Chemotherapy-pretreated Patients Research Articles

Mapping extrachromosomal DNA amplifications during cancer progression

To understand the role of extrachromosomal DNA (ecDNA) amplifications in cancer progression, we detected and classified focal amplifications in 8,060 newly diagnosed primary cancers, untreated metastases and heavily pretreated tumors. The ecDNAs were detected at significantly higher frequency in untreated metastatic and pretreated tumors compared to newly diagnosed cancers. Tumors from chemotherapy-pretreated patients showed significantly higher ecDNA frequency compared to untreated cancers. In particular, tubulin inhibition associated with ecDNA increases, suggesting a role for ecDNA in treatment response. In longitudinally matched tumor samples, ecDNAs were more likely to be retained compared to chromosomal amplifications. EcDNAs shared between time points, and ecDNAs in advanced cancers were more likely to harbor localized hypermutation events compared to private ecDNAs and ecDNAs in newly diagnosed tumors. Relatively high variant allele fractions of ecDNA localized hypermutations implicated early ecDNA mutagenesis. Our findings nominate ecDNAs to provide tumors with competitive advantages during cancer progression and metastasis.

Safety and Efficacy of [177Lu]-PSMA-I&T Radioligand Therapy in Octogenarians with Metastatic Castration-Resistant Prostate Cancer: Report on 80 Patients over the Age of 80 Years.

177Lu-labeled prostate-specific membrane antigen (PSMA) radioligand therapy (RLT) is a new treatment option for metastatic castration-resistant prostate cancer (mCRPC). Its low toxicity profile favors use in elderly patients or in patients with critical comorbidities. The purpose of this analysis was to evaluate the efficacy and safety of [177Lu]-PSMA RLT in mCRPC patients at least 80 y old. Methods: Eighty mCRPC patients at least 80 y old underwent [177Lu]-PSMA-I&T RLT and were retrospectively selected. The patients were previously treated by androgen receptor-directed therapy, received taxane-based chemotherapy, or were chemotherapy-ineligible. The best prostate-specific antigen (PSA) response was calculated, as well as clinical progression-free survival (cPFS) and overall survival (OS). Toxicity data were acquired until 6 mo after the last treatment cycle. Results: Of 80 patients, 49 (61.3%) were chemotherapy-naïve and 16 (20%) had visceral metastases. The median number of previous mCRPC treatment regimens was 2. In total, 324 cycles (median, 4 cycles; range, 1-12) with a median cumulative activity of 23.8 GBq (interquartile range, 14.8-42.2) were applied. A PSA decline of 50% was achieved in 37 (46.3%) patients. Chemotherapy-naïve patients showed higher 50% PSA response rates than chemotherapy-pretreated patients (51.0% vs. 38.7%, respectively). Overall, median cPFS and OS were 8.7 and 16.1 mo, respectively. The median cPFS and OS of chemotherapy-naïve patients were significantly longer than those of chemotherapy-pretreated patients (10.5 vs. 6.5 mo and 20.7 vs. 11.8 mo, respectively, P < 0.05). A lower hemoglobin level and higher lactate dehydrogenase level at baseline were independent predictors of shorter cPFS and OS. Treatment-emergent grade 3 toxicities were anemia in 4 patients (5%), thrombocytopenia in 3 patients (3.8%), and renal impairment in 4 patients (5%). No nonhematologic grade 3 and no grade 4 toxicities were observed. The most frequent clinical side effects were grade 1-2 xerostomia, fatigue, and inappetence. Conclusion: [177Lu]-PSMA-I&T RLT in mCRPC patients at least 80 y old is safe and effective, comparable to previously published data on non-age-selected cohorts with a low rate of high-grade toxicities. Chemotherapy-naïve patients showed a better and longer response to therapy than taxane-pretreated patients. [177Lu]-PSMA RLT seems to be a meaningful treatment option for older patients.

MP33-07 ANTI-PROGRAMMED DEATH RECEPTOR 1 PLUS ANTI-EPIDERMAL GROWTH FACTOR RECEPTOR ANTIBODIES AND COMBINATION CHEMOTHERAPY FOR RELAPSED LOCALLY ADVANCED AND/OR METASTATIC PENILE SQUAMOUS CELL CARCINOMA

You have accessJournal of UrologyCME1 Apr 2023MP33-07 ANTI-PROGRAMMED DEATH RECEPTOR 1 PLUS ANTI-EPIDERMAL GROWTH FACTOR RECEPTOR ANTIBODIES AND COMBINATION CHEMOTHERAPY FOR RELAPSED LOCALLY ADVANCED AND/OR METASTATIC PENILE SQUAMOUS CELL CARCINOMA Longbin Xiong, Lichao Wei, Ting Xue, Ru Yan, Tingyu Liu, Lijuan Jiang, Huali Ma, Yanxia Shi, Xin An, Yijun Zhang, Shengjie Guo, Kai Yao, Fangjian Zhou, and Hui Han Longbin XiongLongbin Xiong More articles by this author , Lichao WeiLichao Wei More articles by this author , Ting XueTing Xue More articles by this author , Ru YanRu Yan More articles by this author , Tingyu LiuTingyu Liu More articles by this author , Lijuan JiangLijuan Jiang More articles by this author , Huali MaHuali Ma More articles by this author , Yanxia ShiYanxia Shi More articles by this author , Xin AnXin An More articles by this author , Yijun ZhangYijun Zhang More articles by this author , Shengjie GuoShengjie Guo More articles by this author , Kai YaoKai Yao More articles by this author , Fangjian ZhouFangjian Zhou More articles by this author , and Hui HanHui Han More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003266.07AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Relapsed locally advanced and/or metastatic penile cancer has an extremely poor prognosis with a need for effective therapy. This study retrospectively estimated the efficacy and tolerability of anti-programmed death receptor-1 (PD1) plus anti-epidermal growth factor receptor (EGFR) antibodies and combination chemotherapy in relapsed locally advanced and/or metastatic penile squamous cell carcinoma. METHODS: A retrospective review of 30 relapsed locally advanced and/or metastatic (T4/N2-3/M1) penile squamous cell carcinoma received anti-PD1 plus anti-EGFR antibodies and cisplatin-based chemotherapy in Sun Yat-sen University Cancer Center from Jan 2018 to Aug 2022. Of 15 were chemotherapy-pretreated patients, and the remaining 15 were chemotherapy-naïve patients. Clinical responses were assessed using the Response Evaluation Criteria in Solid Tumours (RECIST v1.1) in 27 evaluable patients. Adverse events (AEs) were graded according to Common Terminology Criteria for Adverse Events (CTCAE v5.0). Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. RESULTS: Partial responses were observed in 63% (17/27) patients, and 14 were chemotherapy-naïve patients. The objective response rate (ORR) was 100% (14/14) and 23% (3/13) in chemotherapy-naïve and chemotherapy-pretreated patients, respectively. Fourteen patients subsequently received consolidated surgery. Eight patients achieved pathological complete response, and six were chemotherapy-naïve patients. The median follow-up time was 11.4 (range: 2.3-36.2) months. The median PFS and OS were 15.6 (1.0-32.6) and 20.9 (10.5-30.3) months in chemotherapy-pretreated patients, respectively. However, these were not reached in overall cohort and chemotherapy-naïve patients. 2-year PFS (OS) was 53% (62%) in overall cohort, whereas 75% (79%) and 35% (47%) in chemotherapy-naïve and chemotherapy-pretreated patients, respectively. Treatment-related AEs were experienced by all patients, with 60% (18/30) experiencing a grade 3 or 4 AEs. The most common grade 3-4 treatment-related AEs were lymphopenia (40%), anemia (23%), and neutropenia (13%). CONCLUSIONS: Anti-PD1 antibody plus anti-EGFR antibody and cisplatin-based combination chemotherapy were effective, well-tolerated, and satisfying long-term survival outcome for relapsed locally advanced and/or metastatic penile squamous cell carcinoma. However, prolonged follow-up and large prospective clinical trials are needed to validate the findings on this important issue. Source of Funding: This study was supported by the National Natural Science Foundation of China (No. 81772755). © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e452 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Longbin Xiong More articles by this author Lichao Wei More articles by this author Ting Xue More articles by this author Ru Yan More articles by this author Tingyu Liu More articles by this author Lijuan Jiang More articles by this author Huali Ma More articles by this author Yanxia Shi More articles by this author Xin An More articles by this author Yijun Zhang More articles by this author Shengjie Guo More articles by this author Kai Yao More articles by this author Fangjian Zhou More articles by this author Hui Han More articles by this author Expand All Advertisement PDF downloadLoading ...

Diminishing the Gender-Related Disparity in Survival among Chemotherapy Pre-Treated Patients after Radical Cystectomy—A Multicenter Observational Study

There is a well-documented problem of inferior outcome of muscle-invasive bladder cancer (MIBC) after radical cystectomy (RC) in women. However, previous studies were conducted before neoadjuvant chemotherapy (NAC) was widely adopted to multidisciplinary management of MIBC. In our study, we assessed the gender-related difference in survival between patients who received NAC and those who underwent upfront RC, in two academic centers. This non-randomized, clinical follow-up study enrolled 1238 consecutive patients, out of whom 253 received NAC. We analyzed survival outcome of RC according to gender between NAC and non-NAC subgroups. We found that female gender was associated with inferior overall survival (OS), compared to males (HR, 1.234; 95%CI 1.046-1.447; p = 0.013) in the overall cohort and in non-NAC patients with ≥pT2 disease (HR, 1.220 95%CI 1.009-1.477; p = 0.041). However, no gender-specific difference was observed in patients exposed to NAC. The 5-year OS in NAC-exposed women in ≤pT1 and ≥pT2 disease, was 69.333% 95%CI (46.401-92.265) and 36.535% (13.134-59.936) respectively, compared to men 77.727% 95%CI (65.952-89.502) and 39.122% 95%CI (29.162-49.082), respectively. The receipt of NAC not only provides downstaging and prolongs patients' survival after radical treatment of MIBC but may also help to diminish the gender specific disparity.

Complete response in patient with liver metastasis of HER2-positive breast cancer following therapy with margetuximab: a case report.

Metastatic human epidermal growth factor receptor 2 (HER2) positive breast cancer has a poor prognosis and few effective targeted therapies. However, several anti-HER2 agents are emerging in conjunction with chemotherapy, which may lead to increased rates of pathological complete response in patients with HER2-positive metastatic breast cancer. Among them, margetuximab demonstrated a significant improvement in progression-free survival compared with trastuzumab, when combined with chemotherapy in pretreated patients. Here we present a case of a 67-year-old female patient who was diagnosed with HER2-positive, histological grade III and invasive ductal carcinoma of the left breast in September 2018. She received postoperative adjuvant therapy with EC-TH plus radiotherapy, followed by therapy with HER2-targeted trastuzumab for 1 year (till December 2019). In May 2020, routine reexamination showed a supraclavicular lymph node and bone metastasis. Patient was then treated with pyrotinib, capecitabine and bisphosphonate for a period of 3 months. In December 2020, liver MRI revealed multiple liver metastases. The patient received eight cycles of second-line therapy (vinorelbine plus margetuximab) from January 2021. Since the ninth cycle, the patient was continued with only margetuximab. In March 2021, MRI showed a 70% decrease in the liver metastasis lesions. By June 2021, liver lesions were totally disappeared. During therapy, patient experienced only grade-1 anemia. This case demonstrates that margetuximab plus chemotherapy is safe and might bring clinical benefits for patients with HER2-positive breast cancer with liver metastasis. Further studies evaluating the efficacy and safety of margetuximab in Chinese HER2-positive breast cancer patients are needed.

Efficacy and safety of camrelizumab plus apatinib in previously treated patients with advanced non-small cell lung cancer harboring EGFR or ALK genetic aberration.

BackgroundCamrelizumab plus apatinib shows encouraging antitumor activity and acceptable toxicity in chemotherapy-pretreated patients with advanced non-small cell lung cancer (NSCLC); however, clinical benefits from this combination regimen in NSCLC patients with EGFR mutations or ALK rearrangements (EGFR+/ALK+) have not been reported. We assessed the efficacy and safety of this combined regimen in pretreated patients with advanced NSCLC and defined EGFR/ALK status (EGFR+/ALK+) in a phase 1b/2 trial.MethodsPreviously treated patients with advanced EGFR+/ALK+ NSCLC were enrolled and given camrelizumab 200 mg intravenously every 2 weeks plus apatinib at the recommended dose of 250 mg orally once daily. Patients harboring sensitive EGFR mutations or ALK fusion genes had received at least one EGFR/ALK TKI and a platinum-based chemotherapy regimen before the enrollment. The primary endpoint was objective response rate (ORR).ResultsAll 43 enrolled patients comprised the efficacy and safety analysis population. The confirmed ORR was 18.6% (95% CI: 8.4–33.4%) and the clinical benefit response rate was 27.9% (95% CI: 15.3–43.7%). Median progression-free survival (PFS) was 2.8 months (95% CI: 1.9–5.5 months) and median overall survival was not reached (95% CI: 7.3 months–not reached), with a median follow-up period of 15.7 months (range, 0.5–24.4 months). The most common grade ≥3 treatment-related adverse events (TRAEs) were hypertension (16.3%), proteinuria (11.6%) and palmar-plantar erythrodysaesthesia syndrome (9.3%). No unexpected adverse events were recorded.ConclusionsCamrelizumab plus apatinib showed moderate antitumor activity and acceptable safety profile in previously treated patients with advanced NSCLC and EGFR or ALK genetic aberrations, which warranted further validation.Trial RegistrationClinicalTrials.gov identifier: NCT03083041. Registered March 17, 2017.

Lenvatinib Plus Pembrolizumab vs. Chemotherapy in Pretreated Patients With Advanced Endometrial Cancer: A Cost-Effectiveness Analysis.

BackgroundIn the international, randomized, open-label, phase 3 study 309-KEYNOTE-775 trial, lenvatinib plus pembrolizumab (LP) showed improved progression-free survival (PFS) and overall survival (OS) compared with chemotherapy in pretreated patients with advanced endometrial cancer. This study aimed to investigate whether LP is cost-effective compared with chemotherapy.Materials and MethodsThe clinical data for this model was derived from the 309-KEYNOTE-775 trial. Costs and utilities were either derived from the standard fee database or extracted from previously published literature. A three-state Markov model was developed to simulate the disease process of patients with advanced endometrial cancer. One-way sensitivity analyses were conducted to investigate the impact of variables in the analysis model. Probabilistic sensitivity analysis was performed based on 10,000 Monte-Carlo simulations. A subgroup analysis was performed to test whether LP is cost-effective in patients with mismatch repair–proficient (pMMR) disease.ResultsLenvatinib plus pembrolizumab provided an incremental 0.64 quality-adjusted life years (QALYs) with an incremental cost of $241,278.18, compared with chemotherapy, resulting in the incremental cost-effectiveness ratio (ICER) of $378,251.44/QALY, which exceeded the willingness to pay (WTP) threshold. While in the pMMR subgroup, the ICER increased to $413,256.68/QALY. The variance of the utility of PFS state, the cost of LP, and the utility of the progressive disease state were the most influential factors in the sensitivity analysis.ConclusionUnder the current WTP threshold, LP is not cost-effective compared with chemotherapy in pretreated patients with advanced endometrial cancer.

Camrelizumab Plus Apatinib in Treatment-Naive Patients With Advanced Nonsquamous NSCLC: A Multicenter, Open-Label, Single-Arm, Phase 2 Trial

IntroductionOur preclinical work suggests that low-dose angiogenesis inhibition could potentiate programmed cell death protein 1 and programmed death-ligand 1 (PD-L1) blockade. In a cohort of our multicenter phase 1b and 2 study (NCT03083041), promising antitumor activity was observed with camrelizumab plus low-dose apatinib in chemotherapy-pretreated patients with advanced nonsquamous NSCLC. We hereby reported the results in treatment-naive patients (cohort 4) from the same study. MethodsEligible patients had untreated advanced nonsquamous NSCLC with a high tumor mutational burden (TMB) (tissue TMB >10 mutations per megabase or blood TMB ≥1.54 mutations per megabase) and without sensitizing EGFR or ALK alterations. Patients received camrelizumab 200 mg intravenously every 2 weeks plus apatinib 250 mg orally once daily. The primary end point was the objective response rate (ORR) per investigator. ResultsA total of 25 patients were enrolled and treated. A total of 10 (40.0%) confirmed partial responses and 13 (52.0%) stable diseases were observed. The ORR was 40.0% (95% confidence interval [CI]: 21.1–61.3) and disease control rate was 92.0% (95% CI: 74.0–99.0). With a median follow-up of 19.5 months, the median progression-free survival was 9.6 months (95% CI: 5.5–not reached), whereas the overall survival was not reached; the median duration of response was 15.6 months (95% CI: 3.8–not reached). Similar ORR and progression-free survival were observed regardless of PD-L1 tumor proportion score (≥1% versus <1%). The most common treatment-related grade 3 or higher adverse events were increased gamma-glutamyltransferase (24.0%), increased alanine aminotransferase (16.0%), and abnormal hepatic function (16.0%). ConclusionsFrontline camrelizumab plus low-dose apatinib exhibited promising clinical activity with acceptable safety in patients with advanced nonsquamous NSCLC regardless of PD-L1 expression.

Margetuximab Versus Trastuzumab in Patients With Advanced Breast Cancer: A Cost-effectiveness Analysis

BackgroundIn the international, randomized, open-label, phase III study SOPHIA trial, margetuximab plus chemotherapy showed improved progression-free survival (PFS), and overall survival (OS) compared with trastuzumab plus chemotherapy. This study aimed to investigate whether margetuximab plus chemotherapy is cost-effective compared with trastuzumab plus chemotherapy in pretreated patients with ERBB2-positive advanced breast cancer. Materials and MethodsThe clinical data for this model was derived from the SOPHIA trial. Costs and utility were either derived from the standard fee database or extracted from previously published literature. A three-state Markov model was developed to simulate the disease process of patients with advanced breast cancer. One-way sensitivity analyses were conducted to investigate the impact of variables in the analysis model. Probabilistic sensitivity analysis was performed based on 10,000 Monte-Carlo simulations. A subgroup analysis was performed to test whether margetuximab is cost-effective in CD16A-158F allele carriers. ResultsMargetuximab plus chemotherapy provided an incremental 0.04 QALYs with an incremental cost of $66,109.78, compared with the trastuzumab plus chemotherapy, resulting in the incremental cost-effectiveness ratio (ICER) of $1,486,442.35/QALY, which exceeded the willingness to pay (WTP) threshold. While in the CD16A-158F allele carriers subgroup, the ICER decreased to $592,669.73/QALY. The variance of the utility of PFS state, costs of margetuximab, and utility of progressive disease state were the most influential factors in the sensitivity analysis. ConclusionUnder current WTP threshold, margetuximab plus chemotherapy is not cost-effective compared with trastuzumab plus chemotherapy in pretreated patients with ERBB2-positive advanced breast cancer. Selecting CD16A-158F allele carriers might be a considerable option to optimize the cost-effectiveness of margetuximab.

MA13.01 Camrelizumab Plus Apatinib in Treatment-Naive Patients With Advanced Non-Squamous NSCLC: A Multicenter, Open-Label, Single-Arm, Phase 2 Trial

Our preclinical work suggests that appropriate angiogenesis inhibition could potentiate PD-1/PD-L1 blockade, and promising anti-tumor activity was already observed with camrelizumab plus apatinib in chemotherapy-pretreated patients (pts) with advanced non-squamous NSCLC in the phase Ib/II study (NCT03083041). We hereby further investigated its efficacy in treatment-naive advanced NSCLC pts as in cohort 4 of this study.

Three-year follow-up of ATTRACTION-3: A phase III study of nivolumab (Nivo) in patients with advanced esophageal squamous cell carcinoma (ESCC) that is refractory or intolerant to previous chemotherapy.

204 Background: Previous results from the ATTRACTION-3 phase 3 trial demonstrated a significant improvement in overall survival and a favorable safety profile compared with taxane chemotherapy (CT) in previously-treated ESCC patients. To our knowledge, no long-term efficacy and safety data of this immune checkpoint inhibitor has been reported in ESCC. Herein, we report the three-year survival data of Nivo in ESCC. Methods: In ATTRACTION-3, 419 patients with unresectable advanced or recurrent ESCC refractory or intolerant to 1 prior fluoropyrimidine/platinum-based CT were randomized in a 1:1 ratio to receive Nivo (N = 210) or the investigator’s choice of CT (paclitaxel or docetaxel) (N = 209) until disease progression or unacceptable toxicity. The primary endpoint was overall survival (OS). A subgroup analysis of OS according to the best overall response (BOR) was performed. The onset of treatment-related adverse events of special interest over time in the Nivo arm was also evaluated. Results: As of data cut-off on 25 May 2020, 3 years after the last patient was enrolled, the median OS (mOS) was 10.91 months with Nivo versus 8.51 months with CT [hazard ratio (HR) 0.79; 95% confidence interval (CI) 0.64-0.97]. The OS rates of patients with Nivo and CT were 20.2 % and 13.5 % at 24 months, and 15.3% and 8.7% at 36 months, respectively. In the subgroup analysis of OS by BOR, mOS in CR/PR patients were 19.91 and 15.41 months (HR 0.84, 95%CI 0.46-1.54) and that in SD patients were 17.38 and 9.36 months (HR 0.45, 95%CI 0.26-0.78) in the Nivo and CT arm, respectively. Furthermore, mOS in PD patients were 10.91 and 6.18 months (HR 0.56, 95%CI 0.33-0.95) in the Nivo and CT arm, respectively. No new safety signals were detected during the three-year follow-up. Time to onset of the event of special interest was within the range of events previously observed in other indications. Conclusions: At three-year follow up, Nivo continued to show improved OS over CT in pretreated patients with advanced ESCC patients. Nivo showed a longer mOS than CT regardless of BOR. During the three-year follow-up, no new safety signals were observed. Clinical trial information: NCT02569242.

CDK12-Mutated Prostate Cancer: Clinical Outcomes With Standard Therapies and Immune Checkpoint Blockade.

Translational studies have shown that CDK12 mutations may delineate an immunoresponsive subgroup of prostate cancer, characterized by high neo-antigen burden. Given that these mutations may define a clinically distinct subgroup, we sought to describe outcomes to standard drugs and checkpoint inhibitors (CPI). Clinical data from consecutive patients with CDK12 mutations were retrospectively collected from 7 centers. Several clinical-grade sequencing assays were used to assess CDK12 status. Descriptive statistics included PSA50 response rate (≥ 50% decline in prostate-specific antigen from baseline) and clinical/radiographic progression-free survival (PFS). Of 52 patients with CDK12-mutated prostate cancer, 27 (52%) had detected biallelic CDK12 alterations. At diagnosis, 44 (88%) had Gleason grade group 4-5, 52% had T3-T4, and 14 (27%) had M1 disease. Median follow-up was 8.2 years (95% CI, 5.6 to 11.1 years), and 49 (94%) developed metastatic disease. Median overall survival from metastasis was 3.9 years (95% CI, 3.2 to 8.1 years). Unconfirmed PSA50 response rates to abiraterone and enzalutamide in the first-line castration-resistant prostate cancer setting were 11 of 17 (65%) and 9 of 12 (75%), respectively. Median PFS on first-line abiraterone and enzalutamide was short, at 8.2 months (95% CI, 6.6 to 12.6 months) and 10.6 months (95% CI, 10.2 months to not reached), respectively. Nineteen patients received CPI therapy. PSA50 responses to CPI were noted in 11%, and PFS was short; however, the estimated 9-month PFS was 23%. PFS was higher in chemotherapy-näıve versus chemotherapypretreated patients (median PFS: not reached v 2.1 months, P = .004). CDK12 mutations define an aggressive prostate cancer subgroup, with a high rate of metastases and short overall survival. CPI may be effective in a minority of these patients, and exploratory analysis supports using anti-programmed cell death protein 1 drugs early. Prospective studies testing CPI in this subset of patients with prostate cancer are warranted.

Efficacy of nab-paclitaxel in treating metastatic melanoma

ABSTRACTIntroduction: Systemic treatment of metastatic melanoma has been revolutionized by the advent of checkpoint inhibitors and targeted agents which are widely accepted as standard front-line therapies. However, despite these major advances, a substantial portion of patients still fail checkpoint inhibitors and/or targeted agents and are not candidates for clinical trials.Commonly used cytotoxics in these patients include paclitaxel, dacarbazine, platins, and temozolomide. The overall response rates of these agents are usually disappointing and short-lived.Areas covered: Herein, the author provides a literature review of the role of nab-paclitaxel in metastatic melanoma including coverage of its pharmacokinetics, pharmacodynamics and efficacy.Expert opinion: The role of chemotherapy in the treatment of metastatic melanoma is limited to patients who failed checkpoint inhibitors and, when applicable, targeted agents, and those not appropriate for clinical trials. nab-Paclitaxel has single agent activity in chemotherapy-naïve untreated metastatic melanoma which compares favorably to the activity of weekly paclitaxel or single agent dacarbazine. However, the activity in chemotherapy-pretreated patients is modest. Data on nab-paclitaxel in patients pretreated with targeted agents or check point inhibitors are lacking. Further advances are expected from new checkpoint inhibitors and targeted agents for the treatment of metastatic melanoma in addition to the optimal combination and sequencing of these agents.

Hyperprogressive Disease in Patients With Advanced Non–Small Cell Lung Cancer Treated With PD-1/PD-L1 Inhibitors or With Single-Agent Chemotherapy

Hyperprogressive disease (HPD) is a new pattern of progression recently described in patients with cancer treated with programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) inhibitors. The rate and outcome of HPD in advanced non-small cell lung cancer (NSCLC) are unknown. To investigate whether HPD is observed in patients with advanced NSCLC treated with PD-1/PD-L1 inhibitors compared with single-agent chemotherapy and whether there is an association between treatment and HPD. In this multicenter retrospective study that included patients treated between August 4, 2011, and April 5, 2017, the setting was pretreated patients with advanced NSCLC who received PD-1/PD-L1 inhibitors (8 institutions) or single-agent chemotherapy (4 institutions) in France. Measurable disease defined by Response Evaluation Criteria in Solid Tumors (RECIST version 1.1) on at least 2 computed tomographic scans before treatment and 1 computed tomographic scan during treatment was required. The tumor growth rate (TGR) before and during treatment and variation per month (ΔTGR) were calculated. Hyperprogressive disease was defined as disease progression at the first evaluation with ΔTGR exceeding 50%. The primary end point was assessment of the HPD rate in patients treated with IO or chemotherapy. Among 406 eligible patients treated with PD-1/PD-L1 inhibitors (63.8% male), 46.3% (n = 188) were 65 years or older, 72.4% (n = 294) had nonsquamous histology, and 92.9% (n = 377) received a PD-1 inhibitor as monotherapy in second-line therapy or later. The median follow-up was 12.1 months (95% CI, 10.1-13.8 months), and the median overall survival (OS) was 13.4 months (95% CI, 10.2-17.0 months). Fifty-six patients (13.8%) were classified as having HPD. Pseudoprogression was observed in 4.7% (n = 19) of the population. Hyperprogressive disease was significantly associated with more than 2 metastatic sites before PD-1/PD-L1 inhibitors compared with non-HPD (62.5% [35 of 56] vs 42.6% [149 of 350]; P = .006). Patients experiencing HPD within the first 6 weeks of PD-1/PD-L1 inhibitor treatment had significantly lower OS compared with patients with progressive disease (median OS, 3.4 months [95% CI, 2.8-7.5 months] vs 6.2 months [95% CI, 5.3-7.9 months]; hazard ratio, 2.18 [95% CI, 1.29-3.69]; P = .003). Among 59 eligible patients treated with chemotherapy, 3 (5.1%) were classified as having HPD. Our study suggests that HPD is more common with PD-1/PD-L1 inhibitors compared with chemotherapy in pretreated patients with NSCLC and is also associated with high metastatic burden and poor prognosis in patients treated with PD-1/PD-L1 inhibitors. Additional studies are needed to determine the molecular mechanisms involved in HPD.

Predictors of overall and recurrence-free survival after neoadjuvant chemotherapy for gastroesophageal adenocarcinoma: Pooled analysis of individual patient data (IPD) from randomized controlled trials (RCTs)

BackgroundNeoadjuvant chemotherapy improves prognosis of patients with locally advanced gastroesophageal adenocarcinoma. The aim of this study was to identify predictors for postoperative survival following neoadjuvant therapy. These could be useful in deciding about postoperative continuation of chemotherapy. MethodsThis meta-analysis used IPD from RCTs comparing neoadjuvant chemotherapy with surgery alone for gastroesophageal adenocarcinoma. Trials providing IPD on age, sex, performance status, pT/N stage, resection status, overall and recurrence-free survival were included. Survival was calculated in the entire study population and subgroups stratified by supposed predictors and compared using the log-rank test. Multivariable Cox models were used to identify independent survival predictors. ResultsFour RCTs providing IPD from 553 patients fulfilled the inclusion criteria. (y)pT and (y)pN stage and resection status strongly predicted postoperative survival both after neoadjuvant therapy and surgery alone. Patients with R1 resection after neoadjuvant therapy survived longer than those with R1 resection after surgery alone. Patients with stage pN0 after surgery alone had better prognosis than those with ypN0 after neoadjuvant therapy. Patients with stage ypT3/4 after neoadjuvant therapy survived longer than those with stage pT3/4 after surgery alone. Multivariable regression identified resection status and (y)pN stage as predictors of survival in both groups. (y)pT stage predicted survival only after surgery alone. ConclusionAfter neoadjuvant therapy for gastroesophageal adenocarcinoma, survival is determined by the same factors as after surgery alone. However, ypT stage is not an independent predictor. These results can facilitate the decision about postoperative continuation of chemotherapy in pretreated patients.

Safety and Antitumour Activity of ODM-201 (BAY-1841788) in Castration-resistant, CYP17 Inhibitor-naïve Prostate Cancer: Results from Extended Follow-up of the ARADES Trial

BackgroundPatients with castration-resistant prostate cancer (CRPC) had extended responses to the androgen receptor antagonist ODM-201, in phase 1/2 studies. ObjectiveTo evaluate the safety and antitumour activity of prolonged ODM-201 treatment in patients with CRPC. Design, setting, and participantsThe ARADES trial was a multicentre phase 1 (dose escalation) and phase 2 (dose expansion) trial; 134 patients with CRPC were stratified by previous chemotherapy to receive ODM-201. This paper reports extended follow-up in CYP17 inhibitor (CYP17i)-naïve patients. InterventionPatients (n=77) received oral ODM-201 twice daily at daily doses of 200–1800mg. Outcome measurements and statistical analysisSafety, measured as the occurrence of adverse events (AEs), prostate-specific antigen (PSA), and radiographic progression. Results and limitationsThe safety profile of extended ODM-201 treatment (median treatment duration 8.2 mo, 95% confidence interval [CI] 5.6–11.0) was consistent with that reported at the time of the original data cutoff in the main ARADES trial, with no unexpected safety concerns over time. The majority of AEs (61.1%) were mild (grade 1); the most common AE was fatigue/asthenia (35.1% of patients), with no clear relationship to ODM-201. Median time to PSA progression was 25.2 mo (95% CI 11.3–25.2) for chemotherapy-naïve men and not reached (NR; 95% CI 5.5–NR) for chemotherapy-pretreated patients; a trend for improved antitumour response was observed for chemotherapy-naïve patients. The median time to radiographic progression was longer for chemotherapy-naïve (14.0 mo, 95% CI 8.1–33.3) than for chemotherapy-pretreated (7.2 mo, 95% CI 2.7–11.0) patients. ConclusionsProlonged exposure to ODM-201 was well tolerated, with no additional safety concerns; disease suppression was sustained, especially in chemotherapy-naïve patients. These data support further development of ODM-201 in men with CYP17i-naïve CRPC. Patient summaryExtended ODM-201 therapy was well tolerated, with beneficial antitumour activity in men with advanced prostate cancer, indicating that ODM-201 may represent a new active treatment for men with CRPC.This extension trial is registered at ClinicalTrials.gov (www.clinicaltrials.gov) under identification number NCT01429064.

SC26.03 Predictive Biomarkers for Angiogenesis Inhibitors: An Update

The concept of tumor-induced neoangiogenesis has been shown to be a relevant factor for tumor proliferation and metastasis already a couple of years ago.1 Therefore interaction with proangiogenic pathways appears to be a promising therapeutic target across several solide tumors. In eligible patients with advanced non-squamous NSCLC the addition of the anti-vascular endothelial growth factor (anti VEGF) antibody bevacizumab to platinum based chemotherapy has shown consistent improvement of response, progression free survival (PFS) and overall survival. However, the combination did increase the incidence of characteristic adverse events like hypertension, arterial and venous vascular events, bleeding events, proteinuria and other.2 Recently two large randomized phase III trials revealed a significant increase in efficacy by the combination of antiangiogenic agents and chemotherapy in pretreated patients with advanced NSCLC. In the LUME 1 trial the combination of the oral angiokinase inhibitor nintedanib and docetaxel revealed a significant improvement of PFS (median PFS 3.4 vs 2.7 months, HR 0.79, 95% CI 0.68-0.92) and OS in patients with adenocarcinoma histology (median OS 12.6 vs 10.3 months, HR 0.82, 95% CI 0.7-0.99) compared to docetaxel.3 The combination of the anti VEGF receptor 2 antibody ramucirumab and docetaxel did show a significant improvement of response (response rate: 23% versus 14%, p<0.0001), PFS (median PFS 4.5 versus 3.0 months, HR 0.76, 95% CI 0.68-0.86) and OS (median OS 10.5 versus 9.1 months, HR 0.86, 95% CI 0.75-0.98) compared to docetaxel in pretreated patients with NSCLC regardless of histology.4 The identification of potential predictive biomarkers remains a challenge due to the complexity of angiogenesis, the interaction between the tumor and the host and due to dynamic changes of the system. In a very large trial (Abigail), specifically designed to identify potential tissue based or blood based markers of efficacy, no predictive markers could be determined. However the relevant prognostic nature of angiogenesis marker could be confirmed.5 Recent analyses revealed that besides molecular markers clinical factors like rapid progressive diseases or tumors refractory to conventional chemotherapy could be associated with improved outcomes of angiogenesis inhibitors. Preplanned as well as exploratory analyses did show pronounced efficacy for the combination of antiangiogenic agents like nintedanib, ramucirumab and bevacizumab compared to chemotherapy alone supporting the hypothesis that fast progressing tumors are more dependant on neo angiogenesis. The translational exploration of these clinical findings is on the way in several programs and trials. The understanding of this correlation will be important for the optimal placement of antiangiogenic agents e.g. in the combination with immunotherapies. 1. Folkman J, Merler E, Abernathy C et al. Isolation of a tumor factor responsible for angiogenesis. J Exp Med 1971; 133: 275-288. 2. Soria JC, Mauguen A, Reck M et al. Systematic review and meta-analysis of randomized phase II/III trials adding bevacizumab to platinum based chemotherapy as first-line treatment in patients with advanced non-small-cell lung cancer. Ann Oncol 2013; 24: 20-30. 3. Reck M, Kaiser R, Mellemgaard A et al. Docetaxel plus nintedanib versus docetaxel plus placebo in patients with previously treated non-small-cell lung cancer (LUME-Lung 1): a phase 3, double blind, randomized controlled trial. Lancet Oncol 2014; 15: 143-50. 4. Garon E, Ciuleanu TE, Arrieta O et al. Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum based therapy (REVEL): a multicentre, double-blind, randomized phase 3 trial. Lancet 2014; 384: 665-773. 5. Mok T, Gorbunova V, Juhasz E et al. A correlative biomarker analysis of bevacizumab and carboplatin-based chemotherapy for advanced nonsquamous non-small cell lung cancer: results of the phase II randomized ABIGAIL study (BO21015). J Thorac Oncol 2014; 9: 848-55. Angiogenesis, Biomarker, NSCLC, rapid progressive tumors

Erlotinib has comparable clinical efficacy to chemotherapy in pretreated patients with advanced non-small cell lung cancer (NSCLC): A propensity-adjusted, outcomes research-based study

ObjectivesControversy exists about the integration of erlotinib in patients with EGFR wildtype, advanced NSCLC. Materials and methodsWe included patients with advanced NSCLC receiving at least two lines of palliative systemic treatment between January 2005 and December 2014 and not harbouring targetable driver mutations. Primary study endpoint was overall survival (OS), secondary endpoint progression-free survival (PFS). We used Kaplan-Meier statistics, multivariate Cox regression and Propensity score or Inverse Probability Weights (IPW) matching to compare clinical outcome between patients receiving erlotinib in second or further line and those receiving chemotherapy only. The study had a power of 90% to detect a survival superiority of 30%. ResultsFrom a total of 827 patients, we excluded 171 patients with potentially curative treatment, 189 receiving treatment outside of our institute, 206 receiving no or only one line of systemic treatment, 6 with ALK translocations and 28 with EGFR mutations. From 227 patients in the final efficacy analysis, 125 patients received erlotinib in second (89 patients), third (28) or further-line (8), and 102 patients received chemotherapy only. Women and never smokers were significantly overrepresented in the erlotinib group. Both OS (hazard ratio (HR)=1.14, 95% CI 0.80-1.63, P=0.448) and PFS (HR=1.20, 95% CI 0.95–1.52, P=0.119) were similar in the erlotinib compared to the chemotherapy group using IPW-adjusted Cox regression analysis treating the use of erlotinib as a time-dependent covariate starting from second-line treatment and stratified for ECOG performance status and treatment line. ECOG performance status was the most powerful covariate to select patients for erlotinib treatment. ConclusionThe present study suggests erlotinib to have similar clinical efficacy compared to chemotherapy in patients with pretreated advanced NSCLC and no known molecular targetable alterations.

Population pharmacokinetic analysis of abiraterone acetate in healthy volunteers and chemotherapy-naive and chemotherapy-pretreated metastatic castration-resistant prostate cancer patients.

58 Background: Abiraterone acetate (AA) is an effective therapy for patients with metastatic castration-resistant prostate cancer (mCRPC). AA is metabolized to abiraterone, an androgen biosynthesis inhibitor. We performed population pharmacokinetic (PK) analyses to estimate PK parameters after a 1,000 mg/d oral dose of AA in patients with mCRPC with and without prior chemotherapy and after a one-time 1,000 mg dose in healthy volunteers, to determine consistency between groups. Methods: Studies included in analysis: COU-AA-302 (pre-chemotherapy mCRPC); COU-AA-301 and COU-AA-006 (post-docetaxel mCRPC); and COU-AA-008, COU-AA-009, and COU-AA-014 (healthy subjects). A total of 4,627 plasma concentrations from 360 subjects were analyzed using nonlinear mixed-effects modeling. Results: A two-compartment model with three-transit compartments following sequential zero-first order kinetics was used to characterize the systemic absorption of abiraterone. Absorption-related parameters were affected by food intake. Abiraterone PK was characterized by an extensive apparent clearance, which was lower in patients with mCRPC (1505 L/h) compared with healthy subjects (2240 L/h), and by large apparent central (5630 L) and peripheral volumes of distribution (17,400 L). PK of abiraterone was similar in chemotherapy-naïve and chemotherapy-pretreated patients and was characterized by a relatively high between- and within-subject variability (eg, between-subject coefficient of variation [CV%] for relative bioavailability in the clinical studies was 61.1% and the CV% for within-subject variability was 71.3%). No factors other than food intake and patient-healthy volunteer status impacted PK. Conclusions: Based on this population PK model, the recommended 1,000 mg/d dose of AA results in similar abiraterone exposure for patients with mCRPC regardless of prior chemotherapy status. The food effect on absorption-related parameters in this analysis confirms current dosing instructions for AA. Clinical trial information: NCT00638690, NCT00887198.

Hypofractionated Image-Guided IMRT in Advanced Pancreatic Cancer With Simultaneous Integrated Boost to Infiltrated Vessels Concomitant With Capecitabine: A Phase I Study

To determine the maximum tolerated radiation dose (MTD) of an integrated boost to the tumor subvolume infiltrating vessels, delivered simultaneously with radical dose to the whole tumor and concomitant capecitabine in patients with pretreated advanced pancreatic adenocarcinoma. Patients with stage III or IV pancreatic adenocarcinoma without progressive disease after induction chemotherapy were eligible. Patients underwent simulated contrast-enhanced four-dimensional computed tomography and fluorodeoxyglucose-labeled positron emission tomography. Gross tumor volume 1 (GTV1), the tumor, and GTV2, the tumor subvolume 1 cm around the infiltrated vessels, were contoured. GTVs were fused to generate Internal Target Volume (ITV)1 and ITV2. Biological tumor volume (BTV) was fused with ITV1 to create the BTV+Internal Target Volume (ITV) 1. A margin of 5/5/7 mm (7 mm in cranium-caudal) was added to BTV+ITV1 and to ITV2 to create Planning Target Volume (PTV) 1 and PTV2, respectively. Radiation therapy was delivered with tomotherapy. PTV1 received a fixed dose of 44.25 Gy in 15 fractions, and PTV2 received a dose escalation from 48 to 58 Gy as simultaneous integrated boost (SIB) in consecutive groups of at least 3 patients. Concomitant chemotherapy was capecitabine, 1250 mg/m(2) daily. Dose-limiting toxicity (DLT) was defined as any treatment-related G3 nonhematological or G4 hematological toxicity occurring during the treatment or within 90 days from its completion. From June 2005 to February 2010, 25 patients were enrolled. The dose escalation on the SIB was stopped at 58 Gy without reaching the MTD. One patient in the 2(nd) dose level (50 Gy) had a DLT: G3 acute gastric ulcer. Three patients had G3 late adverse effects associated with gastric and/or duodenal mucosal damage. All patients received the planned dose of radiation. A dose of 44.25 Gy in 15 fractions to the whole tumor with an SIB of 58 Gy to small tumor subvolumes concomitant with capecitabine is feasible in chemotherapy-pretreated patients with advanced pancreatic cancer.