Summary Background Evidence from retrospective studies suggests that disease progression after first-line chemotherapy for metastatic non-small-cell lung cancer (NSCLC) occurs most often at sites of ...disease known to exist at baseline. However, the potential effect of aggressive local consolidative therapy for patients with oligometastatic NSCLC is unknown. We aimed to assess the effect of local consolidative therapy on progression-free survival. Methods In this multicentre, randomised, controlled, phase 2 study, eligible patients from three hospitals had histological confirmation of stage IV NSCLC, three or fewer metastatic disease lesions after first-line systemic therapy, an Eastern Cooperative Oncology Group performance status score of 2 or less, had received standard first-line systemic therapy, and had no disease progression before randomisation. First-line therapy was four or more cycles of platinum doublet therapy or 3 or more months of EGFR or ALK inhibitors for patients with EGFR mutations or ALK rearrangements, respectively. Patients were randomly assigned (1:1) to either local consolidative therapy (chemoradiotherapy or resection of all lesions) with or without subsequent maintenance treatment or to maintenance treatment alone, which could be observation only. Maintenance treatment was recommended based on a list of approved regimens, and observation was defined as close surveillance without cytotoxic treatment. Randomisation was not masked and was balanced dynamically on five factors: number of metastases, response to initial therapy, CNS metastases, intrathoracic nodal status, and EGFR and ALK status. The primary endpoint was progression-free survival analysed in all patients who were treated and had at least one post-baseline imaging assessment. The study is ongoing but not recruiting participants. This study is registered with ClinicalTrials.gov , number NCT01725165. Findings Between Nov 28, 2012, and Jan 19, 2016, 74 patients were enrolled either during or at the completion of first-line systemic therapy. The study was terminated early after randomisation of 49 patients (25 in the local consolidative therapy group and 24 in the maintenance treatment group) as part of the annual analyses done by the Data Safety Monitoring Committee of all randomised trials at MD Anderson Cancer Center, and before a planned interim analysis of 44 events. At a median follow-up time for all randomised patients of 12·39 months (IQR 5·52–20·30), the median progression-free survival in the local consolidative therapy group was 11·9 months (90% CI 5·7–20·9) versus 3·9 months (2·3–6·6) in the maintenance treatment group (hazard ratio 0·35 90% CI 0·18–0·66, log-rank p=0·0054). Adverse events were similar between groups, with no grade 4 adverse events or deaths due to treatment. Grade 3 adverse events in the maintenance therapy group were fatigue (n=1) and anaemia (n=1) and in the local consolidative therapy group were oesophagitis (n=2), anaemia (n=1), pneumothorax (n=1), and abdominal pain (n=1, unlikely related). Interpretation Local consolidative therapy with or without maintenance therapy for patients with three or fewer metastases from NSCLC that did not progress after initial systemic therapy improved progression-free survival compared with maintenance therapy alone. These findings suggest that aggressive local therapy should be further explored in phase 3 trials as a standard treatment option in this clinical scenario. Funding MD Anderson Lung Cancer Priority Fund, MD Anderson Cancer Center Moon Shot Initiative, and Cancer Center Support (Core), National Cancer Institute, National Institutes of Health.
Summary Background Vorinostat is a histone deacetylase inhibitor that changes gene expression and protein activity. On the basis of the clinical benefit reported in patients with malignant pleural ...mesothelioma treated in a phase 1 study of vorinostat, we designed this phase 3 trial to investigate whether vorinostat given as a second-line or third-line therapy improved patients' overall survival. Methods This double-blind, randomised, placebo-controlled trial was done in 90 international centres. Patients with measurable advanced malignant pleural mesothelioma and disease progression after one or two previous systemic regimens were eligible. After stratification for Karnofsky performance status, histology, and number of previous chemotherapy regimens, patients were randomly assigned (1:1) by use of an interactive voice response system with a block size of four to either treatment with vorinostat or placebo. Patients received oral vorinostat 300 mg (or matching placebo) twice daily on days 1, 2, 3, 8, 9, 10, 15, 16, and 17 of a 21-day cycle. The primary endpoints were overall survival and safety and tolerability of vorinostat. The primary efficacy comparison was done in the intention-to-treat population, and safety and tolerability was assessed in the treated population. This trial is registered with ClinicalTrials.gov , number NCT00128102. Findings From July 12, 2005, to Feb 14, 2011, 661 patients were enrolled and randomly assigned to receive either vorinostat (n=329) or placebo (n=332) and included in the intention-to-treat analysis. Median overall survival for vorinostat was 30·7 weeks (95% CI 26·7–36·1) versus 27·1 weeks (23·1–31·9) for placebo (hazard ratio 0·98, 95% CI 0·83–1·17, p=0·86). The most common grade 3 or worse adverse events for patients treated with vorinostat were fatigue or malaise (51 16% patients in the vorinostat group vs 25 8% in the placebo group) and dyspnoea (35 11% vs 45 14%). Interpretation In this randomised trial, vorinostat given as a second-line or third-line therapy did not improve overall survival and cannot be recommended as a therapy for patients with advanced malignant pleural mesothelioma. Funding Merck & Co, Inc.
Vidutolimod, a CpG-A TLR9 agonist, was investigated in a phase 1b study (CMP-001-003; ClinicalTrials.gov, NCT03438318) in combination with atezolizumab with and without radiation therapy (RT) in ...patients with advanced NSCLC.
Patients with progressive disease after anti–programmed cell death protein 1 or programmed death-ligand 1 therapy received either vidutolimod and atezolizumab (part A) or vidutolimod, atezolizumab, and RT (part B). The primary objective was to evaluate the safety of vidutolimod and atezolizumab with and without RT. Key secondary end point was best objective response rate per Response Evaluation Criteria in Solid Tumors, version 1.1.
Between March 28, 2018, and July 25, 2019, a total of 29 patients were enrolled and received at least one dose of vidutolimod (part A, n = 13; part B, n = 16). Intratumoral injections of vidutolimod were administered successfully, including injection of visceral lesions. The most common treatment-related adverse events (≥30%) were flu-like symptoms and hypotension. No objective responses were observed; 23.1% and 50.0% of the patients in parts A and B, respectively, had stable disease as best response. In parts A and B, 15.4% and 25.0% of the patients, respectively, had tumor shrinkage (<30% decrease in tumor size, nonirradiated). Enrollment was stopped owing to lack of objective responses. In the two patients with initial tumor shrinkage in part A, a strong serum induction of C-X-C motif chemokine ligand 10 was observed.
Vidutolimod and atezolizumab with and without RT had a manageable safety profile, with minimal clinical activity in heavily pretreated patients with programmed cell death protein 1 or programmed death-ligand 1 blockade–resistant NSCLC.
To investigate safety, efficacy, and recurrence after hemithoracic intensity modulated radiation therapy after pleurectomy/decortication (PD-IMRT) and after extrapleural pneumonectomy (EPP-IMRT).
In ...2009-2013, 24 patients with mesothelioma underwent PD-IMRT to the involved hemithorax to a dose of 45 Gy, with an optional integrated boost; 22 also received chemotherapy. Toxicity was scored with the Common Terminology Criteria for Adverse Events v4.0. Pulmonary function was compared at baseline, after surgery, and after IMRT. Kaplan-Meier analysis was used to calculate overall survival (OS), progression-free survival (PFS), time to locoregional failure, and time to distant metastasis. Failures were in-field, marginal, or out of field. Outcomes were compared with those of 24 patients, matched for age, nodal status, performance status, and chemotherapy, who had received EPP-IMRT.
Median follow-up time was 12.2 months. Grade 3 toxicity rates were 8% skin and 8% pulmonary. Pulmonary function declined from baseline to after surgery (by 21% for forced vital capacity, 16% for forced expiratory volume in 1 second, and 19% for lung diffusion of carbon monoxide P for all = .01) and declined still further after IMRT (by 31% for forced vital capacity P=.02, 25% for forced expiratory volume in 1 second P=.01, and 30% for lung diffusion of carbon monoxide P=.01). The OS and PFS rates were 76% and 67%, respectively, at 1 year and 56% and 34% at 2 years. Median OS (28.4 vs 14.2 months, P=.04) and median PFS (16.4 vs 8.2 months, P=.01) favored PD-IMRT versus EPP-IMRT. No differences were found in grade 4-5 toxicity (0 of 24 vs 3 of 24, P=.23), median time to locoregional failure (18.7 months vs not reached, P not calculable), or median time to distant metastasis (18.8 vs 11.8 months, P=.12).
Hemithoracic intensity modulated radiation therapy after pleurectomy/decortication produced little high-grade toxicity but led to progressive declines in pulmonary function; OS and PFS were better in PD-IMRT compared with EPP-IMRT.
Background Persistent pathologic mediastinal nodal involvement after induction chemotherapy and surgical resection is a negative prognostic factor for stage III-N2 non-small cell lung cancer ...patients. This population has high rates of local-regional failure and distant failure, yet the effectiveness of additional therapies is not clear. We assessed the role of consolidative therapies (postoperative radiation therapy and chemotherapy) for such patients. Methods In all, 179 patients with stage III-N2 non-small cell lung cancer at MD Anderson Cancer Center were treated with induction chemotherapy followed by surgery from 1998 through 2008; 61 patients in this cohort had persistent, pathologically confirmed, mediastinal nodal disease, and were treated with postoperative radiation therapy. Local-regional failure was defined as recurrence at the surgical site or lymph nodes (levels 1 to 14, including supraclavicular), or both. Overall survival was calculated using the Kaplan-Meier method, and survival outcomes were assessed by log rank tests. Univariate and multivariate Cox proportional hazards models were used to identify factors influencing local-regional failure, distant failure, and overall survival. Results All patients received postoperative radiation therapy after surgery, but approximately 25% of the patients also received additional chemotherapy: 9 (15%) with concurrent chemotherapy, 4 (7%) received adjuvant sequential chemotherapy, and 2 (3%) received both. Multivariate analysis indicated that additional postoperative chemotherapy significantly reduced distant failure (hazard ratio 0.183, 95% confidence interval: 0.052 to 0.649, p = 0.009) and improved overall survival (hazard ratio 0.233, 95% confidence interval: 0.089 to 0.612, p = 0.003). However, additional postoperative chemotherapy had no affect on local-regional failure. Conclusions Aggressive consolidative therapies may improve outcomes for patients with persistent N2 disease after induction chemotherapy and surgery.
Recent major advances in metastatic non–small cell lung cancer have occurred with the identification of molecular biomarker targets and administration of novel agents with resulting improvement in ...clinical outcomes. In the early-stage setting, personalized therapy with novel agents and molecular profiling are being incorporated into neoadjuvant “window-of-opportunity” trials. These important studies enable biomarker research and an expedited analysis of the efficacy of the targeted agent. However, there are significant limitations to window-of-opportunity trials. The aim of this article is to review the current window-of-opportunity trials of neoadjuvant targeted agents for thoracic malignancies, discuss the benefits and limitations of these trials, and propose more optimal alternative trial end points. Neoadjuvant trials of resectable non–small cell lung cancer and mesothelioma that are ongoing or under development and relevant to thoracic surgeons are also discussed. The success of these trials will depend on a collaborative multidisciplinary effort, especially from the field of thoracic surgery.
Background Malignant pleural mesothelioma is a locally aggressive tumor that is usually fatal. Extrapleural pneumonectomy (EPP) followed by hemithoracic irradiation has shown promise, but local ...failure remains a significant problem. To improve local control, we have used intensity-modulated radiation therapy (IMRT) as it allows better dose distribution to regions at risk of recurrence as well as reduced radiation to surrounding organs. Methods One hundred consecutive patients underwent EPP. At a median interval of 2.5 months from surgery, 63 patients received IMRT (median dose 45 Gy) with curative intent. Chemotherapy was not routinely administered. Results Tumors were right sided in 66 patients (66%) and nonepithelioid in 33 (33%). American Joint Committee on Cancer pathology stage was I in 6 patients (6%), II in 7 (7%), III in 72 (72%), and IV (T4) in 15 (15%). Fifty-four patients (54%) had ipsilateral nodal metastases. Perioperative mortality was 8%. Median overall survival (n = 100) was 10.2 months. For patients who received IMRT (n = 63), median overall and 3-year survival was 14.2 months and 20%. Of these, node-negative patients with epithelioid histology (n = 18) had median and 3-year survival of 28 months and 41%. Distant recurrences occurred in 33 of 61 evaluable patients (54%). Eight patients (13%) had local or regional recurrence, 5 of whom also recurred distally. Only 3 patients (5%) had recurrence within the irradiated field. Conclusions Intensity-modulated radiation therapy after EPP results in excellent local control for malignant pleural mesothelioma; however, distant metastases remain a significant problem and limit survival. This provides a strong rationale for combining aggressive local regimens with systemic therapy.
Abstract Context Dexamethasone is often used to treat dyspnea in cancer patients but evidence is lacking. Objectives We determined the feasibility of conducting a randomized trial of dexamethasone in ...cancer patients, and estimated the efficacy of dexamethasone in the treatment of dyspnea. Methods In this double-blind, randomized, controlled trial, patients with dyspnea ≥4 were randomized to receive either dexamethasone 8 mg twice daily x four days then 4 mg twice daily x three days or placebo for seven days, followed by an open-label phase for seven days. We documented the changes in dyspnea (0-10 numeric rating scale NRS), spirometry measures, quality of life and toxicities. Results A total of 41 patients were randomized and 35 (85%) completed the blinded phase. Dexamethasone was associated with a significant reduction in dyspnea NRS of -1.9 (95% confidence interval CI -3.3 to -0.5, P =0.01) by day 4 and -1.8 (95% CI -3.2 to -0.3, P =0.02) by day 7. In contrast, placebo was associated with a reduction of -0.7 (95% CI -2.1 to 0.6, P =0.38) by day 4 and -1.3 (95% CI -2.4 to -0.2, P =0.03) by day 7. The between-arm difference was not statistically significant. Drowsiness improved with dexamethasone. Dexamethasone was well tolerated with no significant toxicities. Conclusion A double-blind, randomized, controlled trial of dexamethasone was feasible with a low attrition rate. Our preliminary data suggest that dexamethasone may be associated with rapid improvement in dyspnea and was well tolerated. Further studies are needed to confirm our findings.
MET amplification is a known resistance mechanism to EGFR tyrosine kinase inhibitor (TKI) treatment in EGFR-mutant NSCLC. Dual EGFR-MET inhibition has been reported with success in overcoming such ...resistance and inducing clinical benefit. Resistance mechanisms to dual EGFR-MET inhibition require further investigation and characterization.
Patients (pts) with NSCLC with both MET amplification and EGFR mutation who have received crizotinib, capmatinib, savolitinib, or tepotinib plus osimertinib (osi) after progression on osi at MD Anderson Cancer Center were included in this study. Molecular profiling was completed by means of fluorescence in situ hybridization (FISH) and/or next-generation sequencing (NGS). Radiological response was assessed on the basis of Response Evaluation Criteria in Solid Tumors version 1.1.
From March 2016 to March 2022, 23 treatments with dual MET inhibitor and osi were identified with a total of 20 pts included. Three pts received capmatinib plus osi after progression on crizotinib plus osi. Median age was 64 (38–89) years old and 75% were female. MET amplification was detected by FISH in 14 pts in the tissue, NGS in 10 pts, and circulating tumor DNA in three pts. Median MET gene copy number was 13.6 (6.4–20). Overall response rate was 34.8% (eight of 23). In assessable pts, tumor shrinkage was observed in 82.4% (14 of 17). Median time on treatment was 27 months. Two of three pts responded to capmatinib plus osi after progression on crizotinib plus osi. Dual EGFR-MET inhibition was overall well tolerated. Two pts on crizotinib plus osi and one pt on capmatinib plus osi discontinued therapy due to pneumonitis. One pt discontinued crizotinib plus osi due to gastrointestinal toxicity. Six pts were still on double TKI treatment. At disease progression to dual EGFR-MET inhibition, FISH and/or NGS on tumor and/or plasma were completed in six pts. Notable resistance mechanisms observed include acquired MET D1246H (n = 1), acquired EGFR C797S (n = 2), FGFR2 fusion (n = 1, concurrent with C797S), and EGFR G796S (n = 1, concurrent with C797S). Four pts lost MET amplification.
Dual EGFR and MET inhibition yielded high clinical response rate after progression on osi. Resistance mechanisms to EGFR-MET double TKI inhibition include MET secondary mutation, EGFR secondary mutation, or loss of MET amplification.
Ipilimumab improves clinical outcomes when combined with nivolumab in metastatic non-small cell lung cancer (NSCLC), but its efficacy and impact on the immune microenvironment in operable NSCLC ...remain unclear. We report the results of the phase 2 randomized NEOSTAR trial (NCT03158129) of neoadjuvant nivolumab or nivolumab + ipilimumab followed by surgery in 44 patients with operable NSCLC, using major pathologic response (MPR) as the primary endpoint. The MPR rate for each treatment arm was tested against historical controls of neoadjuvant chemotherapy. The nivolumab + ipilimumab arm met the prespecified primary endpoint threshold of 6 MPRs in 21 patients, achieving a 38% MPR rate (8/21). We observed a 22% MPR rate (5/23) in the nivolumab arm. In 37 patients resected on trial, nivolumab and nivolumab + ipilimumab produced MPR rates of 24% (5/21) and 50% (8/16), respectively. Compared with nivolumab, nivolumab + ipilimumab resulted in higher pathologic complete response rates (10% versus 38%), less viable tumor (median 50% versus 9%), and greater frequencies of effector, tissue-resident memory and effector memory T cells. Increased abundance of gut Ruminococcus and Akkermansia spp. was associated with MPR to dual therapy. Our data indicate that neoadjuvant nivolumab + ipilimumab-based therapy enhances pathologic responses, tumor immune infiltrates and immunologic memory, and merits further investigation in operable NSCLC.
PDF
