Prior Line Of Platinum-based Chemotherapy Research Articles

Niraparib maintenance therapy using an individualised starting dose in patients with platinum-sensitive recurrent ovarian cancer (NORA): final overall survival analysis of a phase 3 randomised, placebo-controlled trial

Niraparib significantly prolonged progression-free survival versus placebo in patients with platinum-sensitive, recurrent ovarian cancer (PSROC), regardless of germline BRCA mutation (gBRCAm) status, in NORA. This analysis reports final data on overall survival (OS). This randomised, double-blind, placebo-controlled, phase 3 trial enrolled patients across 30 centres in China between 26 September 2017 and 2 February 2019 (clinicaltrials.gov, NCT03705156). Eligible patients had histologically confirmed, recurrent, (predominantly) high-grade serous epithelial ovarian cancer, fallopian tube carcinoma, or primary peritoneal carcinoma (no histological restrictions for those with gBRCAm) and had received ≥2 prior lines of platinum-based chemotherapy. Patients were randomised (2:1) to receive niraparib or placebo, with stratification by gBRCAm status, time to recurrence following penultimate platinum-based chemotherapy, and response to last platinum-based chemotherapy. Following a protocol amendment, the starting dose was individualised: 200mg/day for patients with bodyweight <77kg and/or platelet count <150×103/μL at baseline and 300mg/day otherwise. OS was a secondary endpoint. Totally, 265 patients were randomised to receive niraparib (n=177) or placebo (n=88), and 249 (94.0%) received an individualised starting dose. As of 14 August 2023, median follow-up for OS was 57.9 months (IQR, 54.8-61.6). Median OS (95% CI) with niraparib versus placebo was 51.5 (41.4-58.9) versus 47.6 (33.3-not evaluable [NE]) months, with hazard ratio [HR] of 0.86 (95% CI, 0.60-1.23), in the overall population; 56.0 (36.1-NE) versus 47.6 (31.6-NE) months, with HR of 0.86 (95% CI, 0.46-1.58), in patients with gBRCAm; and 46.5 (41.0-NE) versus 46.9 (31.8-NE) months, with HR of 0.87 (95% CI, 0.56-1.35), in those without. No new safety signals were identified, and myelodysplastic syndromes/acute myeloid leukaemia occurred in three (1.7%) niraparib-treated patients. Niraparib maintenance therapy with an individualised starting dose demonstrated a favourable OS trend versus placebo in PSROC patients, regardless of gBRCAm status. Zai Lab (Shanghai) Co., Ltd; National Major Scientific and Technological Special Project for "Significant New Drugs Development" in 2018, China [grant number 2018ZX09736019].

Maintenance olaparib monotherapy for platinum-sensitive relapsed ovarian cancer in patients without a germline BRCA1/BRCA2 mutation: Secondary safety results from the phase IIIb OPINION study (128)

Maintenance olaparib monotherapy for platinum-sensitive relapsed ovarian cancer in patients without a germline BRCA1/BRCA2 mutation: Secondary safety results from the phase IIIb OPINION study (128)

Final overall survival results from SOLO3: Phase III trial assessing olaparib monotherapy versus non-platinum chemotherapy in heavily pretreated patients with germline BRCA1 - and/or BRCA2-mutated platinum-sensitive relapsed ovarian cancer (026)

<b>Objectives:</b> In the open-label Phase III SOLO3 trial (NCT02282020), olaparib monotherapy provided clinically relevant and statistically significant improvements in objective response rate (ORR; primary endpoint) and progression-free survival (PFS; secondary endpoint), compared with single-agent non-platinum chemotherapy, in patients (pts) with germline <i>BRCA1</i> and/or <i>BRCA2</i>-mutated (g<i>BRCA</i>m) platinum-sensitive relapsed ovarian cancer (PSROC) who had received ≥2 prior lines of platinum-based chemotherapy (Penson <i>et al. JCO</i> 2020). We report final overall survival (OS) and second disease progression results from SOLO3. <b>Methods:</b> Pts were randomized (2:1) to olaparib tablets (300 mg bid) or single-agent non-platinum chemotherapy treatment of physician's choice (TPC; paclitaxel [P], topotecan [T], gemcitabine [G], or pegylated liposomal doxorubicin [PLD]). Study treatment continued until objective radiological disease progression, unacceptable toxicity, or other discontinuation criteria were met. The time from randomization to second progression or death (PFS2) and OS were secondary endpoints. As prespecified, this analysis was performed at approximately 60% data maturity for OS. <b>Results:</b> 266 pts were randomized (olaparib, <i>n</i>=178; TPC, <i>n</i>=88 [PLD, <i>n</i>=47; P, <i>n</i>=20; G, <i>n</i>=13; T, <i>n</i>=8]); 12 (14%) TPC pts withdrew before receiving study treatment. At the final data cut-off (DCO; April 16, 2021), 19 (11%) olaparib pts versus no TPC pts were still receiving study treatment. The percentage of pts who left the study prior to death was approximately 2.3 times higher in the TPC arm (22 pts [25%]) than in the olaparib arm (19 pts [11%]). Following disease progression, the majority of pts received subsequent anticancer therapy (119 of 178 [67%] olaparib pts vs 54 of 88 [61%] TPC pts received ≥1 subsequent anticancer regimen); three of 178 (2%) olaparib pts versus 23 of 88 (26%) TPC pts received a PARP inhibitor in their first subsequent line of therapy, with nine of 178 (5%) versus 33 of 88 (38%) pts, respectively, receiving a PARP inhibitor in any subsequent line of therapy. At the final DCO, PFS2 favored olaparib over TPC, although the between-group difference was not statistically significant, and OS was similar in the olaparib and TPC groups (see Table). Adverse events (AEs) were consistent with the known safety profile of olaparib and with previous SOLO3 analyses; no new safety signals were identified. Discontinuation of study treatment due to AEs occurred in 18 of 178 (10%) olaparib pts versus 15 of 76 (20%) TPC pts in the safety analysis set. Circulating tumor DNA analyses are ongoing. <b>Conclusions:</b> In the primary analysis of SOLO3, olaparib monotherapy improved ORR and PFS compared with single-agent non-platinum chemotherapy in heavily pretreated pts with g<i>BRCA</i>m PSROC. In the final analysis, PFS2 favored olaparib monotherapy over TPC, and OS was similar in both treatment groups, supporting the use of olaparib as a chemotherapy-free treatment option in this pt population. No new safety signals were identified.

Clinical and molecular characteristics of patients with short- and long-term progression-free survival in the phase IIIb OPINION study of maintenance olaparib for patients with non-germline BRCA1/BRCA2-mutated platinum-sensitive relapsed ovarian cancer (306)

<b>Objectives:</b> The OPINION study (NCT03402841) demonstrated the activity of maintenance olaparib in patients (pts) with platinum-sensitive relapsed ovarian cancer (PSR OC) without a germline <i>BRCA1</i>/<i>BRCA2</i> mutation (non-g<i>BRCA</i>m), with an overall median progression-free survival (PFS) of 9.2 months (mo) (Poveda <i>et al</i>. ASCO 2021). We further explored clinical and molecular characteristics in pts with long-term (LT) and short-term (ST) PFS. <b>Methods:</b> Pts with non-g<i>BRCA</i>m PSR OC and ≥2 prior lines of platinum-based chemotherapy (PBC) incomplete/partial response (CR/PR) to their last PBC received maintenance olaparib (300 mg bid) until progression/unacceptable toxicity. Here, pts were grouped by time from the first dose until disease progression (RECIST v1.1) or death: >18 mo for the LT group and <4 mo for the ST group (chosen based on radiologic scan timings and follow up). Pts who discontinued the study >18 mo after the first dose were also in the LT group. Samples were analyzed using the Myriad myChoice HRD plus and BRACAnalysis CDx assays. Molecular analyses included: tumor <i>BRCA</i>m (t<i>BRCA</i>m); somatic <i>BRCA</i>m (s<i>BRCA</i>m), defined as the presence of a t<i>BRCA</i>m and no g<i>BRCA</i>m; homologous recombination deficiency (HRD), defined as a genomic instability score ≥42 and/or t<i>BRCA</i>m; homologous recombination repair (HRR) gene mutations, excluding <i>BRCA</i>m (non<i>-BRCA</i> HRRm), based on a prespecified 13-gene panel; and <i>TP53</i> mutation status. <b>Results:</b> Of 279 pts in OPINION, 67 (24%) and 65 (23%) had LT and ST PFS, respectively. At diagnosis, 45/67 pts (67%) in the LT group had FIGO stage III and 15 (22%) had stage IV disease; 47/65 (72%) in the ST group had stage III and 12 (18%) had stage IV disease. Median (range) prior PBC regimens was 2 (2-5) and 2 (2-6) in the LT and ST groups, respectively. About 34/67 (51%) and 12/65 (18%) pts achieved CR to their last PBC, and 33/67 (49%) and 52/65 (80%) had PR in the LT and ST groups, respectively; 48/67 (72%) and 42/65 (65%) had a platinum-free interval of ≥12 mo in the LT and ST groups, respectively. Fifteen out of 67 (22%) and 5/65 pts (8%) were found to have a t<i>BRCA</i>m in the LT and ST groups, respectively; 47/67 (70%) and 25/65 pts (40%) had HRD-positive tumors. Fifteen (22%) and 5 (8%) pts had a non-<i>BRCA</i> HRRm in the LT and ST groups, respectively, although 65% of pts with a non-<i>BRCA</i> HRRm had HRD-positive tumors. Twenty-five (37%) and 32 (49%) had <i>TP53</i>-disruptive mutations in the LT and ST groups, respectively. Overlap between t<i>BRCA</i>m, HRD, non-<i>BRCA</i> HRRm (including most frequently mutated genes), and <i>TP53</i> mutations is shown in the Figure. <b>Conclusions:</b> Pts with LT PFS (>18 mo) in OPINION more commonly had HRD-positive tumors, with or without a t<i>BRCA</i>m, than pts with ST PFS (<4 mo), consistent with results showing longer PFS among pts with HRD-positive tumors in the overall population. A higher proportion of pts with LT than ST PFS achieved CR to their last PBC. However, pts could achieve LT PFS regardless of clinical and molecular factors, reinforcing the benefit of maintenance PARP inhibition in non-g<i>BRCA</i>m PSR OC.

Olaparib treatment for platinum-sensitive relapsed ovarian cancer by BRCA mutation and homologous recombination deficiency status: Phase II LIGHT study primary analysis

ObjectiveOlaparib treatment resulted in significant improvement in objective response rates (ORRs) and progression-free survival (PFS) over non‑platinum chemotherapy in patients with BRCA1/BRCA2-mutated (BRCAm) platinum-sensitive relapsed ovarian cancer (PSROC) and ≥2 prior lines of platinum-based chemotherapy in the phase III SOLO3 study. LIGHT (NCT02983799) prospectively evaluated olaparib treatment for patients with PSROC and known BRCAm and homologous recombination deficiency (HRD) status. MethodsIn this phase II open-label multicenter study, patients with PSROC and ≥1 prior line of platinum-based chemotherapy were assigned to cohorts by presence of germline BRCAm (gBRCAm), somatic BRCAm (sBRCAm), HRD-positive tumors without BRCAm, or HRD-negative tumors. The primary endpoint was investigator-assessed ORR. Secondary endpoints included disease control rate (DCR) and PFS. Tumors were analyzed using Myriad BRACAnalysis CDx and myChoice HRD assays; HRD-positive tumors were defined using a genomic instability score of ≥42. ResultsOf 272 enrolled patients, 271 received olaparib and 270 were included in efficacy analyses. At data cut-off, ORRs in the gBRCAm, sBRCAm, HRD-positive, and HRD-negative cohorts were 69.3%, 64.0%, 29.4%, and 10.1%, respectively. DCRs were 96.0%, 100.0%, 79.4%, and 75.3% in each cohort, respectively. Median PFS was 11.0, 10.8, 7.2, and 5.4 months, respectively. The most common (≥ 20%) treatment-emergent adverse events included nausea, fatigue/asthenia, vomiting, anemia, constipation, diarrhea, and decreased appetite. ConclusionsOlaparib treatment demonstrated activity across all cohorts. The greatest efficacy was observed in the BRCAm cohorts, regardless of gBRCAm/sBRCAm. For patients without a BRCAm, greater efficacy was observed in the HRD-positive than the HRD-negative cohorts. The safety profile was consistent with that established in previous olaparib studies.

A phase 1b/2 study of nanatinostat and valganciclovir in patients with advanced Epstein-Barr virus positive (EBV+) solid tumors and in combination with pembrolizumab in patients with recurrent/metastatic nasopharyngeal carcinoma (RM-NPC).

TPS6107 Background: Epstein-Barr virus (EBV) is linked to the development and pathogenesis of nasopharyngeal carcinoma (NPC). Most patients present with advanced stage disease at diagnosis (Li 2014); first-line chemoradiation is commonly followed by recurrence and poor prognosis emphasizing the need for new treatment options. Targeting EBV in NPC represents a novel therapeutic approach. EBV is predominantly latent in NPC; pre-clinical studies demonstrated that induction of the viral lytic phase by histone deacetylase inhibitors (HDACi) renders EBV+ tumor cells susceptible to the cytotoxic activity of ganciclovir (GCV) (Hui 2016). Nanatinostat (Nstat), a potent Class-I HDACi, induces the expression of the lytic BGLF4 protein kinase in EBV+ tumor cells, which activates the nucleoside analog GCV via phosphorylation. Phosphorylated GCV becomes incorporated into the cellular DNA causing chain termination and apoptosis. The all-oral combination of Nstat and valganciclovir (VGCV), a pro-drug of GCV, has demonstrated favorable safety and preliminary efficacy in a phase 1/2 study in patients with recurrent EBV+ lymphoma (NCT03397706). This phase 1b/2, open-label, multicenter study will evaluate the safety, tolerability, pharmacokinetics, and preliminary activity of Nstat + VGCV in patients with advanced EBV+ solid tumors. Additionally, the combination of pembrolizumab together with Nstat + VGCV will be evaluated in recurrent/metastatic NPC (RM-NPC) patients. NPC frequently exhibits high PD-L1 expression levels; however, PD-1 inhibitors resulted in limited response rates ranging from 20-30% in the RM-NPC setting. Methods: Phase 1b utilizes a 3+3 dose escalation design to determine the recommended Phase 2 dose (RP2D) of Nstat + VGCV in patients with EBV+ RM-NPC. In Phase 2, up to 60 patients with EBV+ RM-NPC will be randomized 1:1 to receive Nstat + VGCV at the RP2D with or without pembrolizumab to evaluate safety, tolerability, overall response rate, and potential pharmacodynamic markers of drug activity, including plasma EBV DNA levels. Additionally, patients with EBV+ solid tumors other than RM-NPC will receive Nstat + VGCV at the RP2D in a separate Phase 1b dose expansion cohort. Patients eligible for the phase 1b dose escalation and phase 2 will have EBV+ RM-NPC with 1-3 prior lines of platinum-based chemotherapy and no available curative therapies. Patients with advanced EBV+ non-NPC solid tumors (gastric cancer, lymphoepithelioma-like carcinoma, leiomyosarcoma) and no curative therapies are eligible for the phase 1b expansion cohort. All patients must have measurable disease per RECIST v1.1 and adequate bone marrow, liver, and renal function. Enrollment began in January 2022. Clinical trial information: NCT05166577.

Antitumor activity of bintrafusp alfa in previously treated patients with recurrent or metastatic nasopharyngeal cancer (NPC): A single arm, prospective phase II trial.

e18029 Background: Patients with recurrent or metastatic nasopharyngeal cancer (R/M NPC) who failed platinum-based chemotherapy have poor prognoses. We report the clinical activity and safety of bintrafusp alfa, a first-in-class bifunctional fusion protein composed of the extracellular domain of the transforming growth factor (TGF)-βRII receptor fused to a human IgG1 antibody blocking programmed death-ligand 1 (PD-L1), in patients with heavily pretreated R/M NPC. Tumor and plasma-based biomarkers were investigated in an exploratory analysis. Methods: Eligible patients had histologically confirmed NPC that had recurred at distant sites and were not amenable to curative treatment. All patients received at least one prior line of platinum-based chemotherapy for recurrent disease. Patients were treated with bintrafusp alfa (1200mg every 2 weeks) until disease progression. The sample size was estimated to assume a 40% objective response rate (ORR) to bintrafusp alfa compared with 20% for checkpoint inhibitors. Modified Simon two-stage optimal design was used (power, 80%; a = 0.05; P0 = 0.20; P1 = 0.40; n1 = 18; n = 33 with an additional five patients to allow for ineligibility or other reasons). The primary endpoint was ORR and secondary endpoints included survival and toxicity. Expression of PD-L1 in archived tumors, plasma clearance of Epstein-Barr virus (EBV) DNA, plasma clearance of TGF-β, and exosomal PD-L1 were assessed for a potential correlation with ORR. (NCT 04396886). Results: Out of 43 patients screened, 38 patients were enrolled. After a median follow-up of 14.9 months (range: 1.6-23.3 months), the confirmed ORR was 23.7% (95% CI: 12.4-38.8%) (complete response, n = 1; partial response, n = 8). The median treatment duration was 1.8 months (range: 0.5-14.3 months). 8 patients (21.1%) and 2 patients (5.3%) received bintrafusp alfa for &gt; 6 months and &gt; 12 months respectively. The 1-year overall survival (OS) rate was 57.5% (95% CI, 40.2% to 71.5%) and 1-year progression-free survival rate was 23% (95% CI, 10.1% to 39.4%). ORR was higher in patients with a decreasing trend in EBV-DNA at week 4 (40% vs. 6.3%, p = 0.02), whereas high exosomal PD-L1 levels at week 4 were predictive of worse ORR (5.3% vs. 41.7%, p = 0.012). There were no associations between clinical outcome and tissue PD-L1 expression (p = 0.952) or plasma TGF-β clearance (p = 0.28). 16 patients (42.4%) experienced ≥ grade 3 treatment-related adverse events, most commonly anemia (n = 9, 23.7%) and secondary malignancies (n = 4, 10.5%). Conclusions: Bintrafusp alfa has promising activity in heavily pretreated R/M NPC and a favorable 1-year OS rate, though the observed activity was not as high as the study initially aimed. The biomarker results warrant validation in larger cohorts. Clinical trial information: NCT04396886.

Analysis of patients with relapsed small cell lung cancer (SCLC) receiving single-agent lurbinectedin in the phase 3 ATLANTIS trial.

8524 Background: Lurbinectedin, a selective inhibitor of oncogenic transcription, received accelerated approval from the US FDA in June 2020 as monotherapy (3.2 mg/m2 IV every 21 days) for adults with metastatic SCLC with disease progression on or after platinum-based chemotherapy. This approval was based on the overall response rate (35.2%) and duration of response (DOR; 5.3 months) observed in 105 patients from a phase 2 trial. The ATLANTIS trial (NCT02566993) investigated the combination of lurbinectedin 2.0 mg/m2 IV + doxorubicin (DOX) 40.0 mg/m2 IV versus topotecan or CAV. This post hoc analysis explored the efficacy and safety of single-agent lurbinectedin in patients who completed 10 cycles of the combination and then switched to lurbinectedin monotherapy per protocol. Methods: Eligible patients were ≥18 years of age with limited-stage or extensive-stage SCLC, 1 prior line of platinum-based chemotherapy (PD-1/PD-L1 inhibitors were also permitted), ECOG PS ≤2, and chemotherapy-free interval ≥30 days. Tumor assessments were per an independent review committee (IRC). Results: Patients who completed 10 cycles of lurbinectedin + DOX and switched to lurbinectedin monotherapy (n = 50) had a median age of 61.5 years (range: 43, 77); 62% were male; and 100% had an ECOG PS &lt; 2. The overall median number of cycles was 15 (range: 11, 47) and included a median of 5 (1, 37) cycles on monotherapy. The majority of patients who switched to lurbinectedin monotherapy maintained or improved their tumor response (Table). All 3 patients who achieved a complete response (CR) on combination therapy maintained their CR on monotherapy. Of the 26 patients with a partial response (PR) on combination therapy, 3 (12%) achieved a CR and 15 (58%) maintained their PR. Of the 19 patients with stable disease (SD) on combination therapy, 3 (16%) improved from SD to PR (n = 2) or CR (n = 1) and 8 (42%) maintained SD. The median DOR was 8.3 months (95% CI: 7.1, 11.0). The median overall survival (OS) was 20.7 months (95% CI: 15.7, 24.8). Grade 3/4 hematologic abnormalities based on laboratory assessment included lymphopenia (36%), anemia (16%), thrombocytopenia (12%), neutropenia (12%), and leukopenia (10%). Febrile neutropenia was reported in 4% of patients. Conclusions: Patients with relapsed SCLC in ATLANTIS who completed 10 cycles of lurbinectedin + DOX combination and switched to lurbinectedin monotherapy tended to maintain or improve their tumor response (including an increase in CRs), with favorable OS and DOR and acceptable tolerability with no new safety signals. Clinical trial information: NCT02566993. [Table: see text]

Maintenance olaparib in patients (pts) with platinum-sensitive relapsed ovarian cancer (PSROC) by somatic (s) or germline (g) BRCA and other homologous recombination repair (HRR) gene mutation status: Overall survival (OS) results from the ORZORA study.

5519 Background: In the SOLO2 (NCT01874353) trial, maintenance olaparib provided clinically meaningful improvement in OS for PSROC pts with a gBRCA mutation (m) compared with placebo (median 51.7 vs 38.8 months [mo], respectively). The ORZORA trial (NCT02476968) assessed efficacy and safety of maintenance olaparib in PSROC pts with a BRCAm (s or g) or a non-BRCA HRRm. Median progression-free survival (18.0 mo, BRCAm; 16.4, non-BRCA HRRm) was reported at primary data cutoff (DCO). We report final OS analyses. Methods: We conducted an open-label, single-arm, multicenter study of PSROC pts in response to platinum-based chemotherapy (PBC) after ≥2 prior lines of PBC. Pts underwent prospective central screening for tumor BRCAm status (myChoice CDx, Myriad Genetic Laboratories, Inc.), then central gBRCAm testing (BRACAnalysis CDx, Myriad Genetic Laboratories, Inc.) to determine s or g status. An exploratory cohort comprised of pts with predefined non-BRCA HRRm (FoundationOne CDx, Foundation Medicine, Inc.). Pts received maintenance olaparib (400 mg bid; capsules) until progression. OS and time to second progression (PFS2) were secondary endpoints. Results: 181 pts were enrolled (BRCAm n = 145 [s, n = 55; g, n = 87; s/g status unknown, n = 3]; non-BRCA HRRm, n = 33; unassigned, n = 3). At DCO (June 25, 2021), median OS follow-up in censored pts was 42.6 mo in BRCAm and 39.3 mo in non-BRCA HRRm pts. OS and PFS2 are reported in the Table. PBC was received as a subsequent therapy by 33.1% BRCAm, 32.7% sBRCAm, 33.3% gBRCAm, and 45.5% non-BRCA HRRm pts. 177 pts received ≥1 dose of olaparib and were included in safety analyses; 6.2% of pts discontinued because of adverse events (AEs). 37.9% of pts reported grade ≥3 AEs, the most common being anemia (16.4%). Since primary DCO, one new primary malignancy and four myelodysplastic syndrome events occurred. Conclusions: In final OS analyses, maintenance olaparib capsules showed consistent clinical activity in BRCAm and sBRCAm PSROC pts. Exploratory analyses suggest similar activity in non-BRCA HRRm pts. No new safety signals were observed. Findings highlight that PSROC pts, beyond those with a gBRCAm, can benefit from maintenance olaparib. Clinical trial information: NCT02476968. [Table: see text]

Olaparib treatment in patients with platinum-sensitive relapsed ovarian cancer by BRCA mutation and homologous recombination deficiency status: secondary safety results from the phase II LIGHT study

Objectives: LIGHT (NCT02983799) evaluated olaparib treatment in patients with platinum-sensitive relapsed (PSR) ovarian cancer by BRCA mutation (BRCAm) and homologous recombination repair deficiency (HRD) status; the primary analysis demonstrated objective response rates (ORRs) of 69%, 64%, 29%, and 10% in cohorts of patients with a germline (g) BRCAm, with tumors with somatic (s) BRCAm, HRD-positive (non-BRCAm), and HRD-negative status, respectively (Cadoo K et al. ASCO 2020). Here, we report pre-specified secondary efficacy endpoints and subgroup analyses. Methods: In this open-label, non-randomized study, patients with PSR ovarian cancer and ≥1 prior line of platinum-based chemotherapy received olaparib monotherapy (300 mg bid). Patients were assigned to one of four cohorts based on whether they had a gBRCAm, tumors with sBRCAm, had HRD-positive (non-BRCAm) tumors, or HRD-negative tumors. Testing for gBRCAm was completed using Myriad BRACAnalysis CDx; sBRCAm testing was done with Myriad myChoice CDx. Genomic instability (GI) was assessed using the Myriad myChoice HRD test; tumors were deemed HRD-positive if they had a GI score ≥42. Secondary efficacy endpoints included investigator-assessed progression-free survival (PFS; RECIST v1.1) and cancer antigen (CA)-125 response. Time to any progression (TTAP) was calculated from the date of the first dose of olaparib until the earliest date of RECIST v1.1 or CA-125 disease progression, or death. Results: Conclusions: Secondary efficacy data and subgroup analyses from the LIGHT study of olaparib monotherapy as treatment for PSR ovarian cancer support the primary analysis. Efficacy was observed in all cohorts, particularly in the gBRCAm and sBRCAm cohorts, where similar efficacy was observed. For patients without a BRCAm, greater efficacy was seen in the HRD-positive cohort. LIGHT (NCT02983799) evaluated olaparib treatment in patients with platinum-sensitive relapsed (PSR) ovarian cancer by BRCA mutation (BRCAm) and homologous recombination repair deficiency (HRD) status; the primary analysis demonstrated objective response rates (ORRs) of 69%, 64%, 29%, and 10% in cohorts of patients with a germline (g) BRCAm, with tumors with somatic (s) BRCAm, HRD-positive (non-BRCAm), and HRD-negative status, respectively (Cadoo K et al. ASCO 2020). Here, we report pre-specified secondary efficacy endpoints and subgroup analyses. In this open-label, non-randomized study, patients with PSR ovarian cancer and ≥1 prior line of platinum-based chemotherapy received olaparib monotherapy (300 mg bid). Patients were assigned to one of four cohorts based on whether they had a gBRCAm, tumors with sBRCAm, had HRD-positive (non-BRCAm) tumors, or HRD-negative tumors. Testing for gBRCAm was completed using Myriad BRACAnalysis CDx; sBRCAm testing was done with Myriad myChoice CDx. Genomic instability (GI) was assessed using the Myriad myChoice HRD test; tumors were deemed HRD-positive if they had a GI score ≥42. Secondary efficacy endpoints included investigator-assessed progression-free survival (PFS; RECIST v1.1) and cancer antigen (CA)-125 response. Time to any progression (TTAP) was calculated from the date of the first dose of olaparib until the earliest date of RECIST v1.1 or CA-125 disease progression, or death. Secondary efficacy data and subgroup analyses from the LIGHT study of olaparib monotherapy as treatment for PSR ovarian cancer support the primary analysis. Efficacy was observed in all cohorts, particularly in the gBRCAm and sBRCAm cohorts, where similar efficacy was observed. For patients without a BRCAm, greater efficacy was seen in the HRD-positive cohort.

Apatinib combined with pegylated liposomal doxorubicin (PLD) versus PLD for platinum-resistant recurrent ovarian cancer (APPROVE): a multicenter, randomized, controlled, open-label, phase II trial

Objectives: Anti-angiogenic therapy combined with chemotherapy could improve survival in patients with platinum-resistant ovarian cancer (OC). APPROVE was conducted to evaluate the efficacy and safety of apatinib, an oral tyrosine kinase inhibitor that selectively inhibits VEGFR-2, in combination with pegylated liposomal doxorubicin (PLD) in patients with platinum-resistant or refractory recurrent OC. Methods: Eligible patients were histologically confirmed non-mucinous ovarian, primary peritoneal cancer, or fallopian-tube cancer who had experienced disease progression during, or within 6 months of discontinuing, any prior line of platinum-based chemotherapy. Patients with at least 1 lesion (measurable and/or nonmeasurable) that could be accurately assessed at baseline by computed tomography/magnetic resonance imaging. Patients were randomly assigned (1:1) to receive PLD alone (Arm PLD, 40mg/m2 IV every 4 weeks for up to 6 cycles) or with apatinib 250mg orally once daily (Arm A-PLD) until disease progression, unacceptable toxicity, or consent withdrawal. Patients were stratified according to prior platinum-sensitive relapsed (yes vs no) and platinum-free interval (less than 3 vs 3 to 6 months from last platinum therapy to subsequent progression). The primary endpoint was progression-free survival (PFS) by RECIST 1.1 in the intent-to-treat population (ITT population). Secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR) and safety. Results: Between Mar 22, 2018, and Nov 16, 2020, 152 patients were enrolled and randomly assigned to receive A-PLD (n=78) or PLD (n=74). Median follow-up was 8.1months (IQR 3.7-12.8). Median PFS was 5.8 months with A-PLD therapy versus 3.3 months with PLD alone (HR 0.41, 95% CI 0.26-0.64, P=0.0001). In patients with evaluable disease (Arm A-PLD, n=61; Arm PLD, n=63), the ORR was 37.7% (23/61) versus 9.5% (6/63) for A-PLD and PLD, respectively (P=0.0002). The DCR of A-PLD and PLD arms were 82.0% (50/61) and 58.7% (37/63), respectively (P=0.0050). Overall survival data are immature. Hypertension and hand-foot syndrome were more common with apatinib. No adverse events beyond expectation were reported. Conclusions: Apatinib in combination with PLD statistically significant prolonged PFS in patients with platinum-resistant or refractory recurrent ovarian cancer. ORR and DCR were also significantly improved. Adverse events were consistent with the established safety profiles of apatinib and PLD. Anti-angiogenic therapy combined with chemotherapy could improve survival in patients with platinum-resistant ovarian cancer (OC). APPROVE was conducted to evaluate the efficacy and safety of apatinib, an oral tyrosine kinase inhibitor that selectively inhibits VEGFR-2, in combination with pegylated liposomal doxorubicin (PLD) in patients with platinum-resistant or refractory recurrent OC. Eligible patients were histologically confirmed non-mucinous ovarian, primary peritoneal cancer, or fallopian-tube cancer who had experienced disease progression during, or within 6 months of discontinuing, any prior line of platinum-based chemotherapy. Patients with at least 1 lesion (measurable and/or nonmeasurable) that could be accurately assessed at baseline by computed tomography/magnetic resonance imaging. Patients were randomly assigned (1:1) to receive PLD alone (Arm PLD, 40mg/m2 IV every 4 weeks for up to 6 cycles) or with apatinib 250mg orally once daily (Arm A-PLD) until disease progression, unacceptable toxicity, or consent withdrawal. Patients were stratified according to prior platinum-sensitive relapsed (yes vs no) and platinum-free interval (less than 3 vs 3 to 6 months from last platinum therapy to subsequent progression). The primary endpoint was progression-free survival (PFS) by RECIST 1.1 in the intent-to-treat population (ITT population). Secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR) and safety. Between Mar 22, 2018, and Nov 16, 2020, 152 patients were enrolled and randomly assigned to receive A-PLD (n=78) or PLD (n=74). Median follow-up was 8.1months (IQR 3.7-12.8). Median PFS was 5.8 months with A-PLD therapy versus 3.3 months with PLD alone (HR 0.41, 95% CI 0.26-0.64, P=0.0001). In patients with evaluable disease (Arm A-PLD, n=61; Arm PLD, n=63), the ORR was 37.7% (23/61) versus 9.5% (6/63) for A-PLD and PLD, respectively (P=0.0002). The DCR of A-PLD and PLD arms were 82.0% (50/61) and 58.7% (37/63), respectively (P=0.0050). Overall survival data are immature. Hypertension and hand-foot syndrome were more common with apatinib. No adverse events beyond expectation were reported. Apatinib in combination with PLD statistically significant prolonged PFS in patients with platinum-resistant or refractory recurrent ovarian cancer. ORR and DCR were also significantly improved. Adverse events were consistent with the established safety profiles of apatinib and PLD.

Olaparib treatment in patients with platinum-sensitive relapsed ovarian cancer by BRCA mutation and homologous recombination deficiency status: secondary efficacy results from the phase II LIGHT study

<h3>Objectives:</h3> LIGHT (NCT02983799) evaluated olaparib treatment in patients with platinum-sensitive relapsed (PSR) ovarian cancer by <i>BRCA</i> mutation (<i>BRCA</i>m) and homologous recombination repair deficiency (HRD) status; the primary analysis demonstrated objective response rates (ORRs) of 69%, 64%, 29%, and 10% in cohorts of patients with a germline (g) <i>BRCA</i>m, with tumors with somatic (s) <i>BRCA</i>m, HRD-positive (non<i>-BRCA</i>m), and HRD-negative status, respectively (Cadoo K <i>et al.</i> ASCO 2020). Here, we report pre-specified secondary efficacy endpoints and subgroup analyses. <h3>Methods:</h3> In this open-label, non-randomized study, patients with PSR ovarian cancer and ≥1 prior line of platinum-based chemotherapy received olaparib monotherapy (300 mg bid). Patients were assigned to one of four cohorts based on whether they had a g<i>BRCA</i>m, tumors with s<i>BRCA</i>m, had HRD-positive (non<i>-BRCA</i>m) tumors, or HRD-negative tumors. Testing for g<i>BRCA</i>m was completed using Myriad BRACAnalysis CDx; s<i>BRCA</i>m testing was done with Myriad myChoice CDx. Genomic instability (GI) was assessed using the Myriad myChoice HRD test; tumors were deemed HRD-positive if they had a GI score ≥42. Secondary efficacy endpoints included investigator-assessed progression-free survival (PFS; RECIST v1.1) and cancer antigen (CA)-125 response. Time to any progression (TTAP) was calculated from the date of the first dose of olaparib until the earliest date of RECIST v1.1 or CA-125 disease progression, or death. <h3>Results:</h3> The analysis was timed ~6 months after the last patient was enrolled (data cut-off, Aug 27, 2019). Of 271 enrolled patients who had received olaparib, 270 had measurable disease at baseline and were included in efficacy analyses (13 patients whose Myriad test result was failed or missing could not be assigned to a cohort; efficacy in these patients was analyzed separately). ORR and PFS by prior line of chemotherapy, CA-125 response, and TTAP are summarized in the Table. ORRs ~60-70% were observed in the gBRCAm and sBRCAm cohorts and ~30% in the HRD-positive (non-BRCAm) cohort, both in patients with 1 or ≥2 prior lines of chemotherapy. Similarly, median PFS in patients was ~10-11 months in the <i>BRCA</i>m cohorts, and ~5-7 months in the HRD-positive (non<i>-BRCA</i>m) cohort, both in patients with 1 or ≥2 prior lines of chemotherapy. In the <i>BRCA</i>m cohorts, a high proportion of patients achieved a CA-125 response and complete response (CR), with a CA-125 CR rate of 60% and 68% in the <i>BRCA</i>m cohorts and 29% in the HRD-positive non<i>-BRCA</i>m cohort. Median TTAP was ~11 months in the <i>BRCA</i>m cohorts, and 7.2 months in the HRD-positive (non<i>-BRCA</i>m) cohort. <h3>Conclusions:</h3> Secondary efficacy data and subgroup analyses from the LIGHT study of olaparib monotherapy as treatment for PSR ovarian cancer support the primary analysis. Efficacy was observed in all cohorts, particularly in the gBRCAm and sBRCAm cohorts, where similar efficacy was observed. For patients without a <i>BRCA</i>m, greater efficacy was seen in the HRD-positive cohort.

Safety assessment of niraparib individualized starting dose in patients with platinum-sensitive recurrent ovarian cancer: A randomized, double-blind, placebo-controlled, phase III NORA trial.

5535 Background: To present the safety profile of niraparib maintenance therapy in patients with platinum-sensitive recurrent ovarian cancer (PSROC) included in the NORA trial. Methods: The double-blind, randomized, placebo-controlled, multicenter, phase III NORA trial (NCT03705156) included adult (≥18 years) Chinese women with PSROC who received ≥2 prior lines of platinum-based chemotherapy. Post ≤8 weeks of the last chemotherapy, patients were randomized (2:1) to receive oral niraparib (300 mg/day or 200 mg/day for patients with bodyweight &lt;77 kg or platelet count &lt;150 × 103/µL) or matched placebo. The primary endpoint was progression free survival, reported previously. Safety was assessed in terms of treatment emergent adverse events (TEAEs) related to hematologic toxicity (anemia/platelet count decreased and neutrophil count decreased) and non-hematologic toxicity (nausea/vomiting/constipation/insomnia/palpitations/hypertension). Adverse events (AEs) were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) v4.03. The data cutoff was February 1, 2020. Results: Of 265 patients included, the first 16 patients were given oral niraparib or matched placebo at a fixed starting dose of 300mg while 249 patients received individualized starting dose of niraparib (n = 166) or matched placebo (n = 83) based on baseline bodyweight and platelet count. The incidence of any TEAEs and grade ≥3 TEAEs was 100% and 50.8%, respectively in niraparib group, while 95.5% and 19.3%, respectively in placebo. Incidence of all grades of hematologic toxicity, gastrointestinal adverse events (nausea, constipation and vomiting), insomnia, palpitation and hypertension were highest in the first month after treatment with a gradual decrease in the further months. The median time to onset of grade ≥3 anemia, decreased neutrophil count and decreased platelet count were 87, 28, and 22 days, respectively, in the niraparib group. In niraparib group, any TEAEs that lead to dose reduction was observed in 59.9% of patients. Only 2 (1.1%) patients discontinued the treatment due to platelet count decreased and no patients discontinued niraparib treatment due to anemia or neutrophil count decreased. Overall, only 4% of patients in the niraparib group and 5.7% in the placebo group discontinued the treatment due to TEAEs. Conclusions: The lower incidence of TEAEs and the discontinuation rates indicate improved safety profile of niraparib with individualized starting dose in PSROC. Clinical trial information: NCT03705156.

Olaparib treatment (Tx) in patients (pts) with platinum-sensitive relapsed ovarian cancer (PSR OC) by BRCA mutation (BRCAm) and homologous recombination deficiency (HRD) status: Overall survival (OS) results from the phase II LIGHT study.

5515 Background: LIGHT (NCT02983799) evaluated olaparib Tx in pts with PSR OC in cohorts with known BRCAm and HRD status. We report the final OS analyses. Methods: We conducted anopen-label, non-randomized, multicenter study of pts with PSR OC and ≥1 prior line of platinum-based chemotherapy (CTx). Pts were assigned to one of 4 cohorts: germline (g) BRCAm; somatic (s) BRCAm; HRD +ve (non-BRCAm); and HRD -ve. Genomic instability score (GIS) and gBRCAm status were determined by Myriad myChoice and BRACAnalysis CDx tests, respectively. HRD +ve tumors were defined by a GIS ≥42. Pts received olaparib Tx (starting dose 300 mg bid) until disease progression or unacceptable toxicity. OS was a secondary endpoint and was analyzed at 12 months (mo) after the primary analysis and 18 mo after the last pt was enrolled. Safety was assessed in pts who received ≥1 dose. Results: Data cut-off (DCO) was Aug 27, 2020. Of 272 enrolled pts, 271 received olaparib; of these, 270 had measurable disease at baseline and were included in efficacy analyses (Table). At DCO, 40% of pts had died (maturity) with a median follow-up in censored pts of 26.3 mo. Kaplan–Meier 18-mo OS rates were 86%, 88%, 79%, and 60% in the gBRCAm, sBRCAm, HRD +ve (non-BRCAm), and HRD -ve cohorts, respectively. Platinum-based CTx was the most common first subsequent Tx and was received by 39% pts after olaparib discontinuation. At DCO, the median duration of Tx was 7.4 mo and 244 pts had discontinued treatment, mainly due to disease progression (72%); 5% discontinued due to treatment-emergent adverse events (TEAEs). The only TEAE leading to discontinuation in &gt;1 pt was nausea (2 pts). Serious TEAEs were reported in 25% of pts. The most common serious TEAE was small intestinal obstruction (6%). Three adverse events of special interest occurred, each in 1 pt (&lt;1%): acute myeloid leukemia (post discontinuation), pneumonitis, and pulmonary fibrosis. Conclusions: In the final OS analysis, 18-mo OS ranged from 60–88% across the 4 cohorts. Consistent with the primary analysis, the 18-mo OS rate was highest in the BRCAm cohorts (similar OS in g and sBRCAm); among pts without a BRCAm, 18-mo OS was highest in the HRD +ve cohort. No new safety signals were observed compared with the primary analysis and with prior olaparib studies. Clinical trial information: NCT02983799. [Table: see text]

Olaparib maintenance monotherapy for non-germline BRCA1/2-mutated (non-gBRCAm) platinum-sensitive relapsed ovarian cancer (PSR OC) patients (pts): Phase IIIb OPINION primary analysis.

5545 Background: In the Phase II Study 19 trial (NCT00753545; Ledermann et al Lancet Oncol 2014), maintenance olaparib improved progression-free survival (PFS) vs placebo in PSR OC pts, including non-BRCAm pts. A significant PFS benefit was also seen with maintenance olaparib vs placebo in gBRCAm PSR OC pts in the Phase III SOLO2 trial (NCT01874353; Pujade-Lauraine et al Lancet Oncol 2017). To investigate olaparib maintenance monotherapy in non-gBRCAm PSR OC pts who had received ≥2 prior lines of platinum-based chemotherapy (PBC), we performed the Phase IIIb, single-arm, OPINION study (NCT03402841). Methods: Pts had high-grade serous or endometrioid OC and were in complete response (CR) or partial response (PR) to PBC. Pts received maintenance olaparib (tablets; 300 mg bid) until disease progression or unacceptable toxicity. The primary endpoint was investigator-assessed PFS (modified RECIST v1.1). Secondary endpoints included PFS by homologous recombination deficiency (HRD) and somatic BRCA mutation (sBRCAm) status determined by central Myriad tumor and germline testing; and time to first subsequent treatment (TFST). The primary analysis was planned for 18 months (mo) after the last patient was enrolled. Results: 279 pts were enrolled from 17 countries (mean age: 64 years); 253 pts (90.7%) were confirmed non-gBRCAm. At data cut-off (Oct 2, 2020), median PFS was 9.2 mo (95% CI 7.6–10.9), with 210 PFS events (75.3% maturity). 65.3%, 38.5% and 24.3% of pts were progression-free (PF) at 6, 12 and 18 mo, respectively. The Table shows PFS in key subgroups. Median TFST was 13.9 mo (95% CI 11.5–16.4). Median exposure to olaparib was 9.4 mo (range 0.0–31.9). Grade ≥3 treatment-emergent adverse events (TEAEs) occurred in 29.0% of pts and serious TEAEs in 19.7% of pts. TEAEs led to dose interruption, dose reduction and treatment discontinuation in 47.0%, 22.6% and 7.5% of pts, respectively. Conclusions: Our findings support the use of olaparib maintenance therapy in non-gBRCAm PSR OC pts, consistent with our interim analysis and previous trials in this setting. Clinical trial information: NCT03402841. [Table: see text]

Phase I/II study of nivolumab plus vorolanib in patients with thoracic malignancies: Interim efficacy of the SCLC and primary refractory NSCLC cohorts, and safety data across all cohorts.

2578 Background: Combination strategies to improve the efficacy of single agent immune checkpoint inhibitors (ICIs) are increasingly being explored, with one strategy being the addition of vascular endothelial growth factor (VEGF) inhibition. Having shown promise in the treatment of hepatocellular carcinoma and renal cell carcinoma, NCT03583086 is a multi-institutional, phase I/II study of combination vorolanib and nivolumab in both naïve and refractory thoracic tumors that progressed on at least one prior line of platinum-based chemotherapy. Though structurally similar to the tyrosine kinase inhibitor, sunitinib, vorolanib was designed to have a more favorable safety profile with comparable efficacy. Here we present safety data across all cohorts and interim efficacy analyses of the SCLC and NSCLC with primary resistance to ICI-based therapy cohorts, both of which have now completed enrolment. Methods: The maximum tolerated dose determined in phase I was vorolanib 200mg daily and nivolumab 240mg q2 weeks. Phase II uses a two-stage MinMax design across 5 cohorts with objective response rate (ORR) as the primary endpoint: NSCLC (ICI naïve, primary refractory, and acquired resistance), SCLC, and thymic carcinoma. Primary refractory is defined as radiographic progression of disease within 12 weeks of ICI initiation. Results: As of January 2021, 75 patients have been enrolled across all cohorts. Stage 1 of the SCLC and primary refractory NSCLC cohorts have completed accrual at 18 and 15 patients, respectively. In the SCLC cohort, disease-control rate (DCR) was 7% and no objective responses were achieved among 14 evaluable patients. In the primary refractory NSCLC cohort, DCR was 57% and ORR 7% (1 partial response) among 14 evaluable patients. A total of 140 treatment-related adverse events (TRAEs) have been reported, 13 (9%) were grade 3 and there were no grade 4/5 events. Fatigue (9%), nausea (6%), diarrhea (6%), ALT elevation (5%), and AST elevation (5%) were the most common all grade TRAEs. The most common grade 3 TRAEs were ALT elevation and hypertension. Conclusions: This therapeutic strategy of nivolumab plus vorolanib appears to be a well-tolerated combination with a manageable safety profile. Adding VEGF inhibition may offer additional disease control in the setting of NSCLC with primary resistance to ICIs, but neither the SCLC or primary refractory NSCLC cohorts achieved the pre-determined target number of objective responses for progression to stage 2 of the study. Enrolment in the other 3 cohorts as well as exploratory correlatives are ongoing. Clinical trial information: NCT03583086.

Preliminary efficacy data of platinum-pretreated small cell lung cancer (SCLC) cohort of NCI 9881 study: A phase II study of cediranib in combination with olaparib in advanced solid tumors.

9065 Background: Cediranib, a pan-vascular endothelial growth factor receptor tyrosine kinase inhibitor, suppresses expression of BRCA1, BRCA2, and RAD51 and increases sensitivity of tumors to poly-(ADP-ribose) polymerase (PARP) inhibitors in vitro. Olaparib, a PARP inhibitor, demonstrated clinical efficacy in patients with advanced solid tumors carrying a germline BRCA mutation. We therefore tested the anti-tumor activity of cediranib and olaparib combination in patients (pts) with advanced solid tumors. Here, we report the data from the SCLC cohort. Methods: This multi-institutional, two-stage, phase 2 study enrolled pts with metastatic SCLC previously treated with a minimum of one prior line of platinum-based chemotherapy in advanced setting. Patients were treated with cediranib 30mg po daily plus olaparib 200mg po BID until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) by RECIST v1.1. Baseline tumor biopsies were obtained for biomarker analyses. Results: Baseline characteristics of the 25 pts enrolled are summarized below. The overall ORR rate was 28% (95% CI: 0.104,0.456). Median duration of response was 3.8 months (mos). Six of 8 pts had an objective response lasting longer than 3 mos up to 10.3 months. Disease control rate (# of pts with CR, PR or SD / # evaluable pts) was 88% (95% CI: 0.75,1.01). Median progression free survival was 4.1 mos (95% CI: 2.3, 6.2). Median OS was 5.5 mos (95% CI: 3.4, NA). Grade 3/4 adverse events (G3/4 AEs), irrespective of attribution, occurred in 14 of 25 (56%). G3/4 AEs occurring in &gt; 10% of pts were hypertension (21%), fatigue (17%) and weight loss (13%). Conclusions: The cediranib/olaparib combination resulted in promising clinical activity with ORR of 28% in biomarker-unselected pts with platinum-pretreated SCLC. The regimen required prompt initiation of antihypertensives, but AEs were overall manageable. Analyses of mutation status in homologous recombination DNA repair genes are going and will be correlated with clinical activity. Clinical trial information: NCT02498613. [Table: see text]

1009P - Incidence of tumour BRCA1/2 variants in relapsed, platinum-sensitive ovarian, fallopian tube and primary peritoneal cancer

BackgroundRandomised phase 3 trials have demonstrated that poly (ADP-ribose) polymerase (PARP) inhibitors significantly improve progression-free survival in BRCA-mutant high-grade serous and endometrioid ovarian carcinoma. Consequently, the demand for germline and tumour BRCA1/2testing has increased significantly throughout the UK. We report results from a tumour BRCA1/2testing service available to cancer centres across England, Wales and Northern Ireland from July 2017 to February 2019. MethodsDNA extracted from formalin fixed, paraffin-embedded tumour samples underwent next generation sequencing for BRCA1/2 variants. Eligibility criteria included relapsed, platinum-sensitive ovarian, fallopian tube or primary peritoneal cancer with germline BRCA1/2wild-type or unknown germline. Patients also had to have received ≥2 prior lines of platinum-based chemotherapy. A confirmatory histopathology report was requested as part of the tumour BRCA1/2testing service. ResultsTwo hundred and ninety-three histologically-confirmed high-grade serous and/or endometrioid ovarian cancer tumour samples underwent tumour BRCA1/2testing. The prevalence of pathogenic (class 5) or likely pathogenic (class 4) variants was 17.7% (52/293). The germline BRCA1/2was wild-type for 185/293 (63.1%) of patients, with the remaining 36.9% (108/293) with germline BRCA1/2unknown. There were at least 36 (12.3%) pathogenic/likely pathogenic somatic BRCA1/2variants detected. The allele fraction for somatic BRCA1/2pathogenic variants ranged from 0.06 to 0.98, with 50% (18/36) reported with an allele fraction of≥0.5 (50%), in keeping with putative biallelic loss-of-function. ConclusionsProspective evaluation of paired germline and tumour BRCA1/2testing in all women who are diagnosed with platinum-sensitive high-grade serous and/or endometrioid ovarian cancer in the UK is now required to validate these findings. Legal entity responsible for the studyAstraZeneca. FundingAstraZeneca. DisclosureAll authors have declared no conflicts of interest.

1062TiP - A phase II study of pembrolizumab in combination with doxorubicin in advanced, recurrent or metastatic endometrial cancer

1062TiP - A phase II study of pembrolizumab in combination with doxorubicin in advanced, recurrent or metastatic endometrial cancer

A phase II study of bemcentinib (BGB324), a first-in-class highly selective AXL inhibitor, with pembrolizumab in pts with advanced NSCLC: OS for stage I and preliminary stage II efficacy.

9098 Background: AXL is an RTK implicated in epithelial-to-mesenchymal transition and as a resistance mechanism to multiple therapies including anti-PD1. Bemcentinib (BGB324) is a first-in-class, oral, highly selective and potent AXL inhibitor which has been demonstrated to enhance anti-PD1 therapy in the pre-clinical setting. Methods: This is a Phase II single-arm, two-Stage study with bemcentinib (200mg/d) and pembrolizumab (200 mg/q3wk) for previously treated, IO naïve pts (n = 48 in total) with Stage IV lung adenocarcinoma. The primary endpoint was ORR according to RECIST 1.1 with pre-defined minimum requirement for 18% RR in the first Stage (n = 24) to proceed to Stage 2. Secondary endpoints included DCR, PFS, OS and safety. Tumour biopsies were analysed for PD-L1 (22C3 pharmDx), AXL, and infiltrating immune cells. Results: Stage 1 completed enrolment in Apr ‘18. As of Feb ‘19, 38 pts (24 and 14 in Stage 1 and 2, respectively) have been dosed with the combination; median age 66 (range 39-79) yr, 59% male, all previously received one prior line of platinum-based chemotherapy or a licensed EGFR/ALK-directed therapy. The most common TRAEs (occurring in &gt; 15% of pts) were transaminase increases (37%), diarrhoea (29%), and asthenia (17%). All cases of transaminase increase were reversible and resolved with concomitant administration of systemic corticosteroids and interruption of study treatments. At time of writing, Stage 1 had met the efficacy threshold to proceed to Stage 2 with continued enrolment. Among 29 pts evaluable for response 7 PRs were reported (24%). For AXL positive pts (10/21 with available biopsies), ORR was 40%. PD-L1 status was known for 5 responders: 4 pts (80%) were PD-L1 negative or weakly positive. In Stage 1, mPFS was 4.0 months (95% CI 1.9 – NR) and 5.9 months in AXL positive pts (n = 10; 3.0 - NR). mOS was not mature. Conclusions: Overall, bemcentinib in combination with pembrolizumab was well tolerated and promising clinical activity was seen, particularly in pts with AXL positive disease. Updated results will be reported at the meeting, incl 12-month OS for Stage 1 and preliminary efficacy of Stage 2. Clinical trial information: NCT03184571.