If you don't remember your password, you can reset it by entering your email address and clicking the Reset Password button. You will then receive an email that contains a secure link for resetting your password
If the address matches a valid account an email will be sent to __email__ with instructions for resetting your password
Effective Treatment of Lung Adenocarcinoma Harboring EGFR-Activating Mutation, T790M, and cis-C797S Triple Mutations by Brigatinib and Cetuximab Combination Therapy
Department of Medical Oncology, Lung Cancer and Gastrointestinal Unit, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, People’s Republic of China
Department of Medical Oncology, Lung Cancer and Gastrointestinal Unit, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, People’s Republic of China
Corresponding author. Address for correspondence: Yong He, MD, Department of Respiratory Medicine, Daping Hospital, Army Medical University, 10 Changjiang Branch Road, Yuzhong District, Daping, Chongqing 400042, People’s Republic of China.
Acquired resistance to osimertinib mediated by EGFR cis-C797S is now a growing challenge. No effective treatment strategy is currently available to overcome cis-C797S–mediated resistance.
Methods
In this retrospective cohort study, 15 patients with advanced lung adenocarcinoma and EGFR-activating mutation, T790M, and cis-C797S after osimertinib progression were identified by targeted next-generation sequencing. Five of these patients received a combined therapy of brigatinib and cetuximab, and 10 patients received cisplatin-based doublet chemotherapy.
Results
Among the five patients who were positive for EGFR 19del-T790M-cis-C797S mutations, and who received brigatinib and cetuximab combination therapy, three patients achieved partial response, and two had stable disease, resulting in an overall objective response rate of 60% and disease control rate of 100%. Among the 10 patients who were positive for EGFR 19del or L858R-T790M-cis-C797S mutations and received chemotherapy, only one patient achieved partial response, five had stable disease, and the other four did not benefit from chemotherapy, resulting in an overall objective response rate and disease control rate of 10% and 60%, respectively. The median progression-free survival of patients who received combined targeted therapy was 14 months, and 3 months for those treated with chemotherapy. No grade III to IV adverse events were observed in any patient.
Conclusions
Our retrospective study provides clinical evidence that a combined targeted therapy of brigatinib and cetuximab could be of benefit and may potentially be an effective treatment strategy to improve survival outcomes in patients who acquire EGFR T790M-cis-C797S–mediated resistance to osimertinib.
Despite initial response to EGFR tyrosine kinase inhibitors (TKIs), a subset of patients with NSCLC with EGFR-activating mutations eventually develop resistance by acquiring secondary or tertiary EGFR mutations.
The allelic context of the C797S mutation acquired upon treatment with third-generation EGFR inhibitors impacts sensitivity to subsequent treatment strategies.
Acquired resistance of EGFR-mutant lung cancer to a T790M-specific EGFR inhibitor: emergence of a third mutation (C797S) in the EGFR tyrosine kinase domain.
The allelic context of the C797S mutation acquired upon treatment with third-generation EGFR inhibitors impacts sensitivity to subsequent treatment strategies.
The allelic context of the C797S mutation acquired upon treatment with third-generation EGFR inhibitors impacts sensitivity to subsequent treatment strategies.
Lung adenocarcinoma harboring EGFR T790M and in trans C797S responds to combination therapy of first- and third-generation EGFR TKIs and shifts allelic configuration at resistance.
whereas T790M-cis-C797S, the more frequently identified allelic configuration mediating osimertinib resistance, confers resistance to first-, second-, and third-generation EGFR TKIs.
The allelic context of the C797S mutation acquired upon treatment with third-generation EGFR inhibitors impacts sensitivity to subsequent treatment strategies.
With no targeted therapy options, patients with NSCLC harboring EGFR-sensitizing mutation, T790M, and cis-C797S triple mutations are being managed with chemotherapy after osimertinib progression. To further improve the survival outcomes of these patients, novel therapeutic strategies are actively being explored. Two preclinical studies have reported the potential of cetuximab, a monoclonal antibody against EGFR, combined with brigatinib (AP26113), a TKI targeting both ALK and EGFR, to effectively overcome triple-mutant EGFR-mediated osimertinib resistance.
Moreover, the clinical benefit of the brigatinib/cetuximab regimen was also observed in a patient with lung adenocarcinoma who had EGFR 19del-T790M-cis-C797S–mediated osimertinib resistance.
In this retrospective cohort study, we investigated the clinical efficacy of combined targeted therapy of brigatinib and cetuximab in five patients with advanced lung adenocarcinoma harboring EGFR 19del-T790M-cis-C797S and compared their clinical outcome with patients with EGFR triple mutation treated with chemotherapy.
Materials and Methods
Patient Selection
A total of 177 patients with NSCLC who progressed from second- or subsequent-line osimertinib were screened at Daping Hospital (Chongqing, People’s Republic of China) and Hunan Cancer Hospital (Changsha, People’s Republic of China) between January 2016 and September 2019. Patients with NSCLC who received osimertinib and had progression-free survival (PFS) of greater than or equal to 2 months, developed the EGFR T790M-cis-C797S mutation and retained the baseline sensitizing mutation (19del or L858R) were included in the study. This research was approved by the Research Ethics Board of Daping Hospital and conducted in accordance with the Declaration of Helsinki. Written informed consent was provided by all patients.
Capture-Based Targeted Next-Generation Sequencing
Various sample types, including tissue biopsy, plasma, malignant pleural effusion supernatant,
were submitted for targeted next-generation sequencing (NGS) using various commercially available gene panels to elucidate their mutational profile.
Treatment Regimens
Patients in the combined targeted therapy group received cetuximab at a dose of 500 mg/m2, administered intravenously on days 1 and 8 of a 21-day cycle, and brigatinib, taken orally once daily at an initial dose of 90 mg for 7 days and increased to 180 mg from day 8 onward if tolerated. Patients in the chemotherapy group received intravenous cisplatin at a dose of 75 mg/m2 combined with either pemetrexed (given at 500 mg/m2) or paclitaxel (given at 175 mg/m2) once in a 28-day cycle. Bevacizumab was administered at a dose of 15 mg/kg.
Response Assessment
Treatment responses were assessed on the basis of Response Evaluation Criteria in Solid Tumors v.1.1. Objective response rate (ORR) was defined as the percentage of patients who achieved complete or partial response (PR). Disease control rate (DCR) was defined as the percentage of patients who were evaluated with complete response, PR, and stable disease (SD). PFS was defined as the time from the initiation of the treatment regimen until the radiologic evaluation of the progressive disease (PD). Adverse events (AEs) were evaluated according to the Common Terminology Criteria for AEs v.4.03.
Results
Patient Characteristics
This cohort had a median age of 62 years and included 15 patients with advanced lung adenocarcinoma who developed EGFR T790M-cis-C797S–mediated osimertinib resistance. Table 1 summarizes the clinical characteristics of the study cohort. Five of these patients received the brigatinib and cetuximab regimen, whereas 10 patients received the chemotherapy regimen. Figure 1 illustrates the study diagram.
Table 1Summary of the Clinical Features of the Cohort
Figure 1Flow diagram illustrating the study design. A total of 177 patients with NSCLC who progressed from previous osimertinib therapy were screened. Of this pool of patients, only 15 patients with EGFR triple mutation consented to participate in the study. Five patients received the brigatinib and cetuximab regimen, whereas 10 patients received either pemetrexed or paclitaxel plus cisplatin with or without bevacizumab.
Before the administration of the respective treatment regimens, NGS was performed to interrogate the molecular landscape of the cohort after osimertinib progression (Fig. 2). All the patients retained their baseline EGFR-sensitizing mutations (19del or L858R) and T790M. EGFR C797S was acquired after osimertinib progression and confirmed to be in cis to T790M. Most patients (13 of 15, 87%) harbored EGFR 19del-T790M-cis-C797S, and only two patients (13%) harbored EGFR L858R-T790M-cis-C797S. Six patients had other concurrent EGFR mutations, with most of them (4 of 6) harboring amplification. TP53 was the most frequently seen concurrent mutation, occurring in 40% of patients (6 of 15). The detailed molecular landscape of the cohort is shown in Figure 2.
Figure 2The mutation profile of the 15 patients after evaluation of disease progression with osimertinib. The patient number is indicated at the bottom of the oncoprint. The red bar at the bottom indicates patients who received the combined brigatinib (AP26113) and cetuximab regimen. The blue bar at the bottom indicates patients who received the chemotherapy regimen. Each column represents a patient and each row represents a gene. Numbers on the left represent the percentage of patients with mutations in a specific gene. The top plot represents the overall number of mutations a patient carried. Different colors denote different types of mutations.
Figure 3Combined targeted therapy is more effective in reducing tumor size in patients with triple EGFR mutations after osimertinib progression. Waterfall plot illustrating the percentage of maximum tumor size reduction in each of the patients. Red indicates patients who received brigatinib (AP26113) and cetuximab combination therapy. Blue indicates patients who received the chemotherapy regimen. Patient number and specific tumor reduction are indicated on each bar. # indicates that the patients were still receiving the therapy as of the last follow-up on September 1, 2019.
Figure 4Combined targeted therapy improves the progression-free survival of patients with triple EGFR mutations after osimertinib progression. Swimmers plot illustrating the progression-free survival of each of the patients. The x axis denotes the progression-free survival of the patient in each line of treatment received. Colors correspond to all the treatment regimens received by the patient including previous treatment history. Black triangles denote the evaluation of the progressive disease.
Five patients who harbored EGFR 19del-T790M-cis-C797S received the brigatinib and cetuximab combination regimen. Of these, three patients (P1, P3, and P5) achieved PR and two patients (P2 and P4) achieved SD, achieving an ORR of 60% and DCR of 100% (Figs. 3 and 4). Three patients remain on treatment during the preparation of this manuscript. Two patients, P1 and P3, have developed into PD, with a PFS of 15 months and 13 months, respectively.
Of the 10 patients who received the chemotherapy regimen, nine patients received pemetrexed plus cisplatin after osimertinib progression. Six of these patients (P6, P7, P8, P10, P13, and P15) also received bevacizumab concurrently. Meanwhile, one patient (66 years old) received paclitaxel plus cisplatin. The cohort included eight patients with EGFR 19del-T790M-cis-C797S and two patients with L858R-T790M-cis-C797S mutation (Fig. 2). Of the 10 patients, one achieved PR, five achieved SD, and the remaining four patients had PD as their best response, resulting in an ORR of 10% and DCR of 60% (Figs. 3 and 4). Patients with or without concurrent bevacizumab treatment yielded comparable PFS (3.5 mo versus 3 mo, p = 0.56).
Adverse Events
No grade 3 or 4 AE was observed in any patient. A total of 10 patients, four from the brigatinib/cetuximab group and six from the chemotherapy group, experienced grade 1 or grade 2 AEs. One patient had the brigatinib dose reduced to 120 mg owing to grade 1 weakness and vomiting (P5). Among the patients treated with chemotherapy, leukopenia (n = 5) was the most common AE. Table 1 summarizes the AEs reported for all patients. Detailed AE information for each patient is summarized in Table 2 and Supplementary Table 1.
PFS time marked with + indicates the patients were still receiving the treatment regimen and time indicated is based on the last follow-up on September 1, 2019.
mo
Adverse Events
P1
Female
42
IV
Yes
No
Brigatinib + cetuximab
PR
15
Diarrhea (G1), Paronychia (G2)
P2
Female
64
IV
No
Yes
Brigatinib + cetuximab
PR
5+
Loss of appetite (G1), Diarrhea (G1), Rash (G1)
P3
Male
64
IV
Yes
No
Brigatinib + cetuximab
SD
13
Abnormal liver function (G2)
P4
Male
63
IV
No
No
Brigatinib + cetuximab
SD
4+
—
P5
Female
55
IV
Yes
No
Brigatinib 120 mg + Cetuximab
PR
1.5+
Weakness and vomiting (G1)
P6
Female
48
IV
No
Yes
Pemetrexed + cisplatin + bevacizumab
SD
3+
Leukopenia (G1), Proteinuria (G1)
P7
Male
60
IV
No
No
Pemetrexed + cisplatin + bevacizumab
SD
4
—
P8
Male
52
IV
No
No
Pemetrexed + cisplatin + bevacizumab
PD
2
—
P9
Female
62
IV
No
No
Pemetrexed + cisplatin
SD
3
Leukopenia (G1)
P10
Female
66
IV
No
No
Pemetrexed + cisplatin + bevacizumab
SD
4
Abnormal liver function (G1)
P11
Male
66
IV
No
No
Paclitaxel + cisplatin
PD
2
Leukopenia (G2)
P12
Male
74
IV
No
No
Pemetrexed + cisplatin
PR
6
Abnormal liver function (G1), Leukopenia (G1)
P13
Male
56
IV
No
No
Pemetrexed + cisplatin + bevacizumab
PD
2
Proteinuria (G1), Abnormal liver function (G1), Leukopenia (G1)
a PFS time marked with + indicates the patients were still receiving the treatment regimen and time indicated is based on the last follow-up on September 1, 2019.
Owing to the resistance of T790M-cis-C797S to all available EGFR TKIs, no effective targeted treatment options are currently available after osimertinib progression.
The allelic context of the C797S mutation acquired upon treatment with third-generation EGFR inhibitors impacts sensitivity to subsequent treatment strategies.
Recent preclinical studies have revealed that as a dual-target inhibitor of ALK and EGFR, brigatinib can suppress the growth of tumor cells carrying triple EGFR mutations L858R-T790M-cis-C797S and delay osimertinib-induced acquired resistance.
The allelic context of the C797S mutation acquired upon treatment with third-generation EGFR inhibitors impacts sensitivity to subsequent treatment strategies.
To date, the clinical efficacy of brigatinib has only been reported in two patients with lung adenocarcinoma who acquired cis-C797S–mediated osimertinib resistance.
Effective treatment of pulmonary adenocarcinoma harboring triple EGFR mutations of L858R, T790M, and cis-C797S by osimertinib, bevacizumab, and brigatinib combination therapy: a case report.
As per another report, a woman with lung adenocarcinoma, harboring 19del-T790M-cis-C797S, achieved disease control for 9 months with brigatinib at 90 mg daily combined with a monthly infusion of cetuximab at 600 mg/m2.
Meanwhile, the combination treatment of brigatinib (100 mg once daily), osimertinib (80 mg once daily), and bevacizumab (15 mg/kg once every 21 days) resulted in improved clinical symptoms and tumor shrinkage within 1 month, evaluated as PR in one patient with L858R-T790M-cis-C797S; however, the response only lasted for 2 months.
Effective treatment of pulmonary adenocarcinoma harboring triple EGFR mutations of L858R, T790M, and cis-C797S by osimertinib, bevacizumab, and brigatinib combination therapy: a case report.
our study revealed the effectiveness and promising treatment outcomes of combined therapy with brigatinib and cetuximab in five patients with lung adenocarcinoma who acquired EGFR cis-C797S–mediated osimertinib resistance. The synergistic inhibitory activity of brigatinib and cetuximab was able to overcome the osimertinib resistance, as indicated by the notable tumor shrinkage achieved in three patients (50% in P1; 30% in P3; 40% in P5) with durable response/disease control in two patients (15 mo in P1; 13 mo in P3), ongoing response in two patients (P2 and P5), and ongoing disease control in one patient (P4). It is worth mentioning that the brigatinib and cetuximab combination was also effective in patients with EGFR triple mutation previously treated with chemotherapy (P1, P3, and P5) and in one patient with concurrent EGFR amplification (P1). Moreover, the initial daily oral dose of 90 mg of brigatinib in the first week and later escalation to 180 mg, combined with a biweekly cetuximab infusion at 500 mg/m2, was found to be safe and tolerable with manageable toxicity profile. Only one patient (P5) had the dose reduced from 180 mg to 120 mg owing to grade 1 weakness and vomiting. However, despite the lower dose, she achieved remarkable tumor shrinkage of approximately 40% within 1.5 months of combination therapy. Based on better clinical outcomes and tolerable safety profile, our real-world study provides clinical evidence of the benefit afforded by the combined brigatinib and cetuximab regimen. Our preliminary findings suggest that the combined brigatinib/cetuximab regimen is a promising treatment strategy for managing patients with EGFR-sensitizing mutation-T790M-cis-C797S after osimertinib progression. However, a multicenter prospective clinical study with a larger cohort should be conducted to establish our findings. The discovery of an effective treatment strategy that could overcome osimertinib resistance in patients with the triple mutation is clinically relevant.
Despite our clinically relevant findings, our conclusion is limited by its retrospective nature and the small number of patients included in the cohort, which could potentially introduce a bias in patient selection.
Taken together, our findings provide clinical evidence of the effectiveness of a combined therapy of brigatinib and cetuximab in overcoming osimertinib resistance mediated by EGFR cis-C797S, indicating the potential of this combination regimen as a possible treatment option after progression from osimertinib therapy.
Acknowledgments
This work was supported by grants from the National Natural Science Foundation of the People’s Republic of China (grant no. 81702291) and Talent Pool Fund of the Army Medical University. The authors thank all the patients who participated in this study and their families. The authors also thank the investigators, study coordinators, operation staff, and the whole project team who worked on this study.
The allelic context of the C797S mutation acquired upon treatment with third-generation EGFR inhibitors impacts sensitivity to subsequent treatment strategies.
Acquired resistance of EGFR-mutant lung cancer to a T790M-specific EGFR inhibitor: emergence of a third mutation (C797S) in the EGFR tyrosine kinase domain.
Lung adenocarcinoma harboring EGFR T790M and in trans C797S responds to combination therapy of first- and third-generation EGFR TKIs and shifts allelic configuration at resistance.
Effective treatment of pulmonary adenocarcinoma harboring triple EGFR mutations of L858R, T790M, and cis-C797S by osimertinib, bevacizumab, and brigatinib combination therapy: a case report.
Drs. Wang, Yang, and Zhang contributed equally to this work and should be regarded as co-first authors.
Disclosure: Dr. Lizaso and Mr. Qin are employees of Burning Rock Biotech. Ms. Liu is an employee of OrigiMed. The remaining authors declare no conflict of interest.
30328-2&id=gr1.jpg){kind=link}
30328-2&id=gr2.jpg){kind=link}
30328-2&id=gr3.jpg){kind=link}
30328-2&id=gr4.jpg){kind=link}