Phase III study of adjuvant ovarian suppression combined with tamoxifen or anastrozole, +/- zoledronic acid in early breast cancer in premenopausal women with hormone-receptor positive, stage I and II breast cancer.

Michael Gnant, MD, presented the first outcome data from the ABCSG-12 clinical trial as a late-breaking abstract (LBA-4). Between 1999 and 2006, 1803 premenopausal women with stage I or II (<10 positive nodes), ER and/or PR+, invasive breast cancer were randomly assigned to one of 4 arms of the study after having undergone definitive surgery. All women underwent ovarian suppression with goserelin 3.6 mg q 28 days followed by either tamoxifen +/- zoledronic acid or anastrozole +/- zoledronic acid. The hormone manipulation was continued for 3 years, as was the zoledronic acid (4 mg q 6 months). The primary statistical endpoint was disease-free survival (DFS). The trial was developed as a two pair-wise comparison intending to compare the use of tamoxifen vs anastrozole, and zoledronic acid vs no zoledronic acid. Women could not receive chemotherapy in the adjuvant setting, although about 5% of women had received neoadjuvant chemotherapy. The median follow-up of the trial was 60 months and included 137 first DFS events of which 30 were locoregional, 70 distant, and 16 contralateral breast cancers, with an additional 19 new nonbreast primary malignancies.

The trial is particularly interesting, because the DFS was not different between the tamoxifen and anastrozole arms with 72 of 903 events on the anastrozole arm, and 65 of 900 events on the tamoxifen arm (P = .593). What were different were the arms randomizing women to hormone therapy +/- zoledronic acid. There were 54 of 904 events on the zoledronic acid arm and 83 of 899 events on the nonzoledronic acid arm (P = .014; hazard ratio [HR], 0.653). With regard to adverse events, there were more episodes of arthralgia, bone pain, and fever in those women receiving zoledronic acid, and more episodes of thrombosis and uterine polyps in those women receiving tamoxifen.

There were no confirmed cases of renal insufficiency or osteonecrosis of the jaw. Several conclusions were drawn from this presentation. With 5 years of follow-up, there was a surprisingly high DFS and overall survival (OS) in this group of women receiving only endocrine therapy, suggesting that there is probably a population of premenopausal women who can expect very little absolute benefit from chemotherapy. Secondly, despite multiple clinical trials showing the advantage of an aromatase inhibitor over tamoxifen in postmenopausal women, this trial did not show a difference in outcome, possibly secondary to the dominant effect of ovarian suppression in premenopausal women with breast cancer. Both the ongoing Suppression of Ovarian Function Trial (SOFT) and Tamoxifen and Exemestane Trial (TEXT) should be informative on this issue. Lastly, the use of zoledronic acid in addition to hormone therapy reduced the risk of DFS events by 36%; this benefit was seen in and outside bone including contralateral breast cancer, locoregional recurrence, and distant non-bone recurrence. The ongoing AZURE (Does Adjuvant Zoledronic Acid Reduce Recurrence in Patients with High-Risk, Localized Breast Cancer?) trial, comparing standard systemic therapy +/- zoledronic acid in 3360 patients with stage II/III breast cancer, should inform us further as to whether the addition of zoledronic acid to systemic therapy should become a new standard of care.

A randomized study of lapatinib +/- trastuzumab in patients with heavily pretreated HER2+ metastatic breast cancer progressing on trastuzumab therapy.

Joyce O’Shaughnessy, MD, presented this provocative trial, on behalf of multiple investigators, looking at heavily pretreated women with HER2+ metastatic breast cancer. The trial involved 296 women who had progressed on an anthracycline, a taxane, and trastuzumab, half of whom were given lapatinib (L) 1500 mg/day, and half of whom were given L 1000 mg/day along with trastuzumab (T) 4 mg → 2 mg/kg q week. Of note, the median number of prior chemotherapy regimens was 4 and 5 in the L and L+T arms respectively, and about 30% of patients had received ≥ 6 prior regimens. The combination showed a 27% improvement in progression-free survival (PFS) compared to L alone (8.1 weeks vs 12.0 weeks, P =.008). In addition, the combination showed higher response rates (10.3% vs 6%) and clinical benefit rates (24.7% vs 12.4%). Improvement in OS also trended toward significance with the L+T arm having a median survival of 51.6 weeks, and the L arm having a median survival of 39 weeks.

Adverse events were similar between the 2 arms with the exception of diarrhea, which was somewhat higher on the combination arm (60% vs 48% all grades). There were 8 cardiac events on the L+T arm and 5 on the L arm. Dr O’Shaughnessy concluded that L+T is an effective treatment for HER2+ metastatic breast cancer progressing on trastuzumab and that the combination significantly improved PFS, doubled the clinical benefit rate, and showed a trend toward improvement in OS. She also emphasized the need to evaluate this combination in earlier metastatic breast cancer and that it is important to support the ongoing Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization (ALTTO) adjuvant study.

FLEX: A randomized, multicenter, phase III study of cetuximab in combination with cisplatin/vinorelbine (CV) versus CV alone in the first-line treatment of patients with advanced non-small cell lung cancer (NSCLC).

Robert Pirker, MD, presented data on the FLEX trial that comprised 1125 patents with stage wet IIIB or IV, EGFR+ (by IHC) NSCLC. Patients were randomized to receive cisplatin 80 mg/m² day 1 and vinorelbine 25 mg/m² days 1 & 8 every three weeks for up to 6 cycles +/- cetuximab 400 mg/m² initial dose followed by 250 mg/m² weekly with OS as the statistical endpoint. Although cetuximab improved the response rate from 29% to 36%, there was no improvement in PFS. Overall survival was improved from 10.1 months to 11.3 months (P = .044). FLEX did evaluate the differences in outcome by ethnicity and found that the median OS, which was 9.6 months in white patients, was significantly better in Asians at 19.5 months.

Febrile neutropenia, acne-like rash, diarrhea, and infusion-related reactions were more common on the cetuximab arm of the trial.

Thomas J. Lynch, Jr, MD, discussant for this trial, provided some insight on this trial in comparison to other lung cancer trials during the plenary session. He suggested scenarios where one should consider adding cetuximab in NSCLC. He suggested that it should be restricted to patients with metastatic NSCLC receiving chemotherapy in the front-line who are ineligible for bevacizumab, and that maintenance cetuximab should be given when the chemotherapy has been discontinued after a maximum number of cycles have been completed. He also suggested that there continues to be a need for discovery of more specific targets and biomarkers that will predict for benefit from cetuximab, making the cost/risk–to-benefit ratio more acceptable.

KRAS status and efficacy in the first-line treatment of patients with metastatic colorectal cancer treated with FOLFIRI with our without cetuximab: The CRYSTAL experience

Eric Van Cutsem, MD, PhD, presented an overview of previously reported colorectal trials, which have included anti-EGFR antibodies in metastatic colorectal cancer. In addition, he cited multiple retrospective studies supporting the correlation between KRAS mutations and the lack of response to EGFR inhibitors. The Cetuximab Combined with Irinotecan in First-Line Therapy for Metastatic Colorectal Cancer (CRYSTAL) trial was first presented at ASCO 2007 and is a randomized front-line trial in which 1217 patients received FOLFIRI +/- cetuximab. The results from that trial showed that PFS was improved from 8 months to 8.9 months with the addition of cetuximab with a HR = 0.85, and response rates were improved from 39% to 47%, respectively.

The objective of the current presentation was a retrospective analysis investigating the impact on PFS and response rate of the KRAS mutation status of tumors in this CRYSTAL trial. Tumor specimens were analyzed on 587 of the original 1198 subjects, of which 540 (45%) were successfully completed. Of these specimens, 348 (64.4%) were KRAS wild-type and 192 (35.6%) were KRAS mutant. The results confirmed a lack of benefit for the addition of cetuximab to FOLFIRI for patients whose cancer expressed mutant KRAS and a significant benefit for cetuximab when the KRAS was wild-type. Progression-free survival was 8.1 months vs 9.9 months (P = .017), and response rates were 43% vs 59% (P = .0025) without and with cetuximab in KRAS wild-type patients, respectively. Conversely, in patients with mutant KRAS, PFS was 8.7 months vs 7.6 months, and response rate was 40% vs 36% without and with cetuximab, respectively. The authors suggested that KRAS testing should be performed on the tumors of patients with metastatic colorectal cancer, and that cetuximab in combination with a standard first-line treatment is an important new option of therapy.

Randomized phase III study of capecitabine, oxaliplatin, and bevacizumab with or without cetuximab in advanced colorectal cancer (ACC), the CAIRO2 study of the Dutch Colorectal Cancer Group (DCCG)

Cornelis Punt, MD, presented data from the CAIRO2 study on behalf of the DCCG. He presented data to suggest that preclinical models have shown additive effects of VEGF and EGFR inhibitors. He suggested that in irinotecan-resistant colorectal cancer the combination of irinotecan, cetuximab, and bevacizumab (BOND2 study) was feasible and showed greater efficacy than irinotecan + cetuximab (BOND study).

Seven hundred fifty-five patients were randomized to receive oxaliplatin, capecitabine, and bevacizumab +/- cetuximab. The median duration of follow-up was 18.7 months. The results of the study showed a significantly decreased PFS without affecting survival when adding cetuximab to the oxaliplatin, capecitabine, and bevacizumab therapy. The median PFS without and with cetuximab were 10.7 months and 9.6 months respectively (P = .018), and the response rate was 44% in both arms. Other additional observations were that the addition of cetuximab to chemotherapy + bevacizumab significantly increased skin toxicity and diarrhea, and that the grade of the cetuximab-related skin toxicity significantly correlated with PFS.

In contrast to the CRYSTAL study, KRAS wild-type status did not influence the results with the addition of cetuximab. However, it was noted that patients with a KRAS mutation had a significant reduction in PFS with the addition of cetuximab.

Cathy Eng, MD, who discussed the presentation, suggested that the use of combined biologic therapy (anti-VEGF/EGFR) should only be conducted as part of a clinical trial. In addition, the use of anti-EGFR therapy in KRAS mutant tumors in combination with chemotherapy negatively impacts PFS and possibly response rate.

RAD001 plus best supportive care (BSC) vs BSC plus placebo in patients with metastatic renal cell carcinoma (RCC) that has progressed on VEGFr-TKI therapy: Results from a randomized, double-blind, multicenter phase III study

Robert Motzer, MD, presented data on behalf of the RECORD-1 Study Group. Dr Motzer noted that the use of sunitinib or sorafenib has become the standard of care for patients with RCC. He suggested that effective treatments are needed for the patients when their cancer progresses on this biologic therapy. Everolimus (RAD001) is an oral inhibitor of mTOR. This trial was conducted as a phase III, double-blind, randomized trial of everolimus vs placebo (BSC). The primary statistical endpoint was PFS with multiple secondary endpoints. Patients were required to have metastatic RCC with a clear cell component and had to have developed progressive disease on or within 6 months of treatment with sunitinib, sorafenib, or both.

Four hundred ten patients were randomized in a 2:1 fashion to receive everolimus 10 mg po daily + BSC (n = 272) vs placebo + BSC (n = 138). Median PFS improved from 1.9 months to 4.0 months comparing placebo to everolimus (HR = 0.30). For the most part, the everolimus was well-tolerated, but the adverse events requiring discontinuation of everolimus was seen in 10% of patients.

Dr Motzer suggested that everolimus is the first and only agent with established clinical benefit for the treatment of patients with RCC after VEGFR-TKI therapy and should be considered as a standard of care in this setting.

Abiraterone acetate and prednisone in patients (Pts) with progressive metastatic castration resistant prostate cancer (CRPC) after failure of docetaxel-based chemotherapy

Daniel Danila, MD, presented the preliminary results of a phase II study of abiraterone acetate in patients with CRPC on behalf of the multiple investigators involved with this study. Patients with CRPC may remain sensitive to hormone manipulation. Abiraterone is an oral irreversible inhibitor of CYP17 and inhibits testosterone production in the testis, adrenal glands, and prostate. It has been noted to be at least 10-fold more potent than ketoconazole in vitro.

The primary statistical endpoint of this trial is that the abiraterone will cause a 50% decline in the prostate-specific antigen (PSA) levels in ≥ 30% of patients. Thirty-eight patients were enrolled on the trial and received abiraterone acetate 1000 mg orally daily with prednisone 5 mg orally twice daily. Patients had been exposed to multiple lines of hormonal therapy, including 45% who had received ketoconazole, and 37% receiving more than 4 lines of hormone therapy. All patients had received chemotherapy.

Nadir PSA of 50% or more was reached in 17 of 38 patients (44.7%). Toxicities were mild, however it was noticed that 11 patients developed a grade 3 elevation of alkaline phosphatase. Building on this compelling data is a phase III randomized trial in post-docetaxel chemotherapy patients with CRPC. Patients will be randomized to abiraterone 1000 mg daily with prednisone 10 mg daily vs placebo daily + prednisone.

Christy Russell, MD

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