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PURPOSE Overexpression of c-Met protein and epidermal growth factor receptor ( EGFR) mutations can co-occur in non–small-cell lung cancer (NSCLC), providing strong rationale for dual targeting. Telisotuzumab vedotin (Teliso-V), a first-in-class antibody-drug conjugate targeting c-Met, has shown a tolerable safety profile and antitumor activity as monotherapy. Herein, we report the results of a phase Ib study (ClinicalTrials.gov identifier: NCT02099058 ) evaluating Teliso-V plus erlotinib, an EGFR tyrosine kinase inhibitor (TKI), in patients with c-Met–positive (+) NSCLC. PATIENTS AND METHODS This study evaluated Teliso-V (2.7 mg/kg once every 21 days) plus erlotinib (150 mg once daily) in adult patients (age ≥ 18 years) with c-Met+ NSCLC. Later enrollment required presence of an EGFR-activating mutation ( EGFR-M +) and progression on a prior EGFR TKI. End points included safety, pharmacokinetics, objective response rate (ORR), and progression-free survival (PFS). The efficacy-evaluable population consisted of c-Met+ patients (confirmed histology [H]-score ≥ 150) who had at least one postbaseline scan; c-Met+ patients with H-scores ≥ 225 were classified as c-Met high. RESULTS As of January 2020, 42 patients were enrolled (N = 36 efficacy-evaluable). Neuropathies were the most common any-grade adverse events reported, with 24 of 42 patients (57%) experiencing at least one event. The pharmacokinetic profile of Teliso-V plus erlotinib was similar to Teliso-V monotherapy. Median PFS for all efficacy-evaluable patients was 5.9 months (95% CI, 2.8 to not reached). ORR for EGFR-M + patients (n = 28) was 32.1%. Of EGFR-M + patients, those who were c-Met high (n = 15) had an ORR of 52.6%. Median PFS was 6.8 months for non-T790M+ and for those whose T790M status was unknown, versus 3.7 months for T790M+. CONCLUSION Teliso-V plus erlotinib showed encouraging antitumor activity and acceptable toxicity in EGFR TKI-pretreated patients with EGFR-M+, c-Met+ NSCLC.

9013 Background: Osi (third-generation tyrosine kinase inhibitor) is a standard frontline treatment (Tx) for advanced/metastatic EGFR-mutated NSCLC. However, tumors invariably progress after an initial response, with c-Met protein overexpression (OE) often associated with acquired resistance. Second- and third-line Tx options are limited to chemotherapy-based regimens with limited efficacy and significant toxicities. Teliso-V (ABBV-399), an anti–c-Met antibody-drug conjugate, delivers a cytotoxic payload (monomethyl auristatin E) into c-Met OE tumor cells. In a phase 1/1b study (NCT02099058) in patients (pts) with c-Met OE NSCLC, Teliso-V alone or in combination with erlotinib demonstrated an acceptable safety profile and antitumor activity. Interim safety and efficacy data from the Teliso-V + Osi cohort (arm E) of this trial are presented. Methods: Pts (≥18 yr) with metastatic EGFR-mutated, c-Met OE (by central immunohistochemistry) NSCLC who had progressed on a prior Osi regimen were eligible. Pts received Teliso-V (IV Q2W) + Osi (oral; 80 mg QD). Teliso-V was evaluated at 1.6 mg/kg and, after review of safety data, escalated to 1.9 mg/kg (safety evaluation). An expansion cohort was opened at 1.9 mg/kg for pts who had received ≤2 prior lines of systemic therapy. Pharmacokinetics (PK) were assessed throughout the study. Pts received study Tx until disease progression, unacceptable toxicity, or for up to 24 months. Results: As of 20 Dec 2021, 25 pts received Teliso-V (1.6 mg/kg, n = 7; 1.9 mg/kg, n = 18) + Osi. Median age was 60.0 yr; 14 (58%) pts were on prior Tx with Osi for > 12 mo. No dose-limiting toxicities (grade [Gr] ≥3 non-hematologic or Gr 4 hematologic Tx-related adverse events [AEs]) were reported during the safety lead-in or evaluation phases. All-Gr AEs considered possibly related to Teliso-V occurred in 22/25 (88%) pts: the most common (≥20%) were peripheral sensory neuropathy (36%), nausea, and peripheral edema (20% each); Gr ≥3 AEs (> 5%) were anemia (12%) and peripheral motor neuropathy (8%). No Gr 5 events related to Tx were reported. PK of Teliso-V + Osi was similar to single-agent Teliso-V. Efficacy data (19/25 pts) are in the table. The overall objective response rate (ORR) was 58% (67% at 1.9 mg/kg). Conclusions: Teliso-V + Osi is well tolerated with an ORR of 58% (67% at 1.9 mg/kg) in pts with c-Met OE NSCLC who progressed on prior Osi. Clinical trial information: NCT02099058. [Table: see text]

9016 Background: Teliso-V is an antibody-drug conjugate composed of a c-Met antibody (ABT-700) and a microtubule inhibitor (monomethyl auristatin E). The phase 2 M14-239 trial (LUMINOSITY, NCT03539536) aims to identify the c-Met OE NSCLC populations best suited to Teliso-V (Stage 1) and expand selected groups for further evaluation of efficacy (Stage 2). In Stage 1, pts were enrolled into cohorts defined by histopathology (non-squamous [NSQ] or squamous [SQ]) and EGFR mutation status (mutant or wild type [WT]); NSQ cohorts were further divided in groups on the basis of c-Met expression (high or intermediate). Updated data from the fourth interim analysis (IA4) are presented. Methods: Pts had locally advanced/metastatic NSCLC, ≤2 prior lines of systemic therapy, ≤1 line of chemotherapy, and tumors that were c-Met OE by central immunohistochemistry (IHC; Ventana; Tucson, AZ). c-Met OE was defined for the NSQ cohort as ≥25% 3+ by IHC (high, ≥50% 3+; intermediate, 25 to

3013 Background: ABBV-621 is a potent tumor-necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor agonist fusion protein that induces apoptotic cell death, particularly in DR4/5 expressing tumor models. Methods: Patients (pts) with previously treated solid tumors and ECOG 0–2 were administered ABBV-621 (2.5–15 mg/kg IV) on day (D) 1 (dose level [DL] 1) or D1D8 (DL2 and beyond) of each 21-day cycle. Dose escalation (DE) was guided by a Bayesian continual reassessment method. In addition to PK studies, blood-based PD markers of apoptosis (M30, M65) and drug binding were assessed. Results: As of 14 December 2018, 57 pts were enrolled in the DE portion, of which 30% had pancreatic, 23% colorectal cancer, and 47% other tumor types; 13 were KRAS mutant. Median age was 61 yrs. 60% were male; pts had a median of 4 prior regimens (range 1–10). Pts per DL: 2.5 (5 on D1, 16 on D1D8), 3.75 (12), 5 (6), 6.5 (6), 8.5 (4), 11 (4), and 15 mg/kg (4). Median duration of ABBV-621 exposure was 2 cycles (range 1–11). Seven pts had dose-limiting toxicities: respiratory failure (5 mg/kg; Grade 5, the only treatment-related death), blood bilirubin increased (3.75, 6.5 mg/kg), nausea (3.75 mg/kg), fatigue (3.75 mg/kg), increased ALT (2.5, 3.75, 6.5, 15 mg/kg), and increased AST (6.5 mg/kg). Summary of AEs is shown in Table. Clinical trial information: NCT03082209. A partial response (duration 20 weeks) was observed in a pt with pancreatic cancer (2.5 mg/kg D1D8). 27 pts had stable disease (6 pts for > 12 weeks). ABBV-621 PK was linear (mean ± SD clearance was 1.79 mL/h/kg ± 0.44) with a terminal half-life of 36.7 ± 5.55 h (n = 49). ABBV-621 bound to decoy receptors on neutrophils for up to 168 h; the duration of binding was dose-dependent. M30 and M65 increased at 8, 24, and 48 h following ABBV-621, but effect was independent of dose. Conclusions: ABBV-621 shows evidence of antitumor activity and effect on blood-based markers of apoptosis, with acceptable toxicity (MTD not reached). NCT03082209.[Table: see text]

3061Background: Veliparib (V), a PARP inhibitor, combined with platinum (Pt) doublet CT has shown promise in a Phase 2 study of NSCLC. Nivolumab (N), a PD-1 inhibitor, has demonstrated single-agent...

8032Background: The anti-apoptotic protein BCL-2 has been implicated in the survival of multiple myeloma (MM) cells. Venetoclax (VEN) is an oral, highly selective BCL-2 inhibitor, which induces cel...

7527Background: Venetoclax (VEN) is an orally bioavailable BCL2 selective inhibitor. Patients (pts) with relapsed or refractory CLL or small lymphocytic lymphoma were treated in a phase 1 trial (M1...

2579Background: Veliparib is a potent oral PARP1/2 inhibitor. Monotherapy trials with immediate release formulation veliparib (IR-v) showed antitumor activity in BRCA+ cancers. An extended release formulation (ER-v) may lower the peak-to-trough concentration ratio while maintaining exposure and improving tolerability, providing a rationale to conduct a phase 1 study (NCT01853306) of ER-v in pts with advanced tumors. Methods: Eligible pts had metastatic BRCA+ cancer, BRCA± high-grade serous ovarian/primary peritoneal/fallopian tube cancer (OC), (part 1/2), or BRCA+ breast cancer (BC), or OC (part 3). Part 1 – PK assessment: pts received ER-v (3 different ER-vs tested) or IR-v 200 mg in fed/fasted state on days 1/3/5 (3-group, single-sequence crossover). Part 2 – 3+3 dose escalation: pts received ER-v daily (QD or BID) starting at 200 mg. Part 3 – safety expansion: ER-v was administered continuously at the RP2D. Primary objectives were to determine the bioavailability and food effect of ER-v vs IR-v, the MT...

7007Background: Treatment options for older patients (pts) with acute myelogenous leukemia (AML) unfit for intensive chemotherapy are limited. Expected complete remission rates for low-dose cytarabine (LDAC) are about 10% in this population. Targeting the pro-survival molecule BCL-2 has demonstrated clinical efficacy as a therapeutic strategy in various hematologic malignancies. Venetoclax (VEN), a selective BCL-2 inhibitor, shows synergy with cytarabine in several AML cell lines and primary samples. Methods: This is a non-randomized, open-label phase 1/2 dose-escalation/expansion study of VEN + LDAC, in treatment-naive AML pts ≥ 65 years not eligible for intensive chemotherapy. Pts receive oral VEN once daily (QD) on days 1‒28 and subcutaneous LDAC 20 mg/m2 QD on days 1‒10 of each 28-day cycle. VEN dose escalation follows a 3 + 3 design; dose-limiting toxicities (DLTs: grade 4 toxicity, platelet count < 25,000/μL, or absolute neutrophil count < 500/μL within 14 days of last VEN dose) areassessed during c...

8535 Background: Venetoclax (VEN) is a selective, potent, orally bioavailable BCL-2 inhibitor that has shown single agent activity in R/R NHL. The current study evaluates VEN with BR, an active reg...

8576 Background: The anti-apoptotic protein BCL-2 has been implicated in mediating the survival of MM cells. Venetoclax (VEN) is a potent, selective, orally bioavailable small-molecule BCL-2 inhibi...

8038 Background: Tobacco-related non-small cell lung cancer (NSCLC) is associated with reduced survival and greater genomic instability. Veliparib (V) is a PARP inhibitor that augments platinum-ind...

7015 Background: Overexpression of Bcl-2 in relapsed CLL/SLL is associated with dysregulated apoptosis and chemoresistance. ABT-199 is an orally bioavailable, selective Bcl-2 inhibitor that trigger...

8522 Background: The anti-apoptotic protein Bcl-2 is a highly expressed in NHL and contributes to chemotherapy resistance. ABT-199 is a selective, orally bioavailable, small molecule Bcl-2 inhibitor that is a promising agent for the treatment of patients (pts) with NHL. Methods: Objectives of this Phase I, dose-escalation study include evaluations of safety, pharmacokinetics (PK), and preliminary efficacy in pts with R/R NHL. ABT-199 was given on Week 1 Day -7 (W1D-7), followed by continuous, once-daily dosing from W1D1 until progressive disease or unacceptable toxicity. A 2 to 3 week lead-in period with stepwise dose titration was implemented. Final cohort doses of 200 - 900 mg have been evaluated. Results: As of December 4, 2013, 44 pts have been enrolled, 15 (35%) with mantle cell lymphoma (MCL), 11 (26%) with FL, 10 (23%) with DLBCL, 4 (9%) with Waldenstrom macroglobulinemia (WM), 2 (5%) with marginal zone (MZL), 1 (2%) with primary mediastinal B-cell lymphoma (PMBCL), and 1 (2%) with multiple myeloma...

2584^ Background: Veliparib (V) is an oral inhibitor of poly(ADP-ribose) polymerases (PARP)-1 and -2, which are essential for base excision repair of ssDNA breaks. BRCA deficient tumors are more sensitive to PARP inhibitors when used as monotherapy or in combination with DNA-damaging agents. The objectives of this study were to determine the maximum tolerated dose (MTD), pharmacokinetic interactions, and safety/tolerability profile of V in combination with carboplatin (C) and gemcitabine (G). Methods: Eligibility criteria included patients (pts) with metastatic or unresectable solid tumors for which C/G was a treatment option. During the study, eligibility was amended to limit prior chemotherapy regimens to ≤ 2. C AUC 4 /G 800 mg/m2was given intravenously on Day 1 and G given on Day 8 of 21 day cycles. To assess tolerability of C/G prior to V, V was started in Cycle 2. When C/G was stopped, pts could stay on monotherapy V until progression. Dose-escalation used a Bayesian continual reassessment method. Results: 59 pts (51 female, median age 52) were enrolled. The most common tumor types were ovarian (n=39) and breast (n=10). Germline BRCA mutations were known in 24 ovarian pts. 58 pts had prior chemotherapy (1-6 regimens, median 2), and 51 had prior platinum. Grade 3/4 AEs in >10% of pts were neutropenia, thrombocytopenia, anemia, and leukopenia. Dose limiting toxicities were thrombocytopenia (n=3) and neutropenia at V 310 mg twice daily (BID) and thrombocytopenia at 250 mg BID. Other frequent AEs were nausea, constipation, and fatigue. Preliminary results showed co-administration of V did not affect C or G pharmacokinetics. Treatment cycles (range, median) were 1-28, 5 for V; 2-10, 5 for C; and 2-10, 4 for G. Day 8 G was stopped in some pts to improve tolerability. 28 pts stayed on monotherapy V (1-23 cycles). Partial and complete responses were seen in 11 and 2 pts. Response rates were 47% (8/17) in known BCRA deficient ovarian, 25% (3/12) in other ovarian, and 13% (2/15) in other evaluable pts. Conclusions: V combined with C and G was tolerated with a safety profile similar to C and G alone. The MTD was V 250 mg BID, C AUC 4.0, G 800 mg/m2. Promising anti-tumor activity was observed in BRCA deficient ovarian pts. Clinical trial information: NCT01063816.