Abstract: Following the demonstrated efficacy and safety of eribulin mesylate in heavily pretreated patients with metastatic breast cancer, an exploratory analysis was performed to investigate the effect of age in these patients. Methods. Data were pooled from two single-arm phase II studies and one open-label randomized phase III study in which patients received eribulin mesylate at 1.4 mg/m2 as 2- to 5-minute intravenous infusions on days 1 and 8 of a 21-day cycle. The effect of age on median overall survival (OS), progression-free survival (PFS), overall response rate (ORR), clinical benefit rate (CBR), and incidence of adverse events (AEs) was calculated for four age groups ( & lt;50 years, 50–59 years, 60–69 years, ≥70 years). Results. Overall, 827 patients were included in the analysis ( & lt;50 years, n = 253; 50–59 years, n = 289; 60–69 years, n = 206; ≥70 years, n = 79). Age had no significant impact on OS (11.8 months, 12.3 months, 11.7 months, and 12.5 months, respectively; p = .82), PFS (3.5 months, 2.9 months, 3.8 months, and 4.0 months, respectively; p = .42), ORR (12.7%, 12.5%, 6.3%, and 10.1%, respectively), or CBR (20.2%, 20.8%, 20.4%, and 21.5%, respectively). Although some AEs had higher incidence in either the youngest or the oldest subgroup, there was no overall effect of age on the incidence of AEs (including neuropathy, neutropenia, and leukopenia). Conclusion. Eribulin monotherapy in these selected older patients with good baseline performance status led to OS, PFS, ORR, CBR, and tolerability similar to those of younger patients with metastatic breast cancer. The benefits and risks of eribulin appear to be similar across age groups.

Abstract: Background: KEYNOTE-522 (NCT03036488) is a phase 3 study of neoadjuvant pembro + chemo vs placebo + chemo, followed by adjuvant pembro vs placebo in patients with early-stage TNBC. The primary analysis showed a statistically significant and clinically meaningful improvement in event-free survival (EFS) with pembro + chemo followed by pembro. To assess the robustness and consistency of the primary EFS result, prespecified sensitivity and subgroup analyses for EFS were performed. Methods: Patients with previously untreated, non-metastatic, centrally confirmed TNBC (stage T1c N1-2 or T2-4 N0-2 per AJCC) were randomized 2:1 to pembro 200 mg Q3W or placebo, both given with 4 cycles of paclitaxel + carboplatin, then with 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). Patients were stratified by nodal status (positive or negative), tumor size (T1/T2 or T3/T4), and carboplatin schedule (Q3W or QW). Dual primary endpoints are pCR rate and EFS. Five prespecified sensitivity analyses for EFS were performed, including 2 that assessed the impact of different censoring rules and 3 that assessed the impact of different event definitions. Treatment effects on EFS were examined in prespecified patient subgroups defined by nodal involvement (positive or negative), disease stage (II or III), menopausal status (pre-menopausal or post-menopausal), HER2 status (2+ by IHC but FISH- or 0-1+ by IHC), and LDH ( & gt;ULN or ≤ULN). Results: Among 1174 patients randomized, 784 were randomly assigned to the pembro + chemo group and 390 were randomly assigned to the placebo + chemo group. Median follow-up was 39.1 months at the time of the March 23, 2021 data cutoff. The benefit of neoadjuvant pembro + chemo followed by adjuvant pembro vs neoadjuvant chemo alone was generally consistent with the primary EFS results for all five sensitivity analyses and in each subgroup evaluated (Table). Conclusion: EFS sensitivity analyses show a robust treatment benefit of neoadjuvant pembro + chemo followed by adjuvant pembro for previously untreated non-metastatic TNBC. This benefit was generally consistent across a broad selection of patient subgroups. Table. EFS Sensitivity and Subgroup Analyses in KEYNOTE-522EFS Analyses (ITT Population)Pembro + Chemo n/N (%)*Placebo + Chemo n/N (%)*HR (95% CI)†Primary Analysis‡123/784 (15.7)93/390 (23.8)0.63 (0.48 - 0.82)Sensitivity Analyses1. Alternate censoring rules§112/784 (14.3)84/390 (21.5)0.64 (0.48 - 0.84)2. “New anticancer therapy for metastatic disease” considered an EFS event123/784 (15.7)93/390 (23.8)0.63 (0.48 - 0.82)3. “Positive margin at last surgery” removed from EFS definition122/784 (15.6)90/390 (23.1)0.65 (0.50 - 0.85)4. “Positive margin at last surgery” and “second primary malignancy” removed from EFS definition116/784 (14.8)88/390 (22.6)0.63 (0.48 - 0.84)5. “Second breast malignancy” included in EFS definition126/784 (16.1)95/390 (24.4)0.63 (0.48 - 0.82)Subgroup AnalysesNodal involvement‖Positive80/408 (19.6)57/196 (29.1)0.65 (0.46 - 0.91)Negative43/376 (11.4)36/194 (18.6)0.58 (0.37 - 0.91)Overall disease stageII69/590 (11.7)54/291 (18.6)0.60 (0.42 - 0.86)III54/194 (27.8)39/98 (39.8)0.68 (0.45 - 1.03)Menopausal statusPre-menopausal60/438 (13.7)47/221 (21.3)0.62 (0.42 - 0.91)Post-menopausal63/345 (18.3)46/169 (27.2)0.64 (0.44 - 0.93)HER2 status2+ by IHC (but FISH-)32/188 (17.0)24/104 (23.1)0.73 (0.43 - 1.24)0-1+ by IHC91/595 (15.3)69/286 (24.1)0.60 (0.44 - 0.82)LDH & gt;ULN29/149 (19.5)23/80 (28.8)0.65 (0.37 - 1.12)≤ULN93/631 (14.7)69/309 (22.3)0.63 (0.46 - 0.86)*Number of events/total number of patients (%). †Hazard ratios (HR) and 95% CIs in the primary analysis and sensitivity analyses were based on a stratified Cox regression model; analyses in subgroups were based on an unstratified Cox model. ‡EFS was defined as the time from randomization to the time of first documentation of disease progression that precludes definitive surgery, local or distant recurrence, a second primary cancer or death from any cause, whichever occurs first; patients who did not experience an event at the time of data cutoff were censored at the date they were last known to be alive and event-free. §Events after 2 consecutive missed disease assessments or initiation of post-surgery new anticancer therapy were censored at last disease assessment prior to the earlier date of ≥2 consecutive missed disease assessments and initiation of post-surgery new anticancer therapy; if no events before new anticancer therapy, events were censored at last disease assessment before initiation of post-surgery new anticancer treatment. ‖Determined by the study investigator by physical exam, sonography/MRI and/or biopsy. Data cutoff: March 23, 2021. Citation Format: Peter Schmid, Javier Cortes, Rebecca Dent, Lajos Pusztai, Heather McArthur, Sherko Kümmel, Jonas Bergh, Carsten Denkert, Yeon Hee Park, Rina Hui, Nadia Harbeck, Masato Takahashi, Michael Untch, Peter A. Fasching, Fatima Cardoso, Jay Andersen, Debra Patt, Michael Danso, Marta Ferreira, Marie-Ange Mouret-Reynier, Seock-Ah Im, Jin-Hee Ahn, Maria Gion, Sally Baron-Hay, Jean-Francois Boileau, Yalin Zhu, Wilbur Pan, Konstantinos Tryfonidis, Vassiliki Karantza, Joyce O’Shaughnessy. KEYNOTE-522 study of neoadjuvant pembrolizumab + chemotherapy vs placebo + chemotherapy, followed by adjuvant pembrolizumab vs placebo for early-stage TNBC: Event-free survival sensitivity and subgroup analyses [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr GS1-01.

Abstract: 503 Background: KEYNOTE-522 (NCT03036488) tested the benefit from adding pembrolizumab (pembro) to chemotherapy (chemo) in patients (pts) with early TNBC. The primary results showed statistically significant and clinically meaningful improvements in pCR and EFS with pembro.Prior studies have shown the prognostic value of the residual cancer burden (RCB) method to quantify the extent of residual disease after neoadjuvant chemo. In this exploratory analysis, we assessed EFS by RCB in KEYNOTE-522. Methods: 1174 pts 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 (pbo) given with 4 cycles of paclitaxel + carboplatin, then 4 cycles of doxorubicin or epirubicin + cyclophosphamide. After definitive surgery, pts received pembro or pbo for 9 cycles or until recurrence or unacceptable toxicity. Dual primary endpoints are pCR and EFS. RCB was assessed by the local pathologist at the time of surgery. The association between RCB categories (RCB-0, -1, -2, -3, corresponding to increasingly larger residual cancer) and EFS was assessed based on a Cox regression model with treatment as a covariate. Results: Median follow-up was 39.1 months at data cutoff (23 MAR 2021). Pembro shifted RCB to lower categories across the entire spectrum (Table). The HRs (95% CI) for EFS were 0.70 (0.38 - 1.31) for RCB-0 (equivalent to pCR), 0.92 (0.39 - 2.20) for RCB-1, 0.52 (0.32 - 0.82) for RCB-2, and 1.24 (0.69 - 2.23) for RCB-3. The most common EFS event in both arms was distant recurrence, which occurred in fewer pts in the pembro arm in all RCB categories. Conclusions: Increased RCB score was associated with worse EFS. Pts with residual disease had lower RCB values in the pembro arm, including fewer pts with RCB-3. Pembro + chemo prolonged EFS vs chemo alone in the RCB-0, -1, and -2 categories; the small sample size limits interpretation in the RCB-3 category. The small subset of pts with extensive residual disease (RCB-3) in both arms, 5.1% and 6.7%, respectively, had a poor prognosis. These results highlight the importance of neoadjuvant treatment with pembro for improving survival in pts with early TNBC, and identified a subset of pts for whom additional therapies will be needed. Clinical trial information: NCT03036488. [Table: see text]