Dose Expansion Cohort Research Articles

Phase 1 trial safety and efficacy of ragistomig, a bispecific antibody targeting PD-L1 and 4-1BB, in advanced solid tumors.

2529 Background: Activation of T cells in the tumor microenvironment by 4-1BB agonist antibodies is a promising approach to augment PD-(L)1 inhibitor efficacy. Ragistomig(ABL503/TJ-L14B) is a bispecific antibody combining PD-L1 antagonist with 4-1BB agonistic activity, designed to induce 4-1BB signaling only when bound to the PD-L1 tumor antigen on cancer cells, which may overcome resistance to PD-(L)1 inhibition and avoid hepatoxicity seen with traditional 4-1BB mAbs. Methods: ABL503 was investigated at doses ranging from 0.7 mg (flat dose) to 10 mg/kg (weight-based dose) IV every 2 weeks (Q2W) in patients with advanced or relapsed/refractory solid tumors, to assess safety, preliminary anti-tumor effect and pharmacokinetic (PK)/pharmacodynamic (Pd) activity. The BOIN design was utilized during dose escalation (regardless of CPS/TPS score). Additional patients were enrolled in dose expansion cohorts at 3 and 5 mg/kg (CPS/TPS>=1 required). Results: As of Jan 2024, the study enrolled 49 patients (30 dose escalation, 19 dose expansion). At least 1 treatment related adverse event (TRAE) occurred in 37 patients (75.5%); most common TRAE (≥ 10%, any grade/grade 3-4) were elevated AST (30.6%/18.4%), elevated ALT (26.5%/18.4%), rash (14.3%/4.1%), nausea (12.2%/0%), pyrexia (12.2%/2.0%) and fatigue (10.2%/0%). Dose limiting toxicities occurred in 5 patients and were observed at dose levels of 1, 5, and 10 mg/kg. All DLTs were recovered/recovering. MTD was not reached. Based on the safety, efficacy, PK and Pd analysis, the optimal dose was determined to be 5 mg/kg Q2W. Objective responses were observed in 6 out of 39 efficacy-evaluable patients, and all responses were observed at 3 and 5 mg/kg, including 1 complete response (CR) in a patient with ovarian cancer who received 6 prior lines of treatment and 5 partial responses (PRs) in patients with ovarian (n=1), melanoma (n=1), gastric (n=1), head and neck squamous cell (n=1), and esophageal cancer (n=1). Overall response rate (ORR) for all dose levels was 15.3%, and ORR at 5 mg/kg was 30% (3/10). Clinical benefit rate (CBR) for all dose levels was 61.5%, and CBR at 5 mg/kg was 80% (8/10). 66.7% of responders received prior PD-(L)1 inhibitors. One patient achieved sustained tumor regression over 6 months, even after treatment discontinuation. PK was dose proportional, and half-life was ~5 days. Dose-dependent increase of Pd marker s4-1BB was observed, demonstrating target engagement. Conclusions: ABL503 had a manageable safety profile and demonstrated promising anti-tumor activity, with objective responses in 6 out of 39 efficacy-evaluable patients across multiple tumor types in heavily pre-treated patients, including patients previously treated with checkpoint inhibitors. The data support continued development of ABL503 alone and in combination with other compounds, as a potential therapeutic option for patients with solid tumor cancers. Clinical trial information: NCT04762641 .

Updated study results of novel FAK/ALK/ROS1 inhibitor APG-2449 in patients (pts) with non-small-cell lung cancer (NSCLC) resistant to second-generation ALK inhibitors.

3124 Background: ALK inhibitors increase FAK pathway gene expression in ALK+ NSCLC cell lines, with the highest induced expression in drug-tolerant persister cells. This suggests that FAK pathway activation is involved in ALK inhibitor-induced early adaptive tolerance in ALK+ NSCLC. Investigational APG-2449 is a novel, orally active FAK inhibitor and a third-generation (3G) ALK/ROS1 tyrosine kinase inhibitor (TKI) with potent activity in preclinical models. APG-2449 is well tolerated at the recommended phase 2 dose (RP2D) and showed preliminary efficacy in pts resistant to 2G ALK TKIs. Here, we provide further safety and efficacy results and demonstrate associations between this therapy and FAK signaling pathways. Methods: After the RP2D was determined as 1,200 mg daily (QD), pts with NSCLC were enrolled into 2 dose expansion cohorts. Cohort 1 included pts who were resistant to 2G ALK TKIs. Cohort 2 included those who were ALK or ROS1 TKI naïve. Results: As of December 9, 2023, 144 pts (median [range] age, 53 [21-78] years; 53.5% female) with NSCLC, mesothelioma, or ovarian cancer were treated with APG-2449 at doses of 150 to 1,500 mg. A total of 129 (89.6%) pts had treatment-related adverse events (TRAEs), the most frequent of which were elevated serum creatinine (49.3%), ALT (42.4%), and AST (36.1%); nausea (28.5%); vomiting (23.6%); diarrhea (22.9%); and decreased leukocyte count (22.2%). In all, 20 (13.9%) TRAEs were grade ≥ 3. Of pts with TKI-naïve NSCLC (n = 36) treated at the RP2D, the overall response (ORR) and disease control rates (DCR = CR + PR + SD) were 68.2% (15/22) and 90.1% (20/22) in ROS1 TKI-naïve pts; and 78.6% (11/14) and 100% (14/14) in ALK TKI-naïve pts. Median progression-free survival (mPFS) in ALK TKI-naïve pts was not reached. Of 22 pts with NSCLC resistant to 2G ALK inhibitors and without targetable bypass gene mutations (e.g., KRAS G12C, BRAF V600E), 9 had PRs (9/22; 40.9%) and the mPFS during APG-2449 treatment at RP2D was 11.86 months. Nine of 12 pts in the RP2D group achieved intracranial PR, resulting in an intracranial ORR of 75.0%. Before APG-2449 administration, 17 tumor tissue samples were collected from pts with NSCLC resistant to 2G ALK inhibitors (in the RP2D group), and IHC was used to assess protein levels of phosphorylated FAK (pFAK). The PFS of pts treated with APG-2449 correlated with pFAK levels in baseline tumor tissue, and pts with higher pFAK levels were more likely to benefit from APG-2449 treatment. Conclusions: APG-2449 demonstrated preliminary efficacy in pts with NSCLC whose disease was TKI naïve and resistant to 2G ALK inhibitors, especially in brain metastases. High pFAK expression levels in baseline tumor tissue correlated with improved APG-2449 treatment responses in pts with NSCLC resistant to 2G ALK inhibitors. Internal study identifier: APG2449XC101. Clinical trial information: NCT03917043 .

Pharmacokinetics and safety of asciminib (ASC) in pediatric patients (pts) with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia in chronic phase (CML-CP): Interim results from the ASC4KIDS study.

6562 Background: For pediatric pts with Ph+ CML-CP, treatment options with improved efficacy and long-term safety are needed. ASC is a first-in-class tyrosine kinase inhibitor (TKI) Specifically Targeting the ABL Myristoyl Pocket (STAMP), approved for adults with Ph+ CML-CP treated with ≥2 prior TKIs. The phase Ib/II ASC4KIDS study (NCT04925479) aims to characterize the pharmacokinetics (PK) and long-term safety profile of ASC in pediatric pts. Methods: This multi-center, open-label study included pts aged 1–<18 years (yrs) with Ph+ CML-CP, without T315I mutation, treated with ≥1 prior TKIs. The primary endpoint is to characterize the PK of ASC in pediatric pts and identify a dose using the pediatric formulation (PF, taken with food) leading to an ASC exposure comparable to the adult dose and formulation (AF, 40 mg tablet twice daily [BID] fasted). Secondary endpoints include safety, molecular responses and acceptability/palatability of the pediatric formulation. In an exploratory group, pts 14‒<18 yrs old were treated with the AF (fasted). In study Part 1 (dose-determining cohort), pts received PF at an initial dose of 1.3 mg/kg BID (with food) to assess ASC exposure (measured by area under the curve from dosing to the time of the last measured concentration [AUClast] and maximum plasma concentration [Cmax]) and safety. In Part 2 (dose expansion cohort), additional pts will be treated with the dose confirmed in Part 1 (across Part 1 + Part 2; 10 pts per age group: 1‒<12 yrs and 12‒<18 yrs, for a total of 20 pts). In Part 3, another 10 pts will be enrolled (5 pts per age group), who will receive the same total ASC dose as a once daily regimen. Results: 4 and 9 pts were enrolled in the Part 1 AF and PF groups, respectively. At interim data cutoff (03-Aug-2023), all pts were receiving ongoing treatment. Age ranges were 15‒16 yrs (AF group) and 2‒16 yrs (PF group). Averaged ASC exposure in the AF group was comparable to that observed in adults. 3/4 (75.0%) pts on ASC AF experienced adverse events (AEs); none were Grade ≥3. There were no new safety signals as compared to the known safety profile of ASC in adults. Averaged ASC exposure in the PF group was comparable to that observed in adults (median AUClast: 5051 vs 5130 hr*ng/mL; median Cmax: 711 vs 939 ng/mL, respectively). Based on these data, the PF dose of 1.3 mg/kg BID (with food) was confirmed as the pediatric dose. All pts on ASC PF experienced AEs; Grade ≥3 AEs were reported for 2/9 pts (22.2%). No predefined dose-limiting toxicities, serious AEs, or AEs leading to discontinuation were reported in either group. Conclusions: ASC exposure with the PF (with food) in pediatric pts was comparable to that of adult pts treated with ASC 40 mg BID (fasted); the confirmed PF dose of 1.3 mg/kg BID will continue to be tested in Part 2 of the study. ASC was safe and well tolerated in pediatric pts. Clinical trial information: NCT04925479 .

A phase 1, first-in-human study of CUSP06, a cadherin-6 (CDH6) -directed antibody-drug conjugate, in patients with platinum-refractory/resistant ovarian cancer and other advanced solid tumors.

TPS3166 Background: Cadherin-6 (CDH6) is a transmembrane glycoprotein involved in cancer metastasis and invasion expressed in various tumor types including ovarian cancer (OC), renal cell carcinoma (RCC), papillary thyroid cancer, cholangiocarcinoma, hepatocellular cancer, glioma, uterine serous carcinoma and non-small cell lung cancer. CUSP06 is an antibody-drug conjugate composed of a human IgG1 monoclonal antibody against CDH6 conjugated with a protease-cleavable linker, T1000, to exatecan, a topoisomerase I inhibitor payload. In preclinical studies, CUSP06 showed CDH6-dependent cell growth inhibition in ovarian cancer cell lines. High CDH6-expressing ovarian and renal CDX and PDX models demonstrated tumor regression after treatment with CUSP06, as did low CDH6-expressing PDX models of other solid tumors. Methods: This is a Phase 1a/1b, open-label, multicenter dose escalation and expansion study to evaluate safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), recommended Phase 2 dose (RP2D), and preliminary efficacy of CUSP06 in patients with platinum-refractory/resistant ovarian cancer (PRROC), advanced RCC and other advanced CDH6-positive solid tumors. Patients with advanced solid tumors previously treated with standard of care systemic therapy, or for whom no standard therapy is available are eligible for enrollment. Prescreening for CDH6 expression will be required for those patients with solid tumors other than PRROC or RCC. CUSP06 will be administered intravenously every 21 days. Phase 1a will follow a standard 3+3 dose escalation design. Phase 1a also includes up to 3 dose enrichment cohorts at doses that have demonstrated safety, each with a maximum of 18 patients, to generate additional safety, PK, PD, and preliminary efficacy data to support an optimized dose for expansion. Phase 1b consists of several dose expansion cohorts including PRROC, RCC, and other CDH6-positive solid tumors, to be enrolled according to Simon's 2-stage design. Mandatory pre- and on-study biopsies in dose expansion cohorts will support a robust exploratory biomarker plan that may include correlation of CDH6 levels with response, and other RNA and protein markers of sensitivity and resistance. The study is currently enrolling in Phase 1a dose-escalation. Clinical trial information: NCT06234423 .

Phase Ia/Ib trial on the safety and efficacy of mobocertinib in combination with T-DM1 for patients with HER2-mutant solid tumors (WJOG16022M).

3025 Background: Safety and efficacy of HER2 tyrosine kinase inhibitor (TKI) and anti-HER2 antibody-drug conjugate (ADC) in HER2-mutant solid tumors have not been investigated. Methods: Mobocertinib, a potent HER2 TKI plus T-DM1, an anti-HER2 ADC was evaluated in this phase I study. In a dose-finding cohort (phase Ia, pIa), the maximum tolerated dose was estimated in patients (pts) irrespective of HER2 mutational status. To further establish safety and evaluate preliminary efficacy, additional pts with HER2 mutations were enrolled in a dose-expansion cohort (phase Ib, pIb). Mobocertinib of 80, 120 to 160 mg was orally administered with intravenous T-DM1 3.6 mg/kg every 3 weeks. The primary endpoint was to determine the recommended dose (RD) (pIa), and to evaluate the confirmed objective response rate (ORR) (pIb). Results: Between Nov 2022 and Jun 2023, a total of 28 pts, 6 in the pIa and 22 in the pIb were enrolled to this study (14 NSCLC; 4 cervical; 2 duodenal papilla; 2 pancreatic, median follow-up, 6.4 mo [range, 1.9 to 12.9 mo]). The median age was 54 (range, 40-84) years, 17 pts were female. Among 27 pts with HER2-mutant tumors, mutations in kinase domain were most common (66.7%). In the pIa cohort, 3 DLTs were observed with mobocertinib 120 mg, including grade 3 thrombocytopenia, grade 4 acute kidney injury, and drug withdrawal due to nausea and anorexia, while there was no DLT with 80 mg. The RD was therefore determined to be mobocertinib 80 mg plus T-DM1 3.6 mg/kg. Among 22 pts in the pIb, grade ≥ 3 AE occurred in 72.7% of pts; the common events (>5%) being thrombocytopenia (50.0%), diarrhea (13.6%), and anorexia (13.6%). No interstitial lung disease/pneumonitis was observed. The ORR was 28.6%, the disease control rate (DCR) was 71.4%, and median progression-free survival (mPFS) was 3.2 mo (95% CI 1.6, 6.1) in the pIb. In 27 pts with HER2 mutations across all cohorts, the ORR was 42.3%, the DCR was 76.9%, and mPFS was 4.3 mo (95% CI 2.7, 6.7). Additionally, in 13 pts with HER2-mutant NSCLC including those who had developed resistance to trastuzumab deruxtecan, the ORR was 53.8%, the DCR was 84.6%, and mPFS was 6.1 mo (95% CI 2.9, 6.3). Conclusions: The RD of this study treatment is mobocertinib 80 mg plus T-DM1 3.6 mg. Combination therapy of HER2 TKI and HER2 ADC demonstrated feasibility and potential efficacy for HER2-mutant solid tumors. Clinical trial information: 2051220070 .

Impact of renal impairment (RI) on pharmacokinetics (PK) and clinical outcomes with mezigdomide plus dexamethasone (DEX) in relapsed/refractory multiple myeloma (RRMM).

7539 Background: RI is a common complication in MM and may alter drug elimination, leading to increased systemic exposures, risk of adverse events (AEs), and dosing adjustments. The novel CELMoD agent mezigdomide (MEZI) is being investigated alone or with DEX in the CC-92480-MM-001 (NCT03374085) phase 1/2 trial. MEZI has shown dose-dependent linear PK with rapid absorption and is mainly eliminated through hepatic metabolism, with renal elimination playing a smaller role. Here we investigate the impact of RI on the efficacy, safety, and PK of MEZI + DEX in RRMM. Methods: Eligible patients (pts) had RRMM, ≥ 3 prior lines of therapy, triple-class refractoriness, and disease progression ≤ 60 days of last therapy. Pts were stratified by creatinine clearance (CrCl), excluding those with CrCl < 45 mL/min or needing dialysis. Oral MEZI (1 mg) was given on days 1–21 per 28-day cycle + weekly DEX. MEZI doses were not adjusted based on RI. Responses, AEs, and PK were assessed descriptively over the full population and in pts with no RI (CrCl ≥ 90 mL/min), mild RI (CrCl 60–< 90 mL/min), and moderate RI (CrCl 30–< 60 mL/min) at baseline. MEZI clearance and PK exposure were estimated from an integrated population PK model. PK exposure parameters were stratified by chronic kidney disease (CKD) staging. Results: 101 pts received MEZI + DEX in the dose-expansion cohort; 37 had no RI, 41 had mild RI, and 23 had moderate RI. Grade (Gr) 3/4 treatment-emergent AEs (TEAEs) were similar, occurring in 91.1% (overall), 89.2% (no RI), 90.2% (mild RI), and 95.7% (moderate RI) of pts. TEAEs were mostly hematologic, with neutropenia the most common Gr 3/4 TEAE; its occurrence did not differ in no RI (75.7%), mild RI (75.6%), and moderate RI (73.9%) cohorts. Non-hematologic Gr 3/4 TEAEs were low. Eighty-nine (88.1%) and 32 (31.7%) pts had MEZI dose interruptions and reductions, respectively. Overall response rate (ORR) was 40.6% in all pts, 56.8% in no-RI pts, 29.3% in mild-RI pts, and 34.8% in moderate-RI pts (Table). Evaluated as a continuous variable, CrCl showed no apparent relationship with MEZI oral clearance or systemic exposures. This was supported by subgroup evaluation of MEZI exposures by CKD stage. Results showed MEZI exposures in mild or moderate RI are consistent with no RI. Conclusions: Based on renal function, there was no adverse trend between efficacy, safety, and PK of MEZI + DEX. MEZI dose modifications are likely not required for pts with mild to moderate RI. Clinical trial information: NCT03374085 . [Table: see text]

Xevinapant with radiation and concurrent carboplatin and paclitaxel in patients ineligible for cisplatin with locoregionally advanced squamous cell carcinoma of the head and neck (EXtRaCT study).

TPS6126 Background: Locoregionally advanced (LA) head and neck cancer (HNC) patients undergoing chemoradiotherapy (CRT) who are ineligible for cisplatin have comparatively poor outcomes, with only ~40% alive at 5 years. There is an urgent unmet need to improve survival in these vulnerable patients with no standard therapeutic approach. Xevinapant, an oral inhibitor of XIAP and cIAP1/2, sensitizes cancer cells to apoptosis. Randomized phase II results in patients eligible for cisplatin combining xevinapant with CRT showed improved locoregional control, manageable toxicity, and promising survival outcomes. (Sun et al. Lancet Oncol. 2020) The current trial aims to extend these benefits to patients ineligible for cisplatin using xevinapant with carboplatin-paclitaxel-based CRT, hypothesizing safety and tolerability in this high-risk group. Methods: This phase I dose escalation/expansion study investigates xevinapant combined with carboplatin and paclitaxel to treat LA HNC in patients ineligible for cisplatin. Key eligibility includes previously untreated LA HNC and specific cisplatin ineligibility criteria, including >=70yo with moderate to severe comorbidity or vulnerability (Geriatric-8 score ≤ 14 and/or CARG score ≥ 30%) or <70yo with severe comorbidity and/or vulnerability, or >=18yo with an absolute contraindication to cisplatin. The treatment regimen comprises escalating doses of oral xevinapant (50-200 mg daily) on days 1-14 of a 21-day cycle for 3 cycles concurrent with CRT and 3 cycles adjuvant, weekly carboplatin AUC 1.5 IV, and paclitaxel 30 mg/m2 IV for 7 doses, and radiotherapy to 70 Gy in standard 2Gy fractions over 7 weeks with primary endpoint of tolerability and recommended phase 2 dose. A Bayesian-modified toxicity probability interval design will identify the maximum tolerated dose (MTD), targeting a 25% dose-limiting toxicity rate, with a sample size of 24 patients in dose-finding. 18 additional patients will be enrolled in the dose-expansion cohort at the MTD, totaling 42 patients. Secondary objectives include safety, response, progression-free, overall survival, and locoregional and distant control. Exploratory aims: in-clinic geriatric evaluations (Katz ADL, Lawton iADL, MMSE), QoL surveys, symptom tracking via smartphone, and wearable-derived steps and sarcopenia assessment. Recruitment began 02/2024. Clinical trial information: NCT06110195 .

Dendrimer-enhanced (DEP) SN38 (DEP irinotecan) in patients (pts) with advanced solid tumors: A phase 1/2 trial.

3014 Background: Dendrimer nanoparticles enable prolonged cytotoxic drug targeting to tumors. DEP SN38 is a water-soluble version of SN38, the active metabolite of irinotecan, attached to a dendrimer, so avoiding usual metabolic pathways of conventional irinotecan (c-IRI). This phase 1/2 (P1/2) trial evaluated safety, tolerability and efficacy of DEP SN38 in pts with advanced solid tumors, including colorectal (CRC), platinum-resistant high-grade serous ovarian (HGSOC) and breast (BC). Methods: Pts who had exhausted standard therapy were enrolled in dose assessment (P1)/dose expansion (P2) cohorts of DEP SN38 given IV 3-weekly (Q3W) or Q2W alone or in combination with 5-fluorouracil & leucovorin (5FU/LV combo). Efficacy was evaluated by RECIST 1.1 and serum tumor markers. (EudraCT 2019-001318-40). Results: 114 pts were enrolled. The Q3W Recommended Dose (RD) was 12.5 mg/m2 SN38 with dose limiting toxicity (DLT) in 1/7 pts (grade (G) 4 neutropenia > 7d). The Q2W RD was 12.5 mg/m2 for SN38 alone or with 5FU/LV. DEP SN38 was well-tolerated for all dose regimens with mostly mild/moderate (G1/2) treatment-related adverse events (TRAEs) & no new events compared with c-IRI. TRAEs in ≥ 10% pts included neutropenia, thrombocytopenia, anemia, fatigue, nausea, vomiting, diarrhea, constipation and alopecia. Of734 DEP SN38 cycles only 1 event of G3 diarrhea (0.9% pts) and no cholinergic symptoms have been observed, contrasting with c-IRI (~20% & 47% pts respectively). G3 nausea (1.8% pts) and vomiting (0.9% pts) occurred less frequently than with c-IRI (both ~10% pts). Febrile neutropenia was the DLT at 15 mg/m2 Q2W monotherapy (2/6 pts), with neutropenia otherwise essentially uneventful and managed with G-CSF. 38 CRC pts received DEP SN38 monotherapy (31 evaluable) and 17 received the 5FU/LV combo (14 evaluable). CRC pts had a mean 4 prior lines with 97% receiving ≥ 1 c-IRI containing line. The disease control rate (DCR) in monotherapy was 48% (stable disease (SD) up to 72 wks). The 5FU/LV combo cohort DCR was 85.7%, the objective response rate (ORR) was 14.3%, with disease control observed for at least 35 wks. Several CRC pts continue combo treatment. 23 HGSOC pts with a mean of 6 prior lines received DEP SN38 monotherapy (18 evaluable). The DCR for Q2W was 100% with 33.3% ORR, and 72% DCR for all HGSOC pts. 3 pts have PRs for at least 36 wks; with 1 pt achieving complete tumor & ascites resolution. Reduced CA-125 of up to 98% was observed in 75% pts. Several HGSOC pts continue DEP SN38 treatment. 8 BC pts with a mean of 7 prior lines received DEP SN38 monotherapy Q3W (5 evaluable). The DCR was 100% with SD up to 72 wks. Conclusions: DEP SN38 shows promising clinical utility with encouraging antitumor activity including prolonged disease control & durable PRs in heavily pre-treated CRC, HGSOC & BC pts. DEP SN38 is well-tolerated with significantly fewer severe gastrointestinal TRAEs compared to c-IRI, & warrants further clinical assessment. Clinical trial information: 2019-001318-40 .

CTEP 10492, a phase 1/1b study of the AKT inhibitor ipatasertib with chemoradiation for locally advanced head and neck squamous cell carcinoma.

TPS6127 Background: Locally advanced head and neck squamous cell carcinoma (HNSCC) is commonly treated with definitive chemoradiation therapy (CRT). However, locoregional recurrence rates of approximately 50% may occur in high risk patients. As such, there is an unmet need for up-front treatment intensification in this patient population. Preclinical evidence suggests that both radiation therapy (RT) and cisplatin activate the PI3K/AKT pathway, leading to treatment resistance through multiple processes, including increased DNA repair, decreased apoptosis, and modulation of the tumor microenvironment by promoting angiogenesis, immune escape and hypoxia. Furthermore, AKT inhibitors have been shown to sensitize a subset of HNSCC models to RT and platinum chemotherapy in vitro and in vivo. However, radiosensitization using a specific AKT inhibitor has not yet been studied in humans. This phase I studywill bethe first to establish safety and preliminary efficacy of ipatasertib combined with standard of care definitive CRT for HNSCC. Methods: The primary objective of this study is to determine the maximum tolerated dose and recommended Phase 2 dose (RP2D) of ipatasertib in combination with definitive CRT in locally advanced HNSCC based on dose-limiting toxicities (DLTs). Secondary objectives include assessment of acute and late toxicities, long term swallowing function, and a preliminary assessment of efficacy. Eligible subjects must have pathologically confirmed, previously untreated, non-metastatic HNSCC that is either human papilloma virus (HPV)-negative clinical stage III-IVB, or HPV-positive clinical stage III. The study schema includes dose escalation and expansion cohorts. All subjects will receive RT for a standard 70 Gy in 7-week course, with concurrent weekly cisplatin. Two 28-day cycles of orally administered ipatasertib will be given concurrently with CRT. The four dose levels of ipatasertib range from 100-400 mg daily. Dose escalation of ipatasertib will follow a Time-to-Event Bayesian Optimal Interval (TITE-BOIN) design, with DLT window extending from the start of CRT, through 28 days after completion of RT. The expansion cohort will enroll an additional 10 subjects at the RP2D, and incorporate pharmacodynamic biopsies for each subject to evaluate whether the addition of ipatasertib to CRT will result in increased gamma-H2AX, consistent with radiosensitization, and also decreased pS6 and pPRAS40 to evaluate AKT pathway inhibition. Additional correlative studies include assessment of the pharmacokinetic profile of ipatasertib with CRT, as well as correlation of efficacy with tumor genotype, based on whole exome sequencing of pre-treatment biopsy specimens. Enrollment is currently at dose level 2 in the escalation phase, and is expected to complete accrual in 2025. Clinical trial information: NCT05172245 .

First-in-human study of ABBV-400, a novel c-Met–targeting antibody-drug conjugate, in advanced solid tumors: Results in colorectal cancer.

3515 Background: c-Met (MET protein) is frequently overexpressed in several advanced solid tumors including colorectal cancer (CRC). There are no approved therapies specific for c-Met–overexpressing tumors in CRC. The antibody-drug conjugate ABBV-400 comprises c-Met–targeting antibody telisotuzumab conjugated to a novel topoisomerase 1 inhibitor payload. A phase 1 study of ABBV-400 was initiated for adults with advanced solid tumors and progression on standard therapies (NCT05029882); results from dose escalation (ESC) at doses 1.6–6.0 mg/kg once every 3 weeks (Q3W) were previously presented and showed preliminary efficacy (Sharma et al. ASCO 2023. Abstract 3015). We present data from dose ESC and expansion (EXP) cohorts in CRC. Methods: During EXP, patients (pts) with CRC were randomized to receive ABBV-400 at 1.6, 2.4, or 3.0 mg/kg Q3W. Primary objectives were to evaluate the safety, tolerability, pharmacokinetics, preliminary efficacy, and the recommended phase 2 dose of ABBV-400. Results: As of Oct 2023, 122 pts (ESC: 29; EXP: 93) were included. Median age: 56 years; 65 (53%) males. Median prior treatments was 4. Follow-up was longer in ESC vs EXP (14.8 vs 3.8 months). Seventy-eight (64%) pts had a grade (G)≥3 treatment-emergent adverse event (TEAE); 41% had a serious TEAE. Most frequent hematologic TEAEs were anemia (52%; G≥3: 30%), neutropenia (37%; G≥3: 25%), leukopenia (25%; G≥3: 12%), and thrombocytopenia (23%; G≥3: 12%); nonhematologic TEAEs were nausea (57%, G≥3: 3%), fatigue (43%; G≥3: 2%), and vomiting (39%, G≥3: 4%). G≥3 diarrhea was < 1%. Unadjudicated interstitial lung disease/pneumonitis rate was 7% (G≥3: 2%). Treatment-related AEs leading to discontinuation occurred in 11 (9%) pts. Preliminary efficacy outcomes are shown in the Table. The majority of tissues expressed c-Met. In pts with higher c-Met expression, an increased ORR of > 30% was observed at efficacious doses (≥2.4 mg/kg). Activity was also seen at lower c-Met expression levels (10–15% ORR). Conclusions: ABBV-400 at 2.4 and 3.0 mg/kg Q3W has a tolerable and manageable safety profile, with promising antitumor activity. Long-term tolerability appears improved at 2.4 relative to 3.0 mg/kg, with higher relative dose intensity and generally lower TEAEs. The study is also evaluating ABBV-400 with bevacizumab in pts with CRC. Clinical trial information: NCT05029882 . [Table: see text]

Sequential combination of sacituzumab govitecan and talazoparib in metastatic triple negative breast cancer (mTNBC): Results from a phase II study.

1102 Background: The antibody-drug conjugate (ADC) sacituzumab govitecan (SG) has demonstrated improvement in overall survival for patients with metastatic triple negative breast cancer (mTNBC). Despite great interest in enhancing efficacy of ADCs using combination therapy, there are no approved regimens. Preclinical data suggest that SG synergizes with Poly ADP-ribose polymerase inhibitors (PARPi) to induce DNA damage and cell death. Though the phase 1b study demonstrated intolerable myelosuppression with simultaneous dosing, tolerability was improved with sequential administration of SG and the PARPi talazoparib (Bardia AACR 2022). Here we report clinical outcomes from the phase II dose expansion cohort (NCT04039230). Methods: In a single-arm phase II study, adult patients with measurable mTNBC (per ASCO/CAP guidelines) were eligible. Starting dose was SG at 10mg/kg on days 1 and 8 with talazoparib 1mg on days 15-21. Growth factor (G-CSF) prophylaxis was required. The primary endpoint was the confirmed Objective Response Rate (ORR) calculated per RECIST v1.1 and secondary endpoints included progression-free survival (PFS) and overall survival (OS). The Clinical Benefit Rate (CBR) at 6 months was also measured. Results: From June 2021 to March 2023, 26 patients were enrolled. The median age was 54 (range, 35 to 81). Patients received a median of 2 prior therapy lines for metastatic disease (range, 0 to 7). 6/26 patients remain on treatment at time of data cutoff. Median PFS was 6.2 months (95% CI, 3.7 to 12.8), and median OS was 18.0 months (95% CI, 10.7 to not evaluable). The confirmed ORR was 30.1% (95% CI, 14 to 52) and the CBR at 6 months was 53.8% (95% CI, 33 to 73). Serious adverse events (AEs) were seen in 10 (38.5%) of patients; in 7 (26.9%) serious AEs were treatment related. The most common treatment related AEs were anemia (92.3%), neutropenia (88.5%), nausea (84.6%) fatigue (80.7%), and thrombocytopenia (65.3%). Grade ≥3 neutropenia and anemia were seen in 80.7% and 34.6% of cases, respectively. One or more dose reductions were required in 58.0% of patients. One patient with a germline BRCA mutation was treated for 625 days before disease progression. Updated biomarker and survival data will be presented at the meeting. Conclusions: In this single-arm phase II study, SG in combination with talazoparib was feasible and demonstrated preliminary evidence of efficacy. A randomized clinical trial is needed to determine if the SG-PARPi combination is superior to SG monotherapy. Clinical trial information: NCT04039230 .

A phase 1/2 study of the TBL1 inhibitor, tegavivint (BC2059), in patients (pts) with advanced hepatocellular carcinoma (aHCC) with β-catenin activating mutations.

TPS4192 Background: β-catenin mutations are present in up to 40% of aHCC pts. Elevated nuclear β-catenin expression levels correlate with poor responses to standard of care and β-catenin regulates both tumor metabolism and the immune microenvironment. Tegavivint is a first-in-class small molecule inhibitor of TBL1, a novel downstream Wnt-signaling pathway target. Tegavivint binds to TBL1 in the β-catenin pocket, disrupting the formation of the activation complex necessary for oncogenic activity, and enabling degradation of free nuclear β-catenin. The safety, clinical activity, and PK/PD of tegavivint was demonstrated through a proof-of-concept study in pts with desmoid tumors and is being studied through multiple Investigator Initiated Trials in AML (NCT04874480), pediatric solid tumors (NCT04851119), NSCLC (NCT04780568), and lymphoma (NCT05755087). Tegavivint was also studied in preclinical mouse models of β-cateninexon3 mutant HCC and the H22 syngeneic HCC model. In these models tegavivint decreased Wnt target gene expression and enhanced CD3+ T-cell infiltration in liver tumors. Tegavivint treatment of established β-cateninexon3 activated tumors resulted in reduced tumor growth and burden. Based on these promising preclinical results, the following phase 1/2 exploratory study was designed. Methods: This is a phase 1/2 study of tegavivint in pts with aHCC to characterize safety, PK/PD, and preliminary antitumor activity (NCT05797805). Eligibility includes aHCC pts ≥18 years old, with AXIN1or CTNNB1 mutation for all pts, except those in the single agent dose escalation; have BCLC Stage C or Stage B disease not amendable to local therapy or curative approaches, have Child-Pugh class A or B7 liver score, and must have received at least one prior line of systemic therapy. This study will be conducted in 2 parts. First, tegavivint will be administered as a single agent in a dose escalation/optimization and subsequent dose expansion cohort. Upon completion of the dose escalation via a 3+3 design, two dose levels will be selected for the dose selection optimization to determine the recommended phase 2 dose (RP2D) for use in the dose expansion. If sufficient clinical benefit is observed, the combination of tegavivint plus pembrolizumab will be explored in the second part of the study in aHCC pts previously treated with a PD-1/PD-L1 inhibitor. Tegavivint will be administered intravenously weekly. Primary objective is safety and secondary objectives are preliminary efficacy and PK/PD. The first patient began treatment in October of 2023 and the first dose escalation cohort was completed in January. Three institutions are open for enrollment; 5 other sites are pending site activation; all sites are in the United States and Canada. Clinical trial information: NCT05797805 .

Tazemetostat in combination with topotecan and pembrolizumab in patients with recurrent small cell lung cancer.

TPS8130 Background: Small-cell lung cancer (SCLC) is the most fatal type of lung cancer characterized by exquisite chemo-sensitivity at diagnosis and chemoresistance at relapse. Despite a highly mutated genome, patients with SCLC derive little benefit from immunotherapy. EZH2 (enhancer of zeste homolog 2) is a master epigenetic regulator of SCLC neuroendocrine cell fate and plasticity. EZH2 inhibition 1) promotes upregulation of Schlafen 11 (SLFN11) which irreversibly blocks replication in response to DNA damaging agents and 2) enhances intrinsic immune signaling, leading to constitutive MHC I recovery, sensitizing resistant SCLC models to DNA damaging chemotherapy and immunotherapy. Tazemetostat is a selective oral EZH2 inhibitor. Methods: This is an investigator-initiated, NCI Cancer Therapy Evaluation Program (CTEP) sponsored, phase I dose escalation and dose expansion study which will evaluate safety and tolerability of combination of tazemetostat with topotecan, a selective TOP1 inhibitor, and programmed cell death protein 1 (PD-1) inhibitor antibody pembrolizumab. Adult patients with relapsed/recurrent SCLC after at least platinum doublet (limited stage-SCLC) or chemo-immunotherapy (extensive stage-SCLC) and ECOG performance 0-1 are eligible. The regimen design involves a 7-day “run-in” of oral tazemetostat BID followed by 21-day cycles of tazemetostat (1-21 days), intravenous (IV) topotecan (day 1-5) and IV pembrolizumab (Day 1). The dose escalation cohort aims to determine safety and optimal doses of tazemetostat and topotecan (with standard dose of pembrolizumab) using a 3+3 design by assessing for dose limiting toxicities. The dose expansion cohort aims to assess safety, tolerability and preliminary efficacy of the combination in 15 additional patients with relapsed SCLC. The study involves collection of mandatory biopsies at pre-treatment and post-treatment (cycle 1) to gain insights into mechanism of action and resistance of the combination using single cell and spatial transcriptomic approaches. For more questions regarding enrollment and eligibility please contact Rasa.vilimas@nih.gov or anish.thomas@nih.gov . Clinical trial information: NCT05353439 .

Livmoniplimab with or without budigalimab in patients with advanced solid tumors: Results from the combination therapy in the urothelial carcinoma dose expansion cohort.

Livmoniplimab with or without budigalimab in patients with advanced solid tumors: Results from the combination therapy in the urothelial carcinoma dose expansion cohort.

A phase I/II study of talazoparib and axitinib in patients with advanced clear cell renal cell carcinoma.

4541 Background: Targeting the VEGF pathway is a backbone therapeutic for patients with advanced clear cell renal cell carcinoma (ccRCC). Tumor and tissue hypoxia may also lead to DNA repair suppression and PARPs are key regulators of DNA damage and genomic maintenance which interact with HIF proteins. Pairing a potent VEGFR TKI with a selective PARP inhibitor (PARPi) may lead to improved outcomes in ccRCC patients. Methods: This was a phase I/II, investigator-initiated, single-center, open-label study (NCT04337970) of talazoparib plus axitinib in previously treated ccRCC patients. In the phase Ib dose escalation, patients must have been previously treated with a PD-1/PD-L1 inhibitor with no maximum lines of prior therapy, and those in dose expansion were required to have prior treatment with a PD-1/PD-L1 inhibitor and prior VEGFR TKI, with a maximum of 2 prior lines of therapy. Patients received escalating doses of talazoparib (0.5 mg, 0.75 mg and 1 mg daily) with axitinib (5 mg twice daily) in a 3+3 design, with primary endpoint of safety and tolerability. After establishing the recommended phase II dose (RP2D), a dose expansion cohort enrolled patients in a Simon two-stage design with a primary endpoint of objective response (ORR), and secondary endpoints including progression-free survival (PFS). Results: From 2020-2023, 23 ccRCC patients were enrolled and treated on study. In the dose escalation, 15 patients enrolled across all 3 dose levels and there were 2 observed DLTS (1 in dose levels 2 and 3). Both DLTs was due to a lack of minimum exposure to study drugs during cycle 1 due to treatment-related toxicities. The maximum tolerated dose and RP2D established was 1 mg talazoparib daily with axitinib 5 mg twice daily. In the phase II dose expansion portion, an additional 9 patients were enrolled to evaluate preliminary efficacy. In total, 13/14 patients treated at the RP2D discontinued therapy due to progressive disease. The objective response rate (ORR) was 7% (90% CI 0, 30), with 1 patient achieving a partial response and 12 patients achieving stable disease (86%). With a median follow-up of 13.2 months (R: 6.6 -29), the median PFS was 6.1 months (95% CI 3.5, 8.4) and median overall survival (OS) was 27 months (95% CI 12- NE). Across the study, 13 (56%) patients had at least one treatment-emergent AE of grade 3+, and 9 (39%) patients had at least one treatment-related AE of grade 3+. Most common grade 3+ AEs included diarrhea, nausea, and anemia. Conclusions: This is the first clinical study evaluating combination PARPi and VEGFR TKI in metastatic ccRCC patients. This study established the RP2D and MTD of combination talazoparib and axitinib and demonstrated a tolerable safety profile across all dose escalation cohorts. The study did not meet the pre-defined efficacy threshold for further enrollment per Simon stage two design. Exploratory efforts to evaluate this treatment approach with tissue biomarker data remain ongoing. Clinical trial information: NCT04337970 .

A phase 1 study of REGN6569, a GITR mAb, in combination with cemiplimab in patients (pts) with advanced solid tumor malignancies: Initial dose-escalation results.

2650 Background: REGN6569 is a fully human immunoglobulin G1 monoclonal antibody (mAb) that is highly specific for glucocorticoid-induced tumor necrosis factor receptor–related protein (GITR). GITR is expressed on several immune cell subtypes, notably regulatory T cells (Tregs), and activated natural killer (NK) cells. REGN6569 demonstrated greater in vitro antibody-dependent cell-mediated cytotoxicity against GITR-expressing Tregs, as compared to GITR-expressing CD8+ T cells. Mouse studies showed that REGN6569 + cemiplimab (anti-PD-1) combination treatment achieved longer-term tumor responses compared with either drug alone. Methods: This is a first-in-human study (NCT04465487) evaluating the safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor activity of REGN6569 administered intravenously (IV) every 3 weeks (Q3W) + cemiplimab 350 mg IV Q3W, in pts with advanced solid tumors for which immune checkpoint inhibitor therapies have not been approved or are not available. The study includes a dose-escalation part with 5 dose levels (DL1-DL5) for REGN6569 (“4+3” design), with an initial dose of REGN6569 monotherapy given as a safety lead-in followed by REGN6569 + cemiplimab in subsequent doses. Results: As of the data cutoff date Oct 20, 2023, the dose-escalation part has been completed. 29 pts (median age 58.0 years, 62.1% male) were treated with REGN6569 + cemiplimab, up to the 1200 mg dose level (DL5), across many solid tumor types. The most common tumor type was colorectal cancer (34.5%). One pt (40 mg DL2) experienced a dose-limiting toxicity (Grade 3 hepatic failure); maximum tolerated dose was not reached. Twelve pts (41.4%) had a Grade ≥3 treatment-emergent adverse event (TEAE) and 16 pts (55.2%) had a treatment-related TEAE (any grade). The most frequent TEAEs (any grade) were arthralgia (24.1%), infusion-related reactions, and abdominal pain (20.7% each). There were no treatment-related deaths; 19 (65.5%) pts had disease progression leading to death. Two pts achieved ongoing partial responses by investigator assessment with REGN6569 + cemiplimab treatment: 1 pt with mucoepidermoid tumor of the parotid gland treated with 120 mg (DL3) REGN6569 and 1 pt with B3 thymoma treated with 400 mg (DL4) REGN6569, with duration of responses, 5.6 and 10.4 months, respectively. Full receptor occupancy on circulating Tregs was observed in all dose cohorts following REGN6569 treatment. Increased frequency (~10–50%) of proliferating NK cells in peripheral blood was observed post REGN6569 treatment across all dose cohorts. Conclusions: In this dose-escalation study, REGN6569 was administered up to 1200 mg (DL5) in combination with cemiplimab with one dose-limiting toxicity. The study has progressed to dose-expansion cohorts in anti–PD-1-resistant head and neck cancer, with pts treated with REGN6569 (DL5) + cemiplimab. Clinical trial information: NCT04465487 .

A phase 1 trial evaluating the safety, tolerability, PK, and preliminary efficacy of QTX3034, an oral G12D-preferring multi-KRAS inhibitor, in patients with solid tumors with KRASG12D mutation.

TPS3172 Background: KRAS is one of the most mutated driver oncogenes across solid tumors, and KRAS G12D missense mutations have high prevalence in pancreatic, colorectal (CRC), and endometrial cancers. QTX3034 is a highly-selective, non-covalent, orally bioavailable, multi-KRAS inhibitor with potent activity across several KRAS variants, particularly G12D. QTX3034 binds to GDP-bound forms of mutant and wild-type KRAS with (sub)nanomolar affinities, allosterically inhibiting its conversion to the active state. QTX3034 inhibits KRAS signaling in in vitro studies and displays synergy with EGFR inhibitors. In vivo evaluation of QTX3034 resulted in significant tumor growth inhibition across various tumor models, with tumor regressions observed in 100% of animals in both HPAC pancreatic and GP2D colorectal KRAS G12D xenograft models. QTX3034 exhibits brain penetration in preclinical studies, including an orthotopic model of intracranial efficacy. This clinical trial is now enrolling patients with advanced solid tumors harboring a KRASG12D mutation. Methods: This is a first-in-human, multicenter, open-label phase 1 study in adult patients with advanced solid tumors with KRASG12D mutations, without prior direct KRAS inhibitor treatment (NCT06227377). The primary objectives are to evaluate the safety and tolerability and to determine maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of QTX3034 alone, and in combination with cetuximab. Secondary objectives are characterization of the PK profile and preliminary antitumor activity. Part 1 consists of two dose-escalation arms: QTX3034 monotherapy (advanced solid tumors) and QTX3034 plus cetuximab (CRC) and will enroll 3-4 subjects per cohort in a Bayesian Logistic Regression Model (BLRM) design. QTX3034 will be administered orally in 21-day cycles until disease progression, intolerable toxicity, or withdrawal from treatment. Exploratory paired biopsies will be collected in Cycle 2 in a group of patients in the dose-escalation phase. Serial ctDNA will be collected in all patients. Following identification of a RP2D, QTX3034 will be evaluated in dose-expansion cohorts of up to 30 patients with various KRASG12D mutated tumor types to determine preliminary activity: pancreatic cancer, CRC, non-small cell lung cancer and endometrial cancer. To further optimize the recommended dose, patients will be randomized between two dose levels in the pancreatic cancer cohort. QTX3034 plus cetuximab will be explored following identification of a recommended combination dose in patients with CRC. Clinical trial information: NCT06227377 .

Divarasib in the Evolving Landscape of KRAS G12C Inhibitors for NSCLC.

Kristen Rat Sarcoma viral oncogene (KRAS) mutations are one of the most common oncogenic drivers found in 12-14% of non-small cell lung cancer (NSCLC) and 4% of colorectal cancer tumors. Although previously difficult to target, sotorasib and adagrasib are now approved for previously treated NSCLC patients with KRAS G12C mutations. In preclinical studies, divarasib was 5 to 20 times as potent and up to 50 times as selective as sotorasib and adagrasib. While sotorasib met its primary endpointin the phase III second line study against docetaxel, the progression-free survival (PFS) benefit was small and no overall survival (OS) benefit was observed. Adagrasib has demonstrated clinical benefitin the phase I/II KRYSTAL-1 study setting, however, 44.8% of patients reported grade 3 or higher toxicities. Divarasib has been studied in a phase I dose expansion cohort with promising efficacy [objective response (ORR) 53.4% and PFS 13.1 months]. Although most patients reported toxicities, the majority were low-grade and manageable with supportive care. Here we discuss these results in the context of the evolving KRAS G12C landscape.

Abstract CT110: A first-in-human phase I study of CTX-712 in patients with advanced, relapsed or refractory malignant tumors (CTX-712-CL-01 study): Efficacy and safety in solid tumor cohorts

Abstract Background: Aberrant splicing contributes to the progression of cancer but lacks targeted drugs. CTX-712 is a potent oral CDC2-like kinase (CLK) inhibitor affecting RNA splicing, CTX-712 demonstrated potent inhibition of proliferation in human tumor cell lines and elicited robust anti-tumor activity in xenograft models. This study aimed to evaluate CTX-712’s maximum tolerated dose (MTD), dose-limiting toxicity (DLT), safety, pharmacokinetics (PK)/pharmacodynamics (PD) profiles, and preliminary efficacy in patients with advanced solid tumors. Methods: This study consisted of a dose escalation cohort (A) and three dose expansion cohorts (C, D and E) for solid tumors. The dose escalation cohort (A) was initiated with accelerated titration and then switched to a 3+3 design (10, 20, 40, 70, 105, 140 and 175 mg twice a week [TW]). The dosing regimens for dose expansion cohorts were 105 mg TW (C), 70 mg TW (D), and 105 mg once a week (QW) (E). Results: As of November 20, 2023, a total of 46 patients with solid tumors were enrolled in the dose escalation cohort (16 patients) and dose expansion cohorts (30 patients total). In the dose escalation cohort, CTX-712 was administered at a dose of 10/20/40/70 mg TW (n=1 each), 105/175 mg TW (n=3 each) and 140 mg TW (n=6). DLTs were observed in 2 patients (140 mg TW [platelet count decreased, hypokalemia], 175 mg TW [dehydration]) and MTD was determined to be 140 mg TW. Among the safety analysis population (n=46), median treatment duration was 77 days (Range 1-413+ days); 1 patient is ongoing, and 45 patients discontinued. The common any-grade related adverse events (AEs) (≥30%) were nausea (93.5%), vomiting (65.2%), diarrhea (54.3%), decreased appetite (45.7%) and blood creatinine increase (32.6%). The most common related Grade 3 or higher AE was platelet count decrease (6.5%). Among all the patients (n=46), partial responses were observed in 4 (8.7%) patients (40 (n=1)/70 (n=2)/105 (n=1) mg TW cohorts), who were all patients with ovarian cancer; the median treatment duration of ovarian cancer (n=14) was 84 days (Range 1-413+ days). In PK analysis, a dose-dependent increase in systemic exposure of CTX-712 was observed. PD response was assessed in RNA extracted from peripheral blood cells. Dose-dependent increases of exon skipping in two marker RNAs (S6K and THAP9-AS1) demonstrated mRNA splicing modification induced by CTX-712. Conclusions: CTX-712 demonstrated an acceptable safety profile in patients with solid tumors. Additionally, CTX-712 demonstrated favorable clinical efficacy for patients with ovarian cancer and further investigation is warranted. Clinical trial information: jRCT2080224127 Citation Format: Noboru Yamamoto, Takafumi Koyama, Yuki Katsuya, Jun Sato, Toshio Shimizu, Yasushi Tanoue, Maki Yamamoto, Hirokazu Tozaki, Eiji Takahara, Shingo Shoji, Akio Mizutani, Daisuke Morishita, Robert W. Oda, Hiroshi Miyake, Kan Yonemori. A first-in-human phase I study of CTX-712 in patients with advanced, relapsed or refractory malignant tumors (CTX-712-CL-01 study): Efficacy and safety in solid tumor cohorts [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 CT110.

Abstract CT095: Phase 1 evaluation of triple therapy with boserolimab (anti-CD27 agonist), pembrolizumab, and chemotherapy in patients with triple-negative breast cancer (TNBC) with PD-L1 combined positive score (CPS) <10: Safety, antitumor activity, and association between biomarkers and response

Abstract Background: Pembrolizumab (pembro) plus chemotherapy (chemo) is an approved therapy for patients (pts) with locally recurrent unresectable or metastatic TNBC whose tumors express PD-L1 (CPS ≥10) based on results from KEYNOTE-355. However, there is unmet need for effective treatment options in pts with PD-L1 CPS <10. In a first-in-human, open-label, phase 1 study (NCT03396445), treatment with escalating doses of the humanized anti-CD27 agonist boserolimab (MK-5890) alone and with pembro had acceptable safety and preliminary evidence of antitumor activity in pts with advanced solid tumors. We report results for a dose-expansion cohort of this study in pts with metastatic TNBC and PD-L1 CPS <10 tumors who received first-line triple therapy with boserolimab, pembro, and chemo. Exploratory analyses in this cohort assessed the association of baseline T-cell-inflamed gene expression profile (TcellinfGEP) and tumor mutational burden (TMB) with ORR. Methods: This dose-expansion cohort enrolled pts aged ≥18 y with previously untreated locally recurrent inoperable or metastatic TNBC, measurable disease per RECIST v1.1, ECOG PS of 0/1, and tumors expressing PD-L1 at the cutoff of CPS <10 per PD-L1 IHC 22C3 pharmDx (local or central testing). Pts received boserolimab 30 mg IV Q6W plus pembro 400 mg IV Q6W for 18 cycles plus nab-paclitaxel 100 mg/m2 (3 weeks on [days 1, 8, and 15]/1 week off). Primary objectives were safety/tolerability. A secondary objective was ORR per RECIST v1.1 by investigator assessment. Baseline TcellinfGEP was assessed using the NanoString PCI assay (N=31); TMB was assessed using the Illumina TSO500 mutational panel assay (N=21). Results: 41 pts were enrolled in the dose-expansion cohort. Median study follow-up at data cutoff (Apr 25, 2023) was 11.1 (range, 2.2-20.5) mo. The most common treatment-related AEs were fatigue (51.2%), pruritus (51.2%), and alopecia (46.3%). Grade 3/4 treatment-related AEs occurred in 56.1% of pts (23/41); no grade 5 treatment-related AEs occurred. 9.8% of pts (4/41) discontinued ≥1 study treatment due to treatment-related AEs. Confirmed ORR was 46.3% (95% CI, 30.7%-62.6%), with 2 CRs and 17 PRs; 14 pts had SD, 5 had PD, and 3 had no postbaseline assessment at data cutoff. Median PFS was 10.3 (95% CI, 4.2-not reached) mo. No clear association between TcellinfGEP or TMB and confirmed ORR was observed; responses were observed in pts with non-TcellinfGEP-high (less than −0.318) and non-TMB-high (<10 mut/Mb) tumors. Conclusions: In pts with TNBC and tumors expressing PD-L1 at the cutoff of CPS <10, triple therapy with boserolimab, pembro, and chemo had acceptable safety and showed preliminary evidence of antitumor activity regardless of baseline TcellinfGEP expression or TMB status. Citation Format: Carlos Rojas, Bernard Gaston Doger de Spéville, Seock-Ah Im, Ronnie Shapira-Frommer, María De Miguel, Lucía González Cortijo, Margarita Romeo Marin, Maja de Jonge, Mark Ayers, Yiwei Zhang, Song Zhai, Elliot Chartash, Konstantin Dobrenkov, Joohyuk Sohn. Phase 1 evaluation of triple therapy with boserolimab (anti-CD27 agonist), pembrolizumab, and chemotherapy in patients with triple-negative breast cancer (TNBC) with PD-L1 combined positive score (CPS) <10: Safety, antitumor activity, and association between biomarkers and response [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 CT095.