US Food and Drug Administration-approved anti-human epidermal growth factor receptor 2 agents for breast cancer

However, in certain clinical scenarios, the treatment decision-making becomes arduous due to limited availability of evidence. Moreover, the interpretation and applicability of Western data in Indian population could be challenging given the diverse socio-cultural-economic environment. This article discusses some representative scenarios commonly seen in India, examines the available high-level evidence relevant to such scenarios, and provides treatment recommendations based on the consensus of a panel of experts. However, the panel acknowledges that for any given patient, the clinical judgment of the treating physician, considering all factors, should take precedence over expert recommendations.

Drugs used in various treatment protocols used to treat acute lymphoblastic leukemia

The CLEOPATRA trial investigated single-versus-dual HER2 blockade (trastuzumab plus placebo versus trastuzumab plus pertuzumab, a HER2 dimerization inhibitor), in combination with a taxane, in HER2-positive mBC.[10],[14] In this trial, approximately 50% of patients were treatment naïve and only 10% of patients had received trastuzumab in the (neo) adjuvant setting, as recruitment began <2 href="https://www.thieme-connect.com/products/ejournals/html/10.4103/ijmpo.ijmpo_201_17#JR_19" xss=removed>19] Median PFS in the pertuzumab arm was significantly longer than that in the comparator arm [Table 2]; the between-group difference was statistically significant across all subgroups. In the subgroup of patients who had received adjuvant or neoadjuvant therapy with trastuzumab, the median PFS was increased by 6.5 months in the pertuzumab arm (hazard ratio [HR], 0.62; 95%-confidence interval, 0.35–1.07).[15] Despite the presence of visceral metastasis in 78% of the patients, the median survival approached 5 years in the pertuzumab arm. Indeed, at the time of reporting, patients had spent more time off pertuzumab than on it (18 months of PFS followed by approximately 38 months of post-PFS).[14] Similar to the “carryover” effect observed after cessation of tamoxifen,[20] the survival curves continued to diverge; this phenomenon is usually not seen with other oncology drugs. Post the trial treatment, nearly 72% of the patients received additional HER2-directed treatment and this proportion was comparable in both the study arms. There was a 10-month difference in the post-PFS between the pertuzumab and the control arm,[14] although the OS was comparable in patients with and without prior trastuzumab exposure.[15] The adverse events reported in the study included neutropenia, which was primarily attributed to concomitant treatment with docetaxel.[21] It may be noted that in the safety analysis of the ongoing PERUSE study (n = 1436), the preliminary toxicity profile of first-line pertuzumab, trastuzumab, and the investigator's choice of taxane regimen was generally consistent with the previous clinical experience of pertuzumab and the known taxane safety profile.[22]

A real-world, retrospective noninterventional study [23] assessed the clinical outcomes of patients treated with pertuzumab containing therapy as first-line treatment in US community oncology practices. Most patients (93.6%) were treated with a combination of pertuzumab, trastuzumab, and a taxane (docetaxel or paclitaxel or nab-paclitaxel). In line with the current practice, 61.5% of patients received (neo) adjuvant trastuzumab. The median PFS (16.9 months) and toxicity profile were similar to that observed in the CLEOPATRA trial.

Blockade of the HER2 receptor may trigger signaling via alternate pathways.[24] Thus, it may be hypothesized that dual blockade (of the HER2 receptor and of a component of the downstream PI3K/AKT/mammalian target of rapamycin [mTOR] canonical pathway) could potentially lead to more effective outcomes than those achieved with HER2 targeting alone. However, in the BOLERO-1 trial that tested dual blockade of HER2 and mTOR in early mBC, there was no significant difference in PFS between the trastuzumab plus everolimus and the trastuzumab plus placebo arms in the overall population [Table 2], although there was a potential signal of benefit in patients with hormone receptor-negative disease.[16]

The noninferiority MARIANNE trial compared T-DM1 with or without pertuzumab against trastuzumab and docetaxel. A more resistant population was also enrolled in this trial (>6 months of prior [neo] adjuvant vinca alkaloid or taxane chemotherapy). Thirty percent of the patients in both arms had received prior (neo) adjuvant HER2-targeted (trastuzumab/lapatinib) therapy. No significant between-group difference in outcomes was observed in this trial [Table 2].[17] Of note, the combination of trastuzumab, pertuzumab, and taxane was not approved at the time of this trial and was, therefore, not tested.

A prospective observational study (registHER) by Yardley et al.[25] revealed significantly better outcomes in patients with de novo HER2-positive mBC as compared to those with recurrent HER2-positive mBC (OS: 41.7 vs. 32.8 months, respectively; HR: 0.766). Prior adjuvant chemotherapy perhaps renders the mBC more refractory to treatment because of the selection of resistant or aggressive clones of HER2-positive cells.

In the EMILIA study, a Phase 3 trial, patients treated with the antibody drug conjugate T-DM1 had significantly longer PFS and OS than those treated with a combination of lapatinib and capecitabine [11] [Table 2]. T-DM1 significantly improved PFS and OS among patients with HER2-positive mBC with a disease-free interval of <6 href="https://www.thieme-connect.com/products/ejournals/html/10.4103/ijmpo.ijmpo_201_17#OR_18" xss=removed>18]

Economic impact of various human epidermal growth factor receptor 2-directed treatments

In this context, some Indian centers have reported that there is limited access to HER2-targeted therapies for their patients,[3],[6] although this situation is now improving (Sudeep Gupta, personal communication). Anti-HER2 therapy has substantial cost implications, especially for low- and middle-income countries.[26] Durkee et al. assessed the cost-effectiveness of pertuzumab therapy in HER2-positive mBC based on modeling the survival from the raw data of the CLEOPATRA study and also took into account other associated costs (cost of other drugs, hospitalization, toxicity, and subsequent treatments). They concluded that the addition of pertuzumab to trastuzumab and taxane was unlikely to be cost-effective in the United States.[27]

In India, the cost of pertuzumab is currently capped under a patient assistance program. A patient pays for 13 vials over 36 weeks (9 months), and drugs for subsequent treatment cycles are supplied free until the progression of disease. Therefore, the incremental cost-effectiveness ratio may be more favorable in the Indian context under this assistance program.

Panel recommendation

Pertuzumab in combination with trastuzumab and taxane is recommended as the first-line therapy for HER2-positive patients, including patients with or without prior (neo) adjuvant trastuzumab (relapsed >12 months after [neo] adjuvant use), as well as those with de novo mBC.

For patients who have relapsed within 6 months of adjuvant trastuzumab, T-DM1 can be considered as a preferred therapeutic option. The panel acknowledges that there is insufficient level-one data to make recommendations for the group that relapse between 6 and 12 months from the end of adjuvant therapy. The use of pertuzumab-trastuzumab-taxane, T-DM1, or other anti-HER2 combinations can be considered by treating physicians in this scenario.

Clinical Scenario 2: Second-Line Treatment for Human Epidermal Growth Factor Receptor 2-Positive Metastatic Breast Cancer, Progressed on Trastuzumab

A 45-year-old woman was diagnosed 6 years ago with HER2-positive and hormone receptor negative breast cancer (T2N1M0; 20 mm in size, Grade 2). Following a mastectomy and axillary dissection, she underwent adjuvant treatment with doxorubicin and cyclophosphamide (AC; 4 cycles), weekly paclitaxel (12 cycles), and trastuzumab for a total duration of 1 year. She developed HER2-positive, hormone receptor-negative hepatic metastases 5 years later and was treated with weekly paclitaxel in combination with trastuzumab. After 6 months of trastuzumab monotherapy, a new lesion was found in the liver.

The following treatment regimens were considered for discussion in this scenario:

1. Lapatinib in combination with capecitabine

2. T-DM1

3. Vinorelbine in combination with trastuzumab and everolimus

4. Vinorelbine in combination with afatinib.

Literature analysis

The EGF100151 study included patients with HER2-positive mBC who progressed after treatment with regimens containing anthracyclines, taxanes, and trastuzumab. A significant improvement in median TTP and overall response rate was observed with lapatinib combined with capecitabine versus. monotherapy;[28] however, there was no significant difference in median OS [29] between the two treatment arms.

In the EMILIA trial, patients with HER2-positive mBC previously treated with trastuzumab in combination with a taxane were randomized to either lapatinib plus capecitabine or T-DM1. PFS and OS in the T-DM1 arm were superior than that in the lapatinib plus capacitabine arm [Table 3].[11] In a subgroup of patients (n = 118) who had relapsed within 6 months of completion of adjuvant treatment, PFS with T-DM1 (10.8 months) was significantly longer than that with the combination of lapatinib and capecitabine (5.7 months).[18] The commonly reported adverse effects of T-DM1 were elevation of liver enzymes and thrombocytopenia and both these adverse effects were manageable.[11]

Overview of trials in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer who progressed on trastuzumab therapy

Overview of trials involving human epidermal growth factor receptor 2-positive patient population with and without central nervous system metastasis at baseline

In the CLEOPATRA study, the combination of pertuzumab, trastuzumab, and docetaxel was superior to that of placebo, trastuzumab, and docetaxel in delaying the onset of CNS disease [Table 4], an effect that is likely attributable to the superior systemic disease control achieved with pertuzumab-based treatment.[38]

Overview of clinical trials on patients with human epidermal growth factor receptor 2-positive metastatic breast cancer progressed on two anti-human epidermal growth factor receptor 2 agents

In the EGF104900 trial, the median number of prior anti-HER2 therapies for mBC was 3. PFS and OS in the lapatinib plus trastuzumab arm were significantly longer than that with lapatinib alone [Table 5]. Improvement in absolute OS rate at 6 and 12 months was 10% and 15%, respectively, in the combination arm compared with the monotherapy arm.[45],[46]

Panel recommendations

For patients with HER2-positive mBC who progress on anti-HER2 agents (trastuzumab and lapatinib), T-DM1 should be the treatment of choice. An alternative option may be chemotherapy in combination with trastuzumab. For heavily pretreated patients who have received multiple lines of treatment, a dual HER2-targeted regimen (i.e., trastuzumab and lapatinib) may be considered.

Conclusion

Based on evidence from multiple well-conducted clinical trials, anti-HER2 therapy has become a central element in the therapeutic strategy for HER2-positive mBC leading to a paradigm shift in the management of HER2-positive breast cancer. In the Indian scenario, in addition to available evidence, socioeconomic variables would need to be considered by treating physicians. The panel of experts has summarized the evidence and made recommendations pertaining to commonly encountered clinical scenarios in HER2-positive mBC that may potentially improve patient outcomes.

Acknowledgment

The authors would like to acknowledge medical writing and editing support provided by A Dharman, S Verma, and KS Saini of Quantum Health Analytics SPRL, Belgium.

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Publication History

Article published online:
17 June 2021

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