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SAN ANTONIO -- Adjuvant-only immunotherapy with atezolizumab (Tecentriq) added to a standard chemotherapy backbone failed to improve invasive disease-free survival (iDFS) compared with chemotherapy alone in patients with early-stage triple-negative breast cancer (TNBC), an interim analysis of a phase III trial showed.

At a median follow-up of approximately 25 months, no significant difference was seen between arms, with iDFS events occurring in 11.5% of the atezolizumab arm and 10.2% of the chemotherapy-alone arm (HR 1.12, 95% CI 0.87-1.45, P=0.37), reported Michail Ignatiadis, MD, PhD, of the Institut Jules Bordet and l'Université Libre de Bruxelles in Belgium.

That HR in the intent-to-treat population crossed the prespecified futility boundary, a result that according to statisticians "will not change at the final analysis," he said here at the annual San Antonio Breast Cancer Symposium.

Also absent with the inclusion of atezolizumab was any effect on overall survival (OS), a secondary endpoint (HR 1.20, 95% CI 0.82-1.75), although these data are immature, with OS events in 5% of the overall study group.

Findings from the global ALEXANDRA/IMpassion030 trial therefore do not support the addition of the PD-L1 immune checkpoint inhibitor to adjuvant chemotherapy following primary surgery for early TNBC, but rather contribute to an "improved understanding about the optimal use of immunotherapy" in these patients, said Ignatiadis.

Current standard of care for early-stage TNBC is neoadjuvant chemotherapy and immunotherapy, he said. "It seems that not only in TNBC, but also in other tumor types, that neoadjuvant administration is the preferred approach. We hope that the translational data [from this trial] will help us understand why this is the case."

The timing of immunotherapy does seem to matter in early TNBC, said invited discussant Laura Huppert, MD, from the University of California San Francisco Comprehensive Cancer Center.

A proposed rationale of administering immunotherapy in the neoadjuvant setting is that the presence of the tumor promotes activation of a more diverse T-cell repertoire, she said, such that even after surgical removal of the lesion a greater number of these more diverse T cells may be present.

The possibility also exists that the PD-L1 inhibitor atezolizumab underperformed, and that outcomes may have been different with a PD-1 inhibitor.

"We will await the event-free survival data from " -- a neoadjuvant/adjuvant trial -- "to understand the role of atezolizumab in breast cancer," Huppert said, as well as data from other pending adjuvant immunotherapy trials such as , which is testing the PD-1 inhibitor pembrolizumab (Keytruda) in early TNBC.

Two unanswered questions are whether both neoadjuvant and adjuvant immunotherapy are needed for patients with early-stage TNBC, particularly for those who achieve pathologic complete response (pCR) after neoadjuvant chemotherapy plus immunotherapy; and whether outcomes can be improved with better adjuvant treatment in those patients with early-stage TNBC who do not achieve a pCR after neoadjuvant chemotherapy plus immunotherapy.

Patients enrolled in the phase III had completed surgery for stage II-III TNBC, with 2,199 randomized in a 1:1 ratio to adjuvant atezolizumab and chemotherapy or chemotherapy alone. Adjuvant chemotherapy consisted of weekly paclitaxel for 12 weeks followed by a dose-dense anthracycline-based chemotherapy regimen for four cycles. Adjuvant atezolizumab was started at 840 mg every 2 weeks, for up to 10 doses, followed by maintenance at 1,200 mg every 3 weeks for 1 year of total therapy.

At the time of the interim analysis, 975 patients in the atezolizumab/chemotherapy arm and 963 in the control arm were still on treatment or in follow-up.

Baseline characteristics were well balanced between the two arms, and the "race distribution reflected the global footprint of this trial," said Ignatiadis, with 51% white and 38% Asian; median participant age was 53 years.

About three-fourths had tumors with ductal histology, 6% had well-differentiated tumors at screening, and 61% had poorly differentiated tumors. Most patients (94%) had a primary tumor stage of pT1 or pT2, 48% had axillary node-positive disease, and 85% had stage II disease at surgery. Just under half (48%) received breast-conserving surgery.

PD-L1 tumor status was positive in 71%, though here atezolizumab still showed no benefit for the primary efficacy endpoint of iDFS (HR 1.03, 95% CI 0.75-1.42). The iDFS results for all other subgroups examined were in line with the main results.

Treatment-related serious adverse events were more common in the atezolizumab arm versus the control arm (18% vs 10%). Rates of fatigue, diarrhea, rash, and changes in liver enzymes were numerically greater in the atezolizumab arm. Immune-related adverse events (mainly rash, hepatitis, hypothyroidism) in the atezolizumab arm were primarily low grade, consistent with the profile of the checkpoint inhibitor.

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