Landmark Approvals Lead to Continual Progress in HER2+ Breast Cancer

Cindy Osborne, MD

Since landmark approvals in HER2-positive breast cancer, the field continues to gain traction in terms of therapeutic developments, explained Cindy Osborne, MD, in a presentation during the 2019 OncLive^® State of the Science Summit™ on Breast Cancer.

At the meeting, Osborne, a medical oncologist at Texas Oncology, Baylor Charles A. Sammons Cancer Center, highlighted the many advances that have been made in the treatment paradigms of locally advanced and metastatic HER2-positive disease.

Locally Advanced Setting

Once a therapy has demonstrated utility in the metastatic setting, it is often evaluated in earlier lines of treatment, as was the case with pertuzumab (Perjeta) in the phase II NeoSphere and TRYPHAENA trials. In both studies, investigators noted an improvement in pathologic complete response (pCR) rates with the addition of pertuzumab to trastuzumab (Herceptin) and chemotherapy. These findings led to the FDA approval of neoadjuvant pertuzumab, trastuzumab, and chemotherapy for the treatment of high-risk patients with node-positive disease or tumors ≥2 cm.

Given the promise of pertuzumab in the neoadjuvant setting, there was interest in evaluating the agent in the adjuvant space to determine whether it could provide a similar advantage, said Osborne. To this end, investigators launched the phase III APHINITY trial, in which patients with node-positive disease or other high-risk features were randomized to receive either trastuzumab, chemotherapy, and pertuzumab, or trastuzumab, chemotherapy, and placebo.

Although the trial was positive overall, indicating a 20% reduction in the risk of disease recurrence or death with the pertuzumab-containing regimen,¹ the absolute benefit of 1.7% at 4 years of follow-up was largely underwhelming, said Osborne.

However, results from a subset analysis revealed that patients with node-positive, hormone receptor (HR)—negative disease derived the greatest benefit with pertuzumab. This ultimately led to the FDA’s decision to approve the agent in December 2017 for use in combination with trastuzumab and chemotherapy in patients with HER2-positive, early-stage disease who are at high-risk of recurrence.

“Most patients who have HER2-positive disease with node-positive tumors >2 cm are receiving pertuzumab preoperatively,” said Osborne.

Due to the limited benefit observed with adjuvant pertuzumab in the overall population, Osborne reiterated that its use in this setting should only be reserved for high-risk patients.

However, the decision of whether to continue adjuvant pertuzumab must be revisited in the context of the results of the phase III KATHERINE trial.² In this study, patients who did not achieve a pCR to neoadjuvant therapy containing a taxane and trastuzumab were randomized to receive 1 year of ado-trastuzumab emtansine (T-DM1; Kadcyla) or trastuzumab. By substituting T-DM1 for trastuzumab, investigators noted a 50% reduction in the risk of invasive disease recurrence or death, and a 10.5% incidence of distant recurrence in the T-DM1 arm compared with 15.9% in the trastuzumab arm.

At the interim analysis, 12.2% of patients in the T-DM1 arm and 22.2% of patients in the trastuzumab arm had experienced invasive disease or death. Although there was a trend toward improved overall survival (OS) with T-DM1, it was not determined to be statistically significant (HR, 0.7; 95% CI, 0.47-1.05; P = .08), said Osborne.

Notably, however, the benefit of T-DM1 was observed irrespective of subgroup, including patients with estrogen receptor—positive disease who had received prior trastuzumab and other HER2-directed therapy, she added.

Neratinib (Nerlynx), a potent, irreversible, pan-HER inhibitor, is another option available for use in the adjuvant setting. In an effort to capitalize on the fact that the agent has a different mechanism of action than that of trastuzumab and pertuzumab, investigators tested its utility as extended adjuvant therapy in the phase III ExteNET trial. In the study, patients with high-risk disease who had residual disease after neoadjuvant therapy, prior adjuvant trastuzumab and chemotherapy, and endocrine therapy if they were HR positive, were randomized to receive 1 additional year of either neratinib or placebo.

At the 2-year and 5-year analysis, HR-positive patients experienced superior rates of invasive disease-free survival (iDFS) with neratinib compared with placebo, whereas in HR-negative patients, the curves converged after 2 years, noted Osborne.

Although an exploratory analysis of patients who failed to achieve a pCR after neoadjuvant therapy revealed an absolute iDFS benefit of 7.4% at 5 years with neratinib (HR, 0.60; 95% CI, 0.33-1.07),³ Osborne cautioned that the agent’s toxicity profile, specifically the rate of grade 3 diarrhea, must be weighed against its efficacy.

In preliminary results from the phase II CONTROL trial, antidiarrheal prophylaxis was found to reduce the incidence, severity, and duration of neratinib-associated diarrhea in patients with early-stage HER2-positive breast cancer. Although more mature data from this trial are pending, Osborne said that the high rates of diarrhea seen in the ExteNET trial can be offset with 1 to 2 months of antidiarrheal prophylaxis.

“There may be a select high-risk, node-positive subset where it’s worth trying to get neratinib in,” she added.

Metastatic Setting

Current standards of treatment in the metastatic setting include a variation of frontline chemotherapy or endocrine therapy and HER2-targeted therapy followed by T-DM1, or frontline T-DM1 if the DFS is less than 6 months, said Osborne.

Seeking to expand on the efficacy of existing regimens, a single-arm phase II trial was designed as an alternative approach to that examined in the phase III CLEOPATRA trial, which looked at the use of pertuzumab, trastuzumab, and docetaxel in the first-line setting. By replacing docetaxel with eribulin (Halaven), investigators reported comparable efficacy with greater tolerability. These data hope to be confirmed in the ongoing phase III, taxane-controlled EMERALD trial (NCT03264547).

For patients with postmenopausal HR-positive/HER2-positive disease, the phase III ALTERNATIVE study⁴ demonstrated the superior utility of frontline lapatinib, trastuzumab, and aromatase inhibitor (AI) therapy versus trastuzumab/AI therapy and lapatinib/AI therapy, with progression-free survival (PFS) rates of 11 months, 5.7 months, and 8.3 months, respectively.

Even more pronounced was the PFS benefit observed in the phase II PERTAIN trial,⁵ in which investigators randomized patients to receive pertuzumab/trastuzumab plus an AI or trastuzumab plus an AI, with an optional chemotherapy run-in phase. In the subset of women who forewent chemotherapy, the rates of median PFS were 21.7 months in the pertuzumab-containing arm versus 12.5 months in the trastuzumab/AI-alone arm (HR, 0.55; 95% CI, 0.34-0.88; P = .0111). However, the addition of pertuzumab resulted in a 3-month extension in median PFS in the overall population—a benefit that extended to all subgroups, said Osborne.

To expand upon available regimens in the second-line setting, the phase III PHEREXA trial was designed to evaluate the effectiveness of adding pertuzumab to trastuzumab and capecitabine. The triplet failed to meet its primary endpoint of PFS compared with trastuzumab and capecitabine alone, but it demonstrated improved OS. Although investigators could not formally claim the OS benefit due to hierarchical testing, it may still be a suitable approach for certain subsets of patients.

In terms of novel agents on the horizon, Osborne referenced the promise of newer monoclonal antibodies and antibody-drug conjugates (ADCs), including margetuximab and [fam-] trastuzumab deruxtecan (DS-8201), the latter of which was granted a breakthrough therapy designation by the FDA in 2017, and has since shown activity in HER2-positive and HER2-low breast cancers.

Although the agent is being investigated in several of the phase III DESTINY trials, Osborne cautioned that providers will have to stay vigilant regarding toxicity, as several cases of interstitial lung disease and pneumonitis-associated deaths have been reported.

In a phase I basket trial, margetuximab induced notable partial responses, which led to the launch of the ongoing randomized phase III SOPHIA trial of margetuximab and chemotherapy versus trastuzumab and chemotherapy in the third-line setting. The trial met its primary endpoint of PFS, boasting a reduction in the risk of progression or death of 24% in the overall population and 32% in a prespecified subpopulation of carriers of the CD16A 158F allele, according to a press release.⁶

Finally, an area of need that continues to remain unmet in the field is effective treatment for patients with brain metastases, explained Osborne. Since the majority of drugs, such as trastuzumab, pertuzumab, and T-DM1, are larger molecules, the question of whether they have the ability to penetrate the blood-brain barrier has remained unanswered. However, results from a planned interim analysis from the single-arm, phase II PATRICIA study seem to indicate that high-dose trastuzumab and pertuzumab can reach the brain in patients with CNS progression postradiotherapy.

Moreover, small molecule TKIs also have the capacity to penetrate the CNS, said Osborne. Although neratinib monotherapy failed to elicit encouraging responses in the past, the combination of neratinib plus capecitabine has demonstrated an objective volumetric response rate of 49% and a median PFS of 5.5 months among patients with HER2-positive breast metastases in a phase II trial.⁷

Another agent in the metastatic space is tucatinib, which is incredibly well tolerated, allowing it to be paired with a number of cytotoxic agents, said Osborne.

In the ongoing phase II HER2CLIMB trial (NCT02614794), patients who have received prior trastuzumab, pertuzumab, and T-DM1 will be randomized 2:1 to receive tucatinib with capecitabine and trastuzumab or capecitabine/trastuzumab with placebo.

References

1. 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). J Clin Oncol. 2017;35(suppl 8; abstr LBA500). doi: 10.1200/JCO.2017.35.18_suppl.LBA500.
2. von Minckwitz G, Huang CS, Mano MS, et al. Trastuzumab emtansine for residual invasive HER2-positive breast cancer. N Eng J Med. 2019;380(7):617-628. doi: 10.1056/NEJMoa1814017.
3. Gnant M, Martin M, Holmes F-A, et al. Efficacy of neratinib in hormone receptor-positive patients who initiated treatment within 1 year of completing trastuzumab-based adjuvant therapy in HER2+ early stage breast cancer: subgroup analyses from the phase III ExteNET trial. Presented at: 2018 San Antonio Breast Cancer Symposium; December 4-8, 2018; San Antonio, TX. Poster P2-13-01. abstracts2view.com/sabcs18/view.php?nu=SABCS18L_1477&terms=.
4. Johnston SRD, Hegg R, Im SA, et al. Phase III, randomized study of dual human epidermal growth factor receptor 2 (HER2) blockade with lapatinib plus trastuzumab in combination with an aromatase inhibitor in postmenopausal women with HER2-positive, hormone receptor-positive metastatic breast cancer: ALTERNATIVE. J Clin Oncol. 2018;36(8):741-748. doi: 10.1200/JCO. 2017.74.7824.
5. Arpino G, Ferrero J-M, de la Haba-Rodriguez J, et al. Primary analysis of PERTAIN: a randomized, two-arm, open-label, multicenter phase II trial assessing the efficacy and safety of pertuzumab given in combination with trastuzumab plus an aromatase inhibitor in first-line patients with HER2-positive and hormone receptor-positive metastatic or locally advanced breast cancer. Presented at: 2016 San Antonio Breast Cancer Symposium; December 6-10, 2016; San Antonio, TX. Abstract S3-04. abstracts2view.com/sabcs16/view.php?nu=SABCS16L_973&terms=.
6. MacroGenics Announces Positive Results from Pivotal Phase 3 SOPHIA Study of Margetuximab [news release]. MacroGenics. Published February 6, 2019. https://bit.ly/2SaTHh7. Accessed February 6, 2019.
7. Freedman RA, Gelman RS, Melisko ME, et al. TBCRC 022: phase II trial of neratinib + capecitabine for patients (pts) with human epidermal growth factor receptor 2 (HER2+) breast cancer brain metastases (BCBM). J Clin Oncol. 2017;35(suppl 15; abstr 1005). doi: 10.1200/JCO.2017.35.15_suppl.1005.