Comparative efficacy of later-line therapies for metastatic colorectal cancer: a network meta-analysis of survival curves.

INTRODUCTION: We evaluated the comparative efficacy of 6 later-line (≥3) therapies for metastatic colorectal cancer (mCRC) over placebo. We applied a novel statistical method of reconstructing pseudo patient-level data (pseudo-IPD) to inform a network meta-analysis of survival curves that considers shape in addition to scale parameters. METHODS: A literature search yielded 10 phase II/III trials. We digitized all survival curves and applied a novel method incorporating curve coordinates, patients-at-risk, and events reported to generate pseudo-IPD. Using fitted random effects lognormal distributions, we estimated the survival proportions and HRs(95CrI) of progression-free (PFS) and overall survival(OS) over 12 months of follow-up. RESULTS: Compared to placebo, in ascending order, 12-month OS HRs were 0.50(95%CrI = 0.35, 0.69; PFS = 0.11(95%CrI = 0.06, 0.14)) for TAS+bevacizumab; 0.71(95%CrI = 0.51, 0.97; PFS = 0.26(95%CrI = 0.16, 0.41)) for regorafenib; 0.75(95%CrI = 0.61, 0.91; (PFS = 0.24(95%CrI = 0.17, 0.31)) for TAS-102; 0.80(95%CrI = 0.79, 0.90; PFS = 0.18(95%CrI = 0.13, 0.24)) for fruquintinib; 0.83(95%CrI = 0.50, 0.99; PFS = 0.42(95%CrI = 0.20, 0.75)) for atezolizumab+cobimetinib; and 1.03(95%CrI = 0.55, 1.65; PFS = 0.67(95%CrI = 0.29, 1.01)) for atezolizumab. CONCLUSION: In this independent NMA of survival data all later-line mCRC therapies but atezolizumab monotherapy exhibited superiority in 12-month PFS and OS over placebo. TAS+bevacizumab emerged as the most dominant option and may be the preferred choice; with fruquintinib, regorafenib and TAS-102 monotherapy showing statistically significant but lower PFS and OS benefits. REGISTRATION: PROSPERO: CRD42022371953.

Percutaneous tibial neuromodulation initial therapy compliance and subsequent third-line treatment patterns.

PURPOSE: Percutaneous Tibial Neuromodulation (PTNM) is used to treat Overactive Bladder (OAB). This analysis summarizes patient adherence to PTNM treatment and examines trends of other third-line therapy use during and after PTNM. METHODS: Optum's deidentified Clinformatics® Data Mart Database (CDM) and CMS Research Identifiable Files were queried for adults with OAB symptoms and who underwent PTNM treatment (2019-2020). We evaluated the proportion of patients who completed 12 visits within 1 year, and defined patients as treatment compliant if 12 PTNM visits were completed within 12 weeks. We then identified the proportion of patients who used other third-line therapies after PTNM and stratified these patients based on their PTNM therapy compliance status. RESULTS: 2302 patients met selection criteria from CDM and 16,473 patients from CMS. The proportion of patients completing a full PTNM treatment course increased over time; from 16% at week 12% to 42% by week 52 (CDM) and 24% to 38% (CMS). Other third-line therapy use increased over time and was higher for PTNM noncompliant versus compliant patients at 52 weeks: onabotulinumtoxinA was 6.5% versus 5.7% for noncompliant versus compliant (CMS, p = 0.0661) and 6.4% versus 4.9% (CDM, p = 0.035), SNM trial procedure was 6.5% versus 2.5% (CDM, p = 0.002) and 4.2% versus 2.0% (CMS, p = 0.010). CONCLUSIONS: Most patients are noncompliant with recommended PTNM treatment regimen. Albeit low, third-line therapy was pursued more frequently by noncompliant patients. Given low compliance, the effectiveness of PTNM may be compromised. Alternative implantable technologies may be needed to assure effectiveness of neuromodulation.

Real-world outcomes of third-line immune checkpoint inhibitors versus irinotecan-based chemotherapy in patients with advanced gastric cancer: a Korean, multicenter study (KCSG ST22-06).

BACKGROUND: Immune checkpoint inhibitor (ICI) or irinotecan-based chemotherapy is frequently used after failure of second-line paclitaxel plus ramucirumab treatment for patients with locally advanced unresectable or metastatic advanced gastric cancer (AGC). This study aimed to compare the efficacy between ICI and irinotecan-based chemotherapy as third-line treatment in patients with AGC. METHODS: We retrospectively reviewed patients with AGC, whose third-line treatment started between July 2019 and June 2021 at 17 institutions in Korea. The ICI group included patients who received nivolumab or pembrolizumab, and the irinotecan-based chemotherapy group included patients who received irinotecan or FOLFIRI (5-fluorouracil, leucovorin and irinotecan). RESULTS: A total of 363 patients [n = 129 (ICI) and n = 234 (irinotecan-based chemotherapy)] were analyzed. The median progression-free survival was 2.3 and 2.9 months in ICI and irinotecan-based chemotherapy groups, respectively (p = 0.802). The median overall survival (OS) was 5.5 and 6.0 months in ICI and irinotecan-based chemotherapy groups, respectively (p = 0.786). For all patients included in this study, multivariable analysis showed that weight loss, peritoneal metastasis, low serum sodium or albumin, and short duration of second-line treatment were associated with inferior OS (p < 0.05). ICI showed significantly longer OS than irinotecan-based chemotherapy in patients without peritoneal metastasis. Whereas ICI showed significantly shorter OS in patients without PD-L1 expression than irinotecan-based chemotherapy. CONCLUSIONS: No significant difference in survival outcome was observed between ICI and irinotecan-based chemotherapy as third-line treatment for AGC patients. ICI might be preferred for patients without peritoneal metastasis and irinotecan-based chemotherapy for patients with tumors without PD-L1 expression. TRIAL REGISTRATION: This study was registered in the Clinical Trial Registry of Korea ( https://cris.nih.go.kr : KCT 0007732).

Comparing the efficacy of regorafenib and 5-fluorouracil-based rechallenge chemotherapy in the third-line treatment of metastatic colorectal cancer.

BACKGROUND: The optimal treatment for metastatic colorectal cancer (mCRC) after the second line is still controversial. Regorafenib has been the standard of care in this setting as it improved overall survival (OS) compared to placebo. In real-world practice chemotherapy rechallenge is also a preferred option even though supporting evidence is not enough. We aim to compare the efficacy of regorafenib and 5-fluorouracil-based (5-FU) rechallenge treatment in the third line setting of mCRC. METHODS: In this retrospective multi-institutional trial, mCRC patients from 21 oncology centers who progressed after 2 lines of chemotherapy were analyzed. Patients who were treated with regorafenib or rechallenge therapy in the third-line setting were eligible. Rechallenge chemotherapy was identified as the re-use of the 5-FU based regimen which was administered in one of the previous treatment lines. OS, disease control rate (DCR), progression free survival (PFS) and toxicity were analyzed. RESULTS: Three hundred ninety-four mCRC patients were included in the study. 128 (32.5%) were in the rechallenge, and 266 (67.5%) were in the regorafenib group. Median PFS was 5.82 months in rechallenge and 4 months in regorafenib arms (hazard ratio:1.45,95% CI, p = 0.167). DCR was higher in the rechallenge group than regorafenib (77% vs 49.5%, respectively, p = < 0.001). Median OS after the third-line treatment was 11.99 (95% CI, 9.49-14.49) and 8.08 months (95% CI, 6.88-9.29) for rechallenge and regorafenib groups, respectively (hazard ratio:1.51, 95% CI, p < 0.001). More adverse effects and discontinuation were seen with regorafenib treatment. CONCLUSION: Our study revealed that higher disease control and OS rates were achieved with rechallenge treatment compared to regorafenib, especially in patients who achieved disease control in one of the first two lines of therapy.

Real-world treatment patterns in patients initiating third-line therapy for relapsed or refractory multiple myeloma in Germany, Italy, the United Kingdom, France, and Spain.

OBJECTIVES: To retrospectively analyze real-world treatment patterns in patients with relapsed/refractory multiple myeloma (RRMM) who initiated third-line treatment in Europe. METHODS: German and Italian administrative claims data were sourced from the German AOK PLUS health insurance fund and Italian local health units (2016-2020). Data for the United Kingdom (UK), France, and Spain were sourced from medical chart reviews (MCRs) from 2016 to 2018 (historical) and 2019 to 2021 (new) using electronic case report forms. RESULTS: Across all countries, immunomodulatory imide drug (IMiD)-based regimens were prominent in the third-line setting. From 2016 to 2020, lenalidomide-dexamethasone was most common in Italy (18.0%) and Germany (12.7%). From 2019 to 2021, the most common regimen was ixazomib-lenalidomide-dexamethasone (67.5%) in the UK, pomalidomide-dexamethasone (17.1%) in France, and daratumumab-bortezomib-dexamethasone (15.0%) in Spain. In the historical data (2016-2018), third-line lenalidomide- and pomalidomide-dexamethasone doublet use across the UK (>47%), France (>46%), and Spain (>33%) was high. From historical to new, triplet use increased in Spain (>19% to >60%) as did anti-CD38 agent use in France (15.1% to 51.9%) and Spain (19.7% to 42.1%). CONCLUSIONS: From 2016 to 2021, third-line regimens were mostly IMiD based. The MCR data demonstrated evolving treatment choices from 2016 to 2018 and 2019 to 2021, providing insights into uptake of novel agents and current RRMM European clinical practice.

Real world analysis of third-line treatment with anlotinib in combination with radiotherapy for extensive-stage small-cell lung cancer / 中华放射肿瘤学杂志

Objective:To investigate the clinical efficacy and safety of anlotinib combined with radiotherapy as a third-line treatment regimen for extensive stage small-cell lung cancer (ES-SCLC) in a real-world background.Methods:Forty ES-SCLC patients enrolled in a single center of Affiliated Cancer Hospital of Xinjiang Medical University in China between November 2018 and July 2021 were treated with radiotherapy added on anlotinib as a third-line treatment regimen. Overall survival (OS), progression-free survival (PFS), safety, and quality of life were analyzed, and the survival status was statistically analyzed using Kaplan-Meier method.Results:Among the 40 patients, partial remission, stable disease, and progressive disease was confirmed in 7, 24 and 9 patients, respectively. The obtained objective remission rate (ORR) was 18%, the disease control rate (DCR) was 78%, and median PFS and median OS were 4.5 months and 9 months, respectively. The most common adverse reactions included fatigue (28%), bleeding (20%), anorexia (13%), and hand-foot syndrome (8%). Most of them were grade 1-2 in severity, 4 cases were documented as ≥grade 3, and no grade 5 toxicity was recorded.Conclusions:In the real world, radiotherapy added on anlotinib as a third-line regimen can prolong PFS and OS of the ES-SCLC patients, and the adverse reactions are generally tolerated. This combination treatment regimen is worthy of further investigation.

Third-line treatment options in metastatic pancreatic cancer patients: a real-world study.

Background: There are currently no standard therapy regimens for the third-line treatment of metastatic pancreatic cancer (mPC) patients. The aim of the present study was to compare the efficacy and safety of different third-line therapy regimens for mPC in the real-world. Methods: This study retrospectively analyzed mPC patients admitted to Zhejiang Provincial People's Hospital between June 2013 and January 2023. All patients' diagnoses were pathologically confirmed and their treatment was continued after the second-line therapy failed. The primary study endpoints included median overall survival (mOS), median progression-free survival (mPFS), and disease control rate (DCR). Results: A total of 72 patients were enrolled in the study. Of these, 36 patients received chemotherapy alone, 16 received chemotherapy combined with targeted therapy or immunotherapy, 14 received chemotherapy-free antitumor therapy, and six received palliative care. The mPFS value for these groups was 4.40 months, 5.20 months, 2.33 months, and 0.80 months, respectively. The mOS value was 6.90 months, 5.90 months, 3.33 months, and 0.80 months, respectively. The DCR was 33.4%, 31.3%, 21.4%, and 0.0%, respectively. Overall, there were significant differences in prognosis between the palliative care group and the other treatment groups (mOS, P < 0.001; mPFS P < 0.001; DCR, P < 0.001). The differences among the mPFS, mOS, and DCR for different antitumor therapy regimens were not statistically significant. Compared to the chemotherapy alone group, the chemotherapy combined with targeted therapy or immunotherapy group experienced more adverse events (100% vs. 75.0%; P = 0.002). Chemotherapy combined with targeted therapy or immunotherapy was associated with a higher risk of grade 3/4 hyperaminotransferemia compared to chemotherapy alone (31.3% vs. 0.0%; P = 0.020) and chemotherapy-free antitumor therapy (31.3% vs. 0.0%; P = 0.020). Conclusions: Third-line antitumor therapy can prolong the survival time of patients with mPC. Targeted therapy or immunotherapy failed to further improve survival benefits based on chemotherapy results. Patients who underwent the third-line treatment with good physical status and family history of cancer were independent prognostic factors for longer mOS. The sequencing of fluorouracil and gemcitabine in the front-line therapy did not affect third-line mOS.

Comparison of the efficacy and safety of third-line treatments for advanced gastric cancer: A systematic review and network meta-analysis.

Background: Many options for third-line treatment of advanced gastric cancer (GC) or gastroesophageal junction carcinoma (GEJC) have been developed. Therapies including immunotherapy (nivolumab), chemotherapy (irinotecan, FTD/TPI), targeted therapy (apatinib), and antibody drug conjugates (ADC) have shown to increase the survival rates in patients, but few studies have compared the relative efficacy of these treatments. Here, we compared the efficacies of these regimens using network meta-analysis (NMA) to provide guides in selecting the best regimen and formulating a precise individualized treatment plan. Methods: The published RCTs of phase II/III in PubMed, the Cochrane Central Register of Controlled Trials, and Embase were searched. The median overall survival (mOS) was the primary outcome of NMA, and the other outcomes were median progression-free survival (mPFS), disease control rate (DCR) (proportion of patients with confirmed CR, PR, or stable disease (SD)) and incidence of grade 3 or above adverse events (≥3AEs). Results: Five phase II/III RCTs involving 1674 patients and 7 treatment regimens were analyzed. It showed that Trastuzumab Deruxtecan (DS-8201) prolonged the OS of patients significantly comparing with chemotherapy (HR: 0.59; 95% CI: 0.39-0.89) for the overall population. DS-8201 (HR: 0.27; 95% CI: 0.17-0.42) and chemotherapy (HR: 0.57; 95% CI: 0.47-0.7) improved the PFS significantly over nivolumab. Apatinib (RR: 3.04; 95% CI: 1.65-5.95) and DS-8201 (RR: 2.67; 95% CI: 1.51-4.83) were more effective than nivolumab in improving DCR. DS-8201 achieved greater OS benefits compared to chemotherapy (HR: 0.59; 95% CI: 0.39-0.88) for patients who were HER2-positive. We ranked the Bayesian surface under the cumulative ranking curve according to OS benefit, and showed that ADC ranked first for the general patient population and for patients with a HER2-positive diagnosis, intestinal histopathology, previous gastrectomy history, gastric origination cancer, ages over 65 and ECOG PS=0/1, followed by nivolumab and apatinib. For patients with GEJC, nivolumab ranked first. Conclusions: Nivolumab, apatinib, chemotherapy, and ADC all improved the OS of GC/GEJC patients significantly. ADC may be the best option for the overall population of GC, as well as for patients with HER2-overexpression, intestinal histopathology, previous gastrectomy history, gastric origination cancer, ages over 65 and ECOG PS=0/1, followed by nivolumab and apatinib. Nivolumab may be the first treatment option for GEJC patients. Systematic review registration: https://www.crd.york.ac.uk/prospero, identifier CRD42022364714.

FOLFOX regimen after failure of fluorouracil and leucovorin plus nanoliposomal-irinotecan therapy for advanced pancreatic cancer: a retrospective observational study.

BACKGROUND: Fluorouracil, leucovorin (5FU/LV), and nanoliposomal-irinotecan (nal-IRI) combination therapy has been established as the second-line treatment for advanced pancreatic ductal adenocarcinoma. Oxaliplatin with 5FU/LV (FOLFOX) is often used as a subsequent treatment, although its efficacy and safety are yet to be fully elucidated. We aimed to evaluate the efficacy and safety of FOLFOX as a third- or later-line treatment for patients with advanced pancreatic ductal adenocarcinoma. METHODS: We conducted a single-centre, retrospective study that enrolled 43 patients who received FOLFOX after failure of gemcitabine-based regimen followed by 5FU/LV + nal-IRI therapy between October 2020 and January 2022. FOLFOX therapy consisted of oxaliplatin (85 mg/m2), levo-leucovorin calcium (200 mg/m2) and 5-FU (2400 mg/m2) every 2 weeks per cycle. Overall survival, progression-free survival, objective response, and adverse events were evaluated. RESULTS: At the median follow-up time of 3.9 months in all patients, the median overall survival and progression-free survival were 3.9 months (95% confidence interval [CI], 3.1-4.8) and 1.3 months (95% CI, 1.0-1.5), respectively. Response and disease control rates were 0 and 25.6%, respectively. The most common adverse event was anaemia in all grades followed by anorexia; the incidence of anorexia and grades 3 and 4 was 21 and 4.7%, respectively. Notably, grades 3-4 peripheral sensory neuropathy was not observed. Multivariable analysis revealed that a C-reactive protein (CRP) level of > 1.0 mg/dL was a poor prognostic factor for both progression-free survival and overall survival: hazard ratios were 2.037 (95% CI, 1.010-4.107; p = 0.047) and 2.471 (95% CI, 1.063-5.745; p = 0.036), respectively. CONCLUSION: FOLFOX as a subsequent treatment after failure of second-line treatment with 5FU/LV + nal-IRI is tolerable, although its efficacy is limited, particularly in patients with high CRP levels.

An economic evaluation of cabazitaxel versus a second androgen receptor-targeted agent (ARTA) for patients with metastatic castration-resistant prostate cancer previously treated with docetaxel and an ARTA: the United States payer perspective.

BACKGROUND: Cabazitaxel significantly improves clinical outcomes compared with a second androgen receptor-targeted agent (ARTA) in patients with metastatic castration-resistant prostate cancer (mCRPC) previously treated with docetaxel and an ARTA (abiraterone or enzalutamide), as demonstrated in the CARD trial (NCT02485691). We aimed to estimate healthcare costs avoided with the use of cabazitaxel as a third-line (3 L) treatment versus a second ARTA from a US payer perspective. METHODS: Model inputs were based on the CARD trial, published sources, and estimates of typical clinical care patterns by genitourinary oncologists (n = 3). Assessed time points were 6, 12, 18, and 24 months. Outcomes included progression-free survival (PFS), radiographic PFS (rPFS), and overall survival (OS); hospitalization and intensive care unit (ICU) days; and costs (reported in 2020 US dollar [USD] and converted into Euro) to manage symptomatic skeletal events (SSEs), adverse events (AEs), and end-of-life care. RESULTS: At 18 months, in a cohort of 100 patients, the use of cabazitaxel was estimated to result in 9 more patients achieving rPFS, 2 more patients achieving PFS, and 17 more survivors versus a second ARTA. The costs of SSEs, AEs, and end-of-life care were $498,909 (€424,073), $276,198 (€234,768), and $808,785 (€687,468), respectively, for cabazitaxel and $627,569 (€533,434), $251,124 (€213,455), and $1,028,294 (€874,050), respectively, for a second ARTA. Cabazitaxel was estimated to be associated with a 21% reduction in both SSE management and end-of-life care costs. Hospitalization cost was $1,442,870 (€1,226,440) for cabazitaxel and $1,728,394 (€1,469,135) for a second ARTA, representing an estimated 17% reduction in these costs. Cabazitaxel, as compared with a second ARTA, was associated with 58 fewer hospitalization days and 2 fewer ICU days and was estimated to avoid $323,095 (€274,630, 17%) in total costs, driven by SSEs management and end-of-life care. CONCLUSION: The use of cabazitaxel as a 3 L treatment after docetaxel and an ARTA in patients with mCRPC is estimated to result in clinical benefits (longer rPFS, PFS, and OS) and lower healthcare resource utilization (fewer hospitalization and ICU days), compared with a second ARTA.

Efficacy and Safety of Anlotinib in the Treatment of Small Cell Lung Cancer: A Real-World Observation Study.

Aims: This study aimed to observe the efficacy and safety of anlotinib in the treatment of small cell lung cancer (SCLC) in the real world, as first-line maintenance therapy, second-line, and above. Methods: Clinical data of 109 patients with SCLC treated with anlotinib and hospitalized at The First Affiliated Hospital of Zhengzhou University from June 2018 to June 2020 were retrospectively analyzed. Analysis of short-term efficacy and survival was performed, with p<0.05 being considered statistically significant. Results: The median progression-free survival (mPFS) of anlotinib monotherapy used as first-line maintenance treatment of SCLC was 6.3 months (11.7 months in the limited phase and 5.8 months in the extensive phase) and median overall survival (mOS) was 16.7 months (not reached in limited phase, 12.6 months in extensive phase). In second-line treatment, anlotinib with chemotherapy prolonged PFS and OS as compared to anlotinib monotherapy (p<0.05). In third-line and above treatment, there was no improvement in mPFS with the chemotherapy combination regimen compared to anlotinib monotherapy (3.6 months vs. 3.8 months, p=0.398), with a trend toward impaired mOS (8.5 months vs. not achieved, p=0.060). Univariate analyses and multivariate analyses revealed that Eastern Cooperative Oncology Group performance status and liver metastases were independent prognostic factors affecting PFS and OS. No new anlotinib-related adverse reactions were identified. Conclusion: Anlotinib was effective for first-line maintenance and second-line treatment, and the chemotherapy combination regimen was superior to monotherapy when applied as second-line treatment. However, this trend was not observed in third-line and above therapy.

Oral phenazopyridine vs intravesical lidocaine for bladder onabotulinumtoxinA analgesia: a randomized controlled trial.

BACKGROUND: The efficacy of intradetrusor onabotulinumtoxinA injections for the management of idiopathic overactive bladder has been well-established. The injections are typically performed in the office setting using local analgesia, most commonly a 20 to 30-minute intravesical instillation of lidocaine. There are limited data evaluating alternative bladder analgesics. OBJECTIVE: To compare pain scores with preprocedure oral phenazopyridine vs intravesical lidocaine in women undergoing intradetrusor onabotulinumtoxinA injections for idiopathic overactive bladder. STUDY DESIGN: Nonpregnant adult females with idiopathic overactive bladder, scheduled for office injection of 100 units of intradetrusor onabotulinumtoxinA were randomized to either 200 mg of oral phenazopyridine taken 1 to 2 hours preprocedure or a 20-minute preprocedure intravesical instillation of 50 mL of 2% lidocaine. We excluded participants with neurogenic bladders, and those who had received intradetrusor onabotulinumtoxinA injections in the previous 12 months. The primary outcome was pain measured by a 100-mm visual analog scale. Demographic characteristics and overall satisfaction with the procedure were also recorded. Providers answered questions about cystoscopic visualization, ease of procedure, and perception of participant comfort. Prespecified noninferiority margin was set to equal the anticipated minimum clinically important difference of 14 mm. A planned sample of 100 participants, 50 in each treatment arm, provided 80% power to detect noninferiority at a significance level of.05. We performed a modified intention-to-treat analysis and compared variables with the t test or the Fisher exact test. RESULTS: A total of 111 participants were enrolled, and complete data were obtained for 100 participants; 47 participants were randomized to phenazopyridine and 53 to lidocaine. Baseline characteristics did not differ between groups. There were 19.6% and 20.8% of participants in the phenazopyridine and lidocaine groups, respectively, who previously underwent intradetrusor onabotulinumtoxinA injections. The mean postprocedure pain was 2.7 mm lower in the phenazopyridine group than in the lidocaine group (95% confidence interval, -11.3 to 10.7), demonstrating noninferiority. More than 90% of participants in both groups stated that the pain was tolerable. Slightly more participants reported being "very satisfied" in the lidocaine group, although this was not statistically significant (50.0% vs 40.4%; P=.34). Providers reported clear visualization in 89.4% of participants in the phenazopyridine group and in 100% of participants in the lidocaine group (P=.02). Provider perception of participant comfort and overall ease of procedure were not different between groups. Length of time in the exam room was significantly shorter in the phenazopyridine than in the lidocaine group (44.4 vs 57.5 minutes; P=.0003). CONCLUSION: In women receiving intradetrusor onabotulinumtoxinA injections for idiopathic overactive bladder, oral phenazopyridine was noninferior to intravesical lidocaine for procedural pain control. Phenazopyridine is well-tolerated by participants, allows for the procedure to be performed with similar ease, and is associated with shorter appointment times.

Long-term outcomes of patients with Chronic Myeloid Leukemia who commenced treatment with imatinib: a 20-year single-centre experience.

We report on long-term outcomes of 267 patients (pts) with chronic myeloid leukemia (CML) treated with imatinib administered as initial therapy. The median follow-up time was 11.4 years. 38 (14.2%) pts attempted to discontinue imatinib therapy after achieving sustained deep molecular response (≥MR4), 15 of them achieved treatment-free remission (TFR). 144 pts (53.9%) have been switched to other TKI during the follow-up period. The estimated OS for 267 pts for 10, 15 and 18 years was 98.8%, 75.6% and 52.1%. According to prognostic scores (Sokal, Euro, ELTS), OS and PFS were significantly better in low-risk pts than in high-risk pts. According to ELTS, low-risk pts have a better chance of achieving MR4 than both intermediate (p = 0.03) and high-risk (p = 0.04) groups. It suggests that a specific ELTS-adapted treatment could help to optimize treatment results. In the study population, imatinib has demonstrated sustained efficacy and an acceptable rate of late toxic effects.

MAPKinase inhibition after failure of immune checkpoint blockade in patients with advanced melanoma - An evaluation of the multicenter prospective skin cancer registry ADOREG.

OBJECTIVES: Forty to sixty percent of patients with advanced melanoma show primary resistance to PD-1-based immunotherapy, 30-40% of initial responders also progress. Here, we evaluated the outcome of second-line targeted therapy (TT) after progression on PD-1-based immune checkpoint inhibition (ICI) in BRAFV600-mutated melanoma. In addition, we report data on the activity of re-exposure with PD-1-based regimes. METHODS: Patients with advanced (non-resectable stage III or IV, AJCC 2017, 8th edition) melanoma progressing on PD-1-based ICI (nivolumab, pembrolizumab or ipilimumab plus nivolumab) and receiving second-line BRAF plus MEK inhibition were identified from the prospective multicenter skin cancer registry ADOREG. RESULTS: We identified 108 patients with unresectable stage III or stage IV melanoma progressing on first-line ICI (nivolumab, pembrolizumab or ipilimumab plus nivolumab) and receiving second-line combined BRAF/MEK inhibition. Seventy-three percent of the cohort presented with primary PD-1 resistant disease. Median progression-free survival (PFS) on ICI was 2.6 (95% CI 2.2-2.9) months. Median PFS on subsequent TT was 6.6 (95% CI 5.4-7.8) months. Median OS from start of second-line TT was 16.0 (95% CI 11.2-20.8) months. The 3-year PFS and OS rates on second-line TT were 16% and 30%. The objective response rate (ORR) and disease control rate (DCR) to TT were 42.6% and 55.6%. In patients with brain metastases, the ORR and DCR were 31.4% and 43.1%. Patients without brain metastases showed an ORR and DCR of 52.6% and 66.7%, respectively. Response to first-line ICI was associated with a numerically higher ORR and DCR to second-line TT and improved OS on TT. Twenty-three patients received third-line ICI of whom two patients showed an objective response. CONCLUSIONS: BRAF plus MEK inhibition shows meaningful activity and outcome in patients with advanced melanoma resistant to anti-PD-1-based immunotherapy. Rates of long-term benefit and survival in our study were similar to those reported for treatment-naïve patients receiving first-line MAPKi.

ALK Inhibitors or Chemotherapy for Third Line in ALK-positive NSCLC? Real-world Data.

OBJECTIVES: ALK inhibitors (ALKi) are the standard-of-care treatment for metastatic ALK-rearranged non-small cell lung cancer (NSCLC) in the first- and second-line setting. We conducted a real-world multi-institutional analysis, aiming to compare the efficacy of third-line ALKi versus chemotherapy in these patients. METHODS: Consecutive ALK-positive metastatic NSCLC patients treated with at least one ALKi were identified in the working databases of 7 Israeli oncology centers (the full cohort). Demographic and clinical data were collected. Patients receiving any systemic treatment beyond 2 ALKi comprised the third-line cohort, whether a third ALKi (group A) or chemotherapy (group B). Groups A and B were compared in terms of overall survival (OS) and time-to-next-treatment line (TNT). RESULTS: At a median follow-up of 41 months (95% confidence interval [CI]: 32-55), 80 (47.1%) have died. Median OS (mOS) in the full cohort (n = 170) was 52 months (95% CI: 32-65). Number of ALKi (hazard ratio [HR] 0.765; 95% CI: 0.61-0.95; P = .024) and age (HR 1.02, 95% CI: 1.01-1.04, P = .009) significantly associated with OS in the full cohort. The third-line cohort included 40 patients, of which 27 were treated with third ALKi (group A) and 13 treated with chemotherapy (group B). mOS from third-line initiation was 27 months in group A (95% CI: 13-NR) and 13 months for group B (95% CI: 3-NR); the difference was not significant (NS; P = .12). Chemotherapy as first line (HR 0.17, 95% CI: 0.05-0.52, P = .002) and a higher number of ALKi (HR 0.38, 95% CI: 0.20-0.86, P = .011) associated significantly with longer OS of the third-line cohort. TNT was 10 months for group A (95% CI: 5-19) and 3 months for group B (95% CI: 0-NR); the difference was NS (P = .079). CONCLUSION: We report mature real-world data of more than 4-year mOS in ALK-positive patients. The number of ALKi given was associated with a better outcome. OS and TNT demonstrated a statistically nonsignificant trend for a better outcome in patients receiving a third-line ALKi.

Apatinib plus 5-fluorouracil as a third or subsequent-line treatment option for metastatic colorectal cancer: a phase-II, single-arm, prospective study.

Background: For metastatic colorectal cancer (mCRC) patients for whom at least 2 lines of previous standard therapies have failed, the prognosis is often unfavorable due to very limited subsequent treatment options. We sought to explore the efficacy of apatinib, an oral small-molecule vascular endothelial growth factor receptor-2 inhibitor, plus 5-fluorouracil (5-FU) as a third- or subsequent-line treatment for mCRC. Methods: In this phase-II, single-arm, prospective study, the eligible patients had been histologically confirmed to have adenocarcinoma of the colon or rectum for which at least 2 previous regimens of standard therapies had failed. All the patients were treated with a daily dose of 250 mg of apatinib, in combination with capecitabine, Tegafur Gimeracil Oteracil Potassium Capsule (S-1), or 5-FU, until disease progression, unacceptable toxicity, or consent withdrawal. Results: From June 2017 to April 2018, 16 patients were enrolled in this study. Among them, 4 achieved partial response, 7 had stable disease, and 5 had progression disease, resulting in an objective response rate of 25.00% [95% confidence interval (CI): 7.27-52.38%], and a disease control rate of 68.75% (95% CI: 41.34-88.98%). The median progression-free survival (PFS) was 4.83 months (95% CI: 2.17-8.90 months), and the median overall survival (OS) was 9.10 months (95% CI: 5.59-15.18 months). The common treatment-related adverse events (AEs) were hand-foot syndrome (56.25%), hypertension (37.50%), proteinuria (37.50%), gingival bleeding (18.75%) and abdominal pain (18.75%). Grade 3 AEs, including hand-foot syndrome (18.75%), hypertension (12.50%), and proteinuria (12.50%), were observed in 7 patients. Conclusions: The combination regimen of apatinib plus 5-FU had encouraging anti-tumor efficacy, and is a feasible third- or subsequent-line treatment option for mCRC. Trial Registration: ClinicalTrials.gov Identifier: NCT03210064.

Cost-effectiveness of trifluridine/tipiracil as a third-line treatment of metastatic gastric cancer, including adenocarcinoma of the gastrohesophageal junction, among patients previously treated in Greece.

OBJECTIVE: To evaluate the cost-effectiveness of trifluridine/tipiracil (FTD/TPI) compared with best supportive care (BSC) for the treatment of patients with metastatic gastric cancer(mGC), including gastroesophageal junction adenocarcinoma(GEJ), who have received at least two prior therapies for metastatic disease and are eligible for third-line treatment, in Greece. METHODS: A partitioned survival model was locally adapted from a public payer perspective over a 10-year time horizon. Clinical, safety and utility data were extracted from literature. Resource consumption data obtained from a panel of local experts using a questionnaire developed for the study was combined with unit costs obtained from official sources. All costs reflect the year 2020 (€). Outcomes of the model were patients' life years (LYs) and quality-adjusted life years (QALYs), total costs and incremental cost-effectiveness ratio (ICER) per QALY and LY gained. RESULTS: The total cost per patient was estimated to be €6,965 for FTD/TPI and €1,906 for BSC, while FTD/TPI was associated with 0.180 and 0.107 increments in LYs and QALYs, respectively, compared with BSC, resulting in an ICER of €47,144 per QALY gained and €28,112 per LY gained. CONCLUSION: FTD/TPI was estimated to be a cost-effective treatment option for eligible third line mGC patients, including GEJ in Greece.

Patient demographics and management landscape of metastatic colorectal cancer in the third-line setting: Real-world data in an australian population.

BACKGROUND: Colorectal cancer is the third most common cancer and second leading cause of cancer mortality in Australia, thus carrying a significant disease burden. AIMS: This analysis aims to explore real-world treatment landscape of metastatic colorectal cancer in the third-line setting. METHODS: We retrospectively analysed treatment of recurrent and advanced colorectal cancer (TRACC) registry database from 2009 onwards. Patients treated with palliative intent who progressed after two lines of therapies were included. One treatment line was defined as any combination of systemic therapy given until progression. RESULTS: Out of 1820 patients treated palliatively, 32% (590 patients) met study criteria. Of these, 43% (254 patients) proceeded to third-line therapy, equating to 14% of all metastatic patients. In KRAS mutant or unknown tumours (97 patients), fluoropyrimidine (FP)-oxaliplatin combination was the most common choice (51%), followed by FP-irinotecan (15%), trifluridine/tipiracil (11%), mono-chemotherapy (10%), regorafenib (5%) and others (7%). Majority of FP-doublet (83%) was given as rechallenge. In 157 patients with KRAS wildtype disease, monotherapy with EGFR inhibitor was most commonly used (41%), followed by EGFR inhibitor with chemotherapy (20%), FP-doublet (18%), mono-chemotherapy (6%), trifluridine/tipiracil (6%), regorafenib (1%) and others (8%). Median overall survival was 7.1 months (range 0.4-41.2), and median time on third-line treatment was 3 months (range 0.1-40). CONCLUSIONS: In real-world Australian population, treatment choices differed based on KRAS status and will likely change with the availability of newer drugs on the pharmaceutical benefits scheme. Survival outcomes are comparable to newer agents in clinical trials for select patients.

Irinotecan monotherapy as third- or further-line treatment for patients with small cell lung cancer.

BACKGROUND: Small cell lung cancer (SCLC) is a very aggressive cancer and recurrence is inevitable. Treatment of recurrent disease is important for improving the prognosis of patients with SCLC. METHODS: We conducted a retrospective observational study to investigate the efficacy and safety of irinotecan monotherapy as third- or further-line treatment in patients with SCLC. RESULTS: Data of 15 patients who had received irinotecan monotherapy as third- or further-line treatment between 2004 and 2019 were analyzed. The median progression-free survival duration (95% confidence interval) from the initiation of treatment with irinotecan was 2.7 (1.4-3.8) months, and the median overall survival duration (95% confidence interval) from the initiation of irinotecan treatment was 10.0 (3.9-12.9) months. Partial response, stable disease or non-complete response/non-progressive disease, and progressive disease were observed in 1, 6, and 8 patients, respectively. Adverse events ⩾ grade 3 in severity were observed in 2/2 (100%) patients who were homozygous for UGT1A1 mutation, 2/3 (66.7%) patients who were heterozygous for UGT1A1 mutation, 4/6 (66.7%) patients who had wild-type UGT1A1, and 2/4 (50.0%) patients in whom the UGT1A1 mutation status was unknown. CONCLUSION: Our results suggest that irinotecan monotherapy can be a useful alternative treatment option in the third-line setting for patients with SCLC.

Anlotinib Combined with S-1 in Third- or Later-Line Stage IV Non-Small Cell Lung Cancer Treatment: A Phase II Clinical Trial.

LESSONS LEARNED: The combination of anlotinib and S-1 exhibited good antitumor activity in third- or later-line treatment for stage IV non-small cell lung cancer (NSCLC). Combination therapy of anlotinib with S-1 has manageable toxicities in patients with NSCLC. BACKGROUND: This study aimed to evaluate the efficacy and safety of anlotinib combined with S-1 as a third- or later-line treatment for patients with stage IV non-small cell lung cancer (NSCLC). Anlotinib was approved in 2018 by the Chinese Food and Drug Administration (FDA) as a third-line treatment for patients with refractory advanced NSCLC and is under study in the U.S. and Europe. METHODS: Simon's phase II clinical trial design with an α error of 5% and a power ß of 80% was used, anticipating a 10% objective response rate (ORR) of anlotinib and a 30% ORR of anlotinib combined with S-1; the required sample size was 29. A total of 29 patients were enrolled in the clinical trial. Patients were treated with anlotinib plus S-1 over a 21-day treatment course until disease progression or unacceptable toxic effects. If the efficacy was assessed as stable disease, partial response, or complete response after six cycles, anlotinib was maintained until disease progression or death. The primary endpoint was the objective response rate. Somatic mutations were not required for study enrollment. RESULTS: The median follow-up time was 11.1 months. Objective responses were observed in 11 of 29 (37.9%) patients making up the intention-to-treat population, which reached the target primary endpoint of 30% ORR. The median overall and progression-free survival were 16.7 and 5.8 months, respectively. The most common grade 3 adverse events (AEs) were gastrointestinal, including nausea, vomiting and diarrhea, fatigue, and hypertension. No grade 4 treatment-related AEs or treatment-related deaths occurred. CONCLUSION: The combination of anlotinib with S-1 in the third- or later-line treatment of stage IV NSCLC shows promising antitumor activity and manageable toxicity in patients with NSCLC; phase III trials will be planned in the future.