Long-term Clinical Benefit Research Articles

Sustained Remission and Decreased Severity of CAR T-Cell Related Adverse Events: A Pivotal Study Report of CNCT19 (inaticabtagene autoleucel) Treatment in Adult Patients with Relapsed/Refractory B-Cell Acute Lymphoblastic Leukemia (R/R B-Cell ALL) in China

CNCT19 (inaticabtagene autoleucel) is an autologous CD19-specific chimeric antigen receptor (CAR) T-cell product. The patent protected CAR structure of CNCT19 contains a unique CD19 scFv, HI19a, which is different from commonly used FMC63. Together with using 4-1BB co-stimulatory domain in the CAR structure, CNCT19 is expected to reduce the severity of treatment-associated cytokine release syndrome (CRS) and neurologic toxicities (NT) while maintaining a stronger and longer durable anti-tumor effect.CNCT19 has been granted Breakthrough Therapy Designation by China National Medical Products Administration and Orphan Drug Designation by the U.S. FDA for the treatment of ALL.The trial of CNCT19 in adult Chinese patients with R/R B-cell ALL (NCT04684147) is a single-arm, open-label pivotal study conducted at 10 centers in China. The primary endpoint was the overall complete response rate (OCR) of complete response (CR) and CR with incomplete hematological recovery (CRi) within 3 months and at the end of Month 3 after CNCT19 infusion by central assessment.All 39 patients diagnosed with B-cell ALL were refractory and relapsed to multiple lines of prior therapy. Among the 39 patients 32 (82.1%) had reached MRD-negative OCR within 3 months after CNCT19 infusion, The median duration of response and OS have not been reached. 25 patients (64.1%) remained on CR (51.3%) or CRi (12.8%). at the end of Month 3 after CNCT19 infusion These patients had sustained long-term remission regardless of whether subsequent allo-HSCT treatment was done or not. The most common CNCT19-related adverse events (AEs) were CRS and NT and there were 4 cases of Grade ≥ 3 CRS (n=4, 10.3%) and 3 cases of Grade ≥ 3 NT (n=3, 7.7%). Following CNCT19 infusion, all the patients recovered. No death cases were reported due to CRS or NT.CNCT19 CAR-T cell therapy achieved a high rate of MRD-negative complete remission in adult patients with R/R B-cell ALL. Thus, with its distinct CAR structure containing a unique CD19 scFv (HI19a), CNCT19 provides effective treatment with potential long-term clinical benefits for adult patients with R/R B-cell ALL.

Breakthrough Study Develops Potential Cure for Hemophilia A

A phase 1-2 clinical trial of hemophilia A gene therapy demonstrated that the oversized FVIII gene could be packaged into an AAV5 vector and provide sustained expression of the deficient factor VIII for long-term clinical benefit while producing no immune response.

Long-term safety and efficacy of frameless subthalamic deep brain stimulation in Parkinson’s disease

BackgroundBilateral deep brain stimulation (DBS) of the subthalamic nucleus (STN) is standard of care for Parkinson’s disease (PD) patients and a correct lead placement is crucial to obtain good clinical outcomes. Evidence demonstrating the targeting accuracy of the frameless technique for DBS, along with the advantages for patients and clinicians, is solid, while data reporting long-term clinical outcomes for PD patients are still lacking.ObjectivesThe study aims to assess the clinical safety and efficacy of frameless bilateral STN-DBS in PD patients at 5 years from surgery.MethodsConsecutive PD patients undergoing bilateral STN-DBS with a frameless system were included in this single-center retrospective study. Clinical features, including the Unified Parkinson’s Disease Rating Scale (UPDRS) in its total motor score and axial sub-scores, and pharmacological regimen were assessed at baseline, 1 year, 3 years, and 5 years after surgery. The adverse events related to the procedure, stimulation, or the presence of the hardware were systematically collected.ResultsForty-one PD patients undergone bilateral STN-DBS implantation were included in the study and fifteen patients already completed the 5-year observation. No complications occurred during surgery and the perioperative phase, and no unexpected serious adverse event occurred during the entire follow-up period. At 5 years from surgery, there was a sustained motor efficacy of STN stimulation: STN-DBS significantly improved the off-stim UPDRS III score at 5 years by 37.6% (P < 0.001), while the dopaminergic medications remained significantly reduced compared to baseline (− 21.6% versus baseline LEDD; P = 0.036).ConclusionsOur data support the use of the frameless system for STN-DBS in PD patients, as a safe and well-tolerated technique, with long-term clinical benefits and persistent motor efficacy at 5 years from the surgery.

Efficacy of risdiplam in spinal muscular atrophy: A systematic review and meta-analysis.

This systematic review and meta-analysis aimed to assess the efficacy and safety of risdiplam on motor and respiratory function in spinal muscular atrophy (SMA). We systematically searched Medline, Scopus, Web of Science, and the Cochrane Library from inception to March 2023. We included pre-post studies that determined the effect of risdiplam on the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND), the 32-item Motor Function Measure (MFM32), the Revised Upper Limb Module (RULM), the Hammersmith Functional Motor Scale - Expanded (HFMSE), respiratory function, and the proportion of risdiplam-related adverse events in a population with SMA (phenotypes 1 and 2/3). Meta-analyses were also performed where possible. Eleven studies were included. After 12 months of treatment, 57% of participants with SMA1 achieved a CHOP-INTEND score ≥ 40 points, and more than half were able to feed orally and had head control. In SMA2/3, MFM32, RULM, and HFMSE increased by 2.09 (1.17, 3.01), 1.73 (1.25, 2.20), and 1.00 (0.40, 1.59) points, respectively. Efficacy on respiratory function in SMA2/3 was inconsistent. Finally, 16% of participants experienced adverse events, but serious adverse events could not be quantified due to a lack of cases. The limited available evidence suggests that risdiplam is an effective and safe drug for the treatment of SMA. In addition, long-term clinical benefit may be partly determined by the stage of disease at which treatment is initiated.

Partial response to RC-48 as palliative treatment in a patient with locallocally advanced carcinoma ex pleomorphic adenoma harboring a HER2 mutation: a case report

BackgroundCarcinoma ex pleomorphic adenoma (CXPA) is a neoplasm of the salivary gland that causes 3.6% of salivary gland tumors and 12% of salivary gland malignancies. Its prognosis is determined by the histological progression beyond the adenoma capsule. CXPA is thought to be a malignant transformation of a primary or recurrent pleomorphic adenoma and is associated with both benign and malignant lesions. Salivary gland cancers represent a rare heterogeneous group of neoplasms with complex clinicopathological characteristics and distinct biological behavior. Case descriptionThis case report summarizes the treatment of a 57-year-old male patient with CXPA of the left parotid gland, harboring HER2 amplification with poor prognosis. The overall survival of the patient has been > 3.5 years. The application and outcome of an immune checkpoint inhibitor and targeted therapy combination regimens in the treatment of CXPA carcinoma are discussed. ConclusionTargeted therapy combined with immunotherapy has long-term clinical benefits and targeted therapy which has a high clinical response rate (immunotherapy + dual-targeting three-drug regimens) may present an ideal choice for the treatment of patients with rare and/or refractory tumors without compromising patient safety.

Ferric Carboxymaltose in Patients with Acute Decompensated Heart Failure and Iron Deficiency: A Real-Life Study.

Background: The correction of iron deficiency (ID) with ferric carboxymaltose (FCM) is a recommended intervention in heart failure (HF) with reduced ejection fraction. Our aim is to evaluate, in a real-life setting, the clinical significance of ID screening and FCM treatment in acute decompensated HF (ADHF). Methods: In a cohort of ADHF patients, the prevalence of ID and FCM administration were investigated. Among the 104 patients admitted for ADHF, in n = 90 (median age 84, 53.5% with preserved left ventricular ejection fraction-LVEF), a complete iron status evaluation was obtained. ID was detected in n = 73 (81.1%), 55 of whom were treated with in-hospital FCM. The target dose was reached in n = 13. Results: No significant differences were detected in terms of age, sex, comorbidities, or LVEF between the FCM-supplemented and -unsupplemented patients. During a median follow-up of 427 days (IQR 405-466) among the FCM-supplemented patients, only 14.5% received FCM after discharge; the mortality and rehospitalizations among FCM-supplemented and -unsupplemented patients were similar (p = ns). In a follow-up evaluation, ID was still present in 75.0% of the FCM-supplemented patients and in 69.2% of the unsupplemented patients (p = ns). Conclusions: In this real-life ADHF cohort, FCM was administered at lower-than-prescribed doses, thus having no impact on ID correction. The significance of our findings is that only achieving the target dose of FCM and pursuing outpatient treatment can correct ID and produce long-term clinical benefits.

First-line nivolumab plus ipilimumab in metastatic non-small cell lung cancer: 5-year outcomes in Japanese patients from CheckMate 227 Part 1

BackgroundIn CheckMate 227 Part 1 (NCT02477826), first-line nivolumab plus ipilimumab demonstrated long-term durable overall survival (OS) benefit versus chemotherapy in patients with metastatic non-small cell lung cancer (NSCLC), regardless of tumor programmed death ligand 1 (PD-L1) expression. We report results in Japanese patients with ≥ 5-year follow-up.MethodsAdults with stage IV/recurrent NSCLC without EGFR/ALK aberrations were randomized 1:1:1 to nivolumab plus ipilimumab, nivolumab alone, or chemotherapy (patients with tumor PD-L1 ≥ 1%), or nivolumab plus ipilimumab, nivolumab plus chemotherapy, or chemotherapy (patients with tumor PD-L1 < 1%). Five-year efficacy and safety were assessed in Japanese patients.ResultsAt 62.1 months’ minimum follow-up, 143 Japanese patients with PD-L1 ≥ 1% or < 1% were randomized to nivolumab plus ipilimumab (n = 66) or chemotherapy (n = 77). Five-year OS rates were 46% with nivolumab plus ipilimumab versus 34% with chemotherapy (PD-L1 ≥ 1%) and 36% versus 19% (PD-L1 < 1%). Median duration of response was 59.1 versus 7.1 months (PD-L1 ≥ 1%) and 17.3 versus 3.0 months (PD-L1 < 1%). Among 5-year survivors treated with nivolumab plus ipilimumab (PD-L1 ≥ 1% and < 1%; n = 27), 59% (95% CI, 39%–75%) were off treatment for ≥ 3 years without receiving subsequent therapy. No new safety signals were observed.ConclusionsAt 5-year follow-up, nivolumab plus ipilimumab continued to show long-term durable clinical benefit versus chemotherapy, regardless of tumor PD-L1 expression. Consistent with findings for the global population, these data support the use of nivolumab plus ipilimumab as first-line treatment in Japanese patients with metastatic NSCLC.

Outcomes in patients with BRAFV600-mutated melanoma and brain metastases at baseline treated with dabrafenib plus trametinib.

Brain metastases (BM) and lactate dehydrogenase (LDH) levels above the upper limit of normal (ULN) are associated with poor prognosis in patients with melanoma. Although treatment with the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib have demonstrated long-term clinical benefit in patients with melanoma, data on their efficacy in patients with BM are limited. DESCRIBE Italy is an observational, retrospective, real-world study evaluating dabrafenib plus trametinib in 499 patients with BRAFV600-mutant stage III unresectable or stage IV melanoma from various sites across Italy. Here, we analyzed the clinical outcomes for the subgroup of patients receiving first-line treatment and presenting with BM at diagnosis and assessed the impact of predictive factors such as LDH levels and the presence of other metastases on median progression-free survival (mPFS). Overall, 325 evaluable patients were on first-line therapy and are the focus of this analysis; of these, 76 patients (23.4%) had BM at baseline. mPFS was lower for patients with BM at baseline compared with overall patients (8.7 months vs 9.3 months, respectively). Patients with BM at diagnosis and LDH >ULN had a considerably shorter mPFS compared with patients with LDH ⩽ULN (5.3 months vs 9.9 months, respectively). mPFS was noticeably longer for patients with cerebral metastases only compared with patients with cerebral and other metastases (15.0 months vs 8.7 months, respectively). Dabrafenib plus trametinib showed effectiveness in a real-world population of patients with advanced BRAFV600-mutated melanoma and BM at baseline, supporting its use in this population with poor outcomes.

677-P: Exploring the Impact of CGM on Perceived Control of Non-Intensive Insulin Treated Type 2 Diabetes—“I liked keeping my line with as few spikes as possible”

Background and Aims: Progression of type 2 diabetes (T2D) demands complex treatment modalities, which may impair patients’ confidence and psychological health. Technologies allowing improved understanding of the dynamic disease process may improve engagement with therapy. Methods: As part of a larger observational study, we previously reported findings highlighting the impact of using Dexcom G6 real-time CGM (rtCGM) with T2D adults (diverse therapies) and prediabetes over a 12-week period. We now explored qualitative data generated from a subsample of T2D participants (N=38) on non-intensive insulin therapy (Basal only=24%, No insulin=76%). Participants answered open-ended questions about their experiences using CGM including self-reported learnings and changes in behavior. Primary themes from qualitative data were derived using content analysis and confirmed with inter-coder reliability. Results: Overall, most participants (&amp;gt;90%) ended the study with high levels of perceived control (PC) of their diabetes. For further analysis, participants’ change in PC at study end were plotted based on low, medium, or high PC before CGM use. Interesting group differences emerged wherein fewer participants reporting medium PC at baseline reported high PC at study end (vs. others with low and high baseline PC). Qualitative themes around perceived illness severity, depressive symptoms, and self-efficacy along with differences in demographics and glycemic metrics helped translate these meaningful findings. Conclusions: rtCGM use provided valuable improvements in participants’ engagement and understanding of their diabetes with potential for long-term clinical benefits. Future studies exploring relationships between perceived control of diabetes and progression of T2D may indicate potential areas for improved engagement with diabetes technology. Disclosure M.A.Crawford: Employee; Dexcom, Inc. C.Hicks: Employee; Dexcom, Inc. P.Genge: Employee; Dexcom, Inc. K.Greenawald: Employee; Dexcom, Inc. M.Tressler: Employee; Dexcom, Inc. D.R.Cherñavvsky: None. H.Singh: Employee; Tandem Diabetes Care, Inc., Dexcom, Inc. Funding Dexcom, Inc.

Effectiveness and safety of central pancreatectomy in benign or low-grade malignant pancreatic body lesions: a systematic review and meta-analysis.

The best approach for treating benign or low-grade malignant lesions localized in the pancreatic neck or body remains debatable. Conventional pancreatoduodenectomy and distal pancreatectomy (DP) are associated with a risk of impairment of pancreatic function at long-term follow-up. With advances in technology and surgical skills, the use of central pancreatectomy (CP) has gradually increased. To compare the safety, feasibility, and short-term and long-term clinical benefits of CP and DP in matched cases. The PubMed, MEDLINE, Web of Science, Cochrane, and EMBASE databases were systematically searched to identify studies published from database inception to February 2022 that compared CP and DP. This meta-analysis was performed using R software. Twenty-six studies matched the selection criteria, including 774 CP and 1713 DP cases. CP was associated with significantly higher rates of operative time (P<0.0001), blood loss (P<0.01), overall and clinically relevant pancreatic fistula (P<0.01), postoperative hemorrhage (P<0.0001), reoperation (P=0.0196), delayed gastric emptying (P=0.0096), hospital stay (P<0.01), and morbidity (P<0.0001) but with a significantly lower incidence of overall endocrine and exocrine insufficiency (P<0.0001), and new-onset (P<0.0001) and worsening diabetes mellitus (P<0.0001) than DP. CP should be considered as an alternative to DP in selected cases such as without pancreatic disease, length of the residual distal pancreas ≥5cm, branch-duct IPMNs, and a low risk of POPF after adequate evaluation.

DIRECT ANTERIOR APPROACH OR POSTERIOR APPROACH TOTAL HIP ARTHROPLASTY: IS THERE A DIFFERENCE IN LONG-TERM REVISION RATES AND TEN-YEAR PATIENT-REPORTED OUTCOME MEASURES?

The Posterior and Lateral approaches are most commonly used for Total Hip Arthroplasty (THA) in the United Kingdom (UK). Fewer than 5% of UK surgeons routinely use the Direct Anterior Approach (DAA). DAA THA is increasing, particularly among surgeons who have learned the technique during overseas fellowships. Whether DAA offers long-term clinical benefit is unclear.We undertook a retrospective analysis of prospectively collected 10-year, multi-surgeon, multi-centre implant surveillance study data for matched cohorts of patients whose operations were undertaken by either the DAA or posterior approach. All operations were undertaken using uncemented femoral and acetabular components. The implants were different for the two surgical approaches. We report the pre-operative, and post operative six-month, two-year, five-year and 10-year Oxford Hip Score (OHS) and 10-year revision rates.125 patients underwent DAA THA; these patients were matched against those undergoing the posterior approach through propensity score matching for age, gender and body mass index. The 10-year revision rate for DAA THA was 3.2% (4/125) and 2.4% (3/125) for posterior THA. The difference in revision rate was not statistically significant. Both DAA and Posterior THA pre-operative OHS were comparable at 19.85 and 19.12 respectively. At the six-month time point, there was an OHS improvement of 20.89 points for DAA and 18.82 points for Posterior THA and this was statistically significant (P-Value &lt;0.001). At the two, five and 10-year time-points the OHS and OHS improvement from the pre-operative review were comparable. At the 10-year time point post-op the OHS for DAA THA was 42.63, 42.10 for posterior THA and the mean improvement from pre-op to 10-years post op was 22.78 and 22.98 respectively. There was no statistical difference when comparing the OHS or the OHS mean improvements at the two, five and 10-year point.Whilst there was greater improvement and statistical significance during the initial six month time period, as time went on there was no statistically significant difference between the outcome measures or revision rates for the two approaches.

Cured or Not? Long-term Outcomes of Immunotherapy Responders. Focus on Melanoma.

Immune checkpoint inhibitors (ICIs) demonstrated robust antitumor activity and tolerable safety in advanced melanoma. Data on long-term outcome of patients who benefited from this therapy and who are still free of progression despite ICI discontinuation is now available. We review here the characteristics of long-term ICI responders and address the critical question of cure. Long-term outcome of patients with metastatic melanoma enrolled in large phase 2 and phase 3 clinical trials evaluating ICI in metastatic melanoma is now available. Durable responses, with more than 6 years of median follow-up, may persist after discontinuation. They occur more frequently in patients who achieved a complete response rather than in patients who had partial response or stable disease. Although long-term clinical benefit is more frequent in patients with high PDL-1 expression and smaller tumor burden, durable response may also be observed regardless of baseline characteristics. In patients with asymptomatic brain metastasis, combined immunotherapy (ipilimumab plus nivolumab) may also lead to long-term remission. Clinical trials confirm the durable antitumor activity of ICI. Although the hope for cure seems reasonable for many patients in this situation, late relapses may occur and no relapse-predictive biomarkers have been identified yet. Long-term responders who relapse can respond to a rechallenge of ICI although data are limited concerning the rate and the duration of this new response.

Five-year subgroup analysis of tafasitamab + lenalidomide from the phase II L-MIND study in patients with relapsed or refractory diffuse large B-cell lymphoma.

e19522 Background: The Phase II L-MIND study led to accelerated US approval and EU conditional authorization of the CD19-targeted immunotherapy, tafasitamab, + lenalidomide (LEN) followed by tafasitamab monotherapy for patients (pts) with R/R DLBCL ineligible for autologous stem cell transplant (ASCT). Long-term L-MIND data further support the regimen. Here we present exploratory analyses of final 5-year (yr) efficacy in subgroups of interest. Methods: Pts (≥18 years) with ASCT-ineligible R/R DLBCL, 1–3 prior systemic therapies (incl. ≥1 targeting CD20) and ECOG PS 0–2 received tafasitamab for ≤12 28-day cycles (+ LEN), then alone until disease progression. Primary endpoint was objective response rate (ORR). Secondary endpoints included duration of response (DoR), progression-free survival (PFS) and overall survival (OS). Exploratory subgroup analyses including by International Prognostic Index (IPI) and time to progression after 1L (in pts with only 1 prior line) used Kaplan-Meier estimates of 5-yr endpoints. Results: As of 14 Nov, 2022 in the full analysis set (FAS; n=80), ORR was 56.2% [95% CI: 44.7–67.3]. Median treatment duration was 9.0 months (mo) [0.5–73.6] and median follow-up (mFU) for OS was 65.6 mo [59.9–70.3]). Median DoR was not reached (mFU: 43.7 mo [29.9–58.4]). Of 18 patients in follow-up for ≥5 years, 9 received tafasitamab until end of study per protocol, 9 discontinued while in remission. RR and 5-yr rates for DoR, PFS and OS showed long-term clinical activity in all pt subgroups (Table). Conclusions: In this 5-yr subgroup analysis, a long-term clinical benefit with tafasitamab + LEN followed by tafasitamab monotherapy was observed in all subgroups of clinical interest, including pts with poor prognosis risk factors. These data suggest this immunotherapy may have curative potential, which is being explored in further studies. Clinical trial information: NCT02399085 . [Table: see text]

Durable clinical outcomes in patients (pts) with advanced melanoma and progression-free survival (PFS) ≥3y on nivolumab (NIVO) ± ipilimumab (IPI) or IPI in checkmate 067.

9542 Background: NIVO + IPI has demonstrated durable clinical benefit at 7.5 y in pts with advanced melanoma in the phase 3 CheckMate 067 study. PFS curves plateaued at ~3 y in this study, suggesting that being alive and progression-free for ≥ 3 y (PFS ≥ 3y) may be a good surrogate for long-term clinical benefit. We conducted analyses to quantify this association. Methods: Pts with treatment (tx)-naive, unresectable stage III/IV melanoma (stratified by PD-L1 expression, BRAF mutation status, and metastasis stage) received NIVO 1 mg/kg + IPI 3 mg/kg for 4 doses Q3W, followed by NIVO 3 mg/kg Q2W (n = 314); NIVO 3 mg/kg Q2W + placebo (n = 316); or IPI 3 mg/kg Q3W for 4 doses + placebo (n = 315) until progression or unacceptable toxicity. Exploratory post hoc analysis was performed in pts with PFS ≥ 3y. Results: In the NIVO + IPI, NIVO, and IPI arms, respectively, 99 (32%), 78 (25%), and 21 (7%) pts had PFS ≥ 3y. Objective response rates (ORRs) in these pts were ≥ 95% (table). The majority of responses were complete responses (CRs; table); in almost all pts with partial responses (PRs) on NIVO + IPI or NIVO, target-lesion size decreased by ≥ 50%. At 7.5 y of follow-up among pts alive and progression-free at 3 y, PFS rates were ≥ 68%, overall survival (OS) rates were ≥ 85%, and melanoma-specific survival (MSS) rates were ≥ 95% in the 3 tx groups (table). Among pts in this group who died after 3 y on study, the majority of deaths were unrelated to disease (table). The majority of pts with PFS ≥ 3y who were alive and in follow-up were tx-free at the 7.5-y data cutoff (77/84, 57/64, and 13/16). Pts who received NIVO + IPI were off tx (median) for 75.5 mo (NIVO, 55.7 mo; IPI, 59.2 mo). Among pts with PFS ≥ 3y in the 3 tx groups, 4%, 5%, and 19% received subsequent systemic tx (table). No new safety signals were observed in pts with PFS ≥ 3y. Conclusions: This exploratory post hoc analysis suggested that PFS ≥ 3y may be a good surrogate for long-term MSS with NIVO + IPI or NIVO, with very few occurrences of progression or death due to melanoma in this population through 7.5 y. Most pts were tx-free without having received subsequent systemic tx after demonstrating PFS ≥ 3y. Further study of pts with PFS ≥ 3y may allow the burden of imaging and follow-up visits to be reduced in this group. Clinical trial information: NCT01844505 . [Table: see text]

ID: 198326 Pain Relief Using an Interspinous Spacer for Treatment of Lumbar Spinal Stenosis Among Severe-Pain Patients

Patients with impaired physical function who experience leg, buttock and/or groin pain due to lumbar spinal stenosis (LSS) may be ideally suited for treatment using Indirect Decompression Systems (IDS) or Interspinous Spacers. Excellent long-term clinical benefit with sustained pain relief, improved quality of life, and medication reduction up to 5-years post-implant has been recently reported.1-3 Additionally, real-world reports demonstrated excellent long-term clinical benefit for patients including leg pain responder rate and pain severity of 75% and 60% respectively at 12-months post operation.4 Here, we provide real-world outcomes in patients with severe pain who received an Indirect Decompression System (IDS) for LSS related pain and symptoms as part of an ongoing multi-center observational case series

Real-world outcomes of brexucabtagene autoleucel (brexu-cel) for relapsed or refractory (R/R) mantle cell lymphoma (MCL): A CIBMTR subgroup analysis by prior treatment.

7507 Background: Brexu-cel is a CAR T therapy approved for adult patients (pts) with R/R MCL. In a 3-year follow-up of ZUMA-2 (Wang et al., 2022), ORR was 91% (CR 68%). Median DOR, PFS and OS were 28.2, 25.8 and 46.6 mo respectively. Here, we describe real-world outcomes of brexu-cel by receipt of prior BTK inhibitor (BTKi), bendamustine, autoHCT, and 1-2 vs ≥ 3 prior lines of therapy. Methods: From 07/2020-08/2022, 397 pts receiving brexu-cel for R/R MCL from 79 US centers were registered in the CIBMTR observational database. In this analysis, 272 were included (median follow-up 6.6 mo; range 0.3-16.5), excluding pts with prior non-HCT cellular therapy (n = 7), missing data on prior treatment, or no follow-up. Descriptive analyses were used for all outcomes. Results: Median age was 65.8 years (range 34.1-84.9); pts were mostly male (78%). Prior to infusion, 7% had ECOG PS ≥ 2; 76% had clinically significant comorbidities; 4% had extranodal CNS involvement. At diagnosis, Ki-67 ≥ 30%, Ki-67 ≥ 50% and TP53/17p deletion were seen in 69% (n = 111/160), 44% (n = 70/160) and 19% (n = 29/153) of pts respectively. Pts had a median of 4 lines of prior therapy (range 1-12; 6% as 2L). Prior to leukapheresis, 87% were BTKi-exposed; 54% received bendamustine; 31% were autoHCT recipients. Median time from leukapheresis to infusion was 28 d (IQR 26-34 d), during which 18% received bridging therapy. ORR for all was 89% (CR 78%). At 6 mo, cumulative incidence of relapse/PD was 21%; DOR, PFS and OS were 76%, 73% and 83% respectively. Grade ≥ 3 (ASTCT consensus) CRS and ICANS occurred in 9% and 27% of pts (88% and 62% for any grade). Most CRS (94%) and ICANS (79%) resolved within 3 weeks. Prolonged cytopenia by 30 d occurred in 23% pts. NRM at 100 d and 180 d were 3% and 6% respectively, mainly due to infections. ORR for BTKi-naïve (n = 36) vs -exposed (n = 233) pts was 85% (CR 79%; 6-mo DOR 84%) vs 89% (CR 77%; 6-mo DOR 74%); for pts with (n = 145) vs without (n = 124) prior bendamustine was 88% (CR 75%; 6-mo DOR 75%) vs 89% (CR 80%; 6-mo DOR 77%); for pts with (n = 83) vs without (n = 188) prior autoHCT was 90% (CR 82%; 6-mo DOR 83%) vs 88% (CR 76%; 6-mo DOR 72%). Higher CR rates were seen in pts with brexu-cel as 2/3L (n = 56) vs 4L+ (n = 213) (91% vs 74%; ORR 92% vs 88%; 6-mo DOR 77% vs 75%). Similar safety profiles were seen regardless of prior BTKi or autoHCT. Pts with prior bendamustine had fewer Grade ≥ 3 ICANS (19% vs 36%) but more prolonged cytopenia (29% vs 16%) vs pts without. Conclusions: These early findings suggest that real-world outcomes of brexu-cel are consistent regardless of prior BTKi, bendamustine, or autoHCT. Use of brexu-cel in earlier lines may help achieve a higher CR rate. Further studies with longer follow-up are warranted to contextualize response rates in relation to long-term clinical benefits of brexu-cel. Updated data with longer follow-up will be reported at the time of presentation. SK and NA contributed equally.

Clinical outcomes with neoadjuvant nivolumab (N) + chemotherapy (C) vs C by definitive surgery in patients (pts) with resectable NSCLC: 3-y results from the phase 3 CheckMate 816 trial.

8521 Background: In CheckMate 816, neoadjuvant N + C demonstrated statistically significant and clinically meaningful improvements in event-free survival (EFS) and pathologic complete response (pCR) vs C in pts with resectable NSCLC. Here, we report clinical outcomes in pts with or without definitive surgery following neoadjuvant treatment (tx). Methods: Adults with stage IB (tumors ≥ 4 cm) to IIIA (per AJCC 7th ed) resectable NSCLC, ECOG PS ≤ 1, and no known EGFR/ ALK mutations were randomized 1:1 to 3 cycles of N 360 mg + C Q3W or C Q3W, followed by definitive surgery within 6 wk of tx. Primary endpoints were EFS and pCR, both per blinded independent review. Exploratory analyses included EFS (secondary definition; no censoring for subsequent tx), time to death or distant metastasis (TTDM), and EFS2 (EFS on next-line tx) in pts with or without surgery. Results: Among 358 randomized pts, 149 (83%; N + C) and 135 (75%; C) had definitive surgery. Baseline characteristics were similar in pts with or without surgery (N + C, 30; C, 44) and between tx arms, except that a higher proportion of pts who did not have surgery had ECOG PS 1 (both arms) or were from Europe (N + C arm). Surgery was canceled due to progressive disease (PD) in 11 (N + C) and 17 (C) pts; PD was locoregional in 4 and 15 pts and distant in 3 and 2 pts, while 4 pts in the N + C arm had both locoregional and distant PD. At database lock (October 14, 2022; median f/u: 41.4 mo), EFS, TTDM, and EFS2 were numerically improved in pts with vs without surgery, regardless of tx arm. In pts with surgery, median TTDM was not reached (NR) vs 46.8 mo (HR, 0.55) with N + C vs C, respectively; 3-y TTDM rates were 77% vs 59%. In pts without surgery, median TTDM was 24.8 vs 15.6 mo (HR, 0.63) with N + C vs C; 3-y rates were 36% vs 13%. Among pts without surgery, 17 (57%) vs 28 (64%) pts in the N + C vs C arms, respectively, received subsequent tx: radiotherapy 37% vs 41%; surgery 3% vs 2%; systemic tx 50% vs 52%. Grade 3/4 tx-related AEs occurred in 38% (N + C) and 36% (C) in pts with surgery, and 26% and 46% in pts without surgery. Conclusions: In CheckMate 816, neoadjuvant N + C demonstrated long-term clinical benefit vs C in pts with resectable NSCLC who received definitive surgery. In pts who did not receive definitive surgery, these exploratory analyses showed that neoadjuvant N + C was associated with numerically improved TTDM. Clinical trial information: NCT02998528 . [Table: see text]

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]

Percentage of negative urine drug screens as a clinically meaningful endpoint for RCTs evaluating treatment for cocaine use

BackgroundThis study examined a threshold based on the percentage of cocaine-negative (CN) urine drug screens (UDS) collected during treatment as a potential meaningful endpoint for clinical trials. We hypothesized that individuals providing at least 75% CN UDS would have better long-term outcomes than those providing less than 75% CN UDS. MethodsTwo separate pooled datasets of randomized clinical trials conducted at different institutions were used for analyses: one composed of eight trials (N = 760) and the other composed of three trials (N = 416), all evaluating behavioral and/or pharmacological treatments for cocaine use. UDS were collected at least once per week (up to three times per week) during the 8- or 12-week treatment period across all trials, with substance use and psychosocial functioning measured up to 12 months following treatment. Chi-squares and ANOVAs compared within-treatment and follow-up outcomes between the groups. ResultsCompared to those who did not achieve the threshold, participants who achieved the 75%-CN threshold were retained in treatment longer and had a longer period of continuous abstinence, and were more likely to report problem-free functioning. Additionally, participants who achieved the 75%-CN threshold were more likely to report sustained abstinence and better psychosocial functioning throughout a follow-up period up to 12 months than those who did not achieve the threshold. ConclusionsA threshold of 75%-CN UDS is associated with short- and long-term clinical benefits. Future clinical trials may consider this a meaningful threshold for defining treatment responders.

SP06. Regenerative Peripheral Nerve Interface Surgery and its Four-year Pain and Medication Intake Outcomes for Treatment or Prevention of Postamputation Pain

PURPOSE: Regenerative peripheral nerve interface (RPNI) surgery is a validated method for mitigating pain in postamputation patients. However, the long-term efficacy of RPNI surgery has yet to be fully characterized. The purpose of this clinical study was to assess long-term pain outcomes and opioid medication intake in amputation patients who have undergone RPNI surgery for the treatment or prevention of postamputation pain. METHODS: Patients included in this study underwent RPNI surgery between 2014 and 2021 for the treatment or prevention of postamputation pain and had at least one-year follow-up. A retrospective review was performed to collect preoperative demographic and clinical information. Outcomes for neuroma pain and PLP were assessed from the medical records at both the 1-year and the most recent follow-up visits. Postoperative pain was compared to preoperative pain and categorized into the following outcomes: no symptoms, improved symptoms, stable symptoms, or worsened symptoms. Opioid prescriptions were obtained through the EMR at preoperative and follow-up visits and converted to morphine milliequivalents (MME) based on dosage and type of opioid medication. RESULTS: Seventy-seven patients met inclusion criteria in this study. Thirty-seven patients underwent RPNI surgery to treat preexisting postamputation pain (treatment group) and 40 patients underwent prophylactic RPNI surgery at the time of amputation (prophylactic group). Fifty-five patients (26 in the treatment group and 29 in the prophylactic group) had additional follow-up visits after the one-year postop time frame. Average time from surgery at most recent follow-up was 50 months (4.2 years). For the treatment group, at time of most recent follow-up, favorable neuroma pain and PLP outcomes (no reported symptoms or improved symptoms) were seen in 77% and 61% of patients, respectively. For patients treated prophylactically, 97% of patients had no recorded neuroma pain or PLP at time of most recent follow-up visit. Average MME at time of most recent follow-up was also lower for both the treatment group (-12 +/- 83) and prophylactic group (-40 +/- 103). CONCLUSIONS: This study demonstrates the long-term clinical benefits of RPNI surgery on improving neuroma pain and PLP as well as a reduction of opioid intake for amputation patients who underwent the procedure. These findings suggest that the benefits of RPNI surgery on pain outcomes are highly favorable, and thus this surgery should be considered for all amputation patients.