Erlotinib Produces Responses in Patients With Bronchoalveolar Cell Carcinoma, Ongoing Phase II Trial Suggests

NEW YORK-Bronchoalveolar cell carcinoma (BAC) appears responsive to erlotinib (OSI-774, Tarceva) in an ongoing phase II trial. Interim findings also suggest that BAC might be more common than previously believed and perhaps behaves differently in smokers than in nonsmokers. Vincent Miller, MD, of Memorial Sloan-Kettering Cancer Center in New York City reported a 26% response rate using erlotinib to treat BAC in 50 evaluable patients and a trend toward higher response in nonsmokers (ASCO abstract 2491). While 46% of patients who never smoked responded to erlotinib, only 19% of former or current smokers did so. "Erlotinib is an active drug in this disease. We believe the duration of response is encouraging, and the treatment is certainly well tolerated," Dr. Miller said in reporting interim results from the ongoing study. Speaking for co-investigators at his center and Vanderbilt-Ingram Cancer Center in Nashville, he said a phase III trial comparing erotinib to platinum-based chemotherapy was warranted. BAC Component in NSCLC
As defined by World Health Organization criteria, BAC accounts for only 3% of cases of non-small-cell lung cancer (NSCLC). Dr. Miller suggest- ed, however, that as many as 20% of NSCLC cases might have a BAC component. "Our previous work suggests that pure BAC, BAC with focal invasion, and adenocarcinoma with BAC features have a similar clinical course," he said. Screening and monitoring of patients for the current trial supported that observation, he added. From July 2002 to April 2003, a reviewer at Memorial Sloan-Kettering screened 98 patients whose prior pathology and/or clinical presentation suggested the possibility of a BAC diagnosis. Dr. Miller said surgical pathology material was reviewed for twothirds of the patients and cytologic material for the rest. The review ruled out BAC in 27 patients. Among the remainder of screened patients, 52 had adenocarcinoma with BAC features, 2 had BAC with focal invasion, and 17 had pure BAC. Only one patient previously diagnosed with BAC was ruled out. Conversely, the review found BAC features in 45 patients whose samples had previously been classified as adenocarcinoma or NSCLC. "This is not a rare bird to find when you start to look at your patients," Dr. Miller advised. "So one of the messages is, one can't accept a pathology report that just says NSCLC. The physician needs to ask his or her pathologist for more information particularly whether or not a BAC component might be present." Three-Quarters Were Smokers
Of 71 patients potentially eligible for the trial, 55 consented for treatment and 50 were evaluable for response. Their median age was 66 with a range of 33 to 85 years. Two-thirds of the patients were women, and threequarters were former or current smokers. The majority, 38 patients, had never received chemotherapy, while 12 patients had undergone one prior regimen. The patients received 150 mg of erlotinib daily. Erlotinib is a small molecule inhibitor of the HER1/epidermal growth factor receptor (HER1/ EGFR) tyrosine kinase. Little is known about EGFR expression in BAC, Dr. Miller said. Anecdotally, however, he reported that BAC patients appeared to have some of the most dramatic responses to erlotinib and gefitinib(Drug information on gefitinib) (ZD1839, Iressa), another EGFR inhibitor, in phase I trials with advanced NSCLC patients. Responses and Progression
Investigators noted partial responses in 13 patients enrolled in the phase II study and all but one has been confirmed. One patient who responded progressed after 3 months and another patient after 7 months, but 11 responses are ongoing. "The response can be quite dramatic and long lasting," he said. At 3 months, 48 of 55 patients originally enrolled in the trial were still alive, according to Dr. Miller. The median duration of follow-up is 6 months, he said, and the median duration of response had not yet been reached. While four deaths occurred on study, Dr. Miller said two were due to disease progression in the first month, and a patient who died suddenly 9 days after starting treatment had appeared better symptomatically. No autopsy was performed. Rash and diarrhea were dose limiting in phase I. Only one responding patient did not have a rash in phase II. Four patients had grade 3 rash, and two patients reported grade 2 rashes to be intolerable, but none discontinued because of rash, according to Dr. Miller. Predicting Response
In searching for clinical characteristics that might identify the subset of patients who were most likely to respond to erlotinib, the investigators found that females were only slightly more likely to respond. The response rate was also slightly higher in invasive variants of BAC than in pure BAC, but Dr. Miller said that both groups responded similarly. Although the data did not reach statistical significance, a history of never smoking appeared to correlate with being more sensitive to erlotinib. Dr. Miller called the data provocative and speculated that "lung cancer may have a different biology in never smokers." He said the investigators plan to construct a tissue microarray comparing erlotinib-sensitive and erlotinib- resistant patients and to examine the frequency of tobacco-related mutations in both groups.