Bevacizumab Improves Survival In Advanced Lung Cancer

Zosia Chustecka

June 03, 2007

June 3, 2007 (Chicago) – A second large multicenter study has shown that adding the angiogenesis inhibitor bevacizumab (Avastin, Genentech) to chemotherapy improves survival in patients with advanced non–small-cell lung cancer (NSCLC).

This latest study was conducted in Europe and used a different chemotherapy regimen from that used in the first trial, which was carried out in the United States. But the results from both trials were similar — adding bevacizumab significantly improved progression-free survival (PFS). This second trial confirms the original results and "adds credibility" to the finding, commented Roy Herbst, MD, PhD, from the University of Texas MD Anderson Cancer Center. He was speaking at a press briefing here during the American Society of Clinical Oncology (ASCO) 43rd Annual Meeting, at which the latest trial results were presented.

Bevacizumab is already approved for use with a combination of carboplatin and paclitaxel in patients with advanced NSCLC, based on the positive results from a US study conducted by the Eastern Cooperative Oncology Group (ECOG 4599), published last year (Sandler A et al. N Engl J Med 2006; 355; 2542-2550). This tends to be the standard chemotherapy regimen used in the United States for NSCLC, Dr. Herbst explained, although there are other regimens that are also used, including the combination of gemcitabine plus cisplatin, which is popular in Europe.

This is the combination that was used in the new European study, which was presented at the meeting by Christian Manegold, MD, professor of medicine at the University of Heidelberg, Mannheim, Germany. This trial (known as Avastin in Lung [AVAIL]) involved 1043 patients with previously untreated advanced or recurrent nonsquamous NSCLC and no brain metastases, who were randomized to receive either chemotherapy alone or chemotherapy with 1 of 2 doses of bevacizumab (7.5 mg/kg or 15 mg/kg). The gemcitabine/cisplatin regimen was given with bevacizumab for up to 6 cycles, and then patients were given bevacizumab alone until the tumor progressed.

Median progression-free survival (PFS) was 6.1 months in the control group receiving chemotherapy alone, compared with 6.7 months in the group who also received the lower dose of bevacizumab and 6.5 months in the group on the higher dose. The hazard rations were 0.75 (= .002) for the lower dose and 0.82 (P = .03) for the higher dose, which represents a 20% to 30% improvement, Dr. Manegold commented. This is statistically significant, and it is also clinically important, he commented: "It is a small step forward." He predicted that these results will lead to an increase in the use of bevacizumab in NSCLC.

Asked to comment, Dr. Herbst agreed that the increase in PFS was clinically important and said that it represents an advance over standard therapy. He added, however, that it is "only a small step and we need to do better. Nevertheless, it is a step forward in a killer disease." Lung cancer remains the number-one cause of cancer deaths in both men and women, he pointed out, adding: "Unfortunately, the patient with advanced lung cancer will ultimately die."

One delegate questioned the benefit of bevacizumab, pointing out that the improvement in median PFS over control was only 2 weeks or so, and yet the drug increases the risk for adverse events and costs thousands of dollars. Dr. Manegold answered, "Society has to decide on such issues, but I would say that the 20% to 30% improvement in PFS is clinically relevant in a very difficult-to-treat disease."

The AVAIL trial also showed an improved response rate (20% in controls vs34% with lower dose and 30% with higher dose of bevacizumab) and an increase in the duration of response (4.7 months with control vs 6.1 months with both doses of bevacizumab).

The incidence of adverse effects was slightly increased in the 2 groups who received bevacizumab as well as chemotherapy, but the combination was "well tolerated," Dr. Manegold commented. The most common serious adverse effects were hypertension (2% in control group vs 6% in low-dose group and 9% in high-dose group), and hemoptysis (bleeding from the lungs), which was seen in 1.5% of patients on the low-dose bevacizumab group, but in fewer than 1% of patients in the other 2 arms of the study. The percentage of serious adverse effects was similar across all 3 groups, as were deaths resulting from adverse effects (4% for control, 4% for low-dose, and 5% for high-dose groups).

Dr. Manegold concluded that the addition of bevacizumab to the combination of gemcitabine plus cisplatin "adds efficacy to a standard therapy and is a new well-tolerated option for patients with advanced NSCLC."

Discussing the trial after its presentation at the oral session, Thomas Lynch, MD, from Massachusetts General Hospital, in Boston, said the results from AVAIL "clearly support" the findings from the earlier US study, ECOG 4599, and show that the benefit of bevacizumab is independent of the chemotherapy regimen used. Safety data are now being collected on bevacizumab with other regimens, including docetaxel, pemetrexed, and vinorelbine, and he predicts that these regimens will also show similar results.

Dr. Lynch pointed out that the hazard ratio of 0.66 in ECOG 4599 was lower than the 0.75 and 0.82 seen in AVAIL and speculated that this may be due to subtle differences in the patient population, in the assessment being made after 2 cycles of therapy rather than 3 cycles in AVAIL, or a possible difference between carboplatin and cisplatin, although he acknowledged that the latter suggestion is controversial.

One question that remains unanswered is the value of maintenance therapy, and this is "clearly a critical question for future trials," Dr. Lynch said. "However, unless data emerge to show otherwise, I will continue to use maintenance therapy." Another issue is which dose is best, and this is still being investigated in clinical trials. However, there is a strong rationale for using the 7.5-mg dose, and unless there is a "surprise" when the survival data from AVAIL mature, then 7.5 mg is the dose going forward and appears to be the optimal dose for the practicing doctor to use, he said.

In conclusion, Dr. Lynch said that the addition of bevacizumab to chemotherapy is a "clear standard of care in eligible first-line non–small-cell lung cancer" and suggested that the drug be used at the 7.5-mg dose and continued until progression.

American Society of Clinical Oncology 43rd Annual Meeting: Abstract LBA7514. Presented June 2, 2007.

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