Failure Of Platinum-based Chemotherapy Research Articles

The Association of Clinical Outcomes with Posttreatment Changes in the Relative Eosinophil Counts and Neutrophil-to-Eosinophil Ratio in Patients with Advanced Urothelial Carcinoma Treated with Pembrolizumab.

BackgroundTo evaluate the association of clinical outcomes with posttreatment changes in the relative eosinophil count (REC) and neutrophil-to-eosinophil ratio (NER) in patients with advanced urothelial cancer (UC) treated with pembrolizumab.Materials and MethodsWe retrospectively analyzed 105 patients with advanced UC who received pembrolizumab after the failure of platinum-based chemotherapy. The REC and NER before and three weeks after pembrolizumab were recorded. A receiver operating characteristic curve was used to determine the optimal cut-off values for analyzing the risk.ResultsThere were no significant differences in the overall survival (OS) between the REC ≥4.8% and <4.8% groups and the NER ≥13.7 and <13.7 groups before pembrolizumab (p=0.997 and 0.669, respectively). However, a significant difference in the OS was confirmed between the increased and decreased REC groups and between the decreased and increased NER groups at 3 weeks after pembrolizumab (p<0.001 and 0.002, respectively). Multivariate analyses revealed that an Eastern Cooperative Oncology Group Performance Status ≥2 (P=0.003), albumin <3.7 g/dl (p=0.002), LDH >246 U/L (p=0.011), disease site ≥3 organs (p=0.019), decreased posttreatment REC (3 weeks later) (p=0.002) and increased posttreatment NER (3 weeks later) (p=0.022) were independent prognostic factors for a worse OS.ConclusionAn increased REC and decreased NER after pembrolizumab may be significant early predictive markers of improved clinical outcomes in patients with advanced UC receiving pembrolizumab.

LBA66 Efficacy and safety of nivolumab for patients with pre-treated type B3 thymoma and thymic carcinoma: Results from the EORTC-ETOP NIVOTHYM phase II trial

Thymic malignancies are rare intrathoracic tumors which still represent a therapeutic challenge in the advanced/metastatic setting, with limited treatment options after the failure of platinum-based chemotherapy.

Molecular predictors of response to pembrolizumab in thymic carcinoma

SummaryThymic carcinoma is rare and has a poorer prognosis than thymomas. The treatment options are limited after failure of platinum-based chemotherapy. We previously performed a single-center phase II study of pembrolizumab in patients with advanced thymic carcinoma, showing a 22.5% response rate. Here, we characterize the genomic and transcriptomic profile of thymic carcinoma samples from 10 patients (5 non-responders versus 5 responders) in this cohort, with the main aim of identifying potential predictors of response to immunotherapy. We find that expression of PDL1 and alterations in genes or pathways that correlated with PD-L1 expression (CYLD and BAP1) could be potential predictors for response or resistance to immunotherapy in patients with advanced thymic carcinoma. Our study provides insights into potential predictive markers/pathways to select patients with thymic carcinoma for anti-PD-1 immunotherapy.

Efficacy and safety of low-dose albumin-bound paclitaxel plus tislelizumab as second- or further lines treatment for elderly patients with metastatic non-small cell lung cancer.

e21066 Background: Lung cancer ranks first globally in morbidity and mortality rates among cancers. There are few studies focused on the different doses of chemotherapy drugs in combination with programmed cell death-1 (PD-1) inhibitors in non-small-cell lung cancer (NSCLC). Tislelizumab, a novel PD-1 monoclonal antibody, has been shown to improve antitumor activity when combined with chemotherapy as first-line treatment for patients with NSCLC. Elderly patients usually have poor physical conditions and many complications, resulted in higher risks of chemotherapy. This study aimed to preliminarily assess the efficacy and safety of low-dose chemotherapy plus tislelizumab for elderly patients with metastatic NSCLC. Methods: Eligible patients should be diagnosed as metastatic NSCLC, aged ≥65 years, and failed in one or more lines treatment. Patients with epidermal growth factor receptor (EGFR) / anaplastic lymphoma kinase (ALK) inhibitor resistance could be enrolled in the study. Participants received albumin-bound paclitaxel (130mg/m2) plus tislelizumab (200mg) every 3 weeks. Chemotherapy lasted for no more than 6 cycles. Once chemotherapy intolerance occurred or at end of 6 cycles, patients with objective response or stable disease would continue to receive tislelizumab until confirmed disease progression, death, and unacceptable toxicity. Primary endpoints were progression free survival (PFS) and safety. Secondary endpoints were objective response rate (ORR), disease control rate (DCR), as well as overall survival (OS). Results: Total 23 patients were enrolled from May 2019 to March 2020: 43.5% (10/23) male, 39.1% (9/23) smokers, 26.1% (6/23) with squamous cell carcinoma and 56.5% (13/23) with ECOG 2. Median age was 71 yr (range: 65, 82). Patients had received 1 (47.8%) or ≥2 (52.2%) lines of therapy. 13 (56.5%) patients with EGFR/ALK TKI resistance participated in the study. As of data cut-off on December 1, 2020, the median PFS was 9.5 months (95% CI: 5.7–13.3 months). Nine patients achieved partial response (PR). The ORR was 39.1% (9/23) and DCR was 87.0% (20/23). Only 4 participants died in the study and the mOS was not reached. Sixteen (69.6%) patients had a decrease in tumor size as compared with baseline and the median change from baseline was −22%. 13 (56.5%) participants suffered at least one adverse event (grade 3 in 3 (13.0%) patients). The main adverse events were fatigue (17.4%), fever (17.4%), abnormal liver function (17.4%), rash (13.0%) and numbness (13.0%). No grade 4 adverse event was reported. Conclusions: Low-dose albumin-bound paclitaxel plus tislelizumab might be an optional choice for elderly patients with metastatic NSCLC after the failure of platinum-based chemotherapy or targeted therapy. Perspective clinical studies with large sample size are needed to validate our results.

The BURAN study of buparlisib (AN2025) in combination with paclitaxel compared to paclitaxel alone, in patients with recurrent or metastatic head and neck squamous cell carcinoma.

TPS6090 Background: Buparlisib (AN2025) is a 2,6-dimorpholino pyrimidine derivative oral pan-class I PI3K inhibitor. The PI3K signaling pathway is one of the most frequently altered pathways in HNSCC. A previous randomized, double-blind, placebo-controlled phase II study (BERIL-1)assessed patients with recurrent/metastatic HNSCC after PD on or after platinum-based chemotherapy in the metastatic setting. Patients assigned 1:1 to receive second-line oral buparlisib or placebo, plus intravenous weekly paclitaxel in 28-day cycles. Median PFS 4.6 months buparlisib arm, 3.5 months placebo arm (hazard ratio 0.65 [95% CI: 0.45–0.95], nominal one-sided p=0.011). Median OS 10.4 months buparlisib arm, 6.5 months placebo arm (hazard ratio 0.72 [95% CI: 0.49-1.04], nominal one-sided p=0.041). Best ORR buparlisib arm 39%, placebo arm 14%. Safety in buparlisib arm was manageable and comparable to placebo arm. (Soulieres, Lancet Oncology). Results suggest that buparlisib in combination with paclitaxel could be effective treatment following failure of platinum-based chemotherapy. Methods: The treatment algorithm for HNSCC was recently modified with inclusion of anti-PD-1/PD-L1 agents that provide a survival advantage, defining an unmet need after their use. The BURAN study is initiated as a confirmatory study to define activity in this setting. Methods: A multicenter, randomized, open-label phase III trial evaluating efficacy and safety of daily buparlisib (100 mg) in combination with weekly paclitaxel (80 mg/m2), compared to weekly paclitaxel alone, in patients with refractory, recurrent, or metastatic HNSCC, progressing after prior anti PD-1/anti PDL-1 therapy either as monotherapy or with a platinum-based regimen (in combination or sequence), and no more than two prior lines of treatment. 483 patients will be randomized 2:1, to receive either buparlisib in combination with paclitaxel or paclitaxel alone, stratified according to historical HPV status. Primary Objective: OS of buparlisib in combination with paclitaxel compared to paclitaxel alone. Secondary Objectives: Comparative PFS, ORR, and DoR, by Investigator and Independent Radiological Review Committee. Efficacy in subgroups of patients by randomization strata. Effect on symptoms and health related QOL. Efficacy related to biomarkers, microbiome analysis. Pharmacokinetics (PK) of buparlisib in combination with paclitaxel. Safety Objective: Comparative safety and tolerability. Primary analysis is OS in the ITT population, once 383 events have occurred, to demonstrate a 20% reduction in risk of death. Survival follow-up is to a maximum of five years. Trial opened December 12, 2020; X patients currently enrolled. Clinical Trial registry number: NCT04338399. Clinical trial information: NCT04338399.

Nonplatinum‐based therapy with Paclitaxel and Capecitabine for advanced squamous cell carcinomas of the anal canal: A population‐based Danish anal cancer group study

BackgroundFirst‐line platinum‐based therapy for advanced squamous cell carcinomas of the anal canal (SCCA) implies a risk of substantial side effects, and data on second‐line treatment options are limited. Paclitaxel and Capecitabine are a well‐known regimen with a moderate toxicity profile, but its efficacy has not been evaluated.MethodsWe conducted a retrospective study using Danish Hospital Registers of patients treated with Paclitaxel and Capecitabine for inoperable, recurrent, or advanced metastatic SCCA in Denmark, between January 2000 and July 2018.ResultsA total of 52 patients met the eligibility criteria. Median age was 60.7 years (range 42–83). Efficacy was observed, with an overall response rate in patients receiving first‐line (N = 28) and second‐line (N = 23) Paclitaxel and Capecitabine of 39.3% (2 with complete responses) and 17.4%, respectively. Median progression‐free survival (PFS) was 4.5 months (95% CI 3.3–5.9) and 3.8 months (95% CI 2.4–5.5) with OS of 6.7 months (95% CI 5.9–8.5) and 5.9 months (95% CI 3.9–14), respectively. Performance status ≥2 and neutrophil to lymphocyte ratio ≥4 were significantly associated with a short PFS.ConclusionThis study recognizes Paclitaxel and Capecitabine as a potential regimen for advanced SCCA, when recommended first‐line therapy is not feasible or as a potential second‐line treatment after failure of platinum‐based chemotherapy.

Paclitaxel and carboplatin chemotherapy after platinum-based chemotherapy and pembrolizumab for metastatic urothelial carcinoma.

Pembrolizumab has been available for the treatment of radical resectable urothelial carcinoma (UC) when it is exacerbated after chemotherapy since December 2017 in Japan. However, the efficacy of chemotherapy for cases progressing after pembrolizumab is unclear. The present study compared the outcomes and toxicities in patients with metastatic UC after failure of platinum-based chemotherapy and pembrolizumab, who were selected to receive paclitaxel and carboplatin (TC) chemotherapy, with those in patients who received the best supportive care (BSC). A total of 36 patients received pembrolizumab for metastatic UC at four institutions between January 2018 and August 2019. Of the 21 patients who progressed after pembrolizumab, 7 received TC chemotherapy (TC group) and 14 selected BSC (BSC group). The median observation period was 4.1 months. The 7 aforementioned patients who received TC chemotherapy (4 male and 3 female; median age, 62 years; range, 57-79 years) were analyzed in the present study. The ECOG performance status was 0 in three patients, 1 in one patient, 2 in two patients and 3 in one patient. Two patients had upper urinary tract UC, two had bladder UC and three had both types of UC. Six patients had visceral metastasis. The number of chemotherapy regimens before pembrolizumab was one in four patients, two in two patients and three in one patient. The objective response rate was 28.6% (partial response, 2 patients; stable disease, 4 patients; progressive disease, 1 patient), the median progression-free survival time was 3.4 months and the median overall survival time was 10.9 months (vs. 2.7 months in BSC group; P=0.0156). Although grade ≥3 adverse events developed in five patients, there were no treatment-associated deaths. The present results suggested that TC chemotherapy may be a preferred option for patients who require aggressive treatment after the failure of platinum-based chemotherapy and pembrolizumab.

Real-world outcomes of anti-PD1 antibodies in platinum-refractory, PD-L1-positive recurrent and/or metastatic non-small cell lung cancer, and its potential practical predictors: first report from Korean Cancer Study Group LU19-05.

Although immune-checkpoint inhibitors have become a new therapeutic option for recurrent/metastatic non-small cell lung cancers (R/M-NSCLC), its clinical benefit in the real-world is still unclear. We investigated 1181 Korean patients with programmed death-1 ligand 1 (PD-L1)-positive [tumor proportion score (TPS) ≥ 10% by the SP263 assay or ≥ 50% by the 22C3 assay] R/M-NSCLC treated with pembrolizumab or nivolumab after failure of platinum-based chemotherapy. The median age was 67years, 13% of patients had ECOG-PS ≥ 2, and 27% were never-smokers. Adenocarcinoma was predominant (61%) and 18.1% harbored an EGFR activating mutation or ALK rearrangement. Pembrolizumab and nivolumab were administered to 51.3% and 48.7, respectively, and 42% received them beyond the third-line chemotherapy. Objective response rate (ORR) was 28.6%. Pembrolizumab group showed numerically higher ORR (30.7%) than the nivolumab group (26.4%), but it was comparable with that of the nivolumab group having PD-L1 TPS ≥ 50% (32.4%). Median progression-free survival (PFS) and overall survival (OS) were 2.9 (95% CI 0-27.9) and 10.7months (95% CI 0-28.2), respectively. In multivariable analysis, concordance of TPS ≥ 50% in both PD-L1 assays and the development of immune-related adverse events (irAEs) were two significant predictors of better ORR, PFS, and OS. EGFR mutation could also predict significantly worse OS outcomes. The real-world benefit of later-line anti-PD1 antibodies was comparable to clinical trials in patients with R/M-NSCLC, although patients generally were more heavily pretreated and had poorer ECOG-PS. Concordantly high PD-L1 TPS ≥ 50% and development of irAE could independently predict better treatment outcomes, while EGFR mutation negatively affected OS.

&lt;p&gt;SNHG6 Interacted with miR-325-3p to Regulate Cisplatin Resistance of Gastric Cancer by Targeting GITR&lt;/p&gt;

BackgroundCisplatin resistance results in the failure of platinum-based chemotherapy and relapse of gastric cancer. We aimed to investigate the potential regulating role of SNHG6/miR-325-3p/GITR in reversing cisplatin resistance.Patients and MethodsA total of 137 gastric cancer patients were recruited. qRT-PCR and ELISA were used to test the expression of target genes. CCK-8 and caspase 3/7 kit were used to test the cell viability and apoptosis rate. Dual luciferase reporter gene and RNA-pull down assay were used to investigate the potential interaction between target genes.ResultsSNHG6 and GITR were up regulated in gastric cancer; however, miR-325-3p was down-regulated. Besides, SNHG6, miR-325-3p and GITR expression were associated with gastric cancer prognosis. Then, we found that GITR and SNHG6 promoted proliferation and inhibited apoptosis of MKN45 and MKN45 cisplatin resistance cell line; however, miR-325-3p inhibited proliferation and promoted apoptosis of these cell lines. Furthermore, SNHG6 might bind to miR-325-3p to regulate its expression, and miR-325-3p directly interacted with the 3`UTR of GITR.ConclusionSNHG6 binds to miR-325-3p, which directly interacted with GITR to regulate cisplatin resistance of gastric cancer.

Organ-Specific Therapeutic Effect of Paclitaxel and Carboplatin Chemotherapy After Platinum-Based Chemotherapy and Pembrolizumab for Metastatic Urothelial Carcinoma.

BackgroundTo evaluate the organ-specific therapeutic effect of paclitaxel and carboplatin (TC) chemotherapy in patients who failed platinum-based chemotherapy and pembrolizumab for metastatic urothelial carcinoma (UC).Patients and MethodsWe retrospectively reviewed the data of patients with metastatic UC who had received TC chemotherapy after the failure of platinum-based chemotherapy and pembrolizumab. The RECIST 1.1 criteria were used to assess the objective response to pembrolizumab and TC chemotherapy at tumor sites.ResultsWe analyzed 8 patients (male, n=5; female, n=3; median age, 65 years old). All patients except one had visceral metastasis. The median overall survival for TC was 10.9 months (95% confidence interval, 1.0‑12.7 months), and the objective response rate was 25.0% (partial response [PR]: 2 cases). The metastatic organs were the lymph nodes in 5 cases (number of tumor sites: 8), lung in 4 cases (number of tumor sites: 12), liver in 3 cases (number of tumor sites: 14), bone in 3 cases (number of tumor sites: 12), and primary lesion in 3 cases (number of tumor sites: 3). There were no cases of a complete response or progressive disease in any metastatic organs due to TC chemotherapy. A PR was seen in 2 cases of lymph node metastasis (40.0%), 2 cases of lung metastasis (50.0%), and 2 cases of liver metastasis (66.7%). All 3 cases of bone metastasis showed stable disease, as did all 3 cases of primary lesion. Improvement in the therapeutic effect of TC chemotherapy compared with pembrolizumab was observed in 2 cases (40.0%) of lymph node metastasis, 2 cases (50.0%) of lung metastasis, and 1 case (33.3%) of liver metastasis.ConclusionLymph node, lung, and liver metastases may respond to TC chemotherapy, even if exacerbated with pembrolizumab after platinum-based chemotherapy in metastatic UC.

Combined lenvatinib and pembrolizumab as salvage therapy in advanced adrenal cortical carcinoma

BackgroundThere is no effective systemic therapy for metastatic adrenal cortical carcinoma (ACC) after failure of platinum-based chemotherapy. The efficacies of single-agent oral multikinase inhibitors (MKIs) or salvage immune checkpoint inhibitors...

Weekly paclitaxel plus bevacizumab versus docetaxel as second- or third-line treatment in advanced non-squamous non–small-cell lung cancer: Results of the IFCT-1103 ULTIMATE study

PurposeSecond-line chemotherapy regimens have demonstrated poor benefit after failure of platinum-based chemotherapy in advanced non-squamous non–small-cell lung cancer (nsNSCLC). MethodsIn this multicentre, open-label phase III trial, patients with advanced nsNSCLC treated with one or two prior lines, including one platinum-based doublet, were centrally randomised to receive 90 mg/m2 of paclitaxel (D1, D8, D15) plus 10 mg/kg of bevacizumab (D1, D15) every 28 days or docetaxel (75 mg/m2) every 21 days; crossover was allowed after disease progression. Primary end-point was progression-free survival (PFS). ClinicalTrials.gov registration number: NCT01763671. ResultsOne hundred sixty six patients were randomised (paclitaxel plus bevacizumab: 111, docetaxel: 55). The median PFS was longer in patients receiving paclitaxel plus bevacizumab than in patients receveing docetaxel [5·4 months versus 3·9 months, adjusted hazard ratio (HR) 0·61 (95% confidence interval [CI]: 0·44–0·86); p = 0·005]. Objective response rates (ORRs) were 22·5% (95% CI: 14·8–30·3) and 5·5% (95% CI: 0·0–11·5) (p = 0·006), respectively. Median overall survivals were similar (adjusted HR 1·17; p = 0·50). Crossover occurred in 21 of 55 (38·2%) docetaxel-treated patients. Grade III-IV adverse events (AEs) were reported in 45·9% and 54·5% of patients treated with paclitaxel and bevacizumab or docetaxel, respectively (p = NS), including neutropenia (19·3% versus 45·4%), neuropathy (8·3% versus 0·0%) and hypertension (7·3% versus 0·0%). Three patients died due to treatment-related AEs (1·8% in each group). ConclusionWeekly paclitaxel plus bevacizumab as second- or third-line improves PFS and ORR compared with docetaxel in patients with nsNSCLC, with an acceptable safety profile. These results place weekly paclitaxel plus bevacizumab as a valid option in this population. Clinical trials registration numberClinicalTrials.gov Identifier: NCT01763671.

Lurbinectedin as second-line treatment for patients with small-cell lung cancer: a single-arm, open-label, phase 2 basket trial

Few options exist for treatment of patients with small-cell lung cancer (SCLC) after failure of first-line therapy. Lurbinectedin is a selective inhibitor of oncogenic transcription. In this phase 2 study, we evaluated the acti and safety of lurbinectedin in patients with SCLC after failure of platinum-based chemotherapy. In this single-arm, open-label, phase 2 basket trial, we recruited patients from 26 hospitals in six European countries and the USA. Adults (aged ≥18 years) with a pathologically proven diagnosis of SCLC, Eastern Cooperative Oncology Group performance status of 2 or lower, measurable disease as per Response Criteria in Solid Tumors (RECIST) version 1.1, absence of brain metastasis, adequate organ function, and pre-treated with only one previous chemotherapy-containing line of treatment (minimum 3 weeks before study initiation) were eligible. Treatment consisted of 3·2 mg/m2 lurbinectedin administered as a 1-h intravenous infusion every 3 weeks until disease progression or unacceptable toxicity. The primary outcome was the proportion of patients with an overall response (complete or partial response) as assessed by the investigators according to RECIST 1.1. All treated patients were analysed for activity and safety. This study is ongoing and is registered with ClinicalTrials.gov, NCT02454972. Between Oct 16, 2015, and Jan 15, 2019, 105 patients were enrolled and treated with lurbinectedin. Median follow-up was 17·1 months (IQR 6·5-25·3). Overall response by investigator assessment was seen in 37 patients (35·2%; 95% CI 26·2-45·2). The most common grade 3-4 adverse events (irrespective of causality) were haematological abnormalities-namely, anaemia (in nine [9%] patients), leucopenia (30 [29%]), neutropenia (48 [46%]), and thrombocytopenia (seven [7%]). Serious treatment-related adverse events occurred in 11 (10%) patients, of which neutropenia and febrile neutropenia were the most common (five [5%] patients for each). No treatment-related deaths were reported. Lurbinectedin was active as second-line therapy for SCLC in terms of overall response and had an acceptable and manageable safety profile. Lurbinectedin could represent a potential new treatment for patients with SCLC, who have few options especially in the event of a relapse, and is being investigated in combination with doxorubicin as second-line therapy in a randomised phase 3 trial. Pharma Mar.

Prognostic outcomes and safety in patients treated with pembrolizumab for advanced urothelial carcinoma: experience in real-world clinical practice.

Prognostic outcomes and safety following treatment with pembrolizumab in patients with advanced urothelial carcinoma (UC) have not been fully elucidated in clinical practice. The aim of this study was to evaluate the oncological efficacy and safety of pembrolizumab after failure of platinum-based chemotherapy in Japanese patients with advanced UC in a routine clinical setting. This retrospective study included 41 consecutive Japanese patients with advanced UC treated with pembrolizumab as second-line or greater therapy at Iwate Medical University Hospital from January 2018 to April 2019. The mean follow-up period was 6.2months. The objective response rate, median progression-free survival, and median overall survival were 15%, 2.5months, and 11.9months, respectively. Univariate analysis identified poor performance status (> 1), liver metastasis, two or more metastatic organs, low hemoglobin levels, two or more prior regimens, high baseline C-reactive protein levels, higher relative C-reactive protein level change after 6weeks, and higher relative neutrophil-to-lymphocyte ratio change after 6weeks as significant predictors of overall survival. Among these factors, poor performance status (> 1), two or more metastatic organs, and higher relative neutrophil-to-lymphocyte ratio change after 6weeks were identified as independent predictors of overall survival in multivariate analysis. The introduction of pembrolizumab can result in favorable cancer control outcomes in Japanese patients with advanced UC, and the prognosis of these patients can be stratified according to three potential parameters, including poor performance status, high number of metastatic organs, and higher relative neutrophil-to-lymphocyte ratio change.

Impact of peripheral neuropathy induced by platinum in first-line chemotherapy on second-line chemotherapy with paclitaxel for advanced gastric cancer.

Fluoropyrimidine plus platinum, followed by paclitaxel (PTX) plus ramucirumab is a recommended treatment strategy for advanced gastric cancer (AGC). We investigated how peripheral neuropathy (PN), induced by platinum in first-line chemotherapy, affected the tolerability of second-line chemotherapy with PTX (2nd-PTX). The subjects were AGC patients who received second-line chemotherapy with PTX (2nd-PTX) after the failure of platinum-based chemotherapy between March 2015 and June 2018. We retrospectively reviewed PN severity, and dose reduction and/or discontinuation due to PN during 2nd-PTX, and compared the cumulative incidence of grade 2 PN between the two groups according to first-line chemotherapy containing oxaliplatin (L-OHP) or cisplatin (CDDP). The L-OHP and CDDP groups consisted of 50 patients each. PN severity before 2nd-PTX was grade 1/2 in 46/12% of patients in the L-OHP group, and 100/0% in the CDDP group. The worst grades of chemotherapy-induced PN during 2nd-PTX were grades 1/2/3 in 40/34/14% of patients in the L-OHP group, and 36/18/0% in the CDDP group. Median time to grade 2 PN after starting second-PTX was 2.5months in the L-OHP group and 8.6months in the CDDP group (hazard ratio 3.34, p = 0.002). The frequencies of a PN-related dose reduction and/or discontinuation of PTX were 18% in the L-OHP group and 8% in the CDDP group (p = 0.234). The severity of PN and tolerability of 2nd-PTX may be affected by first-line chemotherapy with L-OHP or CDDP for AGC.

1260P - Impact of previous corticosteroid (CS) exposure on efficacy of programmed cell death-(Ligand) 1 blockade in patients with advanced non-small cell lung cancer (NSCLC): A single center retrospective analysis

BackgroundThe impact of previous cumulative exposure to CS before treatment start is unknown, while its use for the treatment of immune-related adverse events during PD-(L)1 therapy does not seem to reduce efficacy. We used real-world data to evaluate the effect of CS immunosuppressive dose (cumulative dose of>700mg of prednisone equivalent) or CS delivery modality (prolonged, daily dose >10mg of prednisone equivalent lasting >5 days, or pulsed, duration ≤5 days) over 3 months before treatment start. MethodsPatients with advanced NSCLC treated at our Institution with single agent PD-(L)1 blockade after failure of platinum-based chemotherapy and on CS treatment in the previous 3 months were included. Clinical and pharmacy records were reviewed to identify CS dose and duration. According to the label, patients must not have received CS>10mg prednisone or equivalent over 10 days before start of anti-PD-(L)1 therapy and had PS≤1. Patients must also have received >2 cycles of PD-(L)1 blockade to be eligible for efficacy analysis. ResultsWe identified 62 patients fulfilling our inclusion criteria, 28 (45%) and 36 (58%) of them received a CS immunosuppressive dose and pulsed CS, respectively, 8 (13%) had brain metastases, and 20 (32%) had squamous histology. As of the general population, 36 (58%) patients achieved a durable clinical benefit (DCB, partial response or stable disease >6 months). The median PFS was 4.3 months, and the 1-year survival rate was 39%. CS immunosuppressive dose was not associated with decreased DCB (44% vs 55%; p-value 0.9), nor with shorter median PFS (3.7 vs 4.4 months; HR 1.2; p-value 0.2), nor with lower 1-year survival rate (31% vs 43%; p-value 0.6). CS prolonged exposure was significantly associated with either decreased DCB (30% vs 69%; p-value 0.01) and shorter median PFS (2.7 vs 4.5 months; HR 1.8; p-value 0.05), but not with lower 1-year survival rate (29% vs 41%; p-value 0.06). ConclusionsProlonged exposure to>10mg of prednisone equivalent through pretreatment 3 months was associated with poorer outcome in patients with advanced NSCLC treated with second-line PD-(L)1 blockade. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

Mitomycin and 5-fluorouracil for second-line treatment of metastatic squamous cell carcinomas of the anal canal.

BackgroundMetastatic squamous cell carcinomas (SCC) of the anal canal are rare and there is no international consensus on their second‐line management. 5‐Fluorouracil (5‐FU) and mitomycin in combination with radiotherapy is the standard for locally advanced forms but its efficacy in metastatic stage has never been evaluated.Patients and methodsWe report a retrospective analysis of patients treated with 5‐FU and mitomycin from 2000 to 2017 in our institution for a metastatic SCC of the anal canal after failure of platinum‐based regimen. The main outcome was progression‐free survival (PFS) and the secondary outcomes were overall survival (OS), response rate, and toxicity.ResultsNineteen patients, 15 women and four men, with a median age of 57 years were identified (range, 40‐79 years). Patients received a median of three cycles (1‐7) of mitomycin 5‐FU. A dose reduction was necessary in six patients (31.6%), one patient had to discontinue treatment following toxicity and no death was due to treatment toxicity was reported. An objective response was observed in five patients (26.4%, 95% CI 6.6‐46.2) including one complete response, six patients (31.6%, 95% CI 10.7‐52.5) showed tumor stabilization. Median PFS and OS were 3 months [95% CI 1‐5] and 7 months [95% CI 2.2‐11.8]. Responder had a median duration of response of 4 months [95% CI 1.8‐6.1] and one patient had 23 months duration of response. No significant difference was noted for PFS and OS for patients previously treated with mitomycin and 5‐FU at a local stage.ConclusionMitomycin and 5‐FU regimen provides tumor control with acceptable tolerance. It is an option for patients with metastatic SCC of the anal canal after failure of platinum‐based chemotherapy. [Correction added on 9 October 2019, after first online publication: '5‐FU' was inadvertently removed from the Results and Conclusion and has now been added to the text.]

Long-term efficacy of afatinib in a patient with squamous cell carcinoma of the lung and multiple ERBB family aberrations

In the phase 3 LUX-Lung 8 study, the ERBB family blocker, afatinib, significantly prolonged progression-free survival and overall survival relative to erlotinib in patients with relapsed/refractory squamous cell carcinoma of the lung. We describe the case of a 53-year-old Asian male enrolled in LUX-Lung 8 who experienced long-term benefit from afatinib following failure of platinum-based chemotherapy. The patient received afatinib, and remained progression-free for 14.7 months according to investigator review. Overall survival was 17.7 months. Tolerability-guided dose adjustments helped facilitate long-term afatinib use by mitigating drug-related adverse effects. Next-generation sequencing revealed that multiple genetic aberrations were present, including epidermal growth factor receptor copy number amplification, and mutations in ERBB4, ALK, RET, and BRCA2. These findings may help to explain the enhanced response to afatinib and highlight the importance of biomarker analysis in guiding treatment decisions in patients with squamous cell carcinoma of the lung.

Weekly Paclitaxel Plus Bevacizumab versus Docetaxel As Second- or Third-Line Treatment in Advanced Non-Squamous Non-Small Cell Lung Cancer (NSCLC): Results of the IFCT-1103 ULTIMATE Study

Purpose: Second-line chemotherapy regimens have demonstrated poor benefit after failure of platinum-based chemotherapy in advanced non-squamous non-small-cell-lung cancer (nsNSCLC). Methods: In this multicentre, open-label phase 3 trial, patients with advanced nsNSCLC treated with one or two prior lines, including one platinum-based doublet, were centrally randomised to receive paclitaxel 90 mg/m² (D1, D8, D15) plus bevacizumab 10 mg/kg (D1, D15) every 28 days or docetaxel (75 mg/m²) every 21 days; crossover was allowed after disease progression. Primary endpoint was progression-free survival (PFS). Results: Between May 2013 and August 2014, 166 patients were randomized (paclitaxel plus bevacizumab: 111, docetaxel: 55). Median PFS was longer in paclitaxel plus bevacizumab patients than in docetaxel patients [5·4 months vs 3·9 months, adjusted hazard ratio (HR) 0·61 (95% CI 0·44-0·86); p=0·005]. Objective response rates (ORR) were respectively 22·5% (95% CI 14·8-30·3) and 5·5% (95% CI 0·0-11·5) (p=0·006). Median overall survivals were similar (adjusted HR 1·17; p=0·50). Crossover occurred in 21/55 (38·2%) docetaxel-treated patients. Grade 3-4 adverse events were reported in 45·9% and 54·5% of patients treated with paclitaxel and bevacizumab or docetaxel, respectively (p=NS), including neutropenia (19·3% vs 45·4%), neuropathy (8·3% vs 0·0%), and hypertension (7·3% vs 0·0%). Three patients died due to treatment-related adverse events (1·8% in each group). Conclusion: Weekly paclitaxel plus bevacizumab as second- or third-line improves PFS and ORR compared to docetaxel in nsNSCLC patients, with an acceptable safety profile. These results place weekly paclitaxel plus bevacizumab as a valid option in this population. Trial Registration: This trial is registered with ClinicalTrials.gov, number NCT01763671. Funding Statement: The study was sponsored by IFCT. Roche (Boulogne Billancourt, France) supplied bevacizumab, and a complementary grant but had no role in the study design, conduct of the study, and data analysis and had no other involvement in the study. The study was also supported by the French National Cancer Institute (INCa) and French League Against Cancer. Declaration of Interests: ABC has received honoraria from Roche, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, MSD, Novartis, Pfizer, and travel grants from Roche, AstraZeneca, Boehringer Ingelheim, Novartis and Pfizer. CAV has declared grants, personal fees and non-financial support from Roche. OM has declared personal fees from BMS, Boehringer Ingelheim, Astra Zeneca, Novartis, ans Hoffman-Roche. FB has declared personal fees from Astra Zeneca, BMS, Boehringer Ingelheim, Clovis Oncology, Eli Lilly Oncology, Hoffman-Roche, Novartis, Merck, MSD, Pierre Fabre and Pfizer. GZ has declared grant from Roche and BMS, personal fees from Roche, BMS, Astra Zeneca, and MSD, and non-financial support from BMS, Astra Zeneca and Pfizer. DP has declared has declared personal fees from Roche Hoffman, Astellas, Lilly, Janssen, BMS, Merck, Astra Zeneca, Novartis, Sanofi and Pfizer. CFD has declared other from MSD (CPLF 2017), Laidet Medical (ERS 2016), and Boehringer Ingelheim (CPLF 2016). EP has declared personal fees and non-financial support from Astra Zeneca, BMS and personal fees from Pfizer. DMS has declared personal fees from Roche, BMS, MSD and Eli Lilly. BB has received institutional grants for clinical and translational research from AstraZeneca, BMS, Boehringer-Ingelheim, Lilly, Pfizer, Roche-Genentech, Sanofi-Aventis, Clovis, GSK, Servier, EOS, Onxeo, OncoMed, Inivata, OSE Pharma. Ethics Approval Statement: This study was approved by a local Ethic Committee (CPP Nord-Ouest III, France), and complied with French legislation, Good Clinical Practices, and the principles outlined in the latest version of Declaration of Helsinki. After approvals, the study was implemented in 36 hospitals and cancer centres in France.

Precision medicine in head and neck cancer

Head and Neck cancer is among the most common cancers worldwide, with a high prevalence in south East Asia, Brazil and central Europe. Head and Neck Squamous cell carcinoma (HNSCC) is associated with elevated mutational load but lacks specific genetic mutations. Exposure to carcinogens including tobacco and alcohol are the most dominant etiologic factors of HNSCC, while Epstein-Barr (HBV) and Human Papilloma Viruses (HPV) are associated with nasopharyngeal and oropharyngeal carcinoma, respectively. Surgery including open and minimally invasive procedures is considered the standard of care for the majority of oral cavity and early larynx cancers, while radiation therapy or concurrent chemoradiation are used for the other head and neck cancers. The treatment of patients with head and neck cancer is complex and has undergone considerable transformation in the last decade. These modalities include immunotherapy, targeted therapy (small molecule inhibitors or antibodies), or combined modality treatments. Emerging evidence supports a vital role of the immune system in eradicating HNSCC. Cancer cells express programmed death ligand 1 or 2 (PD-L1/2) which binds to the PD receptor on the T-cell, leading to an inactivation of the cytotoxic response of the T-cell. Cytotoxic T lymphocytes antigen-4 (CTLA-4) is another key player, expressed by cancer-activated T-cells, which binds to B7 ligand on the cancer cells, leading to inhibition of T-cells activation. Checkpoint inhibitors such as anti-PD-1 and anti-PD-L1 antibodies, were shown to significantly improve disease free survival and overall survival after failure of platinum-based chemotherapy. In addition, expression of HPV is associated with better response to single modality treatment (e.g. radiotherapy or surgery) and improved survival. In future years we expect to see the establishment of precision medicine modalities in an attempt to extend survival and improve quality of life of advanced stage HNSCC patients. Several phase III clinical trials are in progress to evaluate the utility of checkpoint inhibitors at different treatment settings, including combinations with adjuvant surgery, radiation therapy and chemotherapy.