Lyudmila A. Bazhenova, MD

Lyudmila A. Bazhenova, MD, medical oncologist and professor of Medicine at the University of California San Diego, explains the impact of having larotrectinib (Vitrakvi) results in a lung cancer cohort, as seen in a presentation of data from 14 patients, given during the 2020 World Conference on Lung Cancer (WCLC) Singapore.

Prior to WCLC, the data available for larotrectinib covered solid tumors generally, Bazhenova explains. Despite not having results from a lung cancer cohort, the larotrectinib data were convincing and the drug has been widely used for the treatment of TRK fusion-positive solid tumors. Bazhenova says the efficacy of the drug appears to be similar across all solid tumor types.

The key benefit of now having around larotrectinib specifically in the TRK fusion-positive lung cancer population is that oncologists can tell their patients what to expect with the drug, Bazhenova explains. According to the data, patients can achieve a response rate of up to 77%.

Articles

Lyudmila A. Bazhenova, MD, explains the impact of having larotrectinib results in a lung cancer cohort, as seen in a presentation of data from 14 patients, given during the 2020 World Conference on Lung Cancer Singapore.

Outcomes of Larotretinib Confirmed in TRK Fusion-Positive Lung Cancer

 The ALTA-1L trial had built-in health-related quality-of-life end points. Brigatinib showed an increase in median time to worsening quality-of-life scores of almost 27 months, versus 8 months with crizotinib. Also, patients who were randomized to brigatinib had a longer duration of improvement in quality of life, which is expected because the durability of response on the brigatinib arm was much better than the durability of the response on the crizotinib arm.

My personal experience is very consistent with what the quality-of-life metrics show in the study. In patients who have 

-fusion non–small cell lung cancer, once you start them on ALK TKIs [tyrosine kinase inhibitors], you’ll usually see improvements in cancer-related symptoms within 2 to 3 weeks. That’s what was shown in brigatinib. The median improvement in cancer-related symptoms was higher in the brigatinib arm compared with the crizotinib arm, again consistent with the fact that brigatinib may have deeper responses than crizotinib.

-mutant non–small cell lung cancer, in my opinion, is a poster child for drug development in oncogenic driven tumors. In a very short time from the discovery of 

 fusions, we now have 5 ALK tyrosine kinase inhibitors approved. Even though those medications are actually quite effective and responses are durable, we still can improve on those in the first line. There have been some thoughts on maybe testing the combination of tyrosine kinase inhibitors and chemotherapy to see if adding chemotherapy to tyrosine kinase inhibitors will improve outcomes.

What still is unsettled in patients with stage IV non–small cell lung cancer who have 

 fusions is how to correctly sequence agents. For example, if you give the patient alectinib as a first-line therapy, what should your second-line choice be? Should you go to lorlatinib, which has data, or should you try brigatinib first and then go to lorlatinib later?

I do want to put in a plug for something that’s called the Lung Cancer Master Protocol. There is an NCI [National Cancer Institute] effort going on right now trying to learn what the correct sequencing is, so when the patients are treated with ALK tyrosine kinase inhibitors, upon progression a biopsy is performed and treatment assignment is done based on what was found in the post-progression biopsy.

For example, if you find that the patient has a 

 amplification, it makes complete sense to use crizotinib as a second-line drug because crizotinib should have ALK efficacy and also inhibits MET. At this point, the sequencing is pretty much trial and error, and we do not have any results from the comprehensive clinical trials telling us what should be our drug A and what should be our drug B.

A 58-year-old woman presented with cough, fatigue and anorexia

Chest x-ray showed multiple left upper lobe mass and mediastinal lymphadenopathy

Chest/abdomen/pelvic CT scan confirmed left upper lobe mass measuring 6.2 cm

PET scan showed PET positivity in bilateral LUL mass and mediastinal LN

MRI of the brain showed widespread scattered small lesions; consistent with multifocal brain metastases

Bronchoscopy with transbronchial biopsy of the left upper lobe confirmed lung adenocarcinoma

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

Videos

The Future of ALK+ Non–Small Cell Lung Cancer

 Despite the fact that our ALK tyrosine kinase inhibitors [TKIs] are very effective, resistance eventually develops. As you can see from the alectinib trial, the median progression-free survival is 34 months. Based on the brigatinib trial, the median progression-free survival is about 29 months. Eventually, the patient will develop resistance.

The medication that we have and that has looked at extensively for use after failure from prior second-generation tyrosine kinase inhibitors is lorlatinib. Lorlatinib has shown a response rate of approximately 30% in patients who failed second-generation tyrosine kinase inhibitors.

The role of the biopsy is controversial at this point. In my practice, I do a post-progression biopsy for a couple of reasons. No. 1, small cell transformation has been described as a mechanism of resistance for 

 patients, and treatment for small cell transformation will be different. You would want to use chemotherapy rather than an ALK TKI as monotherapy. The second possibility is you can find a bypass pathway. Patients have been described to develop other molecular alterations as mechanisms of resistance, and you can consider targeting those. There’s also acquired on-target or 

 domain mutations that predict sensitivity to tyrosine kinase inhibitors.

In May 2020, the FDA approved brigatinib for patients with 

-positive non–small cell lung cancer. This was based on the ALTA-1L trial. ALTA-1L took patients who were ALK TKI-naїve and randomized them to brigatinib versus crizotinib. Enrollment on that trial was based on local testing. Prior chemotherapy treatment was allowed, and 27% of the patients in that trial had received prior chemotherapy. The primary end point was blinded independent review committee progression-free survival.

The study showed that brigatinib is better than crizotinib in regard to progression-free survival. For example, the independent committee review of progression-free survival was 24 months with brigatinib versus 11 months with crizotinib. And the investigator-determined progression-free survival was 29 months with brigatinib versus 9.2 months with crizotinib.

Brigatinib was superior to crizotinib in patients with or without CNS [central nervous system] metastases. For example, the median progression-free survival for those patients was 24 months in the brigatinib arm and 5.6 and 13 months in the crizotinib arms—5.6 months was for the patients who had brain metastases, and 13 months was for patients without. Brigatinib was effective for patients with brain metastases, showing a confirmed intracranial response of 78% in the brigatinib arm versus a 29% response in the crizotinib arm.

In the ALTA-1L trial, brigatinib showed an overall response rate of 74%, versus 62% with crizotinib. Responses were durable, as expected with ALK tyrosine kinase inhibitors. Duration of response was not reached with brigatinib. It was about 13.8 months with crizotinib. Responses were also durable in CNS. Intracranial progression-free survival was 24 months in the brigatinib arm and about 5.6 months in the crizotinib arm.

The ALTA-1L trial safety outcomes were consistent with prior experience with brigatinib. The drug’s adverse effects are common to those of other ALK tyrosine kinase inhibitors. The most common adverse effect of brigatinib was diarrhea, at about 49%. The majority of those symptoms were early in grade, with only 1% of diarrhea reported as grade 3 and above. Increased blood CPK [creatinine phosphokinase] was also noticed in the brigatinib arm—at about 39%—and some of the cases were grade 3. Other notable adverse effects of brigatinib are nausea and some elevated transaminitis.

If one compares brigatinib versus crizotinib, you can see that excess toxicity with brigatinib was dominated mostly by amylase elevations, lipase elevations, and increases in CPK. It is important to note that amylase and lipase elevations with brigatinib are generally not associated with clinical symptoms of pancreatitis. In the crizotinib arm, excess toxicity was dominated by GI [gastrointestinal] symptoms; transaminitis; swelling, or edema; and visual effects.

In the brigatinib arm, dose reductions happened in about 30% of patients. A majority of those dose reductions were due to increased CPK. Some of them were due to increased lipase and increased amylase. The rest of the dose reductions were due to hypertension, rash, and pneumonitis.

Understanding the ALTA-1L Trial

-positive stage IV non–small cell lung cancer, several ALK tyrosine kinase inhibitors have approval in the first line: crizotinib, ceritinib, alectinib, and brigatinib. We have 2 randomized trials comparing alectinib versus crizotinib and brigatinib versus crizotinib. Both of those trials showed that later-generation tyrosine kinase inhibitors, or second-generation tyrosine kinase inhibitors, as we call them, definitely have more efficacy compared with crizotinib. In my view, there are 2 front-runners for newly diagnosed 

-mutant stage IV non–small cell lung cancer, and those are alectinib and brigatinib.

The patient has asymptomatic small brain metastases. We know that second-generation ALK tyrosine kinase inhibitors are highly CNS [central nervous system] penetrant and have established CNS activity. In the patient who has no symptoms and small brain metastases without significant edema, it would have been very reasonable to delay brain radiation, give that patient alectinib, repeat a brain MRI in about 6 weeks, and then use radiation as salvage therapy if the tumors did not respond to tyrosine kinase inhibitors.

In my opinion, it is important to make decisions in collaboration with your radiation oncologist. Sometimes you may have a tumor in the brain that is in a dangerous location, like close to the midbrain, where even small enlargement of the tumor can cause adverse effects. So as long as your radiation oncologist is comfortable with delaying radiation for 6 weeks to see if tyrosine kinase inhibitors will work, I think it is reasonable to do so.

First-Line Treatment Options in ALK+ Lung Cancer

 Molecular testing has to be part of the management for a patient with stage IV non–small cell lung cancer. Current guidelines recommend molecular testing for patients with nonsquamous non–small cell lung cancer and select patients with squamous cell lung cancer. Comprehensive molecular sequencing is encouraged, preferably with a next-generation sequencing panel. We have to test all patients regardless of gender, ethnicity, and smoking status.

Currently in lung cancer there are 7 molecular abnormalities with FDA-approved targeted therapies, and those are 

 exon 14 skipping mutations. In addition, there are 3 other abnormalities—

 [human epidermal growth factor receptor 2] exon 20 insertions, for which there are compounds in clinical trials with preliminary evidence of efficacy. Therefore, it is important to make sure you are testing your patients for those mutations.

Currently, I believe that next-generation sequencing [NGS] is preferred because it does have ability to save tissue. You need less tissue to do NGS testing compared with if you do single-gene sequencing. Also, take into account the fact that we now need to test for at least 7, maybe even 10, molecular abnormalities. It is very possible that next-generation sequencing will also be cost saving.

My personal approach is to actually use both liquid and tissue next-generation sequencing at the time of the diagnosis, because I believe those tests are complementary. An alternative approach would be to do next-generation sequencing of tissue and save plasma next-generation sequencing, or what we also call the liquid biopsy, for patients whose tissue is insufficient. It’s very important to note that we need to wait until the molecular testing is back before we initiate therapy.

If you look at the turnaround times, the turnaround time for PD-L1 testing is actually about 2 to 3 days. The turnaround time for a liquid biopsy is about 10 days or so, and it is about 2 to 3 weeks for tissue next-generation sequencing results. So you will have the PD-L1 test results come in before you have molecular testing results, and unless your patient is rapidly declining, it is very important to wait for the molecular testing results before you start therapy. If you have to start therapy right away and don’t feel like you can wait for the molecular testing results, I recommend you just give chemotherapy. We do have emerging evidence that suggests that tyrosine kinase inhibitors may cause immune-related adverse events, such as pneumonitis and in some cases hepatitis, when given after immunotherapy.

Molecular Testing in ALK+ Non–Small Cell Lung Cancer

 We have a 58-year-old woman who presented with cough, fatigue, and anorexia. She has no other medical history. Her physical exam was unremarkable. Her labs were within normal limits. A chest x-ray showed multiple left upper-lobe masses and mediastinal lymphadenopathy. Then she had a chest CT scan that confirmed presence of a left upper-lobe mass measuring 6.2 cm. A PET [positron emission tomography] scan showed the mass to be PET positive, and mediastinal lymph nodes were positive as well.

An MRI of the brain showed widespread scattered small lesions consistent with multifocal brain metastases. She received a bronchoscopy with transbronchial biopsy of the left upper lobe, and that confirms adenocarcinoma. Molecular testing is positive for an 

In summary, we have a patient with stage IVA adenocarcinoma with a performance status of 1. This patient is 

 positive. The patient was started on brigatinib given as 90 mg once a day for 7 days. The dose was well tolerated. Then the dosage was increased to 180 mg once a day.

This patient, unfortunately, has an incurable cancer. The good news is that there is an 

 fusion that we know predicts efficacy to ALK tyrosine kinase inhibitors. Despite the fact that she has a metastatic lung cancer, her expected progression-free survival is long. Current data estimate the progression-free survival to be anywhere from 25 to 30 months with the use of novel ALK tyrosine kinase inhibitors.

Brigatinib is 1 of the approved treatment options for treatment-naïve 

-positive metastatic lung cancer patients. Brigatinib is CNS [central nervous system] penetrant, and would be appropriate in any 

-positive patient—with or without CNS metastases. This approval is based on the ALTA-1L trial.

The ALTA-1L trial was a randomized trial that compared first-line therapy with brigatinib vs crizotinib. The study showed an improvement in progression-free survival with brigatinib—approximately 24 months. The progression-free survival was approximately 13 months if the patient did not have brain metastases and was about 5.6 months if the patient had brain metastases.