Showing papers by "Amit M. Oza published in 2019"

Epithelial ovarian cancer: Evolution of management in the era of precision medicine

Abstract: Ovarian cancer is the second most common cause of gynecologic cancer death in women around the world. The outcomes are complicated, because the disease is often diagnosed late and composed of several subtypes with distinct biological and molecular properties (even within the same histological subtype), and there is inconsistency in availability of and access to treatment. Upfront treatment largely relies on debulking surgery to no residual disease and platinum-based chemotherapy, with the addition of antiangiogenic agents in patients who have suboptimally debulked and stage IV disease. Major improvement in maintenance therapy has been seen by incorporating inhibitors against poly (ADP-ribose) polymerase (PARP) molecules involved in the DNA damage-repair process, which have been approved in a recurrent setting and recently in a first-line setting among women with BRCA1/BRCA2 mutations. In recognizing the challenges facing the treatment of ovarian cancer, current investigations are enlaced with deep molecular and cellular profiling. To improve survival in this aggressive disease, access to appropriate evidence-based care is requisite. In concert, realizing individualized precision medicine will require prioritizing clinical trials of innovative treatments and refining predictive biomarkers that will enable selection of patients who would benefit from chemotherapy, targeted agents, or immunotherapy. Together, a coordinated and structured approach will accelerate significant clinical and academic advancements in ovarian cancer and meaningfully change the paradigm of care.

Niraparib monotherapy for late-line treatment of ovarian cancer (QUADRA): a multicentre, open-label, single-arm, phase 2 trial

Abstract: Summary Background Late-line treatment options for patients with ovarian cancer are few, with the proportion of patients achieving an overall response typically less than 10%, and median overall survival after third-line therapy of 5–9 months. In this study (QUADRA), we investigated the activity of niraparib monotherapy as the fourth or later line of therapy. Methods QUADRA was a multicentre, open-label, single-arm, phase 2 study that evaluated the safety and activity of niraparib in adult patients (≥18 years) with relapsed, high-grade serous (grade 2 or 3) epithelial ovarian, fallopian tube, or primary peritoneal cancer who had been treated with three or more previous chemotherapy regimens. The study was done in the USA and Canada, and 56 sites screened patients (50 sites treated at least one patient). Patients received oral niraparib 300 mg once daily continuously, beginning on day 1 and every cycle (28 days) thereafter until disease progression. The primary objective was the proportion of patients achieving an investigator-assessed confirmed overall response in patients with homologous recombination deficiency (HRD)-positive tumours (including patients with BRCA and without BRCA mutations) sensitive to their last platinum-based therapy who had received three or four previous anticancer therapy regimens (primary efficacy population). Efficacy analyses were additionally done in all dosed patients with measurable disease at baseline. Findings Between April 1, 2015 and Nov 1, 2017, we screened 729 patients for eligibility and enrolled 463 patients, who were initiated on niraparib therapy. At the time of database lock (April 11, 2018), enrolment had closed and the study was ongoing, with 21 patients still on treatment. Patients had received a median of four (IQR 3–5) previous lines of therapy, and the median follow-up for overall survival was 12·2 months (IQR 3·7–22·1). 151 (33%) of 463 patients were resistant and 161 (35%) of 463 patients were refractory to the last administered platinum therapy. 13 (28%) of 47 patients in the primary efficacy population achieved an overall response according to RECIST (95% CI 15·6–42·6; one-sided p=0·00053). The most common drug-related grade 3 or worse treatment-emergent adverse events were anaemia (113 [24%] of 463 patients) and thrombocytopenia (95 [21%] of 463 patients). The most common treatment-emergent serious adverse events were small intestinal obstruction (34 [7%] of 463 patients), thrombocytopenia (34 [7%] of 463 patients), and vomiting (27 [6%] of 463 patients). One death due to gastric haemorrhage was considered treatment related. Interpretation We observed clinically relevant activity of niraparib among women with heavily pretreated ovarian cancer, especially in patients with HRD-positive platinum-sensitive disease, which includes not only patients with a BRCA mutation but also a population with BRCA wild-type disease. We identified no new safety signals. Our data support expansion of the treatment indication for poly(ADP-ribose) polymerase inhibitors to include patients with HRD-positive ovarian cancer beyond those with BRCA mutations. Funding Tesaro.

BRCA Reversion Mutations in Circulating Tumor DNA Predict Primary and Acquired Resistance to the PARP Inhibitor Rucaparib in High-Grade Ovarian Carcinoma

Abstract: A key resistance mechanism to platinum-based chemotherapies and PARP inhibitors in BRCA-mutant cancers is the acquisition of BRCA reversion mutations that restore protein function. To estimate the prevalence of BRCA reversion mutations in high-grade ovarian carcinoma (HGOC), we performed targeted next-generation sequencing of circulating cell-free DNA (cfDNA) extracted from pretreatment and postprogression plasma in patients with deleterious germline or somatic BRCA mutations treated with the PARP inhibitor rucaparib. BRCA reversion mutations were identified in pretreatment cfDNA from 18% (2/11) of platinum-refractory and 13% (5/38) of platinum-resistant cancers, compared with 2% (1/48) of platinum-sensitive cancers (P = 0.049). Patients without BRCA reversion mutations detected in pretreatment cfDNA had significantly longer rucaparib progression-free survival than those with reversion mutations (median, 9.0 vs. 1.8 months; HR, 0.12; P < 0.0001). To study acquired resistance, we sequenced 78 postprogression cfDNA, identifying eight additional patients with BRCA reversion mutations not found in pretreatment cfDNA. SIGNIFICANCE: BRCA reversion mutations are detected in cfDNA from platinum-resistant or platinum-refractory HGOC and are associated with decreased clinical benefit from rucaparib treatment. Sequencing of cfDNA can detect multiple BRCA reversion mutations, highlighting the ability to capture multiclonal heterogeneity.This article is highlighted in the In This Issue feature, p. 151.

Niraparib Maintenance Therapy in Patients With Recurrent Ovarian Cancer After a Partial Response to the Last Platinum-Based Chemotherapy in the ENGOT-OV16/NOVA Trial.

Abstract: PURPOSEIn the ENGOT-OV16/NOVA trial (ClinicalTrials.gov identifier: NCT01847274), maintenance therapy with niraparib, a poly(ADP-ribose) polymerase inhibitor, prolonged progression-free survival in...

FIGO 2018 stage IB2 (2-4 cm) Cervical cancer treated with Neo-adjuvant chemotherapy followed by fertility Sparing Surgery (CONTESSA); Neo-Adjuvant Chemotherapy and Conservative Surgery in Cervical Cancer to Preserve Fertility (NEOCON-F). A PMHC, DGOG, GCIG/CCRN and multicenter study.

Abstract: Background There are limited data regarding the optimal management of pre-menopausal women with cervical lesions measuring 2–4 cm who desire to preserve fertility. Primary objectives To evaluate the feasibility of preserving fertility. Study hypothesis Neo-adjuvant chemotherapy will be effective in reducing the size of the tumor and will enable fertility-sparing surgery without compromising oncologic outcome. Trial design Pre-menopausal women diagnosed with stage International Federation of Gynecology and Obstetrics (FIGO) IB2, 2–4 cm cervical cancer who wish to preserve fertility will receive three cycles of platinum/paclitaxel chemotherapy. Patients with complete/partial response will undergo fertility-sparing surgery. Patients will be followed for 3 years to monitor outcome. Patients with suboptimal response (residual lesion ≥2 cm) will receive definitive radical hysterectomy and/or chemoradiation. Major eligibility criteria Patients must have histologically confirmed invasive cervical cancer, 2–4 cm lesion, by clinical examination and magnetic resonance imaging (MRI), negative node, and pre-menopausal (≤40 years old). Following three cycles of neo-adjuvant chemotherapy, patients must achieve a complete/partial response (residual lesion Primary endpoints Assess the rate of functional uterus defined as successful fertility-sparing surgery and no adjuvant therapy. Sample size A total of 90 evaluable patients will be needed to complete the study. Estimated dates for completing accrual and presenting results Expected complete accrual in 2022 with presentation of results by 2025. Trial registration number Pending ethics submission.

Evaluation of Prophylactic Corticosteroid Eye Drop Use in the Management of Corneal Abnormalities Induced by the Antibody–Drug Conjugate Mirvetuximab Soravtansine

Abstract: Purpose: Reversible, low-grade ocular adverse events (AE) are associated with administration of mirvetuximab soravtansine, a folate receptor alpha (FRα)-targeted antibody–drug conjugate undergoing phase III clinical evaluation in platinum-resistant ovarian cancer. This study investigated the underlying mechanisms of ocular toxicity and evaluated primary prophylactic use of corticosteroid eye drops in patients receiving mirvetuximab soravtansine. Patients and Methods: Target expression in the human eye was determined by IHC. The ocular toxicity profile of mirvetuximab soravtansine was assessed preclinically using Dutch-Belted rabbits. In a phase I clinical study, patients with ovarian cancer were treated with 6 mg/kg mirvetuximab soravtansine intravenously once every 3 weeks, including one expansion cohort with corticosteroid eye drops administered daily for the first 10 days of each treatment cycle. Results: FRα expression was absent from human corneal tissues. Ocular abnormalities in the rabbit eye appeared phenotypically consistent with off-target effects on the cornea. Forty patients were enrolled in the expansion cohort. Reversible grade 1 or 2 blurred vision and keratopathy occurred in 16 (40%) and 12 (30%) patients, respectively; no grade 3/4 ocular events were observed. Compared with those patients who did not receive primary prophylaxis, corticosteroid eye drop use resulted in fewer dose reductions (5% vs. 15%) and none discontinued due to ocular AEs. Conclusions: Preclinical modeling was predictive of the corneal-related symptoms seen in some patients dosed with mirvetuximab soravtansine. Primary prophylactic use of topical corticosteroid eye drops resulted in a trend toward symptomatic improvement and a reduction in ocular AE-related dose modifications in patients treated with mirvetuximab soravtansine.

TP53 mutations in high grade serous ovarian cancer and impact on clinical outcomes: a comparison of next generation sequencing and bioinformatics analyses

Abstract: Objective Mutations in TP53 are found in the majority of high grade serous ovarian cancers, leading to gain of function or loss of function of its protein product, p53, involved in oncogenesis. There have been conflicting reports as to the impact of the type of these on prognosis. We aim to further elucidate this relationship in our cohort of patients. Methods 229 patients with high grade serous ovarian cancer underwent tumor profiling through an institutional molecular screening program with targeted next generation sequencing. TP53 mutations were classified using methods previously described in the literature. Immunohistochemistry on formalin-fixed paraffin embedded tissue was used to assess for TP53 mutation. Using divisive hierarchal clustering, we generated patient clusters with similar clinicopathologic characteristics to investigate differences in outcomes. Results Six different classification schemes of TP53 mutations were studied. These did not show an association with first platinum-free interval or overall survival. Next generation sequencing reliably predicted mutation in 80% of cases, similar to the proportion detected by immunohistochemistry. Divisive hierarchical clustering generated four main clusters, with cluster 3 having a significantly worse prognosis (p Conclusions Different classifications of TP53 mutations did not show an impact on outcomes in this study. Immunohistochemistry was a good predictor for TP53 mutation. Cluster analysis showed that a subgroup of patients with gain of function mutations (cluster 3) had a worse prognosis.

High EMSY expression defines a BRCA‐like subgroup of high‐grade serous ovarian carcinoma with prolonged survival and hypersensitivity to platinum

Abstract: Background Approximately half of high-grade serous ovarian carcinomas (HGSOCs) demonstrate homologous recombination repair (HR) pathway defects, resulting in a distinct clinical phenotype comprising hypersensitivity to platinum, superior clinical outcome, and greater sensitivity to poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors. EMSY, which is known to be amplified in breast and ovarian cancers, encodes a protein reported to bind and inactivate BRCA2. Thus, EMSY overexpression may mimic BRCA2 mutation, resulting in HR deficiency. However, to our knowledge, the phenotypic consequences of EMSY overexpression in HGSOC patients has not been explored. Methods Here we investigate the impact of EMSY expression on clinical outcome and sensitivity to platinum-based chemotherapy using available data from transcriptomically characterized HGSOC cohorts. Results High EMSY expression was associated with better clinical outcome in a cohort of 265 patients with HGSOC from Edinburgh (overall survival multivariable hazard ratio, 0.58 [95% CI, 0.38-0.88; P = .011] and progression-free survival multivariable hazard ratio, 0.62 [95% CI, 0.40-0.96; P = .030]). Superior outcome also was demonstrated in the Medical Research Council ICON7 clinical trial and multiple publicly available data sets. Patients within the Edinburgh cohort who had high EMSY expression were found to demonstrate greater rates of complete response to multiple platinum-containing chemotherapy regimens (radiological complete response rate of 44.4% vs 12.5% at second exposure; P = .035) and corresponding prolonged time to disease progression (median, 151.5 days vs 60.5 days after third platinum exposure; P = .004). Conclusions Patients with HGSOCs demonstrating high EMSY expression appear to experience prolonged survival and greater platinum sensitivity, reminiscent of BRCA-mutant cases. These data are consistent with the notion that EMSY overexpression may render HGSOCs HR deficient.

Patient-Centered Outcomes in ARIEL3, a Phase III, Randomized, Placebo-Controlled Trial of Rucaparib Maintenance Treatment in Patients with Recurrent Ovarian Carcinoma

Abstract: PURPOSETo investigate quality-adjusted progression-free survival (QA-PFS) and quality-adjusted time without symptoms or toxicity (Q-TWiST) in a post hoc exploratory analysis of the phase III ARIEL3...

Antitumor activity of the poly(ADP-ribose) polymerase inhibitor rucaparib as monotherapy in patients with platinum-sensitive, relapsed, BRCA-mutated, high-grade ovarian cancer, and an update on safety.

Abstract: Objective To report results from an integrated efficacy and safety analysis supporting the European Commission9s approval of the poly(ADP-ribose) polymerase inhibitor rucaparib as monotherapy treatment for relapsed, platinum-sensitive, BRCA-mutated ovarian cancer. Methods Efficacy was analyzed in platinum-sensitive patients from Study 10 (NCT01482715) and ARIEL2 (NCT01891344) who had high-grade serous or endometrioid epithelial ovarian, fallopian tube, or primary peritoneal cancer and a deleterious BRCA1 or BRCA2 mutation and received two or more prior chemotherapies (including two or more platinum-based therapies). The primary end point was investigator-assessed, confirmed objective response rate (visit cut-off: April 10, 2017). Safety was analyzed in patients with ovarian cancer, regardless of BRCA mutation status or lines of prior chemotherapies, who received at least one dose of rucaparib 600 mg in either study (visit cut-off: December 31, 2017). Results In the integrated platinum-sensitive efficacy population (n=79), objective response rate was 64.6% (95% CI, 53.0 to 75.0); 10.1% (8/79) of patients had a complete response and 54.4% (43/79) had a partial response. Median duration of response was 294 days (95% CI, 224 to 393). In the integrated safety population (n=565), the most common any-grade treatment-emergent adverse events were nausea (77.7%, 439/565), asthenia/fatigue (74.7%, 422/565), vomiting (45.8%, 259/565), and hemoglobin decreased (44.2%, 250/565). Treatment-emergent adverse events led to treatment interruption, dose reduction, or discontinuation in 60.2% (340/565), 46.0% (260/565), and 16.8% (95/565) of patients. Conclusions In patients with platinum-sensitive, BRCA-mutated ovarian cancer, rucaparib demonstrated antitumor activity and is the first and currently the only poly(ADP-ribose) polymerase inhibitor approved by the European Commission as treatment for this population. The safety analysis used a more recent visit cut-off date and larger population than previously published, was consistent with prior reports, and was the basis for the treatment-indication safety population in rucaparib’s recently updated European Union label.

Adavosertib with chemotherapy (CT) in patients (pts) with platinum-resistant ovarian cancer (PPROC): An open label, four-arm, phase II study.

Abstract: 5513Background: Adavosertib (AZD1775; A), a highly selective WEE1 inhibitor, demonstrated activity and tolerability in combination with carboplatin (C) in primary PROC. This study (NCT02272790) ass...

Abstract CT025: Phase Ib study of adavosertib in combination with olaparib in patients with refractory solid tumors: Dose escalation

Abstract: Background: Preclinical data suggest that adavosertib (AZD1775), a highly selective Wee1 inhibitor, enhances the antitumor effect of PARP inhibitors such as olaparib. The dose-escalation part of this Phase Ib study (NCT02511795) investigated the safety and tolerability of adavosertib plus olaparib in patients (pts) with refractory solid tumors to determine a maximum tolerated dose (MTD) and recommended Phase II dose (RP2D). Methods: Pts received adavosertib (QD or BID) for 3 consecutive days with 4 days off treatment (3/4), or 5 consecutive days with 2 days off (5/2), plus olaparib (BID) for 14 or 21 days of a 21-day cycle (Table). The MTD was the highest dose at which 7 days, gr 3 thrombocytopenia with gr ≥2 bleeding, non-hematologic gr ≥3 AEs (excluding nausea, vomiting or diarrhea that responds to supportive care), liver function gr ≥3 AEs lasting >48 hours or changes consistent with Hy’s Law, or any other toxicity that disrupted dosing for >7 days. Results: 119 pts were treated (84 female; median age 59; most common primary tumor sites: ovary [21%], breast [16%], lung [12.6%]) (Table). The most common gr ≥3 AEs were anemia (n=28, 23.5%), neutropenia (n=26, 21.8%), and thrombocytopenia (n=20, 16.8%) (all grouped terms). The most common DLTs were thrombocytopenia (n=4) and neutropenia (n=4); two pts experienced both. There were 4 SAEs with an outcome of death, 1 was treatment related. ORR for the total population, cohort 4.2 and cohort 7.4 was 11.1%, 30.8% and 0%, respectively. DCR was 55.7%, 76.9% and 53.8%, respectively. PK and biomarker data will be presented. Conclusions: Treatment with adavosertib plus olaparib showed antitumor activity, mostly at the MTD/RP2D for the BID schedule, which was determined to be adavosertib 175 mg (3/4) for 2/3 weeks plus olaparib 200 mg BID. The RP2D for QD schedule was adavosertib 200 mg (3/4) for 2/3 weeks plus olaparib 200 mg BID. Citation Format: Erika Hamilton, Gerald S. Falchook, Judy S. Wang, Siqing Fu, Amit Oza, So Karen, Esteban Rodrigo Imedio, Sanjeev Kumar, Lone Ottesen, Ganesh M. Mugundu, Juliann Chmielecki, Suzanne Jones, David R. Spigel, Bob T. Li. Phase Ib study of adavosertib in combination with olaparib in patients with refractory solid tumors: Dose escalation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT025.

A randomized double-blind placebo-controlled phase II trial comparing gemcitabine monotherapy to gemcitabine in combination with adavosertib in women with recurrent, platinum resistant epithelial ovarian cancer: A trial of the Princess Margaret, California, Chicago and Mayo Phase II Consortia.

Abstract: 5518Background: Platinum resistant ovarian cancer (OC) remains a therapeutic challenge. High grade serous OC (HGSOC) harbors TP53 mutations leading to increased dependency on S- and G2-phase checkp...

Optimizing the Care of Malignant Bowel Obstruction in Patients With Advanced Gynecologic Cancer

Abstract: PURPOSE:Malignant bowel obstruction (MBO) is a common and distressing complication in women with advanced gynecologic cancer. A pilot, interprofessional MBO program was launched in 2016 at a large ...

Evolve: A post PARP inhibitor clinical translational phase II trial of cediranib-olaparib in ovarian cancer—A Princess Margaret Consortium – GCIG Phase II Trial.

Abstract: 5521Background: PARP inhibitors (PARPi) are approved therapies in high grade serous ovarian cancer (HGSOC). There are few studies after PARPi progression and correlation with dynamic changes in res...

Wanna Get Away? Maintenance Treatments and Chemotherapy Holidays in Gynecologic Cancers.

Abstract: Epithelial ovarian cancer has a very high rate of relapse after primary therapy; historically approximately 70% of patients with a complete clinical response to surgery and adjuvant chemotherapy will relapse and die of the disease. Although this number has slowly improved, cure rates remain less than 50%. As such, maintenance therapy with the aim of preventing or delaying disease relapse and the goal of improving overall survival has been the subject of intense study. Numerous earlier studies with agents ranging from radioactive phosphorus to extended frontline therapy or to monthly taxol administration demonstrated encouraging improvements in progression-free survival (PFS) only to find, disappointingly, no benefit in overall survival. In addition, the PFS advantage of maintenance therapy was associated with disconcerting side effects such that maintenance therapy was not adapted as standard of care. Studies with bevacizumab and PARP inhibitors have demonstrated a PFS advantage with a manageable side-effect profile. However, an overall survival advantage remains unclear, and the use of these approaches thus remains controversial. Furthermore, in recurrent disease, the length of chemotherapy and benefits of extended chemotherapy is unclear. Thus, additional trials assessing maintenance strategies in ovarian and other gynecologic malignancies are needed.

Abstract CT158: ATHENA (GOG-3020/ENGOT-ov45): a randomized, double-blind, placebo-controlled, Phase III study of rucaparib + nivolumab following front-line platinum-based chemotherapy in ovarian cancer

Abstract: Background: The poly(ADP-ribose) polymerase (PARP) inhibitor rucaparib has demonstrated clinical activity in patients with ovarian cancer with or without homologous recombination (HR) deficiency (HRD; eg, a BRCA mutation or high genome-wide loss of heterozygosity [LOH high]). ATHENA (NCT03522246) is evaluating rucaparib + the anti-PD-1 antibody nivolumab as maintenance treatment following front-line platinum-based chemotherapy in patients with newly diagnosed, high-grade ovarian, fallopian tube, or primary peritoneal cancer. The rationale for evaluating this combination includes the following: tumors with a deleterious BRCAmutation express novel, tumor-specific protein sequences (neoantigens), which can attract PD-L1-expressing, tumor-infiltrating lymphocytes; ovarian tumors with HRD have more neoantigens relative to HR-proficient tumors and may respond preferentially to immune checkpoint inhibitors; and rucaparib combined with anti-PD-1 or anti-PD-L1 demonstrated improved antitumor activity in a syngeneic ovarian cancer BrKras (BRCA1-/-; TP53-/-; MYC; KRAS-G12D; AKT) model. Furthermore, it is hypothesized that DNA damage induced by PARP inhibition may increase neoantigens regardless of HRD status. Methods: Eligible patients must have completed first-line platinum doublet chemotherapy and surgery. Patients had to have achieved an investigator-assessed response without disease progression or rising CA-125 at any time during first-line platinum doublet treatment. Cytoreductive surgery (R0 permitted) could have been completed either prior to chemotherapy (primary surgery) or following neoadjuvant chemotherapy (interval debulking). Patients will be randomized 4:4:1:1 to receive maintenance treatment in Arm A (oral rucaparib 600 mg BID + intravenous [IV] nivolumab 480 mg on day 1 of every 4-week cycle), Arm B (oral rucaparib + IV placebo), Arm C (oral placebo + IV nivolumab), or Arm D (oral placebo + IV placebo). Stratification factors include centrally determined tumor HRD status (BRCA mutant, non-BRCA mutant/LOH high, non-BRCA mutant/LOH low, or non-BRCA mutant/LOH indeterminate), posttreatment disease status (residual vs no residual disease), and timing of surgery (primary vs interval debulking). The primary endpoint of investigator-assessed progression-free survival (per RECIST version 1.1) will be evaluated in 3 independent comparisons between arms: A vs B, A vs D, and B vs D. Secondary endpoints include blinded independent central review of progression-free survival, overall survival, investigator-assessed objective response rate, investigator-assessed duration of response, and safety. Enrollment is ongoing; patients (n≈1000) will be enrolled at >270 sites worldwide. Citation Format: Shannon N. Westin, Rebecca S. Kristeleit, Robert L. Coleman, Keiichi Fujiwara, Amit M. Oza, David M. O’Malley, Thomas J. Herzog, Frederik Marme, Ana Oaknin, Ramez Eskander, Domenica Lorusso, Tamar Safra, Jacob Korach, Kevin K. Lin, Danny Shih, Lisa Caunt, Sandra Goble, Stephanie Hume, Lara Maloney, Iain McNeish, Bradley J. Monk. ATHENA (GOG-3020/ENGOT-ov45): a randomized, double-blind, placebo-controlled, Phase III study of rucaparib + nivolumab following front-line platinum-based chemotherapy in ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT158.

Abstract CT012: Open-label, multicenter, Phase Ib study to assess safety, tolerability and efficacy of adavosertib monotherapy in patients with advanced solid tumors: Expansion cohorts

Abstract: Background Adavosertib (AZD1775) is a first-in-class, selective, small-molecule inhibitor of Wee1. Previously we reported safety and efficacy of adavosertib monotherapy in patients (pts) with advanced solid tumors (NCT02482311; Bauer et al Cancer Res 2016;76[14 Suppl]); here we report safety and efficacy data from expansion cohorts based on tumor type. Methods A total of 80 pts grouped into 6 biomarker-matched cohorts (Table) received adavosertib (175 mg PO bid; days 1–3 and 8–10 per 21-day cycle). Eligible pts had: confirmed diagnosis of ovarian cancer (OC), small-cell lung cancer (SCLC) or triple-negative breast cancer (TNBC); prior treatment (Tx) for metastatic/recurrent disease (≥3 prior Tx for pts with BRCAwt OC; progression following PARPi Tx for BRCA1/2m OC pts; ≤1 chemotherapy-based Tx for SCLC and ≥1 chemotherapy-based Tx for TNBC); measurable disease. Primary objective assessments: ORR; DCR; PFS (RECIST v1.1); safety. Tumor assessments were performed every 6 weeks in year 1 and every 12 weeks thereafter until disease progression or intolerable toxicity. Blood and tumor samples were collected for correlative biomarker and pharmacokinetic (PK) analyses. Results Median total Tx duration was 2.4 months. Most frequently reported adverse events (AEs) were diarrhea (61%), nausea (50%) and fatigue (43%). Most commonly reported grade ≥3 AEs were diarrhea (7.5%), nausea, fatigue and small intestine obstruction (6%). AEs leading to dose interruptions (22.5%), reductions (11.3%) or discontinuations (16.3%) were reported. The study showed preliminary antitumor activity, particularly in BRCAwt as well as PARPi-failure BRCAm OC pts (Table). PK and biomarker analyses will be presented. Conclusions Adavosertib was generally well tolerated and showed preliminary antitumor activity. DCR was modest across all patient cohorts. Citation Format: Todd M. Bauer, Kathleen Moore, Janet S. Rader, Fiona Simpkins, Alain Mita, J Thaddeus Beck, Lowell Hart, Quincy Chu, Amit Oza, Anna V. Tinker, Karen So, Esteban Rodrigo Imedio, Sanjeev Kumar, Ganesh M. Mugundu, Suzanne Jenkins, Juliann Chmielecki, Suzanne Jones, David R. Spigel, Siqing Fu. Open-label, multicenter, Phase Ib study to assess safety, tolerability and efficacy of adavosertib monotherapy in patients with advanced solid tumors: Expansion cohorts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT012.

Maintenance olaparib after platinum-based chemotherapy in patients (pts) with newly diagnosed advanced ovarian cancer (OC) and a BRCA mutation (BRCAm): Efficacy by surgical and tumor status in the Phase III SOLO1 trial.

Abstract: 5541Background: In SOLO1 (NCT01844986), maintenance olaparib significantly improved progression-free survival (PFS) vs placebo (HR 0.30; 95% CI 0.23–0.41; Moore et al. N Engl J Med 2018) in pts wit...

Heterogeneous alteration of the ERBB3–MYC axis associated with MEK inhibitor resistance in a KRAS-mutated low-grade serous ovarian cancer patient

Abstract: Low-grade serous ovarian cancer (LGSOC) is relatively chemoresistant, and no precision therapy is approved for this indication. Despite promising results in phase II trials, MEK inhibitors have failed to show improved progression-free survival in a phase III trial when compared to physician's choice chemotherapy. We report for the first time temporal changes in the tumor genome assessed in sequential tumor samples of a 48-yr-old patient with a KRAS-mutated LGSOC treated with the MEK inhibitor binimetinib. After an initial long-lasting partial response, rapidly progressive brain metastasis occurred, ultimately leading to patient death. Our study demonstrates that novel genomic alterations accumulated during the course of treatment as a result of therapeutic pressures led to MEK inhibitor resistance and, ultimately, disease evolution with an aggressive behavior observed in this patient. In particular, we describe the presence of ERBB3 amplification and aberrant ERBB3-MYC signaling as a potential mechanism of acquired MEK inhibitor resistance in a patient with LGSOC, which is similar to previous observations in KRAS-mutated colon and lung cancers. Our study highlights the need for an individualized approach to better understand tumor genome evolution and suggests that LGSOC patients may derive improved therapeutic benefit by using a combinatorial strategy used in other cancers in order to overcome emergent resistance to targeted therapies.