In this second installment of the 2023 ASCO Highlights, we put the spotlight on de-escalation strategies. De-escalation cancer studies look at whether we can reduce the intensity or duration of treatment without compromising survival and perhaps even improve quality of life. When almost everything in the cancer treatment world is focused on finding more, new, and better drugs, it is important to remind ourselves and others that de-escalation is just as important. How can we minimize the harms of a cancer drug without minimizing the benefits of the drug? This question is significant to breast cancer patients. We discussed the CDK4/6 inhibitor de-escalation of the SONIA trial in our first installment of the 2023 ASCO Highlights, and here, we explore two trials that investigate the de-escalation of chemotherapy (PHERGain and X-7/7).
Chemotherapy is notorious for its adverse side effects. In the age of HER2-targeting drugs like trastuzumab (Herceptin), can some patients with HER2+ early breast cancer safely forego chemotherapy? Results from the PHERGain trial1,2, presented at ASCO, suggest that a subset of these breast cancer patients may indeed safely avoid the additional toxicity that comes with chemotherapy.
The PHERGain trial is a Phase II clinical trial in which HER2+ early breast cancer patients were randomized 1:4 to one of the following two groups:
Each patient’s response to treatment was measured twice – once after two cycles of neoadjuvant treatment and again after surgery. In Group B, if a patient was responding well to the chemotherapy-free treatment, they were allowed to stay on the de-escalated track. Those who were not responding or who did not have a pathological complete response at the time of surgery escalated to TCHP. This unique approach is referred to as “response-adaptive”.
Of the entire Group B cohort, approximately 30% of the patients were able to remain on the de-escalated treatment (no chemotherapy) for the duration of the study and, after 3 years median follow-up, investigators observed the following:
The de-escalation strategy (no chemotherapy) did not jeopardize recurrence or survival outcomes.
The PHERGain trial shows that approximately 1 out of 3 HER2+ early breast cancer patients can safely forgo the harmful toxicities of chemotherapy without sacrificing their 3-year recurrence or survival outcomes.
Patients with metastatic breast cancer are on continuous treatment, such as an FDA approved dosing regimen of capecitabine, which is associated with high rates of discontinuance due to significant toxicity. The X-7/7 trial3 investigates if a different dosing regimen could spare patients from capecitabine’s toxicity? The X-7/7 results presented at ASCO suggest that it can.
In this Phase II clinical trial, metastatic breast cancer patients were randomized 1:1 to either receive the FDA-approved capecitabine regimen (1250 mg/m2 twice daily, 14 days on followed by 7 days off; N=73) or the experimental capecitabine regimen (1500 mg twice daily, 7 days on followed by 7 days off; N=80). While the experimental regimen uses a higher dose, the patients are subjected to fewer total days of treatment (14 days on vs 7 days on per cycle).
There were no differences in median progression-free survival (PFS) (8.7 months vs 12.07 months, p=0.98) nor in median OS (19.8 months vs 17.5 months, p=0.17) between the two regimens. However, the de-escalated regimen showed statistically significant decreases in toxicity, including the following:
The X-7/7 trial shows that de-escalation of the capecitabine regimen reduces toxicity without risking survival. For metastatic breast cancer patients, this means that they can safely reduce their risk of toxic side effects.
Adding more drugs and using higher doses is not always better. De-escalation studies seek to decrease patients’ exposure to the toxic effects of cancer treatment while maintaining the best survival outcomes. But this sometimes means less product sold, translating to less profit for industry. This is one reason why de-escalation trials are not as common, despite their potential benefit on quality of life.
NBCC applauds research that seeks to improve the quality of life for breast cancer patients through evidence-based de-escalation strategies. It is an area of research that needs more attention and action despite its lack of financial incentives. Breast cancer patients deserve treatment options that improve survival outcomes without subjecting them to excessive toxicity. We encourage NBCC advocates to keep the conflicting interests of industry and breast cancer patients in mind in your research advocacy endeavors. It is our job to keep research focused on outcomes that matter to patients – living longer and better lives.
