Management of Adverse Events for ALK-Targeted TKIs

Mohammad Jahanzeb, MD:In terms of CNS [central nervous system] penetrance and toxicity, we have data from randomized trials. As you know, ALTA1 compared it directly with crizotinib, and so did J-ALEX and ALEX. We know that CNS penetration of crizotinib doesn’t even come close to these 2 agents. They are clearly far superior. They are so superior in CNS penetration response—in the 70%, 80% range, which is better than radiation therapy—that we no longer refer these patients to a radiation oncologist if there is no dire or urgent need. They can respond to these pills and postpone the need for brain irradiation, particularly whole-brain irradiation.

And then if there’s an isolated progression, you can still keep the drug going and do SBRT [stereotactic body radiation therapy] to 1 or 2 or 3 lesions. We have already cut the rate of whole-brain irradiation way down in the advent of these effective compounds.

When we look at the tolerability of brigatinib, it actually is a very well-tolerated drug. You have to monitor liver function tests [LFTs]. You can have LFT abnormalities that can be mild, with GI [gastrointestinal] toxicity. We already talked about very limited pulmonary toxicity, which is a tiny percentage and only in the early, initial phase of the drug. It’s not a cumulative or delayed toxicity. It’s really a very well-tolerated drug. Alectinib, which is also very well tolerated, does have this problematic adverse effect of myalgias. There can be peripheral edema, LFT abnormalities, and again, some kind of GI toxicities.

In terms of lorlatinib, that was more metabolic. You may have to intervene for some of these abnormalities. I think that as effective as lorlatinib is, it does have more toxicity compared with alectinib and brigatinib.

In terms of dose modification of these agents, because we have access to the protocol, the dose-reduction guideline, I usually follow how the drug was developed. And generally, for grade 3 and 4 toxicities, you would hold the drug until the toxicity resolves to about grade 1. Then you try 1 level lower of the drug. Most patients would tolerate it well at that level—at 1 dose reduction. Occasionally you have to do 2 or 3 dose reductions, but very few patients come off the drug completely because of toxicity.

In terms of pneumonitis monitoring, the best thing is to call the patient. We have our nurse call the patient daily during the first week to make sure we are not missing it. After the first couple of weeks, if the patient has not developed a toxicity, then you do your usual follow-up. I usually see my patients at least once a month in the clinic and draw their bloodwork for liver functions, etc.

Imaging can be initially be done every 2 months. However, after the first couple of evaluations, if you know that the patient is responding and maintaining a response, you can decrease the frequency of scans to every 3 months.

Because of the predilection of brain metastases, we do brain surveillance every 6 months. I do that in patients who have no brain metastases every 6 months with an MRI [magnetic resonance imaging], so that we catch it early if it’s developing. Again, there is not going to be standardized evidence for it. This is just something that many of my colleagues who deal with a lot ofALK-positive patients do in their clinic.

Mohammad Jahanzeb, MD:In terms of CNS [central nervous system] penetrance and toxicity, we have data from randomized trials. As you know, ALTA1 compared it directly with crizotinib, and so did J-ALEX and ALEX. We know that CNS penetration of crizotinib doesn’t even come close to these 2 agents. They are clearly far superior. They are so superior in CNS penetration response—in the 70%, 80% range, which is better than radiation therapy—that we no longer refer these patients to a radiation oncologist if there is no dire or urgent need. They can respond to these pills and postpone the need for brain irradiation, particularly whole-brain irradiation.

And then if there’s an isolated progression, you can still keep the drug going and do SBRT [stereotactic body radiation therapy] to 1 or 2 or 3 lesions. We have already cut the rate of whole-brain irradiation way down in the advent of these effective compounds.

When we look at the tolerability of brigatinib, it actually is a very well-tolerated drug. You have to monitor liver function tests [LFTs]. You can have LFT abnormalities that can be mild, with GI [gastrointestinal] toxicity. We already talked about very limited pulmonary toxicity, which is a tiny percentage and only in the early, initial phase of the drug. It’s not a cumulative or delayed toxicity. It’s really a very well-tolerated drug. Alectinib, which is also very well tolerated, does have this problematic adverse effect of myalgias. There can be peripheral edema, LFT abnormalities, and again, some kind of GI toxicities.

In terms of lorlatinib, that was more metabolic. You may have to intervene for some of these abnormalities. I think that as effective as lorlatinib is, it does have more toxicity compared with alectinib and brigatinib.

In terms of dose modification of these agents, because we have access to the protocol, the dose-reduction guideline, I usually follow how the drug was developed. And generally, for grade 3 and 4 toxicities, you would hold the drug until the toxicity resolves to about grade 1. Then you try 1 level lower of the drug. Most patients would tolerate it well at that level—at 1 dose reduction. Occasionally you have to do 2 or 3 dose reductions, but very few patients come off the drug completely because of toxicity.

In terms of pneumonitis monitoring, the best thing is to call the patient. We have our nurse call the patient daily during the first week to make sure we are not missing it. After the first couple of weeks, if the patient has not developed a toxicity, then you do your usual follow-up. I usually see my patients at least once a month in the clinic and draw their bloodwork for liver functions, etc.

Imaging can be initially be done every 2 months. However, after the first couple of evaluations, if you know that the patient is responding and maintaining a response, you can decrease the frequency of scans to every 3 months.

Because of the predilection of brain metastases, we do brain surveillance every 6 months. I do that in patients who have no brain metastases every 6 months with an MRI [magnetic resonance imaging], so that we catch it early if it’s developing. Again, there is not going to be standardized evidence for it. This is just something that many of my colleagues who deal with a lot ofALK-positive patients do in their clinic.

Transcript edited for clarity.

Case: A 61-Year-Old Man WithALK-Rearranged NSCLC

• A 61-year-old man presented with recent onset shortness of breath and swelling above left clavicle.
• Relevant PMH:
  • Nonsmoker, no previous CV- or pulmonary-related complications
• PE: Lungs, right-sided wheezing on auscultation; left supraclavicular lymphadenopathy, palpable
• Diagnostic workup:
  • Labs: WNL
  • Lymph node biopsy showed adenocarcinoma
  • CT CAP showed a 2.5-cm solid pulmonary lesion in the left inferior lobe and multiple liver lesions
  • CT‐guided core needle biopsy of the lung lesion revealed lung adenocarcinoma
  • Molecular testing:
    • EGFR, BRAF, KRAS, MET, RET, NTRKwild-type
    • IHC;ALK-rearrangement
    • PD-L1 TPS, 0%
  • Contrast‐enhanced MRI of the head showed multiple brain metastases
• Treatment:
  • Started on alectinib 600 mg BID; achieved a partial response including regression of CNS disease
  • Patient developed grade 3 myalgia; dose reduced to 450 mg BID, sustained at grade 2
• Imaging at 9 months showed disease progression in the lung mass and liver; stable CNS disease
  • Lung biopsy, mutation analysis;ALKG1202R
• He was started on brigatinib 90 mg once daily and tolerated the dose well; after 1 week, her dose was increased to 180 mg once daily (2 90-mg tablets)
  • Partial response with significant shrinkage in lung, liver, and CNS lesions