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Aim: This study aims to evaluate the prognostic role of the KRAS G12C mutation in patients with advanced non-small cell lung cancer and PD-L1 expression ≥50% who are treated with immune checkpoint inhibitor monotherapy., Methods: We conducted a systematic review of clinical studies fulfilling the following criteria: (1) enrolling patients with advanced/metastatic non-small cell lung cancer with high PD-L1 tumour expression receiving first-line therapy with anti-PD-(L)1 immune checkpoint inhibitors; (2) comparing the outcomes of patients with the KRAS G12C mutation to those without this mutation, and (3) reporting overall survival and progression-free survival (PFS). The electronic databases Medline, EMBASE, Cochrane and Google Scholar, along with reference lists, were systematically searched., Results: We identified four publications that fulfilled the inclusion criteria, comprising a total of 469 patients. Of these, two studies reported hazard ratios (HR) for PFS, resulting in a final pooled patient sample of 163 for the meta-analysis. In patients with non-small cell lung cancer who received anti-PD-(L)1 monotherapy, the presence of a KRAS G12C mutation was associated with improved PFS compared to patients with KRAS wild-type tumours, with a pooled hazard ratio of 0.39 and a 95% Confidence Interval (CI) of 0.25-0.63. Among all patients with KRAS mutations, those harbouring a KRAS G12C mutation had improved PFS compared to patients with any other KRAS mutation (pooled HR 0.33, 95% CI 0.19-0.57)., Conclusions: Patients with non-small cell lung cancer who have the KRAS G12C mutation and high PD-L1 expression demonstrate favourable PFS with first-line PD-(L)1 immune checkpoint inhibitor monotherapy compared to patients with KRASwt or other KRAS mutations and high PD-L1 expression.

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., (©2024 American Association for Cancer Research.)

Purpose: Many studies on cancer patients investigate the impact of treatment on health-related quality of life (QoL). Typically, QoL is measured longitudinally, at baseline and at predefined timepoints thereafter. The question is whether, at a given timepoint, patients who return their questionnaire (available cases, AC) have a different QoL than those who do not return their questionnaire (non-AC)., Methods: We employed augmented inverse probability weighting (AIPW) to estimate the average QoL of non-AC in two studies on advanced-stage cancer patients. The AIPW estimator assumed data to be missing at random (MAR) and used machine learning (ML)-based methods to estimate answering probabilities of individuals at given timepoints as well as their reported QoL, as a function of auxiliary variables. These auxiliary variables were selected by medical oncologists based on domain expertise. We aggregated results both by timepoint and by time until death and compared AIPW estimates to the AC averages. Additionally, we used a pattern mixture model (PMM) to check sensitivity of our AIPW estimates against violation of the MAR assumption., Results: Our study included 1927 patients with advanced pancreatic and 797 patients with advanced breast cancer. The AIPW estimate for average QoL of non-AC was below the average QoL of AC when aggregated by timepoint. The difference vanished when aggregated by time until death. PMM estimates were below AIPW estimates., Conclusions: Our results indicate that non-AC have a lower average QoL than AC. However, estimates for QoL of non-AC are subject to unverifiable assumptions about the missingness mechanism., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: Available treatments for older patients with primary diffuse large B-cell CNS lymphoma (PCNSL) offer progression-free survival of up to 16 months. We aimed to investigate an intensified treatment of high-dose chemotherapy and autologous haematopoietic stem-cell transplantation (HSCT) in older patients with PCNSL., Methods: MARTA was a prospective, single-arm, phase 2 study done at 15 research hospitals in Germany. Patients aged 65 years or older with newly diagnosed, untreated PCNSL were enrolled if they had an Eastern Cooperative Oncology Group performance status of 0-2 and were fit for high-dose chemotherapy and autologous HSCT. Induction treatment consisted of two 21-day cycles of high-dose intravenous methotrexate 3·5 g/m 2 (day 1), intravenous cytarabine 2 g/m 2 twice daily (days 2 and 3), and intravenous rituximab 375 mg/m 2 (days 0 and 4) followed by high-dose chemotherapy with intravenous rituximab 375 mg/m 2 (day -8), intravenous busulfan 3·2 mg/kg (days -7 and -6), and intravenous thiotepa 5 mg/kg (days -5 and -4) plus autologous HSCT. The primary endpoint was progression-free survival at 12 months in all patients who met eligibility criteria and started treatment. The study was registered with the German clinical trial registry, DRKS00011932, and recruitment is complete., Findings: Between Nov 28, 2017, and Sept 16, 2020, 54 patients started induction treatment and 51 were included in the full analysis set. Median age was 71 years (IQR 68-75); 27 (53%) patients were female and 24 (47%) were male. At a median follow-up of 23·0 months (IQR 16·8-37·4), 23 (45%) of 51 patients progressed, relapsed, or died. 12-month progression-free survival was 58·8% (80% CI 48·9-68·2; 95% CI 44·1-70·9). During induction treatment, the most common grade 3-5 toxicities were thrombocytopenia and leukopenia (each in 52 [96%] of 54 patients). During high-dose chemotherapy and autologous HSCT, the most common grade 3-5 toxicity was leukopenia (37 [100%] of 37 patients). Treatment-related deaths were reported in three (6%) of 54 patients, all due to infectious complications., Interpretation: Although the primary efficacy threshold was not met, short induction followed by high-dose chemotherapy and autologous HSCT is active in selected older patients with PCNSL and could serve as a benchmark for comparative trials., Funding: Else Kröner-Fresenius Foundation, Riemser Pharma, and Medical Center-University of Freiburg., Competing Interests: Declaration of interests ES received research funding to her institution from the Else Kröner-Fresenius Foundation, Riemser Pharma, Roche Pharma, and Bundesministerium für Bildung und Forschung Germany; received honoraria for lectures from Riemser Pharma and SERB SAS Pharmaceuticals; is on the advisory board for SERB SAS Pharmaceuticals; and is an unpaid member of the steering committee of the German Lymphoma Alliance. AK received honoraria from Roche, Celgene, Sobi, AbbVie, Takeda, and Bristol Myers Squibb; and support for attending meetings or travel from AbbVie, BeiGene, ENSA Pharma, Sobi, and Takeda. ARö received honoraria from Alexion, Amgen, Apellis, Novartis, Roche, Sanofi, and Sobi, and support for attending meetings or travel from Sobi; and is on a data safety monitoring board or advisory board from Alexion, Amgen, Apellis, Novartis, Roche, Bioverativ, Sanofi, Sobi, and Samsung. BK received consulting fees from Dayton Therapeutics and Incyte and honoraria from Dayton Therapeutics, Incyte, and Roche. LP received travel support from Medac and Gilead. JW is an unpaid member of the steering committee of the German Lymphoma Alliance. FS received research funding from Roche Sequencing Solutions, Gilead, and Takeda, and honoraria from AstraZeneca. GIh is part of the data safety monitoring board for Novartis trials. EB-M and HF received institutional research funding from the Else Kröner-Fresenius Foundation and Riemser Pharma. AO received honoraria for presentation from SERB SAS Pharmaceuticals. JF received honoraria from Medac, Neovii, and Riemser; payment for expert testimony from Sanofi; and support for attending meetings or travel from Medac and Neovii. GIl received research funding from Bundesministerium für Bildung und Forschung Germany; honoraria from Roche, Gilead, and Incyte; support for attending meetings or travel from Roche, Janssen, and Lilly; and is on an advisory board for Miltenyi Biotec. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)