Trastuzumab deruxtecan effective in both second-line and neoadjuvant setting

In patients with ER-positive/HER2-positive breast cancer, the antibody-drug conjugate trastuzumab deruxtecan (T-DXd) has (superior) clinical efficacy in the second-line as well as in the neoadjuvant setting, results from the DESTINY-Breast02, DESTINY-Breast03, and TRIO-US B-12 TALENT trials showed.

DESTINY-Breast02

In DESTINY-Breast01 (NCT03248492), T-DXd demonstrated robust activity in a pre-treated patient population with HER2-positive metastatic breast cancer, leading to regulatory approvals globally [1].  However, DESTINY-Breast01 was a modestly sized, single-arm, phase 2 trial. DESTINY-Breast02 (NCT03523585) was designed to confirm the results of DESTINY-Breast01 in a randomised, phase 3 trial. Dr Ian Krop (Yale Cancer Center, CT, USA) presented the primary results [2].

The study enrolled 608 patients with previously-treated, HER2-positive, unresectable or metastatic breast cancer. Over 70% of patients had 2 or 3 prior lines of therapy, all patients were pre-treated with trastuzumab and/or trastuzumab emtansine (T-DM1). Patients were randomised 2:1 to receive T-DXd or treatment of physicians’ choice (TPC: trastuzumab/capecitabine or lapatinib/capecitabine). The primary endpoint was progression-free survival (PFS).

T-DXd appeared to be superior to chemotherapy-based treatment: the median PFS in the T-DXd arm was 17.8 months versus 6.9 months in the TPC arm (HR 0.359; P<0.000001). PFS rate at 24 months of follow-up was 42.2% versus 13.9% (see Figure). PFS benefit of T-DXd over TPC was observed in all pre-specified subgroups. The median overall survival (OS; key secondary endpoint) was 39.2 months compared with 26.5 months in the T-DXd arm and the TPC arm, respectively (HR 0.658; P=0.0021). In the TPC arm, 26% of patients received T-DXd in the post-trial setting. The objective response rate was 69.7% in the T-DXd arm versus 29.2% in the TPC arm (14% vs 5% complete response, respectively). No new safety signals were observed for T-DXd. Drug-related interstitial lung disease (any grade) was observed in 10.4% and interstitial lung disease grade ≥3 was observed in 1.2% of patients treated with T-DXd.

Figure: Progression-free survival of T-DXd by blinded independent central review [2].

T-DXd, trastuzumab deruxtecan; TPC, treatment of physicians’ choice.

“DESTINY-Breast02 confirms the favourable benefit/risk profile of T-DXd in patients with advanced HER2-positive metastatic breast cancer, as previously demonstrated by DESTINY-Breast01,” Dr Krop concluded.

DESTINY-Breast03

The DESTINY-Breast03 trial (NCT03529110) compared the efficacy and safety of T-DXd with those of T-DM1 in patients with HER2-positive, unresectable or metastatic breast cancer that progressed on or after first-line treatment. A total of 524 patients were 1:1 randomised to receive T-DXd or T-DM1. The primary endpoint was PFS and the key secondary endpoint was OS. At the previously reported PFS interim analysis, in the T-DXd arm, the risk of disease progression or death was reduced by 72% [3]. Prof. Sara Hurvitz (David Geffen School of Medicine, CA, USA) presented the updated results based on 169 OS events [4].

The median OS was not yet reached for either treatment arm. However, the HR was statistically significant in favour of T-DXd versus T-DM1 (HR 0.64; P=0.0037). The OS rates at 24 months were 77.4% and 69.9%, respectively. The updated median PFS was 28.8 months versus 6.8 months (HR 0.33; P<0.000001). The ORR was 78.5% for T-DXd and 35% for T-DM1 (21.1% vs 9.5% complete response, respectively).

Based on these results, Prof. Hurvitz concluded: “These updated results further support the use of T-DXd as the second-line standard-of-care in patients with HER2-positive metastatic breast cancer.”

TRIO-US B-12 TALENT

In addition, Prof. Aditya Bardia (Harvard Medical School, MA, USA) presented the first results of the phase 2 TRIO-US B-12 TALENT trial (NCT04553770) [5]. This study evaluated the efficacy of T-DXd as a neoadjuvant treatment for patients with localised HR-positive/HER2-low breast cancer. Because of the bystander effect of antibody-drug conjugates, HER2-low breast cancer is actionable by T-DXd. This was recently demonstrated in patients with metastatic, HER2-low breast cancer [6]. The efficacy of (neo-adjuvant) T-DXd in localised HER2-low breast cancer is not known. Given the cross-talk between ER and HER2, addition of endocrine therapy to T-DXd was also evaluated in this setting.

TRIO-US B-12 TALENT enrolled 58 patients with HR-positive/HER2-low, stage II or III breast cancer. Patients were randomised 1:1 to receive T-DXd (6 or 8 cycles) or T-DXd plus anastrozole followed by surgery. The primary objective was to evaluate the pathological complete response (pCR) in breast and lymph nodes. Secondary objectives were the objective response rate (ORR) and the change in HER2 and safety.

Of the patients treated with T-DXd, 5% achieved pCR (RCB-0) and 10% achieved near-pCR (RCB-I). The ORR in these patients was 68% (8% complete response). Of the patients treated with T-DXd plus anastrozole, 0% achieved pCR and 15% achieved near-pCR. The ORR in these patients was 58% (8% complete response). Of note, at data cut-off, surgical outcomes were pending for 24% of patients treated with T-DXd and 31% of patients treated with T-DXd plus anastrozole.

“These first results demonstrate preliminary evidence of clinical activity of neoadjuvant T-DXd in HR-positive/HER2-low localised breast cancer. Addition of endocrine therapy does not appear to enhance the efficacy of T-DXd,” concluded Prof. Bardia.

1. Modi S, et al. N Engl J Med. 2020;382:610–62.
2. Krop I, et al. Trastuzumab deruxtecan vs physician’s choice in patients with HER2+ unresectable and/or metastatic breast cancer previously treated with trastuzumab emtansine: Primary results of the randomized phase 3 study DESTINY‑ Abstract GS2-01, SABCS 2022, 6–December, San Antonio, TX, USA.
3. Cortes J, et al. N Engl J Med. 2022;386:1143–1154.
4. Hurvitz SA, et al. Trastuzumab deruxtecan versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer: Updated results of the randomized, phase 3 study DESTINY-Breast03. Abstract GS2-02, SABCS 2022, 6–10 December, San Antonio, TX, USA.
5. Hurvitz S, et al. TRIO-US B-12 TALENT: Neoadjuvant trastuzumab deruxtecan with or without anastrozole for HER2-low, HR+ early stage breast cancer. Abstract GS2-03, SABCS 2022, 6–10 December, San Antonio, TX, USA.
6. Modi S, et al. N Engl J Med. 2022;387:9–20.

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Posted on 1 February, 2023