Crizotinib Superior to Chemotherapy, Extends Median Survival in First Head-to-Head Trial

Audrey Andrews

October 2012, Vol 3, No 7 - ESMO 2012 Conference


Vienna, Austria—In the first head-to-head phase 3 clinical trial, the anaplastic lymphoma kinase (ALK) inhibitor crizotinib (Xalkori) proved more effective than standard chemotherapy with pemetrexed (Alimta) or docetaxel (Taxotere) as a second-line treatment for patients with non–small-cell lung cancer (NSCLC) and the ALK genetic abnormality.

Alice Tsang Shaw, MD, PhD, a thoracic oncologist at Massachusetts General Hospital in Boston reported the results of the global PROFILE 1007 trial at the 2012 European Society for Medical Oncology (ESMO) Congress. In this trial, crizotinib was compared with pemetrexed or with docetaxel in 347 patients with ALK-positive stage IIIB or stage IV NSCLC who had been treated with chemotherapy.

Crizotinib was superior to standard single-agent chemotherapy in objective response, progression-free survival (PFS), and quality of life (QOL) in ALK-positive patients who progressed after first-line, platinum-based chemotherapy. “These results establish crizotinib as the standard of care for patients with advanced, previously treated, ALK-positive NSCLC,” Dr Shaw reported.

Rearrangements of the ALK gene are found in approximately 5% of patients with NSCLC. In previous studies, crizotinib was shown to induce significant clinical responses in patients with advanced ALK-positive NSCLC, but this is the first phase 3 study to directly compare this novel agent with standard chemotherapy.

Survival Rates
At a median follow-up of 12 months, crizotinib prolonged the median PFS to 7.7 months compared with 3.0 months with chemotherapy, a significant 51% reduction in progression risk (P <.001). The objective response rate was also significantly higher with crizotinib at 65% versus 20% with chemotherapy (P <.001).

All subgroups showed a PFS ben­-efit with crizotinib, with the great­est advantages seen in patients with nonadenoma histology (hazard ratio [HR], 0.12).

At this point, the survival analysis is immature, with only 40% of events occurring; therefore, overall survival (OS) differences have not yet been observed. Also, 87% of the chemotherapy-treated patients have crossed over to receive crizotinib on progression, which would dilute any OS differences, Dr Shaw said.

The median OS at this point is approximately 22 months in each arm. When the results were adjusted for confounding by crossovers, a 17% reduced mortality risk was still seen for the patients who received the ALK inhibitor, she noted.

Adverse Events
Side effects were more frequent with crizotinib, but Dr Shaw pointed out that crizotinib-treated patients received an average of 11 cycles compared with 4 cycles with pemetrexed or docetaxel, which partly explains the differences. Toxicities with crizotinib are, however, distinct from those seen with chemotherapy, but are “generally tolerable and manageable,” said Dr Shaw.

The most adverse events (AEs) associated with crizotinib were diarrhea (60%), vision disturbance (60%), nausea (55%), and vomiting (47%). Patients receiving chemotherapy had more fatigue, alopecia, dyspnea, and rash. Grade 3 or 4 toxicity rates were similar between the groups, except
for an increased rate of elevated trans­aminases (16%) in the crizotinib arm.

Of note, 10% of patients in the pemetrexed/docetaxel arm discontinued the trial because of treatment-related AEs compared with 6% in the crizotinib arm.

Improved Quality of Life with Crizotinib
Patients taking crizotinib reported improved QOL compared with chemo­therapy. “They reported greater improvement from baseline in cough, dyspnea, fatigue, alopecia, insomnia, and pain with crizotinib,” Dr Shaw said, “and all of these were statistically significant.”

The patients showed significant improvement from baseline in global QOL, and “time to deterioration in lung cancer symptoms” was also significantly extended with crizotinib treatment, to 5.6 months compared with 1.4 months with chemotherapy (HR, 0.54; P <.001).

Crizotinib “Changes the Natural History” of Lung Cancer
Discussing the study at ESMO 2012, Jean-Charles Soria, MD, PhD, Professor of Medicine and Medical Oncology at South-Paris University, and a cancer specialist at Institut Gustave Roussy in Villejuif, Paris, France, noted that 2 months of extended survival with advanced NSCLC is essentially “unheard of” in the general population of patients with NSCLC.

“Comparison with historical data suggests that crizotinib has changed the natural history of the disease, with a median OS now of 22 months versus 9 months in the past,” Dr Soria said, “and this is accomplished with very mild toxicity.”

Even patients in the trial who initially received chemotherapy had a median OS of nearly 23 months, “because they received crizotinib,” he added.

Delayed Approval in Europe
Dr Soria took advantage of the podium to voice his disapproval of the “reluctance” of the European Medicines Agency (EMA) to approve crizotinib. He noted that the US Food and Drug Administration (FDA) “welcomed the filing of single-arm data for accelerated approval,” whereas the EMA stated that any “conditional approval can only be granted on an established positive benefit-risk assessment.”

Although the FDA approved crizotinib less than 5 months after the submission of the single-arm data, the EMA has taken 14 months to review those data and is requiring additional randomized data, Dr Soria said. The EMA approval is expected by the end of October 2012.

Crizotinib the Poster Child of Precision Medicine?

If abstracts presented at the 2012 ESMO Congress were any indication, the FDA approval of crizotinib opened the door to a virtual roomful of next-
generation ALK inhibitors. Although crizotinib targets only the 5% of patients with NSCLC who have the ALK genetic translocation, it makes a huge impact on this subset, doubling the time that patients with advanced disease spend in remission.

“Crizotinib is the poster child for precision medicine,” according to Mace Rothenberg, Senior Vice President of Clinical Development and Medical Affairs at Pfizer Oncology. At a press briefing, Mr Rothenberg said that the robust responses with crizotinib observed in phase 1 clinical trials of ALK-positive patients have led to a “rapid reduction of our clinical development program.”

Data from phase 1 and 2 clinical trials presented at ESMO suggest that these next-generation ALK inhibitors currently in development may follow in the footsteps of crizotinib:

  •  AP26113, an oral agent that also targets mutations in the epidermal growth factor receptor (EGFR). A study of 29 patients with NSCLC showed activity in the first-line and the resistant cohorts
  • LDK378, a potent, oral, small-molecule ALK inhibitor, showed a high level of activity in patients who progressed after having received crizotinib
  • CH5424802, an oral agent, produced 3 complete responses and 36 partial responses among 46 patients with NSCLC who had no previous ALK therapy; 40 patients remain on treatment
  • AUY922, a heat shock protein 90 inhibitor that is delivered by weekly infusion, was highly active in 121 patients with previously treated NSCLC who had ALK or EGFR mutations. Responses were observed in 32% of ALK-positive patients and 20% of EGFR-mutated patients.

Investigators of NSCLC who were at the meeting emphasized that new ALK inhibitors will be needed for treating patients who will inevitably become resistant to crizotinib despite its initial efficacy. They added that next-generation ALK inhibitors appear to be even better tolerated than crizotinib.