Frontline Treatments for Metastatic NSCLC With Actionable Mutations
Key Points
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When seeing patients with metastatic non-small cell lung cancer (NSCLC), next-generation sequencing (NGS) is critical to identify patients with targetable mutations.
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Frontline treatments for metastatic NSCLC with actionable mutations primarily consist of targeted therapies, such as tyrosine kinase inhibitors.
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EGFR alterations account for the majority of NSCLC cases with mutations, and the frontline standard of care is osimertinib plus chemotherapy or amivantamab plus lazertinib.
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Outside of EGFR mutations, patients with NSCLC can carry a variety of rarer alterations that have distinct approved targeted agents in the frontline setting.
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Clinical trials are investigating promising novel targeted therapies across a variety of mutational subgroups, and patients should be enrolled whenever possible.
Frontline Treatments for Metastatic NSCLC With Actionable Mutations
On the Oncology Brothers podcast, cohosts Rahul Gosain, MD, MBA, of Wilmot Cancer Institute, and Rohit Gosain, MD, of Roswell Park Comprehensive Cancer Center, discussed frontline treatments for metastatic NSCLC with actionable mutations with Eric Singhi, MD, of The University of Texas MD Anderson Cancer Center.
During the discussion, the doctors emphasized the need for upfront comprehensive NGS and immunohistochemistry before frontline therapy to screen for targetable alterations and identify patients eligible for clinical trials. In addition, repeat testing should be performed if patients progress on frontline therapy to investigate potential mechanisms of resistance and plan further treatment.
Frontline Treatments for Metastatic NSCLC With Common EGFRMutations
Most patients with targetable alterations in metastatic NSCLC carry EGFR exon 19 deletion or EGFR exon 21 L858R mutation. The frontline standard of care for metastatic NSCLC with these classical EGFR mutations is combination therapy with either osimertinib and chemotherapy, as per the FLAURA2 trial, or amivantamab and lazertinib, as per the MARIPOSA trial. Osimertinib monotherapy may be appropriate for elderly patients or those with multiple comorbidities, but most patients will start on a combination regimen, said Dr. Singhi.
There is a lack of biomarker data to guide selection between the two regimens, but based on available subgroup analyses, the MARIPOSA regimen may be preferred for patients with central nervous system involvement, liver metastases, or visceral disease, said Dr. Singhi. Generally, when selecting between the two regimens, oncologists should consider side-effect profiles, associated management strategies, and logistical and financial toxicities. Notably, a subcutaneous formulation of amivantamab was recently approved, which may have more favorable safety and logistics.
If patients with EGFR–mutated metastatic NSCLC progress on a frontline combination regimen, a repeat biopsy must be performed to screen for emergent resistance mutations. In subsequent treatment lines, patients who started on the MARIPOSA regimen can switch to datopotamab deruxtecan (Dato-DXd) or platinum-based chemotherapy. Patients who started on osimertinib monotherapy or the FLAURA2 regimen may be able to switch to amivantamab and chemotherapy.
Frontline Treatment of Metastatic NSCLC With Uncommon EGFR Mutations
While most patients with EGFR–mutated NSCLC will carry one of the classical mutations, there are additional EGFR alterations seen in metastatic NSCLC, including EGFR exon 20 insertion and a number of PACC (P-loop and αC-helix compression) mutations, including S768I, L861Q, or G719X. For patients with exon 20 insertion, the frontline standard of care is amivantamab and chemotherapy based on the PAPILLON trial, and patients can swap to Dato-DXd upon progression. For patients with PACC mutations, afatinib is the standard of care, though emerging data support amivanatab and lazertinib in some subgroups, said Dr. Singhi.
Frontline Treatment of Metastatic NSCLC With Rare Mutations
While seen much less frequently than EGFR mutations, several other actionable alterations in NSCLC are targeted by approved therapies, including ALK and ROS1 rearrangements, BRAF V600E mutation, NTRK gene fusions, MET exon 14 skipping mutation, RET rearrangement, and HER2.
For ALK–positive NSCLC, lorlatinib is Dr. Singhi’s preferred frontline option for most patients based on its extremely favorable survival data from the CROWN trial. Alternatively, alectinib has favorable long-term overall survival data and may be more tolerable than lorlatinib. If patients progress on targeted therapy, switching to brigatinib or incorporating chemotherapy are viable next-line options, though Dr. Singhi prefers to get patients into clinical trials whenever possible.
For patients with ROS1 rearrangement, Dr. Singhi prefers the most recent approval, talectretinib, based on the safety and efficacy data from the TRUST-I and TRUST-II trials. Dr. Singhi also highlighted zidesamtinib, a novel ROS1 inhibitor, which has shown extremely promising response and safety data in early trials.
In BRAF V600E–mutated NSCLC, Dr. Singhi’s preferred targeted therapy is encorafenib and binimetinib, given updated data from the PHAROS study. In addition, immunotherapy is known to be effective in NSCLC with the BRAF V600E mutation, unlike most other NSCLC alterations. Retrospective data from the FRONT-BRAF study suggest immunotherapy may be most effective in patients with a history of smoking, with PD-L1–positive disease, or without brain metastases.
For NTRK gene fusions, Dr. Singhi slightly favors larotrectinib over entrectinib and repotrectinib based on its safety and efficacy profile. For RET rearrangements, selpercatinib, pralsetinib, and cabozantinib are approved frontline options, among which Dr. Singhi favors selpercatinib or pralsetinib.
Contemporary approved options for MET exon 14 skipping mutation include capmatinib and tepotinib. Data show slight differences in pneumonitis rates with either agent, and tepotinib may be more appropriate for patients with relevant risk factors, said Dr. Singhi.
The HER2–positive NSCLC space has seen several developments, including, most recently, the approval of zongertinib in frontline settings for patients with HER2 tyrosine kinase domain activating mutations. If patients progress on zongertinib, Dr. Singhi advocated for repeat next-generation sequencing, as some case reports have suggested ERBB2 amplification or HER2 protein overexpression may drive zongertinib resistance, and salvage therapy with T-DXd can still be effective.