Datopotamab-deruxtecan in early-stage breast cancer: the sequential multiple assignment randomized I-SPY2.2 phase 2 trial

Abstract

Among the goals of patient-centric care are the advancement of effective personalized treatment, while minimizing toxicity. The phase 2 I-SPY2.2 trial uses a neoadjuvant sequential therapy approach in breast cancer to further these goals, testing promising new agents while optimizing individual outcomes. Here we tested datopotamab-deruxtecan (Dato-DXd) in the I-SPY2.2 trial for patients with high-risk stage 2/3 breast cancer. I-SPY2.2 uses a sequential multiple assignment randomization trial design that includes three sequential blocks of biologically targeted neoadjuvant treatment: the experimental agent(s) (block A), a taxane-based regimen tailored to the tumor subtype (block B) and doxorubicin-cyclophosphamide (block C). Patients are randomized into arms consisting of different investigational block A treatments. Algorithms based on magnetic resonance imaging and core biopsy guide treatment redirection after each block, including the option of early surgical resection in patients predicted to have a high likelihood of pathological complete response, the primary endpoint. There are two primary efficacy analyses: after block A and across all blocks for the six prespecified breast cancer subtypes (defined by clinical hormone receptor/human epidermal growth factor receptor 2 (HER2) status and/or the response-predictive subtypes). We report results of 103 patients treated with Dato-DXd. While Dato-DXd did not meet the prespecified threshold for success (graduation) after block A in any subtype, the treatment strategy across all blocks graduated in the hormone receptor-negative HER2^-Immune^-DNA repair deficiency^- subtype with an estimated pathological complete response rate of 41%. No new toxicities were observed, with stomatitis and ocular events occurring at low grades. Dato-DXd was particularly active in the hormone receptor-negative/HER2^-Immune^-DNA repair deficiency^- signature, warranting further investigation, and was safe in other subtypes in patients who followed the treatment strategy. ClinicalTrials.gov registration: NCT01042379 .

Figure 1.. I-SPY2.2 study schematic.

Participants receive up to three round (or ‘blocks’) of treatment, depending upon response assessed by MRI. Block A is a platform trial design that randomises participants to one of several arms testing experimental agents or combinations. Patients not responding to treatment in Block A, receive paclitaxel-based standard of care therapy in Block B assigned (or randomised) based on their response-predictive subtype. Those not responding in Block B proceed to treatment in Block C and receive a minimum of AC chemotherapy. All patients complete treatment with definitive surgery. Patients who meet the threshold to have a high probability of RCB 2/3 disease at 6 weeks (based on MRI at 0,3,6 weeks in A or after 6 weeks in B) have the option of skipping the remained of treatment in that block (early treatment redirection to next block).

Figure 2.. CONSORT diagram.

Enrolment period was defined as date of first screening consent from arm to date of arm closure to randomisation (6/27/2022 – 9/1/2023). Numbers of patients that adhered to the protocol specified treatment recommendations for early de-escalation to surgery were also included.

Figure 3.. Efficacy of Dato-DXd treatment in Block A.

A) Sankey diagram illustrating how the response-predictive subtypes (RPS) relate to standard HR/HER2 subtypes in the trial, with number of patients of each subtype; B-G) Posterior probability distributions of pCR rate following treatment in Block A with Dato-DXd in each of the four RPS subtypes and HER2− subtypes. Shown is the mean pCR rate with 95% confidence interval (CI), along with the probability [P(> Th)] that the agent is greater than a preset pCR rate threshold set for a specific subtype. If the P(>Th) is greater than 85% for the threshold (dotted vertical line), the agent is said to ‘graduate.’

Figure 4.. Efficacy of treatment strategies spanning Blocks A-C.

Posterior pCR rate distributions are shown for each RPS subtype (and HR-HER2−) and associated treatment strategy (D = Dato-DXd; T=paclitaxel; C=carboplatin; Pe=pembrolizumab; AC=doxorubicin/cyclophosphamide) along with the mean pCR rate and 95% confidence interval (CI).The intent-to-treat population is the solid line. The dashed line represents a sensitivity analysis that considers only patients who adhered to preRCB recommendations following Block A and B treatment to either proceed to surgery. P(>DC) is the probability that the pCR rate of the treatment strategy is superior to a subtype-specific dynamic control (filled grey distribution) that was predefined using cumulative data from I-SPY2 reflecting current best-in-subtype treatment. The threshold for graduation of a treatment strategy is P(> DC) ≥ 0.85. Note that within the HER2-Immune-DRD+ subtype (n=10), 7 patients went to surgery or received non-protocol therapy after Block A and did not proceed to receive Block B treatment. Among the 3 patients proceeding to Block B, 2 were randomised to TCPe; and yielded 9 patients who followed the treatment strategy D/TCPe/ACPe shown in panel D.

Figure 5.. Incidence of most frequently observed adverse events.

(A) Incidence of AE of any grade that were experienced by greater than 20% of participants during Block A treatment with Dato-DXd (n=103); (B) Incidence of AE of any grade that were experienced by greater than 20% of patients during any block of treatment (n=103); Note that all grade 3/4 adverse events observed in the study are represented here. The adverse events that were associated only with Blocks B and C are bolded. (C) Immune-related adverse events experienced by participants in any treatment block. Note that 36 participants received pembrolizumab + paclitaxel + carboplatin in Block B and 16 received AC + pembrolizumab in Block C. Note that this does not include the 7 patients who withdrew or received offstudy therapy (which may include pembrolizumab). AEs listed as “combined” refer to iMedDRA combined terms as follows: Stomatitis (Combined): stomatitis, oropharyngeal pain, mouth ulceration, mouth injury, oral pain, gingival pain; Rash (Combined): rash, rash maculo-papular, dermatitis, rash pustular, skin disorder, dermatitis acneiform, rash pruritic, rash erythematous, eczema, urticaria, and rash macular; Ocular events (Combined): keratitis, eye pain, vision blurred, eye irritation, photophobia, eye pruritus, dry eye, photopsia, conjunctivitis, eye infection, eyelid irritation, corneal ulcer, uveitis, corneal opacity, eye disorder; Neuropathy (Combined): peripheral sensory neuropathy, peripheral motor neuropathy, neuropathy peripheral; Neutropenia (combined): febrile neutropenia, neutropenia, and neutrophil count decreased.