Citations

e14531 Background: Afami-cel is an autologous, T-cell receptor T-cell therapy engineered to target melanoma-associated antigen A4 (MAGE-A4) in human leukocyte antigen (HLA) A*02–eligible patients (pts) with advanced solid tumors. SPEARHEAD-1 (NCT04044768) is a Phase 2, two cohort, open-label trial to evaluate the efficacy and safety of afami-cel in pretreated pts with advanced/metastatic synovial sarcoma or myxoid/round cell liposarcoma. Here we report data on cytokine release syndrome (CRS) in the pts with advanced synovial sarcoma treated with afami-cel across Cohort 1 and Cohort 2. Methods: Eligible pts had advanced synovial sarcoma and were HLA-A*02 positive with MAGE-A4–positive tumors. Pts received afami-cel after lymphodepleting chemotherapy containing fludarabine and cyclophosphamide. Tocilizumab administration was permitted for Grade 1 CRS if symptoms persisted for ≥ 24 hours or if the pt had co-morbidities, and for Grade ≥2 CRS. Results: As of August 29, 2022, 72 pts with synovial sarcoma received afami-cel (n = 44 Cohort 1; n = 28 Cohort 2). Afami-cel dose range was 1.92–10.00×109 transduced T-cells. The median age was 39.5 years (range: 16–73 years), 47.2% of pts were female, 88.3% of pts were white, and tumor MAGE-A4 expression H-score was 244.5 (range: 66–300). CRS occurred in 72.2% of the pts with synovial sarcoma receiving afami-cel, including Grade 1 in 50% (36/72), Grade 2 in 20.8% (15/72), and Grade 3 in 1.4% (1/72) of pts as per American Society for Transplantation and Cellular Therapy grading. The median time to onset was 2.5 days (range: 1–5 days), and the median time to resolution was 3 days (range: 1 to 14 days). Twenty-seven of 72 (37.5%) pts received at least one dose of tocilizumab. Consistent with expectations, higher serum IL-6 levels were associated with CRS events and the indicated use of tocilizumab for management. RECIST v1.1 responses were observed in pts with and without CRS. Correlation of clinical factors and CRS with response will be presented. Conclusions: CRS was common after afami-cel administration but was mostly low grade. Administration of tocilizumab in SPEARHEAD-1 was effective in the management of CRS. Clinical trial information: NCT04044768 .

11536 Background: Ripretinib is a switch-control tyrosine kinase inhibitor approved for patients (pts) with gastrointestinal stromal tumor (GIST) who received prior treatment with ≥3 kinase inhibitors, including imatinib. Exploratory baseline circulating tumor DNA (ctDNA) next-generation sequencing (NGS) analysis from INTRIGUE showed pts with second-line advanced GIST with primary KIT exon 11 mutations and secondary resistance mutations exclusively in KIT exons 17/18 derived clinical benefit from ripretinib but not sunitinib (Bauer S et al. J Clin Oncol. 2023; Abs 397784). Outcomes in pts with advanced GIST with ctDNA not detected (ctDNA-ND) had not been evaluated. Here, we present exploratory data from INTRIGUE in pts who had baseline ctDNA-ND vs ctDNA detected (ctDNA-D). Methods: INTRIGUE is an open-label, phase 3 study that enrolled pts with advanced GIST who had disease progression on or intolerance to imatinib (NCT03673501). Pts were randomized 1:1 to ripretinib 150 mg once daily (QD) or sunitinib 50 mg QD (4 wks on/2 wks off) and stratified by mutation according to local pathology report. Baseline peripheral whole blood was analyzed by Guardant360, a 74-gene ctDNA NGS-based assay. Pts with ctDNA-D had ≥1 somatic alteration in the 74 genes analyzed. Results: Pts with ctDNA-ND (82/362, 22.7%) were younger (median: 55.5 vs 62.0 years) and had smaller sums of longest diameters of target lesions (median [range]: 57.6 [11–459] vs 108.8 [15–418] mm) vs ctDNA-D (280/362, 77.3%). Progression-free survival (PFS) was longer in pts with ctDNA-ND vs ctDNA-D and numerically higher with ripretinib vs sunitinib in pts with ctDNA-ND (Table). Pts with ctDNA-ND categorized as not having a KIT exon 9 mutation at randomization ( KIT exon 11, other KIT/PDGFRA, or KIT/PDGFRA wild-type; n = 71) had longer PFS with ripretinib vs sunitinib (median not estimable [NE] vs 11 months; HR = 0.56; 95% CI 0.28 to 1.12). Objective response rate (ORR) and overall survival (OS) were higher with ctDNA-ND vs ctDNA-D. Safety was similar between groups and consistent with the primary analysis. Conclusions: Pts with ctDNA-ND had better efficacy outcomes vs pts with ctDNA-D in both treatment arms; PFS was numerically higher with ripretinib vs sunitinib in pts with ctDNA-ND. Although little is known about the biology driving ctDNA in GIST, these data suggest pts may have improved outcomes and different treatment sensitivity based on ctDNA detectability. Clinical trial information: NCT03673501 . [Table: see text]

11524 Background: Ripretinib is a switch-control tyrosine kinase inhibitor approved for patients (pts) with gastrointestinal stromal tumor (GIST) who received prior treatment with ≥3 kinase inhibitors, including imatinib. Sunitinib is approved for advanced GIST after imatinib failure. In the first interim analysis (IA) for overall survival (OS) in the INTRIGUE trial, data were immature (OS event rate, 22.3%), and median OS was not reached in either arm for the KIT exon 11 intent-to-treat (ITT) and all-patient (AP) ITT populations (S Bauer, et al. J Clin Oncol. 2022). Additionally, ripretinib had a more favorable safety profile with fewer grade 3/4 treatment-emergent adverse events (TEAEs) than sunitinib. Here, we present the second IA of OS and updated safety from INTRIGUE. Methods: INTRIGUE is a global, open-label, phase 3 study that enrolled adult pts with advanced GIST who had disease progression on or intolerance to imatinib (NCT03673501). Randomization was 1:1 to ripretinib 150 mg once daily (QD) or sunitinib 50 mg QD (4 wks on/2 wks off) and was stratified by KIT mutational status and imatinib intolerance. OS was a key secondary endpoint; data cutoff for the second IA was Sept 1, 2022. Results: Of 453 pts in the AP ITT population, 444 received treatment; 51 remain on treatment (33/223 [14.8%] with ripretinib and 18/221 [8.1%] with sunitinib). Common reasons for treatment discontinuation were progressive disease (PD) assessed by independent radiologic review (55.4%), PD assessed by investigator (10.6%), clinical PD (5.9%), withdrawal of consent (5.4%), and adverse event (AE; 4.5%); fewer pts discontinued due to an AE for ripretinib vs sunitinib (2.7% vs 6.3%). Following study treatment discontinuation, 58 pts (25.6%) from the sunitinib arm received ripretinib; 139 pts (61.5%) from the ripretinib arm later received sunitinib. There were 185 OS events (40.8%) in the AP ITT population; median duration of follow-up was 28.7 and 28.5 months for ripretinib and sunitinib, respectively. OS was similar with ripretinib vs sunitinib in the AP ITT (median 35.5 vs 30.9 months; HR 0.88, 95% CI 0.66 to 1.18; nominal P = 0.39) and KIT exon 11 ITT populations (median 34.0 vs 31.5 months; HR 1.05, 95% CI 0.75 to 1.48; nominal P = 0.77). The updated safety profile was consistent with the primary analysis; fewer pts had grade 3/4 TEAEs with ripretinib vs sunitinib (95 [42.6%] vs 149 [67.4%]). Dose interruptions and reductions were lower with ripretinib vs sunitinib. The median (range) treatment duration was 7.9 (0.2–38.2) months for ripretinib and 6.5 (0.2–38.3) months for sunitinib. Conclusions: In the second IA from INTRIGUE, OS was similar between treatment arms. The safety profile remained consistent with additional data, and results demonstrate favorable safety with ripretinib in pts with advanced GIST previously treated with imatinib. Clinical trial information: NCT03673501 .

397784 Background: Ripretinib, a switch-control tyrosine kinase inhibitor (TKI), is indicated for patients (pts) with gastrointestinal stromal tumor (GIST) who received prior treatment with ≥3 TKIs, including imatinib. Sunitinib is approved for advanced GIST after imatinib failure. Circulating tumor DNA (ctDNA) analysis may provide insight into the efficacy of these agents in second-line advanced GIST. Here, we present exploratory baseline ctDNA results from INTRIGUE. Methods: INTRIGUE is an open-label, phase 3 study that enrolled adult pts with advanced GIST who progressed on or had intolerance to imatinib (NCT03673501). Randomization was 1:1 to ripretinib 150 mg once daily (QD) or sunitinib 50 mg QD (4 wks on/2 wks off). Baseline peripheral whole blood was analyzed by Guardant360, a 74-gene ctDNA next-generation sequencing (NGS)-based assay. Only KIT mutations are reported here. Results: Of 453 pts in the overall intent-to-treat (ITT) population, 362 (80%) samples were analyzed. ctDNA was detected in 280/362 (77%), with KIT mutations detected in 213/280 (76%). Common resistance mutations were in the KIT activation loop (AL; exons 17/18; 89/213, 42%) and ATP-binding pocket (ATP-BP; exons 13/14; 81/213, 38%). Efficacy in pts with detectable ctDNA in the KIT exon 11 and overall ITT populations was consistent with the primary analysis based on tumor data used for randomization. Pts with KIT exon 11 + 17/18 (−9/13/14) mutations had superior progression-free survival (PFS), objective response rate (ORR), and overall survival (OS) with ripretinib vs sunitinib, whereas pts with exon 11 + 13/14 (−9/17/18) mutations had better PFS, ORR, and OS with sunitinib vs ripretinib (Table). Subgroup safety profiles were consistent with the primary analysis. Conclusions: While KIT ATP-BP mutations predicted clinical benefit from sunitinib vs ripretinib, pts harboring resistance mutations in the KIT AL derived meaningful clinical benefit from ripretinib but not sunitinib. This study demonstrates the value of ctDNA NGS-based sequencing of the complex landscape of KIT mutations to predict the clinical benefit of ripretinib or sunitinib as second-line therapy in pts with advanced GIST. Clinical trial information: NCT03673501 . [Table: see text]

Background. The Banff classification scheme provides a framework for interpreting transplant kidney biopsies and has undergone various updates in the past 2 decades especially related to antibody-mediated rejection. The clinical significance of early glomerulitis seen within 4 mo on protocol biopsies has received limited attention. We hypothesized that early glomerulitis seen on protocol biopsies will lead to significant adverse outcomes as assessed by histopathology and allograft outcome. Methods. A single-center retrospective study of a cohort of patients who underwent protocol biopsies within 4 mo after transplantation with timely follow-up protocol biopsies were assessed. Patients with recurrent glomerulonephritis were excluded. Results. We calculated glomerulitis (g) scores for 2212 biopsy specimens and identified 186 patients with glomerulitis (g > 0) and 2026 patients without glomerulitis (g = 0). The progression to chronic transplant glomerulopathy at 1 and 2 y was higher in patients with g > 0 as compared with g = 0 (year 1, 10.7% versus 2.3% [P < 0.001]‚ respectively; year 2, 17.2% versus 4.3% [P < 0.001], respectively) with no difference in other chronic lesions. The death-censored graft failure rate was higher in patients with g > 0 as compared with g = 0 (hazard ratio, 1.68 [95% CI, 1.07-2.65]; P = 0.02). We did not find any difference in outcomes in glomerulitis group based on donor-specific antibody. Conclusion. Our findings suggest that early glomerulitis (seen within 4 mo after transplantation) may lead to clinically significant long-term changes and thus could be a target for early intervention therapies.

11562 Background: Afami-cel is an autologous, HLA-A*02-restricted, specific peptide enhanced affinity receptor, T-cell therapy engineered to target MAGE-A4+ solid tumors. The pivotal, 2-cohort, single-arm, Phase 2, SPEARHEAD-1 trial (NCT04044768) with afami-cel met its primary endpoint based on Cohort 1 data. As of September 1, 2021, in 47 patients (pts) with metastatic synovial sarcoma (SyS) or myxoid/round cell liposarcoma (MRCLS), the overall response rate (ORR) per independent review was 34% with encouraging durability (Van Tine, et al. Paper 30: CTOS 2021; Virtual). To identify potential stratification factors for response and assess whether response is a proxy for progression-free survival (PFS), we present pooled analyses using data from the prior Phase 1 trial (NCT03132922) and Cohort 1 of the SPEARHEAD-1 trial. Methods: Eligible pts (16–75 years) were HLA-A*02+ with MAGE-A4+ tumors. Pts received afami-cel after lymphodepleting chemotherapy. The pooled analyses evaluated ORR per RECIST v1.1 by investigator review, stratified by 7 factors, and safety. Results: In the pooled data, 69 pts received afami-cel (2.12–9.99×109 transduced T-cells) and were evaluable for response (Phase 1, n = 18; Phase 2, n = 51); all expressed one eligible HLA-A*02 allele. Median (range) for: age was 42 years (19–76), number of prior lines of therapy was 2 (1–12), and tumor MAGE-A4 H-score was 230 (60–300). Median (range) H-score was higher in SyS (256 [60–300]) than in MRCLS (180 [112–230]). The pooled investigator-assessed ORR was 36.2% (40.7% in SyS; 10.0% in MRCLS). Responses occurred across a wide MAGE-A4 H-score range (134–300). Median (range) duration of response was 52 weeks (8.29–75.14). Response rate was higher in the 59 pts with SyS: with ≤2 vs ≥3 prior lines of therapy (55.2% vs 26.7%), baseline target lesion sum of longest diameters <10cm vs ≥10cm (53.1% vs 25.9%), MAGE-A4 H-score ≥200 vs <200 (46.3% vs 27.8%), without vs with bridging therapy (48.6% vs 29.2%), who were female vs male (46.4% vs 35.5%), aged ≥40 vs <40 years (45.7% vs 33.3%), and from North America vs Europe (42.6% vs 33.3%). In responders vs non-responders with SyS, respectively, median PFS was 58.3 vs 11. 0 weeks (log-rank p-value <0.0001); the probability of being progression-free at 24 weeks was 0.8 vs 0.2. The pooled benefit:risk profile of afami-cel was similar to that in the SPEARHEAD-1 trial (Van Tine, et al. Paper 30: CTOS 2021; Virtual.). Conclusions: We show that baseline tumor burden, prior systemic treatment history, and MAGE-A4 tumor expression levels are potential factors associated with response to afami-cel, although their true predictive value for response status awaits confirmation. Our findings will inform the ongoing clinical development of afami-cel in sarcoma, especially for prognostic studies with PFS or overall survival endpoints. Clinical trial information: NCT04044768, NCT03132922.

11541 Background: Ripretinib (R) is a switch-control tyrosine kinase inhibitor (TKI) indicated for the treatment of patients (pts) with advanced gastrointestinal stromal tumor (GIST) after prior treatment with ≥3 TKIs. In the INTRIGUE study (NCT03673501) there was no significant difference in median PFS (primary endpoint) between R and sunitinib (S). We present exploratory analyses of tolerability data and selected pt reported outcomes (PROs). Methods: Pts were randomized 1:1 to R 150 mg QD or S 50 mg QD 4 weeks on/2 weeks off.Dose modification was allowed for toxicity management. The event of interest was severe or life-threatening (grade ≥3) treatment-related adverse event prior to progression (sTRAE). Days with at least one sTRAE were summed for all treated pts and for pts with ≥1 sTRAE event. PROs were assessed using questions from EORTC QLQ-C30 and Dermatology Life Quality Index (DLQI) at cycle 1 (C1) day 1 (D1), D15, and D29; D1 and D29 of all other cycles; as well as at end of treatment. Differences in PRO scores between baseline and later assessments were calculated across visits. Long-term data will be presented. Results: Pts receiving R (n = 223) versus (vs) S (n = 221) experienced fewer sTRAEs (24% vs 51%, respectively). For all treated pts, the mean time with sTRAEs was 11 days for R and 42 days for S (ratio 0.27, P<0.0001). For pts with ≥1 sTRAE, the mean number of days with a sTRAE was 48 days for R vs 81 days for S (ratio 0.59, p = 0.037). Completion of PRO assessments across the two treatment arms was similar (baseline: R [n = 199], S [n = 199]; C1 D29: R [n = 167], S [n = 177]). Significant differences in self-reported functioning and symptoms were observed by C1 D29. For PROs relating to commonly reported sTRAEs, except constipation, pts in the R arm reported better outcomes than pts in the S arm. Pts in the R arm reported significantly (p<0.05) less decline compared to baseline in pt-reported role function as well as less increase, or improvement, in symptoms of fatigue, appetite loss, diarrhea, nausea/vomiting, and pain vs pts in the S arm. Moderate or severe effect of skin toxicity on pt life, as measured by DLQI in the R arm (n = 165) and in the S arm (n = 175), was observed in 6.6% of pts in the R arm vs 14.8% of pts in the S arm (p = 0.015). Conclusions: In the INTRIGUE study the total number of days with sTRAEs was fewer for pts receiving R vs S. Pts in the R arm also reported significantly less decline in pt-reported role function and less increase in symptoms related to commonly reported sTRAEs, except constipation, vs pts in the S arm. Medical writing provided by Costello Medical. Clinical trial information: NCT03673501.

359881 Background: Sunitinib is approved for advanced gastrointestinal stromal tumor (GIST) after imatinib failure. Ripretinib, a broad-spectrum KIT and PDGFRA switch-control tyrosine kinase inhibitor (TKI), is indicated for the treatment of adult patients (pts) with GIST who received prior treatment with 3 or more TKIs, including imatinib. We compared the efficacy and safety of ripretinib vs sunitinib in pts with advanced GIST who progressed on or were intolerant to imatinib. Methods: This multicenter, global, randomized, open-label phase 3 study (NCT03673501) enrolled adult pts with GIST who progressed on or had intolerance to imatinib. Pts were randomized 1:1 to ripretinib 150 mg once daily (QD) or sunitinib 50 mg QD (4 wks on/2 wks off). Randomization was stratified by KIT mutational status and imatinib intolerance. The primary endpoint was progression-free survival (PFS) by independent radiologic review (IRR) using modified RECIST version 1.1. Key secondary endpoints were objective response rate (ORR) by IRR and overall survival (OS). Hierarchical testing was performed for primary and key secondary endpoints in a prespecified sequence; testing pts with a KIT exon 11 primary mutation (Ex11 intention-to-treat [ITT] population) preceded the all-patient (AP) ITT population. Data cutoff was 1 Sep 2021; final analyses of PFS and ORR and the first interim analysis of OS were conducted. Results: A total of 453 pts were randomized to ripretinib (n = 226; Ex11 ITT, n = 163) or sunitinib (n = 227; Ex11 ITT, n = 164). Median age was 60 yrs (range 18–88) and most pts were white (66.2%) males (62.0%). PFS was not statistically different between ripretinib and sunitinib in the Ex11 ITT (hazard ratio [HR] 0.88, 95% CI 0.66, 1.16; P = 0.36; median 8.3 vs 7.0 mos) or in the AP populations (HR 1.05, 95% CI 0.82, 1.33; P = 0.72; median 8.0 vs 8.3 mos). ORR was numerically higher for ripretinib vs sunitinib in the Ex11 ITT (23.9% vs 14.6%; difference 9.3%, 95% CI 0.7, 17.8; nominal P = 0.03) and AP ITT populations (21.7% vs 17.6%; difference 4.2%, 95% CI −3.2, 11.5; nominal P = 0.27). OS data was highly immature; median OS was not reached in either arm. Fewer pts in the ripretinib arm experienced Grade 3-4 (G3-4) treatment-emergent adverse events (TEAEs) vs sunitinib (41.3% vs 65.6%). Among G3-4 TEAEs with a difference ≥5% between arms, ripretinib had fewer events vs sunitinib (hypertension [8.5% vs 26.7%], palmar-plantar erythrodysesthesia [1.3% vs 10.0%], neutropenia [0% vs 6.3%], and neutrophil count decreased [0% vs 7.2%]). Conclusions: The PFS in both arms was longer than PFS achieved by sunitinib in its pivotal phase 3 trial. While the PFS for ripretinib did not meet the primary endpoint of superiority vs sunitinib, meaningful clinical activity and fewer G3-4 TEAEs were observed in pts with advanced GIST treated with ripretinib after imatinib failure. Clinical trial information: NCT03673501.

AbstractHistologic findings on 1‐year biopsies such as inflammation with fibrosis and transplant glomerulopathy predict renal allograft loss by 5 years. However, almost half of the patients with graft loss have a 1‐year biopsy that is either normal or has only interstitial fibrosis. The goal of this study was to determine if there was a gene expression profile in these relatively normal 1‐year biopsies that predicted subsequent decline in renal function. Using transcriptome microarrays we measured intragraft mRNA levels in a retrospective Discovery cohort (170 patients with a normal/minimal fibrosis 1‐year biopsy, 54 with progressive decline in function/graft loss and 116 with stable function) and developed a nested 10‐fold cross‐validated gene classifier that predicted progressive decline in renal function (positive predictive value = 38 ± 34%%; negative predictive value = 73 ± 30%, c‐statistic = .59). In a prospective, multicenter Validation cohort (270 patients with Normal/Interstitial Fibrosis [IF]), the classifier had a 20% positive predictive value, 85% negative predictive value and .58 c‐statistic. Importantly, the majority of patients with graft loss in the prospective study had 1‐year biopsies scored as Normal or IF. We conclude predicting graft loss in many renal allograft recipients (i.e., those with a relatively normal 1‐year biopsy and eGFR > 40) remains difficult.