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Myeloid cells are known to suppress antitumour immunity 1 . However, the molecular drivers of immunosuppressive myeloid cell states are not well defined. Here we used single-cell RNA sequencing of human and mouse non-small cell lung cancer (NSCLC) lesions, and found that in both species the type 2 cytokine interleukin-4 (IL-4) was predicted to be the primary driver of the tumour-infiltrating monocyte-derived macrophage phenotype. Using a panel of conditional knockout mice, we found that only deletion of the IL-4 receptor IL-4Rα in early myeloid progenitors in bone marrow reduced tumour burden, whereas deletion of IL-4Rα in downstream mature myeloid cells had no effect. Mechanistically, IL-4 derived from bone marrow basophils and eosinophils acted on granulocyte-monocyte progenitors to transcriptionally programme the development of immunosuppressive tumour-promoting myeloid cells. Consequentially, depletion of basophils profoundly reduced tumour burden and normalized myelopoiesis. We subsequently initiated a clinical trial of the IL-4Rα blocking antibody dupilumab 2 – 5 given in conjunction with PD-1/PD-L1 checkpoint blockade in patients with relapsed or refractory NSCLC who had progressed on PD-1/PD-L1 blockade alone (ClinicalTrials.gov identifier NCT05013450 ). Dupilumab supplementation reduced circulating monocytes, expanded tumour-infiltrating CD8 T cells, and in one out of six patients, drove a near-complete clinical response two months after treatment. Our study defines a central role for IL-4 in controlling immunosuppressive myelopoiesis in cancer, identifies a novel combination therapy for immune checkpoint blockade in humans, and highlights cancer as a systemic malady that requires therapeutic strategies beyond the primary disease site. Single-cell transcriptomics studies on human and mouse non-small cell lung cancer and conditional knockout mouse models show that IL-4 from bone marrow basophils drives the development of granulocyte-monocyte progenitors to myeloid cells that suppress antitumour immunity.

BackgroundEpidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) remain the frontline standard of care for patients with EGFR-mutant non-small cell lung cancer. An updated toxicity profile of EGFR-TKIs proves valuable in guiding clinical decision making.ObjectiveThis study comprehensively assessed the risk of EGFR-TKI-related adverse events (AEs) involving different systems/organs.MethodsWe systematically searched PubMed, Embase, Web of Science, and Cochrane library for phase III randomized controlled trials comparing EGFR-TKI monotherapy with placebo or chemotherapy in patients with non-small cell lung cancer. The odds ratio (OR) of all-grade and high-grade adverse events (AEs) including dermatologic, gastrointestinal, hematologic, hepatic, and respiratory events was pooled for a meta-analysis. Subgroup analyses based on the control arm (placebo or chemotherapy) and individual EGFR-TKIs (erlotinib, gefitinib, afatinib, dacomitinib, and osimertinib) were conducted.ResultsThirty-four randomized controlled trials comprising 15,887 patients were included. The pooled OR showed EGFR-TKIs were associated with a significantly increased risk of all-grade dermatologic AEs including paronychia, pruritus, rash, skin exfoliation, and skin fissures, gastrointestinal AEs including abdominal pain, diarrhea, dyspepsia, mouth ulceration, and stomatitis, hepatic AEs including elevated alanine aminotransferase and aspartate aminotransferase, and respiratory AEs including epistaxis, interstitial lung disease and rhinorrhea. Furthermore, a significantly increased risk of high-grade rash (OR 7.83, 95% confidence interval [CI] 5.11, 12.00), diarrhea (OR 2.10, 95% CI 1.44, 3.05), elevated alanine aminotransferase (OR 3.93, 95% CI 1.71, 9.03), elevated aspartate aminotransferase (OR 3.22, 95% CI 1.05, 9.92) and interstitial lung disease (OR 2.35, 95% CI 1.38, 4.01) was observed in patients receiving EGFR-TKIs. When stratified by individual EGFR-TKIs, gefitinib showed a significant association with all-grade and high-grade hepatotoxicity and interstitial lung disease.ConclusionsEpidermal growth factor receptor tyrosine kinase inhibitors were associated with a significantly increased risk of various types of AEs. Clinicians should be vigilant about the risks of these EGFR-TKI-related AEs, particularly for severe hepatotoxicity and interstitial lung disease, to facilitate early detection and proper management.

Summary Background Metformin has been shown to have anti-neoplastic activity in non-small cell lung cancer (NSCLC) in both preclinical and observational studies, however this has never been prospectively evaluated. This single-arm phase II trial, while not fully accrued, is the first known prospective study evaluating the use of metformin with chemotherapy in advanced NSCLC. Methods Patients received carboplatin AUC 5 + pemetrexed 500 mg/m2 IV every 21 days for 4 cycles. For patients who achieved at least stable disease, maintenance pemetrexed was administered until progression or toxicity. Metformin was initiated at 1000 mg/day for week 1, 1500 mg/day for week 2, then 2000 mg/day thereafter, in divided doses. The primary endpoint was progression-free survival (PFS). Secondary endpoints were overall survival (OS), objective response rate (ORR), disease control rate (DCR), duration of response (DOR), and adverse events (AE). Tumor tissue was tested for LKB1/STK11 mutations, and non-fasting serum insulin levels were longitudinally assessed. Results Of a planned 50 patients, 14 were enrolled. ORR was 23% and median PFS was 3.9 months. Median OS was 11.7 months. No LKB1/STK11 mutations were identified. The most common AE were fatigue (42.9%), anemia, and nausea (28.6% each). The most common grade III AE was nausea (14.3%). No grade IV AE occurred. Mean duration of metformin treatment was 5.6 months. Conclusion Adding metformin to chemotherapy for advanced NSCLC was safe but did not significantly improve clinical outcomes compared to historical phase III controls. These results are limited by the small sample size; larger trials are needed.

In patients with lung cancer (LC), understanding factors that impact the dynamics of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) anti-spike antibody (SAb) titers over time is critical, but challenging, due to evolving treatments, infections, vaccinations, and health status. The objective was to develop a time-dependent regression model elucidating individual contributions of factors influencing SAb levels in LC patients using a prospective, longitudinal, multi-institutional cohort study initiated in January 2021. The study evaluated 296 LC patients—median age 69; 55% female; 50% stage IV. Blood samples were collected every three months to measure SAb levels using FDA-approved ELISA. Asymptomatic and unreported infections were documented through measurement of anti-nucleocapsid Ab levels (Meso Scale Discovery). Associations between clinical characteristics and titers were evaluated using a time-dependent linear regression model with a generalized estimating equation (GEE), considering time-independent variables (age, sex, ethnicity, smoking history, histology, and stage) and time-dependent variables (booster vaccinations, SARS-CoV-2 infections, cancer treatment, steroid use, and influenza vaccination). Significant time-dependent effects increasing titer levels were observed for prior SARS-CoV-2 infection (p < 0.001) and vaccination/boosters (p < 0.001). Steroid use (p = 0.043) and chemotherapy (p = 0.033) reduced titer levels. Influenza vaccination was associated with increased SAb levels (p < 0.001), independent of SARS-CoV-2 vaccine boosters. Prior smoking significantly decreased titers in females (p = 0.001). Age showed no association with titers. This GEE-based linear regression model unveiled the nuanced impact of multiple variables on patient anti-spike Ab levels over time. After controlling for the major influences of vaccine and SARS-CoV-2 infections, chemotherapy and steroid use were found to have negatively affected titers. Smoking in females significantly decreased titers. Surprisingly, influenza vaccinations were also significantly associated, likely indirectly, with improved SARS-CoV-2 titers.

\"With distinct but complementary mechanisms of action, nivolumab [Opdivo, BristolMyers Squibb] plus ipilimumab [Yervoy, Bristol-Myers Squibb] improved long-term survival for patients with melanoma, renal cell carcinoma and NSCLC,\" Suresh S. Ramalingam, MD, FASCO, deputy director of Winship Cancer Institute of Emory University, said during a presentation. Researchers also observed higher 3-year PFS rates with nivolumab plus ipilimumab vs. chemotherapy alone among patients in the higher PD-L1 expression group (18% vs. 4%) and the lower PD-L1 expression group (13% vs. 2%). [...]38% of patients with PD-L1 expression of 1% or greater who responded to nivolumab plus ipilimumab remained in response at 3 years, compared with 4% of those who responded to chemotherapy (median duration of response, 23.2 months vs. 6.7 months). Ramalingam reports consultant/advisory roles with AbbVie, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly/ ImClone, Genentech/Roche, Loxo Oncology, Merck, Nektar, Takeda and Tesaro; research funding from AbbVie, Advaxis, AstraZeneca/ MedImmune, Bristol-Myers Squibb, EMD Serono, Genmab, Merck, Pfizer, Takeda and Vertex; and travel expenses from AstraZeneca.

A lower-dose, less-toxic regimen of oxaliplatin and capecitabine conferred PFS comparable to that of the higher-dose regimen among frail and/or elderly patients with advanced gastroesophageal cancer, according to results from the randomized phase 3 GO2 trial. Evaluation of overall treatment utility- which included factors such as clinical benefit, tolerability, patient satisfaction and quality of life - occurred at week 9 week, at which point therapy continued at the clinicians' discretion. \"Low-dose treatment may be offered to patients who are suitable for chemotherapy but considered too frail or elderly for a full-dose standard regimen, in the confidence that it can produce superior outcomes without compromising cancer control or survival.\" - by Jennifer Byrne ? PERSPECTIVE This is the kind of data that oncologists love to see.

A combination of nivolumab and lowdose ipilimumab significantly improved OS compared with chemotherapy as first-line treatment for patients with advanced non-small cell lung cancer, according to results of the randomized phase 3 CheckMate 227 study. \"The landscape of lung cancer has become very complex,\" Solange Peters, MD, PhD, head of the thoracic malignancies program in the department of oncology at University of Lausanne in Switzerland, said during her presentation. Marina Garassino, MD National Cancer Institute of Milan Disclosure: Garassino reports contract/research support grants from AstraZeneca, Bayer, Bristol-Myers Squibb, Celgene, Clovis Oncology, Eli Lilly, Genentech/Roche, GlaxoSmithKline, Incyte, Merck Serono, Merck Sharp & Dohme, Novartis, Otsuka, Pfizer, Takeda and Tiziana Life Sciences.