Amivantamab plus chemotherapy vs. chemotherapy in participants with EGFR-mutant advanced non-small cell lung cancer after progression on osimertinib: a MARIPOSA-2 analysis of the Asian subgroup

Introduction

Background

Almost 2.5 million cases of lung cancer occur worldwide each year, of which 63% (1.57 million cases) are diagnosed in Asia (1). Mutations in the epidermal growth factor receptor (EGFR) gene occur in up to 50% of Asian patients with non-small cell lung cancer (NSCLC), compared to 15% in North America (2,3). In the vast majority of cases (up to 90%), these mutations involve deletions in exon 19 or leucine to arginine substitutions (L858R) in exon 21 [together referred to as common (EGFR) mutations] (2,4). Until recently, targeted therapy with third-generation tyrosine kinase inhibitors (TKIs), including osimertinib monotherapy, has been recommended by guidelines for first-line treatment of advanced or metastatic EGFR-mutated NSCLC. Unfortunately, around one-third of patients who commence osimertinib monotherapy die before receiving second-line treatment, with only 58% of patients surviving 2 years following diagnosis (5). This significant attrition is due to emergence of complex and heterogenous escape pathways providing resistance to TKI treatment. More recent evidence suggests that the use of combination therapies in first-line treatment, such as amivantamab plus lazertinib, provides significant and clinically meaningful improvement in overall survival (OS) outcomes and reduces development of acquired resistance vs. osimertinib monotherapy (6-9). Despite the superior efficacy of combination treatments, TKI monotherapy remains an option in first-line, resulting in poor outcomes and limited effective treatment options in second-line. The role of immunotherapy in TKI-refractory EGFR-mutated NSCLC is not clear (10,11). Historically, the standard of care treatment for this group of patients was mainly platinum-based chemotherapy, which generally has a poor prognosis (12).

Acquired resistance to TKIs is complex and polyclonal, creating tumour-escape pathways that cannot be easily treated with targeted therapies (13). The most common pathways of resistance to TKIs are mediated by secondary mutations in EGFR and MET-proto-oncogene (MET)-based alterations, and together, these pathways may account for 25–50% of osimertinib resistance (14-16). Amivantamab is a bispecific antibody that targets both EGFR and MET and has immune-cell directing activity (17-19). Its triple mechanism of action includes EGFR inhibition, MET inhibition and enhanced immune-mediated tumour cell destruction through trogocytosis and antibody-dependent cellular cytotoxicity (17-19). Unlike EGFR TKIs, amivantamab binds to the extracellular domain of EGFR, and is thus not affected by the intracellular mutations of the tyrosine kinase domain of EGFR. Amivantamab has shown clinical activity across the EGFR mutation spectrum, including secondary acquired EGFR mutations such as C797S, hard-to-treat mutations such as EGFR exon 20 insertions (Ex20ins), and atypical mutations (20-22).

Efficacy of amivantamab in patients with advanced and metastatic EGFR-mutated NSCLC was evaluated in two Phase 3 studies: MARIPOSA and MARIPOSA-2. The MARIPOSA trial investigated the combination of amivantamab plus lazertinib, a selective central nervous system-penetrant third-generation EGFR TKI, as first-line therapy. Median progression-free survival (PFS) was 7.1 months longer when amivantamab was combined with lazertinib in first-line (23.7 months) compared to osimertinib monotherapy (16.6 months) [hazard ratio (HR) 0.70, 95% confidence interval (CI): 0.58–0.85; P<0.001] (21). At a median follow-up of 37.8 months, amivantamab-plus lazertinib demonstrated a significant, 25% reduction in the risk of death vs. osimertinib monotherapy (HR 0.75, 95% CI: 0.61–0.92, P=0.005), with median OS not reached in the amivantamab plus lazertinib arm (95% CI: 42.9 to not estimable) vs. 36.7 months in the osimertinib monotherapy arm (95% CI: 33.4–41.0) (23). The outcomes and safety profile of the Asian subset in MARIPOSA study, that contributed 59% of the total study population, were consistent with the global study outcomes, showing a significant PFS (HR 0.65; 95 % CI: 0.50–0.83; P<0.001) and OS (HR 0.74; 95% CI: 0.56–0.97) benefit of amivantamab plus lazertinib over osimertinib monotherapy (24). Amivantamab plus lazertinib is the first targeted regimen to show significant and clinically meaningful OS benefit in previously untreated Asian patients with EGFR-mutated advanced or metastatic NSCLC (24,25).

The MARIPOSA study showed that the acquired resistance mechanisms are significantly reduced for MET amplifications (3.4% of patients vs. 13.1% treated with osimertinib monotherapy) and secondary EGFR mutations (1.4% vs. 7.6%), as well as resistance complexity (defined as ≥2 pathogenic alterations; P=0.02) following amivantamab + lazertinib treatment vs. osimertinib monotherapy (8,9). Amivantamab-based regimens are currently approved in multiple regions for first- and second-line treatment of patients with advanced NSCLC harbouring EGFR exon 20 insertion mutations, EGFR exon 19 deletions, or exon 21 L858R substitution mutations.

For those patients who are still treated with TKI monotherapy in first-line, we wanted to investigate the potential utility of amivantamab in second-line after progression on EGFR TKI therapy. The MARIPOSA-2 study evaluated amivantamab combined with chemotherapy (carboplatin/pemetrexed) compared with chemotherapy alone in patients with advanced EGFR-mutated NSCLC who had progressed on or after osimertinib monotherapy (26).

Rationale and knowledge gap

In the primary analysis of the MARIPOSA-2 full analysis set (median follow-up 8.7 months), the combination of amivantamab-chemotherapy showed superior PFS over chemotherapy (6.3 vs. 4.2 months; HR 0.48, 95% CI: 0.36–0.64; P<0.001) (26). The objective response rate (ORR) was 64% in the amivantamab-chemotherapy group vs. 36% in the chemotherapy group (P<0.001), and median intracranial PFS was 12.5 vs. 8.3 months (HR 0.55, 95% CI: 0.38–0.79). At the second analysis of OS (median follow-up 18.1 months), OS was 17.7 months in the amivantamab-chemotherapy group and 15.3 months in the chemotherapy group (HR 0.73, 95% CI, 0.54–0.99; P=0.04) (27). In view of the high burden of disease caused by EGFR-mutated NSCLC in Asia and the high unmet need in the second-line setting, it is critical to understand the efficacy of this regimen in Asian patients.

Objective

This study was a post hoc exploratory analysis to assess the efficacy and safety of second-line amivantamab plus chemotherapy in Asian participants in the MARIPOSA-2 trial using data from the primary analysis with a clinical cutoff of 10 July 2023.

Methods

Study design and participants

MARIPOSA-2 (NCT04988295) is a Phase 3, open, randomised trial conducted in 29 countries/territories in Europe, Asia, North, and South America. The study included 657 participants randomised 2:2:1 to receive either amivantamab combined with platinum doublet chemotherapy (carboplatin and pemetrexed) and lazertinib (N=263), amivantamab plus chemotherapy (amivantamab-chemotherapy) (N=131), or chemotherapy alone (N=263). Randomisation of the main study cohort was stratified by osimertinib used in either first-line or second-line, a history of brain metastases (yes vs. no), and Asian race (yes vs. no). The amivantamab-chemotherapy-lazertinib treatment regimen was modified during the study due to an observed increase in gastrointestinal and haematologic toxicities in this group, and consequently, follow-up of the modified schedule is ongoing (26). Here, we report the results from the amivantamab-chemotherapy vs. chemotherapy group for Asian patients enrolled in MARIPOSA 2. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The MARIPOSA-2 trial was approved by the Ethics Committees of all participating institutions, and informed consent was obtained from all individual participants. Safety data were periodically reviewed by an Independent Data Monitoring Committee.

The study population comprised participants from 18 years of age with locally advanced or metastatic EGFR-mutated, non-squamous NSCLC, with measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, an Eastern Cooperative Oncology Group performance status (ECOG PS) score of 0 or 1, and adequate organ and bone marrow function. Participants must have had disease progression on or after osimertinib monotherapy as the most recent line of treatment, as either first-line for locally advanced or metastatic disease, or as second-line after prior treatment with first- or second-generation EGFR TKI monotherapy. Participants who had received prior systemic chemotherapy in the locally advanced or metastatic setting for the same non-squamous NSCLC intended for treatment in the study were excluded. Participants who received either neoadjuvant and/or adjuvant treatment were eligible if progression to locally advanced or metastatic disease occurred at least 12 months after the last dose of such therapy, with disease progression that had occurred on or after osimertinib in the locally advanced or metastatic setting. Participants with brain metastases at enrolment were included if their disease was stable and asymptomatic. Prior treatment for brain metastases was not required.

Study objectives

The study objective was to demonstrate superior PFS as assessed by blinded independent central review (BICR) in the amivantamab-chemotherapy group compared with the chemotherapy group. Secondary objectives reported here were the ORR by BICR, duration of response (DoR) by BICR, intracranial PFS by BICR, and safety.

Treatment and study procedures

Amivantamab was administered intravenously as 1,400 mg (or 1,750 mg for body weights ≥80 kg) weekly for the first 4 weeks, with the first infusion split over 2 days (350 mg on the first day and 1,050 mg on the second day). From the first day of cycle 3 (or week 7), 1,750 mg dose of amivantamab (2,100 mg if ≥80 kg) was given every 3 weeks until disease progression.

Carboplatin (area under the concentration-time curve of 5 mg/mL/min) and pemetrexed (500 mg/m²) were administered on the first day of each 21-day cycle for four cycles. Pemetrexed treatment continued until disease progression.

Disease assessments were conducted at baseline and every 6 weeks for the first year, then every 12 weeks until disease progression. Serial brain imaging was required for all patients on the following schedule: brain magnetic resonance imaging was conducted at baseline, week 6, week 12 and then every 12 weeks until intracranial disease progression. Computerised tomography was allowed if magnetic resonance imaging was contraindicated. Tumour response was assessed using RECIST 1.1.

Treatment-emergent adverse events (TEAEs), vital signs and the results of laboratory haematological and biochemical tests were graded using National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0. Adverse events of special interest of infusion-related reactions (IRRs), pneumonitis/interstitial lung disease (ILD), rash, and venous thromboembolic events (specific to the amivantamab-lazertinib-chemotherapy group) were prospectively identified based on the identified safety profile of amivantamab.

Statistical analysis

The primary objective of MARIPOSA-2 was evaluated in the global study population. The analysis methods used here are the same as those applied to the overall study population, but this is a post hoc analysis of the Asian sub-group, no hypotheses were pre-defined, and no adjustment was made for multiplicity.

Efficacy was assessed on the full analysis set of all randomized participants who identified as Asian. The safety population included all randomised participants who received at least one dose of any study treatment.

Median PFS and corresponding 95% CI were estimated by the Kaplan-Meier method. HRs and 95% CIs were calculated using a Cox regression model stratified by osimertinib line of therapy and history of brain metastases. For the secondary analysis of intracranial PFS, intracranial disease progression was defined as progression of brain metastasis or occurrence of new brain lesion. Intracranial PFS was analysed using a similar method to the primary analysis of PFS. A sensitivity analysis was conducted to assess intracranial PFS in participants with a history of brain metastases who had not received brain radiotherapy. Tumour response rates were compared using an odds ratio (OR) with 95% CIs. Statistical analyses were performed using SAS version 9.4 (Cary, NC).

The protocol and statistical analysis plan for the MARIPOSA-2 study have been published previously (26).

Results

Study population

The study was initiated on 17 November 2021, and the results presented here are those of the primary analysis with a clinical cutoff of 10 July 2023 after a median follow-up of 9.5 months. There were 190 participants in the Asian subgroup (full analysis set), of whom 63 were randomised to the amivantamab-chemotherapy group and 127 were randomised to the chemotherapy group (Figure 1). Demographic and baseline disease features were similar in the two groups and were similar to the overall MARIPOSA-2 population (Table 1). The median age of participants was 61 years in both groups, 67% in the amivantamab-chemotherapy group and 58% in the chemotherapy group were female, and 63% and 61%, respectively, had received osimertinib as first-line treatment. The percentage of participants with an ECOG PS of 1 at enrolment was 62% in the amivantamab-chemotherapy group and 66% in the chemotherapy group, 43% and 46%, respectively, had brain metastases, and 22% and 26%, respectively, had a history of tobacco exposure. The distribution of exon 19 deletion and exon 21 L858R EGFR mutations was similar in each group.

Figure 1 Participant disposition. A total of 44 participants in the amivantamab-chemotherapy group and 84 in the chemotherapy group remained in the study at the cutoff date.

The median duration of treatment was 7.4 months (range, 0.1–14.7 months) in the amivantamab-chemotherapy group and 4.0 months (range, 0–15.9 months) in the chemotherapy group. Participants in the amivantamab-chemotherapy group received a median of four cycles of carboplatin (range, 1–4) and 10 cycles of pemetrexed (range, 1–22) vs. four cycles of carboplatin (range, 1–5) and six cycles of pemetrexed (range, 1–23) in the chemotherapy group.

Subsequent therapies were received by 22.2% of all participants in the amivantamab-chemotherapy group and by 48.0% in the chemotherapy group, reflecting lower PFS in the chemotherapy group at the analysis timepoint. Systemic therapies were used in 20.6% of participants in the amivantamab-chemotherapy group and 48.0% in the chemotherapy group, radiotherapy in 6.3% and 16.5%, and surgery/procedure in 0.0% and 10.2%, respectively.

Clinical efficacy

Median PFS by BICR was 6.8 months (95% CI: 5.5–11.1) in the amivantamab-chemotherapy group and 4.2 months (95% CI: 4.1–5.4) in the chemotherapy group (HR 0.54, 95% CI: 0.37–0.81; nominal P=0.002) (Figure 2A). At 6 months, 53% of participants were progression-free in the amivantamab-chemotherapy group vs. 30% in the chemotherapy group, decreasing to 21% and 16%, respectively, by 12 months. The PFS benefit was also observed by investigator-assessment, with median PFS of 10.3 months in the amivantamab-chemotherapy group vs. 4.2 months in the chemotherapy group (HR 0.39, 95% CI: 0.26–0.59; nominal P<0.0001).

Figure 2 PFS by blinded independent central review in the Asian subgroup. (A) Kaplan-Meier curve. (B) Forest plot by patient subgroups. ^†, nominal P value; endpoint is not part of hierarchical hypothesis testing for the total population. CI, confidence interval; ECOG PS, Eastern Cooperative Oncology Group performance status; EGFR, epidermal growth factor receptor; HR, hazard ratio; NE, not estimable; PFS, progression-free survival.

Subgroup analyses showed that the direction of the change in PFS was consistent in the different subgroups, although the low number of participants in some subgroups included in each analysis means that the results should be interpreted with caution (Figure 2B).

The ORR was 66% in the amivantamab-chemotherapy group and 32% in the chemotherapy group (OR 4.0, 95% CI: 2.1–7.7; nominal P<0.001). The median duration of response amongst confirmed responders was 6.9 months (95% CI: 4.3 to not estimable) in the amivantamab-chemotherapy group and 7.2 months (95% CI: 4.1 to not estimable) in the chemotherapy group (Table 2).

OS was not assessed in the subgroup analysis as the data were immature at the data cut-off date for this analysis.

Intracranial PFS

Median intracranial PFS was 12.5 months (95% CI: 10.8–13.9) in the amivantamab-chemotherapy group vs. 8.5 months (95% CI: 7.5–13.8) in the chemotherapy group (HR 0.58, 95% CI: 0.34–1.00; nominal P=0.049; Figure 3A). The percentage of participants without intracranial disease progression was 84% in the amivantamab-chemotherapy group and 69% in the chemotherapy group at 6 months.

Figure 3 Intracranial PFS by blinded independent central review: (A) in the Asian subgroup; (B) in Asian participants with a history of brain metastases and no prior brain radiotherapy. ^a, nominal P value; endpoint is not part of hierarchical hypothesis testing for the total population. CI, confidence interval; HR, hazard ratio; icPFS, intracranial progression-free survival; NE, not estimable; PFS, progression-free survival.

The sensitivity analysis included 14 participants in the amivantamab-chemotherapy group and 25 in the chemotherapy group. Median intracranial PFS in participants with a history of brain metastases who had not received brain radiotherapy was not reached in the amivantamab-chemotherapy group vs. 4.3 months in the chemotherapy group (HR 0.33, 95% CI: 0.11–1.03; nominal P=0.04) (Figure 3B).

Safety

The safety population included 62 participants in the amivantamab-chemotherapy group and 116 participants in the chemotherapy group. All Asian participants in the amivantamab-chemotherapy group and 93% in the chemotherapy group reported TEAEs during the study. Grade ≥3 TEAEs were reported for 79% (49/62) participants in amivantamab-chemotherapy group, and 46% (53/116) in the chemotherapy group (Table 3). Cytopenias were the most frequently reported Grade ≥3 TEAEs in both groups. As observed in the analysis of the total MARIPOSA-2 safety population, TEAEs associated with EGFR or MET inhibition were reported almost exclusively in the amivantamab-chemotherapy group. Most EGFR/MET-associated TEAEs were Grade 1 or 2 in intensity, and Grade ≥3 EGFR/MET-associated TEAEs were reported by no more than two participants (3%) (Table 4).

The most frequently reported TEAE related to chemotherapy in both groups was neutropenia, reported for 60% (37/62) in the amivantamab-chemotherapy group, and 44% (51/116) in the chemotherapy group. Febrile neutropenia was reported for two participants (3%) in the amivantamab-chemotherapy group and three participants (3%) in the chemotherapy group (Table 4). The most frequently reported related Grade ≥3 TEAEs in the amivantamab-chemotherapy group were neutropenia and dermatitis acneiform (each in 8%, n=5) and neutropenia in the chemotherapy group (35%, n=40) (Table S1).

There were 29 participants (47%) who had an IRR in the amivantamab-chemotherapy group, of whom three had Grade ≥3 events. Two participants (3%) discontinued treatment due to an IRR. The composite AESI of “rash” was reported by 40% (25/62) of participants in the amivantamab-chemotherapy group [two (3%) were Grade ≥3] and by 3% (4/116) of participants in the chemotherapy group (all Grade 1 or 2) (Table 4). One patient in the Asian sub-cohort had pneumonitis/ILD (amivantamab-chemotherapy group, 2%). This 66-year-old female was diagnosed with Grade 3 ILD on day 39. The event was considered related to amivantamab and all further treatment was discontinued. Chest X-ray showed multiple spots in both lungs, considering the possibility of inflammatory lesions. The event resolved by day 52. Venous thromboembolic events were infrequent, pulmonary embolism was reported for 3% of participants in each group, and embolism (unspecified) for 2% in the chemotherapy group.

Other TEAEs reported by at least 15% of participants in either group were preferred terms associated with gastrointestinal symptoms, elevated liver function tests, fatigue, and biochemical abnormalities. Most were Grade 1 or 2 in intensity (Table 4).

Serious TEAEs (SAEs) were reported for 40% (25/62) of participants in the amivantamab-chemotherapy group and 17% (20/116) in the chemotherapy group (Table 3). SAEs reported by at least two participants in either group were febrile neutropenia, anaemia, myelosuppression, coronavirus disease 2019 (COVID-19), sepsis, supraventricular tachycardia, thrombocytopenia, and dyspnoea (Table S2).

There were three participants in the Asian sub-population who died due to adverse events (AEs), all in the amivantamab-chemotherapy group. One 75-year-old male participant presented with an infectious pleural effusion and right pneumonia, thrombocytopenia, abnormal liver functions tests and raised creatinine platelets on day 14. Pseudomonas aeruginosa was detected from pleural culture. The participant died from sepsis (unrelated to treatment) the following day. A 66-year-old female participant developed dyspnoea on day 453, 4 days after the last treatment (amivantamab cycle 20), and died on the same day (unrelated to treatment). Pleural thickening was noted at the lung apices and other clinical information is lacking. A 49-year-old female participant developed ventricular fibrillation on day 357 (16 cycles of amivantamab) and died despite resuscitative attempts. The event was considered treatment-related by the investigator.

AEs leading to treatment interruption or dose reductions were common in both groups but more frequent in the amivantamab-chemotherapy group (Table 3), as anticipated with addition of amivantamab to the platinum doublet chemotherapy vs. chemotherapy alone. In total, 23% (14/62) participants in the amivantamab-chemotherapy group had TEAEs resulting in discontinuation of any agent vs. 1% (1/116) in the chemotherapy group. This difference was largely driven by AEs associated with amivantamab’s known EGFR inhibitory activity (rash/dermatitis acneiform and paronychia). Seven participants (11%) had at last one treatment-related TEAE leading to discontinuation of amivantamab, including IRR (two participants), ventricular fibrillation (participant died), ILD, vomiting, dermatitis acneiform, palmar-plantar erythrodysaesthesia syndrome, and paronychia. Of these, four discontinuations were due to TEAEs that were EGFR/MET-associated.

Discussion

Key findings

This exploratory sub-analysis of the MARIPOSA-2 trial showed a clinically meaningful improvement of amivantamab-chemotherapy over chemotherapy alone in Asian participants with EGFR-mutated advanced NSCLC who had progressed on osimertinib monotherapy. The magnitude of the benefit, a 46% reduced risk of disease progression or death, was similar to that observed in the overall MARIPOSA-2 trial population (52% risk reduction). A consistent magnitude of benefit (61%) was observed with investigator assessment of PFS. Across all prespecified subgroups such as age group, sex, weight, history of brain metastasis, osimertinib line of therapy, ECOG PS score, EGFR mutation type, and tobacco history, PFS consistently favoured the amivantamab-chemotherapy group, confirming the robustness of the clinical benefit. The ORR was higher in the amivantamab-chemotherapy group than the chemotherapy group and the median duration of response was similar between groups, although the upper limit of the 95% CI was not reached in either group.

The median PFS point estimate in the amivantamab-chemotherapy arm was shorter by BICR (6.8 months) than by investigator assessment (10.3 months). However, with an observed HR of 0.54 and median PFS of 4.2 months by BICR in the chemotherapy arm, the expected median PFS by BICR in the amivantamab-chemotherapy arm is estimated to be approximately 7.8 months under the exponential distribution assumption, suggesting that the observed median PFS estimate of 6.8 months by BICR might be underestimated. This is supported by the sustained improvement in the landmark PFS analyses beyond the reported median.

Amivantamab-chemotherapy was also associated with a marked improvement in intracranial PFS compared to chemotherapy alone, including participants with known brain metastases who had not previously received brain radiotherapy. The benefit on intracranial PFS observed after amivantamab-chemotherapy in the MARIPOSA-2 study was unexpected. Amivantamab was not initially expected to cross the blood–brain barrier due to the large size of the molecule. Consequently, lazertinib, a known central nervous system-active TKI, was added to the amivantamab-chemotherapy regimen in a third arm of MARIPOSA-2. The MARIPOSA-2 study showed that amivantamab-chemotherapy without lazertinib could prevent or delay brain recurrences.

The similar improvement observed in participants with a history of radiologically untreated brain metastasis strengthens this conclusion. We believe that amivantamab improves intracranial PFS through either direct antitumor effects or indirect immune-based mechanisms (28).

There is now a substantial body of evidence demonstrating the benefits of amivantamab for patients with intracranial lesions. In the MARIPOSA study, the combination of amivantamab–lazertinib in first-line substantially improved median intracranial-PFS as compared with osimertinib (27.5 months, 95% CI: 22.1 to not estimable vs. 18.4 months, 95% CI: 16.5–20.2) (21). Lazertinib has similar efficacy to osimertinib as monotherapy (29), suggesting an additional benefit of amivantamab for intra-cranial disease. This is supported by a recent real-world study recently showed the effectiveness of amivantamab monotherapy in patients with refractory brain or leptomeningeal metastases (30). Intra-cranial effectiveness of amivantamab was also demonstrated in patients EGFR exon 20 insertion-mutated advanced NSCLC in the PAPILLON study (31). For both MARIPOSA and PAPILLON, intra-cranial effectiveness was also demonstrated in the subgroup of Asian patients (32,33). Based on the available information National Comprehensive Cancer Network (NCCN) and European Society for Medical Oncology (ESMO) guidelines recommend amivantamab-containing regimens as preferred systemic options for managing EGFR-mutated advanced NSCLC with central nervous system metastases whether in first-line or after progression on TKIs.

The clinical evidence of prolonged PFS and OS supports the pre-clinical evidence of amivantamab’s immune-directing activity, whereby the antibody is harnessing immune system components to kill tumour cells, in addition to receptor blocking and degradation. This hypothesis is further supported by emerging clinical evidence in colorectal cancer, whereby tumours treated with amivantamab monotherapy have shown a substantial increase in the immune cell signatures, indicative of immune cell infiltration within the tumour microenvironment (34).

The toxicity profile of the addition of amivantamab to chemotherapy is characterised by higher rates of haematological toxicity, and of specific TEAEs associated with the inhibition of EGFR and MET that are usually Grade 1 or 2 severity. Although rates of cytopenia were higher in the amivantamab-chemotherapy cohort, the rates of febrile neutropenia were low and comparable between arms in the Asian population. The events of neutropenia and thrombocytopenia tended to cluster in cycle 1 when blood was collected weekly for haematology assessments as compared to once every cycle thereafter, indicating that the toxicity is mostly asymptomatic and recorded as part of the trial monitoring. In the global MARIPOSA-2 population, neutropenia and thrombocytopenia were transient and were associated with low rates of febrile neutropenia and no clinically significant bleeding. Rates of IRR were consistent with previous reports following intravenous administration, and most were Grade 1 or 2 in severity. Treatment discontinuations due to AEs were more frequent in the amivantamab-chemotherapy group than the chemotherapy group although the only preferred term reported more than once was IRRs (two participants). Evidence from the SKIPPirr study indicates that the frequency and severity of IRRs following intravenous amivantamab (plus oral lazertinib) can be reduced substantially by oral dexamethasone prophylaxis (8 mg) given twice on Day –1 and Day –2, and one hour before the first infusion (35). The PALOMA-3 study showed that that subcutaneous injection of amivantamab (plus oral lazertinib) was also effective in reducing the incidence or IRRs and was associated with higher treatment completion rates than intravenous administration (36). Although no direct evidence has been published using the subcutaneous formulation of amivantamab with chemotherapy, Cohorts 2 and 3b in PALOMA-2 (NCT05498428) are currently investigating the combination. Subcutaneous amivantamab is approved for use on the basis of PALOMA-3 study in Japan and China, as well as many other countries worldwide.

The observed rate of EGFR-associated (rash, paronychia, and stomatitis), and MET-associated AEs (peripheral oedema and hypalbuminaemia) in Asian participants receiving second-line amivantamab-chemotherapy was similar or lower than rates observed in the total MARIPOSA-2 safety population (26). Available data indicate that EGFR- and MET-associated AEs occur in similar proportions of patients treated with amivantamab-chemotherapy and amivantamab monotherapy across treatment lines (21,31,37). A Phase II study, COCOON, conducted in patients with advanced EGFR-mutated NSCLC treated in first-line with amivantamab plus lazertinib, has also since demonstrated that an enhanced dermatological regimen consisting of an oral tetracycline for 12 weeks followed by clindamycin 1% scalp lotion, chlorhexidine for nails and ceramide-based moisturizer to body and face, reduced the incidence of grade ≥2 dermatologic AEs by 50% compared to standard of care (38). These newly published data demonstrating successful prophylactic management strategies further provides an opportunity to improve outcomes by providing optimal supportive care, thereby keeping patients on therapy for longer (35,38).

Strengths and limitations

Strengths of the MARIPOSA-2 study were that it was stratified by race, allowing for a robust analysis and comparison with a control arm in Asian participants. Limitations of this subanalysis are the restricted sample size and post hoc nature of the analysis which can hinder the ability to make statistical conclusions. Notably, subgroup analysis of PFS by EGFR mutation type was limited by the sample size in each group and remains an area for further study. No comparison between Asian and non-Asian participants was conducted, and OS data were too immature for meaningful presentation. Nevertheless, the efficacy and safety results were within the range reported for the main MARIOSA-2 study analysis, suggesting that the clinical benefit of amivantamab plus chemotherapy in Asian patients with EGFR-mutated, advanced NSCLC is projected to be similar to the overall MARIPOSA-2 population.

Comparison with similar research

To date there has been little success in developing new therapies for patients with EGFR-mutated advanced NSCLC with disease progression on third-generation TKIs and the optimal treatment strategy is not yet established (39). Combinations of chemotherapy plus an immune checkpoint inhibitor and an anti-angiogenic agent have been explored in first and second-line for advanced NSCLC (40). Atezolizumab with bevacizumab plus chemotherapy was assessed in the IMPOWER150 study (41). However, only a small number of study participants (n=78) had EGFR-mutated NSCLC with progression on TKIs and very few were of Asian heritage (42). In the second-line subgroup, gains observed in OS after atezolizumab-containing treatment were not statistically significantly different compared to control (bevacizumab plus chemotherapy) (42). Other studies of atezolizumab with bevacizumab plus chemotherapy in second-line have been restricted in size and efficacy has been modest (43). In a small cohort of 12 patients with advanced EGFR-mutated NSCLC with acquired resistance to TKIs, treated with SMET12 (anti-EGFR/CD3 bispecific antibody), immunotherapy and chemotherapy, the ORR was 41.7% and median PFS was 7.2 months, although no control group was included (44). Antibody-drug conjugates that link highly specific monoclonal antibodies to chemotherapeutic agents are new approaches that are currently being evaluated (45), and clinical trials of drugs targeting EGFR, HER3 and c-Met are ongoing (39).

Implications

The combination of amivantamab plus chemotherapy provides a much-needed option for the second-line treatment of patients with EGFR-mutated advanced NSCLC after progression on third-generation TKIs in whom the prognosis is otherwise poor. The absolute increase in PFS with amivantamab plus chemotherapy was modest, but represented a 46% improvement compared to chemotherapy alone, which was statistically and clinically significant in these patients who have few or no other treatment options. Up to one-third of patients with progression on TKIs die before receiving second-line treatment (5). When amivantamab is used in second-line, the resistance that has developed to TKIs is already complex, heterogenous, and difficult to treat. While our study demonstrates that amivantamab is active in second-line, the benefit of amivantamab was substantially greater when used in first-line (with lazertinib) for patients with EGFR-mutated advanced NSCLC (21), where there is an opportunity to inhibit tumour escape mechanisms from the start.

Much of the haematologic toxicity observed in MARIPOSA-2 was recorded as part of the trial monitoring and required no intervention. The discontinuation rate due to related TEAEs was 11%, but more than half were due to either IRRs or EGFR-specific events that are potentially mitigable (35,38). Recent publication of patient-reported outcomes in the MARIPOSA-2 trial found that adding amivantamab to chemotherapy prolonged the time to symptomatic progression and achieved clinical benefits without compromising health-related quality of life (46). With its unique mechanism of action, and highly significant clinical outcomes, amivantamab could address a currently unmet need for patients with TKI-resistant EGFR-mutated NSCLC. Therefore, the benefit-risk of amivantamab plus chemotherapy is considered positive in this population.

Areas for further research include assessment of potential associations between adverse events and response to treatment.

Conclusions

In conclusion, amivantamab plus chemotherapy significantly improved PFS, including intracranial PFS, and ORR, compared with chemotherapy in the Asian subpopulation of the MARIPOSA-2 trial. Estimates of efficacy and safety were in line with the global population. Amivantamab combined with chemotherapy is the first targeted treatment regimen to show clinical benefit over chemotherapy alone in patients with advanced NSCLC who have relapsed on a third-generation TKI. The toxicity profile of amivantamab-chemotherapy is manageable, as evidenced by the longer duration of treatment achieved by participants in the amivantamab-chemotherapy group. The regimen of amivantamab-chemotherapy provides an efficacious targeted treatment option for patients with disease progression on osimertinib.

Acknowledgments

The authors thank Marija Mcgeachie and Anthea Lee (Johnson & Johnson) for publication initiation and management. Medical writing assistance was provided by Joanne Wolter (independent on behalf of Johnson & Johnson). These data were presented at ESMO 2023 and the abstract has been published: Lu S, Cho BC, Lee J-S, et al. Amivantamab plus lazertinib vs osimertinib as first-line treatment among Asian patients with EGFR-mutated, advanced non-small cell lung cancer (NSCLC): MARIPOSA subgroup analysis. Ann Oncol. 2023 34 (S4): S1661.

Footnote

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-0202/prf

Funding: This study was supported by Johnson & Johnson.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-0202/coif). All authors report that this study was supported by Johnson & Johnson. J.Y.S. received grants from Roche; honoraria from Abbvie, ACTgenomics, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Chugai Pharmaceutical, Daiichi-Sankyo, Eli Lilly, GlaxoSmithKline, Guardant Health, Illumina, Johnson & Johnson, Lotus, Merck Sharp & Dohme, Merck KGaA, Ono Pharmaceutical, Orient EuroPharma, Pfizer, Roche, Synmosa, Takeda, TSH Biopharm, TTY Biopharm, Welgene Biotech, and Zuellig Pharma; and meeting-related fees from AstraZeneca, Chugai, Pfizer, and Roche. S.H.L. received research grants or contracts from AstraZeneca, BeOne, Daiichi Sankyo, MSD, and Yuhan, consulting fees from Abion, AimedBio, AstraZeneca, BeOne, Bristol Myers Squibb, Daiichi Sankyo, Dong-A ST, Eli Lilly, Genexine, IMBdx, ImmuneOncia, Janssen, Merck, MSD, Novartis, Pfizer, Roche, and Takeda; and speaker fees from Amgen, AstraZeneca/MedImmune, Eli Lilly, MSD, Roche, and Yuhan. K.A. received institutional research grants or contracts from multiple pharmaceutical and related companies, including MSD, Bristol Myers Squibb, AstraZeneca, Taiho Pharmaceutical, Amgen, Daiichi Sankyo, IQVIA, EPS, and Syneos; and honoraria for lectures or educational activities from MSD, Johnson & Johnson, AstraZeneca, Chugai Pharmaceutical, Takeda Pharmaceutical, Ono Pharmaceutical, Taiho Pharmaceutical, Amgen, and Bristol Myers Squibb. T.T. received grants from AstraZeneca K.K., MSD K.K., Janssen Pharmaceutical K.K., Amgen K.K., and AnHeart Therapeutics Inc.; consulting fees from NIPPON KAYAKU Co., Ltd.; and honoraria from Amgen K.K., AstraZeneca K.K., BMS Japan, Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Eli Lilly Japan K.K., Janssen Pharmaceutical K.K., MSD K.K., Ono Pharmaceutical Co., Ltd., Pfizer Japan Inc., Taiho Pharmaceutical Co., Ltd., and Takeda Pharmaceutical Co., Ltd. J.L.T. received payment or speaker honoraria from Merck Sharp & Dohme, Boehringer Ingelheim, Johnson & Johnson, Novartis, GSK, and Pfizer; received support for attending meetings and/or travel from Merck Sharp & Dohme, Takeda, and Pfizer; and received consulting fees from Merck KGaA, GSK, AstraZeneca and Bristol Myers Squibb. C.C.L. received consulting fees and payment or honoraria for lectures, presentations, and speakers bureaus from Boehringer Ingelheim, AstraZeneca, and Pfizer Inc.; and support for attending meetings from Boehringer Ingelheim and Pfizer Inc. S.G. received institutional fees from Novartis and AstraZeneca for unrelated research. P.L.C., S.S., and B.D. are employees of Johnson & Johnson and own stock and stock options in Johnson & Johnson. B.C.C. received research grants from CJ Bioscience, Cyrus, ImmuneOncia, JINTSbio, MSD, Yuhan, Dong-A ST, and Ligachem Bioscience; institutional royalties or licenses from Champions Oncology, Crown Bioscience, Imagen, and PearlRiver Bio GmbH; institutional consulting fees from Amgen, ArriVent, AstraZeneca, Bristol Myers Squibb, Boehringer-Ingelheim, CJ Bioscience, Cyrus Therapeutics, Gilead, GSK, Regeneron, Johnson & Johnson, MSD, and Yuhan; and speakers fees from ASCO, AstraZeneca, Guardant, Roche, ESMO, IASLC, Korean Cancer Association, Korean Society of Medical Oncology, Korean Society of Thyroid-Head and Neck Surgery, Korean Cancer Study Group, Novartis, MSD, The Chinese Thoracic Oncology Society, Pfizer, and Zailab. He has also participated in advisory boards for KANAPH Therapeutic Inc., Cyrus Therapeutics, and J INTS Bio; served as a member of the board of directors for J INTS Bio; holds stock options in J INTS Bio and KANAPH Therapeutics Inc.; and is a founder of DAAN Biotherapeutics and an employee of Yonsei University Health System. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The MARIPOSA-2 trial was approved by the Ethics Committees of all participating institutions, and informed consent was obtained from all individual participants.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. International Agency for Research on Cancer. GLOBOCAN 2022. Absolute numbers, Incidence, Both sexes, in 2022 World vs Asia. [accessed 28 Nov 2024]. Available online: https://gco.iarc.who.int/today/en/dataviz/bars-compare-populations?mode=cancer&group_populations=1&populations=900_935&key=total&sort_by=value1&types=0.
2. Melosky B, Kambartel K, Häntschel M, et al. Worldwide Prevalence of Epidermal Growth Factor Receptor Mutations in Non-Small Cell Lung Cancer: A Meta-Analysis. Mol Diagn Ther 2022;26:7-18. [Crossref] [PubMed]
3. Shi Y, Au JS, Thongprasert S, et al. A prospective, molecular epidemiology study of EGFR mutations in Asian patients with advanced non-small-cell lung cancer of adenocarcinoma histology (PIONEER). J Thorac Oncol 2014;9:154-62. [Crossref] [PubMed]
4. Chevallier M, Borgeaud M, Addeo A, et al. Oncogenic driver mutations in non-small cell lung cancer: Past, present and future. World J Clin Oncol 2021;12:217-37. [Crossref] [PubMed]
5. Sabari JK, Yu HA, Mahadevia PJ, et al. Overall Survival in EGFR-Mutant Advanced NSCLC Treated With First-Line Osimertinib: A Cohort Study Integrating Clinical and Biomarker Data in the United States. J Thorac Oncol 2025;20:1268-78. [Crossref] [PubMed]
6. Yang JC, Lu S, Hayashi H, et al. Overall Survival with Amivantamab-Lazertinib in EGFR-Mutated Advanced NSCLC. N Engl J Med 2025;393:1681-93. [Crossref] [PubMed]
7. Felip E, Cho BC, Gutiérrez V, et al. Amivantamab plus lazertinib versus osimertinib in first-line EGFR-mutant advanced non-small-cell lung cancer with biomarkers of high-risk disease: a secondary analysis from MARIPOSA. Ann Oncol 2024;35:805-16. [Crossref] [PubMed]
8. Besse B, Lee SH, Lu S, et al. LBA55 Mechanisms of acquired resistance to first-line amivantamab plus lazertinib versus osimertinib in patients with EGFR-mutant advanced non-small cell lung cancer: An early analysis from the phase III MARIPOSA study. Annals Oncol 2024;35:S1245-6.
9. Hayashi H, Cho BC, Spigel DR, et al. Long-Term Impact of First-Line Amivantamab Plus Lazertinib Versus Osimertinib on Mechanisms of Acquired Resistance in MARIPOSA: A Brief Report. J Thorac Oncol 2025;20:103894. [Crossref] [PubMed]
10. To KKW, Fong W, Cho WCS. Immunotherapy in Treating EGFR-Mutant Lung Cancer: Current Challenges and New Strategies. Front Oncol 2021;11:635007. [Crossref] [PubMed]
11. Hong L, Lewis WE, Nilsson M, et al. Limited Benefit from the Addition of Immunotherapy to Chemotherapy in TKI-Refractory EGFR-Mutant Lung Adenocarcinoma. Cancers (Basel) 2022;14:3473. [Crossref] [PubMed]
12. Yang JC, Lee DH, Lee JS, et al. Phase III KEYNOTE-789 Study of Pemetrexed and Platinum With or Without Pembrolizumab for Tyrosine Kinase Inhibitor‒Resistant, EGFR-Mutant, Metastatic Nonsquamous Non-Small Cell Lung Cancer. J Clin Oncol 2024;42:4029-39. [Crossref] [PubMed]
13. Kashima Y, Shibahara D, Suzuki A, et al. Single-Cell Analyses Reveal Diverse Mechanisms of Resistance to EGFR Tyrosine Kinase Inhibitors in Lung Cancer. Cancer Res 2021;81:4835-48. [Crossref] [PubMed]
14. Wood GE, Hockings H, Hilton DM, et al. The role of MET in chemotherapy resistance. Oncogene 2021;40:1927-41. [Crossref] [PubMed]
15. Passaro A, Jänne PA, Mok T, et al. Overcoming therapy resistance in EGFR-mutant lung cancer. Nat Cancer 2021;2:377-91. [Crossref] [PubMed]
16. Yu HA, Kerr K, Rolfo CD, et al. Detection of MET amplification (METamp) in patients with EGFR mutant (m) NSCLC after first-line (1L) osimertinib. J Clin Oncol 2023;41:9074.
17. Moores SL, Chiu ML, Bushey BS, et al. A Novel Bispecific Antibody Targeting EGFR and cMet Is Effective against EGFR Inhibitor-Resistant Lung Tumors. Cancer Res 2016;76:3942-53. [Crossref] [PubMed]
18. Yun J, Lee SH, Kim SY, et al. Antitumor Activity of Amivantamab (JNJ-61186372), an EGFR-MET Bispecific Antibody, in Diverse Models of EGFR Exon 20 Insertion-Driven NSCLC. Cancer Discov 2020;10:1194-209. [Crossref] [PubMed]
19. Vijayaraghavan S, Lipfert L, Chevalier K, et al. Amivantamab (JNJ-61186372), an Fc Enhanced EGFR/cMet Bispecific Antibody, Induces Receptor Downmodulation and Antitumor Activity by Monocyte/Macrophage Trogocytosis. Mol Cancer Ther 2020;19:2044-56. [Crossref] [PubMed]
20. Krebs MG, Cho BC, Hiret S, et al. Amivantamab in Participants With Advanced NSCLC and MET Exon 14 Skipping Mutations: Final Results From the CHRYSALIS Study. J Thorac Oncol 2025;20:1289-301. [Crossref] [PubMed]
21. Cho BC, Lu S, Felip E, et al. Amivantamab plus Lazertinib in Previously Untreated EGFR-Mutated Advanced NSCLC. N Engl J Med 2024;391:1486-98. [Crossref] [PubMed]
22. Cho BC, Wang Y, Felip E, et al. Amivantamab plus lazertinib in atypical EGFR-mutated advanced non-small cell lung cancer (NSCLC): Results from CHRYSALIS-2. J Clin Oncol 2024;42:8516.
23. Yang J, Kim Y, Lee S, et al. Amivantamab plus lazertinib vs osimertinib in first-line EGFR-mutant advanced NSCLC.Final overall survival from the phase 3 MARIPOSA study. J Thor Oncol 2025;20:S6-8.
24. Hayashi H, Cho BC, Kim YJ, et al. Overall survival for amivantamab plus lazertinib versus osimertinib as first-line treatment in Asian participants with EGFR-mutant advanced NSCLC: A MARIPOSA subset analysis. Lung Cancer 2026;214:109305. [Crossref] [PubMed]
25. Yang JCH, Kobayashi K, Chewaskulyong B, et al. 630MO First-line (1L) osimertinib (osi) ± platinum-pemetrexed chemotherapy (CTx) for EGFR-mutated (EGFRm) advanced non-small cell lung cancer (NSCLC): FLAURA2 Asian cohort. Annals Oncol 2024;35:S1635-6.
26. Passaro A, Wang J, Wang Y, et al. Amivantamab plus chemotherapy with and without lazertinib in EGFR-mutant advanced NSCLC after disease progression on osimertinib: primary results from the phase III MARIPOSA-2 study. Ann Oncol 2024;35:77-90. [Crossref] [PubMed]
27. Popat S, Reckamp K, Califano R, et al. LBA54 Amivantamab plus chemotherapy vs chemotherapy in EGFR-mutated, advanced non-small cell lung cancer after disease progression on osimertinib: Second interim overall survival from MARIPOSA-2. Annals Oncol 2024;35:S1244-5.
28. Kim J, Chung LI, Choi H, et al. Durable complete response in leptomeningeal disease of EGFR mutated non-small cell lung cancer to amivantamab, an EGFR-MET receptor bispecific antibody, after progressing on osimertinib. Oncotarget 2025;16:411-8. [Crossref] [PubMed]
29. Lee SH, Lu S, Hayashi H, et al. Lazertinib Versus Osimertinib in Previously Untreated EGFR-Mutant Advanced NSCLC: A Randomized, Double-Blind, Exploratory Analysis From MARIPOSA. J Thorac Oncol 2025;20:1655-68. [Crossref] [PubMed]
30. Ganesh S, Zhang L, Bangolo A, et al. Real-world outcomes of amivantamab monotherapy in advanced EGFR-mutant non-small cell lung cancer. J Clin Oncol 2026;44:e20717.
31. Zhou C, Tang KJ, Cho BC, et al. Amivantamab plus Chemotherapy in NSCLC with EGFR Exon 20 Insertions. N Engl J Med 2023;389:2039-51. [Crossref] [PubMed]
32. Zhou C, Tang KJ, Liu B, et al. Amivantamab plus chemotherapy versus chemotherapy for first-line treatment of participants with EGFR exon 20 insertion-mutated advanced non-small cell lung cancer: PAPILLON Asia subgroup analysis. Lung Cancer 2026;213:109302. [Crossref] [PubMed]
33. Cho BC, Hayashi H, Lee JS, et al. Amivantamab plus lazertinib versus osimertinib as first-line treatment in EGFR-mutated advanced non-small cell lung cancer: MARIPOSA Asian subset. Lung Cancer 2025;204:108496. [Crossref] [PubMed]
34. Eng C, Oberstein PE, Hecht JR, et al. Amivantamab treatment and intra-tumoral gene expression and immune cell changes in refractory metastatic colorectal cancer (mCRC): Whole transcriptome RNA-sequencing analysis from the OrigAMI-1 study. J Clin Oncol 2025;43:3550.
35. Spira AI, Paz-Ares L, Han JY, et al. Preventing Infusion-Related Reactions With Intravenous Amivantamab-Results From SKIPPirr, a Phase 2 Study: A Brief Report. J Thorac Oncol 2025;20:809-16. [Crossref] [PubMed]
36. Leighl NB, Akamatsu H, Lim SM, et al. Subcutaneous Versus Intravenous Amivantamab, Both in Combination With Lazertinib, in Refractory Epidermal Growth Factor Receptor-Mutated Non-Small Cell Lung Cancer: Primary Results From the Phase III PALOMA-3 Study. J Clin Oncol 2024;42:3593-605. [Crossref] [PubMed]
37. Park K, Haura EB, Leighl NB, et al. Amivantamab in EGFR Exon 20 Insertion-Mutated Non-Small-Cell Lung Cancer Progressing on Platinum Chemotherapy: Initial Results From the CHRYSALIS Phase I Study. J Clin Oncol 2021;39:3391-402. [Crossref] [PubMed]
38. Girard N, Li W, Spira A, et al. 10MO: Preventing moderate to severe dermatologic adverse events in first-line EGFR-mutant advanced NSCLC treated with amivantamab plus lazertinib: Early success of the COCOON trial. J Thoracic Oncol 2025;20:S14-6.
39. Le X, Popat S, Heymach JV, et al. Treatment options and considerations for acquired resistance in EGFR mutation-positive non-small-cell lung cancer. ESMO Open 2026;11:106027. [Crossref] [PubMed]
40. Wang Y, Zhang L, Zhan J, et al. Comparative efficacy and safety of post-TKI treatments for advanced EGFR-mutant non-small-cell lung cancer: a systematic review and network meta-analysis. Lung Cancer 2026;212:108914. [Crossref] [PubMed]
41. Socinski MA, Jotte RM, Cappuzzo F, et al. Atezolizumab for First-Line Treatment of Metastatic Nonsquamous NSCLC. N Engl J Med 2018;378:2288-301. [Crossref] [PubMed]
42. Nogami N, Barlesi F, Socinski MA, et al. IMpower150 Final Exploratory Analyses for Atezolizumab Plus Bevacizumab and Chemotherapy in Key NSCLC Patient Subgroups With EGFR Mutations or Metastases in the Liver or Brain. J Thorac Oncol 2022;17:309-23. [Crossref] [PubMed]
43. Tanaka T, Tamiya M, Miyazaki A, et al. Efficacy of Atezolizumab, Bevacizumab, Carboplatin, and Paclitaxel Therapy in Patients With Genetic Alterations in Non-Small Cell Lung Cancer. Thorac Cancer 2025;16:e70162. [Crossref] [PubMed]
44. Lin J, Chen S, Li M, et al. Efficacy and safety of SMET12 in combination with toripalimab and chemotherapy in advanced non-small-cell lung cancer patients tested positive for EGFR protein who are treatment-naïve or harbor acquired resistance to standard therapy: a phase 2, multi-cohort clinical trial. Front Immunol 2025;16:1706961. [Crossref] [PubMed]
45. Liu H, Lin W, Tian H, et al. A data-driven cartography of NSCLC vaccine research: Quantifying the paradigm shift toward immuno-oncology combination therapies. Hum Vaccin Immunother 2026;22:2615515. [Crossref] [PubMed]
46. Tomasini P, Juan-Vidal O, Califano R, et al. Patient-Relevant Outcomes From the Phase III MARIPOSA-2 Trial: Amivantamab-Chemotherapy Versus Chemotherapy in EGFR-Mutant Advanced Non-Small-Cell Lung Cancer Following Disease Progression on Osimertinib. Clin Lung Cancer 2026;27:38-47. [Crossref] [PubMed]