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For patients with non-small-cell lung cancer (NSCLC) tumors without currently targetable molecular alterations, standard-of-care treatment is immunotherapy with anti-PD-(L)1 checkpoint inhibitors, alone or with platinum-doublet therapy. However, not all patients derive durable benefit and resistance to immune checkpoint blockade is common. Understanding mechanisms of resistance—which can include defects in DNA damage response and repair pathways, alterations or functional mutations in STK11 /LKB1, alterations in antigen-presentation pathways, and immunosuppressive cellular subsets within the tumor microenvironment—and developing effective therapies to overcome them, remains an unmet need. Here the phase 2 umbrella HUDSON study evaluated rational combination regimens for advanced NSCLC following failure of anti-PD-(L)1-containing immunotherapy and platinum-doublet therapy. A total of 268 patients received durvalumab (anti-PD-L1 monoclonal antibody)–ceralasertib (ATR kinase inhibitor), durvalumab–olaparib (PARP inhibitor), durvalumab–danvatirsen (STAT3 antisense oligonucleotide) or durvalumab–oleclumab (anti-CD73 monoclonal antibody). Greatest clinical benefit was observed with durvalumab–ceralasertib; objective response rate (primary outcome) was 13.9% (11/79) versus 2.6% (5/189) with other regimens, pooled, median progression-free survival (secondary outcome) was 5.8 (80% confidence interval 4.6–7.4) versus 2.7 (1.8–2.8) months, and median overall survival (secondary outcome) was 17.4 (14.1–20.3) versus 9.4 (7.5–10.6) months. Benefit with durvalumab–ceralasertib was consistent across known immunotherapy-refractory subgroups. In ATM -altered patients hypothesized to harbor vulnerability to ATR inhibition, objective response rate was 26.1% (6/23) and median progression-free survival/median overall survival were 8.4/22.8 months. Durvalumab–ceralasertib safety/tolerability profile was manageable. Biomarker analyses suggested that anti-PD-L1/ATR inhibition induced immune changes that reinvigorated antitumor immunity. Durvalumab–ceralasertib is under further investigation in immunotherapy-refractory NSCLC. ClinicalTrials.gov identifier: NCT03334617 In the phase 2 HUDSON study, patients with advanced non-small-cell lung cancer received anti-PD-L1 combined with biomarker-guided therapy targeting ATR kinase, PARP, STAT3 or CD73, leading to encouraging clinical benefit in response to combination of the ATR kinase inhibitor ceralasertib with durvalumab.

Although comprehensive biomarker testing is recommended for all patients with advanced/metastatic non-small cell lung cancer (NSCLC) before initiation of first-line treatment, tissue availability can limit testing. Genomic testing in liquid biopsies can be utilized to overcome the inherent limitations of tissue sampling and identify the most appropriate biomarker-informed treatment option for patients. The Blood First Assay Screening Trial is a global, open-label, multicohort trial that evaluates the efficacy and safety of multiple therapies in patients with advanced/metastatic NSCLC and targetable alterations identified by liquid biopsy. We present data from Cohort D ( ROS1 -positive). Patients ≥18 years of age with stage IIIB/IV, ROS1 -positive NSCLC detected by liquid biopsies received entrectinib 600 mg daily. At data cutoff (November 2021), 55 patients were enrolled and 54 had measurable disease. Cohort D met its primary endpoint: the confirmed objective response rate (ORR) by investigator was 81.5%, which was consistent with the ORR from the integrated analysis of entrectinib (investigator-assessed ORR, 73.4%; data cutoff May 2019, ≥12 months of follow-up). The safety profile of entrectinib was consistent with previous reports. These results demonstrate consistency with those from the integrated analysis of entrectinib in patients with ROS1 -positive NSCLC identified by tissue-based testing, and support the clinical value of liquid biopsies to inform clinical decision-making. The integration of liquid biopsies into clinical practice provides patients with a less invasive diagnostic method than tissue-based testing and has faster turnaround times that may expedite the reaching of clinical decisions in the advanced/metastatic NSCLC setting. ClinicalTrials.gov registration: NCT03178552 . Results from this single-arm cohort of the BFAST trial showed that the clinical efficacy of entrectinib in patients with ROS1 -positive NSCLC, selected using liquid biopsies, is consistent with that seen in previous reports where patients were selected using tissue-based testing methods.

Tarlatamab is a delta-like ligand 3 (DLL3)-directed bispecific T-cell engager immunotherapy that has improved survival in patients with previously treated small-cell lung cancer (SCLC). We evaluated the safety and activity of tarlatamab in combination with atezolizumab or durvalumab as first-line maintenance therapy in patients with extensive-stage (ES)-SCLC. In this multicentre, non-randomised, phase 1b study, patients aged 18 years and older, with Eastern Cooperative Oncology Group performance status of 0–1 and without disease progression after four to six cycles of platinum–etoposide chemotherapy plus a programmed cell death ligand 1 (PD-L1) inhibitor (if available), received tarlatamab 10 mg intravenously once every 2 weeks, after an initial tarlatamab 1 mg dose, with atezolizumab intravenously (1680 mg once every 4 weeks) or durvalumab intravenously (1500 mg once every 4 weeks) as maintenance until disease progression. Patients were enrolled from 30 centres in 13 countries. The primary objective was to evaluate safety and to determine the recommended phase 2 dose or maximum tolerated dose of tarlatamab in combination with a PD-L1 inhibitor through assessment of dose-limiting toxicities, treatment-emergent adverse events, treatment-related adverse events, and changes in vital signs, electrocardiograms, and clinical laboratory tests. All patients who received at least one dose of tarlatamab were included in the analyses. Because overall survival data were immature at the primary analysis, in this Article, we report a non-specified interim analysis to provide an updated examination of overall survival and longer-term safety. This study is registered with ClinicalTrials.gov, NCT05361395; the EU Clinical Trials registry, 2021-005462-17; and EudraCT, 2024-511021-58. Between Aug 31, 2022, and Jan 30, 2024, 88 patients received tarlatamab with atezolizumab or durvalumab after standard-of-care first-line chemo-immunotherapy. The median time from start of standard-of-care first-line chemo-immunotherapy to start of tarlatamab maintenance was 3·6 months (IQR 3·2–4·3). The median follow-up from the start of maintenance was 18·4 months (15·2–23·0) and the median exposure to tarlatamab was 35 weeks (8–75). The most common grade 3–4 adverse events were hyponatraemia (nine [10%] of 88 patients), anaemia (seven [8%] of 88 patients), and neutropenia (six [7%] of 88 patients). Serious adverse events occurred in 50 (57%) of 88 patients. The most common serious adverse events were cytokine release syndrome (21 [24%] of 88 patients), pyrexia (six [7%] of 88 patients), immune effector cell-associated neurotoxicity syndrome (four [5%] of 88 patients), and pneumonia (four [5%] of 88 patients). There were no deaths due to treatment-related adverse events. Median overall survival was 25·3 months (95% CI 20·3–not estimable). Tarlatamab plus a PD-L1 inhibitor as maintenance after first-line chemo-immunotherapy showed a manageable safety profile with promising anticancer activity, supporting the ongoing phase 3 trial (NCT06211036). Amgen.

Immune checkpoint inhibitors have made a paradigm shift in the treatment of non-small cell lung cancer (NSCLC). However, clinical response varies widely and robust predictive biomarkers for patient stratification are lacking. Here, we characterize early on-treatment proteomic changes in blood plasma to gain a better understanding of treatment response and resistance. Pre-treatment (T0) and on-treatment (T1) plasma samples were collected from 225 NSCLC patients receiving PD-1/PD-L1 inhibitor-based regimens. Plasma was profiled using aptamer-based technology to quantify approximately 7000 plasma proteins per sample. Proteins displaying significant fold changes (T1:T0) were analyzed further to identify associations with clinical outcomes using clinical benefit and overall survival as endpoints. Bioinformatic analyses of upregulated proteins were performed to determine potential cell origins and enriched biological processes. The levels of 142 proteins were significantly increased in the plasma of NSCLC patients following ICI-based treatments. Soluble PD-1 exhibited the highest increase, with a positive correlation to tumor PD-L1 status, and, in the ICI monotherapy dataset, an association with improved overall survival. Bioinformatic analysis of the ICI monotherapy dataset revealed a set of 30 upregulated proteins that formed a single, highly interconnected network, including CD8A connected to ten other proteins, suggestive of T cell activation during ICI treatment. Notably, the T cell-related network was detected regardless of clinical benefit. Lastly, circulating proteins of alveolar origin were identified as potential biomarkers of limited clinical benefit, possibly due to a link with cellular stress and lung damage. Our study provides insights into the biological processes activated during ICI-based therapy, highlighting the potential of plasma proteomics to identify mechanisms of therapy resistance and biomarkers for outcome.

BackgroundLittle is known regarding the efficacy of immune checkpoint inhibitors (ICI) in patients with advanced large-cell neuroendocrine lung carcinoma (aLCNEC).Methods125 consecutive patients with aLCNEC were identified in the electronic databases of 4 participating cancer centers. The patients were divided into group A (patients who received ICI, n=41) and group B (patients who did not receive ICI, n=84). Overall survival since advanced disease diagnosis (OS DX) and OS since ICI initiation (OS ICI) were captured.ResultsWith a median follow-up of 11.8 months (mo) (IQR 7.5–17.9) and 6.0mo (IQR 3.1–10.9), 66% and 76% of patients died in groups A and B, respectively. Median OS DX was 12.4mo (95% CI 10.7 to 23.4) and 6.0mo (95% CI 4.7 to 9.4) in groups A and B, respectively (log-rank test, p=0.02). For ICI administration, HR for OS DX was 0.59 (95% CI 0.38 to 0.93, p=0.02—unadjusted), and 0.58 (95% CI 0.34 to 0.98, p=0.04—adjusted for age, Eastern Cooperative Oncology Group (ECOG) performance status (PS), presence of liver metastases and chemotherapy administration). In a propensity score matching analysis (n=74; 37 patients in each group matched for age and ECOG PS), median OS DX was 12.5 mo (95% CI 10.6 to 25.2) and 8.4 mo (95% CI 5.4 to 16.9) in matched groups A and B, respectively (log-rank test, p=0.046). OS ICI for patients receiving ICI as monotherapy (n=36) was 11.0 mo (95% CI 6.1 to 19.4).ConclusionsWith the limitations of retrospective design and small sample size, the results of this real-world cohort analysis suggest a positive impact of ICI on OS in aLCNEC.

BackgroundImmune-related adverse events (irAEs) resulting from immune checkpoint inhibitors (ICIs) can substantially affect patient quality of life and treatment trajectory. Currently, there are no reliable pre-treatment biomarkers for predicting the development of irAEs; hence, there is a clinical need for irAE predictive biomarkers.MethodsPlasma samples were obtained at baseline from 426 non-small cell lung cancer (NSCLC) patients treated with ICIs as part of an ongoing multi-center clinical trial (NCT04056247; approved by local IRB committees from each site) with irAE-related information. Proteomic profiling of plasma samples was performed using the SomaScan® assay (SomaLogic Inc.), enabling deep coverage of approximately 7000 proteins in each sample. A machine learning-based model was developed to predict significant irAEs arising up to 3 months from treatment initiation; significant irAEs were defined as irAEs with CTCAE grade ≥3 or irAEs that induced treatment discontinuation. Using the model, we identified a set of plasma proteins, termed Toxicity Associated Proteins (TAPs), that serve as indicators of irAEs depending on their plasma level in the individual patient. Bioinformatic analysis was performed to decipher the biology underlying immune-related toxicity implied by the TAPs.ResultsOverall, 60 patients experienced significant irAEs at early onset; 197 patients had low grade irAEs, irAEs at late onset or AEs that are not immune-related; and 169 patients did not display any adverse event. A computational model was generated to predict significant irAEs, showing a strong correlation between the predicted probability of significant irAEs and the observed rate of such events (R2= 0.92; p-value <0.0001), implying good prediction capabilities. The prediction was based on a set of 449 TAPs. Interestingly, nearly half of these TAPs were previously identified as proteins associated with clinical benefit from ICI therapy, suggesting a close relationship between irAEs and clinical benefit, in accordance with previous reports. A detailed examination of the TAPs revealed some key findings. Patients who experienced irAEs had a larger number of TAPs related to neutrophils, inflammation, and cell death resistance, while the number of lymphocyte-related TAPs was low in these patients. Patients who did not experience irAEs displayed higher levels of extracellular matrix-related proteins.ConclusionsWe describe a novel computational model for predicting significant irAEs in patients with NSCLC based on proteomic profiling of pre-treatment plasma samples. The TAPs provide insights into the biological processes underlying irAEs. Early prediction of irAEs could enable personalized management plans and mitigation strategies to reduce the risk of irAEs in NSCLC.Ethics ApprovalParticipants gave informed consent before taking part. Institutional Review Board of the following institutes gave ethical approval for this work: Asklepios Kliniken GmbH; Rambam Medical Center; Hadassah Hebrew University Medical Center; Meir Medical Center; Emek Medical Center; Kaplan Medical Center; Rabin Medical Center Davidoff Cancer Centre; Shamir Medical Center; Bnai Zion Medical Center; Roswell Park Comprehensive Cancer Center; Asklepios Kliniken GmbH; Sheba Medical Center; Cheltenham General Hospital; Aberdeen Royal Infirmary Grampian NHS; Barzilai Medical Center; Sunderland Royal Hospital; Shrewsbury and Telford Hospital.

Oxaliplatin is a common chemotherapy drug, used mainly for colon and gastric cancer. Most common side effects are peripheral sensory neuropathy, hematological toxicity, and allergic reactions. A less common side effect is pulmonary toxicity, characterized mainly by interstitial pneumonitis. The incidence of this side effect is unknown, but the toxicity can be fatal. Twenty-six cases of pulmonary toxicity have been described in the literature, seven in the setting of adjuvant treatment. We describe two fatal cases of pulmonary injury related to oxaliplatin and a review of the literature.

Cannabis or its derivatives are widely used by patients with cancer to help with cancer symptoms and treatment side effects. However, cannabis has potent immunomodulatory properties. To determine if cannabis consumption during immunotherapy affects therapy outcomes, we conducted a prospective observatory study including 102 (68 immunotherapy and 34 immunotherapy plus cannabis) consecutive patients with advanced cancers who initiated immunotherapy. Cannabis consumption correlated with a significant decrease in time to tumor progression and overall survival. On the other hand, the use of cannabis reduced therapy-related immune-related adverse events. We also tested the possibility that cannabis may affect the immune system or the tumor microenvironment through the alteration of the endocannabinoid system. We analyzed a panel of serum endocannabinoids (eCBs) and eCB-like lipids, measuring their levels before and after immunotherapy in both groups. Levels of serum eCBs and eCB-like lipids, before immunotherapy, showed no significant differences between cannabis users to nonusers. Nevertheless, the levels of four eCB and eCB-like compounds were associated with patients’ overall survival time. Collectively, cannabis consumption has considerable immunomodulatory effects, and its use among cancer patients needs to be carefully considered due to its potential effects on the immune system, especially during treatment with immunotherapy.

Trastuzumab is considered a cornerstone in the treatment of human epidermal growth factor receptor-2 (HER2)-positive breast cancer. Cardiac toxicity is an important side effect of treatment and can limit the use of this drug known to act synergistically with cardiotoxicity from anthracyclines. A retrospective study was performed on breast cancer patients with early breast cancer, and HER2 overexpression treated with adjuvant/neoadjuvant chemotherapy and trastuzumab between 2005 and 2010. Cardiac events (CE) were recorded if left ventricular ejection fraction (LVEF) reduction was more than 10 % from baseline echocardiography. Treatment-related potential risk and protective factors were recorded. Median age of the 124 patients included in this analysis was 51 years (range 29–70 years). Treatment regimens were anthracycline-cyclophosphamide (AC)-Taxol (105 patients), TCH (12 patients), and CAF/Taxol combination (7 patients). CE were observed in 26 (21 %) patients. Trastuzumab was stopped in 9 (7 %) patients and rechallenged in five after periods ranging from 19 to 120 days. There was a significant decrease in LVEF between baseline/post-AC and during trastuzumab treatment (mean LVEF 64.29 vs. 61.97 %, p  < 0.001). Treatment-related risk factors were age and interval since last AC. Trastuzumab loading dose (8 vs. 4 mg) did not influence CE rate. 56 (45 %) patients received left chest wall irradiation with significantly increased CE rates, 16 (31.4 %) versus 10 (15.4 %), in patients without radiotherapy ( p  < 0.05). The presence of any cardiac risk factor caused a trend toward increased risk, not statistically significant. No connection was found between possible cardioprotective drugs and reduced rates of toxicity. The incidence of cardiac toxicity with trastuzumab adjuvant treatment in our study is similar to other reports. Only radiotherapy to the left chest wall increased the risk for CE. Further prospective studies are needed, including echocardiographic measurement and biochemical data (troponin I), for early recognition and monitoring of high-risk patients.

This retrospective study evaluated the impact of intermediate Recurrence Score ® results on adjuvant treatment decisions in estrogen receptor-positive (ER+) early invasive breast cancer, comparing treatment recommendations pre-testing with actual treatments received post-testing. Of the 111 patients included in the analysis, 78 (70.3%) had hormonal therapy (HT) and 33 (29.7%) had chemohormonal therapy (CHT) recommendations pre-testing. The Recurrence Score was significantly higher in those with a pre-testing CHT recommendation compared with those with a pre-testing HT recommendation (median of 24 vs. 22; P  = 0.047; Mann–Whitney–Wilcoxon [MWW] test). Post-testing, treatment of 24 patients (21.6%) was different from their pre-testing recommendation. The difference between CHT recommendation rate pre-testing and the rate of CHT received post-testing was nonsignificant for the entire cohort and for patients’ subgroups (by age, tumor size, and grade) ( P >0.17; McNemar’s test). Following classification of the cohort into two Recurrence Score subcategories (low-intermediate, [18-25]; high-intermediate, [26-30]), changes in treatment decisions (pre-testing recommendations vs. actual treatments received post testing) were reported for 16.5% of low-intermediate and 34.4% of high-intermediate patients. Post-testing, the rate of CHT decreased (by 58%) in the low-intermediate subcategory and increased (by 64%) in the high-intermediate subcategory ( P <0.01, both subcategories). In logistic regression analyses, the Recurrence Score subcategory was the only significant predictor of changes in treatment decisions (pre-testing recommendations vs. actual treatments received post testing; P <0.01). The only significant difference between the two subsets of patients with such a change (HT to CHT, 11 patients; CHT to HT, 13 patients) was the Recurrence Score (median of 28 vs. 20, respectively; P  = 0.0014; MWW test). These findings demonstrate that intermediate Recurrence Score results provide clinically relevant information and impact treatment decisions in ER + early breast cancer.