Abstract
Background
Efficacy of necitumumab [recombinant human monoclonal antibody that blocks the ligand binding epidermal growth factor receptor (EGFR)] in patients with squamous (SQ) non-small-cell lung cancer (NSCLC) has been confirmed in two randomized clinical trials (SQUIRE and JFCM). This study evaluated the association between efficacy and initial skin toxicity with necitumumab treatment by analyzing pooled data from two clinical trials (SQUIRE and JFCM).
Materials and methods
Data of 635 patients with SQ-NSCLC (intent-to-treat population) treated with necitumumab plus gemcitabine and cisplatin (N + GC) were pooled from two clinical trials (SQUIRE and JFCM). The relationship between skin toxicities developed by the end of the second cycle and efficacy was evaluated. Efficacy endpoints included overall survival (OS), progression-free survival (PFS), and objective response rate (ORR). Univariate and multivariate analyses were carried out for these endpoints.
Results
OS and ORR were associated with skin toxicity, whereas PFS was not. Patients with grade ≥2 or grade 1 skin toxicity had significantly longer OS compared to patients without skin toxicity (grade 0) in the N + GC group [median = 15.0 (grade ≥2); 12.7 (grade 1); 9.4 (grade 0) months; hazard ratio (HR) = 0.51 (grade ≥2 to grade 0); 95% confidence interval (CI) 0.40-0.64, P < 0.001 and HR = 0.64 (grade 1 to grade 0); 95% CI 0.52-0.80, P < 0.001]. In multivariate analysis, OS was significantly associated with skin toxicity.
Conclusions
A significant association was found between necitumumab-induced skin toxicity and efficacy. These results are consistent with the previously reported association between other EGFR inhibitors-induced skin toxicity and efficacy.
Key words: necitumumab, squamous non-small-cell lung cancer, skin toxicity, survival, multivariate analysis
Highlights
-
•
This is a pooled analysis to evaluate an association between necitumumab-induced skin toxicity and efficacy.
-
•
Skin toxicity was associated with OS and ORR.
-
•
Skin toxicity and performance status were associated with OS by multivariate analysis.
-
•
Skin toxicity was not associated with necitumumab trough concentration.
-
•
Prompt management of skin toxicity should be implemented for effective necitumumab treatment.
Introduction
The treatment of non-small-cell lung cancer (NSCLC) includes surgery, radiation, and systemic therapy, which are selected based on the disease stage.1 Molecular targeted therapy2,3 and immunotherapy4 are currently the standard of care options for patients with oncogene- and non-oncogene-driven advanced NSCLC, respectively. Both options have resulted in prolongation of survival in these patients. The wild-type epidermal growth factor receptor (EGFR) is highly expressed in NSCLCs, particularly in squamous (SQ) NSCLC compared to non-squamous disease, and it has been hypothesized to play a critical role in tumorigenesis.5,6 EGFR is commonly over-expressed in lung cancer, 62% of all tumors, 89% of squamous tumors, and 41% of adenocarcinomas.7 Mutations in EGFR are more common in adenocarcinomas than in SQ-NSCLC.8
Targeted therapies against EGFR include tyrosine kinase inhibitors (TKIs) such as gefitinib9,10 and erlotinib11and EGFR-targeting monoclonal antibodies such as necitumumab.12,13 Necitumumab is a second-generation, recombinant, human IgG1 EGFR monoclonal antibody that binds to EGFR with high affinity, thereby preventing receptor activation and activation of downstream signaling pathways. Necitumumab plus gemcitabine and cisplatin (N + GC) therapy is approved in Europe, the United States, and Japan. In particular, it has been used in Japan as a treatment option for recurrent squamous NSCLC in or after the second-line therapy following immune checkpoint inhibitors, as reported in the retrospective NINJA study.14 In the global phase III SQUIRE study,12 overall survival (OS) was significantly longer in the N + GC group compared with the GC-alone group {median 11.5 months [95% confidence interval (CI) 10.4-12.6 months] versus 9.9 months (95% CI 8.9-11.1 months); stratified hazard ratio (HR) 0.84 (95% CI 0.74-0.96; P = 0.01)}. The overall incidence of skin reactions and rash in the N + GC group was 79% and 76%, respectively, and the incidence of these events at grade 3 or higher was 8% and 7%, respectively. In the Japanese phase I/II JFCM study,13 OS was significantly improved in the N + GC group compared to the GC group (median 14.9 months versus 10.8 months; HR = 0.66, 95% CI 0.47-0.93, P = 0.0161). The overall incidence of skin reaction and rash in the N + GC group was 98% and 80%, respectively, and the incidence of these events at grade 3 or higher was 10% and 6%, respectively.
EGFR-targeting drugs are known to be associated with a high incidence of skin toxicity in EGFR-positive cancer patients, and efficacy of these drugs has been associated with skin toxicity. Disease control rate, OS, and progression-free survival (PFS) were significantly associated with skin toxicity in a clinical trial of gefitinib,15 and OS was associated with the onset of rash in a clinical trial of erlotinib.16,17 The efficacy of cetuximab, an anti-EGFR antibody, was also associated with skin toxicity in patients with colorectal cancer.18,19 Similarly, early appearance of rash was associated with better efficacy of cetuximab in patients with advanced NSCLC.20 Also, an association between efficacy and grade of skin toxicity was suggested in a clinical trial of panitumumab in metastatic colorectal cancer.21
The potential association between necitumumab-induced skin toxicity and efficacy in patients with advanced SQ-NSCLC has not yet been investigated. In this study, we evaluated the association between efficacy and initial skin toxicity with necitumumab treatment by analyzing pooled data from two clinical trials (SQUIRE and JFCM).
Materials and methods
Population
This study was conducted using pooled data from the SQUIRE and JFCM studies (NCT00981058 and NCT01763788), which evaluated the efficacy and safety of necitumumab in treatment-naive patients with SQ-NSCLC. The two studies were conducted in compliance with the Declaration of Helsinki and Good Clinical Practice, after obtaining written informed consent from all the patients. The ethics committee of each center approved the protocol. Details of the two studies have been reported previously.12,13 Briefly, in both the studies patients were randomly assigned in a 1 : 1 ratio to 3-week treatment cycles with N + GC or GC. Patients aged ≥18 years and performance status (PS) ranging between 0 and 2 were included in the SQUIRE study, while those aged ≥20 years and with PS of 0 to 1 formed the study population of the JFCM study.
In this study, individual patient data were pooled from the N + GC arms of the SQUIRE trial (n = 545) and the JFCM trial (n = 90) and analyzed.
Outcome and parameters
Efficacy endpoints were OS, PFS, and ORR. Skin toxicity was classified as grade 1-3, according to the National Cancer Institute-Common Terminology Criteria for Adverse Events Ver.4.0.
We analyzed the association between patient characteristics and skin toxicity which developed by the end of the second cycle (day 42) in the SQUIRE and JFCM trials. We also analyzed the relationship between skin toxicity developed for the same duration and efficacy. In addition, the association between efficacy and patient characteristics was evaluated. The preferred terms applicable to skin toxicities are listed in Supplementary Table S1, available at https://doi.org/10.1016/j.esmoop.2024.102975.
We analyzed the skin toxicities that developed by the end of the second cycle since the target period for skin toxicity could be a confounding factor for efficacy. Moreover, the majority of patients included in the pooled analysis (n = 328, 86.3%) developed skin toxicities by the end of the second cycle of therapy.
The association between EGFR expression level and efficacy outcome (OS, PFS, and ORR), or skin toxicity grade was evaluated using the H-Score, the marker of EGFR expression level, which is an immunohistochemical score calculated by integrating data on staining intensity and frequency and has been reported in some papers.12,22 In this analysis, H-Score ≥200 was defined as the high EGFR expression group and <200 as the low expression group.
Statistical analysis
The association between the occurrence of skin toxicities and patient characteristics (age, sex, PS, region, race, and study) was examined using Fisher’s exact test. The relationship between skin toxicity (grade ≥2, 1, and 0), and median OS and median PFS were evaluated using survival curves of the Kaplan–Meier method, and their HR and 95% CIs were calculated by the Cox proportional hazard model. The 95% CIs of OS and PFS were calculated using the Brookmeyer–Crowley method. Logistic regression analysis was carried out for ORR of patients by skin toxicity grade, and odds ratios (ORs) along with their 95% CIs were calculated.
To examine the relationship between efficacy and some factors including patient characteristics and skin toxicity, a multivariate proportional hazard analysis was conducted with median OS or PFS as the outcome variable, and their respective HRs and 95% CIs were calculated. Similarly, logistic regression analysis was carried out for ORR. Results were provided for each of the univariate analysis, multivariate analysis with all variables, and multivariate analysis with variables selected through stepwise selection.
The association between necitumumab trough concentration and skin toxicity was evaluated by skin toxicity grade using one-way analysis of variance (ANOVA). Data for trough concentrations were obtained before necitumumab administration on day 1 of the third cycle, which was the closest time point from the end of assessment of skin toxicity in this study.
The association between H-Score (<200, ≥200) and OS or PFS were evaluated using survival curves of the Kaplan–Meier method, and their HRs and 95% CIs were calculated by the Cox proportional hazard model. The 95% CIs of OS and PFS were calculated using the Brookmeyer–Crowley method. Logistic regression analysis was carried out for ORR of patients by H-Score, and ORs along with their 95% CIs were calculated. In addition, the association between H-Score and the occurrence of skin toxicities by grade was examined using Fisher’s exact test.
The statistical significance level was P < 0.05. Statistical analyses were carried out using SAS version 9.4 (SAS Institute, Cary, NC).
Results
Association between patient characteristics and skin toxicity
Table 1 shows the patient characteristics at baseline. Most patients were male in the N + GC group of the SQUIRE and JFCM study (82.3% and 87.8%, respectively) and had a PS of 1 (60.9% and 70.0%, respectively). In the JFCM study, the majority of patients were aged 65 years or older, while in the SQUIRE trial the majority were younger than 65 years of age. The majority of the patients in the SQUIRE study were Caucasians and from regions of North America, Europe, and Australia (Table 1).
Table 1.
Patient baseline clinical characteristics and demographic
| Study group | SQUIRE |
JFCM |
SQUIRE + JFCM |
|||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| GC + N (n = 545) |
GC (n = 548) |
GC + N (n = 90) |
GC (n = 91) |
GC + N (n = 635) |
GC (n = 639) |
|||||||
| Characteristics | No. of patients | (%) | No. of patients | (%) | No. of patients | (%) | No. of patients | (%) | No. of patients | (%) | No. of patients | (%) |
| Age, years | ||||||||||||
| <65 | 330 | 60.55 | 338 | 61.68 | 36 | 40.00 | 36 | 39.56 | 366 | 57.64 | 374 | 58.53 |
| ≥65 | 215 | 39.45 | 210 | 38.32 | 54 | 60.00 | 55 | 60.44 | 269 | 42.36 | 265 | 41.47 |
| Sex | ||||||||||||
| Male | 450 | 82.57 | 458 | 83.58 | 79 | 87.78 | 81 | 89.01 | 529 | 83.31 | 539 | 84.35 |
| Female | 95 | 17.43 | 90 | 16.42 | 11 | 12.22 | 10 | 10.99 | 106 | 16.69 | 100 | 15.65 |
| PS | ||||||||||||
| 0 | 164 | 30.09 | 180 | 32.85 | 27 | 30.00 | 30 | 32.97 | 191 | 30.08 | 210 | 32.86 |
| 1 | 332 | 60.92 | 320 | 58.39 | 63 | 70.00 | 61 | 67.03 | 395 | 62.20 | 381 | 59.62 |
| 2 | 49 | 8.99 | 47 | 8.58 | 0 | 0.00 | 0 | 0.00 | 49 | 7.72 | 47 | 7.36 |
| Region | ||||||||||||
| North America, Europe, Australia | 472 | 86.61 | 475 | 86.68 | 0 | 0.00 | 0 | 0.00 | 472 | 74.33 | 475 | 74.33 |
| South America, South Africa, India | 54 | 9.91 | 55 | 10.04 | 0 | 0.00 | 0 | 0.00 | 54 | 8.50 | 55 | 8.61 |
| East Asia | 19 | 3.49 | 18 | 3.28 | 90 | 100.00 | 91 | 100.00 | 109 | 17.17 | 109 | 17.06 |
| Unknown | 0 | 0.00 | 0 | 0.00 | 0 | 0.00 | 0 | 0.00 | 0 | 0.00 | 0 | 0.00 |
| Race | ||||||||||||
| White | 457 | 83.85 | 456 | 83.21 | 0 | 0.00 | 1 | 1.10 | 457 | 71.97 | 457 | 71.52 |
| Asian | 43 | 7.89 | 42 | 7.66 | 90 | 100.00 | 89 | 97.80 | 133 | 20.94 | 131 | 20.50 |
| Others | 45 | 8.26 | 50 | 9.12 | 0 | 0.00 | 1 | 1.10 | 45 | 7.09 | 51 | 7.98 |
| Unknown | 0 | 0.00 | 0 | 0.00 | 0 | 0.00 | 0 | 0.00 | 0 | 0.00 | 0 | 0.00 |
GC, gemcitabine and cisplatin; N, necitumumab; PS, performance status.
We found that the following five characteristics were significantly associated with skin toxicity: sex (P = 0.018), PS (P = 0.008), region (P < 0.001), race (P < 0.001), and study (P < 0.001) (Table 2). Patient rate of female and PS 2 seems to be lower in high skin toxicity grade. Also, that of Caucasian and from regions of North America, Europe, and Australia was lower in high skin toxicity grade. In contrast, patient rate of Asian and from region of East Asia seems higher in high skin toxicity grade.
Table 2.
Association between patient characteristics and skin toxicity
| Characteristic | Skin toxicity |
Fisher’s exact test | ||||||
|---|---|---|---|---|---|---|---|---|
| Any (n = 635) |
Grade 0 (n = 184) |
Grade 1 (n = 255) |
Grade ≥2 (n = 196) |
|||||
| No. of patients | No. of patients | (%) | No. of patients | (%) | No. of patients | (%) | P value | |
| Age, years | ||||||||
| <65 | 366 | 105 | 28.69 | 153 | 41.80 | 108 | 29.51 | 0.570 |
| ≥65 | 269 | 79 | 29.37 | 102 | 37.92 | 88 | 32.71 | |
| Sex | ||||||||
| Male | 529 | 146 | 27.60 | 208 | 39.32 | 175 | 33.08 | 0.018 |
| Female | 106 | 38 | 35.85 | 47 | 44.34 | 21 | 19.81 | |
| PS | ||||||||
| 0 | 191 | 54 | 28.27 | 78 | 40.84 | 59 | 30.89 | 0.008 |
| 1 | 395 | 104 | 26.33 | 164 | 41.52 | 127 | 32.15 | |
| 2 | 49 | 26 | 53.06 | 13 | 26.53 | 10 | 20.41 | |
| Region | ||||||||
| North America/Europe/Australia | 472 | 155 | 32.84 | 189 | 40.04 | 128 | 27.12 | <0.001 |
| South America/South Africa/India | 54 | 15 | 27.78 | 25 | 46.30 | 14 | 25.93 | |
| East Asia | 109 | 14 | 12.84 | 41 | 37.62 | 54 | 49.54 | |
| Race | ||||||||
| Caucasian | 457 | 149 | 32.60 | 187 | 40.92 | 121 | 26.48 | <0.001 |
| Asian | 133 | 21 | 15.79 | 51 | 38.35 | 61 | 45.87 | |
| Other | 45 | 14 | 31.11 | 17 | 37.78 | 14 | 31.11 | |
| Study | ||||||||
| SQUIRE | 545 | 179 | 32.84 | 219 | 40.18 | 147 | 26.97 | <0.001 |
| JFCM | 90 | 5 | 5.56 | 36 | 40.00 | 49 | 54.44 | |
Skin toxicity grade was evaluated based on skin toxicities developed by the end of the second cycle.
PS, performance status.
Association between efficacy response and skin toxicity
Patients with grade ≥2 or grade 1 skin toxicity had a significantly longer OS compared to patients without skin toxicity (grade 0) in the N + GC group [median = 15.0 (grade ≥2); 12.7 (grade 1); 9.4 (grade 0) months; HR = 0.51 (grade ≥2 to grade 0); 95% CI 0.40-0.64, P < 0.001 and HR = 0.64 (grade 1 to grade 0); 95% CI 0.52-0.80, P < 0.001] (Figure 1).
Figure 1.
(A) A Kaplan–Meier curve of the overall survival in the N + GC group plotted by the grade of skin toxicity. (B) A table of hazard ratios of overall survival calculated using patients with skin toxicity grade 0 as reference.
CI, confidence interval; GC, gemcitabine and cisplatin; N, necitumumab.
Patients with grade ≥2 or grade 1 skin toxicity also had significantly higher ORR than patients without skin toxicity in the N + GC group [ORR = 37.8% (grade ≥2); 38.0% (grade 1); and 24.5% (grade 0), OR (grade ≥ 2 versus grade 0) = 1.87; 95% CI 1.20-2.92, P = 0.005 and OR (grade 1 versus grade 0) = 1.90; 95% CI 1.25-2.89, P = 0.003]. In contrast, the median PFS of patients with grade ≥2, grade 1, and grade 0 skin toxicities in the N + GC group were 5.6, 5.9, and 5.5 months, respectively, with no significant difference between the groups [HR (grade ≥2 versus grade 0) = 0.91; 95% CI 0.72-1.14, P = 0.412 and HR (grade 1 versus grade 0) = 0.84; 95% CI 0.68-1.04, P = 0.11, respectively] (Table 3, Supplementary Figure S1, available at https://doi.org/10.1016/j.esmoop.2024.102975).
Table 3.
Association between progression-free survival or objective response rate and skin toxicity grade
| Skin toxicity | No. of patients | No. of events | Median PFS (months) | Hazard ratio (95% CI) | P value |
|---|---|---|---|---|---|
| Any grade | 635 | 515 | — | — | — |
| Grade 0 | 184 | 138 | 5.5 | Reference | — |
| Grade 1 | 255 | 217 | 5.9 | 0.84 (0.68-1.04) | 0.11 |
| Grade ≥2 | 196 | 160 | 5.6 | 0.91 (0.72-1.14) | 0.412 |
| Skin toxicity | No. of patients | No. of response patients | ORR (%) | Odds ratio (95% CI) | P value |
|---|---|---|---|---|---|
| Any grade | 635 | 216 | — | — | — |
| Grade 0 | 184 | 45 | 24.5 | Reference | — |
| Grade 1 | 255 | 97 | 38.0 | 1.90 (1.25-2.89) | 0.003 |
| Grade ≥2 | 196 | 74 | 37.8 | 1.87 (1.20-2.92) | 0.005 |
CI, confidence interval; ORR, objective response rate; PFS, progression-free survival.
Evaluation of the relationship between efficacy and patient characteristics including skin toxicity
Multivariate analysis showed that skin toxicity grade and PS were significantly associated with OS (P < 0.001 and P < 0.001, respectively). HRs (95% CI) of the skin toxicity grade ≥2 and grade 1 groups were 0.51 (0.41-0.65) and 0.66 (0.53-0.82), respectively, against the grade 0 group used as the reference. In addition, HRs (95% CI) of PS 2 and PS 1 were 2.09 (1.47-2.98) and 1.42 (1.16-1.75), respectively, against PS 0 as the reference (Table 4). On the other hand, PS and study were significantly associated with PFS (P = 0.042 and P < 0.001, respectively) and ORR (P = 0.009 and P = 0.001, respectively); however, skin toxicity grade was not associated with PFS and ORR.
Table 4.
Relationship between overall survival and patient characteristics including skin toxicity grade
| Item (explanatory variable included in final model) | No. of patients | No. of events | Median survival time (months) | Univariate |
Multivariate |
||||
|---|---|---|---|---|---|---|---|---|---|
| All variables |
Variable selectiona |
||||||||
| Hazard ratio (95% CI) | P value | Hazard ratio (95% CI) | P value | Hazard ratio (95% CI) | P value | ||||
| Skin toxicity | |||||||||
| Grade 0 | 184 | 153 | 9.4 | Reference | <0.001 | Reference | <0.001 | Reference | <0.001 |
| Grade 1 | 255 | 193 | 12.7 | 0.64 (0.52-0.80) | 0.67 (0.54-0.83) | 0.66 (0.53-0.82) | |||
| Grade ≥2 | 196 | 135 | 15.0 | 0.51 (0.40-0.64) | 0.53 (0.42-0.67) | 0.51 (0.41-0.65) | |||
| PS | |||||||||
| 0 | 191 | 134 | 14.8 | Reference | <0.001 | Reference | <0.001 | Reference | <0.001 |
| 1 | 395 | 306 | 11.4 | 1.37 (1.11-1.67) | 1.42 (1.15-1.74) | 1.42 (1.16-1.75) | |||
| 2 | 49 | 41 | 9.5 | 2.32 (1.63-3.30) | 2.01 (1.41-2.88) | 2.09 (1.47-2.98) | |||
| Age, years | |||||||||
| <65 | 366 | 278 | 12.0 | Reference | 0.465 | Reference | 0.711 | — | — |
| 65≤ | 269 | 203 | 12.6 | 0.93 (0.78-1.12) | 0.97 (0.80-1.16) | — | |||
| Sex | |||||||||
| Male | 529 | 397 | 12.0 | Reference | 0.767 | Reference | 0.433 | — | — |
| Female | 106 | 84 | 13.0 | 0.96 (0.76-1.22) | 0.91 (0.71-1.15) | — | |||
| Region | |||||||||
| North America/Europe/Australia | 472 | 365 | 11.5 | Reference | 0.044 | Reference | 0.933 | — | — |
| South America/South Africa/India | 54 | 38 | 10.0 | 1.01 (0.72-1.40) | 1.08 (0.69-1.69) | — | |||
| East Asia | 109 | 78 | 14.9 | 0.73 (0.57-0.94) | 1.04 (0.44-2.41) | — | |||
| Race | |||||||||
| Caucasian | 457 | 355 | 11.4 | Reference | 0.050 | Reference | 0.810 | — | — |
| Asian | 133 | 94 | 14.4 | 0.76 (0.60-0.95) | 0.94 (0.48-1.83) | — | |||
| Other | 45 | 32 | 12.6 | 0.88 (0.61-1.26) | 0.88 (0.61-1.28) | — | |||
| Study | |||||||||
| SQUIRE | 545 | 418 | 11.5 | Reference | 0.004 | Reference | 0.502 | — | — |
| JFCM | 90 | 63 | 14.9 | 0.68 (0.52-0.88) | 0.82 (0.46-1.46) | — | |||
CI, confidence interval; OS, overall survival; PS, performance status.
Stepwise method was used for variable selection.
Association between necitumumab trough concentration and skin toxicity
Trough concentration [median (mean)] of necitumumab in patients with grade ≥2, grade 1, and grade 0 skin toxicity were 88.750 (88.724), 94.500 (96.434), and 91.250 (91.539) μl/ml, respectively (Supplementary Figure S2, available at https://doi.org/10.1016/j.esmoop.2024.102975). One-way ANOVA of trough concentration of necitumumab by skin toxicity grade showed no association between trough concentration and skin toxicity (P = 0.271).
Association between EGFR protein expression and efficacy outcome, or skin toxicity
In the 573 patients whose H-Score was evaluated in the studies, OS, PFS, and ORR were compared between the high EGFR expression group (H-Score ≥200) and the low expression group (H-Score <200). No significant differences were found between these two groups in OS, PFS, and ORR. Median OS (H-Score ≥200 and <200) were 12.5 months and 12.3 months [HR (95% CI) = 1.00 (0.82-1.22), P = 0.974], median PFS were 5.6 months and 5.6 months [HR (95% CI) = 0.97 (0.80-1.17), P = 0.727], and ORR were 36.0% and 32.4% [OR (95% CI) = 0.85 (0.59-1.22), P = 0.375] (Supplementary Figures S3 and S4, and Table S2, available at https://doi.org/10.1016/j.esmoop.2024.102975).
Also, no significant difference was found between the groups in these efficacy outcomes in multivariate analysis (OS: P = 0.240, PFS: P = 0.941, ORR: P = 0.936) (Supplementary Tables S3-S5, available at https://doi.org/10.1016/j.esmoop.2024.102975).
Further, there was no significant difference in the frequency of skin toxicity by grade between the two groups (P = 0.087, Supplementary Table S6, available at https://doi.org/10.1016/j.esmoop.2024.102975).
Discussion
This is the first paper to demonstrate an association between efficacy outcomes and skin toxicity in patients with SQ-NSCLC receiving treatment with necitumumab. We evaluated the association between efficacy and skin toxicity, a well-known adverse reaction to EGFR-targeting drugs including necitumumab, using pooled data from two clinical trials of necitumumab.
Two points were considered when selecting the target period for skin toxicity analysis. Firstly, the target period for skin toxicity could be a confounding factor for efficacy. Secondly, the onset of rash caused by EGFR inhibitors has been observed to maximize within 2-3 weeks after starting of treatment.23 Therefore, we selected the end of the second cycle of drug administration as the target period for skin toxicity analysis. Notably, the majority (∼90%) of skin toxicity in the pooled data occurred within this time period.
In this analysis, sex, PS, region, race, and study were identified as significant baseline characteristics associated with skin toxicity in patients treated with necitumumab. Of note, because the JFCM study enrolled only Japanese subjects, ‘region’, ‘race’, and ‘study’ were considered synonymous during data extraction. Male sex and younger age were reported to be significantly associated with skin toxicity in cetuximab clinical trials.18 Similarly, in the present study, sex was found to be significantly associated with skin toxicity, with male patients being more likely to develop high-grade skin toxicities. In contrast, no association between age and skin toxicity was observed.
We found that OS was significantly prolonged in the patients experiencing grade ≥2 or grade 1 skin toxicity compared to patients with no skin toxicity, confirming the association between skin toxicity and OS. Similarly, ORR was significantly higher in patients experiencing grade ≥2 or grade 1 skin toxicity compared to the patients with no skin toxicity. Conversely, no difference was observed between PFS and degree of skin toxicity.
Although analysis showed that skin toxicity and PS were associated with OS in the N + GC group, we confirmed that skin toxicity was not associated with OS in the GC group. We analyzed pooled data in the GC group (a total of 639 patients) to determine whether skin toxicity was also a prognostic factor for OS. The median OS of patients with grade ≥2, grade 1, and grade 0 skin toxicity was 10.9, 10.6, and 10.0 months, respectively, with no difference between the various grades in the GC group (Supplementary Figure S5, available at https://doi.org/10.1016/j.esmoop.2024.102975). From this finding, we concluded that skin toxicity induced by other factors (excluding necitumumab) was not a prognostic factor of OS.
Moreover, we considered that the difference in the treatments provided after the administration of necitumumab among the patients with different grades of skin toxicity may have ultimately affected the OS. In the present study, patients with a higher grade of skin toxicity were more likely to receive second-line therapy [61.7% in grade ≥2, 47.1% in grade 1, 31.5% in grade 0, P < 0.001 (Fisher’s exact test)].
Our results also demonstrated that the trough concentration of necitumumab did not contribute to the association between necitumumab-induced skin toxicity and efficacy.
Similarly to the results of our study, an association between skin toxicity and efficacy outcomes, including OS, PFS, and ORR, has been reported for other EGFR inhibitors, such as erlotinib16 and cetuximab.20
Some studies for other EGFR inhibitors have also suggested predictors of survival. The time elapsed since diagnosis and PS were reported to be significant prognostic factors of survival in patients with NSCLC16 treated with erlotinib. In addition, skin toxicity (grade ≥2) was found to be associated with survival in squamous cell carcinoma of the head and neck.17 Regarding cetuximab, patients with first-cycle cetuximab-induced skin toxicity had significantly longer survival in metastatic colorectal cancer18 and advanced NSCLC20 and skin toxicity along with early tumor shrinkage were proven to be predictors of survival in patients with metastatic colorectal cancer.19
Since the necitumumab is the EGFR antibody, it is important to investigate whether EGFR expression level is a predictive factor for efficacy. It has been reported that EGFR expression was associated with the efficacy outcome of cetuximab.22 Thus, we investigated any differences in OS, PFS, ORR, and skin toxicity grade between the high EGFR expression group (H-score ≥200) and the low expression group (H-Score <200) in 573 out of 635 patients included in this analysis, whose H-Score was evaluated as the EGFR expression level. The results showed that there was no significant difference in OS, PFS, and ORR between the two groups, suggesting that the efficacy of necitumumab was not associated with the EGFR expression level. Similarly, there was also no difference in skin toxicity grade between the groups. Therefore, it is considered that the EGFR expression level was not associated with the efficacy outcome and skin toxicity grade of necitumumab.
The development of skin toxicity is a characteristic feature of EGFR antagonists. Therefore, it is important to manage skin toxicity and continue administration of EGFR antagonists, since OS has been found to be associated with skin toxicity. Treatment and management strategies for EGFR-TKI-associated24 and panitumumab-associated skin toxicities25 have been reported.
This study has some limitations. We analyzed pooled data from two existing clinical trials with distinct study designs, and hence, the effect of bias was not ruled out since this study was a post hoc analysis.
Our study demonstrated significant association between necitumumab-induced skin toxicity and efficacy. Based on these results, prompt management of skin toxicity should be implemented for the effective and safe continuation of necitumumab treatment.
Conclusion
A significant association was found between necitumumab-induced skin toxicity and efficacy. These results are consistent with the previously reported association between other EGFR inhibitors-induced skin toxicity and efficacy.
Acknowledgements
We thank Nippon Kayaku Co., Ltd. and third-party EPS Corporation for analysis and medical writing support, and Maria Teresa Rizzo, M.D. of Eli Lilly and Company for her critical review of the manuscript.
Funding
This work was supported by Nippon Kayaku Co., Ltd (no grant number). Nippon Kayaku supported Software, Validation, Formal analysis, Investigation, Resources, Data Curation, Writing-Review & Editing with third-party EPS Corporation under the direction of the authors.
Disclosure
SW reports receiving personal fees from Novartis Pharma, Chugai Pharmaceutical, Boehringer Ingelheim, Ono Pharmaceutical, Taiho Pharmaceutical, AstraZeneca, Bristol-Myers Squibb, MSD, and Daiichi Sankyo. HY reports receiving personal fees from Delta Fly Pharma, Chugai Pharmaceutical, MSD, AstraZeneca, Boehringer Ingelheim, Taiho Pharmaceutical, Ono Pharmaceutical, Bristol-Myers Squibb, Novartis Pharma, Kyowa Kirin, Nippon Kayaku, Eli Lilly, Otsuka Pharmaceutical, Daiichi Sankyo, Amgen, Pfizer, and Nipro Pharma. HS reports receiving personal fees from Merck, Ono Pharmaceutical, Bristol-Myers Squibb, Chugai Pharmaceutical, and AstraZeneca. KH reports receiving grants from MSD, AstraZeneca, Chugai Pharmaceutical, Eli Lilly, Bristol-Myers Squibb, and AbbVie; and personal fees from Pfizer, AstraZeneca, Chugai Pharmaceutical, Eli Lilly, Takeda Pharmaceutical, MSD, Bristol-Myers Squibb, Ono Pharmaceutical, Taiho Pharmaceutical, and Boehringer Ingelheim. MT reports receiving grants from Chugai Pharmaceutical, Ono Pharmaceutical, and Pfizer. KY reports personal fees from Healios, Chugai Pharmaceutical, AstraZeneca, and Bristol-Myers Squibb. SS reports receiving personal fees from MSD, Nippon Kayaku, Chugai Pharmaceutical, AstraZeneca, Ono Pharmaceutical, Bristol-Myers Squibb, Boehringer Ingelheim, Taiho Pharmaceutical, Eli Lilly, Novartis Pharma, Kyowa Kirin, Yakult Honsha, Takeda Pharmaceutical, Pfizer, Merck, Amgen, AbbVie, Otsuka Pharmaceutical, Thermo Fisher Scientific, and Towa Pharmaceutical. YT reports receiving grants from Ono Pharmaceutical, AstraZeneca, MSD, AbbVie, Bristol-Meyers Squib, Taiho Pharmaceutical, Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly, Boehringer Ingelheim, Eisai, Nippon Kayaku, and Takeda Pharmaceutical; and personal fees from Ono Pharmaceutical, AstraZeneca, Bristol-Meyers Squib, Taiho Pharmaceutical, Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly, Boehringer Ingelheim, Eisai, MSD, Takeda Pharmaceutical, Amgen, Novartis Pharma, Merck BioPharma, and Kyowa Kirin. YH reports receiving personal fees from AstraZeneca, Eli Lilly, Taiho Pharmaceutical, Chugai Pharmaceutical, Ono Pharmaceutical, Bristol-Myers Squibb, Kyowa Kirin, Nippon Kayaku, Takeda Pharmaceutical, Eisai, Novartis Pharma, and Pfizer. KT reports receiving personal fees from AstraZeneca, Boehringer Ingelheim, Chugai Pharmaceutical, Daiichi Sankyo, Kyowa Kirin, MSD, and Taiho Pharmaceutical. SN reports receiving grants from AstraZeneca, Merck BioPharma, Chugai Pharmaceutical, and GlaxoSmithKline; and personal fees from AstraZeneca, Ono Pharmaceutical, Chugai Pharmaceutical, Pfizer, Eli Lilly, Takeda Pharmaceutical, Merck BioPharma, Boehringer Ingelheim, Taiho Pharmaceutical, Novartis Pharma, Daiichi Sankyo, KYORIN Pharmaceutical, and MSD. MN reports receiving personal fees from Ono Pharmaceutical, Bristol-Myers Squibb, Pfizer, Chugai Pharmaceutical, Eli Lilly, Taiho Pharmaceutical, AstraZeneca, Astellas Pharma, Boehringer Ingelheim, MSD, Novartis Pharma, Daiichi Sankyo Healthcare, Taiho Pharmaceutical, and Merck Serono. TK reports receiving grants from AbbVie, Amgen, AstraZeneca, BeiGene, Blueprint Medicines, Boehringer Ingelheim, Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly, Haihe Biopharma, Merck, MSD, Novartis Pharma, Pfizer, Regeneron Pharmaceuticals, Takeda Pharmaceutical, and Turning Point Therapeutics; and personal fees from Amgen, AstraZeneca, BeiGene, Boehringer Ingelheim, Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly, GlaxoSmithKline, Janssen Pharmaceutical, Merck, MSD, Novartis Pharma, Ono Pharmaceutical, Pfizer, Taiho Pharmaceutical, and Takeda Pharmaceutical. TT reports receiving grants from AstraZeneca, Amgen, Boehringer Ingelheim, Merck Biopharma, Chugai Pharmaceutical, Eli Lilly, Ono Pharmaceutical, MSD, and Pfizer; and personal fees from AstraZeneca, Chugai Pharmaceutical, Eli Lilly, Ono Pharmaceutical, MSD, Pfizer, Boehringer Ingelheim, Roche Diagnostics, Takeda Pharmaceutical, and Yakult Honsha. HE reports receiving personal fees from Nippon Kayaku. MA reports receiving personal fees from Nippon Kayaku. NY reports receiving grants from Boehringer Ingelheim, Taiho Pharmaceutical, Chugai Pharmaceutical, Shionogi Pharma, Eli Lilly, Daiichi Sankyo, Tsumura, Nippon Kayaku, Asahikasei-pharma, AstraZeneca, Janssen Pharmaceutical, Sanofi, Amgen, Novartis Pharma, Astellas Pharma, MSD, Eisai, Bristol-Myers Squibb, AbbVie, and Tosoh; and personal fees from MSD, AstraZeneca, Amgen, Ono Pharmaceutical, Otsuka Pharmaceutical, Guardant Health, Tsumura, Kyowa Kirin, KYORIN Pharmaceutical, GlaxoSmithKline, Sanofi, Daiichi Sankyo, Taiho Pharmaceutical, Takeda Pharmaceutical, Chugai Pharmaceutical, Eli Lilly, Nippon Kayaku, Boehringer Ingelheim, Novartis Pharma, Pfizer, Bristol-Myers Squibb, Miyarisan Pharmaceutical, Merck, and Janssen Pharmaceutical. YO reports receiving grants from AstraZeneca, Chugai Pharmaceutical, Eli Lilly, Ono Pharmaceutical, Bristol-Myers Squibb, KYORIN Pharmaceutical, Sumitomo Pharma, Pfizer, Taiho Pharmaceutical, Novartis Pharma, Takeda Pharmaceutical, Kissei Pharmaceutical, Daiichi Sankyo, and Janssen Pharmaceutical; and personal fees from AstraZeneca, Chugai Pharmaceutical, Eli Lilly, Ono Pharmaceutical, Bristol-Myers Squibb, Boehringer Ingelheim, Bayer Yakuhin, Pfizer, MSD, Taiho Pharmaceutical, Nippon Kayaku, Kyowa Kirin, and Eisai. KN reports receiving grants from AstraZeneca, MSD, Ono Pharmaceutical, Boehringer Ingelheim, Novartis Pharma, Pfizer, Bristol-Myers Squibb, Eli Lilly, Chugai Pharmaceutical, Daiichi Sankyo, Merck Biopharma, PAREXEL International, PRA HEALTHSCIENCES, EPS, Kissei Pharmaceutical, EPS International, Taiho Pharmaceutical, PPD-SNBL, SymBio Pharmaceuticals, IQVIA Services, SYNEOS HEALTH CLINICAL, Nippon Kayaku, EP-CRSU, Mebix, Janssen Pharmaceutical, AbbVie, Bayer Yakuhin, Eisai, Mochida Pharmaceutical, Covance, Japan Clinical Research Operations, Takeda Pharmaceutical, GlaxoSmithKline, Sanofi, Sysmex, Medical Research Support, Otsuka Pharmaceutical, SRL, Pfizer R&D, and Amgen; and personal fees from Eli Lilly, KYORIN Pharmaceutical, Ono Pharmaceutical, Pfizer, Amgen, Nippon Kayaku, AstraZeneca, Chugai Pharmaceutical, MSD, Boehringer Ingelheim, Taiho Pharmaceutical, Bayer Yakuhin, CMIC ShiftZero, Life Technologies, Neo Communication, Roche Diagnostics, AbbVie, Merck Biopharma, Kyowa Kirin, Takeda Pharmaceutical, 3H Clinical Trial, Care Net, Medical Review, Medical Mobile Communications, YODOSHA, Nikkei Business Publications, Japan Clinical Research Operations, CMIC, Novartis Pharma, TAIYO Pharma, and Bristol-Myers Squibb.
Supplementary data
References
- 1.David S., Ettinger M.D., Douglas E., et al. Non-small cell lung cancer version 3. 2022. NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw. 2022;5:497–530. doi: 10.6004/jnccn.2022.0025. [DOI] [PubMed] [Google Scholar]
- 2.Forde P.M., Ettinger D.S. Targeted therapy for non-small-cell lung cancer: past, present and future. Expert Rev Anticancer Ther. 2013;13:745–758. doi: 10.1586/era.13.47. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Zhao D., Chen X., Qin N., et al. The prognostic role of EGFR-TKIs for patients with advanced non-small cell lung cancer. Sci Rep. 2017;7 doi: 10.1038/srep40374. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Reck M., Rodríguez-Abreu D., Robinson A.G., et al. Updated analysis of KEYNOTE-024: pembrolizumab versus platinum-based chemotherapy for advanced non-small-cell lung cancer with PD-L1 tumor proportion score of 50% or greater. J Clin Oncol. 2019;37:537–546. doi: 10.1200/JCO.18.00149. [DOI] [PubMed] [Google Scholar]
- 5.López-Malpartida A.V., Ludeña M.D., Varela G., García Pichel J. Differential ErbB receptor expression and intracellular signaling activity in lung adenocarcinomas and squamous cell carcinomas. Lung Cancer. 2009;65:25–33. doi: 10.1016/j.lungcan.2008.10.009. [DOI] [PubMed] [Google Scholar]
- 6.Pirker R., Pereira J.R., Szczesna A., et al. Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): an open-label randomised phase III trial. Lancet. 2009;373:1525–1531. doi: 10.1016/S0140-6736(09)60569-9. [DOI] [PubMed] [Google Scholar]
- 7.AI Olayan A., AI Hussaini H., Jazieh A.R. The roles of epidermal growth factor receptor (EGFR) inhibitors in the management of lung cancer. J Infect Public Health. 2012;5:550–560. doi: 10.1016/j.jiph.2012.09.004. [DOI] [PubMed] [Google Scholar]
- 8.Dearden S., Stevens J., Wu Y.L., Blowers D. Mutation incidence and coincidence in non small-cell lung cancer: meta-analyses by ethnicity and histology (mutMap) Ann Oncol. 2013;24:2371–2376. doi: 10.1093/annonc/mdt205. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Mitsudomi T., Morita S., Yatabe Y., et al. Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial. Lancet Oncol. 2010;11:121–128. doi: 10.1016/S1470-2045(09)70364-X. [DOI] [PubMed] [Google Scholar]
- 10.Maemondo M., Inoue A., Kobayashi K., et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med. 2010;362:2380–2388. doi: 10.1056/NEJMoa0909530. [DOI] [PubMed] [Google Scholar]
- 11.Zhou C., Wu Y.L., Chen G., et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. Lancet Oncol. 2011;12:735–742. doi: 10.1016/S1470-2045(11)70184-X. [DOI] [PubMed] [Google Scholar]
- 12.Thatcher N., Hirsch F.R., Luft A.V., et al. Necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone as first-line therapy in patients with stage IV squamous non-small-cell lung cancer (SQUIRE): an open-label, randomized, controlled phase 3 trial. Lancet Oncol. 2015;16:763–774. doi: 10.1016/S1470-2045(15)00021-2. [DOI] [PubMed] [Google Scholar]
- 13.Watanabe S., Yoshioka H., Sakai H., et al. Necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone as first-line treatment for stage IV squamous non-small cell lung cancer: a phase 1b and randomized, open-label, multicenter, phase 2 trial in Japan. Lung Cancer. 2019;129:55–62. doi: 10.1016/j.lungcan.2019.01.005. [DOI] [PubMed] [Google Scholar]
- 14.Murata Y., Tanzawa S., Misumi T., et al. Multicenter, retrospective study to evaluate necitumumab plus cisplatin and gemcitabine after immune checkpoint inhibitors in advanced squamous cell lung cancer in Japan: the NINJA study. JTO Clin Res Rep. 2023;4 doi: 10.1016/j.jtocrr.2023.100593. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Cohen E.E., Rosen F., Stadler W.M., et al. Phase II trial of ZD1839 in recurrent or metastatic squamous cell carcinoma of the head and neck. J Clin Oncol. 2003;21:1980–1987. doi: 10.1200/JCO.2003.10.051. [DOI] [PubMed] [Google Scholar]
- 16.Pérez-Soler R., Chachoua A., Hammond L.A., et al. Determinants of tumor response and survival with erlotinib in patients with non-small-cell lung cancer. J Clin Oncol. 2004;22:3238–3247. doi: 10.1200/JCO.2004.11.057. [DOI] [PubMed] [Google Scholar]
- 17.Soulieres D., Senzer N.N., Vokes E.E., Hidalgo M., Agarwala S.S., Siu L.L. Multicenter phase II study of erlotinib, an oral epidermal growth factor receptor tyrosine kinase inhibitor, in patients with recurrent or metastatic squamous cell cancer of the head and neck. J Clin Oncol. 2004;22:77–85. doi: 10.1200/JCO.2004.06.075. [DOI] [PubMed] [Google Scholar]
- 18.Stintzing S., Kapaun C., Laubender R.P., et al. Prognostic value of cetuximab-related skin toxicity in metastatic colorectal cancer patients and its correlation with parameters of the epidermal growth factor receptor signal transduction pathway: results from a randomized trial of the GERMAN AIO CRC Study Group. Int J Cancer. 2013;132:236–245. doi: 10.1002/ijc.27654. [DOI] [PubMed] [Google Scholar]
- 19.Holch J.W., Held S., Stintzing S., et al. Relation of cetuximab-induced skin toxicity and early tumor shrinkage in metastatic colorectal cancer patients: results of the randomized phase 3 trial FIRE-3 (AIO KRK0306) Ann Oncol. 2020;31:72–78. doi: 10.1016/j.annonc.2019.10.001. [DOI] [PubMed] [Google Scholar]
- 20.Gatzemeier U., von Pawel J., Vynnychenko I., et al. First-cycle rash and survival in patients with advanced non-small-cell lung cancer receiving cetuximab in combination with first-line chemotherapy: a subgroup analysis of data from the FLEX phase 3 study. Lancet Oncol. 2011;12:30–37. doi: 10.1016/S1470-2045(10)70278-3. [DOI] [PubMed] [Google Scholar]
- 21.Van Cutsem E., Peeters M., Siena S., et al. Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol. 2007;25:1658–1664. doi: 10.1200/JCO.2006.08.1620. [DOI] [PubMed] [Google Scholar]
- 22.Piker R., Pereira J.R., Von Pawel J., et al. EGFR expression as a predictor of survival for first-line chemotherapy plus cetuximab in patients with advanced non-small-cell lung cancer: analysis of data from the phase 3 FLEX study. Lancet Oncol. 2012;13:33–42. doi: 10.1016/S1470-2045(11)70318-7. [DOI] [PubMed] [Google Scholar]
- 23.Segaert S., Van Cutsem E. Clinical signs, pathophysiology and management of skin toxicity during therapy with epidermal growth factor receptor inhibitors. Ann Oncol. 2005;16:1425–1433. doi: 10.1093/annonc/mdi279. [DOI] [PubMed] [Google Scholar]
- 24.Kozuki T. Skin problems and EGFR-tyrosine kinase inhibitor. Jpn J Clin Oncol. 2016;46:291–298. doi: 10.1093/jjco/hyv207. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Bouché O., Ben Abdelghani M., Labourey J.L., et al. Management of skin toxicities during panitumumab treatment in metastatic colorectal cancer. World J Gastroenterol. 2019;25:4007–4018. doi: 10.3748/wjg.v25.i29.4007. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.