Drug Holiday Research Articles

Topical 5-fluorouracil as monotherapy for ocular surface squamous neoplasia

Ocular surface squamous neoplasia (OSSN) comprises a gamut of diseases, which encompass conjunctival intraepithelial neoplasia, conjunctival carcinoma in situ, and squamous cell conjunctival neoplasia. Gold standard treatment for OSSN entails excision with cryotherapy. A lot of progress has been made recently that shows that chemotherapeutic drugs, such as mitomycin C, 5-fluorouracil (5-FU), and interferon alfa2b, can be just as effective. This is a case report that includes two cases: An 81-year-old Filipino female and a 65-year-old Filipino male who presented with a pinkish lesion on the bulbar conjunctiva. Documentation was done through clinical observation, slit-lamp examination, and the use of anterior segment optical coherence tomography (OCT). 1% topical 5-FU was given as chemotherapy administered at 1 drop 4×/day for 1 week with a 3-week drug holiday. During the course of treatment, we noted clinical resolution of the lesions grossly on slit-lamp examination. On anterior segment OCT, a decrease in diameter and thickness was noted, but with remaining areas of hyperreflectivity and thickened epithelium at the site of the lesion. No decrease in visual acuity was noted during the course of treatment, as well as any adverse effects such as eye pain or inflammation. Considering its safety and efficacy profile, 5-FU has great potential to be considered as a first-line therapy in the topical treatment of OSSN. Topical chemotherapy can target microscopic diseases that may be missed surgically and decrease adverse effects. As seen in this case report, 5-FU shows much promise as a possible alternative in the treatment of OSSN.

Real-world data on the efficacy and safety of hedgehog pathway inhibitors in patients with basal cell carcinoma: Experience of a tertiary Australian centre.

Basal cell carcinomas (BCCs) are the most common cancers worldwide. Although most BCCs are amenable to local treatment, there are limited therapeutic options for surgically unresectable locally advanced and metastatic BCCs. Activation of the sonic hedgehog signalling pathway plays a significant role in the development of most BCCs. Hedgehog pathway inhibitors (HPIs) can be used to inhibit this pathway. Efficacy and safety data on HPI use in Australia is scarce. This study aims to present the effectiveness and safety of HPI at a tertiary dermatology referral centre. We conducted a retrospective analysis of the clinical charts of all patients with BCC treated with an HPI at a tertiary Dermatology referral centre in New South Wales, Australia from 1 January 2016 to 1 July 2023. Twenty-three patients with BCCs were treated with an HPI; 11 locally advanced, 8 multiple, 3 basal cell naevus syndrome and 1 metastatic. All patients were of Caucasian background, with a median age of 56. Across 41 treatment cycles, the median treatment duration was 4 months. The overall response rate (ORR) was 20/23 (87%) and complete response (CR) rate was 9/23 (39%); patients treated with sonidegib achieved an ORR of 11/12 (92%) and CR of 4/12 (33%), and vismodegib-treated patients achieved an ORR of 9/11 (82%) and CR of 5/11 (45%). Patients who responded to HPI treatment also responded to a subsequent HPI rechallenge. Common treatment emergent adverse events (TEAEs) included muscle spasms, dysgeusia and alopecia. Dysgeusia was more frequent with vismodegib than sonidegib (p = 0.0001). There was no evidence to suggest a difference in other TEAEs between the two HPIs. Four treatment cycles were stopped due to grade 3 muscle spasm. In our cohort of 23 patients being treated with HPI, the ORR was 87% and CR was 39%. All patients who experienced TEAEs and had a drug holiday successfully responded to HPI rechallenge.TEAEs, particularly muscle spasms, are common reasons for treatment cessation. Clinicians should implement strategies to mitigate TEAE to improve drug survivability.

Risk factors affecting relapse after discontinuation of biologics in children with Crohn's disease who maintained deep remission.

Biologics are important therapeutic agents for pediatric Crohn's disease. Discontinuation of biologics is known to increase the relapse rate up to 71.4% in these patients; however, their long-term use increases the risk of opportunistic infections and causes economic burden and psychological fatigue. Therefore, taking a drug holiday is meaningful, even if the biologics cannot be completely discontinued. This study aimed to analyze the risk factors affecting relapse after discontinuation of biologics in children with Crohn's disease. We retrospectively reviewed the data of 435 children with Crohn's disease who visited a single health center between March 2013 and March 2021. Subsequently, we analyzed data from the patients who discontinued biologics after deep remission. Among the enrolled patients, 388 were followed up for ≥2 years, and of these, 357 were administered biologics. A total of 103 patients discontinued biologics after deep remission, subsequently 31 maintained remission and 72 relapsed. The shorter the duration of biologic treatment (odds ratio of 0.444, P = 0.029), the higher the ESR (odds ratio of 1.294, P = 0.009) and fecal calprotectin (odds ratio of 1.010, P = 0.032), and the less histological remission at the time of discontinuation of biologics (odds ratio of 0.119, P = 0.026), the greater the risk of relapse after discontinuation of biologics. We identified factors associated with relapse after discontinuation of biologics. The results suggest that biologics can be discontinued in the absence of these factors after deep remission. However, because the relapse rate may increase after the discontinuation of biologics, close monitoring is important, and if necessary, re-administration of biologics should be actively considered.

7740 Adult-Onset Hypophosphatasia Presenting As Low Alkaline Phosphatase Level Following Denosumab Use For Osteoporosis

Abstract Disclosure: J. Ocampo Mascaro: None. P. Wax: None. M. Al Mukaddam: Grant Recipient; Self; Ipsen, Incyte Research Funding. Background: Hypophosphatasia (HPP) is a genetic disease characterized by low activity of the tissue non-specific alkaline phosphatase. It has a broad range of clinical phenotypes, with adults usually presenting with an incidental low alkaline phosphatase (ALP) finding. Differentiating this from other causes of low ALP is challenging, especially when treating osteoporosis, as antiresorptive therapy such as denosumab and bisphosphonates may cause low ALP and carry the potential of increasing risk of atypical femoral fractures in patients with undiagnosed HPP. Clinical Case: A 64-year-old woman with history of nephrolithiasis, hypercalciuria, and osteoporosis (screening DXA lowest T-score -3.3 in femoral neck (FN)) but no prior fractures or dental issues was seen in clinic. Initial bloodwork showed normal range calcium, 25-OH vitamin D, and intact PTH. Pre-treatment ALP was 42 IU/L (N 39-117). Work up for secondary causes of osteoporosis was negative. Three yearly doses of IV zoledronic acid resulted in +4.2% BMD increase in lumbar spine (LS) but no changes in FN. She had no side effects but was found to have a decrease in ALP to 33 IU/L. This normalized back to 42 IU/L during a three-year drug holiday. Follow up DXA noted significant decline in BMD, hence denosumab was initiated. ALP decreased back to the 30-35 IU/L range. Fasting Vitamin B6 level (off B6 supplements for 1 week) was 23.4 ng/ml (N 2.1-21). Urine phosphoethanolamine was mildly elevated at 5 mmol/mol creatinine (N ≤4). Genetic testing evidenced a pathogenic ALPL variant (Exon 6, c.575T>C (p.Met192Thr), heterozygous) compatible with HPP. She had tolerated three doses of denosumab by then with BMD improvement of 5.0% in LS but no changes in FN and no atypical femoral fracture. Denosumab was stopped. Abaloparatide was started for osteoporosis with close monitoring for worsening hypercalciuria. Conclusion: This case demonstrates that adult HPP patients may present with subtle findings and lower range of normal ALP and may tolerate short courses of antiresorptive agents. There is a need for better screening and diagnostic criteria for adult HPP patients whose ALP levels may not be initially low before initiating antiresorptive drugs for osteoporosis. The risk of adverse effects from therapy will likely vary significantly based on the clinical severity/presentation of HPP as some adults with lower ALP ranges might be more susceptible to developing atypical femur fractures (1). Balancing atypical femur fracture risk with the benefits of antiresorptive treatment in decreasing risk of osteoporotic fractures highlights the need for better risk stratification to prevent undertreatment of osteoporosis. Reference: 1. Warren AM, Ebeling PR, Grill V, Seeman E, Sztal-Mazer S. Bilateral atypical femoral fractures during denosumab therapy in a patient with adult-onset hypophosphatasia. Endocrinol Diabetes Metab Case Rep. 2021 Sep 1;2021:21-0096. Presentation: 6/2/2024

Assessment of prolonged safety and tolerability of erenumab in migraine patients in a long-term open-label study (APOLLON)

BackgroundEfficacy and safety of human monoclonal antibody erenumab used for migraine prophylaxis have been shown in clinical studies. APOLLON is an open-label, multi-center, single arm study, which permits dose adjustments of erenumab and includes an option for a drug holiday. The findings contribute to the accumulating long-term evidence regarding erenumab’s tolerability and safety profile in individuals experiencing episodic and chronic migraines.MethodsThe study population consisted of adult patients with episodic or chronic migraine, who had successfully completed the HER-MES study (NCT03828539). Patients were treated with erenumab for 128 weeks at a flexible dose of either 70 mg or 140 mg. Treatment discontinuation attempts were allowed as voluntary single treatment interruption (‘drug holiday’) of up to 24 weeks.Results701 patients were enrolled in APOLLON. The exposure associated incidence rate (EAIR) of adverse events (AEs) (N = 601) per 100 subject years was 101.71 (95% CI [92.28; 111.14]) meaning a patient could expect having about one adverse event per each year of treatment. EAIR was higher in females (n = 524, EAIR: 104.40, 95% CI [93.93; 114.86]) than in males (n = 77, EAIR: 86.55, 95% CI [65.39; 107.71]) and increased with initial monthly migraine days (MMD) and prior prophylactic treatment failures. A total of 155 patients discontinued erenumab treatment during open-label treatment phase. Of these, 29 were due to AEs (4.1% of total cohort) and out of these 65.5% (N = 19) were considered treatment-related. Safety parameters were in line with HER-MES data and did not reveal new safety signals. Drug holidays were realized by 108 patients (15.4%), of which 64.8% (N = 70) returned to treatment. The mean number of monthly headache days (MHDs), MMDs, and days with acute headache medication significantly increased during drug holiday. After resumption of erenumab treatment, a rapid reduction of the migraine parameters was observed.ConclusionsAPOLLON provides long-term safety and tolerability data confirming the beneficial safety profile of erenumab over a period of 128 weeks. In addition, reversibility of migraine deterioration during drug holiday was shown and most patients returned to their treatment with similar response rates compared to initial treatment.Trial registrationClinicalTrials.gov ID: NCT04084314 (https://clinicaltrials.gov/study/NCT04084314), First submitted: 2019-09-06.

Real-life effects of pharmacological osteoporosis treatments on bone mineral density by quantitative computed tomography.

Monitoring of bone mineral density (BMD) is used to assess pharmacological osteoporosis therapy. This study examined the real-life effects of antiresorptive and osteoanabolic treatments on volumetric BMD (vBMD) of the spine by quantitative computed tomography (QCT). Patients aged ≥ 50years with a vBMD < 120mg/ml had ≥ 2 QCT. For analysis of therapy effects, the pharmacological treatment and the duration of each therapy were considered. Identical vertebrae were evaluated in all vBMD measurements for each patient. A linear mixed model with random intercepts was used to estimate the effects of pharmacological treatments on vBMD. A total of 1145 vBMD measurements from 402 patients were analyzed. Considering potential confounders such as sex, age, and prior treatment, a reduction in trabecular vBMD was estimated for oral bisphosphonates (-1.01mg/ml per year; p < 0.001), intravenous bisphosphonates (-0.93mg/ml per year; p = 0.015) and drug holiday (-1.58mg/ml per year; p < 0.001). Teriparatide was estimated to increase trabecular vBMD by 4.27mg/ml per year (p = 0.018). Patients receiving denosumab showed a statistically non-significant decrease in trabecular vBMD (-0.44mg/ml per year; p = 0.099). Compared to non-treated patients, pharmacological therapy had positive effects on trabecular vBMD (1.35mg/ml; p = 0.001, 1.43mg/ml; p = 0.004, 1.91mg/ml; p < 0.001, and 6.63mg/ml; p < 0.001 per year for oral bisphosphonates, intravenous bisphosphonates, denosumab, and teriparatide, respectively). An increase in trabecular vBMD by QCT was not detected with antiresorptive agents. Patients treated with teriparatide showed increasing trabecular vBMD. Non-treatment led to a larger decrease in trabecular vBMD than pharmacological therapy.

Optimal STI controls for HIV patients based on an efficient deep Q learning method

We investigate an efficient computational tool to suggest useful treatment regimens for people infected with the human immunodeficiency virus (HIV). Structured treatment interruption (STI) is a regimen in which therapeutic drugs are periodically administered and withdrawn to give patients relief from an arduous drug therapy. Numerous studies have been conducted to find better STI treatment strategies using various computational tools with mathematical models of HIV infection. In this paper, we leverage a modified version of the double deep Q network with prioritized experience replay to improve the performance of classic deep learning algorithms. Numerical simulation results show that our methodology produces significantly more optimal cost values for shorter treatment periods compared to other recent studies. Furthermore, our proposed algorithm performs well in one-day segment scenarios, whereas previous studies only reported results for five-day segment scenarios.

Do children with ADHD who utilize drug holidays note more long-term benefits compared with those who undergo continuous therapy?

Do children with ADHD who utilize drug holidays note more long-term benefits compared with those who undergo continuous therapy?

Leflunomide-Associated Wound Complication After Cochlear Implantation: A Case Report.

Cochlear implantation has become an increasingly common strategy for aural rehabilitation in patients with severe to profound hearing loss who no longer benefit from conventional amplification. In conjunction, immunosuppressive therapies (e.g. disease-modifying anti rheumatic drugs (DMARDs) have become the keystone of management in numerous autoimmune conditions. Given the increasing prevalence of both, a greater proportion of patients will undergo cochlear implantation while on immune-modulating medications. While these medications are usually well tolerated, immunosuppression may put patients a higher risk for device infections. At present, this is not extensively studied within the cochlear implant literature. We conducted a retrospective chart review and review of the literature.Results:We present the case of an 81-year-old male who experienced wound dehiscence and infection secondary to leflunomide use for treatment of rheumatoid arthritis. Resolution of these issues was noted with a therapeutic drug holiday, and the patient has subsequently undergone re-implantation without issue.Conclusions:The case highlights a potential CI-associated wound complication in the setting of DMARD therapy. Given the increasing prevalence of both CIs and immunosuppressive therapy, future study on the potential for interaction is warranted to identify the best management strategy in the perioperative setting.

Physical exercise as part of the rehabilitation in primary osteoporosis: insights into the signal transduction bone formation pathways

Primary osteoporosis, a geriatric bone metabolic condition affecting both the mineral density and the microarchitecture, comes with a complex burden. Bone turnover markers tidily reflect the changes of skeleton status that are part of the physiological process or theyhighlight the abnormal status including in osteoporosis in addition to other biomolecules evaluation such as hormones, inflammatory markers, myokines and adipokines. In this narrative review, we aimed to highlight several aspects regarding osteoporosis-related rehabilitation amid mitigating the role of physical exercise as bone formation booster. Bone turnover markers assays, by capturing the essence of the bone remodelling, registered a great progress during latest years, thus show-ing an enhanced index of applicability in daily practice (despite being known and studied for more than three decades). Irisin, a novel player in the muscle-bone-metabolism cross-talk, represents a muscle-derivate hormone that is expected to highlight the interplay between physical exercise and bone formation. Other concurrent signal transduction pathways include recently described biomarkers such as preptin or the spectrum associated with serotonin-LRP5-Wnt/beta catenin canonical and non-canonical loops. Current pitfalls of the topic include the personalized recommendation of physical activity due to severe co-morbidities, the lack of homogenous studies to measure the intervention and the consecutive bone health and great variations of using the bone turnover markers amid daily practice in different centers. To conclude, part of the monitoring protocol in osteoporotic patients under specific medication against osteoporosis or during bisphosphonates drug holiday, bone turnover markers assays stands for a practical insight in every day practice. The contributing role of physical exercise to boost bone formation as reflected by these biomolecules is well understood across a multitude of signal transduction pathways. However, a current gap in practical use and surveillance of the prescription of physical activity, mechanical load and rehabilitation programs in these patients is confirmed so far. Keywords: osteoporosis, bone, fracture, rehabilitation, physical exercise, bone turnover markers, osteocalcin.

LGG-51. SYSTEMIC IMMUNE TOXICITY OF BRAF AND MEK-INHIBITORS IN CHILDREN: A PAN-CANADIAN SERIES

Abstract BACKGROUND BRAF/MEK-inhibitors have been transformative for pediatric gliomas with RAS/MAPK pathway aberrations. The RAS/MAPK pathway has a complex role in immune regulation. Though well-known in adults, the systemic immune-related adverse effects (irAE) of BRAF/MEKi in children are not widely reported. METHODS We performed a retrospective chart review for irAE following BRAF/MEKi in children treated at SickKids between 2016-2023. Additional patients were included through a pan-Canadian survey. RESULTS 136 patients on BRAF/MEKi were included (MEKi: 74%, BRAFi: 13%, BRAF+MEKi: 13%); irAE was reported in 6/136 (4.5%). One additional patient was included through the national survey. Median age was 14 years (range: 7-16). Male:female was 3:4. Three patients were on BRAFi, and two each on MEKi, and BRAF+MEKi. Early events developing within weeks of drug initiation included hyper-immune systemic inflammatory responses in three children on BRAFi and one child on MEKi. There was no evidence of any concomitant infection. Two children needed intensive care and showed evidence of multi-organ dysfunction. Delayed irAE developing after months to years on therapy included multi-systemic sarcoid-like reaction, parasympathetic dysautonomia (both on BRAF+MEKi) and brachial neuritis/Parsonage-Turner syndrome (MEKi). Management included drug holidays, dose reductions, and immunosuppressive treatment with steroids. Long-term steroids were needed in two of these seven patients. CONCLUSIONS Pediatric oncologists need to be aware of rare yet possibly under-reported systemic immune toxicity in children treated with BRAF/MEKi. They can present acutely, or while on chronic therapy. Management may be challenging in view of issues with rebound tumor growth on stopping some of these drugs, with select patients needing concomitant, long-term immunosuppressive therapy. Genetic susceptibility and biomarkers may need to be systematically studied in future clinical trials of novel RAS/MAPK inhibitors. Continued surveillance and reporting are needed for the marketed compounds, especially for children on long-term use of these inhibitors.

Planned Drug Holidays Seems Safe and Effective in the Treatment of Differentiated Thyroid Cancer

Planned Drug Holidays Seems Safe and Effective in the Treatment of Differentiated Thyroid Cancer

#2861 Real-life efficacy of tolvaptan for polycystic kidney disease (PKD) and association with patient adherence in London North-West specialist clinic

Abstract Background and Aims Tolvaptan is approved by NICE in the treatment of PKD afterrandomised controlled trials demonstrated a reduction in decline in eGFR. Aquaresis occurs as an effect, and this may limit tolerability as the second dose in a day causes nocturia and disturbed sleep. Thirty-three patients in our specialist PKD clinic were treated based on criteria of bipolar renal length &amp;gt;=15cm and decline in eGFR by &amp;gt; −5 ml/min/yr. We evaluated their real-life outcome regarding measures of adherence including an adapted Basel Assessment of Adherence to Immunosuppressive Medication Scale © (by permissions.nursing.unibas.ch/) originally validated for immunosuppression medications in transplant patients. A further 24 patients had finished treatment at our centre and were excluded as BAASIS could not be applied in hindsight. However, they illustrated a notably high level of intolerance leading to cessation in 16/24 (9 with nocturia, 4 transaminitis, 1 angioedema, 1 rash, 1 fatigue) emphasizing the importance of this work on adherence and response. Method BAASIS addresses recall of treatment adherence in the preceding 4 weeks, all 33 patients currently treated as of 16/1/24 were screened on telephone by two independent auditors with a standard non-judgemental introductory script designed to result in candid engagement. Investigators were blinded to renal outcomes. A decline in eGFR of less than 5 ml/min/yr was defined as treatment response. Results Of the 33 patients included, 14 males and 19 females, median age 49yrs (range 32-72), were on treatment for a mean of 2.7yr (SD 2.2, range 0.3-7.5). Mean eGFR (CKD-EPI) was 58 ml/min (SD 19, range 28-110) at start and 48 ml/mi (SD 23, range 17-102) at end of treatment. Median total daily dose was 120 mg/d (range 60-120). Attendance at clinic for monitoring was 100%. 18/33 patients had responded to treatment, with delta eGFR –0.1 ml/min/year (SD 3.4) versus non-responders’' delta eGFR –13 ml/min/year (SD 8.7) There was a total of 35 instances of non-implementation in 23/33 patients with missed (20 instances), delayed (13 instances) or self-alteration in doses (2 instances). Only 10/33 patient made no failure to implement Tolvaptan at any time. There were 9 patients with non-persistence of Tolvaptan treatment. Associative analysis of renal outcome with adherence was made for all 31 patients who had more than 6 months treatment, 2 patients being excluded because treatment had been too short-term. 25/31 had non-adherence defined by non-implementation or non-persistence or both, but this did not statistically associate with treatment failure ChiSq 1.951 p = 0.16. The element of non-implementation alone was however associated with treatment failure ChiSq 4.949 p = 0.03, this term includes patient behaviour of not taking and mistiming drug taking, and patient-initiated dose reduction and drug holidays. Conclusion Just over half (55%) of currently treated patients had made a clinical response to Tolvaptan. 23/33 patients had non-implementation within the 4 weeks preceding the validated adherence survey, and this was significantly associated with treatment failure. This study is limited to a small single-centre patient cohort but could easily be applied more widely. This study informs shared-decision making and we should encourage our patients to take this high-cost drug in the right amount and at the right times, and notably not to miss doses, thereby to achieve higher clinical response rates.

Topical 5-Fluorouracil 0.5% as primary treatment for Ocular Surface Squamous Neoplasia.

To evaluate the efficacy of topical treatment with 5-Fluorouracil (5-FU) 0.5% in cases of Ocular Surface Squamous Neoplasia (OSSN), and to assess the tolerance of patients undergoing treatment. Patients with clinical diagnosis of OSSN referred to the Ocular Oncology division from the Federal University of Sao Paulo, Brazil, were recruited for the current study. Patients were treated with topical 5-FU 0.5% using a regimen of 4 times daily for 10 days, followed by a 3-week drug holiday, continued up to 3 cycles before an alternative treatment. Lesions were evaluated at baseline and throughout treatment. Treatment adherence was assessed using the Morisky Medication Adherence scale. Any adverse events along the treatment were noted. A total of 30 eyes of 30 patients adherent to the treatment were included in the study. Among the total cases treated with 5-FU 0.5%, 24 patients achieved therapeutic success after a mean treatment duration of 21.71 ± 7.77 days, representing a success rate of 80.00% (95% CI: 60.75-91.18%). For each 1 mm2 increase in the lesion area, the odds of treatment success decrease by 6% (OR: 0.94; 95%CI: 0.88-0.99; p = 0.033). Only mild adverse events such as ocular discomfort, ocular burning and tearing were observed along the treatment in 8 patients. Topical 5-FU 0.5% is an effective therapeutic option in the treatment of OSSN, with an 80% therapeutic success rate, showing good tolerability. The size of the lesion was identified as a factor influencing treatment success, therefore it should be taken into consideration when defining treatment approaches.

Clinical status of established MRONJ in oncology patients continuing bone-modifying agents.

The continuation of bone-modifying agents (BMAs) in patients with established medication-related osteonecrosis of the jaw (MRONJ) is a common concern among dentists and oncologists. There is little evidence supporting or refuting the continued use of BMAs or drug holidays and their impact on established MRONJ. This paper evaluates the outcome of continued BMAs use on the patient's MRONJ status. A retrospective review of 29 oncology patients undergoing active cancer care for either metastatic disease or multiple myeloma was conducted. Data on demographics, oncological status, BMA history and MRONJ status were collected. In total, 90% of patients were judged to have healed or stable MRONJ while continuing BMAs. Most patients (69%) continued the same BMA regime (three- or four-weekly) that they were on before developing MRONJ. The average number of BMAs doses received after an MRONJ diagnosis was 12 (range 1-48). Three patients (10.3%) were found to have MRONJ progression, with two patients developing new sites of necrosis. This real-world dataset suggests that the majority of MRONJ cases remain stable and will not worsen with the continuation of BMAs.

Abstract PO3-04-03: Drug Holidays in Patients with HER-2 Positive Metastatic Breast Cancer

Abstract Background Treatment of HER-2 positive metastatic breast cancer (MBC) involves the use of HER-2-targeted therapy in combination with cytotoxic chemotherapy and/or hormone therapy. Treatment duration for HER2-targeted agents is not standardized, and patients are often kept on these drugs indefinitely. Drug holidays can be initiated due to poor tolerance of drug or can be considered when trying to limit drug toxicity. Our study aims to determine the safety of utilizing drug holidays for patients receiving HER2-targeted therapies and the effect on overall survival and disease progression. Methods Study Design This retrospective study included patients who were diagnosed with metastatic HER2 positive breast cancer and had complete clinical and survival data available within UPMC Magee Women’s Hospital. The patients were divided into two groups based on whether they had a drug holiday or not. A drug holiday was defined as the temporary cessation of antiHER2 therapy for a minimum of three months in patients receiving HER2-targeted treatments. This involved the discontinuation of earlier- and later-line medications without considering the cessation of hormone therapy. Statistical Analysis The chi-square test or Fisher's exact test was used to compare categorical variables and the Mann-Whitney U test was used to compare continuous variables. The results were reported as proportions for categorical variables and as medians with 25th-75th percentiles for continuous variables. Survival rates and Hazard ratios were estimated using Kaplan-Meier log-rank tests and Cox models, respectively. The significance level was set at p &amp;lt; 0.05 for all analyses. Results 83 patients with HER2+ MBC treated with HER2-targeted therapy were identified, of which 54 patients were in the drug holiday group. Of noted patient variables, there was no significant difference in the tumor histology, distribution of estrogen receptor (ER) status (p= 0.38) and progesterone receptor (PR) status (p = 0.64). The use of hormonotherapy, immunotherapy, radiotherapy to the primary tumor, and radiotherapy to metastasis did not significantly differ between the two groups (p &amp;gt; 0.05 for all comparisons). Subgroup analysis was conducted within the hormonotherapy subgroup to assess the survival difference in the no drug holiday group and to evaluate the impact of drug holiday on antiHER2 therapy cessation while continuing hormonotherapy. There was a trend towards a higher proportion of patients who were deceased in the no drug holiday group (62%) compared to the drug holiday group (42%), although this difference did not reach statistical significance (p = 0.16). The disease status differed significantly between the two groups (p &amp;lt; 0.0001). In the no-drug holiday group, 72% of patients had progressive disease, while 20% had stable disease with the anti-HER2 therapy and 7% had no-evidence of disease. In contrast, the drug holiday group had a higher proportion of patients with no-evidence of disease (48%) compared to progressive disease (38%) and stable disease (14%). The drug holiday group demonstrated higher overall survival (61% with median follow-up 1719 days 25th-75th percentile: 963-2222) compared to the no drug holiday group (39% with median follow-up time of 803 days 25th-75th percentile: 216-1510) (p= 0.04). Conclusion Overall, our findings suggest that utilization of a drug holiday in stable and NED HER2+ MBC is not associated with decreased survival. Analysis within the hormonotherapy subgroup indicated no survival difference in the drug holiday group, highlighting the potential for cessation of antiHER2 therapy while continuing hormonotherapy in this specific subgroup. However further prospective studies with long drug holiday intervals, larger sample size, and control of other potential confounding factors are needed to validate these results. Citation Format: Saba Kurtom, Kazim Senol, Qurat Ul Ain Sabih, Efe Sezgin, Adam Brufsky, Vikram Gorantla, Shannon Puhalla, Atilla Soran. Drug Holidays in Patients with HER-2 Positive Metastatic Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-04-03.

Abstract PO5-23-10: Development of a long-term in vitro assay able to identify compounds that can overcome resistance to CDK4/6 inhibitor plus endocrine therapy in ER+ HER2- breast cancer

Abstract CDK4/6 inhibitor plus endocrine therapy (ET) has emerged as the standard of care first line therapy in ER+ HER2- breast cancer. While this combination has shown the ability to extend overall survival, nearly all patients acquire resistance and progress after 2-3 years. Subsequently, interest has turned to identifying a third partner compound that can be integrated into the CDK4/6i plus ET backbone regimen with the goal of overcoming resistance and driving a deeper response. However, a comprehensive assay-based workflow proficient in identifying compounds with the most promising potential is lacking. To fill this need, we set out to develop a high-throughput in vitro assay with relevant multi-faceted readouts to assess the efficacy of potential triplet combinations using 12 human ER+ breast cancer lines. For this assay, cells were engineered to express nuclear RFP to enable accurate cell counting using basic imaging techniques in 384 well plates. Each third partner compound was tested at two different doses and, in addition to the triplet combination (CDK4/6i + ET + third partner), single agent as well as double agent combinations were investigated. The assay was imaged and re-dosed every 5 days until day 15. On day 15, the compounds were washed out and the cells underwent a 25-day drug holiday to monitor relapse. Duplicate plates of all conditions were monitored and imaged every two hours for 24 hours for live cell staining of apoptosis markers. Additional duplicate plates were fixed and stained on days 5 and 15 for markers of senescence and cell cycle. Images were subsequently fed into a python-based algorithm to determine the percentage of cell population expressing the various markers and phenotypic correlates were extracted. We are looking for triplet combinations that induce a deeper cell cycle arrest, senescence, and/or cell death compared with the CDK4/6 inhibitor plus ET only treatment. Our drug holiday results will help elucidate the treatments able to continue to induce suppression once washed out, indicating treatment options that may induce long-lasting, possibly irreversible effects on the cells. Finally, by extracting phenotypic correlates from brightfield images we hope to cluster the various compounds in their effects across cell lines of diverse backgrounds to help understand the best way to benefit multiple patient populations. Overall, the assay will be able to identify and differentiate various therapeutic combinations based on cell count, senescence, and cell death. The format of this assay enables depth of analysis not accessible using other techniques such as FACS, including full dose-response curves, combination matrices, and longitudinal analyses. Additionally, the assay can be modified to evaluate any number of cellular markers and can be useful across a number of applications. The approach developed here will be foundational in discovering next-step strategies for patients with therapy resistance. Citation Format: Stephanie Kronstadt, Neil Umbreit, Matt Niederst, Rens Janssens. Development of a long-term in vitro assay able to identify compounds that can overcome resistance to CDK4/6 inhibitor plus endocrine therapy in ER+ HER2- breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-23-10.

A Prospective Cohort Study Exploring the Effect of Lenvatinib Planned Drug Holidays in Treatment of Differentiated Thyroid Cancer.

Background: Although lenvatinib is the preferred treatment for unresectable radioactive iodine-refractory differentiated thyroid cancer (RR-DTC), this agent exerts considerable toxicities, which can lead to frequent dose interruptions and modifications. The adoption of planned drug holidays has been recently suggested as one means of minimizing or avoiding these severe adverse events. Our retrospective study demonstrated that planned drug holidays appear to be a promising strategy for continuing of lenvatinib. However, the benefits of planned drug holidays in a prospective study have yet to be clarified. Here, we investigated the impact of planned drug holidays on clinical outcomes in patients treated with lenvatinib in the COLLECT study. Methods: In COLLECT, a prospective observational study, patients with RR-DTC were treated with lenvatinib in a real-world clinical setting. Lenvatinib was administered orally at a dose of 24 mg daily. Dose modification for toxicities was permitted. Furthermore, planned drug holidays were allowed to avoid severe or intolerable toxicities. The present post hoc analysis focused on evaluating the impact of planned drug holidays on clinical outcomes, including overall survival (OS), time to treatment failure (TTF), time to failure strategy (TFS), and progression-free survival (PFS), in patients in the COLLECT study who were treated with lenvatinib. Results: In total, 262 patients were included. Of the 253 patients evaluable for efficacy, 73 undertook a planned drug holiday at the discretion of the attending physician. OS, TTF, TFS, and PFS were significantly longer in patients who used a planned drug holiday than in those who did not. The planned drug holiday group demonstrated notable clinical outcomes, with a 1-year OS of 95.8% and a 1-year PFS of 94.5%. Moreover, planned drug holidays demonstrated a clinically meaningful advantage in clinical outcomes. The planned drug holiday group had a significantly longer duration of administration at a dose of ≥10 mg. Conclusions: Planned drug holidays for lenvatinib were associated with significantly improved clinical outcomes compared to daily oral administration. Further investigation of the optimal treatment schedule for lenvatinib is warranted. Clinical Trial Registration: UMIN000022243.

E020 Osteoporosis service improvement audit

Abstract Background/Aims Osteoporosis referrals are sent to rheumatology departments for consideration of parenteral treatments in those who are unable to tolerate oral bisphosphonates or have failed treatment. The rheumatology services at Croydon University Hospital (CUH) are oversubscribed which results in long waiting times for appointments and increased workload on clinicians. The aim of this audit is to identify the scope of osteoporosis workload, the source of referrals, to improve distribution of the osteoporosis workload in CUH and redesign the pathway for osteoporosis referrals. A secondary aim is to identify patients that could be managed without referral enabling more consultation slots within the rheumatology department for patients that present with early inflammatory arthritis. Methods Data was collected retrospectively from all the patients that had been referred to the rheumatology department, either internally or externally and offered a new osteoporosis appointment from June to mid-September 2022 (104 patients in total). A data collection sheet was created from electronic patient records. The data included the patients’ hospital number, age, sex, height, weight, BMI, race, source of referral, reason for referral, fractures sustained, admissions for fracture, prior treatment with IV/ oral bisphosphonates, which oral bisphosphonate treatment and reasons for stopping, co-prescription of calcium/ vitamin D and the follow up plan. Results Among patients who were surveyed, 33 were internal referrals. Referring departments were as follows: 18 from fracture liaison service (FLS), 7 from care of the elderly (COTE), 3 from orthopaedics, 1 from rheumatology, 1 from nephrology, 1 from endocrinology, 1 from haematology and 1 from respiratory. In the GP cohort (71 patients), many were intolerant to oral bisphosphonates due to gastrointestinal upset. Reasons for referral were as follows: 36 for intolerance to oral medication, 14 for declining BMD, 11 for restarting medication after drug holding, 9 for complexity of cases (including young age/ male/ anorexia/ osteogenesis imperfecta), 8 unspecified, 7 had sustained a fracture on treatment, 6 received breast cancer treatment, 6 had renal impairment, 6 for a second opinion and 1 for considering a drug holiday. Conclusion This audit highlights the issues associated with osteoporosis workload and suggests improvements for managing the referrals both internally and externally. GP education is important for managing patients not tolerating oral bisphosphonates before accepting referrals. We have started recommending GP to try alternative oral bisphosphonates or effervescent alendronic acid prior to referral. Some internal workload can be managed by the referring team with advice being provided by the rheumatology team in order to reallocate rheumatology appointments for other conditions. The rheumatology department at Croydon University Hospital met with stakeholders from COTE and FLS and discussed the audit results. The COTE team agreed to initiate and continue IV zoledronate to reduce the osteoporosis burden on the rheumatology department. Disclosure S. Taheri: None. R. Suresh: None. J. Burton: None. S. Adil: None. T. Ahmed: None. N. Horwood: None. R. Sathananthan: None.

Review of recommendations for bisphosphonate treatment interruption-discontinuation

Bisphosphonates are the main medications in the treatment of osteoporosis, which are effective in reducing the risk of fractures in patients with osteoporosis. It is known that after treatment with bisphosphonates, bone mineral density remains quite stable for a certain time, as well as markers of bone metabolism remain reduced, which, along with the side effects of long-term bisphosphonate therapy, determines the possibility of “Drug holidays”. At the same time, during a break in bisphosphonate treatment, the risk of fractures begins to increase, which is a reason to resume therapy.Currently, there is no uniform worldwide data of starting a “drug holidays” on bisphosphonates. The duration of the “drug holidays” also differs in clinical recommendations from different countries. When to conduct a risk assessment of fractures during a “drug holidays”? To answer these questions, we assessed existing clinical recommendations for treatment interruption/discontinuation of bisphosphonates. A literature search was conducted using the following resources: PubMed®, the Cochrane Library, websites of major international osteoporosis associations, and other targeted Internet searches. The main search terms were “Clinical Guideline of Osteoporosis”, “Bisphosphonates”, “Drug holidays in osteoporosis”, “Discontinuation of bisphosphonates”. Тhe search was carried out using articles in Russian and English published between January 1, 2016 and September 15, 2023. 17 clinical guidelines from different countries (Russian, American, European, Asian and Australian) were found and analyzed in which was information about the break in the treatment and withdrawal of bisphosphonates.The majority of clinical recommendations have the same opinion on the issue of starting “drug holidays”: with a moderate risk of fractures, you can take a break from treatment with tableted bisphosphonates after 5 years, after zoledronic acid — after 3 years of therapy. At high and very high risk of fractures, the duration of treatment is 10 and 6 years, respectively. The duration of “drug holidays” vary in the recommendations, but in most cases the decision-making is based not on the duration, but on the assessment of the risk of fractures with their regular reassessment, which includes previous and new low-energy fractures, the emergence of new risk factors, a decrease in BMD, the dynamics of bone markers, re-evalua­tion of FRAX®.