In Practice: Systemic Treatment for Metastatic NSCLC

Grace K. Dy, MD

Grace K. Dy, MD, is an associate professor in the department of Medicine at Roswell Park Cancer Institute in Buffalo, New York. Her areas of research interest include phase I clinical trials and novel targets for lung cancer therapy.

Q: What is your overall approach when evaluating the need for systemic treatment for patients with metastatic NSCLC?

A:In terms of an overall approach, we take into consideration not just the tumor characteristics, but also the patient’s psychosocial setting. In addition, the standard medical parameters, such as performance status and comorbidities, are some of the key features that help us to devise a treatment plan.  In patients with poor performance status, hospice is most appropriate; however, with the new developments in targeted therapies over the past 5 to 10 years, there has been a change in our approach. Nowadays, even in patients with poor performance status, it is imperative that we determine if there are oncogenic drivers in their tumors that might respond to a targeted therapy that is more effective and better tolerated than traditional cytotoxic chemotherapy.  For example, the “Lazarus effect” is well-recognized with the use of EGFR TKIs. Thus, whenever possible, particularly if there’s tissue available, you want to check the mutation profile of the tumor. This is because there are several well-tolerated and efficacious targeted agents approved for frontline treatment. This list will likely expand because the field is changing so rapidly.  On the other hand, we recognize the limitations with the use of these targeted agents in lung cancer. Cancer cells evolve very fast and develop resistance to targeted therapies as a rule rather than exception. Thus to this date, we still frequently employ cytotoxic chemotherapies in our treatment regimens. The use of standard cytotoxic agents continues to have a role in our lung cancer patients.

Q: Do you have a go-to regimen for systemic treatment in patients who initially present with metastatic disease?

A:As an academician, I have available to me multiple clinical trials in various stages of development. Generally, if a patient is fit and can qualify for a suitable clinical trial, my go-to recommendation would be a clinical trial, unless I know there is a certain treatment that would be more advantageous. If the patient is not eligible for a clinical trial, or if there is no identifiable tumor mutation for which there is an FDA-approved drug, then my go-to regimen would be a platinum combination. That combination would be determined by the histology (ie, squamous cell vs nonsquamous cell NSCLC).

Q: To what extent do molecular testing and the availability of targeted therapies influence your treatment decisions for the patient with metastatic NSCLC?

A:It’s a major component of the overall management plan. Age, gender, and performance status are generally not factors that contraindicate the use of targeted treatments. Even in patients with poor performance status, as long as their life expectancy is projected to be longer than a month, it is worth performing molecular testing since the therapeutic index may be very favorable depending on the corresponding targeted agent matched to the genomic alteration. However, due to the lag-time between requesting the test and having the results available, in patients who are highly symptomatic, it is imperative to initiate systemic therapy immediately if there is no contraindication otherwise to the use of cytotoxic chemotherapy. On the other hand, even in patients with good performance status who are candidates for platinum-based combination therapy, if their  cancer-related symptoms are relatively controlled,  waiting for the test results before instituting therapy is reasonable as the targeted agents may have better efficacy and tolerability compared with cytotoxic chemotherapy.

Hongbin Chen, MD, PhD

Hongbin Chen, MD, PhD, is an assistant professor in the Department of Medicine at Roswell Park Cancer Institute in Buffalo, New York. His research interests include targeted personalized therapy in lung cancer.

Q: What is your overall approach when evaluating the need for systemic treatment for patients with metastatic NSCLC?

A:When a patient presents with metastatic disease, our first step is usually a positron emission tomography (PET)/computed tomography (CT) scan to evaluate the extent of disease. After this, we offer the patient systemic treatment consisting of either chemotherapy or targeted therapy. We look at the histology or pathology report to see what type of NSCLC the patient has; typically, patients are classified as having squamous cell NSCLC versus nonsquamous cell NSCLC. Under the nonsquamous cell NSCLC umbrella, the most common type is adenocarcinoma. This is important information; nowadays, we offer specific treatment regimens based on histology. If the patient has adenocarcinoma or any other type of nonsquamous cell NSCLC, we usually order a mutational test. 

We use a next-generation sequencing test developed at Roswell Park Cancer Institute (OmniSeq Target™) that can evaluate actionable DNA alterations in tumors. Patient specimens are evaluated for mutations in about 20 genes, includingEGFR, KRAS, BRAF,and others. In addition, we do fluorescence in situ hybridization to identify translocations, such asALK, RET, andROS-1,as well as to evaluate copy number variations inFGFR-1, MET, andHER-2. We order this testing (which typically takes 1 week to 10 days to be completed) to determine whether there is an actionable mutation, and to determine if there is a relevant clinical trial in which the patient can be enrolled.  If he or she is positive for any actionable mutations, we can also offer one of the tyrosine kinase inhibitors (TKIs), such as erlotinib, afatinib, or crizotinib. If the patient is negative, then we would initiate systemic chemotherapy. 

For patients with squamous cell NSCLC, we do not routinely order the mutational test because mutations very rarely occur in this setting. For these patients, we would offer chemotherapy, which would be different from the type of chemotherapy that is used in nonsquamous cell NSCLC.

Q: Do you have a go-to regimen for systemic treatment in patients who initially present with metastatic disease?

A:When patients present with metastatic disease, we begin by evaluating their tolerance level, ECOG performance status, and comorbidity status. The preferred regimen indicated by the guidelines, as well as the results of clinical trials, is platinum-based doublet chemotherapy. This includes cisplatin or carboplatin plus one additional agent, making it a doublet regimen. Several years ago, a study came out that showed there are survival differences when you give different chemotherapies to patients with squamous cell versus nonsquamous cell NSCLC.¹So, for a patient with nonsquamous cell adenocarcinoma NSCLC who has tested negative on all the mutational tests and who is eligible for a platinum-based doublet regimen, I usually offer cisplatin or carboplatin with pemetrexed, given for 4 to 6 cycles as frontline chemotherapy.¹Another effective regimen in this setting is adding an anti-angiogenic monoclonal antibody bevacizumab to chemotherapy of carboplatin and paclitaxel. We usually do a scan, such as a CT scan, every 2 cycles for disease evaluation.

On the other hand, for a patient with squamous cell NSCLC, we would offer the preferred regimen of a platinum doublet, cisplatin or carboplatin (depending on kidney function and general tolerance level) and an additional agent, such as gemcitabine or nab-paclitaxel; pemetrexed is contraindicated in squamous cell NSCLC. As in nonsquamous cell NSCLC, we do a total of 4 to 6 cycles of first-line chemotherapy, with a CT scan after every 2 cycles to evaluate disease response.

After the first 4 to 6 cycles of frontline chemotherapy, we may also offer maintenance therapy—that is, continuation of a single agent, such as pemetrexed or bevacizumab for nonsquamous cell NSCLC, or gemcitabine for squamous cell NSCLC. This would be offered and continued until the patient could not tolerate the chemotherapy regimen or the disease had progressed. This is also based on studies showing that maintenance therapy improves survival.²

Q: To what extent do molecular testing and availability of targeted therapies influence your treatment decisions for the patient with metastatic NSCLC?

A:Nowadays, when patients present from the community for a second opinion in our institute, in most cases, the community oncologist has already adopted the practice of ordering these tests upfront. We want to know the patient’s mutational status before we start systemic therapy, as this can really be beneficial. Although only a minority of patients are tested positive for a mutation, targeted therapy using a specific TKI has been shown to be more effective than just offering chemotherapy.

References

1. Scagliotti GV, Parikh P, von Pawel J, et al. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer.J Clin Oncol.2008;26(21):3543-3551.
2. Paz-Ares LG, de Marinis F, Dediu M, et al. PARAMOUNT: final overall survival results of the phase III study of maintenance pemetrexed versus placebo immediately after induction treatment with pemetrexed plus cisplatin for advanced nonsquamous non-small-cell lung cancer.J Clin Oncol.2013;31(23):2895-2902.