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Open Access 08.02.2024 | short review

Rare oncogenic alterations in NSCLC—focus on atypical EGFR mutations

Invited short review

verfasst von: Yana Sharapova, PhD, Sonja Loges, MD, PhD, Melanie Janning, MD

Erschienen in: memo - Magazine of European Medical Oncology

Summary

In non-small cell lung cancer (NSCLC), mutations within the epidermal growth factor receptor (EGFR) gene are very common driver mutations. EGFR tyrosine kinase inhibitors (TKIs), have shown remarkable efficacy in patients with common classical EGFR mutations (L858R and exon 19 deletions). However, the landscape becomes intricate with atypical (also known as uncommon) EGFR mutations, comprising up to 30% of cases. This brief review provides an insight into recent studies, shedding light on the challenges and opportunities posed by uncommon mutations. The exploration encompasses clinical outcomes, treatment responses, and innovative approaches such as structure-based classifications, offering insights into the evolving paradigm of precision medicine for NSCLC patients with diverse EGFR mutations.
Hinweise

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In non-small cell lung cancer (NSCLC) mutations in the epidermal growth factor receptor (EGFR) gene are common driver mutations. In the metastatic setting, EGFR tyrosine kinase inhibitors (EGFR-TKIs) are generally more efficient than chemotherapy [1]. Comparative studies such as LUX-Lung 7, ARCHER and FLAURA have demonstrated better outcomes with second- and third-generation EGFR-TKIs (afatinib, dacomitinib and osimertinib) compared to first-generation EGFR-TKIs with median progression-free survival (mPFS) of 11.7, 14.7 and 18.9 months, respectively [24]. Despite missing comparative trials, osimertinib is considered the standard first-line option in the metastatic setting due to favourable outcomes and safety profile [1]. Improvements in detection methods have shown that so-called uncommon or atypical mutations can constitute up to 30% of the cases, including exon 20 insertions (ex20ins), major uncommon mutations (G719X, S768I, L861Q including compounds of those), exon 19 insertions (e.g. K745_E746insTPVAIK), exon 18 deletions and many others [5, 6]. However, most comparative studies only included the classical EGFR mutations L858R and exon 19 deletions, neglecting atypical mutations.
This short review aims to provide an overview of available clinical data for atypical EGFR mutations.

Exon 20 insertions

Insertions predominately occur between amino acids (AA)762 and AA775. With few exceptions (e.g. A763_Y764FQAE), patients with ex20ins generally exhibit poor response to first- and second-generation EGFR-TKIs [68]. Platinum-based chemotherapy has been the recommended treatment option [1]. Currently, amivantamab, a bispecific MET and EGFR antibody, is the only treatment approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) other than chemotherapy, based on data from the CHRYSALIS study [9]. Here, overall response rate (ORR) was 40% and mPFS was 8.3 months for patients who progressed after platinum-containing chemotherapy. Thirty-five percent of the patients experienced ≥ grade 3 adverse events (AE). Most common AEs (all grades) were rash (86%), paronychia (45%) mostly related to EGFR inhibition, and hypoalbuminaemia (27%) and peripheral oedema (18%) related to MET inhibition. Five patients (4%) were reported with interstitial lung disease [9].
The recent PAPILLON phase 3 study compared the combination of amivantamab plus chemotherapy with chemotherapy alone in advanced-stage, treatment-naive NSCLC patients. Median PFS was significantly longer with the amivantamab combination, 11.4 months vs. 6.7 months for chemotherapy alone (hazard ratio 0.4). However, 75% of the patients treated with the combination reported ≥ grade 3 AEs vs. 54% ≥ grade 3 AEs in the chemotherapy alone arm. The most common treatment-emergent AEs for the combination were neutropenia, paronychia, rash, anaemia, infusion-related reactions and hypoalbuminaemia. The rate of treatment discontinuation was also higher in the combination arm (24%) than in the chemotherapy alone arm (10%) [10]. While the combination of amivantamab plus chemotherapy may become the first-line standard of care for patients with ex20ins, side effects could become unpleasant and should be closely monitored and treated as soon as they appear.
Significant progress has also been made in development of ex20ins-specific EGFR-TKIs, with many currently under investigation in clinical trials. One example, sunvozertinib (DZD9008) showed an ORR of 61% (n = 59) in a phase II study conducted in China, including patients who progressed from chemo(immuno)therapy, with a promising safety profile. Grade ≥ 3 AEs were mostly elevated blood creatinine phosphokinase levels (18%) and diarrhoea (8%) [11]. However, another promising contender, mobocertinib, was recently withdrawn from the market because the confirmatory phase 3 study (EXCLAIM2) did not meet its primary endpoint, although it was initially granted accelerated approval by the FDA in 2021 [12]. The full data of this study have not been released yet. However, one might speculate that the overall lack of efficacy could be due to the high degree of heterogeneity of ex20ins. In this regard, insertions into the regulatory αC-helix domain (AA762-AA766) and those in the loop following it may be considered distinct subgroups. Furthermore, loop insertions can be divided into near-loop (AA767–AA772) and far-loop (AA773–775) insertion leading to potentially different responses with specific TKIs [5, 13].

Major uncommon EGFR mutations

The first landmark publication demonstrating efficacy of afatinib in patients with atypical EGFR mutations was published by Yang and colleagues in 2015 [8]. In a post hoc analysis, the authors investigated the outcomes of patients with atypical EGFR mutations from LUX Lung studies 2, 3 and 6. Of the 100 identified patients, 25 had received chemotherapy, and 75 patients had been treated with afatinib. Atypical EGFR mutations were categorized into three groups: ex20ins, de novo T790M mutations and a third group that included point mutations and duplications, or both, in exons 18–21. The latter group mainly consisted of L861Q, G719X and S768I mutations, either individually or in combination with each other or classical EGFR mutations. This set of mutations is now often referred to as uncommon or major uncommon EGFR mutations. While this study revealed the general ineffectiveness of afatinib in ex20ins (mPFS 2.7 months) and T790M de novo mutations (mPFS 2.9 months), it notably reported a mPFS of 10.7 months for afatinib in patients with major uncommon mutations, compared to 8.5 months for platinum-based chemotherapy (Table 1). This initial study has been expanded over time and was last updated in 2022, now including data from over 1000 patients taken from clinical trials, early access and compassionate use programs, and case reports from the literature [14]. In the EGFR-TKI-naive cohort (n = 587 patients), the time to treatment failure (TTF) was 10.7 months and ORR was 49.8% (Table 1). Of these mutations, 52% (305/587) were major uncommon mutations, 23% were ex20ins, and 10% were T790M mutations. For major uncommon mutations (G719X, L861Q and S768I including compounds of such) mTTF was 12.6 months and 10.7 months for other atypical mutations (excluding T790M and ex20ins). The efficacy of afatinib in atypical EGFR mutations was also confirmed by other studies, some of which are summarized in Table 1.
Table 1
Overview of selected studies investigating outcomes of atypical EGFR mutations
Reference
Region
Type of study
Patients
EGFR-TKI
Mutations
n
Outcome in months (95% CI)
Overall response %, (95% CI)
KCSG-LU15-09, Cho et al., 2020 [15]
Korea
Prospective, single arm, multicentre
EGFR-TKI naive
Osimertinib
Total cohort
36
mPFS:
8.2 (5.9–10.5)
50 (33–67)
G719X (incl. compounds)
19
8.2 (6.2–10.2)
53 (28–77)
L861Q (incl. compounds)
9
15.2 (1.3–29.1)
78 (44–100)
S768I (incl. compounds)
8
12.3 (0–28.8)
38 (0–81)
Villaruz et al., 2023 [17]
USA
Prospective, single arm, multicentre
EGFR-TKI naive
Osimertinib
Total cohort (G719X, S768I and L861Q)
17
mPFS:
10.5 (5.0–15.2)
47 (23–72)
UNICORN, Okuma et al., [16]
Japan
Prospective, multicentre
1L EGFR-TKI
Osimertinib
Total cohort (G719X, S768I and L861Q)
40
mPFS:
9.4 (3.7–15.2)
Solitary: 45.5 (26.9–65.3)
compound: 66.7 (43.7–83.7)
Pu et al., 2023 [20]
China
Single-centre, ambispective
1L EGFR-TKI
Dacomitinib
Total cohort (mostly L861Q, G719X, S768I and compounds of these)
16
mPFS:
14.0 (4.3–23.7)
68.8 (41.3–89.0)
Yang et al., 2022 [14]
Global
Retrospective (data from Lux Lung studies 2, 3, 6, EAP, CUP and case reports)
EGFR-TKI naive
Afatinib
Overall
587
mTTF:
10.7 (9.7–11.5)
49.8 (NR)
Uncommon mutations
305
12.6 (11.5–15.9)
59.0 (NR)
G719X (incl. compounds)
194
14.2 (11.5–17.0)
61.3 (NR)
L861Q (incl. compounds)
109
11.5 (10.5–13.8)
57.7 (NR)
S768I (incl. compounds)
61
15.9 (11.5–20.5)
71.4 (NR)
Others (excl. exon 20ins and T790M)
88
10.7 (7.0–12.0)
63.9 (NR)
E709X
15
11.4 (3.8–19.3)
84.6 (NR)
L747X
18
14.7 (9.0–19.8)
80.0 (NR)
Chang et al., 2023 [21]
Taiwan
Retrospective, multicentre
1L EGFR-TKI
Afatinib
Erlotinib/gefitinib
Uncommon mutations (G719X, S768I, L861Q, excl. compounds)
24
mPFS:
9.9 (2.7–17.1)
58.3 (NR)
Uncommon mutations (G719X, S768I, L861Q, excl. compounds)
48
8.3 (4.2–12.5)
31.3 (NR)
Hsu et al., 2023 [22]
Taiwan
Retrospective, multicentre
1L EGFR-TKI
Afatinib
Uncommon mutations (G719X, S768I, L861Q, incl. compounds)
90
mPFS:
17.3 (12.1–22.5)
63.3 (NR)
G719X alone
37
24.9 (12.1–32.6)
NR
S768I alone
12
12.3 (9.7–14.9)
NR
L861Q alone
28
15.6 (7.2–22.5)
NR
UNICORN, Bar et al., 2023 [23]
USA, Europe, Israel
Retrospective, multicentre
EGFR-TKI naive
Osimertinib
Total cohort
60
mPFS:
9.5 (8.5–17.4)
61 (74–73)
Uncommon only
44
8.6 (7.3–13.5)
60 (45–74)
Uncommon compounds with L858R, ex19del, T790M
16
30 (12.7–NE)
61 (35–82)
L861Q (incl. compounds)
12
16 (11–NE)
80 (49–94)
L861Q only
11
15.7 (8.9–18.8)
78 (45–94)
G719X (incl. compounds)
18
8.8 (7.9–NE)
47 (26–69)
G719X only
12
8.6 (6.9–NE)
53 (30–75)
Ji et al., 2023 [24]
USA
Retrospective, multicentre
1L EGFR-TKI
Osimertinib
Total cohort
20
mTTD:
10.7 (3.2–18.1)
41.2 (18.4–67.1)
Excl. ex20ins
NR
14.2 (3.7–24.7)
46.7 (21.3–73.4)
S768I, L861Q, G719X
15
17.2 (5.5–27.1)
38.4 (13.9–68.4)
G719X
4
5.8 (1.1–15.0)
33.3 (8.0–90.6)
L861Q
10
19.3 (13.2–25.4)
40 (12.2–90.6)
ARTICUNO, Pizzutilo et al., 2022 [25]
Italy
Retrospective, multicentre
EGFR-TKI naive
Osimertinib
Total cohort
57
mPFS:
11.00 (7–18)
49 (34–64)
G719X
19
11 (5–15)
50 (26–74)
L861X
15
9 (5–14)
50 (23–77)
S768I
11
17 (7–24)
55 (23–83)
Janning et al., 2022 [6]
Germany
Retrospective, multicentre
1L EGFR-TKI
1st–3rd gen EGFR-TKIs
Uncommon mutations (E709X, G719X, S768I, L861Q and incl. compounds with other UC mutations or classical)
41
mPFS:
8.0 (2.5–13.6)
NR
Very rare uncommon EGFR mutations
39
6.7 (5.3–8.2)
NR
UpSwinG, Popat et al., 2022 [26]
Europe & Asia
Retrospective, multicentre
EGFR-TKI naive (1st or 2nd line)
43% 1st gen TKIa, 54% 2nd gen TKIb, 3% 3rd gen TKISc
Total cohort
246
mTTF:
9.9 (7.8–11.6)
43.3 (NR)
Any
G719X, S768I, L861Q
179
11.3 (9.2–14.3)
49.1 (NR)
1st gen TKI
G719X, S768I, L861Q
80
9.8 (7.6–12.9)
47.3 (NR)
2nd gen TKIb
G719X, S768I, L861Q
94
14.3 (10.5–17.8)
50.6 (NR)
Robichaux et al., 2022 [5]
Global
Retrospective, regrouped data from Yang et al., 2020
EGFR-TKI naive
Afatinib
Classical like (mostly compound mutations with a classical partner and L861Q, incl. few very rare such as L833V, D761Y)
58
mTTF:
10.0 (NR)
NR
T790M like (mostly compounds with T790M)
68
5.6 (NR)
NR
PACC (mostly G719X, S768I, E709X)
156
17.1 (NR)
NR
 
USA
Retrospective, MD Anderson GEMINI database & Mofitt Cancer Center database
PACC mutations
1st gen
17
10.0
NR
2nd gen
25
21.7
NR
3rd gen
11
4.1
NR
EGFR-TKI epidermal growth factor receptor – tyrosin kinase inhibitor, 1L first line, EAP early access program, CUP compassionate use programealy, CI confidence intervall, mPFS median progression free survival, mOS median overall survival, mTTF median time to treatment failure, mTTD median time to treatment discontinuation, NR not reported, NE not estimable, excl. exlcuding, incl. including, gen generation, PACC P loop and αC-helix compressing, UC uncommon
agefitinib or erlotinib
bafatinib
cosimertinib
The Korean multicentre, phase II KCSG-LU15-09 study evaluated the efficacy of osimertinib in patients with mostly major uncommon EGFR mutations. Thirty-six EGFR-TKI-naive patients with recurrent or metastatic NSCLC were included. The overall mPFS was 8.2 months, and the ORR was reported to be 50% (Table 1; [15]). These data were corroborated by the prospective UNICORN study conducted in Japan (n = 40 patients, mPFS 9.4 months, first-line EGFR-TKI [16]), a prospective study from the USA (n = 17 patients, mPFS 10.5 months, ORR 47%, EGFR-TKI-naive [17]) and other retrospective studies summarized in Table 1.
Despite slight variations in patient cohorts and reported outcome parameters, together these data provide evidence for the efficacy of EGFR-TKI in patients with major uncommon EGFR mutations. It is noteworthy that the efficacy is comparatively lower than that observed for classical EGFR mutations. Both afatinib and osimertinib are now recommend as preferred first-line treatment options by international guidelines for patients with major uncommon EGFR mutations [1, 18].

Other uncommon EGFR mutations and future directions

A recent retrospective, multicentre analysis from the national Network Genomics Medicine in Germany, including 856 patients and 276 different atypical EGFR aberrations (excluding T790M mutations), highlighted the fact that next to ex20ins and major uncommon EGFR mutations, the very heterogenous group of very rare atypical EGFR mutations was the largest group (45%, 382/856) [6]. This group included exon 18 deletions, exon 19 insertions, different compound mutations not included in the group of major uncommon mutations, and a very large group of very rare point mutations (26.1% of the total cohort, 223/856). While confirming the benefit of EGFR-TKIs in major uncommon EGFR mutations, this study surprisingly also reported a numerical benefit for EGFR-TKIs compared to chemotherapy for very rare EGFR mutations in the first-line setting: mPFS was 6.7 months for EGFR-TKIs compared to 5.5 months for chemotherapy. However, this difference was not statistically significant, but detailed analyses of subgroups and individual mutations in this large group of very rare atypical EGFR mutations revealed high variability in responses to different EGFR-TKIs.
These data raise the question of how we can accumulate more evidence for this large group of patients with very rare atypical EGFR mutations, especially since the frequency of each individual very rare mutation is most likely far too low for evaluation in standard clinical trials. Is there a better way to classify atypical EGFR mutations than simply by their location in the gene or by their frequency?
In this context, Robichaux and colleagues investigated a structure-based approach [5]. Employing a combination of in vitro sensitivity analyses and in silico modelling, they identified four subgroups characterized by distinct structural features: (1) Classical-like EGFR mutations, situated distant from the ATP binding pocket, with sensitivity to first-, second- and third-generation EGFR-TKI. (2) So-called PACC (P-loop and alpha-helix compressing) mutations, located at the interior face of the ATP binding pocket with sensitivity primarily to second-generation EGFR-TKI. (3) Exon20 loop insertions and (4) T790M-like mutations with increased affinity to ATP compared to classical EGFR mutations. They validated their hypothesis regarding PACC mutations by comparing time to treatment failure (mTTF) of first-, second- and third-generation EGFR-TKIs in patients with PACC mutations in a retrospective analysis. Their results demonstrated better efficacy of second-generation EGFR-TKIs (mostly afatinib), with an mTTF of 21.7 months (n = 25). In contrast, mTTF for first-generation EGFR-TKI was 10.0 months (n = 17), and only 4.1 months for third-generation EGFR-TKI (n = 11; Table 1).
S768I and G719X are considered PACC mutations according to Robichaux’s classification, and patients with these mutations exhibited more favourable outcomes than with L861Q in afatinib studies highlighted in Table 1. Conversely, L861Q is considered a classical-like mutation, and patients with this mutation tend to have better outcomes than those with S768I and G719X mutations in most osimertinib studies (Table 1). This observation may provide additional support for Robichaux’s classification.
While this strongly indicates that structure-based approaches may enhance a better classification and subsequent treatment of patients with rare EGFR mutations, some questions remain unanswered. For instance, the precise criteria for classifying a mutation into one of the four groups lacks clarity. Consequently, the course of action for mutations not yet classified by Robichaux and colleagues remains uncertain. Although this approach does not yet present a ready-to-use solution for routine clinical oncology practice, it undeniably provides a promising initial strategy that warrants further development. The dataset can serve as a valuable resource by experts in molecular tumour boards aiding clinical decisions making.
In summary, recent data substantiate the activity for afatinib and osimertinib, particularly in major uncommon EGFR mutations, albeit with overall responses lower than what was observed for classical EGFR mutations. This information has been incorporated into clinical recommendations and guidelines [1, 18]. Amivantamab in combination with chemotherapy may become the first-line standard of care treatment for ex20ins, but toxicities are high. Other atypical EGFR mutations should be discussed in molecular tumour boards on a case-by-case basis. Structure-based approaches, estimated binding energies and in vitro sensitivities as elucidated by Robichaux and other researchers [5, 19] could be used in molecular tumour boards for clinical decision making. Moreover, these approaches may contribute to generating more robust evidence for rare variants of driver mutations even beyond EGFR mutations in the future.

Conflict of interest

S. Loges: Advisory role for Lilly, Sanofi, BerGenBio, Novartis, Boehringer Ingelheim BMS, Roche, AstraZeneca, MSD, Merck, Sanofi-Aventis, Janssen, Takeda, Pfizer, Amgen, Bayer, Medac, Daiichi-Sankyo; honoraria and travel costs from Lilly, Sanofi, BerGenBio, Novartis, Boehringer Ingelheim, BMS, Roche, AstraZeneca, MSD, Merck, Sanofi-Aventis, Janssen, Takeda, Pfizer, Amgen, Bayer, Medac, Daiichi-Sankyo; research grants (to institution) from Roche, BerGenBio, Lilly, ADC Therapeutics, Daiichi-Sankyo. M. Janning: honoraria and/or advisory board from Roche, Amgen, AstraZeneca, Novartis, Takeda and travel support from AstraZeneca. Y. Sharapova declares that she has no competing interests.
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Literatur
1.
Zurück zum Zitat Passaro A, Leighl N, Blackhall F, et al. ESMO expert consensus statements on the management of EGFR mutant non-small-cell lung cancer. Ann Oncol. 2022;33:466–87. CrossRefPubMed Passaro A, Leighl N, Blackhall F, et al. ESMO expert consensus statements on the management of EGFR mutant non-small-cell lung cancer. Ann Oncol. 2022;33:466–87. CrossRefPubMed
2.
Zurück zum Zitat Park K, Tan E‑H, O’Byrne K, et al. Afatinib versus gefitinib as first-line treatment of patients with EGFR mutation-positive non-small-cell lung cancer (LUX-Lung 7): a phase 2B, open-label, randomised controlled trial. Lancet Oncol. 2016;17:577–89. CrossRefPubMed Park K, Tan E‑H, O’Byrne K, et al. Afatinib versus gefitinib as first-line treatment of patients with EGFR mutation-positive non-small-cell lung cancer (LUX-Lung 7): a phase 2B, open-label, randomised controlled trial. Lancet Oncol. 2016;17:577–89. CrossRefPubMed
3.
Zurück zum Zitat Wu Y‑L, Cheng Y, Zhou X, et al. Dacomitinib versus gefitinib as first-line treatment for patients with EGFR mutation-positive non-small-cell lung cancer (ARCHER 1050): a randomised, open-label, phase 3 trial. Lancet Oncol. 2017;18:1454–66. CrossRefPubMed Wu Y‑L, Cheng Y, Zhou X, et al. Dacomitinib versus gefitinib as first-line treatment for patients with EGFR mutation-positive non-small-cell lung cancer (ARCHER 1050): a randomised, open-label, phase 3 trial. Lancet Oncol. 2017;18:1454–66. CrossRefPubMed
4.
Zurück zum Zitat Soria JC, Ohe Y, Vansteenkiste J, et al. Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N Engl J Med. 2018;378:113–25. CrossRefPubMed Soria JC, Ohe Y, Vansteenkiste J, et al. Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N Engl J Med. 2018;378:113–25. CrossRefPubMed
6.
Zurück zum Zitat Janning M, Suptitz J, Albers-Leischner C, et al. Treatment outcome of atypical EGFR mutations in the German National Network Genomic Medicine Lung Cancer (nNGM). Ann Oncol. 2022;. Janning M, Suptitz J, Albers-Leischner C, et al. Treatment outcome of atypical EGFR mutations in the German National Network Genomic Medicine Lung Cancer (nNGM). Ann Oncol. 2022;.
7.
Zurück zum Zitat Friedlaender A, Subbiah V, Russo A, et al. EGFR and HER2 exon 20 insertions in solid tumours: from biology to treatment. Nat Rev Clin Oncol. 2021;. Friedlaender A, Subbiah V, Russo A, et al. EGFR and HER2 exon 20 insertions in solid tumours: from biology to treatment. Nat Rev Clin Oncol. 2021;.
8.
Zurück zum Zitat Yang JC, Sequist LV, Geater SL, et al. Clinical activity of afatinib in patients with advanced non-small-cell lung cancer harbouring uncommon EGFR mutations: a combined post-hoc analysis of LUX-Lung 2, LUX-Lung 3, and LUX-Lung 6. Lancet Oncol. 2015;16:830–8. CrossRefPubMed Yang JC, Sequist LV, Geater SL, et al. Clinical activity of afatinib in patients with advanced non-small-cell lung cancer harbouring uncommon EGFR mutations: a combined post-hoc analysis of LUX-Lung 2, LUX-Lung 3, and LUX-Lung 6. Lancet Oncol. 2015;16:830–8. CrossRefPubMed
9.
Zurück zum Zitat 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. CrossRefPubMedPubMedCentral 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. CrossRefPubMedPubMedCentral
10.
Zurück zum Zitat 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. CrossRefPubMed 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. CrossRefPubMed
11.
Zurück zum Zitat Wang M, Fan Y, Sun M, et al. Sunvozertinib for the treatment of NSCLC with EGFR Exon20 insertion mutations: The first pivotal study results. JCO. 2023;41:9002–9002. CrossRef Wang M, Fan Y, Sun M, et al. Sunvozertinib for the treatment of NSCLC with EGFR Exon20 insertion mutations: The first pivotal study results. JCO. 2023;41:9002–9002. CrossRef
13.
Zurück zum Zitat Elamin YY, Robichaux JP, Carter BW, et al. Poziotinib for EGFR exon 20-mutant NSCLC: Clinical efficacy, resistance mechanisms, and impact of insertion location on drug sensitivity. Cancer Cell. 2022;40(e756):754–67. CrossRefPubMedPubMedCentral Elamin YY, Robichaux JP, Carter BW, et al. Poziotinib for EGFR exon 20-mutant NSCLC: Clinical efficacy, resistance mechanisms, and impact of insertion location on drug sensitivity. Cancer Cell. 2022;40(e756):754–67. CrossRefPubMedPubMedCentral
14.
Zurück zum Zitat Yang JC, Schuler M, Popat S, et al. Afatinib for the Treatment of Non-Small Cell Lung Cancer Harboring Uncommon EGFR Mutations: An Updated Database of 1023 Cases Brief Report. Front Oncol. 2022;12:834704. CrossRefPubMedPubMedCentral Yang JC, Schuler M, Popat S, et al. Afatinib for the Treatment of Non-Small Cell Lung Cancer Harboring Uncommon EGFR Mutations: An Updated Database of 1023 Cases Brief Report. Front Oncol. 2022;12:834704. CrossRefPubMedPubMedCentral
15.
Zurück zum Zitat Cho JH, Lim SH, An HJ, et al. Osimertinib for Patients With Non-Small-Cell Lung Cancer Harboring Uncommon EGFR Mutations: A Multicenter, Open-Label, Phase II Trial (KCSG-LU15-09). J Clin Oncol. 2020;38:488–95. CrossRefPubMed Cho JH, Lim SH, An HJ, et al. Osimertinib for Patients With Non-Small-Cell Lung Cancer Harboring Uncommon EGFR Mutations: A Multicenter, Open-Label, Phase II Trial (KCSG-LU15-09). J Clin Oncol. 2020;38:488–95. CrossRefPubMed
16.
Zurück zum Zitat Okuma Y, Kubota K, Shimokawa M, et al. First-Line Osimertinib for Previously Untreated Patients With NSCLC and Uncommon EGFR Mutations: The UNICORN Phase 2 Nonrandomized Clinical Trial. JAMA Oncol. 2023;. Okuma Y, Kubota K, Shimokawa M, et al. First-Line Osimertinib for Previously Untreated Patients With NSCLC and Uncommon EGFR Mutations: The UNICORN Phase 2 Nonrandomized Clinical Trial. JAMA Oncol. 2023;.
17.
Zurück zum Zitat Villaruz LC, Wang X, Bertino EM, et al. A single-arm, multicenter, phase II trial of osimertinib in patients with epidermal growth factor receptor exon 18 G719X, exon 20 S768I, or exon 21 L861Q mutations. Esmo Open. 2023;8:101183. CrossRefPubMedPubMedCentral Villaruz LC, Wang X, Bertino EM, et al. A single-arm, multicenter, phase II trial of osimertinib in patients with epidermal growth factor receptor exon 18 G719X, exon 20 S768I, or exon 21 L861Q mutations. Esmo Open. 2023;8:101183. CrossRefPubMedPubMedCentral
18.
Zurück zum Zitat National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology - Non-Small Cell lung Cancer. Version 1.2024: M18 (nccn.org) National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology - Non-Small Cell lung Cancer. Version 1.2024: M18 (nccn.org)
19.
Zurück zum Zitat Xu H, Yang G, Liu R, et al. EGFR uncommon alterations in advanced non-small cell lung cancer and structural insights into sensitivity to diverse tyrosine kinase inhibitors. Front Pharmacol. 2022;13:976731. CrossRefPubMedPubMedCentral Xu H, Yang G, Liu R, et al. EGFR uncommon alterations in advanced non-small cell lung cancer and structural insights into sensitivity to diverse tyrosine kinase inhibitors. Front Pharmacol. 2022;13:976731. CrossRefPubMedPubMedCentral
20.
Zurück zum Zitat Pu X, Zhou Y, Kong Y, et al. Efficacy and safety of dacomitinib in treatment-naive patients with advanced NSCLC harboring uncommon EGFR mutation: an ambispective cohort study. Bmc Cancer. 2023;23:982. CrossRefPubMedPubMedCentral Pu X, Zhou Y, Kong Y, et al. Efficacy and safety of dacomitinib in treatment-naive patients with advanced NSCLC harboring uncommon EGFR mutation: an ambispective cohort study. Bmc Cancer. 2023;23:982. CrossRefPubMedPubMedCentral
21.
Zurück zum Zitat Chang JW, Huang CY, Fang YF, et al. Epidermal growth factor receptor tyrosine kinase inhibitors for non-small cell lung cancer harboring uncommon EGFR mutations: Real-world data from Taiwan. Thorac Cancer. 2023;14:12–23. CrossRefPubMed Chang JW, Huang CY, Fang YF, et al. Epidermal growth factor receptor tyrosine kinase inhibitors for non-small cell lung cancer harboring uncommon EGFR mutations: Real-world data from Taiwan. Thorac Cancer. 2023;14:12–23. CrossRefPubMed
22.
Zurück zum Zitat Hsu PC, Lee SH, Chiu LC, et al. Afatinib in Untreated Stage IIIB/IV Lung Adenocarcinoma with Major Uncommon Epidermal Growth Factor Receptor (EGFR) Mutations (G719X/L861Q/S768I): A Multicenter Observational Study in Taiwan. Target Oncol. 2023;18:195–207. CrossRefPubMedPubMedCentral Hsu PC, Lee SH, Chiu LC, et al. Afatinib in Untreated Stage IIIB/IV Lung Adenocarcinoma with Major Uncommon Epidermal Growth Factor Receptor (EGFR) Mutations (G719X/L861Q/S768I): A Multicenter Observational Study in Taiwan. Target Oncol. 2023;18:195–207. CrossRefPubMedPubMedCentral
23.
Zurück zum Zitat Bar J, Peled N, Schokrpur S, et al. UNcommon EGFR Mutations: International Case Series on Efficacy of Osimertinib in Real-Life Practice in First-LiNe Setting (UNICORN). J Thorac Oncol. 2023;18:169–80. CrossRefPubMed Bar J, Peled N, Schokrpur S, et al. UNcommon EGFR Mutations: International Case Series on Efficacy of Osimertinib in Real-Life Practice in First-LiNe Setting (UNICORN). J Thorac Oncol. 2023;18:169–80. CrossRefPubMed
24.
Zurück zum Zitat Ji J, Aredo JV, Piper-Vallillo A, et al. Osimertinib in NSCLC With Atypical EGFR-Activating Mutations: A Retrospective Multicenter Study. Jto Clin Res Rep. 2023;4:100459. PubMedPubMedCentral Ji J, Aredo JV, Piper-Vallillo A, et al. Osimertinib in NSCLC With Atypical EGFR-Activating Mutations: A Retrospective Multicenter Study. Jto Clin Res Rep. 2023;4:100459. PubMedPubMedCentral
25.
26.
Zurück zum Zitat Popat S, Hsia TC, Hung JY, et al. Tyrosine Kinase Inhibitor Activity in Patients with NSCLC Harboring Uncommon EGFR Mutations: A Retrospective International Cohort Study (UpSwinG). Oncologist. 2022;27:255–65. CrossRefPubMedPubMedCentral Popat S, Hsia TC, Hung JY, et al. Tyrosine Kinase Inhibitor Activity in Patients with NSCLC Harboring Uncommon EGFR Mutations: A Retrospective International Cohort Study (UpSwinG). Oncologist. 2022;27:255–65. CrossRefPubMedPubMedCentral
Metadaten
Titel
Rare oncogenic alterations in NSCLC—focus on atypical EGFR mutations
Invited short review
verfasst von
Yana Sharapova, PhD
Sonja Loges, MD, PhD
Melanie Janning, MD
Publikationsdatum
08.02.2024
Verlag
Springer Vienna
Erschienen in
memo - Magazine of European Medical Oncology
Print ISSN: 1865-5041
Elektronische ISSN: 1865-5076
DOI
https://doi.org/10.1007/s12254-024-00960-2