Abstract PD3-01: Neoadjuvant pembrolizumab + chemotherapy vs placebo + chemotherapy followed by adjuvant pembrolizumab vs placebo for early TNBC: Post hoc analysis of adjuvant radiation therapy in the phase 3 KEYNOTE-522 study
Authors: McArthur Heather , Cortés Javier , Dent Rebecca , O’Shaughnessy Joyce , Pusztai Lajos , Küemmel Sherko , Foukakis Theodoros , Park Yeon Hee , Hui Rina , Harbeck Nadia , Takahashi Masato , Untch Michael , Fasching Peter A. , Cardoso Fatima , Denkert Carsten , Zhu Yalin , Ding Yu , Pan Wilbur , Schmid Peter 
Published: March 2023

Abstract
Background: The phase 3 KEYNOTE-522 study (NCT03036488) showed that pembrolizumab (pembro) administered in combination with neoadjuvant chemotherapy (chemo) and then continued as adjuvant monotherapy resulted in statistically significant and clinically meaningful improvements in pathological complete response (pCR) and event-free survival (EFS) in patients with early triple-negative breast cancer (TNBC). In this post hoc analysis, we assessed outcomes by patterns of adjuvant radiation therapy (RT) administration.
Methods: Patients with previously untreated, nonmetastatic, stage T1c/N1-2 or T2-4/N0-2 TNBC were randomized 2:1 to pembro 200 mg Q3W or placebo, both given with 4 cycles of paclitaxel + carboplatin, then 4 cycles of doxorubicin or epirubicin + cyclophosphamide (neoadjuvant phase). After definitive surgery, patients received pembro or placebo for 9 cycles or until recurrence or unacceptable toxicity (adjuvant phase). Dual primary endpoints are pCR, defined as ypT0/Tis ypN0, and EFS. EFS and adverse events (AEs) that occurred during the adjuvant phase were examined in patient subgroups defined by receipt of adjuvant RT (yes or no) and the pattern of adjuvant RT and pembro administration, either concurrent (the last adjuvant RT exposure was after the first dose of adjuvant pembro or placebo) or sequential (the last adjuvant RT exposure was before the first dose of adjuvant pembro or placebo).
Results: Among 1174 randomized patients, 715 (60.9%) received adjuvant RT (n=454 pembro; n=261 placebo) and 459 (39.1%) did not (n=330 pembro; n=129 placebo). At data cutoff (March 23, 2021), median follow-up was similar (~38 months) in both subgroups. EFS was longer in the pembro arm compared to the placebo arm in patients who received adjuvant RT (either concurrently or sequentially) and those who did not (Table). Grade 3-5 treatment-related AE rates for pembro vs placebo were 5.9% vs 2.7% with adjuvant RT (4.9% vs 2.2% with concurrent RT; 6.8% vs 3.1% with sequential RT) and 7.5% vs 2.9% without adjuvant RT. Treatment-related AEs led to death in 2 patients (0.4%); both occurred in the pembro arm in patients who received adjuvant RT. Immune-mediated AE rates were 10.6% vs 5.0% with adjuvant RT (9.7% vs 4.4% with concurrent RT; 11.8% vs 5.7% with sequential RT) and 9.0% vs 10.0% without adjuvant RT in the two treatment arms, respectively.
Conclusion: In this post hoc analysis, the addition of pembro to neoadjuvant chemo followed by adjuvant pembro provided a clinically meaningful EFS benefit, independent of adjuvant RT administration. An EFS benefit was observed in patients who received pembro with either concurrent or sequential adjuvant RT. The addition of pembro to adjuvant RT was generally well tolerated. Similar rates of treatment-related AEs and immune-mediated AEs were seen in patients who received adjuvant RT and pembro either concurrently or sequentially, although the sample sizes are modest. These results are consistent with the therapeutic benefit seen with neoadjuvant pembro plus chemo followed by adjuvant pembro in the intention-to-treat population of patients with early TNBC randomized in KEYNOTE-522.
Table: EFS by Adjuvant RT in KEYNOTE-522
Citation Format: Heather McArthur, Javier Cortés, Rebecca Dent, Joyce O’Shaughnessy, Lajos Pusztai, Sherko Küemmel, Theodoros Foukakis, Yeon Hee Park, Rina Hui, Nadia Harbeck, Masato Takahashi, Michael Untch, Peter A. Fasching, Fatima Cardoso, Carsten Denkert, Yalin Zhu, Yu Ding, Wilbur Pan, Peter Schmid. Neoadjuvant pembrolizumab + chemotherapy vs placebo + chemotherapy followed by adjuvant pembrolizumab vs placebo for early TNBC: Post hoc analysis of adjuvant radiation therapy in the phase 3 KEYNOTE-522 study [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD3-01.