Karen Reckamp, MD

The progress we’ve made to date in treating 

-positive metastatic non–small cell lung cancer is astounding. We have a large number of frontline therapies that are incredibly beneficial to patients’ tumor responses and significantly prolong progression-free survival. By sequencing these, we have some of the best overall survival that we’ve ever seen with metastatic non–small cell lung cancer. Moving to the future, we need to keep working on these mechanisms of resistance because we’re still not curing most patients. We need to better understand how to utilize immune checkpoint inhibitors for patients with 

 fusion-positive non–small cell lung cancer.

In small studies, it appears that patients with 

 fusions have less efficacy with immune checkpoint inhibitor therapy, at least as monotherapy. We don’t know how well they do with chemotherapy, or if chemotherapy is sufficient on its own. We need to understand how to make tumors that are generally cold, such as many of the 

tumors, into hot tumors that will respond to immunotherapy, which may lead us toward more cures with this disease. Then we need to think about screening. At this point, many of these patients are light- or never-smokers, they’re not included in our screening algorithms. We are looking for prognostic markers to define who might benefit from early screening. From the early study presented from Taiwan, patients who are nonsmokers who have a family history of lung cancer may benefit from early CT screening. This will also be something that will help improve cures for our patients.

Case: A 68-Year-Old Woman with ALK+ Non–Small Cell Lung Cancer

A 68-year-old woman presented with fatigue, wheezing and decreased appetite

PE: wheezing on auscultation; ECOS PS 1
 

Chest x-ray showed a left lower lobe mass

Chest/abdomen/pelvic CT scan confirmed a 6.8-cm left lower lobe lung mass and a suspicious liver lesion

PET scan showed activity in the left lower lobe mass and liver

MRI of the brain showed several subcentimeter lesions without edema

Bronchoscopy with transbronchial biopsy of the left lower lobe mass confirmed lung adenocarcinoma

Patient was started on brigatinib 90 mg qDay for 7 days; well tolerated; dose was increased to 180 mg qDay

Videos

An expert in the treatment of lung cancer gives insight for the sequencing of ALK inhibitors following disease progression, highlighting the instances of the development of brain involvement and rebiopsy.

ALK+ mNSCLC: Advancements Made and What’s Next

When we think about sequencing ALK inhibitors, that’s a big area of discussion at this time. There are some studies that are evaluating the sequencing. We do need to think about resistance and overcoming resistance. A drug that is more specific and can overcome resistance mechanisms, generally has turned out to have longer progression-free survival because these drugs continue to be developed and patients have many options following frontline therapy. The overall survival continues to get longer, so it is more difficult to compare overall survival across these different trials. For patients who have brain involvement and have progression within the brain, lorlatinib has the best efficacy post–third-generation ALK TKI [tyrosine kinase inhibitor], and sometimes we have to move toward radiation for the brain if they’re progressing on our current therapies.

When a patient has systemic progression, we consider rebiopsy. Many of these patients are going on clinical trials, but even without a clinical trial, understanding the mechanisms of resistance can help us choose the appropriate therapy. At this time, lorlatinib is the only approved agent post–third-generation ALK TKI and has broad coverage across resistance mechanisms. Brigatinib also has efficacy across most of the point mutations and alterations that occur as resistance mechanisms. In this case, the patient received brigatinib; there are few data utilizing other inhibitors post-brigatinib at this time. We also know that patients do well utilizing pemetrexed-based chemotherapy. This needs to be a part of the patient’s treatment course to provide the longest overall survival. We discussed that at some point, after receiving usually 2 TKIs, that pemetrexed-based chemotherapy will be part of their treatment regimen. For somebody with brain metastases, we often do continue the ALK TKI to maintain the brain penetrants.

Sequencing ALK Inhibitors

In thinking of the design of the ALTA-1L trial, which was published in 2019, brigatinib is a specific ALK inhibitor and overcomes many of the mechanisms of resistance associated with crizotinib and alectinib. Patients first receive a 7-day run-in of the 90-mg tablets followed by 180 mg, if well tolerated. This was shown to have an improvement in progression-free survival over the use of crizotinib. There was a significant benefit in a delay to brain metastasis and in control of brain metastasis. There was a prolonged duration of response, and much of this has not yet been reached as the initial follow-up is still shorter than what we’ve seen with alectinib.

We know from that frontline trial that these numbers continue to lengthen as the follow-up goes on. For adherence to this medication, brigatinib is a once-daily drug, and it comes in both 90-mg and 180-mg tablets, which makes it easy for a patient to take once a day. In these patients, they’re starting with 90 mg, and we’re evaluating for any pulmonary symptoms, and if they can tolerate it over the first week, they are increased to 180 mg. We’re checking in with patients by phone call and evaluating after that first week and then after the first week on 180 mg. These are generally phone calls, and the visits don’t change based on utilizing brigatinib. Patients tolerate these medications well, and the quality of life is significantly improved on brigatinib when they’re starting to experience tumor regression on the drug.

We were part of the second-line study utilizing brigatinib and have many patients who have had excellent responses, and some who are still on brigatinib years later with continued tumor response. In addition, we’re just starting to use brigatinib in the frontline setting, but several patients are doing well and tolerating the brigatinib without significant toxicity. Most patients are able to go up to the 180 mg, though I’ve had some who have required staying at the 90-mg dose.

Karen Reckamp, MD, discusses the design, practical implications, and important findings from the ALTA-1L clinical trial.

ALTA-1L Trial: Brigatinib

Moving specifically to this patient’s treatment with brigatinib, there was a recent FDA approval in 2020 for brigatinib for the frontline setting. This had previously been approved for patients post-crizotinib, and then because of the ALTA-1L trial, where brigatinib was compared to crizotinib, there was an approval for the frontline setting. This is important for patients with 

-positive non–small cell lung cancer, as more choices improve the chances of patients having long-term benefits and being able to choose the best drug based on toxicity and efficacy in the frontline setting. For this patient, utilizing brigatinib is well tolerated, and the importance of taking the 90-mg dose for the first week, evaluating pulmonary symptoms and other toxicity, then moving up to the 180 mg if tolerated, again, is important for this patient.

An expert in the treatment of lung cancer discusses the use of brigatinib in this patient case and in general use for ALK+ metastatic NSCLC.

FDA Approval of Frontline Brigatinib in ALK+ mNSCLC

-positive non–small cell lung cancer. What we know about 

 non–small cell lung cancer is that there are a multitude of treatments now, even in the frontline setting, and we know that patients do well. Median survival for patients is about 80 months, and that’s spectacular; it’s getting longer as we have more therapies available for patients. In the frontline setting, we have about 5 choices for drugs to use. The medication that shows the longest overall survival thus far is alectinib, and it has the longest follow-up. It is well tolerated and has excellent penetration in the brain. This was one of the first studies to show improvement over crizotinib in the frontline setting and has a long-term follow-up associated with it.

Drugs like brigatinib have shown excellent tumor response, intracranial response, and prolonged progression-free survival, both in the frontline and second-line setting. The follow-up has been shorter, and we are awaiting longer follow-up for some of these. Lorlatinib most recently was approved and has excellent penetration into the brain and excellent tumor control. At this point it has the shortest follow-up, but does cover many of the resistance mutations that alectinib does not cover.

At this point in my practice, I’m utilizing alectinib or brigatinib with some of the longer data follow-up. Both of these drugs are well tolerated, and a drug like lorlatinib has more toxicity. They have some toxicity-elevated triglycerides and cholesterol that need to be monitored, and based on this, I’ve used this less in the frontline setting. For patients, once they start on their treatment, we follow up closely early on. We’re evaluating liver function tests, looking for bradycardia with these drugs. Usually, on a monthly basis, we’ll be seeing these patients and performing laboratory evaluations. For patients on brigatinib, they get the first week of 90 mg followed by the 180 mg. We check in with them after the first week and once they start on the 180 mg to make sure they haven’t experienced new [adverse] effects.

Once they’ve been on the drug and are doing well, we do a follow-up about every 2 to 3 months and we do scans at that interval. An important piece for this patient too is the brain metastases. When somebody has baseline brain metastases, it’s important to use our next-generation ALK inhibitors, which have shown to have excellent brain penetration. In this setting, the early data from the lorlatinib trial did show a significant hazard ratio for patients with brain metastases. All of these drugs have excellent brain penetration, and in this patient, the brain would not require radiation but could be treated with the ALK inhibitor.

Karen Reckamp, MD, reviews recent therapeutic findings and the treatment spectrum for ALK+ NSCLC, as well as her clinical experience in using some of these treatments.

Treatment Options in ALK+ NSCLC

Hello, I’m Karen Reckamp. I’m the division director for medical oncology at Cedars-Sinai, and we’ll be talking about 

-positivenon–small cell lung cancer today, starting with a case. This is a 68-year-old woman who presented with fatigue, decreased appetite, and some shortness of breath. The past medical history was unremarkable, and on a physical examination, wheezing was heard on auscultation in the lower lobes. Her ECOG performance status was 1. For her clinical work-up, laboratory test results were within normal limits, and a chest x-ray showed a left lower lobe mass. Subsequently, a CT scan of the chest, abdomen, and pelvis showed a 6.8-cm mass in the left lower lobe and a lesion within the liver that was suspicious for metastatic disease. A PET [positron emission tomography]/CT showed activity in the left lower lobe and in the liver. An MRI of the brain showed several subcentimeter lesions without edema. She underwent a bronchoscopy with transbronchial biopsy of the left lower lobe mass, and this confirmed lung adenocarcinoma, TTF-1 [thyroid transcription factor 1]-positive, and napsin A-positive. The tissue was sent for comprehensive molecular testing. First PD-L1 came back, and the tumor proportion score was 0%. Next-generation sequencing revealed 

 were all negative for alteration. At this time, she was started on brigatinib at 90 mg daily for the first 7 days. This was well tolerated, and the dose was escalated to 180 mg daily.

Initially being diagnosed with metastatic non–small cell lung cancer with a lung mass and metastatic disease to the liver, her prognosis has changed over the years. Now that we have more targeted therapies for patients, and we have immunotherapy for patients, this has extended the lifespan. We have some data in 

 that showed that even patients with metastatic disease are living longer now than they were a decade ago, and this is largely because of targeted therapy. The fact that she had molecular testing is important. Generally, we do get PD-L1 testing to evaluate for the use of immune checkpoint inhibitor therapy as monotherapy. In this case, this was low, but even if this is a high level, we want to make sure that patients’ comprehensive molecular testing returns before we start frontline therapy.

We do comprehensive molecular testing on all patients with lung cancer and recommend that this should be a comprehensive test, next-generation sequencing. The optimal way to test is both DNA and RNA, which can increase the detection of fusions and rare mutations. This should be done at the time of diagnosis so that we don’t delay frontline therapy. With this patient, this was done and the tissue was sufficient. If there’s not sufficient tissue, we do perform a liquid biopsy, which can be beneficial in the frontline setting when there’s a significant tumor burden. If that liquid biopsy demonstrates a genetic alteration, this is something we’ve learned we can treat based on [the alteration].

Karen Reckamp, MD, provides an overview of the case of a 68-year-old woman with ALK+ NSCLC, including the initial presentation, clinical work-up, treatment, and the importance of molecular testing.

Karen Reckamp, MD | Authors

Articles

ALK+ mNSCLC: Advancements Made and What’s Next

Sequencing ALK Inhibitors

ALTA-1L Trial: Brigatinib

FDA Approval of Frontline Brigatinib in ALK+ mNSCLC

Treatment Options in ALK+ NSCLC

Case Overview: 68-Year-Old Woman with ALK+ NSCLC