Median Relative Dose Intensity Research Articles

Real-World Clinical Outcomes With Sacituzumab Govitecan in Metastatic Triple-Negative Breast Cancer.

Sacituzumab govitecan (SG) is approved for the treatment of metastatic triple-negative breast cancer (mTNBC). We report the real-world clinical effectiveness and toxicity data of SG in patients with mTNBC. A multi-institution retrospective study of patients with mTNBC treated with SG from January 2021 to May 2023 was conducted. Demographic and clinicopathologic variables were collected. Univariate and multivariate Cox regression models were used for survival analysis. A total of 115 patients were included. The median age at SG initiation was 60 years (range, 31-85). All patients were female; 73 (63.5%) were White and 31 (27.0%) were Black. The median number of previous therapies in the metastatic setting was two (range, 0-8). Sixty-one (56.0%) patients had primary refractory disease. Median relative dose intensity was 92% (range, 33%-100%). Grade 3 or higher adverse events (AEs) were seen in 50.9% of patients, which included neutropenia (35.7%), anemia (27.0%), vomiting (16.5%), fatigue (8.7%), and diarrhea (7.0%). Dose reductions and treatment discontinuation due to AEs were required in 51.3% and 13.2%, respectively. The objective response rate (ORR) was 27.8%. Median overall survival was 9.6 months (95% CI, 7.8 to 12.9) and median progression-free survival (PFS) was 4.8 months (95% CI, 3.6 to 5.9). In patients with human epidermal growth factor receptor 2 (HER2)-low mTNBC who received trastuzumab deruxtecan (T-DXd) after SG, the ORR to T-DXd was 34.8% and median PFS was 7 months (95% CI, 4.6 to 10.1). In a real-world cohort of heavily pretreated patients with mTNBC, SG retains its clinical activity. In a subgroup with HER2-low disease, T-DXd continues to demonstrate promising clinical activity after SG, supporting the use of sequential antibody-drug conjugates in this population.

Ibrutinib plus rituximab and mini-CHOP in older patients with newly diagnosed DLBCL: a phase 2 ALLG study

AbstractThe multicenter, prospective phase 2 Australasian Leukaemia & Lymphoma Group NHL29 trial was conducted to assess the addition of ibrutinib to R-mini-CHOP (dose attenuated R-CHOP; rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) in patients aged ≥75 years with newly diagnosed diffuse large B-cell lymphoma (DLBCL). Treatment consisted of six 21-day cycles of ibrutinib–R-mini-CHOP followed by two 21-day cycles of R-ibrutinib. Coprimary end points were deliverability and 2-year overall survival (OS). The median average relative total dose and average relative dose intensity for the entire regimen were both 97% (interquartile range, 82-100 and 88-100, respectively). With a median follow-up of 35.5 months, the 2-year OS was 68% (95% confidence interval [CI], 55.6-77.4) with a 2-year progression-free survival (PFS) of 60.0% (95% CI, 47.7-70.3). Median OS and PFS were 72 months (95% CI, 35 to not reached) and 40 months (95% CI, 20.4 to not reached), respectively. The overall response rate was 76% (61/79) of patients, with a complete response rate of 71% (56/79). Deaths occurred in 34 of 79 patients (43%), including 17 from progressive disease and 5 treatment related. Overall, 67% patients experienced at least 1 serious adverse event. Most common adverse events were infections and diarrhea (the majority grade 1-2). In both health-related quality of life measures, there was an improvement in functional and symptom scales, median health state classification score, and median visual analogue scale in responders over time. In conclusion, this study showed that the addition of ibrutinib to R-mini-CHOP was both deliverable and efficacious in elderly DLBCL patients.

Sequential high-dose methotrexate and cytarabine administration improves outcomes in real-world patients with primary central nervous system lymphoma: A report from the Australasian Lymphoma Alliance.

Despite recent advances, optimal therapeutic approaches applicable to subpopulations with primary central nervous system (CNS) lymphoma outside of clinical trials remain to be determined. We performed a retrospective study of immunocompetent, adult patients with histologically confirmed diffuse large B-cell lymphoma of the CNS (PCNSL). 190/204 (93%) patients (median age: 65) received one of five high-dose methotrexate (HD-MTX) containing chemotherapy regimens: MPV/Ara-C (HD-MTX, procarbazine, and vincristine, followed by cytarabine [Ara-C]) (n=94, 50%), MATRix (HD-MTX, Ara-C, thiotepa, and rituximab) (n=19, 10%), HD-MTX/Ara-C (n=31, 16%), HD-MTX monotherapy (n=35, 18%) and MBVP (HD-MTX, carmustine, teniposide, prednisolone) (n=11, 6%). Cumulative median HD-MTX and Ara-C doses were 17g/m2 (range: 1-64g/m2) and 12g/m2 (0-32g/m2) respectively. Using 14g/m2 as the reference dose, the median HD-MTX relative dose intensity (HD-MTX-RDI) was 1.25 (0.27-4.57) with 84% receiving>0.75. The overall response rate (ORR) was 72% (complete response: 50%) after completing HD-MTX. At a median follow-up of 3.41 years (0.06-9.42), progression-free survival (PFS) and overall survival (OS) were different between chemotherapy cohorts, with the best outcomes achieved in the MPV/Ara-C cohort (2-year PFS 74%, 2-year OS 82%; p=0.0001 and p=0.0024 respectively). On multivariate analysis, MPV/Ara-C administration and HD-MTX-RDI>0.75 were associated with longer PFS and OS. Sequential, response-adapted approaches can improve outcomes, even in older patients who are ineligible for a high-intensity concurrent chemotherapy approach and do not undergo traditional consolidative strategies.

Efficacy and safety of dose-dense gemcitabine plus cisplatin as neoadjuvant chemotherapy for muscle-invasive bladder cancer.

The objective of this study was to evaluate the efficacy and safety of dose-dense gemcitabine and cisplatin (ddGC) as neoadjuvant chemotherapy for muscle-invasive bladder cancer (MIBC). Patients with locally advanced MIBC (cT2aN0M0-cT4N1M0) who received ddGC between December 2017 and December 2023 were included. Regimens of ddGC with pegfilgrastim were administered every 2 weeks for 4 cycles, followed by radical cystectomy. The pathological complete response (CR) (pT0N0) and objective response (OR) (<pT2N0) rates were evaluated in patients who underwent radical cystectomy. Tolerability was assessed using relative dose intensity (RDI). Adverse events (AEs) were documented according to the Common Terminology Criteria for Adverse Events in all patients who received ddGC. Disease-free survival (DFS) and overall survival (OS) were estimated using the Kaplan-Meier method. A total of 45 patients (cT2N0, 60%; cT3N0, 22%; cT4N0, 9%; and cTanyN1, 9%) were included. Of the 41 who underwent cystectomy, 38 (92.7%) completed all planned cycles, with a median RDI of 0.96 (interquartile range [IQR], 0.89-1.00). Overall, CR and OR were achieved in 12 (29.3%) and 17 (41.5%) patients, respectively, increasing to 32.4% and 45.9%, respectively, in cN0 patients. Severe AEs (grade ≥ 3) were observed in eight patients (17.8%), including four hematological toxicities. At a median follow-up of 31 months, 2-year DFS and OS were 70.8% and 89.2%, respectively. Neoadjuvant ddGC demonstrated good tolerability, efficacy, and safety, suggesting its potential as a treatment option for MIBC.

Clinical prognostic factors to guide treatment strategy for HPV‑positive oropharyngeal cancer using treatment outcomes of induction chemotherapy: A real‑world experience.

The role of induction chemotherapy (IC) in locally advanced oropharyngeal cancer (OPC) remains debatable, and suitable candidates for de-escalation treatment in these patients have not been fully identified. Therefore, the present study aimed to identify high-risk candidates for human papillomavirus (HPV)-positive OPC by analyzing patients who underwent IC followed by chemoradiotherapy (CRT) to guide optimal treatment strategies. Patients diagnosed with stage III-IVA OPC and treated with a minimum of two cycles of IC followed by CRT, between 2004 and 2020, were retrospectively reviewed. All the patients were restaged according to the American Joint Committee on Cancer, 8th edition. The overall response rate and survival outcomes associated with clinical factors based on HPV status were analyzed using univariate and multivariate analyses. The present study analyzed 105 patients with a median age of 60 years (range, 40-76 years). Among 105 patients, 40 (38.1%) were HPV-negative and 65 (61.9%) HPV-positive. In all patients, survival outcomes were notably poorer in patients aged ≥60 years (P=0.006) and those who did not achieve complete response post-CRT (P<0.001), irrespective of the HPV status. The median relative dose intensity of IC was ≥80%, indicating adequate treatment, regardless of age. In contrast to patients with HPV-negative OPC, age ≥60 years (P=0.011) and T4 stage (P=0.019) emerged as substantial poor prognostic factors for survival outcomes in patients with HPV-positive OPC. Patients with HPV-positive OPC were categorized into three groups based on the number of clinical factors at diagnosis (such as age and T4 stage). The progression-free and overall survival showed significant stratification across each group as the number of high-risk factors increased despite IC and CRT. The findings indicated that patients with these high-risk factors require a cautious therapeutic strategy even when they are diagnosed with HPV-positive OPC, and the role of combined modality, including IC, will need to be investigated in a randomized trial to be routinely incorporated into clinical practice.

First-in-human phase 1 trial of the safety, tolerability, pharmacokinetics of BY101298: Initial report from dose escalation cohort.

e15132 Background: Radiotherapy (RT) is a cornerstone of cancer treatment, leveraging the effect of ionizing radiation to induce DNA damage, primarily through DNA double-strand breaks (DSBs). Non-homologous end joining (NHEJ) stands as the predominant pathway for repairing DSBs, with DNA-dependent protein kinases (DNA-PK) playing a pivotal role in NHEJ pathway. DNA damage repair can compromise tumor cells sensitivity to RT, potentially leading to the development of radiation resistance. BY101298, an innovative and highly selective DNA-PK inhibitor, works to diminish DSBs repair. In synergy with RT or chemotherapy, BY101298 enhances tumor cells eradication, preventing local recurrence and metastasis, thereby improving clinical benefits for cancer patients. Methods: This phase Ⅰa multicenter, open-label, dose-escalation study assessed the safety, tolerability, and clinical efficacy of BY101298. Oral doses ranged from (50 mg to 400 mg once/day [QD]) in continuous 28-day cycles. Primary outcome was safety and tolerability; secondary outcome was PK; exploratory outcome was DNA-PK phosphorylation (PD). Adverse events (AEs) were monitored per the Common Terminology Criteria for Adverse Events (CTCAE version5.0). Responses were assessed every other cycle using Response Evaluation Criteria in Solid Tumors (RECIST version 1.1). Results: Data from 9 pts with advanced solid tumors (cutoff: 26 December 2023; 2 men, 7 women; median age 58.0) revealed a linear increase in BY101298 AUC exposure and Cmax with dose escalation. Daily dosing for 15 consecutive days showed no AUC increase. Serum drug concentration correlated significantly with DNA-PK phosphorylation. All pts, previously systemic treated, received doses of 50 mg QD (n = 2), 100 mg QD (n = 3), and 200 mg QD (n = 4). Median treatment duration was 30 days (range: 1-57), with one patient (11.1%) continuing. Median relative dose intensity was 100%. Common treatment-related AEs (≥25%), primarily grade 1, included hypoalbuminemia (n = 5, 55.56%); anemia (n = 4, 44.44%); nausea (n = 3, 33.33%); weight decreased (n = 3, 33.33%). No pts experienced ≥Gr3 AEs. Two pts experienced serious AEs (none of which were considered treatment-related). No treatment discontinuations, dose reductions, or deaths attributed to treatment-related. The final dose group, representing the fourth cohort, is scheduled to commence shortly and is expected to conclude in April as per our estimation. Conclusions: In pts with advanced solid tumors, BY101298 exhibits a favorable safety profile and manageable toxicity. Vomiting was noted as a potential risk associated with BY101298. Further studies are imperative to elucidate the efficacy of BY101298 in combination with radiotherapy among pts with advanced solid tumors. Research Sponsor: This study received support from Chengdu Baiyu Pharmaceutical Co., Ltd. Clinical trial information: CTR20230997.

Final safety results from ATHENA–MONO (GOG-3020/ENGOT-ov45), a randomized, placebo-controlled, double-blind, phase 3 trial evaluating rucaparib monotherapy as maintenance treatment in patients with newly diagnosed ovarian cancer.

5554 Background: Rucaparib provided a sustained progression-free survival benefit in patients (pts) with newly diagnosed advanced ovarian cancer after first-line treatment in the phase 3 ATHENA-MONO study (NCT03522246). We report final safety analyses (data cutoff 09 Mar 2023). Methods: Rucaparib was administered in 28-day cycles. Eligible pts were randomized 4:1 to oral rucaparib 600 mg BID (N=427) or placebo (N=111), with a treatment cap defined as 24 months. The safety population included randomized pts who received at least 1 dose of study drug (rucaparib, n=425; placebo, n=110). Results: All ATHENA-MONO pts discontinued treatment as of 24 Nov 2022 with a median treatment duration of 15 months and 35% of pts reaching the 24-month treatment cap. The median (range) relative dose intensity was 89% (30-110) for rucaparib. The rate of treatment-emergent adverse events (TEAEs), grade ≥3 TEAEs, TEAEs leading to interruption, dose reduction, or discontinuation with rucaparib remained consistent with the primary endpoint analysis with some minor changes (see Table below). Most common grade ≥3 TEAEs were anemia/decreased hemoglobin (28.7%), neutropenia/decreased neutrophils (14.6%), increased ALT/AST (10.6%), and thrombocytopenia/decreased platelets (7.3%). The most common TEAEs leading to discontinuation were anemia/decreased hemoglobin (3.5%), asthenia/fatigue (4.9%), and nausea (2.1%). Hypertension continued to be the most common TEAE observed in the placebo group (3.6%) compared with 1.6% in the rucaparib group. There were no changes in the incidence of serious adverse events or TEAEs leading to death since the primary endpoint analysis. Myelodysplastic syndromes (MDS)/acute myeloid leukemia (AML) were reported in a total of 3 pts in the rucaparib group (1 MDS during treatment [0.2%] and 1 AML and 1 MDS during long-term follow-up [0.5%]), of which the latter occurred since the primary readout. The initial MDS event that occurred during treatment, included in these incidence numbers, was considered resolved by the investigator since the initial analysis. Conclusions: Long-term maintenance treatment with rucaparib demonstrates a consistent and manageable safety profile in a broad population of pts with newly diagnosed ovarian cancer. No new safety signals were identified. Adverse events were generally manageable and led to discontinuation in a low proportion of pts. Clinical trial information: NCT03522246 . [Table: see text]

Effect of nivolumab combined with definitive chemoradiotherapy on response rate for esophageal cancer: An immune active intrinsic subtype could be its biomarker—The NOBEL trial.

4068 Background: The usefulness of combined therapy with immune checkpoint inhibitors (ICI) and chemoradiotherapy (CRT) and its potential biomarker of treatment efficacy for esophageal cancer remains unclear. We investigated the safety, efficacy, and associated biomarkers of combined therapy with ICI and definitive CRT in operable and inoperable esophageal squamous cell carcinoma (ESCC). Methods: This prospective single-arm phase 2 trial was performed at five hospitals in Japan. Patients aged 20–75 years with histologically confirmed ESCC, an ECOG PS score of 0 or 1, and adequate organ and bone marrow functions were eligible. Inoperable patients did not have distant organ metastasis. Patients did not receive any chemotherapy or surgical resection as an initial therapy. Concurrent radiotherapy (50.4 Gy/28 fractions to the primary lesion and 41.4 Gy/23 fractions to the regional LN area) consisted of 4 courses of CF (cisplatin, 75 mg/m2/day, day 1; 5-fluorouracil, 1000 mg/m2/day, days 1–4) plus nivolumab (240 mg/m2/day, every 2 weeks for up to 1 year). The primary endpoint was safety. The incidence rates of nonhematological toxicity grade ≥ 4 and pneumonitis grade ≥ 3 were ≤10% and ≤15%, respectively. The secondary endpoints included overall survival (OS), progression-free survival (PFS), complete response (CR) rate, and time to esophagectomy-free survival (EFS). Sixty patients were to be accrued, but the trial enrollment was terminated because of slow accrual. This trial was registered as jRCT1091220408. Results: Between January 2019 and September 2021, 42 patients were enrolled. Twenty-five patients had operable disease and 16 had inoperable disease. Two patients (4.8%) experienced grade 3 pneumonitis, suggesting that the primary endpoint was met. The median relative dose intensity of nivolumab was 92.4%. One-year OS, PFS, and EFS rates in all cases were 92.7%, 65.4%, and 78.0%, respectively. One-year OS, PFS, and EFS rates in operable and inoperable cases were 100%, 79.6%, and 84.0% and 81.3%, 43.8%, and 68.8%, respectively. The CR and objective response rates were 73.2% (95% confidence interval [CI]: 58.1%–84.3%) and 87.8% (95% CI: 74.5%–94.7%), respectively. The CR rates in operable and inoperable cases were 84% (95% CI: 65.3%–93.6%) and 56.3% (95% CI: 33.2%–76.9%), respectively. Immune high-active intrinsic subtype before treatment (n=4) with an expression score &gt; 80 of 51 immune-related genes showed a high CR rate (100%, n=4), whereas the immune low-active intrinsic subtype (n=37) with an expression score &lt; 80 showed a relatively high CR rate (70%). Conclusions: Nivolumab combined with definitive CRT provided encouraging efficacy and acceptable toxicity in patients with ESCC. Immune high-active intrinsic subtype before treatment has the potential to predict a high CR rate for this combination treatment. Clinical trial information: jRCT1091220408 .

Abstract PO3-06-10: Real World Outcomes with Sacituzumab Govitecan in Metastatic Triple Negative Breast Cancer Patients: A Multi-Institution Study

Abstract Background Sacituzumab govitecan (SG) is approved for treatment of metastatic triple negative breast cancer (mTNBC) in the second line and beyond. Little is known about the real-world outcomes of SG. We aim to evaluate the real-world effectiveness and toxicity outcomes of SG in heterogenous heavily pretreated mTNBC patients (pts) to investigate the consistency of the outcomes in comparison to the clinical trial population. Methods A multi-center retrospective study of pts with mTNBC treated with SG in the US from January 2021 until May 2023 was conducted. Demographics and clinicopathological variables including site of metastases, prior lines of therapy, relative dose intensity (RDI), adverse events (AEs), HER2 immunohistochemistry (IHC) score at time of metastasis, clinical response, clinical benefit rate (CBR) defined as (complete response, partial response (PR) or stable disease (SD) &amp;gt; 6 months) and last follow-up were collected. For continuous variables, Mann-U Whitney and Kruskal Wallis tests were used to compare mean, median, standard deviation, and range. For categorical variables, Fisher's exact tests and Pearson Chi-square tests were used. Univariate and multivariate cox regression models examined RDI and survival outcomes. SAS v9.4 was used to perform statistical analysis at a significance level of 0.05. Results A total of 111 pts were analyzed. The median age was 58 years (range 29-84). The majority of pts were heavily pretreated: 59.1% received &amp;gt;3 prior lines of treatment (Tx) in the metastatic setting, 54.1% received prior immune checkpoint inhibitor (ICI), 8.1% received prior olaparib. 55% of pts had significant disease burden defined by &amp;gt;=3 organs involved by metastatic disease, with 22.5% having brain metastasis at the time of initiation of SG. Of note, 51% had primary refractory disease defined as relapse within 12 months of completion of adjuvant chemotherapy. 98.1% experienced any grade AEs, with the most common being anemia 63.1%. Grade 3 AEs occurred in 51.4% pts with neutropenia being the highest 32.4% followed by anemia 14.4%, diarrhea 7.2% and fatigue 7.2%. Tx interruptions and dose reductions due to AEs occurred in 52.3% of patients and Tx discontinuation rate due to AEs was 11.8%. Elderly pts (defined as &amp;gt;65 years) did not have higher rates of dose reductions due to AEs compared to young pts (&amp;lt; = 65 years) (37.8% vs 59.7 %), p=0.043). The median RDI is 92% (interquartile range (IQR) 33%-100%). The median RDI in elderly pts was 94% (IQR 50%-100%). Among pts in which response was assessed, objective response rate (ORR) was 26.6% (25 pts had PR), and 38.3% had SD. Interestingly, the rate of alopecia was higher in pts who had PR as the best response (28%), compared to 5.6% in pts who had SD, and 3% in progressive disease (PD) p=0.004. The median prior line of therapy in pts who had PR and SD as best response was 2 (IQR 1, 5) (IQR1, 12), respectively, compared to a median of 3 (IQR 1, 7) in pts with PD, p&amp;lt; 0.001. The CBR was 49% (46/94). The median duration of clinical benefit was 7 months IQR (2, 16) with median overall survival of 13 months IQR (2.5, 39) compared to 5.7 months IQR (0.03, 27) in pts without clinical benefit (p&amp;lt; 0.001). 56.9% (62/109) of pts had HER2 low disease and the clinical benefit rate in this subgroup was 14.3% (23/62). Conclusion: In a heavily pretreated cohort, SG retains clinical activity and tolerability in mTNBC. This is reassuring given pts on clinical trials tend to be healthier compared to real-world clinical practice. Citation Format: Sabah Alaklabi, Arya Mariam Roy, Paola Zagami, Nicole Held, Saba Shaikh, Lubna Chaudhary, Yara Abdou, Shipra Gandhi. Real World Outcomes with Sacituzumab Govitecan in Metastatic Triple Negative Breast Cancer Patients: A Multi-Institution Study [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 PO3-06-10.

Abstract PO4-12-10: Sacituzumab Govitecan Toxicity Outcomes In Arab Patients with Metastatic Breast Cancer

Abstract Background: The Arab population is often underrepresented in clinical trials, which limits our knowledge of drug safety and efficacy in this population due to genetic variability that can affect drug metabolism and adverse events (AEs). Sacituzumab govitecan (SG) is approved for metastatic triple negative breast cancer (mTNBC), and recently hormone receptor positive metastatic breast cancer (HR+ MBC). Here we report toxicity outcomes and RDI in Arab population. Methods: A multi-center retrospective study of patients with mTNBC and HR+ MBC treated with SG from January 2021 until May 2023 was conducted. Demographics and clinical variables including site of metastases, prior lines of therapy, relative dose intensity (RDI), adverse events (AEs) were collected. For continuous variables, Mann-U Whitney and Kruskal Wallis tests were used to compare mean, median, standard deviation, and range. For categorical variables, Fisher's exact tests and Pearson Chi-square tests were used. SAS v9.4 was used to perform statistical analysis at a significance level of 0.05. Results: A total of 35 patients was enrolled. The median age at diagnosis of metastatic breast cancer was 39 years interquartile range (IQR) (35, 44). The median age at starting SG was 44.5 years IQR (38,50). The majority of patients (65%) had an Eastern Cooperative Oncology Group performance status (ECOG PS) of 1, (21%) of the patients had an ECOG PS of 0, and (15%) had an ECOG PS of 2. 48.6% received 3 or more lines of prior therapy in the metastatic setting while 51.4% received less than 3 lines of prior therapy in the metastatic setting. 77.1% of patients had 3 or &amp;gt; organs involved with metastatic disease, while 22.9% of patients had &amp;lt; 3 organ involved. The most common metastatic sites were the lung (54.3%), liver (62.9%), bone (68.6%), and brain (45.7%). The median RDI of SG was 100% for a sample of 34 individuals, with one missing value IQR (94%,100%). The rate of overall AEs was (77.1%), with the most common AEs being; neutropenia (44.4%), diarrhea (37.0%), anemia (22.2%), thrombocytopenia (22.2%), nausea (14.8%), and vomiting (7.4%). Garde 3 AEs rate was 34.3%. The most common grade 3 adverse events were diarrhea (11.4%), fatigue (5.7%), and alopecia (2.9%). The rate of treatment interruption and dose reduction due to AEs was 31.4%. Only one patient (2.9%) had to discontinue SG treatment due to adverse events. Conclusion: The study suggests that SG is safe and well-tolerated in young Arab patient population. The sample consisted of relatively young patients, which may reflect a reluctance to prescribe SG to older Arab patients. Caution should be exercised when generalizing the findings due to limitations of the study. Further studies with larger sample sizes are needed to validate these findings and to explore the efficacy of SG in Arab patients with mTNBC and HR+ MBC. Citation Format: Maymouna Altarturi, Kausar Suleman, Adhar AlSayed, Humaid Al-Shamsi, Aydah Alawadhi, Bassam Basuliamn, Sabah Alaklabi. Sacituzumab Govitecan Toxicity Outcomes In Arab Patients with 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 PO4-12-10.

Comparison of Safety and Treatment Continuity of Palbociclib and Abemaciclib for Hormone Receptor-Positive, HER2-Negative Metastatic/Recurrent Breast Cancer

Background: Appropriate adverse event (AE) management and maintenance of therapeutic intensity are necessary to achieve therapeutic benefits of CDK4/6 inhibitors (palbociclib and abemaciclib) in hormone receptor-positive, HER2-negative metastatic/recurrent breast cancer. Objective: This study was aimed at clarifying the effect of AEs associated with palbociclib and abemaciclib on treatment. Methods: A total of 62 and 49 patients were prescribed palbociclib and abemaciclib, respectively, at our hospital from January 1, 2018 to June 30, 2023. The rate and reasons for treatment discontinuation, interruption of administration, and changes in dose and dosing schedule, treatment duration, and relative dose intensity (RDI) were compared between the groups of patients prescribed the 2 treatments. Results: Treatment discontinuation due to AEs occurred more frequently with abemaciclib (12 patients) because of interstitial lung disease and hepatic and renal events than with palbociclib (5 patients; P = .008). Administration was interrupted in 57 (91.9%) and 35 (71.4%) patients treated with palbociclib and abemaciclib, respectively (P = .004). Dose reduction occurred in 37 (67.3%) and 19 (47.5%) patients treated with palbociclib and abemaciclib, respectively (P = .053). The median [range] treatment duration was 301 [21-1643] days for palbociclib and 238 [70-1526] days for abemaciclib (log-rank test, P = .581). The median RDI was 59.7% and 59.6% for palbociclib and abemaciclib, respectively (P = .539). Although the AEs of palbociclib and abemaciclib affected the treatment considerably, the treatment duration and RDI were similar. Conclusion: CDK4/6 inhibitors should be selected based on the tolerability and manageability of each AE.

Association between albumin–bilirubin grade and plasma trough concentrations of regorafenib and its metabolites M-2 and M-5 at steady-state in Japanese patients

SummaryThe aim of the present study was to determine whether the trough plasma concentrations (C0) of regorafenib and its metabolites, the N-oxide metabolite (M-2) and the desmethyl N-oxide metabolite (M-5), in 21 patients receiving regorafenib therapy were affected by albumin-bilirubin (ALBI) grade. Regorafenib was administered at dosages ranging from 40 to 160 mg once daily on a 3-week-on, 1-week-off cycle. C0 values of regorafenib and its major metabolites were measured by high-performance liquid chromatography on day 8 after treatment initiation. The C0 values of regorafenib and metabolites M-2 and M-5 were significantly lower in patients with ALBI grade 2 as compared with grade 1 (P = 0.023, 0.003 and 0.017, respectively). The total C0 of regorafenib and its metabolites was significantly higher in ALBI grade 1 patients relative to grade 2 (3.489 μg/mL vs. 1.48 μg/mL; P = 0.009). The median relative dose intensity (RDI) of patients categorized as ALBI grade 2 was significantly lower than that of grade 1 patients (21.9% vs. 62.9%; P = 0.006). In 15 colorectal cancer patients among the total 21 patients, patients with ALBI grade 2 (n = 9) had a significantly shorter median overall survival time than patients with grade 1 (n = 6; P = 0.013). Administering a low dose of regorafenib to patients with ALBI grade 2 reduces the RDI of regorafenib and lowers treatment efficacy, as an appropriate C0 of regorafenib is not maintained. Monitoring the C0 of regorafenib regularly is necessary to guide dose adjustment.

Safety and Efficacy of Gemcitabine Plus Cisplatin Against Recurrent/Metastatic Nasopharyngeal Carcinoma: A Retrospective Study.

Although gemcitabine plus cisplatin (GC) prolongs survival in patients with recurrent or metastatic nasopharyngeal carcinoma (R/M NPC) compared with fluorouracil plus cisplatin, no study has evaluated the efficacy and safety of GC in nonendemic regions, including Japan, yet. Therefore, we assessed the safety and efficacy of GC in Japanese patients with R/M NPC. We retrospectively reviewed patients with R/M NPC who received GC treatment at the Aichi Cancer Center Hospital from January 2017 to March 2020. The main eligibility criteria were histologically confirmed NPC, Eastern Cooperative Oncology Group performance status (ECOG PS) of 0-2, and locally recurrent disease unsuitable for local treatment or metastatic disease. The regimen was administered every 3 weeks (gemcitabine, 1,000 mg/m2 on days 1 and 8; cisplatin, 80 mg/m2 on day 1). Fourteen patients (median age, 58 years) were included in the study. Two patients had an ECOG PS of 2 and 11 exhibited nonkeratinizing histology. Of the eight patients with measurable lesions, one exhibited complete response and seven exhibited partial response, with an objective response rate of 75%. Median progression-free survival and overall survival were 7.7 and 24.2 months, respectively. Common grade 3 or 4 adverse events included neutropenia (64%), thrombocytopenia (14%), and febrile neutropenia (14%). The median relative dose intensity of gemcitabine and cisplatin was 62% and 60%, respectively. No treatment-related deaths occurred. The GC regimen demonstrates promising activity and is tolerable in Japanese patients with R/M NPC.

Effect of erythropoietin-stimulating agent use on belzutifan antitumor activity in patients with VHL disease–associated renal cell carcinoma: Post hoc analysis of the LITESPARK-004 study.

3 Background: The ongoing, open-label, phase 2 LITESPARK-004 study (NCT03401788) showed that belzutifan, a HIF-2α inhibitor, exhibited antitumor activity in patients (pts) with VHL disease associated renal cell carcinoma (RCC), pancreatic neuroendocrine tumors (pNETs), and CNS hemangioblastomas. The most common adverse event (AE) of any grade was anemia and pts could have received erythropoietin-stimulating agents (ESA) and/or blood transfusions for management. This exploratory post-hoc analysis described pattern of ESA use and whether use of ESA impacted antitumor activity to belzutifan in pts with VHL disease. Methods: Pts (≥18 years) with germline VHL alterations, ≥1 measurable nonmetastatic RCC tumor, no tumor of &gt;3 cm requiring immediate surgery, and no prior anticancer systemic treatment received oral belzutifan 120 mg once daily until disease progression, unacceptable toxicity, or pt withdrawal. End points included objective response rate (ORR) and duration of response (DOR) in VHL disease–associated RCC and non-RCC neoplasms per RECIST v1.1 by independent central review, and safety. Efficacy and safety outcomes among pts who received and did not receive ESA were evaluated. Data cutoff was April 1, 2022. Results: Of 61 treated pts, 14 (23%) received ESA and 47 (77%) did not. Median (range) time to onset of ESA use was 151 days (59-886) and median dose per pt was 5 injections (range 1-35). Duration of belzutifan exposure for ≥12 months was achieved in 100% of pts who received ESA vs 92% in pts who did not receive ESA. Median (range) relative dose intensity was 97.4 (51.4-100) and 98.8 (26.4-100) for pts who received and did not receive ESA, respectively. ORR for VHL-associated RCC was 71% (10/14, 95% CI, 42-92) for pts who received ESA and 62% (29/47, 46-76) for those who did not. Median DOR was not reached (NR) for pts who received and who did not receive ESA (NR, range 5.5+ to 33.5+ months and NR, range 5.4+ to 35.8+ months). All pts in both groups had a response for ≥12 months. In pts with CNS hemangioblastomas, ORR was 46% (5/11, 17-77) for pts who received ESA and 44% (17/39, 28-60) for those who did not. In pts with pNETs, ORR was 100% (4/4, 40-100) for pts who received ESA and 89% (16/18, 65-99) for those who did not. Median DOR was not reached for both groups in pts with CNS hemangioblastomas and pNETs. Among pts who received and did not receive ESA, 5 (36%) and 6 (13%) pts had at least 1 dose reduction, respectively. All pts reported at least 1 AE but a larger percentage of pts who received ESA had AEs of grade 3 or higher than those who did not receive ESA (57% and 40%). Conclusions: In this exploratory, post-hoc analysis of LITESPARK-004, data suggests that administration of ESA did not adversely impact overall drug exposure or efficacy of belzutifan in pts with VHL disease associated RCC, CNS hemangioblastomas, and pNETs. Clinical trial information: NCT03401788 .

HGCSG 1803: Single-arm phase II study evaluating efficacy of oxaliplatin, irinotecan and S-1 combination therapy (OX-IRIS) in metastatic pancreatic cancer as first line treatment.

647 Background: Combination chemotherapy with oxaliplatin, irinotecan, fluorouracil and leucovorin (FOLFIRINOX) showed improved survival compared to gemcitabine monotherapy for patients with metastatic pancreatic cancer and has become the one of the standard regimens. Despite of its clinical benefit, FOLFIRNIOX needs continuous infusion of 5-FU for 46 hours, which impairs patient’s quality of life. In other gastrointestinal cancer, infusion pump free regimens, in which oral 5-FU drug replace the continuous infusion of 5-FU, have developed as alternative regimen by its convenience. Therefore, we planned to develop new combination chemotherapy with oxaliplatin, irinotecan and S-1 (OX-IRIS) for metastataic pancreatic cancer. Methods: HGCSG1803 study has conducted as a multicenter, non-randomized, single arm, phase II study in Japan. The chemotherapy-naïve patients with metastatic pancreatic cancer were eligible. S-1 (40 mg/m2) orally intake twice daily for 14-day followed by a 14-day rest, and intravenous 65 mg/m2 of L-OHP and 100 mg/m2 of IRI on day 1 and day 15 every four weeks were continued until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) by RECIST ver1.1, with a threshold of 10% and an expected value of 30%. The secondary endpoints were overall survival (OS), progression-free survival (PFS), and safety. Results: Between Jan 2020 and May 2022, forty patients were enrolled and 39 patients were included in full analysis set (one patient were excluded because of consent withdrawal). Median age was 66 (range, 41-75), female/male were 16/23, ECOG PS 0/1; 32/7, UGT1A1 wild /heterozygous for *6 or *28 allele 27/12, liver/lung/peritoneal metastasis 28/9/11, respectively. The median relative dose intensities of S-1, irinotecan, and oxaliplatin were 76%, 72%, and 70%, respectively. Objective response rate and disease control rate were 43.6% (95%CI 27.8-60.4%) and 76.9% (95%CI 60.4-89.1%), respectively. In the median follow-up time was 13.7 months, median progression free survival and overall survival were 4.3 months (95%CI 2.5-6.2 months) and 11.1 months (95%CI 7.2-14.9 months), respectively. Four patients discontinued protocol therapy due to adverse events (AE) without disease progression. Grade 3 or higher AE that occurred in more than 5% of patients were leucopenia (21%), hypokalemia (21%), neutropenia (18%), anemia (15%), hyponatremia (15%), ALT elevation (10%), anorexia (8%), nausea (5%), and febrile neutropenia (5%). One patient died due to protocol therapy (drug induced pneumonitis). Conclusions: OX-IRIS showed high response rate with manageable safety, and the primary endpoint was met. This new triplet regimen could be a useful first line treatment option for patients with metastatic pancreatic cancer. Clinical trial information: jRCTs011190008 .

Time to Cancer Treatment and Chemotherapy Relative Dose Intensity for Patients With Breast Cancer Living With HIV

Patients with breast cancer and comorbid HIV experience higher mortality than other patients with breast cancer. To compare time to cancer treatment initiation and relative dose intensity (RDI) of neoadjuvant and adjuvant chemotherapy among patients with breast cancer with vs without HIV. A retrospective, matched cohort study enrolled women who received a diagnosis of breast cancer from January 1, 2000, through December 31, 2018. The electronic medical records of 3 urban, academic cancer centers were searched for women with confirmed HIV infection prior to or simultaneous with diagnosis of stage I to III breast cancer. Tumor registry data were used to identify 2 control patients with breast cancer without HIV for each participant with HIV, matching for study site, stage, and year of cancer diagnosis. Statistical analysis was performed from December 2022 to October 2023. HIV infection detected before or within 90 days of participants' breast cancer diagnosis. The primary outcome was time to breast cancer treatment initiation, defined as the number of days between cancer diagnosis and first treatment. The secondary outcome was overall RDI for patients who received chemotherapy. These outcomes were compared by HIV status using Cox proportional hazards regression and linear regression modeling, respectively, adjusting for confounding demographic and clinical factors. Exploratory outcomes included instances of anemia, neutropenia, thrombocytopenia, and liver function test result abnormalities during chemotherapy, which were compared using Fisher exact tests. The study enrolled 66 women with comorbid breast cancer and HIV (median age, 51.1 years [IQR, 45.7-58.2 years]) and 132 with breast cancer alone (median age, 53.9 years [IQR, 47.0-62.5 years]). The median time to first cancer treatment was not significantly higher among patients with HIV than those without (48.5 days [IQR, 32.0-67.0 days] vs 42.5 days [IQR, 25.0-59.0 days]; adjusted hazard ratio, 0.78, 95% CI, 0.55-1.12). Among the 36 women with HIV and 62 women without HIV who received chemotherapy, the median overall RDI was lower for those with HIV vs without HIV (0.87 [IQR, 0.74-0.97] vs 0.96 [IQR, 0.88-1.00]; adjusted P = .01). Grade 3 or higher neutropenia during chemotherapy occurred among more women with HIV than those without HIV (13 of 36 [36.1%] vs 5 of 58 [8.6%]). This matched cohort study suggests that patients with breast cancer and HIV may have experienced reduced adjuvant chemotherapy RDI, reflecting greater dose reductions, delays, or discontinuation. Strategies for supporting this vulnerable population during chemotherapy treatment are necessary.

Safety of Elranatamab in Patients with Triple-Class Refractory Relapsed/Refractory Multiple Myeloma (RRMM) in Magnetismm-17, a North American Expanded Access Protocol

BACKGROUND In the phase 2, registrational MagnetisMM-3 (NCT04649359) trial, patients with RRMM who had not previously received a B cell maturation antigen (BCMA)-directed therapy (n=123) achieved an objective response rate of 61% with single-agent elranatamab (ELRA), a BCMA-CD3 bispecific antibody. Common treatment-emergent adverse events (TEAEs) included infections (70%; 40% grade [G] 3/4) and CRS (58%; all G1/2). Here we report on the safety of ELRA in the MagnetisMM-17 (MM-17; NCT05462639) trial, a North American Expanded Access Protocol (EAP). METHODS MM-17 is an ongoing, single-arm, open-label study for patients with triple-class refractory RRMM (refractory to ≥1 proteasome inhibitor, ≥1 immunomodulatory drug, and ≥1 anti-CD38 antibody), and who had no prior BCMA-directed therapy. Patients must be ≥18 years of age and have a confirmed diagnosis of MM, measurable disease by IMWG criteria, an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0-1, adequate organ function, and no active, uncontrolled infection. The study is being conducted in the US and Canada. The primary objective is to provide access to ELRA for patients with RRMM and no access to comparable/alternative therapy. The secondary objective is to evaluate the safety and tolerability of ELRA. Patients received subcutaneous ELRA 76 mg once every week on a 28-day cycle after step-up doses of 12 and 32 mg during week 1. Dose frequency was reduced to once every 2 weeks (Q2W) after ≥6 cycles in patients with persistent response (≥partial response), and then from Q2W to Q4W after ≥6 Q2W cycles. Patients received ELRA until disease progression, unacceptable toxicity, withdrawal of consent, study termination, or ELRA becomes commercially available. TEAEs were graded by NCI CTCAE v5.0, except cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) which were graded according to the American Society for Transplantation and Cellular Therapy criteria (ASTCT). RESULTS As of April 28, 2023, 20 patients had enrolled in the trial. Median patient age was 72.5 years (range 53-82); 50% male, 85% white, and 15% Black/African American. At baseline, most patients had an ECOG PS of 1 (95%), and 40% had R-ISS disease stage III. Patients had a median of 4 prior lines of therapy (range 2-8); 95% and 35% of patients had triple-class and penta-drug refractory disease, respectively. At the time of data cut-off, 2 patients had discontinued due to progressive disease. Median treatment duration was 0.95 months (range 0.26-2.83); median relative dose intensity was 98.3% (range 48-105). TEAEs were reported in all 20 patients, with G3 or G4 events reported in 13 (65%). There were no G5 events. Thirteen (65%) patients developed CRS, all events were G1 (50%) or G2 (15%); no events G ≥3 were reported. After the first step-up dose, 11 (55%) patients had a CRS event. CRS events occurred in 3 patients (15%) and 1 patient (5%) after the second step-up dose and first treatment dose, respectively. The median time to onset was 2 days (range 1-4), and the median time to resolution was 3 days (range 1-5). ICANS occurred in 2 of the 20 patients (10%), both events were G1, with 1 occurring after the first step-up dose and the other after the second step-up dose. The median time to onset was 3 days (range 3-3) and the median time to resolution was 2.5 days (range 2-3). Four (20%) patients had infections, including 1 event each of G1 sinusitis, G2 acute sinusitis, G2 folliculitis, G2 upper respiratory tract infection and G3 bacterial conjunctivitis. Cytopenias were reported in 11 (55%) patients. The most common (occurring in ≥3 [15%] patients) cytopenias were neutropenia (30%; G3/4 25%), lymphopenia (20%; G3/4 15%), and thrombocytopenia (15%; G3/4 10%). CONCLUSIONS Early safety data (median treatment duration &amp;lt;1 month) from this ongoing expanded access protocol of elranatamab in patients with RRMM are consistent with results from the phase 2, registrational MagnetisMM-3 trial, with no new safety signal identified.

The Prognostic Impact of Relative Dose Intensity of Vincristine in R-CHOP for Untreated Patients with Diffuse Large B-Cell Lymphoma: A Supplementary Analysis of JCOG0601

Introduction R-CHOP (rituximab, cyclophosphamide [CY], doxorubicin [DXR], vincristine [VCR], and prednisolone) is the standard of care for diffuse large B-cell lymphoma (DLBCL) and cures around 60% of patients. However, some DLBCL survivors suffer from long-lasting peripheral neuropathy (PN) caused by VCR, and the dose of VCR is usually decreased to prevent severe PN. Though, there is a lack of information regarding the effect of VCR dose reduction on DLBCL prognosis, especially based on data from prospective clinical trials. Recently, VCR dose reduction was not associated with poor prognosis in patients with aggressive B-cell lymphomas, based on the results of the RICOVER-60 trial (NCT00052936) (Bewarder et al., Haematologica 2023). In this trial, R-CHOP was administered in 14-day cycles. To evaluate the clinical impact of relative dose intensity (RDI) of VCR (RDI O) in patients with DLBCL treated with tri-weekly R-CHOP (R-CHOP21), we conducted a supplemental analysis of the JCOG0601: randomized phase II/III trial of the Japan Clinical Oncology Group (jRCTs031180139). In the JCOG0601 trial, RW-CHOP21 (CHOP21 with eight doses of weekly rituximab) and R-CHOP21 were compared for progression-free survival (PFS) (Ohmachi et al., Blood Adv. 2021). Methods Between 2007 and 2014, 422 patients were enrolled in the JCOG0601 trial. Among them, 401 patients who received at least six courses of R-CHOP21 (n=206) or RW-CHOP21 (n=195) were eligible for this supplemental analysis. Those who could not complete six courses of chemotherapy were excluded because their treatment outcomes might be impaired mainly due to their disease aggressiveness and not the dose intensity of chemotherapy. As PFS was not significantly different between the two treatment arms, these 401 patients were analyzed together (Figure A). The impact of decreased RDI O on PFS was assessed using the Cox proportional hazard model and two-sided log-rank p-values with several cutoff values of RDI O (95, 90, 85, 80, 70, 60, or 50%). The VCR dose was reduced according to the protocol. As a subgroup analysis, the impact of RDI O was evaluated in patients whose RDI of CY and DXR (RDI C+H) were retained, defined as RDI C+H were both ≥85% (high RDI C+H), or not retained, defined as either or both of RDI C+H were &amp;lt;85% (low RDI C+H). Clinical factors, including the cell of origin (COO), as defined by the Hans algorithm, were evaluated for their association with poor PFS. Result The baseline clinical characteristics of the 401 patients were as follows: median age, 62 years (range, 20-79), male sex (54.6%); performance status of 0 or 1 (97.5%); Ann Arbor stage Ⅰ or Ⅱ (53.4%); and International Prognostic Index (IPI) of low or low-intermediate (82.6%). The median RDI O of the 401 patients was 97% (interquartile range [IQR], 89-100). The median RDI of CY and DXR were as high (96% each). At the data cut-off date (Dec 2017), the median follow-up time was 59.4 months, and the 3-year PFS was 81.5% (95% confidence interval [CI], 77.3-85.0). Among the cutoff values investigated, 95% of RDI O (&amp;lt;95% [n=161], ≥95% [n=240]) showed the smallest p value (log-rank test, p = 0.0679), and the hazard ratio (HR) of low RDI O against high RDI O was 1.452 (95% CI, 0.971-2.171) (Figure B); RDI O &amp;lt;95% clinically means VCR dose was reduced in one or more times. A cutoff value of 95% was used for further analyses. Patients with RDI O &amp;lt;95% tended to have low RDI C+H. According to RDI O of &amp;lt;95% vs. ≥95%, there was a similar difference in the subgroup of patients with high RDI C+H as in the whole population (n=324, HR 1.508, 95% CI 0.934-2.434), but no remarkable difference in low RDI C+H (n=77, HR 0.932, 95% CI 0.432-2.009). Multivariable analysis revealed that the presence of B symptoms (HR 1.859, 95% CI 1.078-3.207) and high-intermediate or high IPI scores (HR 1.721, 95% CI 1.031-2.873) were risk factors for PFS. However, neither RDI O &amp;lt;95%, low RDI C+H, nor COO subtypes showed no remarkable impact on poor PFS in this patient population. Conclusion Our study demonstrated that among patients with DLBCL who completed six or more courses of R-CHOP21, VCR dose reduction was not associated with poor PFS as much as the presence of B symptoms and high IPI risk. VCR dose reduction driven by toxicity might not impair its efficacy if patients can complete R-CHOP21 therapy.

Efficacy, Safety, and Survival Findings after Long-Term Follow-up from ZGJAK002, a Phase 2 Study Comparing Jaktinib 100 Mg Twice Daily with 200 Mg Once Daily for Myelofibrosis (MF)

Background: Jaktinib, a novel Janus kinase (JAK) and ACVR1 inhibitor, demonstrated promising clinical benefit with good tolerability, not only efficiently shrinking the spleen and reducing symptom burdens, but also improving anemia, in JAK-inhibitor naïve, ruxolitinib-intolerant or -resistant MF patients. We conducted a phase 2 study (the ZGJAK002 trial) to evaluate the effectiveness and safety of jaktinib at doses of 100 mg BID and 200 mg QD in JAK-inhibitor naïve patients with intermediate or high risk MF. Herein we present long-term data with a median follow-up time of 30.7 months. Methods: Patients who completed the 24 weeks of study treatment, tolerated the drug well, and had evidence of clinically significant improvement were allowed to enter an extension phase. Dose modifications were permitted according to the platelet count and neutrophil count. Duration of spleen response (from the first spleen volume reduction of ≥35% [SVR35] to an increase of 25% or more from the nadir), overall survival (OS), and leukemia-free survival (LFS) were evaluated in an intent-to-treat analysis using a Cox proportional hazard model that estimated the treatment effect. Results: A total of 118 patients were enrolled and treated with either jaktinib 100 mg BID (n=66) or 200 mg QD (n=52). The majority of patients remained on treatment after 48 weeks (100 mg BID group: 74.2%; 200 mg QD group: 65.4%). At the data cutoff of June 30, 2022, treatment was continued in 35 (29.7%) patients (30.3% in BID; 28.8% in QD). The best spleen response, defined as SVR35 at any time, was achieved by 59.3% (95% confidence interval [CI]: 49.9%-68.3%) of patients. The 100 mg BID group demonstrated a greater best spleen response (69.7% [95% CI: 57.1%-80.4%]) compared to the 200 mg QD group (46.2% [95% CI: 32.2%-60.5%]). The median maximum reduction from baseline in spleen volume was 49.7%. The median duration of spleen response was not reached, with 51.9% (95% CI: 36.0%-65.7%) of patients from 100 mg BID and 66.5% (95% CI: 41.4%-82.8%) from 200 mg QD maintaining a spleen response for over 108 weeks (Figure 1). The proportion of patients who achieved an improvement of ≥50% in the TSS (TSS50) was 69.6% (95% CI: 55.9%-81.2%) at week 24 and 74.2% (95% CI: 55.4%-88.1%) at week 108 in the 100 mg BID group. The proportion of patients who achieved TSS50 was 57.5% (95% CI: 40.9%-73.0%) at week 24 and 66.7% (95% CI: 44.7%-84.4%) at week 108 in the 200 mg QD group. As of the data cutoff, 25 (21.2%) deaths were reported (12 [18.2%] of 66 in the 100 mg BID group and 13 [25.0%] of 52 patients in the 200 mg QD group). Median OS was not reached, with 12, 24, and 36-month survival rates of 92.3%, 85.8%, and 78.2% in the 100 mg BID and 92.3%, 78.0%, and 73.6% in 200 mg QD groups. Median LFS was not reached, with 12, 24, and 36-month LFS rates of 94.8%, 90.6%, and 84.1% in the 100 mg BID and 95.5%, 85.7%, and 85.7% in 200 mg QD groups. The 100 mg BID induced more increase from baseline in hemoglobin concentration over 144 weeks with a range of 2.18-10.17 g/L compared to -1.74-1.96 g/L with 200 mg QD. The median (range) duration of jaktinib exposure was 672.0 (14-1262) days in the 100 mg BID group and 588.5 (42-1175) days in the 200 mg QD group. The median relative dose intensity for jaktinib was 97.5% (98.1% in BID; 96.3% in QD). There was no unexpected increased incidence of adverse events (AEs) with longer exposure. The most common grade ≥3 adverse drug reactions were anemia (15.2% vs. 21.2%), thrombocytopenia (15.2% vs. 11.5%), and infectious pneumonia (10.6% vs. 1.9%) in the 100 mg BID and 200 mg QD groups, respectively. Notably, infectious pneumonia (10.6%), thrombocytopenia (4.5%), and peripheral neuropathy (3.0%) were the most common drug-related serious AEs. AEs leading to treatment discontinuation occurred in 14 patients (11.9%), with higher rate in the 100 mg BID group compared to the 200 mg QD group (15.2% vs. 7.7%). AEs resulted in death in seven (5.9%) patients, with similar rates in both groups (6.1% in BID; 5.8% in QD). Conclusions: With over 30-month follow-up, jaktinib at doses of 100 mg BID and 200 mg QD demonstrated durable high effective rates and improved survival rates without new safety issue. The long-term data further supports the recommendation of 100 mg BID over 200 mg QD administration. It also concluded that jaktinib remains the treatment strategy that offers excellent chances for improving survival in MF patients.

Fixed-Duration Pirtobrutinib Combined with Venetoclax ± Rituximab in Relapsed/Refractory Chronic Lymphocytic Leukemia: Updated Results, Including MRD Data, from the BRUIN Phase 1b Study

Background: Covalent (c) Bruton tyrosine kinase inhibitors (BTKi) have transformed the management of chronic lymphocytic leukemia (CLL). Recent clinical studies have evaluated the safety and efficacy of fixed-duration regimens with venetoclax and cBTKi. While these combinations are effective, their use may be limited by toxicity. Pirtobrutinib, a highly selective, non-covalent (reversible) BTKi, has shown promising safety and efficacy in heavily pretreated relapsed or refractory (R/R) CLL patients (pts). Here, we report the safety and efficacy of fixed-duration pirtobrutinib combined with venetoclax ± rituximab in pts with R/R CLL. Methods: Pts with R/R CLL were eligible for pirtobrutinib combined with venetoclax ± rituximab in the phase 1b portion of the multicenter phase 1/2 BRUIN study (NCT03740529). Prior cBTKi therapy was allowed, but not prior venetoclax. Pts were enrolled into sequential cohorts, first in the pirtobrutinib + venetoclax (PV) cohort and then the PV + rituximab (PVR) cohort. Pirtobrutinib 200 mg QD was started on cycle 1 day 1, and venetoclax was started on cycle 2 day 1 with the standard 5-week dose ramp to 400 mg QD target dose. PV was given for up to 24 cycles; each cycle was 28 days. For the PVR cohort, rituximab was given at 375 mg/m 2 on cycle 1 day 1 and then 500 mg/m 2 on day 1 of cycles 2-6. The primary endpoint was safety as assessed by treatment-emergent adverse events (TEAEs) graded according to CTCAE v5.0. Other key endpoints included overall response rate (ORR), progression-free survival (PFS), and minimal residual disease (MRD). Undetectable MRD (uMRD) was defined as less than 1 CLL cell/10,000 nucleated cells (&amp;lt;1x10 -4) in peripheral blood by ClonoSEQ® assay (Adaptive Biotechnologies, Seattle, WA). A data cut of May 5, 2023, was utilized. Results: Fifteen pts received PV, and 10 received PVR. Median age was 66 years (range, 49-77) for those who received PV and 69 (range, 39-78) for those who received PVR. Median prior lines of therapy was 1 (range, 1-2) for the PV cohort and 2 (range 1-4) for the PVR cohort. Most pts had received prior chemotherapy (PV=53%; PVR=60%), CD20 monoclonal antibody (73%; 70%), and cBTKi (73%; 60%). The majority of pts had IGHV unmutated CLL (PV=73%; PVR=89%). ORR was 93.3% (95% CI, 68.1-99.8) for the 15 pts receiving PV and 100% (95% CI, 69.2-100.0) for the 10 pts receiving PVR, with 10 complete responses (PV=7; PVR=3). Median duration of follow-up for PFS was 22.1 months (IQR, 20.1-25.7) for PV and 22.1 months (IQR, 20.7-22.1) for PVR; PFS at 18 months was 92.9% (95% CI, 59.1-99.0) for the 15 pts receiving PV and 80.0% (95% CI, 40.9-94.6) for the 10 pts receiving PVR. The overall uMRD rate at cycle 13 was 70.8% (PV=10; PVR=7) for the 24 evaluable pts, with 87.5% (PV=12; PVR=9) of pts achieving uMRD at some time during the trial and all but one pt sustaining uMRD during subsequent MRD assessments ( Figure). Twenty-two pts discontinued treatment (PV=14; PVR=8); of these, 14 completed all 24 cycles of therapy (PV=9; PVR=5) and 8 discontinued early because of progressive disease (PV=2), adverse events (PVR=2), protocol noncompliance (PV=1), death unrelated to treatment (PVR=1), or other reasons (PV=2). Three pts (PV=1; PVR=2) continue to receive treatment. The median relative dose intensity was similar in both cohorts (PV=97.9%; PVR=98.6%). The most common TEAE of any grade included nausea (PV=60.0%; PVR=40.0%), fatigue (53.3%; 50.0%), and diarrhea (46.7%; 60.0%). The most common grade ≥3 TEAE was neutropenia/neutrophil count decreased (PV=46.7%; PVR=60.0%). Grade ≥3 clinical tumor lysis syndrome occurred during venetoclax dose escalation (PV=2), including a grade 3 case that resolved spontaneously after 24 hours and a grade 4 case that resolved after short-term intravenous fluids. Treatment-related adverse events led to dose reductions in three pts (PV=1; PVR=2) and treatment discontinuation in two pts (PVR=2). Conclusions: Fixed-duration pirtobrutinib combined with venetoclax ± rituximab was well tolerated and demonstrated sufficiently promising efficacy to warrant further investigation in pts with R/R CLL. The BRUIN CLL-322 phase 3 trial comparing PVR vs VR in previously treated CLL is currently enrolling pts (NCT04965493).