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At ASCO Meeting, Research Mounts on Established, New Options for ALK-positive NSCLC Patients

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Originally published June 10.

NEW YORK (GenomeWeb) – At the American Society of Clinical Oncology annual meeting last week in Chicago, researchers presented data on new and mainstay ALK inhibitors, suggesting a crowded market for treating ALK-positive non-small cell lung cancer in the near future.

In a Phase I study, called ASCEND-1, led by Dong-Wan Kim from Seoul National University Hospital, researchers examined the efficacy and safety of Novartis' ALK inhibitor Zykadia (ceritinib). The drug received accelerated approval from the US Food and Drug Administration in April and is indicated for advanced, ALK-positive NSCLC patients who have stopped responding to Pfizer's Xalkori (crizotinib).

"All the second-generation inhibitors have much increased potency against ALK, compared to crizotinib by at least 10 fold," Leena Gandhi of Dana-Farber Cancer Center said during a talk at the ASCO meeting reviewing available and emerging treatments for ALK-rearranged NSCLC. "One of these has now been approved … and that is ceritinib."

The wholesale acquisition cost for a one-month supply of Zykadia is around $13,500. Comparatively, Pfizer has priced Xalkori at $9,600 per month.

In the Phase I study presented at ASCO, Kim and colleagues enrolled more than 250 non-small cell lung cancer patients into three arms: those pretreated with Xalkori, those naïve to such treatment, and those with cancers other than NSCLC. All patients received Zykadia at 750 mg/day.

In the overall study population, patients treated with Zykadia achieved an objective response rate of 58.5 percent, had a median progression-free survival of 8.2 months, and a median duration of response of 9.7 months. Among 163 previously treated patients, ORR was 55 percent and PFS was 6.9 months. For the 83 treatment-naïve patients, ORR was 66 percent, and PFS hadn't been reached at the last data cutoff.

The drug also showed efficacy in patients with brain metastases. Among 124 patients, ORR was 54 percent and median PFS was 6.9 months. Additionally, 50 percent of patients with brain metastases and previously on Xalkori experienced tumor shrinkage, while 69 percent of treatment-naïve patients with brain metastases experience tumor shrinkage after treatment with Zykadia.

Common adverse events included diarrhea in 84 percent of patients, nausea in 77 percent of patients, and vomiting in 57 percent of subjects. Serious Grade 3/4 toxicities included increased liver enzymes, alanine transaminase, and aspartate transaminase. Around 10 percent of study subjects discontinued Zykadia treatment due to adverse events.

The researchers concluded that ceritinib at 750 mg/day has "rapid, durable, and high antitumor activity in ALK-positive NSCLC patients, regardless of prior treatment with ALK inhibitors, providing effective treatment in this patient population."

The accelerated approval for Zykadia was based on data from 163 pre-treated patients. The full data from ASCEND-1 opens up the possibility for Novartis to further study and pursue a new, front-line indication for Zykadia in treatment-naïve NSCLC patients with ALK-positive tumors.

At ASCO, another group led by Kazuhiko Nakagawa from Kinki University in Japan presented preliminary data on 35 patients treated with different dosing regimens of alectinib, an ALK inhibitor developed by Roche subsidiary Chugai. In the study, researchers reported similar responses in patients receiving the 20/40-mg and 150-mg doses of the drug. They concluded that the 150-mg capsule was efficacious in patients who are pretreated with Xalkori, as well as those who were treatment naïve.

Approximately 8 percent of lung adenocarcinoma patients have ALK rearrangements in their tumors, which represents "a fair sized group for options for targeted therapy," Gandhi said during her ASCO presentation. Drugmakers clearly see this as a valuable market to enter.

Beyond Novartis's Zykadia and Roche/Chugai's alectinib, a number of pharmaceutical firms are studying ALK inhibitors, including Ariad Pharmaceuticals (AP26113), Ignyta (RXDX-101), Tesaro (TSR-011), Teva (CEP-37440), and Xcovery (X-396). "It's a little bit of an open question, what niche these [next-generation ALK inhibitors] will fill," Gandhi observed during her talk.

Alectinib is the furthest along among the newer ALK targeting agents. Researchers presented data from a study earlier this year investigating alectinib in a Japanese cohort not previously treated with Xalkori and reported a 93.5 percent response rate. "It's by far the highest response rate reported for any ALK inhibitor," Gandhi said, noting that the median duration of treatment in this study has not yet been reached. In the US, alectinib has shown similar response rates to Zykadia in patients who have become resistant to Xalkori, she further observed.

The one to beat, of course, is the current market leader, Pfizer's Xalkori. The drug came on the market in the summer of 2011 as the first ALK inhibitor against ALK-positive NSCLC tumors. Gandhi pointed out in her talk that the timeline from discovery and understanding the gene-disease-drug response relationship to therapeutic approval has been shortened from the 15 years it took for the first targeted EGFR therapy to come to market, down to four years for Xalkori. The development-to-market approval timeline of Zykadia was even shorter – a little over three years.

In the face of competition, however, Pfizer is continuing to study Xalkori in order to maintain it as the standard of care in ALK-positive NSCLC and introduce it as an option for patients with other molecularly defined NSCLC tumors, such as ROS1 rearrangements and MET amplifications (see related story, in this issue).

At ASCO, Pfizer presented the first outcomes data comparing Xalkori and first-line chemotherapy from the Phase III PROFILE 1014. In the study, researchers enrolled 343 previously untreated, advanced NSCLC patients with ALK-positive tumors, and randomized them to receive either Xalkori or a pemetrexed/platinum-based chemo regimen. Upon progression, patients on the chemo arm could cross over to the Xalkori arm.

In PROFILE 1014, median progression-free survival was nearly 11 months in the Xalkori arm compared to seven months for those receiving chemo. ORR was also significantly higher for those receiving Xalkori versus chemotherapy, 74 percent and 45 percent, respectively. At the time of analysis, 109 patients receiving chemo had switched to the Xalkori arm.

The adverse events seen with Xalkori in this study — notably vision and gastrointestinal abnormalities — were in line with those previously observed in patients. "These findings establish crizotinib as the standard of care for patients with previously untreated advanced ALK-positive non-squamous NSCLC,” the study authors concluded.

Gandhi highlighted during her presentation at ASCO that a retrospective comparison by Shah et al. of NSCLC patients with ALK-positive tumors receiving Xalkori, those that had ALK rearrangements but didn't receive the drug, and ALK wild-type patients suggests there is a substantial survival advantage for those with ALK driven tumors when they receive treatments inhibiting the kinase. The data from this 2011 study published in Lancet Oncology show that "there is a clear superiority in overall survival for crizotinib treatment of ALK rearranged patients versus patients who never received crizotinib treatment or wild-type patients," she said at the meeting.

However, most of the patients treated with and responding to Xalkori eventually relapse, and researchers have identified to date a number of resistance mutations, secondary mutations, ALK amplification as possible mechanisms through which the disease reemerges. Gandhi cited a study that reported that more than 70 percent of patients who experience disease progression after Xalkori treatment have disease metastases to the central nervous system. This is "certainly not representing true resistance mechanisms, but represents treatment failure … within the brain primarily," Gandhi observed.

She noted that drugmakers began developing most of the next-generations drugs before many of the resistance mechanisms to ALK targeted therapy were understood. "All of them that have been evaluated, including crizotinib, have a variable efficacy against different ALK mutations," she said. "So, some are more effective against specific mutations, and others are less, and they all have a slightly different spectrum."

She highlighted that Roche and Ariad are focusing on their drugs' ability to treat NSCLC patients with CNS metastases, and these agents have shown good efficacy in this regard thus far. Being able to address CNS metastases "may be a very important niche for a second generation [ALK] inhibitor," Gandhi said.

In an effort to address progression in ALK-positive NSCLC patients, Pfizer is also developing PF-06463922, an inhibitor of ALK and ROS1 for those who have become resistant to Xalkori. The drugmaker has presented data showing that PF-06463922 is active against cell lines characterized by ALK and ROS1 resistance mutations.

Ultimately, according to Gandhi's review of the available options for ALK-positive NSCLC, it remains an open question as to which is the best treatment for this subset of patients. "We still don't know based on the data thus far, is crizotinib the best first line treatment?" Gandhi put forth to the audience at the ASCO meeting. "Should next-generation inhibitors be reserved for second line? What about CNS metastases? What about different lung mutations that arise as secondary resistance mutations?"

Researchers from Roche are conducting a Phase III head-to-head comparison of alectinib and Xalkori in treatment-naïve ALK-positive NSCLC patients, to try answer which is the best agent. The National Cancer Institute has also launched ALCHEMIST, a large study that will enroll early-stage NSCLC patients with ALK and EGFR mutations and sequence their tumor tissue for greater insights into the disease mechanisms.

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