Lung cancer with EGFR PACC mutations: a practical review of available treatment options and novel therapies on the horizon

Introduction

A case from the clinic

A patient with a 30-pack-year smoking history presented with painful bone metastases and was diagnosed with adenocarcinoma of the lung (Figure 1A), stage IVB [T1cNxM1c1, American Joint Committee on Cancer (AJCC) 9th edition]. An isolated epidermal growth factor receptor (EGFR) G719A mutation was detected (Figure 1B). He underwent surgical fixation and radiation of a left femur metastasis. He then presented to the outpatient academic medical oncology clinic to discuss systemic treatment. Intended as a question for the reader, to follow “discuss systemic treatment”. 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 for publication of this article and accompanying images was not obtained from the patient as the patient was deceased prior to the submission of the manuscript.

Figure 1 Pathologic and genomic testing for the clinical case. (A) Core needle biopsy of left femur bony lesion demonstrating metastatic lung adenocarcinoma infiltrating cortical bone (H&E stain, 600× original magnification), with positive immunohistochemical staining for both TTF-1 and Napsin. (B) Comprehensive genomic profiling performed on the tissue specimen revealed key driver mutations, including EGFR G719A mutation. *, truncating mutation. EGFR, epidermal growth factor receptor; H&E, hematoxylin and eosin.

Classical vs. P-loop and αC-helix compressing (PACC) EGFR mutations

EGFR mutations are a heterogeneous group of genomic alterations in non-small cell lung cancer (NSCLC), with variable effects on EGFR function as well as distinct patterns of clinical presentation and treatment response to available generations of EGFR tyrosine kinase inhibitors (TKIs; 1st generation = gefitinib, erlotinib; 2nd generation = afatinib, dacomitinib; 3rd generation = osimertinib, lazertinib). Exon 19 deletions/indels and the L858R point mutation comprise the majority of EGFR mutations in NSCLC (Figure 2). However, other less common mutations are frequently seen in clinical practice. EGFR-PACC, or P-loop alpha-helix compressing, mutations are a structural-functional classification recently proposed by MD Anderson Cancer Center (Figure 2, Table 1) that emphasizes the structural similarity between these mutations and their overlap in response to therapy (1,12,13). Together, PACC mutations comprise ~12.5% of EGFR mutations in NSCLC, with G719X, S768I, and E709X among the most common (2-11).

Figure 2 Structural classification and location of key EGFR mutations.. (A) The MD Anderson Center structure-function classification of EGFR mutations. Classical-like mutations (red) include the most common EGFR exon 19 indels and L858R mutations and are indicated in red. Exon 20 loop insertions (yellow) affect the C-terminal loop of the αC-helix and are insensitive to most available EGFR TKIs. T790M-like mutations (green) affect the hydrophobic core and are resistant to first- and second-generation EGFR TKIs but sensitive to third generation EGFR TKI osimertinib. Individual EGFR mutations are depicted by their location on the tyrosine kinase domain of the EGFR gene. (B) PACC mutations show heterogeneous sensitivity to EGFR TKIs. Example PACC mutations are indicated by their location on the tyrosine kinase domain of the EGFR gene, with the frequency of the most common mutations listed in parenthesis. EGFR, epidermal growth factor receptor; PACC, P-loop and αC-helix compressing; TKI, tyrosine kinase inhibitor.

Selection of systemic therapy for NSCLC with EGFR-PACC mutations can be challenging, as there is less data on treatment of these mutations due to their infrequency and exclusion from randomized trials. However, as treatment options for EGFR-mutated lung cancer have expanded, a growing arsenal of evidence from both retrospective and prospective data is available to inform optimal treatment for this molecularly defined subgroup, with increasing evidence that response to treatment differs between EGFR-PACC and EGFR exon 19 deletion and L858R mutations. In this review, we summarize the current understanding of treatment for EGFR-PACC mutations, with an aim to provide a practical guide for the provider in real-world settings.

Methods

A search of the literature was conducted using PubMed and the search terms “EGFR” and “PACC”, “atypical”, “uncommon”, “G719X” or “S768I”. Relevant papers published within the past 10 years were identified. Studies evaluating atypical or uncommon EGFR mutations were included if they specified the inclusion of G719X, S768I, or other PACC mutations. Clinical trials were identified on Clinicaltrials.gov searching for “EGFR” and “PACC”, “G719X” and “S768I”. Trials that were in phase III and specific to EGFR-PACC mutations were included.

Initial treatment for metastatic disease in the 2020s: afatinib versus osimertinib

Selection of upfront therapy for metastatic disease is informed by clinical efficacy in EGFR-PACC mutations as well as side effect profile and central nervous system (CNS) penetration. Therapeutic options for EGFR-PACC mutations are summarized in Figure 3. In a recent editorial, we reviewed the evidence for treatment with afatinib versus osimertinib in patients with EGFR-PACC mutations, largely drawn from retrospective studies. Acknowledging the limitations of data from small, retrospective studies, the available data suggest that response to osimertinib is less robust in EGFR-PACC mutations when compared to classical EGFR mutations: objective response rate (ORR) 33–50% and median progression-free survival (mPFS) 5.1–9.4 months. However, response to afatinib is preserved and comparable between EGFR-PACC and classical EGFR mutations: ORR 61–71% and mPFS 12.3–24.9 months (1). The use of afatinib over osimertinib in EGFR-PACC mutations is also supported by a systematic review that included 1,836 patients treated for NSCLC with uncommon EGFR mutations from 38 studies, primarily retrospective. This review found that among patients with NSCLC with EGFR-PACC mutations, 2nd generation EGFR TKIs such as afatinib had the highest response rates. The ORR to 2nd versus 3rd generation EGFR TKIs was 59.6% [95% confidence interval (CI): 54.8–64.3%] vs. 46.3% (95% CI: 32.6–60.4%), respectively (4). While the clinical data suggest afatinib may have a higher response rate than osimertinib in EGFR-PACC mutations, toxicities vary between the two regimens and need to be considered when deciding on treatment for an individual patient (Table 2). Osimertinib is generally better tolerated. In the FLAURA trial, which compared osimertinib to first-generation EGFR TKIs in previously untreated metastatic NSCLC with EGFR exon 19 deletion or L858R mutations, the most common adverse events of osimertinib were: rash or acne (58%), diarrhea (58%), dry skin (36%), paronychia (35%), and stomatitis (29%). Grade 3+ adverse events were rare, with the most common being decreased appetite (3%) and prolonged QT (2%) (14). In the LUX-Lung 7 trial, which compared afatinib to first-generation EGFR TKI gefitinib in previously untreated metastatic NSCLC with EGFR exon 19 deletion or L858R mutations, the most common adverse events seen with afatinib were: rash or acne (88%), diarrhea (91%), stomatitis (64%), paronychia (56%), and dry skin (33%). The most common Grade 3+ adverse events were diarrhea (13%), rash or acne (9%), fatigue (6%), stomatitis (4%), and paronychia (2%) (15). Side effects can frequently be managed with supportive medications (topical antibiotics and corticosteroids for rash, loperamide for diarrhea). Overall, these data suggest a higher rate of side effects with afatinib compared to osimertinib, and the risk of side effects must be considered when selecting upfront therapy.

Figure 3 Treatment options for metastatic NSCLC with EGFR mutations. Comparison is made between approved treatment options for EGFR exon 19 deletion or L858R mutations, approved treatment options for EGFR PACC mutations, and possible off-label options for EGFR PACC mutations. *, alternative in NCCN guidelines for G719X or S768I mutations. **, extrapolated from other mutations. ***, if EGFR T790M+ or CNS progression and afatinib used in 1st line. Chemo, chemotherapy; CNS, central nervous system; EGFR, epidermal growth factor receptor; NCCN, National Comprehensive Cancer Network; NSCLC, non-small cell lung cancer; PACC, P-loop and αC-helix compressing; PD-L1, programmed death-ligand 1; TKI, tyrosine kinase inhibitor; Tx, treatment; VEGF, vascular endothelial growth factor.

Dose reductions are often needed for intolerable side effects—and more commonly for afatinib than osimertinib. In a single-center retrospective analysis, dose reductions with afatinib were 24%, versus 19% with osimertinib (16). Notably, prospective available evidence does not demonstrate an association between afatinib dose reduction (≥20 mg daily) and worse PFS (17,18).

Thus, in the setting of an EGFR-PACC mutation, one approach is to start treatment with afatinib based on better clinical efficacy and to consider dose reduction or switch to osimertinib if issues with tolerability arise.

Ongoing trials of EGFR TKIs for EGFR-PACC mutated NSCLC

Firmonertinib is an EGFR inhibitor being studied specifically in exon 20 insertions and EGFR-PACC mutations. The FURTHER trial (NCT 05364073) was a global randomized trial evaluating firmonertinib in TKI-naive patients with advanced NSCLC with EGFR-PACC mutations. This agent demonstrated an 81.8% ORR by blinded independent central review (63.6% confirmed ORR) and an intracranial ORR of 46.2%, n=22 (19,20). Overall survival (OS) data are pending. Firmonertinib is currently being studied as first-line treatment for metastatic NSCLC compared to investigator’s choice of osimertinib or afatinib in a registration phase III trial specifically for EGFR-PACC mutations (ALPACCA trial, NCT07185997) (21). With a planned enrollment of 300 patients, this trial has the potential to contribute substantially to the prospective body of evidence on treatment for this subgroup and could lead to a new treatment option in the near future. Other novel EGFR TKIs that are earlier in development, such as zipalertinib (REZILIENT2 trial, NCT05967689) (22), BH-30643 (SOLARA trial, NCT06706076) (23), sutetinib (NCT05168566), BDTX1535 (NCT05256290), and ORIC-114 (NCT05256290) (24) are also enrolling cohorts with EGFR-PACC mutations in ongoing phase I/II trials.

Special considerations: intracranial metastases and compound EGFR mutations

While data support a higher overall response rate with afatinib when compared to osimertinib for EGFR-PACC mutations, there is less certainty about the relative benefit of these agents in patients with baseline brain metastases. When compared to afatinib and other 2nd generation EGFR TKIs, osimertinib has greater intracranial penetration as shown in preclinical models (25). For EGFR exon 19 deletion or L858R mutation, the intracranial ORR was 91% among patients with at least one CNS metastasis (n=22) and 66% among patients with measurable and/or non-measurable CNS metastasis (n=61) with osimertinib in the FLAURA trial (26). The intracranial ORR was lower on afatinib: 82% for exon 19 deletion (n=28) and 60% (n=20) for L858R in a subgroup analysis of the LUX-LUNG 3 and LUX-LUNG 6 trials (27).

For EGFR-PACC mutations, data on intracranial ORR is limited by low patient numbers in most series. For osimertinib, a retrospective study of 594 patients with uncommon EGFR mutations and brain metastases showed an intracranial ORR with osimertinib of 46% (95% CI: 30–62%) (28). The KCSG-LU15-09 study included 5 evaluable patients with uncommon EGFR mutations—including G719X—with an intracranial ORR of 40% (29). The UNICORN trial included 2 evaluable patients with uncommon EGFR mutations with brain metastases treated with osimertinib with an ORR 100% (30). For afatinib, a retrospective study including 23 patients with CNS evaluable disease with uncommon EGFR mutations showed an intracranial response rate of 60% (95% CI: 26–88%) among patients with evaluable disease, but only 35.3% (95% CI, 14.2–61.7%) in the full analysis set (31). Overall, osimertinib and afatinib have both shown evidence of intracranial activity in EGFR-PACC mutations, though osimertinib demonstrates a more robust response, consistent with its known pharmacologic properties.

Compound mutations are also more frequent with EGFR-PACC mutations than with classical EGFR mutations. Treatment of compound mutations with EGFR-PACC mutations includes the same considerations as single mutations. Notably, both compound and single PACC mutations are associated with improved clinical responses to 2nd generation EGFR TKIs (32).

Upfront EGFR TKI monotherapy versus combination regimens

While now the evidence-based standard of care for upfront treatment of patients with advanced stage NSCLC with a classical EGFR mutation, the role of combination therapy strategies remains less well established for EGFR-PACC mutations. For EGFR-exon 19 deletion or L858R mutations, the FLAURA2 trial evaluated osimertinib monotherapy versus combination osimertinib with chemotherapy and demonstrated improved median PFS (25.5 vs. 16.7 months) and OS (47.5 vs. 37.6 months) with the combination regimen—but did not include any patients with EGFR-PACC mutations (33,34). There is minimal randomized trial data to support the use of combination EGFR TKI and chemotherapy for less common EGFR mutations. EGFR TKI monotherapy in the upfront setting retains the appeal of fewer treatment-related visits and more favorable side effect profile. In the absence of rigorous prospective data regarding the use of combination therapy with EGFR TKI and chemotherapy in EGFR-PACC mutations, providers may choose to start with EGFR TKI monotherapy, adding chemotherapy at time of cancer progression and in subsequent lines of treatment—though this remains an area of unmet need.

Similarly, the landmark MARIPOSA trial comparing amivantamab, an EGFR/MET (mesenchymal-epithelial transition) bispecific antibody, with lazertinib to osimertinib monotherapy demonstrated improved PFS and OS with upfront combination therapy, but this study also only included patients with advanced NSCLC and EGFR exon 19 deletion or L858R mutations (35). However, Cohort C of the CHRYSALIS-2 study did explore use of combination amivantamab-lazertinib in uncommon EGFR-mutated NSCLC. This cohort included 105 patients (54% with EGFR-G719X and 22% with EGFR-S768I), demonstrating an ORR of 57% (95% CI: 42–71%) in the first line setting and an ORR of 48% (95% CI: 35–62%) in patients previously treated with afatinib (36). While this trial did not provide a direct comparison to EGFR TKI monotherapy, a comparison with a propensity score-matched retrospective cohort of patients who received afatinib monotherapy showed favorable ORR and OS with the combination in uncommon EGFR mutations (37). Thus, upfront combination therapy with amivantamab-lazertinib may be considered for EGFR-PACC mutations based on limited data, though with tradeoffs relating to treatment schedule and side effects when compared to TKI monotherapy.

Second- and third-line treatment options

After progression on initial treatment, data in EGFR-PACC mutations is limited. Re-biopsy of an area of progression is suggested when clinically feasible with repeat molecular testing for the presence of new actionable genomic alterations. One option is to treat with an alternative EGFR TKI (e.g., change from afatinib to osimertinib, particularly in the presence of an EGFR-T790M mutation). Chemotherapy can be used regardless of mechanism of resistance, alone or with continuation of EGFR TKI. As above, amivantamab-lazertinib has shown an ORR of 48% in patients with uncommon EGFR mutations following progression on afatinib (36). MET inhibitors (e.g., capmatinib or tepotinib) have been used in patients with common EGFR mutations when MET amplification is identified as a mechanism of resistance; however, as data is limited in uncommon EGFR mutations, this is considered experimental (38).

Clinical data on the recently approved Trop2 antibody-drug conjugate (ADC) datopotamab deruxtecan (Dato-DXd) for EGFR-PACC mutations is relatively limited, with a pooled dataset from the phase II TROPION-Lung05 (NCT04484142) and phase III TROPION-Lung01 (NCT04656652) trials disclosing data on <10 cases; some of these (3/6 partial responses in patients with EGFR-G719X) experienced anti-tumor activity (39). Further study of Dato-DXd and other Trop2 ADCs is warranted in NSCLCs with EGFR-PACC mutations.

The HARMONi-A study of ivonescimab, a PD-1/VEGF (programmed cell death protein 1/vascular endothelial growth factor) bispecific antibody, with chemotherapy compared to chemotherapy alone in patients with NSCLC with EGFR mutations who progressed on an EGFR TKI included patients with “other” (non-exon19del or L858R) EGFR mutations. Subgroup analysis for PFS suggested a treatment effect in this group, with hazard ratio (HR) 0.40 (0.20–0.81) (40). The US trial HARMONi comparing ivonescimab plus pemetrexed and carboplatin versus pemetrexed and carboplatin alone also includes uncommon EGFR mutations and will provide further data to assess the role for this emerging treatment strategy in EGFR-PACC mutations (41).

Management of early stage disease

Adjuvant treatment with osimertinib alone or after chemotherapy is the evidence-based standard of care for patients with resected NSCLC with EGFR exon 19 deletion or L858R, based on improvements in OS as seen in the ADAURA trial (42). However, data for adjuvant EGFR TKI in EGFR-PACC mutations is limited. An ongoing phase III trial is comparing firmonertinib to placebo in the adjuvant setting after chemotherapy (FIRMOST trial, NCT07010419), including exon 20 insertions, PACC mutations, and classical-like mutations (43). Data for using EGFR TKI in the neoadjuvant setting in EGFR-PACC mutations is limited to small case series (44).

Limitations

While there are multiple approved therapeutic options for NSCLC with EGFR exon 19 deletions and L858R mutations, only afatinib has received FDA approval that includes PACC mutations, based on a post-hoc analysis of 32 patients from the LUX-Lung 2, LUX-Lung 3, and LUX-Lung 6 trials (Table 2) (17). Definitive conclusions about optimal upfront treatment for EGFR-PACC mutations are limited by the small number of patients with EGFR-PACC mutations and the nonrandomized, retrospective design of most studies. Second- and subsequent-line treatment options are largely extrapolated from data in patients with EGFR exon 19 deletion and L858R mutations.

Case conclusion & application of the existing evidence

Oral EGFR TKI monotherapy with osimertinib vs. afatinib was discussed with the patient. The absence of CNS disease and desire for a high response rate in the presence of symptomatic bone metastases contributed to the shared decision to start afatinib. In addition, the patient’s desires for less time spent receiving medical care and fewer side effects favored the use of monotherapy over combination regimens. Following informed consent for treatment, EGFR TKI monotherapy with afatinib 40 mg daily with palliative intent was commenced with radiographic response (Figure 4A). He tolerated this for 14 months with mild acneiform dermatitis (treated with topical clindamycin and corticosteroids) and intermittent diarrhea (treated with loperamide), both as needed. He then developed worsening rash and diarrhea impacting quality of life that could no longer be mitigated, and the afatinib was reduced to 20 mg daily. He tolerated the reduced dose of afatinib well but subsequently developed leptomeningeal disease progression after a total of 18 months on afatinib (Figure 4B). Tumor molecular re-profiling with liquid biopsy was pursued but did not demonstrate any new or actionable genetic alterations. In the absence of rigorous data regarding optimal next line therapies, and the desire for a highly CNS penetrant therapy, a trial of osimertinib 80 mg daily was attempted. However, the patient experienced clinical deterioration and died within one month of treatment initiation with 2nd line osimertinib.

Figure 4 Radiologic and pathologic progression after treatment with afatinib. (A) After treatment with afatinib 40 mg for 3 months, CT scan of the lungs revealed a small decrease in the size of the primary lung lesion from 21 to 18 mm. (B) Areas of CNS progression on afatinib. MRI brain shows representative intraparenchymal lesions. Cytologic evaluation of the cerebrospinal fluid was positive for metastatic adenocarcinoma; note size of tumor cells (top) as compared to background lymphocytes (bottom) (Papanicolaou stain, 1,000× original magnification). CNS, central nervous system; CT, computed tomography; MRI, magnetic resonance imaging.

Discussion

This case illustrates the real-world, nuanced considerations in treatment selection for EGFR-PACC mutations and areas of uncertainty and unmet need as they relate to relative efficacy, toxicity, intracranial control, and management of treatment-emergent drug resistance. Discussions regarding care options for patients with NSCLC with EGFR mutations are increasingly nuanced, with need to integrate optimal oncologic outcomes with side effects, treatment schedules, and differences in the lived experience during what can be a protracted course of therapy. These nuances are amplified in the context of EGFR-PACC mutations, where there is greater uncertainty surrounding the relative magnitude of clinical benefit associated with different treatment strategies. Comprehensive and collaborative discussions and decision-making between patient and provider are essential in these and all cases, with close attention to disease and symptom management beyond the point of treatment selection.

Conclusions

EGFR-PACC mutations are a clinically significant subgroup of uncommon EGFR mutations that share structural similarity and response to treatment. A growing body of retrospective and prospective data support the use of afatinib as first-line treatment in metastatic NSCLC. Ongoing questions include the role for novel EGFR TKIs and optimal treatment sequencing with emerging options involving combinations with chemotherapy, EGFR-MET antibodies, PD-1-VEGF antibodies, and Trop2 ADCs, amongst others. As evidence rapidly evolves for the treatment of NSCLC with EGFR mutations, the PACC mutation subgroup is useful to better assess the effectiveness of treatments in patients with uncommon EGFR mutations. As illustrated by this real-world case, optimal treatment selection for patients with NSCLC with EGFR-PACC mutations will need to harmonize the expanding clinical data with the characteristics and preferences of each patient.

Acknowledgments

None.

Footnote

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-1-0061/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-2026-1-0061/coif). P.A.V. serves as an unpaid editorial board member of Translational Lung Cancer Research from October 2025 to September 2027. S.S.K. reports receiving consulting fees and research support from National Institution of Health; consulting fees from Taiho Therapeutics; honoraria from AstraZeneca, Boehringer Ingelheim, Bristol Meyers Squibb, Chugai Pharmaceutical, and Takeda Pharmaceuticals; and royalties from Signosis and Life Technologies. X.L. reports receiving consulting or advisory fees from AbbVie, Abion, Akeso, Allist, ArriVent, AstraZeneca, Avistone, Bayer, BioNTech, BlossomHill, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Dizal, Eli Lilly, EMD Serono (Merck KGaA), Hengrui, Innovent, Johnson & Johnson (Janssen), Merck, Novartis, OncoHost, Pfizer, Regeneron, Summit, SystImmune, Taiho, and Teligene, as well as research funding to the institution from ArriVent, Dizal, Eli Lilly, EMD Serono, and Johnson & Johnson. D.B.C. reports receiving grants from Takeda/Millennium Pharmaceuticals, AstraZeneca, Pfizer, Merck Sharp & Dohme, Merrimack Pharmaceuticals, Bristol-Myers Squibb, Clovis Oncology, Spectrum Pharmaceuticals, Tesaro, Daiichi Sankyo, and Blossom Hill Pharmaceuticals; royalties from Life Technologies; consulting fees from Janssen Pharmaceuticals, Blossom Hill Pharmaceuticals, Teladoc Health Inc., and Included Health Inc.; as well as travel fees from Janssen Pharmaceuticals. D.R. reports receiving personal fees (consulting fees and honoraria) from TelaDoc Health, DynaMed, AstraZeneca, ONVIV, and Johnson & Johnson, as well as nonfinancial support (institutional research support) from Bristol-Myers Squibb, Novocure, Novartis, and AbbVie/Stemcentrx, and travel fees from DAVA Oncology. The other 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 for publication of this article and accompanying images was not obtained from the patient as the patient was deceased prior to the submission of the manuscript.

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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