Successive Lines Of Treatment Research Articles

Everolimus for advanced breast cancer: Is the histological subtype important?

e13165 Background: Invasive lobular (L) breast carcinomas (BC), which account for up to 15% of all BC, had particularly histopathological characteristics: tends to be estrogen/progesterone receptor positive and HER2-neu negative and as such are treated with endocrine therapy (ET). It had been demonstrated a frequent activation of PI3K–AKT–mTOR signaling in LBCs, suggesting this pathway to be a promising therapeutic target for LBC. Interestingly, in some of these patients, the subsequent use of a mTOR inhibitor (everolimus) combined with an ET produced greater clinical benefits. Our aim is to evaluate the efficacy of everolimus in advanced BC (ABC) in the usual clinical practice, focusing on LBC. Methods: We retrospectively analyzed 147 women with ABC from four Spanish hospitals who were treated with everolimus (Ev) in second or successive lines of treatment between 2014-2023. We performed a descriptive statistical analysis of the clinicopathological variables and calculated the investigator-assessed time to treatment failure (TTF), defined as the interval from initiation of treatment to its premature discontinuation (because of progression disease (PD) or toxicity), as well as its association using Kaplan-Meier test. Survival curves were analyzed using long-rank test. Finally, we analyzed the subgroup of those with everolimus TTF (TTF2) longer than previous line TTF (TTF1) by Xi2 test. Results: With a median (m) age of 59, 21 (14%) patients (pts) were diagnosed with advanced LBC. The histopathological characteristics of the pts are shown (Table). Treatment had to be stopped in 24 pts due to toxicity (oral mucositis 21%), and the rest was due to PD or exitus. The response rate (stabilization, partial and complete response (CR)) was 49% with 4% of CR. The overall m of TTF2 was 9,1 months, while the TTF1 m was 9,5 months. Analyzing by histology, TTF2 m was 18.16 months in LBC vs 7.85 in ductal BC (p=0.01). Contrary to expectations, 40 pts (27,2%) had a longer TTF2 compared with TTF1 (p>0.001). When analyzing this subgroup we found 9 pts with LBC and 27 DBC (p>0,05). 26 pts (65%) had not received previous line with HT (p=0.005). On the other hand, when analyzing the subgroup of pts with LBC, up to 47.36% of pts had TTF2>TTF1. Conclusions: The use of everolimus in pts with LBC appears to be more effective than in DBC according to the results reported in our series and its use in initial hormonal lines may be reconsidered. However, we need more prospective studies differentiating histologies to demonstrate our results for others Pi3k inhibitors. [Table: see text]

Real-world use of pharmacological treatments for incident bipolar disorder: A Finnish nationwide cohort study

BackgroundPharmacotherapy remains crucial for treating bipolar disorder (BD), but knowledge on the treatments actually used by newly diagnosed patients in real-world settings is sparse. MethodsIndividuals newly diagnosed with BD during 1996–2018, aged 15–65 years, were identified from national Finnish registers. The patients' use of different drug classes (mood stabilizers, antipsychotics and antidepressants) or combinations of these drug classes were followed from initial pharmacotherapy (first line) after BD diagnosis until the fifth line of treatment or until the two-year follow-up time ended. Clinical and sociodemographic factors associated with antidepressants-only as the first treatment line were assessed with logistic regression. Results82.6 % of all patients used BD medication during the follow-up. 33.9 % had antidepressants-only as the first, 22.9 % as the second and 19.7 % as the third treatment line. Use of combinations of mood stabilizers, antipsychotics and antidepressants increased by successive treatment lines. Factors associated with antidepressants-only as the first treatment line included older age (>45 years aOR 2.20, 95% CI: 2.01–2.40, 25–45 years: 1.55, 1.42–1.68, compared with those aged <25), diabetes (1.35, 1.17–1.55) and female sex (1.29, 1.21–1.37). BD diagnosis registered in 2016–2018 (0.48, 0.42–0.55) and substance abuse (0.77, 0.71–0.83) were associated with decreased odds. LimitationsDue to the register-based nature of this study, not all potentially important clinical factors influencing medication use could be controlled for. ConclusionsA large proportion of patients with bipolar disorder are not treated according to treatment guidelines, as use of antidepressants alone is common. Reasons for not following evidence-based recommendations need to be further researched.

INCIDENCE AND PREDICTIVE FACTORS OF PLATINUM‐ASSOCIATED NEPHROTOXICITY IN PATIENTS WITH LYMPHOID MALIGNANCIES; A 15‐YEAR EXPERIENCE OUTSIDE CLINICAL TRIALS

Introduction: Platinum-based chemotherapy is widely used in patients with lymphoma either in first or successive lines of treatment. However, platinum is well known to be nephrotoxic and could impact in clinical outcomes. Methods: An unicentric retrospective cohort study was carried out including lymphoma patients who received platinum-based chemotherapy between 2007 and 2022. Renal failure (RF) was defined as a decrease in creatinine clearance by 50% or an elevation of plasma creatinine a 50% over the previous level. Patients who received treatment in first line and those who were intended to proceed to cellular therapy were included. Patients on clinical trials were excluded. The final cohort was assessed for incidence of RF and clinical and laboratory variables were evaluated as risk factors. Results: A total of 123 patients were included. Baseline characteristics are summarized in Figure 1A. The incidence of RF was 41.5% (51/123). Median time to RF was 6 days (range: 1–28). RF persisted until data cut-off date in 20/51 (39.2%), and 4/51 (7.8%) patients required dialysis. Following variables: sex, body mass index, diabetes, dyslipidemia, use of anti-CD20 and the type of chemotherapy were not associated to an increased risk of RF. Administration of magnesium supplements and mannitol had no impact on RF. Significant differences were observed between the RF and the no-RF groups in age (58.3 vs. 48.3 years; p < 0.001), hypertension (41.2% vs. 13.9%; p < 0.001), albumin (3.2 vs. 3.7 g/dL; p < 0.001) and hemoglobin (10.9 vs. 12.5 g/dL; p < 0.001). We used the cut-off of 51 years (assessed by the optimal point of the ROC curve) for age to be included in a logistic regression model with categoric predictors. The cut-off values of 3.5 g/dL for albumin and 10 g/dL of hemoglobin were chosen based on a biological basis. These four variables were associated with an increased risk of RF showing univariable odds ratio (OR) of 3.7 (1.7–8) for age, 4.3 (1.8–10.4) for hypertension, 4.3 (2–9.2) for albumin and 4.3 (1.8–10.4) for hemoglobin. A multivariable logistic regression model was built including these variables; having hypertension and hemoglobin <10 remained as significant predictors – OR: 1.8 (1.1–2.9) and 2.8 (1.1–7.6) respectively –, whereas age <51 and albumin kept an OR of 1.9 (0.8–4.9) and 2.3 (0.9–5.5) which resulted non statistically significant. Developing renal failure after platinum treatment was associated with a significant decrease in overall survival (OS); median OS in RF and no-RF groups were: 2.4 versus 6.2 years respectively (Figure 1B, log-rank test: 6.67; p = 0.009). Keywords: late effects in lymphoma survivors, other, risk models No conflicts of interests pertinent to the abstract.

Triple negative breast cancer: second and successive lines of treatment

Triple negative breast cancer: second and successive lines of treatment

Estimating the distribution of ratio of paired event times in phase II oncology trials.

With the rapid development of new anti-cancer agents which are cytostatic, new endpoints are needed to better measure treatment efficacy in phase II trials. For this purpose, Von Hoff (1998) proposed the growth modulation index (GMI), that is, the ratio between times to progression or progression-free survival times in two successive treatment lines. An essential task in studies using GMI as an endpoint is to estimate the distribution of GMI. Traditional methods for survival data have been used for estimating the GMI distribution because censoring is common for GMI data. However, we point out that the independent censoring assumption required by traditional survival methods is always violated for GMI, which may lead to severely biased results. In this paper, we construct both nonparametric and parametric estimators for the distribution of GMI, accounting for the dependent censoring of GMI. Extensive simulation studies show that our nonparametric estimators perform well in practical situations and outperform existing estimators, and our parametric estimators perform better than our nonparametric estimators and existing estimators when the parametric model is correctly specified. A phase II clinical trial using GMI as the primary endpoint is provided for illustration.

A Retrospective Cohort Study of Treatment Outcomes of Adult Patients With Relapsed or Refractory Follicular Lymphoma (ReCORD-FL).

This study (ReCORD-FL) sought to construct a historical control cohort to augment single-arm trials in relapsed/refractory follicular lymphoma (r/r FL). A retrospective study in 10 centers across North America and Europe was conducted. Adults with grade 1–3A FL were required to be r/r after ≥2 therapy lines including an anti-CD20 and an alkylator. After first becoming r/r, patients were required to initiate ≥1 additional therapy line, which defined the study index date. Endpoints were observed from start of each therapy line (including index line) until death, last follow-up, or December 31, 2020. Endpoints were complete response (CR) rate, overall response rate (ORR), time to next treatment or death (TNT-D), event-free survival (EFS), and overall survival (OS). One hundred eighty-seven patients were identified. Most patients’ (80.2%) index therapy occurred in third line (3L) (range, 3L–6L). Median follow-up from FL diagnosis was 9 years (range, 1–21 years). CR and ORR to the index therapy were 39.0% and 70.6%, respectively. Median (95% confidence interval) EFS from index was 14.6 (11.0-18.0) months; median OS from index was 10.6 years. Outcomes worsened across successive treatment lines and for patients who were double refractory (r/r to both an anti-CD20 monoclonal antibody and an alkylator) or POD24 (progressed ≤24 months after front-line anti-CD20) at index. Findings demonstrate the unmet need of FL patients with multiply relapsed, double refractory, or POD24 disease. Based on robustness of the historical data collected and comparability with a previous study (SCHOLAR-5), ReCORD-FL presents a valuable source of control data for comparative studies in r/r FL.

Celastrol and Resveratrol Modulate SIRT Genes Expression and Exert Anticancer Activity in Colon Cancer Cells and Cancer Stem-like Cells.

Simple SummaryThe recovery rate in patients with metastatic colorectal cancer (CRC) remains low and declines with successive lines of treatment. This phenomenon is caused by the development of drug resistance and the presence of colorectal cancer stem cells (CSCs). Phytochemicals, like -celastrol and resveratrol, are very promising for colon cancer therapy, owing to their low or no toxicity and their pleiotropic activity, enabling them to interact with various biological targets. In the present study, the potential anticancer mechanisms of both compounds against metastatic colon cancer cells and the capacity to eradicate CSCs were investigated.Metastatic colorectal cancer (CRC) remains a hard-to-cure neoplasm worldwide. Its curability declines with successive lines of treatment due to the development of various cancer resistance mechanisms and the presence of colorectal cancer stem cells (CSCs). Celastrol and resveratrol are very promising phytochemicals for colon cancer therapy, owing to their pleiotropic activity that enables them to interact with various biological targets. In the present study, the anticancer activities of both compounds were investigated in metastatic colon cancer cells (LoVo cells) and cancer stem-like cells (LoVo/DX). We showed that celastrol is a very potent anti-tumor compound against metastatic colon cancer, capable of attenuating CSC-like cells at the molecular and cellular levels. In contrast, resveratrol has a much greater effect on colon cancer cells that are expressing standard sensitivity to anticancer drugs, than on CSC-like cells. In addition, both polyphenols have different influences on the expression of SIRT genes, which seems to be at least partly related to their anti-tumor activity.

A Retrospective Cohort Study of Treatment Outcomes of Adult Patients with Relapsed or Refractory Low-Grade Follicular Lymphoma (ReCORD-FL)

A Retrospective Cohort Study of Treatment Outcomes of Adult Patients with Relapsed or Refractory Low-Grade Follicular Lymphoma (ReCORD-FL)

Comprehensive Dissection of Treatment Patterns and Outcome for Patients With Metastatic Large-Cell Neuroendocrine Lung Carcinoma.

BackgroundLarge-cell neuroendocrine lung carcinoma (LCNEC) is a rare pulmonary neoplasm with poor prognosis and limited therapeutic options.MethodsWe retrospectively analyzed all patients with metastatic LCNEC in the records of a large German academic center since 2010.Results191 patients were identified with a predominance of male (68%) smokers (92%) and a median age of 65 years. The single most important factor associated with outcome was the type of systemic treatment, with a median overall survival (OS) of 26.4 months in case of immune checkpoint inhibitor administration (n=13), 9.0 months for other patients receiving first-line platinum doublets (n=129), and 4.0 months with non-platinum chemotherapies (n=17, p<0.01). Other patient characteristics independently associated with longer OS were a lower baseline serum LDH (hazard ratio [HR] 0.54, p=0.008) and fewer initial metastatic sites (HR 0.52, p=0.006), while the platinum drug type (cisplatin vs. carboplatin) and cytotoxic partner (etoposide vs. paclitaxel), patients’ smoking status and baseline levels of tumor markers (NSE, CYFRA 21-1, CEA) did not matter. 12% (23/191) of patients forewent systemic treatment, mainly due to tumor-related clinical deterioration (n=13), while patient refusal of therapy (n=5) and severe concomitant illness (n=5) were less frequent. The attrition between successive treatment lines was approximately 50% and similar for platinum-based vs. other therapies, but higher in case of a worse initial ECOG status or higher serum LDH (p<0.05). 19% (36/191) of patients had secondary stage IV disease and showed fewer metastatic sites, better ECOG status and longer OS (median 12.6 vs. 8.7 months, p=0.030). Among the 111 deceased patients with palliative systemic treatment and complete follow-up, after exclusion of oligometastatic cases (n=8), administration of local therapies (n=63 or 57%) was associated with a longer OS (HR 0.58, p=0.008), but this association did not persist with multivariable testing.ConclusionsHighly active systemic therapies, especially immunotherapy and platinum doublets, are essential for improved outcome in LCNEC and influence OS stronger than clinical disease parameters, laboratory results and other patient characteristics. The attrition between chemotherapy lines is approximately 50%, similar to other NSCLC. Patients with secondary metastatic disease have a more favorable clinical phenotype and longer survival.

Abstract 423: Pooled analysis of matching score and patient outcome in I-PREDICT and WINTHER studies

Abstract Introduction: Comprehensive genomic profiling (CGP) of tumors is available at many specialized cancer centers, potentially allowing oncologists to individualize patient therapy based on tumor molecular features. However, clinicians still lack a systematic approach to deal with the wealth of information provided by CGP. The proportion of plausible drug-matched alterations over the total number of alterations detected by CGP (Matching Score, MS) has been postulated to predict the likelihood of patient benefit. We performed a systematic analysis of MS and its association with the outcome of patients treated according to tumor DNA alterations within two recent precision oncology trials. Materials and Methods: We downloaded the supplementary data from WINTHER (NCT01856296) and I-PREDICT (NCT02534675) studies. We included patients who received treatment for one or more single-gene alterations, excluding eight patients that received immunotherapy due to high tumor mutational burden, PD-L1 positivity or microsatellite instability. We used MS cut-offs of 0.25 (as in WINTHER) and 0.5 (as in I-PREDICT) and also MS as a continuous variable to study its association with clinical variables such as age, sex, tumor type, and number of previous treatment lines (Kruskall-Wallis and Wilcoxon-rank tests), as well as disease control rate (DCR), progression-free survival (PFS) and overall survival (OS) (Cox proportional hazards models). Results: The pooled analysis included 144 patients. Median age was 60 years (range 21-86) and 64% had received ≥ 2 lines of therapy. Most patients had colorectal (37%), lung (14%), or breast (11%) tumors, and 58% were treated with 2 or more drugs. MS was not associated with any clinical variable nor with DCR. MS &amp;gt; 0.25 (n=98; 68%) was associated with longer PFS (median 3.5 vs. 1.9 months, HR [95%CI]: 0.60 [0.41-0.87]) but not with OS. In contrast, MS &amp;gt; 0.5 (n=41; 28%) was associated with longer OS (median 14.1 vs. 6.5 months, HR [95%CI]: 0.50 [0.29-0.54]) but not with PFS. As a continuous variable, increasing MS values were associated with better OS (HR [95% CI]: 0.43 [0.20-0.95]) and with a non-significant trend towards better PFS (HR [95% CI]: 0.54 [0.21-1.05]). In a multivariable model adjusted for Age and study, PFS/OS probabilities improved consistently with increasing MS values from 0 to 0.5. With MS values &amp;gt; 0.5, OS probabilities kept increasing while PFS probabilities plateaued. Conclusions: The significant and consistent relationship between MS and OS (in contrast with PFS) may be explained by patients with higher MS values having more targeted therapies available for successive treatment lines, although we cannot exclude the existence of other confounding prognostic variables. We note that, as better drugs are developed and new knowledge is incorporated into the clinic, the value of CGP will probably increase over time, improving the number of patients with actionable alterations and their outcome. Citation Format: David Casadevall, Michal Marczyk, Xavier Monzonis, Lajos Pusztai, Joan Albanell. Pooled analysis of matching score and patient outcome in I-PREDICT and WINTHER studies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 423.

Recent Discoveries in the Androgen Receptor Pathway in Castration-Resistant Prostate Cancer.

The androgen receptor (AR) is the main therapeutic target in advanced prostate cancer, because it regulates the growth and progression of prostate cancer cells. Patients may undergo multiple lines of AR-directed treatments, including androgen-deprivation therapy, AR signaling inhibitors (abiraterone acetate, enzalutamide, apalutamide, or darolutamide), or combinations of these therapies. Yet, tumors inevitably develop resistance to the successive lines of treatment. The diverse mechanisms of resistance include reactivation of the AR and dysregulation of AR cofactors and collaborative transcription factors (TFs). Further elucidating the nexus between the AR and collaborative TFs may reveal new strategies targeting the AR directly or indirectly, such as targeting BET proteins or OCT1. However, appropriate preclinical models will be required to test the efficacy of these approaches. Fortunately, an increasing variety of patient-derived models, such as xenografts and organoids, are being developed for discovery-based research and preclinical drug screening. Here we review the mechanisms of drug resistance in the AR signaling pathway, the intersection with collaborative TFs, and the use of patient-derived models for novel drug discovery.

Gastrointestinal Stromal Tumor: Challenges and Opportunities for a New Decade.

Gastrointestinal stromal tumor (GIST) provides a paradigm to evaluate new molecularly targeted therapies and to identify structural and functional mechanisms for drug response and resistance. Drug development in GIST has successfully exploited the high reliance on KIT/PDGFRA oncogenic signaling as a therapeutic vulnerability. The recent arrival of avapritinib and ripretinib to the GIST arena has aimed to further improve on precision kinase inhibition and address tumor heterogeneity in imatinib-resistant GIST. The two main clinical challenges for the forthcoming years entail tumor eradication in patients with early-stage GIST, and maximization of tumor response in late-stage disease. To succeed, we will need to better understand the mechanisms behind adaptation to KIT inhibition and apoptosis evasion, tumor evolution after successive lines of treatment, and to explore clinically novel creative therapeutic strategies, with the overarching goal to tackle the intrinsic oncogenic complexity while minimizing adverse events.

Follicular lymphoma in the modern era: survival, treatment outcomes, and identification of high-risk subgroups

Patients with follicular lymphoma (FL) frequently require multiple treatments during their disease course; however, survival based on lines of treatment remains poorly described in the post-rituximab era. Also, the Follicular Lymphoma International Prognostic Index (FLIPI) score was developed to predict survival at diagnosis, yet it remains unknown whether increase in FLIPI score following an initial observation period is associated with less-favorable outcomes. To address these knowledge gaps, we retrospectively studied 1088 patients with FL grade 1–3A managed between 1998 and 2009 at our institution. Median overall survival (OS) and progression-free survival (PFS) after first-line treatment were not reached and 4.73 years, respectively. Following successive lines of treatment, years of median OS and PFS were, respectively: after second-line, 11.7 and 1.5; third-line, 8.8 and 1.1; fourth-line, 5.3 and 0.9; fifth-line, 3.1 and 0.6; sixth-line, 1.9 and 0.5. In initially observed, subsequently treated patients, FLIPI score increase after observation was associated with inferior survival following first-line treatment. The reduced survival we observed after second-line and later therapy supports the development of new treatments for relapsed patients and benchmarks historical targets for clinical endpoints. This study also highlights the utility of changes in FLIPI score at diagnosis and after observation in identifying patients likely to have worse outcomes.

FRI0362 COMPARATIVE EFFECTIVENESS OF USTEKINUMAB (UST) AND TNF INHIBITORS (TNFI) IN PATIENTS WITH PSORIATIC ARTHRITIS (PSA) IN THE REAL-WORLD, MULTINATIONAL PSABIO STUDY: 12-MONTH FOLLOW-UP

Background:Among treatment options for PsA, IL-12/23 inhibition with UST was the first new biologic mode of action after TNFi. Few real-world data comparing UST with TNFi are available.Objectives:Comparison of UST and TNFi treatment effectiveness within the prospectively followed PsABio cohort at 12-month (mo) follow-up.Methods:The PsABio study (NCT02627768) evaluates effectiveness, tolerability and persistence of 1st, 2nd or 3rd-line UST or TNFi in PsA. Proportions of patients (pts) reaching MDA/very low disease activity (VLDA) and clinical Disease Activity index for PSoriatic Arthritis (cDAPSA) LDA/remission are described. Comparison across UST and TNFi cohorts was done on last observation carried forward up to 12 (±3) mo, with non-response imputation for pts who had stopped/switched initial treatment. Logistic regression analysis was used, including propensity score (PS) analysis to adjust for imbalanced prognostic baseline (BL) covariates: country, age, sex, BMI, smoking (yes/no), comorbidities (cardiovascular/metabolic syndrome), PsA type (axial, polyarticular, oligoarticular), psoriasis body surface area (BSA), disease duration, cDAPSA, 12-item PsA Impact of Disease (PsAID-12), dactylitis, enthesitis, Fibromyalgia Rapid Screening Tool (FiRST) score, line of biologic (b)DMARD, synthetic DMARD use, and steroid or NSAID use.Results:Of 929 eligible pts, 893 had evaluable data at BL and at follow-up; 438 (95.6%) were treated with UST and 455 (96.6%) with TNFi (including stoppers/switchers). UST and TNFi groups had BL differences in mean age (51.0 vs 48.5 years, respectively), concurrent comorbidities (68.7% vs 60.9%), time since diagnosis (7.5 vs 6.2 years), line of treatment (1st-line 45.0% vs 55.2%; 3rd-line 20.5% vs 12.1%), NSAID use (54.8% vs 68.8%), concomitant MTX use (29.9% vs 42.0%) and psoriasis skin involvement (BSA &gt;10% in 26.6% vs 14.8%).In 714 pts with available data, mean (standard deviation) BL cDAPSA was 30.6 (20.2; n=358) for UST and 29.3 (18.6; n=356) for TNFi. Observed data showed differences in proportion of pts achieving MDA/VLDA and cDAPSA LDA/remission in favour of TNFi, but after PS adjustment for BL differences (such as line of therapy, skin psoriasis, concomitant conventional DMARD, etc.), odds ratios for reaching targets at 12 mo did not significantly differ between UST and TNFi groups (Fig. 1).Comparison of 6- and 12-mo unadjusted data showed sustained MDA/VLDA responses with both UST (21.8%) and TNFi (29.5%), with comparable proportions of additional pts achieving these targets between 6 and 12 mo (17.0% and 20.3%, respectively). Sustained efficacy became lower with successive lines of treatment (data not shown).Conclusion:Various factors, including patient characteristics such as comorbidities, influence the physician’s selection of treatment modality for patients needing a bDMARD. Our real-world results demonstrate differences in observed clinical effectiveness between UST and TNFi. However, after PS adjustment for a number of BL differences, clinical results at 12 mo were comparable between UST and TNFi groups. Data at 12 mo also show sustained response with both UST and TNFi treatment, as well as a similar rate of pts achieving targets after 6 to 12 mo of treatment.Acknowledgments:This study was funded by Janssen.Disclosure of Interests:Josef S. Smolen Grant/research support from: AbbVie, AstraZeneca, Celgene, Celltrion, Chugai, Eli Lilly, Gilead, ILTOO, Janssen, Novartis-Sandoz, Pfizer Inc, Samsung, Sanofi, Consultant of: AbbVie, AstraZeneca, Celgene, Celltrion, Chugai, Eli Lilly, Gilead, ILTOO, Janssen, Novartis-Sandoz, Pfizer Inc, Samsung, Sanofi, Stefan Siebert Grant/research support from: BMS, Boehringer Ingelheim, Celgene, GlaxoSmithKline, Janssen, Novartis, Pfizer, UCB, Consultant of: AbbVie, Boehringer Ingelheim, Janssen, Novartis, Pfizer, UCB, Speakers bureau: AbbVie, Celgene, Janssen, Novartis, Tatiana Korotaeva Grant/research support from: Pfizer, Consultant of: Abbvie, BIOCAD, Bristol-Myers Squibb, Celgene, Eli Lilly, Janssen, Merck Sharp &amp; Dohme, Novartis, Novartis-Sandoz, Pfizer, UCB, Speakers bureau: Abbvie, BIOCAD, Bristol-Myers Squibb, Celgene, Eli Lilly, Janssen, Merck Sharp &amp; Dohme, Novartis, Novartis-Sandoz, Pfizer, UCB, Paul Bergmans Shareholder of: Johnson &amp; Johnson, Employee of: Janssen, Kurt de Vlam Consultant of: Celgene Corporation, Eli Lilly, Novartis, Pfizer, UCB – consultant, Speakers bureau: Celgene Corporation, Eli Lilly, Novartis, Pfizer, UCB – speakers bureau and honoraria, Elisa Gremese Consultant of: AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly, Janssen, Merck Sharp &amp; Dohme, Novartis, Sanofi, UCB, Roche, Pfizer, Speakers bureau: AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly, Janssen, Merck Sharp &amp; Dohme, Novartis, Sanofi, UCB, Roche, Pfizer, Beatriz Joven-Ibáñez Speakers bureau: Abbvie, Celgene, Janssen, Merck Sharp &amp; Dohme, Novartis, Pfizer, Wim Noel Employee of: Janssen Pharmaceuticals NV, Michael T Nurmohamed Grant/research support from: Abbvie, Bristol-Myers Squibb, Celltrion, GlaxoSmithKline, Jansen, Eli Lilly, Menarini, Merck Sharp &amp; Dohme, Mundipharma, Pfizer, Roche, Sanofi, USB, Consultant of: Abbvie, Bristol-Myers Squibb, Celltrion, GlaxoSmithKline, Jansen, Eli Lilly, Menarini, Merck Sharp &amp; Dohme, Mundipharma, Pfizer, Roche, Sanofi, USB, Speakers bureau: Abbvie, Bristol-Myers Squibb, Celltrion, GlaxoSmithKline, Jansen, Eli Lilly, Menarini, Merck Sharp &amp; Dohme, Mundipharma, Pfizer, Roche, Sanofi, USB, Petros Sfikakis Grant/research support from: Grant/research support from Abvie, Novartis, MSD, Actelion, Amgen, Pfizer, Janssen Pharmaceutical, UCB, Elke Theander Employee of: Janssen-Cilag Sweden AB, Laure Gossec Grant/research support from: Lilly, Mylan, Pfizer, Sandoz, Consultant of: AbbVie, Amgen, Biogen, Celgene, Janssen, Lilly, Novartis, Pfizer, Sandoz, Sanofi-Aventis, UCB

EP1.14-01 Major Therapeutic Response to T-DM1 in Metastatic Lung Adenocarcinoma with HER2 Mutation

The HER2 exon 20 mutation is described in 1-5% of patients with Non-small cell Lung cancer, and at the moment no targeted agents are approved in Europe. However, the use of conjugated antibodies such as trastuzumab and ado-trastuzumab emtansine (T-DM1) has shown promising results. We describe the case of a major response to T-DM1 in fourth line treatment in a patient with metastatic adenocarcinoma and HER2 mutation. A 60-year-old male, former smoker (3 packs/year), presented to the emergency room in 2016 for dyspnoea. A bilateral pleural and compressive pericardial effusion with tamponade requiring pericardial drainage were discovered. A lung adenocarcinoma with HER2 mutations was diagnosed. He benefited from two successive treatment lines between September 2016 and September 2017 (carboplatin- paclitaxel and bevacizumab followed by bevacizumab maintenance until progression, then pemetrexed for two cycles). At this time, he developed a new disease progression as a recurrence of tamponade requiring surgical drainage and a third line with docetaxel and trastuzumab was started for twelve cycles. After eight months, he presented an acute respiratory failure due to the recurrence of pericardial and pleural effusions, requiring a pleural drainage (Fig.1A). After discussion at the multidisciplinary meeting, a fourth line of treatment with T-DM1 in compassionate has been proposed. After three cycles, we observed an excellent clinical response, with disappearance of dyspnoea, resumption of normal daily activity. The radiological evolution was also very favourable (Fig.1B). The patient benefited from other six months of treatment before getting a new progression. In this case T-DM1 showed a major clinical and radiological benefit despite its use in fourth line. Other clinical reports and phase II trials confirmed promising results with targeted agents already used in breast cancer. Several studies are exploring the efficacy of these agents, opening up new hopes.

Efficacy of multikinase inhibitors (MKIs) in successive treatment lines of refractory advanced thyroid cancer patients (pts).

e17553Background: Sequential therapy with MKIs in the management of refractory thyroid cancer cannot be standardized with data coming form randomized clinical trials. Methods: We retrospectively an...

Generation of a Large Observational Pan-European Data Platform for Treatment and Outcome Patterns in Patients with Waldenstrom's Macroglobulinemia

IntroductionWaldenström's Macroglobulinemia (WM) is a rare indolent lymphoma with a low incidence of ~3 cases per million per year. There are few randomized trials and no well-established treatment standards in WM. Treatment landscapes for treatment-naïve and relapsed WM are heterogeneous and data on treatment choices and their outcome in patients (pts) outside clinical trials are lacking. The goal of this project was to generate data on epidemiologic/treatment patterns and efficacy outcomes for WM over a prolonged period of time (~10 yr) in a large pan-European effort.MethodsIn this observational chart review, physicians completed a retrospective electronic record for pts who fit the following inclusion criteria: confirmed WM, symptomatic disease at treatment initiation, front line treatment initiated between Jan 2000-Jan 2014, and availability of complete clinical/biologic evaluation at diagnosis/initial therapy. Study endpoints included initial/subsequent lines of treatment, progression-free survival (PFS), and overall survival (OS). The number of pt records per country was prespecified to balance the distribution between European countries.ResultsOf 454 pt records reviewed, cases were from France (n=92), United Kingdom (UK; n=72), Germany (n=66), Spain (n=60), Italy (n=56), Greece (n=25), Netherlands (n=25), Poland (n=21), Austria (n=19), and Czech Republic (n=16). Data were summarized across 5 lines of treatment for 454, 397, 160, 61, and 26 pts, respectively. Median age at initiation of front-line treatment was 65 yr (range, 29-89); 61% were male. The most common reasons for initiating treatment at diagnosis were constitutional symptoms (58%), cytopenias (72%; anemia [69%]), and IgM-related symptoms (57%). Choice of therapy varied with line of treatment; monotherapy fell from 31% in front-line to 20%/21% in 2nd/3rd-line ( Table 1). Combination therapy with antibody increased from 40% in front-line to 64%/56% in 2nd/3rd-line. Across all lines, rituximab followed by cyclophosphamide, and to a lesser extent, chlorambucil, fludarabine, vincristine, and bendamustine, were the most common agents, excluding steroids, that were used as monotherapy or in any combination with use varying between countries (Table 1). Median PFS decreased with successive lines of treatment (29 vs 23 vs 16 mo), (Figure 1) and varied by country and choice of agents (Table 1). Median OS was 123 mo, but significantly lower in pts ≥75 yr (75 mo) or with high-risk IPSSWM risk score (91 mo) and similar for pts with low/intermediate risk groups. Considerable country-specific OS differences were noted. Other malignancies were reported in 12% after diagnosis of WM.ConclusionsThe retrospective chart review of WM pts treated in Europe shows that constitutional symptoms and anemia are the most common reasons for initiating therapy. Rituximab was the most commonly used agent across all lines of treatment. Outside clinical trials, monotherapy is widely used even at first relapse with notable differences between countries. This large observational dataset will be an important tool to improve understanding of treatment practice and survival of WM pts in Europe outside of clinical trials, as well as unmet medical needs in the community.Table 1Use of Monotherapy or Combination Regimens and Median PFS in Front -, 2nd -, and 3rd-Line Settings Overall and by CountryCountryNumber of Cases, nMonotherapy, %Combination Therapy With Antibody†, %Combination Therapy Without Antibody, %Median PFS,Months (95% CI)Front line2nd line3rd lineFront line2nd line3rd lineFront line2nd line3rd lineFront line2nd line3rd lineFront line2nd line3rd lineOverall45439716031202140635628142129.0 (25-31)23.0 (20-26)16.0 (10-18)France9286436226162466701481428.5 (22-32)30.0 (20-37)16.0 (9-32)United Kingdom72641918222119554263233731.5 (25-36)20.0 (11-35)13.0 (9-33)Germany66521898226181503081136.5 (29-44)24.0 (16-29)8.0 (3-16)Spain6058214328383859521812518.0 (15-25)16.0 (12-24)11.0 (9-24)Italy5647202017155768702361530.5 (20-39)30.0 (18-42)17.0 (4-21)Eastern European*37301281383240060479233.0 (26-38)20.0 (16-26)20.5 (4-38)Smaller European**7160273522265667637121123.0 (18-29)16.0 (13-25)16.0 (7-26)* Includes Czech Republic and Poland**Includes Austria, Greece, and Netherlands† Antibodies other than rituximab, <1% [Display omitted] DisclosuresBuske:CELLTRION, Inc.: Consultancy, Honoraria. Sadullah:Roche: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Speakers Bureau; NAPP: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; TEVA: Consultancy; Boehringer: Other: Travel, Accommodations, Expenses. Kastritis:Janssen: Consultancy, Other: Travel, Accommodations, Expenses. Garcia-Sanz:Janssen: Honoraria, Other: Travel, Accommodations, Expenses; Takeda: Honoraria, Other: Travel, Accommodations, Expenses; Novartis: Research Funding. Leleu:Pierre Fabre: Honoraria; BMS: Honoraria; Novartis: Honoraria; TEVA: Honoraria; Amgen: Honoraria; Takeda: Honoraria; Celgene: Honoraria; Janssen: Honoraria; LeoPharma: Honoraria; Chugai: Honoraria. Willenbacher:Celgene: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Roche: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding; Janssen: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding; Amgen: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding; Gilead: Consultancy, Other: Travel, Accommodations, Expenses, Speakers Bureau; Novartis: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; CTI: Consultancy, Other: Travel, Accommodations, Expenses. Hajek:Amgen: Honoraria; Celgene: Consultancy; Janssen: Consultancy. Cheng:Pharmacyclics LLC, an AbbVie Company: Employment. Graef:Pharmacyclics LLC, an AbbVie Company: Employment, Membership on an entity's Board of Directors or advisory committees; AbbVie: Equity Ownership. Dimopoulos:Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Onyx: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Genesis Pharma: Research Funding.

Taking into account successive treatment lines in the analysis of a colorectal cancer randomised trial

The FFCD 2000–05 randomised trial included 410 patients with advanced colorectal cancer and compared a sequential arm S treated with 5-fluorouracil and leucovorin (LV5FU2) followed by FOLFOX (LV5FU2+oxaliplatin) and then FOLFIRI (LV5FU2+irinotecan) and a combination arm C that begins directly with FOLFOX followed by FOLFIRI. The first aim of this study was to analyse the prognostic effects on overall survival of disease progression, and of toxicities under first-line therapy. We also studied the benefit of introducing irinotecan in each arm. Finally, we compared the effect of treatment on repeated progression and toxicities. For this purpose, we used Cox regression models with time-dependent variables and shared gamma frailty regression models.We found that early on during follow-up, the prognostic effect on survival of progression under first-line therapy was greater in C (hazard ratio [HR]=18.0 [7.9–41.2]) than in S (HR=7.7 [3.9–17.4]). This difference was significant, but it decreased over time. The prognostic effect of severe toxicities was greater in S (HR=2.0 [1.4–2.9]) than in C (HR=1.3 [0.9–1.9]). Introducing irinotecan was significantly more beneficial in S (HR=0.2 [0.1–0.4]) than in C (HR=0.3 [0.2–1.5]). The risk of repeated progression was not significantly different between the two groups (HR=0.9 [0.8–1.1]) whereas the risk of toxicities was greater in C (HR=1.7 [1.4–2.1]).Overall, this study suggests that starting with less toxic first-line treatment is a valid option since it does not exert a deleterious effect on the risk of overall progression or death.

The optimize project: beyond first-line therapy in metastatic renal cell carcinoma

The treatment of patients with metastatic renal cell carcinoma (mRCC) has changed dramatically over the past 5 years, and a new paradigm has evolved. Angiogenesis in general, and the vascular endothelial growth factor and mammalian target of rapamycin pathways in particular, are validated targets in renal cell carcinoma. This Supplement Issue examines several interesting topics consequent to the failure of first-line treatment in patients with mRCC, including (1) the reasons why patients fail on first-line treatment with targeted agents; (2) preclinical and clinical rationales for selecting a secondor subsequent-line therapy for these patients; (3) recommendations for managing the main adverse events of targeted therapies, both in normal and special populations; (4) the role of pharmacogenomics in mRCC to date and whether it is possible to predict an individual patient's outcome and level of toxicity experienced; and lastly (5) how quality of life and supportive care for these patients may be improved. Currently, tumor progression is most commonly assessed on the basis of the Response Evaluation Criteria in Solid Tumors (RECIST v 1.0 or v 1.1). Targeted agents tend to stabilize disease, however, rather than significantly decreasing tumor mass. In the first article, the need for additional methods to assess disease response is discussed. It is also important to evaluate existing prognostic and predictive factors after failure of first-line treatment in order to increase the chances of delivering the most effective and personalized therapy possible. Despite significant improvements in the first-line treatment of mRCC, therapies rarely produce complete responses, and all patients eventually develop resistance and progress. In addition, some tumors display intrinsic resistance, which further limits therapeutic options. One approach to overcoming tumor resistance is the use of sequential therapy. Unfortunately, knowledge about the mechanisms of action of new therapies, and the intrinsic and extrinsic mechanism of resistance, has not evolved as rapidly as their development and many questions remain unanswered. In the second article, authors review the available evidence from clinical studies on sequential therapy for mRCC, including those that are still in progress. In addition, information on the mechanisms of resistance or tolerance to first-line therapy, recommendations on the main practice guidelines for second-line treatment, potential therapies for third or successive treatment lines, and the reasons why patients who progress may benefit from a change of mechanism of action are also discussed. In the third article, authors review the toxicity profiles of targeted therapies, and develop important recommendations for treating adverse events to avoid acute, life-threatening situations, dose reductions, interruptions, or early treatment discontinuation. This is essential because the early recognition and management of severe adverse events is one of the most important factors for maintaining the optimum efficacy of sequential therapy. Pharmacogenomics is the topic of the fourth article, in which the authors evaluate how variation in genetic background affects an individual's response to a specific drug and/or its metabolism. Using knowledge about the genes that produce the enzymes to metabolize a specific drug, a physician may decide to raise or lower the dose, or even change to a different drug. Although few studies have identified biomarkers that predict the response to targeted drugs in the treatment of mRCC, some important associations have been found and are described in this article. Pharmacogenomics holds the potential in the near future to hone D. Castellano (*) Medical Oncology Department, University Hospital 12 de Octubre, Madrid, Spain e-mail: cdanicas@hotmail.com

Sequential therapy in metastatic renal cell carcinoma: pre-clinical and clinical rationale for selecting a second- or subsequent-line therapy with a different mechanism of action

Few types of cancer have had their treatment evolve as rapidly as metastatic renal cell carcinoma (mRCC). Since 2005, six new targeted therapies with proven efficacy have been approved for the treatment of mRCC. The downside is that our knowledge about the mechanisms of action of these therapies and the intrinsic and extrinsic mechanism of resistance has not evolved equally fast, and many questions remain unanswered. The only approved agent to date in the European Union for patients who progress on sunitinib or sorafenib is everolimus. The results of the phase III trial comparing axitinib vs. sorafenib after failure on sunitinib, bevacizumab, temsirolimus, or cytokines have recently been published, and axitinib has recently been licensed by the Food and Drugs Administration. Other phase III trials that are being conducted include a comparison between everolimus plus bevacizumab and everolimus after failure on tyrosine kinase inhibitors, and between temsirolimus and sorafenib after failure on sunitinib. In this article, we will review the available evidence from clinical studies on sequential therapy for mRCC, including those that are still in progress. In addition, information on the mechanism of resistance or tolerance to first-line therapy, recommendations of the main practice guidelines for second-line treatment, potential therapies for third or successive treatment lines, and the major reasons why patients who progress may benefit from a change of mechanism of action will also be discussed.