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Trastuzumab Shows Limited Promise in Non-Small-Cell Lung Cancer

Trastuzumab Shows Limited Promise in Non-Small-Cell Lung Cancer

PHILADELPHIA-Mature results from a multicenter phase II study by the Eastern Cooperative Oncology Group (ECOG) suggest trastuzumab (Herceptin) is safe and moderately promising in combination with paclitaxel and carboplatin (Paraplatin) for some patients with non-small-cell lung cancer (NSCLC). Whether the investigation will progress to a phase III trial is unclear, however, as the researchers are uncertain as to how many lung cancer patients are positive for the HER2/neu mutation targeted by trastuzumab. "The problem is, do we have enough patients to mount a study? That is the big issue," investigator Corey Langer, MD, FACP, director of thoracic oncology at Fox Chase Cancer Center, told ONI. The trastuzumab-chemotherapy combination produced a median survival of 10.1 months and a median progression-free survival of 3.25 months (see Table 1), according to a report by Dr. Langer (ASCO abstract 2606). At a median follow-up of 34 months, 6 of 53 evaluable patients were still alive. Only one was free from progression. Across-the-Board Response
Response rates showed that 13 of these patients (24.5%) had partial responses, 21 (39.6%) had stable disease, and 16 (28.3%) had progressive disease (see Table 2). The results are "as good as if not better than what we typically see," Dr. Langer said, adding, "The interesting thing is response occurred across the board. I can't say if a degree of HER2 positivity translated to a better response rate." From August 1999 to May 2000, the investigators screened 139 patients, of whom 82 proved to be HER2 positive. All had advanced NSCLC. Eligi- bility criteria included recurrent, stage IV and stage IIIB (wet) disease and an ECOG performance status of 0 to 1. Prior chemotherapy was not allowed. Of the 56 patients initially enrolled, 53 turned out to be eligible. Among those evaluated, only eight were at the HER2 level of 3+, which Dr. Langer said is used to justify use of trastuzumab in breast cancer. The remainder were closely split with 22 patients at 1+ and 23 patients at 2+. The proportion of HER2-positive lung cancer patients is probably lower than the proportion in the population screened for this study, according to Dr. Langer, as oncologists did not refer patients known to be negative for the mutation. Only five patients had squamous histology, another indication that the HER2 mutation might be uncommon among lung cancer patients. Subgroup Could Benefit
Nonetheless, a subgroup of patients might benefit, according to Dr. Langer, depending on what the median survival is for patients with HER2/neu. That figure is currently unknown. If HER2/neu patients have a median survival of 5 months with standard chemotherapy, 10 months would be a significant increase, Dr. Langer noted. If their median survival is on the order of 8 months, however, the added months suggest less than the potential of some other novel agents also in early trials. Patients in the phase II study received an intravenous loading dose of 4 mg/kg of trastuzumab followed by 2 mg/kg weekly. Paclitaxel and carboplatin were delivered in 3-week cycles. Toxicity appeared similar to chemotherapy alone, and Dr. Langer said the few cases of left ventricular ejection fraction decreases were so trivial that this need not be monitored if patients are not receiving anthracycline in future trials. Ultimately, he predicted that no one novel agent but a combination of therapies will prove most effective. "Lung is a multihit malignancy. Many different genetic abnormalities conspire to create a cancer," Dr. Langer said, adding, "The bottom line is we really don't know what the real targets are, or how drugs interact. We're really in our infancy in understanding this whole field."

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