Lee, Elizabeth K.

PURPOSE The multicenter, open-label, randomized phase 2 NCI-9944 study ( NCT02595892 ) demonstrated that addition of ATR inhibitor (ATRi) berzosertib to gemcitabine increased progression-free survival (PFS) compared to gemcitabine alone (hazard ratio [HR]=0.57, one-sided log-rank P = .044, which met the one-sided significance level of 0.1 used for sample size calculation). METHODS We report here the final overall survival (OS) analysis and biomarker correlations (ATM expression by immunohistochemistry, mutational signature 3 and a genomic biomarker of replication stress) along with post-hoc exploratory analyses to adjust for crossover from gemcitabine to gemcitabine/berzosertib. RESULTS At the data cutoff of January 27, 2023 (>30 months of additional follow-up from the primary analysis), median OS was 59.4 weeks with gemcitabine/berzosertib versus 43.0 weeks with gemcitabine alone (HR 0.79, 90% CI 0.52 to 1.2, one-sided log-rank P = .18). An OS benefit with addition of berzosertib to gemcitabine was suggested in patients stratified into the platinum-free interval ≤3 months (N = 26) subgroup (HR, 0.48, 90% CI 0.22 to 1.01, one-sided log-rank P =.04) and in patients with ATM-negative/low (N = 24) tumors (HR, 0.50, 90% CI 0.23 to 1.08, one-sided log-rank P = .06). CONCLUSION The results of this follow-up analysis continue to support the promise of combined gemcitabine/ATRi therapy in platinum resistant ovarian cancer, an active area of investigation with several ongoing clinical trials.

Abstract Background: DS-8201a is a HER2-targeting antibody drug conjugate with a topoisomerase 1 (top1) inhibitor payload. Preclinical evidence suggests that inhibiting PARP can potentiate top1 inhibitor-induced DNA damage and cytotoxicity. However, the clinical activity of combined top1-inhibiting chemotherapy and PARP inhibition has been limited by toxicity. We hypothesized that targeted delivery of a top1 inhibitor via DS-8201a may reduce systemic toxicity while maintaining synergistic cytotoxic activity in combination with olaparib. This combination is being investigated in the ongoing phase 1 trial CTEP #10355 (NCT04585958) in patients (pts) with advanced solid tumors expressing HER2. We present the safety analysis of pts enrolled to Module 1 (Mod 1) of dose escalation (continuous olaparib). Preliminary efficacy results are explored. Methods: Accrual was limited to pts ≥18 years old with advanced or recurrent solid tumors expressing HER2, defined as HER2 IHC ≥1+ (local testing allowed) or amplification of ERBB2 by NGS or ISH. In Mod 1, pts received DS-8201a IV once every 3 weeks and olaparib twice daily (BID) continuously in a 3+3 dose escalation design. Dose Level 1 (DL1) of Mod 1 evaluated DS-8201a dosed at 4.4mg/kg with olaparib 100mg BID Days 1-21. Dose Level 2 (DL2) of Mod 1 evaluated DS-8201a dosed at 5.4mg/kg with olaparib 100mg BID Days 1-21. The primary objective was to evaluate the safety and tolerability of combined DS-8201a + olaparib as graded by CTCAE v5. Secondary objectives include assessment of clinical activity as measured by objective response rate (ORR), clinical benefit rate (CBR; partial response [PR] + complete response [CR] + stable disease [SD] ≥6 months [mo]), median progression-free survival (PFS), and duration of response (DOR). Results: As of 30-Nov-2022, 10 pts were treated in Mod 1, with median age of 62.5 years. 10% were Asian, 10% were African American, and 80% were white. 40% had endometrial cancer and 60% had ovarian cancer. 6 of 7 pts treated on DL1 were DLT-evaluable, of which 1 patient experienced a DLT of Grade (G) 4 neutropenia. All 3 pts in DL2 were DLT-evaluable, and each experienced a DLT (2 pts with G4 febrile neutropenia, 1 pt with G4 neutropenia). Most common TRAEs in Mod 1 included: ANC decrease (60% G4, 20% G3, 20% G1/2), platelet count decrease (20% G4, 20% G3, 40% G1/2), and anemia (70% G3, 20% G1/2). All Mod 1 pts required dose holds, dose reductions, and/or discontinuation of olaparib. Of the 10 pts in Mod 1, 40% achieved a RECIST response (1 CR, 3 PR). 40% had SD lasting ≥6 mo, for a CBR of 80%. Median PFS is estimated at 7.4 mo (95% CI 4.7mo-not reached), with 7 patients alive and progression-free at 6 mo. Conclusion: Continuous dosing of olaparib in combination with DS-8201a yielded an unacceptable safety profile and dose escalation in Mod 1 was not continued. An alternative dosing schedule was initiated in Module 2 (Mod 2) evaluating DS-8201a IV every 3 weeks and olaparib BID Days 8-14; accrual to Mod 2 is ongoing. There is preliminary evidence of clinical activity of this combination. Citation Format: Elizabeth K. Lee, Andrea E. Wahner Hendrickson, Gerardo Colon-Otero, Cheryl A. Pickett, Niya Xiong, Su-Chun Cheng, Madeline Polak, Hannah Sawyer, Martin Hayes, Ursula A. Matulonis, Geoffrey I. Shapiro, Panagiotis A. Konstantinopoulos. A phase 1 study of DS-8201a in combination with olaparib in HER2-expressing malignancies (CTEP #10355): Results of module 1 dose escalation [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B041.

Abstract Introduction: ATRi and PARPi combinations kill tumor cells via synergistic modulation of complementary DDR pathways but clinical utility is limited by overlapping toxicities. A genome-wide CRISPR-Cas9 screen identified DDR alterations that sensitize tumors to the ATRi camonsertib (cam) plus PARPi. Based on preclinical models, tolerability and efficacy of cam plus PARPi given intermittently at low doses in pts with solid tumors with DDR alterations, including BRCA-mutated PARPi-resistant cancers, was evaluated. Methods: Pts (≥ 18 yrs) with relapsed/refractory (r/r) solid tumors with DDR alterations were treated with cam plus talazoparib (tala), niraparib (nira), or olaparib (ola) in 2 phase I trials (NCT04497116, NCT04972110). An adaptive BOIN design was used to optimize dose/schedule. Endpoints were safety, recommended phase II dose (RP2D), pharmacokinetics (PK), response (RECIST v1.1 [confirmed/unconfirmed], CA 125, or PSA), clinical benefit rate (CBR; RECIST/tumor marker response or treatment duration ≥ 16 wk), and ctDNA molecular response rate (MRR; best reduction in mean variant allele frequency [mVAF] ≥ 50%). Results: As of Nov 2022, 99 pts were enrolled (61 with ≥ 3 prior lines of therapy, 36 PARPi-pretreated); 43, 27, 29 pts in tala, nira, and ola combinations, respectively. Tumors included ovarian (n=20), prostate (n=13), breast (n=17), bile duct (n=3); most common genotypes were ATM (n=26), BRCA1 (n=19), and BRCA2 (n=33). Grade 3+ toxicities included reversible myelosuppression (neutropenia, anemia, and thrombocytopenia in 35%, 28%, and 14% of pts overall; 33%, 16%, and 11% at preliminary RP2Ds), fatigue (3%), and alkaline phosphatase increase (2%). Two pts discontinued treatment due to drug-related toxicity. Forty pts remain on therapy, up to 63 wks. Preliminary RP2Ds: cam 80 mg QD (d 5-7) + tala 0.25 mg QD, 1 wk on/1 wk off; cam 80 mg QD + nira 100 mg QD, 2 d on/5 d off; cam 50 mg QD + ola 100 mg BID, 3 d on/4 d off. As of abstract submission, response rate was 13% in 85 evaluable pts; CBR was 49%. Responders included pts with ovarian (n=6), bile duct (n=2), and breast, pancreatic, and carcinoma of unknown primary (n=1 each) cancers harboring alterations in BRCA1/2 (n=9), IDH1 (n=1), and ATM (n=1). Of 30 evaluable PARPi-pretreated pts, response rate was 23% and CBR was 52%. MRR was 64% (14/22 evaluable); change in mVAF correlated with a change in target lesion size (r=0.63, P=0.001). PK of each drug in the combination was consistent with respective monotherapy PK. Conclusion: Combination of cam plus PARPi at low doses on intermittent schedules was generally well-tolerated with clinical activity in DDR-aberrant tumors, including those pretreated with PARPi. RP2D optimization and translational correlative studies are ongoing. Citation Format: Timothy A. Yap, Siddhartha Yadav, Benjamin Herzberg, Benedito A. Carneiro, Elisa Fontana, Martin Højgaard, Michael J. Pishvaian, Ruth Plummer, Theresa L. Werner, Vaibhav Sahai, Stephanie Lheureux, Elizabeth K. Lee, Niharika B. Mettu, Gregory M. Cote, Joseph D. Schonhoft, Victoria Rimkunas, Ian M. Silverman, Marisa Wainszelbaum, Gerson Peltz, Adrian J. Fretland, Kezhen Fei, Danielle Ulanet, Insil Kim, Maria Koehler, Ezra Rosen, Michael Cecchini. Safety and efficacy of three PARP inhibitors (PARPi) combined with the ataxia telangiectasia- and Rad3-related kinase inhibitor (ATRi) camonsertib in patients (pts) with solid tumors harboring DNA damage response (DDR) alterations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT018.