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

Abstract

Sequential adaptive trial designs can help accomplish the goals of personalized medicine, optimizing outcomes and avoiding unnecessary toxicity. Here we describe the results of incorporating a promising antibody-drug conjugate, datopotamab-deruxtecan (Dato-DXd) in combination with programmed cell death-ligand 1 inhibitor, durvalumab, as the first sequence of therapy in the I-SPY2.2 phase 2 neoadjuvant sequential multiple assignment randomization trial for high-risk stage 2/3 breast cancer. The trial includes three blocks of treatment, with initial randomization to different experimental agent(s) (block A), followed by a taxane-based regimen tailored to tumor subtype (block B), followed by doxorubicin-cyclophosphamide (block C). Subtype-specific algorithms based on magnetic resonance imaging volume change 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 pathologic complete response, which is the primary endpoint assessed when resection occurs. There are two primary efficacy analyses: after block A and across all blocks for six prespecified HER2-negative subtypes (defined by hormone receptor status and/or response-predictive subtypes). In total, 106 patients were treated with Dato-DXd/durvalumab in block A. In the immune-positive subtype, Dato-DXd/durvalumab exceeded the prespecified threshold for success (graduated) after block A; and across all blocks, pathologic complete response rates were equivalent to the rate expected for the standard of care (79%), but 54% achieved that result after Dato-DXd/durvalumab alone (block A) and 92% without doxorubicin-cyclophosphamide (after blocks A + B). The treatment strategy across all blocks graduated in the hormone-negative/immune-negative subtype. No new toxicities were observed. Stomatitis was the most common side effect in block A. No patients receiving block A treatment alone had adrenal insufficiency. Dato-DXd/durvalumab is a promising therapy combination that can eliminate standard chemotherapy in many patients, particularly the immune-positive subtype.ClinicalTrials.gov registration: NCT01042379 .

Figure 1.. Study design and CONSORT diagram.

(A) 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). (B) 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 shown.

Figure 2.. Efficacy of Dato-DXd + durvalumab treatment.

(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 + durvalumab 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 for the agent is greater than 85% for the threshold (dotted vertical line), it is said to ‘graduate.’

Figure 3.. 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 (DD = Dato-DXd + durvalumab; 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.

Figure 4.. Treatment blocks in which pCRs occurred in the HER2−Immune+ subtype.

Of the 47 HER2−Immune+ patients receiving Dato-DXd + durvalumab in Block A, 20 proceeded directly to surgery, forgoing subsequent treatment; all of these patients had pathology-confirmed pCR (RCB 0). 54% of all cases achieving pCR in this subtype did so after the course of the Dato-DXd + durvalumab combination alone. Of the 27 patients receiving to Block B’s paclitaxel-based treatment, 14 of 19 who proceeded to surgery following treatment had pathology-confirmed pCR; 92% of all pCRs recorded in this subtype were achieved without the use of AC chemotherapy. Of the remaining 8 patients who received AC chemotherapy in Block C, 3 additional pCRs were recorded.

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 + durvalumab (n=106); (B) Incidence of AE of any grade that were experienced by greater than 20% of patients during any block of treatment (n=106); 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. Adrenal insufficiency (AdI) events were reported (12) and adjudicated by 2 expert endocrinologists as described in the methods and 7 (6.6%) were determined to be adrenal insufficiency, irrespective of subtype of block of onset. The events are annotated by the block of onset for each irAE event (color) and the Block at which each patient with an irAE exited their neoadjuvant treatment (fill pattern). Note that 48 patients in total received pembrolizumab + paclitaxel + carboplatin in Block B; 16 received AC + pembrolizumab in Block C. 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.