Epidermal growth factor receptor exon 20 insertion mutations (EGFRexon20ins) are detected in approximately 2% of patients with non–small cell lung cancer (NSCLC). Due to a lack of effective therapy, the prognosis of these patients is typically poor. Sunvozertinib (DZD9008) was designed as an oral, potent, irreversible, and selective EGFR tyrosine kinase inhibitor, showing activity against EGFRexon20ins and other mutations. In both cell lines and xenograft models, sunvozertinib shows potent antitumor activity. In the two ongoing phase I clinical studies, sunvozertinib was tolerated up to 400 mg once daily. The most common drug-related adverse events included diarrhea and skin rash. Antitumor efficacy was observed at the doses of 100 mg and above in patients with EGFRexon20ins NSCLC across different subtypes, with prior amivantamab treatment as well as with baseline brain metastasis. The median duration of response has not been reached. Significance: We report the discovery and early clinical development of sunvozertinib, a potential treatment option for the unmet medical need of EGFRexon20ins NSCLC. This article is highlighted in the In This Issue feature, p. 1599

Background: Immune checkpoint inhibitors (ICIs) are the standard treatment for advanced lung cancer, but immune‐related adverse events (irAEs) remain poorly understood, especially in a real‐world setting.Methods: A multicenter observational study was conducted. Medical records of lung cancer patients treated with ICIs at 26 hospitals from January 1, 2015, to February 28, 2021, were retrieved. Types of ICIs included antiprogrammed cell death 1 or antiprogrammed cell death ligand 1 (PD‐L1) monotherapy, anticytotoxic T‐lymphocyte antigen‐4 monotherapy, or combination therapy.Results: In total, 1905 patients with advanced lung cancer were evaluated. The median age was 63 (range 28–87) years, and the male/female ratio was 3.1:1 (1442/463). The primary histological subtype was adenocarcinoma (915). A total of 26.9% (512/1905) of the patients developed 671 irAEs, and 5.8% (110/1905) developed 120 grade 3–5 irAEs. Median duration from ICI initiation to irAEs onset was 56 (range 0–1160) days. The most common irAEs were thyroid dysfunction (7.2%, 138/1905), pneumonitis (6.5%, 124/1905), and dermatological toxicities (6.0%, 115/1905). A total of 162 irAEs were treated with steroids and 11 irAEs led to death. Patients with positive PD‐L1 expression (≥1%) and who received first‐line ICI treatment developed more irAEs. Patients who developed irAEs had a better disease control rate (DCR, 71.3% [365/512] vs. 56.0% [780/1145]; p < 0.001).Conclusions: The incidence rate of irAEs was 26.9% in a real‐world setting. IrAEs might be related to a better DCR, but clinicians should be more aware of irAE recognition and management in clinical practice.

Background: Pretreatment and on‐treatment plasma cytokine levels in predicting clinical benefit in patients with advanced non‐small cell lung cancer (NSCLC) treated with anti‐programmed death‐1 (PD‐1)‐based chemotherapy is still a matter of debate.Methods: We measured 12 kind of plasma cytokines in patients with stage III/IV NSCLC before and during treatment with anti‐PD‐1 based chemotherapy. Associations with best overall response, and survival including progression‐free survival (PFS) and overall survival (OS) were assessed using Chi‐square test and Kaplan–Meier plots with log‐rank test, respectively. Logistic regression and Cox regression were used to determine independent risk factors.Results: Of a total of 60 patients, high‐level of pretreatment interleukin‐2 was associated with longer PFS (log rank p = 0.049), while high‐level of pretreatment interleukin‐8 was associated with shorter OS (log rank p = 0.006). Increased on‐treatment interleukin‐1β (IL‐1β) was associated with both better response (odds ratio [OR] 6.233, 95% confidential interval [CI]: 1.451–26.344, p = 0.013) and longer PFS (hazard ratio [HR] 0.305, 95% CI: 0.127–0.730, p = 0.008). On the contrary, increased on‐treatment interleukin‐6 (IL‐6) was associated with a worse response (OR 0.015, 95% CI: 0.001–0.400, p = 0.012), worse PFS (HR 2.639, 95% CI: 1.163–5.991, p = 0.020) and worse OS (HR 2.742, 95% CI: 1.063–7.074, p = 0.037). Increased interferon‐γ (IFN‐γ) was found to be associated with better PFS (HR 0.336, 95% CI: 0.153–0.745, p = 0.007).Conclusions: In patients with advanced NSCLC who received chemoimmunotherapy, on‐treatment increased IL‐1β and IFN‐γ may serve as positive indicator of efficacy, while on‐treatment increased IL‐6 might play a predictive role of worse clinical outcome.

Background: Real‐world evidence of second‐line treatment and beyond with immune checkpoint inhibitors (ICIs) in Chinese patients is lacking. Here, we aimed to assess the efficacy, responses, and immune‐related side effects of anti‐PD‐1 agents in real‐life practice.Methods: We retrospectively analyzed consecutive patients who received nivolumab or pembrolizumab monotherapy at Peking Medical College Hospital. We collected baseline characteristics, evaluated treatment efficacy, and categorized immune‐related adverse effects (irAEs). Predictive factors of treatment response were also determined.Results: The study included 97 patients with a median age of 64 years. The majority of patients were male, with nonsquamous histological type and advanced stage tumor, and had a history of smoking. Most patients received ICIs as second‐line therapy. Expression of PD‐L1 was detected in 34.11% patients. Overall response rate (ORR) and disease control rate (DCR) were 16.49% and 60.82%, respectively. None of the patients achieved complete response (CR). The median PFS and OS were150 days and 537 days, respectively. The incidence of immune‐related toxicities was similar to the one previously reported. Patients with driver gene mutations had shorter PFS than patients without, while patients who encountered irAE had relatively longer PFS.Conclusions: The real‐world clinical outcome of ICIs in second‐ and further‐line NSCLC therapy is promising. Several characteristics may have predictive value for efficacy. Occurrence of irAEs during treatment was acceptable and could be an independent positive predictive for PFS.Key points: Significant findings of the study: Efficacy and safety profile of ICIs as second‐line treatment or above for patients with NSCLC are promising in real world circumstances Incidence and median time to the occurrence of irAEs vary between organs What this study adds: Driver gene mutations are associated with lower progression‐free survival Occurrence of irAEs is associated with higher progression‐free survival

Immunotherapy has dramatically revolutionized the therapeutic landscape for patients with cancer. Although immune checkpoint inhibitors are now accepted as effective anticancer therapies, they introduce a novel class of toxicity, termed immune‐related adverse events, which can lead to the temporary or permanent discontinuation of immunotherapy and life‐threatening tumor progression. Therefore, the effective prevention and treatment of immune‐related adverse events is a clinical imperative to maximize the utility of immunotherapies. Immune‐related adverse events are related to the intestinal microbiota, baseline gut microbiota composition is an important determinant of immune checkpoint inhibitor‐related colitis, and antibiotics exacerbate these undesirable side‐effects. Supplementation with specific probiotics reduces immune checkpoint inhibitor‐related colitis in mice, and fecal microbiota transplantation has now been shown to effectively treat refractory immune checkpoint inhibitor‐related colitis in the clinic. Hence, modifying the microbiota holds great promise for preventing and treating immune‐related adverse events. Microbiomes and their metabolites play important roles in the potential underlying mechanisms through interactions with both innate and adaptive immune cells. Here we review the gut microbiota and immune regulation; the changes occurring in the microbiota during immune checkpoint inhibitor therapy; the relationship between the microbiota and immune‐related adverse events, antibiotics, probiotics/prebiotics, and fecal microbiota transplantation in immune checkpoint inhibitor‐related colitis; and the protective mechanisms mediated by the microbiome and metabolites in immune‐related adverse events.