Nathan Pennell, MD, PhD

Question

After a patient is diagnosed with advanced nonsqamous non-small cell lung cancer, what are the treatment options you consider? What are the key patient factors that influence your decision making for initial therapy selection and treatment planning?

Answer

When I first meet a new patient who has been diagnosed with advanced nonsquamous non-small cell lung cancer there are a number of different factors that I take into account to decide the best treatment. There are factors that are related to the cancer itself and then there are, of course, factors related to the patient. From the standpoint of the cancer, the first thing I need to know is the histology and the subtype lung cancer. Most patients will have adenocarcinoma, the most common type of nonsquamous non-small cell lung cancer, but even after that it’s important to perform a number of tests in order to help pick the best treatment. One test we perform for all patients with non-small cell lung cancer is immunohistochemical staining for PDL1, which helps guide the appropriate use of immune therapy. We also need a series of molecular tests to look for targetable genes that have treatments that are specific to those genetic derangements, whether they be a mutation or a gene fusion that is driving that cancer to grow. The tests that we absolutely have to test in every nonsquamous patient in 2018 are epidermal growth factor receptor (EGFR) mutations, ALK gene rearrangements, ROS1 gene fusions, BRAF V600E mutations. That is the minimum panel, there are a lot of other potential genetic mutations or gene fusions that are already potentially targetable and useful, such as MET mutations, RET gene fusions, and HER2 mutations. There is also something called tumor mutation burden, which may over the next year or two become much more useful. Typically it makes the most sense to do a broad molecular panel for all of these biomarkers at once, doing it this way is often cheaper and it takes less material, patients don’t run out of tissue and have to get repeat biopsies. So once I get all of these biomarkers, the histology, the PDL1 testing, and then these molecular tests, I typically have all the information I need to pick the best treatment for advanced non-small cell lung cancer.

The other factor that must be taken into account is the patient factor, how healthy is the patient, what kind of other comorbid conditions are present (eg, emphysema, chronic kidney disease, rheumatoid arthritis, lupus) and will those conditions influence the ability to administer certain treatments. It’s also important to consider how healthy the patient is in general — whether the patient is active and taking care of themselves at home independently or if they somewhat frail and debilitated, these are the factors that influence how aggressive treatments can be. Furthermore, the patient’s own attitude towards their cancer is very important, whether or not they are interested in using the most appropriate and potentially cheatreatments for their cancer and potentially willing to put up with some side effects in order to live longer with their disease or if they are more focused on the quality of their life and seeking to minimize symptoms from their treatment.

Considering the individual patient and all of these factors together I will seek to develop a personalized treatment plan that meets the patient’s needs.

Question

For patients that do not have molecular biomarkers for which there are FDA-approved targeted therapies, what are the indicators that a patient is an appropriate candidate for maintenance therapy? What factors do you consider when determining the appropriate treatment for those patients?

Answer

In 2018, despite there being many potential molecular targets to test for, the reality is that the majority of patients with nonsquamous non-small cell lung cancer are not going to have an actionable mutation found in their cancer. Outside of a group of approximately 20% of people, most patients will still need a more traditional treatment. In these cases, the traditional treatment is chemotherapy and the most common type of chemotherapy that is used in the United States is a combination of a platinum drug (most likely carboplatin) and pemetrexed, which are given together every 3 weeks for up to 4 treatments. This is followed by pemetrexed, which is continued more or less indefinitely and is called maintenance therapy. There is very good evidence, via a couple of large randomized trials, that there is a benefit in terms of survival and how long patients live when maintenance pemetrexed is added as long as patients are tolerating the treatment.

A recent change, within the last year, came from the KEYNOTE-189 trial. This trial used the same chemotherapy backbone of carboplatin and pemetrexed and then randomly assigned in a 1:1 ratio patients on the trial to receive either a placebo or pembrolizumab, an immune checkpoint inhibitor antibody against PD1. What the researchers found is that patients who received the combination of chemotherapy and pembrolizumab lived substantially longer and had a longer control of their cancer with the addition of the immune therapy. This was found across all levels of expression of PDL1 immunohistochemical biomarker. In those cases, after the initial 3 drug combination is given for 4 cycles, typically maintenance therapy is given (pemetrexed with pembrolizumab) for as long as the cancer remains under control. There is some debate currently about whether, after a couple of years, you need to continue the immune therapy if the patient is having a good response, it may be possible that they will continue to benefit even without continuing the drug, but that is still under review.

The final factor that is considered when determining treatment for these patients is related to the initial PDL1 test, approximately 30% of people with nonsquamous non-small cell lung cancer will have an extremely high level of expression of PDL1 (> 50%), when that is the case we know that patients have a very good chance of responding to pembrolizumab along (without the addition of chemotherapy). In the KEYNOTE-024 study patients had a higher response rate, longer duration of control, and lived longer on average when they received pembrolizumab alone compared with the standard chemotherapy treatment. For those patients ― approximately one-third of patients — it may not be necessary to give chemotherapy, they may be able to receive pembrolizumab alone, which often results in fewer side effects compared with chemotherapy alone or the combination of pembrolizumab and chemotherapy.

Question

What are some of the common side effects of treatment? Are there specific side effects associated with particular treatments that you look out for?

Answer

There are 3 different buckets of treatment that are used in 2018. There is traditional chemotherapy, which often has side effects such as fatigue (this is commonly seen most in the week of so after each treatment), some patients also experience nausea and vomiting, and there is also a risk of infection for these patients.

Beyond chemotherapy, there are immune checkpoint inhibitors, such as pembrolizumab, nivolumab, atezolizumab, which are all approved for lung cancer. Immune checkpoint inhibitors have completely unique side effects that are very different from chemotherapy. Because these treatments remove one of the protections the body uses to prevent autoimmunity (or self immunity) there is a greater risk that the immune system will also attack other parts of the healthy body. The most common side effects that are seen due to these drugs are skin rash, cramps and diarrhea (associated with inflammation of the bowels), and inflammation in other parts of the body such as the liver or the thyroid gland. The most serious side effect that is important to look out for, but thankfully only occurs in a small percentage of patients, is pneumonitis.

Finally, targeted agents are the third bucket of treatment that need to be considered in terms of potential side effects. There are different types of targeted agents and it is hard to generalize about the side effects that patients might experience, but the most common class are EGFR inhibitors (erlotinib, afatinib, osimertinib) which can be associated with dry skin, rash, and diarrhea.

Question

What are your strategies for managing these side effects and how do you counsel patients on what to expect?

Answer

Upfront education for patients is a big part of my strategy for side effect management. Every time I start a patient on treatment I reiterate the potential side effects. Patients learn best by hearing things over and over and so when the patient comes for their first treatment, whether it be chemotherapy or immune therapy or picking up their prescription for a targeted agent, a nurse will sit down with them, give them literature about the drug, go over the potential side effects in detail, and discuss what to do and who to call if they start to experience any side effects or have any problems.

For patients who are receiving chemotherapy, the management strategy is often instruction on how to take nausea pills when experiencing nausea or what to do if they develop a fever.

For patients receiving immune therapy, I often need to determine if the patient’s side effects are severe enough that they need to be started on steroids, which are the most common treatment for serious side effects related to immune therapy

For targeted agents, for example anti-EGFR medications, I often prescribe oral antibiotics or topical treatments (creams or even topical steroids) to treat rash and antidiarrhea medications for diarrhea.

Ultimately the patient’s specific management plan is tailored to the personalized treatment plan and there is really no substitute for giving patients the opportunity to call their doctor if they are having a problem. I encourage my patients to call me and my team if they are experiencing any symptoms that they are worried about.

Question

Is there any recent research may offer new treatment options for patients with nonsquamous non-small cell lung cancer? What are you looking forward to in terms of research in this area?

Answer

There is so much going on in the lung cancer field right now that it is very difficult to keep up with everything that is happening. It seems as though the way that we treat lung cancer is changing significantly every few months. The major changes that have happened in the last year have been the addition of immune checkpoint inhibitors, such as pembrolizumab, to chemotherapy, which is now the standard for almost everyone with nonsquamous non-small cell lung cancer, as long as they don’t have some type of medical condition that would prevent them from safely receiving these drugs, and recently has expanded to patients with squamous non-small cell lung cancer with a major trial showing that this treatment benefits them as well. There are trials that have been presented that suggest that other chemotherapy regimens that include antiangiogenic drugs, such as bevacizumab, when added to immune checkpoint inhibitors may also prolong patient survival, which will expand the number of choices we have when deciding on treatments for patients. In these cases it doesn’t seem to matter if the patient has high levels of PDL1 or not, it seems that almost all patients are benefitting from the combination of these drugs. Recently a clinical trial has suggested there may be benefit for patients who have PDL1 levels greater than 1%, which would mean that instead of only 30% of patients who would benefit from just an immune therapy without chemotherapy, the number may actually be as high as 66% of patients. However, I think this is still debatable, and for patients who have low levels of PDL1 expression I think they may be better served with chemotherapy and immune therapy but it will be interesting to see what options become available for these patients in the future. Finally, we are always finding new potential targets for the targetable drugs. Probably 20% to 25% of patients are currently eligible for targeted agents, but within the next year I would anticipate that there is going to be at least 2 more targets that we will be looking for, which are mutations in the MET gene (occurring in approximately 5% of patients with nonsquamous non-small cell lung cancer) and RET gene fusions (occurring in approximately 2% of nonsquamous non-small cell lung cancer). Hopefully in the near future we will see one-third or more of patients become eligible for targeted treatments, which potentially have fewer side effects and longer control of cancer than traditional treatments.