Treatment Approach for Nondriver Lung Adenocarcinoma

Heather Wakelee, MD:Bevacizumab is an important addition to chemotherapy for some patients. The challenge is that, despite it being around for over a decade, we haven’t really figured out how to best identify which patients have a significant benefit from it. We know from the ECOG 4599 trial that, when bevacizumab was added to carboplatin/paclitaxel, it significantly more than doubled the response rate. It improved the progression-free survival, and it also did that in combination with cisplatin/gemcitabine. It improved overall survival when added to carboplatin/paclitaxel, but not with cisplatin/gemcitabine, and we don’t know how much it impacts survival when added to platinum/pemetrexed. So, the results are a bit mixed.

There is definitely a group of patients who have significant benefit. I have 1 patient in my practice who has been on maintenance bevacizumab now for 4 years. She had significant liver metastases and then had a beautiful response, and she has not had any progression for all of that time. There’s something about her tumor that makes her specifically sensitive to it, but we don’t know what that is, and there are other cases like that if you talk to people in practice. So, with bevacizumab, it adds time, but at some cost of toxicity—a risk for bleeding, a risk for hypertension. Those risks are higher with people who are older. Risks are higher if they have underlying hypertension, which can increase their risk for cardiac events or stroke, though those numbers are fairly small.

It’s like everything we do: there’s a risk-benefit discussion with the patient. This is the likelihood of it helping; this is the likelihood of it harming. And as a patient becomes frailer, the harm risk goes higher. But as the disease burden goes up, the benefit goes up. So, it’s trying to find where that balance weighs out for that individual patient in making a decision.

In deciding about chemotherapy doublets, there are a lot of factors that go into it. I will occasionally give cisplatin to patients who are younger, fit, and really want to be as aggressive as possible, because there are data that show cisplatin having a higher response rate than carboplatin. Then, when I’m trying to figure out what I pair with the platinum doublet—it’s part of that doublet—there are a lot of factors that go into that as well. With adenocarcinoma, I use more of pemetrexed because of the tolerability profile: no hair loss, limited nausea, and you don’t end up with neuropathy usually. There are good data supporting its efficacy.

It also seems to work particularly well with some of the molecular driver subsets, such as theRET,ROS, orALKmutation. So, that tends to be my preference. But if I think of adding bevacizumab, it’s less clear how much the bevacizumab adds to pemetrexed. We’ll have more of that data when we get the ECOG maintenance trial that was looking at maintenance with either bevacizumab or pemetrexed or both, but we don’t know that answer yet.

With other platinum doublets, if I’m going to use carboplatin with paclitaxel, I’ll usually think about adding bevacizumab, because that’s where we have the strongest data of the additive benefit of bevacizumab. If I’m giving gemcitabine, which I don’t tend to do often outside the squamous setting, in a patient with squamous histology, I’m not going to give bevacizumab. If I’m giving gemcitabine to a patient who does not have squamous histology—maybe it’s renal function or something like that—occasionally I’ll add bevacizumab to it, but not very often. We do have good safety data and good efficacy data from the AVAiL trial, but we don’t have clear survival benefit data from that trial.

When I’m treating a patient with a platinum doublet, I usually aim to give them 4 cycles of that doublet. Occasionally, we’ll go to 6 cycles. I warn patients from the beginning. I talk with them about the fact that we’re going to aim for 4 cycles and that I will consider 6 only if we see the tumor is still shrinking and if they’re tolerating it well. But in general, even if the patient’s feeling okay after 4 cycles and we try to get in 5 or 6, we start having more issues with neutropenia and thrombocytopenia, and so it becomes more and more challenging to do that. That’s why we tend to stop at 4.

If a patient’s getting a platinum doublet with a taxane, I don’t tend to continue the taxane in a maintenance setting. However, there is an ongoing trial looking at maintenance with nab-paclitaxel, and if that comes out positive, I might consider it in that setting. We know that, if a patient’s getting a platinum doublet with pemetrexed, maintenance pemetrexed is superior to not giving maintenance pemetrexed. So, I will always give maintenance pemetrexed unless there’s a toxicity reason not to.

If I’m giving a platinum doublet with gemcitabine, I personally tend to give gemcitabine as maintenance, but there’s a lot more controversy there. The data are positive in an older trial in Europe, but not as clear in some other studies, and so there are a lot of differences in opinion about what’s the right way to go with that. If I give bevacizumab, I always continue it as maintenance; that’s how it’s been done in every trial so far. We don’t have the results from the ECOG maintenance trial yet. It’s looking at the question of whether or not we can stop it after giving the 4 cycles of a platinum doublet with bevacizumab, but we don’t know that yet.

There’s also a question of whether or not we should give pemetrexed and bevacizumab together as maintenance. There have been some data supporting that approach, so if I’ve given platinum with pemetrexed and bevacizumab together for a patient, which I will do sometimes, I tend to continue both drugs together as maintenance.

When I’m starting a patient on platinum doublet chemotherapy, I tend to get a scan after they’ve had the first 2 cycles because I don’t want to be in a situation of not knowing if that combination of drugs is helping the patient. Sometimes, clinically, we know. We know that they’re either getting better or worse and then moving back another cycle or 2 to get the scans or moving up the scans if the patient’s progressing is clearly reasonable.

There are some variations in practice, and scanning after 3 cycles as opposed to 2 is reasonable, but I tend to do it after the first 2. And then I do it after the next 2 so that they’ve had their 4 cycles, because that’s the initiation of maintenance and I want to know what the baseline is. Once a patient’s on maintenance, I tend to scan every 9 weeks or so. That’s after 3 cycles usually, so a little bit over 2 months. As long as the patient’s on active treatment and its chemotherapy, I usually tend to get scans done about every 2 months. We’ll sometimes switch to 3 if they’ve been doing well for a long time and they really hate scans, or there are various other reasons to think about that.

If the patient’s on a targeted agent, which isn’t in this case, I will initially get the scan after about 2 months. Then, if they’re clearly responding, I’ll switch to 3 months unless there’s a reason we’re suspicious that it’s not working as well any longer. There’s some variation in that, but that tends to be my practice. I also tend to get CT scans and not as many PET scans. PET scans are most useful if the patient has bone metastases or something else we’re not going to be able to track as well with the CT scans, but it adds a lot of additional radiation and very rarely does it change our impression beyond what the CT shows. So, I tend to get fewer of those, but that’s another area where there’s some controversy.

Transcript edited for clarity.

• A 70-year-old Caucasian female presented with mild dyspnea and no chest pain.
• She has also experienced recent, rapid weight loss (>10 pounds in 1.5 months) without any changes in her diet or exercise pattern.
• She gave up smoking 7 years ago (2 packs per day for 35 years).
• Her medical history is unremarkable:
  • A few years ago, she was diagnosed with gastroesophageal reflux disease that was clinically and endoscopically confirmed.
  • She has no history of cancer in the family.
  • Her cardiac workup is negative.
• Her PS by ECOG assessment was 0.
• Chest x-ray showed a 2.5-cm lesion in her right lower lobe.
• CT scan of the chest and abdomen confirmed the presence of the lung mass in addition to numerous bilateral nodules, all about 5 to 9 mm, in the right upper and lower lobes and the left upper and lower lobes, as well as enlargement of hilar lymph nodes. In addition, 3 small nodules were seen in the liver, measuring 1 to 2 mm.
• PET/CT imaging showed 18F-FDG uptake in the lung mass, left hilar lymph nodes, and liver.
• MRI of the brain was negative for intracranial metastases.
• A core biopsy of the lung nodule was performed:
  • Its morphology and molecular phenotype (TTF-1-positivity) supported a diagnosis of lung adenocarcinoma.
  • Mutational testing showed absence of driver mutations (i.e., was negative forEGFR, ROS, andALK).
  • PD-L1 testing showed PD-L1 expression of 35%.
• The patient was diagnosed with stage IV metastatic NSCLC.
• The patient was started on therapy with a chemotherapy doublet and bevacizumab (Avastin).
• At her next follow-up 2 months later, her CT scan showed the right lung mass to be stable, with no new lesions. She has improved symptomatically.