Investigators Parse a Crowded Third Line in Relapsed HER2-Positive Metastatic Breast Cancer

OncologyLive, Vol. 22/No. 22, Volume 22, Issue 22

A panel of breast cancer experts shared their insights on 4 recently approved targeted therapies for patients with relapsed HER2-positive metastatic breast cancer.

Multiple targeted therapies including antibody-drug conjugates, tyrosine kinase inhibitors (TKIs), and monoclonal antibodies have been approved by the FDA over the past 2 years for patients with HER2-positive metastatic breast cancer.1 Without comparative sequencing data, clinicians rely on toxicity profiles, lines of prior therapy, and patient characteristics in consider-ing optimal treatments.

Specifically, investigators have reported improved outcomes with several therapies, even in the setting of heavily pretreated metastatic tumors and brain metastases. “The brain is a common site for metastases in HER2-positive disease,” Lee S. Schwartzberg, MD, FACP, said during a recent OncLive Peer Exchange®. “There are population-based studies that suggest that metastases occur at diagno-sis in a fraction of patients, but clearly, as you go further on in the lines of therapy, the brain becomes more at risk for being a new site of disease.”

Joining Schwartzberg were a panel of breast cancer experts, who shared their insights on 4 recently approved targeted therapies for patients with relapsed HER2-positive metastatic breast cancer: tucatinib (Tukysa), fam-trastuzumab deruxtecan-nxki (Enhertu), neratinib (Nerlynx), and margetuximab-cmkb (Margenza). In addition to discussing the data that led to these agents’ approval, they shared their insights on using the agents in clinical practice.

HER2CLIMB (NCT02614794)

On April 17, 2020, the FDA approved tucatinib in combination with trastu-zumab (Herceptin) and capecitabine (Xeloda) for adult patients with advanced unresectable or metastatic HER2-positive breast cancer who have received at least 1 prior anti-HER2–based regimens in the metastatic setting.2 The approval was based on data from the randomized, phase 2 HER2CLIMB trial, in which investigators randomized 612 heavily pretreated patients 2:1 to receive tucatinib or placebo plus trastuzumab and capecitabine. Patients were previously treated with trastuzumab, pertuzumab (Perjeta), and ado-trastuzumab emtansine (T-DM1; Kadcyla).3

“[Tucatinib is] a TKI. It’s very HER2-specific and it doesn’t bind to the HER1 protein that well. It also binds tightly and doesn’t let go, so there’s some thought that once it’s bound, receptor-mediated endo-cytosis occurs and causes clearance of the receptor from the surface,” Vijayakrishna Gadi, MD, PhD, said.

HER2CLIMB showed that adding tucatinib to trastuzumab and capecitabine resulted in better progression-free survival (PFS) and overall survival (OS) compared with placebo.3 At 1 year, the PFS rate was 33.1% in the tucatinib arm vs 12.3% in the placebo arm (HR for disease progression or death, 0.54; 95% CI, 0.42-0.71; P < .001). The median PFS was 7.8 months vs 5.6 months, respectively. At 2 years, the OS rate was 44.9% in the tucatinib HER2CLIMB showed that adding tucatinib to trastuzumab and capecitabine resulted in better progression-free survival (PFS) and overall survival (OS) compared with placebo.3 At 1 year, the PFS rate was 33.1% in the tucatinib arm vs 12.3% in the placebo arm (HR for disease progression or death, 0.54; 95% CI, 0.42-0.71; P < .001). The median PFS was 7.8 months vs 5.6 months, respectively. At 2 years, the OS rate was 44.9% in the tucatinib.

The panelists noted that HER2CLIMB has a unique trial design because it allowed patients with brain metastases were allowed to enroll. “Half the patients had brain metastases, and of the patients with the brain metastases, a large fraction had untreated and progressing brain metastases,” Gadi said. “This is the first study of a large size to randomize and [evaluate] such a patient cohort. It was a big risk in some regards, but the [investigators] were rewarded.”

Specifically, among the patients with brain metastases, the PFS rate at 1 year was 24.9% in the tucatinib arm compared with 0% in the placebo arm (HR, 0.48; 95% CI, 0.34-0.69; P < .001), with a median PFS of 7.6 months vs 5.4 months, respectively.

Crossover from the placebo arm to the tucatinib arm was permitted after the primary analysis. In an updated analysis with a median follow-up of 29.6 months, the OS and PFS benefit with tucatinib were maintained.4 The median OS was 24.7 months in the tucatinib arm vs 19.2 months in the placebo arm (HR, 0.73; 95% CI, 0.59-0.90; P = .004); the median PFS was 7.6 months vs 4.9 months, respectively (HR, 0.57; 95% CI, 0.47-0.70; P < .0001).

In an exploratory analysis of the 291 enrolled patients with brain metastases (198 in the tucatinib arm and 93 in the control arm), the addition of tucatinib to trastuzumab and capecitabine doubled the intracranial objective response rate (ORR; 47.3% vs 20.0%; P = .03). Tucatinib also reduced the risk of intracranial progression or death by 68% (HR, 0.32; 95% CI, 0.22-0.48; P < .0001) and the risk of death by almost 50% (HR, 0.58; 95% CI, 0.40-0.85; P = .005).5

“The study was, in my opinion, wildly positive. Not only did the median survivals push out—median OS, median PFS, etc—but they hit landmarks,” Gadi said. “When you follow those curves along the way and start looking at landmarks at 12 months, 18 months, etc, the curves stay apart and are meaningfully different at those time points. This seems like a not-so-gentle push, but some patients may see some long-term benefits from this.”

Overall, treatment with tucatinib was well tolerated, with a low rate of discontinuation due to adverse effects (AEs) and no new safety signals observed with longer follow-up.3,4 The most common AEs in the tucatinib arm included diarrhea, palmar-plantar erythrodysesthesia, nausea, fatigue, and vomiting. Diarrhea and elevated aminotransferase levels of grade 3 or higher were more common in the tucatinib arm than in the placebo arm.

Based on positive data for tucatinib in heavily pretreated patients, the agent is under investigation in earlier settings. “There’s a trial that the Alliance for Clinical Trials in Oncology is running called CompassHER2 RD [NCT04457596], which is looking at adding tucatinib to T-DM1 in patients with residual disease after neoadjuvant therapy. That trial is open and enrolling now,” Lisa A. Carey, MD, FASCO, said.

DESTINY-BREAST01 (NCT03248492)

On December 20, 2019, the FDA granted accelerated approved to trastuzumab deruxtecan for patients with unresectable or metastatic HER2-positive breast cancer who received at least 2 previous anti-HER2–based regimens in the metastatic setting.6 The approval was based findings from the open-label, single-group, multicenter, phase 2 DESTINY-Breast01 study, which evaluated trastuzumab deruxtecan in 184 heavily pretreated adults with pathologically documented HER2-positive metastatic breast cancer who had previously received T-DM1.7 Trastuzumab deruxtecan is an antibody-drug conjugate composed of an anti-HER2 antibody, a cleavable tetrapeptide-based linker, and a cytotoxic topoisomerase I inhibitor.

In the intention-to-treat analysis, after a median follow-up of 11.1 months (range, 0.7-19.9 months), investigators observed a response to therapy in 112 patients (60.9%; 95% CI, 53.4%-68.0%). The median duration of response was 14.8 months (95% CI, 13.8-16.9) and the median PFS was 16.4 months (95% CI, 12.7-not reached).7 In an updated analysis that had a median follow-up of 20.5 months (range, 0.7-31.4 months), the confirmed ORR with trastuzumab deruxtecan was 61.4% (95% CI, 54.0%-68.5%), with complete responses in 6.5% of patients (n = 12), partial responses in 54.95% (n = 101), and stable disease in 35.9% (n = 66).8 The median duration of response was 20.8 months, the median PFS was 19.4 months, and an estimated 74% of patients were alive at 18 months (95% CI, 67%-80%).

“As we look at how far we’ve come in the treatment of HER2-positive disease, seeing patients survive this far out after receiving prior therapies—the median was 6—it’s impressive to see these results,” Reshma Mahtani, DO, said. She noted, however, that toxicities are a concern with trastuzumab deruxtecan.

The most common grade 3 or higher AEs included a decreased neutrophil count (20.7%), anemia (8.7%), and nausea (7.6%).7 Most disconcerting was that trastuzumab deruxtecan was associated with interstitial lung disease (ILD) and pneumonitis.7,8 Most cases of ILD and pneumonitis occurred during the first 12 months of treatment; thus, there is no indication that the risk of developing these toxicities increases with cumulative treatment.

Carey noted that clinicians are more accepting of toxicities when their patients have few treatment options but that such toxicities may be more problematic in earlier lines, particularly when there is curative intent. Subsequently, she said that clinical trial designs may need to start distinguishing between the various subgroups of patients with metastatic disease. “The nature of the disease, in the metastatic setting, may change dramatically as patients with recurrent disease have received 3, 4, or 5 agents prior to recurrence. But that also means that an increasing proportion of the metastatic population is the de novo group, who are completely naïve. As we design trials, we may have to be explicit about stratifying those 2 groups because they used to be a little different—having been exposed to 1 anti-HER2 drug vs not. It’s going to be a different kettle of fish,” Carey said.

Despite its toxicity risks, trastuzumab deruxtecan is making progress moving to earlier treatment lines. On October 4, 2021, the FDA granted this agent a breakthrough therapy designation for patients with HER2-positive metastatic breast cancer treated who have received at least 1 prior antiHER2–based regimen.9 This designation was based on data from DESTINY-Breast03 (NCT03529110), which showed a highly statistically significant and clinically meaningful improvement in PFS with trastuzumab deruxtecan vs T-DM1 in patients previously treated with trastuzumab and a taxane for HER2-positive metastatic breast cancer.10

According to data from the first head-to-head trial of the antibody-drug conjugate, the median PFS for patients treated with trastuzumab deruxtecan was not reached (95% CI, 18.5-not estimable [NE]) vs 6.8 months (95% CI, 5.6-8.2) with T-DM1 (HR, 0.28; 95% CI, 0.22-0.37; P = 7.8 × 10-22). Among the 261 patients in the trastuzumab deruxtecan arm the 12-month PFS rate was 75.8% (95% CI, 69.8%-80.7%) vs 34.1% (95% CI, 27.7%-40.5%) among the 263 patients treated in the T-DM1 arm.

The median OS was NE in both arms (HR, 0.56; 95% CI, 0.36-0.86; P = .007172). The 12-month OS rates were 94.1% (95% CI, 90.3%-96.4%) vs 85.9% (95% CI, 80.9%-89.7%), respectively.10

NALA (NCT01808573)

On February 25, 2020, the FDA approved neratinib in combination with capecitabine for adult patients with advanced or metastatic HER2-positive breast cancer who have received at least 2 prior anti-HER2–based regimens in the metastatic setting.11 The agency granted approval based on data from the randomized phase 3 NALA trial, which compared neratinib plus capecitabine with lapatinib (Tykerb) plus capecitabine, the previous standard of care, in 621 patients.12 The study included patients with asymptomatic central nervous system (CNS) disease.

“Neratinib, another TKI, [it’s] different from tucatinib in the sense that it’s [an irreversible] pan-HER TKI, it’s slightly older, and it was released earlier,” Schwartzberg said. In contrast, lapatinib is a reversible dual TKI.

Patients in the neratinib arm showed significantly improved PFS (HR, 0.76; 95% CI, 0.63-0.93; stratified log-rank P = .0059), which Schwartzberg said amounted to an approximate 2.2-month improvement. The ORR was 32.8% in the neratinib arm and 26.7% in the lapatinib arm, with a median duration of response of 8.5 months vs 5.6 months, respectively. Fewer interventions for CNS disease occurred in the neratinib arm than in the lapatinib arm (cumulative incidence, 22.8% vs 29.2%; P = .043).

Overall, neratinib was well tolerated. The most common all-grade AEs included diarrhea (83% in the neratinib arm vs 66% in the lapatinib arm) and nausea (53% vs 42%, respectively). Treatment discontinuation rates were similar between the groups.

“There are 2 new, active regimens that we see with tucatinib and trastuzumab deruxtecan,” Schwartzberg said. “In my mind, the neratinib-capecitabine would come afterward. It might be considered for fourth-line therapy, particularly in a patient who had previous exposure to a TKI and showed benefit.”

SOPHIA (NCT02492711)

On December 16, 2020, the FDA approved margetuximab in combination with chemotherapy for adult patients with metastatic HER2-positive breast cancer who have received at least 2 prior anti-HER2 regimens, at least 1 of which was for metastatic disease.13 The agency’s decision was based on results from the SOPHIA trial, which randomly assigned 536 patients with pretreated HER2-positive advanced breast cancer to receive margetuximab plus chemotherapy (n = 266) or trastuzumab plus chemotherapy (n = 270).14

Margetuximab is a fragment crystallizable (Fc)-engineered, immune-activating, HER2-directed monoclonal antibody.14 “What’s interesting about margetuximab is that it may be the first of other drugs in this class [for which] we’re not looking at combining a chemotherapy through an ADC gene, such as trastuzumab deruxtecan, but there’s engineering of the intrinsic antibody molecule,” Schwartzberg said. “Margetuximab differs from trastuzumab because the Fc region of the antibody was engineered to increase allele activity, which the margetuximab binds to.”

Updated data for SOPHIA showed that margetuximab elicited a median PFS of 5.8 months vs 4.9 months with placebo (HR, 0.76; 95% CI, 0.59-0.98; P = .033).14 The confirmed ORR was 22% in the margetuximab arm vs 16% in the trastuzumab arm, with a median duration of response of 6.1 months and 6.0 months, respectively. An exploratory PFS analysis by CD16A genotype suggested that the presence of a CD16A-158F allele may predict margetuximab benefit over trastuzumab. In the SOPHIA trial, patients who were homozygous for the CD16A-158VV allele (15% of participants) received no benefit from margetuximab. “The different magnitude of benefit among the different alleles is interesting. I was surprised that [margetuximab] wasn’t approved based on any genotyping,” Mahtani said.

Schwartzberg said he would consider margetuximab as a fourth- or fifth-line choice for his patients with metastatic HER2-positive breast cancer, despite it being unclear whether the efficacy of this treatment might be affected by previous tucatinib or trastuzumab deruxtecan use. “We don’t have the data there, but we can extrapolate and say that because they’re novel agents, we can probably use them,” he said.

Carey said that the natural direction for margetuximab would be as a replacement for trastuzumab in patients with the low-affinity phenotype, as trastuzumab appears to be more efficacious in the setting of high-affinity alleles, but that the data to support this have yet to emerge. She noted that the Translational Breast Cancer Research Consortium’s phase 2 MARGOT trial (NCT04425018) will help guide the use of margetuximab.15 “[The trial is] directly comparing chemotherapy plus trastuzumab vs chemotherapy plus margetuximab, with a PCR [polymerase chain reaction] end point looking at the additional data, but only in low-affinity allele types,” she said. MARGOT is currently recruiting patients.

References

  1. Martínez-Sáez O, Prat A. Current and future management of HER2-positive metastatic breast cancer. JCO Oncol Pract. 2021;17(10):594-604. doi:10.1200/OP.21.00172
  2. FDA approves tucatinib for patients with HER2-positive metastatic breast cancer. FDA. Updated April 20, 2020. Accessed October 25, 2020. bit.ly/3v0xmD2
  3. Murthy RK, Loi S, Okines A, et al. Tucatinib, trastuzumab, and capecitabine for HER2-positive metastatic breast cancer. N Engl J Med. 2020;382(7):597-609. Published correction in N Engl J Med. 2020;382(6):586.
  4. Curigliano G, Mueller V, Borges VF, et al. Updated results of tucatinib versus placebo added to trastuzumab and capecitabine for patients with pretreated HER2+ metastatic breast cancer with and without brain metastases (HER2CLIMB). J Clin Oncol. 2021;39(suppl 15):1043. doi:10.1200/ JCO.2021.39.15_suppl.1043
  5. Lin NU, Borges V, Anders C, et al. Intracranial efficacy and survival with tucatinib plus trastuzumab and capecitabine for previously treated HER2-positive breast cancer with brain metastases in the HER2CLIMB trial. J Clin Oncol. 2020;38(23):2610-2619. doi:10.1200/JCO.20.00775
  6. FDA approves fam-trastuzumab deruxtecan-nxki for unresectable or metastatic HER2-positive breast cancer. FDA. December 20, 2019. Accessed October 25, 2021. bit.ly/3AqU7Rz
  7. Modi S, Saura C, Yamashita T, et al; DESTINY-Breast01 Investigators. Trastuzumab deruxtecan in previously treated HER2-positive breast cancer. N Engl J Med. 2020;382(7):610621. doi:10.1056/NEJMoa1914510
  8. Enhertu continues to demonstrate durable responses with new data from DESTINY-Breast01 in HER2-positive metastatic breast cancer. News release. AstraZeneca. December 10, 2020. Accessed October 25, 2021. bit.ly/3FAQk8b
  9. Enhertu granted Breakthrough Therapy Designation in US for patients with HER2-positive metastatic breast cancer treated with one or more prior anti-HER2-based regimens. News release. AstraZeneca. October 4, 2021. Accessed October 25, 2021. bit.ly/3a5We2B
  10. Cortés J, Kim SB, Chung WP, et al. Trastuzumab deruxtecan (T-DXd) vs trastuzumab emtansine (T-DM1) in patients with HER2+ metastatic breast cancer (mBC): results of the randomized, phase III study DESTINY-Breast03 study. Ann Oncol. 2021;32(suppl 5):S1287-S1288. doi:10.1016/j.annonc.2021.08.2087
  11. FDA approves neratinib for metastatic HER2-positive breast cancer. FDA. Updated February 26, 2020. Accessed October 25, 2021. bit.ly/3BvNAGB
  12. Saura C, Oliveira M, Feng YH, et al; NALA Investigators. Neratinib plus capecitabine versus lapatinib plus capecitabine in HER2-positive metastatic breast cancer previously treated with ≥ 2 HER2-directed regimens: phase III NALA trial. J Clin Oncol. 2020;38(27):3138-3149. doi:10.1200/JCO.20.00147
  13. FDA approves margetuximab for metastatic HER2-positive breast cancer. FDA. Updated December 17, 2020. Accessed October 25, 2021. bit.ly/3iQesKk
  14. Rugo HS, Im SA, Cardoso F, et al; SOPHIA Study Group. Efficacy of margetuximab vs trastuzumab in patients with pretreated ERBB2-positive advanced breast cancer: a phase 3 randomized clinical trial. JAMA Oncol. 2021;7(4):573-584. doi:10.1001/ jamaoncol.2020.7932
  15. MARGetuximab or trastuzumab (MARGOT). ClinicalTrials.gov. Updated September 16, 2021. Accessed October 25, 2021.