What’s next for metastatic NSCLC without actionable mutations?

Written by Healthcasts Team | Dec 17, 2025 4:02:33 PM

Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, and metastatic recurrence presents unique treatment challenges. Following relapse, clinicians are tasked with navigating prior exposure to therapy, patient fitness, and limited pathways to determine the best first-line approach.

On Healthcasts, practitioners are sharing their real-world approaches to treating NSCLC without actionable mutations. Their suggestions include how they confirm recurrence, incorporate NGS, and decide between a variety of treatment strategies.

What treatment would you recommend for the patient case below? L og in or sign up to share your approach and view the consensus summary.

Post:

72-year-old male, ECOG PS 0, 4/2022 left upper lobe lobectomy, stage II-B, s/p adjuvant chemotherapy with cisplatin, Alimta, then adjuvant Keytruda for one year, which he completed 10/2023. PD-L1-1% and no actionable mutations on NGS. Has relapse with diffuse disease in bilateral lungs with pleural effusion. Would you consider a biopsy, and if so, is a liquid biopsy sufficient? If no new actionable mutations, what are your recommendations for now first-line metastatic NSCLC?

Questions for consult

What first-line treatment for NSCLC metastatic recurrence without an actionable mutation would you recommend?

Comments

Key takeaways about first-line treatment for recurrent NSCLC:

Confirm recurrence and repeat NGS upfront
Clinicians consistently recommend re-biopsy at recurrence to confirm disease and repeat NGS, using liquid biopsy as a complement, but not a substitute for tissue when accessible.
Immunotherapy-based combinations are favored without actionable mutations
When no targetable mutation is identified, clinicians leaned toward immunotherapy-driven regimens, including dual checkpoint inhibition or IO-chemotherapy combinations, guided by performance status and comorbidities.
Prior therapy and timing influence regimen selection
Previous immunotherapy exposure and the interval since adjuvant treatment shaped first-line choices, with IO–chemo often preferred to achieve early response while preserving later options.

Oncology/Hematology

"First, I would rebiopsy and perform NGS on tissue if accessible and liquid bx as well. If no actionable mutation is found and ECOG PS is 0 with no serious comorbidities, I would likely proceed with dual IO and limited upfront chemoRx with carbo/pem x2 cycles to hopefully obtain an early response given diffuse bilateral lung recurrence."

Oncology/Hematology

"I would try to biopsy if there is an accessible site and send for NGS and treat accordingly. I will send liquid NGS. If there is no actionable mutation, I would treat with docetaxel and ramucirumab."

Oncology/Hematology

"I would definitely prove recurrence with biopsy and NGS liquid or otherwise. I also recommend dual immunotherapy."

Oncology/Hematology

"I would recommend a biopsy at recurrence to obtain tissue histology and NGS. Would also send liquid NGS. With recurrence >2 years from the completion of adjuvant therapy, I would consider retreatment with IO + chemo, especially in the setting of limited options in the 2L+ setting."

Oncology/Hematology

"Chemo/IO combination. Would probably go with Platinum/pemetrexed and cemiplimab since he had pembrolizumab previously. Would definitely re-biopsy. A liquid biopsy is not sufficient if good target for tissue."

How would you handle the biopsy and treatment for metastatic NSCLC without an actionable mutation? Share your approach and read other comments on the full post.

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