Molecular Targets Could Be Unraveled for Patients With Non-Driver NSCLC

Millie Das, MD

Within the non—small cell lung cancer (NSCLC) population, patients without known molecular drivers make up the majority of cases, explains Millie Das, MD. However, studies are investigating more regimens to improve the efficacy for these patients.

For example, the ongoing ECOG E-5508 trial is studying bevacizumab (Avastin) and pemetrexed disodium alone or in combination following induction therapy with carboplatin/paclitaxel/bevacizumab to determine whether outcomes are improved in treating patients with advanced nonsquamous NSCLC (NCT01107626).

Additionally, next-generation sequencing platforms are evolving to detect some of the less-common molecular alterations in patients without EGFR, ALK, or ROS1 drivers—including HER2, BRAF, and RET.

“The goal is to identify more of these driving genetic alterations and to come up with treatments that we can target,” said Das in an interview during the 2017 OncLive^® State of the Science Summit^TM on Advanced Non—Small Cell Lung Cancer.

OncLive: What did you highlight regarding these patients with non-driver NSCLC?

How do you currently use bevacizumab? Can you use it in both the frontline and maintenance settings for a patient?

Das, a clinical assistant professor of medicine — oncology at Standard Medicine, explained the difficulties of the non-driver NSCLC patient population, interesting clinical trials that could reshape therapeutic options, and her belief that these patients do have molecular targets that have yet to be identified.Das: I discussed the treatment options for the majority of our patients who actually don’t have known driver genetic alterations. I talked about the data for chemotherapy and targeted agents—pemetrexed as a frontline option, but also as a maintenance option for our patients. I reviewed the data for bevacizumab, as well, to look at it in the frontline and maintenance settings, and touched upon some of the recent data with necitumumab (Portrazza) and ramucirumab (Cyramza) that have gained FDA approval in the treatment of lung cancer. For bevacizumab, the main thing is the patient selection. In the upfront setting, you would want to think about it for patients with good performance status. We know that the ECOG E-4599 study that looked at bevacizumab examined it in ECOG performance score 0 and 1 patients. These are really fit and likely younger patients. We know that, with patients over the age of 70, there is a higher risk of toxicity—so you want to be mindful of that. For patients who are having ongoing hemoptysis, you’re not going to want to offer that.

Are there combination regimens being explored with bevacizumab?

Again, patient selection plays a very important role. [You need to be] talking to the patient about the additional benefit with the addition of bevacizumab to standard chemotherapy, discussing the increased risks and the benefits, and involving them in the decision to add that as part of their treatment strategy. That is an area of ongoing interest and research. The ECOG E-5508 study is looking to see whether the combination of pemetrexed and bevacizumab as maintenance treatment after upfront treatment with carboplatin/paclitaxel/bevacizumab is any better than maintenance bevacizumab alone or maintenance pemetrexed alone. That will be a really interesting study to see what that shows in the end.

What are your guidelines for maintenance therapy?

Can you highlight the activity we have seen with necitumumab and ramucirumab?

For patients who have started on treatment with carboplatin/pemetrexed/bevacizumab, it is very reasonable to continue them on the pemetrexed/bevacizumab maintenance. Again, [you need to be] sitting down with the patient, having a discussion, and talking about how they’re doing with the treatment. Some patients are just glad to be done with their upfront therapy and don’t want to be coming in every 3 weeks, especially if transportation or distance is an issue. You can talk to them about whether this is something they would want to pursue or if they would rather have a break. It is generally for as long as the patients are tolerating it and as long as the treatment is working. I’ll continue to get surveillance imaging every 2 to 3 months, and you’ll obviously be seeing the patient every time they’re coming in for infusions. If they’re starting to develop toxicities, then I’ll have a low threshold to stop that treatment and give patients a break. Certainly, if there is disease progression, you are going to want to stop that and talk about next treatment options. The SQUIRE study looked at the addition of necitumumab to standard cisplatin/gemcitabine in patients with squamous lung cancer, and it did show a survival benefit with the addition of necitumumab; it did lead the FDA to approve this drug.

This non-driver population is the majority of patients with NSCLC. What does the future of this landscape look like to you?

I personally have had a little bit of trouble adding this drug to my patients with squamous cell lung cancer because they do tend to be older and sicker, so just standard chemotherapy is not easy for them—and then, when you’re adding on an additional agent, it can be tough. As we move forward, the major goal here is to continue to identify the driving genetic alterations. Of course, we have the EGFR-mutant and the ALK-positive patients. However, we have recently been able to discover BRAF, HER2, and other driver genetic alterations that we might see mutated in other malignancies. We are seeing that in lung cancer and it is pretty exciting.

We know that the FDA recently approved the combination of trametinib (Mekinist) and dabrafenib (Tafinlar) in patients with BRAF-mutated lung cancer, so that is where we are really headed toward. We will probably not be offering patients systemic intravenous chemotherapy, when we can actually provide them with a targeted drug.

What are the main points for the community oncologist to apply in clinical practice?

We know that KRAS is commonly mutated in lung cancer, but we don’t yet have a drug that’s effective specifically for patients with KRAS-mutant lung cancer. Hopefully, we will develop that in the next 10 years. We could be able to offer that patient with a KRAS mutation a targeted treatment upfront rather than chemotherapy. For all nonsquamous histology, we should be getting adequate tissue—to be able to send for EGFR, ALK, and ROS1. We do have good, oral targeted agents for patients who do have these driving genetic alterations. For these patients who don’t have these mutations, it is very reasonable to send for next-generation sequencing using one of the many available platforms. This is only because we have been able to identify other driving genetic alterations—be it BRAF, HER, or RET—and we do have some targeted agents that are approved for these different alterations. We should really be moving towards that when we don’t find any targets.

We have come a long way with chemotherapy so, with the approval of pemetrexed, that tends to be a drug that most of our patients can tolerate very well. That is a drug that I will offer to a lot of my patients—especially for those who don’t want to lose their hair or have underlying neuropathy, in which paclitaxel might be more of an issue.