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Background Development of immunotherapy/molecular targeted therapy has significantly increased survival/QoL in advanced stages of NSCLC. Aim(s): to analyze outcome predictors, surrogate outcomes, and PROMs after neoadjuvant immunotherapy for initially unresectable NSCLC. Methods Initially unresectable NSCLC (2014-2021) patients who received immunotherapy +/- platinum-based chemo and/or radiotherapy evaluated after response (reduction of primary tumor and/or mediastinal lymphadenopathy/control of distant metastatic disease underwent surgical resection). PROMs were recorded using EORTC QLQ-29. Results 19 underwent salvage surgery after ICI. 14 had partial response (73.6%), 5 stable disease. Diagnosis was achieved by endobronchial ultrasound (EBUS) in 8 (42.1%), fine-needle aspiration biopsy (FNAB) in 7 (36.8%), metastasis biopsy in 4 (21.0%). 11 (57.9%) were treated with neoadjuvant platinum-based chemo before or with ICI, 1 (5.2%) pemetrexed before ICI, 5 (26.3%) radiotherapy for metastatic control. 3 (15.7%) had ICI adverse effects. Radiotherapy was never used preoperatively for pulmonary/mediastinal disease. 7 (36.8%) received adjuvant therapy (5 [26.3%] pembrolizumab, 1 [5.2%] pemetrexed, 1 [5.2%] pemetrexed + pembrolizumab). 4 (21.0%) had local relapse (no systemic relapse). Median OS was 19 months (range: 2-57.4). At 2 months, 94.7% were alive (6 months: 89.5%;31 months: 79.5%). 2 (10.5%) had local recurrence. 2 (10.5%) died due to recurrence, 1 (5.2%) to COVID. 4 (21.0%) relapsed (median DFS: 5.3 months [range: 2.2-13.0]). PROMs were reviewed retrospectively at 30 days/1 year with significant decrease in coughing, side effects of treatment, surgery-related problems. [Formula presented] Conclusions Radical surgical resections following definitive immunotherapy/immune-chemotherapy in selected initially unresectable NSCLC are feasible and safe (low surgical-related mortality and morbidity). Symptoms and surgery-related outcomes were lower with higher QoL due to a selected group of highly motivated patients. Legal entity responsible for the study The authors. Funding Ministero della Salute. Disclosure All authors have declared no conflicts of interest.Copyright © 2023 International Association for the Study of Lung Cancer. Published by Elsevier Inc.
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Background: COVID-19 pandemic has led physicians to change their practice in the treatment of non-small cell lung cancer (NSCLC) to reduce hospital stays of patients. Objective(s): We aimed to assess toxicity and efficacy of extended-interval (EI) dosing of immune checkpoint inhibitors (ICI) compared to standard dose (SD). Method(s): In a retrospective bicentric study, patients with stage III/IV NSCLC treated with ICI +/- pemetrexed in maintenance setting during the month before March 2020 were included. Immune-related adverse events (IRAE) and efficacy were collected until June 2021. Toxicity and survival were assessed using multivariate logistic regression and Cox models. Result(s): Among the 134 identified patients (8 stage III and 126 stage IV, 66 in 1st line and 60 in 2nd or further lines), 70.9% had an EI dosing. In the EI dosing group, 12.6% patients developed grade 3 or more IRAE and 15.4% in the SD group (p=0.8). Treatment was definitively discontinued for toxicity for 9 patients in the EI dosing group and 5 patients in the SD group (p=0.5). Overall survival was not associated with dosage or occurrence of toxicity as timedependent variable (Table). Conclusion(s): Our study suggests that EI dosing of ICI did not affect toxicity, efficacy and survival in NSCLC patients.
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Introduction: There is a subset of NSCLC patients ineligible for benefit from TKIs/Immunotherapy (e.g. STK11 mutation conferring resistance to Immunotherapy). Besides, many patients cannot afford these therapies. Metformin has anticancer properties acting both on glycolytic metabolism and tumor microenvironment. In vitro studies suggest synergism between metformin and pemetrexed. STK11 deficient cell lines are more sensitive to metformin. Clinical studies combining metformin with chemotherapy are limited by small sample size. We conducted an exploratory phase-2 clinical trial of metformin with pemetrexed/carboplatin in advanced non-squamous NSCLC. Methods: This was a single center, open label, single arm phase 2 clinical trial with a Simon’s two stage design. The null hypothesis was that the combination would not improve the 6-month PFS rate by 15%, from 50%. Treatment-naive, non-diabetic patients aged 18-75 years with NSCLC (adenocarcinoma/not-otherwise-specified) with stage IV disease having ECOG PS 0-2 with unmutated EGFR/ALK and without brain metastasis or with asymptomatic brain metastases were treated with pemetrexed-carboplatin chemotherapy and metformin for six months. The primary outcome was 6-month progression free survival (PFS) rate. Secondary outcomes were safety, overall survival (OS), overall response rate (ORR), proportion of STK 11 mutation and effect of STK 11 mutation on 6-month PFS rate. PFS and OS were estimated using the Kaplan-Meier method. Targeted sequencing was attempted for available tissue specimens. Results: The first interim analysis was performed after enrollment of 26 patients for the first stage (before the target accrual of first stage was reached) due to slow accrual, in view of COVID pandemic. The study was terminated after first stage for futility. The median age of patients in the study was 52 years (range, 30 to 68) and 18 patients (69.0%) were males. Half of the patients had ECOG-PS 2. Brain metastases were present in eight (31%) patients and among these four (50%) were symptomatic at presentation. The median follow-up time was 25 months. The median PFS was four months. 6-month PFS rate was 28% (95% CI - 0.12 to 0.46). Of the 25 evaluable patients, five (20%) had a partial response, and eight (32%) had stable disease;13 (52%) of the patients had disease control. The median OS was 16 months. During combined therapy, 14 (54%) and 3 (11%) patients had any grade and grade 3 anemia respectively. One patient had grade 3 neutropenia. Among non-hematological toxicities, gastrointestinal toxicities (nausea, vomiting and diarrhea) were the most common. No grade 4 toxicities were reported. There were no treatment discontinuations, however treatment delay due to grade three toxicities was present in two patients. Dose modification for Metformin was required in four patients. Targeted Sequencing was possible in nine cases. Two of these patients had STK11 mutation and an associated bad outcome (PFS < 2 months). Conclusions: We could not demonstrate the benefit of combination of Metformin with pemetrexed-carboplatin in terms of improvement in 6-month PFS rate. The addition of metformin to pemetrexed-carboplatin has an acceptable safety profile. Future trials should test metformin in specific subsets (STK11 mutated) and in combination with immunotherapy and TKIs. Keywords: Metformin, NSCLC, STK11
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Introduction: There are limited options for the treatment of malignant mesothelioma (MM) following progression with pemetrexed-platinum chemotherapy. Recently, nivolumab showed a survival benefit over placebo in this setting. In the UK, since April 2020, nivolumab has been funded through the interim national COVID-19 cancer plan. We assessed the real-world efficacy and toxicity outcomes in MM patients treated with nivolumab at Guy’s Cancer Centre.Methods: We identified all chemotherapy-pre-treated patients administered single-agent nivolumab for MM. Baseline characteristics, treatment, response, survival and treatment-related adverse events (TRAEs) were assessed. Best responses – disease control or progression – were derived from radiologic and clinical documentation. Results: Twenty patients were identified. Median age was 72 years (range 45 – 85), 80% male and 95% had epithelioid (5% sarcomatoid) disease. Programmed death-ligand 1 (PD-L1) measurements were unavailable. Nineteen (95%) had pleural and one peritoneal MM. ECOG PS was 0, 1 or 2 in 1 (5%), 16 (80%) and 3 (15%) patients respectively. All were previously exposed to pemetrexed-platinum chemotherapy, and 4 (20%) had received rechallenge. Median time from prior treatment to commencement of nivolumab was 6 months. Median follow-up was 10.8 months. Median number of two-weekly 240mg equivalent cycles administered was twelve. Best response was disease control in 17 (85%) patients and progressive disease in 3 (15%). Median progression-free survival was 5.0 months (95% CI 3.7 – 6.2). Six patients (30%) had died by time of analysis, with median overall survival not reached. Twenty TRAEs were seen among 14 patients (70%), all except one graded 1/2 (Table 1). Conclusions: Nivolumab proved a safe and effective way to deliver non-myelosuppressive anticancer therapy at a favourable dosing schedule to a vulnerable population during the COVID-19 pandemic. These real-world outcomes corroborate findings from the CONFIRM trial, although limited by small sample size and retrospective nature.