ABSTRACT
Background
HER2 (ERBB2) gene mutations are associated with poor prognosis in non‐small cell lung cancer (NSCLC). It is important to identify patients with HER2‐mutant (HER2m) NSCLC, as new targeted treatment options are emerging. However, HER2 testing in clinical practice varies across regions, and real‐world data on HER2m NSCLC are limited.
Patients and Methods
This retrospective study included patients from the Epidemio‐Strategy and Medical Economics Lung Cancer database (NCT03848052) diagnosed with locally advanced or metastatic (LAM) NSCLC in France (January 1, 2015–December 31, 2020); patients were followed up until April 1, 2022. Data were extracted on April 2, 2022. Primary objectives were to describe the frequency of HER2 testing and test results. Secondary objectives included describing patient characteristics, treatment patterns, and clinical outcomes (stratified by HER2 testing status/results; landmark analyses were conducted to avoid immortal time bias).
Results
Of 18,069 patients with nonsquamous LAM NSCLC, or squamous LAM NSCLC and no history of smoking, 7530 (41.7%) underwent HER2 testing. Median (interquartile range) time between LAM NSCLC diagnosis and first HER2 test result was 28 days (18–49). Of those tested, 152 (2.0%) had a HER2 mutation (HER2m cohort). In the HER2m cohort, 62.5% (n/N = 85/136) of patients received their first HER2 test result prior to first‐line treatment; platinum‐based chemotherapy was the most frequently received first‐line treatment (52.9%, n/N = 72/136), followed by immunotherapy in the second‐line setting (29.2%, n/N = 26/89). At 6‐month landmark analysis, median (95% confidence interval) overall survival was 18.6 months (14.3–22.5) in the HER2m cohort.
Conclusions
This real‐world study demonstrates the low frequency of HER2 testing and potential poor prognosis for patients diagnosed with LAM HER2m NSCLC in France between 2015 and 2020. Despite the low prevalence of HER2m NSCLC, these data highlight the importance of routine HER2 testing to enable patients with HER2m NSCLC to receive treatments that can improve clinical outcomes.
Keywords: cancer management, clinical cancer research, lung cancer, non‐small cell lung cancer
1. Introduction
Globally, lung cancer is the leading cause of cancer‐related mortality [1]; the most common type of lung malignancy is non‐small cell lung cancer (NSCLC), accounting for ~80%–85% of cases [2]. Human epidermal growth factor receptor 2 (HER2; ERBB2) gene mutations have been identified in approximately 2%–4% of lung adenocarcinomas [3, 4, 5, 6], and are associated with a poor prognosis in patients with NSCLC [7, 8, 9, 10]. A median overall survival (OS) of ~16 months has been reported for patients with HER2‐mutant (HER2m) NSCLC compared with ~31 months for those with HER2‐wild‐type (HER2wt) NSCLC [7].
For several years, first‐ and second‐line standard of care for patients with HER2m advanced/metastatic NSCLC has been chemotherapy with or without immunotherapy, and first‐line standard of care in the European Union (EU) currently remains unchanged [11, 12, 13]; however, these treatments have variable activity and outcomes remain poor in this patient population, highlighting the need for HER2‐directed treatments [9, 14, 15, 16, 17, 18]. Trastuzumab deruxtecan (T‐DXd), a HER2‐directed antibody‐drug conjugate (ADC), was the first HER2‐directed treatment approved in the EU for patients with unresectable or advanced/metastatic HER2m NSCLC who have received prior systemic therapy [19, 20]. Approval was supported by results from DESTINY‐Lung02 (T‐DXd 5.4 mg/kg), which reported an ORR of 49% in patients with pretreated metastatic HER2m NSCLC [21]. However, as T‐DXd was only granted approval in the EU for patients with HER2m NSCLC in late 2023, routine HER2 testing was not recommended prior to this time and, as such, real‐world data on patients with HER2m NSCLC are limited [11, 12, 20].
This retrospective analysis aimed to describe HER2 testing patterns, population characteristics, treatment patterns, and clinical outcomes of patients with locally advanced or metastatic (LAM) NSCLC treated in French medical centers between January 2015 and April 2022, prior to the approval of HER2‐directed therapy for this patient population.
2. Materials and Methods
2.1. Study Design
This study was a retrospective database analysis of patients diagnosed with LAM NSCLC in France. The study used data from the Epidemio‐Strategy and Medical Economics (ESME) Lung Cancer (LC) database (NCT03848052).
2.2. Data Source/Study Database
The ESME LC database compiles data for patients with lung cancer treated at one of 38 participating medical centers in France (i.e., one of the following: 18 private non‐profit French comprehensive cancer centers spread over 20 sites and 18 university and general public hospitals). These data are collected from electronic medical records, inpatient hospitalization records, and pharmacy records, and updated on a yearly basis. Cases selected to enter the database fulfill the following criteria: adult patients ≥ 18 years of age, treated (with systemic treatment or radiotherapy) for lung cancer or diagnosed with metastatic lung cancer in a participating medical center from January 1, 2015, onwards.
2.3. Patients
A subgroup of patients within the ESME LC database was selected for this study; all patients diagnosed between January 1, 2015, and December 31, 2020, who had a histologically confirmed diagnosis of de novo or relapsed LAM (Stage ≥ IIIB) NSCLC were included. Patients with a prior history of cancer not related to LAM NSCLC diagnosis were excluded. Patients were followed up until April 1, 2022, at the latest. The data used for this study were extracted from the ESME LC database on April 2, 2022.
2.4. Objectives and Assessments
The primary objectives were to describe the frequency of HER2 testing and test results in patients with LAM NSCLC. Secondary objectives were to describe patient demographics and clinical characteristics, details of HER2 testing (types of HER2 tests used were not captured in the ESME LC database), HER2 alterations, treatment patterns, and clinical outcomes of patients with LAM NSCLC.
HER2 alterations included HER2 mutation, amplification, or overexpression; HER2 mutation type was categorized as exon 20 insertion/duplication, other exon 20 mutation, exon 20 mutation not specified, other HER2 mutation (non‐exon 20), or HER2 mutation not specified. When describing treatment patterns, the following were considered as HER2‐directed treatments: afatinib, dacomitinib, lapatinib, neratinib, pertuzumab, poziotinib, pyrotinib, trastuzumab emtansine, trastuzumab (including biosimilars), T‐DXd, and tarloxotinib. Clinical outcomes included OS (defined as the time [in months] from LAM NSCLC diagnosis [i.e., index date] to the date of death from any cause; patients alive at the cutoff date were censored at the date of the last available record), time to next treatment or death (TTNTD; defined as the time from the first line of therapy start date to the second line of therapy start date or date of death, whichever occurred first; patients who did not receive a second line of therapy or who had not died were censored at the date of the last available record), and time to treatment discontinuation or death (TTDD; defined as the time from the first line of therapy start date to the first line of therapy stop date or date of death, whichever occurred first; patients who died without treatment discontinuation and with a date of death > 9 months from the last available record were censored at the date of the last available record). The reasons for treatment discontinuation were also assessed.
2.5. Statistical Methods
Descriptive analyses were performed for the primary and secondary objectives on the overall patient population and stratified by HER2 testing status and by HER2 testing results. Continuous variables were summarized using mean and standard deviation, or median and interquartile range (IQR). Categorical data were summarized by number and percentage of patients in each category. Kaplan–Meier estimates and associated 95% confidence intervals (CIs) were used to describe OS, TTNTD, and TTDD. No formal statistical analyses were conducted to compare the clinical outcomes between the study cohorts.
The stratification group (i.e., HER2 testing results) was defined by a classifying event occurring at any time during follow up and not by a baseline characteristic, considering HER2 status at baseline was known for very few patients. Therefore, to avoid immortal time bias, landmark analyses were conducted to assess clinical outcomes in the HER2 testing results subgroups. The landmark timepoints were 3 months and 6 months for TTNTD/TTDD and OS, respectively; timepoints were selected based on clinical relevance to the real‐world setting, per guidance from collaborating oncologists. Consequently, HER2 testing results subgroups were defined according to HER2 status available before the landmark time, and patients who reported an event according to the endpoint definition or were censored before the landmark time were excluded.
Exploratory analyses of prognostic factors associated with OS were assessed using a Cox proportional hazards model. Multivariable Cox proportional hazards models were constructed using a backward step‐by‐step manual selection procedure to identify time‐independent prognostic factors of OS in the HER2‐tested cohort, and by HER2 testing results. The assumption of hazard proportionality was assessed for each parameter by adding an interaction term between the prognostic factor and the time in the model (the significance level was set at 5%) and by plotting the log‐negative‐log of the Kaplan–Meier estimates of the survival function versus the log of time (visual inspection). All factors significant at a conservative 25% level in the univariable analysis were included in the multivariable analysis. The final model was reached when it included only factors at a p < 0.05 significance level. Hazard ratios and 95% CIs for each prognostic factor, and their associated p‐values, are presented.
3. Results
3.1. Patients
Of the 35,563 patients in the ESME LC database, 22,561 patients met the eligibility criteria and were included in this study (referred to hereafter as the LAM NSCLC cohort). A summary of patient selection is shown in Figure S1. Of the 18,069 patients who had nonsquamous NSCLC, or squamous NSCLC and no history of smoking, 7530 (41.7%) were tested for HER2 alterations (includes mutations, amplifications, or overexpression; referred to hereafter as the HER2‐tested cohort). Of those tested, 189/7530 (2.5%) patients were found to have a HER2 alteration; 29 patients with an unknown HER2 alteration type were excluded from the analysis. This report focuses primarily on the population of patients with HER2 mutations (95.0%; n/N = 152/160; HER2m cohort); of whom 75.0% (n/N = 114/152) had a HER2 exon 20 mutation (insertion/duplication, n/N = 98/114; other mutation, n/N = 6/114 [V777M, n = 3; G776V, n = 1; H878Y, n = 1; and D808N + M801T, n = 1]; and not specified, n/N = 10/114), 23.7% (n/N = 36/152) had a non‐exon 20 HER2 mutation, and 2.0% (n/N = 3/152) had an unspecified HER2 mutation. There were 7148 patients without a HER2 alteration (HER2wt cohort).
The demographics and clinical characteristics of patients are described in Table 1. In the overall cohort, the median age at diagnosis of LAM NSCLC was 65.0 years (range, 21–97), which was similar across the HER2‐tested, HER2wt, and HER2m cohorts. Across cohorts, most patients had de novo LAM NSCLC. At initial diagnosis, there was a higher proportion of patients with squamous NSCLC in the LAM NSCLC cohort (21.7%; n/N = 4907/22,561) versus the HER2‐tested cohort (4.7%; n/N = 356/7530). In the HER2wt and HER2m cohorts, 95.2% (n/N = 6803/7148) and 98.0% (n/N = 149/152) of patients had nonsquamous NSCLC, respectively. In the HER2m cohort, there was a greater proportion of female patients (62.5%; n/N = 95/152) compared with the HER2wt (39.7%; n/N = 2835/7148) and LAM NSCLC cohorts (34.2%; n/N = 7705/22,561). Similarly, there was a greater proportion of patients with no history of smoking in the HER2m cohort (49.3%; n/N = 69/152) compared with the HER2wt (14.7%; n/N = 1016/7148) and LAM NSCLC cohorts (11.0%; n/N = 2352/22,561). Bone and brain metastases were reported across all cohorts (Table 1).
TABLE 1.
Patient demographics and clinical characteristics.
|
LAM NSCLC (N = 22,561) |
HER2‐tested cohort (n = 7530) a |
HER2m cohort (n = 152) b |
HER2wt cohort (n = 7148) |
|
|---|---|---|---|---|
| Female, n (%) | 7705 (34.2) | 3016 (40.1) | 95 (62.5) | 2835 (39.7) |
| Median age at LAM diagnosis, years (range) | 65.0 (21–98) | 64.0 (21–97) | 66.0 (25–91) | 64.0 (21–97) |
| Age ≤ 60, n (%) | 7518 (33.3) | 2756 (36.6) | 55 (36.2) | 2627 (36.8) |
| ECOG PS 0/1 at LAM diagnosis, n/N (%) c | 2679/4249 (63.1) | 953/1391 (68.5) | 16/27 (59.3) | 915/1331 (68.7) |
| Smoking status, n/N (%) d | ||||
| Current | 7588/21,380 (35.5) | 2521/7245 (34.8) | 19/140 (13.6) | 2421/6892 (35.1) |
| Former | 11,440/21,380 (53.5) | 3599/7245 (49.7) | 52/140 (37.1) | 3455/6892 (50.1) |
| Never | 2352/21,380 (11.0) | 1125/7245 (15.5) | 69/140 (49.3) | 1016/6892 (14.7) |
| Histology at initial diagnosis, n (%) | ||||
| Squamous | 4907 (21.7) | 356 (4.7) | 3 (2.0) | 345 (4.8) |
| Nonsquamous | 17,654 (78.3) | 7174 (95.3) | 149 (98.0) | 6803 (95.2) |
| Adenocarcinoma | 15,186 (67.3) | 6439 (85.5) | 145 (95.4) | 6090 (85.2) |
| Disease stage at LAM diagnosis, n (%) | ||||
| IIIB, IIIC | 4682 (20.8) | 1191 (15.8) | 11 (7.2) | 1148 (16.1) |
| IV, IVA, IVB | 17,879 (79.2) | 6339 (84.2) | 141 (92.8) | 6000 (83.9) |
| Setting at LAM diagnosis, n (%) | ||||
| De novo | 17,162 (76.1) | 6039 (80.2) | 127 (83.6) | 5724 (80.1) |
| Relapse | 5399 (23.9) | 1491 (19.8) | 25 (16.4) | 1424 (19.9) |
| Number of metastatic sites at LAM diagnosis, n (%) | ||||
| < 3 | 13,958 (78.1) | 4866 (76.8) | 91 (64.5) | 4626 (77.1) |
| ≥ 3 | 3921 (21.9) | 1473 (23.2) | 50 (35.5) | 1374 (22.9) |
| Location of metastases at LAM diagnosis, n (%) | ||||
| Bone | 7255 (40.6) | 2620 (41.3) | 86 (61.0) | 2442 (40.7) |
| Brain | 5758 (32.2) | 1987 (31.3) | 53 (37.6) | 1871 (31.2) |
| Contralateral lung | 4878 (27.3) | 1699 (26.8) | 43 (30.5) | 1599 (26.7) |
| Adrenal glands | 3759 (21.0) | 1375 (21.7) | 32 (22.7) | 1300 (21.7) |
| Liver | 2892 (16.2) | 985 (15.5) | 44 (31.2) | 912 (15.2) |
| Metastatic nodes | 2424 (13.6) | 968 (15.3) | 17 (12.1) | 924 (15.4) |
| Pleural fluid | 1218 (6.8) | 537 (8.5) | 15 (10.6) | 508 (8.5) |
| CSF/meninges | 116 (0.6) | 49 (0.8) | 2 (1.4) | 44 (0.7) |
| Other | 4010 (22.4) | 1559 (24.6) | 35 (24.8) | 1483 (24.7) |
| PD‐L1 status, n/N (%) e | ||||
| < 1% | 4154/10,598 (39.2) | 1461/3743 (39.0) | 33/89 (37.1) | 1388/3570 (38.9) |
| ≥ 1%– < 50% | 3180/10,598 (30.0) | 1134/3743 (30.3) | 38/89 (42.7) | 1077/3570 (30.2) |
| ≥ 50% | 2916/10,598 (27.5) | 1005/3743 (26.9) | 18/89 (20.2) | 965/3570 (27.0) |
Abbreviations: CSF, cerebrospinal fluid; ECOG, Eastern Cooperative Oncology Group; HER2, human epidermal growth factor receptor 2; HER2m, HER2‐mutant; HER2wt, HER2‐wild‐type; LAM, locally advanced or metastatic; NSCLC, non‐small cell lung cancer; PD‐L1, programmed cell death ligand 1; PS, performance status.
Of the patients who underwent HER2 testing, 7148 did not have HER2 alterations (HER2wt cohort), 152 (b) had a HER2 mutation (HER2m cohort), eight had HER2 amplification (b), one had HER2 overexpression, 29 had unknown HER2 alterations, and 193 had non contributive results.
Categories of HER2 alterations were not mutually exclusive; concurrent HER2 mutation and HER2 amplification was observed in one patient.
Based on the number of patients with ECOG PS records.
Based on the number of patients whose smoking status was recorded on arrival at the participating treatment center.
Based on the number of patients who underwent PD‐L1 screening.
3.2. HER2 Testing
Among patients whose tumor samples underwent HER2 testing, 81.4% (n/N = 6132/7530) received their first HER2 test result after LAM NSCLC diagnosis, with a median time from diagnosis to test result of 28 days (IQR 18–49). During the disease course, these patients underwent a median number of one (range 1–6) HER2 tests. Primary tumor tissue was the most common sample used for HER2 testing (71.5%, n/N = 5027/7530), followed by metastatic tissue (27.4%, n/N = 1930/7530), blood (3.9%, n/N = 277/7530), and other (3.1%, n/N = 220/7530). Among patients in the HER2m cohort whose tumor samples were tested for other mutations at any time during the course of the disease, 6.1% (n/N = 8/131), 6.8% (n/N = 8/117), 13.5% (n/N = 15/111), 2.8% (n/N = 3/108), and 4.2% (n/N = 4/96) also had an EGFR mutation, ALK translocation, KRAS mutation, BRAF mutation, and ROS1 rearrangement and/or mutation, respectively. The proportion of patients in the HER2m cohort with co‐mutations was generally similar when assessed prior to the start of first‐line treatment (Table S1). Immune checkpoint screening for programmed cell death ligand 1 (PD‐L1) was undertaken in 49.7% (n/N = 3743/7530) of tumor samples tested for HER2 alterations. Of those tested in the HER2m cohort, 62.9% (n/N = 56/89) were PD‐L1‐positive.
3.3. Treatment Patterns
In the overall population (N = 22,561), 81.0% of patients received at least one line of therapy following diagnosis of LAM NSCLC. The most common systemic anticancer therapies (SACTs) received at first, second, and third line of therapy were platinum‐based chemotherapy (60.4%; n/N = 11,042/18,284), single‐agent immunotherapy (43.1%; n/N = 4013/9308), and non‐platinum‐based chemotherapy (40.5%; n/N = 1668/4120), respectively. For patients in the HER2m cohort, the most common SACT received was platinum‐based chemotherapy in the first‐line setting (52.9%, n/N = 72/136), single‐agent immunotherapy in the second‐line setting (29.2%, n/N = 26/89), and HER2‐directed therapy in the third‐line setting (45.6%, n/N = 26/57); a relatively low proportion of patients received HER2‐directed therapy in the first‐ and second‐line settings (5.1% [n/N = 7/136] and 23.6% [n/N = 21/89], respectively). A summary of the SACT regimens received, including HER2‐directed therapies, can be found in Table S2. Of patients in the HER2m cohort, 62.5% (n/N = 85/136) received their first HER2 test result prior to first‐line treatment, with a median time from test result to treatment start of 20 days (IQR 9–43).
3.4. Clinical Outcomes
The median duration of follow up for the total study population was 36.9 months (95% CI 36.1–37.6). Median OS for the overall LAM NSCLC cohort was 13.8 months (95% CI 13.5–14.2); at 12 months, the OS rate was 53.9% (95% CI 53.2–54.5). To avoid immortal time bias, landmark analyses were conducted in patients without an endpoint‐defined event, who were uncensored, and who had a known HER2 status available before the landmark timepoint. For the 6‐month landmark analysis, median OS was 18.6 months (95% CI 14.3–22.5) and 22.2 months (95% CI 21.3–23.1) for the HER2m and HER2wt cohorts, respectively (Figure 1). At 12 months, the OS rate was 66.0% (95% CI 56.9–75.0) for the HER2m cohort and 73.1% (95% CI 71.8–74.4) for the HER2wt cohort. Several baseline characteristics were associated with OS in the HER2wt cohort, including age, sex, number of metastatic sites, and SACT received in the first‐line setting. However, OS was not found to be significantly associated with any baseline characteristic assessed in the HER2m cohort (Table 2). The median TTNTD for patients in the overall LAM NSCLC cohort who received at least one line of treatment was 7.0 months (95% CI 6.9–7.1; Figure 2A). For the 3‐month landmark analysis, median TTNTD was 7.0 months (95% CI 6.3–8.6) and 9.3 months (95% CI 9.0–9.6) for the HER2m and HER2wt cohorts, respectively (Figure 2B). Median TTDD was 4.7 months (95% CI 4.6–4.8) in the overall LAM NSCLC cohort (Figure 3A). For the 3‐month landmark analysis, median TTDD was 6.0 months (95% CI 5.6–7.1) and 6.8 months (95% CI 6.6–7.0) for the HER2m and HER2wt cohorts, respectively (Figure 3B). Disease progression and physician/protocol‐driven decision were the most common reasons for treatment discontinuation after first‐line treatment in the overall cohort (45.1% and 42.2%, respectively), the HER2m cohort (57.1% and 37.0%, respectively), and the HER2wt cohort (50.3% and 36.9%, respectively; Table S3).
FIGURE 1.
OSa at a 6‐month landmark analysisb in the HER2m and HER2wt cohorts. CI, confidence interval; HER2, human epidermal growth factor receptor 2; HER2m, HER2‐mutant; HER2wt, HER2‐wild‐type; LAM, locally advanced or metastatic; NSCLC, non‐small cell lung cancer; OS, overall survival. Shading indicates 95% CIs. No formal statistical analyses were conducted to compare the clinical outcomes between study cohorts. aOS was defined as the time from the LAM NSCLC diagnosis to the date of death for any cause. bPatients alive, uncensored at 6 months after LAM NSCLC diagnosis and who were tested for HER2 alterations up to 6 months after LAM NSCLC diagnosis were included in this analysis.
TABLE 2.
Prognostic factors associated with OSa in the HER2m cohort and HER2wt cohort assessed at the 6‐month landmark analysisb.
| Parameter | HER2m cohort (n = 152) | HER2wt cohort (n = 7148) | ||
|---|---|---|---|---|
| Hazard ratio (95% CI) | p | Hazard ratio (95% CI) | p | |
| Age at LAM NSCLC diagnosis (versus ≤ 60), years | ||||
| > 60–70 | NA | NA | 1.040 (0.959–1.128) | 0.341 |
| > 70–75 | NA | NA | 1.214 (1.083–1.359) | < 0.001 |
| > 75 | NA | NA | 1.558 (1.401–1.732) | < 0.001 |
| Male (versus female) | NA | NA | 1.146 (1.067–1.230) | < 0.001 |
| De novo at LAM diagnosis (versus relapsed) c | 0.667 (0.299–1.491) | 0.324 | 1.099 (1.002–1.206) | 0.046 |
| Number of metastatic sites at LAM diagnosis (versus none) | ||||
| 1–2 | 0.895 (0.308–2.597) | 0.838 | 1.250 (1.134–1.378) | < 0.001 |
| ≥ 3 | 2.044 (0.678–6.159) | 0.204 | 1.994 (1.760–2.259) | < 0.001 |
| Type of first‐line SACT (versus chemotherapy) c | ||||
| Immunotherapy | 1.796 (0.462–6.978) | 0.398 | 0.720 (0.609–0.852) | < 0.001 |
| Chemotherapy + immunotherapy | 3.926 (0.508–30.313) | 0.190 | 0.604 (0.454–0.803) | < 0.001 |
| Other SACT d | 0.643 (0.315–1.314) | 0.226 | 0.613 (0.555–0.677) | < 0.001 |
| No treatment | 1.211 (0.669–2.190) | 0.527 | 0.857 (0.779–0.942) | 0.001 |
| PD‐L1 status (versus < 1%) c | ||||
| 1– < 50% | 0.869 (0.276–2.737) | 0.810 | 0.916 (0.759–1.105) | 0.359 |
| ≥ 50% | 0.236 (0.041–1.357) | 0.106 | 0.806 (0.655–0.990) | 0.040 |
| Unknown | 0.942 (0.331–2.682) | 0.911 | 1.001 (0.850–1.178) | 0.994 |
Abbreviations: CI, confidence interval; HER2, human epidermal growth factor receptor 2; HER2m, HER2‐mutant; HER2wt, HER2‐wild‐type; LAM, locally advanced or metastatic; NA, not applicable; NSCLC, non‐small cell lung cancer; OS, overall survival; PD‐L1, programmed cell death ligand 1; SACT, systemic anticancer therapy.
OS was defined as the time from the LAM NSCLC diagnosis to the date of death for any cause.
Patients alive, uncensored at 6 months after LAM NSCLC diagnosis and who were tested for HER2 alterations up to 6 months after LAM NSCLC diagnosis were included in this analysis. Multivariate analysis was performed using a Cox proportional hazards model.
Confounding factors in the HER2m cohort.
Any other SACT regimen included, but was not limited to, single‐agent targeted therapy or targeted therapy in combination with any other drug.
FIGURE 2.
TTNTDa in the LAM NSCLC cohort (A), and at a 3‐month landmark analysisb in the HER2m and HER2wt cohorts (B). CI, confidence interval; HER2, human epidermal growth factor receptor 2; HER2m, HER2‐mutant; HER2wt, HER2 wild‐type; LAM, locally advanced or metastatic; NSCLC, non‐small cell lung cancer; TTNTD, time to next treatment or death. Shading indicates 95% CIs. No formal statistical analyses were conducted to compare the clinical outcomes between study cohorts. aTTNTD was defined as time from first line of therapy start date to second line of therapy start date or date of death. bPatients alive, uncensored, without a second line of therapy start date at 3 months after first line of therapy start and who were tested for HER2 alterations up to 3 months after first line of therapy start were included in this analysis.
FIGURE 3.
TTDDa in the LAM NSCLC cohort (A), and at a 3‐month landmark analysisb in the HER2m and HER2wt cohorts (B). CI, confidence interval; HER2, human epidermal growth factor receptor 2; HER2m, HER2‐mutant; HER2wt, HER2 wild‐type; LAM, locally advanced or metastatic; NSCLC, non‐small cell lung cancer; TTDD, time to treatment discontinuation or death. Shading indicates 95% CIs. No formal statistical analyses were conducted to compare the clinical outcomes between study cohorts. aTTDD was defined as the time from LAM NSCLC diagnosis to the stop date of last treatment received in first line of therapy or date of death. bPatients alive, uncensored, without a stop date of last treatment received in first line of therapy reported at 3 months after LAM NSCLC diagnosis and who were tested for HER2 alterations up to 3 months after LAM NSCLC diagnosis were included in this analysis.
4. Discussion
This retrospective analysis of patients within the ESME LC database explored the HER2 testing practices and clinical outcomes of patients with HER2m NSCLC prior to the approval of HER2‐directed therapy for this patient population. Results showed that the frequency of HER2 testing in patients with LAM NSCLC was relatively low, and despite treatment with the standard of care available at the time of study, prognosis appeared to remain poor in patients with HER2m NSCLC (median OS < 2 years).
As is expected in real‐world evidence studies, there were some differences in patient characteristics between the study cohorts, which should be considered when interpreting results. However, characteristics were similar to those previously reported for patients with HER2m NSCLC; 62.5% of patients were female, 49.3% had no history of smoking, and 63.8% were aged over 60 years in the HER2m cohort [16, 22, 23, 24, 25]. Furthermore, data reported here and in previous studies suggest that brain and bone metastases are common in this patient population [8, 26]. Among patients with nonsquamous LAM NSCLC, or those with squamous LAM NSCLC and no history of smoking, only 41.7% were tested for HER2 alterations. The majority of tests for HER2 alterations were undertaken after a diagnosis of LAM disease, with a median time from diagnosis to test result of ~4 weeks. The low proportion of patients that underwent HER2 testing was as expected. This is likely owing to the absence of HER2‐directed treatment outside of clinical trials during the analysis period (January 2015–April 2022) [20]; therefore, routine HER2 testing was not recommended in the EU and was unlikely to be included within the reimbursement policy in France at this time [12, 13]. Furthermore, few patients with squamous histology underwent HER2 testing; genomic alteration testing is not recommended for patients with squamous cell carcinoma unless under specific circumstances (e.g., patients who do not smoke) [11]. Consistent with results herein, a recent study in France reported that 44.1% of patients with advanced NSCLC were tested for HER2 alterations in 2020. Notably, the same study showed that a high proportion of patients were tested for alterations for which approved targeted treatments were available (EGFR mutations, ALK and ROS1 rearrangements, and BRAF mutations) [27]. The proportion of patients with HER2 mutations observed in this study was consistent with other published studies [3, 5, 6]. However, the proportion of patients in the HER2m cohort with genomic co‐alterations was higher than expected given previous reports that HER2 mutations and other oncogenic drivers are mutually exclusive [3, 7, 28]. Interestingly, more recent studies have suggested that HER2 mutations within the non‐tyrosine kinase domain are more likely to be associated with the presence of co‐alterations compared with those within the tyrosine kinase domain [29, 30]. Further analyses are needed to fully assess the variation in co‐alterations data observed here and in other studies [3, 7, 28, 29, 30].
In the current study, chemotherapy and immunotherapy were the most frequently prescribed SACTs in the first‐ and second‐line setting, respectively, regardless of HER2 mutation status. Although European treatment guidelines were updated in 2018 following the approval of first‐line immunotherapies for metastatic NSCLC, chemotherapy remained the most frequently prescribed first‐line treatment in this study, potentially owing to a delay in adoption of these guidelines in clinical practice [13]. Treatment patterns in the LAM NSCLC cohort and HER2m cohort differed only in the third‐line setting, where non‐platinum‐based chemotherapy was more common in the LAM NSCLC cohort and HER2‐directed therapy was more common in the HER2m cohort. The treatment patterns reported in this study are consistent with previous reports and generally as expected per treatment guidelines in the first‐ and second‐line settings, with more variation in the SACTs used in the third‐line setting owing to the absence of approved therapies for HER2m NSCLC [11, 12, 13, 18, 24].
Landmark analyses of OS, TTNT, and TTD were performed for the HER2m and HER2wt cohort to avoid potential immortal time bias where the variable considered for stratification (in this instance, the HER2 testing result) was not available at baseline for all patients. At the 6‐month landmark analyses, the observed median OS for the HER2m cohort was 18.6 months, which was numerically shorter than that seen in the HER2wt cohort (median OS, 22.2 months). Median OS reported by other real‐world studies of HER2m and HER2wt NSCLC has varied widely (10–28 months and 22–31 months, respectively), likely reflecting differences in patient populations, study designs, and potential biases often associated with these types of studies [22, 24, 26, 31, 32]. A similar trend in the HER2m cohort compared with the HER2wt cohort was also seen for the 3‐month landmark analyses of median TTNTD and TTDD (often used as surrogates for progression‐free survival [PFS]) [33]. Following first‐line treatment, patients in the HER2m cohort appeared to initiate their next treatment or discontinue treatment faster than those in the HER2wt cohort. This aligns with other real‐world studies that have reported poor PFS in HER2m NSCLC, with median PFS ranging from 4.0–6.7 months [14, 18, 23]; a real‐world study of metastatic NSCLC without actionable genomic alterations reported a median PFS of 11 months following standard‐of‐care treatment [34]. It is likely that the presence of patients with brain and bone metastases contributed to the poor outcomes observed in the current study; brain metastases are known to be associated with poor prognosis in patients with NSCLC [8, 35]. Overall, the poor clinical outcomes observed in patients with HER2m NSCLC in this study, and in those previously reported, highlight the need for effective HER2‐directed therapies, including those with central nervous system (CNS) activity, in this patient population.
HER2 mutations are now recognized as actionable genomic alterations for patients with advanced or metastatic NSCLC based on the availability of HER2‐directed therapies [11]. T‐DXd (5.4 mg/kg) is approved in more than 50 countries worldwide for previously treated patients with unresectable or metastatic HER2m NSCLC [19, 36, 37]. This approval was first supported by the primary results from DESTINY‐Lung02, and more recently reaffirmed by the findings from a long‐term follow up of this trial (median PFS: 10 months; median OS: 19 months) [21, 38]. T‐DXd has also shown promising CNS activity in patients with HER2m NSCLC and brain metastases [39]. While the current real‐world study did not explore PFS and OS in the second‐line setting, other real‐world studies have, including a US‐based study that reported a median PFS and OS from the start of second‐line treatment of 3.0 months and 8.2 months, respectively, in patients with HER2m NSCLC [40]. It is important to note that cross‐trial comparisons should be made with caution, particularly when considering the broad population of patients included in this real‐world study, as with other similar studies, and the select patient population and controlled environment observed in clinical trials. Notably, panel‐based testing (e.g., next‐generation sequencing [NGS]) for genomic alterations in patients with advanced NSCLC is now recommended by current guidelines and HER2 mutations are listed as one of the genomic alterations for inclusion in these NGS panels, which will allow for routine screening and timely identification of patients with HER2m NSCLC who could benefit from HER2‐directed treatments [11, 41].
There are a number of clinical trials assessing HER2‐directed therapies in HER2m NSCLC. PYRAMID‐1 (NCT04447118) is a phase III study of pyrotinib (a HER2/EGFR dual TKI) versus docetaxel in pretreated patients with advanced HER2m NSCLC [42]. RESOLUTION (NCT06749860) is a phase II study of disitamab vedotin (an ADC) combination regimens in treatment‐naïve and pretreated patients with LAM HER2‐altered NSCLC [43, 44]. In addition, there are several phase III trials of HER2‐directed therapies in the first‐line setting; SOHO‐02 (NCT06452277), Beamion LUNG‐2 (NCT06151574), and DESTINY‐Lung04 (NCT05048797) are evaluating BAY 2927088 (a HER2/mutant EGFR TKI), zongertinib (a selective HER2 TKI), and T‐DXd, respectively, versus standard of care in patients with LAM HER2m NSCLC [45, 46, 47]. The evolving HER2‐directed treatment landscape highlights the importance of routine HER2 testing to identify patients with NSCLC who could benefit from these treatment options in the future.
There are limitations associated with this study. Firstly, data were collected from a single region, and as such extrapolation of HER2 testing patterns, treatment patterns, and clinical outcomes of patients with HER2m NSCLC across different regions is limited. Secondly, the ESME LC database does not provide information on the methods of HER2 testing utilized; therefore, there is limited understanding of when and how different HER2 tests were used. There are also potential biases related to maintaining a database such as the ESME LC database, including patient selection bias, information or misclassification bias, and possible confounding factors. Finally, owing to changes in clinical practice guidelines and the greater availability of HER2‐directed therapies for patients with HER2m NSCLC since the time of this analysis, results may not be reflective of current testing practices and treatment patterns; regardless, these data provide invaluable insights into the clinical management and outcomes of these patients during the study period.
5. Conclusion
Data highlight the importance of HER2 testing in France for patients with NSCLC to identify those who may benefit from HER2‐directed treatments; results further demonstrate the clinical need for these treatments in patients with HER2m NSCLC.
Author Contributions
Didier Debieuvre: conceptualization, validation, writing – review and editing. Pauline Macouillard: methodology, visualization, writing – review and editing, software, formal analysis. Xavier Quantin: conceptualization, validation, writing – review and editing. Mehmet Berktas: conceptualization, investigation, funding acquisition, methodology, validation, visualization, writing – review and editing, formal analysis, project administration. Nicolas Girard: conceptualization, validation, writing – review and editing. Clarisse Audigier‐Valette: conceptualization, validation, writing – review and editing. Thomas Filleron: methodology, writing – review and editing. Stefania Musilli: conceptualization, funding acquisition, methodology, writing – review and editing, project administration. Lise Bosquet: investigation, methodology, visualization, writing – review and editing, project administration. Maurice Pérol: conceptualization, validation, writing – review and editing.
Funding
The ESME LC database receives financial support from industrial partners. Unicancer independently manages ESME databases (in relation to data collection, analysis, and publication) and is the sole data controller for data processing. This work was specifically funded by AstraZeneca. Unicancer and AstraZeneca were both involved in this publication.
Ethics Statement
The ESME research program is managed by Unicancer in accordance with current best practice guidelines and rules and is supervised by an independent steering committee. The ESME LC database was authorized by the French data protection authority (initial authorization no. DE‐2017‐397 [dated October 2017] and subsequent amendment [dated October 2019] in accordance with GDPR). An independent scientific and ethics committee specifically approved the current work (study reference ESME CBP 2022–19). All data were obtained retrospectively with patients' approval for use of their data.
Conflicts of Interest
Didier Debieuvre reports grants, personal fees, and non‐financial support from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Chiesi, Chugai, Eli Lilly, Gilead, GSK, Ipsen, Janssen, MSD, Novartis, OSE Immunotherapeutics, Pfizer, Roche, Sanofi, and Takeda. Mehmet Berktas reports employment by AstraZeneca. Nicolas Girard reports research grants/support from AbbVie, Amgen, AstraZeneca, Beigene, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi‐Sankyo, Eli Lilly, Gilead, Hoffmann‐La Roche, Janssen, Leo Pharma, Merck Serono, MSD, Novartis, Sanofi, and Sivan; consultative services for AbbVie, Amgen, AstraZeneca, Beigene, Bristol Myers Squibb, Daiichi‐Sankyo, Eli Lilly, Gilead, Ipsen, Hoffmann‐La Roche, Janssen, Leo Pharma, MSD, Mirati, Novartis, Pfizer, Pierre Fabre, Sanofi, Sivan, and Takeda; participation on a data safety monitoring board for Hoffmann‐La Roche; and employment of a family member by AstraZeneca. Clarisse Audigier‐Valette reports support for attending meetings and/or travel from Amgen, AstraZeneca, Bristol Myers Squibb, Eli Lilly, GSK, MSD, Novartis, Pfizer, Roche, Sanofi, and Takeda; and participation on a data safety monitoring board or advisory board for AbbVie, AstraZeneca, Bristol Myers Squibb, Eli Lilly, Janssen, MSD, Pfizer, and Sanofi. Thomas Filleron reports receiving personal fees from Janssen outside the submitted work; and institutional fees from Eli Lilly and Roche outside the submitted work. Maurice Pérol reports grants, personal fees, and non‐financial support from AbbVie, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi‐Sankyo, Eli Lilly, Eisai, Gritstone, GSK, Illumina, Ipsen, Janssen, MSD, Novartis, Novocure, Pfizer, Pierre Fabre Oncology, Roche, Sanofi, and Takeda. All other authors have declared no conflicts of interest.
Supporting information
Figure S1: Summary of patient selection.
Table S1: Genomic co‐alterations in the HER2m cohort prior to the start of first‐line treatment.
Table S2: Systemic anticancer therapies received by patients in the HER2m cohort by each line of therapya.
Table S3: Reasons for treatment discontinuation after receiving first‐line treatment.
Acknowledgements
We thank all the patients who participated in the ESME LC database for granting access to their data and allowing us to undertake this work. We thank the participating sites, the ESME central coordinating staff, the LC Scientific Group, and the ESME Strategic Committee for their ongoing support. Under the guidance of the authors, medical writing support was provided by Abbie Dodd, BSc, of Helios Medical Communications, part of Helios Global Group, and was funded by AstraZeneca in accordance with Good Publication Practice (GPP) guidelines (http://www.ismpp.org/gpp‐2022).
Data Availability Statement
The datasets analyzed for the current study were extracted from the ESME LC Data Platform. In accordance with ethical and legal requirements related to the ESME data warehouse, individual data from the ESME databases cannot be made available. For any specific demand, please contact the corresponding author. Each demand will be examined on a case‐by‐case basis by the scientific committee.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Figure S1: Summary of patient selection.
Table S1: Genomic co‐alterations in the HER2m cohort prior to the start of first‐line treatment.
Table S2: Systemic anticancer therapies received by patients in the HER2m cohort by each line of therapya.
Table S3: Reasons for treatment discontinuation after receiving first‐line treatment.
Data Availability Statement
The datasets analyzed for the current study were extracted from the ESME LC Data Platform. In accordance with ethical and legal requirements related to the ESME data warehouse, individual data from the ESME databases cannot be made available. For any specific demand, please contact the corresponding author. Each demand will be examined on a case‐by‐case basis by the scientific committee.