Background

Homologous recombination deficiency (HRD) prevalence and utilization of different HRD testing kits are not well-characterized across geographies. The HALO study (NCT04991051) determined the prevalence of HRD in patients (pts) with high-grade serous or endometrioid ovarian cancer (HGSOC/HGEOC), primary peritoneal cancer (PPC), and/or fallopian tube cancer (FTC) across Asia, Middle East and Africa (MEA) and Russia.

Methods

This cross-sectional multinational study enrolled consenting adult women with newly diagnosed stage III or IV (FIGO 2014) HGSOC or HGEOC, PPC and/or FTC having formalin-fixed paraffin tumour blocks collected within 120 days of enrolment. We present the prevalence of HRD with genomic instability (GI) excluding tumour BRCA1/2 mutation (tBRCA1/2m) and tBRCA1/2m only using next-generation sequencing (NGS).

Results

Overall, 734 pts (median age, 59.0 [range 23.0, 89.0] yrs) recruited between May-21 and Oct-22 across Asia (n=76), MEA (n=195) and Russia (n=463) were analysed. Majority (88.1%) never smoked, had attained menopause (83.9%) and were multiparous (78.8%). 34.1% had family history of cancer. Most (92.9%) had primary tumour in the ovaries, followed by PPC (4.1%) and FTC (3.0%). HRD status was analysed in 662 pts; of whom 56.0% (371) were HRD positive— 30.8% (204) had GI high score excluding tBRCA1/2m, and 25.2% (167) had tBRCA1/2m. HRD prevalence in Asia, MEA and Russia were 52.0%, 52.2% and 58.5%, respectively. Commercial kits were frequently used for HRD testing (374, 56.5%); predominantly Amoydx (329, 88.0%). Table: 285O

Prevalence of HRD

Conclusions

This pioneering real-world study reports HRD prevalence in a large cohort of pts, ranging from 52.0% - 58.5% across the three study regions. Our results highlight the unmet need for capturing biomarker testing data and the utility of different HRD testing kits in real-world in resource-limited settings to inform treatment decisions.

Clinical trial identification

NCT04991051.

Editorial acknowledgement

This study was funded by AstraZeneca. As per the GPP3 guidelines, the authors would like to thank Dr. Soma Santra of Fortrea Scietific Pvt. Ltd, for medical writing support.

Legal entity responsible for the study

AstraZeneca International.

Funding

AstraZeneca International.

Disclosure

A. Tyulyandina: Financial Interests, Personal, Advisory Board, AstraZeneca, Advisory Board, Personal Biocad, Advisory Board, Personal Eisai, Invited Speaker, Personal MSD, Advisory Board, Personal Pfizer, Expert Testimony, Personal Roche, Invited Speaker, Personal Non-Financial Interests AstraZeneca, Principal Investigator Biocad, Principal Investigator MSD, Advisory Role MSD, Principal Investigator Roche, Principal Investigator: AstraZeneca. All other authors have declared no conflicts of interest.

Background

Cervical cancer is the second most common cancer in women in India. Recurrent / metastatic (R/M) cervical cancer carries a poor prognosis with median overall survival of 11 months with chemotherapy alone. Checkpoint inhibitors added to chemotherapy have improved survival. However, the current approved dose is accessible to only 1-3% of patients in low- and middle-income countries because of their cost. Nivolumab does not have a dose-response relationship; therefore, a low dose regimen may be a viable option to reduce financial burden and improve access.

Methods

This is a retrospective study from a single tertiary centre in India from 1/3/2020 to 30/6/2023. Patients with R/M cervical cancer who received low dose Nivolumab as they could not afford to pay for standard Nivolumab dose were analyzed. Response rates and Progression free survival (PFS) were measured.

Results

A total of 20 patients who received low dose Nivolumab were identified during the study period whose mean age was 54.3 years. 75% had ECOG of </=1. 0. 30% underwent prior surgery and 85% received prior RT. Platinum based backbone therapy was used in 55% with Nivolumab. While 25% did not receive any concurrent therapy, Oral chemotherapy, Lenvatinib and Bevacizumab was given in 10%, 5% and 5% respectively. Table: 286MO

Patient and tumor characteristics

The average number of doses received were 4.75 and the mean dose received was 0.84mg/kg. Overall responses were seen in 10 patients (50%) out of which 5 (50%) had stable disease and 5(50%) had a complete response. Median progression free survival was 7.97 months. Treatment related adverse events (TRAE) were seen in 8 patients (40%), out of which most of them are grade 1 and 2. 3 (15%) patients had grade 3 TRAE. No grade 4 and 5 adverse events were recorded.

Conclusions

In patients with R/M cervical cancer, Low dose Nivolumab is effective with manageable toxicity. It can help reduce financial toxicity and make it accessible to more patients especially in low- and middle-income countries where the burden of this disease is higher.

Legal entity responsible for the study

S. Devabhaktuni.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Real world Indian data with maintenance Poly ADP Ribose Polymerase 1 Inhibitors (PARPi) in newly diagnosed advanced ovarian cancer (AOC) are lacking. The purpose of this study was to evaluate optimal dosing, safety and efficacy of olaparib or rucaparib maintenance plus minus bevacizumab in germline BRCA mutations or HRD-positive AOC patients.

Methods

This was a retrospective study from Tata Medical Center, Kolkata, West Bengal, India; included patients with stage III & IV (AJCC 7th) AOC between 2020- 2023. All data captured from electronic medical records of hospital up till June 2023. Either standard dose or reduced dose of tablet olaparib (450mg/day orally) or rucaparib (600mg/day orally) plus minus injection bevacizumab (7.5 mg/kg IV q 3weekly) was offered as a front-line maintenance therapy after completion of surgery and platinum based chemotherapy without any residual disease.

Results

Out of 89 screened patients, 41 received therapy with a median age at diagnosis 57 years (range 41-74). 98% had high grade serous histology with 61% stage III and 39% stage IV diseases. 28(68%) patients had germline BRCA mutations and 13(32%) HRD-positive (high genomic scar score). 34(82%) patients received maintenance bevacizumab up to one year along with PARPi. The duration of exposure of PARPi ranged from 2-24 months and 63% patients started with reduced dose. Dose reductions due to adverse effects (AEs) seen in 42%. With a median follow up of 32 months (95% CI 22.04-41.95); two years predicted progression free survival (PFS) of the entire cohort was 84%, no difference in PFS between standard dose and reduced dose group (30 vs 35 months; log rank p=0.67). There was no significant difference in PFS among olaparib and rucaparib (NR vs 35 months; log rank p=0.20). The most common ≥ grade III AEs (CTCAE V.5) were anemia (24%), thrombocytopenia (7%), fatigue (22%), diarrhea (2%) and transamnitis (5%).

Conclusions

We found that lower doses of PARPi were equally efficacious with good tolerance in comparison with standard dose and can be offered as first-line maintenance therapy in AOC patients with germline BRCA mutation or HRD positive in a resource-limited setting.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Tisotumab vedotin (TV) is an investigational antibody-drug conjugate composed of a tissue factor-directed human monoclonal antibody covalently linked to cytotoxic MMAE. In the US, TV monotherapy received accelerated approval for the treatment of adult pts with recurrent or metastatic cervical cancer (r/mCC) with disease progression on or after chemotherapy. Here, innovaTV 301 (NCT04697628) study results of TV vs investigator’s choice of chemotherapy in pts with r/mCC following 1L therapy are presented.

Methods

Eligible pts had r/mCC with disease progression on/after treatment with standard of care chemotherapy doublet ± bevacizumab ± anti-PD-(L)1 therapy, measurable disease per RECIST v1.1, and ECOG PS 0-1. Pts were randomized 1:1 to TV monotherapy or investigator's choice of topotecan, vinorelbine, gemcitabine, irinotecan, or pemetrexed. The primary endpoint was OS. Key secondary endpoints included PFS and confirmed ORR by investigator.

Results

502 pts were randomized (TV: 253; chemotherapy: 249); median survival follow-up was 10.8 mo (95% CI, 10.3-11.6). Overall, median age was 50 yrs (range: 26-80); arms were balanced for demographics and disease characteristics. 63.9% and 27.5% of pts had prior bevacizumab and prior anti-PD-(L)1 therapy, respectively. The TV arm had a 30% reduction in risk of death vs chemotherapy (HR 0.70; 95% CI 0.54-0.89; P=0.0038), with significantly longer median OS (11.5 mo [95% CI 9.8-14.9] vs 9.5 mo [95% CI 7.9-10.7]). PFS was superior in the TV vs chemotherapy arm (HR: 0.67 [95% CI, 0.54-0.82]; P<0.0001). Confirmed ORR was 17.8% and 5.2% in the TV and chemotherapy arms, respectively (odds ratio: 4.0; 95% CI, 2.1-7.6; P<0.0001). Most pts experienced at least 1 treatment-related adverse event (TV: 87.6% [grade ≥3: 29.2%] vs chemotherapy: 85.4% [grade ≥3: 45.2%]). AEs were consistent with the known TV safety profile, including for ocular, peripheral neuropathy, and bleeding AEs.

Conclusions

In the phase 3 innovaTV 301 study, TV showed a statistically significant and clinically meaningful improvement in OS, PFS, and ORR vs chemotherapy, with a manageable and tolerable safety profile in pts with 2L/3L r/mCC.

Clinical trial identification

NCT04697628; 15Feb2023.

Editorial acknowledgement

The authors thank Jennifer Yang, PhD, of Seagen Inc., who provided medical writing and editorial support in accordance with Good Publication Practices.

Legal entity responsible for the study

Seagen Inc.

Funding

Seagen Inc.

Disclosure

K. Fujiwara: Financial Interests, Personal, Advisory Board: Genmab, Nano Carrier, Daiichi Sankyo, Seagen; Financial Interests, Personal, Invited Speaker: Takeda; Financial Interests, Personal, Other, Travel Expense: Clovis; Financial Interests, Institutional, Coordinating PI: MSD, AstraZeneca; Non-Financial Interests, Personal, Leadership Role: GOTIC, NRG Oncoloogy-Japan. B.M. Slomovitz: Financial Interests, Personal, Advisory Board: AstraZeneca, Clovis, Eisai, GSK, Genentech, Merck, Immunogen, Novocure; Financial Interests, Personal, Other, consultant: GOG Foundation; Non-Financial Interests, Personal, Member of Board of Directors: GOG Foundation. A. Gonzalez Martin: Financial Interests, Personal, Advisory Board: Amgen, AstraZeneca, CLOVIS, GSK, GENMAB, ALKERMES, SUTRO, Roche, SOTIO, PHARMAMAR, ONCOINVENT, Novartis, MERSANA, MSD, Macrogenics, Eisai, Inmunogen, Regeneron, HederaDx, Illumina, Tubulis; Financial Interests, Personal, Invited Speaker: GSK, AstraZeneca, CLOVIS, Roche, NOVOCURE, MSD, Takeda, Zaylab; Financial Interests, Institutional, Coordinating PI, PI of ANITA trial: GSK, Roche; Financial Interests, Personal, Steering Committee Member, Member of ENGOT ov43-SC: MSD; Financial Interests, Institutional, Coordinating PI, ENGOT PI of EPIK-O trial: Novartis; Financial Interests, Institutional, Coordinating PI, ENGOT PI of AVB-500 phase III trial: ARAVIVE. E. Kalbacher: Financial Interests, Personal, Speaker, Consultant, Advisor: AstraZeneca, GSK, Sanofi, Roche, GSK Tesaro, Seagen Inc; Financial Interests, Personal, Other: GSK Tesaro, Seagen Inc. S. Ghamande: Financial Interests, Personal, Invited Speaker: Esai; Financial Interests, Personal, Advisory Board: GSK; Financial Interests, Institutional, Coordinating PI: GSK, Jounce, Merck, Esai, Mersana, AstraZeneca; Non-Financial Interests, Personal, Advisory Role: GOG four. J. Lee: Financial Interests, Personal, Invited Speaker: AstraZeneca, Takeda, MSD, Roche; Financial Interests, Personal, Advisory Board: Eisai, GI Innovation; Financial Interests, Institutional, Local PI: Alkermes, AstraZeneca, BergenBio, Cellid, Clovis Oncology, Eisai, GI Innovation, ImmunoGen, Janssen, Merck, Mersana, MSD, Novartis, OncoQuest, Roche, Seagen, Synthon; Financial Interests, Personal and Institutional, Local PI: BeiGene; Financial Interests, Personal, Steering Committee Member: AstraZeneca, OncoQuest, Seagen, ImmunoGen, MSD; Financial Interests, Institutional, Research Grant: Ono, Takeda. S. Banerjee: Financial Interests, Personal, Advisory Board: Amgen, Immunogen, Mersana, MSD, Roche, AstraZeneca, GSK, Oncxerna, Shattuck Labs, Novartis, Epsilogen, Seagen, Eisai, Regeneron, Verastem; Financial Interests, Personal, Invited Speaker: Clovis, Pfizer, AstraZeneca, GSK, Takeda, Amgen, Medscape, Research to Practice, Peerview, Novacure; Financial Interests, Personal, Stocks/Shares: PerciHealth; Financial Interests, Institutional, Research Grant: AstraZeneca, GSK; Non-Financial Interests, Personal, Principal Investigator, Phase II clinical trial Global lead, ENGOTov60/GOG3052/RAMP201: Verastem; Non-Financial Interests, Personal, Principal Investigator, ENGOT-GYN1/ATARI phase II international trial (academic sponsored): AstraZeneca; Non-Financial Interests, Personal, Principal Investigator, Academic sponsored trial PI (MONITOR-UK): GSK; Non-Financial Interests, Personal, Advisory Role, Medical advisor to UK ovarian cancer charity: Ovacome Charity; Non-Financial Interests, Personal, Leadership Role, Board Member: International Cancer Foundation (ICF). F.C. Maluf: Financial Interests, Personal, Advisory Board: MSD, BMS, AstraZeneca, Astellas, Janssen, Novartis, Roche, Pfizer, Sanofi Aventis; Financial Interests, Personal, Speaker, Consultant, Advisor: MSD, BMS, AstraZeneca, Astellas, Janssen, Novartis, Roche, Pfizer, Sanofi Aventis; Financial Interests, Personal, Other: Janssen; Financial Interests, Personal, Research Funding: Janssen, MSD, BMS, AstraZeneca, Astellas, Roche, Sanofi Aventis, Regeneron. D. Lorusso: Financial Interests, Personal, Advisory Board, Participation in Advisory Boards and Invited Speaker: GSK, Clovis Oncology, Pharmamar; Financial Interests, Personal, Advisory Board, Participation in Advisory Boards and Invited Speakers: AstraZeneca, MSD; Financial Interests, Personal, Other, Consultancy: Pharmamar, AstraZeneca, Clovis Oncology, GSK, MSD, Immunogen, Genmab, Seagen, Novartis; Financial Interests, Personal, Advisory Board, Invited member of advisory board and invited speaker: Seagen, Immunogen, Genmab; Financial Interests, Personal, Advisory Board, Invited member of advisory board: Oncoinvest, Corcept, Sutro; Financial Interests, Institutional, Funding, Grant for founding academic trials: MSD, Clovis Oncology, GSK, Pharmamar; Financial Interests, Institutional, Coordinating PI, ENGOT trial with institutional support for coordination: Clovis Oncology; Financial Interests, Institutional, Coordinating PI, ENGOT trial with insitutional support for coordination: Genmab, MSD; Financial Interests, Institutional, Funding, Clnical trial/contracted research: AstraZeneca, Clovis Oncology, GSK, MSD, Seagen; Financial Interests, Institutional, Funding, Clinical trials/contracted research: Genmab, Immunogen, Incyte, Novartis, Roche; Non-Financial Interests, Personal, Principal Investigator, PI of several trials, no compensation received: GSK; Non-Financial Interests, Personal, Principal Investigator, PI of several trials. No personal compensation received: AstraZeneca, genmab; Non-Financial Interests, Personal, Principal Investigator, PI in several trials. No personal compensation received: MSD; Non-Financial Interests, Personal, Principal Investigator, PI of clinical trial. No personal compensation received: immunogen, Clovis Oncology, roche, Incyte; Non-Financial Interests, Personal, Principal Investigator, PI of several trials, no personal compensation received: Novartis; Non-Financial Interests, Personal, Principal Investigator, PI of clinical trial, no personal compensation received: Seagen; Other, Personal, Other, Grants for traveling: AstraZeneca, Clovis Oncology, GSK; Non-Financial Interests, Personal, Principal Investigator, PI of clinical trials, no personal compensation received: PharmaMar; Non-Financial Interests, Personal, Member, Board of Directors: GCIG. K. Yonemori: Financial Interests, Personal, Advisory Board: Eisai, AstraZeneca, Sanofi, Genmab, Gliad, OncoXerna, Takeda, Novartis, MSD; Financial Interests, Personal, Invited Speaker: Pfizer, Eisai, AstraZeneca, Eli Lilly, Takeda, Chugai, Fuji Film Pharma, PDR Pharma, MSD, Ono, BMS, Boeringer Ingerheim, Daiichi Sankyo, Bayer, Jansen, Sanofi; Financial Interests, Institutional, Local PI: MSD, Daiichi Sankyo, AstraZeneca, Taiho, Pfizer, Novartis, Takeda, Chugai, Ono, Sanofi, Seagen, Eisai, Eli Lilly, Genmab, Boehringer Ingelheim, Kyowa Hakko Kirrin, Nihon Kayaku, Haihe. E. van Nieuwenhuysen: Financial Interests, Institutional, Advisory Board: Regeneron, Oncoinvent; Financial Interests, Institutional, Local PI: Regeneron, Oncoinvent, Roche, Seagen, Merck, Novartis; Financial Interests, Institutional, Steering Committee Member: AstraZeneca; Financial Interests, Institutional, Coordinating PI: AstraZeneca. L.M. Manso Sanchez: Financial Interests, Personal, Full or part-time Employment: Univ Hospital 12 Octubre, Madrid; Financial Interests, Personal, Speaker’s Bureau: GSK, AstraZeneca, Novartis, Pfizer, Daiichi Sankyo, Roche; Financial Interests, Personal, Other, Travel: GSK, AstraZeneca, Roche. L. Woelber: Financial Interests, Personal, Advisory Board: GSK, Roche, MSD, Eisai, Seagen; Financial Interests, Personal, Invited Speaker: Pfizer, Roche, MSD, Seagen; Financial Interests, Personal, Other, scientific board: med update GmbH; Financial Interests, Personal, Other, speaker: med publico GmbH; Financial Interests, Institutional, Coordinating PI: Seagene, medac oncology; Financial Interests, Institutional, Local PI: MSD, Vaccibody AS, Roche. A. Covens: Financial Interests, Personal, Other, Honoraria: GSK; Financial Interests, Personal, Research Grant: GSK, Merck. E. Whalley, M.S.L. Teng: Financial Interests, Personal, Full or part-time Employment: Seagen Inc; Financial Interests, Personal, Stocks or ownership: Seagen Inc. I. Soumaoro: Financial Interests, Personal, Full or part-time Employment: Genmab. I.B. Vergote: Financial Interests, Personal, Advisory Board, Consulting: Agenus (2021-2023), Aksebio China (2021), Bristol Myers Squibb (2021-2023), Deciphera Pharmaceuticals (2021), Eisai (2021-2023), F. Hoffmann-La Roche Ltd (2021-2023), Genmab (2021-2023), GSK (2021-2023), Immunogen Inc. (2021-2023), Jazzpharma (2021-2022), Karyopharm (2021-2023), MSD (2021-2023), Novocure (2020-2023), Novartis (2021-2023), Oncoinvent AS (2021-2023), Seagen (2021-2023), Sotio a.s. (2021-2022); Financial Interests, Institutional, Advisory Board, Consulting: AstraZeneca (2019-2020), Deciphera Pharmaceuticals (2020), Elevar Therapeutics (2020), F. Hoffmann-La Roche Ltd (2019-2020), Genmab (2019-2020), GSK (2019-2020), Mersana (2020-2023), MSD (2019-2020), Oncoinvent AS (2019-2020), Sotio a.s. (2019-2020), Verastem Oncology (2020-2023), Zentalis (2020), Amgen (Europe) 2019, Clovis Oncology Inc (2019), Carrick Therapeutics (2019), Millennium Pharmaceuticals (2019); Financial Interests, Personal, Advisory Board, 2022: Regeneron; Financial Interests, Personal, Advisory Board, 2023: Molecular Partners; Financial Interests, Personal, Advisory Board, 2020-2023: AstraZeneca; Financial Interests, Institutional, Research Grant, Contracted Research ( via KU Leuven): Oncoinvent AS (2019-2020); Financial Interests, Institutional, Research Grant, Contracted Research (via KU Leuven): Genmab (2019); Financial Interests, Institutional, Research Grant, Corporate sponsored research: Amgen (2019-2020), Roche (2019-2020). All other authors have declared no conflicts of interest.

Background

Fruquintinib (F, a highly selective VEGFR inhibitor) plus sintilimab (S, an anti-PD-1 monoclonal antibody) showed promising antitumor activity in both pre-clinical and clinical studies. Here, we reported the results of F plus S from CC cohort in an open-label, multicenter, single-arm phase 2 study.

Methods

Pts with pathologically confirmed advanced CC who had failed at least first-line platinum-containing treatment, or experienced intolerable toxicity during treatment, or were unable to receive standard therapy were eligible. Eligible pts received F (5 mg, 2 weeks [wk] on/1 wk off, orally, once daily) plus S (200 mg, IV, every 3 wk) in 21-day cycles, until disease progression or unacceptable toxicity. Treatment of S was allowed for up to 24 months (mo). The primary endpoint was ORR per RECIST v1.1.

Results

As of May 30, 2023, 34 pts were successfully enrolled and received F plus S, median follow-up duration was 16.4 mo. Median (range) age was 56 (26.2, 73.7) yrs. 6 pts (17.6%) were treatment naïve (naïve pts); 28 pts (82.4%) had received at least first-line treatment (treated pts), including bevacizumab (5/28), for advanced disease. 25 pts (73.5%) had received pelvic radiation therapy. There were 24 pts (70.6%) with PD-L1 status of CPS ≥1. Among tumor evaluable naïve and treated pts, confirmed ORR (cORR) were 50.0% (PR 3/6) and 29.6% (CR 1/27 and PR 7/27); median TTR were 2.7 and 3.1 mo; DCR were both 100%. In naïve (N=6) and treated (N=28) pts, mPFS were 10.3 and 8.2 mo, 15mo-OS rate were 83.3% and 70.0%. In tumor evaluable treated pts stratified by CPS ≥1 vs <1 (N= 17 vs 8), cORR was 41.2% vs 12.5%; in treated pts (N=18 vs 8), mPFS was 19.4 vs 5.2 mo; mOS was not reached vs 13.9 mo, 15mo-OS rate was 76.0% vs 50.0%. All pts experienced TEAEs, and the most common TEAEs included proteinuria (64.7%), hypothyroidism (61.8%), asthenia (44.1%), hyperthyroidism (44.1%), palmar-plantar erythrodysaesthesia syndrome (44.1%), anaemia (41.2%) and urinary tract infection (41.2%).

Conclusions

F plus S provided favorable efficacy in advanced CC pts, especially for treated PD-L1 CPS ≥1 pts. This combination treatment also showed manageable toxicity profile consistent with that seen in other cohorts.

Clinical trial identification

NCT03903705.

Legal entity responsible for the study

HUTCHMED Limited.

Funding

HUTCHMED Limited.

Disclosure

All authors have declared no conflicts of interest.

Background

Exploring enhanced tumor control, we studied concurrent chemoradiotherapy (CRT) with PD-1 blockade, including Californium-252 neutron brachytherapy for advanced gynecological tumors. This trial investigates the combination of local sintilimab injection with this approach to augment treatment outcomes in first-line advanced gynecological squamous cell carcinoma patients.

Methods

A phase II trial was conducted on these patients who underwent CRT and Californium-252 brachytherapy. Concurrently, they received local sintilimab injections (100mg Q3W, 4 cycles). During each procedure, 4-6 hysteroscopy-guided injections were administered to the cervix. Primary endpoints: Objective Response Rate (ORR) and Progression-Free Survival (PFS). Secondary objectives: Duration of Response (DOR), Disease Control Rate (DCR), Overall Survival (OS), and Adverse Events (CTCAE 5.0).

Results

By June 30, 2023, 20 patients were included (median age: 57.5; 19 with cervical and 1 with vaginal carcinoma). With a median follow-up of 24 months (39-76 months range), ORR reached 100%, and PFS is still undetermined. Treatment AEs were seen in 15% (3/20) of patients, grade 3 AEs in 5% (1/20). All AEs were thyroid dysfunctions (2 at grade 2, 1 at grade 3). One death occurred due to cardiovascular-related heart failure.

Conclusions

This is the first evaluation of combined CRT, Californium-252 brachytherapy, and local sintilimab for gynecological tumors. Preliminary results highlight substantial anti-tumor potential and a favorable safety profile. Further research with a larger cohort is warranted.

Clinical trial identification

CHICTR2300074868.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Recurrent CCGC is associated with poor prognosis and low response rates to chemotherapy. Combined anti-angiogenic and immune checkpoint blockade is a rational strategy in CCGC in view of its unique gene expression profile and immune microenvironment. PL has potential to reprogram tumor-associated macrophages and enhance cytotoxic T cell response. We investigate the efficacy of PL in recurrent CCGC.

Methods

LARA is a phase II, academic trial conducted in Singapore and South Korea. Recurrent CCGC patients (pts) with progression on ≥1 prior platinum-based chemotherapy and no prior immunotherapy exposure were eligible. All pts received IV pembrolizumab 200mg on day 1 plus oral lenvatinib 20 mg daily, q21 days. LARA followed a Simon 2-stage minimax design. The primary endpoint (PEP) was objective response rate (RECIST1.1) at 24 weeks (ORR_24wks)(H₀≤10%; H₁≥30%; 5% 1-sided α; 80% power). 15 patients were required for stage 1, ≥2/15 responders to PL were required to progress to stage 2. A total of 25 evaluable pts are to be recruited in total. The study will meet its PEP if ≥6/25 pts respond to PL.

Results

From 26/3/21-12/4/23, 15 evaluable pts (Chinese: 8, Korean: 5, Malay: 2) were enrolled to stage 1. Median age was 58 years (range 41-72), ECOG PS (0: 6, 1: 9), 12/15 (80%) ovarian primary. Median of 1 prior therapy lines. 8/15 (53.3%) pts received prior bevacizumab or anti-antiangiogenic therapy. The median duration of follow-up was 48.9 weeks (IQR 32.3-not reached). 4/15 pts achieved confirmed objective response in the first 24 weeks (ORR_24wks 26.7%; exact binomial 95% CI 7.8-55.1). Confirmed CA125 response (GCIG criteria) occurred in 9/15 (60%, 95% CI 32.3– 83.7) pts. The median PFS was 12 weeks (95% CI 5.4-24.4), PFS at 12 and 24 weeks were achieved in 46.7% (95% CI 21.2-68.7) and 33.3% (95% CI 12.2-56.4) of pts, respectively. The efficacy boundary to proceed to stage 2 was met. Grade ≥3 treatment-related adverse events were hypertension (4/15), hyponatremia (2/15), rash (2/15), adrenal insufficiency (1/15), anemia (1/15), mucositis (1/15), thrombocytopenia (1/15).

Conclusions

PL showed promising efficacy and acceptable safety in recurrent CCGC pts. Final results at trial completion will be reported.

Clinical trial identification

NCT04699071.

Legal entity responsible for the study

Asia-Pacific Gynecologic Oncology Trials Group (APGOT).

Funding

MSD MISP (Drug-only).

Disclosure

N.Y. Ngoi: Financial Interests, Institutional, Advisory Board: MSD, AstraZeneca, Merck/Pfizer; Financial Interests, Institutional, Invited Speaker: MSD, Japanese Society of Gynecologic Oncology; Financial Interests, Institutional, Speaker’s Bureau: Asian Society of Gynecologic Oncology. J. Lee: Financial Interests, Personal, Invited Speaker: AstraZeneca, Takeda, MSD, Roche; Financial Interests, Personal, Advisory Board: Eisai, GI Innovation; Financial Interests, Institutional, Local PI: Alkermes, AstraZeneca, BergenBio, Cellid, Clovis Oncology, Eisai, GI Innovation, ImmunoGen, Janssen, Merck, Mersana, MSD, Novartis, OncoQuest, Roche, Seagen, Synthon; Financial Interests, Personal and Institutional, Local PI: BeiGene; Financial Interests, Personal, Steering Committee Member: AstraZeneca, OncoQuest, Seagen, ImmunoGen, MSD; Financial Interests, Institutional, Research Grant: ONO, Takeda. D.S. Tan: Financial Interests, Personal, Invited Speaker: AstraZeneca, MSD, Merck Serono, Roche, Eisai, GSK, Takeda; Financial Interests, Personal, Advisory Board: AstraZeneca, Bayer, MSD, Eisai, Roche, Genmab, GSK, Boehringer Ingelheim; Financial Interests, Personal, Stocks/Shares: Asian Microbiome Library (AMiLi); Financial Interests, Institutional, Research Grant: Roche, Bayer, Karyopharm Therapeutics, AstraZeneca; Financial Interests, Institutional, Coordinating PI: AstraZeneca, Bergen Bio; Financial Interests, Institutional, Local PI: Zeria Pharmaceutical Co Ltd., Bayer, Byondis B.V.; Non-Financial Interests, Personal, Leadership Role, Ex society president: Gynecologic Cancer Group Singapore; Non-Financial Interests, Personal, Member of Board of Directors: Gynaecologic Cancer Intergroup (GCIG); Non-Financial Interests, Personal, Leadership Role, Ex- Chair: Asia-Pacific Gynecologic Oncology Trials Group (APGOT); Non-Financial Interests, Institutional, Product Samples, Research Study: MSD, Eisai, AstraZeneca, Cyclacel Pharmaceuticals. All other authors have declared no conflicts of interest.

Background

Paclitaxel is an adjunct to cisplatin for hyperthermic intraperitoneal chemotherapy (HIPEC). The purpose of this study was to identify the maximum tolerated dose (MTD) of paclitaxel combined with a fixed dose of cisplatin (75 mg/m2) delivered as HIPEC in patients with ovarian cancer.

Methods

In this multicenter phase I trial, a Bayesian Optimal Interval (BOIN) design was used. The MTD was identified with a target dose-limiting toxicity (DLT) rate of 25%, and the maximum sample size was set at 30 patients. To expedite the trial duration, a cohort size of one was employed for the initial dose escalation, which was then switched to a cohort size of three after observing the first dose-limiting toxicity (DLT). The starting dose of paclitaxel was 175 mg/m². The Data and Safety Monitoring Board made decisions regarding dose escalation or de-escalation in increments of 25 mg/m² for subsequent patient cohorts. This process was repeated until either the prespecified maximum sample size was reached or the number of patients treated at a given dose reached 12.

Results

Between December 2022 and May 2023, 21 patients were treated on the trial. Among the three evaluable patients who received 150 mg/m² paclitaxel, no DLTs were reported. Among the 12 evaluable patients who received 175 mg/m² paclitaxel, two experienced DLTs, including one case of grade 4 neutropenia and one case of grade 4 anemia, neutropenia, and leucopenia. Four out of the six evaluable patients who received 200 mg/m² paclitaxel experienced DLTs, including one case of grade 4 constipation, one case of grade 3 kidney injury, and two cases of grade 4 anemia. The isotonic estimate of the DLT rate in the 175 mg/m² dose group was 0.17 (95% CI, 0.02-0.42), which was the closest to the targeted DLT rate and thus was selected as the MTD.

Conclusions

Paclitaxel, when combined with a fixed dose of cisplatin (75 mg/m²), can be safely administered intraperitoneally at doses of 175 mg/m² in patients with ovarian cancer who received HIPEC (43 °C, 90 minutes) following debulking surgery.

Clinical trial identification

NCT05620654.

Legal entity responsible for the study

The authors.

Funding

Sun Yat-sen Clinical Research Cultivating Program, Grant/Award Number: SYSQ-202207 and SYS-Q-202203. Guangdong Basic and Applied Basic Research Foundation, Grant/Award Number: 2023A1515012647,2021A1515111177 and 2021A1515220142. Guangdong Medical Science and Technology Research Fundation Grant/Award Number: A2022285. Beijing Xisike Clinical Oncology Research Foundation Grant/Award Number: Y-tongshu2021/ms-0133.

Disclosure

All authors have declared no conflicts of interest.