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Bispecific Combination Therapy Leads Paradigm Shift in Advanced NSCLC

*May 2024*

As targeted therapy gets more precise, the treatment paradigms shift, particularly for patients with non–small cell lung cancer (NSCLC). This patient population has seen substantial changes in standard of care as more nuance is added to the understanding of how resistance and mutations within the tumor are targeted. This is most pronounced in treating patients with EGFR-mutated NSCLC who can also harbor other resistance mechanisms to treatment.

“If you know a patient has an EGFR mutation, the data clearly show the survival benefit for the addition of an EGFR-directed therapy,” Joshua K. Sabari, MD, thoracic medical oncologist at NYU Langone Health’s Perlmutter Cancer Center in New York, told a panel of oncologists while moderating a Case-Based Roundtable discussion on the case of a patient with EGFR-mutated NSCLC.

This is also in accordance with National Comprehensive Cancer Network (NCCN) guidelines, which recommend testing patients for actionable mutations, including EGFRALKROS1BRAFNTRK1/2/3METex14 skipping, RETKRAS, and HER2 (now known as ERBB2).1 By confirming a patient’s mutation status using next-generation sequencing (NGS) prior to their first-line systemic therapy, the treatment path will become much clearer. In the case of patients with EGFR-mutated NSCLC, there is further nuance when looking at the kind of EGFR mutation their tumor is harboring prior to deciding on first-line therapy.

For example, in patients with NSCLC positive for an EGFR exon 19 or exon 21 L858R mutation, if the mutation was discovered during initiation of first-line systemic therapy, the NCCN recommends continuing the course of treatment along with maintenance therapy, following that with the preferred use of osimertinib (Tagrisso), an EGFR-targeting tyrosine kinase inhibitor (TKI). Osimertinib is also the preferred category 1 recommended therapy if the EGFR mutation is discovered prior to initiation of first-line therapy, alongside osimertinib combined with chemotherapy. The introduction of the bispecific therapy amivantamab-vmjw (Rybrevant) combined with carboplatin and pemetrexed for the patients who progress after osimertinib treatment is also recommended.1 Amivantamab is also approved for the treatment of patients with EGFR exon 20 insertion– mutated NSCLC and is the immediate category 1 recommendation in this patient population.1,2

Testing for EGFR-Driven Mutations

During the event he moderated, Sabari discussed the case of a woman aged 72 years who was a never smoker but presented to her primary care physician with a persistent, nonproductive cough and loss of appetite; she also experienced pruritus for 4 months. Her contrast-enhanced chest/abdomen/pelvis CT scan showed a 4.1 × 3.8-cm tumor in the left upper lobe with calcification and left hilar lymphadenopathy, but an MRI scan of her brain was negative for any intracranial activity.

After the patient underwent a transbronchial biopsy, her immuno-histochemistry panel came back negative for ALK and TPK1 mutations but was positive for TTF1 mutation, and an antibody assay came back with a PD-L1 measurement of 25%. Her concurrent tissue- and plasma-based next-generation sequencing (NGS) panel was positive for an EGFR exon 21 L858R mutation, and she was diagnosed with stage IV adenocarcinoma.

“The combination of tissue and plasma testing [is] acceptable [by the NCCN guidelines], in any combination: tissue first, liquid first, or the combination of the 2,” explained Martin Dietrich, MD, PhD, medical oncologist at The US Oncology Network and assistant professor of internal medicine at the University of Central Florida College of Medicine in Orlando, during the live virtual event he moderated. “Which test you use depends on the individual case; sometimes you have a beautiful big core biopsy from the liver and that’ll probably be OK in an asymptomatic patient, but the ideal plan is a fast and comprehensive tissue testing approach in the beginning.”

Testing patients for EGFR-driven mutations becomes vital, as EGFR mutation subtypes have different responses to therapy and are seen in 10% to 15% of NSCLC cases in White patients and up to 50% in East Asian patients.3 According to a literature review, about 1% to 2% of all NSCLC cases are EGFR exon 20 insertion mutations, and among cases of EGFR-positive NSCLC this mutation subtype makes up about 4% to 10% of all observed mutations in NSCLC.3

Knowing which mutation is present in the tumor becomes vital, as patients with EGFR-mutated tumors will generally have a low response to immune checkpoint inhibitors (ICIs), but not every subtype has the same outcome.4 For instance, in an analysis of outcomes with ICIs across 4 institutions in this patient population, patients with EGFR L858R and EGFR exon 19 deletions had better outcomes if they received 0 to 2 prior lines of therapy, especially so for patients with EGFR exon 19 deletions.4 However, when compared with patients with EGFR wild-type mutations (n = 212), those with EGFR exon 19 deletions (n = 76) had a significantly lower overall response rate of 7% vs 22%, respectively (= .002). Further, progression-free survival (PFS) was significantly reduced for patients with EGFR exon 19 deletions compared with wild-type mutations (HR, 0.45; 95% CI, 0.412-0.811; < .001) and in patients with EGFR L858R–positive disease (HR, 0.58; 95% CI, 0.41-.81; = .001).

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