Reasons For Treatment Discontinuation Research Articles

1252. A Real-World Observational Study on HIV-Infected Patients who Switched from Nevirapine + 2 Nucleoside Reverse Transcriptase Inhibitors to Dolutegravir/Lamivudine in British Columbia, Canada

Abstract Background Although convenient single-tablet antiretroviral regimens have been developed to treat HIV in recent years, some patients have continued to take a multi-tablet treatment, nevirapine extended-release (NVP XR) plus two nucleoside reverse transcriptase inhibitors (NRTIs) due to its excellent safety profile. This observational study examined the demographic and clinical characteristics of HIV-positive patients who switched to dolutegravir plus lamivudine (DTG/3TC) from NVP XR plus 2 NRTIs, following discontinuation of NVP XR from the Canadian market. Methods Virally suppressed (< 50 cps/mL) HIV-positive adults ≥18 years who switched from NVP XR plus 2 NRTIs to DTG/3TC between 20 August 2019 and 30 April 2020 were retrospectively identified from Electronic Medical Records housed at Spectrum Health in British Columbia, Canada. Baseline demographic and clinical characteristics were summarized using descriptive statistics at the date of first DTC/3TC prescription. Virologic control, CD4 cell count, weight-related changes and exploratory characteristics related to metabolic syndrome were summarized at baseline and at 12 ± 6-months post-switch using descriptive statistics. Reasons for treatment discontinuation were also captured. Results Sixty-nine patients were identified (mean age ± SD = 54.2 ± 8.5 years; 100% male). Mean length of use (±SD) of NVP XR was 4.6 ± 2.6 years. Sixty-three (91.3%) persisted on DTG/3TC at the 12-month timepoint post-switch with 61 (96.8%) virally suppressed < 50 cps/mL and all 63 (100%) virally suppressed < 200 cps/mL. Among persistent patients with CD4 cell counts available, mean CD4 cell count (±SD) remained stable, increasing slightly from 724.4 ± 238.4 to 740.3 ± 240.6 cells/uL. All six (8.7%) patients who discontinued DTG/3TC, discontinued due to tolerability and not effectiveness reasons. Conclusion Our findings are the first to examine real-world use of single-tablet, 2-drug DTC/3TC among patients who switched from multi-tablet, 3-drug NVP XR plus 2 NRTIs in Canada. The majority persisted on DTG/3TC and remained virally suppressed at the < 50 cps/mL level 12-months post-switch. This, coupled with excellent tolerability, demonstrates the effectiveness of DTG/3TC in maintaining viral suppression among a unique and stable group of older men. Disclosures Joss de Wet, MBChB CCFP FCFP, Gilead: Advisor/Consultant|Gilead: Board Member|Gilead: Grant/Research Support|ViiV: Advisor/Consultant|ViiV: Board Member|ViiV: Grant/Research Support Joann K. Ban, PharmD, MSc, GlaxoSmithKline Canada Inc.: Employee Gustavo Verdier, BSc, BPharm, MBA, GlaxoSmithKline: Stocks/Bonds|ViiV Healthcare ULC: Salary Juejing Ling, MSc, GSK: Employee of IQVIA , a company that receives consulting fees from GSK. Andrean Bunko, MPH, GlaxoSmithKline Inc.: GSK contracted with IQVIA for this and other projects. I am acting as an author in capacity of my employment with IQVIA. Michael McKimm, BSc, ViiV Healthcare: employee.

Factors associated with pharmacological and psychotherapy treatments adherence in patients with borderline personality disorder.

Borderline personality disorder is a major mental illness characterized by sustained relationship instability, impulsive behavior, and intense affects. Adherence is a complex behavior, from minor refusals to abandonment of treatment, which can be affected by various factors. Therefore, the present study aimed to investigate the factors affecting pharmacological and psychotherapy adherence, patients' attitude toward medication, and assessing medication and treatment adherence in patients with borderline personality disorder referred to an outpatient referral clinic in Tehran, Iran. The study was a cross-sectional study. The files of patients with borderline personality disorder referred to the outpatient clinic of the Tehran Psychiatric Institute were reviewed as the first step. Data were collected using the Drug Attitude Inventory-10 (DAI-10) questionnaire and a questionnaire to determine the attitude of patients toward pharmacological and psychotherapy treatment as well as therapeutic adherence. After collecting data, patients' therapeutic adherence was divided into poor, partial, and good compliance. Ninety-four patients were involved in the study, and fifty-four were women. Findings of DAI showed that 54 (57.4%) participants had negative attitudes toward medication, while 38 (40.4%) participants showed a negative attitude toward psychotherapy treatment. Additionally, the percentage of patients with good psychotherapy adherence (44.7%) was higher than that of patients with good medication adherence (31.9%). The most common reasons for discontinuation of treatment were medication side effects (53.1%), dissatisfaction with the therapist (40.3%), and then fear of medication dependence (40%). Patients with higher education levels and a positive history of hospitalization in a psychiatric ward had better adherence to psychotherapy (P < 0.05). Results of the current study show that attitude toward psychotherapy is more favorable than pharmacotherapy among patients with BPD. The rationale may be that medications are mainly prescribed for comorbid conditions and do not have substantial effects on the BPD symptoms, resulting in low medication adherence.

First-Line Gemcitabine, Nab-Paclitaxel, and Oxaliplatin Chemotherapy With Itraconazole in Patients With Metastatic Pancreatic Cancer: A Single Institution Experience.

Combination chemotherapy with gemcitabine, nab-paclitaxel, oxaliplatin, and itraconazole (GnPO-ITC) was administered as first-line chemotherapy in patients with metastatic pancreatic cancer (mPC). The efficacy and toxicity of these treatments were retrospectively investigated. A total of 81 patients (mean age=64 years) with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 were enrolled in the study, and administered nab-paclitaxel (125 mg/m2), gemcitabine (1,000 mg/m2), and oxaliplatin (85 mg/m2) on day 1 and itraconazole (400 mg) on days -2 to +2, repeated every 2 weeks. Metastatic sites observed in patients included the liver (n=55, 68%), peritoneum (n=23, 28%), distant lymph nodes (n=24, 30%), and lungs (n=18, 22%). Within 28 days after initiation of chemotherapy, 15 patients (19%) experienced common ≥3 grade hematological adverse events. The major reason for discontinuation of treatment among the responders was peripheral sensory neuropathy in 36 patients (44%). The overall response rate to treatment was 64% [95% confidence interval (CI)=54-75%]. The median progression-free survival and median overall survival were 8.3 months (95% CI=6.8-9.8 months) and 14.4 months (95% CI=11.4-17.3 months), respectively. Among the 52 responders, 24 (46%) underwent conversion surgery, which did not improve survival (p=0.279). Second-line treatment with irinotecan was required in 71 (88%) patients. Hepatic arterial chemotherapy and radiotherapy were administered to 33 (41%) and 27 (33%) patients, respectively. The GnPO-ITC regimen showed promising efficacy with manageable toxicities for controlling disease progression and improving overall survival.

Attrition and Withdrawal Amongst Patients with Multiple Myeloma Participating in Randomized Clinical Trials: A Systematic Review

Introduction: In clinical trials, and in the real-world, patients with multiple myeloma (MM) discontinue treatment for a variety of reasons including death, disease progression, and toxicity of treatments. Patients may also discontinue trial treatment due to the other reasons such as a physician withdrawing the patient from the trial, or patient deciding to withdraw. The proportion of patients discontinuing treatment for each of these reasons has not previously been reported for MM randomized controlled trials (RCTs). Furthermore, a large number of patients withdrawing from one arm of a trial may raise concern for informative censoring and biased data. To date, there is no prior study evaluating MM RCTs analyzing trial discontinuation and attrition. Due to this, we aimed to assess reasons for discontinuing treatment amongst participants in trials, imbalances in attrition between trial arms, and the practice of reporting this data through a systematic review of all MM RCTs published between 2015-2020. Methods: Three databases were searched (MEDLINE/PubMed, Embase, and Cochrane Registry of Controlled Trials) for all RCTs in MM from 2015 to 2020. Studies reported as abstracts (without full manuscript available for review), or those that assessed purely supportive care strategies were excluded. We collected documentation of patient discontinuation and reasons for discontinuation in intervention arms, control arms, and in total. As discontinuation due to progression, toxicity and death is expected, we aimed to quantify and assess for rates of discontinuation due to other reasons beside these, such as patient withdrawal or physician decision to withdraw patient. Trials in which the absolute difference in discontinuation rate for these "other” reasons was greater than 5% between the intervention and control arms were thus determined to be outliers. Trials were also assessed for concordance to recommendations outlined by CONSORT guidelines for RCTs. Results: A total 47 RCTs were analyzed that met our inclusion criteria. Table 1 lists characteristics of included studies. Primary endpoint was progression free survival in 33 (70.2%) of these studies and overall survival in 4 (8.5%) studies. In these RCTs, a total of 21,985 patients were randomized to treatment. A total of 10,572 (48.1%) patients had discontinued the RCT by time of primary endpoint ascertainment. The causes of discontinuation in decreasing order of frequency included disease progression (n=4,893; average rate per study (ARPS)=26.4%); toxicity (n=2,691; ARPS=11.7%); patient or physician withdrawal in absence of toxicity/progression/death (n=1,136; ARPS=7.3%) and death (n=527; ARPS=2.6%). A total of 21,540 (98.4%) patients were included in primary endpoint analyses with 45 of 47 trials citing the use of intention to treat analysis. In regard to withdrawal due to reasons other than toxicity, progression or death, a total of 13 (27.7%) of the RCTs were outliers as defined in methods. Amongst these 13 RCTs, attrition was higher in control arm in 10 trials, and higher in intervention arm in 3 trials. Outliers were more commonly found in trials that met their primary endpoint compared to those that did not (10 vs 3 trials, respectively). In the 10 trials meeting their primary endpoint, attrition rate was higher in 8 trials in control arm, and 2 in intervention arm. Although a minority [19 (40.4%)] of trials followed the full recommended guidelines for RCT reporting, the majority 45 (95.7%) of the trials included a CONSORT diagram. Conclusion: Our analysis demonstrates that although disease progression is the most common reason for discontinuation of treatment in patients with MM on RCT's, over 10% of patients discontinue treatment due to toxicity prior to disease progression or death. Furthermore, 27.7% of trials showed substantial imbalances between the control and intervention arms in the number of patients withdrawn for reasons other than progression, toxicity, or death. This raises concern for informative censoring and bias in results and emphasizes the importance of detailed characterization of reasons for withdrawal in MM RCTs. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Treatment of Immune Thrombocytopenia (ITP) with Eltrombopag - Results of the 5th Interim Analysis of the Study RISA, with Special Consideration of Treatment Discontinuations

Background: Immune thrombocytopenia (ITP) is an autoimmune disease characterized by isolated thrombocytopenia due to increased platelet clearance and decreased megakaryopoiesis. Eltrombopag (EPAG) is an oral thrombopoietin-receptor agonist, which is proved to be effective and safe in the treatment of ITP. Here we present data from the 5th interim analysis of the RISA study, specially considering the reasons for treatment discontinuation and possible links to the safety profile of EPAG. Methods: RISA is a prospective multicenter non-interventional study in Germany. It started in December 2015, and it will continue until December 2023. Statistical analysis is solely descriptive. Results: Data cutoff for this 5th interim analysis was 11th Feb 2022. 313 patients with persistent or chronic primary ITP (pITP) were enrolled. 302 of them received at least one dose of EPAG and completed at least one post baseline visit. Mean duration of participation was 74.1 months. Mean±SD age was 62.8±17.4 years. 54.8% of the patients were female. Mean±SD duration of ITP at baseline was 5.4±7.5 years. Comorbidity was present in 245 (81.1%) patients. Mean±SD number of concomitant diseases was 2.9±3.0. 99 (32.8%) patients completed the entire treatment period of 24 months, which includes all scheduled visits before data cutoff. Median treatment duration was 14 months (minimum 1 day, maximum 6.1 years). Treatment with EPAG was carried out at a median dosage of 50 mg daily. Median platelet counts increased from baseline 34.0x109/L (N=292) to 91.5x109/L (N=262) within one month. From then and until the end of the two-year observation period, platelet counts remained stable above 90x109/L. The proportion of patients whose platelet count was at least 50x109/L increased from 30.1% at baseline to 74.4% after one month and to 85.6% after twelve months. The number of bleeding events per patient-year decreased, from 1.35 at baseline to 0.59 and 0.16 after one and two years, respectively. 128 (42%) patients discontinued treatment, 51 (40%) of them before day 92. Reasons for discontinuation (multiple answers possible) were insufficient effectiveness in 55 (43%) cases, adverse events (AE) in 36 (28%) cases, death in 20 (16%) cases, non-compliance in 16 (13%) cases, lost to follow up in 10 (8%) cases, cessation of therapy due to complete response in 15 (12%) cases and other reasons in 10 (8%) cases. Across the data set, most frequent AE classified as non-serious adverse drug reactions (nsADR) were fatigue (5.3%), thrombocytopenia (3.3%), thrombocytosis (2.3%), diarrhea (3.0%) and dizziness (2.0%). The most common AE leading to discontinuation of treatment and classified as nsADR were thrombocytosis (1.3%), diarrhea (1.7%), fatigue (1.0%) and arthralgia (1.0%). The most frequent serious AE that led to treatment discontinuation and was rated as serious adverse drug reaction was pulmonary embolism, which occurred in 2 (0.7%) patients. Comorbidity was present in 109 (85.2%) of all patients who discontinued treatment. In this subgroup, the mean±SD number of concomitant diseases was 3.4±3.3. Conclusions: We were able to confirm that EPAG therapy in ITP effectively increases platelet counts and reduces the risk of bleeding. For methodological reasons, we were unable to calculate the actual overall response rate. However, based on the proportion of total patients who were shown to discontinue treatment due to insufficient effectiveness (18%), one could assume that all other patients responded to EPAG at least temporarily. This would result in an overall response rate of 82%. This seems to be consistent with the results of the open extension study EXTEND [Wong RSM et al. Blood 2017; 130: 2527-36], in which a similarly high overall response rate (86%) was found. In general, treatment with EPAG was well tolerated, with no new safety signals from our data set. In view of the high discontinuation rate, it should be borne in mind that about one in eight (12%) of these patients responded so well to EPAG therapy that this was taken as an opportunity for a discontinuation attempt. Other factors that may have contributed to treatment discontinuation included age and comorbidity of patients. Notably, the percentage and number of comorbidities in the discontinuation subgroup were even higher than in the overall study population. However, since this is a non-interventional observational study, results are descriptive and need to be interpreted with caution.

Multicentre study on rates and reasons for treatment discontinuation in patients with remaining cryopreserved embryos

Research questionWhat is the discontinuation rate among patients with remaining cryopreserved embryos in Belgium and what are the reasons for discontinuation? DesignMulticentre, cross-sectional study across 11 Belgian fertility clinics. Patients were eligible (n = 1917) if they had previously undergone an unsuccessful fresh embryo transfer (fresh group) or frozen embryo transfer (FET) (in-between group) and did not start a subsequent FET cycle within 1 year despite having remaining cryopreserved embryos. The denominator was all patients with embryos cryopreserved during the same period (2012–2017) (n = 21,329). Data were collected through an online anonymous questionnaire. ResultsThe discontinuation rate for patients with remaining cryopreserved embryos was 9% (1917/21329). For the final analysis, 304 completed questionnaires were included. The most important reasons for discontinuing FET cycles were psychological (50%) and physical (43%) burden, effect on work (29%), woman's age (25%) and effect on the relationship (25%). In 69% of cases, the patient themselves made the decision to delay FET treatment. In 16% of respondents, the decision to delay FET was determined by external factors: treating physician (9%), social environment (4%), close family (3%) and society (3%). Suggested improvements were psychological support before (41%), during (51%) and after (51%) treatment, as well as lifestyle counselling (44%) and receiving digital information (43%). ConclusionsThe discontinuation rate is remarkably high in patients with remaining cryopreserved embryos who have a good prognosis. Respondents stressed the need to improve the integration of psychological and patient-tailored care into daily assisted reproductive technology practice.

CML-344 Adherence to Imatinib Mesylate in Patients Newly Diagnosed With Chronic Myeloid Leukemia in India Over the First Year of Treatment and How to Improve Compliance

Chronic myeloid leukemia (CML) is treated with the first-line agent imatinib; however, it was seen that adherence to treatment had been poor in many patients. Therefore, a study was carried out to find causative reasons for the discontinuation of treatment, with the ultimate goal to improve rates of compliance. The aim of the study was to identify reasons for adherence failure in patients treated with imatinib for CML and to detect a way to improve adherence. A prospective review of 160 patients with newly diagnosed Philadelphia chromosome-positive CML was undertaken to check for rates of adherence to treatment with imatinib. The patients were equally distributed with 77 men and 83 women and had an average age of 40 years. Due to imatinib being the only option for most patients in India for CML, those who discontinued it were reinforced about the importance of being compliant with treatment. The rates of patients who restarted imatinib after reinforcement were recorded. It was found that out of 160 patients over the initial year of treatment, 87 patients (54.3%) continued to take imatinib and 73 patients (45.6%) discontinued treatment. The most common reasons for discontinuation of treatment were due to adverse drug events such as headaches, weight gain, musculoskeletal symptoms, and GI disturbances. Of the 73 patients, 60 (82.3%) stopped taking imatinib due to adverse drug events, 10 (13.6%) patients were lost to follow-up, and 3 (4.1%) patients wanted to pursue holistic methods of treatment. The 60 patients who stopped taking imatinib due to adverse drug events were counseled on the benefits of pursuing treatment despite some adverse effects. Out of the 60 patients who stopped imatinib due to adverse effects after counseling, 43 (71.6%) patients restarted imatinib. The patients' adherence to imatinib in our study was found to be 46%, with the majority of patients discontinuing treatment due to adverse effects. However, after counseling patients on the overall benefits of taking imatinib, compliance improved. The authors believe that compliance can be improved by taking the time to educate patients on the benefits of treatment with reinforcement.

MM-233 Evaluation of the Comparative Effectiveness of In-Class Transition (iCT) to All-Oral Ixazomib-Lenalidomide-Dexamethasone (IRd) After Bortezomib (V)-Based Induction Therapy vs Patients Who Continued to Receive Parenteral V-Based Therapy in Newly Diagnosed Multiple Myeloma (NDMM)

Increasing the duration of proteasome inhibitor-based treatment could improve outcomes in NDMM patients. To evaluate the comparative effectiveness of in-class transition (iCT) to IRd following V-based induction vs continued V-based therapy. A secondary analysis of patients from US MM-6, (NCT03173092; Manda CLML 2020; phase IV, single-arm study) which is evaluating iCT from parenteral V to all-oral IRd ('IRd' cohort), and a comparator ('V-based') cohort of patients from INSIGHT MM (Costello Future Onc 2019; prospective, observational study) who continued to receive V-based therapy. Routine community clinical practice in the US. Non-transplant-eligible NDMM patients with ≥stable disease after 3 cycles of V-based induction and Eastern Cooperative Oncology Group performance status (ECOG PS) ≤2 from US MM-6 (IRd cohort, n=100) and INSIGHT MM (V-based cohort, n=111). First-line duration of treatment (DOT), overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and reasons for treatment discontinuation. Kaplan-Meier methodology was used for time-to-event outcomes. To reduce imbalances between cohorts, inverse probability of treatment weighting (IPTW) was used. Results are presented as IRd vs V-based cohorts. After IPTW, median age was 75.0 vs 74.8 years; 56.7 vs 51.3% of patients were male, 37.4 vs 29.1% had ECOG PS of 2, and 48.8 vs 41.4% were International Staging System stage III at diagnosis. Initial induction therapy was VRd/V-cyclophosphamide (C)-d/VRCd in 79.5/17.7/2.8 vs 77.3/19.5/3.1% of patients. ORRs were 73.2 (95% confidence interval [CI]: 65.0-81.3) vs 57.5% (95% CI: 47.9-67.1; p<0.0001). Median DOT was 10.8 (95% CI: 6.5-24.4) vs 5.3 months (95% CI: 4.3-7.0; p<0.0001; median follow-up, 20.3 vs 15.8 months). Median PFS and OS were not estimable in either cohort. 24-month PFS rates were 85.7 (95% CI: 68.1-94.0) vs 76.5% (95% CI: 62.6-85.8). 24-month OS rates were 94.0 (95% CI: 77.7-98.5) vs 84.9% (95% CI: 70.6-92.6). Overall, 17.6% discontinued IRd and 24.4% discontinued V due to an adverse event. In NDMM patients treated at US community oncology clinics, those who transitioned to IRd following 3 cycles of V-based induction had significantly higher ORR and longer DOT than those who continued to receive V-based therapy.

Treatment for hyperuricemia and gout in Japan: Aspect of prescription and duration.

Treatment for hyperuricemia and gout in Japan: Aspect of prescription and duration.

P947: COMPARATIVE EFFECTIVENESS OF ORAL IXAZOMIB-LENALIDOMIDE-DEXAMETHASONE (IRD) AFTER INITIAL BORTEZOMIB (V)-BASED INDUCTION VS PARENTERAL V-BASED THERAPY IN NEWLY DIAGNOSED MULTIPLE MYELOMA (NDMM)

Background: Long-term proteasome inhibitor (PI)-based treatment can improve outcomes for patients (pts) with multiple myeloma (MM). However, prolonged parenteral PI therapy (e.g. with V) can be challenging to achieve in routine clinical practice, and outcomes for pts are often poorer in this setting compared with clinical trials. The phase IV, community-based, single-arm US MM-6 study (NCT03173092) is assessing in-class transition (iCT) from V-based induction to all-oral IRd in transplant ineligible NDMM pts treated in routine clinical practice, with the objective of increasing the duration of PI-based treatment while maintaining quality of life. INSIGHT MM is the largest global, prospective, observational study of MM pts (>4,200), and provided a subset of patients as the comparator cohort. This enabled assessment of iCT vs V-based therapy in NDMM pts in routine clinical practice in the US. Aims: To examine the comparative effectiveness of IRd following initial V-based induction (3 cycles; US MM-6 pts; ‘IRd’ cohort) vs continued V-based therapy (INSIGHT MM pts; ‘V-based’ cohort) in NDMM pts. Methods: A secondary analysis of non-transplant eligible US NDMM pts with ≥stable disease after 3 cycles of V-based induction and baseline Eastern Cooperative Oncology Group performance status (ECOG PS) of 0, 1 or 2 from the US MM-6 (Manda CLML 2020) and INSIGHT MM (Costello Future Onc 2019) studies was performed. Study outcomes included first-line duration of treatment (DOT), overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and reasons for treatment discontinuation. All analyses were weighted using the inverse probability of treatment weighting (IPTW) approach to reduce the imbalance of potential confounding factors between the two cohorts (adjusted analyses). Kaplan–Meier methods were used to examine DOT, PFS, OS, and associated 95% confidence intervals (CIs); the log-rank test was used to compare distribution of time to events. The Clopper-Pearson method was applied to estimate 95% CIs for ORR. Statistical significance was evaluated at alpha=0.05. Results: 100 pts from the IRd cohort (MM-6) and 111 pts from the V-based cohort (INSIGHT) were included. After IPTW, in the IRd vs V-based cohorts: median age was 75.0 vs 74.8 yrs; 56.7 vs 51.3% of pts were male; 37.4 vs 29.1% had an ECOG PS of ≥2; 48.8 vs 41.4% had International Staging System stage III at initial diagnosis, and 79.5/17.7/2.8 vs 77.3/19.5/3.1% pts had received VRd/ V-cyclophosphamide-d (VCd)/ VRCd as initial induction therapy. Adjusted ORRs in the IRd vs V-based cohorts were 74.1 (95% CI 66.0–82.2) vs 57.5% (95% CI 47.9–67.1; p<0.0001). After a median follow-up of 20.3 and 15.8 months in the IRd and V-based cohorts, respectively, DOT was 10.8 (95% CI 6.5–24.4) vs 5.3 months (95% CI 4.3–7.0; p<0.0001) (see Figure). Median PFS was not estimable (NE) in either cohort; 24-month PFS rates were 85.7 (95% CI 68.1–94.0; IRd cohort) vs 76.5% (95% CI 62.6–85.8; V-based cohort). Median OS was NE in either cohort; 24-month OS rates were 94.0 (95% CI 77.7–98.5; IRd cohort) vs 84.9% (95% CI 70.6–92.6; V-based cohort). In the IRd and V-based cohorts, 16.8 and 16.9% of pts discontinued IRd and V, respectively, due to an adverse event. Image:Summary/Conclusion: US MM-6 NDMM pts who transitioned to IRd after 3 initial cycles of V-based induction had a significantly higher ORR and longer DOT compared with pts who received continued V-based therapy in INSIGHT MM. The results suggest that iCT from continued V-based therapy to all-oral IRd may improve outcomes in pts treated at community oncology clinics.

P706: ASCIMINIB USE IN CML: THE UK EXPERIENCE

Background: Asciminb is an allosteric BCR-ABL1 inhibitor that has been available for patients with chronic myeloid leukaemia (CML) in the United Kingdom under a managed access program (MAP) from Novartis since 2016. Aims: The aim of this project was to share real-world experience of asciminib use in the UK. Methods: Using a national survey proforma (REC reference: 21/HRA/2157), we collated baseline, outcome and toxicity data on 44 patients treated with asciminib in the UK. Responses were assess using BCR-ABL1 IS values and categorised by ELN criteria. Intolerances were reported using CTCAEv5.0 criteria. Results: The median age at treatment was 58 [22-88] years. Vascular comorbidities were seen in 22 (50%) patients, the most frequent being hypertension (n=12, 27%), peripheral vascular disease (n=6, 14%), AF (n=6, 14%) and ischaemic heart disease (n=6, 14%). Chronic kidney disease was present in 7 (16%) patients. All but one patient was in chronic phase at the time of treatment, but tyrosine kinase domain mutations (TKDM) were common prior to treatment initiation (T315I in 11/44 (25%), other TKDM in 8/44 (18%)). The median number of prior TKIs were 4 [2-5], with 44% of prior lines stopped for resistance, and 56% for intolerance. The most recent TKI was discontinued for resistance in 14 (32%) and intolerance in 30 (68%). Eight (18%) patients had developed pleural effusions on a previous TKIs. Most patients had previously received ponatinib (n=30, 68%) which has been discontinued for resistance in 8 (27%) and intolerance in 22 (73%), with 7 (16%) vascular events on treatment. Five (11%) patients had received prior allogeneic stem cell transplant. At the time of data cut-off, 25 (57%) patients remained on treatment with a median treatment duration of 20 [3-51] months. Reason for treatment discontinuation was resistance (n=7, 16%), intolerance (n= 7, 16%), pregnancy (n=1, 2%), treatment-free remission (n=1, 2%) and non-compliance (n=1, 2%). Two patients died whilst on treatment of unrelated causes. The median daily dose delivered was 240mg [20-400] in patients with T315I-TKDM and 80mg [20-80] in others. While 11 patients had no significant response (including those with early treatment discontinuation for intolerance), 23 (53%) patients achieved MR3 or better, with 14 (32%) achieving MR4 or better. Of 9 patients in MR3 or better at asciminib initiation, 3 (33%) did not tolerate treatment, 2 (22%) maintained their response, and 4 (44%) deepened their response by one category or more. The presence of a non-T315I TKDM was associated with a lower incidence of achieving MR3, with 1 of 6 (16%) evaluable patients in this group achieving MR3 or better, compared with 22 of 31 (71%) evaluable patients with no TKDM or a T315I-only TKDM (p=0.04) (Table1). Haematological toxicity was seen in 17 (38%) patients, and was grade 3-4 in 6 (14%) (predominantly anaemia and thrombocytopaenia). Non-haematological toxicity was reported in 19 (43%) patients (most commonly fatigue (n=4), insomnia (n=3), bone pain (n=2), back pain (n=2), nausea (n=2), fluid retention (n=2)), with only 2 (4%) patients experiencing grade 3-4 toxicity (fatigue in both cases). No worsening of baseline vascular co-morbidity or renal dysfunction was noted. One patient developed a new pleural effusion on the 200mg bd dose, which did not recur on dose reduction. Image:Summary/Conclusion: These data show that asciminib is a well-tolerated, effective treatment for patients who are resistant to or intolerant of multiple TKIs, many of whom often have a number of co-morbidities including vascular disease.

Abstract 4089: Time to treatment discontinuation and time to next treatment as proxies of real-world progression-free survival in breast cancer patients

Abstract Background: There is no standardized real-world proxy for progression-free survival (PFS), although it is a key treatment response metric in clinical trials. Real-world PFS (rwPFS) has been curated from clinician-documented progression in unstructured electronic health records (EHRs), a time and resource intensive approach, that is not readily accessible in claims or structured EHRs. Alternatively, time to treatment discontinuation (rwTTD) and time to next treatment (rwTTNT) are used as treatment-based scalable proxies of disease progression. We compared clinician-documented rwPFS to rwTTD and rwTTNT. Methods: The study included patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced or metastatic breast cancer (A/MBC) who initiated first line treatment with palbociclib plus an aromatase inhibitor (1L) between 2015 and 2019 in US community health systems. Demographics, clinical characteristics, and outcomes were extracted from EHRs. rwPFS was captured through EHR-documented confirmation by two clinicians of disease progression based on imaging and/or pathology results. rwPFS, rwTTD and rwTTNT were defined as the time from 1L initiation until the date of clinician-confirmed progression, 1L discontinuation, or 2L initiation, respectively. Patients were censored at the first of: (1) death, (2) date of last contact, (3) study end date, (4) or at 2L for rwPFS. Results: The study included 241 patients with median age 66 at A/MBC diagnosis, among whom 85% were postmenopausal and 57% were de novo A/MBC. During study follow-up (median 22.4 months), 86 (36%) patients had a clinician-confirmed progression (rwPFS events); 130 (54%) discontinued 1L (rwTTD events), and 96 (40%) initiated 2L (rwTTNT events). With clinician-confirmed progression as the “gold standard”, rwTTD had higher sensitivity (90% vs 71%) but lower specificity (66% vs 77%) than rwTTNT. Patient’s choice, hospice referral, and toxicity were common reasons for treatment discontinuation apart from disease progression. The 12, 24, and 48-month survival estimates were closer between rwPFS (0.78, 0.64, 0.51) and rwTTNT (0.80, 0.63, 0.47), than rwTTD (0.69, 0.51, 0.37). Median rwPFS (39 months, 95% confidence interval [95% CI]: 30-NA) and rwTTNT (32 months, 95% CI: 29-46) were also more alike (log-rank p = 0.90) than median rwPFS and rwTTD (24 months, 95% CI: 18-30; log-rank p=0.02). The correlation between rwPFS and rwTTNT was 0.72 (95% CI: 0.56-0.83), compared to 0.73 (95% CI: 0.57-0.84) between rwPFS and rwTTD. Results were similar in sensitivity analyses where death was part of rwPFS, rwTTNT, and rwTTD events rather than a censoring event. Conclusions: Our results suggest that rwTTNT may be a more adequate at-scale proxy for rwPFS than rwTTD. Studies should assess the generalizability of these findings to other tumor types and treatment settings. Citation Format: Monika A. Izano, Mahder Teka, Colden Johanson, Jeanna Wallenta Law, Ronda Broome, Daniele Morgan, Amy Stone, Mary Tran, Thomas D. Brown, Chenan Zhang. Time to treatment discontinuation and time to next treatment as proxies of real-world progression-free survival in breast cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4089.

Racial disparities in the clinical use of durvalumab for patients with stage III unresectable non–small cell lung cancer treated at Veterans Health Administration facilities.

8526 Background: Evidence from the PACIFIC study and real-world data highlight the benefit of durvalumab in patients with stage III unresectable non-small cell lung cancer (UR-NSCLC). However, limited literature exists regarding disparities in durvalumab treatment patterns such as treatment initiation delays (TID), treatment interruptions (TI), number of doses, duration of therapy (DOT), adverse effects (AEs), and treatment discontinuation (TD) in minority populations. Methods: Patients with stage III UR-NSCLC and a self-reported racial identity of Black or White treated with durvalumab following chemoradiotherapy (CRT) at any Veterans Health Administration (VHA) facility from January 1, 2017 to June 30, 2020 were included. Patients were followed from their date of durvalumab initiation through the earliest of their last VHA visit, loss to follow up, death, or end of the study; therefore, all patients had the opportunity to be treated for 12 months. Patients were excluded if durvalumab therapy was ongoing at the end of the study. Patient charts were retrospectively reviewed for baseline characteristics and durvalumab treatment patterns including TID (&gt;42 days from end of CRT to durvalumab start), TI (&gt;28 days between doses), number of doses, DOT, AEs, and TD. Nominal variables were compared using chi-square/Fisher’s exact tests. Continuous variables were compared using Student’s t-tests/Wilcoxon Rank Sum tests. Results: Among 924 patients, Black patients were younger than White patients (median age 67 years [IQR, 63-71] vs. 70 years [IQR, 65-73]; p&lt;0.01), more likely to be current smokers (54% vs. 45%; p=0.03), with more chronic liver disease (22% vs. 9%; p&lt;0.01), but less COPD (63% vs. 72%; p=0.01). Black patients experienced more TI (25% vs. 18%; p=0.03) but TID, number of doses, DOT, and TD were similar between the groups. Black patients were less likely to have an immune-related AE (irAE) (28% vs. 36%; p=0.03) (and less pneumonitis (7% vs. 14%; p&lt;0.01)). Toxicity was the reason for TD in 12% of Black patients vs. 20% of White patients (p=0.01), with no other significant (α &lt; 0.05) differences in reported reasons for TID, TI, or TD between the groups. Conclusions: In this real-world study, Black patients experienced similar TID, number of doses, and DOT as White patients. Black patients were less likely to experience an irAE (including pneumonitis) but experienced more TI; TD were similar but more likely to be from toxicity for White patients. Future research is needed to validate these findings.[Table: see text]

Pilot study to evaluate safety and efficacy of cabozantinib in aged fragile patients with metastatic renal cell carcinoma. Preliminary results of CABOMAYOR-SOGUG study.

e16524 Background: Survival of patients with metastatic renal cell carcinoma (mRCC) has improved with targeted therapies, but they are rarely curative and often result in therapeutic resistance. Cabozantinib is an oral, small-molecule tyrosine kinase inhibitor that targets vascular endothelial growth factor receptor (VEGFR) as well as MET and AXL, known to influence tumor growth, metastasis, and angiogenesis. Aged fragile patients are not usually included in clinical trials and efficacy and tolerability of available treatments in this population are unknown. The aim of this trial is to evaluate safety and efficacy of cabozantinib in aged patients with mRCC. Methods: Pilot open-label, multicenter study that includes previously untreated fragile (G8 scale &lt; 14 points and one or two reversible deficiencies in ADL-activities in daily life- or CISR-G grade 2 comorbidities or weight loss of 5-10% during the last 3 months) patients &gt; 70 years old with histological or cytological diagnosis of mRCC, ECOG 0-2 and adequate organ function. Patients received cabozantinib 40 mg p.o. once daily until unacceptable toxicity or other reasons for treatment discontinuation. Dose can be escalated to 60 mg if 40 mg is considered tolerated and can be reduced to 20 mg if 40 mg is considered not tolerated. Results: Twenty patients are included in this interim analysis, 9 of them are still under treatment. Median age was 78 years, 70% were men and 68% had ECOG 0 and metastatic disease at diagnosis. None of them received radiotherapy. 55% of pts were vulnerable according to G8 score, 5% had grade 3 comorbidities according to CIRS-G scale, 20% had a score &lt; 3 in mini-COG test, 100% had score &lt; 10 in Gijon's social-familial evaluation scale, 25% were vulnerable according to Vulnerable Elders Survey 13 (score ≥3) and 45% were frail and at risk of disability according to Short Physical Performance Battery (score &lt; 10). Median duration of treatment was 3.3 months (max. 20.4). In none of the patients was the dose escalated to 60 mg/d and in 7 patients was the dose reduced to 20 mg/d. Of the 12 patients evaluable for response, 2 achieved partial response and 7 stable disease, with a clinical benefit rate of 75%. Most frequent toxicities (all grades) were: asthenia (30%), diarrhea (25%), mucosal inflammation (15%), dysgeusia (15%) and hypothyroidism (15%). Reported grade 3 toxicities were thrombocytopenia, pyrexia and hypertension (5%). Two patients stopped study treatment due to toxicity: perforated ischemic colitis and skin toxicity. Conclusions: Safety profile in aged people is similar of that observed in previous studies. The frequency of toxicities is slightly lower than expected in this aged fragile population, probably because the patients received treatment at a dose of 40 mg/d, lower than the approved dose. Clinical trial information: NCT04134390.

Retrospective, single-center, real-world experience of belantamab mafodotin in relapsed/refractory multiple myeloma.

8060 Background: Belantamab mafodotin (belamaf) is a BCMA antibody drug conjugate approved for the treatment of relapsed refractory multiple myeloma (RRMM) patients (pts) based on the pivotal phase 2 DREAMM-2 study (Lonial et al, Lancet Oncology, 2019), which demonstrated an overall response rate (ORR) of 32%, median progression free survival (PFS) of 2.8 months, and overall survival (OS) of 13.7 months in triple class (proteasome inhibitor, IMiD, and anti-CD38) refractory (TCR) MM. In this single-center retrospective study, we report the efficacy and safety of belamaf in RRMM pts administered in a real-world, standard of care (SOC) setting. Methods: All MM pts who initiated therapy with SOC belamaf, either as monotherapy or in combination, between 11/1/2020 and 11/30/2021 at MD Anderson were included in this study. Response and progression were evaluated using International Myeloma Working Group standard criteria. Keratopathy and best corrected visual acuity (BCVA) adverse events (AEs) were graded per the Keratopathy and Visual Acuity (KVA) scale. The Kaplan-Meier method was used to estimate time to event endpoints. Results: A total of 39 consecutive pts with a median of 7 prior lines of therapy were included in the analysis, of whom 37 pts (95%) received single agent belamaf. Median age was 66 years (range 39-89), 14 of 37 (38%) pts with available FISH had high risk disease (del 17p, t(4;14, and/or t(14;16)), 14 pts (36%) had extramedullary disease, 37 (95%) pts were TCR, 32 (82%) pts were TCR and alkylator-refractory, and 8 pts (21%) were BCMA-refractory. Notably, the majority (69%) of pts in this analysis would have been ineligible for the DREAMM-2 trial based on key eligibility criteria. Median number of belamaf doses administered was 2 (range 1-9). Among 37 pts with measurable, response evaluable baseline disease, the best ORR (≥ PR) was 27% with ≥ VGPR of 3%. The clinical benefit rate (≥ MR) was 35%. Among 8 BCMA-refractory pts, there was 1 PR and 1 MR. Median PFS was 1.8 months and median OS was 9.2 months with a median follow-up of 10.1 months. Median duration of response has not been reached among 10 responding pts. Among 33 pts with a post-treatment ocular exam, 25 pts (76%) developed any grade keratopathy (Grade 1/2/3/4, 9%/55%/12%/0%, respectively) and BCVA changes (Grade 1/2/3/4, 42%/27%/6%/0%, respectively). Median time to first keratopathy or BCVA AE was 1.3 months. The most common reasons for treatment discontinuation were disease progression (75%) and AEs (9%). Conclusions: Our current study in heavily pretreated RRMM pts, of whom the majority would have been ineligible for the DREAMM-2 study, demonstrates an ORR, PFS, and ocular AE profile with SOC belamaf therapy comparable to outcomes reported in the pivotal registration study. Future studies are needed to further define the optimal use and sequencing of belamaf in MM pts, particularly in context of other BCMA-targeting modalities.

Survival analysis of the randomized phase II trial to investigate androgen signaling inhibitors with or without androgen deprivation therapy (ADT) for castration-sensitive prostate cancer: LACOG 0415.

5076 Background: LACOG 0415 is a phase II, open-label, clinical trial evaluating ADT-free alternatives for advanced castration sensitive prostate cancer (CSPC). Methods: Patients with locally advanced, high-risk biochemical recurrence or metastatic CSPC were randomized (1:1:1) to receive ADT with abiraterone acetate plus prednisone (ADT+AAP), apalutamide alone (APA), or apalutamide with AAP (APA+AAP). The primary endpoint of the trial was the proportion of patients who achieved PSA≤0.2 ng/mL level at week 25. Patients without disease-progression and with clinical benefit after week 25 were allowed to maintain treatment at the discretion of physicians. Herein, we presented the outcomes of 2 year-overall survival (2y-OS) and time-to-treatment failure (TTF). The time-to-event endpoint was estimated by Kaplan-Meier method and compared by stratified log-rank test. Results: 128 patients were randomized to the ADT+AAP (n = 42), APA (n = 42), and APA+AAP (n = 44) arms. At week 25, PSA≤0.2 ng/mL was observed in 75.6% (95%CI 59.7%-87.6%), 60.0% (95%CI 43.3%-75.1%), and 79.5% (95%CI 63.5%-90.7%) of patients in the ADT+AAP, APA, and APA+AAP arms, respectively. 110 patients continued treatment after week 25. At the 2-year visit, 80 (62.5%) patients remained on the study medication. Median TTF was 24.0 months (95%CI 23.3 - 24.0) with ADT+AAP, 24.0 months (95%CI not estimated) with APA, and 24.0 months (95%CI 13.0-24.0) with APA+AAP. The main reasons for treatment discontinuation were disease progression (n = 8, 6.3%), toxicity (n = 10, 7.8%), death (n = 6, 4.7%), withdrawal (n = 4, 3.1%), and other (n = 19, 14.8%). The estimated proportion of patients who were alive at 2 years (2y-OS rate) was 92.5% (95%CI 84.3-100) with ADT+AAP, 87.9% (95%CI 77.9-97.8) with APA, and 92.7% (95%CI 84.8-100) with APA+AAP (p = 0.5926). 2y-OS was 92.9% (95% CI 85.3 - 96.2) in patients with PSA ≤ 0.2 ng/mL at week 25, while 2y-OS was 85.0% (95% CI 72.9-97.1) in patients with PSA &gt; 0.2 ng/mL at week 25 (p = 0.1250). Conclusions: Patients with advanced CSPC treated with ADT+AAP, APA, or APA+AAP had high rates of PSA response and favorable 2y-OS. PSA ≤ 0.2 ng/mL at week 25 seems to be a surrogate prognostic predictor of OS in advanced CSPC. In the overall sample, patients with PSA ≤ 0.2 ng/mL at week 25 had higher 2y-OS rate than those with PSA &gt; 0.2 ng/mL at week 25 (92.9% vs. 85.0%), however without statistical significance. Clinical trial information: NCT02867020.

Trabectedin in advanced retroperitoneal well differentiated/dedifferentiated liposarcoma and leiomyosarcoma (TRAVELL): Results of a phase 2 study from Italian sarcoma group (ISG).

11575 Background: To further explore the activity of T as second/further line treatment in retroperitoneal leiomyosarcoma (LMS) and well differentiated/dedifferentiated liposarcoma (LPS). The primary endpoint of the study was the growth modulation rate (GMR) defined as the ratio between the time to progression under T (TTP) and during previous chemotherapy treatment (TTP-1). The secondary end-points were objective response rate as per RECIST and PFS. Methods: This was a multicenter, single-arm Phase 2 study, conducted in 20 Italian centers. Patients with locally relapsed or metastatic disease, already treated with one or more previous systemic treatments with anthracyclines and/or ifosfamide, were enrolled. T was administered at a dose of 1.3-1.5 mg/mq with a top dose of 2.6 mg per cycle. T was administered as a 24h continuous infusion until progressive disease, major toxicity, patient’s intolerance or medical decision. As per protocol, patients were considered responders if the GMR was &gt; 1.33, non-responders if &lt; 0.75 and neither if 0.76-1.32. Eighty evaluable patients were needed to detect an odds of trabectedin response ≥ 2.5, corresponding to 71.4% of patients with a GMR &gt; 1.33 (80% power, one-sided alpha 2.5%). Results: From August 2014 to February 2019, 104 patients were registered and 91 were evaluable for the primary endpoint (32 pts with LMS and 59 with LPS). Overall, the median number of cycles received was 6.0 (q1-q3 3.0-12.0), the main reason for treatment discontinuation was disease progression in 72% of patients, followed by medical decision (8%). The median TTP was 6.0 months (6.2 and 6.0 for LMS and LPS), while the median TTP-1 was 7.5 months (8.1 and 6.4 for LMS and LPS). Thirty three patients (52% 95%CI: 36-58, p = 0.674, odds of response = 1.1) had a GMR &gt; 1.33 (LMS: 46%, 95%CI 26-67,odds = 0.85; LPS 56%, 95%CI 40-72, odds = 1.3).Overall, response rate (CR+PR) was 16% (24% for LMS and 12% for LPS). Overall, in LPS we observed 15/47 patients with GMR &lt; 0.5 and 15/47 with GMR &gt; 2. Among LMS patients, 9/26 had a GMR &lt; 0.5 and 10/26 &gt; 2. Between LPS six patients had a GMR &gt; 5. Previous treatment had been based on anthracyclines and/or ifosfamide in 85% of patients (91% in LPS population). Conclusions: While the primary end point of the study was not met, we noticed a subgroup of patients with a markedly discrepant TTP with T in comparison to previous therapy (GMR &lt; 0.5 or &gt; 2, the latter including some pts with a long TTP with T). Efforts are ongoing to assess the pathologic counterparts of such discrepancies. T seems to be selectively active in poorly understood subgroups, with a pattern of activity distinct from other available agents. Clinical trial information: 2012-005428-14.

MO025: Long-term follow-up of patients with autosomal dominant polycystic kidney disease treated with tolvaptan

Abstract BACKGROUND AND AIMS Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited renal disease characterized by the formation of cysts that destroy normal renal parenchyma. Tolvaptan (vasopressin antagonist) is the only drug approved today to slow disease progression. To assess the efficacy and tolerability of long-term treatment in patients with ADPKD. METHOD Retrospective observational study of ADPKD patients on tolvaptan treatment after its approval in Spain in 2017. RESULTS Of the 182 patients with ADPKD in follow-up in our practice, 18% (n = 33) initiated treatment because they met criteria for rapid progression. A total of 60.6% (n = 20) males with age 47.64 ± 8.64 years, a baseline GFR of 65.24 ± 20.14 mL/min and a height-adjusted total kidney volume (TKV) of 1137.45 ± 667.58 mL. A total of 72.7% reached the maximum dose (120 mg) with a mean maximum dose of 108.18 ± 22.42 mg and a mean time to reach it of 5.8 ± 9.3 weeks. A total of 90.9% (n = 33) presented side effects: 81.8% (n = 27) aquaretic and 12.1% (n = 4) hepatotoxicity. Other side effects observed were as follows: hypernatremia 9.1% (n = 3), hyperuricemia in 24% (n = 8). No other side effects were described. A total of 39.4% (n = 13) of the patients temporarily abandoned treatment after a mean time of 3.01 ± 2.17 months. The reasons for discontinuation were as follows: aquaretic effects 35.7% (n = 5), hepatotoxicity 35.7% (n = 5), 3.03% desire for pregnancy (n = 1), 3.03% cerebral hemorrhage (n = 1) and 3.03 (n = 1) worsening of renal function. Some 30.76% (n = 4) of the patients restarted treatment at 5.5 ± 6.76 months. The reason for previous withdrawal was hepatotoxicity (n = 2) and aquaretic effects (n = 2). Therefore, the definitive abandonment of treatment was 27.2%. The mean follow-up time of the patients was 39.85 ± 10.04 months. CONCLUSION Long-term use of tolvaptan in patients with ADPKD can be considered safe both from the point of view of renal function and side effects. The aquaretic effects are the most frequent. The aquaretic effects and hepatotoxicity are the main reasons for treatment discontinuation. All cases of hepatotoxicity reverted to normal, thus not being considered a serious effect in our experience.

Feasibility of adjuvant S-1 chemotherapy after major hepatectomy for biliary tract cancers: An exploratory subset analysis of JCOG1202.

408 Background: JCOG1202 (UMIN000011688) is a randomized phase III trial conducted in patients (pts) with biliary tract cancers (BTCs) that showed the superiority of adjuvant S-1, in terms of the overall survival (OS). Previous reports have suggested that major hepatectomy (MH) may affect the dose intensity as well as frequency of adverse events (AEs) and reduce the treatment efficacy of chemotherapy, due to impaired liver function and drug metabolism. Therefore, we investigated whether MH might affect the feasibility of adjuvant S-1 chemotherapy. Methods: Among the 440 pts enrolled in the JCOG1202 study, 207 pts who received adjuvant S-1 were included in this analysis. We compared the rate of treatment completion, the frequency of AEs, and the dose intensity of adjuvant S-1 after MH versus non-major hepatectomy (NMH). MH was defined as right hemi-hepatectomy, right trisectionectomy, left trisectionectomy, and central bi-sectionectomy, with or without pancreatoduodenectomy. Results: Of the 207 pts, 42 pts had undergone MH and 165 pts had undergone NMH. The primary cancers in the MH group were mainly intrahepatic cholangiocarcinoma and hilar cholangiocarcinoma. The pretreatment characteristics of the pts were as follows: performance status 0 (MH vs. NMH: 81.0% vs. 89.1%), biliary reconstruction (performed: 81.0% vs. 82.4%), time from hepatectomy to initiation of adjuvant S-1 therapy (median: 60 vs. 57 days), platelet count (17.7 vs. 23.4 x 104/μL), and serum albumin (3.5 vs. 3.8 g/dL). The treatment completion proportion was lower in the MH group as compared to the NMH group (59.5% vs. 75.8%; treatment completion ratio, 0.786 (95% CI, 0.603-1.023), p = 0.0733), and the median dose intensity was lower in the MH group than in the NMH group (90% vs. 100%, p = 0.0358). The proportion of pts who discontinued adjuvant S-1 due to occurrence of AEs in the MH group vs. the NMH group was 23.8% vs. 10.3%. The major reasons for treatment discontinuation were biliary infection, nausea/vomiting, and diarrhea; these AEs were mainly observed in the first cycle; the frequency of grade 3-4 biliary infection during adjuvant S-1 therapy was 19.0% in the MH group versus 4.2% in the NMH group. Conclusions: In regard to adjuvant S-1 therapy for pts with resected BTC, the treatment completion proportion and dose intensity were lower in the MH group as compared to the NMH group. Caution should be exercised against the development of biliary infections during postoperative adjuvant S-1 therapy after MH in BTC pts.

Phase 1/1b trial of fruquintinib in patients with advanced solid tumors: Preliminary results of the dose expansion cohorts in refractory metastatic colorectal cancer.

93 Background: Fruquintinib (F) is a highly selective, novel, oral tyrosine kinase inhibitor (TKI) of vascular endothelial growth factor receptors (VEGFR) -1, -2, and -3. The phase (Ph) 3 FRESCO study (NCT02314819) that investigated F (5mg daily, 3 weeks (wks) on 1 wk off) showed improved median overall survival in patients (pts) with metastatic colorectal cancer (mCRC) in third line and beyond when compared to placebo (9.3 vs. 6.6 months); hazard ratio 0.65 (P &lt; 0.001) and led to its approval in China. Methods: This is an ongoing Ph 1/1b open-label, dose escalation/expansion study conducted in the US. Here we present the preliminary safety and antitumor efficacy data from pts with refractory mCRC in Cohort (Coh) B (progressed on all standard therapies including TAS-102 [TAS] and/or regorafenib [R]) and in Coh C (did not receive TAS or R). Results: As of data cutoff on 27 July 2021, 81 mCRC pts had been treated (41 in Coh B and 40 in Coh C); median age of 57 years (range: 34─77), Caucasian (81.5%), female (44.4%), and ECOG PS 1 (59.3%). In Coh B, the median number of prior therapies was 5 (range: 3-9), 8 pts (19.5%) received R, 19 (46.3%) received TAS and 14 (34.1%) received both R and TAS. In Coh C, the median number of prior therapies was 4 (range: 1-10). Five pts remain on treatment; reasons for treatment discontinuation included: 56 pts (69.1%) due to progressive disease or death, 8 pts (9.9%) due to adverse events (AE), and 12 pts (14.8%) due to withdrawal of consent or physician decision. The median duration of F treatment was 4.4 months (range: 0.7– 20.0) in Coh B and 3.7 months (range: 0.02-14.3) in Coh C. The most frequently reported AEs of any grade in Coh B were fatigue (53.7%), proteinuria (51.2%), and hypertension (HTN; 48.8%). In Coh C the most frequently reported AEs of any grade were HTN (75.0%), proteinuria (40.0%), and myalgia (32.5%). Hand-foot syndrome (HFS) was reported in 29.3% of Coh B pts and 22.5% of Coh C pts. The disease control rate [DCR] was 68.3% in Coh B (1 partial response [PR] and 27 stable disease [SD]) and 59.5% for the 37 patients with at least one post-baseline tumor assessment in Coh C (2 PRs and 20 SDs). Conclusions: F is generally well-tolerated in heavily-pretreated pts with refractory mCRC. Evidence of antitumor activity was observed in cohorts B and C. The multi-cohort dose expansion is ongoing. F is being further investigated in refractory mCRC in a global Ph 3 study (NCT04322539). Clinical trial information: NCT03251378.