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Associate Professor of Medicine
Division of Oncology
Department of Medicine
Stanford Cancer Institute
Palo Alto, California
Joel W. Neal, MD, has disclosed that he has received consulting fees from Amgen, AstraZeneca, Blueprint, Calithera, D2G Oncology, Exelixis, Genentech/Roche, Iovance Biotherapeutics, Jounce Therapeutics, Lilly, Natera, Regeneron, Sanofi/Regeneron, Surface Oncology, Takeda, and Turning Point and funds for research support paid to his institution from AbbVie, Adaptimmune, Boehringer Ingelheim, Exelixis, Genentech/Roche, GlaxoSmithKline, Janssen, Merck, Nektar Therapeutics, Novartis, and Takeda.
In patients with lung cancer, mutations in EGFR, primarily in exons 18-21, are common, especially among women and patients who have never smoked, have adenocarcinoma, or are of Asian descent. EGFR exon 19 deletions (ex19del) and EGFR exon 21 L858R mutations are also called the “common” EGFR tyrosine kinase inhibitor (TKI) sensitizing mutations (~45% and ~30%, respectively), while the remaining EGFR mutations (~25%) are comprised of a broad spectrum of “uncommon” mutations, the management of which will be discussed here.
Knowing the exact nature of the EGFR mutation in non-small-cell lung cancer (NSCLC) is important because not all mutations are clinically actionable. The common EGFR mutations, ex19del and L858R, are targetable by EGFR TKIs, with FDA-approved first-line options including the first-generation EGFR TKIs erlotinib and gefitinib; the second-generation EGFR TKIs afatinib and dacomitinib; and the third-generation EGFR TKI osimertinib. Over the last few years, osimertinib has become the current first-line standard of care for EGFR-mutated NSCLC due to its superior survival benefit to earlier-generation inhibitors. More recently, the combination of erlotinib and ramucirumab (a VEGFR2 monoclonal antibody) also has been approved for patients with common EGFR mutations. Unfortunately, uncommon EGFR mutations are not as exquisitely sensitive to EGFR TKIs as EGFR ex19del and L858R.
Treating Advanced NSCLC With Uncommon EGFR Mutations
Exon 18 Mutations
G719X, where the “X” can stand for various amino acids, makes up 11.5% of atypical EGFR mutations (based on the mutational landscape analysis of 16,715 patients with EGFR-mutated NSCLC, 7199 of whom had atypical EGFR mutations, published in Nature by Robichaux and colleagues, which will be used as the reference for mutation frequencies for the remainder of the commentary). There is variable sensitivity of G719X to first generation EGFR TKIs, but a more established role for afatinib, which has a unique approval by the FDA based on retrospective studies. Additionally, third-generation EGFR TKIs appear active, with osimertinib being recommended by the National Comprehensive Cancer Network (NCCN) lung cancer guidelines; however, it appears that the response rate and duration of benefit is lower than for the common EGFR mutations.
Closer to the N-terminus of the EGFR protein, we have the E709X and L718Q/V mutations, which comprise 3.6% and 1.3% of the uncommon EGFR mutations, respectively. Treatment for EGFR 709X or L718Q/V is less clear than for G719X. Results from the phase II SUMMIT basket trial (NCT01953926) examining 240 mg neratinib (a TKI of EGFR/HER1, HER2 and HER3) in patients with solid tumors and HER2 or EGFR exon 18 mutations offer some insight. In the EGFR exon 18–mutant lung cancer cohort, the objective response rate was 54% in the efficacy-evaluable population (n = 11) and 40% in TKI pretreated patients (n = 10), with a median duration of response of 7.5 months for both groups. The median progression-free survival was 6.9 months and 9.1 months in the efficacy and pretreated populations, respectively, and the median overall survival was 17.9 months.
For EGFR exon 18 mutation–positive NSCLC, my personal preference is to avoid first-generation EGFR TKIs and instead consider afatinib or osimertinib in the first-line setting. Drugs like neratinib or the EGFR/MET bispecific antibody amivantamab are also possible emerging therapeutic options. More data from clinical trials and real‑world experience will help us determine whether these exon 18 mutations, either alone or in combination, are particularly sensitive to one EGFR targeted strategy vs another.
Exon 19 Mutations
L747P/S, with an incidence of 1.2%, is an uncommon point mutation that has been identified in EGFR exon 19. Some evidence suggests that these mutations may be sensitive to second-generation EGFR TKIs, such as afatinib and dacomitinib, but less sensitive to third-generation EGFR TKI, such as osimertinib, based on their impact on the structure on EGFR.
Exon 20 Mutations
Within exon 20, the T790M mutation is classically described, but is most often present as an acquired resistance mechanism to first-generation and second-generation EGFR TKIs. However, sometimes we will see it de novo in tumors in combination with other mutations, in which case germline genetic testing is indicated. Alone, it makes up <1% of EGFR mutations but can be found in combination with classical mutations in ~11% of cases and ~2% with both a classical and an uncommon EGFR mutation. For the combination of a T790M mutation with a classical EGFR ex19del or L858R mutation, I recommend a third-generation TKI, such as osimertinib.
There are also several uncommon point mutations in exon 20. Afatinib is approved by the FDA for treatment of advanced NSCLC with an S768I mutation, which is relatively frequent at 5.5% of uncommon mutations. For this mutation, the third-generation TKIs may also work, with NCCN lung cancer guidelines recommending osimertinib along with afatinib as preferred options. On the C-terminal end of exon 20 is C797S, which makes up 4.6% of uncommon mutations. As with T790M, this mutation usually occurs in combination with other sensitizing mutations as a resistance mechanism to third-generation TKIs and may revert the EGFR protein back to being sensitive to first-generation TKIs. Personally, I have never seen a C797S mutation in isolation.
Beyond the point mutations are the exon 20 insertion mutations, which make up 20.9% of uncommon EGFR mutations, and have received a great deal of attention regarding drug development in recent years. EGFR exon 20 insertion–positive advanced NSCLC responds poorly to treatment with traditional EGFR TKIs, except for A763insFQEA, which is sensitive (even to first-generation EGFR TKIs) because of its proximity to exon 19 and formation in the C-helix of the EGFR protein. However, most EGFR exon 20 insertions are more distal, in the loop following the C-helix, and now TKIs have been developed with enhanced specificity against the spectrum of these mutations, such as mobocertinib, and other agents, such as amivantamab. Both of these received FDA approval in 2021 for locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations whose disease has progressed on or after platinum-based chemotherapy. There are also other agents in development in this space, such as poziotinib, CLN-081, and DZD-9008.
Exon 21 Mutations
Moving on to exon 21, beyond L858R, we encounter L861Q, which makes up 5.8% of uncommon EGFR mutations. This is another mutation for which afatinib is FDA approved and osimertinib is NCCN guideline–recommended. In addition, in some instances, first-generation TKIs may also be effective for exon 21 L861Q mutations.
The landscape of available tools right now for EGFR-mutated lung cancer is mostly EGFR TKIs, but as we learn more about the EGFR signaling pathway, additional approaches are being developed, including drugs with unique mechanisms of action and combination regimens with EGFR TKIs. As discussed, the novel EGFR‑MET bispecific antibody amivantamab was recently approved by the FDA for the treatment of EGFR exon 20 insertion–positive advanced NSCLC, as well as is being evaluated in combination with the third-generation EGFR TKI lazertinib with or without chemotherapy in patients with metastatic NSCLC who have an EGFR sensitizing mutation and have progressed on standard of care treatment (NCT04965090, NCT04988295) or who are treatment naive (NCT04487080, NCT05299125). We also have the combination of erlotinib plus ramucirumab in our toolbox for advanced NSCLC with classical EGFR ex19del or L858R mutations based on results from the phase III RELAY trial. The strategy of combining an EGFR TKI with a VEGF(R) inhibitor is being further evaluated for advanced NSCLC with any EGFR-activating mutation that is sensitizing to TKIs, including the uncommon mutations, such as in the phase III EA5182 trial of osimertinib with or without the VEGF inhibitor bevacizumab (NCT04181060).
There are also novel antibody–drug conjugates under development, such as the HER3-targeting agent patritumab deruxtecan, which has shown activity in the setting of acquired resistance to osimertinib regardless of the specific resistance mechanism. As clinical trials with patritumab deruxtecan continue, hopefully we will see data for uncommon EGFR mutations as well because many EGFR signals are mediated through HER3.
In the future, I envision we will continue to amass data on the efficacy and tolerability of each of the available and developing therapies by EGFR mutation type so we can treat patients with the most effective and tolerable therapy in the frontline, instead of waiting to the point of acquired resistance for these patients.
The treatment of NSCLC with uncommon EGFR mutations is an exciting area that is continually changing. As someone who gets many inquiries from community medical oncologists, I encourage connecting with your regional academic center to inquire about their experience with lung cancer harboring uncommon EGFR mutations and to see if there are clinical trials available. Through these investigations, we will acquire the data we need to successfully individualize therapy for lung cancer across the spectrum of uncommon EGFR mutations.
What are your experiences treating patients with NSCLC and uncommon EGFR mutations? Answer the polling question and join the conversation by posting a comment in the discussion section.
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