Abstract
Purpose
Little is known about the use of trastuzumab or trastuzumab + lapatinib in older patients. We have performed a sub-analysis of the Adjuvant Lapatinib And/Or Trastuzumab Treatment Optimisation (ALTTO) trial focused on toxicity and treatment completion of both regimens in older patients (≥65 years old)
Methods:
The ALTTO trial randomised 8381 patients with early HER2-positive BC in 4 arms. Eligible patients for this study were those having received at least one dose of assigned treatment in either the trastuzumab or trastuzumab + lapatinib arms. Treatment completion was evaluated through the rate of temporary treatment interruptions, permanent treatment discontinuations and lapatinib dose reductions. Toxicity was evaluated via a selected subset of adverse events of interest (AEI). Risk factors for both treatment completion outcomes and toxicity were investigated, including comorbidities and use of 5 or more co-medications at randomization.
Results:
A total of 430 patients ≥65 year were eligible. Median age was 68 (range 65–80). In comparison with the younger cohort, older patients had a significantly higher number of comorbidities at randomization (p<0.001). Treatment completion outcomes were worse, particularly in the trastuzumab + lapatinib arm. Adverse events of interest were likewise more common in the trastuzumab + lapatinib arm with higher AEI rates (63.4% in younger vs 78.0% in older, p<0.001). Concomitant chemotherapy was associated with worse treatment completion outcomes among older patients.
Conclusion:
Trastuzumab plus lapatinib was significantly more toxic among older patients and had worse treatment completion. Trastuzumab was generally well tolerated.
Keywords: breast cancer, geriatric oncology, anti-HER2
Introduction
Breast cancer is one of the most frequent types of cancer amongst women worldwide[1]. Today, a substantial proportion of women diagnosed with or dying from breast cancer are older (defined as ≥65 years of age), particularly in developed countries[2]. In the near future, as demographic transition continues to unfold[2], this proportion will only become larger.
Despite their epidemiological relevance, older patients remain under-represented in clinical trials, either due to limits on the age of participants or due to stringent exclusion criteria for persons with comorbidities and/or laboratory alterations[3]. Hence, even for widely used drugs and regimens, treatment decisions are made without adequate data showing efficacy and safety among older patients.
The anti-HER2 monoclonal antibody trastuzumab and the reversible anti-HER2 tyrosine kinase inhibitor (TKI) lapatinib are approved for treatment, respectively, in both the early (alone or in various combinations) and in the advanced setting (in combination with capecitabine or with trastuzumab)[4, 5]. Recently, 2 new TKIs have been approved by the FDA for use in the advanced setting which have a similar toxicity profile to lapatinib[6, 7]. Limited data are available on the ability of older patients to complete planned treatment with TKIs, as well as on the incidence of adverse events, given that registration trials for these drugs included very few older patients[6–8].
The Adjuvant Lapatinib And/Or Trastuzumab Treatment Optimisation (ALTTO) trial[9, 10] may allow a better understanding of the safety profile of trastuzumab and trastuzumab + lapatinib and provide valuable insights for newer TKIs. We have, therefore, conducted a subgroup analysis investigating the treatment completion and toxicity of these two regimens in older patients participating in the ALTTO trial.
Materials & Methods
Study design
ALTTO was an adjuvant trial testing 4 different regimens of anti-HER2 therapy[9] including a trastuzumab arm and a trastuzumab + lapatinib arm, the ones to which this analysis is restricted. The remaining arms, lapatinib alone and trastuzumab followed by lapatinib were not included as neither regimen is used in practice in any setting. Both treatments could be given in combination with or sequentially to chemotherapy (Appendix 1). In ALTTO, no restrictions were imposed on patients based on upper age limit, though performance status, laboratory-based and comorbidity exclusion criteria did exist. For the purposes of this sub-study, older was defined as being ≥65 at study randomisation.
Study Objectives
The overall objective of this study was to investigate treatment completion and toxicities in older patients. Treatment completion outcomes measured included: rate of temporary treatment interruptions, permanent treatment discontinuations and lapatinib dose reduction due to reasons other than disease progression, death or administrative issues. Toxicity was investigated through a pre-defined list of adverse events of interest, and the incidence among younger and older patients was investigated. Risk factors for both treatment completion outcomes and adverse events of interest were investigated including comorbidity and polypharmacy. Furthermore, we studied the impact of adverse events of interest on treatment completion outcomes.
Comorbidities of interest for this study included: anaemia, anxiety, arthritis, depression, diabetes, fatigue, and hypertension. They were defined as comorbidities of these categories reported by the patient as ongoing at the time of randomization. Time of occurrence for all end points was defined as the date reported in the clinical database. Lapatinib dose reduction was defined as any reduction in lapatinib dose after the start of treatment (trastuzumab dose reductions were not permitted according to protocol). Temporary treatment interruption was defined as a temporary halt in treatment followed by resumption (of either drug or both) regardless of length. Permanent treatment discontinuation was defined as a permanent halt in treatment (of either drug or both). Adverse events of interest included vomiting, nausea, neutropenia, skin rash, mucositis, elevated liver enzymes, febrile neutropenia, diarrhoea, cardiotoxicity and anaemia. For this analysis, only NCI CTCAE events of grade 2, 3 or 4 are considered and they are defined as reported in the clinical database. Polypharmacy was defined as using 5 or more different drugs at randomization. Appendix 2 describes all the terms included into the different comorbidity and adverse event categories.
Statistical analysis
Patients, tumours and treatment characteristics at baseline were accessed by dichotomised age (<65 vs ≥65) at randomisation. Cross-tabulations were used to report frequencies and proportions across randomised age groups (<65 vs ≥65). The stability of all baseline characteristics measurements is assessed across age groups (<65 vs ≥65) using chi-square tests, and p-values of the tests reported.
Logistic regression models were fitted for the odds of treatment completion outcomes, measured as permanent treatment discontinuations, temporary treatment interruptions and lapatinib dose reductions. Odds ratios comparing the odds in treatment completion outcomes in older patients (≥65) compared to younger patients (<65), are reported herein alongside their 95% confidence intervals. Dichotomised age (<65 vs ≥65) is the only predictor initially included in the logistic regression models for the univariate analysis. In the multivariate setting, covariates found to be associated with treatment outcomes, were further included in the logistic regression models to ascertain whether the odds ratio comparing the odds in older patients (≥65) to the odds in younger patients (<65) observed in the univariate setting remain unchanged when accounting for those covariates.
Logistic regression models were also fitted for the odds of treatment completion outcomes, and the odds ratios reported compare the odds in patients with polypharmacy vs no polypharmacy, patients randomised in the sequential vs concomitant arms, patients with comorbidity vs no comorbidity, patients who experienced any of the adverse events of interest vs no adverse event of interest. Odds ratios and their 95% confidence are reported for both univariate and multivariate analyses.
Time from randomisation to the occurrence of temporary treatment interruptions was evaluated graphically using the Kaplan-Meier method. Ensuing graphs depicts curves of both younger (<65) and older (≥65) patients in each treatment arm.
Results
Patient characteristics, incidence of comorbidities and polypharmacy
In total, 4190 patients were included in this sub-study. Of these 430 (10.2%) were ≥65 years of age and 133 were ≥70 or older (3.1%). The median age of older patients was 68 (range 65–80). Table 1 describes in detail the characteristics of both younger and older patients in the sub-study sample. Of note, comorbidity and polypharmacy were more common among older patients. Anaemia, arthritis, depression, diabetes and hypertension were significantly more common in older patients. Appendix 3 details the distribution of all comorbidities in the older and younger populations. In comparison with the younger cohort, older patients had a significantly higher number of comorbidities at randomization (p<0.001).
Table 1:
Patient, Tumour and Treatment Characteristics for Trastuzumab and Trastuzumab + Lapatinib Arms combined, broken down between older ≥65 and <65
| Patients aged < 65 years (N = 3760) N (%) | Patients aged ≥ 65 years (N = 430) N (%) | |
|---|---|---|
| Ethnicity | ||
| Asian | 1042 (28) | 59 (14) |
| Black | 59 (2) | 4 (<1) |
| White | 2545 (68) | 351 (82) |
| Other/Missing | 114 (3) | 16 (4) |
| Tumor size | ||
| No applicable (neo-adjuvant chemotherapy) | 322 (9) | 27 (6) |
| ≤2cm | 1552 (41) | 168 (39) |
| >2 and ≤5cm | 1658 (44) | 218 (51) |
| >5cm | 212 (6) | 16 (4) |
| Missing | 16 (<1) | 1 (<1) |
| Nodal status | ||
| 1–3 Positive Nodes | 1103 (29) | 117 (27) |
| ≥4 Positive Nodes | 842 (22) | 90 (21) |
| Node Negative | 1493 (40) | 196 (46) |
| Not Applicable | 322 (9) | 27 (6) |
| Hormone receptor status | ||
| Negative | 1583 (42) | 204 (47) |
| Positive | 2177 (58) | 226 (53) |
| Histologic grade | ||
| GX: Differentiation cannot be assessed | 124 (3) | 14 (3) |
| G1: Well differentiated | 84 (2) | 15 (3) |
| G2: Moderately differentiated | 1383 (37) | 135 (31) |
| G3: Poorly differentiated/Undifferentiated | 2150 (57) | 266 (62) |
| Missing | 19 (<1) | 0 |
| Invasive histologic type | ||
| Ductal carcinoma | 3479 (93) | 394 (92) |
| Lobular carcinoma | 89 (2) | 14 (3) |
| Others/missing | 192 (5) | 22 (5) |
| Timing of chemotherapy | ||
| Concurrent | 1676 (45) | 212 (49) |
| Sequential | 2084 (55) | 218 (51) |
| Type surgery | ||
| BCS/Partial Mastectomy | 1666 (44) | 193 (45) |
| Mastectomy | 2094 (56) | 236 (55) |
| Missing | 0 | 1 (<1) |
| Type of chemotherapy | ||
| Anthracycline | 3569 (95) | 399 (93) |
| Non-Anthracycline | 191 (5) | 31 (7) |
| Radiotherapy | ||
| Yes | 2699 (72) | 277 (64) |
| No | 1061 (28) | 153 (36) |
| Randomised treatment arm | ||
| T+L | 1879 (50) | 214 (50) |
| T | 1881 (50) | 216 (50) |
| Comorbidity | ||
| Yes | 1421 (38) | 303 (70) |
| No | 2339 (62) | 127 (30) |
| Polypharmacy at randomization | ||
| Yes | 633 (17) | 111 (26) |
| No | 3127 (83) | 319 (74) |
Legend G= Grade; T= Trastuzumab; L= Lapatinib ; BCS= Breast Conservative Surgery
Treatment completion outcomes
Table 2 details treatment completion outcomes. In the trastuzumab arm, older patients had numerically worse treatment completion outcomes, while in the trastuzumab + lapatinib arm, significantly worse completion outcomes were identified in older vs young population (except lapatinib dose reductions, which were only numerically more frequent in older patients). Furthermore, for older patients in the T + L arm, lapatinib or the combination were more often interrupted or discontinued than trastuzumab. Appendix 4 gives further detail on completion outcomes according to drug in the T+L arm. As Figures 1a and 1b show, in the T + L arm, temporary treatment interruption occurrence was already more common one month after the start of treatment, while in the T arm there was no difference.
Table 2:
Incidence of Dose Reductions, interruptions and discontinuations in the Trastuzumab and Trastuzumab + Lapatinib arms according to age
| Trastuzumab Arm | Trastuzumab + Lapatinib Arm | |||||
|---|---|---|---|---|---|---|
| Patients aged < 65 years (N = 1881) Events (% of N) | Patients aged ≥ 65 years (N = 216) Events (% of N) | Multivariate Analysis OR (95%CI) | Patients aged < 65 years (N = 1879) Events (% of N) | Patients aged ≥ 65 years (N = 214) Events (% of N) | Multivariate Analysis OR (95%CI) | |
| Permanent treatment discontinuations | 300 (15.95) | 44 (20.37) | 1.33 (0.93 to 1.91) P= 0.122 | 625 (33.26) | 115 (53.74) | 2.08 (1.55 to 2.79) P<0.001 |
| Temporary treatment interruptions | 573 (30.46) | 75 (34.72) | 1.09 (0.80 to 1.48) p= 0.602 | 1176 (62.59) | 162 (75.70) | 1.72 (1.23 to 2.42) p=0.002 |
| Lapatinib dose reductions | NA | NA | NA | 341 (18.15) | 47 (21.96) | 1.15 (0.81 to 1.64) P=0.436 |
Multivariate analysis includes comorbidity, polypharmacy, type and timing of chemotherapy
Figure 1:
Time to Occurrence of Temporary Treatment Interruptions in the T (A) and T+L (B) arms – Younger vs older Patients
Risk Factors for Treatment Completion Outcomes in Older Patients
Table 3 details risk factor analysis for prediction of treatment completion outcomes in older patients including factors present at randomization (baseline) and factors occurring during study treatment (adverse events). In multivariate analysis, in both arms, adverse events negatively impacted treatment completion outcomes, with grade 3 being the most strongly associated with interruptions and discontinuations. In the trastuzumab arm, interestingly, polypharmacy was significantly associated with treatment interruption. Combination chemotherapy-anti-HER2 therapy worsened treatment completion outcomes, being particularly associated with temporary treatment interruptions, as compared with patients receiving sequential treatment.
Table 3:
Risk Factors for dose reductions interruptions and discontinuations in the Trastuzumab and Trastuzumab + Lapatinib arms in older patients (≥ 65)
| Tested Risk Factor | Trastuzumab Arm (N= 216) | Trastuzumab + Lapatinib Arm (N=214) | |||
|---|---|---|---|---|---|
| Temporary Treatment Interruptions | Permanent Treatment Discontinuations | Temporary Treatment Interruptions | Permanent Treatment Discontinuations | Lapatinib Dose Reductions | |
| Any Grade 2/3/4 vs No AEI | |||||
| Events (%)* | 41 (47.67) vs 34 (26.15) | 17 (19.77) vs 27 (20.77) | 141 (84.43) vs 21 (44.68) | 91 (54.49) vs 24 (51.06) | 46 (27.54) vs 1 (2.13) |
| Univariate OR (95%CI) | 2.57 (1.45 to 4.58) p= 0.001 | 0.94 (0.48 to 1.85) p=0.858 | 6.71 (3.30 to 13.67) p <0.001 | 1.15 (0.60 to 2.19) p=0.677 | 17.49 (2.34 to 130.5) p=0.005 |
| Multivariate OR (95%CI) | 2.25 (1.18 to 4.30) p= 0.014 | 0.86 (0.41 to 1.79) p=0.685 | 5.18 (2.40 to 11.19) p <0.001 | 0.95 (0.47 to 1.93) p=0.897 | 17.84 (2.33 to 136.5) p=0.006 |
| Any Grade 2 vs No AEI | |||||
| Events (% of N) | 24 (42.11) vs 51 (32.08) | 13 (22.81) vs 31 (19.50) | 56 (73.68) vs 106 (76.81) | 31 (40.79) vs 84 (60.87) | 14 (18.42) vs 33 (23.91) |
| Univariate OR (95%CI) | 1.54 (0.83 to 2.87) p= 0.174 | 1.22 (0.59 to 2.54) p=0.595 | 0.85 (0.44 to 1.61) p=0.610 | 0.44 (0.25 to 0.78) p=0.005 | 0.72 (0.36 to 1.45) p=0.354 |
| Multivariate OR (95%CI) | 1.56 (0.79 to 3.06) p=0.199 | 1.15 (0.54 to 2.44) p=0.721 | 0.92 (0.47 to 1.81) p=0.814 | 0.47 (0.26 to 0.83) p=0.010 | 0.71 (0.35 to 1.45) p=0.351 |
| Any Grade 3 vs no AEI | |||||
| Events (% of N) | 12 (57.14) vs 63 (32.31) | 4 (19.05) vs 40 (20.51) | 76 (92.68) vs 86 (65.15) | 52 (63.41) vs 63 (47.73) | 28 (34.15) vs 19 (14.39) |
| Univariate OR (95%CI) | 2.79 (1.12 to 6.97) p=0.028 | 0.91 (0.29 to 2.86) p= 0.874 | 6.78 (2.74 to 16.75) p<0.001 | 1.90 (1.08 to 3.34) p=0.026 | 3.08 (1.58 to 6.01) p<0.001 |
| Multivariate OR (95%CI) | 1.97 (0.74 to 5.23) p=0.173 | 0.82 (0.25 to 2.67) p=0.741 | 5.25 (2.06 to 13.36) p<0.001 | 1.71 (0.94 to 3.12) p=0.080 | 3.08 (1.51 to 6.29) p=0.002 |
| Any Grade 4 vs No AEI | |||||
| Events (% of N) | 5 (62.50) vs 70 (33.65) | 0 (0.0) | 9 (100.0) vs 153 (74.63) | 8 (88.89) vs 107 (52.20) | 4 (44.44) vs 43 (20.98) |
| Univariate OR (95%CI) | 3.29 (0.76 to 14.15) p= 0.110 | NA | NA | 7.33 (0.90 to 59.65) p=0.063 | 3.01 (0.78 to 11.71) p=0.111 |
| Multivariate OR (95%CI) | 1.98 (0.40 to 9.92) p=0.405 | NA | NA | 6.33 (0.77 to 52.08) p=0.086 | 2.99 (0.75 to 11.97) p=0.121 |
| Comorbidity vs no Comorbidity | |||||
| Events (% of N) | 53 (35.57) vs 22 (32.84) | 32 (21.48) vs 12 (17.91) | 120 (77.92) vs 42 (70.00) | 85 (55.19) vs 30 (50.00) | 32 (20.78) vs 15 (25.00) |
| Univariate OR (95%CI) | 1.13 (0.61 to 2.08) p=0.696 | 1.25 (0.60 to 2.62) p=0.548 | 1.51 (0.77 to 2.96) p=0.226 | 1.23 (0.68 to 2.24) p=0.494 | 0.79 (0.39 to 1.59) p=0.503 |
| Multivariate OR (95%CI) | 0.83 (0.42 to 1.65) p= 0.591 | 1.41 (0.65 to 3.09) p=0.383 | 1.42 (0.69 to 2.91) p= 0.340 | 1.11 (0.60 to 2.06) p=0.742 | 0.78 (0.38 to 1.63) p=0.512 |
| Polypharmacy vs no Polypharmacy | |||||
| Events (% of N) | 31 (51.67) vs 44 (28.21) | 11 (18.33) vs 33 (21.15) | 42 (82.35) vs 120 (73.62) | 32 (62.75) vs 83 (50.92) | 11 (21.57) vs 36 (22.09) |
| Univariate OR (95%CI) | 2.72 (1.47 to 5.03) p=0.001 | 0.84 (0.39 to 1.79) 0.645 | 1.67 (0.75 to 3.72) p=0.208 | 1.62 (0.85 to 3.10) p=0.141 | 0.97 (0.45 to 2.08) p=0.938 |
| Multivariate OR (95%CI) | 2.27 (1.13 to 4.55) p=0.021 | 0.72 (0.31 to 1.66) 0.445 | 1.32 (0.56 to 3.15) p=0.526 | 1.48 (0.75 to 2.95) p=0.261 | 1.00 (0.44 to 2.27) p=0.999 |
| Concomitant vs Sequential | |||||
| Events (% of N) | 52 (46.43) vs 23 (22.12) | 24 (21.43) vs 20 (19.23) | 87 (87.00) vs 75 (65.79) | 59 (59.00) vs 56 (49.12) | 26 (26.00) vs 21 (18.42) |
| Univariate OR (95%CI) | 3.05 (1.69 to 5.53) <0.001 | 1.15 (0.59 to 2.23) p=0.689 | 3.48 (1.73 to 7.00) p<0.001 | 1.49 (0.87 to 2.56) p=0.149 | 1.56 (0.81 to 2.98) p=0.183 |
| Multivariate OR (95%CI) | 2.52 (1.34 to 4.74) 0.004 | 1.28 (0.63 to 2.61) p=0.490 | 3.40 (1.66 to 6.96) p<0.001 | 1.42 (0.81 to 2.47) p=0.219 | 1.59 (0.82 to 3.10) p=0.171 |
| Anthracycline vs Non-Anthracycline | |||||
| Events (% of N) | 66 (33.17) vs 9 (52.94) | 41 (20.60) vs 3 (17.65) | 150 (75.00) vs 12 (85.71) | 106 (53.00) vs 9 (64.29) | 44 (22.00) vs 3 (21.43) |
| Univariate OR (95%CI) | 0.44 (0.16 to 1.20) p=0.108 | 1.21 (0.33 to 4.41) p=0.772 | 0.50 (0.11 to 2.31) p= 0.375 | 0.63 (0.20 to 1.94) p=0.416 | 1.03 (0.28 to 3.87) p=0.961 |
| Multivariate OR (95%CI) | 0.88 (0.30 to 2.60) p=0.824 | 1.33 (0.34 to 5.20) p=0.685 | 0.99 (0.19 to 5.09) p= 0.986 | 0.87 (0.26 to 2.85) p=0.815 | 1.20 (0.30 to 4.78) p=0.799 |
AEI: Adverse event of interest. Patients considered as no AEI include those with AEs not of interest and no AEs
Analysis presented in the format OR (95%IC) and P-value
% of patient with risk factor
Toxicity
Table 4 shows that adverse events of interest of grades ≥2 were more common among older patients in both arms, mostly due to an increase in grade 3 events, though the magnitude of increase is higher in the T + L arm as compared to the T arm (OR 1.93 vs 1.41). Among older patients, T + L nearly doubled the incidence of any adverse event with 39.81% in T arm vs 78.04% in the T + L arm [OR 7.44 (4.60–12.04); P<0.001] (Appendix 5). In the T arm the incidence of most AEs was very similar, including cardiotoxicity (Appendix 6). Diarrhoea was, nevertheless, numerically more common among older than younger patients (10.65% vs 5.69%), though not significant on multivariate analysis. Specific adverse events of interest where more common among older patients in the T+L arm (Appendix 7) and included diarrhoea (38.90% vs 60.75%; OR 2.19 IC 1.62 to 2.98; p<0.001) and mucositis (7.88% vs 12.15%; OR 1.62 IC 1.02 to 2.57; p=0.043).
Table 4:
Incidence of adverse events of interest in the Trastuzumab (T) and Trastuzumab + Lapatinib (T+L) arms according to age
| Adverse Event | Arm | Number of Events (%) | N | Univariate OR (95%CI) | Univariate P-value | Multivariate* OR (95%CI) | Multivariate P-value |
|---|---|---|---|---|---|---|---|
| Any Grade 2/3/4 | |||||||
| T | <65 | 535 (28.44) | 1881 | ||||
| ≥65 | 86 (39.81) | 216 | 1.66 (1.25 to 2.23) | <0.001 | 1.41 (1.02 to 1.94) | 0.038 | |
| T+L | <65 | 1191 (63.38) | 1879 | ||||
| ≥65 | 167 (78.04) | 214 | 2.05 (1.47 to 2.87) | <0.001 | 1.93 (1.35 to 2.75) | <0.001 | |
| Any Grade 2 | |||||||
| T | <65 | 366 (19.46) | 1881 | ||||
| ≥65 | 57 (26.39) | 216 | 1.48 (1.07 to 2.05) | 0.017 | 1.23 (0.88 to 1.73) | 0.225 | |
| T+L | <65 | 663 (35.28) 663 (35.28) | 1879 | ||||
| ≥65 | 76 (35.51) | 214 | 1.01 (0.75 to 1.36) | 0.947 | 1.03 (0.76 to 1.39) | 0.867 | |
| Any Grade 3 | |||||||
| T | <65 | 133 (7.07) | 1881 | ||||
| ≥65 | 21 (9.72) | 216 | 1.42 (0.87 to 2.30) | 0.159 | 1.21 (0.72 to 2.03) | 0.464 | |
| T+L | <65 | 463 (24.64) | 1879 | ||||
| ≥65 | 82 (38.32) | 214 | 1.90 (1.41 to 2.55) | <0.001 | 1.74 (1.26 to 2.38) | <0.001 | |
| Any Grade 4 | |||||||
| T | <65 | 36 (1.91) | 1881 | ||||
| ≥65 | 8 (3.70) | 216 | 1.97 (0.90 to 4.30) | 0.088 | 1.68 (0.74 to 3.81) | 0.211 | |
| T+L | <65 | 65 (3.46) | 1879 | ||||
| ≥65 | 9 (4.21) | 214 | 1.23 (0.60 to 2.50) | 0.576 | 1.23 (0.58 to 2.58) | 0.591 | |
Discussion
Trastuzumab and lapatinib, alone or in various combinations remain an important part of standard treatment of HER2-positive breast cancer despite the availability of newer anti-HER2 agents[11, 12]. The availability of data on the efficacy and safety of these drugs, either in the early or advanced setting for older patients is, however, very limited, as recently re-stated in a International Society of Geriatric Oncology (SIOG) position paper[8]. Though this is a reality for all other target agents – including newer ones – the lack of randomized controlled trial (RCT) data is more serious for older agents – including trastuzumab and lapatinib, which were developed and registered in an era in which severe limits on the participation of older patients were common, including the outright exclusion of patients based on age (usually 65–70 years ), due to concerns about cardiotoxicity[3, 13–20]. This is highlighted by a meta-analysis conducted on the efficacy and cardiac safety of adjuvant trastuzumab in older patients identified which used a definition of 60 year or older and could only include 3 out of 5 trials for efficacy analysis (558/3366 patients in the trastuzumab arms). Though the meta-analysis found a 47% reduction in relative risk of survival outcomes (HR 0.53, 95% IC, 0.36 to 0.77), these results are compromised by the cut-off used[21]. No toxicity other than cardiotoxicity was investigated – nor were completion outcomes investigated. All other data on older patients using trastuzumab in the adjuvant setting come from retrospective cohort studies of SEER-based studies[22, 23]. Therefore, patients taking part in the trastuzumab arm of the ALTTO trial offer the best chance of obtaining high-quality prospectively gathered data. As we have shown, adjuvant trastuzumab alone was well tolerated, with low incidence of adverse events and high completion rates in both young and older patients. Importantly, two baseline risk factors for worse completion outcomes were identified. Both concomitant use of chemotherapy, and the standard regimen used today increased the need for temporary treatment interruptions. Interestingly, the RESPECT trial, which evaluated the efficacy of adjuvant trastuzumab alone vs trastuzumab + chemotherapy in patients 70 year of age or older, suggests trastuzumab monotherapy to be better tolerated (in terms of AEs and quality of life)[24]. Polypharmacy was also identified in our dataset as a predictor of worse treatment completion outcomes. It might be in this case a surrogate of slightly worse health among patients that is not usually captured in RCTs (which do not include comprehensive geriatric assessment as s standard approach)[3]. Based on our data, the use of trastuzumab is safe, and though the standard should remain chemotherapy-based combinations, it is possible that sequential treatment monotherapy with trastuzumab may be an adequate choice for certain patients as a means of guaranteeing treatment completion.
The negative results of the ALTTO trial have prevented lapatinib from registration for early disease. It remains in use in third or further lines, and despite the recently presented results of other TKIs, such as neratinib and tucatinib, it is likely to remain in use for the foreseeable future. Furthermore, as the toxicity profiles of neratinib and tucatinib are similar in terms of what adverse events occurs, though sometimes more intense (in terms of absolute frequency and higher grade frequency); safety data on lapatinib remains relevant[25]. Only one study has tested lapatinib in older patients with advanced HER2-positive disease. This was a small single cohort phase II trial in which 40 patients ≥70 years were exposed to lapatinib + trastuzumab regardless of the number of previous lines of treatment[26]. In this small study, 23% of patients had treatment delay, and 43% a dose reduction. Seventy percent of patients experienced grade ≥2 adverse events. Our study, therefore, is the largest cohort evaluating lapatinib use in older patients. The addition of lapatinib worsened treatment completion and increased the incidence of adverse events substantially, with older patients faring worse than younger patients in all most evaluated endpoints, particularly in association with chemotherapy. Diarrhoea, particularly, is a significant issue in our data set. Even though our data set is in early disease, no substantial differences in toxicity profile have been seen between advanced and early disease trials with lapatinib in previous studies. It is therefore reasonable to propose that in older patients with advanced disease lapatinib-based combinations should be used with caution, as has been recently suggested by a consensus panel[8].
Cardiotoxicity was not worse among older patients as compared to younger in our sample. This differs from data generated by our group both in the HERA trial and in ALTTO itself, in which older age was a risk factor for cardiotoxicity[27]. The key point which explains this difference is that our analysis is based on general AE reporting pages, while the cardiac-specific analysis used data from the detailed reporting of Left Ventricular Ejection Fraction (LVEF) and cardiotoxicity pages which capture this phenomenon in larger detail that the AE pages.
Our study has some limitations that have to be pointed out. First and foremost it is an unplanned retrospective sub-analysis, and therefore should be seen strictly as hypothesis generating. Furthermore, it is important to stress that usual means of evaluating functionality and toxicity in Phase III trials is not adequate for older patients – which should ideally always be treated within the context of comprehensive geriatric assessment. The value of the data herein, therefore, is sub-optimal from a geriatric oncology stand-point. Additionally; the specificity of older patients belonging to other underserved minorities, such as patients with African or Native-American descent cannot be addressed as they represent only a very small number of the patient population of ALTTO[9]. Finally, older patients in phase III trials are usually healthier than real life counterparts. This is due to exclusion criteria which stop patients with comorbidities and/or frail patients to be enrolled. It is interesting to highlight that despite this, in our sample older patients had more co-morbidities than younger patients. In spite of these flaws, taking into consideration that both drugs are currently in use and being prescribed to older patients and that additional prospective trials are unlikely to occur, our study is likely to remain the largest prospectively collected study for both regimens.
In conclusion, older patients with early HER2-positive breast cancer in the ALTTO trial tolerated trastuzumab treatment well. The addition of lapatinib, however, significantly worsened completion outcomes and increased toxicity. Concomitant use of chemotherapy negatively impacted tolerability with both regimens. Caution should be exerted when using anti-HER TKIs in older patients. Specific studies of newer anti-HER2 TKIs in older patients are necessary to determine their safety.
Supplementary Material
Appendix 1 (Figure): ALTTO trial design
Appendix 2 (Text): Programming algorithms
Appendix 3 (Table): Incidence of comorbidities of interest in the study sample arms according to age (≥65 and <65)
Appendix 4 (Table): Temporary Treatment Interruptions and Permanent Treatment Discontinuations per drug in the Trastuzumab + Lapatinib arm according to age (≥65 and <65)
Appendix 5 (Table): Incidence of Adverse events of interest among younger and older patients comparing Trastuzumab and Trastuzumab + Lapatinib arms.
Appendix 6 (Table): Incidence of specific Adverse events of interest in older patients in the Trastuzumab arm
Appendix 7 (Table): Incidence of specific Adverse events of interest in older patients in the Trastuzumab + Lapatinib arm
Acknowledgments
Funding
The ALTTO Trial, as well as this subanalysis, have been funded by GSK and Novartis and by the NIH Grant U10 CA180821.
Presentations:
This study was presented at ASCO 2019 as a poster
Evandro de Azambuja reports honoraria and advisory board from Roche/GNE, Novartis and SeaGen, travel grants from Roche/GNE and GSK/Novartis and research grant to my institution from Roche/GNE, Astra-Zeneca, GSK/Novartis and Servier
Martine Piccart is a board member for Oncolytics and Radius. She has received honoraria from AstraZeneca, Camel-IDS, Crescendo Biologics, Debiopharm, G1 Therapeutics, Genentech, Huya, Immunomedics, Lilly, Menarini, MSD, Novartis, Odonate, Oncolytics, Periphagen, Pfizer, Roche PharmaMar, and Seattle Genetics. Her institute has received research grants from AstraZeneca, Lilly, MSD, Novartis, Pfizer, Radius, Roche-Genentech, Servier and Synthon
Florentine Hilbers reports that her institution has received research grants to fund the ALTTO trial from GSK and Novartis
Christian Jackisch reports grants and fees from Roche, Novartis, and AstraZeneca
Olena Werner is an employee of Novartis
Dr. Richard D. Gelber reports that his institution received grants for partial support for his salary from Novartis, Roche, Merck, Pfizer, AstraZeneca, Celgene, Ipsen, and Ferring.
Footnotes
Conflict of Interest Statement
Dr Noam Pondé reports he has received fees from Novartis, Lilly, AstraZeneca and Roche. He has received travel grants from Novartis, AstraZeneca and Lilly.
Dominique Agbor-Tarh reports no conflicts of interest
Lissandra Dal Lago reports no conflicts of interest
Larissa A. Korde reports no conflicts of interest
Aminah Jatoi reports no conflicts of interest
Amylou C. Dueck reports no conflicts of interest
Alvaro Moreno-Aspitia reports no conflicts of interest
Christos Sotiriou reports no conflicts of interest
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Appendix 1 (Figure): ALTTO trial design
Appendix 2 (Text): Programming algorithms
Appendix 3 (Table): Incidence of comorbidities of interest in the study sample arms according to age (≥65 and <65)
Appendix 4 (Table): Temporary Treatment Interruptions and Permanent Treatment Discontinuations per drug in the Trastuzumab + Lapatinib arm according to age (≥65 and <65)
Appendix 5 (Table): Incidence of Adverse events of interest among younger and older patients comparing Trastuzumab and Trastuzumab + Lapatinib arms.
Appendix 6 (Table): Incidence of specific Adverse events of interest in older patients in the Trastuzumab arm
Appendix 7 (Table): Incidence of specific Adverse events of interest in older patients in the Trastuzumab + Lapatinib arm