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Division of Hematology and Medical Oncology
UC San Diego Moores Cancer Center
La Jolla, California
Sandip P. Patel, MD, has disclosed that he has served on advisory boards/as a consultant for AstraZeneca, Bristol-Myers Squibb, and Merck and has received funds for research support from AstraZeneca, Bristol-Myers Squibb, Nektar, Guardant, Illumina, Lilly, and Tempus.
For patients with metastatic non-small-cell lung cancer (NSCLC) without a targetable driver gene mutation sensitive to existing small molecule inhibitors, there are several frontline immunotherapy options from which to choose. These typically include immunotherapy alone for biomarker‑selected populations: for high PD-L1–expressing (TPS ≥ 50% by 22C3 IHC, or TC3/IC3 by SP142 IHC) tumors, single-agent pembrolizumab or atezolizumab; and for low PD-L1–expressing (≥ 1%) tumors, pembrolizumab monotherapy or combination immunotherapy using nivolumab plus ipilimumab. Chemotherapy plus immunotherapy is my preferred option for most patients with metastatic NSCLC regardless of PD-L1 expression levels, although for patients with lower volume disease and PD-L1 > 50%, I consider immunotherapy without chemotherapy. However, in the absence of clinical trials directly comparing these regimens, the optimal frontline immunotherapy treatment for a given patient with metastatic NSCLC remains unclear. This setting with multiple reasonable treatment options available is ideal for shared decision-making with your patients.
Themes Informing Choice of Optimal Frontline Immunotherapy
There are multiple themes that can help inform patients when discussing which frontline immunotherapy-based regimen may be best for them. The first key theme relates to adequate molecular testing for the patient and making sure that their tumor does not have targetable driver mutations for which small molecule inhibitors represent the optimal therapy.
Once the presence of actionable molecular driver mutations has been ruled out, the next key determinant in treatment decision-making is to assess tumor PD-L1 status—which represents an important layer in identifying the most effective immunotherapy option for a particular patient. For patients with high PD-L1–expressing tumors (≥ 50% of tumor cells or ≥ 10% of immune cells), single-agent immunotherapy may be the best choice, in particular for those with low‑volume disease. However, for patients with high disease burden or acute symptoms that require immediate attention with systemic therapy, chemoimmunotherapy may be the better choice.
For patients with low PD-L1–expressing tumors (≥ 1%), immunotherapy combinations represent their optimal treatment option, including chemotherapy plus pembrolizumab, chemotherapy plus atezolizumab with or without bevacizumab, and nivolumab plus ipilimumab with or without chemotherapy. Patients whose tumors do not express PD-L1 (< 1%) are also candidates for most of these options, with the exception of immunotherapy alone (pembrolizumab or nivolumab plus ipilimumab). As mentioned above, there have not been formal comparisons among these different regimens, so the next layer of decision-making with patients relates to discussing issues around the impact of treatment on their cancer-related symptoms and both medical and financial toxicity.
Discussing Impact of Therapy on Tumor Symptom Burden With Patients
As I discuss therapy options with my patients, it is important to me that they understand that their overall symptom burden from their cancer can improve with treatment over time and that this can be achieved with several of the chemoimmunotherapy options currently available. This can be illustrated with the recent patient‑reported outcomes data from CheckMate 9LA presented by Reck and colleagues at ESMO 2020.
Patient-Reported Outcomes From CheckMate 9LA
In this report, disease‑related symptomatic burden based on the Lung Cancer Symptom Score Average Symptom Burden Index (LCSS ASBI) improved over time with nivolumab/ipilimumab plus 2 cycles of chemotherapy, which is what would be expected in patients who have a response and symptoms related to their cancer abate. Furthermore, overall health status from baseline improved and time to definitive deterioration based on LCSS ASBI score, which also relates to cancer-related symptoms (eg, anorexia, symptom distress, dyspnea), was substantially delayed (HR: 0.66) in patients receiving chemoimmunotherapy as compared with those treated with 4 cycles of chemotherapy. These data show that even patients who receive a quadruplet therapy with 2 chemotherapies and 2 immunotherapies experienced improved quality of life related to a reduction in their overall symptom burden.
Discussing Treatment-Related Toxicities With Patients
I then add the layer that each regimen can also be associated with particular toxicities: Any time we add an immunotherapy to chemotherapy, we get all the adverse events (AEs) of the chemotherapy backbone (eg, cytopenias) as well as immune‑related AEs (eg, most commonly endocrine dysfunction, but more concerningly pneumonitis or colitis), which can vary across the different regimens.
When we think about adding a CTLA-4 antibody to a PD-1 antibody, whether this is ipilimumab plus nivolumab alone or in combination with chemotherapy based on the CheckMate 9LA study, the predominant toxicity of concern driven by ipilimumab is immune‑related colitis. In CheckMate 9LA, approximately 6% of patients receiving ipilimumab plus nivolumab combined with chemotherapy experienced high‑grade colitis. For comparison, in KEYNOTE-189 and KEYNOTE-407, 1.0% and 2.4% of patients receiving chemotherapy plus pembrolizumab, respectively, experienced high-grade colitis. In addition, high-grade immune‑related hepatitis occurred in approximately 4% of patients receiving ipilimumab plus nivolumab and chemotherapy in CheckMate 9LA whereas it was 1% in patients receiving chemotherapy plus pembrolizumab in KEYNOTE-189.
As would be expected, chemotherapy-related AEs are more pronounced in patients who receive more chemotherapy. For example, in KEYNOTE-189, which used the standard 4 cycles of carboplatin and pemetrexed chemotherapy followed by pemetrexed as maintenance therapy, approximately 18% of patients developed high-grade anemia. On the other hand, if we look at similar data in CheckMate 9LA, which included only 2 cycles of platinum-doublet chemotherapy without maintenance chemotherapy, high-grade anemia occurred in only approximately 9% of patients because less chemotherapy was given.
AE kinetics is another important consideration when thinking about immune‑related AEs relative to chemotherapy-related AEs. Many immune-related AEs can emerge weeks, if not months, into therapy and often require a high index of suspicion to identify whereas chemotherapy-related AEs follow a more predictable course that we as oncologists are very familiar with. Both immune colitis and immune hepatitis are generally responsive to corticosteroids as initial treatment, and second-line immunosuppression options are robust. The incidence of immune-related pneumonitis does not appear to be elevated with utilization of ipilimumab-containing regimens in this setting.
Putting It Into Practice
With all that said, what does shared decision-making look like in practice? At an office visit, I typically walk patients through the complete menu of treatment options with high-level evidence for their particular disease scenario and then share with them what I would do if I were in their shoes. I am not telling patients what to do by any means but instead saying that I would recommend drug A over drug B because of specific factors related to PD-L1 status, disease burden, and potential AEs, as discussed above, but also along with details as simple as how often they have to come in for infusions—some regimens require fewer office visits and some require more office visits, which matters in a COVID-19 environment. For patients with metastatic nonsquamous NSCLC, it is crucial to await results of genomic testing to ensure patients receive optimal targeted therapy and avoid the risk of immune-related AEs from ineffective use of immunotherapy in this setting. Patients in need of urgent systemic therapy awaiting genomic results would be best served with chemotherapy alone for the first cycle of therapy, with integration of immunotherapy in subsequent doses.
I also want to understand patients’ goals in fighting their cancer, so we can work together to best tailor their therapy. For example, some of the chemotherapy-related AEs, such as hair loss may be particularly problematic for certain patients, leading us to choose a regimen that will minimize their chance experiencing this AE. As we think about personalized medicine, it is more than just DNA testing and immune profiling, it is really about understanding what is important to a patient and how we can help best inform them so that we can select the optimal therapeutic strategy that takes into account their specific needs and goals.
Because presently there is no specific biomarker that can point you to one particular immunotherapy-based or chemoimmunotherapy-based regimen over another, it is key to have open discussions with our patients about what they might expect with each of these different regimens. Helping patients understand the potential improvement with treatment in their cancer-related symptoms and the potential toxicities associated with each regimen is critical to shared decision-making and making the best choice for each of our patients.
Patient-Focused Online Treatment Decision Tool for Unresectable Stage III or Metastatic NSCLC
For a resource developed by 5 lung cancer experts to help patients better understand their diagnosis and treatment options and to become partners with the oncology team in their cancer care, please share this link, www.clinicaloptions.com/PatientLungTool, with your patients.
How do you discuss available frontline immunotherapy options with your patients diagnosed with metastatic NSCLC? Please share your thoughts and questions in the discussion box below.