A phase 2 trial exploring the significance of homologous recombination status in patients with platinum sensitive or platinum resistant relapsed ovarian cancer receiving combination cediranib and olaparib.

OBJECTIVE: Combination cediranib/olaparib has reported activity in relapsed ovarian cancer. This phase 2 trial investigated the activity of cediranib/olaparib in relapsed ovarian cancer and its association with homologous recombination deficiency (HRD). METHODS: Seventy patients were enrolled to cohorts of either platinum-sensitive or platinum-resistant ovarian cancer and received olaparib tablets 200 mg twice daily and cediranib tablets 30 mg once daily under a continuous dosing schedule. HRD testing was performed on pre-treatment, on-treatment and archival biopsies by sequencing key homologous recombination repair (HRR) genes and by genomic LOH analysis. The primary objective for the platinum-sensitive cohort was the association of HRD, defined as presence of HRR gene mutation, with progression-free survival (PFS). The primary objective for the platinum-resistant cohort was objective response rate (ORR), with a key secondary endpoint evaluating the association of HRD status with activity. RESULTS: In platinum-sensitive ovarian cancer (N = 35), ORR was 77.1% (95% CI 59.9-89.6%) and median PFS was 16.4 months (95% CI 13.2-18.6). Median PFS in platinum-sensitive HRR-HRD cancers (N = 22) was 16.8 months (95% CI 11.3-18.6), and 16.4 months (95% CI 9.4-NA) in HRR-HR proficient cancers (N = 13; p = 0.57). In platinum-resistant ovarian cancer (N = 35), ORR was 22.9% (95% CI 10.4-40.1%) with median PFS 6.8 months (95% CI 4.2-9.1). Median PFS in platinum-resistant HRR-HRD cancers (N = 7) was 10.5 months (95% CI 3.6-NA) and 5.6 months (95% CI 3.6-7.6) in HRR-HR proficient cancers (N = 18; p = 0.23). CONCLUSIONS: Cediranib/olaparib had clinical activity in both platinum-sensitive and -resistant ovarian cancer. Presence of HRR gene mutations was not associated with cediranib/olaparib activity in either setting.

Feasibility of a Serious Illness Communication Program for Pediatric Advance Care Planning.

Importance: Pediatric advance care planning (ACP), which aims to ensure care is aligned with family goals and values, is associated with better end-of-life outcomes; however, ACP in pediatrics remains uncommon. Objectives: To determine the feasibility and acceptability of the Pediatric Serious Illness Communication Program (PediSICP) and explore family-centered outcomes. Design, Setting, and Participants: This cohort study was a single-group pilot study of the PediSICP in adolescents and young adults (AYAs; age ≥13 y) with serious illness, parents of seriously ill children, and interprofessional clinicians from April 2021 to March 2023 in a quaternary care pediatric hospital. Duration of follow-up was 1 month. Data were analyzed from January 2022 to March 2023. Exposure: The PediSICP includes clinician training preceding an ACP communication occasion supported by communication guides and a template for electronic medical record documentation. Main Outcomes and Measures: Outcomes of interest were parent, patient, and clinician experiences with and perceptions of the PediSICP. Feasibility was defined a priori as at least 70% clinician intervention completion rates. Results: A total of 10 virtual trainings were conducted among 40 clinicians, including 27 physicians, 7 nurse practitioners, 5 nurses, and 1 respiratory therapist, and 30 trained clinicians (75%) conducted and documented 42 ACP conversations with 33 parents (median [IQR] age, 43 [35-51] years; 25 [76%] female) and 5 AYAs (median [IQR] age, 19 [17-19] years; 3 [60%] female) who completed the intervention. The median (IQR) conversation duration was 27 (10-45) minutes. Most clinicians (29 clinicians [97%]) agreed that they felt prepared for the conversation, and all clinicians recommended the PediSICP. Parents reported participation was worthwhile (27 parents [84%]), they felt listened to (31 parents [94%]), and would recommend the PediSICP (28 parents [85%]). Parents endorsed higher therapeutic alliance after the PediSICP intervention compared with before (The Human Connection scale mean [SD] score, 57.6 [6.4] vs 55.3 [7.8]; P = .03) and decreased anxiety immediately after the intervention (Generalized Anxiety Disorder-7-item mean [SD] score, 10.1 [7.3] vs 8.4 [6.9]; P = .003), which persisted at the 1-month follow-up (mean [SD] score, 7.7 [6.8]; P = .03). Conclusions and Relevance: This pilot cohort study found that the PediSICP was feasible, acceptable, and highly valued by clinicians and parents of children with serious illness. These findings suggest that the PediSICP may empower interprofessional clinicians and improve ACP with families of children and AYAs who are seriously ill.

Combined aromatase, CDK4/6 and PI3K blockade using letrozole/abemaciclib/LY3023414 in endometrial cancer.

Several lines of preclinical evidence indicate that combining PI3K and CDK4/6 inhibitors may further enhance the efficacy of hormonal therapy by overcoming de novo and acquired resistance to PI3K and CDK4/6 blockade. We evaluated the combination of abemaciclib, letrozole and LY3023414 (an orally available, selective inhibitor of the class I PI3K isoforms and mTORC1/2) in recurrent endometrial cancer (EC). This study was terminated prematurely after 5 patients initiated protocol therapy due to discontinuation of further development of LY3023414. We report our findings from these patients, including one with recurrent endometrioid EC with AKT1, CTNNB1 and ESR1 hotspot mutations who had previously progressed through letrozole/everolimus and achieved a partial response to letrozole/abemaciclib/LY3023414.

Phase I/II Study of Combined BCL-xL and MEK Inhibition with Navitoclax and Trametinib in KRAS or NRAS Mutant Advanced Solid Tumors.

PURPOSE: MEK inhibitors (MEKi) lack monotherapy efficacy in most RAS-mutant cancers. BCL-xL is an anti-apoptotic protein identified by a synthetic lethal shRNA screen as a key suppressor of apoptotic response to MEKi. PATIENTS AND METHODS: We conducted a dose escalation study (NCT02079740) of the BCL-xL inhibitor navitoclax and MEKi trametinib in patients with RAS-mutant tumors with expansion cohorts for: pancreatic, gynecologic (GYN), non-small cell lung cancer (NSCLC), and other cancers harboring KRAS/NRAS mutations. Paired pretreatment and day 15 tumor biopsies and serial cell-free (cf)DNA were analyzed. RESULTS: A total of 91 patients initiated treatment, with 38 in dose escalation. Fifty-eight percent had ≥3 prior therapies. A total of 15 patients (17%) had colorectal cancer, 19 (11%) pancreatic, 15 (17%) NSCLC, and 32 (35%) GYN cancers. The recommended phase II dose (RP2D) was established as trametinib 2 mg daily days 1 to 14 and navitoclax 250 mg daily days 1 to 28 of each cycle. Most common adverse events included diarrhea, thrombocytopenia, increased AST/ALT, and acneiform rash. At RP2D, 8 of 49 (16%) evaluable patients achieved partial response (PR). Disease-specific differences in efficacy were noted. In patients with GYN at the RP2D, 7 of 21 (33%) achieved a PR and median duration of response 8.2 months. No PRs occurred in patients with colorectal cancer, NSCLC, or pancreatic cancer. MAPK pathway inhibition was observed in on-treatment tumor biopsies. Reductions in KRAS/NRAS mutation levels in cfDNA correlated with clinical benefit. CONCLUSIONS: Navitoclax in combination with trametinib was tolerable. Durable clinical responses were observed in patients with RAS-mutant GYN cancers, warranting further evaluation in this population.