Abstract CT042: NCI10217: Phase Ib biomarker-driven tumor-agnostic combination (Combo) trial of copanlisib (Copa) and olaparib (Ola) in molecularly-selected patients (pts) with advanced cancers with PIK3CA hotspot, PTEN and DNA damage response (DDR) mutations
Authors: Yap Timothy A. , Dumbrava Ecaterina E. , Ahnert Jordi Rodon , Tsimberidou Apostolia M. , Hong David , Piha-Paul Sarina A. , Karp Daniel D. , Fu Siqing , Naing Aung , Pohlmann Paula , Rhudy Jessica R. , Berenji-Jalaei Sheila B. , Cole Ashley A. , Valladolid Christian , Dufner Desirae , Bockorny Bruno B. , Bullock Andrea , Fein Daniel , Buchbinder Elizabeth , Choudhury Atish , Haddox Candace , Lee Elizabeth , Wulf Gerburg , Ivy Percy , Said Rabih , Shapiro Geoffrey , Meric-Bernstam Funda 
Published: April 2024

Abstract
Background: Preclinically, PI3K and PARP inhibition synergize in cancers with DDR and PI3K pathway alterations. NCI10217 assessed the combo of Copa (pan-PI3K inhibitor) and Ola (PARP inhibitor) in tumors harboring mutations in PI3K/AKT or DDR pathways.
Materials and Methods: Eligible pts had tumors with pathogenic PIK3CA hotspot, PTEN and DDR mutations. Copa was administered at 45 mg to 60 mg IV on Days (D) 1 and 15 or 1, 8 and 15 with Ola at 200 mg to 300 mg twice daily (BID) orally in 28-days cycles. Prior PARP and PI3K inhibitors were permitted. Fresh tumor biopsies and ctDNA were mandated at baseline and C1D15 and optional at the end of trial. Study objectives were safety, RP2D, pharmacokinetics, antitumor activity and translational analyses of serial tumor (WES; RNA-Seq; RPPA) and ctDNA samples.
Results: 28 pts (M:F 8:20; ECOG PS 0:1 9:19; mean age 58y (28-76y) with breast (n=6), colorectal (n=5), prostate (n=4), endometrial (n=2), gastric (n=2), vaginal (n=2), appendix, cervix, head and neck, leiomyosarcoma, ovarian, peritoneal, and renal (n=1) cancers were enrolled. Pts with BRCA1/2 (n=12), PTEN (n=10), PIK3CA hotspot (n=6), ARID1A (n=4), CHEK2 (n=3), PALB2 (n=3), ATM (n=2), CDK12, CHEK1, MRE11A, RAD51C (n=1 each) mutations were enrolled. 10 pt tumors harbored &gt;1 qualifying mutation. 17 (61%)/28 pts had ≥3 prior lines of therapy; 2 (7%)/28 had prior PARP inhibitors and 1 (4%)/28 had prior PI3K inhibitor. Common treatment-related toxicities included G1/2 mucositis (43%), nausea (43%), diarrhea (36%), anorexia (29%), fatigue (29%), maculo-papular rash (29%), hyperglycemia (25%), vomiting (25%); G3 transient hypertension (29%). Dose-limiting toxicities occurred in 3 (11%)/28 pts: 1 pt (G3 elevated transaminases) at Copa 45 mg (D1, D8 and D15) + Ola 200 mg BID, and 2 pts (G2 mucositis and maculo-papular rash, and G4 hyperglycemia) at Copa 60 mg (D1, D8, and D15) + Ola 300 mg BID. Of 22 pts evaluable for RECISTv1.1 criteria, 6 (27%)/22 pts achieved RECISTv1.1 partial responses (PR): 2 pts with BRCA1 mutation breast cancer; 1 pt with PIK3CA + PTEN + ARID1A mutation breast cancer; 1 pt with PTEN + PALB2 mutation breast cancer and prior PARP inhibitor exposure; 1 pt with BRCA2 mutation prostate cancer; 1 pt with BRCA2 + PTEN mutation prostate cancer. 8 (36%)/22 pts achieved RECISTv1.1 stable disease (SD); 2 (25%)/8 pts had SD≥6 months, including a pt with CA125 response (&gt;50% reduction). Clinical benefit rate (SD≥6 months + PR) was 36%. Responses were deep (up to -100%) and durable (up to 37+ months). Based on these data, the RP2D was established at Copa 60 mg D1 and D15 + Ola 300 mg BID.
Conclusion: Copa + Ola was safe and well-tolerated with clinical benefit observed in 36% of pts with advanced cancers with PIK3CA hotspot, PTEN and/or DDR mutations. Translational analyses are ongoing.
Citation Format: Timothy A. Yap, Ecaterina E. Dumbrava, Jordi Rodon Ahnert, Apostolia M. Tsimberidou, David Hong, Sarina A. Piha-Paul, Daniel D. Karp, Siqing Fu, Aung Naing, Paula Pohlmann, Jessica R. Rhudy, Sheila B. Berenji-Jalaei, Ashley A. Cole, Christian Valladolid, Desirae Dufner, Bruno B. Bockorny, Andrea Bullock, Daniel Fein, Elizabeth Buchbinder, Atish Choudhury, Candace Haddox, Elizabeth Lee, Gerburg Wulf, Percy Ivy, Rabih Said, Geoffrey Shapiro, Funda Meric-Bernstam. NCI10217: Phase Ib biomarker-driven tumor-agnostic combination (Combo) trial of copanlisib (Copa) and olaparib (Ola) in molecularly-selected patients (pts) with advanced cancers with PIK3CA hotspot, PTEN and DNA damage response (DDR) mutations [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 CT042.