Background: There is only limited knowledge of the treatment responses and clinical outcomes of immune checkpoint inhibitors (ICIs) in driver gene‐negative non‐small cell lung cancer (NSCLC) patients with brain metastases (BM). This study aims to assess the efficacy of immunotherapy in these patients in a real world setting.Methods: NSCLC‐BM patients without driver gene mutations who received ICIs were retrospectively identified between July 2017 and December 2019. The primary observation endpoint was intracranial objective response rate (iORR), and secondary objectives were objective response rate (ORR), intracranial and systemic progression‐free survival (iPFS, PFS), and overall survival (OS).Results: We reviewed 1578 patients with lung cancer and BM. According to the exclusion criteria, 41 patients were finally enrolled. Among these 41 patients, iORR was 36.6% (95% confidence interval [CI] = 21.2%–52.0%), whereas iPFS was 6.8 (95% CI = 3.32–10.35) months. Additionally, ORR, PFS, and OS were 24.4% (95% CI = 10.7%–38.1%), 6.2 (95% CI = 4.57–7.83) months and 13.7 (95% CI = 11.20–16.26) months, respectively. ICIs combined with concurrent radiotherapy group exhibited preferred iORR (p = 0.030) compared with no radiotherapy group, and ICIs plus chemotherapy showed improved OS (p = 0.024) compared to ICI monotherapy. Moreover, the lines of ICI treatment ≥2 (p = 0.005) and derived neutrophil‐to‐lymphocyte ratio (dNLR) ≥3 (p = 0.010) were independently negative factors for OS.Conclusion: In NSCLC‐BMs patients lacking driver genes, ICIs exhibited an effective drug regime. A combination of ICIs with concurrent radiotherapy showed a better intracranial response, whereas ICIs plus chemotherapy were associated with superior OS.

Background: Patients with non‐small‐cell lung cancer (NSCLC) and uncommon EGFR alterations typically have worse treatment outcomes than patients with classically EGFR‐mutated NSCLC. This study aimed to investigate the efficacy and safety of PD‐1 blockade with sintilimab plus anti‐angiogenic treatment with anlotinib in patients with NSCLC harboring uncommon EGFR mutations.Methods: Patients with metastatic NSCLC harboring uncommon EGFR mutations after two previous treatments, including a platinum‐based chemotherapy regimen and a targeted treatment (or chemotherapy only for patients harboring EGFR ex20ins), received sintilimab combined with anlotinib. The primary endpoint was objective response rate (ORR).Results: At data cutoff (September 27, 2022), median follow‐up was 22.3 months (range, 1.2–37.6). Among 21 enrolled patients, 12 had EGFR ex20ins and nine had other uncommon EGFR mutations such as L861Q, G719A, and G709X. Overall, eight patients (38.1%) achieved an objective response, and 18 (85.7%) achieved disease control. Median (95% CI) progression‐free survival (PFS) was 7.0 (5.4–8.6) months, and median overall survival (OS) was 20.0 (15.6–24.4) months. The 12‐month PFS rate (95% CI) was 22.2% (7.4–42.0), and the 12‐month OS rate was 66.7% (42.5–82.5). Patients harboring EGFR ex20ins had similar ORR and PFS to those with other mutations. Six patients (28.6%) experienced grade 3 treatment‐related adverse events (TRAEs); hand‐foot syndrome was the most common grade 3 TRAE (2 patients; 9.5%). No grade ≥4 TRAEs were observed.Conclusions: The combination of sintilimab and anlotinib demonstrated durable efficacy and was generally well tolerated in patients with NSCLC and uncommon EGFR mutations who had received prior standard‐of‐care treatments. (ClinicalTrials.gov identifier: NCT04790409).

Background: Few large‐scale studies have been published using real‐world data related to overall survival (OS) improvements in advanced epidermal growth factor receptor (EGFR)‐mutant lung cancer patients; therefore, little is known regarding the characteristics of patients who could benefit most from EGFR‐tyrosine kinase inhibitors (TKIs). Our study aimed to assess whether EGFR‐TKI treatment confers survival benefits among advanced non‐small‐cell lung cancer (NSCLC) patients harboring EGFR mutations in the Chinese population.Patients and Methods: A total of 6451 advanced NSCLC patients were diagnosed between January 1, 2013 and June 30, 2019 in Zhejiang Cancer Hospital. Ultimately, 2864 patients with a confirmed EGFR mutation genotype were enrolled in our study. OS was measured from the time of diagnosis of advanced NSCLC until death or last follow‐up.Results: Median follow‐up for OS of advanced EGFR‐mutant NSCLC patients was 28.33 months in our study. Patients who received EGFR‐TKIs demonstrated better survival compared to those without EGFR‐TKI treatment (mOS: 29.77 vs. 22.97 months, p < 0.0001). A total of 451 patients switched to third‐generation EGFR‐TKI treatment and obtained a significantly better survival than those who adopted first‐line third‐generation EGFR‐TKIs or those who did not receive third‐generation EGFR‐TKIs after disease progression with first‐ or second‐generation EGFR‐TKI treatment (mOS: 38.0 vs. 32.5 vs. 28.3 months, p < 0.0001). As for EGFR genotypes, patients with exon 19 deletion showed better OS, followed by those with L858R mutation (32.4 vs. 24.83 months, p = 0.0013). NGS versus PCR testing showed no statistical differences with respect to survival outcomes (mOS: 27.5 vs. 27.47 months, p = 0.6745).Conclusion: Advanced EGFR‐mutant patients treated with EGFR‐TKIs obtained absolute superior survival in the Chinese population.

KRAS G12D is the most prevalent subtype of KRAS mutation across solid tumors, but no drug is available in the clinic. RNK08954 is a potent and selective KRAS G12D inhibitor that inhibits proliferation of KRAS G12D-mutant cells and demonstrates significant tumor regressions in mouse xenograft models while inhibiting KRAS-mediated signaling. The in vivo effects of RNK08954 are explained by its unique pharmacokinetic (PK) profile and significantly prolonged retention time in tumor tissues. RNK08954 shows synergy with immune check blockade (ICB). In a Phase 1a study, the median follow-up was 4.85 months for 36 evaluable patients. In patients with non-small cell lung cancer (NSCLC), the objective response rate (ORR, unconfirmed) is 58.33%, and in patients with pancreatic ductal adenocarcinoma (PDAC) the ORR (unconfirmed) was 33.33% in the 1000-1200mg cohort. This study supports the clinical potential of RNK08954 in patients with KRAS G12D mutation either as a single agent or in combination.

Background: Osimertinib has been adopted as the standard therapy for T790M-mediated acquired resistance to first-line epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in patients with non-small cell lung cancer (NSCLC). The detection of EGFR T790M can be evaluated using different methods. The association between baseline T790M abundance and osimertinib efficacy has not been fully determined. Methods: A total of 144 advanced NSCLC patients positive for T790M, at the time of progression, were retrospectively enrolled in this study. The effect of abundance of T790M mutation on the efficacy of osimertinib was explored. Results: Among the 144 patients receiving T790M testing, 20 (13.9%) had adopted amplification refractory mutation system (ARMS), 63 (43.8%) adopted droplet digital PCR (ddPCR), and 61 (42.4%) used next-generation sequencing (NGS). The objective response rate was 54.2%, the median progression-free survival was 12.0 months, and the overall survival was 23.0 months for the NSCLC patients treated with osimertinib. Three different technologies to assess T790M mutation (including ARMS, ddPCR, and NGS) could accurately predict the efficacy of osimertinib. There was no significant relationship between the abundance of T790M mutation and the efficacy of osimertinib. Conclusions: ARMS, ddPCR, and NGS are reliable methods to evaluate EGFR T790M mutation. Osimertinib was equally effective for NSCLC patients with various abundance of T790M mutation.