Immune checkpoint inhibitor-related pneumonitis (ICI-P) during cancer treatment is rarely observed (<5%). ICI-P is more often observed in patients with nonsmall cell lung cancer (NSCLC) than in those ...with other cancers. Likewise, it is more common in those receiving programmed cell death (PD)-1/PD-1 ligand inhibitors rather than cytotoxic T-lymphocyte antigen (CTLA)-4 inhibitors alone. The frequency of ICI-P is higher when anti-PD-1 and anti-CTLA-4 are administered concomitantly. Despite the low fatality rate (≈13%), ICI-P is the leading cause of ICI-related deaths. This narrative review focuses on the epidemiology, clinical and radiological presentation and prognosis of ICI-P occurring in patients, especially those with advanced NSCLC. Emphasis is placed on the differences in terms of frequency or clinical picture observed depending on whether the ICI is used as monotherapy or in combination with another ICI or chemotherapy. Other pulmonary complications observed in cancer patients, yet not necessarily immune-related, are reviewed, such as sarcoid-like granulomatosis, tuberculosis or other infections. A proposal for pragmatic management, including differential diagnosis and therapeutic strategies, is presented, based on the ICI-P series reported in the literature and published guidelines.
The current first-line standard treatment for advanced small cell lung cancer (SCLC) is a combination of chemotherapy and immunotherapy. However, few efficacy data are available in a real-life ...settings, including frail patients. The aim of this study is to describe the real-life efficacy of chemoimmunotherapy in an unselected SCLC population. We conducted a retrospective multicenter study, which compared two cohorts of patients with treatment-naive metastatic SCLC treated in six academic centers in the Greater Paris area. Cohort 1 included patients treated with chemotherapy between January 2017 and December 2018, and cohort 2 included patients treated with chemoimmunotherapy between January 2019 and December 2020. A total of 153 consecutive patients were included (cohort 1: n = 96; cohort 2: n = 57). Clinical characteristics were similar between the two cohorts. Overall survival (OS) was statistically higher in cohort 2 (median survival 15.47 months) than in cohort 1 (median survival 9.5 months) (p = 0.0001). OS for patients with a performance status ≥2 and for patients ≥70 years old was not statistically different between the two cohorts. Chemoimmunotherapy efficacy was better compared to chemotherapy alone in case of brain or liver metastases. In conclusion, the combination of chemoimmunotherapy in metastatic SCLC appears to provide a real-life OS benefit. Dedicated clinical trials are needed to test this strategy in patients with impaired performance status or advanced age.
Immune checkpoint inhibitors (ICI) widely improved the treatment of solid and hematologic malignancies. Yet, a remarkable proportion of patients receiving ICI develop immune related adverse events ...(irAEs) which are difficult to define as treatment-related. This underlines the need to develop a biomarker to guide irAE diagnosis. We developed a novel flow cytometry assay combining measurement of anti-PD-1 (programmed cell death protein-1) occupancy and evaluation of remaining PD-1 receptor availability with anti-IgG4 PE and anti-PD-1 BV421. We prospectively collected blood and biological fluids samples from patients treated by IgG4 anti-PD-1 therapy (nivolumab or pembrolizumab), with (n=18) or without (n=12) current irAE. We analyzed PD-1+ and IgG4+ staining pattern and MFI values of these parameters on CD4 and CD8 T cells, and IgG4+/PD-1+ MFI ratios are calculated. A higher mean fluorescence intensity IgG4+/PD-1+ ratio was measured on peripheral CD4+ T cells of irAE cases, when compared to controls (p=0.003). ICI-related toxicity is therefore associated with increased therapeutic antibody occupancy of PD-1 receptors on CD4+ T cells. Furthermore, in one case of ICI-related pneumonitis, binding of therapeutic antibody was stronger on lung CD4+ T cell than in blood. In another case of ICI-related encephalitis, the PD-1 receptor occupancy was total on CSF CD4 T cells, but only partial on peripherical CD4 T cells. Our results suggest that flow cytometry monitoring of ICI occupancy can be used in patients treated with monoclonal ICI to guide irAE diagnosis.
Background: COVID-19 may be more frequent and more severe in cancer patients than in other individuals. Our aims were to assess the rate of COVID-19 in hospitalized cancer patients, to describe their ...demographic characteristics, clinical features and care trajectories, and to assess the mortality rate. Methods: This multicenter cohort study was based on the Electronic Health Records of the Assistance Publique-Hôpitaux de Paris (AP-HP). Cancer patients with a diagnosis of COVID-19 between 3 March and 19 May 2020 were included. Main outcome was all-cause mortality within 30 days of COVID-19 diagnosis. Results: A total of 29,141 cancer patients were identified and 7791 (27%) were tested for SARS-CoV-2. Of these, 1359 (17%) were COVID-19-positive and 1148 (84%) were hospitalized; 217 (19%) were admitted to an intensive care unit. The mortality rate was 33% (383 deaths). In multivariate analysis, mortality-related factors were male sex (aHR = 1.39 95% CI: 1.07–1.81), advanced age (78–86 y: aHR = 2.83 95% CI: 1.78–4.51 vs. <66 y; 86–103 y: aHR = 2.61 95% CI: 1.56–4.35 vs. <66 y), more than two comorbidities (aHR = 2.32 95% CI: 1.41–3.83) and C-reactive protein >20 ng/mL (aHR = 2.20 95% CI: 1.70–2.86). Primary brains tumors (aHR = 2.19 95% CI: 1.08–4.44) and lung cancer (aHR = 1.66 95% CI: 1.02–2.70) were associated with higher mortality. Risk of dying was lower among patients with metabolic comorbidities (aHR = 0.65 95% CI: 0.50–0.84). Conclusions: In a hospital-based setting, cancer patients with COVID-19 had a high mortality rate. This mortality was mainly driven by age, sex, number of comorbidities and presence of inflammation. This is the first cohort of cancer patients in which metabolic comorbidities were associated with a better outcome.
Backgrounds: Malignant pleural mesothelioma (MPM) is a cancer with poor prognosis. Second-line and onward therapy has many options, including immune-checkpoint inhibitors with demonstrated efficacy: ...10−25% objective response rate (ORR) and 40−70% disease-control rate (DCR) in clinical trials on selected patients. This study evaluated real-life 2L+ nivolumab efficacy in MPM patients and looked for factors predictive of response. Methods: This retrospective study included (September 2017−July 2021) all MPM patients managed in 11 French centers. Results: The 109 enrolled patients’ characteristics were: median age: 69 years; 67.9% men; 82.6% epithelioid subtype. Strictly, second-line nivolumab was given to 51.4%. Median PFS and OS were 3.8 (3.2−5.9) and 12.8 (9.2−16.4) months. ORR was 17/109 (15.6%); 34/109 patients had a stabilized disease (DCR 46.8%). Univariable analysis identified several parameters as significantly (p < 0.05) prognostic of OS HR (95% CI): biphasic subtype: 3.3 (1.52−7.0), intermediate Lung Immune Prognostic Index score: 0.46 (0.22−0.99), progression on the line preceding nivolumab: 2.1 (1.11−3.9) and age > 70 years: 2.5 (1.5−4.0). Multivariable analyses retained only biphasic subtype: 3.57 (1.08−11.8) and albumin < 25 g/L: 10.28 (1.5−70.7) as significant and independent predictors. Conclusions: Second-line and onward nivolumab is effective against MPM in real life but with less effectiveness in >70 years. Ancillary studies are needed to identify the predictive factors.
In the recent past, we observed an increased risk of cancer in the population with human immunodeficiency virus (HIV) owing to the development of antiretroviral therapies that decreased mortality ...caused by HIV-specific infections. This particularly fragile population is frequently excluded from clinical trials, and up-to-date recommendations for these patients are lacking. Only few cases of patients with HIV suffering from cancer and undergoing first-line immunotherapy have been reported so far. Here, we report the largest known study of patients with HIV with NSCLC (five patients) undergoing first-line immunotherapy by pembrolizumab, after CANCERVIH group selection. Our results are consistent with those of previous case reports concerning safety of immunotherapy in patients with HIV, revealing no severe or fatal toxicity, opportunistic infections, or immune reconstitution inflammatory syndrome. Moreover, pembrolizumab did not seem to modify HIV viral parameters. We also evaluated the effectiveness of immunotherapy in these HIV-immunosuppressed patients: the average survival was 9.8 months, with three patients having rapid progression and two partial response. Nevertheless, besides safety and drug-to-drug interactions, the effectiveness of first-line immunotherapy in people living with HIV needs to be supported by larger studies.
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Background: Immunotherapy (IO) is the standard of care in 1L stage IV non-small cell lung cancer (NSCLC) cases that are not eligible for targeted therapies. Today, a level of PD-L1 expression ...of 50% or above is the only standard predictive biomarker for IO efficacy as monotherapy. However, a majority of patients fail to respond to the treatment and are exposed to potentially severe immune-related adverse events. There is thus an urgent need to discover new predictive signatures of response to IO in such setting. Methods: A retrospective 1-year cohort of 63 patients with advanced NSCLC, PD-L1 expression > 50%, and treated with 1L pembrolizumab monotherapy was analyzed to develop a machine learning-based algorithm predictive of response to immunotherapy. Multimodal baseline data were collected including clinical, biological, pathology, molecular, baseline CT scan data and clinical outcomes status (objective response at first evaluation, PFS, OS). For each patient, thoracic tumors were segmented in 3D by both an experimented pneumologist and a radiologist using the SOPHiA DDM for Radiomics platform. Radiomics features were then extracted following the IBSI standards and combined with the other data modalities. A filter-based variable selection method was applied before testing several machine learning algorithms to obtain an individual prediction of the response at first evaluation. The optimization criterion was the Area Under the ROC Curve (AUC). Due to the small size of the cohort, a nested leave-pair-out cross-validation was used to properly estimate the model performance. Results: A logistic regression algorithm reached an AUC of 0.85, a precision of 83%, a sensitivity of 77% and a specificity of 74% for predicting response at first evaluation. The algorithm was able to correctly predict 21 progressions among 28 observed and 27 disease controls among 35 observed. Features with highest weight were representative of the full scope of data modalities included in the model, highlighting the importance of a truly multimodal analysis. Indeed, withdrawing any specific data modality (e.g., radiomics features), led to a decrease of at least ̃10% of the AUC. Patients were then stratified into two groups, progression versus disease control, based upon their predicted response status at first evaluation. These two groups displayed a statistically significant difference in PFS (p < 0.001), suggesting that baseline multimodal data analysis could help predict long-term outcomes. Conclusions: This proof-of-concept study suggests that machine learning applied to baseline multi-modal data can help predict response to IO at the individual patient level, as well as stratify patients to inform long-term outcomes. This algorithm is being improved and validated through a large real-world multicentric international observational study including more than 4000 patients (DEEP-Lung-IV study, NCT04994795).
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Background: Novel options are needed for pts with ES-SCLC after the failure of first-line chemotherapy. Lurbinectedin demonstrated efficacy in a landmark phase II study Trigo et al. Lancet ...Oncol. 2020 May;21(5):645, and was granted EAP-ATU in France in June 2020. Methods: Multicenter, retrospective cohort of consecutive pts with histologically or cytologically confirmed ES-SCLC, who received at least one dose of treatment with lurbinectedin as part of the French EAP-ATU from June 2020 until March 2021, and gave consent for the data collection, were enrolled in 47 sites. Primary and secondary endpoints were description of clinical characteristics, and exposure to treatment, response, PFS, OS, safety. Results: 312 pts – 64% male, median age 65 years, 72% PS0-1, 47% with brain metastasis, 58% with previous immunotherapy – were enrolled. Lurbinectedin was administered as second-line in 44% of pts; 58% were chemotherapy-refractory. Pts received a median number of 3 cycles of lurbinectedin. Concurrent radiotherapy on metastases was delivered to 38% of pts. Lurbinectedin was discontinued because of progression/death/toxicity/other reasons in 83%/8%/5%/4% of pts. Grade3/4 events were observed in 9%/5% of pts. Response rate was 22% 95%CI 17-27%, disease control rate was 38% 95%CI 32-44%. After a median follow-up of 20.8 months, median PFS and OS were 1.9 95%CI 1.8-2 and 4.7 95%CI 4-5.4 months; 6-month PFS and OS were 7% 4-10% and 42% 95%CI 37-48%. PS≤2 and chemotherapy-free interval≥90days were associated with significantly longer OS (HR = 0.71 95%CI 0.53-0.95 and HR = 0.58 95% CI 0.44-076 respectively). Main sites of progression were the lung (39% of pts), the brain (39% of pts), the liver (30% of pts), and the mediastinum (30% of pts). Subsequent treatment was administered to 154 pts after discontinuation of lurbinectedin, mostly consisting of topotecan (26% of pts); response/disease control rates, and median PFS of first subsequent treatment were 11% 95%CI 6-17%, 35% 95%CI 27-44%, and 1.9 95%CI 1.7-2.3 months. Conclusions: Lurbinectedin provides an additional option from second-line for ES-SCLC, with efficacy outcomes comparable to that of historical treatments.
•Small cell lung cancer (SCLC) is a highly aggressive type of lung cancer.•Atezolizumab plus chemotherapy improves overall survival in 1st-line treatment of extensive SCLC.•IFCT-1905 CLINATEZO ...studied consecutive patients receiving this regimen in France.•Our studyreproduced in a real life setting thekey survival outcomesof the landmark trial.
Small cell lung cancer (SCLC) has a tendency towards recurrence and limited survival. Standard-of-care in 1st-line is platinum-etoposide chemotherapy plus atezolizumab or durvalumab,based on landmarkclinical trials.
IFCT-1905 CLINATEZO is a nationwide, non-interventional, retrospectivestudy of patients with extensive-SCLC receivingatezolizumab plus chemotherapy as part of French Early Access Program. Objectives were to analyse effectiveness,safetyand subsequent treatments.
The population analyzed included 518 patients who received atezolizumabin 65 participating centers. There were 66.2% male,mean age was 65.7 years; 89.1% had a performance status (PS) 0/1 and 26.6% brain metastases. Almost all(95.9%) were smokers. Fifty-five (10.6%) received at least 1 previous treatment. Median number of atezolizumab injections was 7.0 (range 1.0–48.0) for a median duration of 4.9 months (95% CI 4.5–5.1). Atezolizumab was continued beyond progression in 122 patients (23.6%) for a median duration of 1.9 months (95% CI: 1.4–2.3). Best objective response was complete and partialin 19 (3.9%) and 378 (77.1%)patients. Stable diseasewas observed in 50 patients (10.2%). Median follow-up was30.8 months (95% CI: 29.9–31.5). Median overall survival (OS), 12-, 24-month OS rates were 11.3 months (95% CI: 10.1–12.4), 46.7% (95% CI 42.3–50.9) and 21.2% (95% CI 17.7–24.8). Median real-world progression-free survival, 6-, 12-month rates were 5.2 months (95% CI 5.0–5.4), 37.5% (95% CI 33.3–41.7) and 15.2% (95% CI 12.2–18.6). For patients with PS 0/1, median OS was 12.2 months (95% CI 11.0–13.5). For patients with previous treatment, median OS was 14.9 months (95% CI 10.1–21.5). Three-hundred-and-twenty-six patients(66.4%) received subsequent treatment and27 (5.2%) were still underatezolizumabat date of last news.
IFCT-1905 CLINATEZO shows reproductibility, in real-life,ofIMpower-133survival outcomes, possibly attributed to selection of patients fit for this regimen, adoption of pragmatic approaches,including concurrent radiotherapy and treatment beyond progression.
Immune checkpoint inhibitor (ICPi) rechallenge could represent an attractive option in non–small-cell lung cancer (NSCLC), yet no sufficient data supporting this strategy are available. This ...retrospective observational multicenter national study explored the efficacy of anti–programmed cell death 1 (PD-1)/programmed death ligand 1 (PD-L1) rechallenge in advanced NSCLC patients, looking for potential clinical features associated with greater outcomes.
We retrospectively collected data from 144 advanced NSCLC patients whose disease was rechallenged with ICPis after ≥ 12 weeks of discontinuation. The progression-free survival (PFS) and overall survival (OS) were calculated from first or second ICPi initiation to disease progression (PFS1 and PFSR, respectively), death, or last follow-up (OS1, OSR), respectively.
The median (interquartile range) age was 63 (58-70) years. Most patients were male (67%) and smokers (87%). Most had adenocarcinomas (62%) and/or stage IV disease at diagnosis (66%). The best response at rechallenge was not associated with that under the first ICPi (P = 1.10−1). The median (95% confidence interval) PFS1 and PFSR were 13 (10-16.5) and 4.4 (3-6.5) months, respectively. The median (95% confidence interval) OS1 and OSR were 3.3 (2.9-3.9) and 1.5 (1.0-2.1) years, respectively. Longer PFSR and OSR were found in patients discontinuing first ICPi because of toxicity or clinical decision, those not receiving systemic treatment between the two ICPis, and those with good Eastern Cooperative Oncology Group performance status at rechallenge. Only performance status proved to affect outcomes at multivariate analysis.
Patients discontinuing first ICPi because of toxicity or clinical decision, those able to maintain a treatment-free period, and those with good performance status may be potential candidates for rechallenge.
Immune checkpoint inhibitor (ICPi) rechallenge could represent an attractive option in non–small-cell lung cancer (NSCLC), yet no sufficient data support this strategy. Our retrospective study explored the efficacy of ICPi rechallenge in 144 advanced NSCLC patients. It might be an option in patients discontinuing the first ICPi for toxicity or clinical reasons, those able to maintain a treatment-free period, and those with a good Eastern Cooperative Oncology Group performance status score.
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