Analysis by residual cancer burden further clarifies effect of pembrolizumab

An exploratory analysis of the KEYNOTE-522 trial showed that patients with triple-negative breast cancer (TNBC) who had residual disease at surgery benefitted from pembrolizumab compared with placebo in terms of event-free survival (EFS) events. This was the case even if the patients did not achieve a pathological complete response (pCR), indicating an effect of the adjuvant pembrolizumab component.

The primary results of KEYNOTE-522 (n=1,174, NCT03036488) demonstrated that neoadjuvant pembrolizumab plus chemotherapy was superior to chemotherapy and placebo in patients with early-stage TNBC in terms of pCR, and in terms of EFS if the neoadjuvant treatment was followed by adjuvant pembrolizumab [1,2]. With the current, prespecified, exploratory analysis, Prof. Lajos Pusztai (Yale School of Medicine, CT, USA) investigated the EFS by treatment arm, within residual cancer burden categories (RCB), ranging from 0 (no residual disease) to 3 (most residual disease) [3].

In each RCB category, fewer patients with residual disease at surgery received pembrolizumab compared with placebo: RCB-1 8.8% vs 11.5%; RCB-2 18.5% vs 20.3%; RCB-3 5.1% vs 6.7%. According to Prof. Pusztai, this indicates that the addition of pembrolizumab did not only increase the pCR rate (RCB-0) but shifted other RCB categories as well, in favour of pembrolizumab. The 36-month EFS analysis showed that patients with RCB-2 (n=224) might benefit most from pembrolizumab (HR 0.52), suggesting that adjuvant pembrolizumab is beneficial for patients who did not achieve a pCR. The corresponding hazard ratios in patients with RCB-0 (n=716), RCB-1 (n=114), and RCB-3 (n=66) were 0.70, 0.92, and 1.24 (see Figure). Notably, within the RCB-3 stratum, patients on placebo had a higher rate of distant recurrence as first EFS event (53.8% vs 35.0%), whereas patients on pembrolizumab more frequently displayed local recurrence as first EFS event (25.0% vs 7.7%).

Figure: Event-free survival analysis by residual cancer burden subgroup [3]



RCB, residual cancer burden; No., number; Pembro, pembrolizumab; Chemo, chemotherapy; Pbo, placebo; HR, hazard ratio.

Dr Erica Michelle Stringer-Reasor (University of Alabama, AL, USA) commented that these results show that RCB is a more detailed biomarker than pCR and offers new insights in the KEYNOTE-522 trial. “We noticed that patients in the RCB-0 and RCB-1 categories performed very well regardless of adjuvant immunotherapy, raising the question whether these patients should receive this treatment. Also, it would be interesting to see whether we can further stratify patients with residual disease, for example with circulating tumour DNA, to refine additional adjuvant therapy even more.”

1. Schmid P, et al. N Engl J Med. 2020;382:810‒821.
2. Schmid P, et al. N Engl J Med. 2022;386:556‒567.
3. Pusztai L, et al. Event-free survival by residual cancer burden after neoadjuvant pembrolizumab + chemotherapy versus placebo + chemotherapy for early TNBC: Exploratory analysis from KEYNOTE-522. Abstract 503, ASCO 2022 Annual Meeting, 3‒7 June, Chicago, IL, USA.

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Posted on 5 August, 202225 March, 2024