Median Progression-free Survival Values Research Articles

IBI310 plus sintilimab vs. placebo plus sintilimab in recurrent/metastatic cervical cancer: A double-blind, randomized controlled trial.

It remains unclear whether adding CTLA-4 blockade to PD-1/PD-L1 blockade improves clinical outcomes in cervical cancer (CC). In this randomized, double-blind, placebo-controlled, phase 2 study (ClinicalTrials.gov: NCT04590599), patients with recurrent/metastatic CC (R/M CC) who experienced disease progression after or during platinum-based chemotherapy were enrolled from 37 centers across China and randomly assigned (1:1), stratified by PD-L1 expression and prior treatment lines, to receive either IBI310 plus sintilimab or placebo plus sintilimab intravenously every 3weeks for 12weeks, followed by sintilimab alone. The primary endpoint was the objective response rate (ORR). Pivotal secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety. 205 patients were randomized to receive IBI310-sintilimab (n= 103) or placebo-sintilimab (n= 102). The ORR difference between the IBI310-sintilimab arm (32.3%, 95% confidence interval [CI]: 23.3%-42.5%) and the placebo-sintilimab arm (23.5%, 95% CI: 15.5%-33.1%) was not significant (p= 0.17). IBI310-sintilimab and placebo-sintilimab exhibited median PFS values of 3.6 (95% CI: 2.7-6.3) and 4.2months (95% CI: 2.8-6.2), respectively (hazard ratio [HR]= 0.91, 95% CI: 0.65-1.27; p= 0.58). The median OSs were 13.9months (95% CI: 11.5-25.6) in the IBI310-sintilimab arm and 17.2months (95% CI: 13.7-25.9) in the placebo-sintilimab arm (HR= 1.12, 95% CI: 0.79-1.58; p= 0.54). Adding IBI310 to sintilimab increased the incidence of grade ≥3 treatment-related adverse events (55% versus 19%). Compared to single-agent PD-1/PD-L1 blockade, dual blockade of CTLA-4 and PD-1/PD-L1 did not significantly improve clinical outcomes in R/M CC. This work was funded by Innovent Biologics (Suzhou).

Management of Metastatic Renal Cell Carcinoma Following First-Line Immune Checkpoint Therapy Failure: A Systematic Review.

There is a significant gap in the literature concerning the effective management of second-line therapy for patients with metastatic renal cell carcinoma (RCC) who have received immune checkpoint inhibitors (ICIs). Most of the published articles were small multicenter series or phase 2 studies. To our knowledge, a systematic review that comprehensively outlines the range of treatment options available for patients with metastatic RCC who do not respond to first-line ICIs has not yet been conducted. Our aim was to synthesize evidence on second-line therapies for patients with metastatic RCC after initial treatment with ICIs and to offer recommendations on the best treatment regimens based on the current literature. We conducted a search in PubMed, Embase, and the Cochrane Library on 29 February 2024, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We selected articles that met the predetermined inclusion criteria (written in English, retrospective observational studies, prospective series, and randomized trials reporting second-line therapy for metastatic RCC after failure of ICI-based therapy). Relevant articles were identified in the reference lists. The main endpoint was the overall response rate (ORR), with the median progression-free survival (PFS) and overall survival (OS) as secondary endpoints. We included 27 studies reporting the outcomes of 1970 patients. Salvage therapies were classified as targeted therapy (VEGFR TKIs) in 18 studies and ICIs in 8 studies. In studies where TKIs were the second line of choice, the pooled ORR was 34% (95% CI: 30.2-38%). In studies where ICIs, alone or in combination with TKIs, were used as second-line therapies, the ORR was 25.7% (95% CI: 15.7-39.2%). In studies where TKIs and ICIs were the second-line choices, the pooled median PFS values were 11.4 months (95% CI: 9.5-13.6 months) and 9.8 months (95% CI: 7.5-12.7 months), respectively. This systematic review shows that VEGFR TKIs and ICIs are effective second-line therapies following an initial treatment with anti-PD(L)1 alone or in combination. The treatment choice should be personalized, taking into account the patient's response to first-line ICIs, the site of the disease, the type of first-line combination (with or without VEGFR TKIs), and the patient's overall condition.

Real-world osimertinib pretreatment experience in patients with epidermal growth factor receptor T790M mutation-positive locally advanced or metastatic non-small cell lung cancer.

Osimertinib has demonstrated efficacy in patients with epidermal growth factor receptor (EGFR) T790M-positive non-small cell lung cancer (NSCLC) in clinical trials. However, real-world data on its effectiveness remain scarce. Taiwanese patients with T790M-positive locally advanced or metastatic NSCLC and progressive disease following treatment with at least one EGFR tyrosine kinase inhibitor (TKI) were enrolled from the osimertinib early access program. Of the 419 patients (mean age, 63 years; female, 67%), 53% were heavily pretreated (≥ third-line [3L]), making osimertinib a fourth-line (4L) intervention. The median progression-free survival (PFS) was 10.5 months (95% confidence interval [CI]: 8.95-11.41); the 18-month PFS rate was 26.5%. The median overall survival (OS) was 19.0 months (95% CI: 16.30-20.95); the 24-month OS rate was 40.9%. The objective response rate was 32.46%, and the disease control rate was 86.38%. The median time to treatment discontinuation of osimertinib monotherapy was 11.9 months (95% CI: 10.49-13.11). Subgroup analyses of median PFS and OS in the chemotherapy combination group vs. the osimertinib monotherapy group yielded no difference. Central nervous system (CNS) metastasis, number of prior lines of therapy, and types of initial EGFR-TKIs did not significantly impact outcomes. The median PFS values were 9.0 (95% CI: 5.18-11.34) and 10.9 (95% CI: 9.18-11.90) months with and without CNS metastasis, respectively, and 10.8 (95% CI: 8.59-12.69), 13.6 (95% CI: 10.89-16.3), and 9.2 (95% CI: 7.8-10.62) months for second-line (2L), 3L, and ≥4L therapy, respectively. In patients who received osimertinib as 2L therapy, the median PFS values in response to prior afatinib, erlotinib and gefitinib treatment were 11.2 (95% CI: 4.85-4.79), 10.5 (95% CI: 8.59-20.26) and 8.7 (95% CI: 7.21-16.79) months, respectively. Overall, real-world data from Taiwan support the clinical benefits of osimertinib in EGFR T790M -positive NSCLC.

Inflammatory biomarkers predict outcomes of patients with radioactive iodine refractory thyroid cancer treated with sorafenib.

The objective of this multicenter, retrospective cohort study was to evaluate the ability of inflammatory biomarkers representing the host immune system to predict outcomes in 70 patients with progressive radioactive iodine (RAI)-refractory thyroid cancer who were treated with sorafenib. Patients were divided into low and high inflammatory biomarker groups based on median values. Progression-free survival (PFS) and overall survival (OS) were assessed based on the lymphocyte-to-monocyte ratio (LMR), neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR). The median LMR, NLR, and PLR values were 3.4, 2.2, and 140.1, respectively. No significant differences were observed in baseline characteristics of high and low LMR, NLR and PLR groups. Median PFS values were 6.6 and 19.5 months in the low and high LMR groups, respectively (P < 0.001). Compared with the high NLR and PLR groups, PFS was significantly prolonged in the low NLR and PLR groups (P = 0.003 and P = 0.041 respectively). In the multivariate analysis, low LMR and high NLR were associated with poor PFS after adjusting for multiple confounding factors including age, sex, pathology, disease-related symptoms, serum thyroglobulin level, lung-only metastasis, cumulative RAI dose, time from diagnosis, and longer diameter of the target lesion (hazard ratio, HR = 2.42; 95% confidence interval, CI 1.25-4.71; P = 0.009, and HR = 2.09; CI, 1.06-4.14; P = 0.033, respectively). High LMR, low NLR, and low PLR were significantly associated with prolonged OS (P = 0.011, P = 0.023, and P = 0.007, respectively). Patients with at least one risk factors for inflammatory biomarkers presented a significantly lower PFS (HR 2.29; CI, 1.36-3.84; P = 0.003) and OS (HR 2.95; CI, 1.49-5.81; P = 0.006) than patients without any risk factor. Baseline inflammatory biomarkers successfully predicted PFS and OS in patients with progressive RAI-refractory thyroid cancer treated with sorafenib. These prognostic biomarkers might help arrive at appropriate clinical decisions regarding the use of sorafenib.

Five-gene signature for the prediction of response to immune checkpoint inhibitors in patients with gastric and urothelial carcinomas.

Ample evidence supports the potential of programmed death-ligand 1 (PD-L1) expression, detected by immunohistochemistry, as a predictive biomarker for immunotherapy in patients with advanced cancers. To predict the response to immune checkpoint inhibitors in patients with gastric and urothelial carcinomas, we aimed to replace PD-L1 combined positive score (CPS) with CD274 mRNA in the original four-gene signature and PD-L1 CPS model developed by us. We used quantitative real-time polymerase chain reaction (qRT-PCR) to measure the expression levels of five target genes in a cohort of 49 patients (33 with gastric cancer and 16 with urothelial carcinoma) who had received immunotherapy and whose therapeutic responses were available. The predictive performance was evaluated using R package maxstat. Cutoff values of mRNA expression level were measured using the log-rank statistics for progression-free survival (PFS). Based on these cutoffs, immunotherapy responses were predicted and sorted into responder (n=12, 24.5%) and non-responder (n=37, 75.5%) groups. The median PFS values of predicted responders and non-responders were 14.8 months (95% confidence interval [CI]: 0-34.7) and 4.7 months (95% CI: 1.0-8.4, p=0.02), respectively. Among the 12 predicted responders, 10 had microsatellite-stable tumors with a low tumor mutational burden. The actual clinical responses (complete and partial) were higher in the responder group than those in the non-responder group: 83.3% and 16.2%, respectively. We modified a predictive biomarker for CD274 mRNA expression to predict the response to immunotherapy in patients with gastric or urothelial carcinomas.

Real-World Metastatic Renal Cell Carcinoma Treatment Patterns and Clinical Outcomes in The Netherlands.

The number of treatment options for patients with metastatic renal cell carcinoma (mRCC) has significantly grown in the last 15 years. Although randomized controlled trials are fundamental in investigating mRCC treatment efficacy, their external validity can be limited. Therefore, the efficacy of the different treatment options should also be evaluated in clinical practice. We performed a chart review of electronic health records using text mining software to study the current treatment patterns and outcomes. mRCC patients from two large hospitals in the Netherlands, starting treatment between January 2015 and May 2020, were included. Data were collected from electronic health records using a validated text mining tool. Primary endpoints were progression-free survival (PFS) and overall survival (OS). Statistical analyses were performed using the Kaplan–Meier method. Most frequent first-line treatments were pazopanib (n = 70), sunitinib (n = 34), and nivolumab with ipilimumab (n = 28). The overall median PFS values for first-line treatment were 15.7 months (95% confidence interval [95%CI], 8.8–20.7), 16.3 months (95%CI, 9.3–not estimable [NE]) for pazopanib, and 6.9 months (95% CI, 4.4–NE) for sunitinib. The overall median OS values were 33.4 months (95%CI, 28.1–50.9 months), 39.3 months (95%CI, 29.5–NE) for pazopanib, and 28.1 months (95%CI, 7.0–NE) for sunitinib. For nivolumab with ipilimumab, median PFS and median OS were not reached. Of the patients who finished first- and second-line treatments, 64 and 62% received follow-up treatments, respectively. With most patients starting on pazopanib and sunitinib, these real-world treatment outcomes were most likely better than in pivotal trials, which may be due to extensive follow-up treatments.

Quantitative Analysis of the Efficacy of PARP Inhibitors as Maintenance Therapy in Recurrent Ovarian Cancer.

Objective: This study aimed to establish a pharmacodynamic model and to screen reasonable covariates to quantitatively describe the efficacy of poly (ADP-ribose) polymerase inhibitors (PARPis) as maintenance treatment for recurrent ovarian cancer (ROC). Methods: The log normal hazard function model was established by using progression-free survival (PFS) data of 1,169 patients from published randomized trials on FDA-approved PARP inhibitors (olaparib, niraparib, and rucaparib). Monte Carlo simulation was used to compare PFS values in different scenarios, such as monotherapy (administered alone) and combination therapy (PARPis combined with chemo- or target-therapies), different biomarker statuses, and different PARP inhibitors. PFS was also estimated. Results: The study showed that the median PFS was 8.5 months with monotherapy and 16.0 months with combination therapy. The median PFS of patients with the BRCA mutation, BRCA wild-type, and HRD-positivity were 11.0, 7.5, and 9.0 months in monotherapy, respectively, and 23.0, 14.0 and 17.5 months, in combination therapy, respectively. In addition, the median PFS of olaparib, niraparib, and rucaparib monotherapy were about 9.5, 10.5, and 12.0 months, respectively, and about 19.0, 20.0, and 25 months, respectively, in combination therapy. The median PFS values in combination with cediranib, bevacizumab, and chemotherapy were approximately 17.0, 12.5 and 19.5 months, respectively. Conclusion: PARPi combination therapy is more effective as maintenance treatment for ROC than monotherapy, and the efficacy of PARPis in combination with chemotherapy is higher than that of the combination with antiangiogenic drugs. We found that the PFS of BRCA wild-type was similar to that of HRD-positive patients, and there was no significant difference in PFS between olaparib, niraparib, and rucaparib, which provides necessary quantitative information for the clinical practice of PARPis in the treatment of ROC.

Post-Induction Management in Patients With Left-Sided RAS and BRAF Wild-Type Metastatic Colorectal Cancer Treated With First-Line Anti-EGFR-Based Doublet Regimens: A Multicentre Study.

BackgroundFew data regarding post-induction management following first-line anti-epidermal growth factor receptor (EGFR)-based doublet regimens in patients with left-sided RAS/BRAF wild-type metastatic colorectal cancer (mCRC) are available.MethodsThis multicenter, retrospective study aimed at evaluating clinicians’ attitude, and the safety and effectiveness of post-induction strategies in consecutive patients affected by left-sided RAS/BRAF wild-type mCRC treated with doublet chemotherapy plus anti-EGFR as first-line regimen, who did not experience disease progression within 6 months from induction initiation, at 21 Italian and 1 Spanish Institutions. The measured clinical outcomes were: progression-free survival (PFS), overall survival (OS), adverse events, and objective response rate (ORR).ResultsAt the data cutoff, among 686 consecutive patients with left-sided RAS/BRAF wild-type mCRC treated with doublet plus anti-EGFR as first-line regimen from March 2012 to October 2020, 355 eligible patients have been included in the present analysis. Among these, 118 (33.2%), 66 (18.6%), and 11 (3.1%) received a maintenance with 5-fluorouracil/leucovorin (5FU/LV)+anti-EGFR, anti-EGFR, and 5FU/LV, respectively, while 160 (45.1%) patients continued induction treatment (non-maintenance) until disease progression, unacceptable toxicity, patient decision, or completion of planned treatment. The median period of follow-up for the overall population was 33.7 months (95%CI = 28.9–35.6). The median PFS values of the 5FU/LV+anti-EGFR, anti-EGFR, 5FU/LV, and non-maintenance cohorts were 16.0 (95%CI = 14.3–17.7, 86 events), 13.0 (95%CI = 11.4–14.5, 56 events), 14.0 (95%CI = 8.1–20.0, 8 events), and 10.1 months (95%CI = 9.0–11.2, 136 events), respectively (p < 0.001). The median OS values were 39.6 (95%CI = 31.5–47.7, 43 events), 36.1 (95%CI = 31.6–40.7, 36 events), 39.5 (95%CI = 28.2–50.8, 4 events), and 25.1 months (95%CI = 22.6–27.6, 99 events), respectively (p < 0.001). After adjusting for key covariates, a statistically significant improvement in PFS in favor of 5FU/LV+anti-EGFR (HR = 0.59, 95%CI = 0.44–0.77, p < 0.001) and anti-EGFR (HR = 0.71, 95%CI = 0.51–0.98, p = 0.039) compared to the non-maintenance cohort was found. Compared to the non-maintenance cohort, OS was improved by 5FU/LV+anti-EGFR (HR = 0.55, 95%CI = 0.38–0.81, p = 0.002) and, with marginal significance, by anti-EGFR (HR = 0.67, 95%CI = 0.51–0.98, p = 0.051). No difference was found in ORR. Any grade non-hematological and hematological events were generally higher in the non-maintenance compared to the maintenance cohorts.ConclusionAmong the treatment strategies following an anti-EGFR-based doublet first-line induction regimen in patients affected by left-sided RAS/BRAF wild-type mCRC treated in a “real-life” setting, 5FU/LV+anti-EGFR resulted the most adopted, effective, and relatively safe regimen.

Diagnostic accuracy of pelvic magnetic resonance imaging for the assessment of bone marrow involvement in diffuse large B-cell lymphoma.

We investigated the efficacy of pelvic magnetic resonance imaging (MRI) in the diagnosis of bone marrow involvement (BMinv) in diffuse large B-cell lymphoma (DLBCL) patients. This was a retrospective study of data from a previous study (NCT02733887). We included 171 patients who underwent bone marrow biopsy (BMB) and bone marrow smear (BMS), pelvic MRI, and whole-body positron emission tomography-computed tomography (PET/CT) from January 2016 to December 2019 at a single center. BMB/BMS and whole-body PET/CT results were used as reference standards against which we calculated the diagnostic value of pelvic MRI for BMinv in DLBCL patients. A chi-square test was used to compare detection rates, and a receiver operating characteristic curve was used to evaluate diagnostic value of pelvic MRI. Propensity-score matching was performed according to clinical information, and Kaplan-Meier curves were constructed to compare progression-free survival (PFS) and overall survival (OS) of patients. The BMinv detection rate of pelvic MRI (42/171) was higher (P = 0.029) than that of BMB/BMS (25/171), and similar to that of PET/CT (44/171; P = 0.901). The sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of pelvic MRI were 83.33%, 98.37%, 94.15%, 95.24%, and 93.80%, respectively. Median PFS values were as follows: BMB/BMS-positive, 17.8 months vs. BMB/BMS-negative, 26.9 months (P = 0.092); PET/CT-positive, 24.8 months vs. PET/CT-negative, 33.0 months (P = 0.086); pelvic MRI-positive, 24.9 months vs. pelvic MRI-negative, 33.1 months (P<0.001). Median OS values were as follows: BMB/BMS-positive, 22.3 months vs. BMB/BMS-negative, 29.8 months (P = 0.240); PET/CT-positive, 27.9 months vs. PET/CT-negative, 33.9 months (P = 0.365); pelvic MRI-positive, 27.3 months vs. pelvic MRI-negative, 35.8 months (P = 0.062). Pelvic MRI is effective for detecting BMinv in DLBCL patients, providing a more accurate indication of PFS than BMB/BMS and PET/CT do. It may ultimately be used to improve the accuracy of clinical staging, guide patient treatment, and evaluate prognosis.

An Open-Label Randomized Controlled Trial Comparing the Efficacy and Safety of Pemetrexed-Carboplatin versus (Weekly) Paclitaxel-Carboplatin as First-Line Chemotherapy in Advanced Non-Squamous Non-Small Cell Lung Cancer

Background: Before the approval of first-line immune checkpoint inhibitors, platinum doublets were the standard of care in patients with treatment-naïve advanced non-small cell lung cancer (NSCLC) without targetable driver mutations. Pemetrexed-platinum combinations are preferred in non-squamous NSCLC. However, there has been no direct comparison to paclitaxel-carboplatin. Methods: This open-label randomized trial was designed to compare pemetrexed-carboplatin with (weekly) paclitaxel-carboplatin in treatment-naïve advanced/metastatic non-squamous NSCLC without driver mutations. Patients received either pemetrexed 500 mg/m² and carboplatin AUC 5 every 3 weeks, or paclitaxel 80 mg/m² on day 1, day 8, and day 15 with carboplatin AUC 5 every 4 weeks for 4 cycles. Patients in both arms were allowed to receive pemetrexed maintenance. Results: A total of 180 patients were enrolled. The study was terminated early; however, at the time of analysis 75.8% of the required events had occurred. Finally, 164 patients were evaluable, 83 in the pemetrexed arm and 81 in the paclitaxel arm. After a median follow-up of 17 months, progression-free survival (PFS) rates at 6 months were not different in the two treatment arms (47.45 vs. 48.64%, p = 0.88). The median PFS values were 5.67 months (95% CI 3.73–7.3) and 5.03 months (95% CI 2.63–7.43) in each arm, respectively (HR 1.13, 95% CI 0.81–1.59, p = 0.44). The median overall survival was also not different: 14.83 months (95% CI 9.5–18.73) and 11.3 (95% CI 8.3–19.7; HR 1.19, 95% CI 0.8–1.78, p = 0.37). All grade toxicities were similar except for alopecia and peripheral neuropathy, which were higher in the paclitaxel arm. Conclusion: Pemetrexed-carboplatin is not superior to (weekly) paclitaxel-carboplatin as the first-line regimen in advanced non-squamous NSCLC in terms of PFS.

Evaluating the role of stereotactic body radiation therapy with respect to androgen receptor signaling inhibitors for metastatic prostate cancer.

121 Background: Outcomes of stereotactic body radiation therapy (SBRT) with respect to androgen receptor signaling inhibitors (ARSI) have not been characterized for metastatic prostate cancer. Our purpose is to characterize prostate specific antigen (PSA) response and progression free survival (PFS) following SBRT among men who have received ARSI in castration sensitive and resistant settings. Methods: A single institution retrospective analysis was performed for men treated with SBRT and ARSI and categorized into 4 groups: 1) oligometastatic castration-sensitive prostate cancer (omCSPC), 2) ARSI-sensitive (ARSI-s) oligometastatic castration-resistant prostate cancer (omCRPC), 3) ARSI-resistant (ARSI-r) omCRPC, and 4) polymetastatic CRPC (pmCRPC). We calculated the PSA reduction greater than 50% (PSA50) and median PFS (PSA or radiographic progression) as determined by routine care. We also used Cox regression analysis to determine factors influencing PFS for ARSI-r disease. Results: 73 men with 126 lesions were treated with SBRT and followed for a median of 14.4 months. The percentages of men who achieved a PSA50 for omCSPC, ARSI-s omCRPC, ARSI-r omCRPC and pmCRPC were 100%, 90%, 62.9%, and 16.7%, respectively. Respective median PFS values were: not reached, 17.3, 9.0, and 1.6 months. For the 35 men with ARSI-r omCRPC, incomplete ablation (defined as the presence of untreated lesions after SBRT or prior palliative external beam radiation therapy (EBRT)) (HR 3.51 [1.36, 9.06]; p = 0.01) was associated with worse PFS on multivariable analysis. For the subgroup of 22 men with ARSI-r omCRPC without prior palliative EBRT or untreated metastases, the median PFS was 13.1 months. Conclusions: SBRT may augment the efficacy of ARSI, particularly among men with ARSI-r omCRPC, provided that all lesions received ablative radiation doses. Future prospective study of SBRT for men receiving ARSI is warranted.

Impact of C-reactive protein flare-response on oncological outcomes in patients with metastatic renal cell carcinoma treated with nivolumab

BackgroundThe dynamic change in C-reactive protein (CRP) levels, CRP kinetics, is a prognostic factor for metastatic renal cell carcinoma (mRCC) in the tyrosine kinase inhibitor era. We investigated the impact...

Prevalence and Clinical Impact of Concomitant Mutations in Anaplastic Lymphoma Kinase Rearrangement Advanced Non-small-Cell Lung Cancer (Guangdong Association of Thoracic Oncology Study 1055).

Background: In patients with anaplastic lymphoma kinase (ALK) rearrangement-positive advanced non–small-cell lung cancer (NSCLC), ALK inhibitors are now the standard treatment, but their clinical efficacy varies widely for each patient. In this multicenter retrospective study, we evaluated the clinical efficacy of crizotinib according to the ALK rearrangement variants and concomitant mutations present.Patients and Methods: A total 132 patients with ALK rearrangement advanced NSCLC from 4 centers in Guangdong province, China were evaluated. All patients received crizotinib treatment and their ALK rearrangement status was identified by next-generation sequencing (NGS).Results: The median progression-free survival (PFS) in patients with EML4-ALK rearrangement (n = 121), non-EML4-ALK rearrangement (n = 5), and EML4-ALK arrangement accompanied by non-EML4-ALK rearrangement (n = 6) was 12.8, 7.5, and 7.4 months, respectively, with no significant difference between them (p = 0.1554). Similarly, among patients with various EML4-ALK variants (variant 1, variant 3a/b, and other variants), the median PFS values were again comparable. According to baseline NGS data, the median PFS in patients who had ALK rearrangement only, ALK rearrangement and concomitant tumor-suppressor gene mutations, and ALK rearrangement and concomitant oncogene mutations was 14.2, 10.9, and 4.9 months, respectively; (p = 0.0002). A multivariable analysis indicated that concomitant oncogene mutations and tumor-suppressor gene mutations were both negative factors influencing the efficacy of crizotinib in ALK rearrangement NSCLC.Conclusion: Concomitant oncogene mutations and tumor-suppressor gene mutations had negative effects on the efficacy of crizotinib, while various ALK variants had a similar influence.

Bioinformatics analysis of FOLR1 expression, functional enrichment, related signaling pathways and relationship with prognosis in ovarian cancer

Abstract Objective To investigate folate-receptor 1 (FOLR1) expression in ovarian cancer and its association with patient prognosis. Methods TCGA and Oncomine databases were used to collect data about FOLR1 mRNA expression in multiple carcinomas. FOLR1 mRNA expression levels in ovarian cancer samples and corresponding adjacent normal ovary tissue were compared. A protein-protein interaction (PPI) network was constructed using the STRING database of FOLR1 and relevant genes. The overall survival (OS) and progression free survival (PFS) rates of ovarian cancer patients in high- and low- FOLR1 expression groups were compared by log-rank test. Sixty-six ovarian epithelial carcinoma samples were included in the study, and tumor specimens of the 66 cases were tested for FOLR1 protein expression by an immunohistochemistry assay. Results FOLR1 mRNA was significantly elevated in ovarian cancer compared to other carcinomas. FOLR1 mRNA expression levels were significantly higher in tumor tissues than in the corresponding normal tissues (P&lt;0.05) of ovarian cancer patients. The PPI network indicated that the local clustering coefficient was 0.898, indicating that the PPI network was enriched significantly (P&lt;0.05). The median PFS values were 22.39 and 19.00 months for lowand high-FOLR1 expression groups, respectively, with significant statistical difference between the two (HR=1.26, 95%CI:1.09-1.45, P&lt;0.05). FOLR1 protein expression was correlated with tumor differentiation (P&lt;0.05) in ovarian cancer patients. However, its levels were not correlated with patient age, tumor diameter, lymph node metastasis or FIGO stage (P&gt;0.05). Conclusion FOLR1 is upregulated in epithelial ovarian cancer, and its expression is correlated with patients’ progression free survival, making it a valuable biomarker for prognosis.

PF637 EFFICACY OF LENALIDOMIDE AND LOW‐DOSE DEXAMETHASONE IN NEWLY DIAGNOSED PATIENTS WITH MULTIPLE MYELOMA: RESULTS FROM A META‐ANALYSIS OF RANDOMIZED CONTROLLED TRIAL EVIDENCE

Background:Lenalidomide and low‐dose dexamethasone (Rd) is an established treatment option for patients with newly diagnosed multiple myeloma (NDMM) who are not candidates for autologous stem cell transplantation (ASCT). The efficacy and safety of Rd was demonstrated in the FIRST trial, which showed a significant improvement in overall survival (OS) with Rd compared with combination melphalan, prednisone, and thalidomide. The alkylator‐free Rd regimen is now a recommended treatment option in the European Society for Medical Oncology (ESMO) guidelines (Moreau et al. Ann Oncol. 2017;28:iv52–61). Recent trials comparing Rd + bortezomib or Rd + daratumumab with Rd have contributed to the growing body of evidence regarding the efficacy of Rd in patients with NDMM.Aims:To obtain a consolidated median estimate for OS and progression‐free survival (PFS) outcomes from phase 3 registration studies in NDMM patients not intended for ASCT receiving Rd.Methods:Details of trial characteristics, baseline patient characteristics, and outcomes were extracted from phase 3 registration studies of NDMM patients treated with Rd. Kaplan–Meier curves for OS and PFS were digitized and patient‐level data were estimated numerically. These estimated patient‐level data were then pooled in a Bayesian meta‐analysis. Weibull, Gompertz, and second‐order fractional polynomial models were fit to the data to estimate the survival function.Results:In this meta‐analysis of randomized controlled trials, there was some variance among the three trials, regarding inclusion criteria and baseline characteristics. Notably, SWOG S0777 enrolled patients who were not intended for immediate ASCT, whereas FIRST and MAIA enrolled patients who were ineligible for ASCT. Median follow‐up for MAIA was shorter than FIRST or SWOG S0777 (28 months vs 67 and 84 months, respectively). As this precluded the stable estimation of heterogeneity, a fixed‐effects model was employed. Using the best‐fitting models, the median OS with Rd was estimated to be 67.2 months (95% confidence interval [CI] 61.3–74.2 months) and the median PFS was estimated to be 28.9 months (95% CI 26.8–31.3 months). Estimated results were consistent with the results from the individual trials (median PFS values for FIRST, S0777, and MAIA were 26.0, 30, and 31.9 months, respectively; median OS was 59.1, 64, and not reported, respectively) and subgroups tested (where data were available). The adverse events reported with Rd across these 3 trials were consistent with the known safety profile for this regimen.Summary/Conclusion:This analysis demonstrated a consistent treatment benefit for Rd across the phase 3 trials studied, with estimates for median OS and PFS exceeding 5 years and 2 years respectively, in patients with NDMM ineligible for ASCT. The results support the ESMO guideline recommendation for Rd as a first‐line standard of care in this setting and its role in the development of novel combination regimens.

Single-institution retrospective review of patients with recurrent glioblastoma treated with bevacizumab in clinical practice.

Background and aimsThis retrospective review of patients with recurrent glioblastoma treated at the Preston Robert Tisch Brain Tumor Center investigated treatment patterns, survival, and safety with bevacizumab in a real‐world setting.MethodsAdult patients with glioblastoma who initiated bevacizumab at disease progression between January 1, 2009, and May 14, 2012, were included. A Kaplan‐Meier estimator was used to describe overall survival (OS), progression‐free survival (PFS), and time to greater than or equal to 20% reduction in Karnofsky Performance Status (KPS). The effect of baseline demographic and clinical factors on survival was examined using a Cox proportional hazards model. Adverse event (AE) data were collected.ResultsSeventy‐four patients, with a median age of 59 years, were included in this cohort. Between bevacizumab initiation and first failure, defined as the first disease progression after bevacizumab initiation, biweekly bevacizumab and bevacizumab/irinotecan were the most frequently prescribed regimens. Median duration of bevacizumab treatment until failure was 6.4 months (range, 0.5‐58.7). Median OS and PFS from bevacizumab initiation were 11.1 months (95% confidence interval [CI], 7.3‐13.4) and 6.4 months (95% CI, 3.9‐8.5), respectively. Median time to greater than or equal to 20% reduction in KPS was 29.3 months (95% CI, 13.8‐∞). Lack of corticosteroid usage at the start of bevacizumab therapy was associated with both longer OS and PFS, with a median OS of 13.2 months (95% CI, 8.6‐16.6) in patients who did not initially require corticosteroids versus 7.2 months (95% CI, 4.8‐12.5) in those who did (P = 0.0382, log‐rank), while median PFS values were 8.6 months (95% CI, 4.6‐9.7) and 3.7 months (95% CI, 2.7‐6.6), respectively (P = 0.0243, log‐rank). Treatment failure occurred in 70 patients; 47 of whom received salvage therapy, and most frequently bevacizumab/carboplatin (7/47; 14.9%). Thirteen patients (18%) experienced a grade 3 AE of special interest for bevacizumab.ConclusionsTreatment patterns and outcomes for patients with recurrent glioblastoma receiving bevacizumab in a real‐world setting were comparable with those reported in prospective clinical trials.

P2.12-12 Plasma Vitamin D Level is an Independent Prognosis Factor in SCLC Patients Treated with Platinum Plus Etoposide as First-Line Chemotherapy

Small cell lung cancer accounts for approximately 13.6% of all lung cancer cases, which is a very aggressive form of lung cancer and associated with a very poor prognosis.Investigations into the prognostic factors of SCLC may help in the development of new biotherapeutic regimens.VD deficiency has been well documented to be unfavorable for the prognosis of patients with several types of cancer.However,there is no study focus on the relationship between the plasma VD level and the prognosis of SCLC patients. The primary objective of this study was to examine the prognostic role of the plasma 25-hydroxyvitamin D (25(OH)D) level in SCLC patients treated with platinum plus etoposide as first-line chemotherapy. A total of 178 SCLC patients were consecutively and prospectively hospitalized to receive platinum plus etoposide as first-line chemotherapy. The baseline 25(OH)D level was measured at the time of diagnosis. Main outcome measures included overall survival (OS) and progression-free survival (PFS). The median OS values of patients with 25(OH)D < 10ng/mL and ≥10ng/mL were 12.5 months (95% confidence interval[CI], 9.4–18.0 months) and 21.3 months (95%CI,12.8–29.1months),respectively; the median PFS values were 6.6 months(95%CI,5.1–7.6months) and 12.7months (95%CI,9.1–17.7months), respectively. Both univariate and multivariate analyses showed that having a plasma 25(OH)D level < 10 ng/mL was associated with a significantly shorter OS(P = 0.000; P =0.000) and PFS(P = 0.000; P =0.000).The median OS values of patients with 25(OH)D < 20ng/mL and ≥20ng/mL were 14.7 months (95% confidence interval[CI], 10.7–22.1 months) and 29.1 months (95%CI, 26.9–38.9 months), respectively; the median PFS values were 8.2months(95%CI, 6.5–10.7 months) and 22.4 months (95%CI, 21.2–24.2 months), respectively. Both univariate and multivariate analyses showed that having a plasma 25(OH)D level <20 ng/mL was associated with a significantly shorter OS (P = 0.000), while the baseline plasma 25(OH)D level was not significantly associated with PFS. Plasma vitamin D level is an independent prognosis factor in small cell lung cancer patients treated with platinum plus etoposide as first-line chemotherapy.

BPR1J373, a novel multitargeted kinase inhibitor, effectively suppresses the growth of gastrointestinal stromal tumor

Gastrointestinal stromal tumor (GIST) is a type of KIT‐driven cancer. KIT gene mutations are found in approximately 80% of GISTs, and most of these mutations occur in exon 9 and exon 11. Imatinib has been successfully used as a first‐line treatment for advanced GIST, with a significant improvement in progression‐free survival (PFS) and overall survival. However, disease progression might develop due to primary or secondary resistance to imatinib. Sunitinib and regorafenib have been approved as second‐ and third‐line treatments for advanced GIST patients, with median PFS values of 6.8 and 4.8 months, respectively. However, these relatively modest improvements in PFS underscore the need for more effective KIT inhibitors. BPR1J373 is a multitargeted kinase inhibitor that has been shown to inhibit the proliferation of KIT‐driven acute myeloid leukemia cells in vitro and in vivo. In this study, we found that BPR1J373 inhibited proliferation and induced apoptosis by targeting KIT in GIST cells with KIT gene mutations. BPR1J373 also induced cell cycle arrest and senescent change in KIT‐mutant GIST48 cells, probably by targeting aurora kinase A. In the KIT‐null COS‐1 cell‐based system, BPR1J373 effectively inhibited KIT with single or double mutations of KIT developed in GIST. The antiproliferative effect was also consistently evident in GIST430 tumor‐grafted mice. The results suggest that BPR1J373 could be a potential anticancer drug for GIST and deserves further investigation for clinical applications.

Effectiveness Outcomes in Patients With Recurrent or Refractory Head and Neck Cancers: Retrospective Analysis of Data From a Community Oncology Database

PurposeThe purpose of this study was to provide an understanding of the effectiveness of existing therapies in patients with advanced head and neck cancer (HNC), particularly in clinical practice. MethodsData from the electronic medical records of adult patients diagnosed with locally advanced or metastatic (Stage III-IVc) HNC between January 1, 2007, and October 1, 2015, were retrospectively collected from a network of community oncology practices in the United States. Eligible patients experienced disease progression despite having received prior systemic therapy. Kaplan-Meier and Cox regression analyses of progression-free survival (PFS) and overall survival (OS) were conducted. Patient-reported outcomes were also collected. FindingsThe study included 462 patients (median age 61.0 years; 80.7% male; 77.1% white). Most patients had a history of tobacco use (41.8% current, 41.8% past), and human papillomavirus testing was infrequent overall (11.0%). The median overall duration of follow-up was 16.4 months (range, 2.3–85.2 months). Median PFS values were 8.45 months with first-line treatment and 5.33 months with second-line treatment. PFS with first-line treatment was significantly associated with primary tumor location, performance status, and tobacco use. Performance status was a predictor of PFS in second-line treatment. Median OS values were 21.04 and 9.53 months from the start of the first and second lines of therapy, respectively. Abuse/excessive use of alcohol, older age, and impaired performance status were associated with a significantly increased risk for death in outcomes analyses. Outcomes were worse among patients initially diagnosed with Stage IVc disease versus those who progressed to Stage IVc. Past tobacco use and alcohol abuse were associated with worse patient-reported symptoms such as dry mouth and sore throat (smoking) and trouble swallowing (alcohol). ImplicationsThis study of data from clinical practice shows that there remains a large unmet need for effective therapeutic options in advanced HNC. Patients' characteristics such as alcohol use and performance status were statistically significant predictors of PFS and OS in Stage III-IVc HNC.

Hepatoceliac Lymph Node Involvement in Advanced Ovarian Cancer Patients: Prognostic Role and Clinical Considerations.

The study aimed too investigate the rate of hepatoceliac lymph node (HCLN) involvement, as well as its association with clinicopathologic features, together with morbidity of HCLN resection and the prognostic impact of metastatic HCLN status on patients with advanced ovarian cancer (OC) undergoing cytoreductive surgery. All consecutive patients with stages 3c to 4 epithelial OC who underwent HCLN surgery from January 2010 to September 2016 were analyzed for surgical procedures, pathology, and oncologic outcomes. During the study period, 85 patients underwent HCLN resection. Absence of visible tumor at the end of surgery was documented for 73 of the patients (85.9%). The median number of HCLNs removed was 6 (range 1-18). Histopathologic evaluation was able to identify HCLN metastasis in 45 (52.9%) of the 85 cases. No difference in the rate of surgical morbidity according to pathologic status of HCLN was observed. As of December 2016, the median follow-up period was 36months (range 6-54months). Recurrence of disease was observed in 35 (41.2%) of the 85 cases. Relapse of disease most frequently occurred for the patients with metastatic HCLN involvement (65.7%) compared with the patients who had no HCLN involvement (34.3%) (p=0.048). The median progression-free survival values were 16months (95% confidence interval [CI], 12-19months) for the patients with metastatic HCLNs and 22months (95% CI, 12-19months) for the patients with no HCLN involvement (p=0.035). The study confirmed that HCLN surgery is feasible with acceptable morbidities for patients with advanced OC. Metastatic HCLNs are a marker of disease severity associated with worst oncologic outcome.