Atezolizumab With Neoadjuvant Anti–Human Epidermal Growth Factor Receptor 2 Therapy and Chemotherapy in Human Epidermal Growth Factor Receptor 2–Positive Early Breast Cancer: Primary Results of the Randomized Phase III IMpassion050 Trial

Abstract

PURPOSE Combining standard of care (pertuzumab-trastuzumab [PH], chemotherapy) with cancer immunotherapy may potentiate antitumor immunity, cytotoxic activity, and patient outcomes in high-risk, human epidermal growth factor receptor 2 (HER2)–positive early breast cancer. We report the phase III IMpassion050 primary analysis of neoadjuvant atezolizumab, PH, and chemotherapy in these patients. METHODS Patients with a primary tumor of > 2 cm and histologically confirmed, positive lymph node status (T2-4, N1-3, M0) were randomly assigned 1:1 to atezolizumab/placebo with dose-dense doxorubicin/cyclophosphamide, followed by paclitaxel, and PH. After surgery, patients were to continue atezolizumab/placebo and PH (total: 1 year of HER2-targeted therapy); those with residual disease could switch to ado-trastuzumab emtansine with atezolizumab/placebo. Coprimary efficacy end points were pathologic complete response (pCR; ypT0/is ypN0) rates in intention-to-treat (ITT) and programmed cell death-ligand 1 (PD-L1)–positive populations. RESULTS At clinical cutoff (February 5, 2021), pCR rates in the placebo and atezolizumab groups in the ITT populations were 62.7% (n = 143/228) and 62.4% (n = 141/226), respectively (difference –0.33%; 95% CI, –9.2 to 8.6; P = .9551). The pCR rates in the placebo and atezolizumab groups in patients with PD-L1–positive tumors were 72.5% (n = 79/109) and 64.2% (n = 70/109), respectively (difference –8.26%; 95% CI, –20.6 to 4.0; P = .1846). Grade 3-4 and serious adverse events were more frequent in the atezolizumab versus placebo group. Five grade 5 adverse events occurred (four neoadjuvant, one adjuvant; two assigned to study treatment), all with atezolizumab. Overall, the safety profile was consistent with that of atezolizumab in other combination studies. CONCLUSION Atezolizumab with neoadjuvant dose-dense doxorubicin/cyclophosphamide–paclitaxel and PH for high-risk, HER2-positive early breast cancer did not increase pCR rates versus placebo in the ITT or PD-L1–positive populations. PH and chemotherapy remains standard of care; longer follow-up may help to inform the long-term impact of atezolizumab.

Overcoming Resistance to HER2-Directed Therapies in Breast Cancer

“…The addition of ICIs to standard therapies has also been studied in the neoadjuvant setting. In the IMpassion050 phase 3 trial, 454 patients with early HER2+ breast cancer were randomized to receive a standard anthracycline-containing neoadjuvant regimen, trastuzumab and pertuzumab with or without atezolizumab [ 92 , 93 ]. Patients who were randomized to atezolizumab continued it in combination with trastuzumab and pertuzumab in the post-neoadjuvant setting [ 92 , 93 ].…”

“…In the IMpassion050 phase 3 trial, 454 patients with early HER2+ breast cancer were randomized to receive a standard anthracycline-containing neoadjuvant regimen, trastuzumab and pertuzumab with or without atezolizumab [ 92 , 93 ]. Patients who were randomized to atezolizumab continued it in combination with trastuzumab and pertuzumab in the post-neoadjuvant setting [ 92 , 93 ]. IMpassion050 was discontinued due to an unfavorable benefit–risk profile; with five fatal adverse events in the atezolizumab arm [ 93 ].…”

“…Patients who were randomized to atezolizumab continued it in combination with trastuzumab and pertuzumab in the post-neoadjuvant setting [ 92 , 93 ]. IMpassion050 was discontinued due to an unfavorable benefit–risk profile; with five fatal adverse events in the atezolizumab arm [ 93 ]. The addition of ICI did not improve pCR rates in the ITT or PDL1+ populations, and the one-year event-free survival was also similar in both groups [ 93 ].…”

“…IMpassion050 was discontinued due to an unfavorable benefit–risk profile; with five fatal adverse events in the atezolizumab arm [ 93 ]. The addition of ICI did not improve pCR rates in the ITT or PDL1+ populations, and the one-year event-free survival was also similar in both groups [ 93 ]. The ongoing Astefania trial (NCT04873362) is randomizing patients to receive standard T-DM1 therapy, with or without atezolizumab, for patients with high-risk, HER2+ breast cancer and residual disease after neoadjuvant therapy.…”

Update Breast Cancer 2022 Part 3 – Early-Stage Breast Cancer

“…While data exist from a large randomized study of pembrolizumab (KEYNOTE-522 study) for patients with early-stage triple-negative breast cancer 49 , 50 , and pembrolizumab is approved for neoadjuvant in combination with chemotherapy followed by adjuvant treatment, there are relatively few data for patients with hormone receptor-positive disease and patients with HER2-positive disease. Now, the results of IMpassion050 with reference to pCR have been published 51 . In the IMpassion050 study, 454 HER2-positive patients were enrolled and randomized to neoadjuvant therapy with either dose-dense chemotherapy with doxoribicin/cyclophosphamide followed by therapy with paclitaxel in combination with trastuzumab and pertuzumab, or to the same therapy in combination with atezolizumab.…”