Initiated Study Treatment Research Articles

Cetuximab every second week in combination with daily encorafenib in patients with BRAF V600E mutated metastatic colorectal cancer: Interim analysis from NEW BEACON.

153 Background: Weekly administered cetuximab in combination with the BRAF inhibitor encorafenib has improved survival in pre-treated patients (pts) with BRAF V600E mutated (BRAFmut) metastatic colorectal cancer (mCRC), with a median progression free survival (PFS) of 4.3 months in the BEACON study. It is now standard-of-care in the second line treatment. However, a regimen with cetuximab administered every second week may demonstrate comparable efficacy and is more convenient for the pts. Thus, we initiated the NEW BEACON study investigating cetuximab given every second week together with daily encorafenib. Details on the rationale and aims of the study have previously been published (doi: 10.1186/s12885-022-10420-x.). Methods: NEW BEACON is an open-label, single-arm, multicenter, phase II study including pts with pre-treated BRAFmut mCRC. The primary end point is 2 months PFS rate. We report here the result of a pre-specified interim analysis after treatment of the first 19 included pts. We collected fresh tumor tissues for comprehensive molecular profiling in order to explore features associated with response and resistance. Baseline genomic variants will be reported. Results: From February 2021 to February 2024 20 pts were included in the study. 1 patient never started study treatment due to rapid disease progression. At the data cut-off date 19 pts had initiated study treatment. The 2 months PFS rate was 89% (17/19 pts). We had tumor tissue for molecular profiling available from 12 pts. Pathogenic variants in TP53 were the most frequently detected co-mutations at baseline in 83% of pts (10/12 pts). Available preliminary safety, efficacy, and survival data and more extensive genomic data will be presented at the meeting. Conclusions: The preliminary PFS data from pts with BRAFmut mCRC treated with cetuximab every second week together with daily encorafenib is promising demonstrating a 2 months PFS rate of 89%. This is similar to what was reported from the BEACON study (2 months PFS rate of 84%). Loss-of-function mutations in tumor suppressor genes were frequently detected as co-mutations at baseline. Clinical trial information: EudraCT: 2020-003283-10 .

Betibeglogene autotemcel gene therapy in patients with transfusion-dependent, severe genotype β-thalassaemia (HGB-212): a non-randomised, multicentre, single-arm, open-label, single-dose, phase 3 trial

Transfusion-dependent β-thalassaemia (TDT) is a severe disease, resulting in lifelong blood transfusions, iron overload, and associated complications. Betibeglogene autotemcel (beti-cel) gene therapy uses autologous haematopoietic stem and progenitor cells (HSPCs) transduced with BB305 lentiviral vector to enable transfusion independence. HGB-212 was a non-randomised, multicentre, single-arm, open-label, phase 3 study of beti-cel in patients with TDT conducted at eight centres in France, Germany, Greece, Italy, the UK, and the USA. Patients with β0/β0, β0/β+IVS-I-110, or β+IVS-I-110/β+IVS-I-110 genotypes, clinically stable TDT, and a transfusion history of at least 100 mL/kg per year of packed red blood cells (pRBCs) or at least eight transfusions of pRBCs per year in the 2 years before enrolment were eligible for participation. After undergoing HSPC mobilisation and busulfan-based, pharmacokinetic-adjusted myeloablative conditioning, patients were infused with beti-cel and followed up for 24 months. The primary efficacy outcome was transfusion independence, defined as weighted average haemoglobin level of 9 g/dL or above without pRBC transfusions for 12 or more months. The primary outcome was measured in all patients who received an infusion of beti-cel (transplant population); safety was evaluated in all patients who initiated study treatment (intention-to-treat population). Patients were eligible to enrol in the ongoing 13-year long-term follow-up study (for a total of 15 years), LTF-303 (registered at ClinicalTrials.gov, NCT02633943). This trial, HGB-212, was registered at ClinicalTrials.gov (NCT03207009), and is complete. From June 8, 2017, to March 12, 2020, 20 patients were screened for eligibility. One patient was ineligible and one withdrew consent before HSPC mobilisation and myeloablative conditioning. Of the 18 patients who received beti-cel, ten (56%) were male and eight (44%) were female; 13 (72%) were younger than 18 years at the time of informed consent, and five (28%) were older than 18 years. 12 (67%) patients had β0/β0 genotypes, three (17%) had β0/ β+IVS-I-110, and three (17%) had β+IVS-I-110/β+IVS-I-110. As of Jan 30, 2023, all patients enrolled in the long-term follow-up study and the median follow-up was 47·9 months (range 23·8-59·0). All 18 patients were evaluable for transfusion independence, with 16 (89%) of 18 reaching and maintaining transfusion independence to last follow=up (estimated effect size 89·9% [95% CI 65·3-98·6]). All patients had at least one adverse event after beti-cel infusion. There were no serious adverse events considered to be related to beti-cel, and no deaths. These data demonstrate that beti-cel can allow patients with genotypes that cause severe β-thalassaemia (β0/β0, β0/β+IVS-I-110, or β+IVS-I-110/β+IVS-I-110) to reach transfusion independence. Beti-cel offers the potential to attain near-normal haemoglobin levels for those with severe forms of TDT, and a potentially curative option without the risks and limitations of allogeneic HSPC transplantation. Patients are being followed up for a total of 15 years to assess the durability of transfusion independence and long-term safety profile of beti-cel. Bluebird Bio, Somerville, MA, USA.

First-line (1L) nivolumab (NIVO) + ipilimumab (IPI) in patients (pts) with microsatellite instability-high/mismatch repair deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC): 64-month (mo) follow-up from CheckMate 142.

97 Background: NIVO + IPI demonstrated robust, durable clinical benefit and was well tolerated as a 1L therapy in pts with MSI-H/dMMR mCRC in the phase 2 CheckMate 142 study (NCT02060188), leading to the inclusion of NIVO + IPI in the NCCN guidelines as an initial therapy option for these pts. At 52-mo median follow-up, 1L NIVO + IPI continued to demonstrate durable clinical benefit, and no new safety signals were identified. Here we report longer follow-up results. Methods: Pts with MSI-H/dMMR mCRC and no prior treatment for metastatic disease received NIVO 3 mg/kg Q2W + IPI 1 mg/kg Q6W until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) by investigator assessment (INV) per RECIST v1.1. Other key endpoints were disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), all by INV; overall survival (OS); and safety. Results: In total, 45 pts received 1L NIVO + IPI. With median follow-up of 64.2 mo (range, 59.4–68.9 mo), ORR by INV was 71% (95% CI, 56–84%). The proportion of pts with a best overall response of complete response (CR) was 20%, partial response (PR) was 51%, stable disease (SD) was 13%, and progressive disease was 16%. Median DOR (mDOR) was not reached, and the 60-mo DOR rate was 72%. Median PFS (mPFS) by INV and median OS (mOS) were not reached, with 60-mo PFS and OS rates of 55% and 67%, respectively (Table). Among pts alive at the data cutoff (n = 31), 30 remained treatment-free after initial study treatment without receiving any subsequent systemic therapy, with a median treatment-free interval of 34.7 mo (range, 1.6–61.4 mo). Exploratory analysis by tumor mutational burden status will be presented. Safety data are shown in the Table. Conclusions: At 64-mo follow-up, NIVO + IPI continued to demonstrate clinically meaningful survival and durable responses, with mPFS, mOS, and mDOR still not reached, suggesting the potential for long-term clinical benefit. Safety remained consistent with previous data. These findings further support current recommendations for NIVO + IPI as a 1L treatment for pts with MSI-H/dMMR mCRC. Clinical trial information: NCT02060188 . [Table: see text]

Phase 1 Dose Escalation Study of Pembrolizumab in Combination with Rituximab and Lenalidomide for Relapsed/Refractory Large B-Cell or Follicular Lymphoma Following Progression after Anti-CD19 Chimeric Antigen Receptor (CAR) T-Cell Therapy

Introduction: While autologous CD19-targeting chimeric antigen receptor T-cells (CAR T) can induce high complete response (CR) rates in relapsed and refractory (r/r) large B-cell lymphoma (LBCL) and follicular lymphoma (FL), over 50% of patients experience progressive disease. Survival following CAR T failure is dismal, with only 1 in 5 patients living >2 years. Multiple studies indicated that resistance to CAR T therapy may be driven by CAR T cell intrinsic and/or tumor intrinsic mechanisms. Here, we evaluated the combination of PD-1 blockade with rituximab (R) and lenalidomide (len) with the rationale that it would restore the function of exhausted T cells, enhance CAR T function with len and target the tumor and its immunosuppressive microenvironment. Methods: In this single center, phase I dose-escalation study, eligible patients included adults with r/r LBCL or FL who progressed following CD19 CAR T. Treatment consisted of R (375 mg/m2/day) on days 1, 8, and 15 of cycle 1 and day 1 of cycle 2. Pembrolizumab (200 mg/day) was administered on day 1 of each 21-day cycle with the cycles repeated for up to 2 years (those who attain an investigator-determined CR could stop pembrolizumab after 24 weeks). A standard 3+3 dose escalation of len was pursued to determine the recommended phase 2 dose (RP2D), starting at 2.5 mg and escalated up to 10 mg on days 1-14 of each cycle for up to 12 cycles. The primary endpoint was overall response rate (ORR). Secondary endpoints included safety, CR rate, progression-free survival (PFS), and overall survival (OS). Exploratory objectives sought to determine the effect of combination therapy on peripheral blood T cells and evaluate baseline tumor characteristics that associated with clinical outcomes. Results: Fourteen patients initiated study treatment, 13 had LBCL (high grade B-cell lymphoma n=4; non-GCB DLBCL n=4; GCB DLBCL n=3; transformed FL n=2), 1 had FL. 12 progressed following axicabtagene ciloleucel, 1 progressed after lisocabtagene maraleucel, and 1 following an investigational allogeneic CAR T. The median time from CAR (day 0) to enrollment was 171 days (range 60-1134). The median time to progression following prior CAR T was 104 days (range 22-280). Median age was 57.5 years (range 41-73), 64% were male, all had advanced stage disease (stage III n=1, stage IV n=13), 79% had high-risk IPI, and 79% had an ECOG performance status of 1. Patients had a median of 3 prior lines of therapy (range 2-5), 86% were refractory to their last therapy. Four were treated at dose level 1 (2.5 mg len), 7 at dose level 2 (5 mg len), and 3 at dose level 3 (10 mg len). Five DLTs were observed, 3 at dose level 2 (3 gr 4 neutropenia > 7 days) and 2 at dose level 3 (1 gr 4 neutropenia > 7 days and 1 gr 3 febrile neutropenia). The RP2D was determined to be 2.5 mg of len. The most common all grade treatment-emergent non-hematologic adverse events (TEAEs) included rash (n=6, 43%), hyperglycemia (n=6, 43%), arthralgia/myalgia (n=5, 36%), diarrhea (n=4, 29%), and AST/ALT elevation (n=3, 21%). Grade 3 or higher TEAEs included 79% neutropenia (gr3 n=2; gr4 n=9), 29% lung infection (gr3 n=3; gr5 n=1), 21% febrile neutropenia (gr3 n=3), 21% lymphopenia (gr3 n=3), 21% anemia (gr3 n=3), and 14% thrombocytopenia (gr3 n=1; gr 4 n=1). With a median follow up of 37.5 months, the most common reason for discontinuation was progressive disease (n=7). Four patients (all LBCL) responded with all achieving a CR (ORR and CR rates were 29%) and all 4 patients remain in CR beyond 2 years, Figure 1. Median time to CR was 39.5 days. Median PFS was 2.3 months (95% CI: 1.6 mos-NR). Six patients died due to progressive lymphoma. Two patients died as a result of treatment-related AEs, 1 due to COVID19 infection, and 1 due to pneumonia/respiratory failure. Median OS was 21.3 months (95% CI:4.7 mos-NR). Conclusion: In these heavily pre-treated patients who progressed following CAR T-cell therapy, neutropenia was the dose limiting toxicity that prevented escalation of lenalidomide beyond 2.5 mg when combined with pembrolizumab and R. Four durable CRs were observed, none were observed at the RP2D. Risk mitigating strategies to reduce the incidence of febrile or grade 4 neutropenia and biomarker exploration to identify those likely to achieve a durable response are needed to explore this combination further.

A Phase I Study of Asciminib (ABL001) in Combination with Dasatinib and Prednisone for BCR-ABL1-Positive ALL and Blast Phase CML in Adults

Introduction:Oral ABL1 kinase inhibitors rapidly produce deep remissions in BCR::ABL1+ acute lymphoblastic leukemia (ALL) and chronic myeloid leukemia in lymphoid blast crisis (CML-LBC). Second generation TKIs such as dasatinib (DAS) are more effective than imatinib (Foa et al. Blood 2011) but patients may develop resistance. Asciminib (ASC), previously ABL001, is a STAMP (Specifically Targeting the ABL Myristoyl Pocket) allosteric ABL1 inhibitor that binds to a site spatially distinct from ATP-competitive TKIs. Combination treatment with an allosteric and an ATP-competitive TKI may deepen clinical responses and limit mutational resistance as supported by a cell line xenograft model of CML (Wylie et al. Nature 2017) and patient-derived xenograft models of BCR::ABL1+ ALL. We hypothesized that dual ABL blockade with catalytic domain and allosteric inhibitors would be tolerable and active in BCR::ABL1+ ALL and CML-LBC. Methods: This investigator initiated, phase I study (NCT03595917) of asciminib (ASC) in combination with DAS plus prednisone (pred) for BCR::ABL1+ ALL studied ASC in escalating doses in a 3+3 design with the primary objective to determine the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D); a 10 patient (pt) expansion cohort was then accrued. Secondary objectives define the depth and durability of responses. Pts with BCR::ABL1+ ALL or CML-LBC newly diagnosed ≥ 50 years (yrs), or unfit; or relapsed/refractory (no prior DAS or ASC) were eligible in dose escalation; all pts ≥18 yrs were eligible in dose expansion. Pts received DAS 140 mg/day(d) and pred 60 mg/m 2/d 1-24 (max 120 mg/d, tapered d 25-32) with escalating daily doses of ASC (DL1: 40 mg; DL2: 80 mg; DL3: 160 mg). DAS and ASC were given in 28-d cycles indefinitely in setting of clinical benefit, with allogeneic stem cell transplant (SCT) consolidation after d85 per treating physician. Dose-limiting toxicity (DLT) was initially defined as CTCAEv4 non-heme toxicity grade (gr) 3+; the study was amended to assess DLT via CTCAEv5. Correlative science efforts seek to define biomarkers of response and resistance to dual ABL1 blockade. Results:The study enrolled 25 pts (48% female), with 14 in dose escalation (13 evaluable), and 11 in expansion (10 evaluable). Most (92%) had new ALL (p190: 15/23, p210: 8/23; 8% had CML-LBC. Median age was 65 yrs (range 33 - 85; 8 pts 70+). Median WBC was 15.1 K/μL (range 0.9 - 251.9 K/μL). No pt had CNS disease. DL1 and DL2 enrolled 3 pts each without DLT. Two of 3 pts at DL3 developed asymptomatic CTCAEv4 gr 3 amylase elevation during C1 meeting original DLT criteria. A 4 th pt enrolled on re-opened DL3 under an amendment defining asymptomatic CTCAEv4 gr 3 amylase/lipase elevations persisting ≤5d to not be a DLT. This pt experienced an asymptomatic CTCAEv4 gr 3 lipase elevation meeting DLT criteria. Thus, the study de-escalated to DL2, re-opening under an amendment assessing DLTs via CTCAEv5. Of note, all DLTs at DL3 would be gr <3 per CTCAEv5. Four more pts (3 evaluable) enrolled at DL2 without a DLT. Thus, ASC 80 mg/d was declared the RP2D, and 11 pts age ≥18 yrs enrolled in an expansion cohort, 10 of whom initiated study treatment. No pt had symptomatic pancreatitis. Rates of molecular response after 3 cycles among all evaluable patients were 58.3% (14/24) for MRD 3.0 and 25.0% (6/24) for MRD 4.0. Evaluable pts with new ALL treated at the RP2D achieved molecular response rates after 3 cycles of 78.6% (11/14) for MRD 3.0 and 42.9% (6/14) for MRD 4.0. Both patients with imatinib-refractory CML-LBC progressed (C9, C3). Of those with ALL, 8 bridged to SCT after 2-8 cycles; 2 elected local care (C5, C7); 1 transitioned to ponatinib for inadequate response plus recurrent DAS pulmonary toxicity (C4); 6 remained on study treatment until disease progression (C4 - MRD+, C45, C11, C11); 3 remain on study. Correlative science evaluation of serial pt biospecimens in pursuit of predictive biomarkers will be shared at the meeting. Conclusion: Dual ABL1 kinase inhibition with ASC and DAS plus pred in BCR::ABL1+ ALL and CML-LBC is feasible and tolerable in adults with BCR::ABL1+ ALL and CML-LBC. DLTs at ASC 160 mg/d were asymptomatic amylase and lipase elevation, without clinical sequelae. ASC 80 mg/day was declared the RP2D, and an expansion cohort of 10 pts was completed. High rates of molecular response and bridging to transplant highlight encouraging preliminary activity. A phase II expansion cohort incorporating blinatumomab is now open.

Presurgical Oral Tamoxifen vs Transdermal 4-Hydroxytamoxifen in Women With Ductal Carcinoma In Situ

Oral tamoxifen citrate benefits women with ductal carcinoma in situ (DCIS), but concern about toxic effects has limited acceptance. Previous pilot studies have suggested transdermal 4-hydroxytamoxifen gel has equivalent antiproliferative efficacy to oral tamoxifen, with low systemic exposure. To demonstrate that 4-hydroxytamoxifen gel applied to the breast skin is noninferior to oral tamoxifen in its antiproliferative effect in DCIS lesions. This randomized, double-blind, phase 2 preoperative window trial was performed at multicenter breast surgery referral practices from May 31, 2017, to January 27, 2021. Among 408 women with estrogen receptor-positive DCIS who were approached, 120 consented and 100 initiated study treatment. The most common reasons for nonparticipation were surgical delay, disinterest in research, and concerns about toxic effects. Data were analyzed from January 26, 2021, to October 5, 2022. Random assignment to oral tamoxifen citrate, 20 mg/d, and gel placebo or 4-hydroxytamoxifen gel, 2 mg/d per breast, and oral placebo, for 4 to 10 weeks, followed by DCIS resection. The primary end point was absolute change in DCIS Ki-67 labeling index (Ki67-LI). Secondary end points included 12-gene DCIS Score, breast tissue tamoxifen metabolite concentrations, tamoxifen-responsive plasma protein levels, and patient-reported symptoms. Noninferiority of Ki67-LI reduction by 4-hydroxytamoxifen gel was tested using analysis of covariance; within- and between-arm comparisons were performed with paired t tests for mean values or the Wilcoxon rank sum test for medians. Of 90 participants completing treatment (mean [SD] age, 55 [11] years; 8 [8.9%] Asian, 16 [17.8%] Black, 8 [8.9%] Latina, and 53 [58.9%] White), 15 lacked residual DCIS in the surgical sample, leaving 75 evaluable for the primary end point analysis (40 in the oral tamoxifen group and 35 in the 4-hydroxytamoxifen gel group). Posttreatment Ki67-LI was 3.3% higher (80% CI, 2.1%-4.6%) in the 4-hydroxytamoxifen gel group compared with the oral tamoxifen group, exceeding the noninferiority margin (2.6%). The DCIS Score decreased more with oral tamoxifen treatment (-16 [95% CI, -22 to -9.4]) than with 4-hydroxytamoxifen gel (-1.8 [95% CI, -5.8 to 2.3]). The median 4-hydroxytamoxifen concentrations deep in the breast were nonsignificantly higher in the oral tamoxifen group (5.7 [IQR, 4.0-7.9] vs 3.8 [IQR, 1.3-7.9] ng/g), whereas endoxifen was abundant in the oral tamoxifen group and minimal in the 4-hydroxytamoxifen gel group (median, 13.0 [IQR, 8.9-20.6] vs 0.3 [IQR, 0-0.3] ng/g; P < .001). Oral tamoxifen caused expected adverse changes in plasma protein levels and vasomotor symptoms, with minimal changes in the transdermal group. In this randomized clinical trial, antiproliferative noninferiority of 4-hydroxytamoxifen gel to oral tamoxifen was not confirmed, potentially owing to endoxifen exposure differences. New transdermal approaches must deliver higher drug quantities and/or include the most potent metabolites. ClinicalTrials.gov Identifier: NCT02993159.

#4057 SUPERIOR PROTEINURIA REDUCTION WITH SPARSENTAN IN IMMUNOGLOBULIN A NEPHROPATHY (IGAN): A PROTECT STUDY INTERIM ANALYSIS

Abstract Background and Aims IgAN is the most common glomerular disease worldwide. Despite optimized standard of care, most patients with IgAN progress to kidney failure within 10-15 years, consequently seriously affecting their quality of life and mortality. Treatments that reduce proteinuria and risk of kidney disease progression are urgently needed for IgAN. Sparsentan is a novel, oral, non-immunosuppressive, single molecule that is a dual endothelin and angiotensin receptor antagonist being investigated for IgAN and focal segmental glomerulosclerosis. The Phase 3 PROTECT study is examining the long-term antiproteinuric and nephroprotective potential and safety of sparsentan compared with an active control, angiotensin receptor blocker (ARB) irbesartan, in adults with IgAN. Reported here are the PROTECT pre-specified interim primary efficacy endpoint and safety outcomes. Method PROTECT is an ongoing, global, Phase 3, multicenter, randomized, double-blind, active controlled study designed to evaluate the efficacy and safety of sparsentan versus the active control irbesartan in adults with IgAN with overt proteinuria despite receiving maximized treatment with an angiotensin converting enzyme inhibitor (ACEi) and/or ARB. The study duration is 270 weeks; the double-blind period is 114 weeks (110 treatment and 4 follow-up) with an open-label extension period up to 156 weeks. Adult patients with biopsy-proven IgAN (excluding IgAN secondary to another condition or IgA vasculitis), urine protein excretion value ≥1.0 g/day, eGFR ≥30 mL/min/1.73m2, systolic/diastolic blood pressure ≤150/≤100 mmHg, and on a stable dose of ACEi and/or ARB therapy for at least 12 weeks prior to screening that is both the patient's maximum tolerated dose and at least one-half of the maximum labeled dose were eligible for inclusion. Patients took their last ACEi and/or ARB dose the day before randomization. Patients were randomized 1:1 to sparsentan or irbesartan (target dose 400 and 300 mg/day, respectively), stratified by screening eGFR and urine protein excretion values. The pre-specified interim primary efficacy endpoint of change from baseline in urine protein/creatinine ratio (UP/C, based on a 24-hour urine sample) at Week 36 was analyzed using a mixed model repeated measures analysis. The safety evaluation included assessment of treatment emergent adverse events. Results A total of 671 patients were screened; 406 patients from clinical sites in 18 countries, including sites in North America, Europe, and Asia Pacific, met eligibility criteria and were enrolled and randomized into PROTECT. Two randomized patients withdrew from the study prior to initiating study treatment. The 404 randomized patients who received study drug were included in the primary analysis population. The mean reduction in UP/C from baseline at 36 weeks was significantly greater in the patients who received sparsentan (-49.8%) versus irbesartan (-15.1%, P&amp;lt;0.0001). Proteinuria reduction consistency across baseline demographic and clinical characteristics and rates of complete and partial remission are reported, as well as sustained proteinuria reduction over time. Safety outcomes related to edema and liver function tests are reported. Overall, sparsentan was generally well-tolerated and comparable to irbesartan. Conclusion The interim results of the PROTECT study show that in adult patients with IgAN and persistent proteinuria above 1 g/day despite being treated with ACEis and/or ARBs, once-daily treatment with sparsentan compared head-to-head with maximum labelled or tolerated irbesartan produced a robust and clinically meaningful reduction in proteinuria. The safety of sparsentan was consistent with previous studies in FSGS and comparable to irbesartan.

First-line (1L) nivolumab (NIVO) + ipilimumab (IPI) in patients (pts) with microsatellite instability-high/mismatch repair deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC): 64-month (mo) follow-up from CheckMate 142.

3550 Background: NIVO + IPI demonstrated robust, durable clinical benefit, and was well tolerated as a 1L therapy in pts with MSI-H/dMMR mCRC in the phase 2 CheckMate 142 study (NCT02060188), leading to the inclusion of NIVO + IPI in the NCCN guidelines as an initial therapy option for these pts. At 52-mo median follow-up, 1L NIVO + IPI continued to demonstrate durable clinical benefit, and no new safety signals were identified. Here we report longer follow-up results. Methods: Pts with MSI-H/dMMR mCRC and no prior treatment for metastatic disease received NIVO 3 mg/kg Q2W + IPI 1 mg/kg Q6W until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) by investigator assessment (INV) per RECIST v1.1. Other key endpoints were disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), all by INV; overall survival (OS); and safety. Results: In total, 45 pts received 1L NIVO + IPI. With median follow-up of 64.2 mo (range, 59.4–68.9 mo), ORR by INV was 71% (95% CI, 56–84%). The proportion of pts with a best overall response of complete response (CR) was 20%, partial response (PR) was 51%, stable disease (SD) was 13%, and progressive disease was 16%. Median DOR (mDOR) was not reached, and the 60-mo DOR rate was 72%. Median PFS (mPFS) by INV and median OS (mOS) were not reached, with 60-mo PFS and OS rates of 55% and 67%, respectively (Table). Among pts alive at the data cutoff (n = 31), 30 remained treatment-free after initial study treatment without receiving any subsequent systemic therapy, with a median treatment-free interval of 34.7 mo (range, 1.6–61.4 mo). Exploratory analysis by tumor mutational burden status will be presented. Safety data are shown in the Table. Conclusions: At 64-mo follow-up, NIVO + IPI continued to demonstrate clinically meaningful survival and durable responses, with mPFS, mOS, and mDOR still not reached, suggesting the potential for long-term clinical benefit. Safety remained consistent with previous data. These findings further support current recommendations for NIVO + IPI as a 1L treatment for pts with MSI-H/dMMR mCRC. Clinical trial information: NCT02060188 . [Table: see text]

Treatment of unfavorable bleeding patterns in contraceptive implant users: a randomized clinical trial of curcumin

Some users of the etonogestrel contraceptive implant experience bothersome bleeding, which can reduce contraceptive satisfaction and continuation. Few strategies exist to manage this bleeding. The exact mechanism of progestin-induced bleeding is unknown, but it is likely multifactorial (eg, impaired angiogenesis, "leaky" fragile vasculature, and inflammation). Curcumin, the active ingredient in turmeric, has anti-inflammatory, antiproliferative, and antiangiogenic properties, which may make it a useful agent for implant-associated bothersome bleeding. This study aimed to evaluate whether curcumin decreases frequent or prolonged bleeding or spotting in contraceptive implant users. The study was a randomized, double-blind, placebo-controlled trial. Here, etonogestrel implant users with frequent or prolonged bleeding or spotting were enrolled and randomized to either 600-mg Theracurmin HP (Immunovites, Las Vegas, NV) or placebo daily for 30 days. The term "frequent" was defined as ≥2 independent bleeding or spotting episodes, and the term "prolonged" was defined as ≥7 consecutive days of bleeding or spotting in a 30-day interval. Implant use was confirmed by clinical examination and negative gonorrhea and chlamydia and pregnancy tests. Enrolled participants initiated study treatment after 3 consecutive days of bleeding or spotting; if no bleeding or spotting occurred within 30 days of enrollment, the participants were withdrawn from the study. Study treatments were encapsulated to maintain a similar appearance. Participants used text messages to record daily bleeding patterns and study drug compliance. Bleeding was defined as a day that required the use of protection with a pad, tampon, or liner, and spotting was defined as a day with minimal blood loss that did not require the use of any protection. Our primary outcome was the total number of days without bleeding or spotting during the 30 days of study drug or placebo exposure. The secondary outcomes included total number of bleeding-free days, bleeding episodes, and satisfaction. A sample size of 22 per group provided 80% power at an alpha level of .05 to demonstrate a 6-day difference between groups. From February 2021 to November 2022, 58 individuals enrolled in the study with 54 participants (93%) completing 30 days of treatment (26 in the curcumin group and 28 in the placebo group). Of note, 1 individual in the curcumin arm did not experience a qualifying bleeding event and, thus, never initiated treatment and, per protocol, was withdrawn from the study. Participant characteristics did not differ between groups, including length of implant use at study enrollment (placebo, 521±305 days; curcumin, 419±264 days). The study groups did not differ concerning any bleeding-related outcome (mean days without bleeding or spotting: curcumin, 16.7±6.9; placebo, 17.5±4.8; P=.62; mean bleeding-free days: curcumin, 23.4±4.9; placebo, 22.4±4.5; P=.44; bleeding episodes: curcumin, 2.0±0.8; placebo, 2.1±0.8; P=.63). In addition, satisfaction with the implant as contraception and acceptability of bleeding over the study period did not differ by study group (P=.54 and P=.30, respectively). Daily use of curcumin did not improve bleeding patterns in users of the etonogestrel contraceptive implant experiencing frequent or prolonged bleeding patterns.

Expectations for Improvement: A Neglected but Potentially Important Covariate or Moderator for Chronic Pain Clinical Trials

Variability in pain-related outcomes can hamper assay sensitivity of chronic pain clinical trials. Expectations of outcome in such trials may account for some of this variability, and thereby impede development of novel pain treatments. Measurement of participants’ expectations prior to initiating study treatment (active or placebo) is infrequent, variable, and often unvalidated. Efforts to optimize and standardize measurement, analysis, and management of expectations are needed. In this Focus Article, we provide an overview of research findings on the relationship between baseline expectations and pain-related outcomes in clinical trials of pharmacological and nonpharmacological pain treatments. We highlight the potential benefit of adjusting for participants’ expectations in clinical trial analyses and draw on findings from patient interviews to discuss critical issues related to measurement of expectations. We conclude with suggestions regarding future studies focused on better understanding the utility of incorporating these measures into clinical trial analyses. PerspectiveThis focus article provides an overview of the relationship between participants’ baseline expectations and pain-related outcomes in the setting of clinical trials of chronic pain treatments. Systematic research focused on the measurement of expectations and the impact of adjusting for expectations in clinical trial analyses may improve assay sensitivity.

P914: EFFICACY AND SAFETY OF BELANTAMAB MAFODOTIN MONOTHERAPY IN PATIENTS WITH RELAPSED OR REFRACTORY LIGHT CHAIN AMYLOIDOSIS: A PHASE 2 STUDY BY THE EUROPEAN MYELOMA NETWORK

Background: Managing patients (pts) with relapsed/refractory (RR) light chain (AL) amyloidosis is challenging, as there is no current standard treatment, many available options are associated with low efficacy and toxicity, and options for daratumumab (DARA)- and bortezomib-exposed patients are limited. Belantamab mafodotin (belamaf), a multi-modal antibody-drug conjugate targeting BCMA, has shown efficacy and tolerability in heavily pretreated pts with RR multiple myeloma, including those refractory to DARA. Since clonal plasma cells in AL amyloidosis and MM are phenotypically similar, belamaf could be a novel treatment option in AL amyloidosis. Aims: To evaluate the efficacy and safety of belamaf monotherapy off-label in pts with RR AL amyloidosis. Methods: The ongoing prospective, open-label, multinational, phase 2, EMN27 study (NCT04617925) aims to enroll 36 adult pretreated pts with AL amyloidosis who require therapy. Pts at Mayo cardiac stage 3b are excluded. Belamaf monotherapy at 2.5mg/kg is administered by intravenous infusion every 6 weeks for a maximum of 8 cycles; dosing can be reduced to 1.92mg/kg for toxicity. Per study design, a safety analysis (after 6 pts received ≥1 treatment cycle) and an efficacy analysis (after 13 pts are enrolled) were planned. The safety analysis revealed no new safety signals, and pt accrual continued to 13 pts. The efficacy analysis is currently conducted; however, already 3 pts achieved complete response, or very good partial response (VGPR), or low difference of involved to uninvolved serum free light chains (dFLC) response and enrollment is continuing to include all planned pts. This descriptive analysis included pts initiating study treatment ≥3 months before the cut-off date (15/01/2022). Results: Of 11 pts included in the analysis, 4 (36.4%) continued treatment by the cut-off date, and 7 (63.6%) discontinued (disease progression: 5 [45.5%], death: 2 [18.2%]). The pts median age was 69.0 years (range 46.0–80.0), and most were males (7, 63.6%). At baseline, 3 (27.3%) and 8 (72.7%) pts had New York Heart Association class I and II symptoms, respectively; the median N-terminal pro-brain natriuretic peptide, high-sensitivity troponin T, and dFLC were 1,979 pg/mL (range 190.0–4,135.0), 41.6 pg/mL (range 11.0–80.8), and 34.2mg/dl (range 4.4–279.1), respectively. Except for the heart, commonly involved organs were the nervous system (4 pts, 36.4%) and the soft tissue (2 pts, 18.2%). The median number of previous AL amyloidosis treatments was 3.0 (range 1.0–7.0), including DARA. The median duration of belamaf therapy was 3.1 months (range 1.4–5.7). At a median follow up of 9.4 months (range 3.1–10.0), the overall response rate was 72.7% (8 pts; VGPR: 27.3% [3 pts] and partial response: 45.5% [5 pts]). Median time to first hematological response was 8.5 days (range 1.0–28.0) and to VGPR or better 15.0 days (range 8.0–15.0). The 3-month organ (heart, kidney, or liver) response rate was 36.4% (4 pts). All pts had ≥1 non serious adverse event (SAE). Four (36.4%) pts had ≥1 SAE, including 2 (18.2%) pts with a belamaf-related grade 2 and 4 visual impairment (1 [9.1%] pt each). Eight (72.7%) pts had ≥1 adverse event of special interest. Two (18.2%) pts had a fatal SAE (pneumonia and intestinal perforation, 1 [9.1%] pt each), both unrelated to belamaf. Summary/Conclusion: In this prospective study, belamaf monotherapy induced rapid, clinically meaningful responses with a manageable safety profile in heavily pretreated pts with RR AL amyloidosis. As the study progresses, additional data will be generated.

Amivantamab and lazertinib in patients with EGFR-mutant non–small cell lung (NSCLC) after progression on osimertinib and platinum-based chemotherapy: Updated results from CHRYSALIS-2.

9006 Background: Initial results with the amivantamab (ami) and lazertinib (laz) regimen showed encouraging efficacy in patients (pts) whose disease progressed after standard-of-care osimertinib (osi) and platinum-based chemotherapy (pt-chemo; Shu Ann Oncol 2021; 32:S949-1039; 1193MO). We present updated results of this population (Cohort A) from the CHRYSALIS-2 study (NCT04077463). Methods: Cohort A evaluated ami and laz in pts with EGFR exon 19 deletion or L858R NSCLC whose disease progressed on 1st/2nd-line osi followed by pt-chemo as last line of therapy (target population, n=106) and among a more heavily-pretreated population (n=56) whose disease progressed after osi and pt-chemo ± other therapies without regard to number and sequence of these therapies. Pts received 1050 mg IV ami (1400 mg, ≥80 kg) + 240 mg oral laz. Investigator (INV)- and blinded independent central review (BICR)-assessed response per RECIST v1.1 is reported for efficacy-evaluable pts, defined as pts who initiated study treatment on or before 17 Mar 2021, allowing for ≥6 mo of follow-up for response durability. Results: As of 6 Nov 2021, 162 pts were enrolled in Cohort A (median 62 y, 65% women, 61% Asian, median 3 [range, 2–14] prior lines). Median time between last osi treatment to first dose of ami + laz was 6.3 mo and 2.0 mo for the target and heavily-pretreated populations, respectively. Of 50 efficacy-evaluable pts in the target population, the overall response rate (ORR) by BICR was 36% (95% CI, 23–51), with 1 complete response (CR) and 17 partial responses (PRs), and the clinical benefit rate (CBR) was 58% (95% CI, 43–72); full results for all enrolled pts will be reported at the meeting. Median duration of response (mDOR) was not reached based on BICR. At a median follow-up of 8.3 mo, 7 responders (39%) have achieved a DOR lasting ≥6 mo by BICR. INV-assessed responses were consistent with BICR. Of 56 efficacy-evaluable pts in the heavily-pretreated population (8.7-mo median follow-up), ORR by INV was 29% (95% CI, 17–42), with 1 CR and 15 PRs. CBR was 55% (95% CI, 42–69) and mDOR was 8.6 mo (95% CI, 4.2–NR). BICR results are pending. Preliminary evidence of CNS antitumor activity was reported among 8 pts with baseline brain lesions (7 non-target, 1 target) who had not received radiation within 1 year prior to study enrollment. Most frequent adverse events (AE) were infusion-related reaction (65%), paronychia (49%), rash (41%), and stomatitis (39%). Most common grade ≥3 treatment-related AEs (TRAEs) were infusion-related reactions (7%), acneiform dermatitis (5%), and hypoalbuminemia (4%). TRAEs leading to discontinuation of either or both ami and laz occurred in 12% and 7%, respectively. Conclusions: Among an unselected population that has exhausted SOC osi and pt-chemo, ami and laz demonstrates encouraging antitumor activity with a manageable safety profile. Clinical trial information: NCT04077463.

A phase II multi-arm study to test the efficacy of oleclumab and durvalumab in specific sarcoma subtypes.

TPS11594 Background: Anti-PD 1/PD-L1 blockade alone or in combination with anti-CTLA4 have yielded suboptimal results in most sarcoma subtypes. CD73, an ectonucleotidase, catalyzes the rate-limiting step for adenosine production in the extracellular space, which then aids tumors in evading immune recognition and destruction. Oleclumab, a monoclonal antibody (mAb) selectively binds and inhibits the activity of CD73, and preclinical data suggests additive activity with durvalumab, a mAb that blocks PD-L1. We designed a trial combining oleclumab and durvalumab in certain sarcoma subtypes, selected based on modest activity with anti-PDL-1 and intense staining with CD73 in the tumor microenvironment. Methods: This phase 2 study (NCT04668300) is enrolling patients with age ≥18 years with recurrent/metastatic angiosarcoma (cohort 1) or dedifferentiated liposarcoma (DLPS) (cohort 2) and ≥12 years with recurrent/metastatic osteosarcoma (cohort 3), who have received at least one prior systemic therapy but are checkpoint inhibitor naïve and have measurable disease. Each treatment cycle is 28 days with oleclumab administered at 3000 mg i.v. every 2 weeks x 5 doses, and then every 4 weeks and durvalumab administered at 1500 mg i.v every 4 weeks. Tumor assessments are based on RECIST 1.1 and immune-related response criteria (irRC) and performed at baseline, and every 8 weeks after start of therapy, with an additional scan at 12 weeks for confirmation of response. Planned sample size is ≤ 25 pts in each arm. The primary efficacy endpoint for cohorts 1 and 2 is response rate (RR) at 4 months (per RECIST 1.1). The primary efficacy endpoint for cohort 3 is event free survival (EFS) rate at 4 months. If there is a high probability that the RR4 months is unlikely to be at least 20% for cohorts 1 and 2 or the EFS4 months is unlikely to be at least 40% for cohort 3 then the accrual of the corresponding cohort will be halted. The cohorts will be monitored separately for both futility and toxicity in groups of 5 after a minimum of 10 patients have been enrolled in each cohort. Secondary endpoints for the study include safety, best RR by RECIST and irRC, median PFS, and OS. Core needle biopsies and blood samples are collected at baseline and early on-treatment (week 6). Fresh flow cytometry is being performed to assess changes in T-cell activation, proliferation, and function and CD73 expression in the membrane and cytoplasm is being assessed by immunohistochemistry. Localization of tumor-infiltrating lymphocytes and engagement of the PD-1/PDL1 axis is being assessed using multiplex immunofluorescence staining. As of Jan 30th, 2022, twenty-two patients have initiated study treatment, 3 in cohort 1, 12 in cohort 2, and 7 in cohort 3. Clinical trial information: NCT04668300.

Proton Pump Inhibitor Use and Efficacy of Nivolumab and Ipilimumab in Advanced Melanoma.

Simple SummaryImmune checkpoint inhibitors have been shown to improve survival in patients with advanced melanoma; however, a proportion of patients do not experience durable clinical benefit with these agents. Findings from a previous study suggested that the use of proton pump inhibitors while receiving immune checkpoint inhibitors may lead to worse clinical outcomes. To validate those results, we performed this retrospective analysis using data from three clinical trials involving patients with advanced melanoma treated with immune checkpoint inhibitors. We found that there is not enough evidence to conclude that proton pump inhibitors influence the efficacy of immune checkpoint inhibitors. Prospective studies are needed to conclusively determine if the use of proton pump inhibitors has any meaningful impact on the efficacy of immune checkpoint inhibitors in patients with advanced melanoma.The impact of proton pump inhibitors (PPIs) on clinical outcomes with first-line immune checkpoint inhibitors (ICIs) in patients with metastatic melanoma was previously analyzed in the phase II study, CheckMate 069. This retrospective analysis utilized data from three phase II/III studies of first-line ICI therapy in untreated advanced melanoma: CheckMate 066, 067, and 069. All randomized patients with PPI use ≤ 30 days before initiating study treatment were included in the PPI-use subgroup. Possible associations between baseline PPI use and efficacy were evaluated within each treatment arm of each study using multivariable modeling. Approximately 20% of 1505 randomized patients across the studies reported baseline PPI use. The median follow-up was 52.6–58.5 months. Objective response rate (ORR), progression-free survival (PFS), and overall survival analyses provided insufficient evidence of a meaningful association between PPI use and efficacy outcomes with nivolumab-plus-ipilimumab, nivolumab, or ipilimumab therapy. In five of the six ICI treatment arms, 95% confidence intervals for odds ratios or hazard ratios traversed 1. Significant associations were observed in the CheckMate 069 combination arm between PPI use and poorer ORR and PFS. This multivariable analysis found insufficient evidence to support meaningful associations between PPI use and ICI efficacy in patients with advanced melanoma.

Abstract GS2-10: Nimbus: A phase 2 trial of nivolumab plus ipilimumab for patients with hypermutated her2-negative metastatic breast cancer (MBC)

Abstract Background: While high tumor mutational burden (TMB-H) has been used as a tissue-agnostic biomarker for approval of immune checkpoint inhibitors (ICI), there is a paucity of data regarding efficacy of ICI in TMB-H MBC. The aim of this study was to evaluate if patients with TMB-H HER2-negative MBC benefit from the combination of nivolumab plus ipilimumab. Methods: This is an open-label, single-arm, multicenter, phase 2 study assessing the efficacy of nivolumab 3 mg/kg intravenously (IV) every 14 days plus ipilimumab 1 mg/kg IV every 6 weeks in subjects with TMB-H HER2-negative MBC. Eligible patients were required to have measurable HER2-negative MBC, TMB ≥9 Mut/Mb assessed by a cancer-gene panel evaluating &amp;gt; 300 genes and performed in a CLIA-certified laboratory, and 0-3 prior lines of chemotherapy in the advanced setting. The primary objective was overall response rate (ORR) according to RECIST 1.1. Secondary objectives include safety and tolerability, progression-free survival (PFS), and overall survival (OS). The study followed a two-stage design. In the first stage, 14 patients were enrolled. The study required at least 1 objective response in order to continue to the second stage where an additional 16 patients were enrolled. At least 4 objective responses among the 30 patients would suggest the regimen is worthy of further study. If the true response rate is 25%, the chance that the regimen is declared worthy of further study is &amp;gt; 90%. Tumor biopsies, peripheral blood mononuclear cells, circulating tumor DNA, and stool collection were mandatory and were obtained at baseline and on treatment (end of cycle 1). Results: From February 2019 to June 2021, 31 patients were enrolled across 3 different academic institutions. Among 30 patients who initiated study treatment, the median age was 63 yo, 20 had hormone-receptor positive (HR+) breast cancer and 10 had triple-negative breast cancer (TNBC), and median number of prior lines of chemotherapy was 1.5 (0-3). Among the 10 patients with TNBC, PD-L1 status was known in 7 patients (3 positive and 4 negative). Median TMB was 10.9 Mut/Mb and 16.7% (n = 5) of patients had a TMB ≥14 mut/Mb. After a median follow-up of 9.7 (4.4 - 16.4) months, 4 (13.3%) patients achieved a confirmed objective response (all partial responses) meeting the primary endpoint of this study. The median duration of response has not been reached and 3 of these patients are still progression-free for at least 15 months. Two patients have short follow-up, and one has an unconfirmed partial response and the other has a stable disease at the time of the data cut. Median PFS and OS was respectively 1.4 (95% CI 1.3 - 9.5) months and 8.8 (95% CI 4.2 - not reached). Exploratory analysis did not show a difference in response rate according to HR status and PD-L1 status (data not shown) but tumors with TMB ≥14 mut/Mb had a response rate of 60% vs 4% in the group with TMB between ≥9 and &amp;lt;14 mut/Mb (p = 0.01). The treatment was associated with a favorable toxicity profile, with only three patients developing grade 3 immune-related adverse events (1 had adrenal insufficiency and cardiac troponin elevation, and two other had hepatitis). There were no reported grade 4-5 events. Data regarding TIL, PD-L1 and CD8 immunohistochemistry will be presented at the symposium. Conclusion: This study of nivolumab plus ipilimumab in TMB-H MBC achieved the primary endpoint and demonstrated a confirmed ORR of 13.3%. While patients with TMB ≥ 14 Mut/Mb were minority in this study, the 60% of ORR in this subgroup highlights the need to better evaluate the optimal TMB cutoff to predict benefit to immunotherapy in MBC. Citation Format: Romualdo Barroso-Sousa, Tianyu Li, Sangeetha Reddy, Leisha A. Emens, Beth Overmoyer, Paulina Lange, Molly K Dilullo, Victoria Attaya, Jeffrey Kimmel, Eric P. Winer, Elizabeth A. Mittendorf, Nabihah Tayob, Sara M. Tolaney. Nimbus: A phase 2 trial of nivolumab plus ipilimumab for patients with hypermutated her2-negative metastatic breast cancer (MBC) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr GS2-10.

Safety of Daratumumab Combined with Bortezomib, Cyclophosphamide and Dexamethasone for the Treatment of Patients with Multiple Myeloma Presenting with Extramedullary Disease during the COVID-19 Pandemic

Safety of Daratumumab Combined with Bortezomib, Cyclophosphamide and Dexamethasone for the Treatment of Patients with Multiple Myeloma Presenting with Extramedullary Disease during the COVID-19 Pandemic

Abstract 73: A personal neoantigen vaccine NEO-PV-01 in combination with chemotherapy and pembrolizumab induces broad de novo immune responses in first-line non-squamous NSCLC: Associations with clinical outcomes

Abstract Background: Neoantigens arising from mutations in cancer cell DNA are important targets for T cell-mediated anti-tumor immunity. NEO-PV-01 is a personal neoantigen vaccine of up to 20 peptides (14-35 amino acids) based on a patient's HLA profile and bioinformatic analysis of tumor neoantigens. We report here relationships between baseline tumor characteristics, immune response, and clinical outcomes from NT-002, a Phase 1b study of NEO-PV-01 with pemetrexed, carboplatin, and pembrolizumab as first-line therapy for advanced non-squamous NSCLC (NCT03380871). The primary objective of this study was to evaluate the safety of the combination. Materials: Serial blood and tumor biopsies were collected at: i) prior to treatment, ii) after 12 weeks of chemotherapy-pembrolizumab treatment, and iii) after completion of NEO-PV-01 vaccination. Tumor biopsies were characterized by immunohistochemistry for immune and tumor markers, gene expression, whole-exome and TCR sequencing, and single-cell analysis. Antigen-specific responses were measured in blood samples by IFNγ ELISpot, intracellular cytokine staining and functional phenotyping by FACS. Results: A total of 38 patients initiated study treatment (ITT); 21 patients received at least 1 dose of NEO-PV-01 (VAX). The regimen was well-tolerated and consistent with the pembrolizumab plus pemetrexed/carboplatin safety profile. The overall response rate (ORR)/clinical benefit rate (CBR) for the ITT and VAX were 37%/69% and 57%/95%, respectively. Median PFS was 7.2 months (95% CI: 5.6,16.8) for both the ITT and VAX, and median OS 16.8 months (95% CI: 11.6, NR) for both groups. Immune analysis on 12 patients with available samples revealed neoantigen-specific CD4+ and CD8+ T cell responses in all patients tested with an average of 55% of vaccine peptides generating an immune response post-vaccination. Vaccine-induced immune responses were mutant-specific and durable at 52-week treatment timepoint. T cell responses were polyfunctional, as evident by secretion of multiple cytokines (TNFα, IL2, IFNγ), and were activated memory cells with a cytotoxic phenotype. Epitope spread was observed in 7 of 11 patients analyzed thus far. Comprehensive analysis by gene expression, ctDNA and TCR repertoire analysis demonstrated correlations to extended PFS. Additional data on single-cell sequencing of neoantigen-specific T cells and tumor biopsies and correlates to clinical outcomes will be presented. Conclusions: NEO-PV-01 in combination with pembrolizumab and carboplatin/pemetrexed has a good safety profile and induces de novo immune responses in first-line non-squamous NSCLC. The association of baseline disease characteristics to prolonged PFS suggests future patient enrichment strategies for evaluation of this novel regimen in a phase 2 trial. Citation Format: Mark M. Awad, Ramaswamy Govindan, David R. Spigel, Edward B. Garon, Victoria Kohler, Rohit Vyasamneni, Suchitra Ramesh, Tracey E. Sciuto, Melissa A. Moles, Jennifer Tepper, Amy Wanamaker, Zakaria S. Khondkar, John Srouji, Jesse Z. Dong, Kristen N. Balogh, Asaf Poran, Meghan E. Bushway, Mark DeMario, Richard B. Gaynor, Lakshmi Srinivasan. A personal neoantigen vaccine NEO-PV-01 in combination with chemotherapy and pembrolizumab induces broad de novo immune responses in first-line non-squamous NSCLC: Associations with clinical outcomes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 73.

Dalpiciclib versus placebo plus fulvestrant in HR+/HER2- advanced breast cancer that relapsed or progressed on previous endocrine therapy (DAWNA-1): A multicenter, randomized, phase 3 study.

1002 Background: Dalpiciclib (SHR6390), a novel CDK4/6 inhibitor, as monotherapy has demonstrated tolerability and preliminary antitumor activity in pretreated HR+/HER2− advanced breast cancer (ABC). Here we evaluated dalpiciclib with fulvestrant in ABC. Methods: In this randomized, double-blind, phase 3 trial, patients (pts) with HR+/HER2− locally advanced or metastatic breast cancer who had relapsed or progressed on previous endocrine therapy were enrolled. Eligible pts were randomized 2:1 to receive dalpiciclib (dalp; 150 mg po qd, d1-21, q4w) or placebo (PBO) with fulvestrant (fulv; 500 mg im, cycle 1 d1, d15, then d1 q4w). The primary endpoint was investigator (INV)-assessed PFS. As of Nov. 15, 2020, 162 (71.4% of total projected) events of disease progression or death had occurred and a preplanned interim analysis was done. The corresponding superiority boundary was 1-sided P = 0.0080 (Lan-DeMets [O’Brien-Fleming] boundary). Results: Overall, 361 pts were randomized to receive dalp-fulv (n = 241) or PBO-fulv (n = 120). With a median follow-up of 10.5 mo, dalp-fulv significantly improved INV-assessed PFS versus PBO-fulv (median, 15.7 [95% CI 11.1-NR] vs 7.2 [95% CI 5.6-9.2] mo; HR, 0.42 [95% CI 0.31-0.58]; P &lt; 0.0001). PFS per IRC were consistent with INV assessment (Table). The benefit of dalpiciclib extended beyond initial study treatment based on time to first subsequent chemotherapy (TFSCT; HR, 0.47 [95% CI 0.32-0.69]; P &lt; 0.0001). OS data were not mature with a total of 25 deaths documented. Median duration of exposure was 9.4 (IQR, 4.3-11.4) mo with dalpiciclib and 9.9 (4.7-11.9) mo with fulvestrant in the dalp-fulv group and was 6.1 (3.7-11.0) mo with fulvestrant in the PBO-fulv group. The most common (incidence ≥3%) grade 3 or 4 AEs with dalp-fulv were neutropenia (84.2%; vs 0% with PBO-fulv) and leukopenia (62.1%; vs 0%). Treatment discontinuation due to AE was reported for 2.5% of pts with dalp-fulv vs 3.3% with PBO-fulv. The incidence of SAE was 5.8% with dalp-fulv vs 6.7% with PBO-fulv. Conclusions: The study met its primary endpoint, demonstrating that dalpiciclib plus fulvestrant significantly improved PFS versus placebo plus fulvestrant, with a manageable safety profile. Our findings support dalpiciclib plus fulvestrant as a new treatment option in pts with HR+/HER2- ABC who relapsed or progressed on endocrine therapy. Clinical trial information: NCT03927456 .[Table: see text]

Quadruplet regimen with capecitabine, irinotecan, oxaliplatin, and bevacizumab in chemo-naive patients with metastatic colorectal cancer: Results from the safety lead-in of QUATTRO-II study.

57 Background: FOLFOXIRI plus bevacizumab (BEV) is regarded as the standard of care for selected patients (pts) with metastatic colorectal cancer (mCRC), despite the high incidence of neutropenia and diarrhea. The AXEPT phase III study showed that the modified capecitabine (CAP) + irinotecan (IRI) + BEV (CAPIRI+BEV) [CAP 1600 mg/m2, IRI 200 mg/m2, and BEV 7.5 mg/kg q3wk] treatment was non-inferior to FOLFIRI+BEV, with a lower incidence of hematologic toxicity. We hypothesized that the modified CAPIRI combined with oxaliplatin (OX) and BEV (CAPOXIRI+BEV) would be more feasible than FOLFOXIRI+BEV, without compromising efficacy. Methods: The QUATTRO-II study is an open-label, multicenter, randomized phase II study. In Step 1, the recommended doses (RD) of OX and IRI were investigated as a safety lead-in. In Step 2, pts are randomized to either the RD of CAPOXIRI+BEV or FOLFOXIRI+BEV. In Step 1, four dose levels of CAPOXIRI (fixed dose of CAP 1600 mg/m2 and BEV 7.5 mg/kg plus escalated or de-escalated doses of OX and IRI, q3wk) were investigated in a 3+3 manner. A dose level of ≤ 2/6 of dose-limiting toxicity (DLT) cases was expected as the RD. Results: A total of 9 pts (3 at Level 0, 6 at Level 1) were included in Step 1. The baseline characteristics were as follows: the median age was 62 years; 6 were male; 6 presented with a left-sided tumor; 8 had a performance status of 0; all wild type/ RAS mutant/ BRAF V600E mutant were 8/1/0; and UGT1A1 wild type/*6 single hetero/*28 single hetero were 7/0/2. In Level 0 (IRI 200 mg/m2, OX 100 mg/m2), one grade 4 neutropenia and one grade 3 anorexia were observed, but without DLT. In Level 1 (IRI 200 mg/m2, OX 130 mg/m2), two grade 4 neutropenia and one grade 3 colitis were observed, with 1 DLT (febrile neutropenia) case, fully recovered without G-CSF administration. No treatment-related deaths were observed. Although dose modifications were needed in 4 of the 6 pts, no further safety concerns related to treatment continuity were observed in the 2nd or subsequent cycles. Thus, we determined that the dose administered in Level 1 is the RD for Step 2. According to the preliminary efficacy results at 8 weeks after initiating study treatment, 6 pts achieved a partial response (2 in Level 0 and 4 in Level 1). Conclusions: The RD of CAPOXIRI+BEV was 200 mg/m2 IRI, 130 mg/m2 OX, 1600 mg/m2 CAP, and 7.5mg/kg BEV. The randomized phase II Step (Step 2) of QUATTRO-II is ongoing. Clinical trial information: NCT04097444.

Hydroxyurea to Reduce Stroke Risk in Tanzanian Children with Sickle Cell Anemia

Introduction: Sickle cell anemia (SCA) is highly prevalent in sub-Saharan Africa with &amp;gt;300,000 annual births, and substantial morbidity and mortality due to limited resources. The burden of stroke in this population is of particular concern, given the devastating clinical and neurocognitive sequelae of these events. Hydroxyurea, a potent disease modifying therapy for SCA, is safe and feasible for low-resource and malarial endemic countries within sub-Saharan Africa and when used at maximum tolerated dose (MTD), decreases the incidence of acute painful vaso-occlusive events, infections, malaria, transfusions, hospitalizations, and death. Whether hydroxyurea can prevent primary stroke in SCA within Africa has not yet been determined, due in part to lack of stroke screening programs using transcranial Doppler (TCD) ultrasonography. If effective, hydroxyurea would have even more therapeutic benefits for children with SCA, particularly in settings where blood is not available, affordable, or safe. We designed the Stroke Prevention with Hydroxyurea Enabled through Research and Education (SPHERE) trial to determine the stroke risk among Tanzanian children using TCD screening and to investigate the effects of hydroxyurea to reduce that risk. Methods: The SPHERE trial (NCT03948867) is a single center prospective phase 2 open-label screening and treatment pilot study at Bugando Medical Centre, a teaching and referral hospital in Mwanza, Tanzania. Children 2-16 years old with SCA consented to TCD screening by locally trained and certified examiners; recent febrile illness, red cell transfusion, or hospitalization were temporary exclusions. Study participants with maximum Time-Averaged Mean Velocity (TAMV) on TCD exam categorized as conditional (170-199 cm/sec) or abnormal (≥200 cm/sec) are offered hydroxyurea with escalation to MTD, while those with normal TCD screening exams will be rescreened annually. Hydroxyurea is initiated at ~20 mg/kg/day using 500 mg capsules and a weekly dosing calculator, then escalated every 8 weeks by 5 mg/kg/day up to 35 mg/kg/day. Children on hydroxyurea are seen monthly during dose escalation and every 3 months after reaching MTD. The primary endpoint is change in TCD velocity after 12 months of hydroxyurea therapy. Secondary endpoints include changes in splenic volume and filtrative function; change in renal function; incidence of infection, especially malaria; hydroxyurea pharmacokinetics; and genetic modifiers of disease including pharmacogenomics. Results: From April 2019 to April 2020, a total of 202 children underwent TCD screening, exceeding the projected enrollment pace and goal (Figure). The average age (mean ± SD) at enrollment was 6.8 ± 3.5 years, and 53% were female. A majority had previous dactylitis (75%), painful vaso-occlusive episode (93%), blood transfusion (68%), and malaria (89%). Recurrent hospitalization was common with 30% having &amp;gt;5 previous hospitalizations. Only 4% had previously used hydroxyurea. Baseline labs included hemoglobin = 7.8 ± 1.3 g/dL, HbF = 9.3 ± 5.4 %, and ANC = 5.5 ± 2.4 x 109/L. Baseline assessment revealed a palpable spleen in 46 children (23%), and most of these (29) were ≥5 cm below the costal margin. Abdominal ultrasonography documented splenic tissue in 91% of children with an average volume of 101 ± 123 mL (range 8-1045). TCD examinations were performed in all children at enrollment with average TAMV of 148 ± 27 cm/sec [median 144, IQR 130-169 cm/sec] with 76% normal, 21% conditional, 2% abnormal, and 1% inadequate exams. Of 47 children eligible for hydroxyurea for elevated TCD velocities, 45 successfully initiated treatment, while 1 lived too far away for regular visits, and 1 had low blood counts from acute splenic sequestration and died before initiating study treatment. Conclusion: Children with SCA in Tanzania have a high risk for primary stroke. Identification of elevated TCD velocities through screening by local trained certified examiners, coupled with initiation of hydroxyurea treatment with dose escalation to MTD, offers a feasible and affordable means by which to lower TCD velocities and reduce primary stroke risk. Now fully enrolled, SPHERE has built local clinical capacity, research infrastructure and high-quality TCD screening, and will prospectively determine the benefits of hydroxyurea for stroke prevention, as a prelude for expanding hydroxyurea access for children with SCA in Tanzania. Figure Disclosures No relevant conflicts of interest to declare.