The Frontline Treatment Algorithm for Metastatic NSCLC Without Actionable Mutations
Key Points
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In the absence of actionable mutations with approved upfront targeted therapies, the standard frontline treatment options for metastatic non-small cell lung cancer (NSCLC) are platinum-based chemotherapy and immunotherapy.
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PD-L1 expression score can guide between single-agent or dual immune checkpoint inhibitors, chemotherapy, or a combination of both.
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After frontline therapy, subsequent treatment options for metastatic NSCLC include docetaxel with or without ramucirumab and targeted therapy options like telisotuzumab vedotin (Teliso-V) or KRAS inhibitors.
Frontline Treatment of Metastatic NSCLC Without Actionable Mutations
On the Oncology Brothers podcast, Christine Garcia, MD, MPH, of Weill Cornell Medicine, met with cohosts, Rahul Gosain, MD, MBA, of Wilmot Cancer Institute, and Rohit Gosain, MD, of Roswell Park Comprehensive Cancer Center, to review the upfront treatment algorithm for patients with metastatic NSCLC without actionable mutations that have approved targeted therapies in the frontline setting. Together, the doctors reviewed the choice between upfront single and dual immunotherapy with or without chemotherapy, and considered follow-up treatment options, including targeted agents like KRAS inhibitors and Teliso-V.
Frontline Treatment of Metastatic NSCLC Without Mutations
When planning treatment for a patient with metastatic NSCLC, next-generation sequencing is needed to screen for actionable mutations. In the absence of targetable mutations with approved frontline therapies, PD-L1 score can help guide upfront treatment selection, as a higher PD-L1 score predicts a greater likelihood of response to immunotherapy.
For patients with a PD-L1 score of 50% or greater, the typical frontline treatment is PD-1/PD-L1 inhibitor monotherapy or PD-1/PD-L1 inhibitor plus CTLA-4 inhibitor dual immunotherapy. For patients with a PD-L1 score from 1% to 49%, the standard treatment is chemotherapy plus immunotherapy, although immunotherapy alone may still be used in patients that are elderly or have multiple comorbidities. For PD-L1–negative patients (score under 1%), chemotherapy plus immunotherapy is the standard of care. The standard chemotherapy doublet is a platinum agent plus either pemetrexed for adenocarcinomas or paclitaxel for squamous cell carcinomas.
Selecting Single or Dual Checkpoint Inhibitor Therapy
While a high PD-L1 score may predict a greater likelihood of response to immunotherapy, it is not the only factor when selecting patients for dual immunotherapy, and oncologists should consider a patient’s whole molecular profile, said Dr. Garcia. In particular, patients with STK11 or KEAP1 mutations may not respond adequately to single-agent immunotherapy, even with high PD-L1 expression, and Dr. Garcia is inclined to add a chemotherapy backbone or use a dual immunotherapy combination like ipilimumab and nivolumab. Patients with high tumor mutational burden may also benefit from dual immunotherapy.
The primary dual immunotherapy regimens approved for metastatic NSCLC in the frontline setting are based on the POSEIDON and CheckMate 9LA trials. CheckMate 9LA evaluated 2 cycles of chemotherapy with ipilimumab and nivolumab, followed by indefinite ipilimumab and nivolumab. POSEIDON evaluated 4 cycles of chemotherapy with tremelimumab and durvalumab, followed by durvalumab maintenance with one additional tremelimumab dose at Week 16. Both regimens improved survival outcomes compared with chemotherapy alone in patients with metastatic NSCLC. The difference in CTLA-4 inhibitor exposure between the regimens affects management of potential long-term immune toxicities, said Dr. Garcia.
Subsequent Treatment Options for Metastatic NSCLC
After frontline therapy, subsequent treatment options for metastatic NSCLC include Teliso-V for patients with c-Met overexpression, adagrasib or sotorasib for patients with KRAS G12C mutation, sunvozertinib for patients with EGFR exon 20 insertion, and docetaxel with or without ramucirumab for patients with no mutations. In addition, zongertinib is approved for HER2–mutated metastatic NSCLC, although its approval was recently expanded to the first-line setting.
Compared with sotorasib, adagrasib has more drug interactions and is associated with distinct side effects including QTc prolongation and creatinine elevation. However, adagrasib has more robust central nervous system (CNS) activity, and it may be preferred for patients with brain metastases. When using either KRAS inhibitor, oncologists need to counsel patients upfront and be vigilant for developing toxicities.
Closing the discussion, the doctors noted that incorporating radiation to treat brain metastasis alongside frontline or later lines of therapy is a viable approach, particularly with contemporary modalities like stereotactic radiosurgery. Partnering with radiology colleagues is an important part of a multidisciplinary approach to the treatment algorithm for metastatic NSCLC without actionable mutations.