Tx-related Adverse Events Research Articles

BEAT-meso: A randomized phase III study of bevacizumab (B) and standard chemotherapy (C) with or without atezolizumab (A), as first-line treatment (TX) for advanced pleural mesothelioma (PM)—Results from the ETOP 13-18 trial.

LBA8002 Background: The currently approved frontline TXs for PM are the combination of ipilimumab/nivolumab or platinum plus pemetrexed. The addition of B to C has been shown to improve overall survival in a randomized clinical trial. While combined immunotherapy or single agent immunotherapy with C is superior to C alone, there is potential for a synergistic triple combination of C, B, and immunotherapy. Methods: BEAT-meso (NCT03762018) is an international open-label, 1:1 randomized phase III trial, stratified by histology and stage. The objective is to determine the efficacy and safety of adding A (1200 mg, Q3W until progression) to B (15mg/kg, Q3W until progression) and standard C (4-6 cycles of carboplatin AUC5 with pemetrexed 500 mg/m2, Q3W), as first-line TX for advanced PM. The trial is designed to detect an increase in the median overall survival (OS, primary endpoint) with the addition of A, aiming for a hazard ratio (HR) of 0.708, at 2.5% 1-sided alpha and 82% power (284 deaths, sample size 400 patients (pts)). In the pre-specified interim efficacy analysis (80% of the events, 01/2023), boundary was not crossed, and the trial continued to completion. Secondary endpoints include progression-free survival (PFS), objective response rate (ORR), disease control rate, duration of response (DoR), adverse events (AEs) assessed by CTCAE v5.0 and symptom-specific and global quality of life (QoL). Results: Between 04/2019 and 03/2022, a total of 400 pts was randomized, 200 per arm. The median age was 70 years, 79% were male, 50% were former smokers, 65% had ECOG performance status 1 and 78% had epithelioid histology. At a median follow-up of 35 months (m) (as of 1/09/2023), median OS was 20.5m [95% CI: 17.5-23.3] in the ABC and 18.1m [15.7-20.9] in the BC arm (deaths: 145 & 150; HRABC vs BC=0.84; [0.66 - 1.06], 2-sided stratified p=0.14, ITT final analysis). PFS was significantly longer in ABC with median 9.2m [8.1-10.9] vs 7.6m [6.9-8.3] in BC (HR=0.72; [0.59 - 0.89], 2-sided stratified p=0.0021). Histology shows a significant TX interaction for both PFS and OS. The OS HR is 0.51 [0.32-0.80] for non-epithelioid and 1.01 [0.77-1.32] for epithelioid (interaction p=0.012). In an exploratory analysis, post-progression OS was significantly different between the two arms, adjusted for post-progression TX (HR=0.76; [0.58 - 0.99]). The ORR was 55% in ABC and 49% in BC (p=0.27), while median DoR was 8.2m [6.8-9.7] in ABC and 5.6m [4.8-7.0] in BC (p=0.0041). Global QoL change was not significantly different between the two arms. Grade≥3 TX-related AEs occurred in 55% of pts in ABC and 47% of pts in BC (grade 5: 7 and 1 pt, respectively). Conclusions: The significant increase in median PFS with the addition of A did not translate into a significant increase in median OS. ABC demonstrated superiority over BC in non-epithelioid cases. Clinical trial information: NCT03762018 .

Enfortumab vedotin (EV) in triple-negative breast cancer (TNBC) and HR+/HER2- breast cancer (BC) cohorts of EV-202.

1005 Background: EV, a Nectin-4–directed antibody–drug conjugate, is approved for use in urothelial cancer. Nectin-4 is expressed in several solid tumors, including BC. EV monotherapy was evaluated in TNBC and HR+/HER2- BC in EV-202 (NCT04225117). Methods: In this open-label, multicohort, phase 2 trial, eligible adults had locally advanced or metastatic (la/m) solid tumors, measurable disease, and ECOG PS 0–1. In BC cohorts, patients (pts) had prior taxanes or anthracyclines, ≥1 standard-of-care cytotoxic regimen and ≤2 lines (L) of cytotoxic therapy for la/mBC, and prior PD-1/L1 inhibitor (TNBC) or endocrine treatment (tx) with a CDK4/6 inhibitor (HR+/HER2- BC). Nectin-4 expression was not required but was assessed retrospectively. Pts received EV 1.25 mg/kg intravenously days 1, 8, and 15 of each 28-d cycle until discontinuation criteria (eg, disease progression, unacceptable toxicity) were met. Primary endpoint was confirmed objective response rate (ORR); ≥10 (TNBC) or ≥12 (HR+/HER2- BC) responders out of 40 evaluable pts were needed to claim promising antitumor activity. Secondary endpoints were duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety/tolerability. Antitumor activity was investigator-assessed per RECIST v1.1. Results: In the TNBC cohort, 42 female pts received EV as of Mar 3, 2023 (median follow-up, 11.8 mo). Median age was 53 y, 64% had ≥2L systemic tx for metastatic BC, and 33% had prior sacituzumab govitecan. ORR was 19.0%. Grade ≥3 tx-related adverse events (TRAEs) in >1 pt were decreased neutrophil count (n=3, 7%), decreased white blood cell count (n=2, 5%), and increased aspartate aminotransferase (n=2, 5%). Selected TRAEs of special interest were skin reactions (n=25, 60%), peripheral neuropathy (n=11, 26%), and hyperglycemia (n=2, 5%). In the HR+/HER2- BC cohort (median age, 57.0 y), 45 female pts received EV as of Dec 3, 2022 (median follow-up, 11.2 mo). Most (73%) had ≥3L systemic tx for metastatic BC. ORR was 15.6%. Grade ≥3 TRAEs in >1 pt were maculopapular rash (n=7, 16%), pruritus and increased aspartate aminotransferase (both n=3, 7%), and abdominal pain and erythema (both n=2, 4%). Selected TRAEs of special interest were skin reactions (n=28, 62%), peripheral neuropathy (n=12, 27%), and hyperglycemia (n=5, 11%). Additional efficacy data for both cohorts are in the table. Conclusions: EV showed antitumor activity in heavily pretreated TNBC. Safety in both cohorts was manageable and consistent with previous reports. Clinical trial information: NCT04225117 . [Table: see text]

Preliminary safety and efficacy of oral azacitidine (Oral-AZA) in patients (pts) with low-/Intermediate (Int)-risk myelodysplastic syndromes (MDS): Phase 2 results from the ASTREON trial.

6509 Background: There is an unmet need for new treatment (tx) options in lower-risk MDS (LR-MDS) to address cytopenias and prevent progression to higher-risk MDS and acute myeloid leukemia. Here, we report safety and preliminary efficacy data from phase 2 of the ASTREON study, which evaluated 14-day Oral-AZA regimens in pts with Low-/Int-risk MDS. Methods: ASTREON is a phase 2/3, multicenter study evaluating safety and efficacy of Oral-AZA plus best supportive care (BSC) in pts with Low-/Int-risk MDS (NCT05469737). Phase 2 is an open-label, dose optimization study to determine the recommended phase 3 Oral-AZA dose. Eligible pts (≥ 18 years of age with Revised International Prognostic Scoring System [IPSS-R] Low-/Int-risk MDS and ≥ 1 cytopenia) were randomized 1:1 to receive Oral-AZA 200 mg or 300 mg QD for 14 d per 28-d cycle plus BSC. Primary endpoints are rates of adverse events (AEs) and complete remission (CR) within 6 cycles per International Working Group (IWG) 2006 criteria. Secondary endpoints include achievement of overall response (OR) (including CR, partial remission, marrow CR, hematologic improvement-erythroid response [HI-E], HI-platelet response, and HI-neutrophil response per IWG 2006 criteria); best OR; and OR duration. HI rates within 6 cycles were calculated by investigator assessment per IWG 2006 criteria for pts who received ≥ 75% of the cycle 1 dose and had ≥ 1 post-baseline (BL) efficacy assessment (modified intent-to-treat [mITT] population). Results: As of December 4, 2023, 47 pts were randomized and received ≥ 1 Oral-AZA dose (200 mg, n = 24; 300 mg, n = 23); 6 and 5 pts discontinued tx in the 200 mg and 300 mg arms. The median (range) tx durations were 24.1 (12.1–34.1) and 24.7 (7.7–39.1) wk for the 200 mg and 300 mg arms, respectively. IPSS-R scores and RBC transfusion burden at BL were balanced between tx arms. Most pts (42/47 [89.4%]) had prior MDS tx, including but not limited to erythropoiesis-stimulating agents, lenalidomide, luspatercept, and imetelstat. AE rates were similar between arms: 11/24 (45.8%) vs 12/23 (52.2%) pts in the 200 mg vs 300 mg arms reported ≥ 1 tx-related grade 3 or 4 tx-emergent AE. The most common tx-related AEs in both arms were hematologic and gastrointestinal. Tx-related serious AEs occurred in 1/24 and 3/23 pts in the 200 mg and 300 mg arms, respectively. One death occurred in the 300 mg arm and was considered tx-related. In the mITT population, 8/22 and 7/21 pts achieved any HI in the 200 mg and 300 mg arms, respectively. Six pts in each dose group achieved HI-E. Among mITT pts with anemia at BL, 6/19 (31.6%) pts in the 200 mg and 5/18 (27.8%) pts in the 300 mg arm achieved HI-E. Updated results will be presented. Conclusions: The safety of Oral-AZA 200 mg and 300 mg was consistent with the known Oral-AZA safety profile. Preliminary efficacy data support continued evaluation of Oral-AZA in LR-MDS. Clinical trial information: NCT05469737 .

Nivolumab plus ipilimumab (N+I) in patients (pts) with solid tumors with high tumor mutational burden (HTMB): Results from the Targeted Agent and Profiling Utilization Registry (TAPUR) Study.

3130 Background: TAPUR is a phase II basket study evaluating antitumor activity of commercially available targeted agents in pts with advanced cancers with genomic alterations. Results in a cohort of pts with advanced solid tumors with HTMB treated with N+I are reported. Methods: Eligible pts had measurable disease, ECOG performance status (PS) 0-2, adequate organ function, and no standard treatment (tx) options or prior immune checkpoint inhibitor tx. PD-L1 expression testing was not required. Genomic testing was performed in CLIA-certified, CAP-accredited site selected labs. HTMB was defined a priorias ≥9 mutations/megabase (Muts/Mb) via a qualifying test for TAPUR or approved by the Molecular Tumor Board. Pts received I at 3 mg/kg every 3 weeks (wks) for 4 doses with N at 1 mg/kg IV every 3 wks for 4 doses. N alone was then continued at 240 mg every 2 wks or 480 mg every 4 wks until disease progression. Low accruing histology-specific cohorts with HTMB were collapsed into 1 cohort for analysis. Primary endpoint was disease control (DC) per investigator defined as complete (CR) or partial (PR) response per RECIST v. 1.1, or stable disease (SD) of at least 16 wks duration (SD16+). The hypothesized null DC rate of 15% was evaluated by a 1-sided exact binomial test (α= 0.10; 86% power based on alternative DC rate of 35%). Secondary endpoints were progression-free survival (PFS), overall survival (OS), objective response (OR), duration of response (DOR), duration of SD, and safety. DOR is time from documented OR to progressive disease (PD); duration of SD is time from tx start to PD. Results: 26 pts with 13 tumor types with HTMB were enrolled. Table shows demographics and outcomes. Tissue tumor mutational burden (TMB) ranged from 8 to 374 Muts/Mb (median= 16). 1 CR (small intestine; TMB= 48 Muts/Mb; DOR= 36 wks), 7 PR (biliary tract, site unspecified [3], soft tissue sarcoma, uterus, vagina; median TMB= 17 Muts/Mb; median DOR= 20 wks [range, 5-231]) and 1 SD16+ (pancreas; TMB= 26 Muts/Mb; duration of SD= 26 wks) were observed for a DC rate of 35% (1-sided 90% CI: 22 to 100) and OR rate of 31% (95% CI: 14 to 52). The null hypothesis was rejected (p=0.011). Notably, 1 pt (uterus, 374 Muts/Mb) is still on tx with an ongoing 66-wk PR as of Jan 2024. Most pts, including 8/9 with DC, were microsatellite stable. 10 pts had ≥1 grade 3 tx-related adverse event (AE) or serious AE. Conclusions: N+I showed antitumor activity in pts with advanced solid tumors with HTMB. Additional study is warranted to confirm the efficacy of N+I in pts with HTMB. Clinical trial information: NCT02693535 . [Table: see text]

Afatinib in patients (pts) with solid tumors with neuregulin 1 (NRG1) fusions: Results from the Targeted Agent and Profiling Utilization Registry (TAPUR) study.

3131 Background: TAPUR is a phase II basket study evaluating antitumor activity of commercially available targeted agents in pts with advanced cancers with genomic alterations. Results in a small cohort of pts with advanced solid tumors with NRG1 fusions treated with afatinib are reported. Methods: Eligible pts had measurable, advanced disease, NRG1fusion, ECOG performance status (PS) 0-2, adequate organ function, and no standard treatment (tx) options. Pts with non-small cell lung cancer (NSCLC) were eligible if they had no pathogenic mutations in ALK, BRAF, EGFR or ROS1. Genomic testing was performed in CLIA-certified, CAP-accredited site selected labs. Pts received 40 mg of afatinib daily until disease progression. Primary endpoint was disease control (DC) per investigator defined as complete (CR) or partial (PR) response per RECIST v. 1.1, or stable disease (SD) of at least 16 wks duration (SD16+). Secondary endpoints were progression-free survival (PFS), overall survival (OS), objective response (OR), duration of response, duration of SD, and safety. This cohort was closed after 2 years before completing stage 1 enrollment (n = 10) of the Simon’s 2-stage design used in TAPUR according to a prespecified cohort closure rule. Results: 4 pts with 3 tumor types with NRG1 fusion were enrolled between February 2020 and July 2021. 1 pt had NSCLC with a CD74- NRG1 fusion and achieved a PR that lasted 24 weeks (wks). This pt was a 58-year-old White, non-Hispanic female with ECOG PS 0, 2 prior systemic therapies and progressed after 32 wks on study tx. Co-alterations included CCNE1 amplification (amp), GATA amp, TP53 R65fs*58, and an ALK G1121D variant of unknown significance. 2 pts achieved SD16+: 1 was a 47-year-old White, Hispanic female with colorectal cancer (CRC) with a MATN2- NRG1 fusion, ECOG PS 1, 3 prior systemic therapies and co-alterations in APC, DDX11, FBXW7, FGFR1 and TP53; the other pt was a 49-year-old Black, non-Hispanic male with pancreatic cancer with a NRG1 exon 2 fusion, ECOG PS 1, 5 prior systemic therapies, a comutation in ARID1A. The durations of SD for these 2 pts were 136 and 64 wks, respectively. The pt with CRC underwent resection of a remaining target lesion and is still alive off study drug at 198 wks after the baseline visit as of Dec 2023. 1 pt was a 70-year-old White, non-Hispanic female with CRC with a CD74- NRG1 fusion, ECOG PS 0, 1 prior systemic therapy, and a best response of progressive disease. This pt had comutations in ARID1A, PBRM1 and TP53and progressed at 8 wks. Median OS was 81 wks. No grade 3-5 tx-related adverse events (AE) or serious AEs were reported. Conclusions: Though a small sample size, afatinib demonstrated promising activity in pts with advanced solid tumors with NRG1 fusion, including very durable DC. Additional study in a larger group of pts is warranted to confirm the efficacy of afatinib in pts with NRG1 fusion. Clinical trial information: NCT02693535 .

Pertuzumab plus trastuzumab (P+T) in patients (pts) with solid tumors with ERBB2or ERBB3amplification (amp) or mutations (mut): Results from the Targeted Agent and Profiling Utilization Registry (TAPUR) study.

3142 Background: TAPUR is a phase II basket study evaluating antitumor activity of commercially available targeted agents in pts with advanced cancers with genomic alterations. Results in a cohort of pts with advanced solid tumors with ERBB2/3amp or mut treated with P+T are reported. Methods: Eligible pts had measurable disease, ECOG performance status (PS) 0-2, adequate organ function, and no standard treatment (tx) options. Genomic testing was performed in CLIA-certified, CAP-accredited site selected labs. Dosing of P was 840 mg IV over 60 minutes (m), then 420 mg IV over 30-60 m Q3 weeks (wks); T was 8 mg/kg IV over 90 m, then 6 mg/kg IV over 30-60 m Q3 wks until disease progression. Low accruing histology-specific cohorts with ERBB2/3amp and/or mut were collapsed into 1 cohort for analysis. Primary endpoint was disease control (DC) per investigator defined as complete (CR) or partial (PR) response per RECIST v. 1.1, or stable disease (SD) of at least 16 wks duration (SD16+). The hypothesized null DC rate of 15% was evaluated by a 1-sided exact binomial test (α= 0.10; 82% power based on alternative DC rate of 35%). Secondary endpoints were progression-free survival (PFS), overall survival (OS), objective response (OR), duration of response (DOR), duration of SD, and safety. DOR is time from documented OR to progressive disease (PD); duration of SD is time from tx start to PD. Results: 28 pts with 11 tumor types with ERBB2/3amp +/- mut (25) or mut only (3) were enrolled. The table shows demographics and outcomes. 2 CR (vagina, ERBB2amp, DOR= 151 wks; sweat gland, ERBB2amp, DOR= 48 wks), 6 PR (esophagus [2], small intestine, urothelial carcinoma [UC], site unspecified [SU], vagina; all with ERBB2amp) and 8 SD16+ (cervix [3], small intestine [2], UC, SU, testis; 6/8 pts had ERBB2 amp only, 1 had ERBB2mut only, 1 had ERBB3amp only) were observed for a DC rate of 57% (1-sided 90% CI: 43 to 100) and OR rate of 29% (95% CI: 13 to 49). The null hypothesis was rejected (p<0.001). Median duration of PR was 30 wks (range, 15-116, n=6). Median duration of SD for 8 pts with SD16+ was 28 wks (range, 18-84). 4/19 pts with KRAStesting performed had KRASalterations. 5 pts had ≥1 grade 3 tx-related adverse event (AE) or grade 2-5 serious AE: anemia, cardiac arrest resulting in death, diarrhea, ejection fraction decrease, pleural effusion, supraventricular tachycardia and vomiting. Conclusions: P+T showed antitumor activity in pts with advanced solid tumors with ERBB2/3amp. Additional study is warranted to confirm the efficacy of P+T in this population. Clinical trial information: NCT02693535 . [Table: see text]

Leukocyte immunoglobulin-like receptor (LILRB2)-targeted JTX-8064 plus the anti-PD1 inhibitor JTX-4014 (pimivalimab) in immune-checkpoint inhibitor (ICl) pretreated patients (pts) with advanced or metastatic renal cell cancer (mRCC): Results from the multi-stage phase 1-2 INNATE trial.

4531 Background: Disease progression following treatment of mRCC pts with ICl-based therapy (tx) is nearly universal, warranting evaluation of novel immunotherapeutic approaches. LILRB2 is an immune checkpoint molecule expressed primarily in cells of myeloid origin (e.g., monocytes/macrophages). Inhibition of LILRB2 reprograms macrophages from an immunosuppressive (M2) to an immunostimulatory (M1) phenotype. JTX-8064 is a humanized monoclonal antibody that binds to LILRB2, blocking its interaction with MHC1 molecules. Preclinical studies suggest that JTX-8064 can overcome anti-PD(L)1 resistance mechanisms. Here we report the results of an expansion cohort of previously-treated mRCC pts in INNATE, a multi-stage phase 1-2 trial of JTX-8064 in combination with anti-PD1 agents in solid tumors. Methods: Pts with pathologically-confirmed clear cell mRCC progressing on or after anti-PD(L)1 tx in the most recent prior line, acceptable end-organ function, and ECOG PS 0-1 were treated with JTX-8064 700 mg and JTX-4014 500 mg IV q3 weeks. Primary endpoint was overall response rate (ORR); secondary endpoints were safety, disease control rate (DCR), progression-free survival (PFS), & overall survival (OS). A Simon 2-stage design (n=10+19) was employed where ORR >= 20% was deemed to be of further interest versus null hypothesis of ORR <= 5%, with alpha=0.05. Results: 31 pts were enrolled, with median age of 64 years (range 38-85); 84% males; 16% Hispanic; 93% White; 45% PS=0; 71% one prior tx line. Of 28 pts evaluable for response, 1 CR, 1 PR, 14 SD (6 SD>= 6 months), and 11 PD were seen for an ORR of 7% & DCR of 54%.Median PFS was 4 months (95%CI: 2, 6.8); 12-month OS was 75% (95%CI: 55,88). Tx-related adverse events (AE) of all grades were reported in 11 pts (45%), most commonly fatigue (16%) & diarrhea (10%). Only 4 protocol-related G3-4 AEs were reported: thrombocytopenia (G4); diplopia, diarrhea, & bradycardia (all G3). Three on-study deaths (hypotension; cardiorespiratory arrest; & unknown) were deemed unrelated to protocol tx. Conclusions: While ORR did not meet the protocol-defined efficacy target, evidence of anti tumor activity was seen in ICI pre-treated mRCC pts with combination JTC-8064 + JTX-4014. Treatment was reasonably well-tolerated. Identification & evaluation of clinical and molecular phenotypes most likely to benefit from LILRB2-targeted therapies are warranted. Clinical trial information: NCT04669899 .

Five-year outcomes with first-line (1L) nivolumab + ipilimumab + chemotherapy (N + I + C) vs C in patients (pts) with metastatic NSCLC (mNSCLC) in CheckMate 9LA.

8560 Background: InCheckMate 9LA (NCT03215706), 1L N + I + C demonstrated long-term, durable survival benefit vs C alone in pts with mNSCLC, regardless of tumor PD-L1 expression or histology. Here, we report updated efficacy and safety data with a 5-y follow up (f/u) and outcomes in 5-y survivors. Methods: Adults with stage IV or recurrent NSCLC, ECOG PS ≤ 1, and EGFR/ALK wild-type were randomized 1:1 to N 360 mg Q3W + I 1 mg/kg Q6W + C Q3W (2 cycles; n = 361) or C alone Q3W (4 cycles; n = 358). Maintenance pemetrexed was allowed for pts with non-squamous (NSQ) NSCLC (C arm only). Assessments were OS, PFS, ORR, DOR, treatment (tx)-free interval (TFI; time from last study tx dose to start of subsequent systemic tx or death), and safety. Exploratory analyses included quantifying the number of ipilimumab doses received by 5-y survivors, as well as PFS and TFI in these pts. Results: With a median f/u of 64.5 mo (database lock, 15 Dec 2023), clinical benefit continued to be seen with N + I + C vs C in all randomized pts (Table); 5-y OS rates were 18% vs 11%, respectively. Of pts treated with N + I + C, 11% were tx-free at 5 y. Clinical outcomes favored N + I + C vs C across tumor PD-L1 expression and histology subgroups (Table). In pts with tumor PD-L1 < 1%, 5-y OS and PFS rates with N + I + C were both ~3-fold higher than with C, and 5-y DOR rates were 25% vs 0% in the respective tx arms. Among pts who discontinued N + I + C due to tx-related adverse events (TRAEs; n = 61), 37% were alive at 5 y, and the TFI rate was 22%. In analyses of 5-y survivors, PFS favored N + I + C (n = 48) vs C (n = 30; HR, 0.52 [95% CI, 0.26–1.02]), and 5-y TFI rates were 72% vs 35%, respectively. Of 5-y survivors in the N + I + C arm, 21/48 (44%) received ≥ 17 doses of ipilimumab; of those who received < 17 doses, most had discontinued ipilimumab due to TRAEs. The extended f/u revealed no new safety signals. Conclusions: 1L N + I + C maintained long-term, durable survival benefit vs C in pts with mNSCLC at this 5-y f/u, particularly in pts with tumor PD-L1 expression < 1% or squamous (SQ) histology. N + I + C increased 5-y survivorship, with improved PFS and TFI in 5-y survivors over C. These data further underscore 1L N + I + C as an efficacious tx option for pts with mNSCLC. Clinical trial information: NCT03215706 . [Table: see text]

Abstract PO1-04-03: Phase I/II Trial of Ibrutinib Plus Trastuzumab in HER2-Positive Metastatic Breast Cancer

Abstract Background: Ibrutinib is a first-in-class inhibitor of Bruton’s tyrosine kinase that has demonstrated potent inhibition of ErbB/HER family receptor tyrosine kinases in preclinical models. Ibrutinib also displays immunomodulatory effects, shifting the profile of the immune response from Th2-type to Th1-type cytokines (Dubovsky et al. 2013), resulting in enhanced antitumor immunity. As there is a need for novel HER2-targeted therapies following progression on established anti-HER2–directed therapies, and as combining multiple HER2-directed agents is more effective than single-agent therapy (Blackwell et al. 2012), this study explored the safety and efficacy of ibrutinib in combination with trastuzumab in patients (pts) with HER2-positive metastatic breast cancer (MBC) (NCT03379428). Trial design: Phase I was a dose-escalation study to define the recommended Phase II dose (RP2D) of ibrutinib plus trastuzumab. The primary objective of Phase II was to define the clinical benefit rate (CBR = complete response [CR] + partial response [PR] + stable disease [SD] ≥ 6 months) of ibrutinib plus trastuzumab; secondary objectives were to determine objective response rate (ORR = CR + PR), overall survival (OS), progression-free survival (PFS), and safety/tolerability. Pts had HER2-positive MBC with measurable disease per RECIST v1.1, disease progression on or within 6 months of completing ado-trastuzumab emtansine (T-DM1) therapy, and ≤4 (Phase I) or ≤5 (Phase II) prior chemotherapy regimens for MBC, with no limit on prior endocrine therapies. Results: 26 pts were treated in Phases I and II: median age, 65.1 y; 15.4% Asian, 15.4% Black, 46.2% Caucasian, 19.2% Hispanic, and 3.8% Other; 46.2% with ECOG performance status (PS) of 0, 42.3% with PS of 1, and 7.7% with PS of 2. Median prior lines of therapy for MBC was 2 (range: 0, 6); median prior lines of therapy in any setting was 4 (range: 1, 9). In any setting, 88.5% of pts had prior treatment (Tx) with trastuzumab, 80.8% had prior Tx with pertuzumab, and 100% had prior Tx with T-DM1. 0% of pts had brain, 38.5% had bone, 23.1% had liver, and 42.3% had lung metastases. All pts were HER2+ by local pathology, 61.5% positive by IHC and 42.3% by FISH; 12 pts had ER+ and/or PR+ and 14 pts had ER-/PR- cancers. The starting dose of ibrutinib for Phase I was 560 mg. Of the 3 pts enrolled at this dose level, all experienced grade 3 or higher adverse events (AEs), with 2 of the pts experiencing serious AEs (grade 4 alanine aminotransferase [ALT] increased and grade 5 respiratory failure). As such, 420 mg of ibrutinib was selected as the RP2D. At the time of data extraction, across Phase I/II, 16 pts (61.5%) experienced a Tx-related adverse event (TRAE). The most common (≥5%) TRAEs of any grade were bruising and rash (each 19.2%); fatigue and thrombocytopenia (each 15.4%); anemia, diarrhea, and edema (each 11.5%); and ALT increased, aspartate aminotransferase increased, blurred vision, ecchymoses, mucositis, nausea, pruritus, and vomiting (each 7.7%). A total of 5 pts (19.2%) experienced grade 3 or 4 TRAEs; no grade 5 TRAEs were reported. 26 pts were treated with ibrutinib and trastuzumab, and 26 pts were in the evaluable population. 1 pt had CR for an ORR of 3.8% (95% CIs: 0.1, 19.6); 9 pts had SD, and 4 pts had SD for ≥6 months for a CBR of 19.2% (95% CIs: 6.6, 39.4). Median OS was 27.1 months (range: 0.30, 27.1), and median PFS was 2.0 months (range: 0.03, 27.1). The PFS rate at 12 months was 34.6% (95% CIs: 15.6, 54.6). Conclusion: Ibrutinib plus trastuzumab had a manageable safety profile; however, the CBR did not reach the protocol-specified goal of 28%, and these results do not support further clinical investigation. An in-depth evaluation of the immune effects of ibrutinib in these pts is ongoing. Citation Format: Joyce O'Shaughnessy, Andrea Glidden, Tracy Locke, Amy Scales. Phase I/II Trial of Ibrutinib Plus Trastuzumab in HER2-Positive Metastatic Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-04-03.

Abstract CT268: Palbociclib (P) in patients (pts) with solid tumors with CCND1 amplification (amp) or mutation (mut): Results from the Targeted Agent and Profiling Utilization Registry (TAPUR) Study

Abstract Background: TAPUR is a phase II basket study evaluating antitumor activity of commercially available targeted agents in pts with advanced cancers with specific genomic alterations. Results in a cohort of pts with solid tumors with CCND1 amp or mut treated with P are reported. Methods: Eligible pts had measurable disease, ECOG performance status (PS) 0-2, adequate organ function and no standard treatment (tx) options. Genomic testing was performed in CLIA-certified, CAP-accredited site selected labs. Recommended dosing was one 125 mg capsule taken orally once daily for 21 days followed by 7 days off, until disease progression. Low accruing histology-specific cohorts with CCND1 amp or mut were collapsed into a histology-pooled cohort for analysis. Primary endpoint was disease control (DC) per investigator defined as complete (CR) or partial response (PR) or stable disease (SD) of at least 16 weeks (wks) duration (SD16+) per RECIST v1.1. The hypothesized null DC rate of 15% was rejected if the lower limit of a 1-sided 90% CI was >15%. Secondary endpoints were progression-free survival (PFS), overall survival (OS), objective response (OR), duration of response (DOR) and SD, and safety. Results: 38 pts with 16 tumor types with CCND1 amp (n=36), mut (n=1) or both (n=1) were enrolled. 2 pts left before the 8-wk post-baseline tumor evaluation and were unevaluable for efficacy. Table shows demographics, outcomes and toxicity. 1 pt with CR (melanoma, PTEN Y155fs comutation, DOR= 111 wks), 1 with PR (melanoma, DOR= 9 wks) and 4 with SD16+ (prostate [2], bladder, bile duct) were observed for DC rate of 17% (1-sided 90% CI: 9 to 100) and OR rate of 6% (95% CI: <1 to 19). The null DC rate was not rejected. All pts with DC had CCND1 amp. 14 pts had ≥1 grade 3-4 tx-related adverse event (AE) or serious AE (SAE). Conclusions: P did not meet prespecified criteria for demonstrating activity in pts with solid tumors with CCND1 amp or mut. Table 1. Demographics (N=38); Efficacy Outcomes (n=36); Toxicity Outcomes (N=38) Median (Med) age, years (range) 66 (38-83) Female, No. (%) 15 (40) ECOG PS, No. (%) 0 9 (24) 1 23 (61) 2 6 (16) Prior systemic regimens, No. (%) 1 3 (8) 2 11 (29) ≥3 24 (63) Most common tumor types, No. (%) Head and neck 7 (18) Melanoma 5 (13) Esophageal 4 (11) Prostate 4 (11) Endometrial 4 (11) DC rate, % (OR and SD16+) (1-sided 90% CI) 17 (9, 100) OR rate, % (95% CI) 6 (<1, 19) Med PFS, wks (95% CI) 8 (6, 8) Med OS, wks (95% CI) 20 (15, 31) Med DOR (range), wks, n=2 9 and 111 Med duration of SD for pts with SD16+ (range), wks, n=4 33 (28, 48) Number of pts2 (%) with tx-related AE or SAEs AE3 14 (37) SAE4 4 (11) 1 Percentages may be >100% due to rounding2 Patients may have experienced one or more events3 Anemia, AST increase, lymphopenia, neutropenia, thrombocytopenia, leukopenia4 Febrile neutropenia, hyponatremia, neutropenia, thrombocytopenia Citation Format: Ramya Thota, Michael Rothe, Pam K. Mangat, Elizabeth Garrett-Mayer, Tareq Al Baghdadi, Evan Pisick, Olatunji B. Alese, Herbert L. Duvivier, Ajjai S. Alva, Apar Kishor Ganti, Raghava R. Induru, Apostolia M. Tsimberidou, Mehmet Akce, Navid Hafez, Evthokia Hobbs, Andrew Riddle, Margaret von Mehren, Gina N. Grantham, Abigail Gregory, Dominique C. Hinshaw, Susan Halabi, Richard L. Schilsky. Palbociclib (P) in patients (pts) with solid tumors with CCND1 amplification (amp) or mutation (mut): Results from the Targeted Agent and Profiling Utilization Registry (TAPUR) Study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT268.

Phase 1b/II study of durvalumab (D) and tremelimumab (T) plus PET-adjudicated chemoradiation (CRT) in patients (Pts) with esophageal adenocarcinoma.

355 Background: We previously evaluated adding D, an anti-PD-L1 antibody, to PET-directed CRT and found the combination to be safe and promising in terms of pathologic response and survival outcomes.1 Here, we add T to the combination. Methods: Pts with locally advanced esophageal/GEJ adenocarcinoma were enrolled. Pts received 2 cycles of mFOLFOX6 prior to repeat PET/CT. PET responders (≥35% reduction in SUV (PETr)) received 5-FU/capecitabine and oxaliplatin with RT, while induction PET non-responders (PETnr) received carboplatin/paclitaxel with RT. All Pts received T 300 mg ×1 and D 1,500 mg q4W ×2 starting 2 weeks prior to CRT. Esophagectomy was planned 6-8 weeks after CRT. Pts with R0 resections received adjuvant T 300 mg ×1 and D 1,500mg q4W ×6. The primary endpoint was the pathologic complete response (pCR) rate. Initially, 6 Pts were enrolled to evaluate for toxicity; they received RT to 50.4 Gy. Subsequently, RT was lowered to 41.4 Gy to decrease the length of preop treatment (tx). Results: 16 pts have been enrolled. All Pts had clinical ≥T3 and/or N+ disease. PD-L1 CPS was ≥1 in 9 (60%) of 15 tested. 1 Pt (6%) had a microsatellite unstable (MSI) tumor. 9 (56%) Pts were PETr; 3 Pts (19%) were PETnr but had improved clinical symptoms and other PET parameters (MTV/TLG) and also continued with 5-FU/capecitabine and oxaliplatin during RT. Significant tx-related adverse events (AEs) are shown in the Table. Immune-related AEs (irAEs) were: gd 3 enterocolitis (1 Pt), gd 3/4 colitis (2 Pts, 12%), gd 1 diarrhea (1 Pt), gd 2 pruritis (1 Pt), gd 1 and gd 3 dermatitis (1 Pt each) and gd 2 arthralgias in 1 Pt. 1 Pt died of aspiration pneumonia while being treated for gd 4 colitis during CRT; 1 Pt developed gd 3 enterocolitis and cholecystitis during CRT, achieved a clinical CR and did not undergo surgery. He developed local recurrence and had surgery off-study 16 months after start of tx; 1 Pt developed a bone metastasis after CRT. 4 Pts are awaiting restaging post-CRT. Of 9 Pts who had surgery, 4 achieved a pCR (44%, including the MSI Pt) and 3 (33%) had ypN0 tumors and ³90% tx response. All 9 Pts have initiated/completed adjuvant D+T. Conclusions: The addition of D+T to induction FOLFOX and PET-directed CRT prior to surgery is feasible, although irAEs seem numerically higher than in our prior study of D and CRT. Pathologic response data are promising. Accrual is ongoing and updated data will be presented. 1. Ann Surg 2023;278:e511. Clinical trial information: NCT02962063 . [Table: see text]

Valemetostat for Relapsed or Refractory Peripheral T-Cell Lymphomas: Primary Results from a Phase 1 Trial

Introduction: Treatment (Tx) options for T-cell non-Hodgkin lymphomas (T-NHLs) are limited and prognosis is too often poor for patients (pts) with relapsed or refractory (R/R) disease. Enhancer of zeste homolog (EZH)2 and EZH1 are methyltransferases that catalyze trimethylation of histone H3 at lysine 27 (H3K27me3); this repressive transcriptional profile is broadly associated with gene silencing. Valemetostat tosylate (valemetostat) is a novel, potent, and selective dual inhibitor of EZH2 and EZH1 that prevents H3K27me3 and increases expression of genes involved in immune function ( SLA, PAG1) that can be silenced by H3K27me3. Valemetostat was approved in Japan for the Tx of R/R adult T-cell leukemia/lymphoma (ATLL) in 2022. The clinical activity of valemetostat in pts with R/R NHLs was investigated in the phase 1 DS3201-A-J101 (“J101”; NCT02732275) trial. Interim data were reported previously. Here we report primary outcomes for pts in J101 with R/R T-NHLs treated with valemetostat. Methods: This open-label, multicenter study was conducted in Japan and the United States (US). Eligible pts were ≥ 18 (US) or ≥ 20 (Japan) years (y) of age and relapsed from, refractory to, or ineligible for standard therapies. The trial included a dose-escalation phase (Japan only) followed by a dose-expansion phase (Japan & US). Enrollment in the expansion phase was limited to pts with R/R peripheral T-cell lymphoma (PTCL) or ATLL. Pts received valemetostat once daily in continuous 28-day (d) Tx cycles at 150-300 mg/d in the escalation phase and 200 mg/d in the expansion phase until disease progression or intolerance. Key endpoints for the dose-escalation and dose-expansion cohorts were safety and PK parameters. Preliminary efficacy assessment included objective response rate (ORR), complete response (CR) rate, duration of response (DOR), and progression-free survival (PFS). DOR and PFS were estimated using Kaplan-Meier methods. Results for PTCL and ATLL are reported separately. Results: At the primary data cutoff (Dec 31, 2022), 71 pts were included in the efficacy and safety analyses; 57 with PTCL and 14 with ATLL. Median age at baseline was 68.0 (range 26-83) y in the PTCL group and 66.5 (37-78) y in the ATLL group, and median prior therapies were 2.0 (1-8) and 2.5 (1-8), respectively; 16 (28%; 14 autologous, 2 allogeneic) pts with PTCL and 2 (14%, both allogeneic) with ATLL had previously undergone transplant. The most common PTCL subtypes were PTCL, not otherwise specified (PTCL, NOS; n = 26, 46%) and angioimmunoblastic T-cell lymphoma (AITL; n = 23, 40%). Tx was ongoing for 8 (11%) pts at data cutoff. All 71 pts included at data cutoff experienced ≥ 1 Tx-emergent adverse event; 59 (83%) pts had a Tx-related adverse event (TRAE). The most common all-grade TRAEs were cytopenias, dysgeusia, and alopecia; the most frequent grade ≥ 3 TRAEs were decreased neutrophil (17%), lymphocyte (11%), and platelet (14%) counts ( Table 1). TRAEs led to Tx discontinuation for 4 (6%) pts (1 each: acute myeloid leukemia, myelodysplastic syndrome, colitis, and acute kidney injury), dose reduction for 5 (7%) pts, and Tx interruption for 18 (25%) pts. The ORR was 55% (30/55) in the PTCL group and 64% (9/14) in the ATLL group, with CR rates of 31% (17/55) and 29% (4/14), respectively; within the PTCL group, the ORR among evaluable pts was 50% (13/26) for PTCL, NOS and 64% (14/22) for AITL ( Table 2). Median times to response were 1.8 (range 1.0-5.6) months (mo) in the PTCL group and 1.9 (1.7-19.4) mo in the ATLL group. Median DOR was 21.9 mo (95% confidence interval [CI], 10.2 mo to not reached [NR]) in the PTCL group (median follow-up 16.4 mo) and 21.2 (95% CI, 1.4 to 38.7) mo in the ATLL group (median follow-up 23.0 mo). Median PFS was 7.7 and 4.1 mo, respectively (median follow-up 18.2 mo and NR). Conclusions: Valemetostat was well tolerated and showed encouraging clinical activity in pts with R/R T-NHLs. Cytopenias were common but could usually be managed without Tx discontinuation. Valemetostat induced durable responses, with median DOR of > 1.5 y in both the PTCL and ATLL groups. Results for pts in this trial with R/R B-NHLs (Izutsu et al) and from a phase 2 trial in R/R T-NHLs (Horwitz et al) are reported separately.

First-line (1L) nivolumab (N) + ipilimumab (I) + chemotherapy (C) vs C alone in patients (pts) with metastatic NSCLC (mNSCLC) from CheckMate 9LA: 4-y clinical update and outcomes by tumor histologic subtype (THS).

LBA9023 Background: In CheckMate 9LA (NCT03215706), 1L N + I + C demonstrated durable survival benefit in pts with mNSCLC vs C alone. Here, we report updated efficacy and safety with a 4-y minimum (min) follow-up (f/u) as well as exploratory analyses of efficacy by THS, a known prognostic indicator for NSCLC. Methods: Adults with stage IV/recurrent NSCLC (no known sensitizing EGFR/ALK alterations) and ECOG PS ≤ 1 were randomized 1:1 to N 360 mg Q3W + I 1 mg/kg Q6W + 2 cycles of C (n = 361) or 4 cycles of C alone (n = 358). Pts were stratified by sex, PD-L1 (< 1% vs ≥ 1%), and histology (squamous [SQ] vs non-squamous [NSQ]). Maintenance pemetrexed was allowed in the C arm (NSQ NSCLC). Assessments included OS, PFS, ORR, safety, treatment (tx)-free interval (TFI; time from last study dose to start of first subsequent systemic tx or death), and efficacy by THS (solid, acinar, or other, per modified WHO classification). Results: At a min f/u of 47.9 mo (database lock, Feb 2023; median f/u, 54.5 mo), N + I + C continued to provide long-term, durable OS benefit vs C in all randomized pts (HR, 0.74 [95% CI 0.63–0.87]; 4-y OS rates, 21% vs 16%, respectively). Similar clinical benefit was seen for N + I + C vs C across tumor PD-L1 or histology subgroups (table). In all pts treated with N + I + C (n = 358), median TFI was 2.2 mo, with 11% remaining tx-free and alive at 4y. In pts who discontinued all components of N + I + C due to tx-related adverse events (n = 61), 4-y OS rate was 41%; median TFI was 10.6 mo, with a 4-y TFI rate of 27%. In an exploratory analysis in pts with evaluable NSQ NSCLC tissue (n = 310; min f/u 36.1 mo), median OS was longer with N + I + C vs C in both solid (16.6 vs 9.3 mo) and acinar (18.7 vs 12.9 mo) THS. Updated efficacy by THS will be presented. No new safety signals were identified with longer f/u. Conclusions: With a 4-y min f/u, pts treated with N + I + C continued to derive long-term, durable efficacy benefit vs C regardless of tumor PD-L1 expression or histology, with greater magnitude of benefit in pts with tumor PD-L1 < 1% or SQ histology. Exploratory analyses suggested OS benefit with N + I + C vs C in both solid and acinar subtypes. Together, these data further reinforce the use of N + I + C as an efficacious 1L tx option for pts with mNSCLC. Clinical trial information: NCT03215706 . [Table: see text]

Results from the pivotal phase (Ph) 2b HERIZON-BTC-01 study: Zanidatamab in previously-treated HER2-amplified biliary tract cancer (BTC).

4008 Background: For patients (pts) with locally advanced/metastatic BTC who progress after first-line treatment (tx), standard tx offers limited clinical benefit with modest improvement in survival. HER2-targeted therapies have improved survival in breast and gastric cancer, but there is no approved HER2-targeted therapy for BTC. Zanidatamab (zani), a HER2-targeted bispecific antibody, has shown durable responses in a subset of pts with BTC in a Ph 1 trial. Methods: HERIZON-BTC-01, an open-label, global Ph 2b study (NCT04466891), evaluated zani (20 mg/kg IV every 2 wks) in pts with HER2-amplified, locally advanced unresectable or metastatic BTC (gallbladder cancer [GBC], intra-/extra-hepatic cholangiocarcinoma [ICC/ECC]) who had received prior gemcitabine-containing therapy; pts with prior HER2-targeted therapies were excluded. Pt cohort assignment was based on tumor immunohistochemistry (IHC) status: Cohort 1 for IHC 2+/3+ (HER2 positive), or Cohort 2 for IHC 0/1+. Tumors were assessed every 8 wks per RECIST 1.1. The primary endpoint was confirmed objective response rate (cORR) by independent central review (ICR) in Cohort 1. Secondary endpoints included other efficacy and safety outcomes. Results: Enrollment is complete with 87 pts (Cohort 1, n=80; Cohort 2, n=7) treated. Median age was 64 yrs (range, 32-79); 54% were female; 66% were Asian; 52% had GBC, 30% ICC, and 18% ECC. Pts had a median of 1 line (range, 1-7) of prior therapy in the locally advanced/metastatic setting. In Cohort 1, cORR was 41% with median duration of response (DOR) of 12.9 months (m; 95% CI: 5.95, not estimable); median study follow-up time was 12.4 m. Among the 33 responders at the data cut (10OCT2022), 49% had ongoing responses and 82% had a DOR of ≥16 wks. Median time to first response was 1.8 m (range, 1.6-5.5). Progression-free survival and overall survival are being evaluated. No responses were observed in Cohort 2. In both cohorts (N=87), tx-related adverse events (TRAEs) occurred in 72% of pts; TRAEs in ≥10% of pts were diarrhea (37%) and infusion-related reaction (33%). Gr 3 TRAEs occurred in 18% of pts, with diarrhea (4.6%) and ejection fraction (EF) decreased (3.4%) in >3% of pts. Two pts (2.3%) discontinued zani due to an AE (EF decreased and non-infectious pneumonitis). Seven pts had serious TRAEs; no AE preferred term occurred in >1 pt. No zani-related Gr 4 AEs or deaths were reported. Conclusions: Results of the pivotal HERIZON-BTC-01 study indicate that the HER2 bispecific antibody zani demonstrates rapid, durable responses with a manageable safety profile in pts with tx-refractory HER2-positive BTC. Given these data, zani continues to be developed as a tx option in HER2-positive BTC. Clinical trial information: NCT04466891 . [Table: see text]

Phase I Beamion Lung 1 trial of BI 1810631, a HER2 tyrosine kinase inhibitor (TKI), as monotherapy in patients (pts) with advanced/metastatic solid tumors with HER2 aberrations: Updated data.

8545 Background: There is an unmet need for effective TKIs against HER2 mutations in solid tumors, especially NSCLC. BI 1810631 is a highly potent and selective HER2 TKI that covalently binds to both wild-type and mutated HER2 receptors, including exon 20 insertions (ex20ins), while sparing EGFR. Beamion Lung 1 is an ongoing Phase Ia/Ib study to determine the safety, MTD, PK, PD, and preliminary efficacy of BI 1810631 in pts with HER2 aberration-positive solid tumors (NCT04886804). Preliminary results from Phase Ia are presented. Methods: In Phase Ia, pts with advanced/unresectable/metastatic solid tumors who were refractory or unsuitable for standard treatment (Tx) and had HER2 aberrations (e.g. overexpression, gene amplification, somatic mutation, or gene rearrangements) were enrolled. Pts received escalating doses of BI 1810631 BID starting from 15 mg or BI 1810631 QD starting from 60 mg via a Bayesian model. Phase Ib will initially include 30 pts with advanced HER2 tyrosine kinase domain mutation-positive, pre-treated NSCLC. Additional cohorts may be included. Primary endpoints: MTD based on DLTs; pts with DLTs (Phase Ia); ORR (Phase Ib). Secondary endpoints: number of pts with DLTs throughout entire Tx period and PK parameters (Phase Ia/Ib); DoR, DCR, duration of disease control, and PFS (Phase Ib). Results: As of 23 January 2023, 36 pts had been treated in the US, The Netherlands, Japan, and China. Pts had NSCLC (n = 22), colorectal cancer (n = 3), or other tumors (n = 11). Most pts (n = 26; ex20ins: n = 23) had a pathological HER2 mutation. Median (range) lines of prior systemic Tx: 2.5 (1–8). Prior HER2-targeted Tx: 12 (33%). Pts received BI 1810631 at 15, 30, 60, 100, 150 mg BID (n = 3/3/4/4/3) or 60, 120, 180, 240, 300 mg QD (n = 5/4/5/4/1). Median number of cycles was 4 (range 1–14). Tx is ongoing in 20 pts. To date, 3 DLTs have been observed (grade 2 edema [60 mg BID], grade 3 anemia [60 mg QD], grade 3 elevated ALT [180 mg QD]). The MTD has not been reached with either schedule. Tx-related adverse events (TRAEs) were reported in 25 pts (69%). The most common TRAEs were diarrhea (n = 10), anemia (n = 5), increased alkaline phosphatase, increased creatinine, increased ALT, hypoalbuminemia (all n = 4), hypocalcemia, increased AST, dry skin, increased GGT (all n = 3). Three pts had grade 3 TRAEs (anemia/increased GGT [n = 1], increased ALT [n = 2]). Strong preliminary efficacy signals were observed across all dose levels. Of 22 evaluable NSCLC patients, 10 responded (all PRs; all ex20ins) and 11 had SD. Two patients with other tumors (esophagus; cholangiocarcinoma) also achieved PR. Conclusions: These preliminary data indicate that BI 1810631 is well tolerated and shows encouraging anti-tumor activity in pts with HER2 aberration-positive solid tumors. Recruitment into Phase Ia is ongoing. Updated data, including durability endpoints, will be presented. Clinical trial information: NCT04886804 .

Outpatient administration of mosunetuzumab in US community practice settings: perspectives and learnings from the Phase II MorningSun study

Outpatient administration of mosunetuzumab in US community practice settings: perspectives and learnings from the Phase II MorningSun study

Talazoparib (Tala) in patients (pts) with solid tumors with BRCA1/2 mutation (mut): Results from the Targeted Agent and Profiling Utilization Registry (TAPUR) study.

3115 Background: TAPUR is a phase II basket study evaluating antitumor activity of commercially available targeted agents in pts with advanced cancers with specific genomic alterations. Results in a cohort of pts with solid tumors with BRCA1/2 mut treated with Tala are reported. Methods: Eligible pts had measurable disease, ECOG performance status (PS) 0-2, adequate organ function, and no standard treatment (tx) options. Genomic testing was performed in CLIA-certified, CAP-accredited site selected labs. Pts received 1 mg of Tala orally daily until disease progression. Primary endpoint was disease control (DC) per investigator defined as complete (CR) or partial (PR) response or stable disease (SD) of at least 16+ weeks (wks) duration (SD16+) per RECIST v1.1. The hypothesized null DC rate of 15% was evaluated by a 1-sided exact binomial test (alpha 0.10; 82% power). Secondary endpoints were progression-free survival (PFS), overall survival (OS), duration of response (DOR) and SD, and safety. DOR is defined as time from pt’s first documented objective response (OR) to progressive disease (PD). Duration of SD is defined as time from tx start to PD. Results: 28 pts with 16 solid tumors (6/28 pts had lung cancer) with BRCA1 (n=9) , BRCA2 (n=16) , or BRCA1/2 (n=3) mut were enrolled from Dec 2019 to Sept 2021. All pts were included in efficacy analyses. Demographics and outcomes are shown. 1 CR, 9 PR and 6 SD16+ were observed for a DC rate of 57% (1-sided 90% CI: 43% to 100%) and an OR rate of 36% (95% CI: 19% to 56%); the null hypothesis of a 15% DC rate was rejected (p<0.001). 11/16 pts with OR or SD16+ had a BRCA2 mut, 4 had BRCA1 mut, and 1 had both. The pt with a CR (duration of 93 wks) had non-melanoma skin cancer, with BRCA2 and ATM muts, and was microsatellite instability high with 41 muts per megabase. Pts with PR had various solid tumors; 6/9 pts had BRCA2 mut, 2 had BRCA1 mut , 1 had both. Of pts with DC, 11 had tumor types for which PARP inhibitors are not yet FDA approved. Median duration of PR was 20 wks (range, 11-80). 10/16 pts with DC had a co-alteration in the 24 homologous recombination-related genes examined, mainly ATM (3) or ARID1A (2). 13 pts had ≥1 grade 3 tx-related adverse or serious adverse events including: anemia, AST or bilirubin increase, hyponatremia, nausea, vomiting, neutrophil, platelet, or white blood cell decrease. Conclusions: Tala demonstrated antitumor activity in heavily pretreated pts with advanced solid tumors with BRCA1/2 mut. Additional study is warranted to confirm the efficacy of Tala in non-breast, non-ovarian cancer pts with BRCA1/2 mut. Clinical trial information: NCT02693535 . [Table: see text]

Abstract CT226: Crizotinib (C) in patients (pts) with solid tumors with MET amplification (amp) or mutation (mut): Results from the Targeted Agent and Profiling Utilization Registry (TAPUR) Study

Abstract Background: TAPUR is a phase II basket study evaluating antitumor activity of commercially available targeted agents in pts with advanced cancers with specific genomic alterations. Results in a cohort of pts with solid tumors and MET amp or mut treated with C are reported. Methods: Eligible pts had no standard treatment (tx) options, had measurable disease, ECOG performance status (PS) 0-2, and adequate organ function. Pts with non-small cell lung cancer were excluded. Genomic testing was performed in CLIA-certified, CAP-accredited site selected labs. Pts received C at 250 mg orally BID until disease progression. Low accruing histology-specific cohorts with MET amp or mut were collapsed into 1 histology-pooled cohort for analysis. Primary end point was disease control (DC) per investigator, defined as complete or partial response (PR) or stable disease (SD) of at least 16+ weeks (wks) duration (SD16+) per RECIST v1.1. The primary end point was summarized as a proportion and the hypothesized null DC rate of 15% was evaluated by a 1-sided exact binomial test with α= 0.10. Other end points were progression-free survival (PFS), overall survival (OS), duration of response and SD, and safety. Results: 31 pts with solid tumors (12 tumor types) and MET mut only (n=10), amp only (n=19), or mut and amp (n=1) were enrolled; 1 pt with overexpression was ineligible. 3 additional pts were unevaluable for efficacy. Table shows demographics and outcomes. 2 PR (both esophageal adenocarcinoma with MET amp) and 4 SD16+ (2 renal cell carcinoma, 1 with mut, 1 with amp; colorectal with amp; small intestine with amp) were observed for DC rate of 21% (1-sided 90% CI: 12%, 100%) and objective response rate of 7% (95% CI: 1%, 24%). The null DC rate was not rejected. 5 pts had ≥1 grade 3 tx-related adverse or serious adverse event. Conclusions: C did not meet prespecified criteria to declare a signal of activity in pts with solid tumors with MET amp or mut. Table: Baseline Characteristics (N=31); Efficacy Outcomes (n=28); Toxicity Outcomes (N=31) Median (Med) age, years (range) 61 (30, 82) Female, % 16 (52) ECOG PS, % 0 15 (48) 1 12 (39) 2 4 (13) Prior systemic regimens, % 1 3 (10) 2 5 (16) ≥3 23 (74) DC rate, % (OR and SD16+) (1-sided 90% CI) 21 (12, 100) Objective response rate, % (95% CI) 7 (1, 24) Med PFS, wks (95% CI) 8 (8, 13) Med OS, wks (95% CI) 37 (26, 68) Duration of response, wks (n=2) 14 and 20 Med duration SD, wks (n=4) 27 (26, 28) Number of pts1 with tx-related grade 3 adverse or any grade serious adverse event AE2 5 (16) SAE3 3 (10) 1Pts may have experienced one or more events 2ALT increase, diarrhea and all SAEs 3Acute kidney injury, ALT increase, AST increase, blood bilirubin increase, creatinine increase, dehydration, fatigue, GGT increase, hyperkalemia, nausea, sinus bradycardia Citation Format: Kathryn F. Mileham, Michael Rothe, Pam K. Mangat, Elizabeth Garrett-Mayer, Herbert L. Duvivier, Carmen J. Calfa, Carrie L. Dul, Alissa S. Marr, Eugene R. Ahn, Deepti Behl, Michael J. Hall, Inderjit Mehmi, Anu Gaba, Rom Leidner, Mark M. Zalupski, Gina N. Grantham, Abigail Gregory, Susan Halabi, Richard L. Schilsky. Crizotinib (C) in patients (pts) with solid tumors with MET amplification (amp) or mutation (mut): Results from the Targeted Agent and Profiling Utilization Registry (TAPUR) Study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT226.

Management (mgmt) of futibatinib-associated adverse events (AEs) in patients (pts) with advanced cancers: Results of a pooled analysis.

586 Background: Futibatinib, a covalently binding FGFR1–4 inhibitor, showed a 42% objective response rate with a 9.7 mo median duration of response in pts with advanced intrahepatic cholangiocarcinoma (iCCA) and FGFR2 fusions/rearrangements in the phase 2 FOENIX-CCA2 trial. Futibatinib treatment (tx) was safe and tolerable with a predictable and manageable side effect profile. This pooled retrospective analysis examined mgmt of futibatinib-associated AEs in pts with advanced tumors, including iCCA. Methods: Pts from a global phase 1/2 study (NCT02052778) and a Japanese phase 1 study (JapicCTI-142552) who received futibatinib 20 mg QD (recommended dose) were included. Futibatinib dose modifications and supportive medications (meds) for AE mgmt were analyzed for futibatinib-associated AEs of clinical interest (group terms: hyperphosphatemia, hepatic AEs, retinal disorders, nail disorders, rash, palmar plantar erythrodysesthesia [PPE], cataract). The Kaplan-Meier method was used for time-to-resolution (TTR) analysis. Results: As of October 1, 2020, 318 pts with advanced solid tumors (60% CCA; 98% with ≥1 prior tx) had received ≥1 futibatinib 20 mg QD dose (median tx duration, 3.6 mo). Table includes incidence and mgmt of key AEs of clinical interest. Hyperphosphatemia was the most frequent cause of futibatinib dose modifications; 85% and 30% of pts with hyperphosphatemia received phosphate binders and/or phosphaturic agents, respectively, with no obvious TTR differences. Other common supportive meds included analgesics (in 55% of pts with nail disorders; 71% with PPE) and corticosteroids (37% of pts with rash). Retinal disorders occurred in 8% of pts (all grade [gr] 1-2 and resolved). Cataract, a late-onset AE on continued tx, occurred in 12 (4%; 4 [1%] gr ≥3) pts, leading to dose modifications in 3 pts. One pt underwent cataract surgery and resumed futibatinib tx the next day. Discontinuations due to tx-related AEs were rare (2.5%) and included 1 pt each with retinal detachment, onycholysis, and cataract. Conclusions: This analysis of AE mgmt showed a consistent and manageable safety profile for futibatinib in pts with pretreated advanced tumors. Commonly observed AEs with futibatinib were well managed with dose adjustments and supportive meds and rarely led to tx discontinuation. Clinical trial information: NCT02052778 /JapicCTI-142552. [Table: see text]

Abstract CT503: A phase I/Ib study of the safety and preliminary efficacy of NZV930 alone and in combination with spartalizumab and/or taminadenant in patients (pts) with advanced malignancies

Abstract Background: The over-expression of CD73 has been linked to many cancers. NZV930, an investigational, CD73-targeting monoclonal antibody (mAb), forms bidentate structures with the CD73 dimer, shutting down the catalytic activity of cell surface and soluble CD73. Taminadenant is an investigational A2AR antagonist and spartalizumab is an anti-PD-1 mAb. Preclinical studies provide compelling antitumor activity when combining CD73, A2AR, and PD-1 blockade. Methods: This first-in-human study (NCT03549000) comprised dose-escalation and dose-expansion parts. Here, we present the dose-escalation results of the four treatment (tx) arms: NZV930 single agent (SA; 60-1000 mg Q2W), NZV930 (200-600 mg Q2W) + spartalizumab (400 mg Q4W) or taminadenant (80-240 mg Q2W), or in combination with spartalizumab (400 mg Q4W) + taminadenant (80-240 mg BID). Eligible pts had selected malignancies, and disease progression following standard therapy. Primary objectives included assessing safety and tolerability and determining the recommended dose for expansion (RDE) of NZV930 SA and its combinations. Secondary objectives were to determine efficacy, characterize the pharmacokinetics (PKs) of NZV930 SA and its combinations, and assess the immunogenicity of spartalizumab and NZV930. Biomarker tumor samples were obtained at screening, C2D1, and C4D1. Results: As of June 10, 2021, 105 pts were enrolled for dose escalation, including pts with CRC (n=63), ovarian cancer (n=15), pancreatic cancer (n=11), NSCLC (n=8), TNBC (n=5), RCC (n=2), and prostate cancer (n=1). Most pts (81%) had been treated with ≥3 lines of prior therapy. In total, 98 pts discontinued, mainly due to disease progression (72%); six were ongoing. At least one tx-related adverse event (TRAE) was reported by 89 pts (85%); these were mostly grade 1-2. A triad of headache, fever, and nausea/emesis was observed after the first infusion of NZV930. Most common TRAEs (≥30%) were headache (67%), nausea and vomiting (32% each), and pyrexia (30%). At least one grade ≥3 TRAE was reported in 15 pts (14%); headache (4%) was most common, accounting for 4/7 DLTs (all grade ≥3). There were no tx-related deaths. Overall, no responses were reported; 12 pts (11%) had stable disease and 69 pts (66%) had progressive disease. NZV930 has good PK properties, with target-mediated drug disposition at lower doses, which normalize to typical IgG-like PKs at higher doses. Biomarker data confirm CD73 target engagement in plasma. Adenosine pathway modulation in tumors and plasma was seen post-NZV930 tx. Conclusions: NZV930 reduced adenosine levels in plasma and tumors. The RDE of NZV930 SA or in combination with spartalizumab and/or taminadenant is 600 mg Q2W with a step-up dosing regimen. NZV930 SA and its combinations exhibited a tolerable safety profile in multiple advanced solid tumors and showed good PK properties. Citation Format: Siqing Fu, Udai Banerji, Philippe L. Bedard, Aitana Calvo Ferrándiz, Alberto Chiappori, Jayesh Desai, Rahima Jamal, Desamparados Roda Perez, Noboru Yamamoto, Erica Vieira, Gabrielle Wong, Kulandayan K. Subramanian, Shunguang Wang, Britta Mueller, Javier A. Otero, Si-Lin Koo. A phase I/Ib study of the safety and preliminary efficacy of NZV930 alone and in combination with spartalizumab and/or taminadenant in patients (pts) with advanced malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT503.