High pCR rate after neoadjuvant Dato-DXd plus durvalumab therapy

Neoadjuvant treatment with datopotamab deruxtecan (Dato-DXd) was effective in patients with stage 2–3 breast cancer at a high risk of early recurrence in the I-SPY2.2 trial.

I-SPY2.2 is a part of I-SPY 2 (NCT01042379), a long-standing, adaptive platform trial of neoadjuvant therapy for patients with stage 2–3 breast cancer at a high risk of early recurrence. In I-SPY2.2, novel experimental regimens in the neoadjuvant breast cancer setting are given first in a sequence (Block A), followed by standard chemotherapeutic or targeted therapies (Block B/C) if indicated.

The goal is to identify agents that lead to pathological complete response (pCR) after the administration of novel targeted agents alone or in sequence with optimal therapy assigned based on the tumour’s response-predictive subtype (RPS). RPS incorporates expression-based immune signature, DNA repair deficiency (DRD), and luminal subtype with HR and HER2 status to classify patients (HR⁺/HER2^-/Immune^-/DRD^-; HR^-/HER2^-/Immune^-/DRD^-; HER2^-/Immune⁺; HER2^-/Immune^-/DRD⁺; HER2⁺/non-Luminal; and HER2⁺/Luminal).

De-escalation (proceeding to surgery) is based on the predicted residual cancer burden (preRCB). The estimated pCR rate is compared against a fixed subtype-specific pCR rate threshold. Drugs can ‘graduate’ to a phase 3 study if there is a >85% probability that the estimated pCR rate exceeds the (subtype-specific) threshold.

At ASCO 2024, results of 2 novel ‘Block A’ therapies were presented: datopotamab deruxtecan (Dato-DXd) and Dato-DXd plus durvalumab; by Dr Jane Meisel (Emory School of Medicine, GA, USA) and Dr Rebecca Shatsky (University of California San Diego, CA, USA), respectively [1,2].

In I-SPY2.2, 103 participants (HR⁺/HER2^- or HR^-/HER2^-) were treated with 4 cycles Dato-DXd in Block A, of which 33 participants went to surgery after Block A given favourable preRCB. However, “the drug did not meet the statistical threshold set by the trial for ‘graduation’ to a phase 3 study,” Dr Meisel said.

Also, 106 participants (HR⁺/HER2^- or HR^-/HER2^-) were treated with 4 cycles Dato-DXd plus durvalumab in Block A of which 35 participants went to surgery after Block A given favourable preRCB. “In the HER2^-/Immune⁺ subtype, estimated pCR rate (65%) exceeded the graduation threshold for this subtype (40% pCR) with a probability of 99%,” Dr Shatsky said.

1. Meisel J, et al. Rates of pathologic complete response (pCR) after neoadjuvant datopotamab deruxtecan (Dato): Results from the I-SPY2.2 trial. Abstract LBA509, ASCO Annual Meeting 2024, 31 May–4 June, Chicago, IL, USA.
2. Shatsky R, et al. Rates of pathologic complete response (pCR) after datopotamab deruxtecan (Dato) plus durvalumab (Durva) in the neoadjuvant setting: Results from the I-SPY2.2 trial. Abstract LBA501, ASCO Annual Meeting 2024, 31 May–4 June, Chicago, IL, USA.

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Posted on 18 July 202418 July 2024