Key Studies Help Chart Course in HER2-Positive Breast Cancer

Sara A. Hurvitz, MD

Among the bright spots in the treatment of patients with breast cancer are the successes achieved in the management of HER2-positive disease. And, therapeutic options are continuing to expand, owing to the advent of novel anti-HER2—targeted agents and multitargeted HER2 receptor blockade.

Pertuzumab Plus Trastuzumab

These were among the key take-home messages that breast cancer experts conveyed during a recent OncLive Peer Exchange® roundtable entitled “Update on Advanced Breast Cancer Treatment.” The prognosis for newly diagnosed first-line disease “is very good in terms of median survivals” which are “now approaching 5 years,” said Sara A. Hurvitz, MD. First- and second-line strategies for treatment of patients with HER2-positive, metastatic breast cancer is straightforward, and the therapies are “really well tolerated,” Hurvitz noted. “It’s just not the depressing, horrible story that it was a decade or more ago,” she said.The recent study that decisively changed the therapeutic landscape is the CLEOPATRA trial,¹ which introduced the concept of dual HER2 targeting. CLEOPATRA randomized patients with metastatic breast cancer who had not received previous chemotherapy or anti-HER2 therapy for metastatic disease to trastuzumab and docetaxel with either pertuzumab or placebo.

Patients received 4 to 6 cycles of chemotherapy, and then were allowed to come off of the chemo and continue only the HER2-targeted agent or agents. In CLEOPATRA, progression-free survival (PFS) was 6 months longer among patients who received pertuzumab/trastuzumab/ docetaxel together as compared with those who only received trastuzumab/docetaxel. Patients who received the pertuzumab-containing regimen achieved a median overall survival (OS) of 56.5 months compared with 40.8 months for the placebo group (HR, 0.68; P <.001).

The therapy was well tolerated, and the addition of pertuzumab to trastuzumab did not appear to increase cardiac toxicity, said Hurvitz. However, clinicians should “forewarn patients that, especially during the time they are receiving chemotherapy,” the treatment “increases rates of diarrhea and skin toxicity,” she recommended. Hurvitz expressed dismay that “a lot of community oncologists drop off the pertuzumab somewhere around 8 or 9 cycles.” Additional panel participants responded to this observation by saying they had observed the same pattern. During the trial, the pertuzumab/trastuzumab combination was administered until disease progression or the onset of unmanageable toxicities. “The message I try and get out to referring oncologists is to follow the way the study was done,” Hurvitz said.

Hope S. Rugo, MD

However, she explained, CLEOPATRA did not initiate endocrine therapy with the dual HER2-targeted therapies for estrogen receptor (ER)—positive disease, although “in my practice I do because I think dual blockade is probably beneficial,” athough she does not have data supporting that approach.

The FDA has approved pertuzumab for use in combination with trastuzumab and docetaxel for treatment of patients with HER2-positive metastatic breast cancer (MBC) who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease, and in combination with trastuzumab and docetaxel as neoadjuvant treatment of patients with HER2-positive, locally advanced, inflammatory, or early-stage breast cancer (either >2 cm in diameter or node positive) as part of a complete treatment regimen for early breast cancer.² As to whether either docetaxel or paclitaxel is superior in such a regimen incorporating trastuzumab and pertuzumab, Hurvitz noted that recent data indicate “that paclitaxel is probably just as good,” and so choosing between them should be based on the characteristics of the patient, the timing, and known side effects of the therapy.

Exploring Trastuzumab Emtansine

In CLEOPATRA nearly all patients were in the first-line setting but were not treatment naïve, Hope S. Rugo, MD, pointed out. In contrast, patients in the clinic often have received substantial prior therapy and, for some patients “if we’re going to give them even more therapy in the adjuvant setting, we may not be seeing that same benefit.” Hurvitz agreed, and noted that abundant registry data show that de novo metastatic HER2-positive breast cancer is much more common than had previously been thought.The discussion then moved to trastuzumab emtansine (T-DM1), a compound that generated considerable enthusiasm among panel members. T-DM1 consists of trastuzumab stably linked to the maytansine derivative DM1, a potent microtubule toxin.

The phase III EMILIA study randomized patients with previously treated HER2-positive advanced breast cancer either to T-DM1 or to a combination of capecitabine and lapatinib. Patients who received T-DM1 achieved improved PFS and superior OS, and experienced far less toxicity than the comparator, Hurvitz stated. Adverse events include thrombocytopenia and liver enzyme elevation. EMILIA “established this drug as the standard of care for second- and third-line breast cancer,” she said.

Adam M. Brufsky, MD, PhD

T-DM1 was also studied in the phase III, randomized, open-label TH3RESA trial,³ which compared T-DM1 with a treatment of physician’s choice (TPC) in patients with heavily pretreated HER2-positive metastatic breast cancer.

T-DM1 demonstrated an OS advantage, compared with TPC. Adam M. Brufsky, MD, PhD, who served as moderator for the Peer Exchange session, asked panelists the settings in which they would recommend T-DM1. “Would you then use T-DM1 at any line as long as someone’s never had it based on that data?” he said. In response, Joyce O’Shaughnessy, MD, noted that patients were required to have prior trastuzumab and prior lapatinib therapy before receiving T-DM1 in the TH3RESA trial. “That’s an important point because you get this big survival advantage with T-DM1 after lapatinib,” she said. “Now, we don’t have any data on T-DM1 after pertuzumab.”

O’Shaughnessy said she uses “that particular fact in my practice based on my experience,” since she sees “beautiful T-DM1, multi-year responses, not necessarily right after pertuzumab.”

For patients who have been treated with pertuzumab, O’Shaughnessy might prescribe another regimen in between, such as lapatinib with either capecitabine or trastuzumab.

Christy A. Russell, MD, discussed the fact that patients previously treated with trastuzumab/navelbine do not achieve a robust response to T-DM1. Further, Rugo commented that patients who are convincingly taxane refractory—for example, those who have received 2 years of taxane therapy—frequently do not respond adequately to T-DM1.

The MARIANNE study also explored potential settings for T-DM1. This phase III, randomized, noninferiority trial enrolled patients with progressive or recurrent locally advanced or previously untreated metastatic HER2-positive breast cancer. The three-arm study compared T-DM1 plus pertuzumab, T-DM1 plus placebo, and trastuzumab plus a taxane (either docetaxel or paclitaxel).

Hurvitz pointed out that the study design camouflaged what was for her “the big question,” that being whether there is a role for T-DM1 as a first-line therapy in the HER2-positive setting. “Is it going to beat docetaxel and trastuzumab or paclitaxel and trastuzumab?” she said.

MARIANNE findings demonstrated that the T-DM1 arms were noninferior to trastuzumab plus a taxane, but neither T-DM1 regimen was superior. “Everyone has interpreted this as a negative study because it didn’t show that benefit over first-line trastuzumab and taxane,” Hurvitz said. Yet, there were several plusses associated with both T-DM1 arms: there was less toxicity with the regimens incorporating T-DM1. And, there were advantages in relation to the duration of therapy.

mTOR Inhibition

“Patients did stay on T-DM1 longer when you look at the duration of therapy in the different arms,” said Hurvitz. Nevertheless, “with the survival data that we have for [the pertuzumab regimen} with CLEOPATRA, I don’t think any of us are really using T-DM1 in the frontline setting,” and adding pertuzumab to T-DM1 did not appear to add much value.Hurvitz, lead author of the Lancet Oncology publication of the BOLERO-1 study⁴, spoke on this phase III, double-blind, randomized, multicenter trial that evaluated the efficacy and safety of adding the mTOR inhibitor everolimus to trastuzumab and paclitaxel as first-line treatment for patients with HER2-positive advanced breast cancer. The two primary endpoints were PFS in the full population and in patients with hormone receptor (HR)—negative, HER2-positive breast cancer.

For the full study population, there was little difference in the everolimus arm, where the median PFS was 14.95 months compared with 14.49 months with placebo. For the HR-negative subgroup, the median PFS with everolimus was 20.27 months compared with 13.08 months with placebo (HR, O.66; P = ·0049).

Neoadjuvant Chemotherapy Questioned

However, the subgroup findings did not meet the “very stringent” prespecified P values (P = .0044), Hurvitz said. Yet, the trial was important as a “hypothesis generating” study, she said. BOLERO-1 probably will not impact current clinical practice, Brufsky commented, but is likely to help “drive the next series of research projects forward.”The panel then turned its attention to the ADAPT series of clinical trials, which utilized a biomarker- driven design to evaluate neoadjuvant therapy in subgroups of patients with early breast cancer.⁵ The neoadjuvant setting has been “most successful” in HER2-positive breast cancer, said Rugo, citing the approval of pertuzumab based on pathologic complete response (pCR).

Joyce A. O’Shaughnessy, MD

The ADAPT subgroup for HER2-positive, HR-positive disease was a three-arm trial comparing neoadjuvant T-DM1 with and without endocrine therapy, or trastuzumab plus endocrine therapy. Thus, the ADAPT trial was designed to answer the question of whether this patient population needs chemotherapy or whether they could be effectively treated with something “kinder and gentler” such as T-DM1, said Rugo. The pCR rates were 40.5% and 45.8% for patients who received either T-DM1 or T-DM1 plus endocrine therapy, respectively, but only 6.7% among participants in the trastuzumab plus endocrine therapy arm.⁶

Pan-HER Tyrosine Kinase Inhibitors

“What was fascinating was that the patients who received T-DM1, whether or not they received endocrine therapy, had a higher pathologic complete response rate, which was quite impressive for this group of patients,” said Rugo. She also said that the T-DM1 regimens were “very well tolerated” with “not a lot of toxicity and certainly no unexpected toxicities.” Rugo added that “we’ve always questioned the intensity of treatment” in this population and suggested that ADAPT may have identified “a therapy that’s quite effective in this subset of patients.”One new agent on the horizon in HER2-targeting therapies is neratinib, an irreversible pan-HER tyrosine kinase inhibitor. In the phase III ExteNET trial, neratinib improved the 2-year disease-free survival (DFS) rate among patients with early-stage HER2-positive breast cancer who had already completed adjuvant trastuzumab-based therapy up to 1 year before joining the study.

Christy A. Russell, MD

The 2-year DFS with neratinib was 93.9% for all HER2-positive patients in the study and 95.4% for those with HER2-positive, HR-positive disease compared with 91.6% and 91.2%, respectively, with placebo.⁷

Russell commented that the severe diarrhea accompanying neratinib use has made it “a difficult drug for people to use” but that there are now research efforts aimed at learning how to prevent this side effect. These include a study into the use of prophylactic loperamide for patients taking neratinib.⁸

References

1. Swain S, Baselga J, Kim SB, et al. Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med. 2015;372(8):724-734.
2. Perjeta [prescribing information]. South San Francisco, CA: Genentech, Inc; 2015.
3. Wildiers H, Kim S-B, Gonzalez-Martin A, et al. Trastuzumab emtansine improves overall survival versus treatment of physician's choice in patients with previously treated HER2-positive metastatic breast cancer: Final overall survival results from the phase 3 TH3RESA study. Presented at 2015 San Antonio Breast Cancer Symposium; December 8-12, 2015; San Antonio, TX. Abstract S5—05.
4. Hurvitz SA, Andre F, Jiang Z, et al. Combination of everolimus with trastuzumab plus paclitaxel as first-line treatment for patients with HER2-positive advanced breast cancer (BOLERO-1): a phase 3, randomised, double-blind, multicentre trial. Lancet Oncol. 2015; 16(7):816—829.
5. Hofmann D, Nitz U, Gluz O, et al. WSG ADAPT - adjuvant dynamic marker-adjusted personalized therapy trial optimizing risk assessment and therapy response prediction in early breast cancer: study protocol for a prospective, multi-center, controlled, non-blinded, randomized, investigator initiated phase II/III trial. Trials. 2013;19;14:261.
6. Harbeck N, Gluz O, Christgen M, et al. Efficacy of 12-weeks of neoadjuvant TDM1 with or without endocrine therapy in HER2-positive hormone-receptor-positive early breast cancer: WSG-ADAPT HER2+/HR+ phase II trial. J Clin Oncol. 2015;33(suppl; abstr 506).
7. Chan A, Delaloge S, Holmes FA, et al. Neratinib after trastuzumab-based adjuvant therapy in patients with HER2-positive breast cancer (ExteNET): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial [published online February 10, 2016]. Lancet Oncol. doi:10.1016/S1470-2045(15)00551-3
8. Auerbach AH. Phase II open-label study to characterize incidence and severity of diarrhea in patients with early-stage HER2-positive breast cancer treated with neratinib and intensive loperamide prophylaxis [webcast]. Puma Biotechnology Update Call; December 21, 2015.