Presented by Ana Oaknin, Principal Investigator of VHIO’s Gynecological Malignancies Group, during this week’s American Society of Clinical Oncology’s (ASCO) Annual Meeting, 03 – 07 June 2022, Chicago (IL, USA), results of two early phase clinical trials show promise in extending immune-based therapies for the more effective treatment of patients with advanced and recurrent endometrial cancer and cervical malignancies.
Stepping up in expansion cohorts: PD-1 inhibitor dostarlimab demonstrates durable efficacy
Results of third interim analysis of the phase I, open-label, multicenter single-arm GARNET study in two expansion cohorts of patients with advanced endometrial cancer, selected by ASCO for a poster presentation, demonstrate the efficacy of programmed death 1 (PD-1) inhibitor dostarlimab in the treatment of tumors with mismatch repair deficient/microsatellite instability-high or proficient stable (dMMR/MSI-H or MMRp/MSS) status.
Dostarlimab was the first PD-1 inhibitor approved by the European Medicines Agency (EMA) for recurrent or advanced endometrial cancer. This approval was based on the results of the GARNET study that enrolled 140 women with DNA mismatch repair deficient (dMMR) endometrial cancer, which accounts for up to 30% of patients with this tumor type whose disease has progressed on or after prior treatment with first-line platinum-based chemotherapy.
“Considering that there were no other satisfactory alternative treatment options for this patient population, the approval of this immune-based therapy represented an important and timely advancement in more effectively treating endometrial tumors with dMMR status,” says Ana Oaknin, Head of the Gynecological Tumors Unit, Medical Oncology Department, at the Vall d´Hebron University Hospital – HUVH (Vall d’Hebron Barcelona Hospital Campus).
“New data from the third interim analysis evidences the efficacy and safety of dostarlimab in two expansion cohorts of the GARNET trial. We aimed to establish if microsatellite instability, an alteration that frequently occurs in endometrial cancer, influences clinical outcomes of treatment with dostarlimab,” adds Ana Oaknin, who presented these results during this week’s annual ASCO meeting (1).
For this interim analysis, 153 patients with microsatellite instability status and 161 patients with microsatellite stable disease were enrolled. Objective rate of response for the first group was 45.5%, and in the second it was 15.4%. At 12 months, probability of progression free survival was 46.4% at in the first cohort and 29.4% in the second group of patients. “While dostarlimab showed durable activity in both groups, improved outcomes were observed in those patients with microsatellite instability high endometrial cancer. The safety profile in both cohorts was consistent with other PD-1 antibodies,” concludes Ana Oaknin.
First-line bintrafusp alfa in combination shows promise in more effectively combating persistent, recurrent or metastatic cervical cancer
Persistent human papillomavirus (HPV) is implicated in 99% of cervical cancers and is linked to the activation of the TGF-β y PD-(L)1 signaling pathways. For this reason, investigators of the phase 1b INTR@PID CERVICAL 046 study hypothesized that inhibiting TGF-β activity while simultaneously blocking an additional immunosuppressive cellular mechanism such as the PD-L1 pathway, may provide a novel treatment approach.
“Bintrafusp alfa is a first-in-in-class bifunctional fusion protein that was designed to simultaneously bind to these two proteins that prevent the immune system from effectively combating tumor cells. Results of pooled analysis of patients from phase I and 2 studies have demonstrated the clinical activity and manageable safety profile of this novel agent in patients with heavily pretreated recurrent or metastatic cervical cancer,” explains Ana Oaknin, co-lead investigator of the phase Ib INTR@PID CERVICAL 046 study, preliminary efficacy data of which she revealed in a poster presentation at the 2022 ASCO meeting (2).
Based on the encouraging results of these investigations, the phase Ib non-randomized INTR@PID CERVICAL 046 study was subsequently designed to evaluate the safety and tolerability of bintrafusp alfa in combination with other anti-cancer therapies in patients with locally advanced or advanced cervical cancer. Specifically, the investigators tested the efficacy and safety of this novel immune-based therapy plus chemotherapy with or without bevacizumbab in patients with persistent, recurrent or metastatic cervical cancer, or bintrafusp alfa with chemoradiotherapy for locally advanced cervical cancer.
“Bintrafusp alfa combined with these anti-cancer therapies has shown promising tumor responses with no new safety signals observed. An objective response rate of up to 62% was achieved in patients who received bintrafusp alfa plus chemotherapy and bevacizumab, as well as in those who were treated with this novel immune-based therapy in combination with chemoradiotherapy,” concludes Ana Oaknin.
While this present study only included a small number of patients, these preliminary efficacy data support further investigations assessing the safety and efficacy of this agent in these patient populations. Follow-up analysis of patients enrolled in INTR@PID CERVICAL 046 is ongoing.
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