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Amivantamab has been approved for the treatment of patients with advanced non-small-cell lung cancer (NSCLC) with epidermal growth factor receptor ( ) exon 20 insertions who have had disease progression during or after platinum-based chemotherapy. Phase 1 data showed the safety and antitumor activity of amivantamab plus carboplatin-pemetrexed (chemotherapy). Additional data on this combination therapy are needed. In this phase 3, international, randomized trial, we assigned in a 1:1 ratio patients with advanced NSCLC with exon 20 insertions who had not received previous systemic therapy to receive intravenous amivantamab plus chemotherapy (amivantamab-chemotherapy) or chemotherapy alone. The primary outcome was progression-free survival according to blinded independent central review. Patients in the chemotherapy group who had disease progression were allowed to cross over to receive amivantamab monotherapy. A total of 308 patients underwent randomization (153 to receive amivantamab-chemotherapy and 155 to receive chemotherapy alone). Progression-free survival was significantly longer in the amivantamab-chemotherapy group than in the chemotherapy group (median, 11.4 months and 6.7 months, respectively; hazard ratio for disease progression or death, 0.40; 95% confidence interval [CI], 0.30 to 0.53; P<0.001). At 18 months, progression-free survival was reported in 31% of the patients in the amivantamab-chemotherapy group and in 3% in the chemotherapy group; a complete or partial response at data cutoff was reported in 73% and 47%, respectively (rate ratio, 1.50; 95% CI, 1.32 to 1.68; P<0.001). In the interim overall survival analysis (33% maturity), the hazard ratio for death for amivantamab-chemotherapy as compared with chemotherapy was 0.67 (95% CI, 0.42 to 1.09; P = 0.11). The predominant adverse events associated with amivantamab-chemotherapy were reversible hematologic and EGFR-related toxic effects; 7% of patients discontinued amivantamab owing to adverse reactions. The use of amivantamab-chemotherapy resulted in superior efficacy as compared with chemotherapy alone as first-line treatment of patients with advanced NSCLC with exon 20 insertions. (Funded by Janssen Research and Development; PAPILLON ClinicalTrials.gov number, NCT04538664.).

In a randomized trial involving patients with non–small-cell lung cancer with mutant EGFR (T790M) in whom a tyrosine kinase inhibitor had failed, osimertinib was associated with significantly longer progression-free survival than platinum therapy plus pemetrexed. Among patients with advanced non–small-cell lung cancer with a mutant epidermal growth factor receptor (EGFR), EGFR tyrosine kinase inhibitors (TKIs) are the standard first-line therapy. 1 – 4 Despite high tumor response rates with first-line EGFR-TKIs, disease progresses in a majority of patients after 9 to 13 months of treatment. 5 – 12 At the time of progression, approximately 60% of patients (regardless of race or ethnic background) are found to have a p.Thr790Met point mutation (T790M) in the gene encoding EGFR. 13 – 16 The presence of the T790M variant reduces binding of first-generation or second-generation EGFR-TKIs to the ATP-binding pocket of EGFR, thereby reducing . . .

The efficacy of ceritinib in patients with untreated anaplastic lymphoma kinase (ALK)-rearranged non-small-cell lung cancer (NSCLC) is not known. We assessed the efficacy and safety of ceritinib versus platinum-based chemotherapy in these patients. This randomised, open-label, phase 3 study in untreated patients with stage IIIB/IV ALK-rearranged non-squamous NSCLC was done in 134 centres across 28 countries. Eligible patients were assigned via interactive response technology to oral ceritinib 750 mg/day or platinum-based chemotherapy ([cisplatin 75 mg/m2 or carboplatin AUC 5–6 plus pemetrexed 500 mg/m2] every 3 weeks for four cycles followed by maintenance pemetrexed); randomisation was stratified by World Health Organization performance status (0 vs 1–2), previous neoadjuvant or adjuvant chemotherapy, and presence of brain metastases as per investigator's assessment at screening. Investigators and patients were not masked to treatment assignment. The primary endpoint was blinded independent review committee assessed progression-free survival, based on all randomly assigned patients (the full analysis set). Efficacy analyses were done based on the full analysis set. All safety analyses were done based on the safety set, which included all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT01828099. Between Aug 19, 2013, and May 11, 2015, 376 patients were randomly assigned to ceritinib (n=189) or chemotherapy (n=187). Median progression-free survival (as assessed by blinded independent review committee) was 16·6 months (95% CI 12·6–27·2) in the ceritinib group and 8·1 months (5·8–11·1) in the chemotherapy group (hazard ratio 0·55 [95% CI 0·42–0·73]; p<0·00001). The most common adverse events were diarrhoea (in 160 [85%] of 189 patients), nausea (130 [69%]), vomiting (125 [66%]), and an increase in alanine aminotransferase (114 [60%]) in the ceritinib group and nausea (in 97 [55%] of 175 patients), vomiting (63 [36%]), and anaemia (62 [35%]) in the chemotherapy group. First-line ceritinib showed a statistically significant and clinically meaningful improvement in progression-free survival versus chemotherapy in patients with advanced ALK-rearranged NSCLC. Novartis Pharmaceuticals Corporation.

Malignant pleural mesothelioma is an aggressive cancer with poor prognosis, linked to occupational asbestos exposure. Vascular endothelial growth factor is a key mitogen for malignant pleural mesothelioma cells, therefore targeting of vascular endothelial growth factor might prove effective. We aimed to assess the effect on survival of bevacizumab when added to the present standard of care, cisplatin plus pemetrexed, as first-line treatment of advanced malignant pleural mesothelioma. In this randomised, controlled, open-label, phase 3 trial, we recruited patients aged 18–75 years with unresectable malignant pleural mesothelioma who had not received previous chemotherapy, had an Eastern Cooperative Oncology Group performance status of 0–2, had no substantial cardiovascular comorbidity, were not amenable to curative surgery, had at least one evaluable (pleural effusion) or measurable (pleural tumour solid thickening) lesion with CT, and a life expectancy of >12 weeks from 73 hospitals in France. Exclusion criteria were presence of central nervous system metastases, use of antiaggregant treatments (aspirin ≥325 mg per day, clopidogrel, ticlopidine, or dipyridamole), anti-vitamin K drugs at a curative dose, treatment with low-molecular-weight heparin at a curative dose, and treatment with non-steroidal anti-inflammatory drugs. We randomly allocated patients (1:1; minimisation method used [random factor of 0·8]; patients stratified by histology [epithelioid vs sarcomatoid or mixed histology subtypes], performance status score [0–1 vs 2], study centre, or smoking status [never smokers vs smokers]) to receive intravenously 500 mg/m2 pemetrexed plus 75 mg/m2 cisplatin with (PCB) or without (PC) 15 mg/kg bevacizumab in 21 day cycles for up to six cycles, until progression or toxic effects. The primary outcome was overall survival (OS) in the intention-to treat population. Treatment was open label. This IFCT-GFPC-0701 trial is registered with ClinicalTrials.gov, number NCT00651456. From Feb 13, 2008, to Jan 5, 2014, we randomly assigned 448 patients to treatment (223 [50%] to PCB and 225 [50%] to PC). OS was significantly longer with PCB (median 18·8 months [95% CI 15·9–22·6]) than with PC (16·1 months [14·0–17·9]; hazard ratio 0·77 [0·62–0·95]; p=0·0167). Overall, 158 (71%) of 222 patients given PCB and 139 (62%) of 224 patients given PC had grade 3–4 adverse events. We noted more grade 3 or higher hypertension (51 [23%] of 222 vs 0) and thrombotic events (13 [6%] of 222 vs 2 [1%] of 224) with PCB than with PC. Addition of bevacizumab to pemetrexed plus cisplatin significantly improved OS in malignant pleural mesothelioma at the cost of expected manageable toxic effects, therefore it should be considered as a suitable treatment for the disease. Intergroupe Francophone de Cancérologie Thoracique (IFCT).

There is a strong unmet need to improve systemic therapy in mesothelioma. Chemotherapy with cisplatin and pemetrexed improves survival in malignant pleural mesothelioma, and immune checkpoint inhibitors are an emerging treatment in this disease. We aimed to evaluate the activity of durvalumab, an anti-PD-L1 antibody, given during and after first-line chemotherapy with cisplatin and pemetrexed in patients with advanced malignant pleural mesothelioma. DREAM was a multicentre, single-arm, open-label, phase 2 trial done in nine hospitals in Australia. Eligible patients were aged 18 years or older and had histologically confirmed malignant pleural mesothelioma considered unsuitable for cancer-directed surgery, an Eastern Cooperative Oncology Group performance status of 0 or 1, and measurable disease as per the modified Response Evaluation Criteria in Solid Tumors version 1.0 (mRECIST) for mesothelioma that was previously untreated with systemic therapy. All histological subtypes were eligible. The first six participants were treated for two cycles in a safety run-in. All participants received cisplatin 75 mg/m2, pemetrexed 500 mg/m2, and durvalumab 1125 mg intravenously on day 1 of a 3-weekly schedule for a maximum of six cycles. Change from cisplatin to carboplatin with an area under the curve of 5 was permitted. Durvalumab was continued for a maximum of 12 months. The primary endpoint was progression-free survival at 6 months, measured according to mRECIST for malignant pleural mesothelioma and analysed in the intention-to-treat population. Safety analyses included all participants who receive at least one dose of any study drug. This study is registered with the Australia New Zealand Clinical Trials Registry, ACTRN12616001170415. Between Dec 28, 2016, and Sept 27, 2017, 55 participants were enrolled. 54 patients were eligible and were followed up for a median of 28·2 months (IQR 26·5–30·2). 31 (57%; 95% CI 44–70) of 54 patients were alive and progression-free at 6 months. The most common grade 3–4 adverse events were neutropenia (seven [13%] patients), nausea (six [11%]), and anaemia (four [7%]). A total of 60 serious adverse events occurred in 29 participants, five of which were considered possibly related to durvalumab. Five patients died during the study treatment; none of these five deaths were attributed to study treatment. The combination of durvalumab, cisplatin, and pemetrexed has promising activity and an acceptable safety profile that warrants further investigation in a randomised phase 3 trial. AstraZeneca.

In EGFR -mutated non–small-cell lung cancer, first-line osimertinib plus platinum–pemetrexed extended overall survival to 47.5 months, as compared with 37.6 months with osimertinib alone, but increased the risk of adverse events.

Sacituzumab tirumotecan (sac-TMT) is an antibody-drug conjugate targeting trophoblast cell-surface antigen 2 that has shown significant survival benefits in patients with -mutated non-small-cell lung cancer (NSCLC) that has progressed after epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy and platinum-based chemotherapy. In this phase 3 trial, we enrolled patients with -mutated locally advanced or metastatic nonsquamous NSCLC that had progressed after EGFR-TKI therapy. The patients were randomly assigned, in a 1:1 ratio, to receive sac-TMT monotherapy or pemetrexed plus platinum-based chemotherapy. The primary end point was progression-free survival as assessed by blinded independent review. Overall survival was a hierarchically tested key secondary end point. In the interim analysis of progression-free survival as assessed by blinded independent review, sac-TMT monotherapy met the prespecified criterion for significance (two-sided P<0.0001); we report here the prespecified final analysis of progression-free survival and the preplanned interim analysis of overall survival. Overall, 376 patients underwent randomization, with 188 assigned to each group. After a median follow-up of 18.9 months, the median progression-free survival was 8.3 months in the sac-TMT group and 4.3 months in the chemotherapy group (hazard ratio for disease progression or death, 0.49; 95% confidence interval [CI], 0.39 to 0.62). Overall survival was significantly longer with sac-TMT than with chemotherapy (hazard ratio for death, 0.60; 95% CI, 0.44 to 0.82; two-sided P = 0.001); 18-month overall survival was 65.8% and 48.0%, respectively. Treatment-related adverse events of grade 3 or higher occurred in 58.0% of patients receiving sac-TMT and in 53.8% of those receiving chemotherapy, with the most common being a decreased neutrophil count (39.9% vs. 33.0%); treatment-related serious adverse events occurred in 9.0% and 17.6%, respectively. In patients with -mutated advanced or metastatic NSCLC that had progressed after previous EGFR-TKI therapy, progression-free survival and overall survival outcomes were significantly better with sac-TMT than with platinum-based chemotherapy. (Funded by Sichuan Kelun-Biotech Biopharmaceutical; OptiTROP-Lung04 ClinicalTrials.gov number, NCT05870319.).

Osimertinib is a third-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) that is selective for EGFR-TKI-sensitizing and T790M resistance mutations. Evidence suggests that the addition of chemotherapy may extend the benefits of EGFR-TKI therapy. In this phase 3, international, open-label trial, we randomly assigned in a 1:1 ratio patients with -mutated (exon 19 deletion or L858R mutation) advanced non-small-cell lung cancer (NSCLC) who had not previously received treatment for advanced disease to receive osimertinib (80 mg once daily) with chemotherapy (pemetrexed [500 mg per square meter of body-surface area] plus either cisplatin [75 mg per square meter] or carboplatin [pharmacologically guided dose]) or to receive osimertinib monotherapy (80 mg once daily). The primary end point was investigator-assessed progression-free survival. Response and safety were also assessed. A total of 557 patients underwent randomization. Investigator-assessed progression-free survival was significantly longer in the osimertinib-chemotherapy group than in the osimertinib group (hazard ratio for disease progression or death, 0.62; 95% confidence interval [CI], 0.49 to 0.79; P<0.001). At 24 months, 57% (95% CI, 50 to 63) of the patients in the osimertinib-chemotherapy group and 41% (95% CI, 35 to 47) of those in the osimertinib group were alive and progression-free. Progression-free survival as assessed according to blinded independent central review was consistent with the primary analysis (hazard ratio, 0.62; 95% CI, 0.48 to 0.80). An objective (complete or partial) response was observed in 83% of the patients in the osimertinib-chemotherapy group and in 76% of those in the osimertinib group; the median response duration was 24.0 months (95% CI, 20.9 to 27.8) and 15.3 months (95% CI, 12.7 to 19.4), respectively. The incidence of grade 3 or higher adverse events from any cause was higher with the combination than with monotherapy - a finding driven by known chemotherapy-related adverse events. The safety profile of osimertinib plus pemetrexed and a platinum-based agent was consistent with the established profiles of the individual agents. First-line treatment with osimertinib-chemotherapy led to significantly longer progression-free survival than osimertinib monotherapy among patients with -mutated advanced NSCLC. (Funded by AstraZeneca; FLAURA2 ClinicalTrials.gov number, NCT04035486.).

Abstract Background Leptomeningeal metastasis (LM) is an advanced complication of lung cancer with a poor prognosis. It remains unknown whether intrathecal pemetrexed (IP) can improve the outcomes of patients with LM from lung adenocarcinoma (LUAD). This study explored the efficacy of intrathecal pemetrexed (IP) and proteomic biomarkers in LM from LUAD. Patients and Methods We conducted a retrospective survival analysis of 157 confirmed LM patients (54 IP vs 103 non-IP). To balance the baseline, propensity score matching (PSM) was implemented. We investigated clinical baseline characteristics and treatment factors to identify those influencing the outcomes of LM patients. Plasma and cerebrospinal fluid (CSF) samples underwent proteomic profiling using Olink Immuno-Oncology panels to identify IP response biomarkers and build a prediction model. Results After PSM, 82 patients were included in two matched cohort (41 IP vs 41 non-IP). IP treatment (HR = 0.427, P = .022) and ECOG performance status (HR = 2.737, P = .005) were independent predictors of overall survival (OS). Stratified analysis showed IP significantly improved OS in patients with poor performance status (ECOG 3-4: IP vs non-IP, 11.2 vs 2.5 months, P = .0029). Proteomics revealed low plasma MCP-2 (AUC = 0.873) and high CSF ARG1 (AUC = 0.875) levels distinguished IP responders from nonresponders. Conclusions IP therapy improves OS in LUAD patients with LM, particularly offering significant benefit as salvage treatment for those with ECOG 3-4. Proteomic analysis suggests plasma MCP-2 and CSF ARG1 are promising predictive biomarkers for IP response. The small sample size in biomarker analysis may limit these findings, necessitating validation through multicenter studies.

Limited evidence exists to show that adding a third agent to platinum-doublet chemotherapy improves efficacy in the first-line advanced non-small-cell lung cancer (NSCLC) setting. The anti-PD-1 antibody pembrolizumab has shown efficacy as monotherapy in patients with advanced NSCLC and has a non-overlapping toxicity profile with chemotherapy. We assessed whether the addition of pembrolizumab to platinum-doublet chemotherapy improves efficacy in patients with advanced non-squamous NSCLC. In this randomised, open-label, phase 2 cohort of a multicohort study (KEYNOTE-021), patients were enrolled at 26 medical centres in the USA and Taiwan. Patients with chemotherapy-naive, stage IIIB or IV, non-squamous NSCLC without targetable EGFR or ALK genetic aberrations were randomly assigned (1:1) in blocks of four stratified by PD-L1 tumour proportion score (<1% vs ≥1%) using an interactive voice-response system to 4 cycles of pembrolizumab 200 mg plus carboplatin area under curve 5 mg/mL per min and pemetrexed 500 mg/m2 every 3 weeks followed by pembrolizumab for 24 months and indefinite pemetrexed maintenance therapy or to 4 cycles of carboplatin and pemetrexed alone followed by indefinite pemetrexed maintenance therapy. The primary endpoint was the proportion of patients who achieved an objective response, defined as the percentage of patients with radiologically confirmed complete or partial response according to Response Evaluation Criteria in Solid Tumors version 1.1 assessed by masked, independent central review, in the intention-to-treat population, defined as all patients who were allocated to study treatment. Significance threshold was p<0·025 (one sided). Safety was assessed in the as-treated population, defined as all patients who received at least one dose of the assigned study treatment. This trial, which is closed for enrolment but continuing for follow-up, is registered with ClinicalTrials.gov, number NCT02039674. Between Nov 25, 2014, and Jan 25, 2016, 123 patients were enrolled; 60 were randomly assigned to the pembrolizumab plus chemotherapy group and 63 to the chemotherapy alone group. 33 (55%; 95% CI 42–68) of 60 patients in the pembrolizumab plus chemotherapy group achieved an objective response compared with 18 (29%; 18–41) of 63 patients in the chemotherapy alone group (estimated treatment difference 26% [95% CI 9–42%]; p=0·0016). The incidence of grade 3 or worse treatment-related adverse events was similar between groups (23 [39%] of 59 patients in the pembrolizumab plus chemotherapy group and 16 [26%] of 62 in the chemotherapy alone group). The most common grade 3 or worse treatment-related adverse events in the pembrolizumab plus chemotherapy group were anaemia (seven [12%] of 59) and decreased neutrophil count (three [5%]); an additional six events each occurred in two (3%) for acute kidney injury, decreased lymphocyte count, fatigue, neutropenia, and sepsis, and thrombocytopenia. In the chemotherapy alone group, the most common grade 3 or worse events were anaemia (nine [15%] of 62) and decreased neutrophil count, pancytopenia, and thrombocytopenia (two [3%] each). One (2%) of 59 patients in the pembrolizumab plus chemotherapy group experienced treatment-related death because of sepsis compared with two (3%) of 62 patients in the chemotherapy group: one because of sepsis and one because of pancytopenia. Combination of pembrolizumab, carboplatin, and pemetrexed could be an effective and tolerable first-line treatment option for patients with advanced non-squamous NSCLC. This finding is being further explored in an ongoing international, randomised, double-blind, phase 3 study. Merck & Co.