 We need to look back and realize that what we’ve achieved in the management of 

 translocation-positive non–small cell lung cancer is magical on a certain level. We just learned a couple of months ago that long-term outcomes on the ALEX study suggest that 5-year overall survival of our patients is more than 50%. The average patient with 

 translocated lung cancer at the time of diagnosis, despite having stage IV disease, can anticipate living at least 5 years. That 5 years is improving as we introduce novel drugs and agents. We’ve achieved a lot, but why not stay greedy and try to achieve more? We need to continue to focus on advancing research. Advancing research in this field can be in terms of learning more about and overcoming acquired resistance with novel agents—matching the alterations, secondary mutations, or bypass mechanisms.

Also, invest in the up-front treatment setting, where the sequencing of agents has been very successful; maybe we could achieve more by combinations up front. There are a number of studies investigating that—combining ALK inhibitors with VEGF inhibition, other targeted agents, MEK inhibitors, etc. The science is definitely expanding to offer us scientifically based alternatives for up-front management.

Lastly, testing in terms of the ctDNA [circulating tumor DNA] platforms now enhances and facilitates patient care. We want to continue to invest in those, not just in terms of understanding molecularly defined subsets but also how we use ctDNA to monitor the progress of the patient. Could we use that as an early surrogate to look for response? Could we monitor a patient in terms of tumor dynamics, with the potential for recurrence after definitive treatment, early stage disease, things of that nature? There’s still a lot to do, but this is a field where we have accomplished a lot, and our patients are doing so much better than in the past. It’s just wonderful to witness and participate in this progress as a team.

 The most recent ALK TKI approved is the drug lorlatinib. This is what we call third-generation ALK TKI; this is the medication that has the most evidence of using it after failure of second-generation ALK TKI, such as brigatinib, alectinib, and lorlatinib. In a lorlatinib clinical trial, the overall response rate was approximately 30%. Your response was higher if you had an on-target 

 mutation as a resistant mechanism to previous ALK TKI.

-rearranged non–small cell lung cancer changing the landscape of treatment, there are a couple of exciting developments on the horizon. Lorlatinib, which is approved after progression of prior ALK TKI, is being studied in the CROWN trial as first-line therapy, so it will be interesting to see those results. It may have some more activity against some of those 

-resistance mutations that we talked about previously and bring that up to the front line.

It also has some potential adverse effects as well in terms of tolerability in first line. It would be interesting to see how that plays out. Targeting those mutations and bringing it up front could potentially detect and target bypass track mutations, such as MET amplification. We have a trial, and colleagues at UCSF [University of California San Francisco] are looking at MEK inhibition on top of ALK inhibition and targeting bypass tracks as well and then potentially bringing these up front. There are other trials with other ALK inhibitors, such as repotrectinib and others, that are exciting to look at.

 fusion non–small cell lung cancer, we’ve made a tremendous amount of progress where we now can match patients whose tumors harbor these molecular aberrations to highly effective drugs. Some of the principles I look at that we discussed are forestalling and treating CNS [central nervous system] metastatic disease and not doing so in a way where you’re bringing in radiation therapy early on—particularly whole brain—to maximize quality of life and prevent those neurocognitive adverse effects as patients are living, as we start with the updates to the ALEX trial.

Even in the crizotinib arm, median progression-free survival was almost 5 years. At 5 years, 62% of alectinib patients undergoing first-line treatment were still alive. I really want to emphasize those types of things, and the high response rates and activity of these next-generation inhibitors has really changed the landscape of how we treat these oncogene-driven tumors.

Videos

Future of ALK-rearranged mNSCLC

-rearranged non–small cell lung cancer, you have a couple of options. One is broad-based genomic profiling with next-generation sequencing, which is typically what I send out because it enables us to at least initially get an identification of trying to find different mutations that you can match to targeted therapies rather than focusing on 1. 

 FISH [fluorescence in situ hybridization] and 

 IHC [immunohistochemistry] are also methods that are used.

 IHC and FISH may have a quicker turnaround time. Sometimes, if I really suspect 

, for example, they can be associated with pericardial effusions, pleural effusions. I’ve had patients with that. You send off an 

 IHC and potentially get that and intervene quicker. We have had cases like that at our institution. That could be done as either a standalone or screening test, followed by confirmation, which is approved as a standalone as well.

Those are the different methods used. In terms of using circulating tumor DNA [ctDNA], I often send that out if I need a quick result because that may come back faster than looking at tissue biopsy or repeat tissue biopsy, or if you think there may be insufficient tissue. Sometimes, there’s not enough circulating tumor DNA being shed in the blood where a negative test doesn’t disprove it. It could be a false negative, where tissue is important, but those are the techniques that I use. There are some folks that think more about RNA-based methodologies that may be more accurate in detecting 

 fusions, but the general standard is broad-based genomic profiling with next-generation sequencing.

 In my institutions, I have options. I can choose my own next-generation sequencing, or I can send it to a reference company. I test all my patients with nonsquamous, non–small cell metastatic for 

 rearrangement and other rearrangements we’ve discussed. I also test my patient’s squamous cell carcinoma if they have certain phenotypic characteristics. If I see a patient with squamous cell carcinoma who was a nonsmoker, or if I see patients with squamous cell carcinoma who have a small biopsy on FNA [fine needle aspiration], which made the basis for the diagnosis for those patients, it is certainly possible that you’re dealing with what’s called a mixed histology or adenosquamous lung cancer. Those patients can harbor 

 rearrangements. If you remember, the first patient with 

 rearrangement described by Dr [Manabu] Soda was a patient with squamous cell carcinoma, so for a certain subset of patients with squamous cell carcinoma, I do test for 

 B-FAST is a very interesting study. We participated in it at our institution. It utilizes ctDNA testing up front to allow quick introduction of targeted agents or immunotherapeutic drugs dependent on findings. It is easy to force the integration of that into our practices since we use ctDNA already. In a way, it will be a very smooth transition toward practice. The study has shown that if you use ctDNA and the type of 

 alterations in ctDNA, you can offer alectinib with a great chance of success.

This really confirms the paradigm that we’ve seen from other studies, especially for 

—for example, in FLAURA2, we could see that ctDNA-detected 

 alterations yield excellent outcomes in terms of 

 targeting, similar to what we see with tissue-based testing. This will be a slam dunk in terms of incorporating into our practices for the care of our patients.

Testing for ALK Rearrangements in mNSCLC

 What do we do with acquired resistance? Do we rebiopsy? Do we retest? We’ve learned so much in this field. We started with the 

 paradigm, and we’ve learned that retesting can help because some patients will have secondary mutations that can guide us to overcome that resistance with new generation molecules. Some patients will have bypass resistance mechanisms. Some patients will have other types of alterations, ie, small cell transformation. I view retesting as helpful in both treating the patient in front of you and in terms of how we educate ourselves with the next generation of studies in the overall field. I do promote retesting but not blindly for everyone.

Some patients could benefit with what’s called locally ablative therapy, adding radiation to ongoing treatment to a few sites of illness. Maybe the same treatment can continue. In some patients, biopsy is not safe to pursue. Think about CNS [central nervous system] progression; ctDNA is there for us to utilize as well. It’s an additional tool before we perform a tissue biopsy since it seems that the secondary 

 mutations can be detected quite well from ctDNA [circulating tumor DNA]. We want to look at each patient carefully.

What do we do with the information? Realistically, in the field of 

-translocated lung cancer, lorlatinib in the secondary setting is effective and is realistically the only choice for many of our patients. Many of the paths will converge toward lorlatinib, but there are novel drugs in development, some very potent ALK inhibitors that we could also guide our patients toward. There are definitely treatment alternatives, and we do not want to forget that our conventional tools, such as chemotherapy and radiation, can provide additional benefit to our patients through their treatment continuum.

 Even though decisions on what you give to our patients with 

-rearranged metastatic non–small cell lung cancer are relatively simple—you have to give them ALK TKI—we are still struggling as to what we should tell patients once they progress. The way I approach postprogression therapy in patients with 

-rearranged lung cancer is very similar to how I approach the issue of oncogenic-driven tumors. First, you need to establish where your patient is progressing. Is it a CNS-only progression? Is it a diffuse systemic progression or localized progression? If it’s a localized progression, such as CNS or a single site, it is appropriate to do local therapy of those parts, such as radiation. However, if your progression is systemic, then we need to switch therapies. Where we are struggling at this point is how to decide the best therapy and the role of postprogression biopsy for those patients.

I personally believe in the benefit of postprogression biopsy. There is a rare occasion where your 

-rearranged lung cancer can transform into small cell; the treatment will be different, and you can determine the likelihood of response to a third-generation ALK TKI, such as lorlatinib, based on the presence or absence of 

 domain mutation. I currently put all my patients in a clinical trial, which we call ALK master protocol. It’s NRG-LU003.

In that protocol, patients who progressed on ALK TKI will get a postprogression biopsy, and the treatment assignment depends on what was found in the postprogression biopsy. For example, if your patient was found to have a MET amplification, then their appropriate treatment would be crizotinib, which, in addition to having ALK inhibition, also inhibits MET. I believe in doing clinical trials for our patients because that’s how we can improve. We strongly encourage you look at where the nearest site for ALK NRG-LU003 is and refer your patients to that clinical trial.

 In general, there have been some great advances in targeting 

-rearranged non–small cell lung cancer, specifically targeting these resistance mechanisms, because alectinib and/or brigatinib as first-line treatment shows great activity. There was also meaningful improvement in PFS [progression-free survival] and OS [overall survival] that we saw in recent updates with alectinib. Invariably, these patients still develop resistance. They still progress. The main, broad overview of resistance mechanisms are histologic transformations, so adeno going to squamous or to neuroendocrine small cell-type histologies.

That happens infrequently, but it happens on target 

-resistance mutations, bypass tracks, and on-target resistance mutations—as mentioned with 

 is that we are able to gauge differences in terms of spectrum and frequency by whether it’s crizotinib, alectinib, etc, based on a heat map of 

 resistance mutations to potentially match to other ALK inhibitors that could be successful.

For example, lorlatinib is approved and has activity against some of these resistance mutations that others don’t. There are new drugs in development, such as repotrectinib and others, that may have additional activity beyond that. Lorlatinib is now approved after progression on prior ALK TKI for these patients, with about a third of patients having a good response.

There are also bypass tracks that may not respond as well to a change in direct ALK inhibitors, such as MET amplification; you could potentially go back to crizotinib because it was initially developed not only in ALK but as a MET inhibitor and has some activity there. There’s RAS/RAF and MET kinase alterations, such as 

 mutations and amplifications that may also signal around 

. The main one that we are concerned with is the G1202R, which is resistant to many ALK inhibitors. We’re looking at additional clinical trials to try to address that.

Subsequent Lines of Therapy in ALK-rearranged mNSCLC

: NCCN [National Comprehensive Cancer Network] guidelines list 4 agents appropriate in first-line 

mutated non–small cell lung cancer. Two of them are crizotinib and sorafenib, gaining their approval based on the trials that compared ALK tyrosine kinase inhibitors to chemotherapy. The other 2, brigatinib and alectinib, were approved based on randomized head-to-head comparisons to crizotinib. Both brigatinib and alectinib improved progression-free survival [PFS] over crizotinib. Both have CNS [central nervous system] efficacy, so I prefer to go with either brigatinib or alectinib when I treat my patients with 

-rearranged metastatic non–small cell lung cancer.

: There have been some great updates in clinical trial data that show the fantastic activity of next-generation ALK inhibitors in 

-rearranged non–small cell lung cancer. Updates to the ALEX trial, which randomized patients to receive alectinib versus crizotinib, show progression-free survival was about 3 years, and overall survival in the alectinib arm was not reached compared to median overall survival at 57.4 months with crizotinib.

Even with crizotinib, the median overall survival was over 5 years, which is amazing, but not even reached for alectinib. With the median progression-free survival of about 3 years, with all these other ALK inhibitors in development, it's really exciting that we’re able to bring some fantastic treatments to these patients, to meaningfully improve their lives and clinical outcomes. Five-year overall survival was 62.4% with alectinib compared to 45.5% with crizotinib, so well over half the patients are alive after 5 years.

If you look a few years ago, the SEER [Surveillance, Epidemiology, and End Results] database of 5-year survival for stage IV non–small cell lung cancer was 5%. Now, were looking at these 

 subsets where the majority, over 60%, are alive after5 years. We need to do better. We need to work on curing patients, but this is fantastic. On top of that, the J-ALEX trial, which was conducted in Japan, had comparable PFS, up to 34.1 months median with alectinib, compared with crizotinib at 10.2 months.

The median overall survival was not reached with alectinib versus 43.7 months for crizotinib. This was backed up by the ALESIA study, which was done with the East Asian population, with a hazard ratio of 0.374 for progression-free survival. So there is an amazing benefit from alectinib in terms of PFS and OS [overall survival] compared with crizotinib. The ALTA-1L study median PFS was 24 months with brigatinib versus 11 months for alectinib, with a hazard ratio of 0.49 and reduced disease progression or death by 51%. There are some fantastic updates and pivotal advances in the treatment of 

-rearranged non–small cell lung cancer.

 translocation-positive lung cancers has exploded in the last couple of years. It was 10 years ago or so that the disease was identified and the first patient with an 

 translocation was diagnosed. Since that time, we’ve seen the development of multiple generations of agents, and we now have the luxury to have a number of frontline agents to pick from. The one that was first developed, crizotinib, has fallen to the wayside because it does not have good CNS penetration, which is a major deficiency in the management of this particular patient subset, with a very high frequency of brain metastases, up to 40% to 50% in different series. Every drug that you want to use in the front line, we want to make sure there’s good CNS penetration and appropriate control of CNS disease. Luckily, a series of drugs that includes alectinib, brigatinib, and now lorlatinib and ensartinib, are joining the crew and have that defining feature. Each of them surpass crizotinib dramatically, doubling or more than doubling the progression-free survival. That includes CNS disease control as well.

Just last week, we heard that lorlatinib came out with a positive study, the CROWN study, as compared with crizotinib. A few days ago at the World Conference on Lung Cancer, we heard positive results with ensartinib, so the list grows regarding the number of agents that we can choose from. How do we choose for each patient? At the moment, alectinib is in the lead because it was the first drug that showed positive results compared with crizotinib. It doesn’t seem to have any glaring weaknesses. It has great CNS activity, and it has a favorable adverse event profile. We have to continue to watch the data; maybe we’ll see some studies comparing these outstanding molecules. Lorlatinib, brigatinib, and ensartinib have great data as well, but there might be some slight weaknesses. Lorlatinib has a bit more of a problematic adverse effect profile. Brigatinib tends to be well tolerated, but it does have an early pulmonary toxicity that some physicians are a bit worried about, but most patients are able to get through fine.

Ensartinib seems to have a favorable adverse event profile, but it’s coming a bit too late to the market. Alectinib will remain in the lead for the time being, but it’s nice to have a number of different treatment choices because not every patient will tolerate a drug as well as the average. Having alternatives is nice, and some of these drugs can also be used at the time of resistance. For example, lorlatinib seems to have great efficacy, even in patients who have developed resistance to one of the earlier-generation ALK inhibitors.

There are some differentiators in terms of adverse event profiles. Alectinib is very favorable, nothing outstanding regarding major adverse events or of significant concern for the average patient. With brigatinib, the sore point is that early pulmonary toxicity, but we’ve learned how to deal with it. We have dose uptitration. It really seems to be a transient issue and not a serious one. Lorlatinib is a bit trickier to use because it has some longer-term management issues regarding lipid profile changes—high cholesterol, hypertriglyceridemia—which many times needs to be comanaged. There’s also some potential for mood disorders, which also need to be comanaged. Many clinicians view lorlatinib as a great drug in the second-line setting but a bit challenging for first-line use.

Ensartinib is a new molecule that I don’t have a lot of experience with, but it does seem, based on reported data, to have a fairly favorable adverse event profile similar to alectinib without a whole lot of major issues that stand out.

Updates Informing the Management of ALK-rearranged mNSCLC

 fusion pathway lung cancers and tissue agnostic 

 fusion-positive cancers in general, for entrectinib, again, we have a very active molecule here. The response rate is quoted in this study in the 60% range. When you look at the waterfall plots, practically all patients seem to derive some benefit. There’s documented CNS [central nervous system] activity, CNS responses, and durable responses as well. We’re looking at an active, highly potent, and well-tolerated drug that’s an excellent choice for our patients.

 As I mentioned before, entrectinib and other NTRK tyrosine kinase inhibitors are generally well tolerated. We see some unusual adverse effects, which are due to inhibition of the TRK pathway. Those are dizziness, perioral numbness, and weight gain. The majority of adverse effects, however, are mild. Discontinuation of the drug due to adverse event is very rare.

I've seen similar adverse effect profiles with larotrectinib, which is another agent approved for 

-rearranged cancers. As with entrectinib, weight gain, dizziness, and perioral numbness are reported. Discontinuation rate is also very low with larotrectinib.

 When considering data from basket trials and whether I put more stock in efficacy in a particular tumor type or a drug's overall efficacy across all tumor types, I think the answer is that it depends. For 

 fusion, when comparing non–small cell lung cancer to other tumor types, the non–small cell lung cancer group is so rare that you have to look at the activity in other tumor types as well.

What you see, whether it's larotrectinib or entrectinib, is (1) activity in non–small cell lung cancer, and (2) potent activity across other tumor types. For 

 fusions, I put a lot of stock in the overall activity among multiple tumor types because it's so rare in non–small cell lung cancer, and within those patients, there is also activity.

It depends on the molecular aberration. Histology and tumor type are important, potentially in other genomic aberrations that drive cancer. Examples of this are dabrafenib and trametinib, with 

mutated melanoma with V600E; they are very effective, but potentially less so when looking at colon cancer. That's a type where tumor histology and tumor type may be more relevant.

We're developing KRAS G12C specific inhibitor, and it’s early days, but we see more activity in non–small cell lung cancer, at least as an early snapshot. We need more patients, compared to other tumor types that we saw presented in the CodeBreak 100 trial at ASCO [the American Society of Clinical Oncology annual meeting] this year, where there were fewer responses in patients treated who did not have non–small cell lung cancer. It also depends on what the genomic aberration is.

, I put a lot of stock in the basket trial and tumor type activity, on top of the activity we see in non–small cell lung cancer.

 Nowadays, the ideal is to develop targeted drugs with CNS penetration, especially in my field of thoracic oncology where practically all patient subsets are at risk for CNS metastasis. If you think about it, tissue agnostic approval of these drugs—not all of the cancers would have a high likelihood of CNS metastasis, but many of them do. Lung cancer belongs to them, so it might not be an absolute must-have as a feature for this drug for every single patient, but for a very good subset, it is. It’s a nice thing to have, especially for patients with lung cancer. Some of these fusions occur in CNS malignancies as well. It’s important to have that additional characteristic, so I’m very happy with that.

 fusion testing is recommended across the board for metastatic cancers with limited management options. All of us have to think about not just tissue specifically. For lung cancer, we have the mandate to test a number of actionable markers. 

 is one of them. It’s a rare member, 0.3% or so, but an important one. Across tumor types, the clinicians need to remember that if you face a patient with an advanced cancer of probably any origin, that expanded molecular testing, including 

 fusion testing; that expanded profile will be beneficial to the clinician to feel comfortable guiding your patient to the best treatment choice and will definitely benefit your patient as well to make sure that all opportunities are exhausted and that they can reach the best life expectancy and best quality of life they can have, even in the face of an advanced malignancy.

Updates Informing the Management of NTRK+ NSCLC

 gene fusions in non–small cell lung cancer, as well as its incidence, natural history, and prognosis, 

 fusions are really rare. Previously, we talked about 

 being about 1.5% to 2% of non–small cell lung cancer. 

 is probably a lot lower, 0.2%, so infrequent. There is a higher frequency in other tumor types and certain salivary gland tumors.

 fusion is that when you find it, you have great drugs that are approved with larotrectinib and entrectinib. The TRK family is a kinase domain with a lot of sequence homology, and its standard function is to play a role in neurite outgrowth, pain, and sensory modulation. It’s a low frequency, but 1 of the advantages with raw genomic profiling is that when you find it, you have great drugs you can match to it.

 NCCN [National Comprehensive Cancer Network] Guidelines currently list 2 agents that are appropriate for 

-rearranged cancers, lung cancers, and others. Those are larotrectinib and entrectinib.

–fusion-positive lung cancers, we need to remind ourselves that the tissue-agnostic FDA approval of both larotrectinib and entrectinib 

fusions occurs very rarely in many common cancers, including lung cancers, and can occur very commonly in some fairly rare cancers. That includes a number of pediatric malignancies but also certain salivary gland cancers and breast cancers, very specifically the secretory type of breast and salivary gland cancers. Their 

 fusions are practically pathognomonic, occurring in almost 100% of patients.

 fusions occur maybe in just 0.3%, but in any 

–fusion-positive cancer, the presence of this fusion indicates a very high likelihood of response and durable response to these NTRK inhibitors. Identifying these patients is very important. They are a small number, so we have to identify them. When we find them, it benefits these patients so much. I don’t think any of us would want to lose the opportunity for our patients to derive the benefit. This is the beauty of the next-generation sequencing platforms. In just 1 setting, we’d run tests. You can do comprehensive testing. You’re not necessarily looking for 

. You’re looking at the overall makeup of the cancer and using that to guide your treatment. If it includes 

, and it should, then you’ll be able to identify the 

-positive patients and offer them highly effective treatment.

Both larotrectinib and entrectinib seem to have response rates that are very high, 80% or something in that range, with very durable responses. As I mentioned, these are highly tolerable agents that match the need for high quality of life for patients who have survived many years after proper identification of their actionable targets. It’s very important, especially for these patients who will have long survival, to use agents that provide a good quality of life. These drugs do for the majority of patients. As I mentioned beforehand, there are some adverse effects to remember. Besides some organ toxicities that are rare, you want to watch out for liver toxicity. The neurological toxicity very specifically stands out as a class effect of TRK inhibitors. We spoke about it a little beforehand in terms of neuropathies, dizziness, potentially syncopal episodes, polyphagia, weight gain; these are very specific adverse effects that you can see. Rarely is there a significant need for dose reductions, and it is unlikely to guide us in stopping the management of these patients. We should be able to come up with a schedule that patients should tolerate over the long term.

The reality is that both these molecules are highly potent and active in the clinic. I have a very hard time separating them in terms of seeing major benefit with one over the other. We’re lucky to have 2 excellent molecules on the market for our patients. The toxicities seem similar as well, so I cannot pick a champion here. Maybe others can. I’m just glad we have these excellent drugs available to our patients.

NTRK Gene Fusions in NSCLC

 It’s important to remember that we built a paradigm in molecular oncology to look for mechanisms of acquired resistance, to learn from that and try to guide the next line of treatment based on that understanding. I can’t say that that’s fully established for 

, but I don’t see any reason why we wouldn’t want to continue to learn. It’s good to retest the patient for the development of secondary mutations. We’ve learned there are some very specific 

 mutations that can potentially match patients for potentially active second-line therapy, such as lorlatinib, which is a highly potent next-generation drug for the management of both 

 translocation-positive patients. I tend to use the same paradigm that we use for 

-positive patients in terms of ctDNA [circulating tumor DNA] with tissue-based retesting and learn from that experience. Fortunately, we have second-line agents to possibly be used. There are others under development, such as repotrectinib, which is a very potent and highly promising agent as well.

 In terms of mechanisms of resistance to ROS1 inhibition, there have been a lot of exciting developments. As we do for many oncogene-driven lung cancers, I really look at mechanisms of resistance in 2 categories. One is the on-target resistance mechanisms, for example, within 

 that eventually cause changes that prevent the drug from binding. Then there are bypass tracks and off-target resistance mechanisms that signal around 

, bypassing track signals that allow the tumor to grow despite the inhibition of the target with the drug.

There are a number of secondary on-target resistance mutations and bypass tracks. In terms of on-target mutations, there are mutations such as G2032R, in which response to lorlatinib occurred about over 20% of the time. There are solvent front mutations as well. Some of these mutations looking at structural modeling that causes interference with binding of these ALK and ROS1 TKIs [tyrosine kinase inhibitors]; some of these mutations—lorlatinib, crizotinib, and entrectinib—may be more sensitive to certain ROS1 inhibitors than others.

 lung cancer, there is some type of a heat map you could use, where you can look at what you would expect the relative inhibitory concentrations to be and then potentially pick a ROS1 inhibitor that may have efficacy. A tougher one to target is G2032R. With that, there is a drug called repotrectinib that’s now being looked at. You could look to potentially match those up in clinical trials. There are also bypass tracks, for example, as a resistance mechanism to lorlatinib; MET amplification has been noted as well.

-resistance mechanism, and that’s a major bypass track that signals around the drug. I divide it into these on-target mutations, which may differ a bit among crizotinib and then lorlatinib and entrectinib, and off-target mutations. Plus, molecular aberrations such as MET amplification, where going back to crizotinib—crizotinib is also a MET inhibitor—may have some additional activities. We’ve certainly seen that in 

-rearranged non–small cell lung cancer. That could apply to 

Future Directions for ROS1 rearranged mNSCLC

 Entrectinib approval was certainly welcome because it gives our patients another option. Entrectinib approval was based on the combined analysis of 3 trials, which are called ALKA-372-001, STARTRK-1, and STARTRK-2. It is a very effective drug, and a response rate of 78% is excellent. In addition, entrectinib has confirmed CNS (central nervous system) efficacy, which is important for our patients with oncogenic-driven cancers.

-positive non–small cell lung cancer that's metastatic, there's been the development of several exciting therapies. As mentioned, crizotinib has been around for several years and does have good activity. Entrectinib has recently been approved as well. The approval was based on a pooled analysis of 3 studies with entrectinib, as it's also an NTRK and ALK inhibitor and was studied in a cross section of these patients.

 in the ALKA-372-001, STARTRK-1 and STARTRK-2 studies, overall response rates were over 70%, and median duration of response came out to be 24.6 months. The major advantage of entrectinib is that it does have additional CNS activity and penetration. There are potential adverse effects: weight gain; neutropenia; some nervous system disorders, such as paresthesias; GI (gastrointestinal) upset with nausea; myalgia; dysgeusia; and attention disturbance.

Overall, it's an excellent option for patients with 

 rearranged non–small cell lung cancer. In terms of the pharmacodynamics and pharmacokinetics of entrectinib compared with crizotinib and ceritinib, I think the big advantage is CNS activity, and we've seen that. We've seen CNS activity play a role, for example, with alectinib and brigatinib versus crizotinib in 

 rearranged non–small cell lung cancer, as well as osimertinib compared with erlotinib and gefitinib in 

 mutated lung cancer, where those have become first-line treatments.

One could look at entrectinib in a similar way. It is a selected ATP (adenosine triphosphate)-competitive inhibitor of TRK

ROS1, and ALK and does have great potency in terms of its pharmacokinetics and pharmacodynamics, with maximal concentration reaching 2 to 4 hours. Half-life is about 21 hours in the fed state, so it can be taken with food. It is a good option for these patients.

 Coming now to entrectinib, a recently developed and very potent NTRK and ROS1 inhibitor, we’ve seen great success with this agent in both 

-fusion positive cancers, including a fair number of lung cancers. This is an agent that’s also very selective. It doesn’t have a lot of off-target adverse effects. It’s a very safe molecule. It’s also designed to be CNS-penetrant, which is very important in the treatment of these patients.

Non–small cell lung cancer has a great predilection for CNS metastases, in particular 

-positive cancers have a great likelihood of ultimately metastasizing to the CNS. Having targeting agents with CNS penetrants is critical, and entrectinib is a molecule that fits the profile and has shown great efficacy in the combined analysis of the phase 1 and phase 2 studies, showing a PFS (progression-free survival) of 19 to 20 months. It’s shown a great benefit in the overall group of patients,specifically patients with CNS disease, with a response rate surpassing 50% in the CNS and a substantial duration of response, maybe a year or so in the CNS as well. This is a highly promising agent for the management of 

 translocation-positive non–small cell lung cancers.

I think we’re fortunate to be able to witness the treatment of patients with this targeted agent. 

-positive cancers stand out as having great benefits from 

-targeting drugs. Crizotinib is sort of the historical molecule that we’ve used for these patients with great success. In fact, some of the longest responders among advanced lung cancers tend to be patients with 

translocation-positive disease. Entrectinib seems to have a profile analogous to crizotinib in terms of overall benefit and has the advantage of the CNS penetration. That’s significant for this subset of patients, so it’s a favorable asset to entrectinib and offers a great alternative for our patients with 

fusion-positive non–small cell lung cancer.

 The overall response rate to entrectinib in the entrectinib trials was 78%. Responses were durable, with median duration of response of almost 25 months. It's important that responses were seen in patients with and without brain metastases. The median progression-free survival was 19 months. We also saw that entrectinib appears to have a very good CNS penetration, with intracranial overall response rate of 55%. Entrectinib is well tolerated.

Even though nearly all the patients in that trial experienced adverse events, the majority of them were grade 1 or 2. There are certain adverse events that are expected for NTRK inhibitors, and those are called on-target treatment-emergent adverse events, which we think are due to inhibition of TRK. Those are dizziness, sometimes perioral numbness. Interestingly enough, TRK TKIs (tyrosine kinase inhibitors) also cause weight gain in our patients due to inhibition of the TRK pathway.

Despite the fact some of the patients had adverse events, discontinuation was very rare in that trial. Only 3% of the patients discontinued the drug due to adverse events. About one-third of the patients required dose interruption, and 20% required dose reduction. Evidence of serious adverse events was also very low, about 9%. Overall, entrectinib is well tolerated by our patients.

I have experience with entrectinib, and I have given it for both 

 rearranged cancers. My experience is very similar to what has been described. Dizziness is something we commonly see, as well as perioral numbness. Another interesting adverse effect that we see with NTRK inhibitors is if you hold the drug for one reason or another, your patient will experience pain. It's important to be aware of withdrawal symptoms and manage that pain with any kind of pain medication.

 Intracranial response is important, particularly in patients with CNS disease or in oncogene-driven lung cancers that have a propensity to develop CNS disease. It can be a sanctuary site for recurrence as well. It's a very good option for patients with 

 rearranged non–small cell lung cancer, particularly regarding the CNS activity as a potential sanctuary site.

Like I said with alectinib and brigatinib in 

 rearranged lung cancer, and osimertinib in 

 mutated lung cancer, the longer you can forestall metastases to the brain, the better off you are. The other thing is for small asymptomatic brain metastases: If you can forestall radiation to the brain, these are patients who will sometimes live 4 to 6 years or longer. If you do brain radiation upfront, particularly whole-brain radiation, you're risking some serious neurocognitive toxicities down the road. If you give a TKI that has CNS activity, you'd be able to forestall that and potentially save the patient from some life-impactful toxicities down the road.

 Entrectinib is a molecule, a drug that’s easy for patients to take. It has a simple administration schedule, 600 mg once daily, if I remember correctly. It can be taken with or without food. The adverse effect profile is very favorable. Whenever we look at studies of these targeted compounds, it’s nice to see the number of patients who needed to dose reduce due to adverse effects. It’s also important to look at the number of patients who had to stop the drug due to adverse events. Those percentages are very low with entrectinib. It’s a very well-tolerated compound.

It’s important to remember that it also blocks the NTRK pathway, and that’s an important pathway in the CNS. That explains some of the unique adverse effects of the molecule, as well as any molecule blocking the TRK pathway. There can be CNS adverse effects, such as dizziness, and neuromuscular adverse effects, such as neuropathies, polyphagia, and potentially weight gain. These patients have a very good appetite, which is nice on a certain level, but it can sometimes yield to significant weight gains.

ALKA-372-001, STARTRK-1, and STARTRK-2 Trials

-mutated translocated lung cancers is very important. It’s a small percentage of our patients, maybe 0.5% to 1%. This particular subset derives tremendous benefit from targeted therapy. We have different generations of agents to offer, so identifying these patients is absolutely critical. To integrate 

testing into your platform is an absolute must and cannot be forgotten.

What is the proper test? Well, there are different tests we can perform. The most commonly used platforms are either FISH (fluorescence 

 hybridization), looking for very specific translocations, or next-generation sequencing (NGS) technology. The latter allows us to do more…testing, allowing complete molecular testing. IHC (immunohistochemistry) testing is also under development. It’s not as good for 

, we’re not so confident yet. Usually, it’s FISH or NGS testing that we want to integrate into the molecular testing paradigms, with NGS providing a one-stop shop for molecular testing with 1 single test integrating all the molecular needs.

You can have translocations that do not yield a functional protein, but that’s unusual. When you see a 

translocation, you have to think this might be an actionable alteration, and the largest majority of those are. Testing companies will do their best to make sure that the information is relayed in an appropriate fashion in regard to the reliability of detection. Was the translocation detected in both directions? Most of the time, when we see a 

 fusion detected, that’s an actionable abnormality. It’s most commonly seen in lung cancers but can be seen rarely in other cancers and cholangiocarcinomas, as well as certain CNS (central nervous system) malignancies.

, there are certain subsets of patients where these abnormalities are enriched, usually younger patients, nonsmokers. With 

 mutations, there’s a gender predilection for females. That’s not the case for 

. The gender balance seems to be about 50/50. At the same time, it tends to be younger patients with adenocarcinoma histology. That being said, there’s always a certain percentage of patients who are smokers, who are elderly, sometimes with nonadenocarcinoma histology. The best is not to use the phenotype to drive testing, but to make sure that all of our patients with advanced non–small cell lung cancer get appropriate testing at the end of the day.

 non–small cell lung cancer, my first-line treatment is an ROS1 TKI (tyrosine kinase inhibitor). That could either be crizotinib, which has a median progression-free survival of over 19 months and a response rate of about 70% in the pivotal trial, or entrectinib, which was recently approved for 

 non–small cell lung cancer and has additional CNS activity. That's a consideration, particularly in patients with

 rearranged non–small cell lung cancer who have CNS disease. Its duration of response was in excess of 20 months in the pooled clinical trials with entrectinib, looking specifically at 

 rearranged non–small cell lung cancer. Those are the preferred agents. Ceritinib has also been looked at and has some activity, but it’s unclear if it's any better than crizotinib or entrectinib. I don't think it's been studied as extensively in 

Lorlatinib in subsequent lines of therapy appear to have some activity, and there are clinical trials with additional agents, such as repotrectinib, that are particularly of interest. I would also like to mention that beyond ROS1 TKIs, pemetrexed-based therapy, like in 

 non–small-cell lung cancer, does appear preferentially sensitive to pemetrexed-based therapy in terms of chemotherapy combinations in the future. My initial approach is a ROS1 TKI first, based upon the extraordinary PFS (progression-free survival) benefit observed with crizotinib and entrectinib.

 As I mentioned, it is best to hold your treatment until you know that your patient has 

 rearranged non–small cell lung cancer. There are several agents available. The data behind efficacy of immunotherapy in that population are quite limited. The only thing we have is a retrospective registry, which is called IMMUNOTARGET. In that registry, patients with 

 rearranged lung cancer were given immunotherapy, and the response rate was only 16%.

Eighty-three percent of the patients with 

 rearranged lung cancer progressed on immunotherapy. We also know that PD-L1 expression in patients with oncogenic-driven tumors can be falsely elevated and does not necessarily predict efficacy of immunotherapy in that population. That's why I would wait for the molecular testing results. I would like to treat patients with 

 rearranged lung cancer with oncogenic-driven therapies and use target therapy instead of immunotherapy.

Current Management of ROS1 rearranged NSCLC

 There are a couple of things to keep in mind when looking at the prevalence and natural history of 

 rearranged non–small cell lung cancer. The prevalence of 

 is about 1.5% to 2% of non–small cell lung cancer adenocarcinoma histology. It is predominantly adenocarcinoma histology and occurs in patients who have never smoked or have a light smoking history, whose age tends to skew younger. They tend to be metastatic, and like with many oncogene-driven lung cancers, there can be a propensity for CNS (central nervous system) metastatic disease.

The prognosis for these patients is generally better than the overall population because we have good targeted therapies we can bring to bear. Crizotinib has been the most extensively studied. It is also an ALK inhibitor, as well as an ROS1inhibitor. It was initially developed as a MET inhibitor. In the most known clinical trial, which was published in 

, response rates were about 70%, with median progression-free survival a bit over 19 months, so it was highly clinically active.

In other studies with crizotinib, progression-free survival was a bit less but still highly active for well over a year. There is entrectinib, which is an ALK and NTRK inhibitor but recently approved for 

. Its duration of response in an analysis of patients with 

 rearrangement treated in multiple clinical trials with entrectinib was over 20 months. There is also a drug, ceritinib, which is approved as an ALK inhibitor. It's not quite as active as alectinib or brigatinib, and it does have more of a toxicity profile. It does have some activity in 

as well, although it is unclear whether it has any benefit over crizotinib or entrectinib and may have less activity in 

. There are newer drugs that have been studied with activities, such as lorlatinib and repotrectinib. For practicing clinicians, a common question I get is: Can you use alectinib for 

 because it's a potent ALK inhibitor? The answer is no.

Alectinib is an ALK inhibitor, and it has some RET inhibitory activity but has no ROS1 inhibitory activity. That's a question I get sometimes. There is a spectrum of drugs in development for this uncommon mutation, but one that we detect frequently in patients who have never smoked or have a light smoking history.

ROS1 Rearrangements in mNSCLC

: In terms of best approaches for molecular testing for patients with metastatic non–small cell lung cancer, there are different methodologies that could be used with either plasma or tissue. My general approach is to look at broad molecular profiling because we have 7 approved targeted therapies for 

 mutated lung cancer matching the TKI (tyrosine kinase inhibitor) to a great targeted therapy. We have osimertinib for 

, among others; alectinib and brigatinib for 

 fusions; larotrectinib and entrectinib for really rare 

 mutations; and dabrafenib and trametinib for 

To capture all of those, I look at broad-based genomic profiling, next-generation sequencing (NGS). You could look at tissue. You could look at plasma. There are pros and cons for each one. If I need something quickly, I will often send plasma since you don't need to set up a biopsy if you need additional tissue, and you get the results in a week. If there's a big surgical specimen sitting in the bank, I'll often use tissue. Where I don't have tissue, I'll first try with plasma as I'm setting up the biopsy.

There are methodologies, such as IHC (immunohistochemistry) and FISH (fluorescence 

 For IHC, there is an FDA-approved test, and those can come back quickly. There are certain situations where, if I really suspect there's an 

 fusion and I need to start treatment quickly, I will occasionally send that as part of a targeted panel to get the results quicker. Generally, I send next-generation sequencing for broad genomic profiling.

Jonathan Riess, MD, MS, UC Davis Comprehensive Cancer Center

Articles

Future of ALK-rearranged mNSCLC

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Subsequent Lines of Therapy in ALK-rearranged mNSCLC

Updates Informing the Management of ALK-rearranged mNSCLC

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NTRK Gene Fusions in NSCLC

Future Directions for ROS1 rearranged mNSCLC

ALKA-372-001, STARTRK-1, and STARTRK-2 Trials

Current Management of ROS1 rearranged NSCLC

ROS1 Rearrangements in mNSCLC

Molecular Testing for NSCLC

Overview of Rare Driver Alterations in NSCLC

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Current Management of Oncogene-Driven NSCLC