Funda Meric-Bernstam

Phase I study of bevacizumab and temsirolimus combination therapy in advanced malignancies: safety, efficacy, and ovarian cancer expansion

Abstract Background Bevacizumab and temsirolimus target angiogenic and mTOR pathways in cancer progression. Methods This phase I study enrolled 48 heavily pretreated patients with advanced solid tumors, including an ovarian cancer expansion cohort. Patients received bevacizumab biweekly plus temsirolimus weekly in a 3 + 3 design to assess safety, maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs). Exploratory analyses included tumor genomic profiling and dynamic contrast-enhanced MRI (DCE-MRI). Results Patients had a median age of 59 and median four prior therapies. Common tumor types were ovarian (27%) and head and neck (15%). Treatment-related adverse events occurred in 93.8%, with 31.3% ≥grade 3. Five patients experienced DLTs, including grade 3 enteritis, fatigue, bowel obstruction/abdominal ileus/pulmonary embolism, bowel perforation and grade 3/4 elevated liver enzymes. MTD was bevacizumab 10 mg/kg biweekly plus temsirolimus 20 mg weekly. Overall, objective response rate (ORR) was 7.3% and 19.5% achieved stable disease ≥6 months (clinical benefit rate [CBR] 26.8%). In ovarian cohort, ORR was 16.7% and CBR 33.3%. Patients with tumor regression on DCE-MRI had lower ΔKtrans values. Conclusion Combination therapy showed acceptable safety and modest activity. Molecular and imaging findings were exploratory and limited. These preliminary observations could inform future biomarker studies. (ClinicalTrials.gov Identifier: NCT01552434)

Advances in Targeting HER2 across Cancer Subtypes: A Pan-Tumor Approach

Abstract Human epidermal growth factor receptor 2 (HER2) is an established therapeutic target in multiple solid tumors, particularly breast and gastric cancers. Significant advancements have been made in the development of HER2-targeted therapies, including monoclonal antibodies, tyrosine kinase inhibitors, antibody–drug conjugates (ADC), and novel bispecific antibodies. These agents have revolutionized the treatment landscape for HER2-positive metastatic cancers, resulting in improved progression-free and overall survival, and quality of life for patients. Beyond breast and gastric cancers, HER2 expression/amplification has been observed in other solid tumors, such as colorectal, lung, bladder, ovarian, and biliary tract cancers, offering new opportunities for personalized therapy in a larger patient population. In this review, we highlight the current state of HER2-targeted treatment strategies across HER2-expressing solid tumors, discussing the clinical efficacy, adverse event profiles, and challenges of existing therapies. We explore emerging treatment approaches, including novel agents such as HER2-targeting ADCs, combination therapies, and strategies to overcome resistance mechanisms. Additionally, we examine the role of HER2 expression heterogeneity, biomarker-driven patient selection, and diagnostic tools for patient selection and optimization of treatment outcomes. This review also investigates ongoing challenges in expanding HER2-targeted therapies, including addressing intrinsic and acquired resistance and tailoring strategies to low HER2-expressing or HER2-mutant tumors. Lastly, we provide insights into future directions, emphasizing the importance of precision oncology to broaden the therapeutic opportunities of HER2-targeted therapies across diverse HER2-driven malignancies.

HERTHENA-PanTumor01: a phase II study of patritumab deruxtecan (HER3-DXd) in previously treated advanced solid tumors

Clinical and Genomic Landscape of RAS Mutations in Gynecologic Cancers

Abstract Purpose: We aimed to describe RAS mutations in gynecologic cancers as they relate to clinicopathologic and genomic features, survival, and therapeutic implications. Experimental Design: Gynecologic cancers with available somatic molecular profiling data at our institution between February 2010 and August 2022 were included and grouped by RAS mutation status. Overall survival was estimated by the Kaplan–Meier method, and multivariable analysis was performed using the Cox proportional hazard model. Results: Of 3,328 gynecologic cancers, 523 (15.7%) showed any RAS mutation. Patients with RAS-mutated tumors were younger (57 vs. 60 years nonmutated), had a higher prevalence of endometriosis (27.3% vs. 16.9%), and lower grades (grade 1/2, 43.2% vs. 8.1%, all P < 0.0001). The highest prevalence of KRAS mutation was in mesonephric-like endometrial (100%, n = 9/9), mesonephric-like ovarian (83.3%, n = 5/6), mucinous ovarian (60.4%), and low-grade serous ovarian (44.4%) cancers. After adjustment for age, cancer type, and grade, RAS mutation was associated with worse overall survival [hazard ratio (HR) = 1.3; P = 0.001]. Specific mutations were in KRAS (13.5%), NRAS (2.0%), and HRAS (0.51%), most commonly KRAS G12D (28.4%) and G12V (26.1%). Common co-mutations were PIK3CA (30.9%), PTEN (28.8%), ARID1A (28.0%), and TP53 (27.9%), of which 64.7% were actionable. RAS + MAPK pathway-targeted therapies were administered to 62 patients with RAS-mutated cancers. While overall survival was significantly higher with therapy [8.4 years [(95% confidence interval (CI), 5.5–12.0) vs. 5.5 years (95% CI, 4.6–6.6); HR = 0.67; P = 0.031], this effect did not persist in multivariable analysis. Conclusions: RAS mutations in gynecologic cancers have a distinct histopathologic distribution and may impact overall survival. PIK3CA, PTEN, and ARID1A are potentially actionable co-alterations. RAS pathway-targeted therapy should be considered.

Phase 1/2 trial of avelumab combined with utomilumab (4‐1BB agonist), PF‐04518600 (OX40 agonist), or radiotherapy in patients with advanced gynecologic malignancies

AbstractBackgroundImmune checkpoint blockade has shown mixed results in advanced/recurrent gynecologic malignancies. Efficacy may be improved through costimulation with OX40 and 4‐1BB agonists. The authors sought to evaluate the safety and efficacy of avelumab combined with utomilumab (a 4‐1BB agonist), PF‐04518600 (an OX40 agonist), and radiotherapy in patients with recurrent gynecologic malignancies.MethodsThe primary end point in this six‐arm, phase 1/2 trial was safety of the combination regimens. Secondary end points included the objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors and immune‐related Response Evaluation Criteria in Solid Tumors, the disease control rate (DCR), the duration of response, progression‐free survival, and overall survival.ResultsForty patients were included (35% with cervical cancer, 30% with endometrial cancer, and 35% with ovarian cancer). Most patients (n = 33; 83%) were enrolled in arms A–C (no radiation). Among 35 patients who were evaluable for efficacy, the ORR was 2.9%, and the DCR was 37.1%, with a median duration of stable disease of 5.4 months (interquartile range, 4.1–7.3 months). Patients with cervical cancer in arm A (avelumab and utomilumab; n = 9 evaluable patients) achieved an ORR of 11% and a DCR of 78%. The median progression‐free survival was 2.1 months (95% CI, 1.8–3.5 months), and overall survival was 9.4 months (95% CI, 5.6–11.9 months). No dose‐limiting toxicities or grade 3–5 immune‐related adverse events were observed.ConclusionsThe findings from this trial highlight that, in heavily pretreated patients with gynecologic cancer, even multidrug regimens targeting multiple immunologic pathways, although safe, did not produce significant responses. A DCR of 78% in patients with cervical cancer who received avelumab and utomilumab indicates that further research on this combination in select patients may be warranted.

Efficacy and Safety of Trastuzumab Deruxtecan in Patients With HER2-Expressing Solid Tumors: Primary Results From the DESTINY-PanTumor02 Phase II Trial

PURPOSE Trastuzumab deruxtecan (T-DXd) is a human epidermal growth factor 2 (HER2)–directed antibody-drug conjugate approved in HER2-expressing breast and gastric cancers and HER2-mutant non–small-cell lung cancer. Treatments are limited for other HER2-expressing solid tumors. METHODS This open-label phase II study evaluated T-DXd (5.4 mg/kg once every 3 weeks) for HER2-expressing (immunohistochemistry [IHC] 3+/2+ by local or central testing) locally advanced or metastatic disease after ≥1 systemic treatment or without alternative treatments. The primary end point was investigator-assessed confirmed objective response rate (ORR). Secondary end points included safety, duration of response, progression-free survival (PFS), and overall survival (OS). RESULTS At primary analysis, 267 patients received treatment across seven tumor cohorts: endometrial, cervical, ovarian, bladder, biliary tract, pancreatic, and other. The median follow-up was 12.75 months. In all patients, the ORR was 37.1% (n = 99; [95% CI, 31.3 to 43.2]), with responses in all cohorts; the median DOR was 11.3 months (95% CI, 9.6 to 17.8); the median PFS was 6.9 months (95% CI, 5.6 to 8.0); and the median OS was 13.4 months (95% CI, 11.9 to 15.5). In patients with central HER2 IHC 3+ expression (n = 75), the ORR was 61.3% (95% CI, 49.4 to 72.4), the median DOR was 22.1 months (95% CI, 9.6 to not reached), the median PFS was 11.9 months (95% CI, 8.2 to 13.0), and the median OS was 21.1 months (95% CI, 15.3 to 29.6). Grade ≥3 drug-related adverse events were observed in 40.8% of patients; 10.5% experienced adjudicated drug-related interstitial lung disease (ILD), with three deaths. CONCLUSION Our study demonstrates durable clinical benefit, meaningful survival outcomes, and safety consistent with the known profile (including ILD) in pretreated patients with HER2-expressing tumors receiving T-DXd. Greatest benefit was observed for the IHC 3+ population. These data support the potential role of T-DXd as a tumor-agnostic therapy for patients with HER2-expressing solid tumors.

Multicenter Phase II Trial of the WEE1 Inhibitor Adavosertib in Refractory Solid Tumors Harboring CCNE1 Amplification

PURPOSE Preclinical cancer models harboring CCNE1 amplification were more sensitive to adavosertib treatment, a WEE1 kinase inhibitor, than models without amplification. Thus, we conducted this phase II study to assess the antitumor activity of adavosertib in patients with CCNE1-amplified, advanced refractory solid tumors. PATIENTS AND METHODS Patients aged ≥ 18 years with measurable disease and refractory solid tumors harboring CCNE1 amplification, an Eastern Cooperative Oncology Group performance status of 0-1, and adequate organ function were studied. Patients received 300 mg of adavosertib once daily on days 1 through 5 and 8 through 12 of a 21-day cycle. The trial followed Bayesian optimal phase II design. The primary end point was objective response rate (ORR). RESULTS Thirty patients were enrolled. The median follow-up duration was 9.9 months. Eight patients had partial responses (PRs), and three had stable disease (SD) ≥ 6 months, with an ORR of 27% (95% CI, 12 to 46), a SD ≥ 6 months/PR rate of 37% (95% CI, 20 to 56), a median progression-free survival duration of 4.1 months (95% CI, 1.8 to 6.4), and a median overall survival duration of 9.9 months (95% CI, 4.8 to 15). Fourteen patients with epithelial ovarian cancer showed an ORR of 36% (95% CI, 13 to 65) and SD ≥ 6 months/PR of 57% (95% CI, 29 to 82), a median progression-free survival duration of 6.3 months (95% CI, 2.4 to 10.2), and a median overall survival duration of 14.9 months (95% CI, 8.9 to 20.9). Common treatment-related toxicities were GI, hematologic toxicities, and fatigue. CONCLUSION Adavosertib monotherapy demonstrates a manageable toxicity profile and promising clinical activity in refractory solid tumors harboring CCNE1 amplification, especially in epithelial ovarian cancer. Further study of adavosertib, alone or in combination with other therapeutic agents, in CCNE1-amplified epithelial ovarian cancer is warranted.

Phase 2 Study of Zilovertamab Vedotin in Participants with Metastatic Solid Tumors

Abstract Purpose: Zilovertamab vedotin, an antibody–drug conjugate targeting receptor tyrosine kinase–like orphan receptor 1 (ROR1), had manageable safety and promising antitumor activity in participants with relapsed or refractory non–Hodgkin lymphomas. We evaluated zilovertamab vedotin in participants with previously treated metastatic solid tumors. Patients and Methods: This phase 2, open-label, nonrandomized study (NCT04504916) enrolled participants with metastatic triple-negative breast cancer, hormone receptor–positive breast cancer, nonsquamous non–small-cell lung cancer, platinum-resistant ovarian cancer, or pancreatic cancer. Participants received zilovertamab vedotin ≤2.5 mg/kg once every 3 weeks (Q1/3W) or <1.75 mg/kg twice every 3 weeks (Q2/3W). The primary endpoint was objective response rate per RECIST version 1.1 by blinded independent central review. ROR1 protein expression was correlated with clinical outcomes. Results: A total of 102 participants were enrolled (Q1/3W, n = 70; Q2/3W, n = 32). The objective response rate was 1% [95% confidence interval (CI), 0%–8%] with Q1/3W dosing (one partial response, hormone receptor–positive/HER2-negative breast cancer cohort) and 0% with Q2/3W dosing. The median progression-free survival (95% CI) was 2.3 (2.0–4.1) and 1.9 (1.7–2.1) months, respectively; the median overall survival (95% CI) was 8.3 (5.2–10.3) and 5.5 (4.4–11.0) months, respectively. Across dosing regimens, treatment-related adverse events were reported in 85 participants (83%), most commonly fatigue (29%) and nausea (28%). Treatment-related peripheral neuropathy occurred in 8%. Treatment-related adverse events led to dose interruption/reduction in 32 participants (31%) and permanent treatment discontinuation in 7 (7%). Tissue for ROR1 IHC was available on 17 participants, with only 3 (all nonresponders) showing ROR1 expression. Conclusions: Zilovertamab vedotin had minimal antitumor activity, with only a single responder, and manageable safety in participants with previously treated metastatic solid tumors. Significance: Zilovertamab vedotin had minimal antitumor activity and manageable safety in participants with previously treated metastatic solid tumors of various histologic subtypes. The results suggest that further development of zilovertamab vedotin in these solid tumors is not warranted.

A Study of HER3-DXd in Subjects With Locally Advanced or Metastatic Solid Tumors

This is a proof-of-concept study designed to investigate HER3-DXd monotherapy in locally advanced unresectable or metastatic solid tumors. The study is enrolling cohorts of participants with melanoma \[cutaneous/acral\], squamous cell carcinomas of the head and neck (SCCHN), HER2-negative gastric cancer ovarian carcinoma, cervical cancer, endometrial cancer, bladder cancer, esophageal carcinoma, pancreatic carcinoma, prostate cancer, second-line gastric cancer, lung cancer, and breast cancer.