Charles A. Leath

GEN-1 in Combination with Neoadjuvant Chemotherapy for Patients with Advanced Epithelial Ovarian Cancer: A Phase I Dose-escalation Study

Abstract Purpose: GEN-1 (phIL-12-005/PPC), an IL12 plasmid formulated with polyethyleneglycol-polyethyleneimine cholesterol lipopolymer, has preclinical activity when combined with platinum-taxane intravenous chemotherapy and administered intraperitoneally in epithelial ovarian cancer (EOC) models. OVATION I was a multicenter, nonrandomized, open-label phase IB trial to evaluate the safety, preliminary antitumor activity, and immunologic response to GEN-1 in combination with neoadjuvant chemotherapy (NACT) carboplatin-paclitaxel in patients with advanced EOC. Patients and Methods: A total of 18 patients with newly diagnosed stage IIIC and IV EOC were enrolled. A standard 3+3 dose-escalation design tested four GEN-1 doses (36, 47, 61, 79 mg/m2) to determine the maximum tolerated dose and dose-limiting toxicities (DLTs). GEN-1 was administered in eight weekly intraperitoneal infusions starting at cycle 1 week 2 in combination with three 21-day cycles of NACT carboplatin AUC 6 and weekly paclitaxel 80 mg/m2. Results: The most common treatment-emergent adverse events at least possibly related were nausea, fatigue, abdominal pain/cramping, anorexia, diarrhea, and vomiting. Eight patients experience grade 4 neutropenia attributed to NACT. No DLTs occurred. A total of 14 patients were evaluable for response and 12 (85.7%) had radiological response (two complete response and 10 partial response) prior to debulking; nine were R0 at debulking and one patient had complete pathologic response. IL12 and its downstream cytokine, IFNγ, increased in peritoneal washings but not as much in blood. Increased levels of myeloid dendritic cells and T-effector memory cells in peritoneal fluid, plus elevated CD8+ T cells and reduced immunosuppression within the tumor microenvironment were found. A median time to treatment failure of 18.4 months (95% confidence interval, 9.2–24.5) was observed in the intention-to-treat population. Conclusions: Adding GEN-1 to standard NACT is safe, appears active, and has an impact on the tumor microenvironment.

Novel Therapeutics for Recurrent Cervical Cancer: Moving Towards Personalized Therapy

While screening programs and HPV vaccination have decreased the incidence of cervical cancer, still over 13,000 cases occur in the USA annually. Early-stage cervical cancer has an excellent long-term prognosis, with 5-year survival for localized disease being > 90%. Survival decreases markedly for both locally advanced and metastatic disease, and both are associated with a higher risk of recurrence. Few effective treatment options exist for persistent, recurrent, or metastatic cervical cancer. In 2014, the anti-VEGF antibody bevacizumab was approved in combination with chemotherapy based on the results of the Phase III GOG-240 study. As the majority of cervical cancers have a viral etiology, which impairs the immune system, immunotherapy using checkpoint inhibitors and other agents, appears to be a promising approach. In June 2018, the US FDA approved the anti-PD1 antibody pembrolizumab for recurrent or metastatic cervical cancer with PD-L1 expression that progressed after one or more lines of chemotherapy. Another anti-PD1 antibody, cemiplimab also shows potential in this setting, either as monotherapy or combined with radiotherapy, and it is currently being evaluated in a Phase III trial. Additional checkpoint inhibitors including nivolumab, durvalumab, atezolizumab, and camrelizumab are in different stages of clinical development for the disease. Finally, an additional targeted approach being pursued involves PARP inhibitors (rucaparib and olaparib are both in Phase II) based on earlier study results.

Randomized phase III trial of adjuvant radiation versus chemoradiation in intermediate-risk, early-stage cervical cancer following radical hysterectomy and lymphadenectomy: results from NRG Oncology/GOG-263/KGOG 1008

To determine whether adjuvant chemoradiation (CRT) with weekly cisplatin improves recurrence-free survival (RFS) compared with radiation (RT) in pathologically proven intermediate risk early-stage cervical cancer following radical hysterectomy and lymphadenectomy. Post-surgical patients with stage I-IIA cervical cancer with pathologically noted intermediate risk factors including combinations of capillary lymphatic space involvement, stromal invasion, and tumor size were randomly assigned in a 1 : 1 ratio to receive either adjuvant CRT or RT (NCT01101451). Patients received conformal RT, or intensity modulated radiation therapy. In the CRT arm, 6 weekly cycles of cisplatin 40 mg/m Of the 340 randomized patients, 316 were eligible and most had Federation of Gynecology and Obstetrics (2009) stage IB Although RFS and OS favored CRT, the addition of cisplatin during RT did not statistically improve RFS or OS in cervical cancer patients with intermediate pathological risk factors following radical hysterectomy and lymphadenectomy. CRT increased grade 3 and 4 AEs with a transient decline in QoL.

Cediranib and Olaparib Combination Compared With Cediranib or Olaparib Alone, or Chemotherapy in Platinum-Resistant or Primary Platinum-Refractory Ovarian Cancer: NRG-GY005

PURPOSE We assessed the efficacy of cediranib, olaparib, and cediranib/olaparib compared with standard-of-care chemotherapy (SOC) in platinum-resistant or platinum-refractory epithelial ovarian cancer (PROC). PATIENTS AND METHODS NRG-GY005 is an open-label, four-arm, phase II/III superiority trial enrolling patients with high-grade serous/endometrioid PROC and one to three previous therapies. Key exclusion criteria included previous receipt of poly(ADP-ribose) polymerase inhibitor or receipt of antiangiogenic therapy in the recurrent setting. Treatment arms (SOC [once weekly paclitaxel, topotecan, or pegylated liposomal doxorubicin], cediranib, olaparib, or cediranib/olaparib) were equally randomized. A preplanned interim futility analysis on the basis of progression-free survival (PFS) selected treatment arms to advance to phase III. PFS and overall survival (OS) were phase III coprimary end points, with hierarchical testing of PFS followed by OS to preserve type 1 error control, designed to have 90% power for a 0.625 PFS hazard ratio (HR). OS was tested after PFS in the multiple hierarchical testing procedure. Secondary end points included objective response rate (ORR) and patient-reported outcomes. RESULTS Five hundred sixty-two eligible patients were enrolled for phase II/III. Three arms met PFS criteria to carry forward to phase III (SOC, cediranib/olaparib, and cediranib). Median PFS was 3.4, 5.2, and 4 months with SOC, cediranib/olaparib, and cediranib, respectively, with a median follow-up duration of 42.2 months. PFS HR estimates for cediranib/olaparib and cediranib ( v SOC) were 0.796 (98.3% CI, 0.597 to 1.060) and 0.972 (98.3% CI, 0.726 to 1.300), respectively. Median OS was 13.6, 12.8, and 10.5 months, and of 443 patients with measurable disease, ORR was 8.6%, 24.7%, and 13.1% for SOC, cediranib/olaparib, and cediranib, respectively. No new safety signals were identified. In patients receiving cediranib/olaparib, no statistically significant difference was observed on the NFOSI-DRS-P subscale compared with SOC (98.3% CI, –1.3 to 1.5, P = .8725). CONCLUSION The cediranib-containing arms demonstrated clinical activity on the basis of PFS but were not superior compared with SOC.

Image guided brachytherapy quality assurance on NRG GY017 investigating immunotherapy in addition to chemoradiation for locally advanced cervical cancer

Brachytherapy is a critical component of curative treatment in locally advanced cervical cancer. NRG GY-017 is a randomized Phase I trial of the anti-PD-L1 antibody atezolizumab administered neoadjuvantly and concurrently with chemoradiation (Arm A) or only concurrently with chemoradiation (Arm B) in patients with node positive locally advanced cervical cancer. Image guided brachytherapy (IGBT) was mandated in the protocol with a quality assurance (QA) workflow. Herein, we report the BT quality data on NRG GY-017 trial and practice patterns from the participating centers in this trial as a guide for future protocol brachytherapy QA. The participating sites were to submit brachytherapy plans online after BT was completed. IROC QA center compiled the BT fractions for each patient using the trial specific dosimetry evaluation template. An expert physician reviewer scored the contours and plans as per protocol, variation acceptable or major deviation as prespecified in the protocol dose metrics. The BT dosimetry results were available for 32 patients. Seventeen patients (53%) had intracavitary applicator, and 15 patients (47%) had hybrid or interstitial applicators. Point A directed planning was performed for 4 patients (12.5%) and 28 patients had volume directed plans (87.5%). For imaging use, 2 patients had MRI based plans, and 30 had CT based planning (94%). For the dose constraints compliance per protocol, 7 patients had 9 events scored as major deviations (22%). BT trial specific QA has the potential to enhance BT quality for clinical trials. This report will help guide future gynecologic BT trial data collection and QA process.

Olaparib as Treatment Versus Nonplatinum Chemotherapy in Patients With Platinum-Sensitive Relapsed Ovarian Cancer: Phase III SOLO3 Study Final Overall Survival Results

Olaparib treatment significantly improved objective response rate (primary end point) and progression-free survival versus nonplatinum chemotherapy in patients with BRCA-mutated platinum-sensitive relapsed ovarian cancer in the open-label phase III SOLO3 trial (ClinicalTrials.gov identifier: NCT02282020 ). We report final overall survival (OS; prespecified secondary end point), post hoc OS analysis by number of previous chemotherapy lines, and exploratory BRCA reversion mutation analysis. Two hundred sixty-six patients were randomly assigned 2:1 to olaparib tablets (300 mg twice daily; n = 178) or physician's choice of single-agent nonplatinum chemotherapy (pegylated liposomal doxorubicin, paclitaxel, gemcitabine, or topotecan; n = 88). OS was similar with olaparib versus chemotherapy (hazard ratio [HR], 1.07 [95% CI, 0.76 to 1.49]; P = .71, median 34.9 and 32.9 months, respectively, full analysis set). OS with olaparib was favorable in patients with two previous chemotherapy lines (HR, 0.83 [olaparib v chemotherapy] [95% CI, 0.51 to 1.38]; median 37.9 v 28.8 months); however, a potential detrimental effect was seen in patients with at least three previous chemotherapy lines (HR, 1.33 [95% CI, 0.84 to 2.18]; median 29.9 v 39.4 months). BRCA reversion mutations might have contributed to this finding. No patient randomly assigned to olaparib with a BRCA reversion mutation detected at baseline (6 of 170 [3.5%]) achieved an objective tumor response.

Health disparities in cervical cancer: Estimating geographic variations of disease burden and association with key socioeconomic and demographic factors in the US

Background Despite advances in cervical cancer (CC) prevention, detection, and treatment in the US, health disparities persist, disproportionately affecting underserved populations or regions. This study analyzes the geographical distribution of both CC and recurrent/metastatic CC (r/mCC) in the US and explores potential risk factors of higher disease burden to inform potential strategies to address disparities in CC and r/mCC. Methods We estimated CC screening rates, as well as CC burden (number of patients with CC diagnosis per 100,000 eligible enrollees) and r/mCC burden (proportion of CC patients receiving systemic therapy not in conjunction with surgery or radiation), at the geographic level between 2017–2022 using administrative claims. Data on income and race/ethnicity were obtained from US Census Bureau’s American Community Survey. Brachytherapy centers were proxies for guideline-conforming care for locally advanced CC. Associations among demographic, socioeconomic, and healthcare resource variables, with CC and r/mCC disease burden were assessed. Results Between 2017–2022, approximately 48,000 CC-diagnosed patients were identified, and approximately 10,000 initiated systemic therapy treatment. Both CC and r/mCC burden varied considerably across the US. Higher screening was significantly associated with lower CC burden only in the South. Lower income level was significantly associated with lower screening rates, higher CC and r/mCC burden. Higher proportion of Hispanic population was also associated with higher CC burden. The presence of ≥1 brachytherapy center in a region was significantly associated with a reduction in r/mCC burden (2.7%). Conclusion CC and r/mCC disparities are an interplay of certain social determinants of health, behavior, and race/ethnicity. Our findings may inform targeted interventions for a geographic area, and further highlight the importance of guideline-conforming care to reduce disease burden.

Phase II Trial of Cisplatin, Gemcitabine, and Intensity-Modulated Radiation Therapy for Locally Advanced Vulvar Squamous Cell Carcinoma: NRG Oncology/GOG Study 279

PURPOSE To assess efficacy and toxicity of cisplatin (C) and gemcitabine (G) with intensity-modulated radiation therapy (IMRT) in patients with locally advanced vulvar cancer not amenable to surgery. METHODS Patients enrolled in a single-arm phase II study. Pretreatment inguinal-femoral nodal assessment was performed. Sixty-four Gy IMRT was prescribed to the vulva, with 50-64 Gy delivered to the groins/low pelvis. Radiation therapy (RT) plans were quality-reviewed pretreatment. C 40 mg/m2 and G 50 mg/m2 were administered once per week throughout IMRT. Complete pathologic response (CPR) was the primary end point. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method, and adverse events were assessed with Common Terminology Criteria for Adverse Events v 4.0. RESULTS Fifty-seven patients enrolled, of which 52 were evaluable. The median age was 58 years (range, 25-58), and 94% were White. Forty (77%) had stage II or III disease, and all had squamous histology. A median of six chemotherapy cycles (range, 1-8) were received. Eighty-five percent of RT plans were quality-reviewed with 100% compliance to protocol. Seven patients came off trial because of toxicity or patient withdrawal. Of 52 patients available for pathologic assessment, 38 (73% [90% CI, 61 to 83]) achieved CPR. No pelvic exenterations were performed. With a median follow-up of 51 months, the 12-month PFS was 74% (90% CI, 62.2 to 82.7) and the 24-month OS was 70% (90% CI, 57 to 79). The most common grade 3 or 4 adverse events were hematologic toxicity and radiation dermatitis. There was one grade 5 event unlikely related to treatment. CONCLUSION Weekly C and G concurrent with IMRT sufficiently improved CPR in women with locally advanced vulvar squamous cell carcinoma not amenable to surgical resection.