Assessing personalized responses to anti-PD-1 treatment using patient-derived lung tumor-on-chip.

There is a compelling need for approaches to predict the efficacy of immunotherapy drugs. Tumor-on-chip technology exploits microfluidics to generate 3D cell co-cultures embedded in hydrogels that recapitulate simplified tumor ecosystems. Here, we present the development and validation of lung tumor-on-chip platforms to quickly and precisely measure ex vivo the effects of immune checkpoint inhibitors on T cell-mediated cancer cell death by exploiting the power of live imaging and advanced image analysis algorithms. The integration of autologous immunosuppressive FAP+ cancer-associated fibroblasts impaired the response to anti-PD-1, indicating that tumors-on-chips are capable of recapitulating stroma-dependent mechanisms of immunotherapy resistance. For a small cohort of non-small cell lung cancer patients, we generated personalized tumors-on-chips with their autologous primary cells isolated from fresh tumor samples, and we measured the responses to anti-PD-1 treatment. These results support the power of tumor-on-chip technology in immuno-oncology research and open a path to future clinical validations.

CD74 supports accumulation and function of regulatory T cells in tumors.

Regulatory T cells (Tregs) are plastic cells playing a pivotal role in the maintenance of immune homeostasis. Tregs actively adapt to the microenvironment where they reside; as a consequence, their molecular and functional profiles differ among tissues and pathologies. In tumors, the features acquired by Tregs remains poorly characterized. Here, we observe that human tumor-infiltrating Tregs selectively overexpress CD74, the MHC class II invariant chain. CD74 has been previously described as a regulator of antigen-presenting cell biology, however its function in Tregs remains unknown. CD74 genetic deletion in human primary Tregs reveals that CD74KO Tregs exhibit major defects in the organization of their actin cytoskeleton and intracellular organelles. Additionally, intratumoral CD74KO Tregs show a decreased activation, a drop in Foxp3 expression, a low accumulation in the tumor, and consistently, they are associated with accelerated tumor rejection in preclinical models in female mice. These observations are unique to tumor conditions as, at steady state, CD74KO-Treg phenotype, survival, and suppressive capacity are unaffected in vitro and in vivo. CD74 therefore emerges as a specific regulator of tumor-infiltrating Tregs and as a target to interfere with Treg anti-tumor activity.

Recommendations for Post-Operative RadioTherapy After Complete Resection of Thymoma-a French DELPHI Consensus Initiative.

INTRODUCTION: Thymomas are rare intrathoracic malignancies that can relapse after surgery. Whether or not Post-Operative RadioTherapy (PORT) should be delivered after surgery remains a major issue. RADIORYTHMIC is an ongoing, multicenter, randomized phase 3 trial addressing this question in patients with completely R0 resected Masaoka-Koga stage IIb/III thymoma. Experts in the field met to develop recommendations for PORT. METHODS: A scientific committee from the RYTHMIC network identified key issues regarding the modalities of PORT in completely resected thymoma. A DELPHI method was used to question 24 national experts, with 115 questions regarding the following: (1) imaging techniques, (2) clinical target volume (CTV) and margins, (3) dose constraints to organs at risk, (4) dose and fractionation, and (5) follow-up and records. Consensus was defined when opinions reached more than or equal to 80% agreement. RESULTS: We established the following recommendations: preoperative contrast-enhanced computed tomography (CT) scan is recommended (94% agreement); optimization of radiation delivery includes either a four-dimensional CT-based planning (82% agreement), a breath-holding inspiration breath-hold-based planning, or daily control CT imaging (81% agreement); imaging fusion based on cardiovascular structures of preoperative and planning CT scan is recommended (82% agreement); right coronary and left anterior descending coronary arteries should be delineated as cardiac substructures (88% agreement); rotational RCMI/volumetric modulated arc therapy is recommended (88% agreement); total dose is 50 Gy (81% agreement) with 1.8 to 2 Gy per fraction (94% agreement); cardiac evaluation and follow-up for patients with history of cardiovascular disease are recommended (88% agreement) with electrocardiogram and evaluation of left ventricular ejection fraction at 5 years and 10 years. CONCLUSION: This is the first consensus for PORT in thymoma. Implementation will help to harmonize practices.

Management of sotorasib-related adverse events and hepatotoxicities following anti-PD-(L)1 therapy: Experience with sotorasib in two French anti-cancer centers and practical guidance proposal.

INTRODUCTION: Sotorasib is a first-in-class KRASG12C inhibitor that showed significant clinical activity in KRASG12C-mutated non-small cell lung cancer (NSCLC). The most frequent grade 3 or 4 sotorasib-related adverse events (AEs) were diarrhea (4-12 %) and hepatotoxicity (10.1-15.1 %). Data is lacking about the management of these AEs, especially in patients receiving sequential anti-PD-(L)1 and sotorasib therapy. Our aim was to report the management of grade ≥ 2 sotorasib-related AEs in real-world setting and to propose practical guidance for the management of grade ≥ 2 sotorasib-related AEs and more generally KRASG12C inhibitors-related AEs. MATERIALS AND METHODS: Records from all consecutive patients who initiated sotorasib through expanded access program in two French anti-cancer centers from January 1st 2021 to April 1st 2023 were reviewed to identify and grade sotorasib-related AEs, according to NCI-CTCAE v5.0., and to collect AEs management data. Patients were included in the analysis if they presented a grade ≥ 2 sotorasib-related AE. RESULTS: From 57 patients identified, 21 met inclusion criteria including eighteen (86 %) who received sequential anti-PD-(L)1 and sotorasib therapy. Hepatotoxicity (76 %) and diarrhea (24 %) were the most common grade ≥ 2 sotorasib-related AEs. Among the 16 patients with a grade ≥ 2 hepatotoxicity, 12 (75 %) definitely discontinued sotorasib, among which 9 (56 %) after dose reductions and rechallenge, and five (32 %) received corticosteroids, allowing only one patient to resume sotorasib. Diarrhea and nausea were usually manageable and not associated with sotorasib discontinuation. We propose a step-by-step management practical guidance for sotorasib-related hepatotoxicity based on dose-reduction and careful monitoring. Liver biopsy is strongly encouraged for grade 3 and 4 hepatotoxicity to assess candidates for corticosteroids. DISCUSSION: The experience with sotorasib might help better prevent, screen and manage sotorasib-related and other KRASG12C inhibitors-related AEs, particularly hepatotoxicity.

Promising Candidate Prognostic Biomarkers in [18F]FDG PET Images: Evaluation in Independent Cohorts of Non-Small Cell Lung Cancer Patients.

The normalized distances from the hot spot of radiotracer uptake (SUVmax) to the tumor centroid (NHOC) and to the tumor perimeter (NHOP) have recently been suggested as novel PET features reflecting tumor aggressiveness. These biomarkers characterizing the shift of SUVmax toward the lesion edge during tumor progression have been shown to be prognostic factors in breast and non-small cell lung cancer (NSCLC) patients. We assessed the impact of imaging parameters on NHOC and NHOP, their complementarity to conventional PET features, and their prognostic value for advanced-NSCLC patients. Methods: This retrospective study investigated baseline [18F]FDG PET scans: cohort 1 included 99 NSCLC patients with no treatment-related inclusion criteria (robustness study); cohort 2 included 244 NSCLC patients (survival analysis) treated with targeted therapy (93), immunotherapy (63), or immunochemotherapy (88). Although 98% of patients had metastases, radiomic features including SUVs were extracted from the primary tumor only. NHOCs and NHOPs were computed using 2 approaches: the normalized distance from the localization of SUVmax or SUVpeak to the tumor centroid or perimeter. Bland-Altman analyses were performed to investigate the impact of both spatial resolution (comparing PET images with and without gaussian postfiltering) and image sampling (comparing 2 voxel sizes) on feature values. The correlation of NHOCs and NHOPs with other features was studied using Spearman correlation coefficients (r). The ability of NHOCs and NHOPs to predict overall survival (OS) was estimated using the Kaplan-Meier method. Results: In cohort 1, NHOC and NHOP features were more robust to image filtering and to resampling than were SUVs. The correlations were weak between NHOCs and NHOPs (r ≤ 0.45) and between NHOCs or NHOPs and any other radiomic features (r ≤ 0.60). In cohort 2, the patients with short OS demonstrated higher NHOCs and lower NHOPs than those with long OS. NHOCs significantly distinguished 2 survival profiles in patients treated with immunotherapy (log-rank test, P < 0.01), whereas NHOPs stratified patients regarding OS in the targeted therapy (P = 0.02) and immunotherapy (P < 0.01) subcohorts. Conclusion: Our findings suggest that even in advanced NSCLC patients, NHOC and NHOP features pertaining to the primary tumor have prognostic potential. Moreover, these features appeared to be robust with respect to imaging protocol parameters and complementary to other radiomic features and are now available in LIFEx software to be independently tested by others.

International reproducibility study of thymic epithelial tumors staging: pT stage is an issue. proposals for improvement. A RYTHMIC/ITMIG study.

INTRODUCTION: Pathologists are staging thymic epithelial tumors (TET) according to the 8th UICC/AJCC TNM system. Within the French RYTHMIC network, dedicated to TET, agreement on pathologic tumor stage (pT) among the pathology panelists was difficult. The aim of our study was to determine the interobserver reproducibility of pT at an international level, to explore the source of discrepancies and potential interventions to address these. METHODS: An international panel of pathologists was recruited through the International Thymic Malignancy Interest Group (ITMIG). The study focused on invasion of mediastinal pleura, pericardium, and lung. From a cohort of cases identified as challenging within the RYTHMIC network, we chose a series of test and validation cases (n = 5 and 10, respectively). RESULTS: Reproducibility of the pT stage was also challenging at an international level as none of the 15 cases was classified as the same pT stage by all ITMIG pathologists. The agreement rose from slight (κ = 0.13) to moderate (κ = 0.48) between test and validation series. Discussion among the expert pathologists pinpointed two major reasons underlying discrepancies: 1) Thymomas growing with their "capsule" and adhering to the pleurae, pericardium, or lung were often misinterpreted as invading these structures. 2) Recognition of the mediastinal pleura was identified as challenging. CONCLUSION: Our study underlines that the evaluation of the pT stage of TET is problematic and needs to be addressed in more detail in an upcoming TNM classification. The publication of histopathologic images of landmarks, including ancillary tests could improve reproducibility for future TNM classifications.

Management of patients with rare adult solid cancers: objectives and evaluation of European reference networks (ERN) EURACAN.

About 500,000 patients with rare adult solid cancers (RASC) are diagnosed yearly in Europe. Delays and unequal quality of management impact negatively their survival. Since 2017, European reference networks (ERN) aim to improve the quality of care of patients with rare disease. The steering committee of EURACAN, including physicians, researchers and patients review here the previous actions, present objectives of the ERN EURACAN dedicated to RASC. EURACAN promoted management in reference centres, and equal implementation of excellence and innovation in Europe and developed 22 clinical practice guidelines (CPGs). Additionally, fourteen information brochures translated in 24 EU languages were developed in collaboration with patient advocacy groups (ePAGs) and seventeen training session were organized. Nevertheless, connections to national networks in the 26 participating countries (106 centres), simplification of cross-border healthcare, international multidisciplinary tumour boards, registries and monitoring of the quality of care are still required. In this Health Policy, evaluation criteria of the performances of the network and of health care providers are proposed.

EORTC-SPECTA Arcagen study, comprehensive genomic profiling and treatment adaptation of rare thoracic cancers.

Arcagen (NCT02834884) is a European prospective study aiming at defining the molecular landscape of rare cancers for treatment guidance. We present data from the cohort of rare thoracic tumors. Patients with advanced pleural mesothelioma (PM) or thymic epithelial tumors (TET) underwent genomic profiling with large targeted assay [>300 genes, tumor mutational burden (TMB), microsatellite instability (MSI) status] on formalin-fixed paraffin-embedded (FFPE) or plasma samples. EORTC molecular tumor board (MTB) advised for biomarker-guided treatments. 102 patients recruited from 8 countries between July 2019 and May 2022 were evaluable: 56 with PM, 46 with TET (23 thymomas, 23 thymic carcinomas). Molecular profiling was performed on 70 FFPE samples (42 PM, 28 TET), and 32 cases on ctDNA (14 PM, 18 TET), within a median turnaround time of 8 days from sample reception. We detected relevant molecular alterations in 66 out of 102 patients (65%; 79% PM, 48% TET), 51 of 70 FFPE samples (73%; 90% PM, 46% TET), and 15 of 32 plasma samples (47%; 43% PM, 50% TET). The most frequently altered genes were CDKN2A/B, BAP1, MTAP in PM and TP53, CDKN2A/B, SETD2 in TET. The TMB was low (mean 3.2 Muts/MB), 2 PM had MSI-high status. MTB advised molecular-guided treatment options in 32 situations, for 17 PM and 15 TET patients (75% clinical trial option, 22% off-label drug or compassionate use, 3% early access program). Molecular testing and MTB discussion were feasible for patients with rare thoracic cancers and allowed the broadening of treatment options for 30% of the cases.

Optimizing lung cancer radiation therapy: A systematic review of multifactorial risk assessment for radiation-induced lung toxicity.

BACKGROUND: Radiation therapy (RT) is essential in treating advanced lung cancer, but may lead to radiation pneumonitis (RP). This systematic review investigates the use of pulmonary function tests (PFT) and other parameters to predict and mitigate RP, thereby improving RT planning. METHODS: A systematic review sifted through PubMed and on BioMed Central, targeting articles from September 2005 to December 2022 containing the keywords: Lung Cancer, Radiotherapy, and pulmonary function test. RESULTS: From 1153 articles, 80 were included. RP was assessed using CTCAEv.4 in 30 % of these. Six studies evaluated post-RT quality of life in lung cancer patients, reporting no decline. Patients with RP and chronic obstructive pulmonary disease (COPD) generally exhibited poorer overall survival. Notably, forced expiratory volume in one second (FEV1) and diffusing capacity of the lung for carbon monoxide (DLCO) declined 24 months post-RT, while forced vital capacity (FVC) stayed stable. In the majority of studies, age over 60, tumors located in the lower part of the lung, and low FEV1 before RT were associated with a higher risk of RP. Dosimetric factors (V5, V20, MLD) and metabolic imaging emerged as significant predictors of RP risk. A clinical checklist blending patient and tumor characteristics, PFT results, and dosimetric criteria was proposed for assessing RP risk before RT. CONCLUSION: The review reveals the multifactorial nature of RP development following RT in lung cancer. This approach should guide individualized management and calls for a prospective study to validate these findings and enhance RP prevention strategies.

Nivolumab Plus Chemotherapy in Epidermal Growth Factor Receptor-Mutated Metastatic Non-Small-Cell Lung Cancer After Disease Progression on Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors: Final Results of CheckMate 722.

PURPOSE: The phase III CheckMate 722 trial (ClinicalTrials.gov identifier: NCT02864251) evaluated nivolumab plus chemotherapy versus chemotherapy in patients with epidermal growth factor receptor (EGFR)-mutated metastatic non-small-cell lung cancer (NSCLC) after disease progression on EGFR tyrosine kinase inhibitors (TKIs). METHODS: Patients with disease progression after first- or second-generation EGFR TKI therapy (without EGFR T790M mutation) or osimertinib (with/without T790M mutation) were randomly assigned 1:1 to nivolumab (360 mg once every 3 weeks) plus platinum-doublet chemotherapy (once every 3 weeks) or platinum-doublet chemotherapy alone (once every 3 weeks) for four cycles. Primary end point was progression-free survival (PFS). Secondary end points included 9- and 12-month PFS rates, overall survival (OS), objective response rate (ORR), and duration of response (DOR). RESULTS: Overall, 294 patients were randomly assigned. At final analysis (median follow-up, 38.1 months), PFS was not significantly improved with nivolumab plus chemotherapy versus chemotherapy (median, 5.6 v 5.4 months; hazard ratio [HR], 0.75 [95% CI, 0.56 to 1.00]; P = .0528), with 9- and 12-month PFS rates of 25.9% versus 19.8%, and 21.2% versus 15.9%, respectively. Post hoc PFS subgroup analyses showed a trend favoring nivolumab plus chemotherapy in patients with tumors harboring sensitizing EGFR mutations (HR, 0.72 [95% CI, 0.54 to 0.97]), one line of previous EGFR TKI (0.72 [95% CI, 0.54 to 0.97]), or both (0.64 [95% CI, 0.47 to 0.88]). Median OS was 19.4 months with nivolumab plus chemotherapy versus 15.9 months with chemotherapy, while ORR was 31.3% versus 26.7%, and median DOR was 6.7 versus 5.6 months, respectively. Grade 3/4 treatment-related adverse events occurred in 44.7% and 29.4% of patients treated with nivolumab plus chemotherapy and chemotherapy alone, respectively. CONCLUSION: Nivolumab plus chemotherapy did not significantly improve PFS versus chemotherapy in patients with EGFR-mutated metastatic NSCLC previously treated with EGFR TKIs. No new safety signals were identified.

Surgical Treatment of Facial Abscesses and Jaw Osteomyelitis of Dental Origin Using Extraoral Tooth Extraction in the Domestic Rabbit: A Case Series.

The treatment of facial abscesses of dental origin is difficult as jaw osteomyelitis in rabbits is mainly associated with a thick caseous pus that is particularly difficult to drain. Precise identification of the teeth involved in the infected site with the use of cone beam computed tomography (CBCT) was expected to ensure a favorable surgical treatment plan without a long-term local antibiotic strategy or local marsupialization. The first part of the study compared multi-planar reconstruction (MPR) and 3D reconstruction complemented by a maximum intensity projection filter (MIP). The surgical part of the study included rabbits with documentation of the treatment outcome for a period greater than one month after surgery and having had at least one post-operative CBCT demonstrating the achievement of surgical extraction. MPR is significantly more efficient than MIP techniques for alveolar bone (P < 10-7), spongious bone (P < 10-10) and apical elongation (P < 10-5) parameters. Nineteen of 20 surgical sites gave radiological confirmation of the success of the surgical plan. Eighteen of 20 of the abscess sites were clinically healed within one month. Seven out of 20 of the abscess sites presented evidence of one dental structure regrowth following the CBCT recheck. Two out of these seven cases presented with a concomitant persistent chronic facial fistula. Both cases healed after second-stage surgery to extract the tooth structure. The mean number of teeth extracted was 2.85, and seven of the 20 procedures included one incisor.

Postoperative Radiation Therapy for Thymic Carcinoma: An Analysis of the International Thymic Malignancy Interest Group/European Society of Thoracic Surgeons Database.

INTRODUCTION: R0 resection and radiation therapy have been associated with improved overall survival (OS) in patients with thymic carcinoma (TC). Here, we analyzed which subgroups of patients derive the greatest benefit from postoperative radiation therapy (PORT). METHODS: Clinical, pathologic, treatment, and survival information of 462 patients with TC from the International Thymic Malignancy Interest Group/European Society of Thoracic Surgeons database were analyzed. Variables included age, sex, continent of treatment, paraneoplastic syndrome, carcinoma subtype, tumor size, pathologic Masaoka stage, resection status, and use of chemotherapy. OS was the primary end point using the Kaplan-Meier method. Time to recurrence (TTR) was the secondary end point using a competing risk analysis. A 3-month landmark analysis was performed. RESULTS: PORT was associated with a significant OS benefit (5-y OS 68% versus 53%, p = 0.002). In patients with R0 resection, PORT was associated with increased OS for advanced (stages III-IV, p = 0.04), but not early (stages I-II, p = 0.14) stage TC. In patients with an R1/2 resection of advanced-stage TC, PORT was associated with significantly longer OS (5-y OS 53% versus 38%; p < 0.001). Subset analyses did not reveal clear associations of PORT with TTR. On multivariable analysis, lower pathologic stage, PORT, and R0 resection status were associated with an OS benefit, whereas only higher age and lower pathologic stage had an association with longer TTR. CONCLUSIONS: In the largest individual patient data set on patients with TC reported to date, PORT was associated with a meaningful OS benefit in patients with advanced-stage TC after an R0 or R1/2 resection.

The International Association for the Study of Lung Cancer Thymic Epithelial Tumors Staging Project: Proposals for the N and the M Components for the Forthcoming (Ninth) Edition of the TNM Classification of Malignant Tumors.

INTRODUCTION: Stage classification is an important underpinning of management in patients with cancer and rests on a combination of three components-T for tumor extent, N for nodal involvement, and M for distant metastases. This article details the revision of the N and the M components of thymic epithelial tumors for the ninth edition of the TNM classification of malignant tumors proposed by the Thymic Domain of the International Association for the Study of Lung Cancer Staging and Prognostic Factors Committee. METHODS: The N and M components of the eighth edition staging system were verified by a large international collaborative data source through a data-driven analysis. A total of 9147 cases were included for analysis, including 7662 thymomas, 1345 thymic carcinomas, and 140 neuroendocrine thymic tumors. RESULTS: Lymph node involvement rates were 1.5% in thymomas and 17.6% and 27.7% in thymic carcinomas and neuroendocrine thymic tumors, respectively. Rates of lymph node metastasis were increasingly higher in tumors with higher T stage and higher-grade histologic type. Survival analysis validated the differences in the N and M categories proposed in the eighth edition staging system. Good discrimination in overall survival was detected among pathologic (p)N and pM categories in patients with thymoma and thymic carcinoma. CONCLUSIONS: No changes are proposed from the eighth edition for the N and M components. The proposed stage classification will provide a useful tool for management of the disease among the global thymic community.

Association between pathologic response and survival after neoadjuvant therapy in lung cancer.

Neoadjuvant immunotherapy plus chemotherapy improves event-free survival (EFS) and pathologic complete response (0% residual viable tumor (RVT) in primary tumor (PT) and lymph nodes (LNs)), and is approved for treatment of resectable lung cancer. Pathologic response assessment after neoadjuvant therapy is the potential analog to radiographic response for advanced disease. However, %RVT thresholds beyond pathologic complete response and major pathologic response (≤10% RVT) have not been explored. Pathologic response was prospectively assessed in the randomized, phase 3 CheckMate 816 trial (NCT02998528), which evaluated neoadjuvant nivolumab (anti-programmed death protein 1) plus chemotherapy in patients with resectable lung cancer. RVT, regression and necrosis were quantified (0-100%) in PT and LNs using a pan-tumor scoring system and tested for association with EFS in a prespecified exploratory analysis. Regardless of LN involvement, EFS improved with 0% versus >0% RVT-PT (hazard ratio = 0.18). RVT-PT predicted EFS for nivolumab plus chemotherapy (area under the curve = 0.74); 2-year EFS rates were 90%, 60%, 57% and 39% for patients with 0-5%, >5-30%, >30-80% and >80% RVT, respectively. Each 1% RVT associated with a 0.017 hazard ratio increase for EFS. Combining pathologic response from PT and LNs helped differentiate outcomes. When compared with radiographic response and circulating tumor DNA clearance, %RVT best approximated EFS. These findings support pathologic response as an emerging survival surrogate. Further assessment of the full spectrum of %RVT in lung cancer and other tumor types is warranted. ClinicalTrials.gov registration: NCT02998528 .

Matching-adjusted indirect comparison of amivantamab vs mobocertinib in platinum-pretreated EGFR Exon 20 insertion-mutated non-small-cell lung cancer.

Aim: We assessed relative efficacy and safety of amivantamab versus mobocertinib in patients with non-small-cell lung cancer with EGFR exon 20 insertion (exon20ins) mutations who progressed on prior platinum-based chemotherapy. Materials & methods: This matching-adjusted indirect comparison used patient-level data from CHRYSALIS (NCT02609776) and aggregate data from a mobocertinib trial (NCT02716116) to match populations on all clinically relevant confounders. Results: While both agents had similar efficacy for time-to-event outcomes, objective response rate was significantly higher for amivantamab. 15 of 23 any-grade treatment-related adverse events reported for mobocertinib were significantly less common for amivantamab versus only two for mobocertinib. Conclusion: Results suggest that amivantamab has an improved response rate with similar survival and a more favorable safety profile versus mobocertinib in EGFR exon20ins non-small-cell lung cancer.

Amivantamab Compared with Real-World Physician's Choice after Platinum-Based Therapy from a Pan-European Chart Review of Patients with Lung Cancer and Activating EGFR Exon 20 Insertion Mutations.

Patients with advanced non-small cell lung cancer (NSCLC) with epidermal growth factor receptor gene (EGFR) Exon 20 insertions (Exon20ins) at the second line and beyond (2L+) have an unmet need for new treatment. Amivantamab, a bispecific EGFR- and MET-targeted antibody, demonstrated efficacy in this setting in the phase 1b, open-label CHRYSALIS trial (NCT02609776). The primary objective was to compare the efficacy of amivantamab to the choices made by real-world physicians (RWPC) using an external control cohort from the real-world evidence (RWE) chart review study, CATERPILLAR-RWE. Adjustment was conducted to address differences in prognostic variables between cohorts using inverse probability weighting (IPW) and covariate adjustments based on multivariable regression. In total, 114 patients from CHRYSALIS were compared for 55 lines of therapy from CATERPILLAR-RWE. Baseline characteristics were comparable between the amivantamab and IPW-weighted RWPC cohorts. For amivantamab versus RWPC using IPW adjustment, the response rate ratio for the overall response was 2.14 (p = 0.0181), and the progression-free survival (PFS), time-to-next-treatment (TTNT) and overall survival (OS) hazard ratios (HRs) were 0.42 (p < 0.0001), 0.47 (p = 0.0063) and 0.48 (p = 0.0207), respectively. These analyses provide evidence of clinical and statistical benefits across multiple outcomes and adjustment methods, of amivantamab in platinum pre-treated patients with advanced NSCLC harboring EGFR Exon20ins. These results confirm earlier comparisons versus pooled national registry data.

Amivantamab compared with real-world therapies in patients with advanced non-small cell lung cancer EGFR Exon 20 insertion mutations after platinum-based chemotherapy.

BACKGROUND: In the single-arm CHRYSALIS trial, advanced non-small cell lung cancer patients harboring epidermal growth factor receptor (EGFR) exon 20 insertion (Exon 20ins) showed durable responses to amivantamab, an EGFR-MET bispecific antibody targeting tumors with EGFR Exon 20ins. This study compared the effectiveness of amivantamab to real-world systemic anti-cancer therapies in Japan. PATIENTS AND METHODS: External control patients were selected by applying CHRYSALIS eligibility to Japanese patients from LC-SCRUM-Asia. External control patients were included for every qualifying line of therapy after platinum-based chemotherapy. Propensity score weighting was applied to external control patients to adjust for differences in baseline characteristics. Outcomes were compared between external control patients, and all and Asian-only CHRYSALIS patients using weighted Cox proportional hazards regression models for progression-free survival (PFS), time to next therapy (TTNT), and overall survival (OS), and generalized estimating equations with repeated measurements for overall response rate (ORR). RESULTS: One hundred fifteen CHRYSALIS and 94 external control patients were identified. Compared to external control patients, amivantamab-treated patients had significantly longer OS (median OS 19.88 vs 14.09 months, HR [95% CI] 0.59 [0.40-0.88]), PFS (median PFS 6.74 vs 4.73 months, HR 0.59 [0.45-0.78]), TTNT (median TTNT 12.16 vs 5.09 months, HR 0.39 [0.29-0.53]), and significantly higher ORR (41.7% vs 14.1%). Analyses of amivantamab-treated Asian patients (n = 61) showed similar clinical benefits. CONCLUSION: In the absence of clinical evidence from randomized clinical trials, this study reflects the benefit of amivantamab after platinum-based chemotherapy for advanced non-small cell lung cancer patients harboring EGFR Exon 20ins, compared to current real-world therapies.

Characterization of 164 patients with NRAS mutated non-small cell lung cancer (NSCLC).

BACKGROUND: NRAS mutations are observed in less than 1% of non-small cell lung cancer (NSCLC). Clinical data regarding this rare subset of lung cancer are scarce and response to systemic treatment such as chemotherapy or immune checkpoint inhibitors (ICI) has never been reported. METHODS: All consecutive patients with an NRAS mutated NSCLC, diagnosed between August 2014 and November 2020 in 14 French centers, were included. Clinical and molecular data were collected and reviewed from medical records. RESULTS: Out of the 164 included patients, 106 (64.6%) were men, 150 (91.5%) were current or former smokers, and 104 (63.4%) had stage IV NSCLC at diagnosis. The median age was 62 years, and the most frequent histology was adenocarcinoma (81.7%). NRAS activating mutations were mostly found in codon 61 (70%), while codon 12 and 13 alterations were observed in 16.5% and 4.9% of patients, respectively. Programmed death ligand-1 expression level <1%/1-49%/≥50% were respectively found in 30.8%/27.1%/42.1% of tumors. With a median follow-up of 12.5 months, median overall survival (OS) of stage IV patients was 15.3 months (95% CI 9.9-27.6). No significant difference in OS was found according to the type of mutation (codon 61 vs. other), HR = 1.12 (95% CI 0.65-1.95). Among stage IV patients treated with platinum-based doublet (n = 66), ICI (n = 48), or combination of both (n = 10), objective response rate, and median progression free survival were respectively 45% and 5.8 months, 35% and 6.9 months, 70% and 8.6 months. CONCLUSION: NRAS mutated NSCLC are characterized by a high frequency of smoking history and codon 61 mutations. Further studies are needed to confirm the encouraging outcome of immunotherapy in combination with chemotherapy.

Selective control of transposable element expression during T cell exhaustion and anti-PD-1 treatment.

In chronic infections and cancer, T cells are exposed to prolonged antigen stimulation, resulting in loss of function (or exhaustion) and impairment of effective immunological protection. Exhausted T cells are heterogeneous and include early progenitors (Tpex) and terminally exhausted cells (Tex). Here, we used bulk and single-cell transcriptomics to analyze expression of transposable elements (TEs) in subpopulations of mouse and human CD8+ tumor-infiltrating T lymphocytes (TILs). We show that in mice, members of the virus-like murine VL30 TE family (mostly intact, evolutionary young ERV1s) are strongly repressed in terminally exhausted CD8+ T cells in both tumor and viral models of exhaustion. Tpex expression of these VL30s, which are mainly intergenic and transcribed independently of their closest gene neighbors, was driven by Fli1, a transcription factor involved in progression from Tpex to Tex. Immune checkpoint blockade (ICB) in both mice and patients with cancer increased TE expression (including VL30 in mice), demonstrating that TEs may be applicable as ICB response biomarkers. We conclude that expression of TEs is tightly regulated in TILs during establishment of exhaustion and reprogramming by ICB. Analyses of TE expression on single cells and bulk populations open opportunities for understanding immune cell identity and heterogeneity, as well as for defining cellular gene expression signatures and disease biomarkers.