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Dr Elisa Agostinetto, a medical oncologist and research fellow at the Institut Jules Bordet in Brussels, gave her insights on the second rapid-fire session at SABCS 2023. 

The first abstract reported by Dr Agostinetto pertains to the outcomes of the ASPIRE phase I/II study, which explored the efficacy of a novel treatment combination for HER2+/HR+ breast cancer. This innovative regimen comprised palbociclib, anastrozole, trastuzumab, and pertuzumab, offering a chemotherapy-free approach that concurrently inhibits both the estrogen receptor pathway and the HER2 pathway. This phase I/II trial, denoted as a study with a primary focus on clinical benefit, assessed the treatment’s effectiveness as a first-line intervention. The primary endpoint, the clinical benefit rate at six months, defined as the proportion of patients achieving a complete response, partial response, or maintaining stable disease for six months or more, was remarkably high at 97%. The overall response rate was approximately 70%, indicating that 70% of patients exhibited either a complete or partial response to the treatment. While these results are promising, it is essential to approach them with caution due to the limited size of the study cohort and the early phase nature of the investigation. Nevertheless, these findings are encouraging, warranting further exploration of this regimen in the specified clinical setting.

The second highlighted abstract involves a preclinical investigation showcasing a novel PI3K inhibitor distinguished by its unique characteristic of not impacting glucose metabolism. This attribute is particularly intriguing given that conventional PI3K inhibitors, such as alpelisib, are associated with metabolic side effects, including hyperglycaemia and hyperinsulinemia. The absence of these adverse events makes this new PI3K inhibitor a promising alternative in the field. The data presented in this preclinical study, conducted as part of ongoing research, indicate a promising signal for anti-tumour activity exhibited by the new agent. It is essential to emphasise that these findings are based on preclinical data and, as such, necessitate further clinical validation to ascertain their applicability and efficacy in human subjects. Despite the preliminary nature of the results, the absence of adverse metabolic effects marks this PI3K inhibitor as a potentially valuable candidate for future clinical investigation.

The third highlighted abstract concerns the findings from the phase I study, DESTINY-Breast08, which investigated the combination of trastuzumab deruxtecan (T-DXd) with either fulvestrant or anastrozole for patients diagnosed with HER2-low HR+ breast cancer. Being a phase I study, the primary focus was on evaluating the safety profile of this treatment combination. The study enrolled a relatively modest number of patients in both cohorts: those treated with T-DXd and fulvestrant, and those treated with T-DXd and anastrozole. From a safety perspective, the results indicated a consistency with the known safety profile of T-DXd. Nausea emerged as the most common adverse event. Notably, the study observed three cases of grade 2 interstitial lung disease in the cohort treated with T-DXd and fulvestrant. As of the data cutoff, one case was completely resolved, one was resolving, and one had not yet resolved. Additionally, preliminary data on activity and response rates appeared promising, along with some initial survival data. However, it is crucial to note that these findings are preliminary and require a more extended follow-up for robust conclusions.

The final abstract of interest that Dr Agostinetto presented, delves into a study that scrutinized the metabolic alterations induced by a fasting-mimicking diet, a particularly intriguing area given the growing interest in the connection between diet and cancer. Dr. Claudio Vernieri, a medical oncologist from Istituto Nazionale Tumori in Milan, Italy, presented the findings from the BREAKFAST trial—a randomized study examining patients with early triple-negative breast cancer. In this relatively small study involving 30 patients, participants were randomised to receive either neoadjuvant chemotherapy in combination with a fasting-mimicking diet or neoadjuvant chemotherapy along with the fasting-mimicking diet and Metformin. The overall rate of pCR was notably higher, at around 56%, than what is typically expected with standard neoadjuvant chemotherapy regimens based on existing literature. The fasting-mimicking diet induced metabolic changes, including reductions in blood glucose, blood insulin levels, and LDH levels. Some of these metabolic changes were correlated with pCR. Interestingly, no significant differences in pCR were observed between the group receiving Metformin and the group without Metformin. As a result, the investigators have initiated a larger randomized phase three trial, BREAKFAST-2, where patients are treated with neoadjuvant chemoimmunotherapy alongside the fasting-mimicking diet. Notably, the new trial excludes Metformin due to the lack of observed differences in the previous phase of the study, and it aligns with the evolving standard of care for stage two and stage three triple-negative breast cancer, emphasizing chemoimmunotherapy over chemotherapy alone based on data from Keynote 522.

References:

Tiersten A. et al., A Multicenter, Phase I/II Trial of Anastrozole, Palbociclib, Trastuzumab, and Pertuzumab in Hormone Receptor (HR)-Positive, HER2-Positive Metastatic Breast Cancer (ASPIRE) –   SABCS 2023, #RF02-01

Beltran P. et al., BBO-10203, a first-in-class, orally bioavailable, selective covalent small molecule that inhibits RAS-driven PI3Kalpha activity without affecting glucose metabolism – SABCS 2023, #RF02-02

Jhaveri K. et al., Trastuzumab deruxtecan (T-DXd) in combination with anastrozole or fulvestrant in patients with HER2-low HR+ advanced/metastatic breast cancer: a Phase 1b, open-label, multicenter, dose-expansion study (DESTINY-Breast08) – SABCS 2023, #RF02-03

Vernieri C. et al., Precocious modulation of metabolic and immunological parameters predicts tumor response to fasting-mimicking diet plus chemotherapy in patients with early stage TNBC –  SABCS 2023, #RF02-07