Abstract
Purpose
Lapatinib (L) is approved in combination with capecitabine or letrozole for patients with trastuzumab-resistant HER2-positive metastatic breast cancer (MBC). However, there is no efficacy data of L in patients who received prior pertuzumab (P) and ado-trastuzumab emtansine (T-DM1), now included as standard first- and second-line therapies, respectively. The goal of this study was to assess the efficacy of L in a contemporary patient population that received prior P and/or T-DM1.
Methods
We identified patients with HER2-positive MBC who received L (n = 520) between 2003 and 2017 at MD Anderson Cancer Center and selected a target cohort who received L after prior P or T-DM1 (n = 43) with the remaining included in the comparison cohort (n = 477). We evaluated outcome measures including clinical benefit rate (CBR), best tumor response (BTR), duration on L, and time to progression (TTP). Survival analyses used Kaplan–Meier statistics.
Results
CBR was 28% (95% CI 10–32) for the target cohort and 40% (95% CI 36–45) for the comparison cohort. The median duration on L was 5 months (95% CI 3.0–9.0) in the target cohort and 6.7 months (5.9–8.0) in the comparison cohort. In both cohorts, the median time to progression (TTP) and overall survival (OS) were longer in patients with de novo metastatic disease compared to patients with disease recurrence.
Conclusion
L-based therapy is an active therapeutic option and remains a viable option for HER2 + MBC after prior trastuzumab, P and/or T-DM1.
Introduction
The discovery of the HER-2 (erbB2/neu) gene and recognition of its overexpression in approximately 20% of invasive breast carcinomas have led to the subsequent development of HER2-targeted therapies and have dramatically improved outcomes for women with early-stage and advanced HER2-positive breast cancer. The gene encodes a growth factor tyrosine kinase receptor [1] and its overexpression is associated with increased metastatic potential, resistance to hormonal and chemotherapy, higher relapse rates, and decreased OS rate [2]. Despite the remarkable success of trastuzumab (Herceptin; Genentech, South San Francisco, CA), nearly all patients with HER-2 positive metastatic breast cancer will eventually progress on trastuzumab and a number experience relapse after trastuzumab—containing adjuvant and neoadjuvant therapy [3,4,5,6]. A number of newer anti-HER2 targeted therapies have been approved including lapatinib (metastatic, 2007) [7,8,9]; pertuzumab (metastatic, 2012) (neoadjuvant, 2013) [10,11,12,13]; ado-trastuzumab emtansine (T-DM1) (metastatic 2013) [14].
The FDA initially approved lapatinib (Tykerb; Novartis Pharmaceuticals Co., East Hanover, New Jersey) in combination with capecitabine in March 2007 based on a randomized control trial of patients who progressed on an anthracycline, taxane, and trastuzumab, which showed statistically significant increase in response rates and TTP, but not OS when compared to capecitabine alone [7]. At the time of lapatinib’s approval, the standard first-line metastatic treatment was trastuzumab in combination with a taxane resulting in a 2nd line indication for lapatinib [3, 15, 16]. The use of lapatinib was also studied in combination with trastuzumab in a randomized, phase 3 trial, EGF104900, of patients having progressed on prior trastuzumab-based therapy. This trial showed that despite progression on prior trastuzumab, patients receiving combination lapatinib and trastuzumab had increased progression-free survival (PFS) and OS compared to patients receiving lapatinib alone [8]. Furthermore, lapatinib alone and in combination with capecitabine has also shown activity in clinical trials for the treatment of breast cancer brain metastases [17,18,19]. The LANDSCAPE trial, a single-group phase 2 study, showed a nearly 2/3 objective CNS volumetric response rate in forty-four patients receiving combination lapatinib and capecitabine as first-line treatment of breast cancer brain metastases [17].
With the introduction of pertuzumab (Perjeta; Genentech, South San Francisco, CA) and T-DM1 (Kadcyla; Genentech, South San Francisco, CA), lapatinib is commonly used after patients have received 2 or more lines of HER 2-directed therapy in the metastatic setting. Currently, the standard first-line therapy for metastatic HER2-positive breast cancer is pertuzumab in combination with trastuzumab and a taxane based on the landmark randomized phase 3 CLEOPATRA trial that showed a PFS and OS benefit, resulting in FDA approval for pertuzumab in the metastatic setting in June 2012 [10, 11]. Since 2013, T-DM1 has been established as the preferred second-line agent based on the results of the landmark, randomized phase 3 EMILIA trial, which demonstrated increased PFS and OS for T-DM1 compared to lapatinib plus capecitabine in patients previously treated with trastuzumab and a taxane [14, 20, 21]. In a subsequent randomized phase 3 study (TH3RESA trial), T-DM1 showed an increased PFS and OS when compared to physician’s choice therapy in patients having received and progressed on prior treatment with both trastuzumab and lapatinib [22, 23]. Based on these data, T-DM1 is the current 2nd-line therapy for metastatic HER2-positive MBC after progression on one previous line of taxane and trastuzumab-based therapy. T-DM1 is also used in the first-line metastatic setting in patients who have received neoadjuvant pertuzumab and/or have progressed within 1 year of completing adjuvant trastuzumab. Prior to the FDA approval of T-DM1, lapatinib was used in earlier lines and now, lapatinib is commonly used after progression on trastuzumab, pertuzumab, and T-DM1. There are no published data to predict tolerability and efficacy of lapatinib in this setting. The goal of this project is to assess the efficacy and tolerability of lapatinib in routine clinical practice in a contemporary patient population that includes patients who have received prior therapy with trastuzumab, pertuzumab, and/or T-DM1.
Methods
Patient population
Electronic pharmacy records and a prospectively maintained departmental database were used to identify patients with HER2- positive MBC who received L-based therapy between August 1, 2003 and January 1, 2017 at MD Anderson Cancer Center. Most patients received HER2 targeted therapy as per standard guidelines and routine clinical care. Only18 patients were treated in the comparison cohort with L-based therapy prior to the approval in 2007 (lapatinib was approved by the US Food and Drug Administration in the United States on March 13th, 2007); however, these patients were all treated with standard lapatinib-based combinations (in combination with capecitabine, trastuzumab, or endocrine therapy). This study was approved by the institutional review board at MD Anderson Cancer Center, and waivers for obtaining informed consent were granted.
Data collection
For each record, a data acquisition form was completed and the following data items were collected: patient demographics including date of birth and race; tumor characteristics, including date of diagnosis of primary breast cancer and metastatic recurrence; estrogen receptor (ER) and progesterone receptor (PR) status of the primary tumor and metastatic lesions if the receptor status was reassessed; HER2 status including immunohistochemistry (IHC) and fluorescent in-situ hybridization (FISH) results if both were available; and sites of metastases at the time of starting lapatinib including bone, visceral, brain, or soft tissue (i.e., skin, lymph node, or breast). ER/PR status and HER2 status were assigned according to the 2010 and 2013 ASCO/College of American Pathologists guidelines, respectively, on the basis of local pathology results [24, 25]. Treatment history was also collected including prior neoadjuvant and/or adjuvant chemotherapy regimens, adjuvant endocrine regimens, and the number and types of chemotherapy given in the metastatic setting. The first treatment administered for metastatic disease was counted as the first-line therapy. The next new treatment administered at the time of progression during or after first-line therapy was recognized as second-line therapy, and the numbering of the lines of treatment continued in this manner. The dates of first and last courses of trastuzumab, pertuzumab, T-DM1, and lapatinib as well as the combinations of chemotherapy used in conjunction with lapatinib were also included. Tumor response was based on the treating physician assessment and judgment in the context of routine clinical care. Radiology reports and results of clinical assessments during lapatinib-based therapy were reviewed as documented in the medical record to assign tumor response. Reasons for discontinuation of lapatinib were also extracted from medical records as well as date of death, if applicable.
Statistical analysis
The primary outcome measure was clinical benefit rate (CBR), defined as complete response, partial response, or stable disease for more than 6 months on L-based therapy. Other outcomes measured include best tumor response (BTR), median duration on L, time to progression (TTP), and overall survival (OS). Best tumor response (BTR) was based on Response Evaluation Criteria in Solid Tumors (RECIST) criteria, defined as physician-reported response on the basis of imaging and clinical assessment: PD, progressive disease; SD, stable disease; PR, partial response; CR complete response. Duration on L-based therapy was measured from the date of a patient’s first lapatinib treatment to the date of the last lapatinib treatment. TTP was measured from the date of a patient’s first L treatment to the date of progression. OS was measured from the date of a patient’s first L treatment to date of death or last follow-up. Descriptive statistics were calculated for all patients and reported with point estimates and 95% exact binomial confidence intervals. These metrics were calculated for the target cohort and the comparison cohort separately as well as by subsets: ER-positive and/or PR-positive (HR-positive) tumors, ER-negative and PR-negative (HR-negative) tumors, de novo metastatic disease, metastatic recurrence < 1 year after initial diagnosis, and metastatic recurrence > 1 year after initial diagnosis. The Kaplan–Meier method was used to estimate survival curves from the time of first L-based treatment and to calculate time on L and time to progression distributions for each cohort.
Results
Of 520 patients identified, a target cohort of 43 patients was identified who received lapatinib-based therapy after receiving trastuzumab, pertuzumab, and/or T-DM1. The remaining 477 patients who received lapatinib without prior exposure to pertuzumab or T-DM1 were labeled as the comparison cohort. In both cohorts, all patients were available for response analysis; One patient in the comparison cohort, had missing follow-up data for overall survival and freedom from progression analyses. Table 1 shows the patient characteristics. Median age at primary diagnosis was higher for the comparison cohort compared to the target cohort; 30% of the comparison cohort had de novo disease versus 19% in the target cohort; 33% of the comparison cohort had brain metastases versus 19% in the target cohort. The median number of lines of therapy prior to lapatinib was higher in the target cohort versus the comparison cohort, 2.5 and 1.0, respectively. Of note, 35% of patients received lapatinib-based therapy in the first-line setting in the comparison cohort. In the target cohort, nearly 48% (n = 21) had received 3 or more lines of therapy prior to lapatinib compared to 21% (n = 101) in the comparison cohort. Similar distribution of metastatic sites was found in both cohorts; there were fewer brain metastases in the target cohort 19% compared to 33% in the comparison cohort. Discontinuation of lapatinib due to toxicity was low in both groups with only 2 patients (5%) stopping lapatinib in the target cohort due to thrombocytopenia and 43 patients (9%) discontinuing lapatinib in the comparison cohort. Reasons for discontinuation in the comparison cohort include diarrhea (n = 21), skin toxicity (n = 4), hepatotoxicity (n = 3), intractable emesis (n = 2), cardiotoxicity (n = 2), hand-foot syndrome (n = 3), pancreatitis (n = 1), and not otherwise specified (n = 7).
Table 1.
Patient characteristics
| Target cohort (N = 43) | Comparison cohort (N = 477) | |
|---|---|---|
| Median age, years (range) | 44 (26,70) | 51 (24,85) |
| Hormone receptor status, n (%) | ||
| ER and/or PR positive | 27 (63) | 253 (53) |
| ER and/or PR negative | 16 (37) | 224 (47) |
| Disease-free interval, n (%) | ||
| De Novo | 8 (19) | 140 (30) |
| Recurrent | 35 (81) | 337 (70) |
| Metastatic recurrence ≤ 1 year after diagnosis | 7 (16) | 48 (10) |
| Metastatic recurrence > 1 year after diagnosis | 28 (65) | 289 (60) |
| Sites of metastasis at start of L, n (%) | ||
| Soft tissuea | 31 (72) | 255 (53) |
| Lung | 18 (42) | 152 (32) |
| Liver | 20 (47) | 166 (35) |
| Bone | 22 (51) | 225 (47) |
| Brain | 8 (19) | 156 (33) |
| Prior lines of metastatic therapy prior to lapatinib, n (range) | ||
| 0 | 1 (2) | 168 (35) |
| 1 | 7 (16) | 133 (28) |
| 2 | 13 (30) | 75 (16) |
| 3 | 11 (25) | 49 (10) |
| 4 | 3 (7) | 25 (5) |
| ≥ 5 | 7 (16) | 27 (6) |
| Number of distinct sites of metastases, n | ||
| 1 | 10 (23) | 190 (40) |
| 2 | 16 (37) | 152 (32) |
| 3 | 11 (26) | 89 (19) |
| 4 | 6 (14) | 37 (7) |
| 5 | 0 (0) | 9 (2) |
| Discontinuation of lapatinib due to toxicity, n (%) | 2 (5) | 43 (9) |
Soft tissue includes lymph nodes, skin, pleura, and peritoneum
ER estrogen receptor, PR progesterone receptor
Table 2 shows the types of prior therapies for metastatic disease before lapatinib in the target cohort. The majority 93% had received trastuzumab, 77% had received pertuzumab, and 77% had received TDM-1. Most patients received L in combination with capecitabine (L + C), followed by L in combination with trastuzumab (L + T) and only a small proportion of patients received L with endocrine therapy (L + E) or other chemotherapies (as shown in Fig. 1).
Table 2.
Type of prior therapies for metastatic disease before lapatinib in target cohort (n = 43)
| Prior therapy | Number of patients (%) |
|---|---|
| Trastuzumab | 40 (93) |
| Pertuzumab | 33 (77) |
| TDM-1 | 33 (77) |
| Taxane | 35 (81) |
| Hormonal therapy | 11 (26) |
| Capecitabine | 4 (9) |
| Vinorelbine | 6 (14) |
| Doxorubicin | 6 (14) |
| Cyclophosphamide | 5 (12) |
| Carboplatin | 5 (12) |
| Gemcitabine | 2 (5) |
| Ixabepilone | 1 (2) |
| Eribulin | 1 (2) |
| Tucatinib (ONT-380) | 4 (9) |
Fig 1.
Duration on lapatinib-based therapy by regimen in the target cohort (n = 43)
Table 3 shows the overall efficacy results. Median duration on lapatinib was 5 months (95% CI 3.0–9.0) for the target cohort versus 6.7 months (95% CI 5.9–8.0) for the comparison cohort. The duration on L-based therapy by regimen for the target cohort is shown in Fig. 1. CBR was 28% (95% CI 10–32) in the target cohort versus 41% (95% CI 36–45) in comparison cohort. Median TTP was 6.0 months (95% CI 4.7–9.0) in the target cohort and 8.7 months (95% CI 7.7–10.0) in the comparison cohort (Fig. 2). Longer median TTP was seen with de novo metastatic disease compared to recurrent disease in both the target and comparison cohorts. The median TTP was shortest for patients with recurrence within 1 year of diagnosis: 2.8 months (95% CI 2.3, NR) in the target cohort compared to 8.3 months (6.5,11.0) in the comparison cohort. Median OS was 23.9 months (95% CI 18.4-NR) in the target cohort and 25.8 months (95% CI 22.8–30.7) in the comparison cohort (Fig. 3). Longer OS was seen in patients with de novo compared to recurrent disease and in patients with HR+ compared to HR- in both groups.
Table 3.
Results
| Characteristic | Target cohort (N = 43) | Comparison cohort (N = 477) |
|---|---|---|
| Median duration on lapatinib, months (95% CI) | 5.0 (3.0, 9.0) | 6.7 (5.9, 8.0) |
| De novo | 7.8 (7.4, NR) | 5.9 (5.0, 9.0) |
| Recurrence < 1 year | 2.8 (2.3, NR) | 6.9 (5.8, 10.0) |
| Recurrence > 1 year | 4.9 (3.0, 9.0) | 6.8 (5.8, 8.3) |
| HR positive | 5.0 (3.0, 10.1) | 6.5 (5.8, 8.2) |
| HR negative | 4.9 (2.3, NR) | 6.7 (5.7, 8.8) |
| BTR, n (%) | ||
| PD | 25 (58%) | 155 (32%) |
| SD | 15 (35%) | 267 (56%) |
| PR | 3 (7%) | 26 (5%) |
| CR | 0 (0%) | 6 (1%) |
| Too early? | 23 (5%) | |
| CBR, n (%) | 12 (28%) | 186/454 (41%) |
| De novoa | 2 (25%) | 39/97 (40%) |
| Recurrence ≤ 1 yearb | 0 (0%) | 37/79 (47%) |
| Recurrence > 1 yearc | 10 (36%) | 110/278 (40%) |
| HR positive | 8 (30%) | 85/213 (40%) |
| HR negative | 4 (25%) | 101/240 (42%) |
| Median TTP, mo. (95% CI) | 6.0 (4.7, 9.0) | 8.7 (7.7, 10.0) |
| De novoa | 7.8 (7.4, NR) | 9.0 (5.9, 16.3) |
| Recurrence ≤ 1 yearb | 2.8 (2.3, NR) | 8.3 (6.5, 11.0) |
| Recurrence > 1 yearc | 5.0 (3.0, 10.1) | 8.7 (7.7, 10.8) |
| HR positive | 5.0 (4.7, 10.1) | 9.0 (7.3, 11.0) |
| HR negative | 6.1 (2.3, NR) | 8.5 (6.9, 10.0) |
| Median OS, mo. (95% CI) | 23.9 (18.4, NR) | 25.8 (22.8, 30.7) |
| De novo | 23.9 (NA, NR) | 23.4 (18.7, 37.2) |
| Recurrence ≤ 1 year | 18.4 (14.0, NR) | 22.5 (18.7, 35.8) |
| Recurrence > 1 year | 19.3 (15.3, NR) | 26.5 (23.2, 35.8) |
| HR positive | NR (15.3, NR) | 31.9 (26.0, 39.4) |
| HR negative | 19.3 (18.4, NR) | 20.7 (16.3, 25.5) |
HR hormone receptor, BTR best tumor response, PD progressive disease, SD stable disease, PR partial response, CR complete response, CBR clinical benefit rate, TTP time to progression, OS overall survival, NR not reached, CI confidence interval
Presented with de novo stage IV disease; de novo defined as identified to have metastatic disease within 3 months of diagnosis
Presented with recurrent disease within 1 year of initial diagnosis
Presented with recurrent disease after 1 year from initial diagnosis
Fig 2.
Kaplan–Meier estimate of freedom from progression
Fig 3.
Kaplan–Meier estimate of overall survival
Discussion
This is the first report demonstrating the efficacy of L in a contemporary patient population that has received prior trastuzumab, pertuzumab, and/or T-DM1 (target cohort) compared to the efficacy of L in a comparison cohort who received L in a different setting. Our findings show that the CBR of L in the target cohort is lower at 28% and the CBR of L in the comparison cohort is higher at 41% compared to historical trials. In the pivotal phase 3 trial, which led to the establishment of capecitabine plus lapatinib as the 2nd line treatment, the CBR was 29% [7]. Later, a chemotherapy-free treatment option with lapatinib plus trastuzumab was evaluated in a more heavily treated patient population with a slightly lower CBR of 25% [8, 9]. The target cohort in our study was heavily treated with over 48% of patients receiving 3 or more lines of therapy and 16% of patients receiving at least 5 lines of therapy. Further, patients in the target cohort had a lower incidence of brain metastases, which may be explained by the higher exposure to effective HER2-directed therapies early in the disease course. In both cohorts, TTP and OS were higher for patients with de novo stage IV metastatic breast cancer compared to recurrence disease. Additionally, L was well tolerated with 5% discontinuing L-based therapy in the target cohort due to thrombocytopenia and 9% in the comparison cohort mainly due to diarrhea.
Regarding limitations, this is a retrospective study performed at a single institution, which is a high volume referral center. Given the heterogeneous patient population, only limited comparisons can be made with prior trial results. Our comparison cohort includes patients with similar criteria to historical trials; however, we note higher response rates which may be due to selection bias. We use duration on therapy as an approximation of PFS or time to treatment failure. This is a reasonable surrogate for PFS given that the majority of patients discontinued L-based therapy due to disease progression and not toxicity. Other limitations of this study are inherent to the retrospective comparison of non-randomized and unbalanced groups which may introduce bias of unmeasured variables. Further, the target cohort is a small number of patients as illustrated by the wide confidence intervals reported in some of the clinical outcomes, thereby limiting statistical comparisons that can be made between the two cohorts. Additionally, there is inherent selection bias in the target cohort as all of these patients had prior exposure to trastuzumab, pertuzumab, and TDM-1 and were well enough to receive lapatinib-based therapy.
Our data provide context for ongoing clinical trials and future trials being designed which may enroll a similar population of patients as our target cohort, who have exposure to trastuzumab, pertuzumab, and/or T-DM1. Of note, 9% of patients in the target cohort had received treatment on a clinical trial with an investigational HER2-specific inhibitor, tucatinib (ONT-380) that is currently being evaluated in a randomized phase 2 clinical trial is actively enrolling patients who have received prior taxane, trastuzumab, pertuzumab, and T-DM1(HER2CLIMB; NCT02614794) [26, 27]. Despite prior exposure to a kinase inhibitor, this small number of patients received varying levels of benefit from L-based treatment as noted in Fig. 1.
In conclusion, L remains a therapeutic option for patients with HER2-positive metastatic breast cancer despite being previously treated with multiple anti-HER2 therapies. The target cohort experience reported here provides additional information for the activity of L-based therapy and management of a contemporary patient population after treatment with multiple novel HER2-directed therapies. Although only 28% of patients experienced clinical benefit after prior trastuzumab, P, and T-DM1, toxicity was limited and patients with de novo stage IV metastatic disease gained more benefit than patients with recurrent disease. Our findings are in alignment with what is known in the treatment of metastatic breast cancer—that the chance of responding to and benefiting from therapy diminishes with each successive line of therapy. Yet, L continues to be active in later lines in a clinically relevant manner.
Funding
The database used for this work is supported by the Breast Medical Oncology departmental funds at MD Anderson Cancer Center. KR Hess was supported by the NIH/NCI under award number P30CA016672 and used the Biostatistics Resource Group shared resource.
Conflict of interest
Luiz Baez-Vallecillo, Akshara S. Raghavendra, Kenneth R. Hess, Carlos H. Barcenas, and Vicente Valero report no conflict of interest relevant to this work. Stacy L. Moulder serves or has served as a consultant for Novartis, Oncothyreon, Pfizer, and Immunogenics. Debu Tripathy serves as a consultant for Novartis and Pfizer, and also receives funding from Novartis. Rashmi K. Murthy receives research funding from Cascadian therapeutics, Daiichi Sankyo, Genentech, and Pfizer (all in research support paid to the institution).
Footnotes
Ethical approval
This article does not contain any studies with human participants or animals.
Informed consent
This study was approved by the institutional review board at MD Anderson Cancer Center, and waivers for obtaining informed consent were granted.
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