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Prostate-specific membrane antigen (PSMA)-directed radioligand therapy (PSMA-RLT) with lutetium-177 ((177)Lu-PSMA) has been used in metastatic castrate-resistant prostate cancer (mCRPC), and retrospective data have shown this therapy to be favourably safe with attractive clinical responses. Re-challenge (177)Lu-PSMA therapy in early responders has been shown to be safe and effective. We report the use of low-dose Taxol-based chemotherapy (modified dose 25 mg/m(2) weekly × 6 weeks) as a radiosensitizer with re-challenge (177)Lu-PSMA therapy (4 cycles). In a period of 3 years, the patient underwent a total of 8 cycles of (177)Lu-PSMA with a cumulative dose of 51.8 GBq. All therapies were uneventful and well tolerated. There was a good response to re-challenge (177)Lu-PSMA therapy and low-dose docetaxel (Taxol-(177)Lu-PSMA) with no recorded tumour resistance.

Background: Given the inconclusive evidence behind the safety and efficacy of immune checkpoint inhibitors re-challenge, herein, we have conducted a systematic review and meta-analysis to synthesize available data. Results/methodology: PubMed, Embase, Cochrane Database, and ASCO and ESMO were searched for studies published from conception to March 2020. Pooled incidence of recurrent immune-related adverse events (irAEs), objective response rates, and odds ratios for irAEs at initial versus re-treatment were calculated. Overall, 437 patients (ten studies) were included. Incidence of any grade, grade 3/4, and steroid-requiring recurrent irAEs were 47%, 13.2%, and 26% respectively. Objective response rate in previous non-responders was 12.5% (5.8–24.8%). Odds ratio for severe irAEs was 0.28 (0.11–0.72) and steroid-requiring irAEs 0.19 (0.06–0.56). Discussion/conclusion: This analysis suggests that immune checkpoint inhibitors re-challenge is safe and potentially efficacious.

**Background:** The role of platinum rechallenge in head and neck cancer (HNC) has not yet been fully evaluated. **Objectives:** It is our goal to assess the real-world treatment patterns and usefulness of platinum rechallenge in patients with platinum-refractory recurrent or metastatic HNC receiving platinum rechallenge. **Methods:** This is a retrospective study using data from a Japanese hospital claims database stored in electronic hospital information systems. Patients with HNC or undefined histology with an HNC diagnosis using the disease code, between January 1, 2013 and September 30, 2016, were included. Patients diagnosed with other malignancies on or before the initial diagnosis of HNC and those without cancer stage information in the database were excluded from the study. **Results:** A total of 43 994 patients were identified from the database as HNC patients. Of those, in patients who had cancer progression within 6 months after platinum-based chemotherapy administered for primary or recurrent disease (N=842), the median treatment duration of platinum rechallenge for platinum refractory patients was only 1 cycle. The second-line treatment continuation rate at 6 months was 20.1% for patients who received platinum rechallenges and 32.8% for those who received non–platinum-based regimens. **Conclusions:** The findings from this study of data from routine clinical practice suggest that the benefit of platinum rechallenge in a platinum-refractory setting would be limited.

Objective: Clozapine remains the most effective intervention for treatment resistant schizophrenia; however, its use is prohibited following neutropenias. We review neutrophil biology as applied to clozapine and describe the strategies to initiate clozapine following neutropenia used in a case series of 14 consecutive patients rechallenged in a United Kingdom (UK) high-secure psychiatric hospital. We examine outcomes including the use of seclusion and transfer. Methods: A case series of 14 male patients with treatment resistant schizophrenia treated with clozapine despite previous episodes of neutropenia between 2006 and 2015 is presented. Data were collected during 2015 and 2019. Using this routinely collected clinical data, we describe the patient characteristics, causes of neutropenia, the strategies used for rechallenging with clozapine and clinical outcomes. Results: Previous neutropenias were the result of benign ethnic neutropenia, clozapine, other medications and autoimmune-related. Our risk mitigation strategies included: granulocyte-colony stimulating factor (G-CSF), lithium and watch-and-wait. There were no serious adverse events; at follow up half of the patient’s had improved sufficiently to transfer them to conditions of lesser security. There were dramatic reductions in the use of seclusion. Conclusion: Even in this extreme group, clozapine can be safely and effectively re/initiated following neutropenias, resulting in marked benefits for patients. This requires careful planning based on an understanding of neutrophil biology and the aetiology of the specific episode of neutropenia.

Re-challenge of erlotinib after gefitinib failure is reported to yield some benefit in patients with non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutation. However, little is known about the re-challenge of afatinib after 1st generate on EGFR tyrosine kinase inhibitor (TKI) failure.From May 2015 to August 2018, 62 patients with advanced NSCLC harboring sensitive EGFR mutation received afatinib after gefitinib and/or erlotinib failure at our institution was included in our retrospective study.The overall response rate (ORR) and disease control rate (DCR) of afatinib as re-challenge were 17.0% and 79.2%, respectively. The median time on treatment of 1st generation EGFR-TKI (1st TKI) was 14 months. By multivariate analysis, smoking, performance status (PS), and time on treatment of 1st TKI with more than 10 months were confirmed to be independent prognostic factors predicting a worse progression-free survival (PFS), and significant prognostic markers for overall survival (OS) were PS and time on treatment of 1st TKI with more than 10 months, especially in patients with exon 19 deletion.Re-challenge of afatinib was identified as one of the therapeutic options after 1st TKI failure in the patients with advanced NSCLC harboring EGFR mutation when the time of treatment by prior 1st TKI is more than 10 months.

The application of erythropoietin (EPO) can bring about a rare but serious complication called anti‐EPO antibody‐mediated pure red cell aplasia (PRCA). Once the disease is diagnosed, EPO administration should be stopped immediately. However, after the removal of the anti‐EPO antibody, treating anaemia in these patients with chronic renal disease with EPO therapy is difficult, as restarting EPO therapy risks the recurrence of anti‐EPO antibody‐mediated PRCA. A 26‐year‐old man with anaemia related to renal failure, who was administered recombinant human EPO subcutaneously, developed anti‐EPO antibody‐mediated PRCA. After removal of antibodies by treatment with corticosteroids and cyclosporine, therapy for anaemia of chronic renal disease with roxadustat achieved good results. Roxadustat is a new type of drug for the treatment of anaemia, and it can stimulate endogenous EPO within or near the physiologic range and increase haemoglobin levels.

Introduction: Methotrexate (MTX), a classic antifolate, is one of the most widely used and well-studied anticancer agents. High-dose methotrexate (HD-MTX) with folinic acid (leucovorin) rescue is one of the standard therapies for osteosarcoma. High-dose methotrexate (HDMTX) can exert significant toxicity and requires complex pharmacokinetic monitoring and leucovorin rescue. The side effect profile of MTX varies markedly according to the dose. Regimens containing MTX are classified as high, intermediate, or low-dose. High-dose methotrexate (HD-MTX; 12 g/m2) is a part of the golden standard therapy for pediatric osteosarcoma (OS). Risk factors associated with MTX toxicity in children with OS are not well defined. Case Presentation: We report here a case of pediatric osteosarcoma with nephrotoxicity associated with delayed MTX excretion who was successfully managed using supportive measures that encouraged us to re-challenge with a full dose of MTX then we reduced the dose to 50% to attain the final critical decision about continuation or changing the regimen of treatment for the patient. Our patient developed moderate renal complications during therapy that improved with supportive care, so we challenged with more cycles of a high dose MTX, but the patient developed serious renal complications. A reduced dose of MTX with 50% was given successfully without any renal impairment. Conclusion: Methotrexate toxicity that might not occur during the initial courses of high-dose MTX is not a predictive of the tolerability of further courses and re-challenging with HDMTX is risky, but reduced dose methotrexate is a good option rather than changing the regimen, with good tolerability and rapid clearance of HDMTX. HDMTX-induced renal impairment occurs in a low percentage of patients with osteosarcoma and can be managed successfully by maximum supportive care. MTX clearance can be affected by gender and age.

Summary Introduction Immune checkpoint inhibitor (ICPis) re-challenge could be an attractive therapeutic option considering its good safety profile. However, little data is available regarding anti-PD-1/anti-PD-L1 retreatment. We conducted a meta-analysis focusing on outcomes of solid cancer patients performing this strategy. Methods Fourteen full papers involving 74 patients were included. Individual data about best response or progression-free survival (PFS) upon the first and second course of anti-PD-1/anti-PD-L1 were collected. Results Non-small-cell lung cancer (53%) and melanoma (34%) were the most represented cancers. Higher objective response (46% versus 24%, P = 4.10−4) and disease control rates (73% versus 52%, P = 7.10−3) were obtained upon the first ICPi course compared to re-challenge. No association between responses obtained with the two ICPis courses was found (P = 3.10−1). The PFS upon the first ICPi (PFS1) was longer than after re-challenge (PFSR) (6.6 versus 2.8 months, hazard ratio (HR) 0.57, P = 2.10−3). A longer PFSR was obtained in patients with a longer PFS1 (P = 6.10−3), in those who discontinued the first ICPi due to toxicity or per protocol (8.8 versus 2.1 months if disease progression occurs, P = 2.10−3), and in those not receiving intercalated treatment between the two ICPis (6.6 versus 2.1 months for the treated ones, P = 1.10−3). Discussion Anti-PD-1/anti-PD-L1 re-challenge showed interesting clinical activity in selected patients, mainly in those achieving a long-term response upon the first ICPi course, that do not discontinue therapy because of disease progression, or that are able to keep a treatment-free period.

Background Immune checkpoint inhibitor (ICPis) re-challenge could be an attractive therapeutic option considering its good safety profile. However, little data is available regarding anti-PD-1/anti-PD-L1 retreatment. We conducted a meta-analysis focusing on outcomes of solid cancer patients performing this strategy. Methods Fourteen full papers involving 74 patients were included. Individual data about best response or progression-free survival (PFS) upon the first and second course of anti-PD-1/ anti-PD-L1 were collected. Results Non-small-cell lung cancer (53%) and melanoma (34%) were the most represented cancers. Higher objective response (46% versus 24%, p = 4.10 -4 ) and disease control rates (73% versus 52%, p = 7.10 -3 ) were obtained upon the first ICPi course compared to re-challenge. No association between responses obtained with the two ICPis courses was found ( p = 3.10 -1 ). The PFS upon the first ICPi (PFS1) was longer than that after re-challenge (PFSR) (6.6 versus 2.8 months, hazard ratio (HR) 0.57, p = 2.10 -3 ). A longer PFSR was obtained in patients with a longer PFS1 ( p = 6.10 -3 ), in those who discontinued the first ICPi due to toxicity or per protocol (8.8 versus 2.1 months if disease progression occurs, p = 2.10 -3 ), and in those not receiving intercalated treatment between the two ICPis (6.6 versus 2.1 months for the treated ones, p = 1.10 -3 ). Conclusion Anti-PD-1/anti-PD-L1 re-challenge showed interesting clinical activity in selected patients, mainly in those achieving a long-term response upon the first ICPi course, that do not discontinue therapy because of disease progression, or that are able to keep a treatment-free period.

Introduction Pembrolizumab is an immune checkpoint inhibitor targeting the programmed death receptor with clinical effect on multiple malignancies including sarcoma. Associated cardio-toxicities include myocarditis, cardiomyopathy, heart failure, and arrhythmias. Although in most cases of immune checkpoint inhibitor cardiotoxicity the offending agent is discontinued, we report a case of successful and safe re-challenge with a checkpoint inhibitor in a patient with mild myocarditis. Case report We describe a 37-year-old female with alveolar soft part sarcoma, metastatic to the lungs on cycle 13 of pembrolizumab who presented with dyspnea, cough, and vague chest discomfort. Telemetry showed bigeminal bradycardia that transitioned to self-terminating torsades de pointes. Cardiac MRI showed subtle patchy T2 signal increase within the left ventricular septum without late gadolinium uptake, suggesting mild focal myocarditis. Management and outcome: The patient was started on a steroid taper without additional arrhythmias. We have re-challenged the patient who safely tolerated re-challenge with pembrolizumab despite an episode of torsades de pointes and documented myocarditis. She continues to receive pembrolizumab at seven months after the initial event without further cardiovascular events. Discussion To the best of our knowledge, this is the first reported case of successful re-challenge of pembrolizumab after an episode of myocarditis. In patients with mild myocarditis and no evidence of left ventricular dysfunction, re-challenge may be a viable option. However, close monitoring for the development of heart failure, cardiomyopathy, or serious arrhythmias is necessary to ensure patient safety.

A 76-year-old man was admitted to our hospital with cough and dyspnea. He was diagnosed with advanced lung cancer. Nivolumab was given as second-line treatment, cytotoxic chemotherapy was given as third-line treatment, and nivolumab re-challenge was given as fourth-line treatment. Thereafter, 41 chemotherapy courses were administered over 2 years. Currently, he is being followed with no recurrence at least 10 months after treatment. Thus, the case of a patient with advanced lung cancer who was previously unsuccessfully treated with nivolumab and then demonstrated a long-term clinical response to a re-challenge with nivolumab after cytotoxic chemotherapy and radiation therapy is presented. Keywords: Lung cancer, Nivolumab, Immune checkpoint inhibitors, PD-L1

Objective: Clozapine remains the most effective intervention for treatment resistant schizophrenia. But its use is limited because of the risk of neutropenia and agranulocytosis. In the absence of effective alternatives its use after blood dyscrasias is possible. Methods: A case series of 14 male patients with treatment resistant schizophrenia treated with clozapine despite previous episodes of neutropenia between 2006 and 2015 is presented. Data were collected during 2015 and 2019. Using routinely collected clinical data we describe the patient characteristics, causes of neutropenia, the strategies used and outcomes. Results: Previous neutropaenia was due to varying aetiologies: benign ethnic neutropaenia; clozapine induced; other medication; autoimmune. A range of risk mitigation strategies were used to prevent neutropaenia on clozapine rechallenge: G-CSF; lithium; watch and wait. There were no serious adverse events associated with clozapine or risk mitigation treatments. At follow up during 2019, half of the original 14 patients had improved sufficiently to transfer to conditions of lesser security. Conclusion: With careful planning and monitoring, taking into account what is known about neutrophil biology, clozapine can be successfully reinitiated following CIN or in the face of preexisting neutropenia resulting in significant benefits for patients.

창업의 성공 시 연속 기업가 혹은 글로벌 진출, 실패 시 재도전 혹은 도덕적 해이로 인한 실패 시 퇴출하는 일련의 과정들은 자연스러운 창업의 선순환 생태계 과정이다. 이러한 자연스러운 과정을 움직이는 기반은 바로 혁신 안전망이라 할 수 있다. 그러나 혁신의 안전망이 없어 실패 후 신용불량 문제나 제도적 장벽 때문에 재도전을 어렵게 하는 것이 대한민국의 현실이다. 현 정부는 창업의 부진과 저성장 기조 속에서 일자리 창출을 위해 ‘창업국가 건설’을 목표로 연대보증폐지, 재도전 펀드 조성 등과 같은 여러 가지 정책을 추진 중에 있다. 창업 활성화를 가로막는 신용불량이나 자금 부족 문제를 해결하겠다는 정부의 의지를 엿볼 수 있다. 그러나 정부의 정책 방향은 재도전을 가로막는 채무 부종성, 배임죄 등과 같은 여러 가지 규제들의 꼬인 실타래가 있음에도 불구하고 여전히 단기적이고 부분적인 개선에만 중점을 두고 있어 완전한 혁신 안전망이 작동되지 못하고 있다. 본 연구에서는 이러한 현실에 주목하여 복잡하게 얽힌 다양한 제도들을 분석하기 위해 역사적 맥락에서 살펴보고자 한다. 이는 재도전을 가로막는 제도들이 만들어진 시대적 배경을 이해함으로써 혁신 안전망 조성을 위한 근본적인 규제 개선 방향을 제시할 수 있을 것이다. 1970년대 유가상승과 악화된 국제여건 속에서 국내 기업들의 재무 건전성이 악화되자 정부는 다양한 금융적 지원을 하였다. 그러나 이를 악용하여 부정한 방법으로 부를 축적하는 기업인들이 생겨나고, 정경유착과 불투명한 기업경영 사례가 급증했다. 이후 기업인 연대보증, 과점주주에 대한 과세, 채무부종성 등 다양한 규제를 적용했고, 그 결과 금융 거래 투명성이 증가하고, 엄격한 회계감사가 이루어지는 등 많은 상당한 시스템이 개선이 이루어졌다. 그러나 과거의 규제들이 현재까지 여전히 남아있어 정직하고 혁신적인 기업가를 옭아매고 있었다. 따라서 꼬인 실타래를 푸는 방법은 선별적 재도전이 아닌 원칙적 재도전을 허용하는 창업 생태계를 조성하는 것이며, 이것이 제도 개선의 방향이 되어야 한다. 이를 토대로 재도전을 저해하는 제도를 개선하여 선순환 창업 생태계를 조성할 수 있을 것이다.

Background: Treatment modalities for small-cell lung cancer (SCLC) with pre-existing interstitial lung disease (ILD) are limited. Although re-challenge with first-line chemotherapy can be effective for sensitive relapse SCLC, its safety and efficacy are uncertain in cases with ILD. This study aimed to investigate both the efficacy and safety of re-challenge chemotherapy in patients with sensitive relapse SCLC with ILD. Methods: Patients with sensitive relapse SCLC with ILD who received re-challenge chemotherapy were studied retrospectively. Sensitive relapse was defined as a treatment-free interval (TFI) of more than 60 days after first-line platinum-based treatment. The endpoints were progression-free survival (PFS), overall survival (OS), and safety. Results: Re-challenge platinum and etoposide were administered in 11 patients, with the median re-challenge cycle of 3. The overall response rate was 55%. The median PFS and OS from the time of re-challenge treatment were 4 months (95% CI, 2.9–NA) and 9.2 months (95% CI, 8.0–NA), respectively. One patient developed acute exacerbation of ILD 173 days after the last course of re-challenge treatment. Conclusions: Re-challenge chemotherapy can be effective and considered in SCLC patients with pre-existing ILD.

BACKGROUND: There is an increasing number of case reports in which clozapine was re-initiated or maintained after an initial neutropenia. However, there are relatively few systematic case series that have been published, and their follow-up duration was relatively modest. The present report describes characteristics and trajectories of 22 clozapine treated SZ patients (15 men, 7 women) who have been rechallenged (n=16) or maintained (n=6) on clozapine following the occurrence of a significant neutropenia and who have been followed for an average of 7.2 years. METHODS: This is a complete sample of patients who experienced such as a situation rom 1998 until 2017 while treated at the Institut de Santé Mentale de Québec, where the vast majority of clozapine patients in the Québec City Metropolitan area (population = 750,000) are treated. The following variables were collected from extensive medical records review: demographic information, detailed hematological information, medication and other active medical diagnoses that could have contributed to the neutropenia, clozapine regimen and use of GCS-F and lithium. RESULTS: The mean age at clozapine introduction was 35,9 yrs (range 16–56). The mean observation period following the index neutropenia lasted 7.2 years (range 4 months -19,4). The mean delay between the index neutropenia and the re-challenge was 2.4 months. Five out of these 22 patients experienced additional neutropenias, and 3 of these 5 patients experienced more than one additional neutropenias, one undergoing a total of 11 neutropenias. At the end of the observation period, 17/22 patients were still on Clozapine; among the five patients in whom clozapine was stopped, three had died, one from a paralytic ileus that was deemed clozapine-related, and 2 from non-clozapine related causes. One stopped Clozapine for a non-hematological side-effect, and only one stopped due to neutropenia, i.e., after an eleventh neutropenia despite concomitant GCS-F use. DISCUSSION: This study adds to available evidence that a clozapine re-challenge or continuation following a neutropenia can be reasonably considered once potential risks and benefits have been carefully analyzed and then discussed with the patient and his/her family in order to make a shared decision. Furthermore, the present results raise the possibility that continuing clozapine with stringent hematological monitoring may be considered in some cases of neutropenia that do not reach the agranulocytosis threshold. These results also support that conclusion that conditions other than hematological ones (e.g., severe constipation) should be closely monitored and rigorously addressed in order to ensure the safety of Clozapine use.

Contains fulltext : 203015.pdf (Publisher’s version ) (Open Access) BACKGROUND/AIM: Treatment options for patients with metastatic soft tissue sarcomas are limited. Re-challenge with a previously successful gemcitabine-based regimen is common. There are no published data to support this practice. PATIENTS AND METHODS: We conducted a retrospective search to identify patients re-challenged with gemcitabine-based chemotherapy (GBC) from 2003 to 2015. RESULTS: Twenty-nine patients re-challenged with gemcitabine were identified. The response rate for initial GBC was 55% (n=15) and for re-challenge GBC 26% (n=6). The median progression-free survival was 11.1 months (95%CI=7.2-11.9) for initial GBC and 5.3 months (95%CI=2.0-7.5) for re-challenge GBC. Overall survival following gemcitabine re-challenge was 12.2 months (95%CI=7.0-18.2). Twelve out of 26 evaluable patients (46%) treated with re-challenge GBC experienced grade 3-4 adverse events (CTCAE 4.03) with 31% (n=8) of patients requiring dose reduction. CONCLUSION: In selected patients, gemcitabine re-challenge can be considered in advanced sarcomas, however, this approach is associated with toxicity.

Definitive causality for medication-induced illnesses is difficult to determine, as often there are other causes for the condition. Additionally, for disease management there are often alternative treatment paths, and it is therefore clinically unnecessary to re-challenge with the suspected drug causing an adverse reaction; however, that was not the case in this clinical situation. Providers augmented treatment for this patient, but returned to the only therapy that controlled her condition, clozapine, as there appeared to be limited suitable alternatives. As outlined in this medical case, because the patient clinically responded only to clozapine, this forced providers to order multiple de-challenges and re-challenges resulting in confirmed drug-induced pancreatitis. Through courses of re-challenge, they were forced to find an effective dose and timing to maximize options for care using the drug despite inducing pancreatitis. At the time of this submission, providers had resumed a tolerated lower dose of clozapine without inducing pancreatitis. This case adds to the literature of drug-induced pancreatitis confirmation due to clozapine therapy being de-challenge and re-challenge. .

459 Background: First-line platinum-based combination chemotherapy (fPBC) is standard of care for fit patients with mUC. Further lines of therapy include immuno-oncology agents, erdafitinib, and enfortumab vedotin, but patients ineligible for these therapies or who subsequently progress may be considered for further chemotherapy. As the choice of chemotherapy regimen is unclear for these patients, we compared the efficacy of subsequent platinum-based chemotherapy (sPBC) and subsequent non-platinum-based chemotherapy (sNPBC) in patients with mUC. Methods: Data was analyzed from the Retrospective International Study of Cancers of the Urothelium (RISC), comprising patients from 28 international centers treated 2005-2012. Inclusion criteria were diagnosis of mUC, receipt of fPBC for mUC, and receipt of ≥2 cycles of subsequent chemotherapy. Patients who had received prior platinum-based chemotherapy in the non-metastatic setting were excluded. A multivariate Cox proportional hazards model was used to compare overall survival (OS), while χ2 and student’s t-test were used for univariate analyses. A two-sided p value of

A 63-year-old woman presented with ulcerations of both lower legs. Symptom onset was 2006. In 2013 she saw a dermatologist and a biopsy suggested livedoid vasculopathy. In 2016 a whole food plant-based diet (WFPB) was advised as a potential treatment in the community setting. The patient changed her diet accordingly, but was not otherwise treated. The symptoms remitted completely with close adherence to the WFPB diet and recurred on multiple occasions associated with poor dietary adherence. There was a self-identified dose–response relationship with degree of adherence and number and intensity of flares. There were no known adverse side effects from the diet change, although the patient felt adherence to be difficult at times. The mechanism is not completely clear; we speculate that the dietary changes directly affect vascular endothelial health, which in turn affects propensity towards a prothrombotic state. More research is needed to elucidate potential mechanisms.

Purpose: The delayed neuronal toxicity after high dose methotrexate (HD-MTX) followed by radiotherapy (RT) is a serious problem for elderly primary CNS lymphoma patients. We started maintenance therapy (MT) with MTX after achieving complete remission (CR) to defer RT for elderly and poor Karnofsky Performance Scale (KPS) patients. Methods: We performed HD-MTX (3.5g/m2) therapy until achieving CR for the patients over 70 years whose KPS were equal to or less than 60%. After having CR, 3 courses of MT of MTX (3g/patient) for 3 weeks were introduced every 3–4 months for 2 years. At the time of recurrence, HD-MTX was repeated. But when CR was not achieved by HD-MTX alone, RT was introduced. Moreover, additional use of rituximab was considered if patients’ condition became better. Results: Number of patients was 9. Median age, median KPS, and median follow up periods were 73y.o. (71–78), 40% (30–60), and 14.0 months (1–55), respectively. CR rate was 78% and two patients were not achieved CR due to the adverse events (AEs) which were acute tubular necrosis and pneumocystis pneumonia. But meanwhile, there was no AE by MT. Median OS, median PFS, median time of radiation free period and delayed neuronal toxicity were 19.5 months (95%CI 3-NA), 5.0 months (95%CI 2–22), 2.5 months, and 8.2 months, respectively. Discussion: The results of this study might be inferior to other reports of elderly patients due to poor median KPS. And low introduction rate of MT was undesirable. However, once MT was introduced, MT itself was safe and easy to manage and the long-term prognosis was excellent. Conclusion: Rechallenge of HD-MTX and maintenance therapy of MTX might be promising but the problems of some serious AEs and low CR rate with HD-MTX alone should be resolved.

Background/aim In our previous study, first-line eribulin (ERI) showed 25 weeks of progression-free survival (PFS). This study investigated the efficacy and safety of ERI re-administration in metastatic breast cancer (MBC) patients. Patients and methods HER2-negative MBC patients who had never received chemotherapy for MBC received first-line ERI for 18 weeks if they did not have disease progression, and then one cycle of S-1 before ERI re-administration. Results Twelve patients received ERI re-administration. The PFS of re-administered ERI was 13 weeks. Total duration of ERI use was 30 weeks. The incidence and severity of adverse events were consistent with previous reports. Conclusion In the first-line setting, the total PFS of eribulin was extended by S-1 administration before disease progression, compared with that of our previous report.

5039 Background: We investigated challenging/re-challenging pts with ipilimumab (ipi) after progression on CaboNivo or CaboNivoIpi. Methods: In a phase I expansion study, patients with mUC post-platinum chemotherapy and other GU tumors patients who progressed on Cabo 40 mg daily plus nivolumab, 3 mg/kg every 21 days (CaboNivo) alone or with ipi, 1 mg/kg every 21 days for 4 cycles (CaboNivoIpi)-and achieved a PR or SD≥6 mo, were challenged/re-challenged with ipi, 1 mg/kg every 21 days for up to 4 cycles. Restaging scans were done every 6 wks for the first 12 wks, then every 8 wks and evaluated by RECIST 1.1. Results: In total, 24 patients were evaluated: 18 pts (8 UC (5 bladder and 3 upper tract), 4 clear cell renal cell carcinoma (RCC), 3 urachal adenocarcinoma (adeno), 2 bladder adeno, and 1 sarcomatoid clear cell RCC) who progressed on CaboNivo were challenged with ipi. In the challenge group, median (m) follow-up was 21.2 months. One pt achieved a PR in the LNs, but was found to have brain metastases before the next restaging, 13 had SD and 4 had PD. Median duration of PR or SD was 3.6 months (95% CI: 1.4 – 7.8 months). The mOS from start of ipi challenge was 13.9 months (95% CI: 5.8 months- not estimable); mPFS was 4.6 months (95% CI: 1.9 – 8.7 months). Grade 1/2 treatment related adverse events (AEs) occurred in all 18 pts (100%) and ≥Grade 3 (G≥3) AEs occurred in 11 pts (61%). The most common G≥3 AEs were hypophosphatemia (22%), hypertension (6%), adrenal insufficiency (6%), increased AST (6%), and ALT (6%). Six patients (3 bladder UC, 1 penile squamous cell (SCC) carcinoma, 1 urethral SCC, and 1 clear cell RCC with sarcomatoid features) who progressed on CaboNivoIpi were re-challenged with Ipi. On re-challenge, mfollow-up was 20.9 months. There were no PRs, 3 SDs and 3 PDs. mOS from start of re-challenge was 4.0 months (95% CI: 2.2 – 23.3 months) and mPFS was 1.9 months (95% CI: 1.1 – 2.6 months). Grade 1/2 treatment related AEs occurred in all 6 pts (100%) and ≥Grade 3 (G≥3) AEs occurred in 2pts (33%). G≥3 AEs included 1 hypertension (17%) and 1 hyperphosphatemia (17%). Conclusions: Ipi challenge/re-challenge showed low response rates in pts previously treated with CaboNivo or CaboNivoIpi. However, pts treated with CaboNivo who were challenged with ipi had a better OS than patients who had progressed on CaboNivoIpi and were re-challenged with ipi. Larger trials are warranted testing the ipi challenge in pts progressing on CaboNivo. Clinical trial information: NCT02496208 .

e19355 Background: Immune checkpoint inhibitors (CIs) have been shown to improve overall survival in lung cancer and are FDA approved in multiple settings, both as single agents and in combination with chemotherapy. Immune related adverse events (irAEs) are common and frequently manifest as dermatitis, pneumonitis, colitis, and hepatitis, among others. Managing grade 2 or higher irAEs often requires multiple outpatient visits and sometimes inpatient admissions, which can significantly increase patient morbidity and healthcare cost. There is limited evidence on the safety of restarting CIs after moderate to severe irAE. Identifying high-risk factors for developing severe irAEs again after re-challenge can improve patient care and cost efficiency. Methods: We searched our electronic medical records to identify patients with NSCLC and SCLC treated with one or more PD-1, PD-L1, or CTLA-4 CIs at our institution between 2013 and 2019. We reviewed 452 patients and identified 44 patients who developed irAE requiring treatment discontinuation. Of these 44 patients, 19 were re-challenged with same or different CIs. The primary end point of this study is to assess the rate of grade 2 or higher irAE after CI re-challenge. Secondary endpoints are mortality rate, overall survival, and disease status. Results: Median follow up for the 19 patients who were re-challenged with CI was 15 months. Median duration of CI treatment after re-challenge was 6 months (range 0.5 to 25 months). 7 patients (37%) developed irAEs (grade 2 or above) again (5 pts with same irAE as prior). Multivariate logistic regression analysis revealed that age≥70 and requirement of steroid for initial irAEs were associated with a higher risk of recurrent irAEs. Median overall survival has not yet been reached; 32% of patients have died. No deaths were related to irAE. After re-challenge with CIs, 42% of the patients had partial response or stable disease, and 58% had progression of disease. Conclusions: Our study demonstrated that re-challenge with immunotherapy is feasible in some patients who had treatment held due to irAEs, though recurrent irAEs were common. Caution should be taken when restarting CIs after moderate to severe toxicities, especially in older adults.

123 Background: CHEIRON trial was a phase II study which randomized previously untreated mCRPC pts to receive D 75 mg/m2 IV d1 q3w for 8 courses alone or plus E 160 mg PO daily. As per protocol, E was administered in experimental arm for only 24 wks until D conclusion. The study met its primary endpoint since the rate of pts without disease progression at 6 mos was significantly higher in DE arm compared to D arm (89.1% vs 72.8%; p = 0.002). The clinicians were asked to consider an E re-challenge as first post-progression treatment for those pts without disease progression at the chemotherapy end in the experimental arm. We presented the preliminary analysis of E activity in post-progression setting of CHEIRON DE arm. Methods: We evaluated all patients enrolled in the experimental arm, focusing on pts who received E as first post-progression treatment. We collected data concerning the treatment duration and disease control and compared the outcomes of pts treated with E re-challenge with those of pts who received other treatments at the time of first progression after experimental therapy. Results: Among the 120 pts who received DE experimental arm, 101 did not show a disease progression and 82 received a second-line active treatment: 54 (66%) were treated with E, the other received abiraterone (10 pts), cabazitaxel (13 pts), and radium 223 (5 pts). The median interval between the end of DE and the start of E re-challenge was 7.6 mos (range 0.9-18.4 mos). At a median follow-up of 15.5 mos, the median duration of E re-challenge was 9.8 mos (range 1.9-30.9) with 22 pts still on treatment. Pts who received E rechallenge showed a median progression free survival of 11.4 mos which was significantly longer compared to 4.5 mos showed in pts who received other treatments (p < 0.0001). The median overall survival was 20.4 mos and 12.3 mos, respectively (p = NS). Conclusions: In pts who received first-line DE in the CHEIRON trial, the reintroduction of E after a per-protocol discontinuation demonstrated to be feasible, with a prolonged disease control compared to the other post-progression therapeutic options. Clinical trial information: NCT02453009.

// Maiko Niki 1 , Aya Nakaya 1 , Takayasu Kurata 1 , Hiroshige Yoshioka 1 , Toshihiko Kaneda 1 , Kayoko Kibata 1 , Makoto Ogata 1 and Shosaku Nomura 1 1 First Department of Internal Medicine, Kansai Medical University, Shin-machi, Hirakata, Osaka 573-1010, Japan Correspondence to: Aya Nakaya, email: nakaya1016@yahoo.co.jp Keywords: immune checkpoint inhibitor; nivolumab; pembrolizumab; re-challenge; non-small cell lung cancer Received: June 11, 2018 Accepted: July 21, 2018 Published: August 17, 2018 ABSTRACT Background: Immune checkpoint inhibitors have dramatically changed lung cancer treatment, demonstrating an overall survival benefit. There are limited data about re-challenge in patients with non-small cell lung cancer. We attempted to address this question for re-challenge of immune checkpoint inhibitor in patients with advanced non-small cell lung cancer. Methods: We retrospectively analyzed 11 patients with advanced non-small cell lung cancer treated with nivolumab and re-challenged with nivolumab/pemblorizumab at Kansai Medical University Hospital from December 2015 to December 2017. Results: Three patients achieved PR and two patients were in SD. These patients were apt to be good responders to the initial treatment, to develop immune-related adverse events and to be immediately started on re-challenge with immune checkpoint inhibitor. The median PFS was 2.7 (range, 0.5–16.1) months. Five patients (45%) had mild to moderate immune-related adverse events. Conclusion: Our study shows the effectiveness of re-challenge of immune checkpoint inhibitors in a subset of non-small cell lung cancer patients. Re-challenge might become one of treatment option for advanced non-small cell lung cancer.

Objective: To explore the evidence around clozapine re-challenge following myocarditis. Conclusion: This case adds to the 17 cases of clozapine re-challenge following myocarditis, of which 71% were successful (12 cases). This demonstrates that re-challenge could be performed safely and effectively in the context of clozapine-induced myocarditis, if accompanied by a strict and rigorous monitoring protocol.

683 Background: Anti-EGFR plus chemotherapy (CT) promotes high response rates (RR) and median overall survival (OS) surpasses 30 months in RASwt/BRAFwt mCRC. After disease progression (PD), resistance mechanisms have been described. The aim of our study was to evaluate efficacy of anti-EGFR re-challenge (TRECC). Methods: We retrospectively analyzed a cohort of patients (pts) with mCRC. All pts had received anti-EGFR plus CT and were discontinued for different reasons. During the treatment, there was re-challenge with an anti-EGFR + CT. We aimed to evaluate progression-free survival (PFS) and OS after re-challenge and prognostic factors associated with PFS. Results: Sixty eight pts met the study criteria. Median follow-up after re-challenge was 39.3m. Discontinuation after first exposure was 25% due to PD; 75% for other reasons. Median anti-EGFR free interval was 10.5m. At re-challenge, main CT regime was: FOLFIRI 58.8%, Cetuximab and Panitumumab were used in 59 and 9 pts respectively. mPFS after re-challenge was 6.6m; mOS was 24.4m. Objective response rate (CR + PR) at re-challenge was 42.6%. In an univariate analysis, adverse prognostic factors related to PFS were: absence of objective response at 1st EGFR exposure (HR 2.12, CI:1.20-3.74 p = 0.009); PD as reason for 1st discontinuation (HR 3.44, CI:1.88-6.29 p < 0.0001); re-challenge at fourth or later lines (HR 2,51, CI:1.49-4.23 p = 0.001); panitumumab use (HR 2.26 CI:1.18-5.54 p = 0.017). In a multivariate model, only PD as reason for 1st discontinuation remained statistically significant (HR = 2.63, CI:1.14-6.03 p = 0.022). mPFS was 3.3m and 8.4m and mOS was 7,5m and 33,4m in patients with PD as reason for 1st discontinuation and other reasons respectively. Conclusions: Re-challenge therapy is commonly used due to paucity of effective lines of treament for mCRC. In our analysis, pts that stopped 1st anti-EGFR therapy due to PD have shorter survival, suggesting these pts do not benefit from TRECC. However, interruption due to treatment holiday after PR/CR resulted in longer PFS. In conclusion, for a selected group of pts, TRECC could be considered a strategy of treatment. Due to the limited number of pts, our data should be evaluated in a prospective cohort of patients.

Clozapine is an atypical antipsychotic which is often effective in patients who fail to respond to other antipsychotics, but its use carries substantial risk. Myocarditis is one of the life-threatening adverse effects, which occurs in about 1% of exposed patients. Rechallenge with clozapine is controversial, particularly shortly after the occurrence of the myocarditis, and when there is clear and convincing evidence of cardiac damage. Aggressive use of clozapine, however, may be critical for the recovery of patients early in the course of their illness. Here we report a successful case of clozapine rechallenge following an initial aggressive dosage titration in an inpatient setting.