Tailoring Lung Cancer Treatment: Balancing Immunotherapy, Chemotherapy, and Targeted Therapies


Insight into key patient characteristics and considerations in determining the optimal approach for treating metastatic non-small cell lung cancer, including the role of chemotherapy, immunotherapy, and targeted therapy.


62-year-old woman presented to the ED with vague complaints of voice changes and cough.

  • She gave a history of a recent, 11-pound weight loss.

Past Medical, Family, and Social History

  • Hypertension, controlled with ACEi 10 mg PO QD
  • Hyperlipidemia, treated with atorvastatin 20 mg PO QD
  • COPD, treated with maintenance fluticasone furoate, umeclidinium, and vilanterol (100/62.5/25 mcg oral inhalation QD)
  • Mother: deceased at 65 years-of-age from lung cancer
  • Former smoker: 10-15 pack years. Quit tobacco habit 25 years ago.

Physical Examination

  • Current weight: 125 lbs.
  • ECOG PS 1

Diagnostic Workup

  • CT of Thorax: discovered a 4 cm nodule in the left, upper lobe
  • CT of Abdomen reveals metastases to the liver
  • MRI of Brain: negative for brain metastases

Final Pathology: consistent with squamous cell carcinoma; metastatic stage IV

PD-L1 expression by IHC: 0%

NGS: No actionable mutations


  • Therapeutic options were reviewed with the patient and family.
  • She was initiated on:
    • Nivolumab 360 mg IV Q3W + ipilimumab 1 mg/kg IV Q6W + 2 cycles of chemotherapy Q3W


Sandip P. Patel, MD: There are multiple salient patient characteristics that determine whether to add chemotherapy to the patient’s immunotherapy backbone. One is the patient’s PD-L1 status. For example, patients who are PD-L1 0% or PD-L1 negative, their best therapeutic approach almost universally, whether introducing a CTLA-4 inhibitor or not to the PD-1 backbone, includes chemotherapy. Also, there are certain groups of patients in which the burden of metastases is quite high. The so-called visceral crisis, in which chemotherapy can help debulk the tumor, while it takes the weeks it takes for the immune system to get activated.

For me, I consider adding chemotherapy based on the overall burden of disease with the potential for those patients who have liver metastases maybe to get preferential benefit from chemotherapy because historically, some data sets have showed a lower response rate with immunotherapy approaches. In terms of the site of metastasis, I think one area that’s key is for those patients with brain metastases, the activity of immunotherapy is not so high that I would rely on the immunotherapy or chemoimmunotherapy alone to treat their brain metastases. Working closely with our radiation oncology colleagues to integrate stereotactic radiotherapy approaches to the patient’s brain metastases, I think, is key and something I’ll typically do before I start therapy with immunotherapy or chemoimmunotherapy for these patients. If, in the case we discussed earlier, the patient had brain metastasis, what I would have done is had them start their stereotactic radiosurgery with radiation oncology colleagues first and then started them on chemotherapy plus anti–CTLA-4 plus anti–PD-1–based regimen after the completion of radiation.

The most important tests for a patient with a new diagnosis of metastatic non–small cell lung cancer, particularly nonsquamous histology, are the molecular features for those patients with EGFR, ALK, ROS1, and likely other driver mutations, so BRAF may be unique here and KRAS, of course. Those patients benefit from oral targeted therapy. For everyone else, immunotherapy or chemoimmunotherapy represent their best therapeutic option. For those patients with PD-L1 greater than 50%, the opportunity to use an anti–PD-1 or anti–PD-L1 monotherapy is available. Otherwise, for the remainder, the use of chemotherapy and anti–PD-1 plus chemotherapy approach may make more sense for that patient population.

For those patients who are PD-L1 negative, squamous histology, with brain metastases, or STK11/KEAP1, I do consider the introduction of an anti–CTLA-4 agent in addition to chemotherapy and anti–PD-1 directed approaches. However, much of these data are from retrospective cohorts, and I think the key concept is that if we start with the base of chemoimmunotherapy, understanding whether we can drop chemotherapy…and add CTLA-4 is really focused on the edges of maximizing an immune response, but that the foundation remains appropriate. Molecular testing, giving targeted agents to those patients with actionable driver mutations such as EGFR, ALK, ROS1, and so on. For those patients, typically with smoking-related alterations, adopting a chemoimmunotherapy approach is key.

For those patients who progress on frontline immunotherapy, in the second line or refractory space, there are multiple options. For those patients with oligoprogression, meaning they may have had an initial response, but they may have 1 or 2 sites of disease for which their cancer is growing, continuing the immunotherapy but adding SBRT [stereotactic body radiation therapy] may be a reasonable approach. For those patients with polymetastatic progression in multiple places, switching from immunotherapy to a different treatment would be most reasonable. This can hopefully include a clinical trial, but in the absence of a clinical trial, regimens such as docetaxel, docetaxel/ramucirumab, or other chemotherapeutics such as gemcitabine may be reasonable options for those patients.

Transcript is AI-generated and edited for readability.

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