Durable Efficacy Research Articles

Durable response after tisagenlecleucel in adults with relapsed/refractory follicular lymphoma: ELARA trial update

AbstractTisagenlecleucel is approved for adults with relapsed/refractory (r/r) follicular lymphoma (FL) in the third- or later-line setting. The primary analysis (median follow-up, 17 months) of the phase 2 ELARA trial reported high response rates and excellent safety profile in patients with extensively pretreated r/r FL. Here, we report longer-term efficacy, safety, pharmacokinetic, and exploratory biomarker analyses after median follow-up of 29 months (interquartile range, 22.2-37.7). As of 29 March 2022, 97 patients with r/r FL (grades 1-3A) received tisagenlecleucel infusion (0.6 × 108-6 × 108 chimeric antigen receptor–positive viable T cells). Bridging chemotherapy was allowed. Baseline clinical factors, tumor microenvironment, blood soluble factors, and circulating blood cells were correlated with clinical response. Cellular kinetics were assessed by quantitative polymerase chain reaction. Median progression-free survival (PFS), duration of response (DOR), and overall survival (OS) were not reached. Estimated 24-month PFS, DOR, and OS rates in all patients were 57.4% (95% confidence interval [CI], 46.2-67), 66.4% (95% CI, 54.3-76), and 87.7% (95% CI, 78.3-93.2), respectively. Complete response rate and overall response rate were 68.1% (95% CI, 57.7-77.3) and 86.2% (95% CI, 77.5-92.4), respectively. No new safety signals or treatment-related deaths were reported. Low levels of tumor-infiltrating LAG3+CD3+ exhausted T cells and higher baseline levels of naïve CD8+ T cells were associated with improved outcomes. Tisagenlecleucel continued to demonstrate highly durable efficacy and a favorable safety profile in this extended follow-up of 29 months in patients with r/r FL enrolled in ELARA. This trial was registered at www.clinicaltrials.gov as #NCT03568461.

Tildrakizumab for moderate-to-severe plaque psoriasis in Chinese patients: A 12-week randomized placebo-controlled phase III trial with long-term extension.

There is a need for effective and safe therapies for psoriasis that provide sustained benefits. The aim of this study was to assess the efficacy and safety of tildrakizumab, an anti-interleukin-23p19 monoclonal antibody, for treating moderate-to-severe plaque psoriasis in Chinese patients. In this multi-center, double-blind, phase III trial, patients with moderate-to-severe plaque psoriasis were enrolled and randomly assigned (1:1) to receive subcutaneous tildrakizumab 100 mg or placebo at weeks 0 and 4. Patients initially assigned to placebo were switched to receive tildrakizumab at weeks 12, 16, and every 12 weeks thereafter. Patients in the tildrakizumab group continued with tildrakizumab at week 16, and every 12 weeks until week 52. The primary endpoint was the Psoriasis Area and Severity Index (PASI 75) response rate at week 12. At week 12, tildrakizumab demonstrated significantly higher PASI 75 response rates (66.4% [73/110] vs. 12.7% [14/110]; difference, 51.4% [95% confidence interval (CI), 40.72, 62.13]; P <0.001) and Physician's Global Assessment (60.9% [67/110] vs. 10.0% [11/110]; difference, 49.1% [95% CI, 38.64, 59.62]; P <0.001) compared to placebo. PASI 75 response continued to improve over time in both tildrakizumab and placebo-switching to tildrakizumab groups, reaching maximal efficacy after 28 weeks (86.8% [92/106] vs . 82.4% [89/108]) and maintained up to 52 weeks (91.3% [95/104] vs . 87.4% [90/103]). Most treatment-emergent adverse events were mild and not related to tildrakizumab. Tildrakizumab demonstrated durable efficacy through week 52 and was well tolerated in Chinese patients with moderate-to-severe plaque psoriasis. ClinicalTrials.gov , NCT05108766.

Efficacy of long-term risankizumab treatment for moderate-to-severe plaque psoriasis: Subgroup analyses by baseline characteristics and psoriatic disease manifestations through 256 weeks (LIMMitless trial).

Psoriasis is an inflammatory skin disease that impacts a heterogeneous group of patients and can have multiple clinical manifestations. Risankizumab is approved for the treatment of moderate-to-severe plaque psoriasis. To evaluate the long-term efficacy of risankizumab according to baseline patient characteristics, and for the treatment of high-impact disease manifestations (nail, scalp and palmoplantar psoriasis), through 256 weeks of continuous treatment in the phase 3 LIMMitless study. This subgroup analysis evaluated pooled data from patients with moderate-to-severe plaque psoriasis who were randomized to risankizumab 150 mg during two double-blind, phase 3, 52-week base studies (UltIMMa-1/2; NCT02684370/NCT02684357) and were enrolled in the phase 3 LIMMitless open-label extension study (NCT03047395). Subgroup assessments included the proportion of patients who achieved ≥90%/100% improvement in Psoriasis Area and Severity Index (PASI 90/100). Among patients with nail, scalp and/or palmoplantar psoriasis in addition to skin psoriasis, assessments included changes from baseline in and resolution of these three psoriatic manifestations. Overall, a numerically similar proportion of patients (N = 525) achieved PASI 90/100 through Week 256, regardless of their baseline age, sex, body mass index, weight, PASI or psoriatic arthritis status. Patients with nail, scalp and/or palmoplantar psoriasis experienced substantial improvements in manifestation-specific indices (mean improvement from baseline to Week 256 of >81%, >94% and >97%, respectively); in patients with all three manifestations (N = 121), 44.6% achieved complete clearance of these manifestations at Week 256. Risankizumab demonstrated generally consistent efficacy through 256 weeks across patient subgroups and showed durable long-term efficacy for psoriatic disease manifestations.

Biomarkers of pembrolizumab efficacy in advanced anal squamous cell carcinoma: analysis of a phase II clinical trial and a cohort of long-term responders

BackgroundRecent trials suggest that programmed cell death 1 (PD-1)-directed immunotherapy may be beneficial for some patients with anal squamous cell carcinoma and biomarkers predictive of response are greatly needed.MethodsThis multicenter...

Correlation of changes in inflammatory and collagen biomarkers with durable guselkumab efficacy through 2 years in participants with active psoriatic arthritis: results from a phase III randomized controlled trial

Background: Guselkumab (human monoclonal antibody) selectively inhibits the interleukin (IL)-23p19 subunit. Objectives: Assess the longer-term pharmacodynamic effects of guselkumab and explore associations between such effects and clinical responses in patients with active psoriatic arthritis (PsA). Design: DISCOVER-2 randomized 739 biologic-naïve patients with active PsA (swollen/tender joint counts each ⩾5, C-reactive protein (CRP) ⩾0.6 mg/dL) to guselkumab (100 mg every 4 weeks (Q4W) or at Weeks 0, 4, and then Q8W) or placebo. Guselkumab-randomized participants with available serum biomarker data (randomly selected to reflect demographic and disease characteristics of the DISCOVER-2 population) comprised inflammatory ( N = 100) and collagen ( N = 178) biomarker cohorts. Methods: Pharmacodynamic effects of guselkumab through 2 years on inflammatory and collagen biomarker levels (general linear model) and associations between biomarkers and improvements in composite measures of joint, skin, and overall disease activity (Spearman linear regression) through 2 years were assessed. The relationship between the pharmacodynamic effects of guselkumab and achieving ⩾50% improvement in the American College of Rheumatology response criteria (ACR50) was assessed using a general linear model. Results: With guselkumab, pharmacodynamic effects on inflammatory (CRP, IL-6, serum amyloid A (SAA), IL-17A, IL-17F, IL-22, and beta-defensin 2 (BD-2)) and collagen (matrix metalloproteinase-degradation type I, III, IV, and VI collagen (C1M, C3M, C4M, and C6M)) biomarker levels were sustained or enhanced through Week 100. Throughout follow-up timepoints (Week 24/52/100), decreases in CRP, IL-6, C1M, and C6M levels correlated ( r = 0.26–0.30; p &lt; 0.05) with improved joint disease activity (Disease Activity in Psoriatic Arthritis); decreases in IL-17A, IL-17F, IL-22, and BD-2 levels correlated ( r = 0.34–0.58; p &lt; 0.05) with improved skin disease (Psoriasis Area and Severity Index); and decreases in C1M, C3M, C4M, and C6M correlated ( r = 0.27–0.31; p &lt; 0.05) with improved overall disease activity (Psoriatic Arthritis Disease Activity Score). Significantly ( p &lt; 0.05) greater reductions from baseline at Week 100 in CRP, IL-6, SAA, and C1M levels were observed in participants improving from Week 24 ACR50 nonresponse to Week 100 ACR50 response and were accompanied by a significant decrease in C1M from Week 24 to Week 100 versus nonresponders at both Weeks 24 and 100. Conclusion: In biologic-naïve participants with active PsA, guselkumab elicited substantial and enduring reductions in biomarkers that were associated with durable improvements in joint, skin, and overall disease activity through 2 years of DISCOVER-2. Trial registration: NCT03158285 (clinicaltrials.gov identifier).

Faricimab Treat-and-Extend for Diabetic Macular Edema: Two-Year Results from the Randomized Phase 3 YOSEMITE and RHINE Trials

PurposeTo evaluate the 2-year efficacy, durability, and safety of dual angiopoietin-2/vascular endothelial growth factor (VEGF)-A pathway inhibition with intravitreal faricimab according to a personalized treat-and-extend–based regimen (T&E) with up to every-16-week (Q16W) dosing in the YOSEMITE/RHINE (NCT03622580/NCT03622593) phase 3 trials of diabetic macular edema (DME). DesignRandomized, double-masked, noninferiority phase 3 trials. ParticipantsAdults with visual acuity loss due to center-involving DME. MethodsPatients were randomized 1:1:1 to faricimab 6.0 mg Q8W, faricimab 6.0 mg T&E (previously referred to as personalized treatment interval), or aflibercept 2.0 mg Q8W. The T&E up to Q16W dosing regimen was based on central subfield thickness (CST) and best-corrected visual acuity (BCVA) change. Main Outcome MeasuresIncluded changes from baseline in BCVA and CST, number of injections, durability, absence of fluid, and safety through week 100. ResultsIn YOSEMITE/RHINE (N=940/951), noninferior year 1 visual acuity gains were maintained through year 2; mean BCVA change from baseline at 2 years (weeks 92/96/100 average) with faricimab Q8W (YOSEMITE/RHINE, +10.7/+10.9 letters) or T&E (+10.7/+10.1 letters) were comparable with aflibercept Q8W (+11.4/+9.4 letters). The median number of study drug injections was lower with faricimab T&E (YOSEMITE/RHINE, 10/11 injections) versus faricimab Q8W (15 injections) and aflibercept Q8W (14 injections) across both trials during the entire study. In the faricimab T&E arms, durability was further improved during year 2, with >60% of patients on Q16W dosing and ∼80% on ≥Q12W dosing at week 96. Almost 80% of patients who achieved Q16W dosing at week 52 maintained Q16W dosing without an interval reduction through week 96. Mean CST reductions were greater, and more patients achieved absence of DME (CST <325μm) and absence of intraretinal fluid with faricimab Q8W or T&E versus aflibercept Q8W through year 2. Overall, faricimab was well tolerated, with a safety profile comparable to aflibercept. ConclusionsClinically meaningful visual acuity gains from baseline, anatomic improvements, and extended durability with intravitreal faricimab up to Q16W were maintained through year 2. Faricimab given as a personalized T&E–based dosing regimen supports the role of dual angiopoietin-2/VEGF-A inhibition to promote vascular stability and provide durable efficacy for patients with DME.

Abstract B055: Characterization of highly selective and CNS-penetrant PARP1 inhibitors

Abstract First-generation PARP1/2 inhibitors are FDA-approved for cancers such as breast, ovarian prostate and pancreas and provide significant therapeutic benefit to patients whose tumors harbor BRCA1 or BRCA2 mutations or homologous recombination deficiency (HRD). However, their use is associated with hematological toxicities that narrow their therapeutic index and restrict their application, particularly in combination with standard-of-care chemotherapy. All four FDA-approved PARP1 inhibitors are largely non-selective for the closely related enzyme PARP2, inhibition of which has been shown to drive hematotoxicity. Hence, the development of second-generation molecules highly selective for PARP1 over PARP2 offers a significant opportunity to 1) dramatically enhance therapeutic index, 2) enable additional precision medicine/combination approaches with chemotherapy, radiotherapy, immunotherapy and targeted agents and 3) expand the addressable patient population to those whose tumors harbour additional DDR defects. Utilising X-ray crystallography and structure-based drug design, we describe the characterization of exquisitely selective PARP1 inhibitors. These molecules demonstrate high potency in multiple biochemical and cell-based assays, including viability and colony forming unit read-outs in BRCA-deficient cancer cells, whilst sparing HR-proficient cancer cell lines and primary cells. The molecules are potent PARP1-DNA trappers and exhibit high selectivity across the PARP family and wider secondary pharmacology targets. The molecules potentiate the activity of ATR inhibitors when tested in ATM-deficient cancer cell lines. This chemical series generally exhibits highly desirable physico-chemical and in vitro ADME properties, which translate to high oral bioavailability and low clearance in rodent PK studies. Exemplar molecules also demonstrate high rat CNS penetrance using in vivo microdialysis. Lead molecules yield deep and durable dose-dependent anti-tumor efficacy in a variety of BRCAm xenograft models with responses continuing after cessation of treatment. The compounds demonstrate strong PK/PD relationships which correlate with anti-tumor efficacy using inhibition of tumor PARylation as a PD read-out. Strikingly, the molecules demonstrate compelling anti-tumor efficacy in BRCA-deficient xenograft models that are known to be largely resistant to FDA-approved non-selective PARP1/2 inhibitors. Taken together, these data predict low once daily therapeutic oral dosing based on a highly favorable pre-clinical PK profile and potent in vivo efficacy, with the potential to demonstrate improved efficacy and tolerability compared to marketed PARP inhibitors. In summary, we describe the characterization of next generation potent and selective CNS-penetrant PARP1 inhibitors. These molecules have the potential for an improved safety profile and greater combination potential with standard-of-care and targeted anti-cancer therapies. Citation Format: Phillip M Cowley, Barry E McGuinness, Gillian M Campbell, Alan Wise. Characterization of highly selective and CNS-penetrant PARP1 inhibitors [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B055.

Abstract B012: Validation of the OncoSignature assay, an ACR-368-tailored response-predictive quantitative multiplexed immunofluorescent assay for prediction of sensitivity to the CHK1/2 inhibitor ACR-368 in individual patients with cancer

Abstract Background: The CHK1/2 kinase inhibitor ACR-368 (Prexasertib) demonstrated durable single-agent efficacy in a subset of patients with high grade serous ovarian, anal and head and neck cancers in past trials. Using a quantitative phospho-proteomics approach, we identified three orthogonal candidate biomarkers tailored to predict tumor response to ACR-368 treatment. The OncoSignature® assay is based on immunofluorescent staining of biomarkers in FFPE tumor sections with image acquisition, analysis, and scoring of biomarkers. The sample is OncoSignature positive if all three biomarker scores are above their thresholds. We validated the OncoSignature® assay to predict response to ACR-368 in cancer cell lines and ovarian cancer PDX models. Here, we further validated OncoSignature® assay in novel cancer indications and in patient biopsy samples from ACR-368 clinical trials. Methods: Multiple cancer types were tested with the OncoSignature® assay for prevalence of potential ACR-368 responders. For validation, endometrial cancer PDX models were tested in anACR-368 efficacy study. Blinded untreated PDX tumors were analyzed in the OncoSignature® assay and results locked prior to unblinding and statistical analysis. Adapted [CS1] Oncosignature assay was applied to frozen pretreatment ovarian cancer biopsies from a single center ACR-368 monotherapy Ph2 trial (NCT02203513). OncoSignature® assay was also applied to FFPE pretreatment ovarian cancer biopsies from a multi-center ACR-368 monotherapy Ph 2 trial (NCT03414047) and from the NCT02203513 trial. After biomarker scores were generated and locked, patient treatment outcomes were unblinded and ACR-368 response was compared with OncoSignature prediction. Results: Evaluation of multiple cancer indications revealed a concordance between OncoSignature-predicted prevalence of ACR-368 responders and results of ACR-368 treatment observed in clinical trials. Metastatic ovarian cancer had 30% of predicted responders and 30% and 14% observed RECIST responses the above-cited trials. Squamous lung cancer had no predicted responders and no RECIST responses in a clinical trial. Endometrial and bladder cancer had a high prevalence of predicted responders with 40% and 36%, respectively. The endometrial cancer PDX efficacy study had multiple complete responses predicted by OncoSignature® assay with an AUC of 0.88. For frozen and FFPE patient biopsy samples from Phase 2 ACR-368 trials, OncoSignature positive groups had highly significant response enrichment to 47% and 57%, respectively, and significant increases in progression free survival time. Conclusions: Bladder and endometrial cancers were identified as novel indications with high prevalence of predicted ACR-368 responders. The OncoSignature® assay significantly predicted response in endometrial PDX models and in samples from ovarian cancer patients treated with ACR-368. OncoSignature® assay driven clinical trial (NCT05548296) in ovarian, endometrial and bladder cancers was initiated to test benefit to patients. Citation Format: Ayesha Murshid, Christina Noe, Kailash Singh, Sibgat Choudhury, Jayakumar Nair, James Dunyak, Michail Shipitsin, Jung-Min Lee, Peter Blume-Jensen. Validation of the OncoSignature assay, an ACR-368-tailored response-predictive quantitative multiplexed immunofluorescent assay for prediction of sensitivity to the CHK1/2 inhibitor ACR-368 in individual patients with cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B012.

Abstract PR003: Repotrectinib in patients with ROS1 fusion-positive (ROS1+) non-small cell lung cancer (NSCLC): Update from the pivotal phase 1/2 TRIDENT-1 trial

Abstract Introduction: Repotrectinib, a next-generation ROS1 tyrosine kinase inhibitor (TKI), has demonstrated durable activity and manageable safety in patients (pts) with locally advanced/metastatic ROS1+ NSCLC in the pivotal phase 1/2 TRIDENT-1 trial (NCT03093116). We report efficacy with a minimum follow-up of 14 months (mo) from start of treatment in two ROS1+ NSCLC primary efficacy cohorts and safety in all pts treated at the recommended phase 2 dose (RP2D). Methods: Pts with ROS1+ NSCLC were assigned to 4 cohorts by treatment history: TKI-naïve, 1 TKI and no chemo, 1 TKI and 1 platinum-based chemo, and 2 TKIs and no chemo. Repotrectinib RP2D was 160 mg once daily for 14 days, then 160 mg twice daily. Phase 2 primary endpoint was confirmed objective response rate (cORR) by Blinded Independent Central Review per RECIST v1.1. Secondary endpoints included duration of response (DOR), progression-free survival (PFS), intracranial ORR, cORR in TKI-pretreated pts with ROS1 G2032R NSCLC, and safety. Efficacy analyses included pts with ≥14 mo follow-up. Safety assessments included pts treated at RP2D across all study cohorts. Results: At data cutoff (December 19, 2022), median (range) follow-up in the primary efficacy cohorts was 24.0 (14.2–66.6) mo in the TKI-naïve cohort (n=71) and 21.5 (14.2–58.6) mo in the 1 prior TKI and no chemo cohort (n=56). In the TKI-naïve cohort, cORR was 79% (95% CI, 68–88). Median (95% CI) DOR was 34.1 (25.6–not estimable [NE]) mo; estimated 12- and 18-mo DOR rates were 83% (73–93) and 79% (68–90), respectively. Median PFS (95% CI) was 35.7 (27.4–NE) mo; estimated 12- and 18-mo PFS rates were 77% (66–87) and 70% (59–81), respectively. In the 1 prior TKI and no chemo cohort, cORR was 38% (95% CI, 25–52). Median DOR (95% CI) was 14.8 (7.6–NE) mo; estimated 12-mo DOR rate was 56% (34–77). Median PFS (95% CI) was 9.0 (6.8–19.6) mo; estimated 12-mo PFS rate was 41% (27–56). The median (range) time to response was 1.8 (0.9–5.6) mo in the TKI-naïve cohort and 1.8 (1.6–3.6) mo in the 1 prior TKI and no chemo cohort. Among pts with measurable brain metastasis at baseline, intracranial ORR was 89% (95% CI, 52–100) in the TKI-naïve cohort (n=9), and 38% (95% CI, 14–68) in the 1 prior TKI and no chemo cohort (n=13). In pts with TKI-pretreated ROS1 G2032R NSCLC (n=17), cORR was 59% (33–82). Among pts receiving repotrectinib at RP2D (n=426), treatment-emergent adverse events (TEAEs) occurred in 422 (99%), most commonly dizziness (62%). Grade ≥3 TEAEs occurred in 216 (51%) and were considered treatment-related in 122 (29%). TEAEs led to dose reduction and treatment discontinuation in 38% and 7% of pts, respectively. Additional analysis in CNS efficacy and by subsequent therapies will be presented. Conclusion: With a minimum follow-up of 14 mo in TRIDENT-1, repotrectinib continued to demonstrate durable efficacy in pts with ROS1+ NSCLC, including intracranial activity, in both TKI-naïve and 1 prior TKI and no chemo cohorts. Safety in pts treated at RP2D was manageable, consistent with previous reports in all treated pts. Prior:WCLC(Sep 10). Citation Format: Jessica J Lin, Byoung Chul Cho, D. Ross Camidge, Sang-We Kim, Benjamin Solomon, Rafal Dziadziuszko, Benjamin Besse, Koichi Goto, Adrianus Johannes de Langen, Jürgen Wolf, Ki Hyeong Lee, Sanjay Popat, Christoph Springfeld, Misako Nagasaka, Enriqueta Felip, Nong Yang, Shun Lu, Steven Kao, Vamsidhar Velcheti, Parneet Cheema, Shanna Stopatschinskaja, Minal Mehta, Denise Trone, Felipe Ades, Christophe Y. Calvet, Alexander Drilon. Repotrectinib in patients with ROS1 fusion-positive (ROS1+) non-small cell lung cancer (NSCLC): Update from the pivotal phase 1/2 TRIDENT-1 trial [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr PR003.

Combination of Selinexor with BTK Inhibitor for Central Nervous System Diffuse Large B-Cell Lymphoma, Possible Mechanisms and Therapeutic Potential Exploration

Background: Primary central nervous system lymphoma (PCNSL) is a rare aggressive extra-nodal non-Hodgkin lymphoma (NHL) of which over 90% are diffuse large B-cell lymphoma (DLBCL). High-dose methotrexate (HD-MTX)-based regimens are the dominant therapy for newly diagnosed PCNSL, but the patients' complete remission rate (CRR) is merely about 50%. Bruton tyrosine kinase (BTK), a critical kinase in the B cell receptor (BCR) signaling pathway, contributes to the degradation of FOXO3a and promotes abnormal B cell proliferation. Recent studies revealed that BTK inhibitors (BTKi) play a role in various B cell lymphomas, including DLBCL, and have also shown promising efficacy in PCNSL. However, the clinical management of PCNSL is still challenging for its limited treatment options and poor prognosis, especially when patients developed acquired resistance to BTKi. Selinexor (KPT-330) is a first-ever oral small molecule Exportin-1 (nuclear output protein XPO1) inhibitor with a molecular weight of 443.31 Da, which can efficiently cross the blood-brain barrier. Currently Selinexor was found to promote the aggregation of FOXO3a and could synergistically inhibit PI3K/AKT and NF-κB pathways with BTKi to overcome acquired BTKi resistance. To investigate the therapeutic potential of Selinexor and BTKi in PCNSL, we examined the combination both in DLBCL cells and A20 transplantation mice, and further explored the clinical efficacy in PCNSL patients. Methods and Results: ABC-DLBCL cell lines (OCI-LY3 and OCI-LY10) were treated with Selinexor for 48 hours. Western blot analysis showed that Selinexor inhibited NF-κB, P-STAT3, and NFATc1 signaling pathways in DLBCL in vitro. Combining Selinexor(1μM) with ICP-022(2μM), a BTKi, resulted in more notable inhibition of the above tumor signaling pathways. A20 murine B-cell lymphoma transplantation models were divided into a control group, Selinexor monotherapy group, ICP-022 monotherapy group, and combination group. Tumor volume was measured after 30 days (Figures 1A), and the number of CD4+ T cells and CD8+ T cells and the corresponding cellular expression of PD-1 and TIM-3 in the spleen and tumor tissues of mice were detected. The results showed that the tumor volume in the combination group was minimized, and the number of CD4+ T cells and CD8+ T cells in spleens and tumors in this group was significantly increased, while PD-1 and TIM-3 expression was downregulated (Figures 1B-C). Based on these results, a prospective, open-label, single-arm, multicenter study was conducted with MSZ regimen (MTX, BTKi, Selinexor) for the treatment of PCNSL (Trial Registration Number: ChiCTR2200062154). Newly diagnosed primary and secondary central DLBCL patients (18-80 years old) received a 6-cycle MSZ regimen (HDMTX 3.5 g/m 2 3-h infusion d1, Zanubrutinib 160 mg Bid po, Selinexor 40 mg Biw po, 3 weeks per cycle) and evaluated by MRI/PET. 5 patients (2 GCB-DLBCL, 3 ABC-DLBCL) were enrolled, with a median age of 65 years (range: 54-73 years), 100% achieved metabolic remission (Figure 2A) and maintained long-term efficacy. 4 patients achieved early deep remissions of over 75% reduction with 1 cycle of treatment, and 1 patient had a complete remission after 2 cycles of treatment (Figures 2B). 3 patients chose radiation therapy as consolidation after the end of induction chemotherapy. 2 others were on maintenance therapy with Selinexor combined with Zanubrutinib, one of them has completed the two-year maintenance treatment and maintained sustained remission till now. Only 1 patient experienced several grade 3 adverse events (AEs) including anemia, decreased white blood cell and platelet counts, and elevated alanine aminotransferase.1 patient developed mild renal insufficiency, which recovered 6 months after the end of treatment. Patients were generally well-tolerated and there were no treatment-related deaths. Conclusion: This is the first report describing that Selinexor combined with BTKi can synergistically inhibit the DLBCL tumor signaling pathway and repairing the immune microenvironment. Correspondingly, in treatment of central DLBCL patients, the novel therapeutic strategy of MSZ regimen has achieved impressive results, with a CRR of 100%. Most patients attained early and rapid deep remissions with durable efficacy. This study provides theoretical support and preliminary clinical data for the combined application of Selinexor and BTK inhibitors.

A Single Arm Phase II Pilot Study of Low Dose Vemurafenib Plus Rituximab in the Front-Line and Relapsed/Refractory Treatment of Hairy Cell Leukemia

Introduction: Hairy Cell Leukemia (HCL) is a rare, low-grade B-cell malignancy that is characterized by cytopenias, infections and splenomegaly. Given the chronic and incurable nature of this disorder, limiting therapy-related toxicity is of paramount importance. Though purine nucleoside analogs have an established track record of durable efficacy, they are associated with significant myelosuppression and immunosuppression as well as late secondary malignancies. Mechanistic exploitation of aberrant BRAF V600E activation with vemurafenib in combination with CD20 targeting with rituximab has provided an effective means of eradicating leukemic cells without significant myelosuppression or immunosuppression. However, vemurafenib at the standard dose of 960 mg twice daily is often poorly tolerated and frequently requires dose reduction. We conducted a pilot study of rituximab and low-dose vemurafenib (240 mg twice daily) in patients with untreated or relapsed HCL, with a focus on providing a non-cytotoxic regimen that minimizes toxicity with potentially comparable treatment outcomes. Methods: This phase 2, open-label, single-arm, investigator-initiated pilot trial was designed, conducted, and managed at Scripps Clinic in La Jolla, California. We enrolled adult patients with HCL and mutated BRAF V600E who met standard treatment initiation criteria defined by an ANC ≤1.0, Hgb ≤ 10.0 or PLT ≤100K. The treatment plan consisted of eight weeks of oral vemurafenib 240 mg twice daily and eight intravenous rituximab infusions at 375 mg per square meter of body-surface area administered every two weeks. The primary outcome was complete hematologic response. Secondary endpoints included time to complete hematologic response, clearance of minimal residual disease determined by BRAF V600E allele frequency in the bone marrow, safety and progression-free, relapse-free and MRD-free survival. Results: From March 2022 to July 2023, a total of six patients were enrolled in the study. Three patients had previously received a purine analog and three patients were previously untreated. The median age of patients was 61 years, and all were male. At the interim efficacy analysis, all five (5/5) evaluable patients had demonstrated a complete hematologic response with resolution of cytopenias and splenomegaly. 6-month bone marrow biopsy data were available for 3 patients. In 2 of these patients, MRD assessment by allele-specific PCR for BRAF V600E was absent in the bone marrow. In the third patient, though residual disease was present by MRD assessment, he had a hematologic response and requires no subsequent treatment to date. At a median follow-up time of 303 days, the relapse-free survival rate was 100%. There were no adverse grade 3 or 4 adverse events and no vemurafenib dose limiting toxicity was observed. Conclusions: Interim results to-date suggest that rituximab and low-dose vemurafenib (240 mg twice daily) have efficacy and good tolerability in patients with untreated or relapsed HCL. With accruing patient data and further enrollment on study, more information will guide the durability, efficacy and tolerability of this treatment approach.

365. Durable efficacy and robust CD4+ T-cell count improvement observed across age, race, sex, and geographic subgroups of heavily treatment-experienced people with multidrug-resistant HIV-1 after 240 weeks of fostemsavir treatment

Abstract Background Fostemsavir (FTR), the prodrug of the first-in-class attachment inhibitor temsavir, is indicated in combination with other antiretrovirals (ARVs) for heavily-treatment experienced (HTE) people with multidrug-resistant HIV-1 unable to construct suppressive regimens. After ∼5 years in the phase 3 BRIGHTE study, overall virologic response rate (HIV-1 RNA &amp;lt; 40 c/mL, Snapshot) with FTR + optimized background therapy (OBT) was 45% (120/267) in the Randomized Cohort (RC) and 22% (20/92) in the Non-Randomized Cohort (NRC). We present long-term efficacy of FTR + OBT among subgroups in BRIGHTE. Methods BRIGHTE included HTE adults with HIV-1 (N=371) failing their current ARV regimen (HIV-1 RNA &amp;gt; 400 c/mL) with ≤ 2 fully active and approved ARVs remaining. Participants with 1 or 2 ARVs entered the RC and received open-label FTR + OBT after an 8-day blinded placebo-controlled period; those with 0 ARVs entered the NRC and received open-label FTR + OBT from Day 0. Virologic and immunologic responses were analyzed by baseline (BL) demographics and disease characteristics. Results Of 371 participants (RC, n=272; NRC, n=99), 290 (78%) were male, 166 (45%) were aged ≥ 50 years, and 259 (70%) were White. Virologic response rates were generally comparable among subgroups and consistent with overall response rate (Table 1). Similar efficacy was observed in RC participants with 1 or 2 fully active ARVs in OBT, while both RC and NRC participants with high BL viral loads or low BL CD4+ T-cell counts had lower response rates. Nearly all subgroups demonstrated robust and continuous increases in CD4+ T-cell count from Weeks 96 to 240, with mean change from BL exceeding 200 cells/mm3 in all RC subgroups, including those with BL viral loads ≥ 100,000 c/mL or CD4+ T-cell counts &amp;lt; 20 cells/mm3 (Table 2). Conclusion Virologic response with FTR + OBT in HTE adults with advanced HIV-1 and limited treatment options was durable over ∼5 years, with no major differences among subgroups based on age, sex, race, or geographic region. Robust and continuous CD4+ T-cell increases were also observed, with numerically greater improvements in subgroups with lowest BL CD4+ T-cell counts. These data highlight the role of FTR as a treatment option for HTE people with multidrug-resistant HIV-1 regardless of demographic or disease characteristics. Disclosures Alftan Dyson, PharmD, GSK: Stocks/Bonds|ViiV Healthcare: Employment Judith A. Aberg, MD, Emergent BioSolutions: Institutional research grants|Frontier Technologies: Institutional research grants|Gilead: Institutional research grants|GSK: Advisor/Consultant|GSK: Institutional research grants|Janssen: Institutional research grants|Merck: Advisor/Consultant|Merck: Institutional research grants|Pfizer: Institutional research grants|Regeneron: Institutional research grants|ViiV Healthcare: Advisor/Consultant|ViiV Healthcare: Institutional research grants Jean-Michel Molina, MD; PhD, Aelix: Advisor/Consultant|Gilead: Advisor/Consultant|Merck: Advisor/Consultant|ViiV Healthcare: Advisor/Consultant Isabel Cassetti, MD, Gilead: Advisor/Consultant|Gilead: Institutional research grants|GSK: Advisor/Consultant|Janssen: Institutional research grants|Merck: Advisor/Consultant|Merck: Institutional research grants|ViiV Healthcare: Institutional research grants Michael Kozal, MD, ViiV Healthcare: Grant/Research Support|ViiV Healthcare: Royalties/Licenses for chapters authored for UpToDate Bo Li, PhD, GSK: Employment|GSK: Stocks/Bonds Manyu Prakash, PhD, GSK: Stocks/Bonds|ViiV Healthcare: Employee Andrew Clark, MD, GSK: Stocks/Bonds|ViiV Healthcare: Employee Allan R. Tenorio, MD, GSK: Stocks/Bonds|ViiV Healthcare: Employee Amy Pierce, BS, GSK: Stocks/Bonds|ViiV Healthcare: Employee Max Lataillade, DO, GSK: Stocks/Bonds|ViiV Healthcare: Employee

COVID-19 outbreak in Italy: an opportunity to evaluate extended interval dosing of ocrelizumab in MS patients

IntroductionDuring the COVID-19 pandemic, ocrelizumab (OCR) infusions for MS patients were often re-scheduled because of MS center's disruption and concerns regarding immunosuppression. The aim of the present study was to assess changes in OCR schedule during the first wave of pandemic in Italy and to evaluate the effect of delayed infusion on clinical/radiological endpoints.MethodsData were extracted from the Italian MS Register database. Standard interval dosing was defined as an infusion interval ≤ 30 weeks, while extended interval dosing was defined as an infusion interval > 30 weeks at the time of the observation period. Clinico-demographics variables were tested as potential predictors for treatment delay. Time to first relapse and time to first MRI event were evaluated. Cumulative hazard curves were reported along their 95% confidence intervals. A final sample of one-thousand two patients with MS from 65 centers was included in the analysis: 599 pwMS were selected to evaluate the modification of OCR infusion intervals, while 717 pwRMS were selected to analyze the effect of infusion delay on clinical/MRI activity.ResultsMean interval between two OCR infusions was 28.1 weeks before pandemic compared to 30.8 weeks during the observation period, with a mean delay of 2.74 weeks (p < 0.001). No clinico-demographic factors emerged as predictors of infusion postponement, except for location of MS centers in the North of Italy. Clinical relapses (4 in SID, 0 in EID) and 17 MRI activity reports (4 in SID, 13 in EID) were recorded during follow-up period.DiscussionDespite the significant extension of OCR infusion interval during the first wave of pandemic in Italy, a very small incidence of clinical/radiological events was observed, thus suggesting durable efficacy of OCR, as well as the absence of rebound after its short-term suspension.

Maintenance of Response to Risankizumab in Patients With Psoriatic Arthritis: A 3-year Analysis of the KEEPsAKE 1 and 2 Trials

Introduction: Risankizumab, a humanized immunoglobulin G1 monoclonal antibody, specifically inhibits the p19 subunit of human interleukin 23 and is approved for treatment of active psoriatic arthritis (PsA) in adults. This post hoc analysis evaluated the long-term maintenance of clinical response through ~3 years of risankizumab treatment using data from 2 ongoing phase 3 trials, KEEPsAKE 1 and KEEPsAKE 2.&#x0D; Methods: Eligible patients had active PsA with inadequate response or intolerance to ≥1 conventional synthetic disease modifying antirheumatic drugs (KEEPsAKE 1 [NCT03675308]; KEEPsAKE 2 [NCT03671148]) and/or inadequate response or intolerance to 1–2 biologic therapies (KEEPsAKE 2 only). Patients received double-blinded risankizumab 150 mg or placebo at weeks 0, 4, and 16 and open-label risankizumab 150 mg every 12 weeks thereafter. This analysis includes patients who received continuous risankizumab through both treatment periods. Assessments included improvement of ≥20%/50%/70% in PsA symptoms using American College of Rheumatology criteria (ACR20/50/70), achievement of minimal disease activity (MDA), reduction of ≥90% in Psoriasis Area and Severity Index (PASI 90; in patients with ≥3% body surface area affected by psoriasis at baseline), and clinically meaningful reduction in pain (≥10 mm on a visual analog scale [VAS]). Maintenance of response analyses were based on patients who were responders at weeks 24 or 52 for each endpoint. Nonresponder imputation incorporating multiple imputation (NRI-MI) for missing data due to COVID-19 or geopolitical conflict was used. As-observed data were also reported.&#x0D; Results: Among patients receiving continuous risankizumab, ACR20 was achieved at week 24 in 267/454 (KEEPsAKE 1, 58.8%) and 111/208 (KEEPsAKE 2, 53.4%) patients (as observed). Maintenance of response in week 24 ACR20 responders (NRI-MI) was achieved for ACR20 by most patients at week 52 (KEEPsAKE 1, 89.1%; KEEPsAKE 2, 77.0 %) and week 148 (KEEPsAKE 1, 74.7%; KEEPsAKE 2; 68.5%). Similar patterns of maintenance of response were observed for ACR50 and ACR70. Week 24 responders also maintained MDA at weeks 52 (KEEPsAKE 1, 82.2%; KEEPsAKE 2, 66.7%) and 148 (KEEPsAKE 1, 77.1%; KEEPsAKE 2, 71.9%). The PASI 90 response was maintained at weeks 52 (KEEPsAKE 1, 86.6%; KEEPsAKE 2, 88.4%) and 148 (KEEPsAKE 1, 76.3%; KEEPsAKE 2, 81.2%). Week 24 responders maintained clinically meaningful reductions in pain VAS at weeks 52 (KEEPsAKE 1, 83.9%; KEEPsAKE 2, 74.4%) and 148 (KEEPsAKE 1, 75.0%; KEEPsAKE 2, 72.0%). Comparable maintenance of response was recorded at week 148 for each endpoint among week 52 responders (NRI-MI).&#x0D; Conclusion: Risankizumab demonstrated durable long-term efficacy in patients with active PsA. A high proportion of patients receiving continuous risankizumab treatment in KEEPsAKE 1 and KEEPsAKE 2 achieved responses in ACR20/50/70, MDA, PASI 90, or pain VAS at weeks 24 or 52 and maintained responses through week 148.

Deucravacitinib in Plaque Psoriasis: 3-Year Safety and Efficacy Results From the Phase 3 POETYK PSO-1 and PSO-2 Trials

Introduction: Deucravacitinib, an oral, selective, allosteric tyrosine kinase 2 inhibitor, is approved in the US, EU, and other countries for the treatment of adults with moderate-to-severe plaque psoriasis who are candidates for systemic therapy. Deucravacitinib was superior to placebo and apremilast in the POETYK PSO-1 (NCT03624127) and PSO-2 (NCT03611751) parent trials in moderate to severe plaque psoriasis. The POETYK long-term extension (LTE; NCT04036435) trial enrolled patients who completed PSO-1/PSO-2. We report safety and efficacy of deucravacitinib for up to 3 years (Week 148; through cutoff 6/15/2022).&#x0D; Methods: PSO-1/PSO-2 randomized patients 1:2:1 to oral placebo, deucravacitinib 6 mg once daily (QD), or apremilast twice daily. At Week 52, patients enrolled in the LTE received open-label deucravacitinib 6 mg QD. Safety was evaluated in patients who received ≥1 dose of deucravacitinib using exposure-adjusted incidence rate per 100 person-years (EAIR/PY). Efficacy outcomes (≥75%/≥90% reduction from baseline in Psoriasis Area and Severity Index [PASI 75/90]; static Physician Global Assessment score of 0 [clear] or 1 [almost clear] with a ≥2-point improvement from baseline [sPGA 0/1]) were analyzed using modified nonresponder imputation (mNRI) in patients who received continuous deucravacitinib treatment from Day 1 of the parent trial and were treated in the LTE.&#x0D; Results: Of 1519 patients who received ≥1 dose of deucravacitinib (3294.3 PY cumulative exposure), 513 patients received continuous deucravacitinib treatment from Day 1 in PSO-1/PSO-2 and were treated in the LTE. EAIRs/100 PY were comparable, or decreased, between the 2-year and 3-year cumulative periods, respectively, for AEs (154.4, 144.8), serious AEs (6.1, 5.5), discontinuations due to AEs (2.8, 2.4), herpes zoster (0.7, 0.6), malignancies (0.9, 0.9), major adverse cardiovascular events (0.4, 0.3), venous thromboembolism (0.1, 0.1), and deaths (0.4, 0.3). Response rates were maintained at Week 148 by mNRI (PASI 75, 73.2%; PASI 90, 48.1%; sPGA 0/1, 54.1%).&#x0D; Conclusion: Deucravacitinib maintained a consistent safety profile and durable efficacy for up to 3 years.

Brentuximab vedotin with dacarbazine or nivolumab as frontline cHL therapy for older patients ineligible for chemotherapy

AbstractOlder patients with advanced-stage classical Hodgkin lymphoma (cHL) have inferior outcomes compared with younger patients, potentially due to comorbidities and frailty. This noncomparative phase 2 study enrolled patients aged ≥60 years with cHL unfit for conventional chemotherapy to receive frontline brentuximab vedotin (BV; 1.8 mg/kg) with dacarbazine (DTIC; 375 mg/m2) (part B) or nivolumab (part D; 3 mg/kg). In parts B and D, 50% and 38% of patients, respectively, had ≥3 general comorbidities or ≥1 significant comorbidity. Of the 22 patients treated with BV-DTIC, 95% achieved objective response, and 64% achieved complete response (CR). With a median follow-up of 63.6 months, median duration of response (mDOR) was 46.0 months. Median progression-free survival (mPFS) was 47.2 months; median overall survival (mOS) was not reached. Of 21 patients treated with BV-nivolumab, 86% achieved objective response, and 67% achieved CR. With 51.6 months of median follow-up, mDOR, mPFS, and mOS were not reached. Ten patients (45%) with BV-DTIC and 16 patients (76%) with BV-nivolumab experienced grade ≥3 treatment-emergent adverse events; sensory peripheral neuropathy (PN; 27%) and neutropenia (9%) were most common with BV-DTIC, and increased lipase (24%), motor PN (19%), and sensory PN (19%) were most common with BV-nivolumab. Despite high median age, inclusion of patients aged ≤88 years, and frailty, these results demonstrate safety and promising durable efficacy of BV-DTIC and BV-nivolumab combinations as frontline treatment, suggesting potential alternatives for older patients with cHL unfit for initial conventional chemotherapy. This trial was registered at www.clinicaltrials.gov as #NCT01716806.

RBD5044 - a novel anti-ApoC3 GalNAc-siRNA drug resulted in sustained and profound reduction of triglycerides in mice and Rhesus monkeys

Abstract Introduction Hypertriglyceridemia leads to endothelial dysfunction and contributes to the onset and progression of atherosclerosis as well as an increased risk of acute pancreatitis. Inhibition of Apolipoprotein-CIII (APOC3) via the RNA interference mechanism is supposed to reduce plasma Triglycerides (TG) levels with durable and high efficacy. RBD5044, which targets APOC3 mRNA in the liver, is a chemically-modified double-stranded small interfering RNA (siRNA) conjugated with N-acetylgalactosamine (Ribo-GalSTAR). Purpose To investigate the preclinical efficacy and safety profile of RBD5044. Methods Rhesus monkeys with spontaneously developed hypertriglyceridemia were given a single subcutaneous (sc) injection of RBD5044. Humanized APOC3 transgenic mice were treated with a single dose or repeated doses (once every two weeks for three doses, Q2W×3) of RBD5044. Plasma was collected to quantify APOC3 and lipid biomarkers to evaluate preclinical efficacy of RBD5044. SD rats and cynomolgus monkeys were used to evaluate the preclinical toxicology for subcutaneously injected RBD5044, including single-dose toxicity studies and 4-week repeat-dose pivotal toxicology studies. Results In the rhesus monkeys with spontaneous hypertriglyceridemia, the maximum level of inhibition reached 61.2 % in APOC3 and resulted in a TG reduction by 53.3%. The levels of both APOC3 and TG were recovered to baseline till Day 85 after a single dose of 3 mg/kg RBD5044. In humanized APOC3 transgenic mice, RBD5044 achieved an average maximum inhibition level of over 90% for APOC3 and around 90% for TG after both single and repeated doses. The APOC3 and TG levels were recovered on Day 63 after a single dose of 3 mg/kg. On Day 63 after the last repeated dose at 3 mg/kg, the inhibition level remained at 41.6% for APOC3 and 49.4% for TG, hence did not recover to baseline within the study period. RBD5044 also showed reductions in total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) levels and elevations in high-density lipoprotein cholesterol (HDL-C) levels. Toxicology studies showed there is a sufficient therapeutic margin that supports the clinical development of RBD5044 with NOAEL of 40 mg/kg in rats and 300 mg/kg in monkeys. Conclusions RBD5044 shows high efficacy, long duration and a good safety profile in preclinical studies. The Phase I trial of RBD5044 injection in healthy volunteers has been initiated in Australia.Figure 1Figure 2

Anti-Btla Antibody Tifcemalimab As a Single Agent or in Combination with Toripalimab in Relapsed/Refractory Lymphomas

Background: The B- and T-lymphocyte attenuator (BTLA) is an inhibitory receptor expressed on B, T and NK cells. Using Peripheral Blood Mononuclear Cell (PBMC) derived from cancer patients, co-blockade of the BTLA and PD-1 pathways improved antigen specific T cell response compared to either blockade alone. Tifcemalimab (JS004 or TAB004) is a humanized IgG4 monoclonal antibody with a hinge mutation (S228P) that binds BTLA and blocks its interaction with its ligand Herpesvirus Entry Mediator (HVEM). Tifcemalimab is the first BTLA antibody to enter the clinical development stage. Here, we report the safety and efficacy of tifcemalimab as a single agent or in combination with toripalimab (anti-PD-1) in patients with relapsed/refractory (R/R) lymphoma after long term follow-up. Methods: Eligible patients with R/R lymphoma were enrolled in this open-label, multicenter phase 1 study (NCT04477772). Tifcemalimab was administered as a monotherapy at escalating doses of 1, 3 and 10 mg/kg intravenously Q3W, followed by 3 mg/kg and 200 mg monotherapy dose expansion until disease progression or intolerable toxicity. During combination dose escalation, patients received ascending doses of tifcemalimab (100mg and 200mg) plus toripalimab (240mg). Dose-limiting toxicity (DLT) was evaluated by a safety monitoring committee. Study objectives included safety, pharmacokinetics, and efficacy. Results: By the cutoff date of July 19, 2023, a total of 71 patients were enrolled, including 25 in the monotherapy and 46 in the combination cohorts. The median follow-up time was 57 weeks. The median age was 38 (range 19-70) years with 50 (70%) male patients. The median prior line of therapy was 4 with 54 (76%) progressed upon prior anti-PD-1/L1 therapy. No DLT was observed in either monotherapy or combination dose escalation. Recommended phase 2 dose (RP2D) was determined to be 200 mg tifcemalimab as monotherapy or in combination with toripalimab. Sixty-seven (94%) patients experienced treatment emergent adverse events (TEAEs), 22 (31%) of whom experienced grade 3 or above TEAEs. The most common TEAEs were COVID-19 infection (30%), anemia (30%) and Infusion related reaction (27%). Four treatment-related adverse events led to the discontinuation of the study drug. Among 25 patients receiving monotherapy, 1 PR (follicular lymphoma) and 7 SD were observed with median progression-free survival (PFS) 2.1 months. Among 46 patients receiving combination therapy, 1 CR,16 PR (ORR 37.0%) and 20 SD (DCR 80.4%) were observed and estimated median PFS was 14.7 months. Thirty-four patients with Hodgkin's Lymphoma received RP2D of combination therapy and all of them had received previous chemotherapy and anti-PD-1 or anti-PD-L1 antibody, and 12 PR (ORR 35.3%) and 17 SD (DCR 85.3%) were observed with estimated median progression-free survival was 16.2 months. Conclusions: Tifcemalimab alone or in combination with toripalimab were well tolerated in all doses evaluated. The combination regimen showed favorable safety and durable efficacy in lymphoma patients with heavily pretreatment, providing evidence for future investigation.

Sustained Efficacy and Safety with Asciminib (ASC) after Almost 4 Years of Median Follow-up from Ascembl, a Phase 3 Study of ASC Vs Bosutinib (BOS) in Patients (Pts) with Chronic Myeloid Leukemia in Chronic Phase (CML-CP) after ≥2 Prior Tyrosine Kinase Inhibitors (TKIs): An End of Study Treatment (EOS Tx) Update, Including Results from Switch Population

CONCLUSIONS CML requires chronic therapy, emphasizing the need for Txs that are characterized by high, durable efficacy and a low adverse event (AE) burden. ASC, the first BCR::ABL1 inhibitor Specifically Targeting the ABL Myristoyl Pocket (STAMP), demonstrated significantly superior efficacy and better safety/tolerability compared with BOS in pts with CML-CP who received ≥2 prior TKIs in the phase 3 ASCEMBL study. Major molecular response (MMR) rate was 25.5% with ASC vs 13.2% with BOS at wk 24, meeting the primary objective, and 37.6% vs 15.8% at wk 96, meeting the key secondary objective. Despite the longer duration of exposure to ASC, safety/tolerability remained consistently better with ASC vs BOS, with fewer all-grade and grade ≥3 AEs and AEs leading to Tx discontinuation observed. After a median follow-up of 3.7 y, we report EOS Tx results from ASCEMBL (cutoff: March 22, 2023). We also report the first available data from pts who experienced Tx failure on BOS and switched to ASC. Adults (aged ≥18 y) with CML-CP after ≥2 prior TKIs, with intolerance or lack of efficacy per 2013 ELN recommendations were randomized 2:1 to receive either ASC 40 mg twice daily or BOS 500 mg once daily. Pts who met Tx failure criteria per 2013 ELN while on BOS could switch to ASC and were analyzed separately. Pts who discontinued BOS due to intolerance could not switch. EOS will occur 5 y from when the last enrolled pt received first Tx dose. A total of 233 pts were randomized to ASC (n=157) or BOS (n=76). The most common reason for discontinuation was lack of efficacy in 40 (25.5%) pts on ASC and 28 (36.8%) on BOS. At the time of EOS Tx cutoff, Tx with ASC and BOS was ongoing in 77 (49.4%) and 8 (10.5%) pts, respectively; pts deriving benefit from study Tx at EOS TX, per investigator assessment, continued receiving posttrial access. MMR rate at wk 156 continued to be higher with ASC (33.8%) than with BOS (10.5%) (Figure 1). The difference after adjusting for baseline (BL) major cytogenetic response was 23.2%(95% CI, 13.1%-33.2%; 2-sided P&amp;lt;.001). The BCR::ABL1IS ≤1% rate at wk 156 in pts without this level of response at BL also continued to be higher with ASC (43.0%) than with BOS (11.1%). Despite the longer median duration (range) of exposure to ASC (156.0 [0.1-256.3] wk) vs BOS (30.5 [1.0-239.3] wk), safety/tolerability of ASC continued to be better compared with BOS and were consistent with previous analyses. Two new pts had AEs leading to Tx discontinuation since the wk 96 cutoff (1 pt on ASC reported pregnancy; 1 pt on BOS reported diarrhea), and rates remained lower with ASC vs BOS (8.3% vs 27.6%). The most frequent (≥10%) grade ≥3 AEs with ASC vs BOS were thrombocytopenia (22.4% vs 9.2%), neutropenia (18.6% vs 14.5%), diarrhea (0% vs 10.5%), and increased alanine aminotransferase (0.6% vs 14.5%). Most AEs occurred within the first 6 months (Figure 2). Exposure-adjusted incidence rates of arterial occlusive events (AOEs) with ASC decreased since the wk 96 cutoff, from 3.0 to 2.2 per 100 pt-y, and no new AOEs occurred with ASC, indicating that the risk of AOEs did not increase over time. Among pts who discontinued Tx due to lack of efficacy or disease progression, no new mutations occurred since the wk 96 cutoff. Of 28 pts who discontinued BOS for lack of efficacy, 25 switched to ASC. Almost all switch pts (96%) had BL BCR::ABL1IS &amp;gt;10% prior to switch. No switch pts achieved MMR at or by wk 48 post switch. However, at wk 48, 24% achieved BCR::ABL1IS ≤10% and 8% achieved BCR::ABL1IS ≤1%. The safety profile of ASC in switch pts was consistent with that in pts receiving ASC in the randomized period. Most frequent (≥10%) grade ≥3 AEs were neutropenia (32.0%) and thrombocytopenia (24.0%). AEs leading to Tx discontinuation occurred in 8.0% of switch pts. With almost 4 y of follow-up in ASCEMBL, ASC continued to show greater efficacy and better safety/tolerability than BOS in pts with CML-CP after ≥2 prior TKIs. The robust safety profile of ASC was sustained through each analysis in ASCEMBL (wk 24, wk 96, and EOS Tx), confirming that pts receiving ASC can maintain a high level of response and continue Tx without experiencing late-emerging AEs. Results in the switch population support the use of ASC early in the Tx paradigm. ASCEMBL EOS Tx results continue to strongly support ASC as the therapy of choice for pts with suboptimal responses and/or intolerance to ≥2 prior TKIs, allowing more pts to remain on Tx and achieve their Tx goals without needing to switch.

Durable Efficacy and Manageable Safety in Patients Age ≥ 75 Years with Relapsed/Refractory Large B-Cell Lymphoma Treated with Tisagenlecleucel in the Real-World Setting

Background: Tisagenlecleucel is an autologous CD19-directed chimeric antigen receptor (CAR)-T cell therapy approved for the treatment of patients (pts) with relapsed/refractory (r/r) large B-cell lymphoma (LBCL) who have received ≥2 lines of prior therapy. Previous analysis of the Center for International Blood &amp; Marrow Transplant Research (CIBMTR) registry showed high rates of durable response with progression-free survival (PFS), duration of response, and overall survival (OS) rates at 24 mo of 28%, 53%, and 44%, respectively, as well as similar efficacy outcomes among pts age ≥65 y as compared with pts age &amp;lt;65 y (Landsburg et al, ASH 2022). Although it has been shown that real-world pts treated with CAR-T cell therapy are older than those included in pivotal trials, limited data on CAR-T outcomes among pts age ≥75 y are available. Here, we report the first analysis of clinical outcomes in pts age ≥75 y with r/r LBCL treated with tisagenlecleucel in the real-world setting. Methods: Data were collected as a part of a noninterventional, prospective, longitudinal study using the CIBMTR cellular therapy registry. All pts were treated in the United States, Canada, or Israel. Efficacy outcomes analyzed included overall response rate (ORR), complete response rate (CRR), PFS, and OS. Key safety outcomes included the incidence and severity of adverse events, cytokine release syndrome (CRS), and immune effector cell-associated neurotoxicity syndrome (ICANS). Nominal P values are reported without adjusting for multiplicity. Results: As of May 4, 2023, 1375 pts had received tisagenlecleucel (infused set); 278 pts were age ≥75 y. Pts age ≥75 y had similar baseline characteristics compared with pts age &amp;lt;75 y (Eastern Cooperative Oncology Group 0-1, 85% in both populations; elevated lactate dehydrogenase [LDH], 47% in both populations), received similar lymphodepleting regimens, and received tisagenlecleucel in a similar number of days post relapse (81 d vs 85 d, respectively). Pts age ≥75 y had a lower frequency of prior autologous hematopoietic cell transplantation than pts age &amp;lt;75 y (12% vs 26%, respectively) (Figure). One hundred twenty-one pts age ≥75 y had comorbidities (121/278, 44%), including pulmonary disease (65/278, 23%), cardiac disease (60/278, 22%), and hepatic disease (21/278, 8%). Among 247 pts age ≥75 y who were evaluated for efficacy, the ORR (CR + partial response) was 64% (95% CI, 58.1-70.3) and CRR was 47% (95% CI, 41.0-53.8). ORR was similar in pts age &amp;lt;75 y (n=984; 60% [95% CI, 56.9-63.1]), as was CRR (46% [95% CI, 43.2-49.5]). With a median length of follow-up (infusion to data cutoff) of 30 mo, 24-mo PFS in pts age ≥75 y was 23% (95% CI, 16.7-30.1) compared with 28% in pts age &amp;lt;75 y (95% CI, 25.1-31.7). Twenty-four-mo OS in pts age ≥75 y was 39% (95% CI, 31.2-47.2) compared with 44% (95% CI, 40.1-47.8) in pts age &amp;lt;75 y (Figure). AE frequency in pts age ≥75 y (n=250) was comparable with pts age &amp;lt;75 y (n=1004), including the incidence of all-grade CRS (57% vs 60%, respectively; P=0.31) and grade 3/4 CRS (6% of each subgroup). Grade 5 CRS occurred in 2 pts age ≥75 y and 6 pts age &amp;lt;75 y. Tocilizumab was used to manage CRS in 66% of pts age ≥75 y compared with 56% of pts age &amp;lt;75. All-grade ICANS frequency in pts age ≥75 y was comparable with pts age &amp;lt;75 y (27% vs 22%, respectively; P=0.06). Grade 3/4 ICANS was experienced by 7% of each subgroup. Four pts age ≥75 y experienced grade 5 ICANS compared with 1 pt age &amp;lt;75 y. Median time to ICANS onset was similar in pts age ≥75 y (5 d, range 2.0-6.5) and pts age &amp;lt;75 y (5 d, range 3.0-8.0). Corticosteroids were used with similar frequency to manage ICANS in pts age ≥75 y (68%) compared with pts age &amp;lt;75 y (65%). Conclusions: In the first analysis of pts age ≥75 y, tisagenlecleucel demonstrated similar efficacy and rates of CRS and ICANS in pts with r/r LBCL age ≥75 y as compared with age &amp;lt;75 y. As few pts with r/r LBCL age ≥75 y received CAR-T cell therapy in clinical trials, real-world evidence for this age group is invaluable for guiding treatment decisions in this clinical setting, and supports consideration of tisagenlecleucel, a therapy that results in durable disease control in approximately one quarter of patients with a low risk of severe toxicity.