Actionable Mutations Playing and Increasingly Important Role in the NSCLC Landscape

Both KRAS and EGFR mutations have become increasingly important targets in non–small cell lung cancer. This is especially remarkable as KRAS was once considered an “untargetable mutation.”

Both KRAS and EGFR mutations have become increasingly important targets in non–small cell lung cancer (NSCLC). This is especially remarkable as KRAS was once considered an “untargetable mutation.”

The NSCLC space has seen major progress over the past few years, and it may be difficult to keep up with the pace of practice-changing studies. Advances in KRAS and EGFR directed therapies, especially in the first line and neoadjuvant space, may help to significantly increase survival in early-stage NSCLC cases.

However, the COVID-19 pandemic has disrupted care and treatment for these patients. Many patients are no longer able to have their support network around them as they go through treatment. Radiology, biopsies, and other therapies were disrupted by the COVID-19 pandemic, especially for patients living in New York City.

In an interview with Targeted Oncology, Nicholas Rohs, MD, of Mount Sinai Hospital, discusses KRAS and EGFR mutations in NSCLC, recent advances in the field, how COVID-19 is impacting patients, and challenges cases in his own practice.

TARGETED ONCOLOGY: Could you summarize some of the cases that you're going to be presenting?

ROHS: I presented with a couple of my thoracic colleagues. Each of us discussed 1 challenging case that we've had in our clinic recently. I think my case is really good, because it highlights a couple of important points about lung cancer management.

This is a female who came to me. She's in her 60s with an incidentally found right lower lung nodule on screening, and she had a little bit of workup. Her baseline scan showed both a right upper and right lower lung lesion that were of concern. So, we did biopsy the right lower lung lesion, which confirmed an adenocarcinoma from the lung, which had a KRAS mutation, or a genetic mutation that is an identifier for that type of tumor. Given some of her medical concerns and because she did have a couple of other small areas of concern in her scan, that we weren't sure whether or not they were active tumors or potentially tumors that were evolving. So, she had 2 different small resections in her right upper lung and right lower lung, and this is where the first interesting point of the of the case comes in. She actually has 2 different types of cancer in her lungs. Both are adenocarcinoma, but 1 has a KRAS mutation and one had an EGFR mutation.

Luckily, they were both early stage. Because of these 2 different types of tumors, it was sort of a decision on whether or not we should give any further therapy, which we didn't at that point. Not too long after that she had a recurrence of her disease. But the question at that point was, which disease? Are we dealing with this KRAS-positive disease, or is EGFR-positive disease? We also hoped that there was no primary tumor? But given the fact that she had multiple scattered nodules, it looked like it was probably related to 1 of the known tumors. So, what I did was a liquid biopsy. The blood-based test allowed us to see a KRAS mutation in her blood, which let me know that it was likely the KRAS-mutated, tumor and not the EGFR-positive tumor that had recurred. That helped me guide my therapy. I then put her on pembrolizumab (Keytruda), which she did beautifully on for quite a while. But unfortunately, at one point, we noticed that she had some changes in her liver functions that was probably related to the immune therapy.

It wasn't that clinically impactful. She had some adverse events (AEs), but they were well-tolerated with steroids. We held the immune therapy and gave her steroids and she got much better. The next decision point was, can we restart the immune therapy? She did really well, she felt well, and her labs were back to normal. There's about a 25% recurrence rate of these immune AEs with these therapies. Since she was doing so well and had such a good response, I did rechallenge her with this therapy. And unfortunately, the same AE happened again. Then, I administered steroids again. The patient had an improvement in her liver functions but is taking a little bit longer to get them under control this time. So, at this point, we got an updated scan, and her disease continues to be very well controlled. I have her on a slow steroid taper, and hopefully, we can continue to ride this immune therapy response for a long time without having to worry about any further therapy for a while.

TARGETED ONCOLOGY: Can you expand on how KRAS and EGFR compare and why they're so important in the lung cancer space?

ROHS: Absolutely. I think the bottom line is genetic testing is so critical for lung cancers, particularly 1 subtype, the most common subtype, called lung adenocarcinoma. Among lung adenocarcinomas, we have up to about 2/3 of those diseases where we can find some sort of what we call an actionable mutation or mutation where we're able to treat that disease with some form of targeted therapy. Often these are pills. Occasionally, there are infusions of medications that are targeted to these genetic mutations. The way I describe this is, generally these are not mutations from mom or dad, but mutations in the tumor themselves that cause these tumors to grow or drive them to grow. We occasionally call them driver mutations. EGFR is a classic mutation that we've known for a very long time and has many different pill options that are well tolerated and effective for treatment. So, it was really important for us to sort of understand which tumor we were treating. KRAS has had a slightly different story. We used to think that it was an untargetable mutation, but over the past couple of years, we've had this really amazing evolution in the KRAS space where we've had some really good success by changing the way that we bind that site, and rally getting some very promising early responses in clinical trials. It's a really hot area of research right now in KRAS-mutated lung tumors and I think there's a lot of hope in the future for that. It's really important for us to get this baseline testing, so we can know what type of tumor we're dealing with and the best way to approach it.

TARGETED ONCOLOGY: With these two actionable alterations, where should future research efforts be focused in your opinion?

ROHS: There are so many different areas that we need to focus on, because we're finding out so many new exciting things in lung cancer specifically in KRAS. As I said, we've had some really promising early trials. But what we've seen is that when we combine these KRAS-directed drugs with other types of therapies, like the immunotherapies that we use, we're seeing almost synergistic kind of benefit. Trying to find the right combination of these medications so that we have a really good standard of care for these patients wih KRAS-mutant disease.

For EGFR-mutated lung cancers, we already have some good standard-of-care first-line treatments that can both treat the tumors in the body and have good brain penetration, which is critical for those types of tumors that like to move to the brain. The next research area there is what do we do after these really good first-line therapies? Because we're seeing this wide array of resistance mechanisms, meaning that the tumor is finding ways to grow around these pills. We're also finding that there's so many different ways that these types of tumors learn to do that. Deciding the next best way to treat these types of EGFR-mutated tumors is a really hot area of research as well, and we are making some interesting progress there, too.

TARGETED ONCOLOGY: Are there any other actionable alterations that you wanted to highlight?

ROHS: I think the important thing is, is that we have many of them, EGFR, KRAS, MET, BRAF, ROS, ALK. There are so many different types of mutations. The bottom line is, we have to find them and almost all of these have some form of an approved therapy. Many other far along types of treatments and clinical trials that I think are probably going to go towards approval soon. Just making sure that we find these mutations appropriately, treat them and then watch them just look for these resistance mechanisms, and how we can next best treat these patients. I think it's so critical because of how good these treatments work, and also how well they're tolerated. Patients can buy years of quality life with these types of medications.

TARGETED ONCOLOGY: What are some of the key challenges in the lung cancer space?

ROHS: I think one of our biggest challenges is how successful we've been recently, with all the data that's coming out. It sounds terrible to say, but we're having such a quick evolution in the lung space, that it's almost tough to keep up with how quickly we're evolving. That we're having trials come out multiple times a year that are practice changing. As we look back at the last couple of years, and all the data we've generated, how do we put it all together to really synthesize the correct type of treatment plans for these patients? But this is a fantastic problem to have, and it’s building on the momentum that we have. We've had amazing successes with immune therapies, targeted therapies, but we can definitely do better in those spaces. Also, there are evolving novel therapies, which is always a challenge. Breaking out of the NSCLC cancer space into the small cell lung cancer space, I think that's been a really challenging disease subtype that we have not made a ton of progress in. So, I think that's 1 of the areas that we really need to continue to focus on improving our treatments.

TARGETED ONCOLOGY: Are there any emerging therapies that you're excited about and want to highlight?

ROHS: I think the type of therapy I'm most excited about right now is not a specific therapy, but where we use the therapy, somewhere called the neoadjuvant, or before the definitive treatments, particularly surgery where we've had some really exciting data in the neoadjuvant space with immune therapies. So either immune therapies by themselves or in combination with chemotherapy given before surgery, has shown some exciting results both in just initial responses to therapy, but when we remove those tumors, we're seeing that a large majority of them have really stunning responses, meaning that large parts of the tumor have died off. And even sometimes we see the tumor being fully killed off. And what this may mean for us is if we can continue to evolve this space, the cure rates for these early-stage tumors are likely to jump a lot. Because we're teaching your own body's immune system to fight these tumors while the tumor is in your body, and then removing the tumor and allowing your body to, 'clean up anything of the tumor that's left over. and then hopefully keeping your immune system in tune for any future cancer recurrences that may be able to fight off on its own. I'm really excited to see this data continue to mature, because I think it will be a game changer for us.