QD Cohort Research Articles

First-in-human study of HMPL-295, an ERK1/2 inhibitor, in patients with advanced solid tumors: Dose-escalation results of monotherapy.

e15112 Background: HMPL-295 (’295) is an extracellular signal-regulated kinase 1 and 2 (ERK1/2) inhibitor with potent activity in non-clinical studies. This is a first-in-human, dose escalation study of ’295 in patients (pts) with advanced solid tumors. Here, we report the results of the mono dose escalation stage. Methods: Pts with advanced solid tumors who have failed standard therapy were enrolled to receive ’295 once daily (QD) in 28-day cycles or ’295 QD 2 weeks on/1 week off (2w on/1w off) in 21-day cycles. The mTPI-2 design was used for dose escalation, having explored from 5 to 75 mg QD in 6 cohorts, as well as 75 mg and 100 mg QD 2w on/1w off. The study aims to determine the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D), safety, tolerability, pharmacokinetics/pharmacodynamics (PK/PD), and preliminary efficacy (best of response, BOR). Results: As of Dec 11, 2023, 47 pts with advanced solid tumors were enrolled (n=1, 1, 3, 6, 12, 5, 13, 6 in 5, 10, 20, 40, 50, 75 mg QD cohorts, 75, 100 mg QD 2w on/1w off cohorts, respectively), with a median age of 58 years, 23 (48.9%) male pts. During the dose escalation from 5 to 75 mg QD cohort, 1 pt given 40 mg QD experienced a dose-limiting toxicity (DLT) of grade 3 dermatitis acneiform and 2 pts given 75 mg QD experienced DLTs of grade 3 rash and acute kidney injury (AKI). As for intermittent-administration cohorts, 2 pts given 100 mg QD 2w on/1w off experienced DLTs of grade 3 AKI and rash maculo-papular. After multiple-dose oral administration, ’295 plasma concentrations reach peak at 1.0-2.0 hours post dose and the exposure (Cmax and AUC) displayed dose dependent increase. The accumulation ratio (AUC) was 2.1–3.4 after repeat dosing, reaching steady-state around day 15. ’295 inhibited ribosomal S6 kinase (RSK) phosphorylation which is a downstream signaling molecule regulated by ERK1/2 and stimulated by phorbol 12-myristate 13-acetate (PMA). The BOR was partial response each in 1 pt with duodenal adenocarcinoma in 40 mg QD cohort,1 pt with endometrial cancer in 50 mg QD cohort and 1 pt with non-small cell lung cancer (NSCLC) in 75 mg QD 2w on/1w off cohort. Stable disease with tumor shrinkage was also observed in 2 pts with NSCLC on 50 mg QD and 75 mg QD 2w on/1w off cohort respectively, and 1 pt with pancreatic ductal adenocarcinoma in 100 mg QD 2w on/1w off cohort. 25 (53.2%) pts reported grade ≥3 TEAEs. The most common (≥10.0%) ≥ grade 3 TEAEs were rash (10.6%) and anemia (10.6%). Conclusions: Considering safety, tolerability, PK/PD and preliminary efficacy results, RP2D was determined to be 50 mg QD. Clinical trial information: NCT04908046 .

Pharmacodynamic (PD) and immunophenotyping analyses of ATR inhibitor (ATRi) tuvusertib + ATM inhibitor (ATMi) lartesertib in a phase Ib study in patients with advanced unresectable solid tumors.

2612 Background: Ataxia telangiectasia-mutated (ATM) and Rad3-related (ATR) protein kinases orchestrate the DNA damage response. A synthetic lethal relationship between ATR and ATM genes in cancer has been described1 and ATMi synergistically potentiate the efficacy of ATRi in vitro and in vivo.2 The combination of tuvusertib + lartesertib was investigated in Part A1 of the open-label, multicenter study DDRiver Solid Tumors 320 in patients with advanced unresectable solid tumors. Here, we report results of the PD and immunophenotyping analyses. Methods: PD analysis comprised γ-H2AX in serial blood samples, stimulated ex vivowith 4-NQO, bleomycin, or controls. Flow cytometry was used to measure target inhibition via γ-H2AX modulation in the CD45+ lymphocytes fraction and to explore the effect of tuvusertib + lartesertib on the immunophenotype (myeloid-derived suppressor cells, T and B lymphocytes, monocytes, and natural killer cells subsets) in serial blood samples. Pharmacokinetic samples were analyzed by a validated bioanalytical liquid chromatography/mass spectrometry method. Time-matched blood samples were collected at baseline, 1, 3, 6, and 24 hours after first tuvusertib and lartesertib administration on days 1 and 8 of cycle 1 for the γ-H2AX analysis, and on days 1 and 15 of cycles 1 and 2 before treatment for immunophenotyping. Results: Immunophenotyping data and γ-H2AX levels were obtained from 41 and 34 patients, respectively. For tuvusertib, complete or almost complete target inhibition was seen at 1–6 hours after treatment, followed by a rebound above baseline after 24 hours, on both days 1 and 8 at doses of 130 and 180 mg once daily (QD). For lartesertib, a variable target inhibition of approximately 50 % on average was seen across all time points at doses of 100, 150 and 200 mg QD. No target inhibition was seen for tuvusertib at 90 mg QD and lartesertib at 50 mg QD (cohort 1). Tuvusertib + lartesertib induced a transient decrease of monocytes and natural killer (NK) cells, with partial or complete recovery to baseline levels during treatment breaks in schedules of 2 weeks on treatment followed by a treatment break of 1 or 2 weeks, respectively. Conclusions: Tuvusertib and lartesertib combination PD outcomes were in line with respective monotherapy observations.3,4 The combination did not cause any consistent change in the levels of immune cell subsets at all dose levels tested, except a mild, transient decrease in monocytes and NK cells, in line with the tuvusertib monotherapy observations. 1. Kantidze et al., Trends Cancer 2018;4(11):755–68. 2. Turchick et al., Mol Cancer Ther 2023;22(7):859–72. 3. Yap et al., Ann Oncol 2022;33(suppl_7):S197–S224. 4. Siu et al., Cancer Res 2023;83(8_Suppl):CT171. Clinical trial information: NCT05396833 .

Abstract PO3-05-08: Updated results from VERITAC evaluating vepdegestrant, a PROteolysis TArgeting Chimera (PROTAC) estrogen receptor (ER) degrader, in ER–positive/human epidermal growth factor receptor 2 (HER2)–negative advanced breast cancer

Abstract Background: Vepdegestrant (ARV-471) is an oral PROTAC ER degrader with activity toward wild-type and mutant ER. The phase 2 expansion (VERITAC) of a phase 1/2 study (NCT04072952) tested 2 vepdegestrant doses (200 mg once daily [QD] and 500 mg QD) in heavily pretreated patients with ER+/HER2- advanced breast cancer. Vepdegestrant 200 mg QD was selected as the phase 3 monotherapy dose based on comparable efficacy and favorable tolerability vs 500 mg QD and robust ER degradation (data cutoff: Jun 6, 2022). We present updated data for the vepdegestrant 200 mg QD cohort after 12 additional months of follow-up. Methods: Vepdegestrant was administered to patients with ER+/HER2- locally advanced/metastatic breast cancer who had received ≥1 prior endocrine therapy for ≥6 months, ≥1 cyclin-dependent kinase (CDK)4/6 inhibitor, and ≤1 chemotherapy regimen. The primary endpoint was clinical benefit rate (CBR; rate of confirmed complete response, partial response, or stable disease ≥24 weeks). Results: As of Jun 6, 2023, 35 patients received vepdegestrant 200 mg QD; 34 (97.1%) were female and median age was 63 y (range: 42–79). Patients had received a median of 4 prior regimens (range: 1–9) in all settings and 3 prior regimens (range: 0–7) in the metastatic setting; 100% had prior CDK4/6 inhibitors, 88.6% had prior aromatase inhibitors, 74.3% had prior fulvestrant, and 74.3% had prior chemotherapy (45.7% in metastatic setting). CBR with vepdegestrant 200 mg QD was 37.1% (95% CI: 21.5–55.1) in all evaluable patients (n=35) and the objective response rate was 8.3% (95% CI: 1.0–27.0) among 24 patients with measurable disease at baseline. Median progression-free survival in all evaluable patients was 3.5 months (95% CI: 1.8–8.2). As of the data cutoff date, 14 patients in the 200 mg QD cohort received treatment for ≥24 weeks (4 for ≥48 weeks) with 1 patient ongoing. No patients required a dose reduction due to a treatment-emergent adverse event (TEAE); 2 (5.7%) patients had a TEAE that led to vepdegestrant discontinuation (grade 3 QT prolongation and grade 3 anemia). The most common treatment-related adverse events (≥10%) were fatigue (43%), hot flush (20%), nausea (17%), arthralgia (11%), increased aspartate aminotransferase (11%), and increased blood alkaline phosphatase (11%); all were grade 1/2. Substantial on-treatment decreases in mutant ESR1 circulating tumor DNA levels were observed with vepdegestrant 200 mg QD and sustained for multiple treatment cycles. Conclusions: With 12 months of additional follow-up from the first data report, durable clinical activity with vepdegestrant 200 mg QD was seen in heavily pretreated patients with ER+/HER2- advanced breast cancer, in addition to sustained reduction in circulating mutant ESR1 tumor DNA levels. Vepdegestrant 200 mg QD continued to show a favorable safety profile. The ongoing global, randomized phase 3 VERITAC-2 study (NCT05654623) is evaluating vepdegestrant 200 mg QD vs intramuscular fulvestrant in patients with ER+/HER2- advanced breast cancer after prior combination CDK4/6 inhibitor therapy and endocrine therapy. Citation Format: Sara Hurvitz, Anne Schott, Cynthia Ma, Rita Nanda, George Zahrah, Natasha Hunter, Antoinette Tan, Melinda Telli, Jesus Anampa Mesias, Rinath Jeselsohn, Pamela Munster, Eric Zhi, Elizabeth Duperret, Cecile Mather, Erika Hamilton, Hyo Han. Updated results from VERITAC evaluating vepdegestrant, a PROteolysis TArgeting Chimera (PROTAC) estrogen receptor (ER) degrader, in ER–positive/human epidermal growth factor receptor 2 (HER2)–negative advanced 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 PO3-05-08.

Tailor: Interventional Study Evaluating Physician's Choice of Ibrutinib Monotherapy or Ibrutinib-Venetoclax Combination Using Dose Modifications and Alternate Dosing Approaches in Patients with Untreated Chronic Lymphocytic Leukemia

Background: Ibrutinib is a first-in-class Bruton's tyrosine kinase inhibitor (BTKi) that has changed the treatment paradigm for patients with chronic lymphocytic leukemia (CLL) with durable responses and improved overall survival (OS). In the pivotal Phase 3 GLOW and Phase 2 CAPTIVATE trials, fixed-duration combination of ibrutinib-venetoclax (I+V) resulted in deep and sustained clinical responses, and a broadly manageable safety profile in patients with CLL. Several factors including genetic features, disease status, comorbidities, patient preferences, and safety profiles contribute to selection of the optimal therapeutic option for patients with CLL in the first-line setting. Adverse events (AEs), such as atrial fibrillation, bleeding, and hypertension, have been seen with the BTKi therapeutic class.Long-term clinical and real-world experience with ibrutinib has led to specific guidance regarding AE management, which has been included in the updated ibrutinib prescribing information (US PI, May 2022; EU SmPC, April 2023). Retrospective evidence, including post-hoc analyses of clinical trial data, demonstrates that dose reduction of ibrutinib mitigates recurrence or worsening of AEs while preserving efficacy. Thus, these findings together support the rationale to prospectively evaluate the impact of regimen and dosing flexibility of ibrutinib in patients with untreated CLL. Aim: The key objective of the TAILOR study (NCT05963074) is to assess the efficacy and safety of I+V and ibrutinib monotherapy regimens with both a proactive and reactive dose adjustment in patients with untreated CLL. Methods: TAILOR is a phase 2, two-arm, four-cohort interventional study designed to provide physicians the choice of ibrutinib monotherapy or I+V combination therapy for previously untreated patients with CLL and prospectively evaluate proactive and reactive dose adjustment approaches. Eligible patients will have previously untreated active CLL, needing therapy as per iwCLL 2018 criteria. Key exclusion criteria include significant active or history of cardiovascular disease, uncontrolled hypertension, and ECOG performance status > 2. Patients will be randomized after selection of regimen: I+V fixed-duration regimen (2 cohorts, 80 patients in each cohort) or ibrutinib monotherapy (2 cohorts, 80 patients in each cohort), as per physician's choice. Patients in the I+V arm will receive ibrutinib 420 mg QD as lead-in for 3 cycles plus 12 cycles of either ibrutinib 420 mg QD (Cohort 1a) or 280 mg QD (Cohort 1b) in combination with venetoclax, which will be initiated in cycle 4 with dose ramp-up per label over 5 weeks (20, 50, 100, 200, and 400 mg/day) and continued at 400 mg/day dose from cycle 5 onward. In addition, patients with deletion 17p and/or mutated TP53 will receive optional ibrutinib maintenance. Patients in the ibrutinib monotherapy arm will receive ibrutinib 420 mg QD (Cohort 2a) or 420 mg QD for 3 cycles, then 280 mg QD (Cohort 2b) until progressive disease or unacceptable toxicity ( Figure). All cohorts will follow the dose modification guidance as per protocol based on the US PI/ EU SmPC. The primary endpoint is best overall response rate as assessed by investigators and compared with historic controls. Secondary endpoints include: complete response rate, duration of response, PFS, and OS; undetectable minimal residual disease rate (I+V cohorts only); safety (AEs, discontinuation due to AEs, adherence rates); and patient reported outcomes. The study is currently recruiting patients.

Janus Kinase (JAK) 1 Inhibition Results in Significant Changes in Serum Proteins and Peripheral T-Cell Populations That Correlated with Clinical Scores in Chronic Graft Versus Host Disease (GVHD) Patients (an Analysis from GRAVITAS-309)

Background: Chronic GVHD (cGVHD) occurs in 30-70% of allogeneic hematopoietic cell transplantation patients, and the rate has increased over the past 2 decades. Based on the degree of organ involvement, cGVHD is classified as mild, moderate, or severe. Standard treatment includes systemic corticosteroids (CS), together with immunosuppressive agents. GRAVITAS-309 (NCT03584516) was designed as a 2-part, multicenter, randomized trial to assess efficacy and safety of itacitinib, an orally bioavailable, selective JAK1 inhibitor, in combination with CS as first-line treatment for moderate to severe cGVHD. The dose-finding, open-label, randomized portion of the study initially investigated itacitinib at 200 mg once daily (qd) and 300 mg qd in combination with CS (methylprednisolone or prednisone); both doses were well tolerated. The trial was expanded to test itacitinib 400 mg qd and 300 mg twice daily (bid); the initial 300 mg qd cohort was expanded and a CS monotherapy cohort was added. Results from the expanded portion of the study (n=139 patients) showed improved overall response rate (ORR) at 6 months in patients treated with itacitinib + CS vs CS alone (Im, et al. Blood 2022;140[Suppl 1]:1870). Here, we analyzed samples collected from patients in 4 cohorts (cohort A [300 mg qd], cohort B [400 mg qd], cohort C [300 mg bid], and cohort D [CS alone]) for systemic proteins and immune cell populations, to support investigation into the itacitinib mechanism of action and to correlate with clinical outcomes. Methods: Peripheral blood mononuclear cells (PBMCs) and serum were collected before treatment (baseline, day 1), and day 7, day 14 (PBMCs only), and day 28 following treatment initiation. Serum proteins were analyzed using the OLINK Target 96 platform, and circulating T-cell subsets were measured using flow cytometry of PBMCs and presented as a percentage of parent population. Samples were assessed irrespective of patients' response. Most of the patients (70-100% per cohort) with samples available for analysis were responders (achieved complete or partial responses). Results: Serum levels of proteins, including several proposed as potential prognostic cGVHD biomarkers, changed significantly at day 28 relative to baseline following treatment with itacitinib (Table 1). Levels of elafin, a marker of acute GVHD of the skin, were significantly reduced and levels of dickkopf-3 (DKK3), a marker of sclerotic and nonsclerotic cGVHD, were significantly increased in itacitinib cohorts only. Based on a repeated measures correlation analysis, both markers significantly correlated with overall clinical skin scores (elafin: r=+0.43; DKK3: r=-0.53; both P<0.001). Serum levels of other reported markers of cGVHD, including osteopontin, C-X-C motif chemokine ligand (CXCL) 9 and CXCL10, were significantly decreased exclusively in itacitinib-treated cohorts, and not in the CS only cohort. Some proteins, including matrix metalloproteinase (MMP) 3, increased in all cohorts, suggesting that changes in these proteins cannot be attributed to itacitinib alone, but may reflect response to CS; other proteins, such as suppression of tumorigenicity (ST2), remained unchanged in response to treatment in all cohorts. CS treatment alone resulted in an increase in naive CD4 T cells (CD4 +CD8 ->CD45RA +CCR7 -) and a corresponding reduction of CD4 effector memory T cells (CD4 +CD8 ->CD45RA -CCR7 +) within 28 days (Figure 1, cohort D). Changes in naive CD4 T cells following CS monotherapy were significantly attenuated by itacitinib ( P<0.05 vs CS at day 28), particularly at the 400 mg qd dose (Figure 1, cohort B), which demonstrated the best ORR at 6 months (53% with 400 mg qd vs 36% with CS). Conclusions: Analysis of patient samples from GRAVITAS-309 revealed that serum elafin and DKK3 levels significantly correlated with skin GVHD scores, possibly reflecting the systemic origin of observed skin manifestations. Serum levels of osteopontin, CXCL9, and CXCL10 were specifically reduced by itacitinib in patients with cGVHD and may represent potential pharmacodynamic markers. Observed changes in different peripheral T-cell populations in patients' samples following itacitinib treatment were consistent with those reported in murine GVHD models, suggesting a potential role of naive CD4 + T cells in driving this disease. Planned future analyses will include identification of novel biomarkers that correlate with organ involvement.

Asciminib (ASC) Once-Daily (QD) Dosing Demonstrates Comparable Tolerability and Efficacy to Twice-Daily (BID) Dosing: Results from the ASC in Monotherapy 4 CML (AIM4CML) Study in Patients (Pts) with Chronic Myeloid Leukemia in Chronic Phase (CML-CP)

CONCLUSIONS ASC is the only approved BCR::ABL1 inhibitor that Specifically Targets the ABL1 Myristoyl Pocket, distinguishing it from other approved treatments that target the ATP binding site. In the phase III ASCEMBL trial (NCT03106779) ASC 40 mg BID was well tolerated and demonstrated superior efficacy vs bosutinib 500 mg QD in pts previously treated with ≥2 TKIs, with major molecular response (MMR; BCR::ABL1IS ≤0.1%) rates of 25.5% vs 13.2% at wk 24 and 37.6% vs 15.8% at wk 96. We present an interim analysis of the primary endpoint of the AIM4CML trial (NCT04666259), which was initiated to assess the safety, efficacy, and QD dosing of ASC in a similar population of pts with CML-CP. This is a multicenter, phase IIIb, open-label study of ASC in pts with CML-CP without the T315I mutation after ≥2 prior TKIs and pts with the T315I mutation after ≥1 prior TKI. Adults aged ≥18 years with CML-CP who had treatment failure with or intolerance of the most recent TKI were eligible. Pts without the T315I mutation were randomized to receive ASC 40 mg BID (cohort A) or 80 mg QD (cohort B). Results for pts with the T315I mutation who received ASC 200 mg BID (cohort C) will not be presented for this analysis. The primary endpoints include adverse events (AEs) and serious AEs by wk 24 in cohorts A and B, with additional safety and efficacy secondary endpoints. This study was not powered to detect statistical differences between cohorts. End of study is when the last pt completes 72 wks of treatment or discontinues prematurely. The numbers of enrolled pts in cohorts A, B, and C were 26, 27, and 3, respectively. This interim analysis included 42 pts randomized to cohort A (n=22) or cohort B (n=20), who reached 24 wks after cycle 1 day 1 of treatment by February 17, 2023. Most baseline characteristics in cohorts A and B were comparable, but median time since initial diagnosis and median baseline BCR::ABL1IS levels were longer and higher, respectively in cohort B (Table). Median duration of exposure was 23.1 (range, 2.7-72.3) wks in cohort A and 24.1 (range, 1.3-71.0) wks in cohort B. Prior to wk 24, treatment was discontinued in 7 and 4 pts in cohorts A and B, respectively. Reasons for discontinuation included physician decision (cohort A, n=4; cohort B, n=2), AEs (cohort A, n=2; cohort B, n=1), or pt decision (cohort A, n=1; cohort B, n=1). At the time of this interim analysis, discontinuation due to treatment failure was reported only in cohort B in 2 pts that discontinued due to physician decision. Cohorts A and B had comparable all-grade, grade 3, and grade 4 AEs. Treatment-emergent all-grade AEs occurring in ≥20% in cohorts A and B were fatigue (32% and 25%), headache (27% and 20%), abdominal pain (27% and 15%), rash (23% and 5%), dyspnea (23% and 10%), nausea (14% and 30%), hypertension (14% and 20%), cough (18% and 20%), and arthralgia (9% and 20%). While many pts had AEs requiring additional therapy, few had serious AEs, and similar numbers of pts in cohorts A and B had AEs leading to dose adjustments/interruptions and treatment discontinuation (Figure). One pt in cohort B had a fatal AE due to sepsis that was not attributed to study treatment. This trial is ongoing; data for the wk 24 primary endpoint for all enrolled pts will be available at the time of presentation. Pts with ≥1 molecular response assessment by wks 4, 12, and 24 were 18, 19, and 20 in cohort A, respectively, and 17, 17, and 18 in cohort B, respectively. The proportions of pts who maintained or achieved BCR::ABL1IS ≤1% by wks 4, 12, and 24 were higher in cohort B with 52.9%, 76.5%, and 88.9%, respectively than in cohort A with 50.0%, 63.2%, and 65.0%, respectively, likely due to higher baseline BCR::ABL1IS levels in cohort B (Table). MMR rates by wks 4, 12, and 24 were 33.3%, 42.1%, and 45.0% in cohort A and 23.5%, 47.1%, and 61.1% in cohort B, respectively. Deep molecular response (MR 4; BCR::ABL1IS ≤0.01%) rates by wks 4, 12, and 24 were 27.8%, 31.6%, and 30.0% in cohort A and 5.9%, 11.8%, and 27.8% in cohort B, respectively. This interim analysis of the AIM4CML trial further demonstrates the tolerability and efficacy of ASC and is among the first clinical reports on QD dosing of ASC in pts with CML-CP. Safety was comparable between the 80-mg QD and 40-mg BID doses, with both demonstrating safety profiles consistent with prior reports. Pts receiving ASC at both doses achieved and maintained molecular responses, which deepened over time. These results support the flexibility of QD dosing with ASC.

Risk of Esophagitis in Patients with Limited Stage SCLC Treated with QD or BID Chemoradiotherapy Regimens with Contralateral Esophagus Sparing

Recent randomized phase III trials in limited stage (LS) small cell lung carcinoma (SCLC) demonstrate persistent high rates of grade (G) ≥ 3 esophagitis of 16-19% for 45 Gy BID and 66-70 Gy QD radiotherapy (RT). G3 esophagitis dramatically impairs quality of life and is a barrier to treatment intensification. We previously developed a contralateral esophagus sparing technique (CEST) that reduced esophagitis mainly in patients with locally advanced NSCLC treated with chemoRT to 70 Gy/7 weeks. It is not established whether CEST is effective in LS-SCLC patients, especially those receiving BID RT which may limit mucosal esophageal regeneration during treatment. Here, we report our single-institution experience with this approach. We retrospectively analyzed the records of patients with LS-SCLC who received chemoRT between June 2014 and October 2022. Patients were treated with QD or BID schedules at physician discretion though QD has historically been favored at our institution. The esophageal wall contralateral to the tumor was contoured as an avoidance structure. IMRT or VMAT was used to drive steep dose fall-off across the esophagus while maintaining full tumor coverage. Daily cone-beam CT guidance was employed. Toxicity was assessed using CTCAE v5 criteria. Descriptive statistics were used to analyze outcomes. The study was approved by the IRB. We identified 38 consecutive patients with LS-SCLC treated with definitive chemoRT. Median age was 67 years, and 60.5% were female. Twenty-seven were treated with QD RT to a median dose of 63 Gy (range 55.8-70) in 33 fractions (range 31-35). All remaining patients received BID RT 45 Gy in 30 fractions. Median CTV for the QD and BID cohorts was 205 cc and 214 cc, respectively. Almost all patients (n = 37) had tumor located within 1 cm of the esophagus. There were no ≥G3 esophagitis events (95% CI, 0-9.3%). The rate of G2 esophagitis was 21.1% (11.1-36.3%), with no significant difference between QD (26%) and BID (9%) cohorts (p = 0.3). Only two patients required narcotics. For BID patients, CE planning constraints were scaled to reflect the shortened RT course. The median CE maximum dose, V20, and V30 were 44.8 Gy, 7.9 cc, and 6.4 cc, respectively. For the QD cohort, the median CE maximum dose, V45, and V55 were 59.5 Gy, 3.0 cc, and 0.6 cc, respectively. Treatment breaks occurred in nine QD patients due to neutropenia. Median follow-up was 31.0 months. 3-year overall survival was 70.0% (95% CI, 49.8-83.3%). While we are limited by small patient numbers and possible selection bias, our data suggest that CE sparing can be effective in LS-SCLC, with low severe esophagitis risk even for BID RT regimens. CEST is readily adaptable into clinical practice which should facilitate further refinement of empirically derived CE planning constraints.

Efficacy and safety profile of pimicotinib (ABSK021) in tenosynovial giant cell tumor (TGCT): Phase 1b update.

11559 Background: TGCT is a rare type of locally aggressive neoplasm that is mainly caused by overexpression of colony-stimulating factor 1 (CSF1) gene. Pimicotinib is an oral, highly potent, and selective small-molecule antagonist of CSF-1R with minimum inhibition of c-Kit and PDGFR, and has been granted Breakthrough Therapy Designation for TGCT by FDA in Jan 2023. Here, we report the updates from 50 mg QD cohort as well as the preliminary data from 25 mg QD cohort in TGCT pts. Methods: The study (NCT04192344) is to evaluate the safety and preliminary antitumor activity of Pimicotinib at 50 mg QD and 25 mg QD in TGCT pts not amenable to surgical resection. Results: As of December 31, 2022, 49 TGCT pts were enrolled, including 37 pts treated with 50 mg QD and 12 pts with 25 mg QD. Median age was 39 y (range: 19-76) and 40.8% were male. The tumor location was mainly in knee (53.1%), hip (18.4%) or ankle (12.2%). Thirty-one pts received at least one prior surgery, and 1 pt received prior exploratory systemic therapy (Anlotinib). Median treatment duration was 7.9 mos (range: 0.4-12.5), and 89.8% remained on treatment. The ORR was 77.4% (24/31, including 2 CR) in 50 mg QD and 40% (4/10, including 1 CR) in 25 mg QD by IRC based on RECIST 1.1. Most responses were achieved within 25 wks and median DOR in both cohorts was not reached. Average improvement of flexion range of knee at wk 13 from baseline was 30.2 degrees (n = 13, range: 2, 105) in 50 mg QD and 4.8 degrees (n = 5, range: -12, 24) in 25 mg QD. Proportion of responders based on BPI-30 at wk 25 was 66.7% (16/24) in 50 mg QD and 60% (3/5) in 25 mg QD, along with a similar trend of stiffness. Most TEAEs were Gr 1 or 2. Four Gr 3/4 TEAEs were reported (2 drug-related), including 1 Gr 3 serious TEAE. Most common TEAEs (≥20%) include LDH increase (75.5%), CPK increase (67.3%), α-HBDH increase (63.3%), AST increase (42.9%), amylase increase (26.5%), ALT increase (24.5%), pruritus (20.4%) and rash (20.4%). No hair color changes or serious liver injuries were reported. CPK and transaminase elevations were asymptomatic, on-target and quickly recovered after drug interruptions. nder steady-state, 50 mg QD resulted in ~ 2-fold higher Cmax and Ctrough compared to 25 mg QD, in sync with findings from escalation phase. Significant PD changes were observed in both cohorts, such as increase in plasma CSF-1 levels, decrease in non-classical monocytes and C-terminal telopeptide(CTx). Changes from baselines in both CSF-1 and CTx showed a correlation with pimocetinib plasma concentrations. Conclusions: Pimicotinib has demonstrated a significant antitumor activity, favorable safety, and PK profiles at both 50 mg QD and 25 mg QD with no apparent hepatotoxicity. The changes in PD biomarkers indicate significant CSF-1R inhibition in TGCT pts. Updated data from 50 mg QD cohort showed higher ORR and continuous improvement over a longer treatment time, which supports the further evaluation of Pimicotinib in a phase 3 study. Clinical trial information: NCT04192344 .

Abstract CT150: Result of an open-label phase 2 trial of dual TORC1/TORC2 inhibitor onatasertib (ATG-008) in HBV+ advanced hepatocellular carcinoma (HCC) subjects who have received at least one prior line of systemic therapy (TORCH)

Abstract Background: The mammalian target of rapamycin (mTOR) is a serine/threonine kinase related to the lipid kinases of the phosphoinositide 3-kinase (PI3K) family, which has been confirmed to be closely related to the development of a variety of human cancers. Onatasertib (ATG-008) is a 2nd generation mTOR inhibitor which inactivates both mTORC1 and mTORC2. Our previous clinical investigation (NCT01177397) has demonstrated preliminary evidence of antitumor activity of onatasertib across multiple solid and hematologic malignancies, with encouraging signals of activity in subjects with hepatitis B virus (HBV)+ unresectable, refractory HCC. Methods: Asian patients with advanced HBV+ HCC who had experienced progressive disease after at least 1 line of systemic therapy were enrolled in this study. Onatasertib was administered orally once a day (QD) at 3 dose levels (15 mg, 30 mg and 45 mg) or 20 mg twice daily (BID). The primary endpoints were pharmacokinetics (PK), safety and efficacy (NCT03591965). Results: As of July 11, 2022, 73 patients were enrolled and evaluated. The median age was 52.0 years and the median follow up duration was 26.5 months. The mean number of prior lines was 1.8. 63 patients (86.3%) had at least one Grade 3-4 treatment emergent adverse event (TEAE), and 25 (34.2%) had at least one serious adverse event (SAE). Among the 73 subjects, 3 achieved confirmed partial response (PR), all in the 45 mg QD cohort. 18 pts were enrolled in the 45 mg QD cohort, in which 11 (61.1%) pts had received at least 2 prior lines of systemic therapy and 15 (83.3%) pts had been exposed to an anti-PD-1/PD-L1 antibody. The overall response rate (ORR) in the 45 mg QD cohort was 16.7%. The median progression-free survival (mPFS) was 3.0 months (95% CI 1.9, 4.6) in the intention to treat (ITT) population and was 5.3 months (95% CI 1.9, 7.6) in the 45mg QD cohort. Median overall survival time (mOS) was not evaluable in the 45 mg QD cohort and the mOS was 13.4 months (95% CI 7.4, 19.8) in the ITT population. Onatasertib demonstrated linear pharmacokinetics between 15 mg QD and 45 mg QD in this Asian population and there was no significant exposure accumulation after multiple dosing, as previously seen in the US population. Conclusion: Onatasertib (ATG-008) showed encouraging single agent antitumor activity in patients with HBV+ advanced HCC after at least 1 prior systemic therapy, notably in the 45 mg QD dose level, in which most patients had been previously exposed to anti-PD-L1/PD-1 therapy. The results indicates that onatasertib has potential efficacy in HBV+ HCC patients who failed prior CPI treatment. Further study may be warranted, particularly in HBV+ HCC patients who have failed prior anti-VEGFR and anti-PDL1/PD-1 therapy. Citation Format: Shukui Qin, Xiaoyan Lin, Zhiqaing Meng, Zhenggang Ren, Yuxian Bai, Shanzhi Gu, Li Zheng, Qiu Li, Sun-Yong Oh, Yabing Guo, Yoong-Koo Kang, Wei-Yu Kao, Wei Li, Jung-Hwan Yoon, Helong Zhang, Pei-Jer Chen, Tsai-Sheng Yang, Jeong Heo, Zhendong Zheng, Hui Xie, Zhinuan Yu. Result of an open-label phase 2 trial of dual TORC1/TORC2 inhibitor onatasertib (ATG-008) in HBV+ advanced hepatocellular carcinoma (HCC) subjects who have received at least one prior line of systemic therapy (TORCH) [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 CT150.

Safety, efficacy and pharmacokinetics of BPI-9016M in c-MET overexpression or MET exon 14 skipping mutation patients with locally advanced or metastatic non-small-cell lung cancer: a phase Ib study

BackgroundAs a potential target receptor tyrosine kinase, mesenchymal-epithelial transition factor (MET) exhibits high aberrant expression across various tumors. This study aimed to evaluated the safety, tolerability, efficacy and pharmacokinetics (PK) of BPI-9016M, a novel tyrosine kinase inhibitor (TKI) targeting c-MET, in c-MET overexpression or MET exon 14 skipping mutation patients with locally advanced or metastatic non-small-cell lung cancer (NSCLC).Methods/designIn this two-part multicenter phase Ib study, eligible patients with locally advanced or metastatic NSCLC harboring c-MET overexpression or MET exon 14 skipping mutation were enrolled into Part A (tested positive for c-MET overexpression [immunohistochemical staining score ≥ 2+]; 300 mg quaque die [QD], 450 mg QD and 600 mg QD cohorts) or Part B (tested positive for MET exon 14 skipping mutation; 400 mg bis in die [BID] cohort), respectively. The primary endpoints were safety, objective response rate (ORR) and disease control rate (DCR), the second endpoints were PK parameters, progression-free survival (PFS) and overall survival (OS).ResultsBetween March 15, 2017 and September 18, 2021, 38 patients were enrolled (Part A, n = 34; Part B, n = 4). Of 38 patients, 32 (84.2%) patients completed the treatment protocol. As of the data cut-off date on January 27, 2022, all patients reported at least one treatment-emergent adverse event (TEAE). Ninety-two point one percent (35/38) of patients experienced treatment-related adverse events (TRAEs), and grade ≥ 3 TRAEs were observed in 11 (28.9%) patients. The most common TRAEs were elevated alanine aminotransferase (ALT, 14/38, 36.8%) and elevated aspartate aminotransferase (AST, 11/38, 28.9%). Only one (2.6%) patient had treatment-related serious adverse event (SAE) in 600 mg QD cohort due to thrombocytopenia. PK analysis showed BPI-9016M and its main metabolites (M1 and M2-2) reached steady state after seven days of continuous administration. At the dose of 300 mg QD and 450 mg QD, the exposure of BPI-9016M increased with increasing dose. Exposure of BPI-9016M was similar at 450 mg QD and 600 mg QD, which may exhibit a saturation trend. In all patients, ORR and DCR were 2.6% (1/38, 95% confidence interval [CI] 0.1–13.8%) and 42.1% (16/38, 95% CI 26.3–59.2%), respectively. Only one partial response (PR) patient was observed at a dose of 600 mg QD in Part A. In Part B, DCR was 75.0% (3/4, 95% CI 19.4–99.4%). The median PFS and OS in all 38 patients were 1.9 months (95% CI 1.9–3.7) and 10.3 months (95% CI 7.3–not evaluable [NE]), respectively.ConclusionBPI-9016M showed manageable safety profile in c-MET overexpression or MET exon 14 skipping mutation patients with locally advanced or metastatic NSCLC, but showed limited efficacy.Trial registrationClinicaltrials.gov NCT02929290 (11/10/2016).

Abstract GS3-03: GS3-03 ARV-471, a PROTAC® estrogen receptor (ER) degrader in advanced ER-positive/human epidermal growth factor receptor 2 (HER2)-negative breast cancer: phase 2 expansion (VERITAC) of a phase 1/2 study

Abstract Background: ARV-471 is a selective, orally administered PROteolysis TArgeting Chimera (PROTAC®) protein degrader that targets wild-type and mutant ER. ARV-471 is being evaluated in patients with ER+/HER2- locally advanced or metastatic breast cancer in a first-in-human phase 1/2 study (NCT04072952). In the phase 1 dose escalation, ARV-471 monotherapy (dose range: 30–700 mg total daily dose) showed a manageable safety profile in patients who had previously received endocrine therapy and a cyclin-dependent kinase (CDK) 4/6 inhibitor. The clinical benefit rate (CBR; rate of confirmed complete or partial response or stable disease ≥24 weeks) was 40% (95% CI: 26–56) in 47 evaluable patients. The phase 2 expansion portion of the study (VERITAC) evaluated 2 doses of ARV-471.Methods: In VERITAC, ARV-471 monotherapy was administered at doses of 200 mg once daily (QD) or 500 mg QD to patients with ER+/HER2- locally advanced/metastatic breast cancer who had received ≥1 prior endocrine therapy for ≥6 months, ≥1 CDK4/6 inhibitor, and ≤1 chemotherapy regimen. The primary endpoint of CBR was evaluated in patients enrolled ≥24 weeks prior to the data cutoff. Results: As of June 6, 2022, 71 patients received ARV-471 (200 mg QD [n=35]; 500 mg QD [n=36]) in VERITAC. Across all treated patients, 69 (97.2%) were female and median age was 60 y (range: 41–86). Patients had received a median of 4 prior regimens in all settings (range: 1–10); 100% had prior CDK4/6 inhibitors, 78.9% had prior fulvestrant, and 73.2% had prior chemotherapy. ARV-471 was well tolerated at both doses, with most treatment-related adverse events (TRAEs) grade 1/2; the most common TRAEs were fatigue and nausea (Table). In all, 3 patients (1 in the 200 mg QD cohort and 2 in the 500 mg QD cohort) discontinued ARV-471 due to treatment-emergent adverse events (TEAEs); 3 patients had ARV-471 dose reductions due to TEAEs (all from 500 mg QD to 400 mg QD). CBR was 37.1% (95% CI: 21–55) in 35 evaluable patients treated at 200 mg QD and 38.9% (95% CI: 23–57) in 36 evaluable patients treated at 500 mg QD. CBR in evaluable patients with mutant ESR1 in the 200 mg QD (n=19) and 500 mg QD (n=22) cohorts was 47.4% (95% CI: 24–71) and 54.5% (95% CI: 32–76), respectively. Conclusions: In the phase 2 VERITAC expansion cohorts of patients with ER+/HER2- locally advanced/metastatic breast cancer and prior CDK4/6 inhibitor treatment, ARV-471 monotherapy showed evidence of clinical activity based on CBR, which was further enhanced in the subgroup with ESR1 mutations. The manageable AE profile observed in the phase 1 portion of the study was maintained during cohort expansion at doses of 200 mg QD and 500 mg QD. Additional analyses are ongoing.Table. TRAEs reported in ≥10% of patients overall aNo grade 3/4 TRAE occurred in >1 patient. AST=aspartate aminotransferase Citation Format: Anne F. Schott, Sara Hurvitz, Cynthia Ma, Erika Hamilton, Rita Nanda, George Zahrah, Natasha Hunter, Antoinette R. Tan, Melinda Telli, Jesus Anampa Mesias, Rinath Jeselsohn, Pamela Munster, Haolan Lu, Richard Gedrich, Cecile Mather, Janaki Parameswaran, Hyo S. Han. GS3-03 ARV-471, a PROTAC® estrogen receptor (ER) degrader in advanced ER-positive/human epidermal growth factor receptor 2 (HER2)-negative breast cancer: phase 2 expansion (VERITAC) of a phase 1/2 study [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr GS3-03.

Itacitinib and Corticosteroids As Initial Treatment for Chronic Graft-Versus-Host Disease: Phase 1/2 Results from Gravitas-309

Background: Itacitinib is a potent, selective oral Janus kinase (JAK) 1 inhibitor with broad anti-inflammatory activity. GRAVITAS-309 was designed as a 2-part, multicenter, randomized trial to assess the efficacy and safety of itacitinib in combination with corticosteroids (CS) as first-line treatment for moderate or severe chronic graft-versus-host disease (GVHD). We describe preliminary results from the open-label, dose-finding portion of the study. Methods: The study initially investigated itacitinib at doses of 200 mg once daily (qd; n=11) and 300 mg qd (n=10) in combination with CS. Both doses were well tolerated. The trial was then expanded to test itacitinib 400 mg qd and 300 mg twice daily (bid); the initial 300-mg qd cohort was expanded, and a CS monotherapy cohort was added (Figure 1). The expected CS starting dose was 0.5-1 mg/kg per day prednisone (or methylprednisolone equivalent) with a dose taper initiated on Day 14 or earlier during the second week of treatment and following published recommendations (Flowers and Martin. Blood. 2015;125[4]:606-15). Itacitinib dosage was initially reduced by 100 mg when given concomitantly with a strong CYP3A4 inhibitor (sCYP3A4i; eg, azole antifungals). A total of 140 patients (pts) (35/treatment group) with moderate or severe chronic GVHD were to be randomized 1:1 using chronic GVHD risk status (moderate vs severe) as a stratification factor. The primary objective was to identify the appropriate dose and schedule of itacitinib for further development. The data cutoff was January 31, 2022. Results: 103 pts were enrolled and received at least one dose of itacitinib. The cohorts were well balanced for pt and disease characteristics. Median age was 57 years (range, 23-76) for the itacitinib cohorts and 59 years (range, 28-75) for the CS cohort. Approximately two-thirds of pts had moderate chronic GVHD. At the time of data cut, 39 (38%) pts in the itacitinib cohorts and 10 (28%) pts in the CS cohort continued study treatment. Median duration of study treatment was 27-28 weeks for the itacitinib cohorts (including 13-16 weeks of concomitant CS) and 17 weeks for the CS cohort. The itacitinib 300-mg bid dose cohort was discontinued early due to malignancy relapse occurring in 4/29 (14%) pts and more pts requiring dose reductions compared with the 400-mg qd and 300-mg qd cohorts (28% vs 17% and 8%, respectively), mostly due to cytopenias. Incidence of grade ≥3 treatment-emergent adverse events (AEs) was higher in the itacitinib cohorts than with CS (65% vs 31%) and were reported most commonly in the system organ classes of infections (44% vs 6%) and blood and lymphatic system disorders (23%-34% vs 6%). Cytomegalovirus (CMV) infections occurred in 10%-15% of pts in itacitinib cohorts (including CMV pneumonia [n=3], esophagitis [n=1], enteritis [n=1]) vs 3% with CS. The all-cause mortality rate was 14%-18% in itacitinib cohorts vs 11% with CS, with infections the leading cause. The overall response rate (ORR) at 6 months was 46% (complete response [CR], 14%) with 300-mg qd and 53% (CR, 32%) with 400-mg qd, vs 36% (CR, 18%) with CS. A preliminary exposure-response analysis showed a bell-shaped curve with maximum efficacy decreasing at higher exposures, consistent with increasing incidence of AEs. 60%-70% of patients received coadministration with a sCYP3A4i at any time point during study treatment, which increased itacitinib exposure across all doses, requiring dose reduction by 200 mg qd. Conclusion: Preliminary results for first-line treatment of moderate or severe chronic GVHD showed an increase in ORR and CR rate with itacitinib + CS vs CS alone in both the 300-mg qd and 400-mg qd cohorts, at the expense of increased rates of cytopenias, infections, and mortality. This benefit:risk ratio does not support moving the combination of itacitinib + CS to a later phase of development in first-line therapy of chronic GVHD. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

S286: LONG-TERM EFFICACY AND SAFETY RESULTS FROM AN ONGOING OPEN-LABEL PHASE 2 STUDY OF PARSACLISIB FOR THE TREATMENT OF AUTOIMMUNE HEMOLYTIC ANEMIA (AIHA)

Background: AIHA is a rare condition caused by autoantibody-mediated hemolysis of red blood cells. Few therapies beyond steroids and rituximab are available. Aims: To report updated results from an ongoing multicenter, phase 2, open-label study of the phosphoinositide 3-kinase-δ inhibitor parsaclisib in patients (pts) with AIHA (NCT03538041). Methods: Pts ≥18 years old with warm AIHA (wAIHA), cold agglutinin disease (CAD), or mixed-type AIHA; hemoglobin (Hgb) 7–10 g/dL; and failure of ≥1 standard therapy were eligible. After informed consent, pts were treated with oral parsaclisib for 12 wk at a starting dose of 1.0 mg once daily (QD; cohort 1) or 2.5 mg QD (cohort 2). Increases to 2.5 mg QD were allowed in cohort 1 after 6 wk if no clinical response was achieved and/or transfusion was required; reductions to 1.0 mg QD were permitted in cohort 2 for tolerability issues. Concomitant corticosteroids (≤20 mg/d prednisone) were allowed. After 12 wk of treatment, pts responding on parsaclisib could continue into an extension period. Primary endpoints were efficacy (proportion of pts with complete response [CR; Hgb ≥12 g/dL] or partial response [PR; Hgb 10–12 g/dL or ≥2 g/dL increase from baseline, inclusive of CRs] at any visit from Wk 6–12) and safety (treatment-emergent adverse events [TEAEs]). Results: As of Aug 5, 2021, 25 pts enrolled and received parsaclisib (cohort 1, n=10 [8 with dose increase]; cohort 2, n=15); 20 pts (80%) completed 12 wk of treatment. Sixteen (64%), 6 (24%), and 3 (12%) pts had wAIHA, CAD, and mixed AIHA, respectively. Mean (SD) age was 61.6 (17.0) years; 14 pts (56%) were female and 23 (92%) were White. Mean (SD) Hgb at baseline was 8.9 (0.8) g/dL, and 9 pts (36%) had transfusions in the past year. Mean parsaclisib exposure was 334 (range, 7–819) days. Overall, 8 pts (32%) achieved CR and 16 (64%) had PR at any visit from Wk 6–12. Among pts with wAIHA (n=16), 14 pts (88%) completed 12 wk of treatment; 8 (50%) and 12 (75%) achieved CR and PR, respectively, at any visit from Wk 6–12. Seventeen pts entered the extension period (12 with wAIHA). Increase in Hgb was sustained in the total cohort and among pts with wAIHA during the initial 12-wk treatment and extension periods (Figure). During the 12-wk treatment period, TEAEs occurred in 21 pts (84%) overall. Six pts (24%) had grade (Gr) ≥3 TEAEs, with only neutropenia occurring in >1 pt (n=2 [8%]); 2 pts (8%) had serious AEs (SAEs). Seven pts (28%) had treatment-related AEs, with only pruritic rash reported in >1 pt (n=2 [8%]). Three pts discontinued during the 12-wk treatment period (AE [n=1; thrombocytopenia], lack of efficacy [n=1], withdrawal by subject [n=1]), and 2 pts were of unknown status. During the extension period, 15/17 pts (88%) experienced ≥1 TEAE. Gr ≥3 AEs and SAEs were each reported in 9 pts (53%). Six pts (35%) had treatment-related AEs, with diarrhea and rash reported in >1 pt (n=2 [12%] each). One Gr 3 TEAE (psoriasis) and 3 SAEs (diarrhea [Gr 2], cytomegalovirus reactivation [Gr 2], psoriasis [Gr 3]) were deemed treatment related. Two (12%) pts had TEAEs leading to parsaclisib discontinuation. One fatal TEAE (acute respiratory failure in the extension period) was deemed unrelated to parsaclisib. Image:Summary/Conclusion: Parsaclisib was generally well tolerated and resulted in Hgb improvements as early as Wk 2 that increased over 12 wk of treatment and were sustained through the extension period. Parsaclisib may be an effective oral treatment for AIHA, and a randomized, controlled phase 3 trial in wAIHA is now recruiting (NCT05073458).

A phase I/II study of first-in-human trial of JAB-21822 (KRAS G12C inhibitor) in advanced solid tumors.

3089 Background: KRAS G12C mutation occurs in approximately 4% of non-small cell lung cancer (NSCLC), 1-2% of colorectal cancer (CRC) and other solid tumors in China. JAB-21822 (Jacobio, Beijing, PRC) is a highly selective, covalent oral inhibitor of KRAS G12C. Methods: NCT05009329 is an ongoing first-in-human, open label phase I/II study of JAB-21822 in patients with advanced solid tumors. The primary objective is to evaluate the safety and tolerability of JAB-21822. Other objectives include preliminary efficacy, pharmacokinetics, and biomarkers. Here we report the results from the dose escalation phase of the trial. Results: As of January 28th, 2022, 53 patients with a median age of 62 years (39-79) were enrolled in 5 different dose levels: 200mg QD, 400mg QD, 800mg QD, 400mg BID and 400mg TID. Most patients (55%) had ≥ 2 prior lines of therapy. No dosing-limiting toxicities were observed. Two treatment-related adverse events (TRAEs) were G4 neutropenia (1 in 400mg BID and 1 in 400mg TID). The most common TRAEs (≥ 10%) included anemia (24.5%), total bilirubin increase (20.8%), direct bilirubin increase (15.1%), proteinuria (13.2%) and indirect bilirubin increase (11.3%). Only Grade 1 and 2 TRAEs were observed in the QD cohorts. A total of 33 patients (22 NSCLC, 9 CRC and 2 pancreatic cancer) had at least 1 post-baseline tumor assessment; in the 800mg QD cohort, overall response rate (ORR) and disease control rate (DCR) were 50% (5/10) and 100% (10/10), respectively, including 4 non-confirmed partial response (PR); in the 400mg QD cohort had an ORR and DCR of 80% (4/5) and 100% (5/5) respectively, including 2 non-confirmed PR. Patients with NSCLC (400mg QD and 800mg QD), the ORR and DCR were 70% (7/10) and 100% (10/10), respectively, including 5 non-confirmed PR. With respect to the pharmacokinetics analysis, JAB-21822 was rapidly absorbed with an average Tmax of 2 hr and reached higher plasma exposures (Cmax and AUC0-24h) after a single dose and multiple doses at C1D8. Conclusions: JAB-21822 was well tolerated with impressive preliminary efficacy in patients with heavily treated solid tumors harboring KRAS G12C mutation. The study is enrolling patients in the expansion phase. Multiple JAB-21822-based combination trials are also ongoing. Clinical trial information: NCT05009329.

Abstract PD15-01: Impact of ESR1 mutations on endocrine therapy (ET) plus alpelisib benefit in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), PIK3CA-mutated, advanced breast cancer (ABC) who progressed on or after prior cyclin-dependent kinase inhibitor (CDK4/6i) therapy in the BYLieve trial

Abstract PD15-01: Impact of <i>ESR1</i> mutations on endocrine therapy (ET) plus alpelisib benefit in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), <i>PIK3CA</i>-mutated, advanced breast cancer (ABC) who progressed on or after prior cyclin-dependent kinase inhibitor (CDK4/6i) therapy in the BYLieve trial

Abstract P5-13-03: Alpelisib + endocrine therapy (ET) in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), PIK3CA-mutated advanced breast cancer (ABC) previously treated with cyclin-dependent kinase 4/6 inhibitor (CDK4/6i): Biomarker analyses from the Phase II BYLieve study

Abstract Introduction: Alpelisib (ALP, a PI3Kα inhibitor and degrader) + ET has demonstrated efficacy in patients (pts) with HR+, HER2-, PIK3CA-mutated ABC progressing on/after CDK4/6i + ET in the ongoing Phase II BYLieve study (NCT03056755). The primary endpoint, in pts with centrally confirmed PIK3CA mutation in tumor tissue (modified full analysis set [mFAS]), was met in Cohorts A (ALP + fulvestrant [FUL]) and B (ALP + letrozole [LET]) with 50.4% (95% CI, 41.2%-59.6%) of 121 pts and 46.1% (36.8%-55.6%) of 115 pts alive and without disease progression at 6 mo, respectively. Activating PIK3CA mutations, occurring in ~40% of tumors, confer worse prognosis in the advanced setting. Here, we assess the correlation between progression-free survival (PFS) and other baseline biomarkers among pts in BYLieve Cohorts A and B. Methods: Enrolled pre-/postmenopausal women with HR+, HER2-, PIK3CA-mutated ABC received CDK4/6i + aromatase inhibitor (Cohort A) or FUL (Cohort B), as immediate prior treatment (Tx). Pts received ALP 300 mg PO QD + FUL 500 mg IM Q28D and C1D15 (Cohort A) or ALP 300 mg PO QD + LET 2.5 mg PO QD (Cohort B) as study Tx. This exploratory analysis of baseline biomarkers identified gene alterations using an error-connected sequencing ctDNA assay (Novartis PanCancer gene-panel) in plasma samples from pts with a centrally confirmed PIK3CA mutation in tumor tissue from Cohorts A and B. PFS was estimated using the Kaplan-Meier method in subgroups of pts based on high (≥10%) or low (&amp;lt;10%) ctDNA fraction, high (≥10) or low (&amp;lt;10) tumor mutation burden (TMB), and amplification (amp) status of chromosomes (chr) 8 or 11 amplicons (frequently observed in breast cancer and usually associated with early relapse). Results: In Cohorts A and B, 102 of 127 enrolled pts and 97 of the 126 enrolled pts were included in this analysis, respectively. In this analysis, median PFS (mPFS) was 7.3 mo in Cohort A and 5.7 mo in Cohort B, consistent with observations in the mFAS (Table 1). Pts with a low ctDNA fraction or TMB at baseline had longer mPFS than pts with high ctDNA fraction or TMB (Table 1). In addition to PIK3CA alterations observed in 73% of tumors from pts in Cohorts A and B, the most frequently altered genes in the studied population were ESR1 (27% and 28%) and TP53 (25% and 26%) in Cohorts A and B, respectively. Across both cohorts, pts whose tumors had loss of function alterations in genes known to mediate resistance to CDK4/6i (PTEN, RB1, CHD4, FAT1, NF1, ATM, CDKN2A-C) derived clinical benefit (partial response or stable disease) from ALP + ET. Amp of known amplicons on chr 8 (eg, FGFR1, TACC1) or 11 (eg, CCND1, FGF3, FGF4) were observed in 5%-8% of pts in Cohort A and 8%-11% of pts in Cohort B. Pts whose tumors had no gene amp on chr 8 and/or 11 had longer mPFS than pts whose tumors had an amp (Table 1). Similar results were observed when analyzing chr 8 (6.33 mo vs 4.92 mo) and chr 11 (6.33 mo vs 4.63 mo) separately in pts from Cohorts A plus B. Conclusion: In pts with HR+, HER2-, PIK3CA-mutated ABC, ALP was effective in the post-CDK4/6i setting regardless of ET partner and tumor genomic profile (including in presence of alterations in genes associated with CDK4/6i resistance). The absence of cross-resistance may allow pts with PIK3CA-mutated disease to benefit from ALP after disease progression on/after CDK4/6i. Table 1.mPFS in pts from BYLieve Cohorts A and B based on baseline biomarker statusCohort A (ALP + FUL)Cohort B (ALP + LET)nmPFS, mo (95% CI) nmPFS, mo (95% CI)Overall (mFASa)1,21217.3 (5.6-8.3)1155.7 (4.5-7.2)Patients with available plasma sample for the biomarker analysisb1027.37 (5.60-8.67)975.70 (3.77-7.33)ctDNA fractionHigh (≥10%)655.60 (4.00-7.37)685.43 (3.70-7.20)Low (&amp;lt;10%)37NE297.33 (5.83-11.00)TMBHigh (≥10)103.85 (0.47-8.33)154.60 (1.67-5.73)Low (&amp;lt;10)716.13 (5.43-9.60)645.63 (3.73-7.50)Chr 8 or 11 amplificationWith174.23 (1.70-6.13)213.77 (1.93-7.37)Without858.40 (5.70-9.60)766.00 (5.20-7.53)Chr, chromosome; ctDNA, circulating tumor DNA; NE, not estimable; mPFS, median progression-free survival; TMB, tumor mutation burden. aPatients who received at least 1 dose of study treatment and had centrally confirmed PIK3CA mutation by a Novartis-designated laboratory were included in the mFAS. bOnly includes patients with centrally confirmed PIK3CA mutation in tumor tissue. 1. Rugo HS, et al. Lancet Oncol. 2021;22(4):489-498; 2. Rugo HS, et al. SABCS 2020. Poster PD2-07. Citation Format: Dejan Juric, Nicholas Turner, Aleix Prat, Stephen Chia, Eva M Ciruelos, Manuel Ruiz-Borrego, Pamela Drullinsky, Florence Lerebours, Thomas Bachelot, O. Alejandro Balbin, Mukta Joshi, Estelle Roux, Christina H Arce, Murat Akdere, Hope S Rugo. Alpelisib + endocrine therapy (ET) in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), PIK3CA-mutated advanced breast cancer (ABC) previously treated with cyclin-dependent kinase 4/6 inhibitor (CDK4/6i): Biomarker analyses from the Phase II BYLieve study [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-13-03.

Abstract P05-02: A phase 1b study evaluating the combination of sotorasib, a KRASG12C inhibitor, and afatinib, a pan-ErbB tyrosine kinase inhibitor, in advanced KRAS p.G12C mutated non-small cell lung cancer (NSCLC)

Abstract Background: Sotorasib, a specific, irreversible KRASG12C inhibitor, was recently FDA-approved for adults with KRAS p.G12C-mutated locally advanced or metastatic NSCLC who received prior systemic therapy. The multi-arm phase 1b CodeBreaK101 master study is designed to evaluate the safety and tolerability of sotorasib in combination with both targeted and non-targeted therapies. Here we report the first safety and interim efficacy of sotorasib and afatinib, a pan-ErbB tyrosine kinase inhibitor, that had displayed synergistic antitumor activity in vitro. Methods: Patients with advanced KRAS p.G12C mutated NSCLC who had disease progression on prior therapies, including KRASG12C inhibitors, were enrolled in this dose exploration/expansion study. Patients were treated with 960 mg sotorasib QD and afatinib (20 mg or 30mg QD). Primary endpoint was safety/tolerability. Secondary endpoint was efficacy, including objective response rate (ORR) and disease control rate (DCR) per RECIST 1.1. Results: Based on a July 12, 2021 snapshot, 33 pts with NSCLC (median age: 65.0 yrs) were enrolled. Ten pts received 20 mg afatinib/960 mg sotorasib QD (cohort 1) and 23 pts received 30 mg afatinib/960 mg sotorasib QD (cohort 2). Across both cohorts, the median number of prior therapies was 2 (range 0-7; 66.7% ≥ 2 prior lines) and 5 pts (15.2%) received prior sotorasib. The most common treatment-related adverse events (TRAEs) included diarrhea (23 pts [69.7%], 7 pts [21.2%] grade 3), nausea (7 pts [21.2%], all grade ≤ 2), and vomiting (6 pts [18.2%], all grade ≤ 2). Grade ≥ 3 TRAEs occurred in 30% pts within each dose cohort, with diarrhea being the most common. Eight pts (24.2%) discontinued sotorasib and/or afatinib due to an AE, with diarrhea leading to discontinuation in 5 pts. Median treatment duration of sotorasib/afatinib combination was 64.0 days (Q1, 29.0; Q3, 128.0). For cohort 1 (N=10 that includes 4 pts who received prior sotorasib), the ORR was 20.0% and DCR was 70.0% (2-confirmed partial response (PR), 5-stable disease (SD), 1-progressive disease (PD), 2-not available); among the KRASG12C inhibitor-naïve patients, the ORR was 33.3%. For cohort 2 (N=23 that includes 1 pt who received prior sotorasib), the ORR was 34.8% and DCR was 73.9% (8-confirmed PR, 9-SD, 4-PD, 2-not available). Among 5 pts receiving prior sotorasib, 3 had SD, 1 PD, and 1 withdrew from study due to an AE prior to any scan. EGFR co-mutation at baseline was detected in 4 of 24 pts; 2 of 4 pts responded to combination therapy. Conclusions: In this first report of a combination of sotorasib and a pan-ErbB inhibitor, combining sotorasib with afatinib was feasible in a heavily pre-treated KRAS p.G12C mutated NSCLC population that included 15% who progressed on prior sotorasib. The AEs observed are not new or novel to either agent, with diarrhea being the most common. Investigation is ongoing to further explore this combination in an expansion cohort of the CodeBreaK101 master protocol. Citation Format: David Gandara, Kristen Marrone, Ramaswamy Govindan, Ferdinandos Skoulidis, Gregory Durm, Jeffrey Clarke, Richard Frank, John Krauss, Wendy Snyder, Tian Dai, Omar Mather, Paul Cifuentes, Antreas Hindoyan, Abraham Anderson, Timothy Burns. A phase 1b study evaluating the combination of sotorasib, a KRASG12C inhibitor, and afatinib, a pan-ErbB tyrosine kinase inhibitor, in advanced KRAS p.G12C mutated non-small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P05-02.

A Phase 1 Dose Escalation Study of Dual PI3K and DNA PK Inhibitor, BR101801 in Adult Patients with Advanced Hematologic Malignancies

Background: BR101801 not only blocks the signaling responsible for cell growth caused by PI3K, but also efficiently induces cell cycle arrest and apoptosis through inhibition of DNA-PK activation and stimulates decreasing stability of the oncogenic protein, c-Myc(AACR2020 abstract #655). This phase I study evaluated safety, tolerability, pharmacokinetics and preliminary activity of the BR101801 (PI3Kγ/δ and DNA PK inhibitor) in patients with advanced hematologic malignancies.Method: This is a Phase I, multi-center, open-label, first-in-human study. The Phase Ia (dose escalation) part of the study was designed to determine the maximum tolerated dose (MTD)/recommended dose for expansion (RDE) of BR101801. BR101801 was administered orally once daily in 28-day cycles. The dose escalation part was initiated with a dose titration in the initial cohort, followed by a 3 + 3 design.Results: 11 patients were enrolled and have been treated at 4 dose levels: 50mg, 100mg, 200mg, 325mg and expanded 200mg through fifth cohort escalation. Pathological subtypes include 7 PTCL, 2 DLBCL, 1 MZBL and 1 composite CTCL/MF. 3 females and 8 males have been treated to date. Median age is 58 (range 30-71) and ECOG PS is in the range of 0-1. All patients had taken at least one prior chemotherapy. 10 of total patients have completed at least one cycle except 1 premature drop-out case due to disease progression. First interim analysis after completion of cycle 3 of the last patient of 200mg QD cohort had been conducted, which was to include 5 patients (1 DLBCL and 4 PTCLs). No DLT had been identified in Cohorts 1-3, and 2 patients discontinued the study treatment due to adverse event (G4 thrombocytopenia, not related to IP) and disease progression, respectively. The PK values from multiple dosing range of 50mg to 200mg cohort resulted in an approximate 2.92-fold and 4.97 fold increase in exposure based on Cmax and AUCtau, respectively. BR101801 PK profile showed that the exposure of concentration increased in a dose dependent manner and there was no accumulation observed in the dose range of 50mg to 200mg. 2 DLTs was observed at 325mg QD cohort. The dose was de-escalated to the previous lower dose level (200mg QD) and was expanded to 3 additional patients. The expansion cohort is ongoing at present. 2 of 11 patients had G3 skin reaction and 3 had G3 hepatotoxicites. All adverse effects were manageable and recovered to grade 0-1 upon BR1010801 discontinuation. Total 5 patients have been currently ongoing. For overall tumor response assessment, 4 SDs and 2 PRs have been obsereved.Summary/Conclusion: 200 mg QD of BR101801 was shown to provide target exposure for clinical efficacy with the tolerable and safe profiles. BR101801 was well tolerated and showed preliminary signs of activity in patients with relapsed or refractory hematologic malignancies. The phase Ib/II study of BR101801 is warranted in relapsed/refractory NHL. This study is registered at clinicaltrials.gov identifier NCT04018248. DisclosuresKim: AstraZeneca-KHIDI: Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; GI CELL: Consultancy, Membership on an entity's Board of Directors or advisory committees; Hanmi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Boryung: Consultancy, Membership on an entity's Board of Directors or advisory committees; BeyondBIO: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca/MedImmune: Consultancy, Membership on an entity's Board of Directors or advisory committees. Curran: Servier pharmaceuticals and Amgen: Consultancy. Kim: Boryung pharmaceuticals: Current Employment.

Trial in Progress: Asciminib in Monotherapy 4 CML (AIM4CML), a Phase IIIb Study of Asciminib Monotherapy in Patients with Chronic Myeloid Leukemia in Chronic Phase without or with T315I Mutations

Trial in Progress: Asciminib in Monotherapy 4 CML (AIM4CML), a Phase IIIb Study of Asciminib Monotherapy in Patients with Chronic Myeloid Leukemia in Chronic Phase without or with T315I Mutations

An Open-Label, Phase II Study Of The JAK1 Inhibitor INCB039110 In Patients With Myelofibrosis

An Open-Label, Phase II Study Of The JAK1 Inhibitor INCB039110 In Patients With Myelofibrosis