Impact of metronomic trabectedin combined with low-dose cyclophosphamide on sarcoma microenvironment and correlation with clinical outcome: results from the TARMIC study.

Soft tissue sarcomas (STS) are diverse mesenchymal tumors with few therapeutic options in advanced stages. Trabectedin has global approval for treating STS patients resistant to anthracycline-based regimens. Recent pre-clinical data suggest that trabectedin's antitumor activity extends beyond tumor cells to influencing the tumor microenvironment (TME), especially affecting tumor-associated macrophages and their pro-tumoral functions. We present the phase I/II results evaluating a combination of metronomic trabectedin and low-dose cyclophosphamide on the TME in patients with advanced sarcomas. 50 patients participated: 20 in phase I and 30 in phase II. Changes in the TME were assessed in 28 patients using sequential tumor samples at baseline and day two of the cycle. Treatment notably decreased CD68 + CD163 + macrophages in biopsies from tumor lesions compared to pre-treatment samples in 9 of the 28 patients after 4 weeks. Baseline CD8 + T cell presence increased in 11 of these patients. In summary, up to 57% of patients exhibited a positive immunological response marked by reduced M2 macrophages or increased CD8 + T cells post-treatment. This positive shift in the TME correlated with improved clinical benefit and progression-free survival. This study offers the first prospective evidence of trabectedin's immunological effect in advanced STS patients, highlighting a relationship between TME modulation and patient outcomes.This study was registered with ClinicalTrial.gov, number NCT02406781.

Are DNA Repair Gene Alterations Associated With the Response to Platinum-Based Regimen and Immune Checkpoint Inhibitors in Patients With Solid Tumors?

We analyzed the antitumor activity of platinum-based chemotherapies and then immune checkpoint inhibitors (ICI) in all-comers patients with solid tumors having a somatic DNA damage repair gene alteration (DDR-GA) identified through a prospective precision medicine study (NCT02534649). Each DDR-GA was classified as pathogenic (Pa), probably pathogenic (PPa), and unknown pathogenicity (UPa) according to OncoKB and ClinVAR databases. Between January 2018 and May 2020, 662 patients were screened. One hundred ninety-nine tumors with DDR-GA were found in 121 (18.3%) patients. Ninety-six patients received platinum-based chemotherapy in the advanced setting. No difference in objective response rate (ORR) under platinum regimen was observed between the 3 DDR-GA groups. The only predictor of worse progression-free survival (PFS) in Cox regression was the existence of a Pa alteration compared to the UPa group: HR = 2.11 (95% CI = 1.2-3.7), P = .009. Forty-eight patients received ICI alone or in combination. We observed a significant trend in better ORR to ICI according to the DDR-GA status: 1/11 (9%) patients in UPa, 5/17 (29.4%) patients in PPa, and 9/20 (45%) patients in Pa (P = .003, Cochran-Armitage trend test), and an increased 6-month PFS probability of 11%, 44%, and 50% in the UPa, PPa, and Pa groups, respectively (P = .37, log-rank test). Overall, somatic pathogenic DDR-GAs were not associated with ORR or PFS to platinum-based chemotherapy in patients with unselected advanced solid tumors. However, DDR-GA seemed to impact ORR and PFS to ICI, paving the way for a therapeutic combination with ICI and molecules targeting the DDR mechanisms, which are currently evaluated in ongoing clinical trials.

Pembrolizumab in patients with rare and ultra-rare sarcomas (AcSé Pembrolizumab): analysis of a subgroup from a non-randomised, open-label, phase 2, basket trial.

BACKGROUND: Sarcoma is a heterogeneous group of diseases with few treatment options. Immunotherapy has shown little activity in studies including unselected sarcomas, but immune checkpoint blockers have shown activity in specific histotypes. We evaluated the activity of pembrolizumab in rare and ultra-rare sarcomas. METHODS: AcSé Pembrolizumab is an ongoing phase 2, basket, multitumour study investigating the activity of pembrolizumab monotherapy in rare cancers. Here, we report the results obtained in patients with selected histotypes of rare sarcomas (incidence of less than one case per 1 000 000 people per year) recruited at 24 French hospitals. Key inclusion criteria were age 15 years or older, Eastern Cooperative Oncology Group performance status of 0-1, and advanced disease that was untreated and resistant to treatment. Patients were given pembrolizumab 200 mg intravenously on day 1 of every 21-day cycle for a maximum of 24 months. The primary endpoint was objective response rate at week 12 using Response Evaluation Criteria in Solid Tumours version 1.1, assessed by local investigators. The primary endpoint and safety were analysed in the intention-to-treat population. The AcSé Pembrolizumab study is registered with ClinicalTrials.gov, NCT03012620. FINDINGS: Between Sept 4, 2017, and Dec 29, 2020, 98 patients were enrolled, of whom 97 received treatment and were included in analyses (median age 51 years [IQR 35-65]; 53 [55%] were male; 44 [45%] were female; no data were collected on race or ethnicity). 34 (35%) patients had chordomas, 14 (14%) had alveolar soft part sarcomas, 12 (12%) had SMARCA4-deficient sarcomas or malignant rhabdoid tumours, eight (8%) had desmoplastic small round cell tumours, six (6%) had epithelioid sarcomas, four (4%) had dendritic cell sarcomas, three (3%) each had clear cell sarcomas, solitary fibrous tumours, and myxoid liposarcomas, and ten (10%) had other ultra-rare histotypes. As of data cutoff (April 11, 2022), median follow-up was 13·1 months (range 0·1-52·8; IQR 4·3-19·7). At week 12, objective response rate was 6·2% (95% CI 2·3-13·0), with no complete responses and six partial responses in the 97 patients. The most common grade 3-4 adverse events were anaemia (eight [8%] of 97), alanine aminotransferase and aspartate aminotransferase increase (six [6%]), and dyspnoea (five [5%]). 86 serious adverse events were reported in 37 patients. Five deaths due to adverse events were reported, none of which were determined to be related to treatment (two due to disease progression, two due to cancer, and one due to unknown cause). INTERPRETATION: Our data show the activity and manageable toxicity of pembrolizumab in some rare and ultra-rare sarcoma histotypes, and support the PD-1/PD-L1 pathway as a potential therapeutic target in selected histotypes. The completion of the basket study will provide further evidence regarding the activity and toxicity of pembrolizumab in identified rare types of cancer. FUNDING: The Ligue contre le cancer, INCa, MSD. TRANSLATION: For the French translation of the abstract see Supplementary Materials section.

Circulating tumor DNA landscape and prognostic impact of acquired resistance to targeted therapies in cancer patients: a national center for precision medicine (PRISM) study.

BACKGROUND: Despite the effectiveness of the various targeted therapies currently approved for solid tumors, acquired resistance remains a persistent problem that limits the ultimate effectiveness of these treatments. Polyclonal resistance to targeted therapy has been described in multiple solid tumors through high-throughput analysis of multiple tumor tissue samples from a single patient. However, biopsies at the time of acquired resistance to targeted agents may not always be feasible and may not capture the genetic heterogeneity that could exist within a patient. METHODS: We analyzed circulating tumor DNA (ctDNA) with a large next-generation sequencing panel to characterize the landscape of secondary resistance mechanisms in two independent prospective cohorts of patients (STING: n = 626; BIP: n = 437) with solid tumors who were treated with various types of targeted therapies: tyrosine kinase inhibitors, monoclonal antibodies and hormonal therapies. RESULTS: Emerging alterations involved in secondary resistance were observed in the plasma of up 34% of patients regardless of the type of targeted therapy. Alterations were polyclonal in up to 14% of patients. Emerging ctDNA alterations were associated with significantly shorter overall survival for patients with some tumor types. CONCLUSION: This comprehensive landscape of genomic aberrations indicates that genetic alterations involved in secondary resistance to targeted therapy occur frequently and suggests that the detection of such alterations before disease progression may guide personalized treatment and improve patient outcome.

Safety, pharmacokinetic, pharmacodynamic and clinical activity of molibresib for the treatment of nuclear protein in testis carcinoma and other cancers: Results of a Phase I/II open-label, dose escalation study.

Molibresib is an orally bioavailable, selective, small molecule BET protein inhibitor. Results from a first time in human study in solid tumors resulted in the selection of a 75 mg once daily dose of the besylate formulation of molibresib as the recommended Phase 2 dose (RP2D). Here we present the results of Part 2 of our study, investigating safety, pharmacokinetics, pharmacodynamics and clinical activity of molibresib at the RP2D for nuclear protein in testis carcinoma (NC), small cell lung cancer, castration-resistant prostate cancer (CRPC), triple-negative breast cancer, estrogen receptor-positive breast cancer and gastrointestinal stromal tumor. The primary safety endpoints were incidence of adverse events (AEs) and serious AEs; the primary efficacy endpoint was overall response rate. Secondary endpoints included plasma concentrations and gene set enrichment analysis (GSEA). Molibresib 75 mg once daily demonstrated no unexpected toxicities. The most common treatment-related AEs (any grade) were thrombocytopenia (64%), nausea (43%) and decreased appetite (37%); 83% of patients required dose interruptions and 29% required dose reductions due to AEs. Antitumor activity was observed in NC and CRPC (one confirmed partial response each, with observed reductions in tumor size), although predefined clinically meaningful response rates were not met for any tumor type. Total active moiety median plasma concentrations after single and repeated administration were similar across tumor cohorts. GSEA revealed that gene expression changes with molibresib varied by patient, response status and tumor type. Investigations into combinatorial approaches that use BET inhibition to eliminate resistance to other targeted therapies are warranted.

High-grade soft-tissue sarcoma: optimizing injection improves MRI evaluation of tumor response.

OBJECTIVES: To determine the acquisition delay after gadolinium-chelate injection that optimizes the prediction of the histological response during anthracycline-based neoadjuvant chemotherapy (NAC) for locally advanced high-grade soft-tissue sarcomas (STS). METHODS: Thirty patients (mean age 62 years) were included in this IRB-approved study. All patients received 5-6 cycles of NAC followed by surgery. A good response was defined as ≤ 10% viable cells on histological analysis of the surgical specimen. DCE-MRI was performed before treatment (MRI0) and after two cycles (MRI1). Images were obtained every 8 s. Change in contrast enhancement (CE) between MRI0 and MRI1 was calculated for each acquisition delay 't' on the whole tumor volume. Area under the receiver-operating characteristics curves (AUROC) for change in CE was calculated at each acquisition delay, as well as the accuracy of the Choi criteria. RESULTS: There were 22 (73.3%) poor responders. Acquisition delay had a significant effect on change in CE and on the response status according to Choi (p = 0.0014 and 0.0270, respectively). The highest AUROC was obtained at t = 58 s (0.792) with an optimal threshold of a -30.5% decrease in CE. At t = 58 s, accuracy to predict a poor response was 82.8% above this threshold, while it was 72.4% and 70% with no objective response according to the Choi criteria and RECIST1.1, respectively. CONCLUSION: Optimization of acquisition delay after injection to estimate change in CE improves the prediction of histological response. For STS undergoing NAC, a 60-s delay can be recommended with MRI. KEY POINTS: • Accuracy of response criteria based on contrast enhancement, like the Choi criteria, is dependent on the acquisition delay after gadolinium-chelate injection. • DCE-MRI helps determine the optimal acquisition delay after gadolinium-chelate injection for improving evaluation of tumor response. • In soft tissue sarcoma, an acquisition delay at 60 s optimizes the evaluation of the response and accuracy of the Choi criteria.

Primary tumors of the lung: should we consider thermal ablation as a valid therapeutic option?

Non-small cell lung cancer (NSCLC) remains the leading cause of cancer death; percutaneous thermal ablation (TA) has proven feasibility, good local control and good tolerance in stage I tumors for patients with medical comorbidities and who are ineligible for surgery. In this context, stereotactic body radiotherapy (SBRT) has demonstrated high efficacy in treating T1 NSCLC and will need to be compared with percutaneous ablation. TA is also indicated in oligoprogressive disease; and can be proposed as a salvage treatment option for tumor recurrence after radiotherapy. Besides more advanced NSCLC could be also an indication of TA in combination with systemic treatments. A large majority of diagnosed NSCLC do not exhibit specific targetable genetic aberration. Those tumors present poorer prognosis and have been treated with standard chemotherapy regimen until the recent development of immune checkpoint inhibitors (ICIs) based immunotherapy. Combining TA with immunotherapy is promising and still needs to be explored.

A Chatbot Versus Physicians to Provide Information for Patients With Breast Cancer: Blind, Randomized Controlled Noninferiority Trial.

BACKGROUND: The data regarding the use of conversational agents in oncology are scarce. OBJECTIVE: The aim of this study was to verify whether an artificial conversational agent was able to provide answers to patients with breast cancer with a level of satisfaction similar to the answers given by a group of physicians. METHODS: This study is a blind, noninferiority randomized controlled trial that compared the information given by the chatbot, Vik, with that given by a multidisciplinary group of physicians to patients with breast cancer. Patients were women with breast cancer in treatment or in remission. The European Organisation for Research and Treatment of Cancer Quality of Life Group information questionnaire (EORTC QLQ-INFO25) was adapted and used to compare the quality of the information provided to patients by the physician or the chatbot. The primary outcome was to show that the answers given by the Vik chatbot to common questions asked by patients with breast cancer about their therapy management are at least as satisfying as answers given by a multidisciplinary medical committee by comparing the success rate in each group (defined by a score above 3). The secondary objective was to compare the average scores obtained by the chatbot and physicians for each INFO25 item. RESULTS: A total of 142 patients were included and randomized into two groups of 71. They were all female with a mean age of 42 years (SD 19). The success rates (as defined by a score >3) was 69% (49/71) in the chatbot group versus 64% (46/71) in the physicians group. The binomial test showed the noninferiority (P<.001) of the chatbot's answers. CONCLUSIONS: This is the first study that assessed an artificial conversational agent used to inform patients with cancer. The EORTC INFO25 scores from the chatbot were found to be noninferior to the scores of the physicians. Artificial conversational agents may save patients with minor health concerns from a visit to the doctor. This could allow clinicians to spend more time to treat patients who need a consultation the most. TRIAL REGISTRATION: Clinicaltrials.gov NCT03556813, https://tinyurl.com/rgtlehq.

Patterns of care and outcomes of patients with METAstatic soft tissue SARComa in a real-life setting: the METASARC observational study.

BACKGROUND: Well-designed observational studies of individuals with rare tumors are needed to improve patient care, clinical investigations, and the education of healthcare professionals. METHODS: The patterns of care, outcomes, and prognostic factors of a cohort of 2225 patients with metastatic soft tissue sarcomas who were diagnosed between 1990 and 2013 and documented in the prospectively maintained database of the French Sarcoma Group were analyzed. RESULTS: The median number of systemic treatments was 3 (range, 1-6); 27% of the patients did not receive any systemic treatment and 1054 (49%) patients underwent locoregional treatment of the metastasis. Half of the patients who underwent chemotherapy (n = 810) received an off-label drug. Leiomyosarcoma was associated with a significantly better outcome than the other histological subtypes. With the exception of leiomyosarcomas, the benefit of a greater than third-line regimen was very limited, with a median time to next treatment (TNT) and overall survival (OS) ranging between 2.3 and 3.7 months and 5.4 and 8.5 months, respectively. The TNT was highly correlated with OS. Female sex, leiomyosarcoma histology, locoregional treatment of metastases, inclusion in a clinical trial, and treatment with first-line polychemotherapy were significantly associated with improved OS in the multivariate analysis. CONCLUSIONS: The combination of doxorubicin with a second drug, such as ifosfamide, represents a valid option, particularly when tumor shrinkage is expected to provide clinical benefits. After failure of the second-line therapy, best supportive care should be considered, particularly in patients with non-leiomyosarcoma histology who are not eligible to participate in a clinical trial. Locoregional treatment of metastasis should always be included in the therapeutic strategy when feasible. TNT may represent a useful surrogate endpoint for OS in clinical studies.

CSF-1R Inhibitor Development: Current Clinical Status.

PURPOSE OF REVIEW: Colony-stimulating factor 1 receptor (CSF-1R) and its ligands, CSF-1 and interleukin 34 (IL-34), regulate the function and survival of tumor-associated macrophages, which are involved in tumorigenesis and in the suppression of antitumor immunity. Moreover, the CSF-1R/CSF-1 axis has been implicated in the pathogenesis of pigmented villonodular synovitis (PVNS), a benign tumor of the synovium. As advanced or metastatic malignant solid tumors and relapsed/refractory PVNS remain unresolved therapeutic problems, new approaches are needed to improve the outcome of patients with these conditions. RECENT FINDINGS: In solid tumors, targeting CSF-1R via either small molecules or antibodies has shown interesting results in vitro but limited antitumor activity in vivo. Concerning PVNS, clinical trials assessing CSF-1R inhibitors have revealed promising initial outcomes. Blocking CSF-1/CSF-1R signaling represents a promising immunotherapy approach and several new potential combination therapies for future clinical testing.

PRognostic factor of Early Death In phase II Trials or the end of 'sufficient life expectancy' as an inclusion criterion? (PREDIT model).

BACKGROUND: Optimizing patient selection is a necessary step to design better clinical trials. 'Life expectancy' is a frequent inclusion criterion in phase II trial protocols, a measure that is subjective and often difficult to estimate. The aim of this study was to identify factors associated with early death in patients included in phase II studies. METHODS: We retrospectively collected medical records of patients with advanced solid tumors included in phase II trials in two French Comprehensive Cancer Centers (Bordeaux, Center 1 set; Lille, Center 2 set). We analyzed patients' baseline characteristics. Predictive factors associated with early death (mortality at 3 months) were identified by logistic regression. We built a model (PREDIT, PRognostic factor of Early Death In phase II Trials) based on prognostic factors isolated from the final multivariate model. RESULTS: Center 1 and 2 sets included 303 and 227 patients, respectively. Patients from Center 1 and 2 sets differed in tumor site, urological (26 % vs 15 %) and gastrointestinal (18 % vs 28 %) and in lung metastasis incidence (10 % vs 49 %). Overall survival (OS) at 3 months was 88 % (95 % CI [83.5; 91.0], Center 1 set) and 91 % (95 % CI [86.7; 94.2], Center 2 set). Presence of a 'life expectancy' inclusion criterion did not improve the 3-month OS (HR 0.6, 95 % CI [0.2; 1.2], p = 0.2325). Independent factors of early death were an ECOG score of 2 (OR 13.3, 95%CI [4.1; 43.4]), hyperleukocytosis (OR 5.5, 95 % CI [1.9; 16.3]) and anemia (OR 2.8, 95 % CI [1.1; 7.1]). Same predictive factors but with different association levels were found in the Center 2 set. Using the Center 1 set, ROC analysis shows a good discrimination to predict early death (AUC: 0.89 at 3 months and 0.86 at 6 months). CONCLUSIONS: Risk modeling in two independent cancer populations based on simple clinical parameters showed that baseline ECOG of 2, hyperleukocytosis and anemia are strong early-death predictive factors. This model allows identifying patients who may not benefit from a phase II trial investigational drug and may, therefore, represent a helpful tool to select patients for phase II trial entry.

Managing Endometrial Cancer: The Role of Pelvic Lymphadenectomy and Secondary Surgery.

PURPOSE: In November 2010, the French National Cancer Institute published new guidelines for managing endometrial cancer. Pelvic lymphadenectomy is not indicated for preoperative low-intermediate risk type 1 endometrial cancer, and high-risk patients should undergo secondary surgery with para-aortic lymphadenectomy. This study evaluated these new guidelines with regard to overall survival (OS), relapse-free survival (RFS), and morbidity for patients with low-intermediate risk disease. METHODS: We evaluated all type 1 endometrial cancer patients with low-intermediate risk of recurrence who were treated from 1 January 1997 through 31 December 2012. All patients were classified according to the 2009 International Federation of Gynecology and Obstetrics staging criteria and the European Society for Medical Oncology. RESULTS: Overall, 230 patients were included (159 before and 71 after the new guidelines were issued). Pelvic lymphadenectomies were performed before and after the new guidelines in 77.4 and 28.6 % of patients, respectively (p < 0.001). After 2010, eight patients also underwent secondary surgery, which consisted of a para-aortic lymphadenectomy for lymphovascular space invasion (LVSI). This second surgery changed the adjuvant treatment for one patient. OS and RFS were similar between both groups, and no difference in morbidity was observed between the groups. LVSI was an independent factor for OS [hazard ratio (HR) 7.2, 95 % CI 3.1-17; p < 0.001] and RFS (HR 3.7, 95 % CI 1.6-8.5; p < 0.003). CONCLUSIONS: Fewer pelvic lymphadenectomies in low-intermediate risk patients did not affect OS, RFS, or morbidity, including patients with secondary surgery. We must gather additional data with a longer follow-up period to not only confirm our results but to also fully investigate the paradoxical absence of decreased morbidity that our study has shown.

Low skeletal muscle is associated with toxicity in patients included in phase I trials.

BACKGROUND: Low muscle mass has been associated with chemotherapy toxicity. We conducted this prospective study to evaluate the effects of body composition on the occurrence of toxicity in phase I trials. PATIENTS AND METHODS: Patients were consecutively enrolled irrespective of the type of tumor or the type of drug. The Skeletal Muscle Index (SMIndex) and visceral and subcutaneous adipose tissue were assessed with computed tomography imaging by measuring cross-sectional areas of the tissues (cm(2)/m(2)). Dose-limiting toxicity (DLT) corresponded to toxicities occurring during the 1(st) cycle that necessitated dose reduction, postponement or interruption of drug administration and severe toxicity events (STE) corresponded to DLT or permanent treatment withdrawal due to toxicity. RESULTS: 93 patients were evaluated. Ten percent of patients experienced DLT and had a lower SMIndex: 40.8 ± 4.6 vs. 48.1 ± 9.6 cm(2)/m(2) (p = 0.01). STE occurred in 14 % of the patients. The only factor associated with STE was a low SMIndex: 42.4 ± 5.8 vs. 48.4 ± 9.7 cm(2)/m(2) (p = 0.02). STE were observed in 25.5 % of the patients when the SMIndex was below the median value compared to 6.5 % of patients with a high SMIndex (p = 0.02). CONCLUSION: Muscle mass is a critical predictor of severe toxicity events in phase I patients, suggesting that sarcopenia may be considered in assessing patients for eligibility of phase-1 studies.

Metastatic Lung Adenocarcinomas: Development and Evaluation of Radiomic-Based Methods to Measure Baseline Intra-Patient Inter-Tumor Lesion Heterogeneity.

Radiomics has traditionally focused on individual tumors, often neglecting the integration of metastatic disease, particularly in patients with non-small cell lung cancer. This study sought to examine intra-patient inter-tumor lesion heterogeneity indices using radiomics, exploring their relevance in metastatic lung adenocarcinoma. Consecutive adults newly diagnosed with metastatic lung adenocarcinoma underwent contrast-enhanced CT scans for lesion segmentation and radiomic feature extraction. Three methods were devised to measure distances between tumor lesion profiles within the same patient in radiomic space: centroid to lesion, lesion to lesion, and primitive to lesion, with subsequent calculation of mean, range, and standard deviation of these distances. Associations between HIs, disease control rate, objective response rate to first-line treatment, and overall survival were explored. The study included 167 patients (median age 62.3 years) between 2016 and 2019, divided randomly into experimental (N = 117,546 lesions) and validation (N = 50,232 tumor lesions) cohorts. Patients without disease control/objective response and with poorer survival consistently systematically exhibited values of all heterogeneity indices. Multivariable analyses revealed that the range of primitive-to-lesion distances was associated with disease control in both cohorts and with objective response in the validation cohort. This metrics showed univariable associations with overall survival in the experimental. In conclusion, we proposed original methods to estimate the intra-patient inter-tumor lesion heterogeneity using radiomics that demonstrated correlations with patient outcomes, shedding light on the clinical implications of inter-metastases heterogeneity. This underscores the potential of radiomics in understanding and potentially predicting treatment response and prognosis in metastatic lung adenocarcinoma patients.

Enhancing Immunotherapy Response Prediction in Metastatic Lung Adenocarcinoma: Leveraging Shallow and Deep Learning with CT-Based Radiomics across Single and Multiple Tumor Sites.

This study aimed to evaluate the potential of pre-treatment CT-based radiomics features (RFs) derived from single and multiple tumor sites, and state-of-the-art machine-learning survival algorithms, in predicting progression-free survival (PFS) for patients with metastatic lung adenocarcinoma (MLUAD) receiving first-line treatment including immune checkpoint inhibitors (CPIs). To do so, all adults with newly diagnosed MLUAD, pre-treatment contrast-enhanced CT scan, and performance status ≤ 2 who were treated at our cancer center with first-line CPI between November 2016 and November 2022 were included. RFs were extracted from all measurable lesions with a volume ≥ 1 cm3 on the CT scan. To capture intra- and inter-tumor heterogeneity, RFs from the largest tumor of each patient, as well as lowest, highest, and average RF values over all lesions per patient were collected. Intra-patient inter-tumor heterogeneity metrics were calculated to measure the similarity between each patient lesions. After filtering predictors with univariable Cox p < 0.100 and analyzing their correlations, five survival machine-learning algorithms (stepwise Cox regression [SCR], LASSO Cox regression, random survival forests, gradient boosted machine [GBM], and deep learning [Deepsurv]) were trained in 100-times repeated 5-fold cross-validation (rCV) to predict PFS on three inputs: (i) clinicopathological variables, (ii) all radiomics-based and clinicopathological (full input), and (iii) uncorrelated radiomics-based and clinicopathological variables (uncorrelated input). The Models' performances were evaluated using the concordance index (c-index). Overall, 140 patients were included (median age: 62.5 years, 36.4% women). In rCV, the highest c-index was reached with Deepsurv (c-index = 0.631, 95%CI = 0.625-0.647), followed by GBM (c-index = 0.603, 95%CI = 0.557-0.646), significantly outperforming standard SCR whatever its input (c-index range: 0.560-0.570, all p < 0.0001). Thus, single- and multi-site pre-treatment radiomics data provide valuable prognostic information for predicting PFS in MLUAD patients undergoing first-line CPI treatment when analyzed with advanced machine-learning survival algorithms.

TROP2 Is Associated with Primary Resistance to Immune Checkpoint Inhibition in Patients with Advanced Non-Small Cell Lung Cancer.

PURPOSE: Mechanisms of primary resistance to inhibitors of the programmed cell death-1 (PD-1)/programmed death-ligand 1 (PD-L1) signaling axis in non-small cell lung cancer (NSCLC) are still poorly understood. While some studies suggest the involvement of trophoblast cell surface antigen 2 (TROP2) in modulating tumor cell resistance to therapeutic drugs, its specific role in the context of PD-1/PD-L1 axis blockade is not definitively established. EXPERIMENTAL DESIGN: We performed high-throughput analysis of transcriptomic data from 891 NSCLC tumors from patients treated with either the PD-L1 inhibitor atezolizumab or chemotherapy in two large randomized clinical trials. To confirm our results at the protein level, we complemented this transcriptional approach by performing a multiplex immunofluorescence analysis of tumor tissue samples as well as a proteomic profiling of plasma. RESULTS: We observed a significant association of TROP2 overexpression with worse progression-free survival and overall survival on PD-L1 blockade, independent of other prognostic factors. Importantly, we found increased TROP2 expression to be predictive of survival in patients treated with atezolizumab but not chemotherapy. TROP2 overexpression was associated with decreased T-cell infiltration. We confirmed these results at the proteomic level both on tumor tissue and in plasma. CONCLUSIONS: Our results suggest an important contribution of TROP2 expression to the primary resistance to PD-L1 blockade in NSCLC. TROP2-biomarker-based strategy may be relevant in selecting patients with NSCLC who are more likely to benefit from a combination of immunotherapy and an anti-TROP2 agent.

Overall Survival From the EORTC LCG-1613 APPLE Trial of Osimertinib Versus Gefitinib Followed by Osimertinib in Advanced EGFR-Mutant Non-Small-Cell Lung Cancer.

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.Osimertinib has been established as a standard of care for patients with common sensitizing EGFR-mutant advanced non-small-cell lung cancer (NSCLC) although the sequential approach (first-generation inhibitor gefitinib followed by osimertinib) has not been formally compared. The phase II APPLE trial (ClinicalTrials.gov identifier: NCT02856893) enrolled 156 treatment-naïve patients, and two treatment strategies were evaluated: osimertinib up front or the sequential treatment approach with gefitinib up front followed by osimertinib at the time of progression, either molecular progression (detection of plasma T790M resistance mutation) regardless of the radiologic status or just at the time of radiologic progression. Patients' characteristics were well balanced, except for the higher proportion of baseline brain metastases in the sequential approach (29% v 19%). Per protocol, 73% of patients switched to osimertinib in the sequential arm. Up-front treatment with osimertinib was associated with a lower risk of brain progression versus the sequential approach (hazard ratio [HR], 0.54 [90% CI, 0.34 to 0.86]), but a comparable overall survival was observed between both strategies (HR, 1.01 [90% CI, 0.61 to 1.68]), with the 18-month survival probability of 84% and 82.3%, respectively. The APPLE trial suggests that a sequential treatment approach is associated with more frequent progression in the brain but a similar survival in advanced EGFR-mutant NSCLC.

Biomarker-directed targeted therapy plus durvalumab in advanced non-small-cell lung cancer: a phase 2 umbrella trial.

For patients with non-small-cell lung cancer (NSCLC) tumors without currently targetable molecular alterations, standard-of-care treatment is immunotherapy with anti-PD-(L)1 checkpoint inhibitors, alone or with platinum-doublet therapy. However, not all patients derive durable benefit and resistance to immune checkpoint blockade is common. Understanding mechanisms of resistance-which can include defects in DNA damage response and repair pathways, alterations or functional mutations in STK11/LKB1, alterations in antigen-presentation pathways, and immunosuppressive cellular subsets within the tumor microenvironment-and developing effective therapies to overcome them, remains an unmet need. Here the phase 2 umbrella HUDSON study evaluated rational combination regimens for advanced NSCLC following failure of anti-PD-(L)1-containing immunotherapy and platinum-doublet therapy. A total of 268 patients received durvalumab (anti-PD-L1 monoclonal antibody)-ceralasertib (ATR kinase inhibitor), durvalumab-olaparib (PARP inhibitor), durvalumab-danvatirsen (STAT3 antisense oligonucleotide) or durvalumab-oleclumab (anti-CD73 monoclonal antibody). Greatest clinical benefit was observed with durvalumab-ceralasertib; objective response rate (primary outcome) was 13.9% (11/79) versus 2.6% (5/189) with other regimens, pooled, median progression-free survival (secondary outcome) was 5.8 (80% confidence interval 4.6-7.4) versus 2.7 (1.8-2.8) months, and median overall survival (secondary outcome) was 17.4 (14.1-20.3) versus 9.4 (7.5-10.6) months. Benefit with durvalumab-ceralasertib was consistent across known immunotherapy-refractory subgroups. In ATM-altered patients hypothesized to harbor vulnerability to ATR inhibition, objective response rate was 26.1% (6/23) and median progression-free survival/median overall survival were 8.4/22.8 months. Durvalumab-ceralasertib safety/tolerability profile was manageable. Biomarker analyses suggested that anti-PD-L1/ATR inhibition induced immune changes that reinvigorated antitumor immunity. Durvalumab-ceralasertib is under further investigation in immunotherapy-refractory NSCLC.ClinicalTrials.gov identifier: NCT03334617.

Survival outcomes of patients with metastatic non-small cell lung cancer receiving chemotherapy or immunotherapy as first-line in a real-life setting.

Treatment of metastatic non-small cell lung cancer (mNSCLC) has been modified due to the development of immunotherapy. We assessed survival outcomes (overall [OS] and progression-free [rwPFS] survivals, time-to-next-treatment [TNT]) in mNSCLC patients after first-line immunotherapy and chemotherapy in real-life settings. Association between rwPFS and TNT, two candidate surrogate endpoints (SE), with OS was assessed. This retrospective multi-center study uses data from patients included in the Epidemio-Strategy Medico-Economic program with mNSCLC over 2015-2019. The impact of treatment on rwPFS/OS was evaluated with Cox models. Individual-level associations between SE and OS were estimated with an iterative multiple imputation approach and joint survival models. The population included 5294 patients (63 years median age). Median OS in immunotherapy group was 16.4 months (95%CI [14.1-NR]) and was higher than in chemotherapy group (11.6 months; 95%CI [11.0-12.2]). Improved OS was observed for the immunotherapy group after 3 months for subjects with performance status 0-1 (HR = 0.59; 95%CI [0.42-0.83], p < 0.01). The associations between rwPFS and TNT with OS were close ([Formula: see text]=0.57). Results emphasized a survival improvement with immunotherapy for patients in good health condition. There was moderate evidence of individual-level association between candidate SE and OS.

Upregulation of Indoleamine 2,3-Dioxygenase 1 in Tumor Cells and Tertiary Lymphoid Structures is a Hallmark of Inflamed Non-Small Cell Lung Cancer.

PURPOSE: Overexpression of the tryptophan-catabolizing enzyme indoleamine 2,3-dioxygenase 1 (IDO1) has been reported in several tumor types, including non-small cell lung cancer (NSCLC), and has been shown to promote tumor-immune evasion and inhibit T-cell activation through increased tryptophan degradation and the production of several immunosuppressive metabolites collectively known as kynurenines. However, it remains unclear whether IDO1 expression by tumor cells is detrimental specifically in the context of programmed cell death protein 1 (PD-1)/programmed death ligand 1 (PD-L1) axis blockade. EXPERIMENTAL DESIGN: We analyzed the transcriptome of 891 NSCLC tumor samples from patients enrolled in two large randomized clinical trials investigating the safety and activity of atezolizumab, a humanized IgG1 mAb that targets PD-L1, versus docetaxel in patients with advanced NSCLC. We complemented these transcriptomics results at the protein level by using multiplex immunofluorescence and at the functional level with in vitro experiments. RESULTS: The increased expression of the tryptophan-catabolizing enzyme IDO1 was significantly associated with improved objective response, progression-free survival, and overall survival in patients treated with PD-L1 inhibitors, but not in those treated with chemotherapy. Strikingly, inflamed tumors had higher levels of IDO1, and IDO1 was also expressed in tertiary lymphoid structures (TLS) by mature follicular dendritic cells. L-kynurenine impaired the differentiation of antibody-producing B cells induced by follicular helper T (Tfh)/B-cell interactions, a hallmark process within TLS. CONCLUSIONS: IDO1 pathway in NSCLC is driven by the immune system rather than by tumor cells. Targeting IDO1 in combination with anti-PD-1/PD-L1 might be beneficial only in patients with inflamed tumors and particularly in those bearing TLS.