During last week’s onsite and virtual San Antonio Breast Cancer Symposium (SABCS) 2021, December 07-10, Texas (USA), results from several VHIO (co) led studies were selected to first outing as poster presentations and poster discussions throughout this five-day international celebration of the very latest advances in the experimental biology, etiology, prevention, diagnosis, and therapy of breast cancer and premalignant breast disease.

A duo of VHIO-led SOLTI studies

Among the many studies that counted on the participation of VHIO researchers and clinical investigators at VHIO as first and/or co-authors were several clinical trials developed by the SOLTI academic Breast Cancer Research Group.

Co-led by VHIO’s Cristina Saura, Principal Investigator of our Breast Cancer Group and Mafalda Oliveira, a Clinical Investigator and Medical Oncologist of the same group, first results from the SOLTI-1507 IPATHER study of the safety and efficacy of combining ipatasertib, a potent AKT inhibitor, with trastuzumab with pertuzumab in patients with HER2+ PIK3CA-mutated breast cancer were presented and discussed during Poster Session 1 (Track: Advanced Disease Treatment: Advanced Therapy, Targeted – P1-18-34).

This particular patient population, representing between 30-35% of all HER2+ patients, benefit less from first-line maintenance treatment with trastuzumab and pertuzumab in the metastatic setting. Drawing on results of exploratory analysis from the CLEOPATRA study that pointed to worst prognosis in PI3K/AKT-altered tumors, the IPATHER open-label, single arm, phase Ib study was designed to evaluate the preliminary activity of adding this AKT inhibitor to dual anit-HER2 therapy in these patients.

“Analysis of the results from the first patients enrolled in IPATHER show that this novel combination is safe, well tolerated, with manageable treatment-related adverse events. Encouragingly, our data also show preliminary signs of efficacy,” noted Cristina Saura, who is also Head of the Breast Cancer Unit at the Vall d’Hebron University Hospital’s (HUVH) Medical Oncology Department -led by VHIO’s Director, Josep Tabernero- and a member of SOLTI’s Board of Directors.

“In view of the favorable safety profile, the dose expansion phase of these three agents in combination is underway and will include an additional 19 patients. We hope that this treatment approach will ultimately improve the prognosis of these patients,” added Mafalda Oliveira, co-Principal Investigator of this study, who also serves on SOLTI’s Board.

During Poster Session 1 (Track: Prognostic and Predictive Factors: Predictive Biomarkers for Endocrine Therapies – P1-07-02), primary results of the SOLTI- 1802 ONAWA open-label, single-arm, multicenter window of opportunity clinical trial of onapristone, a type 1 antiprogestin, in postmenopausal women with hormone receptor-positive/HER2-negative early breast cancer, were presented by the study’s Principal Investigator, Meritxell Bellet, also a Clinical Investigator of VHIO’s Breast Cancer Group, Medical Oncologist at HUVH, and SOLTI Board member.

Co-led by Cristina Saura, also in collaboration with VHIO’s Paolo Nuciforo, PI of our Molecular Oncology Group, ONAWA is the very first window of opportunity trial to evaluate whether onapristone can inhibit tumor cell proliferation as preoperative treatment, and enrolled ten patients with a ki-67 proliferation index higher than 10%.

“Results thus far reveal a less aggressive disease evolution and a reduction in proliferation in tumors with high progesterone levels. The safety profile was consistent with that previously reported. We have also observed a shift towards more endocrine sensitive disease which could increase the chances of response to treatment in combination with antiestrogen therapy,” observed Meritxell Bellet, first author of this study.

Ringing in an antibody-drug conjugate in early breast cancer?

In addition to these two-VHIO led SOLTI studies, first results from another window of opportunity trial, SOLTI- 1805 TOT-HER3, were presented and discussed during Spotlight Poster Discussion Session 13 (Track: Novel Therapeutics – PD13-04), by Principal Investigator Aleix Prat, Head of the Medical Oncology Department, Hospital Clínic Barcelona, and SOLTI’s President.

Co-led by VHIO’s Mafalda Oliveira, TOT-HER3 is the first study to evaluate the HER3 directed antibody-drug conjugate (ADC), patritumab deruxtecan, in patients with early hormone-sensitive HR-positive/HER2-negative breast cancer. Prior to this study, this ADC had only demonstrated anti-tumor activity and a tolerable safety profile in patients with heavily pretreated metastatic high or low HER3 expression levels.

Enrolling a total of 80 patients across 10 Spanish hospitals, very preliminary results from the first 30 patients included in this trial showed tumor reduction in 45.8% of cases, and 57% of these patients showed increased immune infiltration and reduced tumor cellularity with only a single shot of the drug.

“These initial results show high antitumor activity of patritumab deruxtecan. In almost one out of two cases, this therapy achieved tumor shrinkage and even the disappearance of disease,” said Mafalda Oliveira.

She continued, “As encouragingly, the treatment was tolerable and the safety profile was consistent with that previously reported for this ADC. These promising findings could ultimately translate into benefits for patients with newly diagnosed early HER2-negative breast cancer.”

Seeking out biomarkers of response to HER3-directed ADC in breast cancer PDXs

HER3 is overexpressed in 30-50% of breast cancers and has been associated with a poor prognosis. Results of a previous phase 1/2 study demonstrated the promising antitumor activity of the HER3 directed antibody-drug conjugate (ADC), patritumab deruxtecan, in hormone receptor-positive metastatic breast cancer patients.

Also considering the aforementioned window of opportunity SOLTI- 1805 TOT-HER3 ongoing clinical trial, research led by Violeta Serra, Principal Investigator of VHIO’s Experimental Therapeutics Group, evaluated the activity of this ADC in 21 diverse breast cancer patient–derived xenograft models (PDXs) in order to identify robust biomarkers of response.

Results presented during Poster Session 5 (Track: Prognostic and Predictive Factors: Predictive Biomarkers for Targeted Therapies – P5-13-14), showed that 38% PDXs were highly sensitive to patritumab deruxtecan, and in 36% PDXs this ADC achieved a superior antitumor activity compared to treatment with chemotherapy irinotecan.

“We observed a potent antitumor response to this HER3 directed antibody-drug conjugate in PDXs, independently of baseline HER3/ERBB3 levels, in line with previously reported clinical data of a phase 1/2 study. Further, basal-like tumors were more sensitive to this therapy than luminal B subtype breast cancer models,” explained Violeta Serra, lead investigator of this research.

Results also point to the effect of this therapy in the parallel HER3/ERK signaling pathway downmodulation and initiation of S-phase DNA damage, driving tumor cell death.

“Advancing molecular insights into the mechanisms of response to this promising antibody-drug conjugate is crucial if we are to more precisely predict which patients would most likely benefit,” added Andreu Òdena, a PhD Student of VHIO’s Experimental Therapeutics Group and co-first author of this study, alongside other investigators of Violeta Serra’s team.

This VHIO-led study was also selected for one of the Guiding Researchers and Advocated to Scientific Partnerships (GRASP) Poster Walkthroughs: Group 1A: Animal models, HER2+ Breast Cancer, HER3 Breast Cancer, Tuesday 14 December.

GRASP is a patient-led organization that brings together patients, clinicians, and researchers to exchange ideas and learn from each other in order to accelerate scientific breakthroughs. GRASP’s Poster Walkthrough discussions are one of SABCS 2021’s official advocacy programs.

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