A defect of amphiregulin release predicted longer survival independently of YAP expression in patients with pleural mesothelioma in the IFCT-0701 MAPS phase 3 trial.

The Hippo pathway effector YAP is dysregulated in malignant pleural mesothelioma (MPM). YAP's target genes include the secreted growth factor amphiregulin (AREG), which is overexpressed in a wide range of epithelial cancers and plays an elusive role in MPM. We assayed the expression of YAP and AREG in MPM pathology samples and that of AREG additionally in plasma samples of patients from the randomized phase 3 IFCT-0701 Mesothelioma Avastin Cisplatin Pemetrexed Study (MAPS) using immunohistochemistry and ELISA assays, respectively. MPM patients frequently presented high levels of tumor AREG (64.3%), a high cytosolic AREG expression being predictive of a better prognosis with longer median overall and progression-free survival. Surprisingly, tumor AREG cytosolic expression was not correlated with secreted plasma AREG. By investigating the AREG metabolism and function in MPM cell lines H2452, H2052, MSTO-211H and H28, in comparison with the T47D ER+ breast cancer cell line used as a positive control, we confirm that AREG is important for cell invasion, growth without anchorage, proliferation and apoptosis in mesothelioma cells. Yet, most of these MPM cell lines failed to correctly execute AREG posttranslational processing by metalloprotease ADAM17/tumor necrosis factor-alpha-converting enzyme (TACE) and extracell secretion. The favorable prognostic value of high cytosolic AREG expression in MPM patients could therefore be sustained by default AREG posttranslational processing and release. Thus, the determination of mesothelioma cell AREG content could be further investigated as a prognostic marker for MPM patients and used as a stratification factor in future clinical trials.

Therapeutic Potential of Afatinib in NRG1 Fusion-Driven Solid Tumors: A Case Series.

BACKGROUND: Neuregulin 1 (NRG1) fusions, which activate ErbB signaling, are rare oncogenic drivers in multiple tumor types. Afatinib is a pan-ErbB family inhibitor that may be an effective treatment for NRG1 fusion-driven tumors. PATIENTS AND METHODS: This report summarizes pertinent details, including best tumor response to treatment, for six patients with metastatic NRG1 fusion-positive tumors treated with afatinib. RESULTS: The six cases include four female and two male patients who ranged in age from 34 to 69 years. Five of the cases are patients with lung cancer, including two patients with invasive mucinous adenocarcinoma and three patients with nonmucinous adenocarcinoma. The sixth case is a patient with colorectal cancer. NRG1 fusion partners for the patients with lung cancer were either CD74 or SDC4. The patient with colorectal cancer harbored a novel POMK-NRG1 fusion and a KRAS mutation. Two patients received afatinib as first- or second-line therapy, three patients received the drug as third- to fifth-line therapy, and one patient received afatinib as fifteenth-line therapy. Best response with afatinib was stable disease in two patients (duration up to 16 months when combined with local therapies) and partial response (PR) of >18 months in three patients, including one with ongoing PR after 27 months. The remaining patient had a PR of 5 months with afatinib 40 mg/day, then another 6 months after an increase to 50 mg/day. CONCLUSION: This report reviews previously published metastatic NRG1 fusion-positive tumors treated with afatinib and summarizes six previously unpublished cases. The latter include several with a prolonged response to treatment (>18 months), as well as the first report of efficacy in NRG1 fusion-positive colorectal cancer. This adds to the growing body of evidence suggesting that afatinib can be effective in patients with NRG1 fusion-positive tumors. KEY POINTS: NRG1 fusions activate ErbB signaling and have been identified as oncogenic drivers in multiple solid tumor types. Afatinib is a pan-ErbB family inhibitor authorized for the treatment of advanced non-small cell lung cancer that may be effective in NRG1 fusion-driven tumors. This report summarizes six previously unpublished cases of NRG1 fusion-driven cancers treated with afatinib, including five with metastatic lung cancer and one with metastatic colorectal cancer. Several patients showed a prolonged response of >18 months with afatinib treatment. This case series adds to the evidence suggesting a potential role for afatinib in this area of unmet medical need.

Treatment strategies and safety of rechallenge in the setting of immune checkpoint inhibitors-related myositis: a national multicentre study.

OBJECTIVES: The occurrence of immune-related myositis (irM) is increasing, yet there are no therapeutic guidelines. We sought to analyse the current therapeutic strategies of irM and evaluate the outcomes of immune checkpoint inhibitors (ICIs) rechallenge. METHODS: We conducted a nationwide retrospective study between April 2018 and March 2020 including irM without myocardial involvement. Depending on the presence of cutaneous signs or unusual histopathological features, patients were classified into two groups: typical or atypical irM. Therapeutic strategies were analysed in both groups. The modalities and outcomes of ICI rechallenge were reviewed. RESULTS: Among the 20 patients, 16 presented typical irM. Regardless of severity, most typical irM were treated with steroid monotherapy (n = 14/16) and all had a complete response within ≤3 weeks. The efficacy of oral steroids for non-severe typical irM (n = 10) was the same with low-dose (≤0.5 mg/kg/day) or high-dose (1 mg/kg/day). Severe typical irM were successfully treated with intravenous methylprednisolone. Atypical irM (n = 4) had a less favourable evolution, including one irM-related death, and required heavy immunosuppression. ICIs were safely reintroduced in nine patients presenting a moderate (n = 6) or a severe (n = 3) irM. CONCLUSION: Our data highlight that steroid monotherapy is an effective treatment for typical irM, either with prednisone or with intravenous methylprednisone pulses depending on the severity. The identification of unusual features is important in determining the initial therapeutic strategy. The outcomes of rechallenged patients are in favour of a safe reintroduction of ICI following symptom resolution and creatin kinase (CK) normalization in moderate and severe forms of irM.

Specific Genomic Alterations in High-Grade Pulmonary Neuroendocrine Tumours with Carcinoid Morphology.

INTRODUCTION: High-grade lung neuroendocrine tumours with carcinoid morphology have been recently reported; they may represent the thoracic counterparts of grade 3 digestive neuroendocrine tumours. We aimed to study their genetic landscape including analysis of tumoral heterogeneity. METHODS: Eleven patients with high-grade (>20% Ki-67 and/or >10 mitoses) lung neuroendocrine tumours with a carcinoid morphology were included. We analysed copy number variations, somatic mutations, and protein expression in 16 tumour samples (2 samples were available for 5 patients allowing us to study spatial and temporal heterogeneity). RESULTS: Genomic patterns were heterogeneous ranging from "quiet" to tetraploid, heavily rearranged genomes. Oncogene mutations were rare and most genetic alterations targeted tumour suppressor genes. Chromosomes 11 (7/11), 3 (6/11), 13 (4/11), and 6-17 (3/11) were the most frequently lost. Altered tumour suppressor genes were common to both carcinoids and neuroendocrine carcinomas, involving different pathways including chromatin remodelling (KMT2A, ARID1A, SETD2, SMARCA2, BAP1, PBRM1, KAT6A), DNA repair (MEN1, POLQ, ATR, MLH1, ATM), cell cycle (RB1, TP53, CDKN2A), cell adhesion (LATS2, CTNNB1, GSK3B) and metabolism (VHL). Comparative spatial/temporal analyses confirmed that these tumours emerged from clones of lower aggressivity but revealed that they were genetically heterogeneous accumulating "neuroendocrine carcinoma-like" genetic alterations through progression such as TP53/RB1 alterations. CONCLUSION: These data confirm the importance of chromatin remodelling genes in pulmonary carcinoids and highlight the potential role of TP53 and RB1 to drive the transformation in more aggressive high-grade tumours.

Epidermal growth factor receptor-mutant non-small cell lung Cancer and Choroidal metastases: long-term outcome and response to epidermal growth factor receptor tyrosine kinase inhibitors.

BACKGROUND: Choroidal metastases are the most common eye metastatic site. The prevalence of choroidal metastases in NSCLC patients has been reported to vary from 0.2 to 7% in historical series. Although previously reported, little is known about choroidal metastasis in Epidermal Growth Factor Receptor (EGFR)-mutant Non-small cell lung cancer (NSCLC). This study sought to describe the prevalence of choroidal metastases among patients with EGFR-mutated NSCLC and their characteristics, and to estimate their impact on prognosis. METHODS: We conducted a single-center retrospective study including all consecutive metastatic EGFR-mutant NSCLC patients, from Sept. 2015 to Oct. 2018. The EGFR-mutant NSCLC patients were identified via the Department of Genetics' files. Patients who exhibited choroidal metastases were compared to patients without choroidal metastases. Kaplan-Meier analysis and log-rank test were conducted to assess median overall survival (OS) from diagnosis for the two groups. The study was approved by the IRB as CEPRO number #2020-010. RESULTS: Prevalence of choroidal metastases in EGFR-mutated NSCLCs was 8.4% (7/83). Five were women, and four current or former smokers. Molecular analysis showed three tumors with exon 19 deletion, three with L858R mutation, and one with complex exon 21 mutation. The choroidal metastases were symptomatic in six/seven patients. Visual disturbances decreased in all but one symptomatic cases upon EGFR TKI, and the choroidal response was maintained over time. Median follow-up was 42.2 mo (95%CI [37.2-47.1]). Median OS in the choroidal metastasis group was 23.4 mo (95%CI [0.1-51.4]) versus 27.9 mo (95%CI [16.9-38.9]) in the non-choroidal metastasis group (p = 0.32). In the choroidal metastasis group, 2-year and 5-year OS were 47.6 and 0%, respectively, versus 55.8 and 26.3% in the non-choroidal metastasis subset. CONCLUSIONS: Choroidal metastases in NSCLC EGFR-mutant patients are rare but should be systematically suspected in case of visual disturbance. TKIs are efficient for treating visual symptoms. Whether choroidal metastases confer a worse prognosis remains unclear owing to the third-generation EGFR TKI osimertinib first-line registration.

MST1/Hippo promoter gene methylation predicts poor survival in patients with malignant pleural mesothelioma in the IFCT-GFPC-0701 MAPS Phase 3 trial.

BACKGROUND: The Mesothelioma Avastin Cisplatin Pemetrexed Study (MAPS/NCT00651456) phase 3 trial demonstrated the superiority of bevacizumab plus pemetrexed-cisplatin triplet over chemotherapy alone in 448 malignant pleural mesothelioma (MPM) patients. Here, we evaluated the prognostic role of Hippo pathway gene promoter methylation. METHODS: Promoter methylations were assayed using methylation-specific polymerase chain reaction in samples from 223 MAPS patients, evaluating their prognostic value for overall survival (OS) and disease-free survival in univariate and multivariate analyses. MST1 inactivation effects on invasion, soft agar growth, apoptosis, proliferation, and YAP/TAZ activation were investigated in human mesothelial cell lines. RESULTS: STK4 (MST1) gene promoter methylation was detected in 19/223 patients tested (8.5%), predicting poorer OS in univariate and multivariate analyses (adjusted HR: 1.78, 95% CI (1.09-2.93), p = 0.022). Internal validation by bootstrap resampling supported this prognostic impact. MST1 inactivation reduced cellular basal apoptotic activity while increasing proliferation, invasion, and soft agar or in suspension growth, resulting in nuclear YAP accumulation, yet TAZ cytoplasmic retention in mesothelial cell lines. YAP silencing decreased invasion of MST1-depleted mesothelial cell lines. CONCLUSIONS: MST1/hippo kinase expression loss is predictive of poor prognosis in MPM patients, leading to nuclear YAP accumulation and electing YAP as a putative target for therapeutic intervention in human MPM.

Safe and effective use of nivolumab for treating lung adenocarcinoma associated with sporadic lymphangioleiomyomatosis: a rare case report.

BACKGROUND: Sporadic lymphangioleiomyomatosis (LAM) is a rare form of diffuse parenchymal lung disease. PD-1 blocking antibodies constitute an essential treatment option for advanced non-small-cell lung cancer (NSCLC). The effect of immune checkpoint inhibitors in lymphangioleiomyomatosis patients with non-small cell lung cancer is unknown: concomitant symptomatic interstitial lung disease or the use of immunosuppressors was a key exclusion criterion in the original studies of immune checkpoint inhibitors, especially regarding the risk of interstitial lung disease exacerbation. CASE PRESENTATION: A 48-year-old female, active smoker (36 pack-years), diagnosed with sporadic LAM since 2004 suffered from metastatic adenocarcinoma of the lung. Third-line therapy with nivolumab was started in 2015, with a major partial response. Due to pulmonary function alterations, sirolimus was also reinitiated in 2017 in conjunction with nivolumab, without any undesirable effects and a major partial response continuing up to May 2018. CONCLUSIONS: This case highlights the safe and effective use of nivolumab for managing metastatic lung adenocarcinoma that occurred in a patient with sporadic LAM. In the current case, immunotherapy proved highly successful in managing the NSCLC tumor that occurred upon LAM follow-up, with both a significantly prolonged partial response and acceptable safety profile.

Bevacizumab for newly diagnosed pleural mesothelioma in the Mesothelioma Avastin Cisplatin Pemetrexed Study (MAPS): a randomised, controlled, open-label, phase 3 trial.

BACKGROUND: Malignant pleural mesothelioma is an aggressive cancer with poor prognosis, linked to occupational asbestos exposure. Vascular endothelial growth factor is a key mitogen for malignant pleural mesothelioma cells, therefore targeting of vascular endothelial growth factor might prove effective. We aimed to assess the effect on survival of bevacizumab when added to the present standard of care, cisplatin plus pemetrexed, as first-line treatment of advanced malignant pleural mesothelioma. METHODS: In this randomised, controlled, open-label, phase 3 trial, we recruited patients aged 18-75 years with unresectable malignant pleural mesothelioma who had not received previous chemotherapy, had an Eastern Cooperative Oncology Group performance status of 0-2, had no substantial cardiovascular comorbidity, were not amenable to curative surgery, had at least one evaluable (pleural effusion) or measurable (pleural tumour solid thickening) lesion with CT, and a life expectancy of >12 weeks from 73 hospitals in France. Exclusion criteria were presence of central nervous system metastases, use of antiaggregant treatments (aspirin ≥325 mg per day, clopidogrel, ticlopidine, or dipyridamole), anti-vitamin K drugs at a curative dose, treatment with low-molecular-weight heparin at a curative dose, and treatment with non-steroidal anti-inflammatory drugs. We randomly allocated patients (1:1; minimisation method used [random factor of 0·8]; patients stratified by histology [epithelioid vs sarcomatoid or mixed histology subtypes], performance status score [0-1 vs 2], study centre, or smoking status [never smokers vs smokers]) to receive intravenously 500 mg/m(2) pemetrexed plus 75 mg/m(2) cisplatin with (PCB) or without (PC) 15 mg/kg bevacizumab in 21 day cycles for up to six cycles, until progression or toxic effects. The primary outcome was overall survival (OS) in the intention-to treat population. Treatment was open label. This IFCT-GFPC-0701 trial is registered with ClinicalTrials.gov, number NCT00651456. FINDINGS: From Feb 13, 2008, to Jan 5, 2014, we randomly assigned 448 patients to treatment (223 [50%] to PCB and 225 [50%] to PC). OS was significantly longer with PCB (median 18·8 months [95% CI 15·9-22·6]) than with PC (16·1 months [14·0-17·9]; hazard ratio 0·77 [0·62-0·95]; p=0·0167). Overall, 158 (71%) of 222 patients given PCB and 139 (62%) of 224 patients given PC had grade 3-4 adverse events. We noted more grade 3 or higher hypertension (51 [23%] of 222 vs 0) and thrombotic events (13 [6%] of 222 vs 2 [1%] of 224) with PCB than with PC. INTERPRETATION: Addition of bevacizumab to pemetrexed plus cisplatin significantly improved OS in malignant pleural mesothelioma at the cost of expected manageable toxic effects, therefore it should be considered as a suitable treatment for the disease. FUNDING: Intergroupe Francophone de Cancérologie Thoracique (IFCT).

Immune-checkpoint inhibitors associated with interstitial lung disease in cancer patients.

Immunotherapy is becoming a standard of care for many cancers. Immune-checkpoint inhibitors (ICI) can generate immune-related adverse events. Interstitial lung disease (ILD) has been identified as a rare but potentially severe event.Between December 2015 and April 2016, we conducted a retrospective study in centres experienced in ICI use. We report the main features of ICI-ILD with a focus on clinical presentation, radiological patterns and therapeutic strategies.We identified 64 (3.5%) out of 1826 cancer patients with ICI-ILD. Patients mainly received programmed cell death-1 inhibitors. ILD usually occurred in males, and former or current smokers, with a median age of 59 years. We observed 65.6% grade 2/3 severity, 9.4% grade 4 severity and 9.4% fatal ILD. The median (range) time from initiation of immunotherapy to ILD was 2.3 (0.2-27.4) months. Onset tended to occur earlier in lung cancer versus melanoma: median 2.1 and 5.2 months, respectively (p=0.02). Ground-glass opacities (81.3%) were the predominant lesions, followed by consolidations (53.1%). Organising pneumonia (23.4%) and hypersensitivity pneumonitis (15.6%) were the most common patterns. Overall survival at 6 months was 58.1% (95% CI 37.7-73.8%).ICI-ILD often occurs early and displays suggestive radiological features. As there is no clearly identified risk factor, oncologists need to diagnose and adequately treat this adverse event.

Bevacizumab in advanced lung cancer: state of the art.

Despite recent advances in metastatic lung cancer treatment with the advent of immune checkpoint inhibitors and molecules targeting addictive genomic abnormalities, prognosis of most of the patients remains unfavorable. Combination approaches with older drugs, such as bevacizumab, should be thus envisioned. Bevacizumab is a monoclonal anti-VEGF antibody, approved by the US FDA and the EMA in first-line and maintenance settings of advanced nonsquamous non-small-cell lung cancer (NSCLC) treatment, in association with platinum-based chemotherapy. In the years to come, bevacizumab might be associated with new molecular therapies or immuno-oncology drugs, in order to optimize response rates and overcome resistances. This review summarizes the pharmacologic properties, clinical efficacy and safety of bevacizumab in advanced lung cancer treatment, with a focus on NSCLC, EGFR-mutant NSCLC and small-cell lung cancer.

A review of bevacizumab in the treatment of malignant pleural mesothelioma.

Malignant pleural mesothelioma (MPM) is an aggressive cancer with poor prognosis. Systemic chemotherapy is the primary treatment modality for the majority of patients. VEGF plays a key mitogen for MPM cells physiopathology. Bevacizumab, a monoclonal anti-VEGF antibody, was a rational approach to be tested in MPM. Based on the results of the Phase III IFCT-0701 mesothelioma avastin cisplatin pemetrexed study, cisplatin-pemetrexed-bevacizumab is now the accepted standard in France. The National Comprehensive Cancer Network guidelines have also included this combination as an option for standard front-line therapy. This review summarized the efficacy and safety data of bevacizumab in the treatment of patients with MPM.

Severe haemoptysis in patients with nonsmall cell lung carcinoma.

Severe haemoptysis due to nonsmall cell lung cancer (NSCLC) is considered a grim condition, and there is still scarce data on its characteristics and outcome, despite new imaging and treatment modalities. This retrospective study sought to describe the clinical characteristics, pathophysiology and outcome of NSCLC-related haemoptysis. We included 125 consecutive patients with severe haemoptysis (>100 mL) at admission, 65 (52%) exhibiting squamous cell carcinoma. Tumour cavitation/necrosis was reported in 26 (21%) patients. 52 patients had received anticancer treatment, but none had received anti-angiogenic agents. Severe haemoptysis was related mainly to the bronchial artery (82%), and major pulmonary artery involvement was rare (6.4%). Interventional radiology was performed in 102 patients. Bleeding cessation was achieved in 108 (87%) out of 125 patients. The overall in-hospital and 1-year survival rates were 69% and 30%, respectively. Performance status (PS) ≥ 2 (OR 3.6, 95% CI 1.3-9.6), advanced stage (OR 8.6, 95% CI 2-37) and mechanical ventilation (OR 13, 95% CI 4.5-36) were independent predictors of in-hospital mortality. Performance status ≥ 2 (hazard ratio (HR) 2.4, 95% CI 1.5-3.7), advanced stage (HR 4, 95% CI 2.1-7.7), cancer progression (HR 2, 95% CI 1.01-2.7) and cavitation/necrosis (HR 1.7, 95% CI 1.21-3.2) were independently associated with 1-year mortality. Management of severe haemoptysis related to NSCLC should be improved, given our observed survival rates after hospital discharge.

Nebulised liposomal amphotericin B for Aspergillus lung diseases: case series and literature review.

Over the past 10 years the incidence of Aspergillus spp. has significantly increased, and it is now the most widespread air transmission fungal pathogen in developed countries. Whatever the clinical expression of the pulmonary disease and despite recent progress in antifungal drug therapy, morbidity and mortality related to aspergillosis lung disease still constitute a serious threat for immunosuppressed or mildly immunocompromised patients. Moreover, the treatments currently used have many limitations due to adverse effects and drug interactions. Finally, subjects exposed to azoles present an increased risk of Aspergillus-resistant strain emergence. We have reported five cases with aspergillosis lung diseases that were either difficult to control or in which patients had a contra-indication to triazole therapy, but which showed durable improvement following the administration of nebulised liposomal amphotericin B. Our alternative strategy could be of interest for patients with aspergillosis lung disease who otherwise cannot be conventionally treated by triazoles.

Dynamic contrast-enhanced MRI parameters as biomarkers for the effect of vatalanib in patients with non-small-cell lung cancer.

AIMS: To assess the utility of dynamic contrast-enhanced MRI parameters in the demonstration of early antiangiogenic effects and as prognostic biomarkers in second-line treatment of advanced-stage non-small-cell lung cancer with vatalanib. PATIENTS & METHODS: The transfer constant (K(trans)) and the initial area under the contrast concentration-time curve at 60 s (AUC60) were assessed in 46 patients. Changes were compared with response evaluation from computed tomography imaging and Response Evaluation Criteria In Solid Tumors guidelines. RESULTS: Statistically significant mean reductions in K(trans) (38.4%; p < 0.0001) and AUC60 (24.9%; p < 0.0001) were found at day 2. After 12 weeks, 16 patients (35%) demonstrated stable disease and 30 (65%) demonstrated progressive disease. No statistically significant differences in day 2 K(trans) and AUC60 reductions between stable disease and progressive disease patients were found. CONCLUSION: Dynamic contrast-enhanced MRI can demonstrate a statistically significant reduction in vascular parameters of non-small-cell lung cancer, but does not predict patient outcome.

VEGFR2 and CD34 expression associated with longer survival in patients with pleural mesothelioma in the IFCT-GFPC-0701 MAPS phase 3 trial.

OBJECTIVES: VEGF/VEGFR autocrine loop is a hallmark of pleural mesothelioma (PM). We thus assayed the prognostic and predictive values of VEGFR-2 [vascular endothelial growth factor receptor 2 or Flk-1] and CD34, a marker of endothelial cells, in samples from patients accrued in the Mesothelioma Avastin Cisplatin Pemetrexed Study ('MAPS', NCT00651456). MATERIALS AND METHODS: VEGFR2 and CD34 expression were assayed using immunohistochemistry in 333 MAPS patients (74.3%), and their prognostic value was evaluated in terms of overall survival (OS) and progression-free survival (PFS) in univariate and multivariate analyses, before validation by bootstrap methodology. RESULTS: Positive VEGFR2 or CD34 staining was observed in 234/333 (70.2%) and 322/323 (99.6%) of tested specimens, respectively. VEGFR2 and CD34 staining correlated weakly, yet significantly, with each other (r = 0.36, p < 0.001). High VEGFR2 expression or high CD34 levels were associated with longer OS in PM patients in multivariate analysis (VEGFR2: adjusted [adj.] hazard ratio [HR]: 0.91, 95% confidence interval [CI] [0.88; 0.95], p < 0.001; CD34: adj. HR: 0.86, 95 %CI [0.76; 0.96], p = 0.010), with only high VEGFR2 expression resulting in significantly longer PFS (VEGFR2: adj. HR: 0.96, 95 %CI [0.92; 0.996], p = 0.032). Stability of these results was confirmed using bootstrap procedure. Nevertheless, VEGFR2 expression failed to specifically predict longer survival in bevacizumab-chemotherapy combination trial arm, regardless of whether the VEGFR2 score was combined or not with serum VEGF concentrations. CONCLUSION: VEGFR2 overexpression independently correlated with longer OS or PFS in PM patients, such biomarker deserving prospective evaluation as stratification variable in future clinical trials.

Brief Report: Severe Sotorasib-Related Hepatotoxicity and Non-Liver Adverse Events Associated With Sequential Anti-Programmed Cell Death (Ligand)1 and Sotorasib Therapy in KRASG12C-Mutant Lung Cancer.

INTRODUCTION: Sequential anti-programmed cell death protein 1 (PD-1) or anti-programmed death-ligand 1 (PD-L1) followed by small targeted therapy use is associated with increased prevalence of adverse events (AEs) in NSCLC. KRASG12C inhibitor sotorasib may trigger severe immune-mediated hepatotoxicity when used in sequence or in combination with anti-PD-(L)1. This study was designed to address whether sequential anti-PD-(L)1 and sotorasib therapy increases the risk of hepatotoxicity and other AEs. METHODS: This is a multicenter, retrospective study of consecutive advanced KRASG12C-mutant NSCLC treated with sotorasib outside clinical trials in 16 French medical centers. Patient records were reviewed to identify sotorasib-related AEs (National Cancer Institute Common Classification Criteria for Adverse Events-Version 5.0). Grade 3 and higher AE was considered as severe. Sequence group was defined as patients who received an anti-PD-(L)1 as last line of treatment before sotorasib initiation and control group as patients who did not receive an anti-PD-(L)1 as last line of treatment before sotorasib initiation. RESULTS: We identified 102 patients who received sotorasib, including 48 (47%) in the sequence group and 54 (53%) in the control group. Patients in the control group received an anti-PD-(L)1 followed by at least one treatment regimen before sotorasib in 87% of the cases or did not receive an anti-PD-(L)1 at any time before sotorasib in 13% of the cases. Severe sotorasib-related AEs were significantly more frequent in the sequence group compared with those in the control group (50% versus 13%, p < 0.001). Severe sotorasib-related AEs occurred in 24 patients (24 of 48, 50%) in the sequence group, and among them 16 (67%) experienced a severe sotorasib-related hepatotoxicity. Severe sotorasib-related hepatotoxicity was threefold more frequent in the sequence group compared with that in the control group (33% versus 11%, p = 0.006). No fatal sotorasib-related hepatotoxicity was reported. Non-liver severe sotorasib-related AEs were significantly more frequent in the sequence group (27% versus 4%, p < 0.001). Severe sotorasib-related AEs typically occurred in patients who received last anti-PD-(L)1 infusion within 30 days before sotorasib initiation. CONCLUSIONS: Sequential anti-PD-(L)1 and sotorasib therapy are associated with a significantly increased risk of severe sotorasib-related hepatotoxicity and severe non-liver AEs. We suggest avoiding starting sotorasib within 30 days from the last anti-PD-(L)1 infusion.