Outcomes of Transplant-Eligible Patients With Relapsed or Refractory Diffuse Large B-Cell Lymphoma After Second-Line Salvage Chemotherapy: The Gustave Roussy Experience

IntroductionAfter failure of frontline therapy, patients with relapsed/refractory diffuse large B-cell lymphoma (RR-DLBCL) that does not respond to first-line salvage chemotherapy can be recommended second-line salvage chemotherapy. The available literature in this regard is weak, although many centers routinely offer this type of second-line salvage chemotherapy to their patients.Patients and MethodsThis retrospective study included transplant-eligible patients with RR-DLBCL treated at Gustave Roussy between January 2008 and April 2020. Eligible patients were those who received second-line salvage chemotherapy using R-DHAP or R-ICE in patients who experienced an insufficient partial response, stable disease, or progressive disease in response to first-line salvage chemoimmunotherapy using an alternative regimen.ResultsForty-six RR-DLBCL patients received second-line salvage regimen, which yielded an objective response rate of 33%, median progression-free survival of 2.1 months, and overall survival of 11.4 months. Twelve patients proceeded to autologous stem-cell transplantation (ASCT), of whom 70% remained alive 1 year after ASCT. To explore the impact of transplantation, a multivariate analysis (excluding response to the first-line salvage regimen because this covariate was totally embedded within the transplantation covariate), ASCT was associated with progression-free survival (hazard ratio = 0.16; 95% confidence interval, 0.06-0.42) and overall survival (hazard ratio = 0.27; 95% confidence interval, 0.08-0.88).ConclusionSecond-line salvage chemotherapy with R-DHAP or R-ICE followed by ASCT leads to a favorable outcome in almost one third of patients with RR-DLBCL and offers a median overall survival of approximately 1 year. These data support the administration of second-line salvage chemotherapy followed by ASCT.     

Prognostic Role of Low-Skeletal Muscle Mass on Staging Computed Tomography in Metastasized Colorectal Cancer: A Systematic Review and Meta-Analysis

BackgroundLow-skeletal muscle mass (LSMM) is defined as skeletal muscle loss, which can be assessed by imaging. Our aim was to establish the effect of LSMM on overall survival (OS) in metastasized colorectal cancer patients based on a large patient sample.Patients and MethodsMEDLINE library, EMBASE, and SCOPUS databases were screened for the associations between LSMM and mortality in metastasized colorectal cancer patients up to March 2022. The primary aim of the systematic review was to investigate the influence of LSMM on overall survival (OS) by means of the effect of measure hazard ratio. Fifteen studies were included into the present analysis.ResultsThe included studies comprised 1744 patients. The frequency of LSMM was 46.2%. Associations between LSMM and OS were as follows: hazard ratio (HR) = 1.34 (95% confidence interval [CI] 0.94-1.91), P = .10 in univariable analysis and HR = 2.05 (95% CI 1.18-3.56), P = .01 in multivariable analysis. LSMM influenced OS in patients undergoing first-line chemotherapy, HR = 1.51 (95% CI 1.20-1.89), P = .0004. In patients undergoing second- and third-line chemotherapy, LSMM was not associated with OS, HR = 1.43 (95% CI 0.65-3.14), P = .37 Also, LSMM did not affect OS in patients with resection of hepatic metastases, HR = 0.93 (95% CI 0.70-1.24), P = .63. LSMM tended to affect progression-free survival, HR = 1.49 (95% CI 0.94-2.35), P = .09. LSMM did not predict treatment toxicity, odds ratio (OR) = 1.52 (95% CI 0.84-2.72), P = .16.ConclusionLSMM occurs in 46.2% of patients with metastasized colorectal cancers. LSMM is associated with OS in patients undergoing first-line chemotherapy. LSMM does not affect OS in second- and third-line chemotherapy and in patients undergoing resection of hepatic metastases. LSMM is not associated with progression-free survival and treatment toxicity.     

Phase I Trial of Selective Internal Radiation Therapy for Chemorefractory Colorectal Cancer Liver Metastases Progressing After Hepatic Arterial Pump and Systemic Chemotherapy

IntroductionThis prospective study assessed the safety and outcomes of selective internal radiation therapy (SIRT) using yttrium-90 (⁹⁰Y) resin microspheres as a salvage therapy for liver-predominant metastases of colorectal cancer in patients with documented progression after hepatic arterial chemotherapy (HAC) and systemic chemotherapy.Patients and MethodsWe recruited 19 patients who had received a mean of 2.9 prior lines of chemotherapy and ≥ 1 line of HAC. Dose-limiting toxicities (grade 3 or higher) were catalogued using Common Terminology Criteria for Adverse Events version 3.0. At 4 to 8 weeks and 3 to 4 months post SIRT, responses were assessed by carcinoembryonic antigen (CEA), and quantitative imaging using Response Evaluation Criteria in Solid Tumors (RECIST) and PET Response Criteria in Solid Tumors (PERCIST). Liver progression-free survival (LPFS), progression-free survival (PFS), and overall survival (OS) were calculated using Kaplan-Meier methodology.ResultsMedian follow-up was 31.2 months after SIRT. Within 6 weeks of SIRT, 3 patients (15.8%) experienced grade 3 toxicity. There was no incidence of radiation-induced liver disease. Responses by RECIST, PERCIST, and CEA were, respectively, 0%, 20%, and 32% at 4 to 8 weeks and 5%, 33%, and 21% at 3 to 4 months post SIRT; 53% of patients had stable disease (by RECIST) at 3 to 4 months. Of 19 patients, 4 (21.1%) had liver ablation, 9 (47%) received additional HAC, and 17 (89%) received systemic chemotherapy after SIRT. Median LPFS, PFS, and OS after SIRT were 5.2 months, 2.0 months, and 14.9 months, respectively.ConclusionSIRT was well tolerated and did not prohibit subsequent treatment, resulting in a median OS of 14.9 months in this heavily pretreated population.     

Maintenance Sunitinib following Initial Platinum-Based Combination Chemotherapy in Advanced-Stage IIIB/IV Non–Small Cell Lung Cancer: A Randomized,Double-Blind,Placebo-Controlled Phase III Study—CALGB 30607 (Alliance)

IntroductionThe aim of this study was to evaluate efficacy of maintenance sunitinib after first-line chemotherapy for stage IIIB/IV NSCLC.MethodsCancer and Leukemia Group B 30607 trial was a randomized, double-blind, placebo-controlled, phase III study that enrolled patients without progression after four cycles of first-line platinum-based doublet chemotherapy with or without bevacizumab. Bevacizumab was allowed only during the four cycles of chemotherapy. Patients were randomized to receive sunitinib, 37.5 mg/d, or placebo and were treated until unacceptable adverse event(s), progression, or death. The primary end point was progression-free survival (PFS).ResultsA total of 210 patients were enrolled, randomized, and included in the intent-to-treat analysis. Ten patients did not receive maintenance therapy (four who received placebo and six who received sunitinib). Grade 3/4 adverse events affecting more than 5% of the patients were fatigue (25%), thrombocytopenia (12%), hypertension (12%), rash (11%), mucositis (11%), neutropenia (7%), and anemia (6%) for sunitinib and none for placebo. There were three grade 5 events in patients receiving sunitinib (one pulmonary hemorrhage, one other pulmonary event, and one death not associated with a Common Terminology Criteria for Adverse Events term) and two grade 5 events in patients receiving placebo (one other pulmonary event and one thromboembolism). Median PFS was 4.3 months for sunitinib and 2.6 months for placebo (hazard ratio = 0.62, 95% confidence interval: 0.47–0.82, p = 0.0006). Median overall survival was 11.7 months for sunitinib versus 12.1 months for placebo (hazard ratio = 0.98, 95% confidence interval: 0.73–1.31, p = 0.89).ConclusionsMaintenance sunitinib was safe and improved PFS as maintenance therapy in stage IIIB/IV NSCLC but had no impact on overall survival. There is no room for future investigations of sunitinib in this setting.     

Systemic and Intracranial Outcomes With First-Line Nivolumab Plus Ipilimumab in Patients With Metastatic NSCLC and Baseline Brain Metastases From CheckMate 227 Part 1

IntroductionIn CheckMate 227 Part 1, nivolumab plus ipilimumab prolonged overall survival (OS) versus chemotherapy in patients with metastatic NSCLC, regardless of tumor programmed death-ligand 1 (PD-L1) expression. Here, we report post hoc exploratory systemic and intracranial efficacy outcomes and safety by baseline brain metastasis status at 5 years’ minimum follow-up.MethodsTreatment-naive adults with stage IV or recurrent NSCLC without EGFR or ALK alterations, including asymptomatic patients with treated brain metastases, were enrolled. Patients with tumor PD-L1 greater than or equal to 1% were randomized to nivolumab plus ipilimumab, nivolumab, or chemotherapy; patients with tumor PD-L1 less than 1% were randomized to nivolumab plus ipilimumab, nivolumab plus chemotherapy, or chemotherapy groups. Assessments included OS, systemic and intracranial progression-free survival per blinded independent central review, new brain lesion development, and safety. Brain imaging was performed at baseline (all randomized patients) and approximately every 12 weeks thereafter (patients with baseline brain metastases only).ResultsOverall, 202 of 1739 randomized patients had baseline brain metastases (nivolumab plus ipilimumab: 68; chemotherapy: 66). At 61.3 months’ minimum follow-up, nivolumab plus ipilimumab prolonged OS versus chemotherapy in patients with baseline brain metastases (hazard ratio = 0.63; 95% confidence interval: 0.43–0.92) and in those without (hazard ratio = 0.76; 95% confidence interval: 0.66–0.87). In patients with baseline brain metastases, 5-year systemic and intracranial progression-free survival rates were higher with nivolumab plus ipilimumab (12% and 16%, respectively) than chemotherapy (0% and 6%). Fewer patients with baseline brain metastases developed new brain lesions with nivolumab plus ipilimumab (4%) versus chemotherapy (20%). No new safety signals were observed.ConclusionsWith all patients off immunotherapy for more than or equal to 3 years, nivolumab plus ipilimumab continued to provide a long-term, durable survival benefit in patients with or without brain metastases. Intracranial efficacy outcomes favored nivolumab plus ipilimumab versus chemotherapy. These results further support nivolumab plus ipilimumab as an efficacious first-line treatment for patients with metastatic NSCLC, regardless of baseline brain metastasis status.     

Effectiveness of Combining Bevacizumab With First-Line Chemotherapy Regimens for Metastatic Colorectal Cancer in Real-World Practice

BackgroundAnti–vascular endothelial growth factor (VEGF) agents have shown clinical benefits against metastatic colorectal cancer (mCRC) when combined with cytotoxic chemotherapeutic drugs. Because randomized controlled trials have restrictive enrollment criteria, and because the participants typically do not resemble actual patients, we here investigated the efficacy of bevacizumab as part of a combination therapy for mCRC in a Korean real-world practice setting.Patients and MethodsWe retrospectively evaluated 3748 patients with an initial diagnosis of mCRC or recurrent colorectal cancer with distant metastasis who received first-line chemotherapy in a tertiary cancer center. The primary study endpoint was overall survival. We used multivariate analysis using the Cox regression hazard model and propensity score matching (PSM) methods to adjust for any confounding clinicopathologic factors. Subgroup analysis was also performed for patients who did not receive local treatments for metastatic lesions before receipt of first-line chemotherapy.ResultsIn an initial crude analysis, patients who received first-line FOLFOX or FOLFIRI showed better survival outcomes if these regimens were combined with bevacizumab (median overall survival, 3.5 vs. 2.3 years; hazard ratio [HR] = 0.66; 95% confidence interval [CI], 0.59-0.73; P < .001). However, Cox regression hazard model adjusted analysis using PSM methods revealed no significant survival differences between these groups (3.0 vs. 2.6 years; HR = 0.92; 95% CI, 0.79-1.07; P = .2612). We performed further survival analysis of 2814 patients with unresectable disease without metastasectomy who received metastatic radiofrequency ablation before chemotherapy. Cox regression and PSM analysis indicated that bevacizumab group showed better survival (HR = 0.82; 95% CI, 0.71-0.94; P = .005; and HR = 0.84; 95% CI, 0.71-0.99; P = .018).ConclusionThe addition of bevacizumab to a first-line chemotherapeutic regimen provides survival benefits in a real-world setting for mCRC patients who cannot undergo curative-intent local treatment for metastatic lesions.     

CCTG BR34: A Randomized Phase 2 Trial of Durvalumab and Tremelimumab With or Without Platinum-Based Chemotherapy in Patients With Metastatic NSCLC

IntroductionFirst-line therapy for patients with metastatic NSCLC includes checkpoint inhibitor monotherapy, dual checkpoint inhibition, or combination with chemotherapy. We compared outcomes with combination chemoimmunotherapy versus dual checkpoint inhibition as first-line treatment for patients with metastatic NSCLC.MethodsThis open-label, randomized clinical trial was conducted at 44 sites in Canada and Australia. Patients with treatment-naive, metastatic NSCLC without sensitizing EGFR or ALK alterations were randomized (1:1) to receive treatment with durvalumab plus tremelimumab with or without platinum-doublet chemotherapy. The primary end point was overall survival (OS). Secondary end points were progression-free survival, overall response rate, and safety.ResultsA total of 301 patients were randomized. Median OS was 16.6 months (95% confidence interval [CI]: 12.6–19.1) with chemotherapy plus immunotherapy and 14.1 months (95% CI: 10.6–18.3) with immunotherapy (hazard ratio = 0.88, 90% CI: 0.67–1.16, p = 0.46). Median progression-free survival with chemotherapy plus immunotherapy was 7.7 months (95% CI: 5.5–8.5) and 3.2 months (95% CI: 2.7–5.1) with immunotherapy (hazard ratio = 0.67, 95% CI: 0.52–0.88). The overall response rate with chemoimmunotherapy was 42.4% and 29.3% with immunotherapy (adjusted OR = 1.69, 95% CI: 1.04–2.76). The percentage of patients with grade 3 or higher adverse events was 82% in the chemotherapy plus immunotherapy group and 70% in the immunotherapy group. Exploratory analyses of programmed death-ligand 1 expression and blood-based tumor mutation burden revealed no differential treatment effect on OS.ConclusionsThe addition of chemotherapy to durvalumab plus tremelimumab in the first-line treatment of stage IV NSCLC did not improve survival compared with durvalumab plus tremelimumab alone. Further study is warranted to identify patients that benefit from initial immunotherapy alone versus combination chemotherapy plus immunotherapy as first-line treatment.     

Chemotherapy plus Vandetanib or Chemotherapy Alone in Advanced Non-small Cell Lung Cancer: A Meta-analysis of Four Randomised Controlled Trials

AimsMost patients with advanced non-small cell lung cancer (NSCLC) require systemic chemotherapy. Vandetanib, targeting epidermal growth factor receptor and vascular endothelial growth factor receptor signalling in NSCLC, has recently been evaluated in combination chemotherapy in advanced NSCLC. However, the advantage of chemotherapy plus vandetanib over chemotherapy alone in advanced NSCLC remains largely unknown. A meta-analysis of randomised controlled trials was carried out to compare the efficacy and toxicity of chemotherapy plus vandetanib with chemotherapy alone in advanced NSCLC.Materials and methodsThe PubMed database, American Society of Clinical Oncology, European Society for Medical Oncology and the Cochrane Library and references of published trials were searched. Two reviewers independently assessed the quality of the trials. Data were extracted and the overall response rate, pooled progression-free survival, overall survival with 95% confidence intervals and main toxicity were analysed.ResultsFour randomised controlled trials involving 2160 patients with advanced NSCLC were ultimately analysed. Compared with chemotherapy alone, chemotherapy plus vandetanib significantly increased the overall response rate (relative risk = 1.96, 95% confidence interval = 1.53––2.52) and progression-free survival (hazard ratio = 0.79, 95% confidence interval = 0.71–0.87), but there was no significant difference in overall survival (hazard ratio = 0.91, 95% confidence interval = 0.79–1.03). Patients who received chemotherapy plus vandetanib had more rash, diarrhoea, hypertension and QTc prolongation (odds ratio = 2.32, 95% confidence interval = 1.93–2.79; odds ratio = 1.64, 95% confidence interval = 1.37–1.97; odds ratio = 4.08, 95% confidence interval = 2.51–6.01, odds ratio = 17.77, 95% confidence interval = 3.54–61.66, respectively), and less nausea and vomiting (odds ratio = 0.70, 95% confidence interval = 0.58–0.85; odds ratio = 0.69, 95% confidence interval = 0.55–0.86, respectively). The incidences of haemorrhage, fatigue and cough were comparable between the two groups.ConclusionsAlthough similar in overall survival, chemotherapy plus vandetanib showed particular advantages over chemotherapy alone in terms of progression-free survival and overall response rate. The toxicity was comparable between the two groups. Therefore, chemotherapy plus vandetanib might be a safe and valid therapeutic option for advanced NSCLC patients.     

Isolated hepatic melphalan perfusion of colorectal liver metastases: outcome and prognostic factors in 154 patients

BackgroundThe aim of this study was to identify prognostic factors for local and systemic failure after isolated hepatic perfusion (IHP) with 200 mg melphalan in patients with colorectal liver metastases.Patients and methodsHundred and fifty-four patients were selected for IHP and underwent laparotomy. Patients were monitored for response, toxicity and survival. Univariate and multivariate analyses were carried out to identify prognostic factors for hepatic response and progression-free and overall survival.ResultsHepatic response rate was 50% with a median progression-free and overall survival of, respectively, 7.4 and 24.8 months. In multivariate analyses, absence of ability to perfuse through the hepatic artery (P = 0.003), severe postoperative complications (P = 0.048) and >10 liver metastases (P = 0.006) adversely influenced overall survival and no adjuvant chemotherapy adversely influenced progression-free survival.ConclusionThis is the first study to report prognostic factors for survival after IHP. Possibly, overall and disease-free survival can increase if preoperative screening is improved. In future studies on IHP, adjuvant chemotherapy should be considered.     

Is Axitinib Still a Valid Option for mRCC in the Second-Line Setting? Prognostic Factor Analyses From the AXIS Trial

BackgroundAxitinib resulted in significantly longer progression-free survival (PFS) versus sorafenib in patients with metastatic renal-cell carcinoma (mRCC) previously treated with sunitinib in the AXIS trial. We report post hoc analyses evaluating patient subgroups that may benefit more from axitinib in this setting.Patients and MethodsAXIS was an open-label randomized phase 3 trial (NCT00678392) in mRCC patients with disease that failed to respond to one prior systemic therapy. Univariate and multivariate analyses evaluated potential prognostic factors for improved PFS and overall survival (OS) after sunitinib. PFS and OS of axitinib versus sorafenib were assessed within subgroups identified according to these factors.ResultsOf 723 patients, 389 received first-line sunitinib; 194 and 195 were randomized to second-line axitinib and sorafenib, respectively. Identified prognostic factors were: nonbulky disease (sum of the longest diameter < 98 mm), favorable/intermediate risk disease (Memorial Sloan Kettering Cancer Center or International Metastatic Renal Cell Carcinoma Database Consortium criteria), and no bone or liver metastases. In patients with all of these prognostic factors (n = 86), significantly longer PFS was observed for axitinib versus sorafenib (hazard ratio = 0.476; 95% confidence interval, 0.263-0.863; 2-sided P = .0126). OS (hazard ratio = 0.902; 95% confidence interval, 0.457-1.780; 2-sided P = .7661) was similar between treatments. Across subgroups, PFS was generally longer in patients treated with axitinib versus sorafenib, and OS was generally similar between the two treatments.ConclusionIn patients with mRCC, axitinib remains a suitable second-line treatment option across multiple subgroups. A relevant reduction in the risk of a PFS event was observed for axitinib compared to sorafenib in selected subgroups of patients.     

A Randomized Phase II Study of Perioperative Chemotherapy Plus Bevacizumab Versus Postoperative Chemotherapy Plus Bevacizumab in Patients With Upfront Resectable Hepatic Colorectal Metastases

IntroductionWhether patients with resectable colorectal liver metastases (CRLM) gain a survival benefit from perioperative chemotherapy remains controversial. The benefit of including bevacizumab in chemotherapy also remains unclear.Material and MethodsSeventy-six patients with CRLM were randomly assigned to either 6 cycles of FOLFOX (folinic acid, 5-fluorouracil, and oxaliplatin)/FOLFIRI (folinic acid, 5-fluorouracil, and irinotecan) with bevacizumab before and after surgery or 12 cycles after surgery. Progression-free survival (PFS) was estimated using the Kaplan-Meier method and compared by the log-rank test.ResultsThe median PFS of all patients was 37.4 months at 5.4 years follow-up, and the median overall survival (OS) was not reached. The PFS between the perioperative group and the postoperative group did not reveal a statistical difference (P = .280). The OS was significantly better in the perioperative group (hazard ratio [HR], 0.60; 95% confidence interval [CI],) 0.35-1.02; P = .049). In subgroup patients with carcinoembryonic antigens (CEA) ≥ 5 ng/mL or those with over 2 liver metastases, perioperative group had longer OS than postoperative group (CEA: HR, 0.49; 95% CI, 0.25-0.93; P = .030; number of liver metastases: HR, 0.55; 95% CI, 0.30-0.99; P = .049). The largest liver metastases size, disease-free interval, and sidedness did not affect PFS or OS. There was no difference between the 2 groups in postoperative complications with bevacizumab or adverse events during chemotherapy.ConclusionsIn patients with resectable CRLMs, perioperative chemotherapy had no effect on PFS, but improved OS. Patients with high CEA levels or over 2 liver metastases may benefit from perioperative chemotherapy.     

EGFR Tyrosine Kinase Inhibitor (TKI) Combined With Concurrent or Sequential Chemotherapy for Patients With Advanced Lung Cancer and Gradual Progression After First-Line EGFR-TKI Therapy: A Randomized Controlled Study

IntroductionContinuing tyrosine kinase inhibitor (TKI) therapy may be beneficial when patients with non–small-cell lung cancer and EGFR mutations experience gradual disease progression after initial EGFR-TKI treatment. We aimed to compare the efficacy of simultaneous EGFR-TKI and chemotherapy with that of sequential treatment after patients’ disease gradually progressed after first-line EGFR-TKI treatment.Patients and MethodsPatients with gradual progression who were EGFR-T790M mutation negative were randomly divided into two groups. In the concurrent group, patients were treated with pemetrexed plus cisplatin along with the same EGFR-TKI. In the sequential group, patients continued with EGFR-TKI until the disease progressed again, according to RECIST, then switched to chemotherapy. We evaluated the patients’ progression-free survival (PFS) and overall survival times.ResultsNinety-nine patients were enrolled: 49 in the concurrent group and 50 in the sequential group. The median PFS (mPFS) was 7.7 months (95% confidence interval [CI], 3.6-11.7) in the concurrent group and 5.7 months (95% CI, 3.5-7.9) in the sequential group (hazard ratio = 0.66; 95% CI, 0.44-1.00; P = .026), respectively. For the sequential group, the mPFS1 and mPFS2 were 1.8 months (95% CI, 1.4-2.3) and 3.8 months (95% CI, 3.1-4.5), respectively. The median overall survival of the concurrent group was longer than that of the sequential group (20.0 vs. 14.7 months; hazard ratio = 0.52; 95% CI, 0.32-0.85; P = .038).ConclusionFor patients with advanced non–small-cell lung cancer and gradual progression who are EGFR-T790M mutation negative after initial EGFR-TKI therapy, EGFR-TKI combined with chemotherapy confers longer PFS and overall survival than sequential EGFR-TKI and chemotherapy does.     

Central Nervous System Efficacy of Furmonertinib (AST2818) Versus Gefitinib as First-Line Treatment for EGFR-Mutated NSCLC: Results From the FURLONG Study

IntroductionFurmonertinib (AST2818) is a pan-EGFR tyrosine kinase inhibitor with central nervous system (CNS) antitumor activity. We report the CNS efficacy of furmonertinib compared with gefitinib in untreated EGFR-sensitizing mutation-positive NSCLC from the FURLONG study.MethodsFURLONG was a randomized, double-blind, phase 3 study conducted in 55 hospitals in the People’s Republic of China. Patients 1:1 randomly received furmonertinib 80 mg once daily or gefitinib 250 mg once daily treatment. At screening, all the patients underwent brain imaging examination. Patients with asymptomatic steady CNS metastases at baseline constituted this preplanned CNS subgroup analysis.ResultsA total of 358 patients were enrolled in the FURLONG study. In the 133 (37%) patients who had measurable or nonmeasurable CNS lesions, CNS progression-free survival was 20.8 months (95% confidence interval [CI]: 15.2–25.3) in the furmonertinib group and 9.8 months (95% CI: 7.2–18.0) in the gefitinib group (hazard ratio = 0.40 [95% CI: 0.23–0.71], p = 0.0011). In the 60 patients (17%) who had measurable CNS lesions, CNS objective response rate was 91% (95% CI: 72–99) with furmonertinib and 65% (95% CI: 48–80) with gefitinib (OR = 6.82 [95% CI: 1.23–37.67], p = 0.0277). The least-square mean of CNS depth of response was 62% (95% CI: 51–72) in the furmonertinib group and 39% (95% CI: 30–47) in the gefitinib group, the mean difference was 23% (95% CI: 10–37, p = 0.0011).ConclusionsFurmonertinib first-line treatment was found to have superior efficacy in CNS progression-free survival, CNS objective response rate, and CNS depth of response compared with gefitinib in patients with EGFR-mutated NSCLC with CNS metastases.     

A Randomized Double-Blind Phase II Study of the Seneca Valley Virus (NTX-010) versus Placebo for Patients with Extensive-Stage SCLC (ES SCLC) Who Were Stable or Responding after at Least Four Cycles of Platinum-Based Chemotherapy: North Central Cancer Treatment Group (Alliance) N0923 Study

IntroductionThe Seneca Valley virus (NTX-010) is an oncolytic picornavirus with tropism for SCLC. This phase II double-blind, placebo-controlled trial evaluated NTX-010 in patients with extensive-stage (ES) SCLC after completion of first-line chemotherapy.MethodsPatients with ES SCLC who did not progress after four or more cycles of platinum-based chemotherapy were randomized 1:1 to a single dose of NTX-010 or placebo within 12 weeks of chemotherapy. The primary end point was progression-free survival (PFS). A prespecified interim analysis for futility was performed after 40 events. Viral clearance and the development of neutralizing antibodies were followed.ResultsFrom January 15, 2010, to January 10, 2013, a total of 50 patients were randomized and received therapy on study (26 received NTX-010 and 24 received placebo). At the specified interim analysis, the median PFS was 1.7 months (95% confidence interval [CI]: 1.4–3.1 months) for the NTX-010 group versus 1.7 months (95% CI: 1.4–4.3 months) for the placebo group (hazard ratio = 1.03, p = 0.92), and the trial was terminated owing to futility. In the NTX-010 group, PFS was shorter in patients with detectable virus at days 7 and 14 versus in those in whom it was not detected after treatment (1.0 month [95% CI: 0.4–1.5 months] versus 1.8 months [95% CI: 1.3–5.5 months, p = 0.008] and 0.9 months [95% CI: 0.4–2.6 months] versus 1.3 months [95% CI: 1.0–5.3 months], respectively [p = 0.04]).ConclusionsPatients with ES SCLC did not benefit from NTX-010 treatment after chemotherapy with a platinum doublet. Persistence of NTX-010 in the blood 1 or 2 weeks after treatment was associated with a shorter PFS.     

Impact of Single-organ Metastasis to the Liver or Lung and Genetic Mutation Status on Prognosis in Stage IV Colorectal Cancer

BackgroundThe impact of primary tumor site on overall survival in patients with stage IV colorectal cancer (CRC) with single-organ metastases to the liver or lung has not been studied. Furthermore, the prognostic significance of commonly tested genetic variants such as KRAS mutation and microsatellite instability (MSI) are not well-described in this population.Materials and MethodsThis National Cancer Database was used to identify 38,328 patients with CRC that presented with synchronous metastases to the liver or lung between 2010 and 2014. The primary outcome was overall survival, and groups were compared using Kaplan-Meier analyses and Cox proportional hazard models.ResultsOn unadjusted analysis, median survival was significantly longer for patients with lung metastases compared with those with liver metastases for left-sided (27 vs. 25 months; P = .02) and right-sided CRC (19 vs. 15 months; P < .001), whereas rectosigmoid and rectal cancers showed no difference. On multivariate analysis, patients with liver metastases demonstrated worse survival compared with those with lung metastasis (hazard ratio, 1.37; 95% confidence interval, 1.31-1.43; P < .001). These trends were confirmed in patients that received chemotherapy but did not have their primary tumor or metastases resected. In patients with genetic testing, both KRAS mutants and MSI tumors had worse survival in left-sided and rectal tumors with liver metastases, but had similar survival to KRAS wild type tumors and microsatellite stable tumors, respectively, across other primary site and metastatic patterns.ConclusionsFor patients with single-organ metastases to the liver or lung, primary tumor site has an impact on overall survival. Further, KRAS mutation and MSI status are of prognostic importance in selected patients with single-organ metastases.     

Efficacy of Platinum/Pemetrexed Combination Chemotherapy in ALK-Positive NSCLC Refractory to Second-Generation ALK Inhibitors

IntroductionThe current standard initial therapy for advanced ALK receptor tyrosine kinase (ALK)–positive NSCLC is a second-generation ALK tyrosine kinase inhibitor (TKI) such as alectinib. The optimal next-line therapy after failure of a second-generation ALK TKI remains to be established; however, standard options include the third-generation ALK TKI lorlatinib or platinum/pemetrexed-based chemotherapy. The efficacy of platinum/pemetrexed-based chemotherapy has not been evaluated in cases that are refractory to second-generation TKIs.MethodsThis was a retrospective study performed at three institutions. Patients were eligible if they had advanced ALK-positive NSCLC refractory to one or more second-generation ALK TKI(s) and had received platinum/pemetrexed-based chemotherapy.ResultsAmong 58 patients eligible for this study, 37 had scans evaluable for response with measurable disease at baseline. The confirmed objective response rate to platinum/pemetrexed-based chemotherapy was 29.7% (11 of 37 patients; 95% confidence interval [CI]: 15.9% – 47.0%), with median duration of response of 6.4 months (95% CI: 1.6 months – not reached). The median progression-free survival for the entire cohort was 4.3 months (95% CI: 2.9 – 5.8 months). Progression-free survival was longer in patients who received platinum/pemetrexed in combination with an ALK TKI compared to those who received platinum/pemetrexed alone (6.8 months vs. 3.2 months, respectively; hazard ratio = 0.33; p = 0.025).ConclusionsPlatinum/pemetrexed-based chemotherapy shows modest efficacy in ALK-positive NSCLC after failure of second-generation ALK TKIs. The activity may be higher if administered with an ALK TKI, suggesting a potential role for continued ALK inhibition.     

A phase III study of belagenpumatucel-L,an allogeneic tumour cell vaccine,as maintenance therapy for non-small cell lung cancer

BackgroundTreatment options after first-line chemotherapy are limited in non-small cell lung cancer (NSCLC). Belagenpumatucel-L is a therapeutic vaccine comprised of 4 transforming growth factor (TGF)-β2-antisense gene-modified, irradiated, allogeneic NSCLC cell lines that may be useful for maintenance after initial treatment.MethodsStage III/IV NSCLC patients who did not progress after platinum-based chemotherapy were randomised 1:1 to receive maintenance belagenpumatucel-L or placebo. Patients were eligible for randomisation between one and four months from the end of induction chemotherapy. The primary endpoint was overall survival.ResultsThis phase III trial enrolled 270 patients in the belagenpumatucel-L arm and 262 in the control arm. Belagenpumatucel-L was well tolerated with no serious safety concerns. There was no difference in survival between the arms (median survival 20.3 versus 17.8 months with belagenpumatucel-L versus placebo, respectively; hazard ratio (HR) 0.94, p = 0.594). There were also no differences in progression-free survival (4.3 months versus 4.0 for belagenpumatucel-L vs placebo, respectively; HR 0.99, p = 0.947). A prespecified Cox regression analysis demonstrated that the time elapsed between randomisation and the end of induction chemotherapy had a significant impact on survival (p = 0.002) and that prior radiation was a positive prognostic factor (median survival 28.4 months with belagenpumatucel-L versus 16.0 months with placebo; HR 0.61, p = 0.032).ConclusionsAlthough the overall trial did not meet its survival endpoint, improved survival for belagenpumatucel-L is suggested in patients who were randomised within 12 weeks of completion of chemotherapy and in those who had received prior radiation. Further studies of belagenpumatucel-L in NSCLC are warranted.     

Primary tumor resection in patients with unresectable colorectal cancer with synchronous metastases could improve the activity of poly-chemotherapy: A trial-level meta-analysis

IntroductionPrimary tumor resection (PTR) in patients with metastatic unresectable colorectal cancer is less and less used to prevent local complications. Although its therapeutic effect is debated, poor data are available about the activity of chemotherapy (CHT) after PTR. The study aims to evaluate trials that compared PTR followed by CHT vs. CHT alone.MethodsAfter a literature search on two databases by predefined criteria, studies published from 2011 to 2021 were selected. All studies evaluating the progression-free survival (PFS) of patients receiving CHT after PTR or not were included in a meta-analysis. Finally, 18 possible moderating variables were extracted from each study and examined.ResultsEleven trials reported a reduced risk of progression after first-line CHT among patients receiving PTR (HR 0.72, CI 0.66–0.79). The heterogeneity was moderate (Q = 17.52; p-value = 0.093) and the grade of inconsistence intermediate (I² = 37.21%). Among moderating variables, female sex and low percentage of patients with liver metastases were related with a stronger effect size of PTR on PFS, whereas a longer OS and a trend to better PFS was evident after poly-chemotherapy regimens.ConclusionPTR could improve the results of first-line CHT in patients with unresectable colorectal cancer with low tumor burden only in the subgroup receiving more aggressive chemotherapy.     

Comparison of Chemotherapy Plus Pembrolizumab vs. Chemotherapy Alone in EGFR-Mutant Non–small-Cell Lung Cancer Patients

IntroductionPlatinum doublet chemotherapy is the standard of care in patients with non–small-cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutation who had disease progression after tyrosine kinase inhibitor (TKI). We aimed to assess immune checkpoint inhibitors efficacy in EGFR-mutant advanced NSCLC.Materials and MethodsWe retrospectively reviewed the data of sensitive EGFR-mutant NSCLC patients who progressed after EGFR-TKIs and received platinum doublet chemotherapy plus immunotherapy between 2015 and 2021. Efficacy outcomes, including overall response rate, progression-free survival, and overall survival, were assessed and compared with those of patients who had received platinum-based doublet chemotherapy.ResultsOf the total 869 patients, 82 treated with pembrolizumab and chemotherapy and 82 with only chemotherapy were selected. The median progression-free survival in patients administered pembrolizumab was significantly longer than those not administered pembrolizumab (6.7 months; 95% confidence interval [CI] 5.0-8.5 vs. 4.2 months; 95% CI 3.3-5.0, hazard ratio [HR] 0.64, 95% CI 0.46-0.89, P = .0076). Improved median overall survival was also observed in patients receiving pembrolizumab plus chemotherapy (26.7 [95% CI 22.6-30.8] vs. 13.4 months [95% CI 10.4-16.4], HR, 0.49 [95% CI 0.31-0.75], P = .0052). In addition, the overall response rate was higher in patients treated with than patients treated without pembrolizumab (34.1% and 20.7%, respectively).ConclusionThe combination of pembrolizumab with chemotherapy is associated with improved efficacy and survival in patients with EGFR-mutant NSCLC after TKI resistance, but these findings need to be confirmed in further prospective studies.     

Efficacy and Safety of First-Line Immunotherapy Combinations for Advanced NSCLC: A Systematic Review and Network Meta-Analysis

IntroductionA series of randomized controlled trials have investigated different first-line immunotherapy combinations, but the optimal combination strategy is yet to be established.MethodsWe performed a systematic review and Bayesian network meta-analysis by retrieving relevant literature from PubMed, EMBASE, Cochrane Library, ClinicalTrials.gov, and major international conferences. We included published and gray sources of randomized clinical trials comparing immunotherapy combinations with other treatments as first-line treatments for patients with advanced NSCLC. This study was registered in the Prospective Register of Systematic Reviews (CRD42020210501) to ensure transparency.ResultsWe analyzed a total of 16 studies involving 8278 patients and including 10 immunotherapy combinations. For patients without programmed death-ligand 1 (PD-L1) selection, pembrolizumab plus chemotherapy was found to be comparable with sintilimab plus chemotherapy in providing the best overall survival (OS) benefit (hazard ratio = 0.96, 95% confidence interval [CI]: 0.72–1.29). Furthermore, atezolizumab plus bevacizumab plus chemotherapy seemed to provide the best progression-free survival (hazard ratio = 0.45, 95% CI: 0.36–0.55) and the best objective response rate (OR = 0.23, 95% CI: 0.12–0.42). Subgroup analysis by PD-L1 suggested that nivolumab plus ipilimumab plus chemotherapy was associated with the best OS in patients with PD-L1 less than 1% and that pembrolizumab plus chemotherapy was associated with the best OS in patients with PD-L1 greater than or equal to 1%. Pembrolizumab and sintilimab were associated with relatively fewer grade greater than or equal to 3 adverse events when compared with other immunotherapies combined with chemotherapy.ConclusionsOur results suggest that antiprogrammed death-1 combinations are associated with potentially higher survival outcomes than anti–PD-L1 combinations with comparable safety profiles. Moreover, pem-chemo and nivo-ipi-chemo seem to be superior first-line immunotherapy combinations for patients with advanced NSCLC with positive and negative PD-L1 expression, respectively. Although atezo-beva-chemo treatment provided the best progression-free survival and objective response rate, the addition of chemotherapy to immunotherapy would increase the toxicity, especially when antiangiogenesis drugs are simultaneously added.