Navigating the Changing Landscape in HER2-Positive Breast Cancer

The paradigm for treating patients with HER2-positive breast cancer is changing throughout the spectrum of the disease as a result of recent clinical trial findings regarding novel and established treatment regimens, according to Sara A. Hurvitz, MD

Sara A. Hurvitz, MD, an associate professor at the David Geffen School of Medicine and medical director of the Jonsson Comprehensive Cancer Center Clinical Research Unit at the University of California, Los Angeles

Sara A. Hurvitz, MD, an associate professor at the David Geffen School of Medicine and medical director of the Jonsson Comprehensive Cancer Center Clinical Research Unit at the University of California, Los Angeles

Sara A. Hurvitz, MD

The paradigm for treating patients with HER2-positive breast cancer is changing throughout the spectrum of the disease as a result of recent clinical trial findings regarding novel and established treatment regimens, according to Sara A. Hurvitz, MD. The focus on new strategies is needed because of the aggressive nature of the HER2- positive subtype; although trastuzumab (Herceptin) has substantially improved outcomes for this patient populations, approximately 25% of patients with earlystage disease will experience relapse within 10 years of a curative-intent, trastuzumab-based chemotherapy regimen.1 “For these reasons, multiple HER2-targeted therapies have been and are being developed to improve outcomes associated with this aggressive type of cancer,” Hurvitz, medical oncologist and medical director, Clinical Research Unit for the University of California, Los Angeles Jonsson Comprehensive Cancer Center, told OncLive®. “Understanding how and when to use each of these drugs is critical as we strive to optimize outcomes for our patients.”

Early-Stage Disease

There have been many data presented relating to neoadjuvant and adjuvant treatment for patients with HER2-positive breast cancer—–including data for trastuzumab, pertuzumab (Perjeta), neratinib (Nerlynx), and ado-trastuzumab (T-DM1; Kadcyla)–– which have contributed to practice changes (Table 12-6). In an interview ahead of the 37th Annual Miami Breast Cancer Conference® (MBCC), Hurvitz previewed a few notable studies. “At the conference I will be reviewing practice-changing trial data from studies including KATHERINE, APHINITY, ExteNET, APT, and ATEMPT and will present a strategy for selection of optimal curative-intent neoadjuvant and/or adjuvant therapy for HER2-positive, early-stage disease,” Hurvitz explained.

In the phase III, open-label KATHERINE trial (NCT01772472), 1486 patients with HER2-positive, early-stage breast cancer and residual invasive disease at surgery following neoadjuvant therapy containing a taxane and trastuzumab were randomized to receive adjuvant T-DM1 or trastuzumab for 14 cycles.1 At the interim analysis, invasive disease or death was reported in 12.2% of patients receiving T-DM1 and in 22.2% of patients receiving trastuzumab. Patients in the T-DM1 group had significantly higher invasive disease-free survival (iDFS) compared with patients in the trastuzumab group (HR, 0.50; 95% CI, 0.39-0.64; P <.001). Distant recurrence as the first invasive disease event occurred in fewer patients receiving T-DM1 compared with trastuzumab (10.5% vs 15.9%, respectively). More adverse events (AEs) were associated with T-DM1 compared with trastuzumab; however, no new safety signals were reported.

Based on these data, the FDA approved T-DM1 for use as an adjuvant treatment for patients with HER2-positive early breast cancer who have residual invasive disease following neoadjuvant trastuzumab and chemotherapy. The agent was approved in May 2019 under the FDA’s Real-Time Oncology Review and Assessment Aid pilot program.7

Click to Enlarge

In the phase III ExteNET trial (NCT00878709), 2840 women with earlystage, HER2-positive breast cancer who completed trastuzumab-based adjuvant therapy were randomized to receive 12 months of neratinib 240 mg/day or placebo. In a 5-year analysis, patients who received neratinib had significantly fewer disease-free survival events (HR, 0.73; 95% CI, 0.57-0.92; P = .0083) and a higher 5-year iDFS rate (90.2% vs 87.7%) compared with those who received placebo.3 Treatment-emergent serious AEs were reported in 7% of women treated with neratinib and in 6% of women who received placebo, with no evidence of increased risk of long-term toxicity or adverse consequences of neratinib-associated diarrhea. Prophylaxis was not mandated by the study protocol.

The phase II APT trial (NCT00542451) included 410 patients with HER2-positive breast cancer with tumors 3 cm or smaller and negative nodes who received paclitaxel with trastuzumab for 12 weeks followed by 9 months of trastuzumab.4 The 3-year iDFS rate was 98.7%. Among 13 patients who experienced significant asymptomatic declines in ejection fraction, 11 were able to resume trastuzumab following a brief treatment interruption. In an analysis of the APT trial, the 7-year iDFS was 93%, the 7-year overall survival (OS) was 95%, and the 7-year recurrence-free interval was 97.5%.5 These data demonstrate excellent long-term outcomes with adjuvant paclitaxel and trastuzumab, along with a similar subtype distribution in small HER2-positive tumors compared with larger tumors, according to Hurvitz.

In the ATEMPT trial (NCT01853748), 497 patients with early-stage HER2-positive breast cancer were randomized to receive T-DM1 (3.6 mg/kg; 17 cycles) or 80 mg/m2 paclitaxel plus 2 mg/kg trastuzumab for 12 cycles, followed by 6 mg/kg trastuzumab every 3 weeks for 13 cycles.6 The 3-year iDFS rate was 97.7% among patients who received T-DM1 compared with 92.8% among patients who received paclitaxel plus trastuzumab.

A similar proportion of patients developed clinically relevant toxicities in both treatment groups; however, patients receiving paclitaxel plus trastuzumab reported more neuropathy (24% vs 11%), neutropenia (13% vs 3%), and infusion-related reactions (11% vs 5%), whereas patients receiving T-DM1 reported more thrombocytopenia (11% vs 1%) and elevated liver function (9% vs 4%). These results suggest that T-DM1 is an alternative treatment for select patients with early HER2-positive disease who are concerned about toxicities associated with paclitaxel/trastuzumab treatment.

Metastatic Disease

Data from a multicenter, open-label, phase I/II study (NCT00398567) demonstrate encouraging tolerability and antitumor activity of neratinib plus trastuzumab in patients with pretreated, advanced HER2-positive breast cancer. Patients with locally advanced or metastatic HER2-positive breast cancer who received ≥1 prior trastuzumab-based regimens demonstrated a 16-week progression-free survival (PFS) rate of 44.8%, with a median PFS of 15.9 weeks among 28 evaluable patients treated with the combination of neratinib and trastuzumab.8 The most common AE was diarrhea, and no clinically significant toxicity was reported.

Click to Enlarge

The fact that tucatinib met 3 major end points—PFS, PFS in the population with brain metastases, and OS&mdash;at its first reporting, with a good safety profile, is incredible news for patients,” Hurvitz noted.

In the phase II DESTINY-Breast01 study (NCT03248492), 184 patients with HER2-positive metastatic breast cancer who received prior T-DM1 were treated with [fam-] trastuzumab deruxtecan-nxki (Enhertu).10 Overall, 112 patients responded to therapy. The median duration of PFS was 16.5 months (95% CI, 12.7 months to not reached). The most frequently reported grade ≥3 AEs were decreased neutrophil count (20.7%), anemia (8.7%), and nausea (7.6%). These data demonstrate durable antitumor activity in pretreated patients with HER2-positive metastatic breast cancer treated with trastuzumab deruxtecan.

“The waterfall plot showing responses from [trastuzumab deruxtecan] was remarkable,” Hurvitz said. “Almost everyone had disease shrinkage with this novel antibody-drug conjugate. This is very exciting for heavily pretreated disease. The FDA’s accelerated approval of [trastuzumab deruxtecan] in December [2019] based on a phase II trial is just 1 example of the rapid availability of new drugs with promising results.”

The confirmatory phase III randomized trial for DESTINY-Breast01, DESTINYBreast02 (NCT03523585), is currently enrolling patients. They will be randomized to either trastuzumab deruxtecan or physician’s choice of capecitabine plus either trastuzumab or lapatinib (Tykerb).

In the phase III SOPHIA trial (NCT02492711), 536 patients with HER2-positive metastatic breast cancer that progressed following 2 or more lines of anti-HER2 therapy were randomized to chemotherapy combined with either margetuximab or trastuzumab.11 Results from an interim analysis after 270 patient deaths demonstrated a median PFS of 5.7 months with margetuximab treatment compared with 4.4 months with trastuzumab treatment. The overall response rate (ORR) was significantly higher among patients treated with margetuximab compared with those treated with trastuzumab (25.2% vs 13.7%; P = .0006). The clinical benefit rate was also significantly higher among those treated with margetuximab (48.1% vs 35.6%; P = .0025). AEs were similar overall; however, infusion-related reactions were more frequent among patients treated with margetuximab (13.3% vs 3.4%). Data from the SOPHIA trial are the first to suggest superior PFS with a novel antibody compared with trastuzumab, Hurvitz said.

Finally, in the phase II monarcHER trial (NCT02675231), patients with advanced hormone receptor—positive, HER2-positive breast cancer were randomized to receive trastuzumab plus chemotherapy or abemaciclib (Verzenio), fulvestrant (Faslodex), and trastuzumab.12 The median PFS was higher among patients who received abemaciclib, fulvestrant, and trastuzumab compared with those who received the combination of trastuzumab and chemotherapy (8.32 vs 5.69 months).

“I was also very happy to see the results from the phase II, randomized monarcHER trial, showing an improved ORR and PFS in patients with HR-positive/HER2-positive metastatic breast cancer treated with abemaciclib, fulvestrant, and trastuzumab compared with those treated with chemotherapy plus trastuzumab,” Hurvitz explained. “These data support preclinical data suggesting that CDK4/6 [inhibitors] should have activity in [patients with] HR-positive/ HER2-positive breast cancer.”

Guiding Treatment Decisions

Treatment decision making has become more complex with the development of novel therapies for patients with HER2-positive breast cancer; however, researchers are investigating methods to guide therapy selection in this patient population. Results from a pooled analysis of over 5000 patients with breast cancer demonstrated that the measurement of residual cancer burden (RCB) index was associated with tightly associated with both event-free survival (EFS) and distant recurrence-free survival (DRFS) and was prognostic for all breast cancer phenotypes (Table 213). “We found that these results were consistently generalizable and could help determine the most appropriate treatment plans for patients with all breast cancer subtypes,” noted W. Fraser Symmans, MD, professor and director of research operations in the Department of Pathology at The University of Texas MD Anderson Cancer Center, in an interview.

Investigators assessed RCB through a number of factors including dimensions of the primary tumor-bed area, the percentage of invasive versus in situ cancer, the number of lymph nodes involved, and the size of the largest metastasis. These data were entered into a calculator developed by MD Anderson following a pathologic examination after neoadjuvant treatment and calibrated to an estimate of the patients’ risk for recurrence over time. The RCB index was classified as RCB-I (minimal burden), RCB-II (moderate burden), or RCB-III (extensive burden).

Among patients with HR-positive/HER2-positive disease, 38% were classified as achieving a pathological complete response (pCR), with 20% classified as RCB-I, 33% as RCB-II, and 8% as RCB-III. After 10 years of follow-up, 9% of patients who had a pCR had experienced a recurrence or had died, compared with 17% of patients classified as RCB-I, 36% of RCB-II, and 55% of RCB-III.13

Among patients with HR-negative/HER2- positive disease, 69% were classified as achieving a pCR, with 11% classified as RCB-I, 16% as RCB-II, and 4% as RCB-III. After 10 years of follow-up, 7% of patients who had a pCR had experienced a recurrence or had died, compared with 15% of patients classified as RCB-I, 37% of RCB-II, and 40% of RCB-III.13

“This pooled analysis confirms and expands upon prior findings that RCB index can predict risk of breast cancer recurrence,” Symmans said. “This assessment of prognostic risk can be used to accurately determine disease progression and inform treatment choice for breast cancer patients inclusive of all subtypes.”

Looking to the Future

“In the early disease setting, I am interested in trials like ATEMPT and APT that are pursuing less toxic approaches for select patients deemed to be at low risk, but hope to see long-term follow-up to ensure that a de-escalation approach is safe,” Hurvitz said. She also explained that, in the metastatic setting, she is interested in data from HER2CLIMB related to the effects of tucatinib in patients with active central nervous system metastases. “I am looking forward to seeing how many patients have responses in the brain with this drug,” she said. “This will potentially be practice changing for the management of this challenging but alltoo- common clinical scenario.”

“Multiple therapeutic options are now available for both early- and late-stage HER2- positive disease,” Hurvitz concluded. “The field is rapidly evolving given the number of agents that can target the HER2 driver. Now, more than ever, it is critical for clinicians to keep up-to-date with emerging trial results, as many studies are yielding practice-changing data. In the next year, it would not be surprising if we see the approval of 1, if not 2, additional agents for this disease.”

References

  1. von Minckwitz G, Huang CS, Mano MS, et al; KATHERINE Investigators. Trastuzumab emtansine for residual invasive HER2-positive breast cancer. N Engl J Med. 2019;380(7):617-628. doi: 10.1056/NEJMoa1814017.
  2. von Minckwitz G, Procter M, de Azambuja E, et al; APHINITY Steering Committee and Investigators. Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer. N Engl J Med. 2017;377(2):122-131. doi: 10.1056/NEJMoa1703643.
  3. Martin M, Holmes FA, Ejlertsen B, et al; ExteNET Study Group. Neratinib after trastuzumab-based adjuvant therapy in HER2-positive breast cancer (ExteNET): 5-year analysis of a randomised, double-blind, placebo-controlled, phase III trial. Lancet Oncol. 2017;18(12):1688-1700. doi: 10.1016/S1470-2045(17)30717-9.
  4. Tolaney SM, Barry WT, Dang CT, et al. Adjuvant paclitaxel and trastuzumab for node-negative, HER2-positive breast cancer. N Engl J Med. 2015;372(2):134-141. doi: 10.1056/NEJMoa1406281.
  5. 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(22):1868-1875. doi: 10.1200/JCO.19.00066.
  6. 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.
  7. FDA approves Genentech’s Kadcyla for adjuvant treatment of people with HER2-Positive early breast cancer with residual invasive disease after neoadjuvant treatment [press release]. South San Francisco: Genentech; May 3, 2019. bit.ly/2UYWOVN. Accessed February 20, 2020.
  8. Blackwell KL, Zaman K, Qin S, et al; 202 Study Group. Neratinib in combination with trastuzumab for the treatment of patients with advanced HER2-positive breast cancer: a phase I/II study. Clin Breast Cancer. 2019;19(2):97-104.e4. doi: 10.1016/j.clbc.2018.12.011.
  9. Murthy RK, Loi S, Okines A, et al. Tucatinib, trastuzumab, and capecitabine for HER2-positive metastatic breast cancer [published online December 11, 2019]. N Engl J Med. 2020;382(7):597-609. doi: 10.1056/NEJMoa1914609.
  10. Modi S, Saura C, Yamashita T, et al; DESTINY-Breast01 Investigators.
  11. Trastuzumab deruxtecan in previously treated HER2-positive breast cancer [published online December 11, 2019]. N Engl J Med. 2020;382(7):610-621. doi: 10.1056/NEJMoa1914510.
  12. 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.
  13. Tolaney SM, Wardley AM, Zambelli S, et al. MonarcHER: A randomized phase 2 study of abemaciclib plus trastuzumab with or without fulvestrant versus trastuzumab plus standard-of care chemotherapy in women with HR+, HER2+ advanced breast cancer. Presented at: 2019 European Society Medical Oncology Congress; September 27-October 1, 2019; Barcelona, Spain. Abstract LBA23.
  14. Yau C, van der Noordaa M, Wei J, et al. Residual cancer burden after neoadjuvant therapy and long-term survival outcomes in breast cancer: a multi-center pooled analysis. Presented at: 2019 San Antonio Breast Cancer Symposium; December 10-14, 2019; San Antonio, TX. Abstract GS5-01. abstractsonline.com/pp8/#!/7946/presentation/1923. Accessed February 17, 2020.

In the HER2CLIMB trial (NCT02614794), 612 patients with HER2-positive metastatic breast cancer, with or without brain metastases, who previously received trastuzumab, pertuzumab, and T-DM1, were randomized to tucatinib or placebo combined with trastuzumab and capecitabine.9 At 1 year, PFS was significantly higher in patients receiving tucatinib compared with those receiving placebo (33.1% vs 12.3%; HR, 0.54; 95% CI, 0.42-0.71; P <.001). Similar results were seen among patients with brain metastases (24.9% vs 0%). At 2 years, OS was significantly higher in the tucatinib group compared with the placebo group (44.9% vs 26.6%). Diarrhea and elevated aminotransferase levels were more frequent among patients receiving the tucatinib combination. These data demonstrate improved survival outcomes with the addition of tucatinib to trastuzumab and capecitabine among heavily pretreated patients with HER2- positive metastatic breast cancer, including patients with brain metastases.

In the APHINITY trial (NCT01358877), 4805 patients with node-positive or high-risk node-negative, HER2- positive operable breast cancer were randomized to receive pertuzumab or placebo plus standard adjuvant chemotherapy and 1 year of trastuzumab.2 Disease recurrence was reported in significantly fewer patients who received pertuzumab compared with those who received placebo (HR, 0.81; 95% CI, 0.55-1.00; P = .045). The 3-year iDFS rate was 94.1% in the pertuzumab group compared with 93.2% in the placebo group. Among those with node-positive disease, the 3-year iDFS rate was significantly higher compared with that of the placebo group (HR, 0.77; 95% CI, 0.62-0.96; P = .02). Grade ≥3 diarrhea was reported almost exclusively during chemotherapy; however, it was more frequent among those treated with pertuzumab compared with those treated with placebo (9.8% vs 3.7%).

Related Videos
View All
Related Content