Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

42nd Annual Meeting of the American Society of Clinical Oncology

Atlanta, Georgia / June 2-6, 2006

As presented by lead author Dr. Louis Fehrenbacher, Medical Director, Oncology Clinical Trials Program, Kaiser Permanente Northern California, Vellejo, 120 patients with recurrent or refractory non-squamous non-small cell lung cancer (NSCLC) were randomized to chemotherapy alone with either docetaxel or pemetrexed, chemotherapy/bevacizumab or dual targeted therapy with bevacizumab/erlotinib. The progression-free survival (PFS) rate at six months was 21.5% for the chemotherapy alone arm, 30.5% for the bevacizumab/chemotherapy arm and 33.6% for the bevacizumab/erlotinib arm. At six months, 62.4%, 72.1% and 78.3% of patients were still alive in the chemotherapy alone arm, the bevacizumab/chemotherapy arm and the bevacizumab/erlotinib arm, respectively.

Ten out of 41 patients treated with chemotherapy alone discontinued treatment due to an adverse event (AE), while over half experienced a serious AE. Discontinuation rates were similar for the bevacizumab/chemotherapy arm, where 10 patients out of 40 discontinued treatment due to an AE. In contrast, only four patients out of 39 in the erlotinib/bevacizumab combination arm withdrew because of an AE. As expected, there was a greater incidence of rash and diarrhea in the bevacizumab/erlotinib arm compared with the other two arms but the incidence of neutropenia was similar for both arms containing chemotherapy. The overall incidence of neutropenia in the bevacizumab/erlotinib arm was approximately 4%. Results prompted investigators to suggest that the bevacizumab/erlotinib combination may represent an alternative to chemotherapy-based treatments in relapsed NSCLC provided a fully powered trial confirm these results. Previous results from a variety of lung cancer histologies suggest that male smokers with squamous cell carcinoma may not be considered ideal candidates for treatment with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). However, as reported by Dr. Gary M. Clark, Boulder, Colorado, results from a new analysis of the previously reported BR.21 placebo-controlled study suggest otherwise. In the original trial, 731 with incurable stage III/IV NSCLC who had failed one or two prior regimens were randomized to either erlotinib 150 mg or placebo. As previously reported, the hazard ratio (HR) for death was 0.73 in favour of erlotinib vs. placebo, suggesting that for the group overall, erlotinib prolongs PFS as well as time to symptom deterioration. The survival benefit was particularly pronounced in never-smokers (HR=0.42) and in HER1/EGFR+ patients (HR=0.65).

A new analysis of a subgroup of 100 male smokers with squamous cell carcinoma from the same study shows that treatment with erlotinib does improve overall survival (OS) in what was considered a poor risk group (HR=0.66). Indeed, females and males benefited equally from erlotinib, as investigators pointed out, as did those with squamous cell carcinoma compared with adenocarcinoma patients. Survival was, however, better in never-smokers compared with current or former smokers. “Tumour response rates are low among male smokers with squamous cell carcinoma,” investigators concluded. “[Nevertheless], male ever-smokers with squamous cell carcinoma do derive a survival benefit from erlotinib compared with placebo.”

A similar conclusion was reached by other investigators under lead author Dr. Alfonso Gurpide, Clínica Universitaria de Navarra, Pamplona, Spain. In this open-label, non-randomized, phase II trial, 277 patients with squamous carcinoma of the lung received erlotinib, 144 of whom were evaluable for response. Among the group, 88% had stage IV disease and 74% had received previous treatment for metastatic disease. Over 90% were either current smokers or had smoked at some point in their lifetime and almost one-quarter of them had an ECOG PS of 2. The primary end point was time to progression (TTP).

Response rates at 50% (three out of six patients) who were never-smokers were higher than response rates of 5.8% in current or ever-smokers. However, the disease-control rate of 66.7% (four out of six) never-smokers was similar to that of 56.2% in 77 out of 137 current or ever-smokers. Response and disease control rates were significantly higher for those who had received fewer lines of previous chemotherapy but they were not statistically significantly different between PS 0 to 1 patients and PS 2 patients. Response and disease control rates in men vs. women were also similar at 6.9% for men vs. 14.3% for women, and 56.2% vs. 57.1% for men and women, respectively. Most cases of rash were mild to moderate (only four cases of grade 4 rash) and diarrhea was observed in approximately 30% of patients, none of it being grade 4. Median TTP was of 4.3 months and median OS was 5.8 months. Responses were again seen in both genders and in patients with and without a smoking history.

Expanded Access Program

Following publication of the pivotal BR.21 trial, the Expanded Access Program (EAP) was designed to give patients with advanced NSCLC access to erlotinib until such time as licensure was granted. Organized as a large phase IV, open-label study, the EAP is evaluating the safety and efficacy of erlotinib monotherapy in over 5000 patients from 48 countries. Under lead author Dr. Martin Reck, Hospital Grosshansdorf, Germany, investigators reported on results for 2548 patients in their interim analysis. The median exposure for all patients was eight weeks and this did not differ substantially between differences in lines of treatment.

According to investigators, interim results from this real-life clinical setting in large numbers of unselected patients with advanced NSCLC confirm the efficacy and tolerability of erlotinib seen in clinical trials, in particular the pivotal phase III study BR. 21, and its tolerability favours full-dose administration to most patients. Dr. Vincent O’Neill, San Francisco, California, and colleagues addressed the question of what effect smoking had on outcome in the same EAP cohort. Most patients were previous smokers, investigators pointed out, and smokers had smoked for a mean of 39.4 years. It is noteworthy that over 30% of patients enrolled in this open-label program had a PS of between 2 to 3 and almost half had two or more lines of chemotherapy. The overall response rate was 26.6% in patients who had never smoked vs. 6% in previous smokers and 7.3% in current smokers.

The median OS for all patients was 6.3 months, but median OS for those who had never smoked was longer (not yet reached in this analysis) compared with previous smokers (5.2 months) or current smokers (6.3 months). There were no differences in survival between patients who were current smokers and patients who were previous smokers, reported investigators. The incidence of treatment-related serious adverse events was low at slightly over 3% and fewer than 20% of patients discontinued study drug because of adverse events and serious adverse events.

Safety data indicated that 69% of patients enrolled in the EAP experienced a rash, 12% being grade 3 or 4. Five per cent of patients experienced a serious adverse event, most commonly gastrointestinal disorders. Eleven per cent required a dose reduction due to an erlotinib-related event and 7% discontinued treatment because of a treatment-related adverse event.

The overall response rate of 8.3% and median survival of 6.3 months compares favourably to the pivotal BR.21 trial, investigators concluded, and consistent with other studies, there were no new safety signals overall.

Well Tolerated Regimen

As reported by Dr. David M. Jackman, Associate Professor of Oncology, Dana Farber Cancer Institute, Boston, Massachusetts, findings from another phase II trial of erlotinib in elderly patients with advanced NSCLC suggest that the elderly often respond well to first-line erlotinib and that treatment is exceptionally well tolerated. In this open-label study, investigators examined its use in chemotherapy-naive elderly patients with advanced NSCLC. In the current analysis, the effect on symptoms and quality of life were the focus of the report. To assess changes in quality of life, investigators used the well-validated Lung Cancer Symptom Scale (LCSS) and a total of 64 patients were available for quality-of-life analysis. Median age of the cohort was 75 years of age and the majority were PS 1 and 2 patients, with approximately 10% being PS 2.

Median survival at the time of this preliminary analysis was 10.9 months. During this time, treatment was associated with symptomatic improvement in the majority of previously symptomatic patients, with scores indicating that treatment improved dyspnea, cough, fatigue, pain and loss of appetite. Significant changes in overall LCSS scores were not noted for the whole group, but patients who achieved either a partial response (PR) or stable disease in response to the TKI did achieve a significant improvement in their overall LCSS score, investigators noted.

Another study investigating first-line treatment with erlotinib in previously untreated stage III/IV NSCLC patients supports its use in good prognosis patients as well. Under lead author Dr. Wallace Akerley, Huntsman Cancer Institute, Salt Lake City, Utah, 40 patients with advanced disease but with good prognostic features received erlotinib and were followed for six months.

Median survival was 49 weeks, and at six months, the PFS rate was 56%. Rash predicted the duration of response, and investigators concluded that both survival and PFS in this group of patients “appears comparable” to that of historical chemotherapy.

Treating Bronchioloalveolar Carcinoma

It is fairly well established that responses to erlotinib are commonly associated with mutations in the EGFR. However, it is not known if these mutations are associated with prolonged TTP and improved OS. As reported by Dr. Vincent Miller, Thoracic Oncology Service, Associate Professor of Medicine, Memorial Sloan-Kettering Cancer Center, New York, investigators studied clinical, pathologic and molecular characteristics of tumour specimens in terms of response, PFS and OS in patients with either pure bronchioloalveolar carcinoma (BAC) (n=12) or patients with adenocarcinoma with BAC features (n=90). The vast majority of patients had stage IV disease.

EGFR sequencing was carried out using both direct techniques and PCR-based assays, while EGFR copy number was determined by chromogenic in situ hybridization (CISH). “Of all patients who received erlotinib, the median PFS was four months and the median OS was 17 months,” Dr. Miller reported. Median PFS was six months and median OS was 29 months in patients whose disease stabilized in response to erlotinib.

For patients whose disease progressed despite treatment, median PFS was one month and median OS was eight months. Breaking down response to erlotinib by mutation status and gene copy number, certain subgroups clearly fared better than others. For example, in patients with EGFR mutations, median PFS was 12 months and median OS was 23 months. Similarly, in patients with a CISH score ³4 (defined as CISH-positive), median PFS of nine months were noted with a median OS of 25 months. Median PFS and OS in CISH-negative patients were much lower at two and six months, respectively.

The most dramatic regressions occurred in the small group of patients with both EGFR mutations and a CISH ³4. In this group, “the combination of an EGFR mutation and CISH ³4 was associated with a 90% response rate, a 15-month median PFS and a median OS of nearly three years,” Dr. Miller added. In contrast, patients who had no EGFR mutation and a CISH <4 had a median PFS of two months and a median OS of 15 months. “In patients with both EGFR mutation and amplification…erlotinib should be considered as initial therapy,” Dr. Miller concluded. In contrast, performance status (PS) does not predict which patients with advanced NSCLC will respond to erlotinib. As noted by Dr. Rogerio Lilenbaum, Director, Thoracic Oncology Program, Mount Sinai Cancer Center, Miami Beach, Florida, erlotinib has activity in NSCLC patients with low PS but it has not been formally tested as first-line therapy in patients with a poor PS. This provided the rationale for a randomized, phase II trial involving previously untreated patients with advanced NSCLC and a PS of 2. Patients received either standard-dose erlotinib (150 mg/day) or standard dose carboplatin/paclitaxel. The primary objective was the estimated PFS. Fifty-two patients were enrolled into the erlotinib arm and 51 into the carboplatin/paclitaxel arm.

Only one patient (2%) achieved a PR in the erlotinib arm vs. 12% in the chemotherapy arm. Disease stabilized in 30% of TKI-treated patients and in 45% of those in the carboplatin/paclitaxel arm. Median PFS was 1.9 months in the TKI arm vs. 3.5 months for the chemotherapy arm, although as Dr. Lilenbaum noted, the 95% confidence intervals did overlap here. Median OS was 6.5 months for erlotinib and 9.6 months for carboplatin/paclitaxel.

Interestingly, patients treated with the TKI who developed a grade 2 rash had a median PFS and OS that approximated rates in the chemotherapy arm, a substantially better result than that seen in patients who did not develop a rash in response to erlotinib, Dr. Lilenbaum noted. There was no significant difference with respect to dyspnea, cough, hemoptysis and mouth sores between the two groups.

“Based on these data, combination chemotherapy remains the preferred first-line therapy for treatment of PS 2 patients with advanced NSCLC and the use of single, targeted agents as first-line therapy in PS 2 patients should be carefully individualized,” Dr. Lilenbaum stated, adding that further studies in this area are needed.

The Role of Mutations

An analysis of the prognostic and predictive importance of K-ras mutational status in the National Cancer Institute of Canada’s Clinical Trials group BR.21 study corroborated earlier observations that patients who harbour the K-ras mutation do not respond well to EGFR TKI therapy.

Under lead author Dr. Ming Sound Tsao, Professor of Laboratory Medicine, UHN-Toronto General Hospital, and Senior Scientist, Ontario Cancer Institute, Toronto, investigators carried out a K-ras analysis in 206 patients randomized to the pivotal BR.21 trial. The conclusion reached by both Dr. Tsao and discussant Dr. Bruce Johnson, Associate Professor of Medicine, Harvard Medical School, Boston, was that indeed, NSCLC patients with K-ras mutations “almost never” respond to EGFR TKIs such as erlotinib and gefitinib and that TTP and OS are both significantly shorter in this group of patients.

Nevertheless, both presenters were careful to point out that any conclusions about the lack of response to EGFR TKIs in the presence of K-ras mutations were based on a small number of patients in the BR.21 trial. Results thus need to be prospectively confirmed in other studies.