Debu Tripathy, MD, professor, chairman, Department of Breast Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, discusses the implications of results from the phase 3 NALA trial (NCT01808573) in patients with HER2-positive metastatic breast cancer with brain metastases.

NALA explored the use of neratinib (Nerlynx) plus capecitabine (Xeloda) vs lapatinib (Tykerb) and capecitabine in patients with HER2-positive metastatic breast cancer who received 2 or more HER2-directed regimens in the metastatic setting. Among patients who had central nervous system (CNS) metastases at baseline, the median progression-free survival (PFS) was 7.8 months in the neratinib arm compared with 5.5 months in the lapatinib arm. Notably, the CNS progression-free survival was 12.4 months in the neratinib arm vs 8.3 months in the lapatinib arm.

The use of TKIs, particularly in an early setting, could reduce the number of patients who develop CNS disease, Tripathy says. In addition to data from the NALA trial, extended follow-up from the phase 2 HER2CLIMB trial (NCT02614794) could also support that notion, Tripathy adds.

Additional trials are exploring the effects of agents on patients with brain metastases. Ultimately, improving outcomes for patients with CNS disease will remain a priority, Tripathy concludes.

Videos

Debu Tripathy, MD, discusses the implications of results from the phase 3 NALA trial in patients with HER2-positive metastatic breast cancer with brain metastases.

Dr. Tripathy on the NALA Trial in HER2+ Breast Cancer With Brain Metastases

Komal Jhaveri, MD, FACP, medical oncologist, associate member, Breast Medicine and Early Drug Development Service, Memorial Sloan Kettering Cancer Center, discusses the implications of the phase 2 TUXEDO-1 trial (NCT04752059) in patients with HER2-positive metastatic breast cancer with brain metastases.

Fam-trastuzumab deruxtecan-nxki (Enhertu) demonstrated superior efficacy to ado-trastuzumab emtansine (Kadcyla; T-DM1) in the phase 3 DESTINY-Breast03 trial (NCT03529110) in patients with HER2-positive metastatic breast cancer. Now early data are beginning to emerge with the use of trastuzumab deruxtecan from the TUXEDO-1 trial in patients with HER2-positive disease with central nervous system metastases, Jhaveri explains. 

In results presented at the ESMO Congress 2021 from the first phase of the trial’s Simon 2-stage design, 5 of 6 patients achieved an objective response, Jhaveri notes, adding that trastuzumab deruxtecan elicited activity despite the presence of brain metastases.

Treating patients with HER2-positive breast cancer with brain metastases remains an unmet need within the space, and more research is being conducted in this patient population to explore the use of antibody-drug conjugates, Jhaveri concludes.

Komal Jhaveri, MD, FACP, discusses the implications of the phase 2 TUXEDO-1 trial in patients with HER2-positive metastatic breast cancer with brain metastases.

Dr. Jhaveri on the TUXEDO-1 Trial in HER2+ Breast Cancer With Brain Metastases

Tiffany A. Traina, MD, medical oncologist, vice chair, Oncology Care, Department of Medicine, section head, Triple Negative Breast Cancer Clinical Research Program, Memorial Sloan Kettering Cancer Center, discusses the implications of the phase 3 EMERALD trial (NCT03778931) in advanced estrogen receptor (ER)–positive, HER2-negative breast cancer.

EMERALD compared standard-of-care endocrine therapy with elacestrant, which is now the first oral selective ER degrader (SERD) to demonstrate efficacy in patients with ER-positive, HER2-negative disease who previously received CDK4/6 inhibition in a phase 3 trial, Traina says.Data presented at the 2021 San Antonio Breast Cancer Symposium by Aditya Bardia, MD, MPH, of Massachusetts General Hospital, showed the SERD achieved a median progression-free survival of 2.79 months vs 1.91 months with standard endocrine therapy in the intent-to-treat population (HR, 0.697; 95% CI, 0.552-0.880; 

Along with a manageable safety profile, elacestrant elicited responses in patients who had prior exposure to fulvestrant (Faslodex), Traina continues. Elacestrant could expand options for this patient population as an additional line of endocrine therapy, Traina concludes.

Tiffany A. Traina, MD, discusses the implications of the phase 3 EMERALD trial in advanced estrogen receptor–positive, HER2-negative breast cancer.

Dr. Traina on the Effects of Elacestrant in ER+, HER2- Breast Cancer

Komal Jhaveri, MD, FACP, medical oncologist, associate member, Breast Medicine and Early Drug Development Service, Memorial Sloan Kettering Cancer Center, discusses the implications of data from the phase 3 DESTINY-Breast03 trial (NCT03529110) in patients with HER2-positive metastatic breast cancer.

Results from DESTINY-Breast03 demonstrated fam-trastuzumab deruxtecan-nxki (Enhertu) elicited superior progression-free survival (PFS) compared with ado-trastuzumab emtansine (Kadcyla; T-DM1) in patients with previously treated HER2-positive breast cancer. The results showed a hazard ratio for PFS of 0.28 (

), which is unheard of with any treatment that has been approved for breast cancer, Jhaveri says.

Moreover, the adjudication of guidelines for managing interstitial lung disease and pneumonitis, which were notable adverse effects (AEs) observed in the phase 2 DESTINY-Breast01 trial (NCT03248492), helped reduce instances of these AEs in DESTINY-Breast03, Jhaveri notes. No fatal AEs were reported in the phase 3 trial, as clinicians improved the ability to identify and monitor patients most susceptible to these toxicities, Jhaveri concludes.

Komal Jhaveri, MD, FACP, discusses the implications of data from the phase 3 DESTINY-Breast03 trial in patients with HER2-positive metastatic breast cancer.

Dr. Jhaveri on Implications of the DESTINY-Breast03 Trial in HER2+ Breast Cancer

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

, assistant professor, Department of Medicine, University of Rochester Medical Center

, professor and chairman, Department of Breast Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center

, medical oncologist, Memorial Sloan Kettering Cancer Center

, associate staff breast medical oncologist, Cleveland Clinic Taussig Cancer Institute

, 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 Findings

: 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.

: 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.

: 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 

. We really haven’t seen this exciting of an HR or

 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 Trial

: 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 Metastases

: 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 Metastases

: 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 Trial

: 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 Metastases

: 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.

: 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.

: 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 

. 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-522

: 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 

 mutations and high-risk HER2-negative early breast cancer.

Trial Design and Primary Results From the Phase 3 OlympiA Trial

: 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 

–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 Trial

: 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.

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. 

. 2021;32(suppl 5):S1283-S1346. doi:10.1016/annonc/ annonc741

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. 

. 2021;32(12):1571-1581. doi:10.1016/j.annonc.2021.09.015

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. 

. 2021;26(8):e1327-e1338. doi:10.1002/onco.13830

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.

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.

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.

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.

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 

 mutations and high-risk HER2-negative early breast cancer. 

. 2021;39(suppl 15):LBA1. doi:10.1200/JCO.2021.39.15_suppl.LBA1

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. 

. 2021;32(suppl 5):457-515. doi:10.1016/annonc/annonc689

Articles

Leading oncologists in breast cancer share their perspectives on the biggest abstracts that were presented throughout 2021 .

Top 8 Trials From 2021 in Breast Cancer

Updated findings from the phase 3 DESTINY-Breast03 (NCT03529110) and NALA (NCT01808573) trials stand out from 2021 in HER2-positive breast cancer, according to Debasish Tripathy, MD, who explained that not only have the trials solidified the roles of fam-trastuzumab deruxtecan-nxki (Enhertu; T-DXd) and neratinib (Nerlynx) in the metastatic setting but have also provided important data on the safety and potential reach of both regimens.

In the updated analysis of DESTINY-Breast03, with a median follow-up of 15.9 months, the median progression-free survival (PFS) was 15.0 months (95% CI, 12.5-22.2) with T-DXd vs 3.0 months (95% CI, 2.8-5.8) with ado-trastuzumab emtansine (T-DM1; Kadcyla) in patients with baseline brain metastases (HR, 0.25; 95% CI, 0.13-0.45).1 The 12-month PFS rates were 72.0% (95% CI, 55.0%-83.5%) vs 20.9% (95% CI, 8.7%-36.6%), respectively.

The median PFS was not evaluable ([NE]; 95% CI, 22.2-NE) with T-DXd vs 7.1 months (95% CI, 5.6-9.7) with T-DM1 in patients without baseline brain metastases (HR, 0.30; 95% CI, 0.22-0.40). The 12-month PFS rates were 76.5% (95% CI, 70.0%-81.8%) vs 36.4% (95% CI, 29.4%-43.4%), respectively.

Notably, interstitial lung disease (ILD)/pneumonitis, which has been a concern with this drug, said Tripathy, occurred in 10.5% of patients on T-DXd vs 1.9% of patients on T-DM1. Moreover, no grade 4 or 5 drug-related ILD/pneumonitis occurred with T-DXd, which compared favorably with rates from the phase 2 DESTINY-Breast01 trial, in which T-DXdwas associated with ILD in 13.6% of the patients (grade 1 or 2, 10.9%; grade 3 or 4, 0.5%; and grade 5, 2.2%).2

Additionally, in an analysis of NALA, which was published in 

, the combination of neratinib and capecitabine (Xeloda) led to a median PFS of 7.8 months vs 5.5 months with lapatinib (Tykerb) and capecitabine in patients with HER2-positive breast cancer who had central nervous system (CNS) metastases at baseline (HR, 0.66; 95% CI, 0.41-1.05).3 Moreover, CNS-PFS, which was an ad hoc composite end point, was a median of 12.4 months in the neratinib arm vs 8.3 months in the lapatinib arm (HR, 0.62; 95% CI, 0.32-1.18).

“Awareness of these treatment options is critical in how you monitor and follow these patients,” said Tripathy.

, Tripathy, professor and chairman in the Department of Breast Medical Oncology and Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center, provided perspective on some of the key data sets that were presented and published in 2021 in HER2-positive breast cancer.

: Looking across HER2-positive breast cancer, what data stand out to you from 2021?

: The update of [the DESTINY-Breast03 trial with] trastuzumab deruxtecan was one [presentation] that was important. [The rate of] interstitial lung disease, 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] that we can avert it, hold treatment, and initiate supportive care more quickly when we know about it. That’s one important feature.

Then the fact that we now have more follow-up [from this study] and we can start to look at subgroups is important, particularly with CNS disease that has led now to prospective trials looking at that [drug] and other antibody-drug conjugates [ADCs] for controlling CNS disease. There are some new ADCs, such as trastuzumab duocarmazine and others that are now in clinical testing, such as ARX788, for example. We are going to be hearing more about [these agents]. There are also bispecific antibodies, and there are even cell-based therapies targeting HER2. It’s hard to know which ones are going to 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] like [in] HER2CLIMB [NCT02614794]. We are going to see a trend there and maybe even some studies within that protocol that will have a separate cohort that can be treated for leptomeningeal disease.

In terms of CNS disease, what important data sets read out in this population?

There were some data on neratinib, for example, 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 that develop CNS [disease]. We are probably going to see more extended follow-up from the HER2CLIMB trial in this regard, as well. 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 from some of the other drugs that are in testing. Margetuximab-cmkb [Margenza] has recently been approved, and there are further studies going on in that area. Of course, we will be looking at CNS metastases from that group as well.

What are the main implications of these advances on clinical practice, and what should community practitioners take away from the results?

The most important thing is that we have to recognize HER2-positive disease as a distinct entity. It’s well recognized now that all patients with cancer need testing for all receptors, including HER2 receptors, and I would add, that whenever someone has a recurrence of disease that the receptors need to be tested again. Oftentimes, you see conversion of hormone receptor status, usually from positive to negative, but every now and then there may be subclonal collection or subclonal enrichment of patients that may have had a heterogeneous disease that was initially diagnosed as HER2 negative where the HER2-positive subclones survive some of the initial treatment and the recurrence is HER2 positive. It’s critical to do the testing and to follow the American Society of Clinical Oncology and College of American Pathology recommendations and guidelines for testing.

Finally, another important message is that we need to recognize that CNS disease is treatable, and patients can live a long time with CNS disease. The threshold for testing someone with neurologic symptoms needs to be very low. We are not yet advocating routine imaging of the brain in asymptomatic patients, but we know that the frequency is high. Any reported symptoms that could be CNS [related] need to be pursued, followed, and appropriate diagnostics need to be done. That is so important. Diagnose early and treat early. We may be able to get away with less aggressive therapies such as whole brain radiation. When patients present with smaller volume disease, they can get stereotactic radiation and now they may even get systemic therapy first. For example, at our institution, when we see someone with 1 or 2 small CNS lesions, yes, we use stereotactic surgery, but if they have more than 5 or 6 [lesions] or [have lesions] in a location where stereotactic radiation might be contraindicated, we might start with systemic therapy rather than whole brain [radiation] which can cause cognitive adverse effects in a majority of the patients, so we can delay or maybe even forestall for a long period the need for that and the associated declining quality of life, which is a very important metric in this group of patients.

Modi S, Saura C, Yamashita T, et al. Trastuzumab deruxtecan in previously treated HER2-positive breast cancer. 

. 2020;382(7);610-621. doi:10.1056/NEJMoa1914510

Debasish Tripathy, MD, provides perspective on some of the key data sets that were presented and published in 2021 in HER2-positive breast cancer. 

Data With Antibody-Drug Conjugates and TKIs Impress in HER2+ Breast Cancer

The Top 2021 Abstracts in Breast Cancer publication provides expert insights on groundbreaking abstracts in breast cancer, with a focus on HER2-positive breast cancer treatment that were presented at medical meetings throughout 2021.