Spira Recognizes Advances in Biomarker-Driven Disease During Lung Cancer Awareness Month

Alexander Spira, MD, PhD

All within about a month's time, 6 different treatments were approved by the FDA for the treatment of select patients with lung cancer, serving as a testament to the strong advances that have been made in this treatment paradigm over the last few years. These approvals are far from the only advances in this space, as many others have seen FDA approval in 2020, and more agents appear promising down the pike.

The bulk of FDA approvals in the biomarker-driven space occurred in May. Ramucirumab (Cyramza) in combination with erlotinib (Tarceva) was approved by the FDA for patients with metastatic non–small cell lung cancer (NSCLC) harboring EGFR exon 19 deletions or exon 21 (L858R) mutations. Nivolumab (Opdivo) plus ipilimumab (Yervoy) was approved for the treatment of metastatic or recurrent patients with NSCLC whose tumors expressed PD-L1. Brigatinib (Alunbrig) was approved for the frontline treatment of ALK-positive metastatic NSCLC. Atezolizumab (Tecentriq) was approved as monotherapy for a subset of PD-L1-positive patients with metastatic NSCLC as well.

In addition, selpercatinib (formerly known as LOXO-292; Retevmo) was approved for the treatment of patients with lung cancer, in addition to thyroid cancer, harboring RET alterations. Capmatinib (Tabrecta) was also approved for the treatment of patients with metastatic NSCLC harboring a MET exon 14 skipping mutation. The approval of each of these different treatment options provides more opportunities for physicians to treat patients selectively based on their biomarkers. This further emphasizes the importance of testing patients with lung cancer.

In an interview with Targeted Oncology, Alexander Spira, MD, PhD, a medical oncologist and director of the Virginia Cancer Specialists Research Institute and the Phase 1 Trial Program, discussed the role of identifying biomarkers in patients with lung cancer based on the vast amount of data and significant number of approved therapies available for biomarker-driven disease.

TARGETED ONCOLOGY: How has the role of targeted therapies and immunotherapies evolved over the last few years?

Spira: The targeted therapy and immunotherapy spaces have had banner years, especially the targeted therapies. I think the biggest news for targeted therapy has been the KRAS G12C drugs. There were 2 that everybody initially thought were going to be home runs like other targeted therapies. They're not quite as good, but they provide 2 things, 1 being the first breakthrough drugs for what we used to call an undruggable target, which is amazing because we never in our wildest dreams thought we would ever have a drug that targeted anything in the KRAS area, and we now have 2 drugs that work well and are very well tolerated. It's great news for those patients, which is a small but real minority in the 10% to 20% range of all lung cancer patients, but it also bodes well for the development of new KRAS inhibitors also. It's been a really exciting field for that.

The other area of insight has been a lot of work in the EGFR field as well. There are a few new EGFR inhibitors both for routine EGFR mutations, so that's very exciting, as well as 2 or 3 drugs for a rare insertion called EGFR exon 20 insertions. We also look forward to some new data, TAK788, now known as mobocertinib (TAK-788), has been exciting, as well as a third drug poziotinib.

Targeted therapy has had a real banner year. Immunotherapy is kind of taken a little bit of a second-tier this year. There's a lot of excitement about 2 things. One is neoadjuvant approaches for those with curable disease, so the preliminary data we have with nivolumab shows that it's pretty active in the neoadjuvant setting, looking at new end points, like the pathological complete response. That's been very exciting. In addition, there's a lot of excitement about a class of compounds called the antigen antibodies, and there's 1 currently in the firstline for PD-L1-high in combination with pembrolizumab, so there's been a little bit of excitement there for the last couple of years. It's been a little bit lacking in the immunotherapy area because a lot of the studies were negative, but there's been some positive stuff in development as well.

We all know that earlier this year that nivolumab and ipilimumab were FDA-approved for PD-L1 greater than 1% exactly where it is still unclear because there's a lot of different things happening in this space. However, there's excitement about that as well, and it does offer some patients a non-chemotherapy option as well.

There's been a lot of new things, especially in the last year in both areas, and I think about how time flies; we've had MET inhibitors, we've had RET inhibitors, also FDA-approved. It seems so passed because it happened like 4 months ago, but in the lung cancer world that seems like an eternity. The approval of these drugs has given us a lot of new targeted options as well. One of the reminders to everybody in the field is you have to test for all these, and I think we have to focus on that as an oncology treatment community to test people for these mutations.

TARGETED ONCOLOGY: How do you go about making your treatment decisions for patients with lung cancer?

Spira: The treatment decisions for patients with lung cancer have gotten a lot more complicated for what we call the non-biomarker-driven cohorts, which are patients without an actionable mutation. It's focusing on whether or not you do chemotherapy first or chemoimmunotherapy. Most of us look at the PD-L1 score, higher PD-L1 scores are likely to benefit from checkpoint inhibitors alone, possibly checkpoint inhibitor with ipilimumab also, depending on a lot of that is dependent upon the individual patient, their risk, how quickly the tumor is growing, what their level of interest in doing chemotherapy, and so that's hotly debated amongst oncologists for targeted therapy.

We all believe that a targeted therapy is the best option for patients in all those situations, so if you can identify which you have to test either by tissue-based or by blood-based assays, which has been a real struggle to do and get everybody testing for all the biomarkers, and that's where liquid biopsies are really coming to the forefront. However, most of our targeted options are the best. The KRAS G12C drugs are interesting because we think they'll likely be approved because the studies have been in second line. When they get approved, there's going to be a lot of studies looking at them in the first-line setting as well, given the desire for a non-chemotherapy option that directly targets your tumor type.

TARGETED ONCOLOGY: What should physicians know about conducting testing in their patients with lung cancer?

Spira: It's important to test, and I always tell people that if you can't put somebody on a targeted therapy, if you don't test for that targeted therapy, and right now we have between 7 to 10, new ones with even more coming down the pike. It is so important to test, and the challenge we have in the lung cancer field is that you run out of tissue early on, so you have to test when they walk in. You have to test for an entire panel because you'll often run out of tissue. The most common is EGFR, ALK, and ROS1, but there are others that need to be tested as well.

In my opinion, we need to do full complete a next-generation sequencing panel upfront in those patients who have lung cancer and can wait for those test results to come back. It's important that we get the timing of that optimized as well. Liquid biopsies are not quite as good, but really, really close and in my mind, needs to be done in almost all patients early on as well. However, if you're going to have enough tissue, so I think it's so important that we test everybody walking in the door. There's lots of clinical studies as well, and there's some new and upcoming events as well. There are agents being looked at for patients who might be resistant to checkpoint inhibitors, there’s some targeting new biomarkers, so I can't emphasize how important it is to test everybody.

TARGETED ONCOLOGY: What other treatments are appearing particularly promising in this biomarker-driven space?

Spira: I think the most promising advances right now are the KRAS G12C drugs coming down the pike. We hope early next year, there are some phase 1 studies for G12D, as well. Those will have some of the most exciting biomarkers out there. There are some newer combinations, looking at other KRAS mutations as well. Those are still a little bit earlier on with some very promising preliminary results. Also, there's a compound looking at combinations with a MEK inhibitor. There's some new interest in there looking at pan-KRAS-targeted combinations also.

The most promising of these caveats being the G12C drugs. Now that we think we figured out how to target and then it does work, I think there's going to be a plethora of looking for specific mutations as well. Those are the most common ones, and they said, this one's looking at KEAP1 and STK11 looking at patients that might be resistant to immunotherapy, so looking at novel approaches for that as well. However, there are others as well. I'm giving you just the top few, but there's a lot of others coming down. It's also vaccine protocols, and we're not as excited about those because those are not quite as targeted or just not as well proven right now.

TARGETED ONCOLOGY: What are the remaining challenges that we need to address in this space?

Spira: The major challenge that we have is a lot of our patients are not being tested, so that's a huge concern, number 1. Number 2 is a lot of our patients still will not have a biomarker, so how do we treat those patients? We need to get better immunotherapy drugs, checkpoint inhibitors pembrolizumab, and nivolumab. Your checkpoint inhibitor of choice has made a big headway in terms of how we treat those patients, but they don't benefit all patients, so that's the next cohort that needs to be studied. A lot of work and energy has been spent there, and there are going to be new immunotherapy combinations, although most of those, unfortunately, have failed. However, there's got to be something out there that has got to be a new approach for that as well. I think the other new exciting thing is new is the human approach.

Most of those studies have looked at what's called pathological complete response as a biomarker, so the concern with that is how well is that going to transfer to overall survival. We're all anxiously awaiting those results. Anybody with an active checkpoint inhibitor is now doing those studies, so there's about 3 or 4 different ones going on with the nivolumab. One first weeding out there's a lot of different combinations and how we interpret that is going to be very exciting, obviously, as well. With the advent of new EGFR inhibitors, are they going to be first line? Are they going to be relaxed? Do they need a new biomarker? How do you test with those biomarkers? What we do for those patients is also a super exciting area. There's a lot of things happening. Lung cancer has become, which used to be the most boring disease, probably the most exciting disease now with a lot of different options for our patients.

TARGETED ONCOLOGY: What advice would you like to share with the community oncologists treating patients with lung cancer?

Spira: I think that's the most important message for the community oncologist. We've got to do a better job of testing our advanced patients. Even amongst my colleagues and partners, it's been very challenging to do. If you don't test for a mutation, you're not going to be able to find it, and I can't tell you how many patients retrospectively have had a mutation that nobody picked up on. That is the most important thing to do.

Also, there are so many things coming down the pike. There are so many opportunities for patients, either get those clinical studies or don't be embarrassed or worried about referring. It is such an important thing to do.

TARGETED ONCOLOGY: Do you have a message that you would like to share with fellow oncologists in the field as we recognize Lung Cancer Awareness Month?

Spira: For lung cancer awareness month, I think it's important to realize what a long strange trip it's been over the last couple of years. I don't think anybody envisioned lung cancer would be the disease that it is right now, and it's a testament to pharmaceutical companies, patients, and most importantly, researchers, clinical trials, everybody involved in the field because we've made such headway over the last 5 to 10 years. It cannot be lost upon what a difference it's made for our patients over these last couple of years. We have to keep going forward because there's so many patients that need more therapies and so many areas that need to be explored such as adjuvant treatment, vaccine treatment, second-line treatment, non-biomarker treatment patients that don't want to do chemotherapy, you can go on and on and on. There's a lot of room for improvement despite these advantages.