Chemo-Free Regimen Shows Promise in High-Risk Early Breast Cancer

A chemotherapy-free neoadjuvant regimen led to similar breast cancer outcomes, while allowing a majority of patients with high-risk early-stage disease to avoid adjuvant cytotoxic therapy, according to updated results from a randomized trial.

Progression-free survival (PFS) at 40 months was 87% for patients who received chemotherapy or the hormonal agent letrozole plus the CDK4/6 inhibitor palbociclib (Ibrance). Of 11 disease-progression events, three occurred in the chemotherapy-free arm as compared with eight in the patients who received neoadjuvant chemotherapy. Invasive disease-free survival (iDFS) and breast cancer-specific survival (BCSS) also did not differ significantly between treatment groups.

Overall survival favored the chemotherapy control arm, but a majority of deaths in the palbociclib-letrozole arm were unrelated to breast cancer, reported Suzette Delaloge, MD, of Gustave Roussy Institute in Villejuif, France, at the European Society for Medical Oncology (ESMO) Breast Cancer Virtual Congress.

“In this high-risk population of early luminal A node-positive and luminal B breast cancer patients — who had a median ROR [risk of recurrence] score of 70 to 73, neoadjuvant letrozole and palbociclib led to pathologic response rates that did not significantly differ from those obtained with chemotherapy,” she said. “Clinical response and breast-conserving surgery rates were equivalent, and the 3-year progression-free survival and invasive disease-free survival were equivalent.”

“Unfortunately, this study was underpowered for definitive conclusions, but it strongly suggests that such a nonchemotherapy preoperative letrozole-palbociclib approach deserves further exploration and could be an option for a chemotherapy-free regimen in some cases,” Delaloge added.

As previously reported, the trial’s primary endpoint was pathologic complete response (pCR), defined as residual cancer burden (RCB) 0/1. More patients achieved the endpoint with upfront chemotherapy, but the difference was not statistically significant, said ESMO invited discussant Hope Rugo, MD, of the University of California San Francisco. However, the RCB 3 rate before surgery did not differ between the groups.

“Overall survival in patients who received chemotherapy appears to be better, but the very small numbers make interpretation of this difference impossible, and the event-free survival, iDFS, and BCSS lack of difference is impressive,” said Rugo. “This is a small study with relatively short follow-up, even for hormone receptor-positive high-risk disease. However, we’ve seen recently from the CDK4/6 inhibitor trials that this short follow-up can be very meaningful, even in high-risk disease.”

“Heterogeneity in postsurgery chemotherapy use in the endocrine therapy arm is difficult to interpret,” she continued. “Given this and small numbers, apparently there is little impact on short-term outcome. Short-term biologic endpoints are clearly more informative following and during neoadjuvant endocrine therapy than pCR. This trial, as well as the data from previous studies, indicate that this is the case. Antiproliferative response is enhanced with CDK4/6 inhibitors, but interestingly, this does not translate into a difference in pCR. The lack of impact on longer-term outcome to date provides support for ongoing trials.”

Delaloge reported secondary findings from the NeoPAL trial that compared the chemotherapy-free regimen with standard preoperative chemotherapy in 106 patients with high-risk luminal breast cancer. Following surgery, patients in both arms received adjuvant endocrine therapy. Patients who did not achieve RCB 0/1 status with the letrozole-palbociclib neoadjuvant regimen were offered chemotherapy in addition to adjuvant endocrine therapy. Subsequently, 23 of the 53 patients in the experimental arm received adjuvant chemotherapy.

The RCB 0/1 rates were 7.6% with the chemo-free regimen and 15.7% with neoadjuvant chemotherapy. Clinical response rates were 55.5% with letrozole-palbociclib and 53.3% with chemotherapy. Two patients had complete responses, both in the chemo-free arm. The rate of breast-conserving surgery was 69% in each arm.

PFS was virtually identical in the two arms at 40 months (HR 1.01, 95% CI 0.36-2.90, P=0.98). The analysis of iDFS favored the letrozole-palbociclib arm but did not reach statistical significance (HR 0.83, 95% CI 0.31-2.23, P=0.71). An analysis of PFS by RCC score showed no difference between patients who achieved RCB 0/1 or RCB 2/3 in either treatment arm. A total of 13 iDFS events occurred: 11 cases of disease progression (eight in the control arm) and two second cancers (both in the experimental arm).

Seven patients died during the study, all but one in the experimental arm, resulting in an advantage for the control group (P=0.047). Of the six deaths in the letrozole-palbociclib arm, two resulted from breast cancer, two from intercurrent disease, one from suicide, and one from alcoholic cirrhosis. Breast cancer accounted for the only death in the chemotherapy arm.

No unexpected safety issues arose during the study, but the chemotherapy-free arm had a more favorable profile.