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Amivantamab plus carboplatin–pemetrexed (chemotherapy) with and without lazertinib demonstrated antitumor activity in patients with refractory epidermal growth factor receptor (EGFR)-mutated advanced non-small-cell lung cancer (NSCLC) in phase I studies. These combinations were evaluated in a global phase III trial. A total of 657 patients with EGFR -mutated (exon 19 deletions or L858R) locally advanced or metastatic NSCLC after disease progression on osimertinib were randomized 2 : 2 : 1 to receive amivantamab–lazertinib–chemotherapy, chemotherapy, or amivantamab–chemotherapy. The dual primary endpoints were progression-free survival (PFS) of amivantamab–chemotherapy and amivantamab–lazertinib–chemotherapy versus chemotherapy. During the study, hematologic toxicities observed in the amivantamab–lazertinib–chemotherapy arm necessitated a regimen change to start lazertinib after carboplatin completion. All baseline characteristics were well balanced across the three arms, including by history of brain metastases and prior brain radiation. PFS was significantly longer for amivantamab–chemotherapy and amivantamab–lazertinib–chemotherapy versus chemotherapy [hazard ratio (HR) for disease progression or death 0.48 and 0.44, respectively; P < 0.001 for both; median of 6.3 and 8.3 versus 4.2 months, respectively]. Consistent PFS results were seen by investigator assessment (HR for disease progression or death 0.41 and 0.38 for amivantamab–chemotherapy and amivantamab–lazertinib–chemotherapy, respectively; P < 0.001 for both; median of 8.2 and 8.3 versus 4.2 months, respectively). Objective response rate was significantly higher for amivantamab–chemotherapy and amivantamab–lazertinib–chemotherapy versus chemotherapy (64% and 63% versus 36%, respectively; P < 0.001 for both). Median intracranial PFS was 12.5 and 12.8 versus 8.3 months for amivantamab–chemotherapy and amivantamab–lazertinib–chemotherapy versus chemotherapy (HR for intracranial disease progression or death 0.55 and 0.58, respectively). Predominant adverse events (AEs) in the amivantamab-containing regimens were hematologic, EGFR- , and MET -related toxicities. Amivantamab–chemotherapy had lower rates of hematologic AEs than amivantamab–lazertinib–chemotherapy. Amivantamab–chemotherapy and amivantamab–lazertinib–chemotherapy improved PFS and intracranial PFS versus chemotherapy in a population with limited options after disease progression on osimertinib. Longer follow-up is needed for the modified amivantamab–lazertinib–chemotherapy regimen. [Display omitted] • Amivantamab–chemotherapy improved PFS and intracranial PFS versus chemotherapy. • Amivantamab–lazertinib–chemotherapy improved PFS and intracranial PFS versus chemotherapy. • Predominant AEs in the amivantamab-containing arms were hematologic, EGFR , and MET related. • MARIPOSA-2 is the first study to demonstrate improved PFS versus chemotherapy after disease progression on osimertinib. [ABSTRACT FROM AUTHOR]

Background Patients receiving first-line afatinib, gefitinib or erlotinib for epidermal growth factor receptor (EGFR) mutant advanced non-small cell lung cancer develop progression of disease (PD) after an average of 9-13 months. Methods A retrospective analysis of PD pattern and prevalence of acquired T790M mutation among patients failing first-line afatinib versus gefitinib or erlotinib at University Malaya Medical Centre from 1st January 2015 to 31th December 2018. Results Of 87 patients who developed PD while on first-line EGFR-tyrosine kinase inhibitor (TKI) treatment, 19 (21.8%) were on afatinib, 49 (56.3%) were on gefitinib, and 19 (21.8%) were on erlotinib. The median progression-free survival (mPFS) of these patients is as shown in the table. Of 20 patients (23.0%) who developed new symptomatic brain metastases, one (5.0%) had new leptomeningeal metastases, three (15.0%) had both new leptomeningeal metastases and solid brain metastases, and the remaining 16 (80.0%) had new solid brain metastases only. New leptomeningeal metastases occurred in one patient treated with afatinib and three patients treated with gefitinib. Forty-nine patients (56.3%) were investigated for acquired T790M mutation either by plasma biopsy or tissue biopsy or both. The prevalence of acquired T790M mutation was 61.2%. There was no difference in the pattern of PD or prevalence of acquired T790M mutation among patients treated with afatinib, gefitinib or erlotinib. Table: 494P Pattern of PD    Patients with PD (n = 87)  Afatinib (n = 19)  Gefitinib (n = 49)  Erlotinib (n = 19)  p-value  Median PFS, months    11.0  13.1  10.9  7.8  0.479  New brain metastases, No. (%)  Yes No  20 (23.0) 67 (77.0)  5 (26.3) 14 (73.7)  12 (24.5) 37 (75.5)  3 (15.8) 16 (84.2)  0.692  New solid brain lesion metastases, No (%)  Yes No  19 (21.8) 68 (78.2)  4 (21.1) 15 (78.9)  12 (24.5) 37 (75.5)  3 (15.5) 16 (84.2)  0.735  New leptomeningeal metastases, No. (%)  Yes No  4 (4.6) 83 (95.4)  1 (5.2) 18 (94.8)  3 (6.1) 46 (93.9)  0 19 (100)  0.550  No. of patients tested for acquired T790M mutation    n = 49  n = 14  n = 27  n = 8  p-value  Acquired T790M mutation detected, No. (%)  Yes No  30 (61.2) 19 (38.8)  9 (64.3) 5 (35.7)  16 (59.3) 11(40.7)  5 (62.5) 3 (37.5)  0.949  Pattern of PD    Patients with PD (n = 87)  Afatinib (n = 19)  Gefitinib (n = 49)  Erlotinib (n = 19)  p-value  Median PFS, months    11.0  13.1  10.9  7.8  0.479  New brain metastases, No. (%)  Yes No  20 (23.0) 67 (77.0)  5 (26.3) 14 (73.7)  12 (24.5) 37 (75.5)  3 (15.8) 16 (84.2)  0.692  New solid brain lesion metastases, No (%)  Yes No  19 (21.8) 68 (78.2)  4 (21.1) 15 (78.9)  12 (24.5) 37 (75.5)  3 (15.5) 16 (84.2)  0.735  New leptomeningeal metastases, No. (%)  Yes No  4 (4.6) 83 (95.4)  1 (5.2) 18 (94.8)  3 (6.1) 46 (93.9)  0 19 (100)  0.550  No. of patients tested for acquired T790M mutation    n = 49  n = 14  n = 27  n = 8  p-value  Acquired T790M mutation detected, No. (%)  Yes No  30 (61.2) 19 (38.8)  9 (64.3) 5 (35.7)  16 (59.3) 11(40.7)  5 (62.5) 3 (37.5)  0.949  Table: 494P Pattern of PD    Patients with PD (n = 87)  Afatinib (n = 19)  Gefitinib (n = 49)  Erlotinib (n = 19)  p-value  Median PFS, months    11.0  13.1  10.9  7.8  0.479  New brain metastases, No. (%)  Yes No  20 (23.0) 67 (77.0)  5 (26.3) 14 (73.7)  12 (24.5) 37 (75.5)  3 (15.8) 16 (84.2)  0.692  New solid brain lesion metastases, No (%)  Yes No  19 (21.8) 68 (78.2)  4 (21.1) 15 (78.9)  12 (24.5) 37 (75.5)  3 (15.5) 16 (84.2)  0.735  New leptomeningeal metastases, No. (%)  Yes No  4 (4.6) 83 (95.4)  1 (5.2) 18 (94.8)  3 (6.1) 46 (93.9)  0 19 (100)  0.550  No. of patients tested for acquired T790M mutation    n = 49  n = 14  n = 27  n = 8  p-value  Acquired T790M mutation detected, No. (%)  Yes No  30 (61.2) 19 (38.8)  9 (64.3) 5 (35.7)  16 (59.3) 11(40.7)  5 (62.5) 3 (37.5)  0.949  Pattern of PD    Patients with PD (n = 87)  Afatinib (n = 19)  Gefitinib (n = 49)  Erlotinib (n = 19)  p-value  Median PFS, months    11.0  13.1  10.9  7.8  0.479  New brain metastases, No. (%)  Yes No  20 (23.0) 67 (77.0)  5 (26.3) 14 (73.7)  12 (24.5) 37 (75.5)  3 (15.8) 16 (84.2)  0.692  New solid brain lesion metastases, No (%)  Yes No  19 (21.8) 68 (78.2)  4 (21.1) 15 (78.9)  12 (24.5) 37 (75.5)  3 (15.5) 16 (84.2)  0.735  New leptomeningeal metastases, No. (%)  Yes No  4 (4.6) 83 (95.4)  1 (5.2) 18 (94.8)  3 (6.1) 46 (93.9)  0 19 (100)  0.550  No. of patients tested for acquired T790M mutation    n = 49  n = 14  n = 27  n = 8  p-value  Acquired T790M mutation detected, No. (%)  Yes No  30 (61.2) 19 (38.8)  9 (64.3) 5 (35.7)  16 (59.3) 11(40.7)  5 (62.5) 3 (37.5)  0.949  Conclusions New leptomeningeal metastases were uncommon in patients receiving first-line EGFR-TKI. The choice of first-line first- or second generation EGFR-TKI did not influence the pattern of PD and prevalence of acquired T790M mutation. However, patients receiving afatinib appeared to have longer mPFS than those on gefitinib or erlotinib. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest. [ABSTRACT FROM AUTHOR]

Background Afatinib is an irreversible second-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) while gefitinib or erlotinib are reversible first-generation EGFR-TKIs. Methods A retrospective analysis of patients with EGFR mutant advanced lung adenocarcinoma receiving first-line afatinib versus gefitinib or erlotinib at University Malaya Medical Centre from 1st January 2015 to 31th December 2018. Results Of 113 patients, 24 (21.2%) received afatinib, 63 (55.8%) received gefitinib and 26 (23.0%) received erlotinib in first-line setting. Their demographic and clinical characteristics are shown in the table. Afatinib was used significantly more frequently in patients with rare or complex EGFR mutations (p = 0.005), and more often in patients with symptomatic brain metastases. The median progression-free survival (mPFS) of patients treated with afatinib (13.1 months) was longer than that of patients treated with gefitinib (10.9 months) or erlotinib (7.8 months) (p = 0.479). Patients receiving afatinib had consistently longer PFS than patients receiving gefitinib for the first 17 months and erlotinib for the first 20 months. The overall response rate was higher in patients on afatinib (75.0%) than those on gefitinib (63.5%) or erlotinib (53.8%). There was no difference in the disease control rate. Three patients (2.7%) had severe side-effects while on EGFR-TKI. Of two patients on afatinib, one had grade-3 diarrhea while another had grade 3 stomatitis, rash and paronychia. One patient had grade 3 rash on gefitinib. Table: 487P Clinical characteristic of 113 patients on first-line EGFR-TKI Characteristics, No (%)    Afatinib (24)  Gefitinib (63)  Erlotinib (26)  p-value  Symp brain mets  No Yes  17 (70.8) 7 (29.2)  53 (84.1) 10 (15.9)  22 (84.6) 4 (15.4)  0.181  EGFR subtype  19 del 21 L858R Rare/complex  16 (66.7) 2 (8.3) 6 (25.0)  39 (61.9) 20 (31.7) 4 (6.3)  22 (84.6) 3 (11.5) 1 (3.8)  0.005  Side-effect  grade 1-2 grade 3  22 (91.7) 2 (8.3)  62 (98.4) 1 (1.6)  26 (100) 0  0.007  Objective response  Yes No  18 (75.0) 6 (25.0)  40 (63.5) 23 (36.5)  14 (53.8) 12 (46.2)  0.298  Disease control  Yes No  23 (95.8) 1 (4.2)  59 (93.7) 4 (6.3)  24 (92.3) 2 (7.7)  0.872  Median PFS  Months Event, No. (%)  13.1 19 (79.2)  10.9 49 (77.8)  7.8 19 (73.1)  0.479  Characteristics, No (%)    Afatinib (24)  Gefitinib (63)  Erlotinib (26)  p-value  Symp brain mets  No Yes  17 (70.8) 7 (29.2)  53 (84.1) 10 (15.9)  22 (84.6) 4 (15.4)  0.181  EGFR subtype  19 del 21 L858R Rare/complex  16 (66.7) 2 (8.3) 6 (25.0)  39 (61.9) 20 (31.7) 4 (6.3)  22 (84.6) 3 (11.5) 1 (3.8)  0.005  Side-effect  grade 1-2 grade 3  22 (91.7) 2 (8.3)  62 (98.4) 1 (1.6)  26 (100) 0  0.007  Objective response  Yes No  18 (75.0) 6 (25.0)  40 (63.5) 23 (36.5)  14 (53.8) 12 (46.2)  0.298  Disease control  Yes No  23 (95.8) 1 (4.2)  59 (93.7) 4 (6.3)  24 (92.3) 2 (7.7)  0.872  Median PFS  Months Event, No. (%)  13.1 19 (79.2)  10.9 49 (77.8)  7.8 19 (73.1)  0.479  Table: 487P Clinical characteristic of 113 patients on first-line EGFR-TKI Characteristics, No (%)    Afatinib (24)  Gefitinib (63)  Erlotinib (26)  p-value  Symp brain mets  No Yes  17 (70.8) 7 (29.2)  53 (84.1) 10 (15.9)  22 (84.6) 4 (15.4)  0.181  EGFR subtype  19 del 21 L858R Rare/complex  16 (66.7) 2 (8.3) 6 (25.0)  39 (61.9) 20 (31.7) 4 (6.3)  22 (84.6) 3 (11.5) 1 (3.8)  0.005  Side-effect  grade 1-2 grade 3  22 (91.7) 2 (8.3)  62 (98.4) 1 (1.6)  26 (100) 0  0.007  Objective response  Yes No  18 (75.0) 6 (25.0)  40 (63.5) 23 (36.5)  14 (53.8) 12 (46.2)  0.298  Disease control  Yes No  23 (95.8) 1 (4.2)  59 (93.7) 4 (6.3)  24 (92.3) 2 (7.7)  0.872  Median PFS  Months Event, No. (%)  13.1 19 (79.2)  10.9 49 (77.8)  7.8 19 (73.1)  0.479  Characteristics, No (%)    Afatinib (24)  Gefitinib (63)  Erlotinib (26)  p-value  Symp brain mets  No Yes  17 (70.8) 7 (29.2)  53 (84.1) 10 (15.9)  22 (84.6) 4 (15.4)  0.181  EGFR subtype  19 del 21 L858R Rare/complex  16 (66.7) 2 (8.3) 6 (25.0)  39 (61.9) 20 (31.7) 4 (6.3)  22 (84.6) 3 (11.5) 1 (3.8)  0.005  Side-effect  grade 1-2 grade 3  22 (91.7) 2 (8.3)  62 (98.4) 1 (1.6)  26 (100) 0  0.007  Objective response  Yes No  18 (75.0) 6 (25.0)  40 (63.5) 23 (36.5)  14 (53.8) 12 (46.2)  0.298  Disease control  Yes No  23 (95.8) 1 (4.2)  59 (93.7) 4 (6.3)  24 (92.3) 2 (7.7)  0.872  Median PFS  Months Event, No. (%)  13.1 19 (79.2)  10.9 49 (77.8)  7.8 19 (73.1)  0.479  Conclusions Patients receiving first-line afatinib demonstrated longer mPFS than those on first-line gefitinib or erlotinib. The lack of statistical significance in this study is because of the small number of patients treated with afatinib, more frequent rare or complex EGFR mutations and more symptomatic brain metastases among afatinib treated patients. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest. [ABSTRACT FROM AUTHOR]