Efficacy and Safety of Trastuzumab and Lapatinib Combined Chemotherapy in Real-World Setting HER2+ MBC

15 May, 20

Introduction

Combination of trastuzumab (T) and lapatinib (L) has been shown to significantly improve the prognosis of HER2+ heavily pretreated metastatic breast cancer (MBC). TL combined chemotherapy (TLC) has become one of the commonly used therapeutic

schemes, but the efficacy and safety of TLC is still lack of large-scale clinical research, especially in the metastatic setting.

Aim

To report the first real-world data of TLC in HER2+ MBC, including the efficacy, safety and treatment patterns

Patient Profile

N= 285 patients
Female patients age > 18 years with “histologically or cytologically confirmed MBC with documentation of HER2 overexpression (i.e., immunohistochemistry 3 + and/or fluorescent in situ hybridization-positive by local assessment)”
Patients received trastuzumab 6 mg/kg weekly (after the initial 8 mg/kg loading dose) plus lapatinib (750 mg−1,250 mg/day) plus chemotherapy regimen (by physicians’ choice), starting from September 2013 to July 2019

Methods

Study Design

Retrospective, multicenter study
Patients were prescribed with TLC in clinical practice.
The combination therapy with cytotoxic drugs and the starting dose, dose modification and treatment discontinuation of TLC was determined by physicians’ choice based on previous clinical trials results, general health status and willing of patients.

Table 1: Treatment Administration

TLC treatment	Number of patients (%) (N = 285)
STARTING REGIMENS
TL+ capecitabine	116 (40.7)
TL+ vinorelbine	61 (21.4)
TL+ paclitaxel	33 (11.6)
TL+ paclitaxel+ carboplatin	17 (6.0)
TL+ gemcitabine	14 (5.0)
TL+ docetaxel	13 (4.6)
TL+ vinorelbine + capecitabine	7 (2.5)
Other	24 (8.4)
Maintenance treatment regimen	93 (33.0)
TL	22 (23.7)
TL+ capecitabine	20 (21.5)
T+ CT	18 (19.4)
L+ CT	18 (19.4)
TL+ endocrine therapy	7 (7.5)
TL+ another CT	5 (5.4)
T	3 (3.2)
LAPATINIB Starting dosage (mg/day)
1,250	141 (49.5)
1,000	99 (34.7)
750	37 (13.0)
500	8 (2.8)
Dose reduction (mg/day)
1,250→ 1,000	27 (9.5)
1,250→ 1,000→ 750	4 (1.4)
1,000→ 750	17 (6.0)
1,000→ 750→ 500	4 (3.5)
1,000→ 750→ 1000	1 (0.4)
750→ 500	3 (1.1)
Dose escalation (mg/day)
500→ 750→ 1,000	1 (0.4)
1,000→ 1,200	5 (1.8)
Interruption of lapatinib treatment	30 (10.5)
Lapatinib treatment discontinuation due to AEs	16 (5.7)
CHEMOTHERAPY
Dose reduction
Yes	53 (18.6)
No	232 (81.4)

T, trastuzumab; L, lapatinib; C; chemotherapy; AEs, adverse events.

Study Outcomes

Primary Outcome
- Progression-free survival (PFS), defined as the time from initiating TLC to date of tumour progression or death of any cause
Secondary Outcomes
- Objective response rate (ORR), defined as the percentage of patients with complete response (CR) or partial response (PR)
- overall survival (OS) defined as the time period from initial treatment of TLC to death or last follow-up
- Adverse events (AEs) were retrospectively collected based on patients’ laboratory

Results

Table 2: Baseline Characteristics

Characteristics	Number of patients (%) (N = 285)
Median age (years, range)	50 (26–87)
ECOG PERFORMANCE-STATUS SCORE
0	78 (27.3)
1	193 (67.7)
2	14 (5.0)
HORMONE RECEPTOR STATUS
HR-positive	115 (40.4)
HR negative	170 (59.6)
DISEASE-FREE INTERVAL
Primary metastatic	69 (24.2)
DFI ≤ 1year	71 (25.0)
DFI > 1year	145 (50.9)
METASTATIC SITES
Lung	112 (39.3)
Liver	107 (37.5)
Bone	119 (41.8)
Brain	69 (24.2)
NUMBER OF METASTATIC SITES
1	77 (27.0)
2	91 (32.0)
≥3	117 (41.1)
VISCERAL METASTASES
Yes	209 (73.3)
No	76 (26.7)
LINES OF ADVANCED SYSTEMATIC THERAPY OF TLC
1	65 (22.8)
2	80 (28.1)
≥3	140(49.1)
TRASTUZUMAB RESISTANCE STATUS
Resistance	118 (41.4)
Refractoriness	133 (46.7)
Unknown	28 (10.0)
PRIOR HER2-TARGETED THERAPY
Trastuzumab	253 (88.8)
Lapatinib	52 (18.2)
T-DM1	15 (5.3)
Pertuzumab	2 (0.7)

88.8% were exposed to trastuzumab, and 49.2% received 2 or more lines of systematic therapy before TLC previously.
The most common chemotherapy regimens combined with TL were capecitabine (40.7%), and vinorelbine (21.4%) and almost 1/3 received maintenance treatment after TLC.

At a median follow-up of 16 months
- 189 patients experienced progressive disease, resulted in a median PFS of 10.9 (9.67–12.07) months
Patients received TLC as a first-line treatment showed the longest median PFS of 20.7 months

Figure 1: Progression-free survival (PFS) for all patients and patients stratified by treatment lines

Patients pretreated with trastuzumab showed a median PFS of 10.2 months.
In patients who were pretreated with trastuzumab, the continuation of trastuzumab based on standard lapatinib plus capecitabine had a median PFS of 11.3 months.
No significant difference in median PFS was reported in patients treated with TL combined with capecitabine or vinorelbine
- TL combined with capecitabine had numerically prolongation (11.4 vs 8.5 months, p = 0.231).

Patients with brain metastasis (BM) also showed a median PFS (intracranial and extracranial lesions considered) of 10.6 months
Univariate analysis indicated that
- number of metastatic sites (<2 vs>2)
- types of metastasis (visceral vs non-visceral)
- lines of metastatic systematic therapy of TLC (1 vs 2 vs>3)
- prior exposure to lapatinib were significantly correlated with PFS

Table 4: Factors associated with progression-free survival

Characteristic	HR	Log-rank analysis P-value	HR	Cox multivariate analysis P-value
Age group (<60 vs ≥60)	1.174	0.356
Hormone receptor status (HR+ vs. HR-)	1.062	0.684
DFI (>1year vs. ≤1year)	1.181	0.370		0.328
Number of metastatic sites (≤2 vs>2)	1.661	0.001	1.373	0.054
Types of metastasis (visceral vs. non-visceral)	1.511	0.018	1.079	0.650
Lines of advanced systematic therapy of TLC (1 vs 2 vs ≥3)	1.891	<0.001	1.778	<0.001
Trastuzumab Resistance Status (resistance vs. refractoriness)	1.244	0.159
Prior exposure to lapatinib (yes vs. no)	1.684	0.005	1.257	0.302

HR, Hormone receptor; DFI, Disease-free interval; TLC, trastuzumab+ lapatinib+ chemotherapy.

Two patients (0.7%) achieved a complete response, 116 patients (41.9%) had Partial response R, resulted in an objective response rate, of 42.6%.

Safety

Overall, the safety of TLC was controllable and tolerable.
- The most common grade 3 and 4 AEs were
  - neutropenia (16.8%)
  - leukopenia (14.7%)
  - diarrhea (9.5%)
  - palmar–plantar erythrodysesthesia syndrome (PPES, 8.4%) anemia (7.7%).
- In patients received initial TL plus capecitabine, the most common grade 3 to 4 AEs were PPES (12.9%) and diarrhoea (6.9%)
- No treatment-related death was reported during TLC

Conclusions

TLC demonstrated promising effects and tolerable safety in HER2+MBC, even in patients with BM, providing a theoretical basis for clinical practice
- TLC therapy resulted in median PFS of 10.9 months and an ORR of 42.6%
The triplet combination of trastuzumab, lapatinib and chemotherapy demonstrated promising efficacy in HER2+ MBC with tolerable toxicity
In patients with BM, TLC also demonstrated promising anti-tumoral activity

Reference

Front Oncol. 2020 Mar 3;10:271. doi: 10.3389/fonc.2020.00271