NEW MORE POTENT ALK INHIBITORS

AMSTERDAM — A new ALK inhibitor, alectinib (under development by Roche/Chugai), for patients with non-small cell lung cancer (NSCLC) positive for anaplastic lymphoma kinase (ALK) rearrangement has shown activity in patients resistant to crizotinib (Xalkori, Pfizer). It also markedly reduces brain metastasis, a finding unseen with other agents in this patient population.

The new data on alectinib were presented here at the European Cancer Congress 2013 (ECCO-ESMO-ESTRO) by Sai-Hong Ignatius Ou, MD, PhD,health science associate clinical professor at the University of California, Irvine School of Medicine.

He emphasized that the findings related to brain metastasis are a first for patients whose lesions are progressing. "These patients normally require radiotherapy or surgery, and such metastases will usually be fatal. Previously we had nothing to offer them, but now these results show that potentially they'll have a pill."

Matthias Preusser, MD, from the Medical University of Vienna, Austria, and cochair of the European Organization for Research and Treatment of Cancer (EORTC) Brain Tumor Group, welcomed the findings. He explained that brain metastases are found in around half of all NSCLC patients, and that local treatments such as radiotherapy, stereotactic radiosurgery, and neurosurgical resection are typically used to treat such advanced cases. "Limited data are available on systemic therapies, but many drugs do not achieve adequate concentrations in brain metastases due to the blood-brain barrier," he said.

Crizotinib-naïve and Crizotinib-resistant Populations

Crizotinib is so far the only ALK inhibitor available globally for the treatment of ALK-positive advanced NSCLC. It is approved for use as any-line treatment in the United States and as second-line therapy in Europe. In a phase 3 trial, crizotinib was found to be superior to standard chemotherapy in advanced NSCLC with ALK gene rearrangement (N Engl J Med. 2013;368:2385-2394).

However, the majority of patients treated with crizotinib usually progress after an average of 8 months, so a more potent ALK inhibitor is needed to overcome resistance, Dr. Ou noted.

He explained that the phase 1 alectinib results he presented are the beginning of a therapy that could move the treatment of advanced and resistant NSCLC forward.

In their study, Dr. Ou's team enrolled 47 crizotinib-resistant patients from 6 sites in the United States.

All study participants had an ALK rearrangement and had failed crizotinib treatment but had not been exposed to any other ALK inhibitors. All had asymptomatic brain metastases, including leptomeningeal carcinomatosis, but were clinically stable for at least 2 weeks without steroid treatment.

In this dose-escalation study, patients were treated with twice-daily alectinib of 300 mg, 460 mg, 600 mg, 760 mg, or 900 mg until progression or lack of clinical benefit.

The primary objective was to establish a dose for the phase 2 study. It was determined that the dose would be 600 mg twice a day.

So far, the overall response rate (ORR), measured by tumor shrinkage and lack of new lesions or growth of existing tumors, has been relatively good — at 54.5% for all cohorts, Dr. Ou said. At the twice-daily dose of 600 mg or above, the ORR was 59.5%.

The median duration has not yet been reached in the ongoing study, "but currently it is longer than 4 months," Dr. Ou reported.

Before enrollment in the phase 2 trial of alectinib in ALK-positive NSCLC that has failed crizotinib, which has started in the United States, patients must undergo a mandatory biopsy after crizotinib failure; they must also undergo a mandatory biopsy after progression on alectinib.

The global phase 2 (Accalia G2L) trial is actively enrolling patients.

Dr. Ou noted that Roche is planning a global phase 3 head-to-head comparison of alectinib and crizotinib with a secondary end point of time to brain relapse. It should start in early 2014.

Reduction in Brain Metastasis

The considerable reduction in brain metastasis with alectinib was the other significant finding in the study, Dr. Ou pointed out. "Control of brain metastasis is a real unmet need in NSCLC. People do progress in the brain as a late 'tumor escape' phenomenon. This occurs at the 7- or 8-month stage, and is due to selection pressure of the crizotinib in this molecular subset of patients where systemic control is excellent."

At baseline, 21 of the 47 patients had central nervous system metastases, which is unusually high for a trial of this size, he noted. "We started out with a high number of patients with brain metastases, but only 4 patients went off study because of progression; all others are active on study," Dr. Ou reported.

He used MRI scans from before and after treatment with alectinib in a patient with brain metastases. The lesions, which were 2.5 cm at the start of treatment, shrank by 47% in 3 weeks.

Two patients with leptomeningeal carcinomatosis, a carcinoma that infiltrates the lining of the meninges, also responded well. One was treated under single-patient compassionate use and achieved a complete response, demonstrated by spinal fluid clear of metastases. This 29-year-old patient was a nonsmoker and had been battling her disease for 7 years, Dr. Ou noted. "With the development of leptomeningeal carcinomatosis, she suffered facial numbness and stroke-like effects, but within 6 weeks she was clear and better."

According to Dr. Ou, alectinib is distinct from other agents used to treat NSCLC because it has very good brain penetration, crossing the blood-brain barrier and reaching higher levels within the brain. '"Unfortunately, with crizotinib, there is a strong selection pressure on the tumor. While it provides excellent control in most of the body, such control elsewhere can actually precipitate relapse in the brain," he told Medscape Medical News.

The clinical activity of alectinib in brain metastasis from ALK-positive NSCLC patients will be presented in more detail at the World Conference in Lung Cancer, being held in Sydney, Australia, later this month.

Although the patient numbers were small in this phase 1 study, the results with this novel ALK inhibitor are of great interest, said Alba A. Brandes, MD, from the Medical Oncology Department at the Azienda USL Bellaria-Maggiore in Bologna, Italy.

"The role of targeted agents in the treatment of brain metastases remains a challenge," she toldMedscape Medical News in an interview. "However, many signals from other agents and in other cancer types seem to point in the same direction, suggesting that the biological sensitivity of specific tumor types — such as ALK-mutant or EGFR-mutant NSCLC, HER2-positive breast cancer, and BRAF-mutant melanoma — is much more important than the site of metastases."

"Moreover, because of the specific activity of this potent anti-ALK agent, even after crizotinib failure, brain metastases should not be considered exclusion criteria for further clinical trials," she said.

"The authors must be congratulated for opening their early clinical trial to patients with brain metastases, a population that has unfortunately been excluded from most clinical studies in the past," Dr. Preusser added.

This study was funded by Roche/Chugai, the manufacturer of alectinib. Dr. Ou reports consulting for Pfizer, Chugai, and Genentech, and serving on the speaker's bureau for Pfizer, Genentech, and Boehringer Ingelheim. Dr. Preusser reports receiving research funding and travel grants for scientific meetings from Roche, Novocure, Boehringer Ingelheim, and GlaxoSmithKline. Dr. Brandes has disclosed no relevant financial relationships.

European Cancer Congress 2013 (ECCO-ESMO-ESTRO): Abstract 44. Presented October 1, 2013.