The prognostic impact of TP53 mutations in advanced or metastatic nonsquamous non-small-cell lung cancer (nsNSCLC) patients treated with chemotherapy and/or immune checkpoint inhibitors (ICI) remains unclear. We retrospectively collected data from patients with nsNSCLC treated in the first line from January 2018 to May 2021. The patient was separated into 2 groups according to their TP53 mutation status (wt vs. mut). Survival was estimated through the Kaplan-Meier method and compared by log-rank test. Of 220 patients included, 126 were in the mutTP53 group, and 94 were in the wtTP53wt group. Median OS (mOS) was not significantly different between the mutTP53 and wtTP53 groups [17.5 months (95% confidence interval (CI), 11.3-21.5) vs. 9.5 months (95% CI, 7.4-14.2), (P = .051)]. In subgroup analyses, the mutTP53 group treated with ICI had a significantly improved mOS compared to the wtTP53 group [(24.7 months (95% CI, 20.8-not reach) vs. 12.0 months (95% CI, 4.7-not reach), (P = .017)] and mPFS [(9.6 months (95% CI, 5.8-not reach) vs. 3.2 months (95% CI, 1.3-13.8) (P = .048)]. There was no difference in terms of mOS and mPFS between the mutTP53 and the wtTP53 group treated by chemotherapy alone or combined with ICI. TP53 mutation had no survival impact in the overall population, but is associated with better outcomes with ICI alone. These results suggest that patients with TP53 mutations could be treated with ICI alone, and wild-type patients could benefit from the addition of chemotherapy.

Background The MOVIE phase I/II trial (NCT03518606) evaluated the safety and antitumor activity of durvalumab and tremelimumab combined with metronomic oral vinorelbine in patients with advanced tumors. We present the results of the recurrent advanced cervical cancer cohort. Methods Patients received tremelimumab (intravenously, 75 mg, every four weeks (Q4W); four cycles max) plus durvalumab (intravenously, 1,500 mg, Q4W; 26 cycles max) and metronomic oral vinorelbine (40 mg, every three weeks (3QW)) until disease progression. The primary efficacy endpoint was the clinical benefit rate (CBR) based on the Response Evaluation Criteria in Solid Tumors V.1.1, which was analyzed using a Bayesian approach Results A total of 31 patients were enrolled and treated in the cervical cancer cohort. The median number of previous lines of chemotherapy for advanced disease was 2 (0–6), with all (100%) and 12 (38.7%) patients pretreated with cisplatin and bevacizumab, respectively. At the data cut-off, the median follow-up duration was 12.8 (Q1–Q3, 6.1–34.6) months. The CBR was 53.1% (95% CI, 36.0% to 69.8%), using a non-informative prior distribution (beta(1, 1)). The overall response rate was 41.9%, five patients achieved a complete response (16.1%), and eight patients (25.8%) had a partial response irrespective of histological subtype or programmed death-ligand 1 (PD-L1) expression. Of the 31 patients, 28 (90.3%) experienced treatment-related adverse events (TRAEs), 13 (41.9%) reported grade ≥3 immune-related adverse events (AEs), and 13 (41.9%) reported grade ≥3 chemotherapy-related AEs. The definitive discontinuation rate due to TRAEs was 16.1%. Conclusions Dual checkpoint blockade of PD-L1 and cytotoxic T-lymphocyte-associated antigen-4 combined with metronomic oral vinorelbine demonstrated meaningful and durable clinical activity in patients with previously treated advanced cervical cancer. Toxicity was significant but manageable.

Introduction: Assessment of actionable gene mutations and oncogene fusions have made a paradigm shift in treatment strategies of non-small cell lung cancer (NSCLC). HRAS mutations involved around 0.2–0.8% of NSCLC patients, mostly on codon 61. For these patients, few data are available regarding clinical characteristics and response to therapies. Methods: Next-Generation Sequencing (NGS) done routinely at Nantes University Hospital was used to identify HRAS molecular alterations in NSCLC patients. We identified and described four HRAS p.GlnQ61Leu mutated patients. Literature of previously HRAS-mutant NSCLC cases was reviewed, and available data in solid tumour with the most advanced H-Ras specific inhibitor, tipifarnib, were presented. Results: Of 1614 patients diagnosed with advanced NSCLC from January 2018 to December 2020, four (0.25%) had HRAS p.Gln61Leu mutation. Three of them died during the first-line systemic therapy. Furthermore, three additional cases were identified in literature. All cases were current or former smokers, most of them had pleural or pericardial effusion at diagnosis. Conclusions: The clinical course of patients with HRAS-mutant NSCLC remains unclear. Furthers cases should be identified in order to clarify prognosis and response to therapies. Tipifarnib, a farnesyl transferase inhibitor, is a promising candidate to target HRAS-mutant tumours and should be explored in NSCLC patients.

Background: HER2-ultralow is an emerging subgroup of metastatic breast cancer (mBC). However, despite an increasing interest, limited data exist on its prevalence and outcomes, especially among patients receiving standard first-line chemotherapy. Objectives: This study assessed the prevalence and outcomes of HER2-ultralow mBC in a real-world cohort of hormone receptor-positive (HR+)/HER2-negative patients receiving first-line standard-of-care (SOC) chemotherapy. Design: A retrospective, single-center cohort study. Methods: We included HR+/HER2-negative mBC patients treated with SOC between January 2016 and February 2023. Patient data were reviewed from electronic health records. HER2-zero tumors (immunohistochemistry 0) were rescored by expert pathologists using the American Society of Clinical Oncology/College of American Pathologists guidelines to distinguish HER2-ultralow from HER2-null cases. Real-world progression-free survival (rwPFS) and real-world overall survival (rwOS) were estimated using Kaplan–Meier and multivariable Cox regression models. Results: Among 320 patients (median age, 62.4 years), 72.8% had visceral metastases, and 17.5% had bone-only disease. Previous CDK4/6 inhibitor treatment was reported in 43.4%. Rescoring identified 15.6% with HER2-ultralow, 61.9% with HER2-low, and 22.5% with HER2-null tumors. The median follow-up was 39.4 months (95% confidence interval (CI), 37.1–47.6). Median rwPFS was 7.9 months (95% CI, 4.6–19.0), 7.3 months (95% CI, 6.4–9.1), and 6.2 months (95% CI, 4.6–8.9) for HER2-ultralow, HER2-low, and HER2-null groups, respectively. Median rwOS was 19.5 months (95% CI, 10.7–33.4), 21.5 months (95% CI, 19.0–25.8), and 16.6 months (95% CI, 11.9–23.6). In patients previously treated with CDK4/6 inhibitors, median rwPFS was 4.6 months (95% CI, 2.7–21.4), 6.1 months (95% CI, 5.5–7.3), and 5.6 months (95% CI, 3.8–8.7). Conclusion: HER2-ultralow accounts for 15.6% of HR+/HER2-negative mBC cases and demonstrates outcomes comparable to HER2-low with SOC chemotherapy.