Background

Accurate and timely evaluation of AEs on ClinT is critical to assure patient (pt) safety. In PM ClinT toxicity is captured in real time with AEs assessed by a ClinT nurse, standardized with CTCAE and electronically sourced, and approved by a physician.

Methods

AEs recorded in the PM ClinT AE database between 01/2016 and 12/2018 were evaluated. Gyne ClinT assessing systemic therapy were included. Inferential statistics on risk factors of grade ≥ 3 (G3+) AE reporting and GEE logistic models with Odds Ratios (OR) were performed. Multivariate (m/v) analysis was adjusted to age, ClinT phase, sponsor, therapy combination and type.

Results

We identified 516 ClinT with 3,467 pts on therapy. Among them, 42 ClinT were launched in the gyne site (52% ovarian, 10% uterine, 10% cervix, 28% multiple). 317 unique pts were accrued in gyne ClinT (38 pt in >1ClinT [range 1–4 ClinT]), yielding 362 pts on therapy (Table). 17,187 AEs were reported, 10.6% were grade ≥3 (G3+), 0.9% G4+ and 0.02% G5 . The most common G3+ AEs were hematological (49%), gastro-intestinal (13%). On m/v analysis, no odds differences of G3+ AEs were detected according to study phase. Pts enrolled in immunotherapy ClinT had lower odds of G3+ AE than pts on targeted or other therapy (OR 0.55; 0.32-0.96). There was greater odds of G3+ AEs in ClinT assessing combination vs single therapeutics (OR 2.27; 1.40-3.69), and in investigator initiated ClinT vs not (OR 2.29; 1.24-4.23). Pts aged <50 (OR 2.13; 1.01-4.48) and >65 (OR 1.72; 1.03-2.83) had greater odds of G3+ AEs than pts aged 50 to 65 years. Overall, when compared to other disease sites, the odds of having a G3+ AE reported in gyne ClinT was no different, but the odds of G4+ AEs (OR 0.54; 0.38-0.74) and G5 AEs (OR 0.08; 0.01-0.26) was lower.

Conclusions

In gyne ClinT the odds of having a G3+ AE reported were more frequent on combination therapy studies and investigator initiated trials. Lower odds of having G3+ AEs were detected in immunotherapy trials and pts aged 50-65.

Background

Current molecular testing of HGOC uses panel testing of fixed tumour tissue. Matched tumour-germline WGS is now in the NHS National Genomic Test Directory for fresh frozen (FF) samples. WGS offers significant advantages over panel tests, particularly for accurate measures of mutational processes (homologous recombination deficiency [HRD], tumour mutational burden [TMB]). We report the experience of integrating WGS into routine NHS pathways for women with HGOC between April and November 2022.

Methods

WGS of somatic (×80) and germline (×30) was performed by the NHS Genomics Medicine Sequencing Centre using Illumina chemistries. Processing of the sequence data and variant triage was performed by Genomics England WGS analysis pipeline. All patients (pts) gave written informed consent for germline and tumour testing.

Results

WGS was performed in 19 pts (table). After an initial 3 month run-in period using banked FF samples, prospective testing was integrated into routine care from July 22. The median time from consent to clinical reporting was 48 days (IQR 44-68).

WGS results changed the diagnosis in 3 patients: 2 with image-guided biopsies were changed from HGOC to low grade subtype and 1 recurrent poorly differentiated gynaecological carcinoma had unusually high TMB and APOBEC signatures that was inconsistent with HGOC enabling compassionate use of pembrolizumab.

Estimating HRD from WGS using the CHORD algorithm showed strong concordance with Myriad MyChoice (9/11; 82%). One clinically platinum-refractory case was proficient by CHORD and had a genomic instability score [GIS] of 42. The second pt had a germline deleterious BRIP1 variant with GIS 36 and was deficient by CHORD. CCNE1 amplification was only present in platinum resistant cases.

Conclusions

Biopsy pathways for FF and WGS are feasible for diagnostic pathways in the NHS. WGS offers clinically relevant measures of mutational processes in HGOC with diagnostic and predictive value.

Background

Paclitaxel and carboplatin remains a backbone treatment of ovarian cancer (OC) inducing peripheral neuropathy in a significant proportion of patients. Meanwhile, long term survival of OC has dramatically increased with the recent therapeutic progress. Predictive factors for long-term CIPN are needed considering the impact on quality of life (Qol) of patients. We investigated the link between the incidence of CIPN and selected genetic polymorphisms in a cohort of ovarian cancer survivors.

Methods

Vivrovaire is a French multi-center long-standing cohort of ovarian cancer patients free of disease 3 years after the end of the primary treatment. Long-term analysis of Qol in linked with neuropathy was performed including peripheral neuropathy assessed by the FACT/GOG-Ntx4 self-questionnaire. CIPN scores were correlated with SNPs in the selected CYP2C8, CYP3A4, ERCC1 and XPC genes.

Results

130 patients were included with a median time from the end of chemotherapy of 63 months [35-180]. Median CIPN score was 37 [18-44] with 35 patients (27 %) having a severe score (< 33). SNPs (homozygotous/heterozygotous) were identified as follows: CYP2C8 [n=32 (24.6%)/ n=99 (76%)]; CYP3A4 [n=0 (0%)/ n=8 (6.1%)], ERCC1 [n=21 (16.1%)/ n=57 (43.8%)] and XPC [n=45 (34.6%)/ n=66 (50.8%)]. In univariate analysis, homozygous SNP (ho SNP) in any of the selected genes was associated with CIPN score as a continuous variable (p=0.045) but not with severe score (< 33) (OR: 1.66; 95% CI [0.74-3.88], p=0.22). Patients with CYP2C8_rs1934951 SNP tend to have CIPN score <33, (OR: 2.22; 95% CI [0.98-5.02], p=0.057). In multivariate analyses including age, interval from the end of chemotherapy, type and number of chemotherapy courses, identification of homozygotous or heterozygotous CYP2C8_rs1934951 SNP was associated with a severe CIPN score (OR: 2.41; 95% CI [1.02-5.70], p=0.043).

Conclusions

Our study shows that residual CIPN is a frequent concern for ovarian cancer survivors. CYP2C8_rs1934951 SNP may be associated with severe residual CIPN in long-term survivors of ovarian cancer.

Background

Ovarian cancer (OC) is the fifth cause of cancer death in women and the deadliest of gynecologic cancers.First-line treatment of newly diagnosed OC includes a combination of surgery and chemotherapy.However, 85% of patients experience recurrence.Prolonging the benefit of first-line platinum with a maintenance therapy is currently the best chance for these patients.PARP inhibitors are essential to improve outcome:Olaparib, Niraparib, and olaparib/bevacizumab are approved with different indications.Niraparib is an highly selective PARP-1 and -2 inhibitor and recent trials showed its activity both in recurrence (NOVA trial) and first diagnosis (PRIMA trial).In the last study, evaluating patients with newly diagnosed advanced OC with residual cancer at primary surgery who had a response to platinum-based chemotherapy, niraparib met the primary endpoint of prolonging progression-free survival (PFS) versus placebo regardless of BRCA mutation or HRD tumor status.A Niraparib Expanded Access Programme (EAP) started in Italy in March 2020 as first-line maintenance treatment option for patients with newly diagnosed advanced OC,before the commercial approval.Until July 2021, 600 patients have been enrolled.This EAP represents an opportunity to evaluate drug efficacy and safety in the real live world.MITO 40 aims to collect retrospectively the data from the patients of the EAP programme that for several characteristics (any residual diseasafter primary surgery, and histotypes) differs from the population enrolled in PRIMA.

Trial Design

This is a no profit observational retrospective real life multicenter study, the promoter is the NCI Fondazione G. Pascale. The involved centers are part of the MITO group (Multicenter Italian Trials in Ovarian cancer and gynecologic malignancies).The primary objective is to observe efficacy of niraparib as maintenance treatment in a real life setting for newly diagnosed ovarian cancer patients within the EAP. The secondary objective is to assess safety and long term clinical outcomes in the same population. Patients retrospectively included in EAP will be followed up prospectively up to 3 years from inclusion in EAP independently of whether they are continuing treatment with niraparib or not.

Background

Human epidermal growth factor 2 (HER2) encoded by the ERBB2 gene. In serous endometrial carcinoma (SEC) , HER2 is amplified in 17-30% cases. ERBB2 alterations are also present across other gynecological histologies. A randomized phase II study showed that the addition of trastuzumab to 1^st line platinum chemotherapy increased PFS and OS in HER2 amplified SEC , yet there is currently no approval for those drugs in gynecological malignancies.

Methods

We retrospectively collected data from patients with gynecological cancers who were screened by next generation sequencing (NGS) on tumor and/or circulating tumor DNA (ctDNA) and discussed at Gustave Roussy’s molecular tumor board between March 2021 and June 2022. The objective of this study was to describe the outcomes of gynecological patients harboring HER2 amplifications or pathogenic mutations that were identified through Gustave Roussy’s molecular program

Results

Between March 2021 and June 2022, 19 patients had a HER2 amplification and/or mutation. 11 patients (58%) exhibited an amplification, 6 (32%) a mutation and 2 (10%) both. All patients had metastatic disease at the time of screening. Regarding tumor types: 10 patients (53%) had endometrial carcinoma, 5 (26%) had ovarian carcinoma and 4 (21%) had cervix carcinoma. Only 9 patients (47%) received a HER2 directed therapy. All patient had ERBB2 amplification.1 patient was treated within a trial and 8 were treated off label with a trastuzumab containing regimen. 2 patients (22%) had a complete response and 5 (55%) had a partial response. Median duration of response was 7,6 months and median progression free survival was 8.1 month [min : 2.6m; max:11.6m]. Overall survival was significantly longer in patients receiving HER2 targeted therapy compared to those harboring HER2 abnormalities who did not receive them (mOS: NR vs 15.06m, HR : 0.18, IC95% 0.037 - 0.89).

Conclusions

Gynecological cancer harboring HER2 amplification and/or mutation are rare but can benefit from HER2 targeted therapy. There is a need to to test patients for ERBB2 alteration and develop trials with HER2 targeted therapies including gynecological tumors in order to obtain approvals in routine care

Background

Ubamatamab (REGN4018) is a mucin 16 x cluster of differentiation 3 (MUC16xCD3) bispecific antibody that promotes T cell–mediated cytotoxicity by binding MUC16-expressing ovarian cancer (OC) cells and CD3+ T cells. We present safety, efficacy and pharmacokinetic (PK) modelling from a first-in-human study of ubamatamab (NCT03564340).

Methods

Patients (pts) with recurrent platinum-experienced OC received ubamatamab 0.3–800 mg intravenously weekly (QW) after initial step-up dosing. Primary endpoints were safety and PK. Secondary and exploratory endpoints included objective response rate per Response Evaluation Criteria in Solid Tumours (RECIST) 1.1, disease control rate (a response or stable disease) and cancer antigen 125 (CA-125) response per Gynecological Cancer InterGroup criteria.

Results

78 pts received ubamatamab 0.3–800 mg without reaching maximal tolerated dose. Median number of prior therapies was 4.5 (range 1–17). Median ubamatamab exposure was 12 (range 1–117) weeks. Commonest treatment-emergent adverse events (TEAEs) were cytokine release syndrome (73.1%, all Grade 1/2) and pain (87.2%), primarily occurring in Weeks 1–2 of step-up dosing. Commonest Grade ≥3 TEAEs were anemia (24.4%) and abdominal pain (20.5%). Objective responses were observed between 20–800 mg. In 42 pts receiving ≥1 full dose of ≥20 mg, ORR was 14.3% (95% CI, 5.4–28.5), disease control rate was 57.1% (41–72.3), and median duration of response was 12.2 months. 23.8% of pts (12.1–39.5%) had a CA-125 response. Serum ubamatamab concentrations increased dose proportionally. No apparent dose-response relationship was observed from 20–800 mg for safety or efficacy. PK modelling supported the selection of 250 and 800 mg every-3-weeks (Q3W) regimens for Phase 2, as both regimens had a maximum concentration (C_max) below the C_max of 800 mg QW, and trough concentration (C_min) above that of the minimal effective dose (20 mg QW).

Conclusions

Ubamatamab resulted in an acceptable safety profile and durable responses in a heavily pretreated OC population across a wide dose range. A randomised Phase 2 expansion trial with initial step-up dosing followed by Q3W dosing has been initiated.

Clinical trial identification

ClinicalTrials.gov: NCT03564340

Editorial acknowledgement

Editorial support was provided by Rachel McGrandle of Prime Medica, Knutsford, UK, funded by Regeneron Pharmaceuticals, Inc.

Background

Mexican women with ovarian cancer have a high prevalence of germline BRCA mutations. The most frequent alteration is the deletion of exons 9 to 12 of BRCA1 (BRCA1-Del Exon 9-12), which has been associated with a founder effect in this population. The Mexican founder mutation is a long genomic rearrangement that could affect not only clinical features but also the prognosis of patients carrying this alteration.

Methods

This retrospective study evaluated the clinical characteristics and prognosis of Mexican patients with BRCA1/2 germline mutations after receiving first line treatment with platinum-based chemotherapy between 2015 and 2022. The aim of the study was to compare the progression-free survival (PFS) of patients with the Mexican founder mutation and patients with other BRCA1/2 mutations. Patients treated with front-line iPARP maintenance treatment were excluded.

Results

Of 531 patients who were tested for a BRCA1/2 mutation, 181 were positive (34.1%). Thirty-seven patients (20.4%) were Mexican founder mutation carriers and 144 (79.6%) had other BRCA1/2 mutations. One hundred fifty-seven patients were included in the final survival analysis. The median follow-up time was 57 months. Patients with the founder mutation had a median PFS of 28.7 months, while patients with other BRCA1/2 mutations had a median PFS of 15.3 months (HR, 0.72; CI 95% 0.46 – 0.95; P= 0.05). (Table 1) Median overall survival was not reached for patients with the founder mutation and 131 months for patients with other BRCA1/2 mutations (HR 0.25; CI 95% 0.0.88 – 0.72; P=0.01).

Conclusions

Patients with the Mexican founder BRCA1 mutation treated with first line platinum-based chemotherapy have better survival compared with patients with other BRCA1/2 mutations.

Background

To investigate the clinicopathologic characteristics and the impact of mismatch repair-deficient/microsatellite instability-high (MMRd/MSI-H) on oncologic outcomes of patients with endometrial cancer.

Methods

In this single-center, retrospective study, patients with endometrial cancer who underwent immunohistochemistry staining for MMR proteins (MLH1/MSH2/MSH6/PMS2) and/or next-generation sequencing for MSI status and genomic alterations between January 2011 and June 2021 were included. Data collected included patient demographics, clinicopathologic characteristics, treatment, and clinical outcomes.

Results

Of the total 234 eligible patients, 182 patients (77.8%) had MMRp/non-MSI-H tumors and 52 patients (22.2%) had MMRd/MSI-H tumors. Between two groups, clinicopathologic characteristics including histologic type, grade, myometrial invasion, LVSI, LN metastasis were not statistically different. A total of 74 out of 234 patients were tested for PD-L1, and PD-L1 expression was observed in 52.6% in the MMRp/non-MSI-H group and 88.2% in the MMRd/MSI-H group (p=0.028). There was no statistically significant difference in recurrence rates and survival outcomes in relation to MMRd/MSI-H status (p=0.244 and 0.240, respectively). Among MMRd/MSI-H patients, six patients were treated with immune checkpoint inhibitors and objective response rate was 50.0%, comprised of 3 partial responses. A grade 3 or higher adverse event occurred in one patient, thrombocytopenia.

Conclusions

In patients with endometrial cancer, MMRd/MSI-H is not associated with oncologic outcomes. In clinical practice, immunotherapy was safe and efficacious in MMRd/MSI-H recurrent endometrial cancer.