Tx-related AEs Research Articles

Pembrolizumab (pembro) in patients (pts) with sorafenib-treated (cohort 1) and treatment (tx)-naive (cohort 2) advanced hepatocellular carcinoma (aHCC) after additional follow-up in the phase 2 KEYNOTE-224 study.

4100 Background: Based on the results of the open-label, phase 2 KEYNOTE-224 study (NCT02702414), pembro received US FDA and the Center for Drug Evaluation of the China National Medical Products Administration approval for pts with sorafenib-treated aHCC (cohort 1). Durable activity and manageable safety were also observed for pts with tx-naive aHCC in cohort 2 of KEYNOTE-224. We report updated efficacy and safety from both cohorts of KEYNOTE-224 after approximately 7 and 5 years of median follow-up, respectively. Methods: Adults with pathology-confirmed aHCC whose disease progressed after or who were intolerant to sorafenib tx (cohort 1) and adults with histologically, cytologically, or radiologically confirmed aHCC with no prior systemic tx (cohort 2) were eligible. Pts in both cohorts had BCLC stage C or B not amenable or refractory to locoregional therapy and not amenable to curative tx, Child-Pugh A liver function, measurable disease per RECIST v1.1, and ECOG PS 0 or 1. Pts received pembro 200 mg IV Q3W for ≤35 cycles (~2 y). Primary end point was ORR per RECIST v1.1 by BICR. Secondary end points included DOR, DCR, TTP, and PFS (all per RECIST v1.1 by BICR), OS, and safety/tolerability. Results: A total of 155 pts enrolled in cohorts 1 (n = 104) and 2 (n = 51) received ≥1 dose of pembro. Median follow-up, defined as time from first dose to data cutoff (Sept 29, 2023), was 83.0 mo (range, 79.3-87.3) for cohort 1 and 58.8 mo (range, 55.3-60.8) for cohort 2. In each cohort, 90% of pts discontinued, mostly due to progressive disease (59%); 10% of pts in each cohort completed 2 y of tx. ORR was 18.3% (95% CI, 11.4-27.1) for cohort 1 (5 CRs [4.8%] and 14 PRs [13.5%]) and 17.6% (95% CI, 8.4-30.9) for cohort 2 (2 CRs [3.9%] and 7 PRs [13.7%]). Median DOR was 21.0 mo (range, 3.1 to 75.8+) for cohort 1 and 24.7 mo (range, 3.1 to 53.4+) for cohort 2; 77%/43% and 76%/64% of responders, respectively, had a response duration of ≥12 mo/≥24 mo per the Kaplan-Meier method for censored data. Data for PFS, TTP, and OS are shown in the Table. Tx-related AEs were reported in 76 pts (73.1%; grade 3-5, 27 [26.0%]) in cohort 1 and 28 pts (54.9%; grade 3-5, 8 [15.7%]) in cohort 2. Conclusions: Pembro continued to provide durable responses in pts with aHCC with or without prior systemic therapy, with some lasting beyond 20 mo; long-term effects on OS beyond 24 mo and manageable safety were also observed. Together with data from KEYNOTE-394 and KEYNOTE-240, these data support the efficacy and safety of pembro as a tx option for aHCC. Clinical trial information: NCT02702414 . [Table: see text]

Clinical outcomes with neoadjuvant nivolumab (N) + chemotherapy (C) vs C by definitive surgery in patients (pts) with resectable NSCLC: 3-y results from the phase 3 CheckMate 816 trial.

8521 Background: In CheckMate 816, neoadjuvant N + C demonstrated statistically significant and clinically meaningful improvements in event-free survival (EFS) and pathologic complete response (pCR) vs C in pts with resectable NSCLC. Here, we report clinical outcomes in pts with or without definitive surgery following neoadjuvant treatment (tx). Methods: Adults with stage IB (tumors ≥ 4 cm) to IIIA (per AJCC 7th ed) resectable NSCLC, ECOG PS ≤ 1, and no known EGFR/ ALK mutations were randomized 1:1 to 3 cycles of N 360 mg + C Q3W or C Q3W, followed by definitive surgery within 6 wk of tx. Primary endpoints were EFS and pCR, both per blinded independent review. Exploratory analyses included EFS (secondary definition; no censoring for subsequent tx), time to death or distant metastasis (TTDM), and EFS2 (EFS on next-line tx) in pts with or without surgery. Results: Among 358 randomized pts, 149 (83%; N + C) and 135 (75%; C) had definitive surgery. Baseline characteristics were similar in pts with or without surgery (N + C, 30; C, 44) and between tx arms, except that a higher proportion of pts who did not have surgery had ECOG PS 1 (both arms) or were from Europe (N + C arm). Surgery was canceled due to progressive disease (PD) in 11 (N + C) and 17 (C) pts; PD was locoregional in 4 and 15 pts and distant in 3 and 2 pts, while 4 pts in the N + C arm had both locoregional and distant PD. At database lock (October 14, 2022; median f/u: 41.4 mo), EFS, TTDM, and EFS2 were numerically improved in pts with vs without surgery, regardless of tx arm. In pts with surgery, median TTDM was not reached (NR) vs 46.8 mo (HR, 0.55) with N + C vs C, respectively; 3-y TTDM rates were 77% vs 59%. In pts without surgery, median TTDM was 24.8 vs 15.6 mo (HR, 0.63) with N + C vs C; 3-y rates were 36% vs 13%. Among pts without surgery, 17 (57%) vs 28 (64%) pts in the N + C vs C arms, respectively, received subsequent tx: radiotherapy 37% vs 41%; surgery 3% vs 2%; systemic tx 50% vs 52%. Grade 3/4 tx-related AEs occurred in 38% (N + C) and 36% (C) in pts with surgery, and 26% and 46% in pts without surgery. Conclusions: In CheckMate 816, neoadjuvant N + C demonstrated long-term clinical benefit vs C in pts with resectable NSCLC who received definitive surgery. In pts who did not receive definitive surgery, these exploratory analyses showed that neoadjuvant N + C was associated with numerically improved TTDM. Clinical trial information: NCT02998528 . [Table: see text]

Abstract OT2-11-01: A phase 1 study of the novel immunotoxin MT-5111 in patients with HER2+ tumors: interim results

Abstract MT-5111 is a 55kD engineered toxin body targeting HER2 in solid tumors that binds to an epitope distinct from trastuzumab and pertuzumab, offering potential combination strategies with other HER2-targeting agents. MT-5111 works by internalizing, self-routing through intracellular compartments to the cytosol, and inducing potent cell-kill via the enzymatic and permanent inactivation of ribosomes. This is a phase 1 study in adults with advanced HER2+ solid tumors. MT-5111 is dosed weekly IV over 30 min in every 21-day cycle until disease progression, unacceptable toxicity, death, or withdrawn consent. The study has dose escalation (Part A) cohorts enrolling patients (pts) with any HER2+ cancer (CA) and expansion (Part B) cohorts for HER2+ breast cancer (BC), Gastric or Gastroesophageal junction adenocarcinoma (GEA), or other HER2+ solid CA. As of 30 June 2022, 42 total pts had enrolled (36 in Part A on 0.5-23 µg/kg/dose, 6 pts with BC in Part B1 on 10 µg/kg/dose). Median age 65 years, 28 (66.78%) pts were female, median of 4 prior systemic and 2 prior HER2-targeting treatment (tx). 17 pts with BC, 6 with biliary CA, 9 with GEA, and 10 with other solid CA have enrolled. Of the 17 BC pts, 15 received ≥ 10 µg/kg/dose. Tx emergent adverse events (TEAEs) have been reported in 40 (95%) pts, and tx-related AEs (TRAE) occurred in 23 (55%) pts. No pt experienced G4-G5 TRAE. G1 troponin elevations were noted in 5 pts without clinical signs of cardiotoxicity (1 pt 6.75 µg/kg, 2 pts 10 µg/kg, 1 pt 17 µg/kg, 1 pt 23 µg/kg). Reversible G1/G2 infusion-related reactions were reported in 2 pts. Tx-related G1-G3 rash was observed in 5 pts (4 pts ≥ 10 µg/kg/dose); maculopapular in 2 pts, acneiform in 1 pt and associated with pruritus in 3 pts. The G3 rash developed one wk after first dose of 23 µg/kg, was declared a DLT, improved with systemic steroid therapy and the pt continued tx at the same dose without recurrence. Best overall response per RECIST thus far is stable disease (SD) in 17 pts, non-CR/non-PD in 1 pt, and progressive disease (PD) in 14 pts. 1 pt had non-CR/non-PD for 30 wks (1 μg/kg, BC); 1 pt had SD for 24wks (10 μg/kg, pancreatic); 1 pt is on tx with SD through 8 cycles (10 μg/kg, BC). Of the 10 BC pts who received ≥ 10 μg/kg/dose, the best response was 5 SD. The mean serum concentration of MT-5111 has increased in a dose-proportional manner starting at 6.75µg/kg/dose (Table 1). The soluble HER2 (sHER2) levels at end of tx were higher compared to baseline in cohorts that received ≤ 4.5µg/kg/dose, but similar or lower in cohorts that received ≥ 6.75µg/kg/dose. Higher MT-5111 doses have been well tolerated and may saturate circulating sHER2, leading to more predictable serum concentrations and tumor penetration. The Cmax in humans at doses ≥6.75 µg/kg/dose is above the in vitro IC50 for high HER2+ cell lines (0.029nM) and at 17 µg/kg/dose, above the IC50 for moderate HER2+ cells (1.6nM). In conclusion, the dose proportionate increase in serum concentration with levels above the in vitro IC50 and the leveling off/reduction of sHER2 indicate exposure to MT-5111 is at clinically therapeutic levels. Skin toxicity at higher doses may indicate on-target effect as observed in other EGFR-targeted therapies where it is associated with clinical response and a better prognosis. sHER2 biomarker data is expected for all cohorts with PK correlation and 23µg/kg safety and efficacy data. PK profile of MT-5111, C1D1 values Citation Format: Meena Okera, Brian A. Van Tine, Joleen M. Hubbard, Minal Barve, Erika Hamilton, Monica M. Mita, Frances Valdes-Albini, Daniel Ahn, Admasu Mamuye, Joshua Pelham, Amy Yuet, Diana Yurewicz, Yanning Liu, Andres Machado Sandri, William J. Edenfield, Aki Morikawa, William Gradishar, Rajiv Kumar, Zev A. Wainberg. A phase 1 study of the novel immunotoxin MT-5111 in patients with HER2+ tumors: interim results [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 OT2-11-01.

994P Efficacy and safety of capmatinib plus spartalizumab in treatment-naïve patients with advanced NSCLC harboring MET exon 14 skipping mutation

Capmatinib (cap) is a selective MET inhibitor approved for patients (pts) with advanced NSCLC (aNSCLC) harboring MET exon 14 skipping mutation (METex14) showing ORR [95% CI] of 66.7% [53.3, 78.3] in treatment (tx)-naïve pts. Spartalizumab (sparta) is a monoclonal antibody targeting programmed death protein-1 (PD-1). Cap enhances T cell mediated antitumor response in mice treated with PD-1 inhibitors. Combining cap with sparta may be beneficial in aNSCLC pts with METex14. This phase II study consisted of 2 parts: open-label, single-arm run-in part, where pts received cap 400 mg orally BID + sparta 400 mg i.v Q4W followed by randomized, double-blind, placebo-controlled part to evaluate the efficacy and safety of cap+sparta vs cap+placebo. Tx-naïve aNSCLC pts with METex14 and without ALK or EGFR alterations were included. The primary endpoint was investigator-assessed ORR as per RECIST v1.1. Herein, we report data from the run-in part. At data cut-off (DCO) of Feb 01, 2022, 31 pts were included in the run-in part; median age: 73 (range: 52-89) years; females (51.6%) and ECOG PS of 0/1 in 38.7%/61.3% of pts. The ORR [95% CI] was 38.7% [21.8, 57.8] and DCR [95% CI] was 77.4% [58.9, 90.4]. Median DOR has not been reached. Median PFS [95% CI] is 13.3 months [9.3, NA] but data remains to mature further. The preliminary PK results of both drugs showed consistency with prior monotherapy studies. Most common Tx-related AEs (any grades [GR], ≥30%) were peripheral edema (71%), elevated serum creatinine (45.2%), elevated ALT and AST (35.5% each). No Tx-related GR 3/4 pneumonitis and no fatal toxicity has been reported. Higher rates of tx-related AEs leading to dose reduction/interruption (80.6%) and/or discontinuation (35.5%) were seen with cap+sparta regimen vs other cap monotherapy studies, suggesting poor tolerability to the combination. Thus, study enrollment was halted, and all ongoing pts were discontinued from sparta. At DCO, 15 pts remain on cap monotherapy. The addition of sparta to cap treatment was not well tolerated and resulted in modest antitumor activity when compared with data from other cap monotherapy studies in tx-naïve aNSCLC pts with METex14.

Abstract PD10-04: Phase Ib/II open-label, randomized trial of atezolizumab (atezo) with ipatasertib (ipat) and fulvestrant (fulv) vs control in MORPHEUS-HR+ breast cancer (M-HR+ BC) and atezo with ipat vs control in MORPHEUS triple negative breast cancer (M-TNBC)

Abstract Background: The MORPHEUS platform consists of multiple, global, open-label, randomized Phase Ib/II trials designed to gauge safety and identify early efficacy signals in treatment (tx) combinations across cancers. Within MORPHEUS, atezo (anti-PD-L1) was evaluated with ipat, an oral AKT inhibitor, with (M-HR+ BC) and without (M-TNBC) fulv. Methods: In 2 separate randomized trials, eligible immune checkpoint inhibitor naive pts with either 2L/3L HR+ chemotherapy-naive BC who had prior CDK4/6 inhibitor treatment or 2L TNBC, received atezo (840 mg D1, 15) with ipat (400 mg D1-21); pts with HR+ BC also received fulv monthly. Control tx for M-HR+ BC (NCT03280563) was fulv and for M-TNBC (NCT03424005) was capecitabine; given the adaptive nature of the MORPHEUS platform only some of the control arm pts were enrolled concurrently with pts in the ipat arms for M-HR+ BC. Primary endpoints were ORR (overall response rate; investigator-assessed RECIST 1.1) and safety. Progression-free survival (PFS) and overall survival (OS) were secondary endpoints. Results: Median duration of survival follow-up was 7.6 months for M-HR+ BC (data cutoff: Aug 2020) and 10.8 for M-TNBC (data cutoff: Mar 2021). In M-HR+ BC, none of whom received prior fulvestrant, 26 pts received atezo + ipat + fulv and 15 received fulv. Confirmed ORRs were 23.1% (95% CI: 9.0, 43.7) and 0% (95% CI: 0, 21.8), respectively. Median PFS was 4.4 mo (95% CI: 1.6, not evaluable) and 1.9 mo (95% CI: 1.6, 3.9), respectively. Updated survival data will be presented. Respectively, 61.5% and 20.0% of pts had Gr 3-4 AEs; no G5 AEs were observed; serious AEs (SAEs) occurred in 38.5% and 13.3% of pts; 7.7% and 0% of pts had tx-related AEs leading to tx withdrawal. The most common tx-related AEs were rash (73.0%), diarrhea (53.8%), nausea (42.3%), fatigue (26.9%), vomiting (23.1%), decreased appetite (19.2%), headache (15.4%), pyrexia (11.5%), hyperglycemia (11.5%), and aspartate aminotransferase (AST) increase (11.5%), in the combination arm; of these, rash (38.4%), diarrhea (7.7%), and AST increase (7.7%) included Grade 3-4 tx-related AEs. In M-TNBC, 29 pts received atezo + ipat and 24 received capecitabine. Confirmed ORRs were 3.4% (95% CI: 0.1, 17.8) and 20.8% (95% CI: 7.1, 42.2), respectively. Median PFS was 1.7 mo (95% CI: 1.5, 2.8) and 4.1 mo (95% CI: 2.3, 5.7), respectively. Median OS was 10.8 mo (95% CI: 7.0, 18.1) and 15.2 mo (95% CI: 14.4, 20.8). Gr 3-4 AEs were seen in 51.7% and 37.5% of pts, respectively; Gr 5 AEs were seen in 1 pt in the combination arm (encephalitis due to atezo). SAEs occurred in 51.7% and 16.7% of pts, respectively; 6.9% and 4.2% of pts had tx-related AEs leading to tx withdrawal. The most common tx-related AEs were rash (55.2%), diarrhea (48.3%), nausea (37.9%), pyrexia (31.0%), and fatigue (24.1%) in the combination arm; of these, rash (24.1%), fatigue (3.4%), and pyrexia (3.4%) included Gr 3-4 tx-related AEs. Biomarker data, including PI3K pathway status, PD-L1 and CD8-panCK expression, will also be presented. Conclusion: Atezo + ipat + fulv was tolerable with a preliminary efficacy signal in HR+ BC. Atezo + ipat had limited efficacy in biomarker unselected TNBC. Citation Format: Sara A. Hurvitz, Valentina Boni, Elizabeth Comen, Seock-Ah Im, Kyung Hae Jung, Sung-Bae Kim, Keun Seok Lee, Sherene Loi, Hope S. Rugo, Amir Sonnenblick, Melinda L. Telli, Kelly DuPree, Marcella Fasso, Ya-Chen Lin, Mina Nikanjam, Frauke Schimmoller, Xiaosong Zhang, Jing Zhu, Peter Schmid. Phase Ib/II open-label, randomized trial of atezolizumab (atezo) with ipatasertib (ipat) and fulvestrant (fulv) vs control in MORPHEUS-HR+ breast cancer (M-HR+ BC) and atezo with ipat vs control in MORPHEUS triple negative breast cancer (M-TNBC) [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 PD10-04.

Abstract CT010: Primary results of phase 2 FOENIX-CCA2: The irreversible FGFR1-4 inhibitor futibatinib in intrahepatic cholangiocarcinoma (iCCA) with FGFR2 fusions/rearrangements

Abstract Background FGFR2 fusions occur in ~15% of patients (pts) with iCCA, a rare cancer with a poor prognosis. Futibatinib, a highly selective, irreversible FGFR1-4 inhibitor, has shown activity across tumor types, including iCCA, in a phase 1 study. The pivotal phase 2 FOENIX-CCA2 trial (NCT02052778) is evaluating futibatinib in iCCA harboring FGFR2 fusions/rearrangements. Here, we report the first efficacy, safety, and quality of life (QoL) data for the complete FOENIX-CCA2 population. Methods Eligible pts had unresectable/metastatic iCCA with an FGFR2 fusion/rearrangement and progressive disease (PD) after ≥1 prior treatment (tx; excluding FGFR inhibitors). Pts received futibatinib 20 mg QD until PD/intolerability. The primary endpoint was objective response rate (ORR) per RECIST v1.1 by independent central review (target ORR: 20%). Secondary endpoints included duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), safety, and patient-reported outcomes (PROs). Subgroup analyses were performed by pt characteristic and molecular alteration. Results Among 103 pts (56% female), 53% had received ≥2 prior tx. FGFR2 fusions were present in 78% (23% had FGFR2-BICC1 fusions) and FGFR2 rearrangements in 22%. At data cutoff (Oct 1, 2020), 72 pts (70%) had discontinued tx. The study met its primary objective with a confirmed ORR of 41.7% (43/103). Responses were durable, with a median (m) DOR of 9.7 mo and 72% of responses ≥6 mo. DCR was 82.5%. mPFS was 9.0 mo; mOS was 21.7 mo, with a 12-mo OS rate of 72%. ORR was consistent across pt demographic subgroups (≥65 y: 65.2%; 2 prior tx: 38.7%). Common tx-related AEs (TRAEs) were hyperphosphatemia (85%), alopecia (33%), and dry mouth (30%). The most frequent grade 3 TRAE, hyperphosphatemia (30%), resolved with adequate management (median 7 d). Retinal disorders (all grade 1-2) were reported in 8% of pts. TRAEs were managed with dosing interruptions (50%)/reductions (54%); 2 pts discontinued tx due to TRAEs. No tx-related deaths occurred. ORRs were consistent in pts with dosing interruptions (40.2%) or reductions (46.8%). PROs were stable through 11.0 mo of tx. In exploratory biomarker analyses, ORR was consistent in pts with FGFR2 fusions (43.8%) and other FGFR2 rearrangements (34.8%) and in pts with BICC1 (41.7%) and non-BICC1 (44.6%) fusion partners. Notably, no obvious differences in ORR were observed in pts with co-occurring genetic alterations, including TP53 comutations (ORR, 38.5% [5/13]). Additional biomarker data will be presented. Conclusions Futibatinib resulted in frequent, durable objective responses in pts with iCCA harboring FGFR2 fusion/rearrangements, regardless of pt baseline characteristic, molecular alteration, or comutation. AEs were manageable with dosing modifications that did not impact response. QoL was maintained. Citation Format: Lipika Goyal, Funda Meric-Bernstam, Antoine Hollebecque, Chigusa Morizane, Juan W. Valle, Thomas B. Karasic, Thomas A. Abrams, Robin Kate Kelley, Philippe Cassier, Junji Furuse, Heinz-Josef Klümpen, Heung-Moon Chang, Li-Tzong Chen, Yoshito Komatsu, Kunihiro Masuda, Daniel Ahn, Yaohua He, Nital Soni, Karim A. Benhadji, John A. Bridgewater. Primary results of phase 2 FOENIX-CCA2: The irreversible FGFR1-4 inhibitor futibatinib in intrahepatic cholangiocarcinoma (iCCA) with FGFR2 fusions/rearrangements [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT010.

Abstract CT003: Nivolumab (NIVO) + platinum-doublet chemotherapy (chemo) vs chemo as neoadjuvant treatment (tx) for resectable (IB-IIIA) non-small cell lung cancer (NSCLC) in the phase 3 CheckMate 816 trial

Abstract Background In patients (pts) with non-metastatic NSCLC, surgery has curative potential but 30-80% who undergo resection experience recurrence. Neoadjuvant or adjuvant chemo is recommended for pts with high recurrence risk; however, benefits are modest and pathological complete response (pCR) with neoadjuvant chemo is low. Although immunotherapy targeting the PD-1 pathway has shown survival benefits in metastatic NSCLC, phase 3 trial results in resectable disease are yet to be reported. Recently, neoadjuvant NIVO, alone or in combination with chemo, has shown encouraging pCR rates in single-arm phase 2 studies. Here, we report the final analysis of one of the primary endpoints, pCR, of CheckMate 816 (NCT02998528)-a randomized, phase 3, open-label study evaluating NIVO + chemo vs chemo as neoadjuvant tx for resectable NSCLC. Methods Adults with clinical stage IB (≥ 4 cm)-IIIA (per AJCC 7th ed), resectable NSCLC, ECOG PS 0-1, and no known EGFR/ALK alterations were randomized to either NIVO 360 mg + platinum-doublet chemo Q3W or chemo Q3W for 3 cycles, followed by surgery. Stratification was by disease stage (IB/II vs IIIA), PD-L1 (≥ 1% or < 1%), and sex. pCR by blinded independent pathological review (BIPR) and event-free survival by blinded independent central review (BICR) are the primary endpoints. pCR was defined as 0% viable tumor cells in resected lung and lymph nodes; pts who did not undergo surgery were counted as non-responders. Overall survival, major pathological response (MPR; ≤ 10% viable tumor in both lung and lymph nodes) per BIPR, and time to death or distant metastases are secondary endpoints. Key exploratory endpoints are objective response rate (ORR) per BICR and potential predictive biomarkers including PD-L1 and tumor mutational burden (TMB). Results Baseline characteristics were balanced between arms (n = 179 each). Neoadjuvant NIVO + chemo significantly increased pCR rates vs chemo in the intent-to-treat population (ITT) (24.0% vs 2.2%; odds ratio 13.94 [99% CI 3.49-55.75]; P < 0.0001). Improvement in pCR with NIVO + chemo vs chemo was consistent across key subgroups including disease stage (IB/II [26.2% vs 4.8%]; ≥ IIIA [23.0% vs 0.9%]), PD-L1 (< 1% [16.7% vs 2.6%]; ≥ 1% [32.6% vs 2.2%]), and TMB (low [22.4% vs 1.9%]; high [30.8% vs 2.7%]). NIVO + chemo also improved MPR rates vs chemo in the ITT (36.9% vs 8.9%), as well as ORR (53.6% vs 37.4%) and radiographic down-staging rates (30.7% vs 23.5%). Definitive surgery occurred for 83.2% of pts treated with NIVO + chemo and 75.4% with chemo; surgery was cancelled rarely due to AEs (2 pts/arm) and due to disease progression in 12 and 17 pts, respectively. Grade 3-4 tx-related AEs and grade 3-4 surgery-related AEs were reported in 33.5% vs 36.9% and 11.4% vs 14.8% of pts in the NIVO + chemo vs chemo arms, respectively. Conclusions CheckMate 816 met its first primary endpoint with a statistically significant improvement in pCR with neoadjuvant NIVO + chemo vs chemo alone per independent review. The safety profile of NIVO + chemo was consistent with the known profile of this combination regimen, and the addition of NIVO did not decrease the ability to perform surgery. CheckMate 816 is the first positive phase 3 trial demonstrating a significant improvement in pathologic response with neoadjuvant immunotherapy plus chemo in resectable NSCLC. Citation Format: Patrick M. Forde, Jonathan Spicer, Shun Lu, Mariano Provencio, Tetsuya Mitsudomi, Mark M. Awad, Enriqueta Felip, Stephen Broderick, Julie Brahmer, Scott J. Swanson, Keith Kerr, Changli Wang, Gene B. Saylors, Fumihiro Tanaka, Hiroyuki Ito, Ke-Neng Chen, Cecile Dorange, Junliang Cai, Joseph Fiore, Nicholas Girard. Nivolumab (NIVO) + platinum-doublet chemotherapy (chemo) vs chemo as neoadjuvant treatment (tx) for resectable (IB-IIIA) non-small cell lung cancer (NSCLC) in the phase 3 CheckMate 816 trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT003.

Abstract CT134: A phase I study of avelumab, palbociclib, and cetuximab (APC) in recurrent or metastatic head and neck squamous cell carcinoma (RM HNSCC)

Abstract Background: Checkpoint inhibitors have activity in RM HNSCC, but response rates to single agent therapy are low. Combination therapy may improve outcomes. We aimed to study a novel combination of palbociclib (P) and cetuximab (C) with the PD-L1 inhibitor avelumab (A) in RM HNSCC. Methods: Eligible patients (pts) with RM HNSCC received P in combination with A 10 mg/kg IV every 2 wks and C 400 mg/m2 IV x 1, then 250 mg/m2 weekly. The starting dose of P was 75 mg PO daily on days 1 to 21 of a 28 day cycle. The 3+3 dose escalation design included planned doses of P 100 mg and P 125 mg, with no intra-patient escalation. The primary objective was to identify the recommended phase II dose (RP2D); secondary objectives included response rate and progression free survival (PFS). Results: As of 10/15/20, 12 pts have been treated in 3 cohorts: P 75 mg PO daily (3 pts), 100 mg PO daily (3 pts), and 125 mg PO daily (6 pts). Median age was 56 yo, 92% were male, with 58% p16+, 25% p16-, 17% p16 unknown. One DLT was observed in cohort 3: a grade 3 infusion reaction related to C. The RP2D was P 125 mg, with A and C at standard doses. Other grade 3 AEs were leukopenia (4 pts), neutropenia (4 pts), acneiform rash (2 pts), cellulitis (1pt), increased WBC (1pt). One pt had grade 4 leukopenia. There were no grade 5 AEs. Tx related AEs occurring in > 30% of pts were: acneiform rash (11pts), fatigue (10pts), mucositis (7pts), dry skin (6 pts), decreased WBCs (5 pts), paronychia (5 pts), nausea (5pts), hypomagnesemia (4pts). Response rate by RECIST 1.1 was 42% (3 CRs, 2PRs); median duration of response has not been reached. Median PFS was 6.5 m. Reasons for discontinuation were disease progression (8 pts), pt choice (1 pt). 3 patients remain on therapy (after 20, 15, and 9 months). Conclusions: The combination of APC was well tolerated in patients with RM HNSCC; no unexpected toxicities were seen. The RP2D is A 10 mg/kg every 2 wks, C 400 mg/m2 x 1 then 250 mg/m2 wkly, and P 125 mg daily, 3 wks on, one wk off. Promising response rates were seen, and several pts have had durable responses. These data support further development of this combination. Biomarker analyses on tissue and blood are ongoing. NCT03498378. Citation Format: Kathryn A. Gold, Assuntina Sacco, Julie Bykowski, Gregory Daniels, Emily Pittman, Karen Messer, Ruifeng Chen, Ezra Cohen. A phase I study of avelumab, palbociclib, and cetuximab (APC) in recurrent or metastatic head and neck squamous cell carcinoma (RM HNSCC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT134.

EV-201 Cohort 2: Enfortumab vedotin in cisplatin-ineligible patients with locally advanced or metastatic urothelial cancer who received prior PD-1/PD-L1 inhibitors.

394 Background: Cisplatin (cis)-ineligible, platinum-naive patients (pts) with locally advanced or metastatic urothelial carcinoma (la/mUC) who progress on/after PD-1/L1 inhibitors (PD-1/L1-i) have a poor prognosis and few treatment (tx) options. Enfortumab vedotin (EV) is an antibody-drug conjugate directed against Nectin-4, an immunoglobulin-like cell adhesion molecule highly expressed in UC. EV-201 (NCT03219333) is a pivotal, single-arm, 2-cohort study of EV in la/mUC; Cohort (C) 1 data led to FDA accelerated approval of EV in adult pts with la/mUC who previously received a PD-1/L1-i and a platinum-containing chemotherapy in the neoadjuvant/adjuvant, la/mUC setting. Here, we present the primary analysis from C2: cis-ineligible pts with prior PD-1/L1-i and no prior platinum for la/mUC. Methods: Pts in this open-label, multicenter, multinational study received 1.25 mg/kg EV on Days 1, 8, and 15 of each 28-day cycle. Primary endpoint was confirmed objective response rate (ORR) per RECIST 1.1 by blinded independent central review (BICR). Secondary endpoints were duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Results: As of 08 Sep 2020 (data cutoff), 91 pts were enrolled and 89 treated in C2. Pts were elderly (median age: 75 y [range: 49-90]) with comorbidities, including moderate/severe renal impairment. Pts were cis-ineligible at study entry due to CrCl < 60 mL/min (66%), Grade ≥2 hearing loss (15%), or ECOG PS 2 (7%); an additional 12% met ≥1 criterion. The primary tumor site was in upper tract in 43%; 79% had visceral mets, including 24% with liver mets. Median (m) tx duration was 6.0 mo (range: 0.3 – 24.6). Confirmed ORR per BICR was 52% (95% CI: 40.8–62.4), including 20% CR among treated pts. mDOR was 10.9 mo (95% CI: 5.8–NR). mPFS and mOS were 5.8 mo (95% CI 5.0-8.3) and 14.7 mo (95% CI 10.5-18.2), respectively. Most common all-grade tx-related AEs were alopecia (51%), peripheral sensory neuropathy (47%), and fatigue (34%). Tx-related AEs of interest included rash (61% all grade, 17% ≥G3), peripheral neuropathy (54% all grade, 8% ≥G3), and hyperglycemia (10% all grade, 6% ≥G3). Four deaths were reported as tx related by investigators, all in pts ≥75 y with multiple comorbidities: 3 events ≤30 d of first EV dose in pts with BMI ≥30(acute kidney injury, metabolic acidosis, and multiple organ dysfunction syndrome) and 1 event > 30 d after last dose (pneumonitis). Conclusions: In EV-201 C2, the majority of platinum-naive, cis-ineligible la/mUC pts who progressed on/after PD-1/L1-i achieved durable responses to EV, with 1/5 achieving CR. PFS and OS were encouraging. Safety was consistent with the previously reported AE profile of EV, within the context of a patient population with advanced malignancy and comorbidity. These data show the potential for EV as a non-platinum option following PD-1/L1-i. Clinical trial information: NCT03219333.

Phase Ib/II open-label, randomized evaluation of efficacy and safety of atezolizumab plus isatuximab versus regorafenib in MORPHEUS-colorectal cancer.

82 Background: The MORPHEUS platform consists of multiple, global, open-label, randomized Phase Ib/II trials designed to identify early efficacy signals and safety of treatment (tx) combinations across tumor types. Isatuximab (isa; anti-CD38) targets CD38 receptors expressed on immunosuppressive cells in the tumor microenvironment. We hypothesized atezolizumab (atezo; anti–PD-L1) + isa would induce an anti-tumor response beyond that of regorafenib (rego), a multi-kinase inhibitor, in patients (pts) with tx-refractory metastatic colorectal cancer (mCRC). Methods: This randomized Phase Ib/II trial (NCT03555149) enrolled pts with microsatellite stable/mismatched repair proficient mCRC who had received ≤ 2 prior tx lines (fluoropyrimidine-, oxaliplatin- or irinotecan-containing chemotherapy plus a biologic agent). Pts received atezo (1200 mg intravenously [IV] every 3 weeks [q3w]) + isa (10 mg/kg IV q3w) or control tx with rego (160 mg orally days 1–21; dose escalation to 160 mg during Cycle 1 allowed per institutional guidelines). The primary endpoint was objective response rate (ORR; investigator-assessed RECIST 1.1); secondary endpoints included progression-free survival (PFS), overall survival (OS), disease control rate (DCR) and safety. Results: Data cutoff date was March 3, 2020. Fifteen pts received atezo + isa and 13 pts received rego. Fourteen atezo + isa pts (93.3%) and 11 control arm pts (84.6%) had received 2 prior lines of tx; 9 atezo + isa pts (60.0%) and 9 control pts (69.2%) had liver metastases at enrollment. No responses were seen in either arm; 3 pts receiving atezo + isa (20.0%) and 8 control pts (61.5%) had stable disease as their best response. DCR (response and/or stable disease ≥ 12 weeks) was 6.7% with atezo + isa and 15.4% with control. One pt treated with atezo + isa beyond progression had prolonged disease stabilization. Median PFS was 1.4 mo (95% CI: 1.4, 1.8) with atezo + isa and 2.8 mo (95% CI: 1.6, 3.1) in the control arm; median OS was 5.1 mo (95% CI: 3.1, 7.8) with atezo + isa and 10.2 mo (95% CI: 4.8, not reached) with control. Tx-related adverse events (AEs, Grade 1-4) occurred in 13 atezo + isa pts (86.7%), and 12 control pts (92.3%). The most common tx-related AEs with atezo + isa were infusion-related reaction (73.3%), nausea (26.7%) and fatigue (20.0%). No Grade 5 AEs occurred in the atezo + isa arm, 1 (7.7%) was reported in the control arm (sepsis, considered unrelated to study tx). No atezo + isa pts and 1 control-arm pt (7.7%) withdrew from treatment due to a tx-related AE. Biomarker analyses did not identify any significant trends related to efficacy. Conclusions: In this trial, superior efficacy of atezo + isa vs rego was not shown. However, the atezo + isa combination was well tolerated, with a manageable safety profile. Clinical trial information: NCT03555149.

528O CC-90011 in patients (Pts) with advanced solid tumours (STs) and relapsed/refractory non-Hodgkin lymphoma (R/R NHL): Updated results of a phase I study

CC-90011 is an oral, potent, selective, reversible inhibitor of lysine-specific demethylase 1A. CC-90011 was well tolerated and had promising antitumor activity in pts with advanced unresectable STs and R/R NHL in the dose-escalation part of the CC-90011-ST-001 study. Here we present updated results from the cohort expansion part of the study. Pts in this phase I, dose-escalation (part A) and -expansion (part B), first-in-human study received CC-90011 once/wk (QW) in 28-d cycles. Primary endpoints were safety, maximum tolerated dose (MTD), and recommended phase II dose (RP2D). Secondary and exploratory endpoints included pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy. Sixty-six pts enrolled, 50 in part A (27 with neuroendocrine neoplasms [NENs] and 1 with R/R NHL) and 16 in part B (all with NENs). The RP2D was 60 mg QW. As of 17 Jan 2020, 4 pts (3 with NENs, 1 with R/R NHL) in part A and 2 pts in part B remained on treatment (tx). The primary reason for tx discontinuation was progressive disease (part A, n=38 [76%]; part B, n=12 [75%]). Thrombocytopenia was the most common tx-related adverse event (AE; 47%), and the only serious AE reported in >1 pt in either part of the study; this on-target toxicity was reversible and manageable. AEs led to discontinuation in 3 pts (6%), all in part A. Two pts in part A and 1 in part B died due to underlying disease; there were no deaths due to tx-related AEs. Clinical benefit rate (partial or complete response [CR] or stable disease [SD] ≥4 mo) was 20% (95% CI, 10.0-33.7) in part A and 44% (95% CI, 19.8-70.1) in part B. In part A, the R/R NHL pt achieved a CR (ongoing in cycle 32) and 5 pts with NENs had SD ≥9 cycles, including 2 with SD ≥21 cycles. In part B, 3 pts with NENs had SD ≥9 cycles. Exposure increased proportional to dose. Negligible accumulation of exposure occurred with repeat dosing and systemic exposures at the same dose were similar in parts A and B. Decreased levels of chromogranin A and peripheral blood PD biomarker, MMD, indicated CC-90011 target engagement. CC-90011 was well tolerated with favorable PK/PD profiles. Promising antitumor activity was observed in pts with NENs and R/R NHL.

A phase I study of the novel immunotoxin, MT-5111, in subjects (subj) with HER-2 positive tumors: Interim results.

e15567 Background: Engineered toxin bodies (ETBs), composed of a Shiga-like Toxin A subunit genetically fused to antibody-like binding domains, can force receptor internalization, self-route through intracellular compartments to the cytosol, and induce potent cell-kill via the enzymatic and permanent inactivation of ribosomes. MT-5111, a de-immunized 55 kD ETB targeting HER2 in solid tumors, binds to an epitope distinct from and non-competitive with trastuzumab and pertuzumab. Methods: The primary objective is to determine the maximum tolerated dose (MTD) of MT-5111 monotherapy in adults with advanced HER2+ solid tumors. Secondary objectives are pharmacokinetics, efficacy, and immunogenicity. Part 1 will identify the MTD via MT-5111 dose escalation (0.5, 1.0, 2.0, 3.0, 4.5, 6.75, 10 µg/kg/dose) according to a modified 3+3 design. Part 2 will further evaluate the safety of MT-5111 at the recommended phase 2 dose (RP2D) in 3 separate cohorts of subjs with a HER2 immunohistochemistry score ≥2 in a metastatic lesion of primary breast, gastroesophageal, or other cancers. All subjs receive MT-5111 as a 30-minute IV infusion on Days 1, 8, and 15 of each 21-day treatment (tx) cycle (C) until disease progression, unacceptable toxicity, death, or withdrawn consent. Details can be found on clinicaltrials.gov (NCT04029922). Results: The first cohort (0.5 µg/kg/dose) enrolled 4 subjs (metastatic breast cancer, n = 2; metastatic cholangiocarcinoma, n = 2). Three subjs were female and the mean age was 69 years (median 65, range 64-78). Subjs received a mean of 5 prior lines of therapy (median 4.5, range 3-8). Three subjs completed C1 of tx without dose-limiting toxicities; 1 subj was inevaluable. Two subjs had progressive disease in C2. A total of 23 AEs occurred in 4 subjs; all were grade (G) 1-2 except one G3 event of hypertension in a subj with a history of hypertension. There were 2 tx-related AEs (G1 chills; G2 aspartate aminotransferase increased in the setting of progressive liver metastases). There was 1 serious, non-tx-related AE (G2 dyspnea) that occurred in the inevaluable subj. No cardiac AEs were noted, nor clinically significant changes in cardiac biomarkers, an important safety parameter given non-human primate toxicity. Conclusions: MT-5111 appears to be well tolerated at the lowest dose with no apparent cardiotoxicity to date. Drug concentrations are expected to be below the level required for in vitro tumor cell killing. Safety and efficacy data from subsequent dose escalation cohorts are expected by May 2020. Clinical trial information: NCT04029922.

Phase Ib/II open-label, randomized evaluation of 2L atezolizumab (atezo) + PEGPH20 versus control in MORPHEUS-pancreatic ductal adenocarcinoma (M-PDAC) and MORPHEUS-gastric cancer (M-GC).

4540 Background: The MORPHEUS platform consists of multiple, global, open-label, randomized Phase Ib/II trials designed to identify early efficacy signals and safety of treatment (tx) combinations across cancers. Within MORPHEUS, atezo (anti–PD-L1) was tested with PEGylated recombinant human hyaluronidase (PEGPH20), an anti–stromal and extracellular matrix modulator, in patients (pts) with metastatic (m) PDAC or advanced/mGC. Methods: In 2 separate randomized trials, eligible pts with 2L mPDAC or mGC received atezo (1200 mg IV q3w) + PEGPH20 (3 µg/kg IV on D1, 8, 15). Control tx for M-PDAC (NCT03193190) was mFOLFOX6 or gemcitabine + nab-paclitaxel. In M-GC (NCT03281369), control tx was ramucirumab + paclitaxel. Primary endpoints were ORR (investigator-assessed RECIST 1.1) and safety. Results: Pts were followed up for ≥ 18 wk in M-PDAC (data cutoff: Aug 5, 2019) and ≥ 24 wk in M-GC (data cutoff, Jul 11, 2019). In M-PDAC, 66 pts received atezo + PEGPH20 and 42 received control in both preliminary and expansion phases. Confirmed ORRs were 6.1% (95% CI: 1.7, 14.8) and 2.4% (95% CI: 0.06, 12.6), respectively. Duration of response ranged from 5.3 to 11.3 mo in tx arm and was 3.9 mo in control. Median PFS was 1.5 mo (95% CI: 1.4, 2.6) and 2.3 mo (95% CI: 1.6, 4.0), respectively. Median OS was 7.1 mo (95% CI: 4.6, 9.5) and 6.8 mo (95% CI: 5.6, 8.3). Updated survival data will be presented. Respectively, 62.2% and 59.5% of pts had Gr 3-4 AEs; Gr 5 AEs were seen in 4.5% and 2.4% of pts; serious AEs (SAEs) occurred in 45.5% and 45.2% of pts; 16.7% and 4.8% of pts had tx-related AEs leading to tx withdrawal. The most common tx-related AEs were myalgia (65.2%) and peripheral edema (28.8%) in the combination arm. In M-GC, 13 pts received atezo + PEGPH20 and 12 received control. Confirmed ORRs were 0% (95% CI: 0, 24.7) and 16.7% (95% CI: 2.1, 48.4), respectively. Gr 3-4 AEs were seen in 30.8% and 75.0% of pts, respectively. No Gr 5 AEs occurred in either arm. SAEs occurred in 7.7% and 50.0% of pts, respectively. Only 1 pt in the control arm had a tx-related AE leading to tx withdrawal. While tumor hyaluronan (HA) appears to be associated with poor prognosis in the M-PDAC control, there was no clear association between HA levels and response to atezo + PEGPH20. PK data will also be presented. Conclusions: Limited efficacy was seen with the chemotherapy-free combination of atezo + PEGPH20 in PDAC. No efficacy was seen in GC. The safety of atezo + PEGPH20 was consistent with each agent’s known safety profile; no new safety signals were identified. Clinical trial information: NCT03193190 .

Phase Ib/II open-label, randomized evaluation of 2L atezolizumab (atezo) + BL-8040 versus control in MORPHEUS-pancreatic ductal adenocarcinoma (M-PDAC) and MORPHEUS-gastric cancer (M-GC).

712 Background: The MORPHEUS platform comprises multiple Ph Ib/II trials to identify early efficacy signals and safety of treatment (tx) combinations across cancers. Due to the immune-mediated effects of BL-8040, a high-affinity antagonist for CXCR4, it was tested with atezo (anti-PD-L1) in pts with advanced/metastatic (m) PDAC and GC. Methods: In 2 separate randomized trials, pts with mPDAC or advanced/mGC who progressed on 1L chemo received either atezo + BL-8040 (BL-8040 1.25 mg/kg SC D1-5, then BL-8040 1.25 mg/kg SC TIW + atezo 1200 mg IV Q3W) or control tx (M-PDAC: mFOLFOX-6 or gemcitabine + nab-paclitaxel; M-GC: paclitaxel + ramucirumab). Primary endpoints were investigator-assessed ORR per RECIST 1.1 and safety. Results: Efficacy from evaluable pts followed for ≥18 wks in M-PDAC and ≥8 wks in M-GC is summarized in the table; 24-wk M-GC data will be presented. There were 15 safety-evaluable pts in each M-PDAC arm, as well as 13 in the atezo + BL-8040 and 12 in the control arm of M-GC. Gr 3-5 AEs were seen in 47% of pts on atezo + BL-8040 and 67% on control in M-PDAC, and 77% on atezo + BL-8040 and 67% on control in M-GC. Tx-related SAEs in M-PDAC occurred in 7% of pts on atezo + BL-8040 and 20% on control, and in M-GC, in 8% of pts on control. No Gr 5 AEs occurred in atezo + BL-8040 arms. Tx-related AEs led to 7% and 8% of pts discontinuing tx in the M-PDAC and M-GC control arms, respectively, and 15% discontinuing BL-8040 in M-GC due to Gr 3 injection-related reactions. Biomarker and PK data will be presented. Conclusions: Atezo + BL-8040 had limited efficacy for PDAC or GC. Tx-related AEs with atezo + BL-8040 were consistent with each agent’s known safety profile. Clinical trial information: NCT03281369; NCT03193190 . [Table: see text]

A phase II study of nab-paclitaxel plus ramucirumab for the second-line treatment of patients with metastatic gastroesophageal cancer.

365 Background: Nab-paclitaxel (NP) is a protein-stabilized formulation of paclitaxel, US FDA approved for treatment of metastatic breast cancer, advanced/metastatic non-small cell lung cancer and metastatic adenocarcinoma of the pancreas. Ramucirumab (R) is an antibody targeting vascular epithelial growth factor receptor 2 (VEGFR-2) approved for treatment of gastric or gastroesophageal (GE) adenocarcinoma in combination with paclitaxel as 2nd line treatment. This phase II study evaluated the efficacy of NP and R for pts with metastatic GE cancer. Methods: Pts with metastatic GE adenocarcinoma were treated with 125 mg/m2 NP on days 1, 8, and 15, and 8 mg/kg R on days 1 and 15 of each 28-day cycle. Pts continued study treatment (tx) until intolerable toxicity, disease progression (PD), or withdrawal of consent. Restaging occurred every 2 cycles. The primary objective was progression-free survival (PFS); secondary objectives were response rate (RR), time to progression (TTP), overall survival (OS) and toxicity. Results: 65 pts were enrolled between 05/15 and 12/18: median age 63 yrs (35-86), 75% male, 71% ECOG 1. Primary tumor sites were stomach (37%), GE junction (35%), and esophagus (28%). 83% were stage IV at initial diagnosis. 29% were HER2+ at study entry. 57% had 1st line chemo, 40% chemo + targeted agent and 3% chemo + immunotherapy. Median tx duration was 13 weeks (.1-55) for NP and 12 weeks (.1-54) for R; at data cutoff 2 pts remained on tx.60% discontinued due to PD; 17% due to AE. 43% and 23% had AE-related dose reductions of NP and R, respectively; 8% and 6% were on day 15. 58% had dose interruptions of R due to AE; 42% on day 15. Median PFS was 3.8 months (CI 95% 3.4, 4.8); median TTP 4.5 months (CI 95% 3.5, 6.3); and median OS 8.8 months (CI 95% 6.1, 11.3). RR was 15% (CI 95% 6.6, 24.2); disease control rate was 68% (CI 95% 56.3, 79.1). Most common tx related AEs were neutropenia (55%), fatigue (40%), peripheral neuropathy (37%), anorexia and mucositis (26% each). Conclusions: There were no unexpected toxicity findings with NP and R in pts with GE cancers. Compared to historical controls, outcomes in this study were similar to those seen in the Western population of pts who received paclitaxel plus R. Clinical trial information: NCT02317991.

37O - Subgroup analysis of IMpassion130: Atezolizumab + nab-paclitaxel (nab-P) in patients (pts) with advanced triple-negative breast cancer (TNBC) in Asian countries

37O - Subgroup analysis of IMpassion130: Atezolizumab + nab-paclitaxel (nab-P) in patients (pts) with advanced triple-negative breast cancer (TNBC) in Asian countries

603P - A phase Ib study of the safety and efficacy of atezolizumab (atezo) + bevacizumab (bev) + cobimetinib (cobi) in patients (pts) with metastatic colorectal cancer (mCRC)

603P - A phase Ib study of the safety and efficacy of atezolizumab (atezo) + bevacizumab (bev) + cobimetinib (cobi) in patients (pts) with metastatic colorectal cancer (mCRC)

457P - First-in-human study of ABBV-621 in patients (pts) with previously treated sold tumours: Dose-optimization cohorts

457P - First-in-human study of ABBV-621 in patients (pts) with previously treated sold tumours: Dose-optimization cohorts

Abstract CT166: A Phase I/II, open-label, two part study of GSK3359609 in combination with tremelimumab in participants with selected, advanced solid tumors

Abstract Background: GSK3359609 (GSK609) is an inducible T cell co-stimulator (ICOS) agonist antibody and tremelimumab (treme) is a cytotoxic T-lymphocyte-antigen 4 (CTLA-4) antagonist antibody. Nonclinical and clinical studies have shown that ICOS expression on T cells is upregulated after anti-CTLA-4 treatment (tx). ICOS+ T cells have a positive association with overall survival (OS) in treme treated chemotherapy-resistant malignant mesothelioma and melanoma patients (pts). Therefore, the combination of these 2 drugs may provide greater antitumoral response than either drug alone (Coutzac C: AACR 2019 meeting abstract). Methods: This is a Phase I/II, open-label, 2-part study. In Part 1, N=~24 pts will be enrolled. The study is designed to assess treme starting at 75 mg followed by GSK609 starting at 8 mg. At dose level (DL) 1, one pt who will receive the lowest doses of both drugs will be enrolled. If no dose limiting toxicity (DLT) is observed in the DLT observation period of 28 days, then 1-3 pts will be enrolled in DL2 - DL6 in a zone-based fashion (zones include the DLs with the next highest dose of one of the two drugs - 2DL are included in each zone in this study) with different dose combinations of the drugs being evaluated. The dose of 1 of the 2 drugs will be escalated with each new DL up to the highest dose of each. If ≥ grade 2 tx-related AEs occur at DL1 or 2, additional pts will be enrolled to collect more safety information. If DLTs are observed, the bivariate Continual Reassessment Method (CRM) model will be used to guide dose recommendations. The primary objective of Part 1 will be to assess safety. Additional pts may be enrolled in Part 1 to further evaluate pharmacokinetics/pharmacodynamics (PK/PD). Part 2 is a randomized expansion enrolling recurrent/metastatic head and neck squamous cell carcinoma pts who have disease progression after platinum chemotherapy and anti-programmed death receptor protein-1 (PD-1)/anti-programmed death-ligand 1 (PD-L1) therapy, in combination or separately. Pts may not have had ≥4 lines of prior tx in either Part 1 or 2. In Part 2, pts will be randomized 2:1 to the doses of GSK609 and treme (n=60) selected from Part 1 or to the Investigator’s choice of SOC single-agent therapy (paclitaxel, docetaxel or cetuximab) (n=30). The primary objective in Part 2 is to evaluate overall survival and the primary analysis is to perform Bayesian predictive probability of success for a future hypothetical Phase III study based on survival data. Secondary endpoints include safety, ORR, PFS, DOR, and PK while pharmacodynamic and other biomarker analyses constitute exploratory endpoints. Pts will be treated for up to 2 years with survival follow-up for up to 2 years post-tx. This study has enrolled 1 pt. Study NCT03693612 funded by GSK. Citation Format: Aaron Hansen, Raghad Abdul-Karim, Naiyer Rizvi, Danny Rischen, John Hilton, Zujun Li, Patrick Ott, Natalie Karpinich-Fedoriw, Sapna Yadavilli, Xiaowei Wang, Laurel Adams, Melody Wyres, Charles Ferte, Marc Ballas, Axel Hoos, Daniel Zandberg. A Phase I/II, open-label, two part study of GSK3359609 in combination with tremelimumab in participants with selected, advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT166.

Adjuvant enzalutamide for the treatment of early-stage androgen receptor-positive (AR+) TNBC.

546 Background: A subset of TNBC is dependent on AR signaling. Enzalutamide (ENZA), an AR-antagonist, has activity in patients (pts) with metastatic AR+ TNBC, with a clinical benefit rate of 33%. This study tests the feasibility of adjuvant ENZA for the treatment (tx) of early stage, AR+ TNBC. We now report the primary endpoint (endpt) and safety. Methods: Eligible pts have centrally confirmed, Stage I-III, ER/PR < 1%, HER2(-), AR ≥1% BC and completed all planned surgery, chemotx and radiation (RT) < 6 months of tx start. AR testing by IHC per MSK methods. Tx consists of ENZA 160mg daily for 1 year (y) with the option to extend tx to 2y. Toxicity per NCI CTCAEv4 every (q) 4 weeks (wk) for 12 wk, then q3 months. Primary endpt: feasibility of 1y ENZA defined as the discontinuation rate due to toxicity, consent withdrawal or tolerability. 50 pts are enrolled to have 46 evaluable pts required to discriminate between feasibility of 50% and 70%, with type I error 5% and 88% power. Pts who have disease progression (PD) or die during 1st y of ENZA and do not have tx discontinuation due to the above will not be included in the primary analysis. If 29 pts complete 1y, adjuvant ENZA will be deemed feasible. Secondary endpts: safety and 3y DFS and OS. Exploratory endpts: PROs and biomarker development. Results: Between 5/2016-6/2018, 50 pts were enrolled. Pt and tumor characteristics (N = 50): Median age 55y (33-81); Stage: I 20 (40%), II 23 (46%), III 7 (14%); Grade (gr): 2 = 26%, 3 = 74%. AR > 10% = 35 (70%), AR ≤10% = 15 (30%). Chemotx 47/50 (94%): Neoadjuvant (neo) 40%, Adjuvant (adj) 60%; Anthracycline/Taxane-based 38/47 (81%), Platinum 1/47 (2%), Docetaxel/Cyclophosphamide 3/47 (6%), other 5/47 (11%). 13/19 who received neo tx failed pCR; 9/13 (69.2%) received adj capecitabine. RT: 38/50 (76%). 27 pts completed 1y of tx. 7 pts will be evaluable by 6/1/19. 1 pt to complete 1y 6/21/19. 15 pts are off tx: PD (3), toxicity (5), noncompliance (4), withdrawal of consent (3). Tx-related AEs, any gr, > 10% (N = 50): fatigue (48%), hot flashes (22%), headache (18%), hyperglycemia (18%), nausea (18%), WBC decreased (16%), dizziness (14%), arthralgia (12%), dyspnea (12%). Tx-related, gr 3 AEs: fatigue (6%), hyperglycemia (2%), hypertension (2%). No gr 4/5 AEs or seizures. 11 pts had dose reduction. Conclusions: Feasibility of adjuvant ENZA will be fully evaluable in 4/2019 and is anticipated to meet the prespecified statistical expectations for primary endpt. ENZA is well tolerated following locoregional tx and standard of care systemic tx. Secondary analyses and correlatives are ongoing to define the role of AR in TNBC. Clinical trial information: NCT02750358.