Discontinued Study Treatment Research Articles

First-line therapy for adults with advanced renal cell carcinoma: a systematic review and network meta-analysis.

First-line therapy for adults with advanced renal cell carcinoma: a systematic review and network meta-analysis.

Compliance and Persistence With Ofatumumab Treatment in Patients With Relapsing Multiple Sclerosis in Clinical Trials for Up to 4 Years (P8-3.002)

Compliance and Persistence With Ofatumumab Treatment in Patients With Relapsing Multiple Sclerosis in Clinical Trials for Up to 4 Years (P8-3.002)

Abstract CT181: A first-in-human (FIH) phase 1 study of SHR-A1921, a TROP-2 targeted antibody-drug conjugate (ADC), in patients with advanced solid tumors

Abstract Background: SHR-A1921 is a novel ADC composed of a humanized anti-trophoblast cell-surface antigen 2 (TROP-2) IgG1 monoclonal antibody attached to a DNA topoisomerase I inhibitor via a tetrapeptide-based cleavable linker. Herein, we present the preliminary clinical results of the FIH study of SHR-A1921. Methods: This is a multi-center, open-label, phase 1 trial (Clinicaltrials.gov, NCT05154604) consisted of dose-escalation, dose-expansion and efficacy-expansion phases. Patients with advanced solid tumors who had failed standard therapy were enrolled. In the dose-escalation phase, SHR-A1921 was planned to be administered from 1.5 mg/kg to 12.0 mg/kg (Q3W, iv) in an i3+3 design, with accelerated titration used for the starting dose; in the dose-expansion phase, additional patients (up to 20-30 per dose level) were enrolled to 2-3 selected tolerable dose levels. The primary objectives were to evaluate the safety and tolerability of SHR-A1921 and to determine the maximum tolerated dose (MTD) and/or recommended phase 2 dose. Results: As of Oct 21. 2022, 38 enrolled patients were included for analysis: 18 enrolled during dose-escalation (1.5 mg/kg, n=1; 3.0 mg/kg, n=4; 4.0 mg/kg, n=8; 6.0 mg/kg, n=5) and 20 during dose-expansion (3.0 mg/kg). 71.1% (27/38) were driver gene-negative non-small cell lung cancer (NSCLC) patients who had previously received platinum-based chemotherapy and anti-PD-(L)1 antibody. 4 patients reported dose-limiting toxicities, with all being grade 3 stomatitis (6.0 mg/kg, n=3; 4.0 mg/kg, n=1). The MTD was established as 4.0 mg/kg. Across all dose cohorts, the most common treatment-related adverse events (TRAEs; ≥30%) were nausea (71.1%), stomatitis (65.8%), anemia (42.1%), vomiting, decreased appetite, decreased weight, and rash (36.8% each). Grade ≥3 TRAEs occurred in 12 patients (31.6%); of these, the most common was stomatitis (n=7, 18.4%), and all other events were reported in ≤2 patients. No patients discontinued study treatment due to TRAEs. As of cut-off date, 10 patients (NSCLC, n=5; triple-negative breast cancer, n=2; ampullary cancer, n=2; ovarian cancer, n=1) had partial response: 4 confirmed and 6 requiring further confirmation. The objective response rate was 33.3% (10/30; 95% CI 17.3-52.8) and disease control rate was 80.0% (24/30; 95% CI 61.4-92.3) in evaluable patients. Conclusion: SHR-A1921 showed a manageable safety profile and promising anti-tumor activity in patients with pretreated advanced cancer. The trial is ongoing to assess SHR-A1921 at different dosing frequency and the efficacy in selected cancer types. Citation Format: Jie Wang, Lin Wu, Zhengbo Song, Xingya Li, Caigang Liu, Tianshu Liu, Yiwen Wu, Ze Zhang, Shuni Wang. A first-in-human (FIH) phase 1 study of SHR-A1921, a TROP-2 targeted antibody-drug conjugate (ADC), in patients with advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT181.

Abstract P3-07-08: Exposure-adjusted incidence rates (EAIRs) of adverse events (AEs) from the phase 3 TROPiCS-02 study of sacituzumab govitecan (SG) vs treatment of physician’s choice (TPC) in HR+/HER2- metastatic breast cancer (MBC)

Abstract Background: SG is a Trop-2-directed antibody-drug conjugate approved by the FDA for patients (pts) with metastatic triple-negative breast cancer who received ≥2 prior chemotherapies (≥1 for MBC). In the phase 3 TROPiCS-02 study, SG demonstrated a 34% reduction in risk of progression or death vs TPC in heavily pretreated, endocrine-resistant HR+/HER2– MBC (Rugo H, et al. ASCO 2022. LBA1001). The safety profile was manageable, with neutropenia and diarrhea as the key AEs. Absolute incidence rate is the most used metric to summarize AEs in routine clinical safety analyses. However, when the treatment duration differs significantly between treatment arms, these rates may need adjustment to account for longer treatment exposure, which may incur a higher incidence of AEs. Given that the median treatment duration was longer for SG in TROPiCS-02, EAIRs were assessed in post hoc safety analyses. Methods: Pts with HR+/HER2– unresectable locally advanced or MBC and 2-4 prior chemotherapy regimens for MBC were randomized 1:1 to receive SG or TPC (capecitabine, eribulin, vinorelbine, or gemcitabine) until unacceptable toxicity or disease progression. The primary endpoint was progression-free survival per RECIST 1.1 by central review. Safety was a secondary endpoint. Time-at-risk EAIR considers pts’ exposure of a specific AE in quantifying the risk of AE, defined as the number of pts who experienced at least 1 specific AE, divided by the total exposure time (pt-year of exposure [PYE]) in each arm. For pts who experienced specific AEs, exposure time was calculated from first dose date up to the first AE onset, and for pts who did not, from first dose up to data cutoff (if still on study treatment) or up to last dose (if discontinued study treatment). The 95% CI of the EAIR difference is a standard method to assess the statistical significance of AE incidence rate differences between arms. Results: Of 543 pts enrolled (median age, 56 y; visceral metastases, 95%; prior CDK4/6 inhibitor for MBC, 99%; median lines of chemotherapy for MBC, 3), 517 pts (SG, n=268; TPC, n=249) received ≥1 dose of study treatment. At data cutoff (Jan 3, 2022), 18 pts (7%) vs 4 pts (2%) remained on treatment in the SG vs TPC arms; median treatment duration was 4.1 months and 2.3 months, respectively. The absolute incidence, EAIRs (incidence per 1 PYE), and EAIR differences for the overall safety summary and most common grade ≥3 TEAEs are provided (Table). Overall, SG had higher absolute incidence rates vs TPC for grade ≥3 treatment-emergent AEs (TEAEs), serious AEs, and TEAEs leading to death, but the EAIRs were similar between arms, suggesting an association with duration of treatment exposure. When adjusted for exposure, the incidence of grade ≥3 diarrhea remained higher for SG vs TPC; however, the incidence of grade ≥3 neutropenia was similar between arms. Conclusions: The safety profile of SG was manageable in pts with heavily pretreated HR+/HER2– endocrine-resistant, unresectable locally advanced or MBC. Though there was a higher absolute incidence of TEAEs leading to death and grade ≥3 neutropenia with SG vs TPC, the EAIRs were similar. Taken together with the efficacy benefit with SG, this supports a favorable risk/benefit profile for SG compared with standard chemotherapy in this pt population with limited therapeutic options. Table. Overall Safety Summary and Summary of Common (Absolute Incidence ≥5%) Grade ≥3 TEAEs With Absolute Incidence, Exposure-Adjusted Incidence Rates (EAIRs),a and EAIR Differencesb,c Citation Format: Sara Tolaney, Peter Schmid, Aditya Bardia, Frederik Marmé, Delphine Loirat, Priyanka Sharma, Hao Wang, Olivia Fu, Wendy Verret, Hope Rugo. Exposure-adjusted incidence rates (EAIRs) of adverse events (AEs) from the phase 3 TROPiCS-02 study of sacituzumab govitecan (SG) vs treatment of physician’s choice (TPC) in HR+/HER2- metastatic breast cancer (MBC) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-07-08.

TRIDENTE trial: A phase II study of rechallenge with encorafenib, binimetinib, and cetuximab in patients with RAS wild-type/BRAF V600E–mutant metastatic colorectal cancer.

TPS264 Background: The BEACON CRC trial demonstrated survival benefit of combination therapy with encorafenib (ENCO) + cetuximab (CET) +/- binimetinib (BINI) in patients with RAS wild-type (WT)/ BRAF V600E mutant metastatic colorectal cancer (mCRC). However, prognosis of those patients still be poor after the refractoriness to the BEACON combination therapy. One of resistant mechanisms to BRAF inhibitor has been reported as MAPK alterations including RAS mutation, similar to those for anti-EGFR antibody in patients with RAS/ BRAF V600E WT mCRC. Promising results of rechallenge therapy with anti-EGFR antibody in patients with RAS/ BRAF V600E WT mCRC and with combination of BRAF inhibitor + MEK inhibitor in patients with BRAF V600 mutant melanoma suggest the treatment strategy of rechallenge therapy with the BEACON triplet therapy in patients with RAS WT/ BRAF V600E mutant mCRC. Methods: TRIDENTE trial is a multicenter phase II trial to assess efficacy and safety of rechallenge therapy with ENCO + BINI + CET in patients with RAS WT/ BRAF V600E mutant mCRC after the refractoriness to either the BEACON doublet or triplet therapy. Key eligibility criteria includes RAS WT/ BRAF V600E mutant mCRC; ≥ 20 years old; ECOG PS 0-1; refractory or intolerant to at least one fluoropyrimidine-based regimen (including irinotecan or oxaliplatin); refractory or intolerant to anti-PD-1 antibody if patients with MSI-high; history of previous combination therapy containing ENCO + CET with at least partial response by RECIST v1.1; confirmed disease progression within 4 weeks after last administration of previous ENCO; ≥ 4 months of period between the last administration of previous ENCO and the start of study treatment. Enrolled patients receive the combination therapy with ENCO (300 mg, QD), BINI (45 mg, BID), and CET (initially 400 mg/m2, and subsequently 250 mg/m2, QW) as the study treatment. Primary endpoint is the objective response rate (ORR) by investigators’ assessment in patients receiving at least one dose of study treatment. A target sample size is calculated to be 21 on the hypothesis that the threshold ORR is 3% and expected ORR is 20%, with a significant level of 5% (one-sided) and power of 80%. Secondary endpoint includes progression-free and overall survivals, disease control rate, and safety. Exploratory molecular analysis is performed using targeted next-generation sequencing in circulating-tumor DNA at the timepoints of baseline and discontinuation of study treatment. As of September 19, 2022, 8 patients have been enrolled. Clinical trial information: jRCTs031210511 .

Effect of non-invasive ventilation after extubation in critically ill patients with obesity in France: a multicentre, unblinded, pragmatic randomised clinical trial

Non-invasive ventilation (NIV) and oxygen therapy (high-flow nasal oxygen [HFNO] or standard oxygen) following extubation have never been compared in critically ill patients with obesity. We aimed to compare NIV (alternating with HFNO or standard oxygen) and oxygen therapy (HFNO or standard oxygen) following extubation of critically ill patients with obesity. In this multicentre, parallel group, pragmatic randomised controlled trial, conducted in 39 intensive care units in France, critically ill patients with obesity undergoing extubation were randomly assigned (1:1) to either the NIV group or the oxygen therapy group. Two randomisations were performed: first, randomisation to either NIV or oxygen therapy, and second, randomisation to either HFNO or standard oxygen (also 1:1), which was nested within the first randomisation. Blinding of the randomisation was not possible, but the statistician was masked to group assignment. The primary outcome was treatment failure within 3 days after extubation, a composite of reintubation for mechanical ventilation, switch to the other study treatment, or premature discontinuation of study treatment. The primary outcome was analysed by intention to treat. Effect of medical and surgical status was assessed. The reintubation within 3 days was analysed by intention to treat and after a post-hoc crossover analysis. This study is registered with ClinicalTrials.gov, number NCT04014920. From Oct 2, 2019, to July 17, 2021, of the 1650 screened patients, 981 were enrolled. Treatment failure occurred in 66 (13·5%) of 490 patients in the NIV group and in 130 (26·5%) of 491 patients in the oxygen-therapy group (relative risk 0·43; 95% CI 0·31-0·60, p<0·0001). Medical or surgical status did not modify the effect of NIV group on the treatment-failure rate. Reintubation within 3 days after extubation was similar in the non-invasive ventilation group and in the oxygen therapy group in the intention-to-treat analysis (48 (10%) of 490 patients and 59 (12%) of 491 patients, p=0·26) and lower in the NIV group than in the oxygen-therapy group in the post-hoc cross-over (51 (9%) of 560 patients and 56 (13%) of 421 patients, p=0·037) analysis. No severe adverse events were reported. Among critically ill adults with obesity undergoing extubation, the use of NIV was effective to reduce treatment-failure within 3 days. Our results are relevant to clinical practice, supporting the use of NIV after extubation of critically ill patients with obesity. However, most of the difference in the primary outcome was due to patients in the oxygen therapy group switching to NIV, and more evidence is needed to conclude that an NIV strategy leads to improved patient-centred outcomes. French Ministry of Health.

Polatuzumab vedotin in previously untreated DLBCL: an Asia subpopulation analysis from the phase 3 POLARIX trial

AbstractIn the phase 3 POLARIX study in previously untreated diffuse large B-cell lymphoma, polatuzumab vedotin combined with rituximab plus cyclophosphamide, doxorubicin, and prednisone (Pola-R-CHP) significantly improved progression-free survival (PFS) compared with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) with similar safety. Patients were randomized 1:1 to 6 cycles of Pola-R-CHP or R-CHOP plus 2 cycles of rituximab alone. For registration of POLARIX in China, consistency of PFS in an Asia subpopulation (defined as ≥50% of the risk reduction in PFS expected in the global population) was evaluated. Overall, 281 patients were analyzed: 160 patients from Asia in the intention-to-treat (ITT) population of the global study and 121 from an ITT China extension cohort. Of these, 141 were randomized to Pola-R-CHP and 140 to R-CHOP. At data cutoff (28 June 2021; median follow-up 24.2 months), PFS met the consistency definition with the global population, and was superior with Pola-R-CHP vs R-CHOP (hazard ratio, 0.64; 95% confidence interval [CI], 0.40-1.03). Two-year PFS was 74.2% (95% CI, 65.7-82.7) and 66.5% (95% CI, 57.3-75.6) with Pola-R-CHP and R-CHOP, respectively. Safety was comparable between Pola-R-CHP and R-CHOP, including rates of grade 3 to 4 adverse events (AEs; 72.9% vs 66.2%, respectively), serious AEs (32.9% vs 32.4%), grade 5 AEs (1.4% vs 0.7%), AEs leading to study treatment discontinuation (5.0% vs 7.2%), and any-grade peripheral neuropathy (44.3% vs 50.4%). These findings demonstrate consistent efficacy and safety of Pola-R-CHP vs R-CHOP in the Asia and global populations in POLARIX. This trial was registered at https://clinicaltrials.gov/ct2/home as # NCT03274492.

1268. Efficacy, safety, and tolerability of bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) in adults with HIV-HBV infection - preliminary results

Abstract Background Coinfection with HIV and hepatitis B (HBV) has been associated with higher risk of morbidity and mortality, especially acceleration of liver disease. HBV-active antiretroviral (ARV) regimens have significantly improved the outcome of people with HIV-HBV coinfection. B/F/TAF has been shown to be highly effective in the treatment of HIV infection based on treatment naïve and switch trials. Although it is an HBV-active regimen, there is scant data on the use of B/F/TAF for people with HIV-HBV coinfection. We hypothesize that B/F/TAF is both safe and efficacious in the treatment of coinfected adults. Methods This open label, single-arm, switch study enrolled HIV/HBV-coinfected adults from two clinical centers (Baltimore, MD and Philadelphia, PA). Patients were switched from their current ARV regimen (regardless of viral suppression) to fixed dose combination B/F/TAF taken once daily for 48 weeks. Primary efficacy endpoints were proportion of patients with HIV RNA &amp;lt; 50 copies/mL by FDA Snapshot Algorithm and HBV DNA &amp;lt; 29 IU/mL at Week 24 by missing = failure method. Results A total of 28 eligible participants were enrolled between May 2019 to December 2021. Median age was 51 years (range 34-71), majority were Black (89%), male gender (86%), and non-Hispanic (96%), 65% HIV and HBV virally suppressed. Two participants, one lost to follow-up and the other removed due to non-adherence prior to week 24, were excluded in the efficacy analysis. At baseline, 73% were HIV suppressed and 81% were HBV suppressed. Of the 21 patients with week 24 data, 20 (95%) had HIV RNA &amp;lt; 50 copies/mL and 19 (90%) had HBV DNA &amp;lt; 29 IU/mL. Eighteen (86%) were HIV and HBV suppressed, which was higher than prior to B/F/TAF use. There were ten treatment-related adverse events (AE), all of which were mild (grade 1) and transient. Most common treatment related AE was nausea (2 of 28). Four patients had elevated alanine aminotransferase at baseline, all of which normalized at week 24. There were no serious adverse events or hepatitis flare. No participants discontinued study treatment due to an AE. Conclusion B/F/TAF is efficacious and safe for patients coinfected with HIV and HBV after 6 months of treatment. Disclosures Helena Kwakwa, M.D., Viiv Healthcare: Grant/Research Support Sunny Choe, PhD, Gilead Sciences: Employee.

Efficacy and Safety of Retreatment with Brentuximab Vedotin in Patients with Relapsed or Refractory Classical Hodgkin Lymphoma or CD30-Expressing Peripheral T Cell Lymphoma

Introduction Brentuximab vedotin (BV) is approved for the treatment of adult patients (pts) with classical Hodgkin lymphoma (cHL), systemic anaplastic large cell lymphomas (sALCL) or other CD30-expressing peripheral T-cell lymphomas (PTCL). BV has been evaluated in combination with doxorubicin, vinblastine, and dacarbazine (A+AVD) in adult pts with advanced stage cHL in ECHELON-1 (Ansell S, 2022) and in combination with cyclophosphamide, doxorubicin, and prednisone (A+CHP) in pts with sALCL, PTCL-not otherwise specified (NOS), and angioimmunoblastic T-cell lymphoma (AITL) in ECHELON-2 (Horwitz S, 2022), demonstrating BV is well tolerated with a favorable efficacy profile in the first-line setting. Moreover, BV is approved as monotherapy for treatment of adults with cHL at high risk of relapse as consolidation therapy post autologous stem cell transplant, as well as in relapsed or refractory (r/r) sALCL. BV has also been studied in r/r cHL after auto-stem cell transplant (Younes A, 2012) and retreatment setting (Trümper L, 2020), with favorable efficacy. CD30 expression persists after BV treatment and SGN35-006 demonstrated that BV monotherapy is an effective retreatment option in pts with r/r cHL or sALCL who previously achieved an objective response with BV monotherapy (Bartlett N, 2014). Herein, we present efficacy and safety results from a phase 2 study, where BV was evaluated in pts with r/r cHL or CD30-expressing PTCL who previously received BV either alone or in combination. Methods SGN35-028 (NCT03947255) is a multicentered, single arm, phase 2 clinical trial that enrolled adult pts with r/r cHL and sALCL or other CD30-expressing PTCL who were previously treated with a BV-containing regimen at least 6 months prior that had evidence of an objective response, and subsequently experienced disease progression or relapse after discontinuing treatment. Pts were treated with BV 1.2 or 1.8 mg/kg intravenously every 3 weeks until disease progression or unacceptable toxicity. The primary endpoints were objective response rate (ORR) and the safety and tolerability of BV retreatment. Results Of the 12 pts enrolled, 11 received at least 1 dose of study treatment including 5 pts with cHL and 6 pts with PTCL (4 pts with sALCL, 1 pt with PTCL-NOS, 1 pt with AITL). Both pts with non-ALCL PTCL had CD30 expression on 1% of tumor cells. Of the 11 pts that received at least 1 dose of study treatment, most were Black or African American (55%), not of Hispanic, Latino, or Spanish origin (91%), and <65 years old (73%). Pts received a median of 8 doses of BV (range: 1, 16) over a median of 25 weeks (range: 3, 55), 3 pts (27%) had dose reductions. Three pts were still on treatment as of data cutoff date. For pts with cHL, median time from initial diagnosis to first dose was 76.2 months (range: 34, 162), 2 pts achieved complete response (CR) and 3 pts partial response (PR) on prior BV therapy, median time from completion of last BV therapy to first dose was 28.2 months, and median age was 31 years (range: 28, 55). The ORR per investigator assessment was 60% (95% CI: 14.7, 94.7) with 1 pt achieving CR. For pts with PTCL, median time from initial diagnosis to first dose was 31.2 months (range: 23, 138), 5 pts achieved CR and 1 pt PR on prior BV therapy, median time from completion of last BV therapy to first dose was 20.1 months, and median age was 63 years (range: 35, 77). The ORR per investigator assessment was 83% (95% CI: 35.9, 99.6) with 4 pts achieving CR. The 4 pts with sALCL had an ORR of 100% with a CR rate of 75%. Eight pts discontinued study treatment, 4 pts discontinued treatment due to disease progression, 2 pts due to investigator decision, and 2 pts due to treatment emergent adverse events (TEAEs), both with peripheral sensory neuropathy. Thirty-six percent of pts experienced ≥ Grade 3 treatment-related TEAEs, 2 (18%) each for neutropenia and peripheral sensory neuropathy and 1 (9%) each for amylase increased, fatigue, malaise, and nausea. One pt experienced a Grade 5 adverse event of decreased appetite related to progressive PTCL disease that was not treatment related. Conclusions Preliminary results from this study show BV is a viable retreatment option for adults with r/r cHL, sALCL, and PTCL. Moreover, safety results were consistent with the known safety profile and no new safety signals were observed. This study is ongoing, updated efficacy and safety results will be presented at the meeting.

Phase II Trial of Venetoclax (Ven) in Combination with Azacitidine (AZA) As Maintenance Therapy for High-Risk Acute Leukemia Following Allogeneic Stem Cell Transplantation (SCT)

Introduction: Allogeneic SCT remains the only potentially curative therapy for acute leukemia patients but with inferior outcomes for high-risk patients. Prior data on maintenance therapies, including AZA, have yielded conflicting results on its efficacy to improve outcomes. Considering the clinical efficacy of VEN in acute myeloid and lymphoid leukemia (AML/ALL) with its known tolerability when used with AZA, we thought VEN and AZA might be an attractive maintenance strategy to improve outcomes after SCT. Methods: This is a single center, open label, Phase II clinical trial to assess the safety and efficacy of VEN with AZA as maintenance therapy after SCT. Inclusion criteria was 1) high risk AML or B cell and T cell ALL or mixed phenotype leukemia, 2) absolute neutrophil count >/= 1.0 x 109/L and platelet >/= 30 x 109/L without any support, 3) absence of active graft versus host disease (GvHD) and infection, 4) absence of minimal residual disease at enrollment. Treatment consisted of up to 12 cycles of VEN 100 mg on Days 1-7 with AZA 32 mg/m 2/day IV/SC on Days 1-5 every 28 days. VEN dosing was adjusted for patients on concomitant CYP3A inhibitors or those with severe cytopenias. After the first 11 patients enrolled, due to myelosuppression observed, VEN dose was changed to 50 mg on days 1-7 if patients were on posaconazole. Treatment delays, up to 70 days, were allowed by toxicity. The primary objectives are relapse-free survival (RFS) after initiation of VEN and AZA and the safety and tolerability of the combination. The study has been ongoing. Results: The study enrolled a total of 30 patients (27 AML, 3 ALL). Demographics across all AML patients included mean age 52 years (range: 40-74), 67% males, 15% second SCT, 48% in first complete remission (CR1) at SCT, 41% adverse risk by European Leukemia Net classification. The majority (63%) received a myeloablative intensity conditioning regimen using intravenous busulfan. The three ALL patients were younger with mean age of 35 and all were in CR1 at SCT. The median time to start the maintenance treatment was 70.5 days (range, 42-103). As of the data cutoff date of 13 July 2022, patients completed a median of 4 cycles (range, 1-12) of study treatment with 9 patients (30%) remaining on study treatment. The primary reasons for study treatment discontinuation among 21 patients were complications like myelosuppresssion, infections and GvHD in 11, relapse in 6 and completion of 12 cycles of treatment in 4. The median follow-up time was 8.67 months (95% CI, 7.23 to 13.6).The median RFS and OS were not reached. The estimates of RFS and OS at 1-year were 69.2% (95% CI, 52.1% to 91.8%) and 90.2% (95%CI, 78% to 100%), respectively, after the initiation of VEN and AZA maintenance (Figure 1&2). Assuming a Bayesian Poisson-Gamma Model with a Gamma (1,1) prior; the mean number of grade≥3 treatment related adverse events (AEs) per patient was estimated. The mean number of AEs were 1.87 (range, 0-8) for decreased white blood cell count; 1.68 (range, 0-7) for decreased absolute neutrophil count; 1.06 (range, 0-6) for decreased platelet count; 0.55 (range, 0-6) for anemia; 0.13 (range, 0-1) for pneumonia and 0.06 (range 0-1) for each event of febrile neutropenia, maculopapular rash, respiratory failure and secondary graft failure (GF). The secondary GF was observed in one patient after the 4th cycle of treatment leading to discontinuation of study treatment. No patient died to due to treatment related AEs. Due to frequent and prolonged myelosuppression observed, 9 patients (30%) required dose reduction of VEN; mostly right after the first cycle of treatment (6 of 9 patients). After the protocol amendment for VEN to be given as 50 mg on days 1-7 on posaconazole, the requirement for dose changes decreased though still some patients required lower doses of VEN (as 30 mg on days 1-5) on subsequent cycles. Conclusion: Post-SCT maintenance therapy with VEN/AZA was safe and tolerable with favorable results in patients with high-risk AML and ALL. The majority of reported AEs was related to myelosuppression which is a known complication of VEN. Many patients required dose modification of VEN and treatment delays between cycles, highlighting the importance of monitoring these patients very closely. On the other hand, the observed RFS and OS data were highly encouraging compared to the historical outcomes for this high-risk group of patients although longer follow-up is needed. The study has been ongoing. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

ASC4FIRST: A Phase III Study of Asciminib vs Investigator-Selected Tyrosine Kinase Inhibitor in Patients with Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase (CML-CP)

Background: The main treatment goal for patients (pts) with newly diagnosed Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia in chronic phase (CML-CP) is disease control. Standard therapy is with any of the tyrosine kinase inhibitors (TKIs) approved for 1st-line (1L) use: the 1st-generation TKI imatinib (IMA) or one of the 2nd-generation (2G) TKIs bosutinib (BOS), dasatinib (DAS), and nilotinib (NILO). However, in 1L CML-CP, >50% of pts treated with IMA develop resistance to or intolerance of therapy, and 30% to 40% of pts treated with a 2G TKI need to switch therapy by 5 years. In addition, only 30% to 55% of pts achieve a deep molecular response (DMR); needed criterion for attempting treatment-free remission. While 2G TKIs yield a higher major molecular response (MMR) than IMA, they are associated with more adverse events (AEs), including arterio-occlusive events. Therefore, treatment options with improved efficacy and tolerability are needed for pts in 1L CML-CP. Asciminib is the first BCR::ABL1 inhibitor that works by Specifically Targeting the ABL Myristoyl Pocket (STAMP) and has been recently approved by the FDA for Ph+ CML-CP patients treated with ≥2 prior TKIs. In the pivotal phase III ASCEMBL trial in pts treated with ≥2 prior TKIs, after over 2 years of follow-up, asciminib demonstrated sustained superior efficacy, safety and tolerability compared with bosutinib. Here we present a phase III trial evaluating asciminib vs an investigator-selected approved TKI in adult pts with newly diagnosed Ph+ CML-CP. Methods: ASC4FIRST (NCT04971226) is a multicenter, open-label, randomized, phase III study of asciminib 80 mg once daily (QD) monotherapy compared with an approved, investigator-selected TKI (~50% IMA; ~50% either BOS, or DAS, or NILO) for adult pts with newly diagnosed Ph+ CML-CP (expected N=402). Eligible pts must not have received prior TKI therapy for CML except for ≤2 weeks of either IMA, NILO, DAS, or BOS and must have Eastern Cooperative Oncology Group performance status of 0 or. Pts could have received prior hydroxyurea (HU) and/or anagrelide treatment. Pts will be randomized 1:1 to asciminib or investigator-selected TKI using 2 strata: European Treatment and Outcome Study Long-Term Survival (ELTS) score and the control arm TKI selected by the investigator before randomization (Figure). Pts randomized to the investigator selected TKI arm will receive their selected TKIs at approved doses: IMA 400 mg QD, BOS 400 mg QD, DAS 100 mg QD, or NILO 300 mg twice daily. Dose recommendations as per local label should be followed for participants with hepatic and renal impairment. The primary objectives are to compare the efficacy of asciminib vs investigator-selected TKIs and to compare the efficacy of asciminib vs IMA in the stratum of investigator-selected IMA. The primary endpoint is MMR at week 48. The study will be positive if either of these objectives is met. The key secondary endpoint is MMR at week 96. Additional secondary endpoints include time to discontinuation of study treatment due to an AE (TTDAE); MMR, MR4, MR4.5, complete hematological response (CHR) and BCR::ABL1 ≤1% at and by all scheduled data collection time points; duration of and time to first MMR, MR4 and MR4.5; time to treatment failure; event-free survival, failure-free survival, progression-free survival, and overall survival. Pts will remain on treatment for 5 years after the last pt.'s first treatment has been administered, unless they have discontinued early due to treatment failure, disease progression, intolerance, or investigator/pt. decision. All pts including those who discontinue early will continue to be followed up for survival and disease progression until the end of the study. Current Status: As of 18th July 2022, 203 participants have been randomized and are receiving treatment. This Novartis-sponsored study is ongoing. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Isatuximab, Carfilzomib, Lenalidomide, and Dexamethasone (Isa-KRd) in Patients with High-Risk Newly Diagnosed Multiple Myeloma: Planned Interim Analysis of the GMMG-Concept Trial

Background: High-risk (HR) multiple myeloma (MM) patients (pts) have a significantly disadvantageous prognosis. Emerging data show that achievement of minimal residual disease (MRD) negativity is associated with better outcome in HR pts. Most recently, several clinical trials demonstrated that addition of monoclonal anti CD38 antibodies (i.e. isatuximab) significantly improve MRD negativity, response rate and survival when added to standard of care regimens. Carfilzomib (K), lenalidomide (R) and dexamethasone (d) is one of the most effective and tolerable regimens in newly diagnosed multiple myeloma (NDMM). The phase II CONCEPT trial (NCT03104842) investigates the quadruplet regimen isatuximab plus KRd (Isa-KRd) in HR NDMM in induction and consolidation including high-dose melphalan (HDM) for pts being transplant-eligible (TE). Here, we report for the first time the planned interim analysis (IA) of the primary endpoint MRD negativity after consolidation for TE-patients and the corresponding final analysis of transplant non-eligible (TNE) pts. Methods: 153 pts with HR NDMM were included into the open-label, academic, multicentre phase II clinical trial, an extension cohort of TE pts is currently recruiting. According to the trial design, 99 of 127 TE pts in study arm A (TE-ITT) were included in the intention-to-treat population (ITT) of the planned IA (TE-ITT-IA); results of the 26 TNE pts in study arm B (TNE-ITT) are finally reported. HR MM was defined by the presence of del17p or t(4;14) or t(14;16) or > 3 copies 1q21 in combination with ISS 2 or 3 stage disease. Pts could be included after a maximum of 1 cycle of MM treatment. Pts received 6 cycles of Isa-KRd induction, followed by HDM for TE pts or 2 Isa-KRd cycles for TNE pts, 4 cycles Isa-KRd consolidation and Isa-KR maintenance. Primary endpoint is MRD negativity at end of consolidation measured by next-generation flow at the minimum sensitivity threshold of 10-5 (H0: MRD-neg-rate ≤ 50% (TE) and ≤ 30% (TNE), tested by one-sided binomial test), this planned IA reports on. Secondary endpoint is progression-free survival (PFS), tertiary endpoints include overall response rate (ORR) and safety. Results: 125 pts (99 TE-ITT-IA, 26 TNE-ITT) were included from August 2017 to April 2020 in the IA population in 17 German Centres. No bias arose in the reduction of the TE-ITT population to the TE-ITT-IA population. Based on inclusion criteria, all pts had cytogenetic HR disease including del17p in 55 pts (44.0%), t(4;14) in 48 (38.4%), t(14;16) in 19 (15.2%) and > 3 copies 1q21 in 45 pts (36.0%). 38 pts (30.4%) had ≥ 2 HR aberrations. 66 pts (52.8%) had ISS 2 and 58 (46.4%) ISS 3 disease. Median age (range) was 58 (35-73) years in the TE-ITT-IA and 74 (64-87) years in the TNE-ITT. The design of the study provides for the MRD-analysis to be performed on 93 patients in the TE-ITT-IA and 24 patients in the TNE-IA. At the end of consolidation, in the TE-ITT-IA population 67.7% (n=63) of pts were MRD negative, 3.2% (n=3) MRD positive, 24.7% (n=23) timepoint not reached, 4.3% (n=4) missing (4 pts not assessable, 2 did not start). In the TNE-ITT population 54.2% (n=13) of pts were MRD negative, 0% MRD positive, 45.8% (n=11) timepoint not reached. The primary endpoint was significantly reached in both study arms (p = 0.0004 for TE-ITT-IA and p=0.012 for TNE-ITT). ORR (best response to treatment) in the TE-ITT-IA was 94.9% (n=94) with 72.7% showing complete remission (CR) or better (n=72), 18.2% (n=18) very good partial remission (VGPR), 4% (n=4) partial remission (PR), 1% (n=1) progressive disease (PD) and 4% (n=4) timepoint not reached. In the TNE-ITT, 57.7% (n=15) showed CR or better 30.8% (n=8) VGPR, 3.8% (n=1) were unknown and 7.7% (n=2) timepoint not reached. Updated PFS data will be shown. Safety-population consists of 122 pts. In total, 85.2% (n=104) developed ≥ grade 3 treatment-emergent adverse events (TEAEs). Serious TEAEs occurred in 64.8% (n=79) of pts. TEAEs leading to discontinuation of study treatment occurred in 5 pts. Conclusions: The CONCEPT trial is the first trial investigating Isa-KRd for HR NDMM in TE and TNE patients. Isa-KRd in induction and consolidation leads to high MRD negativity rates after consolidation in this difficult-to-treat population. Toxicity was consistent with expectations and no new safety signals occurred in this IA. In our view, our data underline the importance of optimized quadruplet treatment in NDMM, especially in HR disease.

ASC4START: A Phase IIIb, Open-Label, Randomized Study of Tolerability and Efficacy of Asciminib Versus Nilotinib in Patients with Newly Diagnosed Philadelphia Chromosome-Positive Chronic Myelogenous Leukemia in Chronic Phase

Objectives: Tyrosine kinase inhibitors (TKIs) have greatly improved treatment outcomes for patients with newly diagnosed chronic myelogenous leukemia in chronic phase (CML-CP), transforming it into a chronic disease requiring long-term treatment. This emphasizes the need for treatments that combine high efficacy with a favorable safety profile, improving over currently available options. Asciminib is a first-in-class BCR::ABL1 inhibitor specifically targeting the ABL myristoyl pocket (STAMP) which has been approved by the FDA with subsequent approvals worldwide for patients with Philadelphia chromosome-positive (Ph+) CML-CP, previously treated with ≥2 prior TKIs based on the results of the ASCEMBL (NCT03106779) trial. The ABL specificity of asciminib compared with the selectivity of second-generation (2G) TKIs can reduce off-target effects and improve tolerability while maintaining efficacy and reducing the probability of developing resistance. The ongoing ASC4FIRST (NCT04971226) study will evaluate the efficacy and safety of asciminib vs investigator-selected TKI in patients with newly diagnosed Ph+ CML-CP. Additional data on asciminib in newly diagnosed Ph+ CML-CP may help to address patient-centric objectives, in particular the ability of patients to remain on treatment without having to permanently discontinue due to adverse events (AEs). The ASC4START study (NCT05456191) will primarily evaluate the tolerability of asciminib vs the 2G TKI nilotinib in adult patients with newly diagnosed Ph+ CML-CP, as measured by the time to study treatment discontinuation due to adverse event (TTDAE). The study will also report on further safety, efficacy and quality of life (QoL) outcomes. Methods: This is a phase IIIb, multi-center, open-label, randomized study in patients ≥18 years of age with newly diagnosed Ph+ CML-CP. The trial will enroll approximately 541 patients with CML-CP diagnosed within 3 months of study entry and an Eastern Cooperative Oncology Group (ECOG) performance status ≤1. Patients cannot be included if they have received previous treatment for CML with any other anticancer agents (except hydroxyurea and/or anagrelide), have confirmed central nervous system infiltration, or present impaired cardiac function or abnormalities in cardiac repolarization. Patients will be randomized 1:1 to receive asciminib 80 mg once daily or nilotinib 300 mg twice daily, both administered orally under fasting conditions; randomization will be stratified based on European Treatment Outcome Study long-term survival (ELTS) score at diagnosis (high vs intermediate vs low) to help achieve balance between the treatment arms (Figure). The primary endpoint is TTDAE, defined as the time from the date of the first dose of study treatment to the date of discontinuation of study treatment due to an AE. Secondary endpoints include type, frequency and severity of AEs; dose modifications due to AE; changes in laboratory values that fall outside pre-determined ranges; clinically notable ECG changes; time to discontinuation due to selected reasons (lack of efficacy/treatment failure/disease progression/suboptimal response/death); major molecular response (MMR), MR4, MR4.5, complete hematological response (CHR), and BCR::ABL1 ≤1% at and by all scheduled data collection time points; duration of and time to first MMR, MR4 and MR4.5; time to treatment failure; event-free survival, progression-free survival and overall survival. Secondary endpoints related to QoL include change from baseline in overall scores and individual scales of the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaires QLQ-C30 and QLQ-CML24. Participants will be treated in the study until approximately 64 discontinuations due to AEs are met; treatment duration for an individual patient is expected to be 2‒4.5 years. Current status: The study is recruiting as of October 2022. This study was sponsored by Novartis Pharmaceuticals. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A Phase 2, Open-Label Study Evaluating the Safety and Efficacy of Combination Pozelimab and Cemdisiran Therapy in Patients with Paroxysmal Nocturnal Hemoglobinuria Who Switch from Eculizumab

Background: Paroxysmal nocturnal hemoglobinuria (PNH) is an ultra-rare, acquired disorder caused by a mutation in the phosphatidylinositol glycan class A (PIGA) gene, which leads to impaired expression of complement-regulating proteins on the surface of hematopoietic cells. Clinical presentation of PNH includes hemolytic anemia, hemoglobinuria, and thrombosis. Complement component C5 inhibitors such as eculizumab are part of the current standard of care for patients with PNH; however, this is an intravenous treatment which relies on nurse administration. In addition, some patients experience an incomplete response to therapy, and may still experience breakthrough hemolytic events. Pozelimab and cemdisiran are investigational agents with a subcutaneous maintenance regimen that may be self-administered. Both agents act together to inhibit terminal complement through complementary mechanisms of action. Pozelimab is a fully human monoclonal antibody inhibitor of C5, while cemdisiran is an N-acetylgalactosamine-conjugated small interfering RNA (siRNA) that suppresses liver production of C5. The efficacy and safety of the combination of pozelimab and cemdisiran is being evaluated in an ongoing, phase 2, open-label single-arm study in patients with PNH who switch from eculizumab therapy (NCT04888507). The interim safety and preliminary efficacy results are presented here. Methods: This ongoing phase 2 trial consists of a screening period (up to 42 days), a 32-week open-label treatment period (OLTP), an optional 52-week open-label extension period, and a 52-week post-treatment safety follow-up period. Patients transitioned from eculizumab therapy to the combination of pozelimab and cemdisiran over a 4-week period, and thereafter received the combination (pozelimab 400 mg and cemdisiran 200 mg) subcutaneously every 4 weeks. Results: At the time of this interim data analysis (data cut-off March 18, 2022) six patients were enrolled and five patients were ongoing. While one patient discontinued after 29 days of treatment, the remaining five patients had a treatment duration of at least 169 days, with one completing the OLTP (Day 225). Up to the time of data cut-off, no patient had a lactate dehydrogenase (LDH) level greater than 1.5 x the upper limit of normal (ULN; Figure 1) or experienced an event of breakthrough hemolysis, including the two patients who were previously treated with higher doses of eculizumab (1200 mg and 1500 mg every 2 weeks, respectively). Furthermore, all but two LDH values remained normal (≤1.0 x ULN) at all timepoints evaluated. All patients achieved hemoglobin stabilization. CH50, a measure of terminal complement activity, remained fully suppressed at 0 kIU/L throughout the study up to the time of the data cut-off. There were no serious or severe treatment emergent adverse events (TEAEs). Importantly, there were no meningococcal infections or adverse events due to potential large drug-target-drug immune complexes, or TEAEs leading to death, in this study. One patient discontinued study treatment due to two mild, non-serious TEAEs of headache at Days 2 and 16. Conclusions: These interim results from a limited data set suggest that in patients with PNH transitioning from eculizumab treatment, including patients treated with higher than standard of care doses, the combination of pozelimab and cemdisiran was generally well tolerated, providing sustained control of intravascular hemolysis without any breakthrough hemolysis events. These findings support the ongoing development of pozelimab and cemdisiran combination therapy. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Daratumumab Plus Lenalidomide and Dexamethasone (D-Rd) Versus Lenalidomide and Dexamethasone (Rd) in Transplant-Ineligible Patients (Pts) with Newly Diagnosed Multiple Myeloma (NDMM): Clinical Assessment of Key Subgroups of the Phase 3 Maia Study

Introduction: The MAIA study (NCT02252172) evaluated D-Rd versus Rd alone in transplant-ineligible pts with NDMM. At a median follow-up of 56.2 months, D-Rd significantly improved progression-free survival (PFS) and overall survival versus Rd (Facon T, Lancet Oncol 2021). Here, we present an analysis of clinically important subgroups in MAIA, including pts aged ≥75 years, pts with International Staging System (ISS) stage III disease, pts with renal insufficiency (defined as baseline creatinine clearance [CrCl] ≤60 mL/min), pts with extramedullary plasmacytomas at baseline, and pts with high cytogenetic risk (defined as having ≥1 of the following high-risk cytogenetic abnormalities: t[4;14], t[14;16], del17p [per IMWG recommendations]). Methods: In MAIA, pts with NDMM who were ineligible for high-dose chemotherapy and autologous stem-cell transplant were randomized 1:1 to receive D-Rd or Rd. All pts received 28-day cycles of oral Rd (R: 25 mg [10 mg recommended if CrCl was 30-50 mL/min] on Days 1-21; d: 40 mg [20 mg if aged >75 years or body-mass index <18.5 kg/m2] on Days 1, 8, 15, 22). Pts in the D-Rd arm received intravenous daratumumab (16 mg/kg QW in Cycles 1-2, Q2W in Cycles 3-6, and Q4W thereafter). Pts in both arms were treated until disease progression or unacceptable toxicity. The primary endpoint was PFS, and key secondary endpoints included overall response rate (ORR) and minimal residual disease (MRD)-negativity rate (10-5 sensitivity). Results: 737 pts were randomized (D-Rd, n=368; Rd, n=369); most subgroups had a similar number of pts per treatment arm: age ≥75 years (n=160; n=161); ISS stage III (n=107; n=110); renal insufficiency (n=162; n=142); extramedullary plasmacytomas (n=15; n=9); and high cytogenetic risk (n=48; n=44). After a 64.5-month median follow-up, PFS (Figure A) and ORR (Figure B) generally favored D-Rd versus Rd across subgroups. MRD-negativity rates were higher with D-Rd versus Rd for pts aged ≥75 years (26.9% vs 9.9%; P<0.0001), pts with ISS stage III disease (27.1% vs 10.9%; P=0.0030), pts with renal insufficiency (29.6% vs 7.7%; P<0.0001), pts with extramedullary plasmacytomas (33.3% vs 0%; P=0.1181), and pts with high cytogenetic risk (25.0% vs 2.3%; P=0.0019). Sustained (≥6 months and ≥12 months) MRD-negativity rates were higher with D-Rd versus Rd across subgroups: age ≥75 years (≥6 months, 15.6% vs 5.0%; ≥12 months, 13.8% vs 3.1%), ISS stage III disease (≥6 months, 17.8% vs 3.6%; ≥12 months, 15.9% vs 2.7%), renal insufficiency (≥6 months, 21.0% vs 1.4%; ≥12 months, 18.5% vs 1.4%), extramedullary plasmacytomas (≥6 months, 26.7% vs 0%; ≥12 months, 13.3% vs 0%), and high cytogenetic risk (≥6 months, 12.5% vs 0%; ≥12 months, 12.5% vs 0%). In an analysis of safety among pts aged ≥75 years, grade 3/4 treatment-emergent adverse events (TEAEs) occurred in 95.5% of D-Rd pts and 95.0% of Rd pts; the most common (≥20%; D-Rd/Rd) were neutropenia (62.4%/41.5%), lymphopenia (21.0%/12.6%), anemia (20.4%/25.2%), and pneumonia (20.4%/14.5%). Serious TEAEs occurred in 80.9% and 79.2% of D-Rd and Rd pts, respectively. TEAEs led to study treatment discontinuation in 15.3% of D-Rd pts and 27.7% of Rd pts. TEAEs with an outcome of death occurred in 11.5% of D-Rd pts and 13.2% Rd pts. Conclusions: In this subgroup analysis of MAIA, D-Rd improved PFS, ORR, and MRD-negativity rates versus Rd across clinically important subgroups, including pts aged ≥75 years, pts with ISS stage III disease, pts with renal insufficiency, pts with extramedullary plasmacytomas, and pts with high cytogenetic risk. In pts aged ≥75 years, the rates of grade 3/4 and serious TEAEs were similar with D-Rd and Rd, with a lower rate of discontinuation due to TEAEs for D-Rd versus Rd. Results for these clinically important subgroups provide confidence in using D-Rd across all pt types, supporting D-Rd as a standard of care for transplant-ineligible pts with NDMM. Results for additional cytogenetic risk subgroups that include pts with gain and/or amp 1q21 will be presented at the meeting. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Daratumumab Plus Lenalidomide, Bortezomib, and Dexamethasone (D-RVd) in Transplant-Eligible Newly Diagnosed Multiple Myeloma (NDMM) Patients (Pts): Final Analysis of Griffin Among Clinically Relevant Subgroups

Introduction: Daratumumab (DARA) is approved across lines of therapy for multiple myeloma. In the primary analysis of the randomized phase 2 GRIFFIN trial (NCT02874742) (median follow-up, 13.5 mo), addition of DARA to RVd improved the stringent complete response (sCR) rate by end of post-autologous stem cell transplant (ASCT) consolidation (D-RVd, 42.4% vs RVd, 32.0%; odds ratio [OR], 1.57; 95% CI, 0.87-2.82; 1-sided P = 0.068, which met the pre-specified 1-sided α of 0.1) (Voorhees PM, et al. Blood. 2020). Here, we present an end-of-study post hoc analysis of clinically relevant subgroups in GRIFFIN (≥65 years; International Staging System [ISS] stage III disease; high cytogenetic risk [defined as ≥1 of the following: del17p, t(4;14), or t(14;16)]; revised high cytogenetic risk [defined as ≥1 of the following high-risk chromosomal abnormalities (HRCA): del17p, t(4;14), t(14;16), t(14;20) or gain/amp1q (≥3 copies of chromosome 1q21)]; gain/amp1q; 1 HRCA (per the revised definition); gain/amp1q plus 1 HRCA; and ≥2 HRCA). The final analysis of GRIFFIN (median follow-up, 49.6 mo) occurred after all pts completed ≥1 year of long-term follow-up after completion of study treatment, discontinued, or withdrew. Methods: In GRIFFIN, pts with transplant-eligible NDMM were randomized 1:1 to D-RVd or RVd. All pts received 4 D-RVd/RVd induction cycles, ASCT, 2 D-RVd/RVd consolidation cycles, and maintenance with lenalidomide (R) ± DARA for 24 months. All pts received 21-day cycles of R (25 mg PO on Days [D] 1-14), bortezomib (1.3 mg/m2 SC on D1, 4, 8, 11), and dexamethasone (40 mg PO QW) ± DARA (16 mg/kg IV QW in Cycles 1-4 and D1 in Cycles 5-6). During maintenance (Cycles 7-32; 28-day cycles), pts received R (10 mg PO on Days 1-21; if tolerated, 15 mg in Cycles 10+) ± DARA (16 mg/kg IV Q8W/Q4W or 1800 mg SC Q4W per protocol amendments). The primary endpoint was the sCR rate by end of consolidation. Results: 207 pts were randomized (D-RVd, n = 104; RVd, n = 103); each subgroup had a similar number of pts per arm: ≥65 years (n = 28; n = 28), ISS stage III disease (n = 14; n = 14), high cytogenetic risk (n = 16; n = 14), revised high cytogenetic risk (n = 42; n = 37), gain/amp1q (n = 34; n = 28), 1 HRCA (n = 32; n = 29), gain/amp1q plus 1 HRCA (n = 9; n = 6), and ≥2 HRCA (n = 10; n = 8). Outcomes for pts with baseline extramedullary plasmacytomas (D-RVd, n = 1; RVd, n = 2) were explored but not included due to small pt numbers. Among response-evaluable pts, the rate of sCR at the end of maintenance therapy was numerically higher for D-RVd versus RVd among pts with age ≥65 years (63.0% vs 40.7%; OR, 2.47; 95% CI, 0.83-7.39), high cytogenetic risk (50.0% vs 38.5%; OR, 1.60; 95% CI, 0.36-7.07), gain/amp1q plus 1 HRCA (55.6% vs 33.3%; OR, 2.50; 95% CI; 0.29-21.40), and ≥2 HRCA (50.0% vs 37.5%; OR, 1.67; 95% CI, 0.25-11.07), but similar for D-RVd and RVd pts with ISS stage III disease (64.3% vs 61.5%; OR, 1.13; 95% CI, 0.24-5.37), revised high cytogenetic risk (56.1% vs 55.6%; OR, 1.02; 95% CI, 0.42-2.52), gain/amp1q (57.6% vs 57.1%; OR, 1.02; 95% CI, 0.37-2.82), and 1 HRCA (58.1% vs 60.7%; OR, 0.90; 95% CI, 0.32-2.54). MRD-negativity (10-5) rates at the end of maintenance favored D-RVd over RVd across all subgroups (Figure A). At 49.6 months of median follow-up, PFS rates among subgroups favored D-RVd over RVd except for pts with ≥2 HRCA (Figure B). In pts ≥65 years, grade 3/4 treatment-emergent adverse events (TEAEs) occurred in 88.9% of D-RVd and 77.8% of RVd pts; the most common grade 3/4 TEAEs (≥20%) were neutropenia (D-RVd, 37.0%; RVd, 29.6%) and lymphopenia (25.9%; 11.1%). TEAEs led to study treatment discontinuation in 37.0% of D-RVd and 25.9% of RVd pts. In pts ≥65 years, death as outcome of a TEAE occurred in 1 D-RVd pt (pneumonia; unrelated to study treatment). Conclusions: In this final analysis of GRIFFIN by clinically relevant subgroups, addition of DARA to RVd induction/consolidation and R maintenance, with ASCT, was associated with higher MRD-negativity (10-5) rates for all subgroups and PFS estimates favored all high-risk groups except pts with ≥2 HRCA. Among pts ≥65 years, the rates of grade 3/4 TEAEs and TEAEs leading to study treatment discontinuation were slightly higher for the D-RVd group, although only 1 pt died due to a TEAE unrelated to study treatment. Results of this subgroup analysis support the use of DARA in transplant-eligible pts with NDMM among both clinically and cytogenetic high-risk subgroups, although larger studies are needed, especially in pts with ≥2 HRCA. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Combination lurbinectedin and doxorubicin versus physician's choice of chemotherapy in patients with relapsed small-cell lung cancer (ATLANTIS): a multicentre, randomised, open-label, phase 3 trial

Lurbinectedin is a synthetic marine-derived anticancer agent that acts as a selective inhibitor of oncogenic transcription. Lurbinectedin monotherapy (3·2 mg/m2 every 3 weeks) received accelerated approval from the US Food and Drug Administration on the basis of efficacy in patients with small-cell lung cancer (SCLC) who relapsed after first-line platinum-based chemotherapy. The ATLANTIS trial assessed the efficacy and safety of combination lurbinectedin and the anthracycline doxorubicin as second-line treatment for SCLC. In this phase 3, open-label, randomised study, adult patients aged 18 years or older with SCLC who relapsed after platinum-based chemotherapy were recruited from 135 hospitals across North America, South America, Europe, and the Middle East. Patients were randomly assigned (1:1) centrally by dynamic allocation to intravenous lurbinectedin 2·0 mg/m2 plus doxorubicin 40·0 mg/m2 administered on day 1 of 21-day cycles or physician's choice of control therapy (intravenous topotecan 1·5 mg/m2 on days 1-5 of 21-day cycles; or intravenous cyclophosphamide 1000 mg/m2, doxorubicin 45·0 mg/m2, and vincristine 2·0 mg on day 1 of 21-day cycles [CAV]) administered until disease progression or unacceptable toxicity. Primary granulocyte-colony stimulating factor prophylaxis was mandatory in both treatment groups. Neither patients nor clinicians were masked to treatment allocation, but the independent review committee, which assessed outcomes, was masked to patients' treatment allocation. The primary endpoint was overall survival in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT02566993, and with EudraCT, 2015-001641-89, and is complete. Between Aug 30, 2016, and Aug 20, 2018, 613 patients were randomly assigned to lurbinectedin plus doxorubicin (n=307) or control (topotecan, n=127; CAV, n=179) and comprised the intention-to-treat population; safety endpoints were assessed in patients who had received any partial or complete study treatment infusions (lurbinectedin plus doxorubicin, n=303; control, n=289). After a median follow-up of 24·1 months (95% CI 21·7-26·3), 303 patients in the lurbinectedin plus doxorubicin group and 289 patients in the control group had discontinued study treatment; progressive disease was the most common reason for discontinuation (213 [70%] patients in the lurbinectedin plus doxorubicin group vs 152 [53%] in the control group). Median overall survival was 8·6 months (95% CI 7·1-9·4) in the lurbinectedin plus doxorubicin group versus 7·6 months (6·6-8·2) in the control group (stratified log-rank p=0·90; hazard ratio 0·97 [95% CI 0·82-1·15], p=0·70). 12 patients died because of treatment-related adverse events: two (<1%) of 303 in the lurbinectedin plus doxorubicin group and ten (3%) of 289 in the control group. 296 (98%) of 303 patients in the lurbinectedin plus doxorubicin group had treatment-emergent adverse events compared with 284 (98%) of 289 patients in the control group; treatment-related adverse events occurred in 268 (88%) patients in the lurbinectedin plus doxorubicin group and 266 (92%) patients in the control group. Grade 3 or worse haematological adverse events were less frequent in the lurbinectedin plus doxorubicin group than the control group (anaemia, 57 [19%] of 302 patients in the lurbinectedin plus doxorubicin group vs 110 [38%] of 288 in the control group; neutropenia, 112 [37%] vs 200 [69%]; thrombocytopenia, 42 [14%] vs 90 [31%]). The frequency of treatment-related adverse events leading to treatment discontinuation was lower in the lurbinectedin plus doxorubicin group than in the control group (26 [9%] of 303 patients in the lurbinectedin plus doxorubicin group vs 47 [16%] of 289 in the control group). Combination therapy with lurbinectedin plus doxorubicin did not improve overall survival versus control in patients with relapsed SCLC. However, lurbinectedin plus doxorubicin showed a favourable haematological safety profile compared with control. PharmaMar.

A phase Ib study of camrelizumab in combination with apatinib and fuzuloparib in patients with recurrent or metastatic triple-negative breast cancer

BackgroundStrategies to improve activity of immune checkpoint inhibitors for triple-negative breast cancer (TNBC) are needed. Preclinical studies showed that antiangiogenic agents and poly (ADP-ribose) polymerase (PARP) inhibitors might sensitize tumors to immunotherapy. Here, we investigated the tolerability, safety, and preliminary antitumor activity of camrelizumab, an anti-PD-1 antibody, in combination with apatinib, a vascular endothelial growth factor receptor-2 inhibitor, and fuzuloparib, a PARP inhibitor, in patients with recurrent or metastatic TNBC.MethodsThis phase Ib study included a dose-finding part and a dose-expansion part. In the dose-finding part, a 3 + 3 dose escalation scheme was introduced. Patients were given camrelizumab (200 mg every 2 weeks) plus apatinib (375 mg or 500 mg once daily) and fuzuloparib (starting dose 100 mg twice daily) every 28-day cycle. After evaluation of the tolerability and safety of the dosing regimens, a clinical recommended dose was determined for the dose-expansion part. The primary endpoint was dose-limiting toxicity (DLT).ResultsA total of 32 patients were enrolled. Three patients received camrelizumab 200 mg + apatinib 375 mg + fuzuloparib 100 mg, and 29 received camrelizumab 200 mg + apatinib 500 mg + fuzuloparib 100 mg (clinical recommended dose). No DLTs were observed in either group. The most common grade ≥ 3 treatment-related adverse events were decreased white blood cell count (20.7%), hypertension (13.8%), decreased neutrophil count (10.3%), and increased aspartate aminotransferase (10.3%). Two patients discontinued study treatment due to immune-mediated hepatitis (n = 1) and anemia, decreased platelet count, decreased white blood cell count, increased alanine aminotransferase, increased aspartate aminotransferase, and increased γ-glutamyltransferase (n = 1). One patient died of unknown cause. Two (6.9% [95% CI, 0.9–22.8]) of 29 patients with camrelizumab 200 mg + apatinib 500 mg + fuzuloparib 100 mg had objective response. The disease control rate was 62.1% (95% CI, 42.3–79.3). The median progression-free survival was 5.2 months (95% CI, 3.6–7.3), and the 12-month overall survival rate was 64.2% (95% CI, 19.0–88.8).ConclusionsCombination of camrelizumab plus apatinib and fuzuloparib showed manageable safety profile and preliminary antitumor activity in patients with recurrent or metastatic TNBC.Trial registrationClinicalTrials.gov NCT03945604 (May 10, 2019).

The efficacy and safety of macitentan in Fontan-palliated patients: results of the 52-week randomised, placebo-controlled RUBATO trial

Abstract Background The clinical utility and long-term effects of endothelin receptor antagonists (ERAs) in Fontan-palliated patients remain unclear and there are currently no approved therapies. A decline in peak VO2 between consecutive cardiopulmonary exercise tests (CPETs) is highly prognostic for death or transplant in adult Fontan patients, hence its use as a primary endpoint in clinical trials of ERAs in patients with Fontan circulation. Purpose The RUBATO trial aimed to assess the efficacy and safety of macitentan, an endothelin receptor antagonist, in Fontan-palliated patients over 52 weeks. Methods In the multicentre, double-blind, randomised, placebo-controlled, phase 3 RUBATO trial, Fontan-palliated patients were randomised 1:1 to macitentan 10 mg once-daily or placebo for 52 weeks. Eligible patients were aged ≥12 years, in New York Heart Association functional class II or III, had no limitations for CPET (including no pacemakers), had undergone lateral tunnel or extracardiac conduit Fontan (total cavopulmonary connection) &amp;gt;1 year before screening and showed no signs of Fontan failure or clinical deterioration within 3 months before screening. Primary efficacy endpoint was change in peak VO2 from baseline to week 16. Secondary endpoints were change in peak VO2 from baseline over 52 weeks and change in mean count per minute of daily physical activity from baseline to week 16 as measured by an accelerometer. Adverse events were also assessed. Results 137 patients were randomised to macitentan (n=68) or placebo (n=69). 92.7% of patients completed 52 weeks of double-blind treatment: 7 and 3 patients prematurely discontinued study treatment in macitentan and placebo arms, respectively. Patient baseline characteristics are shown in Table 1. At week 16, the mean (SD) change from baseline in peak VO2 was –0.16 (2.86) with macitentan vs –0.67 (2.66) mL/kg/min with placebo (median unbiased estimate of the difference between macitentan and placebo: 0.62 mL/kg/min [99% repeated confidence interval –0.62; 1.85], p=0.1930). No treatment effect was observed in the two secondary endpoints (Table 2): mean (SD) count per minute of daily physical activity decreased from baseline to week 16 by 3.02 (92.44) with macitentan and by 14.34 (117.56) with placebo (p=0.4512). The most common AEs were headache (10.3% vs 8.7% on placebo), nasopharyngitis (5.9% vs 4.3%), and pyrexia (5.9% vs 4.3%). AEs leading to treatment discontinuation were reported in 3 (4.4%) and 1 (1.4%) of macitentan and placebo patients. Conclusion The 52-week RUBATO trial provides an important addition to data on the clinical utility of ERAs in Fontan-palliated patients. The primary efficacy endpoint was not met and no treatment effect was observed for the two secondary endpoints. Macitentan was well tolerated; safety findings were consistent with the known safety profile of macitentan 10 mg. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Actelion Pharmaceuticals Ltd., a Janssen pharmaceutical company of Johnson &amp; Johnson.

IBCL-081 MAGNIFY Phase 3b Study of Lenalidomide + Rituximab (R2) Followed by Maintenance in Relapsed/Refractory Indolent Non-Hodgkin Lymphoma: Complete Induction Phase Analysis

Patients with relapsed indolent NHL (iNHL) have limited standard treatment options. Lenalidomide + rituximab (R2) has shown complimentary clinical activity and is tolerable in both untreated and relapsed/refractory (R/R) iNHL. MAGNIFY is a multicenter, phase 3b trial in R/R follicular lymphoma (FL) grades 1-3b, transformed FL (tFL), marginal zone lymphoma (MZL), or mantle cell lymphoma (MCL; NCT01996865). In the induction phase, lenalidomide 20mg PO d1-21 of a 28-d cycle + rituximab IV 375mg/m2/week cycle 1 and then q8w starting with cycle 3 (R2) are administered for 12 cycles. Patients with ≥SD were randomized 1:1 to R2 vs rituximab maintenance for 18 months. Data here are the complete induction phase analysis in efficacy-evaluable patients with FL grades 1-3a or MZL. The focus of this interim analysis was ORR by 1999 IWG criteria in the induction ITT population. As of March 5th, 2021, 394 patients (318 [81%] FL gr1-3a; 76 [19%] MZL) were enrolled. Median follow-up was 40.6 mo (range, 0.6-79.6). Median age was 66 y (range, 35-91), 328 (83%) had stage III/IV disease, with a median of 2 prior therapies (94% prior rituximab-containing). ORR was 71% with 42% CR/CRu. All patients have completed R2 induction (n=232, 59%) or discontinued study treatment (n=162, 41%); 141 patients (36%) prematurely discontinued both lenalidomide and rituximab, primarily due to AEs (n=54, 14%) or PD (n=42, 11%). The majority who have completed induction have been randomized and entered maintenance (n=217). Median DOR in the induction period was NR (95% CI, 43.9 mo-NR); median PFS in the induction safety population was 50.5 mo (95% CI, 39.5-NR). Most common all-grade TEAEs were 47% fatigue, 43% neutropenia, 37% diarrhea. Grade 3/4 AEs occurring in ≥5% of patients included 37% neutropenia (10 patients [3%] had febrile neutropenia), 8% leukopenia, 6% thrombocytopenia, 5% anemia, 5% fatigue. These data represent a complete analysis of all patients in the induction phase of MAGNIFY that continue to support that R2 is active with a tolerable safety profile in patients with R/R FL grade 1-3a and MZL, including rituximab-refractory, double-refractory, and early relapse patients.