1. Goodwin, Peter M.

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MUNICH-Anaplastic lymphoma kinase (ALK) inhibitors are as effective in "real-world" clinical use for treating patients with non-small cell lung cancer (NSCLC) who test positive for ALK gene rearrangements as they are in clinical studies-even though randomized trials "cherry-pick" patients to get statistically valid results. This is the conclusion of a retrospective analysis of data reported at the 2018 ESMO Annual Congress.

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Progression-free survival was prolonged to a median of 7.4 months in the overall group of patients treated with ALK-targeted agents. "We were delighted to find out that these patients do as well as patients on clinical trials," said author Mohammad Jahanzeb, MD, Professor of Clinical Medicine, Hematology-Oncology, and Medical Director of the University of Miami Sylvester Comprehensive Cancer Center in Deerfield, Fla. "Median progression-free survival was in the same ballpark as we see in clinical trials."


Jahanzeb said that prospective clinical trials excluded many real-world patients who had comorbid conditions and factors such as brain metastases-which were often encountered among typical real-world patients.

Mohammad Jahanzeb, M... - Click to enlarge in new windowMohammad Jahanzeb, MD. Mohammad Jahanzeb, MD

"So we thought it was really important to go to a database repository and do a deep dive on the subset of patients positive for ALK," he said, noting that half of these patients typically had brain metastases.


Study Details

The researchers found 592 patients who had been identified as having ALK-positive adenocarcinoma NSCLC, all of whom had been treated at least once with an ALK inhibitor-crizotinib, alectinib, ceritinib, or brigatinib. Nearly three-quarters of all patients had received crizotinib as their first TKI (since this drug had been the first of this class to be licensed). Fewer patients were treated with the other agents-only four in the case of the recently licensed ALK inhibitor brigatinib. Two-thirds of patients had received chemotherapy before having their ALK inhibitor.


Response rates were between 40 and 60 percent-"very effective," noted Jahanzeb. "The newer molecules alectinib and brigatinib penetrate the central nervous system. So you don't have to do whole brain irradiation-which is a major advance of treatment [for] this subset of patients," he said, noting that neuropsychiatric issues a few years after brain irradiation had not been a problem when average survival had been only 10 months. "Now that these patients live nearly 5 years, it's a huge problem. So, we try to avoid whole brain irradiation at all costs."


In randomized studies, first-line crizotinib therapy gave about 10 months progression-free survival, Jahanzeb noted. So the newer drugs compared very favorably. "Alectinib is now at 34 months. And brigatinib data (not mature yet) looks similar to alectinib in terms of its efficacy endpoints at 1-year analysis," he stated.


"Overall survival-of nearly 5 years-is unprecedented and very exciting to those of us who treat lung cancer. It is happening in all of the clinical trial data that has recently been reported," he said. In the retrospective survey, the median overall survival was around 3 years, but 5 years survival had been reported after longer follow-up of trial data and from the use of the second generation of ALK inhibitors, he said.


When he was asked what advice he gave to patients in his own clinic who were candidates for treatment with ALK inhibitor therapy, Jahanzeb said he emphasized the positive message that, despite the bad luck of getting lung cancer, they could consider themselves to be "super lucky" to have ALK-positive lung cancer-because they were likely to do better than any other subset of patients with lung cancer.


"I give them a lot of positive message-a lot of hope. I quote a near 5-year average [survival] and tell them that half the patients will be above average and half below average-so they could even do better than 5 years. So my message is one of hope," Jahanzeb said.


And as far as the choice of ALK inhibitor was concerned, he made it clear that big steps forward had been taken. The baton had already been passed from crizotinib to some of the second-generation agents-except in countries where licensing had not made this possible. "There's no rationale to give an inferior agent when you have a superior agent available," he said.


And the second-generation ALK inhibitors were better because they had overcome some of the cancer cells' resistance mechanisms.


"Patients progress because their cancer cells figure out a mechanism of resistance and escape the treatment. So treatments that cover more escape routes cause longer progression-free survival," Jahanzeb stated. He quoted the example of the mutation G1202R that had been "particularly problematic." Brigatinib covered it, while other ALK inhibitors so far approved did not. "It's the coverage of mutations that increases the progression-free survival for newer agents," he said.


"The take-home message from this abstract is that real-world patients are doing just about the same as clinical trial patients. And patients have many options now. This bodes well for everybody-that knowledge that we have created through research is generalizable to the general population," Jahanzeb concluded.


Peter M. Goodwin is a contributing writer.