MEDSIR’s On Site Experience from SABCS 2021: Update on our 5 studies presented

Last week, after almost two years of closed borders and impossibility of travel, our team joined the San Antonio Brest Cancer Symposium (SABCS) on site. Despite the pandemic, oncological investigation has been unstoppable, and SABCS 2021 offered a varied portfolio, ranging from clinical results to translational studies, COVID-19 and oncology guidelines, novel therapeutics, and much more.

For MEDSIR, 2021 was a fruitful year, with 5 sponsored studies presented to SABCS. We exposed results from DxCARTES and LINGain and introduced the ongoing trials ABIGAIL and PHERGain-2. High expectation was raised from preliminary results of DEBBRAH trial, which secured an oral communication in the spotlight session “Brain Metastases: Managing leptomeningeal disease / targeting HER2”.

DEBBRAH is evaluating the efficacy and safety of the antibody-drug conjugate trastuzumab deruxtecan (T-DXd) in Human Epidermal Growth Factor Receptor 2-Positive (HER2[+]) or HER2-low expressing advanced breast cancer (ABC) patients with brain metastasis (BM) and/or leptomeningeal carcinomatosis (LMD). Depending on primary tumor and metastasis, 39 patients were allocated in 5 different cohorts across 18 Spanish recruiting sites.

On December 8, Dr. Marta Vaz-Batista, medical oncologist at Fernando Fonseca Hospital, Portugal, presented the preliminary results for HER2[+] ABC patients with either stable (cohort 1) or progressing (cohort 3) BMs after previous local therapy. In cohort 1, 87.5% (7 out of 8) of patients had not progressed nor died at week 16, reaching the primary objective of the study. In the cohort 3, 44.4% (4 of 9) of patients experienced an intracranial overall response rate, meaning that 4 patients experienced a partial response with a ≥30% reduction in intracranial lesions, meeting the primary objective as well. Of notice, 1 patient maintained a stable disease (SD) for more than 24 weeks and 4 patients had neither progressed nor died, highlighting the activity of T-DXd on ABC patients with BMs.

We also analyzed safety in the 5 cohorts, registering frequent but manageable adverse events (AEs): only 20.6% of patients (7/34) reported grade 3-4 toxicity.

Although validation in larger cohorts is required, DEBBRAH strongly supports the administration of T-DXd for intracranial and extracranial disease in HER2[+] ABC, fostering the introduction of this molecule for the treatment of this advanced population demanding for novel effective therapies”, affirmed Dr. Vaz-Batista at the end of her speech.

On the same day, in the “Ongoing Trials Poster Session 1”, Dr. José Manuel Pérez-García, deputy director at International Breast Cancer Center (IBCC) in Barcelona, introduced the new study PHERGain-2. Following the outstanding results obtained with PHERGain trial, PHERGain-2 will assess another chemotherapy-free alternative for low-risk HER2[+] early BC (EBC) patients, guided by magnetic resonance imaging (MRI). This is a response-adapted, multicenter, open-label, non-comparative, investigator-initiated phase II trial, that will enroll 393 patients with HER2[+] EBC. An important inclusion criterium is HER2[+] status with immunohistochemical score 3+, in the light of the strong benefit previously obtained by this subgroup of patients who were treated with double HER2 blockade, without the need of chemotherapy.

All the patients will receive the combination of trastuzumab with pertuzumab before surgery (called neoadjuvant treatment), then will receive the post-surgery treatment (called adjuvant treatment) based on the pathological response. Patients achieving a pathological complete response (pCR), will continue trastuzumab and pertuzumab as adjuvant treatment (Cohort A), whereas those with no pCR, will receive the antibody-drug conjugate T-DM1 (Cohort B). If metastatic lymph nodes are detected, patients will be treated with T-DM1 and chemotherapy as per physician decision (Cohort C). Primary objective of efficacy is the analysis of 3-year recurrence-free interval, meaning the proportion of patients not experimenting recurrence of breast cancer, either locally or at distant site, for three years. As primary objective of safety, the quality of life (QoL) after 1-year of treatment will be investigated in the overall population.PHERGain-2 is currently recruiting from 21 institutions in Spain, having a total of 70 sites planned to be opened among 7 European countries.

On the following day, December 9, Dr. Llombart-Cussac, Head of the Medical Oncology Service at the Hospital Arnau de Vilanova [NB3] (Valencia, Spain) presented the second MEDSIR’s ongoing trial, the ABIGAIL: a multicenter, randomized, open-label, investigator-initiated phase II study. In ABIGAIL, 160 ABC patients with poor prognostic factors, meaning that their life expectancy is not optimistic, will be allocated in a 1:1 ratio to receive a 12-week induction therapy of either abemaciclib plus endocrine therapy (Arm A), or paclitaxel (Arm B). The primary objective of this study will be to compare the efficacy of the two treatments as induction (meaning initial) therapy, evaluating the overall response rate (ORR) at 12 weeks. In fact, despite analysis of MONARCH 2 and 3 which demonstrated that patients with indicators of poor prognosis (visceral disease, estrogen receptor negative ER[-], high-grade tumors, etc.) had the largest benefit from the administration of abemaciclib plus ET, currently they are often first submitted to induction chemotherapy to achieve a rapid control of the disease.

By directly comparing the administration of abemaciclib + ET with paclitaxel as first-line therapy, the ABIGAIL study seeks to provide consistent evidence that this approach has the same efficacy as chemotherapy, avoiding all of its known side-effects. Today, ABIGAIL is open for recruitment, with a total of 32 sites foreseen to be opened across 4 EU countries by the end of 2022.

Finally on December 10, last day of the symposium, Dr. Llombart-Cussac exposed the final results from both our DxCARTES and LINGAIN studies.

DxCARTES was a multicenter, open-label, non-comparative, investigator-initiated phase II study, that aimed to assess the biological and clinical activity of letrozole plus palbociclib as neoadjuvant treatment in luminal EBC patients with a molecular signature, based on the Oncotype DX recurrence-score (RS, Genomic Health) that provides an individualized estimate of distant recurrence risk. Patients with stage II-IIIB, HR[+]/HER2[-] EBC) received six cycles of neoadjuvant palbociclib + letrozole. We hypothesized that this combination could be active in patients with intermediate-high risk luminal EBC (RS, and that OncotypeDX RS could help to identify candidates feasible to downscale adjuvant chemotherapy.

After the analysis of baseline tissue biopsies with Oncotype DX RS assay, 67 patients were allocated to cohort A if RS ranged from 18 to 25 and to cohort B if RS ranged from 26 to 100. At surgery, 66.7% of patients in cohort A had a RS stabilization (RS ≤25), failing to reach the primary endpoint (set for 76% of patients, 25/33), whereas 52.9% of patients in cohort B had RS ≤25 or a pCR after treatment, meeting the primary endpoint (positive findings for 24% of patients 8/33).

Results from DxCARTES suggest that patients with high RS at baseline experiment the strongest molecular downstaging after neoadjuvant Palbociclib + ET. However, the prognostic value of this observation is unknown, and investigation in larger cohorts should be performed to determine if this strategy could avoid the use of adjuvant chemotherapy in this specific population”, concluded Dr. Llombart-Cussac.

Finally, also on December 10, Dr. Llombart-Cussac presented the analysis of LINGAIN, a prospective evaluation of predictive immunogenicity biomarkers for targeted therapy in HER2[+] EBC within the PHERGain study. Tumor-infiltrating lymphocytes (TILs) at baseline can be considered a positive prognostic marker in HER2[+] EBC treated with trastuzumab and pertuzumab-based neoadjuvant therapies. Depending on the characteristics of their receptors, TILs are characterized in αβ and γδ T cells. Although the latter are poorly represented in blood, they rapidly expand in response to tumor, representing key effectors of defense. We hypothesized that the activation of circulating γδ T cells in blood after neoadjuvant treatments with double HER2 blockade could represent an initial signal of immune response and considered as an early marker. Thus, the objective of LINGain was to explore changes in the proportion, activation, and apoptosis of circulating αβ and γδ T cell in a subset of patients from the cohort B of PHERGain, treated with neoadjuvant trastuzumab and pertuzumab.

LINGain included 24 patients from the cohort B of PHERGain and 48 healthy donors as control. Blood samples were collected before starting the treatment, and again at the end of the second cycle. These were compared with healthy samples by flow cytometry analysis, detecting specific surface markers on blood mononuclear cells. The analysis revealed that after treatment the absolute count of both γδ and αβ T cells were decreasing, but surprisingly the number of cells undergoing apoptosis (cell-death) was augmenting after 2 cycles of neoadjuvant treatment with respect to the initial number in HER2[+] EBC patients. Moreover, a significantly higher fraction of γδ TEMRA than αβ TEMRA (T effector memory cells re-expressing CD45RA) was observed in CD3+ and CD3+CD8+ T cell subsets, meaning that γδ T cells were in their functional stage, and thus properly acting against the tumor. “To our knowledge, LINGain is the first study to assess the evolution of peripheral αβ and γδ T cells in the context of neoadjuvant chemotherapy-free regimen with trastuzumab and pertuzumab in HER2[+] EBC patients. Although no evidence of T cell association with clinical characteristics was found, we need to keep investigating in this direction, to uncover the role and the prognostic value of the innate immune system in the context of HER2 blockade strategies”, concluded Dr. Llombart-Cussac.

MEDSIR could not be happier about the outcome of the symposium and the feedback we received regarding our studies. We hope to keep contributing to the field of breast cancer oncology and help in providing new information to patients and oncologists.

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