Improving Responses, Minimizing Toxicity Goal of Trastuzumab Combinations in HER2+ Breast Cancer

In the neoadjuvant and adjuvant settings of treating patients with HER2-positive breast cancer, trastuzumab (Herceptin) remains a standard of care. The question has become whether combination regimens with additional HER2-directed therapies or alternative therapies could improve responses in this patient population without added toxicities, according to Sara M. Tolaney, MD, MPH.

Sara M. Tolaney, MD, MPH

In the neoadjuvant and adjuvant settings of treating patients with HER2-positive breast cancer, trastuzumab (Herceptin) remains a standard of care. The question has become whether combination regimens with additional HER2-directed therapies or alternative therapies could improve responses in this patient population without added toxicities, according to Sara M. Tolaney, MD, MPH.

Tolaney explained the state of HER2-directed therapies for patients with HER2-positive breast cancer during the16th AnnualInternational Congress on the Future of Breast Cancer, hosted by Physicians’ Education Resource®, LLC (PER®).

In the BCIRG-006 study, which was a multi-arm study looking at the benefit of added anthracyclines to chemotherapy in the treatment of patients with early stage HER2-positive breast cancer, both arms that included added trastuzumab performed significantly better than the arm in which patients were not treated with trastuzumab.1

In the final analysis of the study at 10.3 years of follow-up, both trastuzumab-containing regimens showed an increased disease-free survival (DFS) rate compared with chemotherapy alone. The DFS rate was 74.6% with doxorubicin (Adriamycin)/cyclophosphamide/docetaxel plus trastuzumab (AC-TH) and 73.0% with docetaxel/carboplatin plus trastuzumab (TCH). In the arm that included patients treated with doxorubicin/cyclophosphamide/docetaxel (AC-T) without added trastuzumab, a DFS of 67.9% was observed.

Tolaney, associate director of clinical research, Breast Oncology, Susan F. Smith Center for Women’s Cancers, Dana-Farber Cancer Institute, and assistant professor of medicine, Harvard Medical School, pointed out that only 10 DFS events separated the 2 trastuzumab-containing regimens.

In patients with higher-risk lymph-node positive disease, treatment-related outcomes mimicked results of the overall population, and again, there was no significant difference between the 2 trastuzumab-containing arms. The DFS was 69.6% with AC-TH compared with 68.4% with TCH. The DFS with AC-T was 62.2%. Tolaney suggested that this could indicate that there is still an advantage for anthracycline-based therapy, even in the higher-risk population.

However, trastuzumab is known to have cardiotoxicity risks, and in the BCIRG-006 trial, there was a 2% incidence of grade 3/4 congestive heart failure in the AC-TH arm, and 0.4% incidence rate with TCH.

Combinations With Trastuzumab

“One approach I have taken is to use TCH in patients with cardiac risk factors and AC-TH in most other patients,” she said.

“While outcomes for HER2-positive disease have dramatically improved with the addition of trastuzumab, approximately 15% of women with early stage HER2-positive disease still recur, so there is a need to do better,” Tolaney commented. Several combination regimens are being explored adding to trastuzumab in order to improve responses in these patients.

One common approach is dual HER2-targeted therapy. Several studies have looked at the addition of lapatinib (Tykerb) to trastuzumab in the neoadjuvant setting, with higher rates of pathologic complete response (pCR) from the combination compared with trastuzumab or lapatinib alone.

“These favorable pCR rates achieved with lapatinib and trastuzumab led many to think that dual inhibition may improve survival outcomes in the adjuvant setting,” she noted. To test this hypothesis, the phase III ALTTO trial explored the combination of trastuzumab and lapatinib in the adjuvant setting in patients with early stage disease, yet no significant role was found when lapatinib was added in this setting.2

The study included 4 arms of single-agent trastuzumab, single-agent lapatinib, lapatinib plus trastuzumab, and trastuzumab followed by lapatinib. At 6 years, the DFS rate with lapatinib and trastuzumab was 85%, compared with 84% for trastuzumab followed by lapatinib, and 82% in patients treated with trastuzumab alone.

In addition, there was a much higher rate of adverse events (AEs) seen with lapatinib monotherapy and in the combination regimen of lapatinib plus trastuzumab, including treatment-related AEs in 93% of patients treated with the combination and in 90% with lapatinib, compared with 64% among those treated with trastuzumab alone.

Pertuzumab (Perjeta) has also been an area of active investigation with trastuzumab therapy in breast cancer. In 2013, the FDA granted an accelerated approval to pertuzumab in combination with trastuzumab and docetaxel in the neoadjuvant setting for patients with HER2-positive breast cancer, based on results of the NeoSphere and TRYPHAENA trials.

Results of APHINITY, which evaluated the role of pertuzumab in the adjuvant setting, were presented at the 2017 ASCO Annual Meeting. With the addition of pertuzumab to trastuzumab and chemotherapy, a slight improvement was demonstrated with a 4-year invasive DFS rate of 92.3% compared with 90.6% with trastuzumab and chemotherapy alone (HR, 0.81;P= .045), for an absolute benefit of 1.7%.3The only real difference between the 2 arms was the higher rate of grade ≥3 diarrhea in the pertuzumab arm (9.8% vs 3.7% with trastuzumab and chemotherapy alone), Tolaney suggested, but there was no great difference in the rate of cardiotoxicity with added pertuzumab.

Alternatives to Trastuzumab

In subset analyses, patients with node-positive and hormone receptor (HR)—negative disease appeared to derive a greater benefit from the addition of pertuzumab, and as such, she suggested that this combination should potentially be reserved for patients with high-risk disease, such as those with node-positive or HR-negative disease. Tolaney noted that the additional toxicity was small, but the financial cost was high, and amounted to an extra $100,000 per patient for 1 year of added pertuzumab therapy.

Other agents are also being considered in the neoadjuvant and adjuvant setting for patients with HER2-positive breast cancer.

The antibody drug conjugate trastuzumab emtansine (T-DM1) has shown similar affinity to trastuzumab in binding to HER2. In the KRISTINE study, T-DM1 was explored in the neoadjuvant setting in combination with pertuzumab (T-DM1+P) and was compared with those randomized to receive docetaxel, carboplatin, trastuzumab, and pertuzumab (TCH+P).4Although the pCR rate was greater in the TCH+P arm (56% vs 44% in the T-DM1+P arm), there were significantly more serious AEs in the TCH+P arm (29%) compared with the T-DM1+P arm (5%). For high-risk patients, Tolaney said, T-DM1 may not be as effective as multi-agent chemotherapy with trastuzumab and pertuzumab.

The Kaitlin and Katherine studies are exploring further the role of T-DM1, with the Kaitlin study comparing T-DM1 as a replacement for trastuzumab alone in the treatment regimen in the adjuvant setting. Tolaney noted that this study has completed accruing patients and the results are pending. The Katherine study is comparing T-DM1 with trastuzumab in patients with residual disease following surgery.

Neratinib (Nerlynx), an irreversible pan-HER inhibitor was investigated in the ExteNET trial, randomizing patients 1:1 to a year of either neratinib or placebo.5Results of this study led to the FDA approval of neratinib on July 17, 2017 for the extended adjuvant treatment of patients with early stage HER2-positive breast cancer.

At 5 years, neratinib showed a 5-year invasive DFS of 90.2% compared with 87.7% with placebo (HR, 0.73; 95% CI, 0.57-0.92; 2-sidedP= .008), for a survival difference of 2.5%. A survival difference was also noted in the HR-positive patient population with a 4.4% survival difference (HR, 0.60; 95% CI, 0.43-0.83; 2-sidedP= .002), but not in the HR-negative subgroup (HR, 0.95; 95% CI, 0.66-1.35; 2-sidedP= .762).

However, Tolaney said, toxicity is of concern with neratinib. In the phase III ExteNET study, there was a 40% incidence rate of grade 3 diarrhea with neratinib. However, she said that these results should be interpreted with caution as the trial did not include the use of prophylactic loperamide, which decreases the rates of diarrhea.

In the phase II CONTROL study,6prophylactic use of antidiarrheal agents showed decreased rates of grade 3 diarrhea. With loperamide, the grade 3 rate was decreased to 31%, and with combination colestipol and loperamide, the rate was reduced to 8%, with 46% of patients experiencing no diarrhea.

Tolaney said that there is currently no data exploring the benefit of neratinib in patients who have been exposed to prior pertuzumab therapy, but the use of neratinib should certainly be considered in patients with high-risk HR-positive, node-positive disease.


  1. Slamon DJ, Eiermann W, Robert NJ, et al: Ten-year follow-up of BCIRG-006 comparing doxorubicin plus cyclophosphamide followed by docetaxel with doxorubicin plus cyclophosphamide followed by docetaxel and trastuzumab with docetaxel, carboplatin and trastuzumab in HER2-positive early breast cancer patients. Abstract presented at: 2015 San Antonio Breast Cancer Symposium; December 8-12, 2015; San Antonio, TX. Abstract S5-04.
  2. Moreno-Aspitia A, Holmes EM, Jackisch C, et al. Updated results from the phase III ALTTO trial (BIG 2-06; NCCTG (Alliance) N063D) comparing one year of anti-HER2 therapy with lapatinib alone (L), trastuzumab alone (T), their sequence (T→L) or their combination (L+T) in the adjuvant treatment of HER2-positive early breast cancer [ASCO abstract 502].J Clin Oncol.2017;35(suppl).
  3. Von Minckwitz G, Procter MJ, De Azambuja E, et al. APHINITY trial (BIG 4-11): A randomized comparison of chemotherapy (C) plus trastuzumab (T) plus placebo (Pla) versus chemotherapy plus trastuzumab (T) plus pertuzumab (P) as adjuvant therapy in patients (pts) with HER2-positive early breast cancer (EBC) [ASCO abstract LBA500].J Clin Oncol.2017;35(suppl).
  4. Hurvitz SA, Martin M, Symmans WF, et al. Pathologic complete response rates after neoadjuvant trastuzumab emtansine (T-DM1) + pertuzumab vs. docetaxel + carboplatin + trastuzumab + pertuzumab (TCH+P) treatment in patients with HER2-positive (HER2+) early breast cancer(KRISTINE/TRIO-021).J Clin Oncol.2016;34(suppl; abstr 500).
  5. Study evaluating the effects of neratinib after adjuvant trastuzumab in women with early stage breast cancer (ExteNET). Updated June 27, 2017. Accessed July 21, 2017.
  6. Ibrahim E, Tripathy D, Wilkinson M, et al. Effects of adding budesonide or colestipol to loperamide prophylaxis on neratinib-associated diarrhea in patients with HER2+ early-stage breast cancer: the CONTROL trial. Poster presented at: 2017 AACR Annual Congress; April 1-5, 2017; Washington, DC. Abstract CT128.
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