Autoimmunity Against Surfactant Protein B Is Associated with Pneumonitis During Checkpoint Blockade.

Rationale: Immune checkpoint inhibitor (ICI)-related pneumonitis is a serious autoimmune event affecting as many as 20% of patients with non-small-cell lung cancer (NSCLC), yet the factors underpinning its development in some patients and not others are poorly understood. Objectives: To investigate the role of autoantibodies and autoreactive T cells against surfactant-related proteins in the development of pneumonitis. Methods: The study cohort consisted of patients with NSCLC who provided blood samples before and during ICI treatment. Serum was used for proteomics analyses and to detect autoantibodies present during pneumonitis. T-cell stimulation assays and single-cell RNA sequencing were performed to investigate the specificity and functionality of peripheral autoreactive T cells. The findings were confirmed in a validation cohort comprising patients with NSCLC and patients with melanoma. Measurements and Main Results: Across both cohorts, patients in whom pneumonitis developed had higher pretreatment levels of immunoglobulin G autoantibodies targeting surfactant protein (SP)-B. At the onset of pneumonitis, these patients also exhibited higher frequencies of CD4+ IFN-γ-positive SP-B-specific T cells and expanding T-cell clonotypes recognizing this protein, accompanied by a proinflammatory serum proteomic profile. Conclusions: Our data suggest that the cooccurrence of SP-B-specific immunoglobulin G autoantibodies and CD4+ T cells is associated with the development of pneumonitis during ICI therapy. Pretreatment levels of these antibodies may represent a potential biomarker for an increased risk of developing pneumonitis, and on-treatment levels may provide a diagnostic aid.

Larotrectinib Response in NTRK3 Fusion-Driven Diffuse High-Grade Glioma.

High-grade glioma (HGG) and glioblastoma are the most common adult malignant brain tumors. The standard treatment consists of surgical resection followed by radiochemotherapy with temozolomide. The prognosis and the therapeutic options of these malignant brain tumors however are limited. Here, we describe a case of a patient with HGG with a previously unknown NTRK3 fusion that showed an extraordinary response to treatment with larotrectinib. This case supports regular testing for NTRK fusion proteins.

Mechanisms of Immune-Related Complications in Cancer Patients Treated with Immune Checkpoint Inhibitors.

Immune checkpoint inhibitors (ICIs) have changed the prognosis of many cancer patients. Blocking antibodies targeting inhibitory cytotoxic T-lymphocyte-associated antigen 4 or programmed cell death protein-1 receptors or the programmed cell death ligand-1 have led to long-lasting remissions in patients with even advanced cancers. Main side effects induced by ICIs are inflammatory complications with sometimes severe sequelae for patients. Recent studies have improved our understanding how such immune-related adverse events (irAEs) develop. Here, we summarize the current knowledge of pathomechanisms involved in the de-velopment of irAEs with a particular focus on potential pathways that could be targeted to prevent severe immune-related complications in patients treated with cancer immunotherapy.

Outcomes with immune checkpoint inhibitors for relapsed small-cell lung cancer in a Swiss cohort.

OBJECTIVES: Early clinical trials showed promising outcomes with immune-checkpoint inhibitors (ICI) in a subset of patients with relapsed small-cell lung carcinoma (SCLC). The aim of this retrospective analysis was to assess the efficacy and safety of ICI for relapsed SCLC in a real-world patient population. METHODS: Nine cancer centres in Switzerland contributed data to this cohort. Responses were assessed by the local investigators using standard RECIST v1.1 criteria. Progression-free survival (PFS) and overall survival (OS) were analysed by the Kaplan-Meier method. Associations between potential predictive markers and survival endpoints were probed by Cox proportional hazards. RESULTS: Forty-five patients were included in the analysis. Median age was 63 years, 73% were males and 18% had an ECOG performance status (PS) ≥ 2. ICIs were given as second-line treatment in 60%. Twenty-four patients (53%) received ipilimumab with nivolumab. Twenty-eight patients (62%) had undergone irradiation (RT) prior to or during ICI. Overall response rate (ORR) was 29% and median PFS and OS were 2.3 and 6.5 months, respectively. Median duration of response was 9 months (95% CI 2.8-NA). Five patients maintained their response for > 6 months, all of them receiving combination treatment. There were no new safety signals. CONCLUSION: This is the first report of "real-world" data on ICI in relapsed SCLC also including patients with poor PS. Promising durable responses were observed. No biological prognostic marker could be identified.

[Paraneoplastic subacute cutaneous lupus erythematosus]. / Paraneoplastischer subakut kutaner Lupus erythematodes.

The genesis of subacute cutaneous lupus erythematosus (SCLE) is multifactorial and includes idiopathic, drug-related and paraneoplastic etiologies. This article reports the case of a 70-year-old female patient with paraneoplastic SCLE in whom a lung adenocarcinoma was detected during the extended examination. A paraneoplastic SCLE should be considered when a patient with SCLE presents with lesions in regions of the skin not exposed to sunlight and beginning B symptoms.

MTAP as an emerging biomarker in thoracic malignancies.

S-methyl-5'-thioadenosine phosphorylase (MTAP) deficiency is an emerging biomarker in non-small cell lung cancer (NSCLC) and beyond. The MTAP gene is located in the chromosomal region 9p21.3, which shows one of the most common homozygous deletions across all human cancers (9p21 loss). Loss of 9p21 is found in the majority of pleural mesotheliomas, where it serves as an established diagnostic marker. Until recently, fluorescence in situ hybridization (FISH) was the gold standard for the detection of 9p21 losses, but loss of MTAP expression by immunohistochemistry (IHC) gains increasing importance as an easy to apply and cost-effective diagnostic surrogate marker. Besides, MTAP loss, which has been reported in 13% of NSCLC, is becoming an emerging predictive biomarker in two different scenarios in NSCLC and other cancer types: 1) MTAP loss seems to negatively predict the response to immune checkpoint inhibitor (ICI) treatment via silencing of the tumor microenvironment, and 2) MTAP loss serves as a predictive biomarker for novel targeted treatment strategies. MTAP deficiency leads to an impaired function of the protein arginine methyltransferase 5 (PRMT5) due to its partial inhibition by MTAP's accumulating substrate methylthioadenosine (MTA). This process leaves MTAP deficient tumor cells heavily dependent on the remaining function of PRMT5, making it a perfect target for synthetic lethality. Indeed, MTA-cooperative PRMT5-inhibitors are now tested in several clinical trials with promising early results in solid malignancies. With its emergence as a predictive biomarker, the implementation of MTAP IHC into diagnostic routine for NSCLC and other tumors is likely to take place soon. In this review article, we summarize the current literature on the role of MTAP in thoracic tumors and evaluate different testing methods, including IHC, FISH and next generation sequencing.

Corticosteroid-resistant immune-related adverse events: a systematic review.

Immune checkpoint inhibitor (ICI) treatment has become an important therapeutic option for various cancer types. Although the treatment is effective, ICI can overstimulate the patient's immune system, leading to potentially severe immune-related adverse events (irAEs), including hepatitis, colitis, pneumonitis and myocarditis. The initial mainstay of treatments includes the administration of corticosteroids. There is little evidence how to treat steroid-resistant (sr) irAEs. It is mainly based on small case series or single case reports. This systematic review summarizes available evidence about sr-irAEs. We conducted a systematic literature search in PubMed. Additionally, we included European Society for Medical Oncology, Society for Immunotherapy of Cancer, National Comprehensive Cancer Network and American Society of Clinical Oncology Guidelines for irAEs in our assessment. The study population of all selected publications had to include patients with cancer who developed hepatitis, colitis, pneumonitis or myocarditis during or after an immunotherapy treatment and for whom corticosteroid therapy was not sufficient. Our literature search was not restricted to any specific cancer diagnosis. Case reports were also included. There is limited data regarding life-threatening sr-irAEs of colon/liver/lung/heart and the majority of publications are single case reports. Most publications investigated sr colitis (n=26), followed by hepatitis (n=21), pneumonitis (n=17) and myocarditis (n=15). There is most data for mycophenolate mofetil (MMF) to treat sr hepatitis and for infliximab, followed by vedolizumab, to treat sr colitis. Regarding sr pneumonitis there is most data for MMF and intravenous immunoglobulins (IVIG) while data regarding infliximab are conflicting. In sr myocarditis, most evidence is available for the use of abatacept or anti-thymocyte globulin (ATG) (both with or without MMF) or ruxolitinib with abatacept. This review highlights the need for prompt recognition and treatment of sr hepatitis, colitis, pneumonitis and myocarditis. Guideline recommendations for sr situations are not defined precisely. Based on our search, we recommend-as first line treatment-(1) MMF for sr hepatitis, (2) infliximab for sr colitis, followed by vedolizumab, (3) MMF and IVIG for sr pneumonitis and (4) abatacept or ATG (both with or without MMF) or ruxolitinib with abatacept for sr myocarditis. These additional immunosuppressive agents should be initiated promptly if there is no sufficient response to corticosteroids within 3 days.

Melanoma Clonal Heterogeneity Leads to Secondary Resistance after Adoptive Cell Therapy with Tumor-Infiltrating Lymphocytes.

Adoptive cell therapy (ACT) with tumor-infiltrating lymphocytes (TIL) is effective in patients with melanoma, although long-term responses seem restricted in patients who have complete remissions. Many patients develop secondary resistance to TIL-ACT but the involved mechanisms are unclear. In this study, we describe a case of secondary resistance to TIL-ACT possibly due to intratumoral heterogeneity and selection of a resistant tumor cell clone by the transferred T cells. To the best our knowledge, this is the first case of clonal selection of a pre-existing nondominant tumor cell clone; this report demonstrates the mechanism involved in secondary resistance to TIL-ACT that can potentially change current clinical practice because it advocates for T-cell collection from multiple tumor sites and analysis of tumor heterogeneity before treatment with TIL-ACT.

Small cell transformation in EGFR-mutated non-small cell lung cancer: DLL3 expression and efficacy of immune checkpoint inhibitors or tyrosine kinase inhibitors combined with chemotherapy.

INTRODUCTION: Small cell transformation (SCT) is a typical mechanism of adaptive resistance to third generation epidermal growth factor receptor inhibitors (EGFRi) which have become the standard of care for EGFR-driven non-small cell lung cancer (EGFR+ NSCLC). Little is known about the optimal management of SCT patients. This study aimed to compare outcomes under platinum/etoposide chemotherapy alone (chemo) or in combination with EGFR inhibitors (EGFRi+chemo) or immune checkpoint inhibitors (ICI+chemo). In addition, DLL3 expression was explored as potential novel therapeutic target. METHODS: We conducted a retrospective study on patients with EGFR+ NSCLC and SCT treated at 19 centers in Europe and the United States. A total of 47 patients were included of whom 17 received chemo, 20 ICI+chemo, and 10 EGFRi+chemo. We analyzed DLL3 expression by immunohistochemistry. RESULTS: In the entire cohort, median overall survival (OS) from start of first SCT therapy was 11 months (95 % confidence interval [95 %CI] 9.1-12.9) and median progression-free survival (PFS) was 5 months (95 %CI 4.2-5.8). Median PFS was similar in all three groups (chemo and ICI+chemo 4 months, EGFRi+chemo 6 months), and 12-months PFS was 12 % (95 %CI 2 %-31 %), 13 % (95 %CI 0 %-43 %), and 0 % for ICI+chemo, EGFRi+chemo, and chemo, respectively. Median OS in the ICI+chemo group was 13 months (95 %CI 5.5-20.5) compared to 10 months (95 %CI 7.6-12.4) with chemo and EGFRi+chemo (95 %CI 8.1-11.9), respectively. Before and after SCT, 0 % and 93 % of tumors were DLL3-positive. CONCLUSIONS: Our results suggest that ICI+chemo and DLL3-targeting agents are worth further exploration in EGFR+ NSCLC undergoing SCT. PRESENTED ELSEWHERE: Part of this work has been presented at ESMO annual meeting in Madrid, Spain in October 2023 (Poster 1336 P).

Real-World Data of Combined Immunochemotherapy in Patients With Nonsquamous Advanced NSCLC. A Single-Center Retrospective Study.

Introduction: On the basis of the landmark trial KEYNOTE-189 (KN-189), pembrolizumab plus chemotherapy has become the standard-of-care first-line treatment for patients with advanced nonsquamous NSCLC without oncogenic driver alterations.KN-189 included a selected patient population and lacks external validity. In clinical practice, many patients do not meet the inclusion criteria of KN-189, although they are treated accordingly. It is unknown whether these patients benefit equally as the trial population. Methods: We retrospectively analyzed all patients with advanced nonsquamous NSCLC without targetable oncogenic alterations who received the KN-189 treatment regimen between April 2018 and May 2021 at the University Hospital Basel, Switzerland. Patients were grouped into those who retrospectively met the inclusion criteria of KN-189 (group A) and those who did not (group B). Outcome parameters included progression-free survival (PFS), overall survival (OS), and objective response rate. Multivariate subgroup analyses were performed. Results: We identified 75 patients, including 29 patients in group A and 46 patients in group B. Median PFS was 9.2 and 4.6 months in group A and B, respectively (p = 0.12). Median OS was 16.5 and 6.5 months in group A and B, respectively (p = 0.11). Objective response rate was 59% in group A and 33% in group B (p = 0.03). Eastern Cooperative Oncology Group performance status greater than or equal to 2 and active infections were significantly associated with shorter PFS and OS. Conclusions: We report real-world data for patients treated according to the KN-189 regimen with inferior outcomes in patients who did not meet the KN-189 inclusion criteria. Better treatment options for this vulnerable patient population are needed.

Changes of peripheral T cell subsets in melanoma patients with immune-related adverse events.

Introduction: Immunotherapies have improved the prognosis of many cancer patients including patients with advanced melanoma. Immune checkpoint receptors including CTLA-4 and PD-1 have been established as main therapeutic targets for immunotherapy of melanoma. Although monotherapy is effective in melanoma patients, a dual therapy approach has been shown to be most effective. Dual checkpoint blockade, however, increases substantially the risk for immune-related adverse events (irAEs). Methods: In this study, we characterized peripheral immune cell subsets in patients with anti-PD-1 monotherapy and with dual immune receptors blockade targeting PD-1 and CTLA-4. Results: We found differences in peripheral T cells between patients who developed severe immune-related side effects and patients with mild irAEs. We identified several mainly changes in CD8+ T cell subsets in patients with severe irAE under dual PD-1 and CTLA-4 blockade. Discussion: This work suggests that peripheral immune cell dynamics could be associated with severe immune-related side effects in patients receiving immune checkpoint inhibitors. These changes could be used as future biomarkers in early diagnosis of irAEs.

Phase 1 first-in-human dose-escalation study of ANV419 in patients with relapsed/refractory advanced solid tumors.

BACKGROUND: ANV419 is a stable antibody-cytokine fusion protein consisting of interleukin-2 (IL-2) fused to an anti-IL-2 monoclonal antibody that sterically hinders binding of IL-2 to the α subunit of its receptor but has selective affinity for the receptor ßγ subunits. Thus, ANV419 preferentially stimulates CD8+ effector T cells and natural killer cells which are associated with tumor killing, while minimizing the activation of immunosuppressive regulatory T cells. METHODS: ANV419-001 is an open-label, multicenter, phase 1 study to evaluate the safety, tolerability, maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of ANV419. Secondary objectives were to characterize the pharmacokinetics, pharmacodynamics and tumor response. Adult patients with advanced solid tumors and disease progression after ≥1 previous line of systemic therapy were enrolled. ANV419 was administered by intravenous infusion once every 2 weeks, with a planned treatment duration of 12 months. The dose escalation part of the study explored doses 3, 6 and 12 µg/kg as single patient cohorts followed by 24-364 µg/kg in a 3+3 design. Interim results are reported here (data cut-off: March 22, 2023). RESULTS: Forty patients were enrolled and received at least one dose of ANV419. The MTD and RP2D were determined to be 243 µg/kg. The most common ANV419-related treatment-emergent adverse events were Grade 1 and 2 fever (31 (77.5%)), chills (23 (57.5%), vomiting (14 (35.0%)), cytokine release syndrome and nausea (12 (30.0%) each). Transient and self-limiting lymphopenia due to lymphocyte redistribution was observed in all patients. In the RP2D cohort, Grade ≥3 thrombocytopenia and fever were reported by one patient (12.5%) each. All events were manageable with standard supportive care. At doses of 243 µg/kg (RP2D/MTD), the estimated T1/2 was approximately 12 hours. At ANV419 doses ≥108 µg/kg, 64% of patients had a best response of at least SD (15 SD and 1 confirmed PR). CONCLUSIONS: ANV419 at doses up to 243 µg/kg (the RP2D) was well tolerated and showed signs of antitumor activity in a heavily pretreated patient population with advanced solid tumors. TRIAL REGISTRATION NUMBER: NCT04855929.

Role of 18F-FDG PET/CT in the postoperative follow-up in patients with stage I-III NSCLC: A retrospective single-institution study.

BACKGROUND: The optimal surveillance strategy in patients with resected non-small cell lung cancer (NSCLC) is unknown. Early detection of recurrences by follow-up imaging might improve survival and whole-body 18F-FDG-PET/CT might be the optimal imaging modality given its high accuracy in preoperative staging. MATERIAL AND METHODS: Data from a single-center cohort of 205 patients with resected stage I-III NSCLC and FDG-PET/CT surveillance was retrospectively collected. Patients had preoperative FDG-positive tumors and FDG-PET/CT at 6, 12, 24 months, chest CT at 18 months. Thereafter, annual chest CT was performed for stage I-II, annual FDG-PET/CT for stage III. RESULTS: With a median follow-up of 26.3 months (range, 4.1-60.6), the rate for recurrence and secondary primary lung cancer (SPLC) was 22 % and 8 %, respectively. Associated symptoms were present in 48 % (recurrence) and 18 % (SPLC) of patients. Overall, 83 % of recurrences, and 65 % of SPLC were detected on FDG-PET/CT. 82 % of recurrences were detected in one of the first two follow-up PET/CT scans. Second curatively intended treatment (SCIT) was possible in 37 % of patients with recurrence and 100 % with SPLC. The 2-year recurrence-free survival rate after SCIT for recurrence was 53 % [95 %CI; 31-91 %]. Non-malignant FDG-positive findings occurred in 25 % of patients (71 % possible infections). CONCLUSION: In our cohort of patients, more than 80% of all recurrences were identified in one of the three FDG-PET/CTs performed as part of our imaging protocol during the first two years after resection. Nearly all patients with non-distant recurrence qualified for a SCIT. Further studies are needed to identify patients who might benefit from an even more intensive surveillance strategy.

Siglec Receptors Modulate Dendritic Cell Activation and Antigen Presentation to T Cells in Cancer.

Interactions between sialylated glycans and sialic acid-binding immunoglobulin-like lectin (Siglec) receptors have been recently described as potential new immune checkpoint that can be targeted to improve anticancer immunity. Myeloid cells have been reported to express a wide range of different Siglecs; however, their expression and functions on cancer-associated dendritic cells (DCs) were not fully characterized. We found that classical conventional DCs (cDCs) from cancer patient samples have a high expression of several inhibitory Siglecs including Siglec-7, Siglec-9, and Siglec-10. In subcutaneous murine tumor models, we also found an upregulation of the inhibitory Siglec-E receptor on cancer-associated cDCs. DC lines and bone marrow-derived DCs (BMDCs) with expression of these inhibitory Siglecs showed impaired maturation states on transcriptome and protein level. Furthermore, ablation of these inhibitory Siglecs from DCs enhanced their capability to prime antigen-specific T cells and induce proliferation. Our work provides a deeper understanding of the influence of inhibitory Siglecs on DCs and reveals a potential new target to improve cancer immunotherapy.

Targeted Therapy in Advanced and Metastatic Non-Small Cell Lung Cancer. An Update on Treatment of the Most Important Actionable Oncogenic Driver Alterations.

Due to groundbreaking developments and continuous progress, the treatment of advanced and metastatic non-small cell lung cancer (NSCLC) has become an exciting, but increasingly challenging task. This applies, in particular, to the subgroup of NSCLC with oncogenic driver alterations. While the treatment of epidermal growth factor receptor (EGFR)-mutated and anaplastic lymphoma kinase (ALK)-rearranged NSCLC with various tyrosine kinase inhibitors (TKIs) is well-established, new targets have been identified in the last few years and new TKIs introduced in clinical practice. Even for KRAS mutations, considered for a long time as an "un-targetable" alteration, promising new drugs are emerging. The detection and in-depth molecular analysis of resistance mechanisms has further fueled the development of new therapeutic strategies. The objective of this review is to give a comprehensive overview on the current landscape of targetable oncogenic alterations in NSCLC.

Binimetinib, pemetrexed and cisplatin, followed by maintenance of binimetinib and pemetrexed in patients with advanced non-small cell lung cancer (NSCLC) and KRAS mutations. The phase 1B SAKK 19/16 trial.

BACKGROUND: KRAS mutations are found in 20-25 % of non-squamous non-small cell lung cancer (NSCLC) and therapies targeting the RAS/MEK/ERK pathway are in development. We performed a multicenter open-label phase 1B trial to determine the recommended phase 2 dose and early antitumor activity of the MEK-inhibitor binimetinib combined with cisplatin and pemetrexed. METHODS: Eligible patients (pts) had stage III-IV NSCLC unsuitable for curative treatment, KRAS exon 2 or 3 (codon 12, 13 or 61) mutations, no prior systemic therapy. Pts were enrolled into part 1: 3 + 3 design with dose escalation in 2 dose levels (DL) of binimetinib and part 2: expansion cohort at the maximum tolerated dose (MTD). Pts received 4 cycles of cisplatin 75 mg/m2, pemetrexed 500 mg/m2and binimetinib 30 (DL1)/45 mg (DL2) orally twice a day (bid) d1-14 q3w followed by pemetrexed and binimetinib until progressive disease (PD) or unacceptable toxicity. RESULTS: From May 2017 to Dec 2019, 18 pts (13 dose escalation, 5 expansion cohort) were enrolled. Median age was 60 (48-73, range). KRAS mutations were 87.5 % at codon 12. No DLT occurred in the dose escalation cohort. Median number of cycles was 2 (1-17, range). Treatment discontinuation was mainly due to PD (33 %) or pts/physicians' decision (27 %). Together with the expansion cohort, 16 pts were evaluable for safety. Most frequent treatment-related grade 3 AEs were lung infection (25 %), fatigue (19 %), anemia (19 %). Overall response rate among 9 evaluable pts receiving binimetinib at MTD (45 mg bid) was 33 % (7-70 %, 95 % CI). Median progression-free survival was 5.7 months (1.1-14.0, 95 % CI) and overall survival 6.5 months (1.8-NR, 95 % CI). CONCLUSIONS: Pts treated with combination of cisplatin, pemetrexed and binimetinib presented no unexpected toxicity. No early signal of increased antitumor activity of binimetinib added to chemotherapy was observed in our pts population.

Successful Treatment of a Resistant Subclone in ALK-Rearranged NSCLC.

Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) are established effective therapies in patients with ALK-rearranged advanced non-small-cell lung cancer (NSCLC). Upon progressive disease, patients normally receive a subsequent ALK TKI. However, when disease progression occurs in a limited number of sites, an oligoprogressive approach is a treatment option. In our case, FDG-PET/CT scan detected a progressive site in a patient with ceritinib therapy. Biopsy of the lesion was not possible because of its location. Progression was therefore confirmed by liquid biopsy with identification of the resistant subclone ALK G1202R. Definitive radiotherapy of the progressive site led to the disappearance of the ALK-resistant mutation. Meanwhile, ceritinib therapy was continued. The absence of disease both on repeated imaging and liquid biopsy indicates that eradication of a resistant subclone with an oligoprogressive treatment approach might be possible.