Homing in on HER2-Targeted Treatment Strategies in Early and Advanced Breast Cancer

Neelima Denduluri, MD, FASCO

Clinical risk continues to guide treatment decisions in early-stage HER2-positive breast cancer, explained Neelima Denduluri, MD, FASCO, who added that the presence of brain metastases has become a driving force for treatment selection in the metastatic setting.

Early-Stage HER2-Positive Breast Cancer

De-escalation

The APT trial evaluated adjuvant paclitaxel and trastuzumab (Herceptin) in patients with small, node-negative tumors. The combination was administered for 12 weeks followed by 1 year of trastuzumab and led to 7-year disease-free survival and relapse-free survival rates of 93.3% and 97.5%, respectively.¹

“This is a wonderful option that is not as toxic as the first-generation trials for our low-risk patients that are node negative with tumors 2 cm or less,” said Denduluri, associate chair of Breast Medical Oncology and medical oncologist, Virginia Cancer Specialists, of the US Oncology Network, in a presentation during a 2020 Institutional Perspectives in Cancer webinar on breast cancer.

The ATEMPT trial was borne out of the APT trial and tested whether T-DM1 could be used as an alternative to trastuzumab/paclitaxel in patients with stage I disease. The results failed to demonstrate noninferior toxicity with T-DM1 compared with trastuzumab/paclitaxel (P = .91). However, the 3-year DFS rate was 97.7% with T-DM^1,2 suggesting that the antibody-drug conjugate could be a suitable alternative for a patient with diabetes who is unable to receive paclitaxel, said Denduluri.

Anthracycline

Anthracyclines have been shown to improve mortality, said Denduluri, but findings from the TRAIN-2 trial suggest that there could be more than 1 suitable chemotherapy backbone in the neoadjuvant setting. In the trial, patients with stage II/III disease were randomized to 5-fluorouracil, epirubicin, and cyclophosphamide followed by paclitaxel and carboplatin, or paclitaxel and carboplatin. Patients in both arms received trastuzumab and pertuzumab (Perjeta) concurrently with all chemotherapy cycles.

The pathologic complete response (pCR) rate was 67% in the anthracycline arm vs 68% in the taxane arm, and the event-free survival rates were 92.7% and 93.5%, respectively (HR, 0.90; 95% CI, 0.50-1.63).³

“These data are very similar to the BCIRG 006 data, which showed that the docetaxel/carboplatin/trastuzumab arm did not seem to be inferior to the anthracycline-containing arm,” said Denduluri. “We now have reassurance that if there’s not a second primary that’s HER2 negative that we can avoid using anthracyclines and spare our patients cardiac toxicity.”

Progress Beyond Trastuzumab

Although trastuzumab has led to improved outcomes, approximately 25% of patients recur. Although the addition of pertuzumab to chemotherapy and trastuzumab led to an improvement in invasive DFS (iDFS) in the APHINITY trial, the benefit was largely restricted to patients with positive nodes, with an absolute benefit in iDFS of 4.5% at 6 years.⁴

“In my practice, for most patients with HER2-positive tumors over 2 cm or node-positive disease, we do discuss preoperative therapy,” said Denduluri. “Generally, if I choose to give pertuzumab in the preoperative setting, I do give the 1 year of pertuzumab, barring any toxicity.”

Failure to achieve to a pCR to neoadjuvant therapy, though still an indicator of poor prognosis, is now also an indication to pursue response-adapted treatment with T-DM1, explained Denduluri. The recommendation is grounded in findings from the phase 3 KATHERINE trial in which patients who did not achieve a pCR to trastuzumab-based therapy and went on receive T-DM1 experienced an 11% improvement in 3-year iDFS versus those who received trastuzumab (HR, 0.50; 95% CI, 0.39-0.64; P < .001).⁵

“The benefit of T-DM1 seemed to be consistent with any residual disease, whether it was T1a, node positive, or node negative, and was irrespective of HER2 status after surgery,” said Denduluri.

Because 17% of node-positive patients did not experience a long-term benefit in iDFS and there was no improvement in CNS recurrence rates with T-DM1, investigators are looking for alternate ways to augment responses. To that end, Denduluri highlighted the COMPASS trial, which is evaluating the addition of tucatinib (Tukysa) to T-DM1, and substitution strategies for T-DM1 with trastuzumab deruxtecan.

With regard to extended adjuvant therapy, 5-year findings from the ExteNET trial showed that an additional year of neratinib (Nerlynx) following prior adjuvant trastuzumab led to an absolute benefit in iDFS of 4.4% in patients with hormone receptor (HR)–positive disease (HR, 0.60; 95% CI, 0.43-0.83; Two-sided P = .002) and an absolute benefit of 7.4% in patients with residual HR-positive disease after neoadjuvant therapy (HR, 0.60; 95% CI, 0.33-1.07).⁶

“In a [2020] exploratory analysis, patients with residual disease after neoadjuvant therapy derived benefit but, additionally, those patients who started the neratinib within a year of completing their adjuvant trastuzumab also seemed to derive about a 5% benefit. We also saw a numerical improvement in the number of CNS recurrences,” said Denduluri.

In practice, Denduluri explained that she reserves neratinib for patients with high-risk cancer, meaning those who have significant residual cancer burden with multiple nodes after receiving trastuzumab, pertuzumab, and T-DM1.

Metastatic HER2-Positive Breast Cancer

There’s not much room for debate when it comes to use of trastuzumab/pertuzumab and a taxane as the frontline standard of care for patients with metastatic HER2-positive breast cancer, explained Denduluri, who stated that patients in the CLEOPATRA trial derived “a significant overall survival benefit” from the regimen. At 8 years, 37% of patients in the experimental arm were still alive compared with 23% of patients in the trastuzumab/taxane arm.⁷

Similarly, T-DM1 largely retains its role as second-line therapy in the absence of significant brain metastases, said Denduluri. However, in the third-line setting, options now include tucatinib, neratinib, trastuzumab deruxtecan, and margetuximab.

Tucatinib was evaluated in the phase 2 HER2CLIMB study and allowed patients with progressive brain metastases to enroll, which comprised approximately 18% of the 48% of patients with brain metastases. The addition of tucatinib to trastuzumab and capecitabine led to about a 2-month improvement in PFS compared with placebo/trastuzumab/capecitabine and about a 4-month improvement in OS in all-comers, as well as about a 5- and 6-month improvement in PFS and OS, respectively, in patients with brain metastases.^8,9

“The PFS in patients [with brain metastases] who received tucatinib versus those that did not was 40% versus 0% at 1 year, and that’s an amazing statistic,” said Denduluri. “The [1-year] OS was also impressive, at 70.1% versus 46.7%, respectively.”

“This has really changed the paradigm in that now I’m telling our radiation oncology colleagues when a patient presents with 7, 8, 9 brain metastases, please don’t give them whole brain radiation. Let’s go ahead and give them a selective TKI, tucatinib, and let’s evaluate their response.”

Neratinib, which was evaluated in the NALA trial in combination with capecitabine showed a benefit in PFS compared with lapatinib (Tykerb) and capecitabine. However, no OS benefit has been reported with current follow-up.¹⁰

Trastuzumab deruxtecan was evaluated in the DESTINY-Breast01 trial and led to not only about a 60% response rate in patients who had received a median of 6 prior lines of therapy, but a median progression-free survival of 16.4 months and an OS that has not been reached with approximately 1 year of follow-up. Among patients with brain metastases, the median PFS was 18.1 months in the exploratory analysis.¹¹

“The main adverse effect we worry about with this drug besides the nausea and alopecia is interstitial lung disease [ILD], and it’s important to remember that it did lead to fatalities, so heightened awareness is very important to recognize,” said Denduluri. “Even with grade 1 [ILD], we should hold the drug and consider multidisciplinary management with our pulmonologist and early implementation of steroids.”

On December 16, 2020, margetuximab-cmkb (Margenza) became the latest addition to the paradigm, receiving approval for use in combination with chemotherapy for patients with metastatic disease who have previously received 2 or more anti-HER2 regimens, at least 1 of which for metastatic disease.¹²

The approval was based on findings from the phase 3 SOPHIA trial in which the Fc-engineered monoclonal antibody plus chemotherapy led to a 24% reduction in the risk of disease progression or death vs trastuzumab in combination with chemotherapy (HR, 0.76; 95% CI, 0.59-0.98; P =.033). The median PFS with margetuximab was 5.8 months vs 4.9 months with trastuzumab. At a median follow-up of 15.6 months, the median OS in the intent-to-treat population was 21.6 months with margetuximab vs 19.8 months with trastuzumab (HR, 0.89; 95% CI, 0.69-1.13; P = .326).¹³ Final OS data are anticipated in the second half of 2021.

“How this translates into clinical practice, we’ll have to see because we will have to have a biomarker to help us use margetuximab effectively,” concluded Denduluri.

References

1. Tolaney SM, Guo H, Pernas S, et al. Seven-year follow-up analysis of adjuvant paclitaxel and trastuzumab trial for node-negative, human epidermal growth factor receptor 2–positive breast cancer. J Clin Oncol. 2019;37(12):1868-1875. doi:10.1200/JCO.19.00066
2. Tolaney SM, Hu J, Dang C, et al. TBCRC 033: A randomized phase II study of adjuvant trastuzumab emtansine (T-DM1) vs paclitaxel (T) in combination with trastuzumab (H) for stage I HER2-positive breast cancer (BC) (ATEMPT). Presented at: 2019 San Antonio Breast Cancer Symposium; December 10-14, 2019; San Antonio, TX. Abstract GS1-05.
3. Three-year follow-up of neoadjuvant chemotherapy with or without anthracyclines in the presence of dual HER2-blockade for HER2-positive breast cancer (TRAIN-2): a randomized phase III trial. J Clin Oncol. 2020;38(15 suppl):501. doi:10.1200/JCO.2020.38.15_suppl.501
4. Piccart M, Procter M, Fumagalli D, et al. Interim overall survival analysis of APHINITY (BIG 4-11): A randomized multicenter, double-blind, placebo-controlled trial comparing chemotherapy plus trastuzumab plus pertuzumab versus chemotherapy plus trastuzumab plus placebo as adjuvant therapy in patients with operable HER2-positive early breast cancer. Presented at: 2019 San Antonio Breast Cancer Symposium; December 10-14, 2019; San Antonio, TX. Abstract GS1-04. https://bit.ly/38XGjSM.
5. Von Minckwitz G, Huang C-S, Mano MS, et al. Trastuzumab emtansine for residual invasive HER2-positive breast cancer. N Engl J Med. 2019;380(7):617-628. doi:10.1056/NEJMoa1814017
6. Chan A, Moy B, Mansi J, et al. Final efficacy results of neratinib in HER2-positive hormone receptor-positive early-stage breast cancer from the phase III ExteNET trial. Clin Breast Cancer. Published online October 5, 2020. doi:10.1016/j.clbc.2020.09.014
7. Swain SM, Miles D, Kim SB, et al. Pertuzumab, trastuzumab, and docetaxel for HER2-positive breast cancer (CLEOPATRA): end-of-study results from a double-blind, randomized, placebo-controlled, phase 3 study. Lancet Oncol. 2020;21(4):519-530. doi:10.1016/S1470-2045(19)30863-0
8. Lin NU, Murthy RK, Anders CK, et al. Tucatinib versus placebo added to trastuzumab and capecitabine for patients with previously treated HER2+ metastatic breast cancer with brain metastases (HER2CLIMB). J Clin Oncol. 2020;38(suppl):1005. doi:10.1200/JCO.2020.38.15_suppl.1005
9. 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
10. Saura C, Oliveira M, Feng Y-H, et al. Neratinib + capecitabine versus lapatinib + capecitabine in patients with HER2+ metastatic breast cancer previously treated with ≥ 2 HER2-directed regimens: findings from the multinational, randomized, phase III NALA trial. J Clin Oncol. 2019;37 (suppl; abstr 1002). doi:10.1200/JCO.2019.37.15_suppl.1002
11. Modi S, Saura C, Yamashita T, et al. Trastuzumab deruxtecan in previously treated her2-positive breast cancer. N Eng J Med. 2020;382(7):610-621 doi:10.1056/NEJMoa1914510
12. MacroGenics announces FDA approval of Margenza for patients with pretreated metastatic HER2-positive breast cancer. News release. MacroGenics, Inc. December 16, 2020. Accessed December 16, 2020. http://bit.ly/3gTMuLq.
13. Rugo HS, Im S-A, Cardoso F, et al. Phase 3 SOPHIA study of margetuximab + chemotherapy vs trastuzumab + chemotherapy in patients with HER2+ metastatic breast cancer after prior anti-HER2 therapies: second interim overall survival analysis. Presented at: 2019 San Antonio Breast Cancer Symposium; December 10-14, 2019; San Antonio, TX. Abstract GS1-02.