Peter Schmid, MD, PhD

According to the invited discussant of UNIRAD,¹Peter Schmid, MD, PhD, Lead of the Centre for Experimental Medicine at Barts Cancer Institute, Queen Mary University of London, it remains unclear whether or not everolimus plus hormone therapy is an effective adjuvant regimen for high-risk patients with early-stage breast cancer. Given the challenges that arose in this study, Dr. Schmid commented: “I’m not sure whether we can really evaluate, by this trial, whether everolimus did work.”

Unanswered Questions

Dr. Schmid phrased his comments around several questions: Could the study results change over time? Has the trial answered the research questions? Was the trial hypothesis valid? Was the trial design optimal?

To begin, Dr. Schmid noted that since the study was terminated early, it thus left key questions unanswered. “The trial set out to see a 3% increase in invasive disease–free survival. That would have required nearly 2,000 patients, but the trial was stopped early for futility and had recruited only about two-thirds of its initial goal,” he noted. “The 147 events account for just 51% of those required, so we have to state it is likely the study was underpowered.” Nevertheless, Dr. Schmid continued, 147 events should be sufficient to establish a lack of efficacy, given that 75% of patients were followed for more than 19 months. “These data are unlikely to change substantially over time,” he predicted.

Issues Clouding Study Findings

In addition, other issues also cloud the study findings, Dr. Schmid commented. For instance, the true degree of endocrine resistance in the population is unknown, since patients entered after any degree of adjuvant hormonal therapy (up to 4 years). Drugs that inhibit mTOR “seem to be more relevant” for secondary resistance than primary resistance, he pointed out.

“The study set out to look into secondary resistance, but this was clearly not a pure secondary resistance population: 85% of patients were less than 3 years from surgery…. It’s also uncertain whether patients received enough everolimus, given the dose reductions in 53% of patients,” Dr. Schmid noted.

Due to toxicity or poor acceptance, only 16% of patients ended the study on the recommended dose of 10 mg, and the majority needed dose reductions. “Whether this impacts efficacy is unknown,” he reminded, noting that 86% of patients with metastatic disease in the BOLERO-2 trial received 10 mg, “and it was a positive trial.” Dr. Schmid continued: “It’s stating the obvious, but a treatment that’s not taken by patients can never be effective. However, we are better now at managing the side effects of everolimus.”

Furthermore, according to Dr. Schmid, there is also a psychological effect. “In talking to patients, I see that it’s difficult to be on single-agent hormone therapy for some time and then restart intensive therapy. The acceptability of additional side effects 3 to 4 years later can be much lower than immediately after diagnosis.”

Closing Thoughts and Next Steps

Although appropriate at the time based on what was known, UNIRAD’s design selected patients according to risk and not tumor biology, as do most trials, Dr. Schmid further noted. “That’s something we may have to take into consideration, as we see increasing levels of primary and secondary resistance and evaluate agents that can potentially target resistance clones,” he suggested. “We are just starting to understand the mechanisms of resistance…. Early on, we would like to know the profile of cancer that leads to late recurrence with a certain mechanism of resistance at a certain time point.”

“We also need to work out whether these compounds are cytostatic in nature or cytotoxic,” Dr. Schmid added. Cytostatic regimens are delaying disease progression, but cytostatic treatments result in continued separation of the curves.

“I congratulate the French group on this excellent trial,” Dr. Schmid concluded. “The study was negative, but I hope with explanation for that outcome, we can make progress for patients in this difficult-to-treat setting.” 

DISCLOSURE: Dr. Schmid has an immediate family member who has been employed by Genentech and Roche; has received honoraria from AstraZeneca, Novartis, Pfizer, and Roche; has served as a consultant or advisor to AstraZeneca, Bayer, Boehringer Ingelheim, Celgene, Eisai, Merck, Novartis, Pfizer, and Puma Biotechnology; has an immediate family member who has served as a consultant or advisor to Genentech/Roche; and has received institutional research funding from Astellas Pharma, AstraZeneca, Genentech, OncoGenex, Novartis, and Roche.

REFERENCE

1. Bachelot T, Dalenc F, Chabaud S, et al: Efficacy of everolimus in patients with HER+/HER2– high-risk early-stage breast cancer. ESMO Virtual Plenary. Presented February 19, 2021.