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Metastatic NSCLC Immunotherapy FAQs
Immunotherapy and Beyond in Metastatic NSCLC: Expert Answers to Your Questions

Released: January 19, 2024

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Key Takeaways
  • In the management of metastatic NSCLC, histology, gene expression, and molecular profiling can help inform selection of systemic therapy.
  • Chemotherapy plus a PD-1/PD-L1 inhibitor with or without a CTLA-4 inhibitor is the standard systemic treatment for metastatic NSCLC with no actionable mutations and <50% PD-L1 expression.
  • For patients with metastatic NSCLC receiving immunotherapy with CNS metastasis, observation can be considered for small (<1 cm), stable, or asymptomatic brain metastasis without edema.

Non-small-cell lung cancer (NSCLC) often is associated with gene mutations (eg, KRAS, STK11, KEAP1) that can modify the disease response to treatment. In recent years, the addition of immunotherapy to chemotherapy has led to patients living longer and to some potentially being cured of their lung cancer. In this commentary, expert faculty answer frequently asked questions about how they make decisions for incorporating chemoimmunotherapy into the management of metastatic NSCLC.

How are systemic therapy decisions made for patients with advanced/metastatic NSCLC?

Elaine Shum, MD:
We are very fortunate to have several immunotherapy and chemoimmunotherapy options and combinations to consider for our patients with advanced NSCLC who do not have actionable mutations. However, there are some selection criteria that often guide us toward the correct treatment. The first is the tumor histology, and there are different indications for different regimens based on that—adenocarcinoma vs squamous cell carcinoma, for example. The PD-L1 expression level/score is another determinant as to whether we should be using immunotherapy alone or if we should combine it with chemotherapy.

The number of treatment options and potential combinations is increasing, making it paramount to select the best regimen for a given patient.

Molecular profiling also is starting to “take off” in terms of improving our understanding of how lung cancers with disease-modifying mutations such as KRAS, STK11, and KEAP1 may respond to immunotherapy and chemotherapy combinations. For this reason, I think that all patients with metastatic NSCLC should receive molecular profiling of their disease. Based on data from subgroups in the phase III POSEIDON study evaluating durvalumab with fixed-duration tremelimumab (for up to 4 cycles) plus platinum-based chemotherapy in patients with metastatic NSCLC, those with KRAS, STK11, and KEAP1—a group of patients with poor prognosis—did well with chemoimmunotherapy when looking at progression-free survival (PFS) (HR: 0.47-0.94) and overall survival (OS) (HR: 0.43-0.62).

Christine M. Bestvina, MD:
We also have seen data from the phase III KEYNOTE-789 looking at the combination of pemetrexed plus platinum-based chemotherapy and pembrolizumab for patients with metastatic NSCLC harboring EGFR mutations and resistantance to tyrosine kinase inhibitor (TKI) therapy. This trial was not significant for PFS or OS. For me, that really brought home the point that chemotherapy alone is the preferred systemic regimen for patients after progression on osimertinib. Other targetable alterations, namely BRAF and MET mutations, tend to have a better response to immunotherapy compared with those carrying EGFR-, ALK-, and ROS1-mutated NSCLC. Having a good understanding of what that mutational profile is and how to make those decisions is paramount.

Another factor that I also take into consideration, particularly for patients whose tumors expressed high levels of PD-L1, is whether they are a smoker or a never smoker. These data suggest that patients who do not have a history of smoking and whose disease is PD-L1 high still need chemotherapy to prime that immunotherapy for a good effect. Also, it may be worth noting that the consensus is to consider chemoimmunotherapy for those with PD-L1 expression <50% and single-agent immunotherapy for those with PD-L1 ≥50%. To reiterate, even with PD-L1–high status in a never smoker and no targetable alterations, I will give combination chemoimmunotherapy.

Another important factor to note is patient preference. When a patient walks into your office, he or she already may have an idea of whether they want a chemotherapy-free treatment option, but you may have a conversation about whether they are open to chemotherapy. I also take into consideration the patient's overall health status or certain comorbidities that will affect choice of chemotherapy. Additionally, we know that patients who have a history of transplant and/or uncontrolled autoimmune disease should not receive immunotherapy.

Can patients benefit from restarting immunotherapy at progression after a previous response?

Christine M. Bestvina, MD:
A pooled analysis from the KEYNOTE trials of patients who had completed 2 years of immunotherapy looked at what happened when patients with progression were rechallenged with immunotherapy. Patients did continue to have a benefit, and duration of response had not been reached at the time of this data publication. Median OS in this group was 27.5 months (95% CI: 21.7 to not reached), with a median PFS of 10.3 months (95% CI: 5.6-14.0). For me, these are solid data to support the practice that many of us already were doing— rechallenging patients with immunotherapy if they previously responded.

Dr Shum, what are you doing for your patients who make it to 2 years on immunotherapy?

Elaine Shum, MD:
Current studies were designed with 2 years of immunotherapy, so we have a discussion with patients to determine whether they want to continue treatment. I think the data that you cite help to support potentially stopping at 2 years and that if they were to have recurrence, you could rechallenge with immunotherapy and start again.

I will say that after 2 years of coming in for infusions, many patients feel uncomfortable not to be receiving any treatment. So, even just from the psychological standpoint, as long as they are not having any major immune-related toxicities or adverse events from this treatment, it is reasonable for patients to continue immunotherapy after the 2-year point.

Christine M. Bestvina, MD:
It can be a tough discussion to have with patients because, as you said, many are hesitant to stop treatment. This is definitely an area where I am hoping that, as the technology behind circulating tumor DNA continues to evolve, we can use additional technology to help us make this decision. I know this is not evidence based, but in my practice, I also may check a PET scan and a circulating tumor DNA test to help with shared decision making.

For patients with asymptomatic brain metastases, can stereotactic radiosurgery be omitted if the patient is receiving immunotherapy? Does immunotherapy have good central nervous system penetration? What do you do for a patient with asymptomatic brain metastases who is starting immunotherapy?

Elaine Shum, MD:
For patients whose tumors have driver mutations, we know that several TKIs do have central nervous system penetration. For immunotherapy, we are seeing that there is disease control in the brain. For someone who has asymptomatic brain metastases, how you manage it will depend on the size and location of the tumor and what can be seen in imaging. At our center, we refer patients with small, asymptomatic brain metastases for stereotactic radiosurgery to achieve disease control early. When patients do go on to receive immunotherapy, we see that they continue to have controlled brain disease.

Christine M. Bestvina, MD:
As oncologists, we have become comfortable monitoring NSCLC brain metastases as long as they are <1 cm, asymptomatic, and not associated with edema. We are seeing mounting clinical evidence to support how much efficacy immunotherapy has in the brain—like what we have seen in the phase II Atezo-Brain study evaluating atezolizumab in combination with carboplatin and pemetrexed in advanced nonsquamous NSCLC with untreated brain metastases. Extrapolating from some of the data in melanoma, we also know that ipilimumab plus nivolumab have good central nervous system penetration, and the dual checkpoint blockade appears to have improved efficacy in patients with brain metastases. To reiterate, as long as brain metastases are small (<1 cm) and asymptomatic and there is no edema, we often observe them with a follow-up brain MRI from diagnosis.

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How do you incorporate chemoimmunotherapy as a standard treatment for your patients with advanced/metastatic NSCLC and no actionable mutations? Join the discussion by answering the polling question and posting a comment.

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