The DESTINY-Breast07 trial will test trastuzumab deruxtecan (T-DXd) combinations in patients with HER2-positive advanced or metastatic breast cancer, as a phase 1b/2, open-label, multicenter, dose-finding and dose-expansion study presented at the American Society of Clinical Oncology (ASCO) Annual Meeting, which was held virtually 4-10 June, 2021 [1]. Physician’s Weekly spoke with Dr Fabrice André (Institut Gustave Roussy, Paris, France) about the potential of combinations with T-DXd.

Despite the fact that HER2-targeted therapies improve survival in patients with HER2+ advanced/metastatic breast cancer, the development to resistance remains a substantial problem. Furthermore, options for patients with brain metastases are few. The landmark phase 2 DESTINY-Breast01 trial (NCT03248492), showed that T-DXd had an objective response rate (ORR) of 61.4% and median progression-free survival (mPFS) of 19.4 months in patients with previously treated HER2+ advanced or metastatic breast cancer  [2,3]. The trial allowed enrollment of patients with stable brain metastases, and, also presented at ASCO 2021, in a subgroup analysis of 24 patients with brain metasases, T-DXd seemed equally effective, with a mPFS of 18.1 and 50%  ORR in patients with complete imaging data [4]. The tentative hypothesis currently is that T-DXd has demonstrated efficacy on brain metastases, and that combining T-DXd with other agents may provide novel treatmement options for this group of patients.

The DESTINY-Breast07 (NCT04538742) study follows up on this hypothesis, and is modular in design allowing assessment of safety, tolerability and anti-tumor activity of T-DXd in combination with other anti-cancer agents. It is a global, multicenter, open-label, phase 1b/2 trial designed to evaluate the safety, tolerability, and preliminary antitumor activity of T-DXd monotherapy and combinations in patients with HER2+ advanced or metastatic breast cancer. Combination-treatment modules will have 2 parts: a dose-finding phase (Part 1), and a dose expansion phase (Part 2); the recommended Phase 2 dose (RP2D) determined in Part 1 will be used for the dose-expansion in Part 2. Enrollment has begun, and first results are expected in the coming years.

The modules to be tested are as follows: a T-DXd monotherapy module (module 0) and 5 combination modules of T-DXd plus (1) durvalumab, (2) pertuzumab, (3) paclitaxel, (4) durvalumab + paclitaxel, or (5) tucatinib, all in patients with no or stable brain metastases. Two additional modules consisting of (6) T-DXd + tucatinib and (7) T-DXd monotherapy will include patients with untreated brain metastases not requiring local therapy or previously treated BM that have progressed since local therapy (active BM). The primary endpoints are determination of the recommended phase 2 doses (part 1 only) and safety and tolerability of T-DXd and combinations (parts 1 and 2). Secondary endpoints include ORR, PFS, PFS2, duration of response (DoR), and overall survival (all assessed in part 2 only) and pharmacokinetics and immunogenicity (parts 1 and 2). To assess central nervous system (CNS) activity, exploratory endpoints were added, including CNS-ORR, CNS-DoR, and CNS-PFS (by RECIST version 1.1 and RANO-BM criteria) as well as cognitive and symptom assessment using CANTAB, MDASI-BT, and NANO.

Physician’s Weekly spoke with Dr Fabrice André about his presentation.

What line of treatment do you see T-DXd as monotherapy or in combination as becoming?

“In the Unites States, in 2021, the NCCN [National Comprehensive Cancer Network guidelines] said that for HER2-positive metastatic breast cancer, THP was the preferred first-line therapy. Second-line therapy should be T-DM1. Regarding the tucatinib triplet and T-DXd, these regimens “may be used as [a] third- or fourth-line option; the optimal sequence for third-line therapy and beyond is not known.”

“According to NCCN guidelines, T-DXd is contraindicated in patients with active pneumonitis or a history of drug-induced pneumonitis, [but it] is preferred in patients with visceral metastasis if they progress on T-DM1. Tucatinib, trastuzumab, and capecitabine is preferred in patients with both systemic and CNS progression on T-DM1. The new subgroup analysis of brain metastases patients treated with T-DXd  presented at ASCO 2021 [4] this year may alter that perception after validation.”

“The main thing we have to watch out for with T-DXd is interstitial lung disease [ILD]. In the DESTINY-Breast01 trial, [the percentage of patients with] any-grade ILD was 15.2%, although most of it was low-grade. We’re hoping to raise awareness among doctors and patients to report any new cough, fever, [or] shortness of breath. This will allow early detection of ILD. If caught early enough, patients can interrupt their treatment temporarily to recover, then continue treatment. If symptomatic, timely intervention with steroids will help. Being of Asian ethnicity is a risk factor. We’re not going to be using T-DXd as a 10th line treatment I suspect. We’re going to be using this earlier, with higher doses. How this will be affected by combination therapy in DESTINY-Breast07 is unknown, but we will be vigilant, and we have learned a lot from using T-DXd in the clinic.”

Outcomes for patients with brain metasatases?

“This is of special interest to us. In the DESTINY-Breast01 trial [of T-DXd], 24 [13%] of the patients had stable, asymptomatic, treated brain metastases at study entry. This group of 24 patients, with stable treated brain metastases, did just as well as the overall population. They had had a mean of 6 prior lines of therapy, exactly the same as the total population. The median PFS of the subgroup with brain metastases was 18.1 months, comparable to the 19.4 months in the overall population. The objective response rate for the 24 [CNS] patients was 58%; for the overall population, it was 61%. In the CNS subgroup, 33% had progression of disease, pretty close to 26% in the overall population. Progression involving the brain occurred in only 4 of 48 patients. Only 4 [instances of progression] involved brain progression. These data really suggest benefit for these patients, and a combination approach might be the next step towards true clinical benefit.“

  1. Andre F et al, Trastuzumab deruxtecan (T-DXd) combinations in patients with HER2-positive advanced or metastatic breast cancer: A phase 1b/2, open-label, multicenter, dose-finding and dose-expansion study (DESTINY-Breast07). DOI: 10.1200/JCO.2021.39.15_suppl.TPS1096 Journal of Clinical Oncology 39, no. 15_suppl
  2. Modi S, et al. Updated results from DESTINYbreast01, a phase 2 trial of trastuzumab deruxtecan (T-DXd) in HER2 positive metastatic breast cancer. Paper presented at: 2020 San Antonio Breast Cancer Symposium; December 6-10, 2020; virtual. https://bit.ly/3ofKAIC
  3. Modi S, et al. DESTINY-Breast01 Investigators. Trastuzumab deruxtecan in previously treated HER2-positive breast cancer. N Engl J Med. 2020;382(7):610-621. doi:10.1056/NEJMoa1914510
  4. Jerusalem G, et al. 138O CNS metastases in HER2-positive metastatic breast cancer treated with trastuzumab deruxtecan: DESTINY-Breast01 subgroup analyses. Ann Oncol. 2020;31(suppl 2):S63- S64. doi:10.1016/j.annonc.2020.03.239
  5. NCCN. Clinical Practice Guidelines in Oncology. Breast cancer, version 4.2021. Accessed May 19, 2021. https://bit.ly/3hInaKE

 

 

 

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