Prolonged complete metabolic response to chemotherapy combined with amivantamab with high grade cutaneous toxicity after osimertinib resistance in an uncommon T751_I759delinsAsp EGFR-mutant lung adenocarcinoma: a case report

Introduction

Lung cancer remains the leading cause of cancer-related mortality worldwide in 2024, affecting both men and women equally (1). While the majority of patients are smokers with a median age of 65 years, a smaller subgroup consists of younger patients with no history of tobacco exposure (2). In this population, identifying epidermal growth factor receptor (EGFR) alterations is of paramount importance, as targeted therapies against EGFR have transformed the prognosis of these cases (3).

EGFR alterations predominantly occur between exons 18 and 21 and are characterized in approximately 90% of cases by the L858R mutation in exon 21 or deletions in exon 19 (del19), with the remaining 10% comprising “uncommon” mutations (4). Del19 mutations typically involve in-frame deletions of five codons. The most frequently observed deletion (E746_A750del) shortens the sequence between the β3 kinase domain strand and its regulatory αC helix, resulting in constitutive activation of the receptor (5).

While the sensitivity of classical EGFR del19 mutations to three generations of tyrosine kinase inhibitors (TKIs) is well documented (6-8), data on the efficacy of these therapies in cases with uncommon EGFR exon 19 alterations remain limited. Amivantamab, an EGFR/MNNG HOS transforming gene (MET) bispecific antibody, plus chemotherapy showed efficacy after priori EGFR TKI, including osimertinib, with a median progression-free survival (PFS) of 6.3 months compared to 4.2 months with chemotherapy alone [hazard ratio (HR) for disease progression or death 0.48; 95% confidence interval (CI): 0.36–0.64; P<0.001] (9). The combination was effective in both classical EGFR alterations. MARIPOSA trial concluded to a PFS benefit with amivantamab plus lazertinib (EGFR TKI) compared to osimertinib in patients with unpreviouly treated classical EGFR-mutant lung cancer (10). Few data reported amivantamab efficacy in uncommon EGFR alteration in second line setting (11).

This report describes a rare case of a deep and prolonged response to amivantamab plus chemotherapy with a high-grade cutaneous toxicity after one-year response to osimertinib, in a young patient with a lymph node and bone metastatic non-small cell lung cancer (NSCLC) harboring a Thr751_Ile759delinsAsp alteration in exon 19, directly affecting the αC helix. We present this article in accordance with the CARE reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-aw-1222/rc).

Case presentation

In October 2023, a 29-year-old male non-smoker with no significant medical history presented with acute dorsolumbar pain following a football match. The pain was not associated with any neurological deficit. A thoracic computed tomography (CT) scan revealed a distal pulmonary embolism, mediastinal lymphadenopathy, and multiple vertebral lesions, including epiduritis at 11th thoracic vertebra. An 18-fluorodeoxyglucose positron emission tomography/computed tomography (¹⁸F-FDG PET/CT) scan further identified a nodular lesion in the left lower lobe of the lung, extensive lymphadenopathy above and below the diaphragm, and widespread osseous lesions (Figure 1). Brain magnetic resonance imaging (MRI) revealed a small (4 mm) lesion in the internal capsule.

Figure 1 Timeline reporting radiological and molecular pattern at diagnosis, until osimertinib progression as first-line therapy and amivantamab plus chemotherapy as second-line. This image is published with the patient’s consent. ¹⁸F-FDG PET/CT, 18-fluorodeoxyglucose positron emission tomography/computed tomography; CTCAE, Common Terminology Criteria for Adverse Events; ddPCR, droplet digital polymerase chain reaction; DNA, deoxyribonucleic acid; EGFR, epidermal growth factor receptor; iRECIST, immune Response Evaluation Criteria in Solid Tumors; MET, MNNG-HOS transforming gene; MIP, maximum intensity projection of ¹⁸F-FDG PET/CT.

Bone marrow analysis excluded a hematological malignancy, such as lymphoma. A liquid biopsy detected 11,500 copies/mL of circulating tumor deoxyribonucleic acid (DNA) in the plasma. However, the next generation sequencing (NGS) performed on the MassARRAY^® system using the Agena iPLEX HS lung amplicons-based panel^® (covering 89 hotspots across EGFR, BRAF, HER2, KRAS and PIK3CA, enabling variant detection as low as 1% allelic fraction) did not identify any molecular alterations. Following the negativity of the NGS panel, a complementary Sanger sequencing of the EGFR gene performed on an ABI 3500xL analyzer (Applied Biosystems^®, Foster City, USA) using the reference sequence NM_005228.4 (mRNA transcript variant 1 for the human EGFR) uncovered a 24-nucleotide deletion in exon 19 (c.2250_2276delinsCGA; p.Thr751_Ile759delinsAsp). The Sanger sequencing was performed following the high suspicion of EGFR mutated lung cancer, due the young age and non-smoking profile of the patient. A left supraclavicular lymph node biopsy revealed a moderately differentiated TTF1 positive adenocarcinoma. The NGS panel performed on the biopsy specimen (same panel employed for the liquid biopsy) was negative. The supplementary EGFR Sanger sequencing (same technique as for the liquid biopsy) confirmed the same EGFR exon 19 deletion-insertion without any other alteration detected. Finally, the diagnosis of metastatic lung adenocarcinoma, with 10% programmed death-ligand 1 (PD-L1) positivity and EGFR exon 19 uncommon mutation was retained.

Treatment with osimertinib (80 mg daily) was initiated in October 2023 as first-line therapy. Stereotactic radiotherapy was concurrently administered to the 11th thoracic vertebra vertebral lesion, and denosumab was introduced due to the presence of lytic bone metastases and a high risk of pathological fractures.

Three months later, in January 2024, follow-up ¹⁸F-FDG PET/CT imaging demonstrated a partial response [>30% reduction according to immune Response Evaluation Criteria in Solid Tumors (iRECIST) criteria]. This response was sustained and further confirmed in May 2024 after 8 months of treatment.

However, in October 2024, imaging revealed disease progression, leading to the discontinuation of osimertinib. A repeat liquid biopsy identified through NGS (same panel employed as the first liquid biopsy covering hotspots from EGFR, BRAF, HER2, KRAS and PIK3CA) the emergence of a C797S mutation in exon 20 with an allelic fraction of 1.5%. A novel EGFR Sanger sequencing (same technique as the previous ones) detected the pre-existing EGFR exon 19 deletion in addition to the novel C797S mutation. Finally, the Bio-Rad^® droplet digital polymerase chain reaction (ddPCR) copy number variation (CNV) assay for HER2 (reference sequence NM_004448.2:NM_001005862.1) and for MET amplification (using RPP30 used as a control gene of copy number analysis) performed did not identify CNV variation in HER2 nor MET amplification (ratio MET/RPP30 =1). Second-line treatment was initiated in November 2024, consisting of platinum-based chemotherapy combined with amivantamab, a bispecific monoclonal antibody targeting both EGFR and MET. A prophylaxis combining doxycycline and skin moisturizing was also introduced. The patient well tolerated the treatment except of grade 2 skin toxicity on the scalp and chest dose management in spite of the prophylaxis. No infusion related reactions (IRRs) occurred. The ¹⁸F-FDG PET/CT imaging 3 months later, on March 2025, depicted an almost metabolic response. Later on, the cutaneous toxicity progressed, with the appearance of multiple erosive pustular lesions coalescing into superficial necrotic areas, resulting in extensive erosions of the scalp, face, and thorax, associated with exuberant granulation tissue. He was clinically diagnosed with a grade 3 pustular reaction (see Figure 2). The patient was subsequently hospitalized in the dermatology department for 3 weeks and treated with topical therapy, including mechanical debridement, topical clobetasol and tulle gras dressings, in combination with low-dose oral isotretinoin, leading to progressive healing of the lesions (see Figure 3). Amivantamab was discontinued on July 2025 with only the pursuit of pemetrexed maintenance as monotherapy. The ¹⁸F-FDG PET/CT imaging on October 2025 confirmed the deep and prolonged complete response.

Figure 2 Erosive pustular dermatosis of the scalp (April 2025). This image is published with the patient’s consent.

Figure 3 Complete healing and hair recovery of the scalp after amivantamab discontinuation (October 2025). This image is published with the patient’s consent.

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Discussion

To the best of our knowledge, this is the first reported case of a patient with lymph node and bone metastatic lung adenocarcinoma harboring an uncommon EGFR T751_I759delinsAsp alteration in exon 19, who demonstrated a 1-year response to osimertinib as a first-line treatment followed by a deep and durable response to combination amivantamab and chemotherapy as second-line.

The EGFR is a highly conserved transmembrane receptor comprising an extracellular N-terminal domain that binds the epidermal growth factor (EGF), a transmembrane domain, a juxtamembrane segment, and an intracellular kinase domain. The kinase domain exhibits a bilobal structure with two distinct lobes: the N-lobe and the C-lobe. The N-lobe primarily consists of β-strands and the αC helix, the conformation of which regulates the kinase’s activity (12). Classical EGFR del19 mutations typically occur between amino acids (AA) 746 and 750, encoding the region between the β3 strand and the αC helix of the kinase domain. This alteration stabilizes the kinase domain in its active conformation, thereby altering its structural configuration and impacting the efficacy of EGFR-targeted therapies (5). In rare instances, EGFR del19 mutations occur within the αC helix, involving AA 753 to 761, with exon 20 beginning at AA 762. These less common EGFR del19 mutations also stabilize the active kinase conformation, but structural changes in the kinase domain may influence the binding affinity for targeted therapies. Genetic profiling remains essential for identifying EGFR alterations. While NGS is the cornerstone of molecular analysis for EGFR mutations (13), its utility is often constrained by the limitations of routinely available gene panels. This can lead to false-negative results and missed opportunities to prescribe EGFR TKIs that could provide clinical benefits. A recent case report by Chang et al., described a 67-year-old non-smoking woman with a rare EGFR T751_I759delinsN mutation. Initial EGFR sequencing in 2013, using a polymerase chain reaction (PCR)-based method, revealed no detectable alterations. Seven years later, in 2020, NGS performed on a newly resected brain metastasis identified the EGFR T751_I759delinsN mutation. Treatment with afatinib (a second-generation EGFR TKI) and osimertinib was subsequently initiated, though the patient died 7 months later (May 2022) (14). This report underscores the necessity of advanced molecular analyses to detect rare EGFR alterations. EGFR lung cancer population had a favorable prognosis due to target therapies, that why in case of clinical features such no-smoker and young age which highly suggested EGFR mutation, a close collaboration between the oncologist and the molecular biologist are recommended. Specialized centers equipped with advanced technical platforms are essential for detecting these uncommon alterations. Hybrid capture-based comprehensive genomic profiling (CGP) with full sequencing coverage has demonstrated its reliability in identifying uncommon EGFR del19 mutations (15,16). In our case, Sanger sequencing was employed, with proven validity for assessing EGFR status (17,18).

In this case, the patient exhibited a sustained 1-year response to osimertinib as a first-line treatment. A similar case report by Li et al. described a patient with lung carcinoma harboring two rare EGFR alterations (750_758del and I759S) at diagnosis, accompanied by tumor protein p53 (TP53) and AKT1 mutations. Initial treatment with icotinib (a first-generation EGFR TKI) resulted in a PFS of 7 months. Subsequently, erlotinib (another first-generation EGFR TKI) provided a 5-month response before brain metastases developed. At this stage, NGS identified an acquired T751_I759delinsS mutation, while the TP53 and AKT1 alterations persisted. Osimertinib (a third-generation EGFR TKI) was introduced, achieving the best response with disease control for 25 months before the patient’s death. This case hypothesized that rare del19 mutations may respond more favorably to third-generation EGFR TKIs (19). Data regarding the therapeutic response to EGFR TKIs in the context of uncommon del19 mutations are still debated in NSCLC (20-22), as responses may vary based on the specific nature of the del19 alteration, which could modulate the receptor’s affinity for EGFR TKIs. Wang et al. conducted a pooled analysis of 196 patients with uncommon EGFR-mutant lung cancer treated with either afatinib (n=125) or osimertinib (n=71) (23). After propensity score matching, the overall objective response was marginally higher in the afatinib group (60.6% vs. 50.3%, P=0.610). Afatinib conferred a PFS benefit (11 vs. 7 months, P=0.039). Both afatinib and osimertinib exhibit favorable tumor responses in NSCLC patients harboring uncommon EGFR mutations. The phase II KCSG-LU15-09 trial reported an 83% response rate at 6 weeks, with a median duration of response of 11.2 months (95% CI: 7.7–14.7 months) in 37 NSCLC patients with EGFR mutations other than exon 19 deletion, L858R, T790M, or exon 20 insertion, treated with osimertinib (24). The median PFS was 8.2 months (95% CI: 5.9–10.5 months). A study by Grant et al., published in 2023, included 200 patients, 36 of whom harbored the uncommon L747_A750 del19 mutation. Their findings demonstrated shorter PFS and overall survival (OS) compared to those with classical E746_A750 del19 mutations (20). These results highlight that the specific EGFR del19 mutation profile affects sensitivity to targeted therapies. Conversely, Xu et al. analyzed a cohort of 38 patients with exon 19 deletions involving the αC helix (AA P747 to P753). No statistically significant differences in PFS were observed between those with uncommon and classical EGFR del19 mutations treated with first-generation EGFR TKIs (gefitinib, erlotinib, or icotinib) (22). Similarly, Nishino et al. reported in 2024 on 449 patients, including 44 with uncommon EGFR del19 mutations and 90 with classical deletions, all treated with erlotinib in combination with ramucirumab [a vascular endothelial growth factor (VEGF)-targeting antibody]. Interestingly, this study found a longer PFS among patients with uncommon EGFR del19 mutations (21). However, none of these prior studies described cases involving the rare EGFR T751_I759delinsAsp mutation in exon 19. These conflicting results may be partly explained by variations in the EGFR TKIs used across studies and by differences in the grouping of distinct EGFR del19 patterns. It is well established that a single nucleotide polymorphism can alter a protein’s conformation (25), thereby influencing its binding affinity for targeted therapies. This suggests that each EGFR del19 variant may exhibit a distinct response to targeted therapies, emphasizing the need for a more granular investigation of these patterns. Another critical aspect is the impact of co-mutations in EGFR-mutant NSCLC. Among these, TP53 is the most frequently observed molecular alteration and is associated with poor prognosis (26). Studies have shown that EGFR-mutant NSCLC is characterized by a higher prevalence of TP53 mutations, which further correlates with worse outcomes (26). Beyond the specific EGFR del19 mutation pattern, co-mutations play a pivotal role in modulating sensitivity to targeted therapies, adding complexity to the mechanisms underlying responses to anti-EGFR treatments (27).

Acquired resistance mechanisms to osimertinib are classified according to biological criterias: on-target resistance, off-target resistance or histological transformation. Off-target resistance mechanisms are led by the activation of an alternative molecular pathway able to fuel cancer cell survival and proliferation despite EGFR inhibition, such as hepatocyte growth factor (HGF)/MET axis activation (28). Amivantamab, a bispecific anti-EGFR/MET antibody, in combination with chemotherapy is a therapeutic option after progression under osimertinib as reported in MARIPOSA-2 trial (9). However, this study included patients with classical EGFR alterations (del19, L858R exon 21). The cohort C of CHRISALYS-2 enrolled 105 patients with atypical EGFR mutations treated with the combination of amivantamab plus lazertinib (TKI against EGFR) and reported a 19.5-month and a 7.8-month median PFS in treatment-naïve group and pre-treated patients, respectively, suggesting also a meaningful activity even in case of atypical EGFR mutation (11). Our patient demonstrated more than the median PFS reported in the literature of amivantamab in second line setting even with its discontinuation, associated with a complete metabolic response yet not reported in any patients in the CHRISALYS-2 cohort C (11). Also, no patient of this trial had the same EGFR alteration as our patient. The biological rationale for amivantamab efficacy in our patient may account for several hypotheses. Our patient demonstrated an on-target resistance to osimertinib (C797S mutation), with no co-alteration detected within the molecular panel. More likely, the addition of chemotherapy provides a cytotoxic activity regardless of mechanism of resistance to osimertinib, with amivantamab overcoming on-target resistance by his extracellularly binding to EGFR and thus bypassing intracellular resistance mutation. In our case, the complete response was observed at first radiological examination after amivantamab, carboplatin and pemetrexed initiation and during pemetrexed maintenance as monotherapy. The historical PARAMOUNT trial brought pemetrexed maintenance as a standard of care in extensive NSCLC (29), which is still a cornerstone in metastatic NSCLC management in combination with immune-checkpoint inhibitor (ICI) or bispecific antibody (30,31). The PAPILLON trial evaluating chemotherapy in combination with amivantamab in first line setting of extensive NSCLC harboring EGFR exon 20 mutation reported a mean administration of 13.5 pemetrexed courses and 14 amivantamab courses suggesting a benefit of the doublet maintenance therapy (31). Pemetrexed as monotherapy could also be effective in case of limiting toxicity of amivantamab. Besse et al. conducted a supplementary analysis among the patients included in the CHRISALYS-2 trial with immunohistochemistry (IHC) on tumor specimen and ctDNA NGS. Patients presenting a MET expression (defined as 3+ staining on ≥25% of tumor cells) had a significant prolonged PFS and objective response rate (ORR) compared to those without MET expression. However, NGS failed to identify a predictive biomarker of response (32). In contrast with literature data, despite no MET amplification, the patient had a deep and durable response to amivantamab.

Amivantamab toxicity is deeply linked to its mechanism of action. Main toxicities are IRR, pneumonitis, diarrhea and skin rash. Cutaneous toxicity is reported in almost half of the patients treated with amivantamab, however grade 3 toxicity occurs in less than 10% of the cases (9). The EGFR gene is highly expressed in keratinocytes, dendritic cells, connective tissue cells, as well as in skin adnexal structures. Its inhibition leads to disruption of the skin barrier, damage to hair follicles, activation of host immune response and the formation of granulation tissue. Mostly, acneiform rash and modification of hair growth is reported. Some patients may develop skin abrasions on the scalp (33). Few cases have been reported in the literature. A series of three cases has been described by George et al. of erosive pustular dermatosis (EPD) (34). All the patients received amivantamab for few months before experiencing cutaneous toxicity. Skin care, local steroids and antibiotics lead to an improvement of the symptoms. Another case of a 67-year-old patient harboring an EGFR mutant metastatic NSCLC presented an EPD after 5 months of amivantamab therapy. She discontinued amivantamab following the high grade toxicity and still was in remission 6 months after (35). Those data suggest that the skin toxicity is delayed contrasting the IRR. Also, high grade cutaneous toxicity could possibly be associated with long term response. Cetuximab, a monoclonal antibody targeting EGFR widely used in oncology, has been well known for its safety profile and skin toxicity. Data from the literature suggests that skin toxicity from EGFR inhibition could be correlated with efficacy as published in the EVEREST trial which evaluated dose escalation of cetuximab. Dose escalation was both linked to improve toxicity and response rate (36). Available data on necitumumab, a monoclonal antibody targeting EGFR, also supports a relationship between efficacy and toxicity with those agent (37).

Conclusions

To our knowledge, this is the first case report of a young patient with metastatic EGFR-mutant NSCLC harboring a T751_I759delinsAsp alteration in exon 19, who exhibited a 1-year response to osimertinib as first-line therapy followed by a durable response to amivantamab plus chemotherapy with a high-grade skin toxicity. This rare case underscores the variability in responses to anti-EGFR therapies linked to specific EGFR del19 mutation patterns, also suggested that bispecific EGFR/MET antibody combined with chemotherapy is an interesting therapeutic option in uncommon EGFR alterations. The relationship between skin toxicity related to amivantamab and efficacy has to be solved. Collaboration between molecular biologists and oncologists is crucial to identifying rare alterations that may go undetected with routine analyses.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-aw-1222/rc

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-aw-1222/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-aw-1222/coif). The authors have no 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. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

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/.

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