The KEYNOTE-756 trial

In a discussion at ESMO  between Dr Eline Naert, medical oncologist from Genth University Hospital and Prof Evandro De Azambuja from Institut Jules Bordet, the focus was on the Keynote 756 trial—a phase 3 randomized study exploring the addition of pembrolizumab to chemotherapy in the neoadjuvant treatment of high-risk stage 2 and 3 hormone-positive breast cancer patients.

The trial, with a follow-up exceeding 30 months, revealed a substantial enhancement in pathologic complete response (pCR) when pembrolizumab was combined with chemotherapy. The pCR rate increased from 15.6% to 24.3%, reflecting an 8% absolute improvement in this at-risk patient group.

Key points of discussion included the comprehensive treatment strategy involving pembrolizumab and paclitaxel, followed by anthracyclines, and its potential applicability to T2N1 tumours. Concerns were raised about immediate practice changes due to the absence of survival outcome data, lack of approval, and reimbursement, along with considerations of added toxicity.

In this dialogue, the primary focus revolves around the comprehensive treatment strategy introduced in the trial: pembrolizumab in conjunction with weekly paclitaxel for 12 weeks, followed by four cycles of anthracyclines. The question arises about its applicability to T2N1 tumours, with a consideration of the current trend among clinicians to opt for surgery and a potential de-escalation strategy, omitting chemotherapy. Prof De Azambuja, acknowledging the absence of survival outcome data and the pending aspects of approval and reimbursement, advocates for maintaining the current approach. They express caution about the potential toxicity of adding pembrolizumab to chemotherapy, emphasising the need to await conclusive evidence before altering established strategies.

In a hypothetical scenario of full reimbursement and positive EFS outcomes, the discussion shifts to the feasibility of employing the strategy in patients over 65. Prof De Azambuja urges a prudent stance, citing the limited representation of this age group in the trial’s subgroup analysis. He emphasises the importance of onco-geriatric assessments to evaluate fitness and engage in informed discussions with patients about risks, benefits, and side effects.

The dialogue then delves into the PD-L1 status aspect, highlighting the insight from Prof Fatima Cardoso that the beneficial effect of pembrolizumab is irrespective of PD-L1 status. However, subgroup analyses indicate a doubling of absolute pCR rates. Prof De Azambuja acknowledges the intricacies of the data, particularly in the context of triple-negative breast cancer.

Shifting gears, the discussion explores a novel perspective on luminal B tumours. Drawing from previous meta-analyses, it was noted that while luminal A shows no correlation between pCR and EFS, luminal B, characterised by greater aggressiveness, demonstrates a notable correlation. Despite this correlation, Prof De Azambuja underscores the need for additional data before integrating it into routine clinical practice.

In essence, the dialogue underscores a cautious approach, emphasising the importance of awaiting comprehensive data and long-term outcomes from the trial before contemplating substantial alterations to current clinical practices. The uncertainties surrounding approval, reimbursement, and potential toxicities warrant a vigilant stance in the face of evolving therapeutic strategies.

Reference

Fatima Cardoso – KEYNOTE-756: Phase 3 study of neoadjuvant pembrolizumab (pembro) or placebo (pbo) + chemotherapy (chemo), followed by adjuvant pembro or pbo + endocrine therapy (ET) for early-stage high-risk ER+/HER2– breast cancer. ESMO 2023, #LBA21