolizumab (34.1% and 20.7%, respectively). ConclusionThe combination of pembrolizumab with chemotherapy is associated with improved efficacy and survival in patients with EGFR-mutant NSCLC after TKI resistance, but these findings need to be confirmed in further prospective studies.

Genetic variations in ABC transporter genes as a predictive biomarker for toxicity in North Indian lung cancer patients undergoing platinum-based doublet chemotherapy.

ATP-binding cassette (ABC) transporters are expressed in various human tissues and play a vital role in the efflux of various chemotherapeutic drugs. The current study has assessed genetic variants of ABCB1, ABCC1, ABCC2, and ABCG2 genes in 407 lung cancer patients undergoing platinum-based doublet chemotherapy. The association of ABCB1(C1236 T, C3435 T, and G2677 T/A), ABCC1(G3173 A and G2168 A),ABCC2 (G4544 A), and ABCG2(C421 A) polymorphisms with chemotherapy-induced adverse events were assessed, and statistical analysis was conducted. Our data showed that patients harboring heterozygous (GA) genotype for ABCC1 G3173 A had an increased risk of developing leukopenia (odds ratio [OR] = 1.88, p = 0.04) and anemia (adjusted odds ratio[AOR] = 2.70, p = 0.03). For ABCC2 G4544 A polymorphism, patients harboring one copy of the mutant (GA) allele showed an increased risk of developing anemia (OR = 4.24, p = 0.03). After adjusting with various confounding factors, the heterozygous (GA) genotype showed a 5.63-fold increased risk of developing anemia (AOR = 5.63, p = 0.03). The ABCB1 G2677 A (OR = 0.37, p = 0.008) and ABCC1 G3173 A (OR = 0.54, p = 0.04) polymorphism showed a lower incidence of developing nephrotoxicity. In ABCG2 C421 A polymorphism, patients harboring heterozygous (CA) genotype had a lower incidence of having diarrhea (OR = 0.25, p = 0.04). An increased risk of having diarrhea was observed in the heterozygous genotype (GA) for ABCC1 G3173 A polymorphism (AOR = 2.78, p = 0.04). An increased risk of liver injury was found in the patients carrying heterozygous genotype of the ABCC1 G3173 A (OR = 2.06, p = 0.02) and ABCB1 C1236 T (OR = 1.85, p = 0.01). This study demonstrates the role of polymorphic variations in ABCB1, ABCC1, ABCC2, and ABCG2 in predicting hematological, nephrotoxicity, gastrointestinal, and hepatotoxicity.