Zosia Chustecka

September 30, 2012

September 30, 2012 (Vienna, Austria) – Crizotinib (Xalkori, Pfizer) should now be the standard of care for the small subgroup of patients with non-small cell lung cancer (NSCLC) whose tumors test positive for the ALK gene rearrangement (ALK+), experts said here at the 2012 European Society for Medical Oncology (ESMO) Congress.

Dr. Alice Shaw

Only 3% to 5% of NSCLC patients have tumors that are ALK+, but because lung cancer is so prevalent, this subgroup amounts to more than 50,000 patients each year worldwide, noted Alice Shaw, MD, from the Massachusetts General Hospital Cancer Center in Boston.

She presented results from the first phase 3 trial with crizotinib, known as PROFILE 1007, here during the presidential session. The trial was a head-to-head comparison with standard chemotherapy (pemetrexed or docetaxel) in a selected patient population with ALK+ NSCLC. The study accrued a total of 347 patients, all of whom had previously received 1 line of chemotherapy.

Crizotinib doubled progression-free survival to a median of 7.7 months, compared with 3 months for chemotherapy (hazard ratio, 0.49; P < .0001).

In addition, crizotinib trebled the response rate of chemotherapy (65% vs 20%, P < .0001), and it improved symptom control and quality of life, Dr. Shaw said.

Overall survival was similar in both groups (20.3 months on crizotinib vs 22.8 months on chemotherapy), but these data are immature, she noted. These data are from an interim analysis, undertaken at a median follow-up of 12 months, when only 96 events had occurred, 40% of the 241 events that are needed for a final analysis, she explained. However, there was also a high crossover rate in this trial, with 86% of patients initially on chemotherapy given crizotinib when they progressed. This confounding makes it unlikely that a survival difference will be seen even when the data are mature, she said.

"This study establishes crizotinib as a standard of care for patients with ALK+ NSCLC," Dr Shaw said, and several experts at the meeting agreed.

Dr. Fortunato Ciardiello

"These new data are practice-changing," said Fortunato Ciardiello, MD, PhD, professor of medical oncology at the Second University of Naples, Italy. "There was a huge difference in favor of crizotinib," he said; "the risk of progression is reduced by 50%, and you rarely see this in any metastatic solid tumor," he commented at a press briefing that he moderated. The results of this trial show that crizotinib "is the best option for treatment in these patients," he said.

"The results of this study are of great clinical relevance," said Enriqueta Felip, MD, head of the lung cancer unit at Vall d'Hebron University Hospital, Barcelona, Spain, who was chair of the ESMO 2012 Metastatic NSCLC track.

"After the worldwide implementation of targeted therapy in lung cancer patients defined by another molecular alteration, the EGFR mutation, this is the second group of lung cancer patients to clearly benefit from a therapy directly targeting molecular alteration," Dr. Felip commented in a statement.

Discussant Jean Charles Soria, MD, professor of medicine at the Institute Gustave Roussy, Villejuif, France, said this "amazing" trial suggests that crizotinib has changed the natural course of this disease. Historical controls show an overall survival of around 9 months for similar patient populations on chemotherapy, whereas the survival in this trial was 20 months, he said.

Well Tolerated, Mild Side Effects

The side effects with crizotinib are mild, Dr. Soria commented. Liver function should be monitored, he suggested, because of potential liver toxicity. He noted that 16% of patients on the drug had grade 3 or 4 liver transaminase elevations. There have also been reports of visual disorders, renal cysts, bradycardia, and low testosterone levels, but "we do not know if this has any impact on sexual function," he added.

Elaborating in an interview, Dr. Shaw told Medscape Medical News that these adverse events were mild. Hypogonadism has been reported in clinical trials, and reduced levels of total testosterone are associated with the drug, but it is unclear whether this is clinically relevant, she said. Sexual dysfunction has not been reported, and "if this was occurring, male patients would certainly tell us," she said. Visual disturbances have been reported in about 60% of patients, but they are transient, she said, lasting about 30 seconds when going from a dark to a light room; no eye damage has been found in ophthalmology tests. Bradycardia has also been reported, with about a 10-point drop in the resting heart rate, but this does not affect functioning, she said. All of these seem to be off-target drug effects, she said, and they do not seem to bother patients, as there is an improvement in overall quality of life.

Not Available Yet in Europe

Crizotinib is not available yet in Europe, although it is expected to be approved in the near future, because it recently received a positive opinion from the Committee for Medicinal Products for Human Use.

The drug was granted an accelerated approval in the United States last year on the basis of single-arm phase 2 studies. The new results from the randomized phase 3 study are likely to be sufficient to turn this into a regular approval.

Another phase 3 trial is underway, this time with crizotinib used as a first-line agent in patients newly diagnosed with ALK+ NSCLC; known as PROFILE 1014, this study is also using platinum-based chemotherapy (pemetrexed with cisplatin or carboplatin) as a comparator.

New Generation of ALK Inhibitors

One of the issues with crizotinib is that with time, resistance develops to the drug. Coming up through research and development pipelines are a number of new-generation ALK inhibitors, some of which have shown activity in patients who have stopped responding to crizotinib.

Dr. Shaw also presented at the meeting (abstract 440_O) a small trial with LDK378 (Novartis) in 56 patients with ALK+ tumors, of whom 50 patients had lung cancer and 36 had previously been treated with crizotinib. The investigational drug showed "striking activity" in ALK+ NSCLC patients treated with >400 mg who had previously progressed following crizotinib therapy, she said.

Another new ALK inhibitor, CH5424802 (Chugai Pharmaceutical), has demonstrated "clinically meaningful antitumor activity" (abstract 441_O) and is now in a clinical trial in patients with ALK+ NSCLC who have been previously treated with or without crizotinib.

In addition, new products with novel mechanisms of action were reported. A new drug that combines ALK inhibition with EGFR inhibition, AP2613 (ARIAD), has also shown some preliminary anticancer activity in ALK+ patients who both had and had not been previously treated with crizotinib (abstract 439_0). In another new approach, the HSP90 inhibitor AUY922 (Novartis) has shown clinical activity (abstract 438_O) in patients with ALK+ tumors who have progressed on crizotinib and also in patients with EGFRm+ tumors who have progressed on EGFR inhibitors (such as erlotinib or gefitinib).

The PROFILE 1007 study was funded by Pfizer, manufacturer of crizotinib. Dr. Shaw reported advisory relationships with Pfizer, ARIAD, Chugai, Novartis, and Daiichi-Sankyo and has received research funding from AstraZeneca and Novartis.

2012 European Society for Medical Oncology (ESMO) Congress. Presented September 30: Abstract LBA1_PR.