Top 8 Trials From 2021 in Breast Cancer

Ajay Dhakal, MBBS

OncLive® heard from leading oncologists in breast cancer who shared their perspectives on the biggest abstracts that were presented throughout 2021 in this space:

• Ajay Dhakal, MBBS, assistant professor, Department of Medicine, University of Rochester Medical Center
• Debu Tripathy, MD, professor and chairman, Department of Breast Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center
• Komal Jhaveri, MD, FACP, medical oncologist, Memorial Sloan Kettering Cancer Center
• Erin Roesch, MD, associate staff breast medical oncologist, Cleveland Clinic Taussig Cancer Institute
• Tiffany Traina, MD, vice chair, Oncology Care, Department of Medicine; section head, Triple Negative Breast Cancer Clinical Research Program, Memorial Sloan Kettering Cancer Center

1. 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.

DESTINY-Breast03 Design and Primary Analysis Findings¹

Dhakal: DESTINY-Breast03 [NCT03529110], which was presented at the 2021 European Society for Medical Oncology Congress [ESMO], was one of the year’s most impactful studies. This large, randomized, open-label, phase 3 trial compared the safety and efficacy of fam-trastuzumab deruxtecan-nxki [Enhertu; T-DXd], a HER2-directed antibody-drug conjugate [ADC] consisting of a cleavable linker and a topoisomerase I inhibitor payload, with ado-trastuzumab emtansine [Kadcyla; T-DM1] in [525] patients with HER2-positive metastatic breast cancer who had been previously treated with a taxane and trastuzumab [Herceptin].

The primary end point was progression-free survival [PFS]. This trial randomized 525 patients. The HR for PFS was 0.2840, favoring T-DXd. The median PFS was not reached for the T-DXd group and was 6.8 months for the T-DM1 group.

Slightly more treatment-emergent adverse effects [AEs] occurred numerically in the T-DXd group than in the T-DM1 group. Interstitial lung disease [ILD] is an AE of particular interest due to the association of serious ILD with T-DXd in prior studies. In the T-DXd arm, 10% of patients developed ILD compared with 2% in the T-DM1 arm, but most of the ILD [events] in the T-DXd arm were grade 1 and 2. There was no grade 5 event in either arm.

In this large, randomized trial, T-DXd has been shown to be more efficacious than T-DM1 in managing patients with metastatic HER2-positive breast cancer who were previously treated with a taxane and trastuzumab. In addition, there appears to be an acceptable increase in the [rate of] AEs with T-DXd compared with T-DM1.

Traina: There has been so much new information to digest in the HER2-positive space, but DESTINY-Breast03, the randomized study of T-DXd vs T-DM1 in second-line or later HER2-positive advanced disease, has [given us] powerful data. We saw high response rates; nearly every patient derived benefit from T-DXd. We’re seeing a significant improvement in PFS with T-DXd vs T-DM1. T-DXd represents a new standard of care in the second-line setting as a preferred agent.

Jhaveri: The biggest effect on the treatment paradigm for our patients with HER2-positive metastatic breast cancer comes from the DESTINY-Breast03 trial. We’d already had approval for the very first ADC, T-DM1 based on the pivotal EMILIA trial [NCT00829166], which was our standard of care in the second-line metastatic setting after patients had progressed on first-line taxane, trastuzumab, and pertuzumab [Perjeta] based on the CLEOPATRA trial [NCT00567190]. Then we had seen results from the DESTINY-Breast01 trial [NCT03248492]; its heavily pretreated patient population had a median of about 5 prior lines of therapy. [The] very exciting activity for T-DXd led to [its] approval in the metastatic setting. That was a single-arm nonrandomized trial.

[Somewhat] concerning from that study were the rate and severity of an important AE that we need to know and learn more about for T-DXd: ILD and pneumonitis. With the DESTINY-Breast03 trial, we tried to see if that, when compared with T-DM1, early in the treatment paradigm would look any different. DESTINY-Breast03 was a head-to-head comparison of T-DM1 vs T-DXd and the data were exciting. Not only did it meet its primary end point of PFS, which was not reached in blinded independent central review compared with about 7 months in the control arm, the HR was 0.28 and the P value was [7.8 ×] 10^–22. We really haven’t seen this exciting of an HR or P value for any treatment that has been approved for breast cancer, let alone HER2-positive disease.

Also reassuring from that data set was that since we have adjudicated some guidelines for monitoring the ILD and pneumonitis, we saw that there were fewer cases. The prevalence of ILD was lower, about 10%, in the DESTINY-Breast03 trial compared with 15% in DESTINY-Breast01. We didn’t see any grade 4 or 5 events, so it was reassuring that no fatal events occurred and that we’re doing a better job at potentially identifying these patients sooner, intervening sooner, and monitoring them very closely. We need to continue to be vigilant about [ILD] with this drug, but these were very exciting data.

We certainly have been blessed with so many new approvals and so many new drugs for our patients that we can utilize in clinic. We’re still trying to figure out the best way to sequence these [many] options to further optimize the outcomes for our patients. Bottom line: If we have a patient in the metastatic setting in the first line, we want to think about the taxane/trastuzumab/pertuzumab regimen from the CLEOPATRA study. In the second-line setting, based on the DESTINY-Breast03 trial, if we are thinking about an ADC for a given patient, we have no doubt that we should be thinking about T-DXd over T-DM1 given the delta of benefit that we saw from that study, favoring [T-DXd].

We do have data for patients with active CNS [central nervous system] metastasis. For patients with active CNS metastasis in the second-line setting, we could still justify using tucatinib [Tukysa] and capecitabine and trastuzumab based on the HER2CLIMB trial [NCT02614794]. This is the only trial to date in which we’ve seen PFS and overall survival [OS] benefit, including in patients with active brain metastases. In the third-line and beyond setting, we can figure out ways of utilizing all the other approvals, but we are still focusing on identifying what is the right sequence and what the best agent is to utilize first. There is a lot of excitement, but a lot of work to do still, so we can hopefully cure HER2-positive metastatic disease.

2. Adjuvant abemaciclib combined with endocrine therapy for high-risk early breast cancer: updated efficacy and Ki-67 analysis from the monarchE study.

Design and Updated Findings From the Phase 3 monarchE Trial²

Traina: In the early-stage setting for patients with hormone receptor–positive disease, we have the monarchE [NCT03155997] data, [showing] an impactful benefit in [invasive] disease-free survival from 2 years of adjuvant abemaciclib [Verzenio]. We hope to see longer follow-up and data over time, but [this] is something that is practice changing [because the results from monarchE] led to a new FDA indication for abemaciclib in the adjuvant setting.

3. Efficacy of neratinib plus capecitabine in the subgroup of patients with central nervous system involvement from the NALA trial.

NALA Design and Subgroup Analysis in Patients With Baseline Brain Metastases³

Tripathy: There were some data on neratinib [Nerlynx] with extended follow-up in the metastatic setting, looking at the [agent in patients with] CNS disease. The use of kinase inhibitors, especially potent ones, could, in fact, when they’re used earlier on, lower the number of patients who develop CNS [disease]. We will probably see more extended follow-up from the HER2CLIMB trial in this regard also. There’s already a hint that patients treated with kinase inhibitors may have fewer CNS metastases. That’s an important development, and we look forward to hearing this [about] some of the other drugs that are in testing. Margetuximab-cmkb [Margenza] has recently been approved, and further studies are going on in that area. Of course, we will be looking at CNS metastases from that group as well.

4. Updated results of tucatinib vs placebo added to trastuzumab and capecitabine for patients with previously treated HER2+ metastatic breast cancer with brain metastases (HER2CLIMB).

HER2CLIMB Trial Design and Updated Results in Patients With Brain Metastases⁴

Roesch: Due to the predilection for CNS involvement with HER2-positive breast cancer, therapies that penetrate the blood-brain barrier are certainly desired. Tucatinib is a highly selective HER2-directed tyrosine kinase inhibitor. The combination of tucatinib/trastuzumab/capecitabine received FDA approval in April 2020 for patients with metastatic HER2-positive breast cancer, including those with brain metastases, based on efficacy results from HER2CLIMB. With additional follow-up in those patients with brain metastases, the tucatinib combination resulted in an absolute OS benefit of 9.1 months. There was an improved intracranial response rate and delay in CNS progression, which are meaningful end points for patients.

Furthermore, another abstract presented at SABCS 2021 (PD4-02 abstract 582), with results from TBCRC049 [NCT03501979], demonstrated evidence of clinical benefit with this same regimen (tucatinib/trastuzumab/ capecitabine) in a small number (n = 17) of patients with leptomeningeal disease, with a median OS of 10 months. The concept of prevention of brain metastases is very intriguing, and it will be interesting to see how perhaps earlier use of tucatinib evolves.

5. Elacestrant, an oral selective estrogen receptor degrader (SERD), vs investigator’s choice of endocrine monotherapy for ER+/HER2– advanced/metastatic breast cancer (mBC) following progression on prior endocrine and CDK4/6 inhibitor therapy: results of EMERALD phase 3 trial.

Design and Primary Findings From the EMERALD Trial⁵

Traina: Aditya Bardia, MD, MPH, of Massachusetts General Hospital, shared the results of the EMERALD trial [NCT03778931] in a hormone receptor–positive subset of patients. This randomized trial looked at the first oral selective estrogen receptor degrader, elacestrant, against treatment of physician’s choice, standard-of-care endocrine therapy. Elacestrant performed quite well in terms of efficacy against standard endocrine therapy. It had a well-tolerated AE profile; also, it was compared with fulvestrant [Faslodex] and showed benefit even in patients who previously were exposed to fulvestrant. I see this as another line of endocrine therapy that offers more options for our patients with hormone receptor–positive advanced disease.

6. Trastuzumab deruxtecan (T-DXd; DS-8201a) versus trastuzumab emtansine (T-DM1) in patients (pts) with HER2+ metastatic breast cancer (mBC): subgroup analyses from the randomized phase 3 study DESTINY-Breast03.

Subgroup Analysis From DESTINY-Breast03 in Patients With Baseline Brain Metastases⁶

Dhakal: The subset analyses of the DESTINY-Breast03 trial were presented at the 2021 San Antonio Breast Cancer Symposium [SABCS]. All key subgroups—including hormone receptor status, prior pertuzumab treatment, visceral disease, prior lines of therapy, and patients with brain metastases—were significantly associated with longer PFS and better response rate in the T-DXd arm compared with the T-DM1 arm. Among patients with brain metastasis at baseline, T-DXd was associated with statistically longer PFS vs T-DM1, at 15.0 months vs 3.0 months, respectively, [translating to an] HR of 0.25. The intracranial response rate among patients with baseline brain metastasis in the T-DXd arm was 64% compared with 33% in the T-DM1 arm. This subgroup analysis has demonstrated strong CNS activity with T-DXd.

After the presentation of the above 2 abstracts, T-DXd has become the standard of care for managing metastatic HER2-positive breast cancer with no brain metastasis or stable and treated brain metastasis. Patients with active or untreated brain metastasis were excluded from DESTINY-Breast03.

Tripathy: The update of [the DESTINY-Breast03 trial with] T-DXd was an important [presentation]. [The rate of] ILD, which has been a concern with that drug, was lower in the randomized DESTINY-Breast03 study than it was in the earlier-phase studies. That probably reflects clinician awareness and better selectivity in patients but also more monitoring. When a new toxicity arises like this, we find that if the patient and the care team are aware [of it], we can avert it, hold treatment, and initiate supportive care more quickly. That’s one important feature.

Also important is that we now have more follow-up [from this study] and we can start to look at subgroups, particularly with CNS disease; that has led now to prospective trials looking at that [drug] and other ADCs for controlling CNS disease.

There are some new ADCs, such as trastuzumab duocarmazine, and others are now in clinical testing, such as ARX788. We will be hearing more about [these agents]. There are also bispecific antibodies, and even cell-based therapies, targeting HER2. It’s hard to know which ones will penetrate the blood-brain barrier the most. We used to think that antibodies didn’t, and that the immune therapy and cell-based therapies might not, but we are finding that the tumor microenvironment in brain metastases does contain those elements and that even antibodies can get through, so that’s good news.

It’s really a matter of doing the studies, maybe making all the trials more permissive, so that they can allow patients with brain metastases [to enroll as they did in] HER2CLIMB. We are going to see a trend there, and maybe even some studies within that protocol will have a separate cohort that can be treated for [patients with] leptomeningeal disease.

Roesch: T-DXd is an ADC composed of an anti-HER2 antibody, a cleavable tetrapeptide-based linker, and a topoisomerase 1 inhibitor payload. DESTINY-Breast03 is the first randomized phase 3 study of T-DXd, with interim PFS results demonstrating a 72% reduction in the risk of progression or death with T-DXd compared with T-DM1, which was statistically significant. The median PFS was not reached with T-DXd vs 6.8 months with T-DM1, with an HR of 0.28 and a P value of 7.8 × 10^–22. The dramatic separation of these Kaplan-Meier curves was striking for viewers to see.

The subgroup analyses discussed at SABCS 2021 were those who had evidence of brain metastases at baseline on imaging, comprising approximately 15% of the population. T-DXd demonstrated greater efficacy vs T-DM1 in patients with and without brain metastases, and [we saw] substantial intracranial responses. An intracranial objective response rate of 63.9% was seen with nearly 28% having a complete response in the brain, which is certainly impressive. These data further support T-DXd becoming the new standard of care for second-line HER2-positive metastatic breast cancer treatment in patients who have previously received trastuzumab and a taxane. Additionally, the CNS activity is very intriguing and warrants further exploration.

7. KEYNOTE-522: phase 3 study of neoadjuvant pembrolizumab plus chemotherapy versus placebo plus chemotherapy, followed by adjuvant pembrolizumab versus placebofor early-stage triple-negative breast cancer.

Design and Updated Findings From KEYNOTE-522⁷

Traina: In triple-negative breast cancer [TNBC], the big news is KEYNOTE-522 [NCT03036488]. Here, we saw not only an improvement in pathologic complete response rates from adding pembrolizumab [Keytruda] to neoadjuvant therapy in the early-stage setting, but we saw follow-up with a significant improvement in event-free survival. We’ve been waiting for some time to move the needle and cure rates for women with high-risk, early-stage TNBC, and this KEYNOTE-522 regimen is now a standard of care for patients with at least 2 cm or node-positive TNBC.

8. OlympiA: a phase III, multicenter, randomized, placebo-controlled trial of adjuvant olaparib after (neo)adjuvant chemotherapy in patients with germline BRCA1/2 mutations and high-risk HER2-negative early breast cancer.

Trial Design and Primary Results From the Phase 3 OlympiA Trial⁸

Traina: OlympiA [NCT02032823] is another adjuvant trial where we’re impacting the natural history of the disease. OlympiA has shown us that the use of the PARP inhibitor olaparib [Lynparza] in patients with high-risk, early-stage, germline BRCA–associated breast cancer had a meaningful impact on survival outcomes. That too has become a standard of care for the appropriate patients. Having an awareness of these data [is important], so that our patients are getting access to these drugs that have a meaningful effect on disease outcomes.

9. Intracranial activity of trastuzumab-deruxtecan (T-DXd) in HER2-positive breast cancer patients with active brain metastases: results from the first stage of the phase II TUXEDO-1 trial.

Design and Primary Findings From the Phase 2 TUXEDO-1 Trial⁹

Jhaveri: We have also started to see some early emerging data for utilizing T-DXd in patients with HER2-positive CNS metastases. The TUXEDO-1 trial was also presented [at ESMO 2021], and a Simon 2-stage design was utilized. The first phase of the Simon 2-stage results were presented and the overall response rate was approximately 80% [n = 5/6]. These patients, despite CNS metastases, did derive activity. We’re looking for more data in the patients with CNS metastases, which is an unmet need, and more definitive concrete data for ADCs.

References

1. Cortes J, Kim S, Chung W, et al. LBA1 - 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. Ann Oncol. 2021;32(suppl 5):S1283-S1346. doi:10.1016/annonc/ annonc741
2. Harbeck P, Rastogi P, Martin M, et al. Adjuvant abemaciclib combined with endocrine therapy for high-risk early breast cancer: updated efficacy and Ki-67 analysis from the monarchE study. Ann Oncol. 2021;32(12):1571-1581. doi:10.1016/j.annonc.2021.09.015
3. Hurvitz SA, Saura C, Oliveira M, et al. Efficacy of neratinib plus capecitabine in the subgroup of patients with central nervous system involvement from the NALA trial. Oncologist. 2021;26(8):e1327-e1338. doi:10.1002/onco.13830
4. Lin NU, Murthy RK, Abramson V, et al. Updated results of tucatinib vs placebo added to trastuzumab and capecitabine for patients with previously treated HER2+ metastatic breast cancer with brain metastases(HER2CLIMB). Presented at: 2021 San Antonio Breast Cancer Symposium; December 7-10, 2021; San Antonio, TX. Abstract PD4-04.
5. Bardia A, Neven P, Streich G, et al. Elacestrant, an oral selective estrogen receptor degrader (SERD), vs investigator’s choice of endocrine monotherapy for ER+/HER2-advanced/metastatic breast cancer (mBC) following progression on prior endocrine and CDK4/6 inhibitor therapy:results of EMERALD phase 3 trial. Presented at: 2021 San Antonio Breast Cancer Symposium; December 7-10, 2021; San Antonio, TX. Abstract GS2-02.
6. Hurvitz SA, Kim SB, Chung WP, et al. Trastuzumab deruxtecan (T-DXd) versus trastuzumab emtansine (T-DM1) in patients with HER2+ metastatic breast cancer: subgroup analyses from the randomized phase 3 study DESTINY-Breast03. Presented at: 2021 San Antonio Breast Cancer Symposium; December 7-10, 2021. San Antonio, TX. Abstract GS3-01.
7. Schmid P, Cortes J, Dent R, et al: KEYNOTE-522: Phase 3 study of neoadjuvant pembrolizumab plus chemotherapy versus placebo plus chemotherapy, followed by adjuvant pembrolizumab versus placebo for early-stage triple-negative breast cancer. ESMO Virtual Plenary. Abstract VP7-2021. Presented July 15, 2021.
8. Tutt A, Garber JE, Kaufman B, et al. OlympiA: A phase III, multicenter, randomized, placebo-controlled trial of adjuvant olaparib after (neo)adjuvant chemotherapy in patients with germline BRCA1/2 mutations and high-risk HER2-negative early breast cancer. J Clin Oncol. 2021;39(suppl 15):LBA1. doi:10.1200/JCO.2021.39.15_suppl.LBA1
9. Bartsch R, Berghoff AS, Furtner J, et al. Intracranial activity of trastuzumab- deruxtecan (T-DXd) in HER2-positive breast cancer patients with active brain metastases: results from the first stage of the phase II TUXEDO-1 trial. Ann Oncol. 2021;32(suppl 5):457-515. doi:10.1016/annonc/annonc689