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Lung Cancer Drugs Yield Benefit in Rare Molecular Patient Subsets, ASCO Studies Show

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CHICAGO – At the American Society of Clinical Oncology annual meeting this week, researchers presented new data on treatments for non-small cell lung cancer patients with ALK rearrangements and MET alterations in their tumors.

The data suggest that the precision oncology drug market in NSCLC will get even more crowded in the coming months and years, and patient populations will be further dissected according to molecular tumor characteristics.

In a head-to-head comparison of Pfizer's Xalkori (crizotinib) and Genentech's Alecensa (alectinib) as treatments for advanced NSCLC patients with ALK rearrangements, those receiving the newer agent Alecensa lived longer without their disease progressing. Another Phase II study, looking at two dosing regimens of Ariad Pharmaceuticals' investigational agent brigatinib, yielded promising results in ALK-positive patients who have become resistant to Xalkori.

Xalkori, which has been on the market since 2011, is currently the only first-line option for advanced NSCLC patients with ALK-positive tumors. Since then, the US Food and Drug Administration has approved two drugs, Novartis' Zykadia (ceritinib) in 2014 and Alecensa last year, both for metastatic, ALK-positive NSCLC for patients who have stopped responding to Xalkori. Neither drug was launched with a companion diagnostic since patients receiving them will already have been tested for ALK rearrangements in the first-line setting when considering treatment with Xalkori.

After treatment with Xalkori, "it is well recognized that all patients eventually develop disease progression and [the brain] is an important site of progression," Shirish Gadgeel from Karmanos Cancer Institute said at a session at ASCO's annual meeting. Next-generation inhibitors appear to block ALK more potently than Xalkori does, he said, which raises the possibility that in the frontline setting these agents could provide even greater clinical benefit.

Alecensa, marketed by Roche subsidiary Genentech, selectively binds to ALK and prevents it from sending signals that promote cell growth. The firm wants to advance this drug as a front-line therapy for the ALK-positive NSCLC population, and the so-called J-ALEX study presented at the meeting is a step in that direction. 

In the head-to-head Phase III trial involving approximately 200 patients, researchers from Roche subsidiary Chugai and several Japanese institutions reported at the meeting that Alecensa demonstrated significantly prolonged progression-free survival compared to Xalkori.

Independent reviewers reported that nearly 92 percent of patients responded to Alecensa, while 79 percent of patients responded to Xalkori. Median progression-free survival was not reached for patients receiving Alecensa, but was around 10 months for patients randomized to Xalkori. Particularly in patients with brain metastases, Alecensa "was far better" than Xalkori, said Hiroshi Nokihara from the National Cancer Center Hospital in Tokyo, who presented data from J-ALEX.

The most common adverse event occurring in more than 30 percent of Alecensa-treated patients was constipation. Those on Xalkori had more frequent grade 3 or 4 adverse events. Fewer patients on Alecensa discontinued participation or required dose reductions in the trial due to adverse events.

"Based on these results, we believe Alecensa is a new standard for first-line therapy for ALK-positive NSCLC," Nokihara proclaimed.

Josina Reddy, senior group medical director at Genentech, told GenomeWeb that Genentech will discuss the results with the FDA. Genentech is also conducting a Phase III randomized trial called ALEX, comparing Alecensa to Xalkori as first-line treatment for advanced ALK-positive NSCLC. Genentech expects to share results from this study next year.

In the J-ALEX trial, patients received centralized testing by IHC, FISH, or reverse transcription PCR. Within the ALEX trial, patients are tested on Ventana's ALK (D5F3) CDx, an IHC test Roche is developing in house. "We would expect that Alecensa would be approved in the first-line setting for people with ALK-positive advanced NSCLC as determined by an FDA approved test," Reddy said.

In another presentation at the meeting, researchers randomized more than 200 patients — the majority of whom had disease that had metastasized to the brain — to receiving either 90 mg of Ariad's brigatinib once daily or 90 mg daily for seven days followed by 180 mg daily in the second arm. The objective response rate was 45 percent in the first arm and 54 percent in the second arm, while median progression-free survival was around nine months and 12.9 months, respectively. Median overall survival hadn't been reached in the study, but at one year, 71 percent of patients were alive on the 90 mg dose and 80 percent on the 180 mg dose.

Gadgeel cautioned that the progression-free survival data in the 180 mg arm was promising, but patients had only been followed for a median of eight months. "A longer follow-up would be required before one can be confident in this median progression-free survival," he said.

Gadgeel added though that brigatinib's response rate was comparable to other next-generation ALK-inhibitors, and its efficacy was particularly promising in patients with brain metastases. In this patient subset, intra-cranial objective response rate was 36 percent and 67 percent, while the median progression-free survival was 18.6 months and not yet reached for the 90 and 180 mg doses.

Patients receiving brigatinib experienced grade 3 or higher adverse events such as increased creatine phosphokinase (which are measured to assess damage to tissues in the muscles, brain, or heart), hypertension, and pneumonia. In the first seven days of treatment, 6 percent of patients had pulmonary events, but no one experienced this in the arm where doses were increased to 180 mg.

Based on this data, researchers will conduct a Phase III trial investigating the 90 mg for seven days followed by a 180 mg daily dosing scheme, and compare brigatinib against Xalkori in patients with ALK-positive NSCLC who haven't previously been treated with an ALK-inhibitor. "This drug is likely to be approved by the FDA, since it has already received breakthrough designation," predicted Gadgeel. "We'll have another option for management of patients with crizotinib-refractory, ALK-positive non-small cell lung cancer."

However, he observed that since oncologists are still awaiting the results of the global ALEX study, they might be hesitant to switch to Alecensa as the front-line option at this time. Gadgeel cautioned that although J-ALEX provided evidence that patients treated with Alecensa derived more benefit and experienced less toxicities than those on Xalkori, there are still unanswered questions. For example, would patients really derive greater benefit by starting out with Alecensa compared to starting with Xalkori followed by Alecensa? And by moving Alecensa to the frontline, would it limit options for patients who develop resistance?

Gadgeel observed that there is limited clinical data suggesting that some next-generation ALK inhibitors, such as Pfizer's lorlatinib, could benefit patients who progress on Alecensa. "We need a lot more data to be confident about this observation, but this suggests that ALK inhibition can continue to be a therapeutic option for patients who progress on alectinib," he said.

Pfizer's third-generation drug lorlatinib is active in patients with brain metastases. In a Phase I study, which researchers presented at ASCO, there was a 26 percent response rate among 54 patients with ALK- or ROS1-positive NSCLC with and without metastases to the brain. As of Nov. 30, 2015, 29 patients remained in the study, but no one discontinued in the trial due to adverse events. Common adverse events were hypercholesterolemia and peripheral edema. Based on these results, researchers are advancing the drug into Phase II studies.

The availability of so many ALK inhibitors means it's even more critical that researchers "make efforts to define which particular patient benefits the most from which particular drug," Gadgeel noted. Although the survival data associated with these new drugs are exciting, at a $12,500 per month price tag for Alecensa, costs are a point of concern, he said.

Meanwhile, Pfizer is also exploring the efficacy of Xalkori in other molecularly defined subpopulations. Before developing Xalkori for the the ALK- and ROS1-positive populations, Pfizer was studying it as a MET inhibitor. At ASCO's annual meeting, researchers from Pfizer and other institutions reported the drug's efficacy and safety in a small number of advanced NSCLC patients with MET alterations that cause exon 14 skipping. Approximately 4 percent of NSCLC patients have this particular molecular alternation.