With antibody-drug conjugates, checkpoint and CDK4/6 inhibitors, three drug classes were in the spotlight at this year’s European Society for Medical Oncology (ESMO) congress in advanced breast cancer. This is not without relevance for the clinic, because trastuzumab deruxtecan could soon significantly change the second-line therapy of HER2-positive metastatic breast cancer. And approval of the checkpoint inhibitor pembrolizumab is also likely to be imminent.
At ESMO 2021, there was news from both HER2-positive and triple-negative and hormone receptor (HR)-positive/HER2-negative advanced breast cancer – some of which had a direct impact on current therapeutic standards (Fig. 1). First and foremost, the antibody-drug conjugate tastuzumab deruxtecan made a big impact in the second-line treatment of HER2-positive breast cancer. However, a survival benefit has also been demonstrated for pembrolizumab in triple-negative cases. In the MONALEESA-2 trial, which evaluated the addition of the CDK4/6 inhibitor ribociclib to endocrine therapy in untreated HR+/HER2- breast cancer, median overall survival (OS) exceeded five years for the first time in the history of advanced breast cancer – a promising sign.
The Star at ESMO 2021: Trastuzumab Deruxtecan
The antibody-drug conjugate ( ADC) trastuzumab deruxtecan (T-DXd) consists of an antibody directed against HER2, a cleavable linker, and a topoisomerase I inhibitor. In contrast to the ADC trastuzumab emtansine (T-DM1), which has been commonly used in second-line therapy, the effect is based on a different chemotherapeutic agent, which is present in a significantly higher ratio to the antibody, namely 8:1. For comparison, in T-DM1, the ratio of cytostatic to antibody is 3-4:1. In addition, the linker of T-DXd is cleaved off when it enters the target cell, leaving the drug as a small molecule. At least in theory, this results in the so-called “bystander effect”: Since the substance is small enough to diffuse out of the cancer cell again, malignant cells are also attacked that do not themselves overexpress HER2 [1].
And the theory seems to be working, according to recently presented data from the Phase III DESTINY-Breast03 trial (NCT03529110) – so well, in fact, that unblinding with early analysis was performed early on. The open-label, randomized study compared T-DXd with T-DM1 in the second-line treatment of metastatic HER2+ breast cancer after pretreatment with trastuzumab and a taxane (Fig. 1) . This is the first randomized phase III study of trastuzumab deruxtecan. A total of 524 patients were included, including those with clinically stable brain metastases. The primary endpoint was progression-free survival (PFS). While median PFS was not achieved in the intervention group, it was 6.8 months in the control arm, consistent with recent studies of T-DM1. The 1-year PFS rate was 75.8% with T-DXd treatment, compared with 34.1% in the T-DM1 arm (hazard ratio 0.28, 95% confidence interval: 0.22-0.37). This effect was present across all subgroups; neither prior therapy nor metastatic site had an effect on efficacy. The response rate (ORR) also showed impressive results. This was 79.7% in the T-DXd group and 34.2% in the T-DM1 group (p<0.0001). Complete remissions were observed twice as often under treatment with the new substance. Overall survival was not yet achieved in either study arm, but a relevant benefit of therapy with T-DXd emerged here as well – despite the very early analysis. Thus, the 1-year OS rate in the intervention group was 94.1%, whereas it was 85.9% in the control arm (hazard ratio 0.56, 95% confidence interval: 0.36-0.86) [1]. A longer follow-up period is certainly necessary for the assessment of OS, but the considerable crossover to be expected must not be disregarded here. A similar situation was seen in the TH3RESA trial of T-DM1, in which significant longer-term survival benefits were observed despite a 43% crossover [2]. This could be an indication that not only the substance is decisive for success, but also the timing of its use. If similar longer-term results are confirmed for T-DXd, this would be further evidence that the earlier antibody-drug conjugates are used, the better their efficacy.
No new safety concerns arose during the course of DESTINY-Breast03. In particular, pulmonary toxicity was a focus, as five lung-related deaths had occurred in the previous study [3]. In the evaluation of DESTINY-Breast03, there were no other pneumological incidents ≥Grad. 4. 0.8% of patients in the intervention group experienced grade 3 interstitial lung disease. Overall, 10.5% of study participants treated with T-DXd developed interstitial lung disease. Thus, proactive management of this known adverse drug reaction appears to be extremely important. One such was performed in the study protocol of DESTINY-Breast03. Apart from pneumological side effects, hematotoxicity, gastrointestinal side effects, fatigue, and hair loss were the most common [1].
Although a new second-line standard for HER2+ metastatic breast cancer has been found in trastuzumab deruxtecan – the experts at ESMO 2021 agreed on this – approval has yet to be granted. While the active ingredient has not yet been approved in Switzerland, it may already be used in the EU in more advanced situations on the basis of earlier studies [4,5]. This application in later lines of therapy was also supported by new data at the ESMO Congress. For example, updated survival data from the phase II DESTINY-Breast01 trial, which included heavily pretreated patients, showed a meaningful and sustained OS benefit with a prolongation of median OS to 28.4 months (95% CI 24.6-37.2 months) and a 2-year OS rate of 58%. The single-arm study included 253 patients with progression on T-DM1 [3]. Previous analyses had shown an ORR of 61.4% with a median response duration of 20.8 months and a median PFS of 19.5 months.
Currently, several additional Phase III studies are pending, which should soon allow a differentiated assessment of trastuzumab deruxtecan. For example, the new drug is being studied in HER2-low (DB-06, NCT04494425), first-line therapy (DESTINY-Breast09, NCT04784715), in the presence of brain metastases, and in the post-neoadjuvant setting (DESTINY-Breast05, NCT04622319). We remain curious.
Spotlight on another antibody-drug conjugate
Another antibody-drug conjugate that was in focus at ESMO 2021 is (Vic-) Trastuzumab Duocarmazine, or – somewhat more simply – SYD985. This ADC is also based on trastuzumab and thus targets HER2. Initial results from a Phase III study were presented at the congress: TULIP. In this, the drug was tested after at least two lines of therapy or T-DM1 treatment. A 2:1 randomization of the 437 patients took place. The new agent was compared with chemotherapy of the treating physician’s choice. There was a significant improvement in PFS with a median PFS of 7 months with SYD985, compared to 4.9 months in the control group, hazard ratio 0.64 (95% CI 0.49 – 0.84, p=0.002) [6]. Whether this absolute difference of about two months will prove clinically relevant remains to be seen. The overall response rate was around 30% in both study arms. Unfortunately, some unexpected toxicities occurred, including serious ones, especially of the eyes (conjunctivitis, keratitis). Overall, about 40% of the study participants were affected. In addition, there were three deaths due to interstitial lung disease. Therapy with SYD985 had to be discontinued in more than one-third of cases due to adverse drug reactions, whereas the toxicity-related discontinuation rate in the control group was 10.2%. Thus, to date, the available data on SYD985 appear less promising than those on T-DXd – yet with significant toxicity. However, it should not be forgotten that in the very advanced situation in which the substance was tested, potentially any new option is welcome.
Immunotherapy in triple-negative breast cancer.
Regarding triple-negative breast cancer, a study update was of particular interest at this year’s ESMO Congress. The final results of the KEYNOTE-355 trial support the benefit of adding pembrolizumab to chemotherapy in the first-line setting. KEYNOTE-355 included 847 patients and compared placebo-controlled chemotherapy alone with chemotherapy + pembrolizumab. Previous analyses have already demonstrated a PFS benefit in patients with PD-L1 expression. The updated data now also show a statistically significant OS benefit in patients with PD-L1 expression (CPS ≥10). While the median OS with the addition of pembrolizumab was 23 months, it was 16.1 months with chemotherapy alone. In terms of toxicity, there was little difference between the study arms, so the toxicity of chemotherapy did not appear to be significantly increased by the addition of pembrolizumab. However, this resulted in immune-mediated side effects such as hypothyroidism in 26.5% of patients treated with the checkpoint inhibitor [7].
The bottom line is that pembrolizumab + chemotherapy is likely to be a new standard option for the first-line setting of metastatic triple-negative breast cancer. The corresponding approvals from the EMA and Swissmedic are expected. To date, of the checkpoint inhibitors, only atezolizumab has been approved for this indication with PD-L1 expression ≥1% [4]. The selection could now soon grow.
Benefit of CDK4/6 inhibitors confirmed
Although the CDK4/6 inhibitors ribociclib and palbociclib are already approved in combination with endocrine therapy for first-line treatment of HR+/HER2- breast carcinoma, longer-term overall survival data have been lacking [4]. These have now been delivered – and were convincing. For example, follow-up data from the first phase III trial of a first-line CDK4/6 inhibitor, MONALEESA-2, showed a significant OS benefit of 12.5 months. While the median OS with ribociclib + letrozole was 63.9 months – the first time an overall survival of more than five years could be reported in metastatic breast cancer – it was 51.4 months with placebo + letrozole (HR 0.76, 95% CI 0.63-0.93, p=0.004). Over the years, the survival advantage became greater and greater. In addition, the duration to first chemotherapy was delayed by nearly one year with the administration of ribociclib (50.6 months vs. 38.9 months) [8].
In addition to data on first-line therapy, new evidence on CDK4/6 inhibitors in second-line HR+/HER2- breast cancer was presented. In the follow-up of the PEARL trial, which evaluated the use of palbociclib + endocrine therapy after aromatase inhibitor failure and compared it to capecitabine, no statistically significant difference in OS or PFS was observed [9]. This confirms previous data from the study. However, CDK4/6 inhibitor therapy proved to be better tolerated and non-inferior to chemotherapy. Thus, the goal should be to treat patients as long as possible on an endocrine basis and to use CDK4/6 inhibitors already in the first line of therapy.
Congress: ESMO 2021
Literature:
- Cortés J, et al: Trastuzumab deruxtecan (T-DXd) vs trastuzumab emtansine (T-DM1) in patients (Pts) with HER2+ metastatic breast cancer (mBC): Results of the randomized phase III DESTINY-Breast03 study. ESMO Congress 2021, Presidential Symposium 1, Abstract #LBA1.
- Krop IE, et al: Trastuzumab emtansine versus treatment of physician’s choice in patients with previously treated HER2-positive metastatic breast cancer (TH3RESA): final overall survival results from a randomised open-label phase 3 trial. Lancet Oncol. 2017; 18(6): 743-754.
- Saura Manich C, et al: Trastuzumab deruxtecan (T-DXd) in patients with HER2-positive metastatic breast cancer (MBC): Updated survival results from a phase II trial (DESTINY-Breast01). ESMO Congress 2021, ePoster Display, Abstract #279P.
- Swissmedic Medicinal Product Information: www.swissmedicinfo.ch (last accessed 28.09.2021).
- EMA Enhertu product information: www.ema.europa.eu/en/documents/product-information/enhertu-epar-product-information_de.pdf (last accessed Sept. 28, 2021).
- Saura Manich C, et al: Primary outcome of the phase III SYD985.002/TULIP trial comparing [vic-]trastuzumab duocarmazine to physician’s choice treatment in patients with pre-treated HER2-positive locally advanced or metastatic breast cancer. ESMO Congress 2021, Proffered Paper Session – Breast cancer, metastatic, Abstract #LBA15.
- Rugo H, et al: KEYNOTE-355: Final results from a randomized, double-blind phase III study of first-line pembrolizumab + chemotherapy vs placebo + chemotherapy for metastatic TNBC. ESMO Congress 2021, Proffered Paper Session – Breast cancer, metastatic, Abstract #LBA16.
- Hortobagyi G, et al: Overall survival (OS) results from the phase III MONALEESA-2 (ML-2) trial of postmenopausal patients (pts) with hormone receptor positive/human epidermal growth factor receptor 2 negative (HR+/HER2-) advanced breast cancer (ABC) treated with endocrine therapy (ET) ± ribociclib (RIB). ESMO Congress 2021, Proffered Paper Session – Breast cancer, metastatic, Abstract #LBA17_PR.
- Martin Jimenez M, et al: Overall survival (OS) of palbociclib (P) plus endocrine therapy (ET) versus capecitabine (CAP) in hormone-receptor+/HER2- metastatic breast cancer (MBC) that progressed on aromatase inhibitors (AIs): Final results of the PEARL study. ESMO Congress 2021, Mini oral session – Breast cancer, metastatic, Abstract #229MO.
InFo ONCOLOGY & HEMATOLOGY 2021; 9(5): 22-24 (published 10/27-21, ahead of print).