ResourcesPER Pulse™ Recap
The Advances in Targeted Therapies series is an online CME activity that includes expert interviews accompanied by a series of clinical vignettes focusing on non-small cell lung cancer (NSCLC), breast cancer, and colorectal cancer.
Medical Writer: Kim Farina, PhD
Module 2: Breast Cancer
Advances in Targeted Therapies: Metastatic Breast Cancer
Ado-Trastuzumab Emtansine for Relapsed HER2+ Metastatic Breast Cancer
In the following interviews, Drs. Kimberly Blackwell and Sunil Vera review some of the clinical implications of emerging data on the safety and efficacy of ado-trastuzumab emtansine for HER2-positive (HER2+) metastatic breast cancer (MBC).
Ado-trastuzumab emtansine (T-DM1), a conjugate of the anti-HER2 monoclonal antibody trastuzumab and the microtubule inhibitor DM1, was approved by the FDA in February 2013 for treatment of patients with HER2+ MBC who have already received a taxane and trastuzumab. Approval was based on the results of the pivotal phase III EMILIA trial. In EMILIA, 991 patients with advanced breast cancer who had progressed after receiving a taxane and trastuzumab were randomized to receive T-DM1 (T) or capecitabine/lapatinib (C+L). Compared with capecitabine/lapatinib, T-DM1 improved median overall survival (OS; T, 30.9 months vs C+L, 25.1 months; P <.001) and median progression-free survival (PFS; T, 9.6 months, vs C+L, 6.4 months; P <.001). Dr. Blackwell noted that this was a groundbreaking advance in the treatment of HER2+ MBC, and the first time an antibody-drug conjugate was proven effective in solid tumors.
In terms of the safety of T-DM1, Dr. Vera remarked, “What is great about this drug is the toxicity profile; patients don’t lose their hair, there is no nausea/vomiting, there is no diarrhea, no risk of infection, and no febrile neutropenia.” In EMILIA, the toxicity profile of T-DM1 was superior to capecitabine/lapatinib. Dr. Vera cautioned, “It is important to keep an eye on liver function and the platelets and monitor doses accordingly.” Based on the risk of thrombocytopenia and elevated liver enzymes (both occurring in fewer than 10% of patients) with T-DM1, these are key toxicities to monitor. There have been reports of severe liver injury, and in rare cases, neuropathy or pneumonitis (1%) may develop. It is recommended that treatment with T-DM1 be discontinued if pneumonitis occurs.
Primary results from the phase III TH3RESA trial presented at the 2013 European Society for Medical Oncology meeting and published ahead of print in May 2014 suggest that third-line T-DM1 is superior to chemotherapy and trastuzumab. TH3RESA enrolled 602 patients to compare T-DM1 with physician’s treatment of choice (approximately 80% trastuzumab-containing regimens) for MBC or unresectable locally advanced, recurrent, HER2+ breast cancer after treatment with a taxane, trastuzumab, and lapatinib. Early data in this trial showed a strong trend for improvement in PFS and OS, with fewer grade 3/4 adverse events for patients who received T-DM1 therapy.
Dr. Blackwell referred to data from a large phase II study (N = 137) that demonstrated superiority of T-DM1 over trastuzumab plus docetaxel for HER2+ MBC or recurrent, locally advanced breast cancer. She summarized that the positive results from these three studies support the use of T-DM1 over taxane/trastuzumab-based regimens, chemotherapy/trastuzumab-based regimens, and capecitabine plus lapatinib.
Dr. Blackwell typically uses T-DM1 in accordance with its US indication (ie, patients who have received prior therapy with a taxane and trastuzumab), which limits its use to the second- and third-line settings. T-DM1 is Dr. Verma’s first choice for second-line therapy after first-line therapy with trastuzumab. He prescribes it as first-line therapy for patients who have relapsed within 6 months of adjuvant trastuzumab therapy.
Dr. Blackwell does not recommend initiating T-DM1 if any uncertainty exists about HER2 status. She cited an approximate 10% to 15% discrepancy in HER2 findings to support retesting prior to the initiation of T-DM1. She cautioned, "If there is any lack of clarity about HER2 expression in metastatic breast cancer or HER2 amplification, I would certainly recommend that people determine the HER2 status of the tumor that the patient is facing prior to initiating T-DM1."
T-DM1 for Central Nervous System Metastasis
The EMILIA trial allowed enrollment of patients with asymptomatic stable central nervous system (CNS) metastases and no history of radiation treatment or steroid use within 2 months of randomization. Data from a retrospective subgroup analysis that were presented at the 2013 San Antonio Breast Cancer Symposium (SABCS) suggest that T-DM1 activity is independent of whether patients are facing brain metastases. “This was important data because we have prior data that lapatinib might be active in CNS metastases,” explained Dr. Blackwell. In this analysis, rates of CNS metastases among patients without CNS involvement at baseline were the same in the T-DM1 and capecitabine/lapatinib arms. Likewise, no differences in CNS progression were observed among patients with CNS metastases at baseline. It is unknown whether T-DM1 can prevent brain metastases.
Neoadjuvant Therapy with Dual HER2 Blockade for HER2+ Breast Cancer
Drs. Blackwell and Vera discussed the use of dual HER2 antibody therapy in the neoadjuvant setting for HER2+ breast cancer, including the approval of pertuzumab, validity of pathologic complete response (pCR) as a surrogate endpoint, and implications for referral patterns.
One of the most exciting developments in the field of targeted therapy, according to Dr. Blackwell, was the September 2013 approval of pertuzumab in combination with docetaxel and trastuzumab as neoadjuvant therapy for HER2-driven, locally advanced, inflammatory, or early-stage breast cancer (>2 cm in diameter or node-positive). First-line activity of pertuzumab for MBC had already been demonstrated in the CLEOPATRA trial. Approval for the neoadjuvant indication was based on results from the phase II NeoSphere trial (N = 417), demonstrating significantly higher pCR rates with docetaxel/pertuzumab/trastuzumab compared with docetaxel /trastuzumab (46% vs 29%; P = .0141). TRYPHAENA was a second phase II trial that evaluated the addition of an anthracycline or carboplatin to neoadjuvant docetaxel/trastuzumab/pertuzumab for patients with operable, locally advanced, or inflammatory breast cancer (N = 225). The 57% to 66% pCR rates seen with pertuzumab in TRYPHAENA further supported its approval in the neoadjuvant setting.
pCR as a Surrogate Marker of Benefit
pCR is a surrogate marker presumed to be predictive of long-term benefits. A recent meta-analysis suggested that pCR correlates with event-free survival (EFS) and OS, especially in hormone receptor–negative (HR-), HER2+ patients. According to Dr. Blackwell, the near doubling of pCR with pertuzumab is very meaningful for patients who are eligible for neoadjuvant treatment. "It makes the surgeon’s job easier and, hopefully, it decreases the risk of positive margins," she remarked. Dr. Verma noted lingering uncertainties regarding the benefits of pertuzumab after surgery or which chemotherapy regimen to use for better response. He explained that the NeoSphere and TRYPHAENA studies evaluated a limited number of patients, and the lack of long-term safety data continues to leaves questions unanswered. In the absence of long-term data, it is uncertain whether response benefits will translate into improvements in PFS or OS. Nonetheless, the higher response rates suggest benefits to patients in the neoadjuvant arena.
"One of the biggest unanswered questions in my mind is should pertuzumab be considered for all HER2+ tumors larger than 2 cm, or should it be restricted to node-positive patients only or locally advanced breast cancer patients," said Dr. Verma. He recommended that clinicians include toxicities and benefits of pCR and long-term effects when discussing treatment options with their patients. He also advised that if a neoadjuvant strategy is implemented, physicians should involve a multidisciplinary team early in and throughout the process. A significant response is anticipated in many of the tumors, with a potential pCR rate >60%. Therefore, he emphasized, frequent monitoring and early involvement of radiologists, radiation oncologists, and surgical oncologists is imperative.
The approval of pertuzumab marked the first approval by the FDA of a novel targeted agent for neoadjuvant treatment of HER2+ breast cancer. "I would hope that this will continue to be an exciting platform to get drugs available to patients who really need them in the curable setting, faster," said Dr. Blackwell. She considers the neoadjuvant approval an exciting development for all solid tumors, not just for breast cancer, and predicted that it will shift the types of patients seen by medical oncologists. As a result, Dr. Blackwell emphasized the need for discussions between medical oncologists and the surgical community to raise awareness that pertuzumab use is limited to the neoadjuvant arena. "I have communicated to my referring surgeons that I would like to see these patients before definitive surgery because that is a setting where we can offer pertuzumab layered on top of trastuzumab and chemotherapy," said Dr. Blackwell. "If we see the patients postop, the recent approval will not allow us to use pertuzumab in that setting."
Data presented at 2013 SABCS confirmed that HER2+ patients (including those with stage 1 disease) achieve high PFS and OS rates when treated with chemotherapy and trastuzumab. Available evidence also suggests that trastuzumab significantly reduced the recurrence of HER2-driven breast cancer. Accordingly, for nearly all HER2+ patients without other comorbidities, regardless of tumor size, Dr. Blackwell routinely offers a chemotherapy/trastuzumab-based regimen. "If I am offering chemotherapy and trastuzumab to most patients, whether it be in the neoadjuvant or adjuvant setting, my preference now will be to see these patients in the neoadjuvant setting so I can offer them the dual therapy of pertuzumab and trastuzumab in the setting of taxane-based neoadjuvant therapy," said Dr. Blackwell. She explained that with the closure of the large APHINITY trial of pertuzumab in the adjuvant setting, no current option for adjuvant pertuzumab therapy exists. For that reason, she advises medical oncologists to educate their colleagues on practicing early referrals of patients who are eligible for neoadjuvant treatment with pertuzumab. In summary, she said, "This has been an exciting year for pertuzumab, and an exciting year in the curable setting for women facing HER2+ breast cancer because physicians can now offer a double antibody approach that has been shown to be efficacious, with very limited toxicity."
Adjuvant Trastuzumab for Stage I HER2+ Breast Cancer
Drs. Blackwell and Vera discussed the use of adjuvant trastuzumab for early-stage HER2+ breast cancer and managing cardiac concerns and toxicities with trastuzumab use.
To date, close to eight to ten years of follow-up data are available from various adjuvant studies with trastuzumab for breast cancer, demonstrating improvements in OS and disease-free survival (DFS). Several known options are currently available, but concurrent anthracyclines followed by docetaxel/trastuzumab or nonanthracycline approaches with docetaxel/carboplatin/trastuzumab are generally accepted in practice.
Dr. Vera predicted that results from the phase II APT trial, presented at the 2013 SABCS by Dr. Sara Tolaney, are likely to impact practice. APT evaluated paclitaxel/trastuzumab for patients with HER2+, node-negative, <3-cm breast cancer (N = 406). At a median follow-up of 3.6 years, a DFS rate of 98.7% (P <.0001) was reported for patients who received paclitaxel/trastuzumab followed by trastuzumab for 1 year. Additionally, few recurrences or deaths were observed (2.5%). Of the 406 patients enrolled, 10 experienced disease recurrence or death. Some of the recurrences were contralateral breast cancer; 2 or 3 patients developed distant disease progression. Despite the limitations of its nonrandomized phase II design, the results of the APT trial were striking. In his own clinical practice, Dr. Vera considers paclitaxel/trastuzumab to be an effective regimen for patients with T1 tumors, and possibly tumors 2 cm to 3 cm.
Risk of Cardiotoxicity in Older Patients with HER2+ Breast Cancer
For the past decade, trastuzumab has been known to induce cardiac toxicity (left ventricular ejection fraction [LVEF] decline and congestive heart failure [CHF]) in all patients independent of age. Use of trastuzumab in combination with anthracyclines is generally avoided for first-line MBC therapy because the rate of clinically symptomatic CHF associated with this combination (16%) exceeds safety rates generally accepted by medical experts.
Two databases were introduced within the last year in the published literature, which suggest that age could be a risk factor for cardiac toxicity. Retrospective analysis of the SEER-Medicare and Texas Cancer Registry-Medicare databases evaluated cardiac toxicity of trastuzumab in older patients (N = 9535; median age, 71 years). Patients over the age of 66 years, and specifically over the age of 75 years, who received trastuzumab in the adjuvant setting were at significantly greater risk of CHF.
In light of these data, Dr. Vera would consider carboplatin/docetaxel/trastuzumab (TCH) or paclitaxel/trastuzumab (AC-TH) in older populations who have T1/T2 node-negative tumors, with selection being patient- and toxicity assessment–dependent. For node-positive tumors, he considers anthracyclines followed by taxane/trastuzumab (the BCIRG 006 trial showed DFS rates of 84% for AC-TH and 81% for TCH), but he tends to use docetaxel/carboplatin/trastuzumab, or now, paclitaxel/trastuzumab, when there are cardiac concerns.
Dr. Blackwell reviewed other risk factors that have been identified from adjuvant trastuzumab studies, including the use of antihypertensives, a borderline LVEF, and previous cardiac history. She recommends careful evaluation of these risk factors at baseline prior to initiation of therapy with trastuzumab. Trastuzumab should not be utilized when a lower-than-normal LVEF is detected unless a full disclosure of the risks and benefits to the patient has taken place.
Strategies to minimize cardiac toxicity should be adopted, such as routinely following the recommended cardiac monitoring for patients at high risk of cardiac toxicity included on approved trastuzumab labeling and temporarily withholding trastuzumab when a decline in the LVEF is observed. Patients can be rechallenged with trastuzumab after regaining normal LVEF on repeat assessments. Several options exist today for the assessment of LVEF, including cardiac echocardiogram, cardiac radionuclide imaging such as a multigated acquisition (MUGA) scan, and the use of cardiac MRI, that produce accurate information about LVEF. One should bear in mind, however, when conducting a LVEF study, that results can be affected by a number of factors such as tachycardia and high blood pressure (often observed in patients experiencing white coat/anxiety hypertension). In summary, Dr. Blackwell stressed the importance of weighing the benefits in addition to the risks of trastuzumab, examining patients thoroughly to identify potential risk factors, and adhering to package guidelines for careful and frequent cardiac monitoring of the patient.
Case 1: HER2+ Metastatic Breast Cancer
A patient presents with recurrent HER2+ MBC. She was originally treated with a trastuzumab-containing regimen in the adjuvant setting, with a disease-free interval of 2 years before relapsing. What would you recommend as first-line therapy at this point? What factors would influence your decision?
Drs. Blackwell and Verma recommended taxane/trastuzumab/pertuzumab as first-line treatment for this patient with HER2+ MBC. Patient preference, underlying disease burden, HR and HER2 status, and prior therapy are essential factors to consider when contemplating the treatment approach. Assuming that patient had HR-negative disease and had received anthracylines/taxanes and trastuzumab in an adjuvant setting, taxane/trastuzumab/pertuzumab could be considered. Dr. Verma tends to use weekly paclitaxel at a dosage of 80 mg/m2. He has found that regimen to be well tolerated and to have a lower risk of febrile neutropenia compared with docetaxel. In her practice, Dr. Blackwell also uses weekly paclitaxel with pertuzumab/trastuzumab for patients who have received adjuvant docetaxel. For patients who have received adjuvant paclitaxel, she uses the same regimen, but with docetaxel.
This combination usually requires a growth factor support, given the high incidence of febrile neutropenia with single-agent, every-2-week docetaxel. Dr. Blackwell typically does not give docetaxel on a weekly schedule, limiting options to a chemotherapy backbone of weekly paclitaxel or every-3-week dosing of docetaxel. Patient preference plays a major role in treatment selection; many women have received adjuvant taxanes and are familiar with their side effects. Being attentive to each patient’s concerns about taking chemotherapy is a key element of care.
For patients with HR+ status and low disease burden (eg, bone-only metastases), Dr. Verma explained that data suggest an aromatase inhibitor (AI) and trastuzumab approach. However, the limitation of pertuzumab to the first-line setting may come into play and point toward giving pertuzumab along with a taxane and trastuzumab. “If it is allowed, then for those patients who are HR+ one could consider an AI with trastuzumab, and then upon progression select a pertuzumab-based regimen for some of those select patients,” said Dr. Vera.
Dr. Blackwell agreed that for estrogen receptor–positive (ER+) disease, especially involving the bone, where a patient wants to avoid chemotherapy, she would consider an optimal endocrine agent (eg, ovarian shutdown in premenopausal woman or an AI in postmenopausal woman) if it could be sequenced and appropriately covered. In her practice, lapatinib plays an important role in this area. She explained that, in a subgroup of patients in a phase III randomized study, the data for lapatinib and letrozole suggested that those drugs can be combined. She considers lapatinib/letrozole/trastuzumab when appropriate coverage can be obtained.
Case 1 (cont'd)
The patient receives treatment with trastuzumab/pertuzumab/docetaxel and experiences a partial response. After 20 months, she progresses. At this point, what treatment would you recommend?
Dr. Blackwell remarked that these cases are not always straightforward, but started off by recommending evaluation of docetaxel-associated toxicities. If, for this patient, docetaxel was discontinued after the standard six cycles, a meaningful response had been reached, and the patient remained on the double-antibody pertuzumab/trastuzumab combination, that would suggest to Dr. Blackwell that her tumor was very HER2-driven. Based on the favorable therapeutic index and survival benefit of T-DM1, Dr. Blackwell considers this her "go to" agent in the second-line setting for patients who experienced a meaningful benefit from combination pertuzumab/trastuzumab.
Dr. Verma concurred; his clinical team would most likely discontinue docetaxel and continue with the double-antibody pertuzumab/trastuzumab. This is consistent with data from the CLEOPATRA trial, where a PFS of 18.5 months was observed. However, the EMILIA trial enrolled just a few patients who had received prior therapy with pertuzumab. The study compared T-DM1 to capecitabine and lapatinib. Even with limited prospective data on the effects of T-DM1, the general perception is that T-DM1 would still be effective in this patient population as the next treatment of choice in a second-line setting.
Case 2: HER2+ Early-Stage Breast Cancer
This patient presents with a 3-cm, HER2+, early-stage breast cancer. What strategy would you recommend? What factors would influence your recommendation?
Dr. Verma described two schools of thought that should factor into treatment options for HER2+ early-stage breast cancer. The first is the utility of neoadjuvant pertuzumab/trastuzumab with a chemotherapy backbone for eligible patients. The addition of pertuzumab potentially leads to an approximately 20% higher pCR rate than chemotherapy plus trastuzumab alone. It is unknown whether improved pCR is indicative of EFS or OS, but data shared at 2013 SABCS indicated that an increase in pCR rate correlated with long-term EFS. The second is the recent report of nearly 99% DFS among patients with tumors larger than 3 cm who received trastuzumab therapy after 12 weeks of weekly paclitaxel/trastuzumab. Dr. Verma offers his patients with HER2+ early-stage breast cancer neoadjuvant therapy so that they are eligible for clinical trials under way evaluating T-DM1 versus trastuzumab in patients with residual disease at the time of surgery and after completion of neoadjuvant therapy.
Alternatively, in the United States, patients with larger tumors or locally advanced disease may be offered docetaxel/trastuzumab/pertuzumab (NeoSphere trial). For patients presenting with smaller tumors of 2 cm or smaller, data suggest that paclitaxel/trastuzumab is sufficient for treatment. In summary, Dr. Verma suggests paclitaxel/trastuzumab for patients with T1 tumors, but neoadjuvant pertuzumab/trastuzumab with chemotherapy for patients with locally advanced or large tumors (≥T3). Decisions for the “in between” patients should be made in consultation with the patient and a multidisciplinary team.
Dr. Blackwell also steers patients with confirmed HER2-driven breast cancer toward neoadjuvant treatment, based on coverage of pertuzumab and the 2013 approval for its use in combination with trastuzumab in the neoadjuvant setting. She does not adhere to a particular tumor size cutoff for incorporation of pertuzumab; she even offers it to clinically node-negative patients. Even with limited data in smaller tumors, there is consensus among regulatory authorities and researchers that pertuzumab offers benefits when given in a neoadjuvant setting, with a fairly low toxicity. Dr. Blackwell tends to incorporate neoadjuvant pertuzumab/trastuzumab and include, at minimum, a docetaxel regimen. Alternatively docetaxel/carboplatin may be used, per the National Comprehensive Cancer Network (NCCN) guidelines. In some cases, doxorubicin is incorporated. In smaller tumors, Dr. Blackwell advises against a doxorubicin/taxane backbone, and recommends docetaxel or docetaxel plus carboplatin/pertuzumab/trastuzumab per the NCCN guidelines. The dilemma is that in the absence of clinical trials, it is difficult to administer pertuzumab to patients who have received definitive surgery. Dr. Blackwell explained, "At least in my geographic area, we are having to have active discussions with the surgical teams to say if you do see patients with these types of tumors, please refer them to us because this is our time to provide them with a double-antibody combination therapy." Dr. Verma agreed.
Dr. Verma added that another consideration for these patients would be their HR status. Data suggest that when compared with HR+/HER2+ patients, HR-/HER2+ patients are much more likely to have pCR, and the pCR is more likely to correlate with EFS. "At least in our group, there has been some discussion that those patients who are HR-/HER2+, given the higher likelihood of pCR, that even in the smaller tumors we are more likely to offer them neoadjuvant therapy than the HR+/HER2+ tumors," he explained.
Case 3: Triple-Negative Metastatic Breast Cancer
This patient is a 42-year-old woman who was originally treated for triple-negative, early-stage breast cancer (TNBC) with surgery followed by adjuvant therapy with doxorubicin/cyclophosphamide followed by paclitaxel. After a disease-free interval of 1 year, she recurs with metastatic disease. What would you recommend at this point? Would you recommend incorporation of a platinum in her first-line regimen, or reserve this for later? Would you rechallenge with a taxane? Single agent or combo regimen?
For this case, Drs. Blackwell and Verma strongly recommend clinical trial participation and genetic susceptibility testing. Dr. Blackwell believes that it is the best option for this patient with aggressive breast cancer with a chemorefractory time course. They also recommend evaluation of BRCA1 and BRCA2 mutation status for this and all patients under age 50 years who present with TNBC. There are many clinical trials for first-line, recurrent, or metastatic TNBC, including evaluation of a PARP inhibitor alone or with a chemotherapy backbone. In young patients, trials with immunotherapy plus chemotherapy may be of value, as clinicians have realized that TNBC mimics difficult-to-treat carcinomas such as ovarian cancer or non-small cell lung cancer.
If a clinical trial is not an option, platinum-based therapy may be considered. Based on the history of sustained and rapid response to platinum-based chemotherapy, these agents are recommended as first-line therapy for high-burden and symptomatic-disease patients. Dr. Verma tends to use platinum-based therapy early in the course of treatment for these patients. In a cohort being followed at his institution, excellent responses to platinum chemotherapy have been observed; he tends to use cisplatin or carboplatin, along with gemcitabine.
For patients who have experienced a short disease-free interval and are relapsing, Dr. Verma recommends capecitabine as a good option. In the setting of low-burden disease, he considers single-agent capecitabine a good choice to gauge response sensitivity. For high-burden symptomatic disease, he recommends a platinum-doublet regimen instead.
Assuming that the BRCA status testing was negative for deleterious mutations, Dr. Blackwell would consider a well-supervised course of single-agent capecitabine based on its favorable tolerability when managed correctly. She explained that the capecitabine approach would partly ensure absence of capecitabine sensitivities before initiation of therapy with platinum chemotherapy. Additionally, both doctors agreed that IV chemotherapy and the significant toxicities that go along with it are not attractive to patients who did not respond to previous adjuvant chemotherapy and that patients may be reluctant to return to the same chemotherapy regimen or approach with which they experienced recurrence.
Dr. Blackwell added that some of the doublet combinations such as gemcitabine/platinum should be considered for patients with a heavy symptomatic burden of disease, due to the longer onset of action seen with antimetabolites (eg, capecitabine). Alternatively, ixabepilone/capecitabine can be given. She bases recommendation of this regimen on it being one of the few regimens studied in this defined population of rapid relapsers who had received an adjuvant taxane within 1 year and that the approval population for ixabepilone/capecitabine was particularly similar to this patient’s characteristics. She acknowledged that this regimen was superior in the first-line setting when added to bevacizumab, with either standard paclitaxel or weekly nanoparticle albumin-bound paclitaxel. "So, there is data to support that this combination is beneficial above capecitabine with added toxicity as a first-line setting, saving the platinums as a second-line,” she concluded. “In particular, with ixabepilone/capecitabine, if you get a meaningful response, you have the option of dropping out one of the doublet agents."
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