Treating Complex Cases of EGFR-Mutated NSCLC
Key Points
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Approved therapies for epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) include osimertinib monotherapy, osimertinib plus chemotherapy, and amivantamab plus lazertinib.
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Amivantamab plus lazertinib has robust data from the phase 3 MARIPOSA study, showing significant activity in patients with central nervous system (CNS) involvement.
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Choice of second- and later-line treatments can be influenced by prior therapy and time since the last platinum-based chemotherapy.
EGFR-Mutated NSCLC Treatment Landscape for Challenging Cases
On the Oncology Brothers podcast, Eric Singhi, MD, of The University of Texas MD Anderson Cancer Center, joined cohosts Rahul Gosain, MD, MBA, of Wilmot Cancer Institute, and Rohit Gosain, MD, of Roswell Park Comprehensive Cancer Center, to review challenging cases in EGFR-mutated NSCLC and discuss treatment selection. Recent approvals have expanded the available frontline treatment options. However, these treatments are currently administered with palliative intent, said Dr. Rahul Gosain.
The approved frontline options are osimertinib monotherapy, amivantamab plus lazertinib based on the MARIPOSA trial, and osimertinib plus chemotherapy based on the FLAURA2 trial. While osimertinib monotherapy has some use cases, the combination regimens are the predominant treatment options for this population.
Common EGFR Mutations With CNS Involvement
The first challenging case described an asymptomatic 58-year-old man with metastatic disease with CNS involvement. The patient had a past history of hypertension, was a smoker, had diabetes mellitus type II, reduced appetite, and weight loss in the past 4 months. CT and MRI scans found evidence of a 5 cm mass in the right lung, bilateral mediastinal lymphadenopathy, multiple liver lesions, and multiple brain lesions. Next-generation sequencing (NGS) revealed EGFR exon 19 deletion.
Due to the CNS involvement, Dr. Singhi said he would collaborate with a multidisciplinary team to determine if radiation or other local therapy is needed before selecting any therapy. Based on the extent of the disease and other risk features, Dr. Singhi said a combination regimen would be his immediate preference. Given robust data from MARIPOSA that showed improved CNS activity with amivantamab plus lazertinib versus osimertinib alone, this patient was ultimately started on amivantamab and lazertinib.
When using the MARIPOSA regimen, effective supportive care for managing infusion reactions and cutaneous toxicities has been described in the SKIPirr and COCOON trials, respectively. Temporary dose interruptions can also help manage treatment-related adverse events without sacrificing progression-free survival outcomes, according to MARIPOSA data. In addition, oncologists should consider the added “time toxicity” of required clinic visits for infusions, at least until a subcutaneous formulation is available, Dr. Rahul Gosain noted.
Treating NSCLC After Progression
The second case reviewed was an 83-year-old woman with a history of smoking over 100 packs per year, chronic obstructive pulmonary disease (COPD), hypertension, and hyperlipidemia. CT imaging found evidence of multiple lung lesions with supraclavicular lymphadenopathy and pleural effusion. Thoracentesis confirmed metastatic disease, and NGS testing identified an EGFR exon 21 L858R point mutation. The patient previously started osimertinib plus chemotherapy, but restaging scans found new liver lesions during maintenance therapy.
The panel emphasized that repeat NGS testing is critical for any patient with progression during therapy to rule out any emergent mutations. “It’s not the most common cause of acquired mechanisms of resistance, but it does happen and you don’t want to miss it,” said Dr. Singhi. If NGS reveals an acquired, targetable mechanism of resistance, that can guide selection of the next therapy, but if no such alteration is found, the choice is more complex.
In FLAURA2, the most common subsequent line of therapy was platinum-based chemotherapy. However, for patients who already received platinum-based chemotherapy in the first line, such as in this case, it’s unclear how much time since last chemotherapy should pass before attempting to rechallenge. Until more data are available, it may ultimately be a clinical judgment based on the patient’s fitness and how well they tolerated platinum-based chemotherapy previously, said Dr. Singhi. Conversely, if a patient progressed on first-line amivantamab plus lazertinib, sequencing osimertinib plus platinum-based chemotherapy may be a more straightforward option.
Another option in this setting is the antibody-drug conjugate datopotamab deruxtecan (Dato-DXD), based on pooled analyses of TROPION-Lung01 and TROPION-Lung05. However, Dato-DXD is associated with interstitial lung disease and pneumonitis, which may complicate its use in this case given the patient’s history of COPD exacerbations. Though also not applicable for this case, if a patient had progression limited to a small number of sites, one subsequent option could be targeted radiation therapy on those sites while continuing the current systemic therapy, Dr. Singhi said.
On a general note, Dr. Singhi pointed out that both cases discussed on the episode featured patients with a history of smoking who also had actionable genomic alterations, and he emphasized that a smoking history should not preclude NGS testing for actionable genomic alterations in patients with NSCLC.