458MO - Efficacy of durvalumab (Durva) in combination with olaparib (Ola) and capivasertib (Cap) in patients (pts) with advanced or metastatic (met) cancers (Ca) (MEDIPAC)

Background

Tumor-specific homologous recombination (HR) DNA defects and the phosphatidylinositol 3-kinase (PI3K)-AKT pathway have been shown in preclinical studies to modulate the tumor immune microenvironment, forming the rationale for triplet combination of Cap+Ola+Durva. Our previous work showed safety of Ola+Durva with Cap at both 200mg and 320mg BD (Lim et al, ESMO2021). Here, we present efficacy data from both dose escalation and expansion cohorts.

Methods

Safety, tolerability and efficacy data in both dose escalation (Cap 4 days on 3 days off, dose level 1 [DL]:160mg BD, DL2:200mg BD, DL3:320mg BD) and dose expansion at DL2 and DL3 of this phase Ib study was analysed. After 2 week run-in Cap, Durva and Ola were commenced at standard doses of 1500mg once 4-weekly and 300mg BD continuous dosing respectively.

Results

39 pts were enrolled (DL1 3pts, DL2 12pts, DL3 24pts); 28 had evaluable disease (DL1 3pts, DL2 10pts, DL3 15 pts). Median age 66 (range 36-81); median lines of prior therapy 3 (range 0-13); most common histology: breast (41.0%), endometrium (17.9%), ovary (15.4%). 64.1% and 5.1% had PIK3CA/AKT pathway or BRCA mutations; 12.8% had PDL1+/high TMB tumors. 15.4% had prior pathway-directed therapy based on known molecular aberration. In the evaluable population, objective response rate (ORR) was 20.0% (3/15) at DL3, including a pt with PIK3CA-mutant breast Ca with ongoing response for 10.9 months (m); median duration of response (DOR) was 8.7m (range 4.1-9.3m). No objective responses were observed at DL1 or DL2. Disease control rate (DCR) >6m was 0%, 30.0% and 33.3% at DL1, DL2 and DL3 respectively, and 44.4% in PIK3CA/AKT pathway enriched population. Both pts with BRCA-mutant cancers (1 breast Ca, 1 ovarian Ca) had progression-free survival of 6.4m and 8.1m respectively, despite prior progression on PARP inhibitors. Most frequent all-grade toxicities (tox) were fatigue (n=22, G3:1), diarrhoea (n=19, G3:2), nausea (n=18, G3:0) and rash (n=15, G3/4:4).

Conclusions

Triplet Cap+Ola+Durva showed anti-tumor activity with meaningful DOR at Cap 320mg BD, with good tolerability. A phase II expansion investigating its role in breast and gynaecological cancers is ongoing.

Clinical trial identification

NCT03772561.

Editorial acknowledgement

Legal entity responsible for the study

National University Health System, Singapore.

Funding

National Medical Research Council, Singapore; AstraZeneca.

Disclosure

J. Lim: Financial Interests, Personal, Advisory Board: pfizer, Novartis, AstraZeneca, DKSH; Financial Interests, Personal, Invited Speaker: DKSH, Roche, Pierre Fabre, AstraZeneca; Financial Interests, Institutional, Invited Speaker: Synthon pharmaceuticals, Daiichi, Taiho pharmaceuticals; Financial Interests, Institutional, Funding: CTI biopharma. S. Raghav: Financial Interests, Personal, Advisory Board: Bristol Myers Squibb, Merck, Eisai, Bayer, Taiho, Novartis, MSD; Financial Interests, Personal, Invited Speaker: MSD, Eli Lilly, BMS, Roche, Taiho, AstraZeneca; Non-Financial Interests, Advisory Role: Paxman Coolers; Non-Financial Interests, Principal Investigator: MSD. A. Wong: Financial Interests, Institutional, Research Grant: Ostuka Pharmaceutical; Financial Interests, Personal, Advisory Board: Pfizer, Novartis, Eisai , AstraZeneca. W.P. Yong: Financial Interests, Personal, Advisory Board: AbbVie/Genentech, Amgen, BMS, Ipsen, Novartis, AstraZeneca; Financial Interests, Personal, Invited Speaker: Eli Lilly, Sanofi/Aventis, Eisai, Bayer, MSD. R.A. Soo: Financial Interests, Personal, Advisory Board: Amgen, Astra-Zeneca, Bayer, BMS, Lilly, Merck, Novartis, Pfizer, Roche, Takeda, Yuhan; Financial Interests, Personal, Invited Speaker: Boehringer Ingelheim; Financial Interests, Personal, Other, Conference sponsorship: Taiho; Financial Interests, Institutional, Research Grant: Astra-Zeneca, Boehringer Ingelheim. C.E. Chee: Financial Interests, Personal, Advisory Board: AstraZeneca, Roche/Genentech; Financial Interests, Personal, Advisory Role: Guardant Health AMEA; Financial Interests, Personal, Other, Travel, accommodations, expenses: Taiho. S.C. Lee: Financial Interests, Personal, Advisory Board, Advisory board, speaker invitations: Pfizer, Novartis, AstraZeneca, Roche, MSD; Financial Interests, Personal, Advisory Board, Advisory Board: Eli Lilly; Financial Interests, Institutional, Research Grant: Pfizer, ACT Genomics, Eisai, Taiho, MSD, Karyopharm, ASLAN Pharmaceuticals; Financial Interests, Institutional, Invited Speaker: Roche, Novartis, Daiichi sankyo, BMS, AstraZeneca; Financial Interests, Personal, Invited Speaker: AstraZeneca. B. Goh: Financial Interests, Institutional, Invited Speaker: MSD, Adagene, Bayer, Pfizer; Financial Interests, Institutional, Advisory Board: Bayer Healthcare; Financial Interests, Personal, Other, Consultancy: Adagene pharmaceutical; Financial Interests, Personal, Stocks/Shares: Gilead Sciences, Regereron; Financial Interests, Institutional, Research Grant, Support for investigator initiated trial: MSD; Financial Interests, Institutional, Other, Pharmaceutical support for clinical trial: BMS; Financial Interests, Institutional, Other, Pharmaceutical support for investigator initiated clinical trial: Taiho pharmaceuticals; Non-Financial Interests, Institutional, Other, Lead clinical trial platform of the Singapore Translational Cancer Consortium: Consortium for Clinical Research and Innovation Singapore; Non-Financial Interests, Member: ASCO. R.A. Dent: Financial Interests, Personal, Advisory Board: AstraZeneca, Roche, Pfizer, Merck, Lilly, Eisai; Financial Interests, Personal, Invited Speaker: AstraZeneca, Roche, Pfizer, Merck, Lilly, AstraZeneca; Financial Interests, Personal and Institutional, Invited Speaker: Roche; Financial Interests, Personal and Institutional, Research Grant, Investigator Initiated Trial: AstraZeneca. J.J. Chan: Financial Interests, Personal, Advisory Board: AstraZeneca, GlaxoSmithKline, Merck Sharp & Dohme, Novartis; Financial Interests, Personal, Invited Speaker: AstraZeneca, DKSH Singapore, Novartis; Financial Interests, Personal, Other, Conference fee: DKSH Singapore, Merck Sharp & Dohme, Pfizer, Roche; Financial Interests, Institutional, Funding, Investigator initiated trial: OncoQuest, Bristol-Myers Squibb; Non-Financial Interests, Other, Track Chair, Breast Track, 6th Annual Scientific Meeting 2021: Singapore Society of Oncology; Non-Financial Interests, Other, Scientific Committee Member, Masterclass: Gynecologic Cancer Group Singapore; Non-Financial Interests, Member: Singapore Society of Oncology, Gynecologic Cancer Group Singapore, Chapter of Medical Oncologists, College of Physicians, Academy of Medicine Singapore.

G. Schiavon: Financial Interests, Personal, Other, Employee: AstraZeneca. A. Foxley: Financial Interests, Personal, Other, Employee: AstraZeneca. D.S. Tan: Financial Interests, Personal, Invited Speaker: AstraZeneca, MSD, Merck Serono, Roche, Eisai; Financial Interests, Personal, Advisory Board: AstraZeneca, Bayer, MSD, Eisai, Roche, Genmab; Financial Interests, Personal, Stocks/Shares: Asian Microbiome Library (AMiLi); Financial Interests, Institutional, Research Grant: Roche, Bayer, Karyopharm Therapeutics, AstraZeneca; Financial Interests, Institutional, Invited Speaker: AstraZeneca, Bergen Bio, Zeria Pharmaceutical Co Ltd, Bayer, Byondis B.V.; Non-Financial Interests, Institutional, Product Samples, Research Study: MSD, Eisai, AstraZeneca. All other authors have declared no conflicts of interest.