Olaparib Plus Pembrolizumab In Patients With Previously Treated Advanced Solid Tumors With Homologous Recombination Repair Mutation (Hrrm) And/Or Homologous Recombination Deficiency (Hrd): Initial Results Of The Phase 2 Keylynk-007 Study.

Abstract Background: Poly-ADP-ribose polymerase (PARP) inhibition plus PD-(L)1 blockade has shown encouraging antitumor activity in patients (pts) with recurrent ovarian or breast cancer with BRCAm and in pts with recurrent ovarian cancer regardless of BRCAm or HRD status. We present initial results of the ongoing KEYLYNK-007 (NCT04123366) study of antitumor activity and safety of olaparib + pembrolizumab in pts with previously treated, advanced, HRRm and/or HRD positive solid tumors. Methods: This phase 2, nonrandomized, multicenter, open-label study enrolled adult pts with histologically/cytologically confirmed, previously treated, advanced solid tumors with centrally-confirmed HRRm and/or HRD positive per Lynparza HRR-HRD assay, and ECOG PS of 0−1, and without prior PARP or PD-(L)1 inhibitor therapy or progression on or ≤4 wks after platinum therapy. Pts received olaparib 300 mg BID and pembrolizumab 200 mg Q3W for 35 cycles or until PD, unacceptable AEs, intercurrent illness, or investigator decision. The primary endpoint was ORR. Results: As of 25 Sep 2020, 168 pts were enrolled (BRCAm, n = 40; HRRm without BRCAm, n = 64; HRD positive without HRRm, n = 64). Median (range) time from first dose to data cutoff was 4.5 (0.1−8.4), 4.5 (0.1−7.5), and 5.3 (0.3−7.9) mo, respectively. Efficacy outcomes in pts with ≥4 mo follow-up are shown in the Table. Grade 3−4 treatment-related AEs occurred in 60 pts (35.7%); 4 pts (2.4%) discontinued treatment due to treatment-related AE; there were no grade 5 treatment-related AEs. Common (≥15%) treatment-related AEs were nausea (39.3%), anemia (30.4%), and fatigue (15.5%), comparable with monotherapy. Conclusions: Olaparib + pembrolizumab showed promising antitumor activity with manageable safety in pts with a range of advanced HRRm and/or HRD positive solid tumors, especially BRCAm. Enrollment is ongoing. Table. Efficacy OutcomesOlaparib Plus PembrolizumabEfficacy Outcomesa, bBRCAmc (n = 21)HRRmd Without BRCAmc (n = 32)HRD Positivee Without HRRmd (n = 47)HRRmd (n = 53)HRD Positivee (n = 76)ORR,f-h (95% CI)28.6 (11.3 to 52.2)6.3 (0.8 to 20.8)19.1 (9.1 to 33.3)15.1 (6.8 to 27.6)21.1 (12.5 to 31.9)- Tumor types with confirmed responsesCervical, endometrial, prostate, duodenalOvarian and neuroendocrineiOvarian (3), breast, peritoneum, NSCLC, cervicalCervical, endometrial, prostate, duodenal, ovarian, neuroendocrineCervical (2), endometrial, prostate, duodenal, ovarian (4), breast, peritoneum, NSCLC- Tumor types with unconfirmed responsesNSCLC, neuroendocrineNoneNSCLC (2)NSCLC, neuroendocrineNSCLC (3), neuroendocrineDOR,f,j median (range), moNR (0.0+ to 2.6+)4.2 (4.1+ to 4.2)NR (0.0+ to 4.2+)4.2(0.0+ to 4.2)NR (0.0+ to 4.2+)PFS,j median (95% CI), moNR (2.3 to NR)3.3 (2.0 to 4.6)4.1 (2.2 to NR)3.9(2.2 to 6.1)4.1(2.3 to NR)Estimated PFS rate at 3 mo,j %66.250.058.456.059.5NR, not reached.“+” indicates no PD by the time of last disease assessment.aTumor imaging assessed by blinded independent central review per RECIST version 1.1 or Prostate Cancer Working Group-modified RECIST version 1.1bIn pts enrolled ≥4 mo before the data cutoff date (25 September 2020).cDeleterious or suspected deleterious mutations in the BRCA1 and/or BRCA2 genes from the tumor tissue-based Lynparza HRR-HRD assay.dDeleterious or suspected deleterious mutations in at least 1 of 15 prespecified HRR genes (BRCA1, BRCA2, ATM, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, and RAD54L) from the tumor tissue-based Lynparza HRR-HRD assay.eDeleterious or suspected deleterious mutation in BRCA1 or BRCA2, or loss of heterozygosity score ≥16 from the tumor tissue-based Lynparza HRR-HRD assay.fIncludes confirmed and unconfirmed responses.gORR (95% CI) in pts with confirmed responses (primary endpoint): BRCAm, 19.0% (5.4%-41.9%); HRRm without BRCAm, 6.3% (0.8%-20.8%); HRD positive without HRRm, 14.9% (6.2%-28.3%); HRRm, 11.3% (4.3%-23.0%); HRD positive, 15.8% (8.4%-26.0%).hNumber of patients with responses: BRCAm, 4 confirmed + 2 unconfirmed; HRRm without BRCAm, 2 confirmed; HRD positive without HRRm, 7 confirmed + 2 unconfirmed; HRRm, 6 confirmed + 2 unconfirmed; HRD positive, 12 confirmed + 4 unconfirmed.iBoth pts had ATM mutation.jFrom Kaplan-Meier method for censored data. Citation Format: Michele Maio, Ronnie Shapira-Frommer, Timothy A. Yap, Tudor Ciuleanu, Henry Gomez, Andrew Hill, Iwona Lugowska, Ozgur Ozyilkan, Karina Vera, Seock-Ah Im, Anna Kryzhanivska, Serhii Lysenko, Michael Schenker, Salomon M. Stemmer, Sanatan Saraf, Razvan Cristescu, PhD, Fan Jin, Alexander Gozman, Miguel Quintela-Fandino. Olaparib plus pembrolizumab in patients with previously treated advanced solid tumors with homologous recombination repair mutation (HRRm) and/or homologous recombination deficiency (HRD): Initial results of the phase 2 KEYLYNK-007 study [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 CT178.