Alexander Drilon, MD, discusses data from the following presentation:

Long-term efficacy and safety of larotrectinib in patients with TRK fusion-positive lung cancer (Lin, 2021 ASCO Annual Meeting, abstract # 9109)

The objective of this presentation is to report updated results in patients with TRK fusion-positive lung cancers from the phase II adult/pediatric NAVIGATE basket trial (NCT02576431) and an adult phase 1 trial (NCT02122913) where patients were treated with larotrectinib.

Central nervous system (CNS) metastases at baseline: 10 (50%) yes, 10 (50%) no

NTRK gene fusions (n = 20): NTRK1 80%; NTRK2 0%; NTRK3 20%

Tumor histology: 19 (95%) adenocarcinoma, 1 (5%) neuroendocrine carcinoma

In all evaluable patients (n = 15), the overall response rate (ORR) was 73%, including 1 (7%) complete response, 10 (67%) partial response, 3 (20%) stable disease, and 1 (7%) progressive disease; responses were durable with a median progression-free survival (PFS) of 35.4 months and median duration of response of 33.9 months. Median overall survival was 40.7 months.

In patients with CNS metastases (n = 10), the ORR was 63%, including 5 (52%) partial response, 2 (25%) stable disease, and 1 (13%) progressive disease.

Treatment-related adverse events (TRAEs) were predominantly grade 1 and 2.

TRAEs were reported by 16 patients (80%); 2 patients (10%) experienced grade 3 TRAE (myalgia, hypersensitivity, and weight increase).

Two patients (10%) required dose reduction due to AEs: grade 2 ALT and grade 2 AST increase in 1 patient and grade 2 neutrophil count decrease in the other patient; there were no treatment discontinuations due to AEs.

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Alexander Drilon, MD presents data from the 2021 American Society of Clinical Oncology annual meeting from trials in adult and pediatric patients with tropomyosin receptor kinase (TRK) fusion-positive lung cancer treated with larotrectinib.

Rapid Readouts: Results from two trials of TRK inhibitor, larotrectinib, in patients with TRK fusion-positive lung cancer

Alexander Drilon, MD, discusses data from the following poster:

Long-term efficacy and safety of larotrectinib in an integrated data set of patients with TRK fusion cancer (Hong, et al. ASCO 2021. Poster 3108.)

The objective of this poster is to report pooled data from 3 clinical trials (NCT02576431, NCT02122913, NCT02637687) of patients with TRK fusion–positive cancers treated with larotrectinib.

Patient population by tumor type (n = 218): soft tissue sarcoma, 26%; infantile fibrosarcoma, 20%; thyroid, 13%; salivary gland, 11%; lung, 9%; colon, 4%; melanoma, 3%; breast, 3%; and other, 3%

NTRK gene fusion (N = 218): NTRK1, 44%; NTRK2, 3%; and NTRK3, 53%

In all evaluable patients (n = 206), the overall response rate (ORR) was 75%, including 45 (22%) complete responses, 109 (53%) partial responses, 33 (16%) with stable disease, 13 (6%) with progressive disease, and 6 (3%) not determined; responses were durable with a median progression-free survival (PFS) of 35.4 months and a median duration of response of 49.3 months. Median overall survival (OS) was not reached.

The 36-month rates for duration of response, PFS, and OS were 54%, 48%, and 77%, respectively.

In patients with central nervous system metastases (n = 15), the ORR was 73%, including 11 (73%) partial responses, 2 (13%) with stable disease, and 2 (13%) with progressive disease.

There were no new or unexpected safety signals.

Treatment-related adverse events (TRAEs) were predominantly grade 1 to 2.

Grade 3 and 4 TRAEs were reported in 18% of patients, with the most common being decreased neutrophil count (7%), increased aminotransferase (3%), and increased aspartate aminotransferase (2%).

Alexander Drilon, MD presents updated results from a pooled analysis of TRK fusion-positive cancers treated with larotrectinib from the 2021 American Society of Clinical Oncology annual meeting. 

Rapid Readouts: Updated data from a pooled analysis of larotrectinib in TRK fusion-positive cancers

There are various KRAS G12C direct inhibitors beyond AMG 510. MRTX849 is another one of these. It was explored in a phase 1 trial that looked at the safety and activity of this drug, and while we've seen fewer patients with lung cancer with 

 G12C mutations, we've certainly seen proof of concept that the drug is active. We've seen responses in 3 out of 5 patients in the last presentation for an objective response rate of 60%, recognizing that we would need to see more patients treated with this drug moving forward, but certainly, it's very exciting. It also shows that the strategy of direct inhibition of a specific mutated KRAS protein works across different molecules that target this mutated protein.

In terms of MRTX849, it's being studied in several clinical trials, including the KRYSTAL-1 trial, which is a phase 1/2 study with expansion cohorts looking at the direct KRAS G12C inhibitor MRTX849 stratified by histology, whether colorectal cancer, non–small cell lung cancer, or pancreatic adenocarcinoma. It's also looking at combination studies in certain histologic subsets that may have activity in combination, such as the PD-1 antibody pembrolizumab in non–small cell lung cancer, the EGFR TKI [tyrosine kinase inhibitor] afatinib in non–small cell lung cancer, and cetuximab in colorectal cancer. MRTX849 is a covalent G12C inhibitor that binds to the GDP downstate of 

 and in this trial there were some adverse events but, generally, it appeared to be well tolerated. Adverse events included mostly grade 1 toxicities, the most common being diarrhea and nausea. Two patients had grade 3 or higher toxicities in the initial clinical trial, including fatigue and decreased appetite. Overall, the drug was well tolerated with a low incidence of grade 3 and 4 toxicities.

KRAS G12C Inhibition in Advanced NSCLC: MRTX849

Thankfully, we now have a variety of different selective direct inhibitors of 

 G12C. As a reminder, it's a specific mutation that you're looking for. One of these drugs is AMG 510, which right now is named sotorasib, and it is in clinical trials for patients who have these G12C mutations, such as lung cancer, and other cancers that might harbor G12C, such as colorectal cancers. We've seen very good activity in 

 G12C-mutated lung cancers, and we’re seeing response rates that approach 50%. That’s a dramatic difference from the older strategies that target 

. This drug has been very exciting for the field in general. The design of these drugs is unique and has been made possible because of the particular configuration of the KRAS G12C mutant protein that’s unique relative to other proteins such as G12D or G12V. In a particular, there is an IL [interleukin] group on the cysteine of 

 G12C that can be targeted with these covalent inhibitors. In general, one thing we haven't mentioned is that these direct inhibitors target the protein and lock it in the inactive state, noting thatthe KRAS mutant protein, shuttles between these active and inactive states for it to trigger continuous downstream signaling.

 Obviously, in an early phase 1/2 study, the goal is to determine the dose, safety, and early signs of efficacy. Those early signs of efficacy are generally, first, objective response rate. And then later, duration of response, progression-free survival, and overall survival.

Most molecular therapies have objective response rates as single agents of 50% or more and median progression-free survival of 9 to 10 months or more. The FDA has determined from other molecular drivers that chemotherapy and other standard treatments in the past have had response rates lower than 50%. The median progression-free survival is in the 4- or 5-month range. They have given accelerated approval to agents that have response rates over 50% and a median progression-free survival of 9 months or more.

These 2 agents do seem to have response rates that are appearing to be in the 50% or higher range. The median progression-free survival is too early to determine, but certainly, could be in the 9 month or more range. The safety profiles have been really good for these agents so far. The rates of grade 3 and 4 serious adverse events is quite low. So far, these agents seem to be as safe or safer than some of the other molecular therapies that we have. That's because normal cells don’t have 

 G12C mutations. These therapies seem to be highly specific and therefore, not causing serious adverse effects. For the grade 2 anemias and so on that have been reported, it's not clear whether those are due to the disease or due to the treatment at this point.

The CodeBreak 100 study is a phase 1/2 trial of the selective KRAS G12C inhibitor AMG 510, or sotorasib, for patients with 

mutated lung cancers and other cancers. In particular, we're looking for that G12C mutation. The goals of the study were to show the safety and activity of this molecule in this molecularly enriched population, and we certainly saw that the drug was not only active, but also safe. I think that's critical to know because 

 G12C doesn't exist in the normal human body, and so there is not a 

 G12C molecule that is harbored by normal tissues. Conceptually, in the design of these drugs you would have a good therapeutic window where you're able to hit the target hard, but not actually hit normal tissues to a substantial extent. You would see a high frequency of drug-related toxicities.

In terms of the development of AMG 510 in KRAS G12C inhibition, I do think it has the potential to be practice changing. In non–small cell lung cancer, overall response rates are about half, about 50%. I think we need to know more about duration of response and progression-free survival among a larger group of patients to see if it stacks up to osimertinib in 

-positive non–small cell lung cancer. We need those data to mature and get the result of larger trials. I'm hopeful it will be practice changing, even if it seems too early to say. I would note that there appears to be some differential activity based on histology. For example, activity in non–small cell lung cancer seems to be better than colorectal cancer where response rates are lower. That's where I think we need to look at the effects of histology and other comutations and how they may impact the activity of KRAS G12C inhibitors.

In terms of the practical implications of AMG 510 as your direct KRAS inhibitor, I do think it has the potential to be practice changing. I also think it's too early to say without further data, without the progression-free survival, duration of response, and having more data with that among a larger group of patients, to say how practice changing it will be and what those practical implications are.

 For these agents, toxicity has been pretty minimal. These have been well tolerated. There have been a couple of cases of diarrhea and anemia, and these have been well controlled and have not been dose-limiting. In fact, when it comes to anemia, it's not totally clear whether it's due to the drug or the disease, but diarrhea and anemia have been quite infrequent and easily managed and have not required discontinuation of the drug.

KRAS G12C Inhibition in Advanced NSCLC: AMG 510

 has long been known to be "undruggable" for a variety of factors. The KRAS protein itself was perceived to lack a good drug binding pocket outside of the nucleotide binding pocket of the RAS molecule. In addition, RAS does complex itself with GTP, or bind to GTP. In fact, it has a very high affinity for GTP, making it difficult for us to design GTP-competitive inhibitors, to outcompete the GTP molecule for that particular pocket. We've tried many different strategies in the past, and to name a few of them, there have been farnesyl transferase inhibitors that inhibit the localization of RAS to the membrane; those didn't work. We tried to leverage the fact that RAS activates downstream pathways, such as the MEK and ERK pathways, and have given either single-agent MEK or ERK inhibitors or combinations that hit these downstream pathways. While we've seen isolated responses in patients here and there, we haven't really seen a single series result in a very large number of patients who benefit from therapy.

KRAS G12C direct inhibitors have been an exciting development and potentially a transformational development in the treatment of non–small cell lung cancer. Several years ago, Kevan Shokat’s, PhD, laboratory and his colleagues identified small molecules that can irreversibly bind to the mutant reactive cysteine at residue 12. They identified a previously unappreciated binding pocket near the KRAS effector region. Small molecules binding to this pocket can inhibit KRAS by locking the protein in a GDP balance in inactive state. That development has spurred these new small molecule, direct KRAS G12C inhibitors that preliminarily looked to be able to induce responses and to be efficacious, particularly in non–small cell lung cancer. That's been an exciting development, that we're now able to take these small molecules to the clinic and see responses.

In terms of the rationale for identifying that cysteine at residue 12, it can target the binding pocket near the KRAS effector region where it locks the protein and its GDP bound in an active state. That underlies its activity as a direct KRAS inhibitor. I think once again that's an exciting development to be able to target that binding pocket.

 in that situation because the G12C substitutes a glycine for a cysteine. Potentially, EGFR inhibition may have some impact on wild-type 

 and that interaction may potentiate activity. That's being studied in future clinical trials.

In terms of tethering approach to drug design, that's a methodology to screen ligands that bind to targeted site proteins via a disulfide tether, where a native cysteine or an introduced cysteine can capture the ligands. That's a way to screen for these direct KRAS inhibitors of G12C. It's the drug development approach that was initially taken to identify these small molecule inhibitors of KRAS G12C.

, there are some covalent drugs that have been developed. These drugs covalently bind to the receptor and prevent GTP binding activation. These G12C agents that bind covalently are called AMG 510 and MRTX849. These are the first KRAS-specific drugs that have entered a clinical trial. Early clinical trial results have established safety, dose, and some efficacy of both of these agents. There's a limited number of patients, less than 30 for both drugs, so we don't actually have anywhere near enough data to have these drugs approved yet. We don't know the median progression-free survival, the overall survival, what it will be with these drugs. But we do know that these drugs can cause responses in 50% or more of 

Development of KRAS G12C-Targeted Therapy in NSCLC

Unfortunately, to date, we have not seen regulatory approval of a specific targeted therapeutic for 

-mutant lung cancers. We certainly hope that will change in the future, but for now, the systemic therapy options that are available to these patients include chemotherapy, immunotherapy, or a combination of both in the upfront setting, and the other second- and third-line options that are approved for non–small cell lung cancers in general.

In terms of EGFR TKIs [tyrosine kinase inhibitors] in 

-mutant non–small cell lung cancer, that's not really a practice that's used anymore. Afatinib is a second-generation EGFR TKI that's approved after platinum-based chemotherapy in squamous non-small cell lung cancer, based upon a modest benefit that was observed in lung adenocarcinoma. Erlotinib used to be approved in lung adenocarcinoma after progression on platinum-based chemotherapy, even without 

 mutation. Sometimes that was used, but it's really not used anymore and it doesn't particularly work in 

There are some interesting data, and I think what's more relevant now is ERBB pathway inhibition with EGFR and HER2 on impacting GDP and GTP loading, in terms of shifting KRAS and the GDP downstate that may help synergize in certain settings with direct KRAS G12C inhibitors. That's where I see the future heading, with EGFR TKIs and 

-mutant non–small cell lung cancer as part of a combinatorial approach, with direct KRAS inhibition or other combination treatments targeting the RAS/RAF/MAP kinase pathway, rather than as a single agent in 

mutant non–small cell lung cancer. With the changing landscape of much more effective therapies, its role has been substantially diminished.

 For many molecular drivers, the immunotherapies are less effective. If you look at 

, the immunotherapies don't seem to work so well. For 

 mutations, the immunotherapies tend to work at about the same frequency in the 

 mutations as in tumors that don't have any actionable driver.

Immunotherapy is a good option for patients who have 

mutations. If they're those, the selection would primarily be based on the PD-L1 expression. Whereas high PD-L1 patients with 

 mutations could receive a checkpoint inhibitor alone, and those with lower PD-L1 expression might receive checkpoint inhibitors plus chemotherapy.

There are some co-occurring molecular changes in 

 such as STK11 or PEAK1, where the chance that immunotherapy might work tends to be lower. The best thing to do in most cases is unknown, but the likelihood that immunotherapy will work in the presence of a 

 mutation plus a PEAK1 mutation, or an LKB1 mutation, may be lower, but we don't have a specific thing to do for them at the moment.

Systemic Therapy for KRAS+ Advanced NSCLC

 mutation on a patient’s molecular report after testing for lung cancer, it’s important to underscore that 

 mutations are really a heterogeneous group of different mutation types, meaning there are different amino acid changes that involve different residues along the 

 G12C mutation is the most common mutation. But in nonsmokers you see other mutations, such as the 

 G12D mutation, that are much more common. Beyond that, it can involve other amino acids, such as the amino acid 13 of the 

 protein. The difference is that we now have drugs for particular mutations or substitutions, such as 

 G12C, versus the other mutation types where we might employ different strategies altogether. The specific mutation that’s identified in a patient’s cancer may dictate the likelihood of us having a more exciting clinical trial for a patient, versus just more standard options for these patients on a targeted-therapy front.

 is found? The discussion we typically have is that previously, it was thought to be a poor prognostic feature, but with the evolution of immunotherapy and also these direct KRAS inhibitors, it’s really unclear if that’s true anymore. In terms of up-front treatment outside a clinical trial, the 

 mutation, I explain to patients that it’s the most common mutation we encounter in their type of lung cancer, and that immunotherapy can still be effective. For example, unlike the 

 lung cancer patients—especially the ones associated with smoking, such as G12C—can still derive good benefit from immunotherapy. But for 

, there’s really limited demonstration of effectiveness of immunotherapy, such as pembrolizumab and atezolizumab, especially as single agents.

I counsel them that they could still respond to immunotherapy or chemoimmunotherapy, stratified by what their PD-L1 status is. For example, PD-L1 high, they get pembrolizumab or chemotherapy with pembrolizumab. I also counsel them that we may have clinical trials for them. If they have 

 G12C, the direct inhibitor trials are very exciting and are in development. We also have trials targeting certain computations of 

. I emphasize that we have potentially excellent treatments for them, whether they are immunotherapy, chemoimmunotherapy, direct RAS inhibitors, or clinical trials with combination therapies.

Counseling Patients With NSCLC When KRAS is Detected

 In general, in the beginning, if the driving alteration was 

, it’s unlikely that the tumor cells would have 

. On the other hand, sometimes in the presence of an 

 drug, some of the cells will become resistant by developing 

 fusions, some cells, minimally, may become resistant by developing 

 mutation. If you have a patient with an 

 mutation, it will make sense in the future when we consider treating the patient with the 

For all these molecular alterations, 1 mechanism of resistance is they develop mutations that will prevent binding of the drug. In another way, it becomes resistant to development activation of another path, which may be 

. In some instances, there are other activating pathways such as the 

 mutations in patients with non–small cell lung cancer, and we’ve done this broadly for all cases, recognizing that we identified this gene a long time ago and well before the discovery of 

fusions. We’ve done this testing in the earlier phases also, in part because we know that these hot spot mutations tend to be mutually exclusive with these other drivers of oncogenesis—meaning, when you find a 

 mutation, there is a low likelihood that you might find another oncogenic driver. The 1 exception that we’ve learned about more recently is that 

 mutations can sometimes co-occur with other drivers like 

 mutation can be found either in a de novo or an acquired fashion. In general, for the other drivers, these tend not to coexist with those other driver states.

 In the old days, 1 strategy was to test 

 first because it’s the most common, and that worked for others only if 

 was negative. In my opinion, that’s not a particularly good strategy. Nowadays, basically every NGS [next-generation sequencing] panel will have 

 mutations as part of the panel because it’s the most common alteration since every panel has 

 mutations as part of the family nowadays.

If we do these tests sequentially, it will take a very long to find out how you’re going to treat a patient. Again, the old strategy was for some people to do 

 first. If it was positive, that’s the end. If it was negative, look for other alterations.

Right now, the common alterations are in the panels. Some panels are larger than others. The foundation, for example, has 400 genes that they’re looking for mutations. In our particular University of Colorado panel, we have only 40 genes, because those are the genes that are most common for which there is a potential treatment. In the foundation panel, there are many genes that may be mutated, but there is nothing you can do clinically. Even now, for many of the 

 mutations you find, there’s no sense to look for another if you have it, because there’s no specific treatment. Right now, the only specific treatments are basically based on G12C, for which there are some covalent drugs, binding drugs, that will prevent 

 My practice, particularly for stage IV metastatic lung adenocarcinoma, is to do broad genomic profiling up front, consistent with National Comprehensive Cancer Network Guidelines. The reason is that things have evolved from what we used to call the big 3: 

, where you can match to EGFR, ALK, and ROS1 TKIs [tyrosine kinase inhibitors], respectively. We have so many other agents now: MET exon 14 capmatinib is approved, 

 fusion, selpercatinib. With all these additional mutations, I approach it from the basis of getting broad genomic profiling to try to find targets that give us the highest percentage chances possible to find targets to match to effective drugs. Beyond that, at University of California, Davis Comprehensive Cancer Center, we have clinical trials for 

 [human epidermal growth factor receptor 2] and other molecular subtypes. It also broadens the scope to bring clinical trials to our patients.

I approach broad genomic profiling, particularly for lung adenocarcinoma. For squamous non–small cell lung cancer, particularly in patients who have a scant tissue specimen or have a never- or light-smoking history, I also pursue up-front genomic testing. At some point in squamous histology, I do get genomic testing if a patient has a heavy-smoking history. Often at University of California, Davis Comprehensive Cancer Center we get it as part of our Lung-MAP master protocol, which is a National Cancer Institute–sponsored clinical trial that looks at next-generation sequencing and includes squamous cell carcinoma to try to match the targeted therapy. The study helps support those getting that sequencing result by foundation medicine.

Testing for KRAS Mutations in NSCLC

 is an important proto-oncogene. In fact, there are 3 different types: 

. For lung cancer in particular, we’ve known that 

 hot spot mutations have existed since the late 1990s, and this was prior to the discovery of 

, in terms of its normal biology, functions as a sensor that integrates external stimuli in the wild-type state and then transduces those stimuli to the inside of the cell, thereby mediating processes such as cell growth and migration.

, in particular, can cycle between 2 different states: the on state, or the active confirmation, and the off state, or inactive confirmation. That cycling is mediated in part by binding to molecules such as GTP when the protein shuffles between these different states.

There are certain molecular alterations that drive cancer, and our belief is that those molecular alterations occur at the very earliest onset of the disease. Therefore, essentially, all the cancer cells have the same molecular alteration.

Of those molecular alterations, the most frequent ones are 

, and these are thought to be driver oncogenes, where all the cells have those particular 

 mutations. Therefore, they are potentially susceptible to treatment aimed at those particular alterations.

For every molecular alteration, there may be 1 or more than 1 molecular alteration that’s a driver. For example, 

 and most common molecular alterations are deletion 19 and a coin mutation that’s now L858R, but there are other molecular alterations in the 

 family. In a similar way, there is more than 1 

 mutation that can drive the tumor. The most common is what we call 

 mutations in other places, such as Q61. But the most common are G12C. The first specific 

 treatments that have been devised thus far are for 

Some lung cancers, even the most common, have this glycine substitution at G12C, and if one does any specific 

 mutation analysis or any next-generation sequencing analysis, one will find which 

 mutation they are, and whether a G12C is present or not. Again, this is really important because just like an 

, it may be that there are different drugs for different mutations. In 

, as far as we know, the prognosis is fairly similar across different 

 mutations, but the treatments may be completely different.

 G12B will have different drugs from what we will have for G12C. In fact, it’s highly unlikely. But if you have a 

 G12C mutation, all the cells will have that, and 1 treatment will likely be effective. Maybe that will be combinations in the future for that resistance. We don’t know how resistance is going to occur, but it’s highly likely that a specific treatment won’t kill all the cells, even though all the cells have that alteration.

 G12C, where there are a lot of exciting direct inhibitors in development, 

 mutations constitute about 25% of all solid tumors on average. That’s the same in lung adenocarcinoma. About half of those mutations, about 13%, have the 

 G12C amino acid substitution. To put that in context of newly diagnosed non–small cell lung cancer, there are about 228,000 new diagnoses of lung cancer per year estimated in the United States, the majority of those with metastatic disease. We’re looking at tens of thousands of patients per year who can be impacted by these direct KRAS inhibitor treatments. In terms of looking at that piece of pie of oncogene-driven subsets of non–small cell lung cancer, it’s probably the largest piece of pie that we could target. It’s exciting that we now have 

 inhibitors in development in clinical trials to address this large unmet need.

 mutations and other solid tumor types, the 

 mutations constitute about a quarter of all mutations across solid tumors. It’s frequently encountered in multiple cancer subtypes, such as colorectal cancer, pancreatic cancer, and others. The frequency between G12C and other 

 amino acid substitutions and that proportion varies by tumor type. But 

 mutations are encountered commonly throughout a broad spectrum of solid tumors.

KRAS Mutations in Solid Tumors

Arguably, in lung cancer, we’ve made as many therapeutic advances as in any cancers, and since lung cancer is the leading cause of cancer death in the United States and in the world, this is incredibly important.

We can summarize some of those therapeutic advances in terms of molecular therapy, which is understanding molecular underpinnings of some of the lung cancers with specific molecular therapies that go along with those molecular alterations. It’s also understanding immunotherapy, which has made incredibly important therapeutic advances, particularly in those lung cancers that don’t have the molecular drivers. One can divide the therapeutic advances into molecular and immunotherapy to a certain extent at this point in time.

The current state of targeted therapies for non–small cell lung cancer is rapidly changing. We’ve had a lot of exciting developments in the field of targeted therapies in lung cancer, particularly for lung adenocarcinoma, which is the most frequent histologic subtype that we encounter. There’s been a lot of great new developments. We move beyond 

-mutant lung cancer, ALK -fusion non–small cell lung cancer, 

-fusion non–small cell lung cancer, and 

-mutant non–small cell lung cancer, where there are targeted therapies approved for those molecular subtypes. We are expanding the pie further in oncogene-driven subsets of non–small cell lung cancer.

In particular, there have been new approvals for 

-fusion lung cancer, which is about 2% of all non–small cell lung cancer with selpercatinib and also another exciting new agent, BLU-667. For 

exon 14 skipping mutations, the MET inhibitor capmatinib has been recently approved. Larotrectinib has also been approved for 

 non–small cell lung cancer, which is an infrequent subtype, but when you encounter it, it has extremely high response rates and clinical activity. This is all really exciting news as we’re finding more pieces of that pie for oncogene subsets of non–small cell lung cancer to bring really effective targeted therapies to patients.

 As we understand that lung cancers are driven by certain gene signatures we’ve come to realize that the proteins that these oncogenes make can be targetable with things like small molecules or tyrosine kinase inhibitors [TKIs]. This started with 

 of course and then blossomed to include other fusions like 

. Now there is really a much longer list of actionable operations, which have changed the way we practice. Many of these targeted therapies are approved for patients with advanced disease, and these result in substantial activity and high response rates, durable disease control, in addition to having favorable safety profiles that make these drugs amenable to long-term administration.

 In terms of prognosis of patients who have oncogene-driven non–small cell lung cancer, it really depends on what the mutation is. For example, recently published data look at osimertinib, which is a next-generation 

 TKI. It was approved as first-line treatment for advanced 

-mutant non–small cell lung cancer based on the FLAURA trial, which compared that with first-generation 

 TKIs. Median overall survival was, on average, about 3 years. For 

-positive non–small cell lung cancer, a drug such as alectinib—a next-generation ALK inhibitor given in the first line—in those trials, for example, the ALEX trial, median progression-free survival, not overall survival but progression-free survival, of the time it takes for the cancer to start growing again was about 3 years.

For a lot of these oncogene subsets we’re being able to match to highly effective targeted therapies that are improving survival for these patients. Other oncogene-driven subsets as well have pretty dramatic progression-free survival benefits with targeted therapies, so we’re really making a lot of progress. As I mentioned, we’re expanding the pie of identifying and targeting these oncogene-driven subsets such as with 

, and others. Hopefully we’ll continue to find more. What is also exciting is that we now have certain 

 inhibitors that also appear to be active. We’re constantly looking for new oncogene-driven subsets to target and to match to potent inhibitors. It’s a really exciting time, and we’re continuing to prove the outcomes in these patients moving forward.

 Over the last few years, we’ve learned that the molecular signature a particular lung cancer harbors might help dictate how well patients do in terms of factors such as survival. We know, for example, that if a lung cancer harbors an 

 mutation, or 1 of a variety of different fusions, these patients can have long overall survival compared with historical standards in unselected non–small cell lung cancers. That is in large part mediated, of course, by the availability of highly active targeted therapies that can result in very durable disease control. For patients being diagnosed with a cancer that has 1 of these alterations is a good thing. However, there may be other genes such as 

 mutations, for example, that in general are known to be poorly prognostic. This is in the era where we looked at things like the response to chemotherapy or how patients with early stage did. By comparison, patients with 

-mutant lung cancers tend to fare a little worse than patients who have unselected non–small cell lung cancers or those that harbor other driver-oncogene genes in particular.

Another important point is there still remains unmet needs. We’re looking at 

 direct inhibitors that appear to have some exciting activity, new drugs for 

 [human epidermal growth factor receptor 2] non–small cell lung cancer, and also trying to find new ways to overcome intrinsic resistance to immunotherapy. Although immune checkpoint inhibitors, such as pembrolizumab, atezolizumab, nivolumab, and so forth, have really changed the landscape of how we treat non–small cell lung cancer. A lot of patients don’t respond to these, especially those patients who have those oncogene-driven subsets not associated with smoking, such as 

. Finding ways to enhance the activity of immunotherapy in patients who don’t respond is another important unmet need that we need to address.

Alexander Drilon, MD, Memorial Sloan Kettering Cancer Center

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