Early Chemotherapy Stop Did Not Hurt Outcomes in KEYNOTE-355 Responders

Patients with advanced triple-negative breast cancer (TNBC) who responded to first-line pembrolizumab (Keytruda) plus chemotherapy had similar progression-free and overall survival whether or not they discontinued chemotherapy early while continuing pembrolizumab, according to post hoc exploratory analyses of the phase 3 KEYNOTE-355 trial (NCT02819518) published in npj Breast Cancer.¹

The analyses also provide a more detailed characterization of immune-mediated adverse events (AEs) in the trial, finding that most were low-grade and manageable with treatment interruption and supportive care, and that their occurrence was not associated with worse efficacy outcomes.

Chemotherapy Discontinuation Findings

Among 317 patients in the pembrolizumab-chemotherapy group who achieved a complete response, partial response, or stable disease lasting at least 24 weeks, 92 (29.0%) discontinued chemotherapy more than 21 days before their last dose of pembrolizumab. The all-patients-as-treated population had a median progression-free survival (PFS) of 14.5 months (95% CI, 11.9-20.2) and median overall survival (OS) of 32.9 months (95% CI, 27.4-38.3), compared with 11.6 months (95% CI, 9.9-12.3) and 26.4 months (95% CI, 23.5-29.7), respectively, in the overall population with clinical benefit. Similar patterns held across PD-L1 combined positive score (CPS) subgroups of ≥1 and ≥10. The authors noted no evidence of an adverse effect on either end point associated with early chemotherapy discontinuation, regardless of PD-L1 expression level.

Immune-Mediated Adverse Events

Immune-mediated AEs of any grade occurred in 26.5% of patients receiving pembrolizumab plus chemotherapy vs 6.4% of those receiving placebo plus chemotherapy, consistent with the trial's previously reported final analysis. Most events were grade 1 or 2 (21.2% of the pembrolizumab group), with grade 3 or 4 events in 5.3% and no grade 5 events. The most common immune-mediated AEs with pembrolizumab were hypothyroidism (15.8%), hyperthyroidism (4.3%), and pneumonitis (2.5%). Immune-mediated AEs led to pembrolizumab interruption in 6.2% of patients and discontinuation in 2.5%; corticosteroids were used to manage 22.2% of patients with these events.

Among the 149 patients who experienced an immune-mediated AE, median pembrolizumab and chemotherapy treatment durations were numerically longer than in the overall pembrolizumab-chemotherapy population (8.8 vs 5.6 months and 7.2 vs 5.1 months, respectively). This group also had numerically longer median PFS (9.7 vs 7.5 months) and OS (23.9 vs 17.2 months) than the overall population, a pattern also seen in the PD-L1 CPS ≥1 and ≥10 subgroups.

Interpretation and Limitations

The study authors cautioned that both sets of analyses were retrospective, exploratory, and not adjusted for multiplicity, and that longer treatment duration among patients with immune-mediated AEs may partly explain the numerically better outcomes in that group rather than reflecting a causal relationship. AE follow-up in the trial was limited to 30 days after treatment discontinuation (90 days for serious AEs), so later-onset immune-mediated events would not have been captured.

Trial Background

KEYNOTE-355 is a phase 3, randomized, double-blind, placebo-controlled trial that enrolled 847 patients with previously untreated, locally recurrent inoperable or metastatic TNBC across 29 countries.^2,3 Patients were randomized 2:1 to pembrolizumab or placebo, each combined with investigator's choice of nab-paclitaxel, paclitaxel, or gemcitabine plus carboplatin. The trial's primary results, previously published in The Lancet and The New England Journal of Medicine, showed statistically significant improvements in PFS and OS with pembrolizumab plus chemotherapy among participants with PD-L1 CPS ≥10, forming the basis for regulatory approvals in this population.

REFERENCES

1. Rugo HS, Cescon DW, Schmid P, et al. Outcomes in KEYNOTE-355 after chemotherapy discontinuation before pembrolizumab discontinuation and with immune-mediated adverse events. npj Breast Cancer. 2026. doi:10.1038/s41523-026-00971-8

2. Cortes J, Cescon DW, Rugo HS, et al. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer (KEYNOTE-355): a randomised, placebo-controlled, double-blind, phase 3 clinical trial. Lancet. 2020 Dec 5;396(10265):1817-1828. doi: 10.1016/S0140-6736(20)32531-9. PMID: 33278935.

3. Cortes J, Rugo HS, Cescon DW, et al. Pembrolizumab plus Chemotherapy in Advanced Triple-Negative Breast Cancer. N Engl J Med. 2022 Jul 21;387(3):217-226. doi: 10.1056/NEJMoa2202809. PMID: 35857659.