Multiple Combinations Show Efficacy for Firstand Second-line HER2-Positive Breast Cancer

Joyce A. O’Shaughnessy, MD

During a Targeted Oncology Case-Based Roundtable event, Joyce A. O’Shaughnessy, MD, co-chair, Breast Cancer Research ay Baylor University Medical Center, and chair, Breast Cancer Prevention Research at Texas Oncology of the US Oncology Network, discussed the case of a 63-year-old woman with HER2-positive breast cancer.

Targeted Oncology™: What are you most likely to recommend to this patient?

O’SHAUGHNESSY: In 2020, the NCCN [National Comprehensive Cancer Network guidelines] said that for HER2-positive metastatic breast cancer, THP was the preferred first-line therapy.¹ But they didn’t have a preferred second-line therapy; they just gave a list: T-DM1; tucatinib [Tukysa], trastuzumab, capecitabine [Xeloda; the tucatinib triplet]; trastuzumab deruxtecan [Enhertu, T-DXd]; and others. They noted that tucatinib, trastuzumab, and capecitabine was supported by level 1 evidence from a prospective phase 3 study of patients who had [received] pertuzumab.²

[They also noted that] T-DM1 was supported by level 2A evidence from a study that predated pertuzumab.³ This year, [the guidelines] changed.⁴ The preferred first-line regimen is [still] THP, but now the second-line regimen is T-DM1, [supported by] level 1 evidence.5 Regarding the tucatinib triplet and T-DXd, these regimens “may be used as [a] third- or fourth-line option; the optimal sequence for third-line therapy and beyond is not known.”

According to NCCN guidelines, T-DXd is contraindicated in patients with active pneumonitis or a history of drug-induced pneumonitis, [but it] is preferred in patients with visceral metastasis if they progress on T-DM1. Tucatinib, trastuzumab, and capecitabine is preferred in patients with both systemic and CNS progression on T-DM1.⁵ This patient progressed systemically with visceral disease, but she did not progress in her CNS.

What is the mechanism of action of T-DXd?

This is an antibody-drug conjugate. It is trastuzumab conjugated by a cleavable linker to deruxtecan, a topoisomerase I inhibitor.^5,6 For every molecule of trastuzumab, there are 7 or 8 molecules of deruxtecan. It’s very heavily loaded. The linker can be cleaved in the acidic environment of the tumor interstitium, [unlike] T-DM1, which has to be internalized [before] the emtansine comes off the trastuzumab.^7,8

[This is why T-DM1] only kills the cell [it enters]. Because T-DXd can be cleaved in the interstitium, the lipophilic deruxtecan can diffuse to a neighboring cell, go through the cytoplasmic membrane and the nuclear membrane, and get into the nucleus and mess up the DNA. It can kill a neighboring cell, even if the neighboring cell has zero HER2 on it. If the cell dies, the deruxtecan can come out of that cell and go to [another] cell. That bystander effect is very handy, because not every cell is strongly HER2-positive.⁹

How did T-DXd perform in the DESTINY-Breast01 trial?

There were 184 patients in the DESTINY-Breast01 phase 2 trial [NCT03248492] who received 5.4 mg/kg intravenously every 3 weeks. Of this group, all patients were HER2 positive, 53% were ER positive, and 13% had a history of brain metastasis. The group had a median of 6 prior lines of therapy. The primary end point was response rate.¹⁰

The objective response rate was 61.4%; the median duration of response was 20.8 months [95% CI, 15.0- not estimable (NE)]. This is an amazing level of activity. Furthermore, the median progression-free survival [PFS] of 19.4 months [95% CI, 14.1-NE] in a heavily pretreated population is remarkable. About 40% of the patients are still progression free [close to] the 2-year mark. Likewise, overall survival [OS] was impressive. Median OS was 24.6 months [95% CI, 23.1-NE], and there are still patients [surviving more than] 2 years.¹¹

The main thing we have to watch out for with T-DXd is interstitial lung disease [ILD]. In the DESTINY-Breast01 trial, [the percentage of patients with] any-grade ILD was 15.2%; for grade 1, [the percentage] was 3.3%; for grade 2, 8.7%; for grade 3, 0.5%; for grade 4, 0.0%; [and for grade 5, 2.7%]. We’re hoping that doctors are aware of this and will [act promptly] and ask the patient all the time whether they have cough, fever, [or] shortness of breath. This will catch ILD earlier and [allow treatment with] steroids right away. Being of Asian ethnicity is a risk factor, as is the degree of pretreatment.10 We’re not going to be using this 10th line. We’re going to be using this earlier, with higher doses.

How did the tucatinib triplet perform in the HER2CLIMB trial?

The decision we make [in the] third line [of therapy] is T-DXd versus the tucatinib triplet. The HER2CLIMB trial [NCT02614794] examined the performance of the tucatinib triplet. These patients were pretreated with trastuzumab, pertuzumab, and T-DM1. They could have asymptomatic, untreated, newly diagnosed, or progressing brain metastases. [That] is really interesting: Postpone the radiation, do systemic therapy, and see if we can get control of the brain without radiation therapy. These patients were randomly assigned to receive either placebo or tucatinib [at 300 mg twice a day], plus capecitabine [at 1000 mg/m2 twice a day, days 1-14] and trastuzumab [at 8 mg/kg loading, then 6 mg/kg, every 3 weeks]. The primary end point was PFS.²

Median PFS was 7.8 months with tucatinib [95% CI, 7.5-9.6] versus 5.6 months with placebo [95% CI, 4.2-7.1]. The hazard ratio for disease progression or death was 0.54 [95% CI, 0.42-0.71; P < .001]. The surprise from this trial was the significant improvement in [median] OS: 21.9 months [95% CI, 18.3-31.0] vs 17.4 months [95% CI, 13.6-19.9]. The hazard ratio for death was 0.66 [95% CI, 0.50-0.88; P < .005]. At 2 years, [about] 45% of patients who received tucatinib were alive versus 27% of patients who received placebo. This is very nice level 1 evidence of survival advantage in a prospective phase 3 trial.³

The main adverse effect with the tucatinib triplet was diarrhea of grade 3 or higher, [which occurred in about] 13% [versus 9%] of patients. This was all manageable; for example, grade 3 diarrhea for 1 day. Grade 3 or higher aspartate transaminase elevation occurred in 4.5% [vs 0.5%] of patients and grade 3 or higher alanine transaminase elevation occurred in 5.4% [vs 0.5%] of patients. There was a little bit more hand-foot syndrome [palmar-plantar erythrodysesthesia; for grade 3 or higher, about 13% vs 9%], but it was quite manageable. Only about 6% [vs 3%] of patients stopped the therapy because of any toxicity.³

In light of this patient’s CNS status and the NCCN guidelines, can you reflect on how T-DXd and the tucatinib triplet each performed with respect to CNS response?

In the DESTINY-Breast01 trial [of T-DXd], 24 [13%] of the patients had stable, asymptomatic, treated brain metastases at study entry.¹⁰ They had 6 prior lines of therapy, the same as the total population. The median PFS [of the CNS subgroup] was 18.1 months [95% CI, 6.7-18.1].^10,12 The median PFS of the overall population was 19.4 months [95% CI, 14.1-NE],¹¹ basically the same. The objective response rate for the 24 [CNS] patients was 58% [95% CI, 36.6-77.9%]¹²; for the overall population, it was 61%.¹¹ In the CNS subgroup, 33% had progression of disease, pretty close to 26% in the overall population.¹² The most common sights of progression for both populations were lung, liver, and lymph nodes. Progression involving the brain occurred in only 4 of 48 patients. Only 4 [instances of progression] involved brain progression, including 2 of the 8 patients who had baseline CNS metastases.12 This group of 24 patients, with stable treated brain metastases, did just as well as the overall population.

[Remember that] in the HER2CLIMB trial, about 48% of the patients entered the study with a presence or history of brain metastases. Of these, about 40% were stable treated, 22% were untreated, and 37% were treated but progressing.³

So, they could look at the intracranial CNS response. The [confirmed objective] response rate [for the tucatinib group] was 47.3% [95% CI, 33.7%-61.2%] versus 20.0% for the placebo group [95% CI, 5.7%-43.7%; stratified P = .03].¹² The duration of response was 6.8 months [95% CI, 5.5-16.4] versus 3.0 months [95% CI, 3.0-10.3]. That’s really good.

In the patients with brain metastases, the survival data are quite good. With tucatinib, the hazard ratio for disease progression or death was 0.45 [95% CI, 0.33- 0.62; P < .001]. The hazard ratio for death was 0.58 [95% CI, 0.40-0.85; P = .005].³ That’s quite impressive. The data are quite impressive for the survival advantage with the tucatinib; also, in the trial of T-DXd, the CNS subgroup had basically the same results as the overall population.

_References:

_{1. NCCN. Clinical Practice Guidelines in Oncology. Breast cancer, version 5.2020. Accessed May 19, 2021. https://bit.ly/342mzeR}

_{2. 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. doi:10.1056/NEJMoa1914609}

_{3. Verma S, Miles D, Gianni L, et al; EMILIA Study Group. Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med. 2012;367(19):1783-1791. doi:10.1056/NEJMoa1209124}

_{4. NCCN. Clinical Practice Guidelines in Oncology. Breast cancer, version 4.2021. Accessed May 19, 2021. https://bit.ly/3hInaKE}

_{5. Nakada T, Sugihara K, Jikoh T, Abe Y, Agatsuma T. The latest research and development into the antibody-drug conjugate, [fam-] trastuzumab deruxtecan (DS-8201a), for HER2 cancer therapy. Chem Pharm Bull (Tokyo). 2019;67(3):173-185. doi:10.1248/cpb.c18-00744}

_{6. Ogitani Y, Aida T, Hagihara K, et al. DS-8201a, a novel HER2-targeting ADC with a novel DNA topoisomerase I inhibitor, demonstrates a promising antitumor efficacy with differentiation from T-DM1. Clin Cancer Res. 2016;22(20):5097-5108. doi:10.1158/1078-0432.CCR-15-2822}

_{7. Lewis Phillips GD, Li G, Dugger DL, et al. Targeting HER2-positive breast cancer with trastuzumab-DM1, an antibody-cytotoxic drug conjugate. Cancer Res. 2008;68(22):9280-9290. doi:10.1158/0008-5472.CAN-08-1776}

_{8. Erickson HK, Park PU, Widdison WC, et al. Antibody-maytansinoid conjugates are activated in targeted cancer cells by lysosomal degradation and linker-dependent intracellular processing. 2006;66(8):4426- 4433. doi:10.1158/0008-5472.CAN-05-4489}

_{9. Ogitani Y, Hagihara K, Oitate M, Naito H, Agatsuma T. Bystander killing effect of DS-8201a, a novel anti-human epidermal growth factor receptor 2 antibody-drug conjugate, in tumors with human epidermal growth factor receptor 2 heterogeneity. Cancer Sci. 2016;107(7):1039-1046. doi:10.1111/cas.12966}

_{10. 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):610-621. doi:10.1056/NEJMoa1914510}

_{11. Modi S, Saura C, Yamashita T, et al. Updated results from DESTINYbreast01, a phase 2 trial of trastuzumab deruxtecan (T-DXd) in HER2 positive metastatic breast cancer. Paper presented at: 2020 San Antonio Breast Cancer Symposium; December 6-10, 2020; virtual. Accessed May 19, 2021. https://bit.ly/3ofKAIC}

_{12. Jerusalem G, Park YH, Yamashita T, et al. 138O CNS metastases in HER2-positive metastatic breast cancer treated with trastuzumab deruxtecan: DESTINY-Breast01 subgroup analyses. Ann Oncol. 2020;31(suppl 2):S63- S64. doi:10.1016/j.annonc.2020.03.239}