PHARMACEUTICAL NEWS JAK2 Inhibitor Therapy for Myeloproliferative Disorders As an example, the histone deacetylase (HDAC) inhibitor ITF2357 inhibits the autonomous proliferation of hematopoietic cells from patients with PV and ET through down modulation of mutated JAK2. ITF2357 was evaluated in a phase IIA safety and efficacy trial in the treatment of patients with JAK2-positive PV, ET, and MF. The oral 50 mg twice daily dosage was well tolerated. In the patients with PV/ET, a complete response (CR) was achieved in 23% and a partial response (PR) in 62%. Rapid improvement of constitutional symptoms, spleen size (75% of patients with splenomegaly), and hematologic response were reported in the great majority of the patients with PV/ET and in some patients with MF.
Will One or Both of These Second Generation Tyrosine Kinase Inhibitors Supplant Imatinib as First-Line Therapy for Chronic Myelogenous Leukemia? Dasatinib (SPRYCEL®) is a multitargeted kinase inhibitor of BCR-ABL and SRC with significant activity in patients with chronic phase CML (CML-CP) resistant to or intolerant of imatinib. A phase II study was designed to investigate the efficacy and safety of dasatinib in patients with previously untreated CML-CP. The primary objective was to estimate the proportion of patients attaining MMR at 12 months. Fifty patients were randomized to either dasatinib 50 mg BID or 100 mg once daily. Median follow-up was 24 months. Results: 98% of evaluable patients achieved a CCyR. Major molecular response was achieved in 34% of patients at 12 months and in 48% at 18 months. Grade 3-4 nonhematologic toxicity: 13% pruritis and 21% pleural effusion. The 24-month event-free survival rate was 81%. While accrual to this trial continues, the investigators have concluded that rapid CCyR occurs in most patients treated with dasatinib front-line therapy.
An Effective, Safe Oral Monotherapy for Relapsed or Refractory Mantle Cell Lymphoma A recent phase II trial (NHL-002) of single-agent lenalidomide (REVLIMID®) in patients with relapsed or refractory mantle cell lymphoma (MCL) demonstrated a promising overall response rate (ORR) of 53% with a median duration of response of 11.9 months. A confirmatory international phase II trial (NHL-003) of lenalidomide was initiated for patients with relapsed/refractory non-Hodgkin lymphoma (NHL) that had received at least one prior treatment and had measurable disease ≥2 cm. Analysis of the 39 patients with MCL in this trial is reported here. Lenalidomide 25 mg was given orally once daily on days 1-21 of every 28-day cycle until disease progression or toxicity. Median time from diagnosis to lenalidomide treatment was 3.4 years. The ORR was 41%, including 13% CR/unconfirmed CR and 28% PR; stable disease was reported in 26%. The most common grade 3 or 4 AE was neutropenia, reported in 10% of patients. Conclusion: These results confirm that lenalidomide oral monotherapy is an effective treatment, with manageable side effects, for patients with relapsed/refractory MCL. Chemoimmunotherapy in Chronic Lymphocytic Leukemia: Is It the New Standard First-Line Therapy and What Will Be the Role of the New Anti-CD20 Antibody? Three previous phase II studies have suggested that the addition of rituximab (Rituxan®/MabThera®, R) to fludarabine plus cyclophosphamide (FC) chemotherapy may increase the outcome of both untreated and relapsed patients with chronic lymphocytic leukemia (CLL). The first randomized phase III trial (CLL 8) compared chemotherapy with FCR versus FC for the first-line treatment of patients with advanced CLL. Six cycles of treatment were planned. Of 817 patients enrolled, 761 were evaluable; median age was 61 years; 64% were Binet B, 32% Binet C, and 5% Binet A. Results: median follow-up was 25.5 months; ORR was 95% for patients treated with FCR vs 88% for patients in the FC arm (P = .001). Progression-free survival at 2 years was 76.6% vs 62.3%, respectively (hazard ratio [HR] 0.59; P<.0001). A 52% CR was reported for the FCR arm vs 27% for the FC arm (P<.0001). There was a trend for increased overall survival (OS) in patients treated with FCR, 91% vs 88% at 2 years (HR = 0.76; P = .18). The longest benefit for FCR was seen in patients with Binet stage A and B with regard to CR, ORR, and PFS. Conclusion: FCR improves response rates (superior ORR and CR) and PFS compared to FC; causes more neutropenia/leukopenia without increasing incidence of severe infections; and is safe and well tolerated in patients 65-70 years old. These findings suggest that FCR could possibly become the new standard first-line treatment for fit elderly patients with advanced CLL. Hallek M, et al. Blood. 2008112: Abstract 325. Ofatumumab (HuMax-CD20®/Arzerra™) is a fully human anti-CD20 monoclonal antibody that is active in NHL and CLL. It was found to have single-agent activity in patients with refractory CLL (double-refractory to both fludarabine and alemtuzumab) achieving an ORR of 58% in double refractory patients and 47% ORR in patients with bulky fludarabine-refractory CLL. Since this monoclonal antibody is fully human and has potential, could it become an alternate to rituximab in the future? Osterborg A, et al. Blood. 2008;112: Abstract 328. Dual Pathway Blockade Regimen Achieves High Quality Responses in High-Risk Myeloma Bortezomib (VELCADE®, Bz) and lenalidomide (Len) affect different pathways; therefore, when used together, multiple pathways may be blocked. A phase I/II study was designed to determine the maximum planned dose of Len/Bz/dDex (RVD) and to assess safety and efficacy in previously untreated patients with myeloma in high-risk groups. Patients with at least a PR could proceed to autologous stem cell transplantation (ASCT) after 4 cycles. Data are available for 66 patients (median age 58 years, 67% IgG disease, 50% International Staging System [ISS] stage II/III). Patients have received a median of 10 cycles and toxicities have been manageable. The ORR (≥PR) is 98%, including 71% ≥ very good partial response and 36% CR/near CR; at the maximum planned dose, ORR is 100%. Efficacy was independent of baseline cytogenetics or ISS stage. Fifteen patients have proceeded to ASCT. After a median follow-up of 8 months, the median time to progression, PFS, and OS have not been reached. Conclusion: RVD produces high quality responses and is well tolerated in this patient population, regardless of cytogenetics and ISS stage. Maximum planned dose was reached at Len 25 mg, Bz 1.3 mg/m2, and Dex 20 mg. Stem cell mobilization was successful in almost all patients. Richardson P, et al. Blood. 2008;112: Abstract 92. SABCS 2008 Meta-analyses of Randomized Trials of Monotherapy and Switching Strategies of Adjuvant Aromatase Inhibitors Meta-analyses by the Early Breast Cancer Trialists Collaborative Group (Lancet. 2005;365(9472):1687-1717) have established that 5 years of adjuvant tamoxifen (Tam) substantially reduces disease recurrence and mortality in patients with estrogen receptor–positive (ER+) breast cancer (BC). Prospective trials in postmenopausal patients have examined the aromatase inhibitors (AIs) anastrozole (Arimidex®), exemestane (AROMASIN®), and letrozole (Femara®) in comparison with Tam either as initial monotherapy (Cohort 1) or after 2 to 3 years of Tam in a switching strategy (Cohort 2); both to a total of 5 years of endocrine therapy. The current meta-analyses of randomized trials of monotherapy and switching strategies were conducted comparing AIs vs Tam as adjuvant therapy for postmenopausal women with hormone receptor–positive BC. A total of 18,871 patients from various randomized trials were included in this analysis. Cohort 1 included 9856 patients with 50,000 women-years of follow-up from the ATAC and BIG 1-98/IBCSG 18-98 trials. Cohort 2 included 9015 patients with 33,000 woman-years of follow-up from the ABCSG 8, ARNO 95, IES/BIG 2-97, and ITA trials. Results:
Conclusions: In 2 separate meta-analyses considering both the initial monotherapy setting and the switch setting after 2-3 years of Tam, AIs produced significantly lower BC recurrence rates compared to Tam. Ingle JN, et al. Cancer Res. 2009;69(Suppl 2): Abstract 12. Updated Results from BIG 1-98 Trial: First Results of the Sequence Analysis Breast International Group (BIG) 1-98 is a randomized, phase III trial designed to evaluate the clinical effectiveness of letrozole versus Tam or Let and Tam given in sequence compared with letrozole alone as initial adjuvant endocrine therapy in postmenopausal women with hormone receptor–positive BC. The initial Primary Care Analysis and the subsequent Monotherapy Analysis both demonstrated that Let significantly prolonged disease-free survival (DFS), particularly reducing the risk of relapse in distant sites compared to Tam in these patients. Based on these findings, the Tam arm was unblinded and patients randomized to Tam alone arm were allowed to switch to Let, and about one-third of these patients opted to receive Let. The other 3 arms receiving Let-containing treatment remained blinded. Results of the trial evaluating Let and Tam given in sequence compared with Let alone and an update of the comparison of Let alone and Tam alone are presented. A total of 6182 patients were randomized to the 4-arm option containing Tam alone (5 years), Let alone (5 years), Tam (2 years) followed by Let (3 years), or Let (2 years) followed by Tam (3 years). Another 1828 patients were randomized to receive either Tam alone or Let alone. The primary endpoint of the trial was DFS. The findings presented at the meeting include the head-to-head comparison of Tam and Let from the monotherapy arms and the sequential therapy analysis evaluating Tam followed by Let versus Let alone and Let followed by Tam versus Let alone. Results:
Conclusions: Updated results from the monotherapy arm comparisons suggest superior OS in patients receiving Let alone compared with those receiving Tam alone. These findings indicate that consideration should be given for upfront endocrine therapy with Let for patients at higher risk of early recurrence. However, patients on Let for at least 2 years can be switched to Tam, if required. Mouridsen HT, et al. Cancer Res. 2009;69(Suppl 2): Abstract 13. Click here to view a discussion with Dr Mouridsen about this study.
Exemestane (E) is a steroidal aromatase inactivator that has been demonstrated to be more effective than Tam in patients with metastatic BC (MBC). The role of E in adjuvant therapy has been established after 2 to 3 years of Tam compared to 5 years Tam as Tam-E demonstrated early improvement in DFS in the Intergroup Exemestane Study (IES; Lancet. 2007;369(9561):559-570). The TEAM (Tamoxifen Exemestane Adjuvant Multinational) prospective randomized phase III trial evaluated E compared to Tam as initial adjuvant endocrine therapy in postmenopausal women with hormone receptor–positive early BC. In 2004, after first results of IES that showed that patients who crossed over to E after 2-3 years of Tam had an improved DFS became available, the TEAM trial was amended to compare sequential therapy of Tam followed by E monotherapy for 5 years. However, the presented analysis at 2.75 years follow-up focused on Tam vs E monotherapy. A total of 9775 patients were randomized to receive either Tam or E; 99% were ER+ and/or progesterone receptor positive (PgR+), 50% were node negative. The primary endpoint was DFS. The first planned analysis included 740 events or 9300 patients with at least 2.75 years follow-up. Results:
Conclusions: The TEAM trial represents the largest of the 3 major trials to compare the efficacy of an aromatase inhibitor/inactivator verses tamoxifen as initial endocrine therapy. Exemestane demonstrated improvement in DFS, RFS, and time to distant metastases compared with Tam. No unexpected toxicities occurred with either E or Tam. The importance of monitoring compliance was highlighted during the presentation as early discontinuation may have affected outcomes (DFS). Jones SE, et al. Cancer Res. 2009;69(Suppl 2): Abstract 15.
A prospective planned pathology study within the TEAM trial was designed to analyze the interaction between PgR status and the efficacy of an AI versus Tam as initial endocrine therapy. The prospective hypotheses defined in 2001 were that PgR-poor and HER2-positive tumors derive additional benefit from E versus Tam therapy. Pathology blocks were analyzed for ER/PgR status (positive or negative and rich or poor). When analyzed for the interaction between PgR status and E versus Tam, no evidence for a treatment by marker effect for PgR with E was observed. However, PgR was a significant prognostic factor in univariate (PgR-rich versus PgR-poor HR = 0.49; P<.0001) and multivariate (P<.0001) regression analyses. Conclusion: This study supports the prognostic value of PgR in ER-rich early BC but does not provide evidence that PgR-poor tumors respond preferentially better to AIs versus Tam. The authors conclude that PgR status is not a predictive marker for improved benefit with AI versus Tam. Bartlett JM, et al. Cancer Res. 2009;69(Suppl 2): Abstract 81.
Neratinib (HKI-272) is an orally administered irreversible inhibitor of the tyrosine kinase inhibitors erbB1 (epidermal growth factor receptor; EGFR) and erbB2 (HER2). This open-label, 2-arm phase II trial evaluated the efficacy and safety of neratinib (240 mg daily oral dose) in 136 patients with advanced HER2-positive BC (stage IIIB, IIIC, or IV). ErbB2 gene amplification in tumor tissue by fluorescence in situ hybridization (FISH) was required for study entry. Patients were assigned one of 2 arms: those with prior treatment with trastuzumab were assigned to arm A and those who had no prior treatment with trastuzumab or any other erbB2-targeted drug were assigned to arm B. Primary endpoint was PFS rate at 16 weeks. Results: One hundred twenty-seven patients were evaluable for the efficacy analysis. Objective response rates (CR or PR) were 26% in arm A (prior trastuzumab) and 56% in arm B (no prior trastuzumab). The 16-week PFS rate in arm A was 60% and median PFS was 23 weeks. The 16-week PFS rate in arm B was 77% with a median PFS of 40 weeks. Safety analysis: AEs of any grade in more than 15% of patients were diarrhea, nausea and vomiting, fatigue, headache, and rash. The most common AE, diarrhea, occurred in 93% of patients and was manageable and reversible. Conclusion: Neratinib demonstrates robust antitumor activity with ORRs of 26% in patients who received prior treatment with trastuzumab and 56% in those with no prior trastuzumab treatment. These results warrant further study to determine neratinib’s role in the anti-erbB armamentarium. Burstein HJ, et al. Cancer Res. 2009;69(Suppl 2): Abstract 37.
Cross talk between growth factor and ER pathways has been implicated in endocrine resistance in BC. Combining EGFR/HER2-targeted therapy with AIs for postmenopausal patients with hormone receptor–positive BC may enhance endocrine responsiveness and delay the onset of resistance. Lapatinib (TYKERB®/TYVERB®), an oral dual tyrosine kinase inhibitor of EGFR and HER2, is effective against HER2-positive advanced or MBC. Previous studies have shown that lapatinib in combination with letrozole was well tolerated with encouraging clinical antitumor activity in patients with advanced BC. A randomized phase III trial (EGF 30008) was designed to assess the clinical benefit of lapatinib plus Let versus Let alone as first-line treatment of patients with hormone receptor–positive MBC. The first results from the trial were presented at SABCS. A total of 1286 postmenopausal patients as described above were randomized to receive Let plus lapatinib or Let alone. Of the 1286 patients, 219 were HER2-positive (IHC 3+ and/or FISH). Only 3 patients had received trastuzumab therapy. The primary endpoints included ORR, OS, time to and duration of response, and safety. Results:
Conclusion: The combination of lapatinib and Let is a new treatment option in postmenopausal patients with HER2-overexpressing MBC who are candidates for endocrine therapy. Johnson S, et al. Cancer Res. 2009;69(Suppl 2): Abstract 46.
Aromatase inhibitors, including letrozole, anastrozole, and exemestane, have increased the adjuvant therapy options for postmenopausal patients with hormone receptor–positive BC. However, AI therapy is frequently associated with loss of bone mineral density (BMD) leading to increased risk of fractures. Zoledronic acid (ZA), a potent novel bisphosphonate, has been shown to maintain or increase BMD in premenopausal and postmenopausal women with early BC being treated with adjuvant endocrine therapy, as well as healthy postmenopausal women with low BMD. The 36-month follow-up results from the ZO-FAST trial involving 1065 postmenopausal women with hormone receptor–positive early BC and a BMD T-score of ≥[-2.0] who received either upfront or delayed ZA 4 mg IV q 6 months if the BMD T-score fell less than [-2] or the presence of a fragility fracture are presented here. The primary endpoint was a change in lumbar spine and total hip; secondary endpoints include incidence of fractures, time to disease recurrence, OS, and safety. Results:
Conclusion: The 36-month follow-up analysis continues to show the advantage of upfront ZA in preventing BMD loss in postmenopausal women with hormone receptor–positive early BC receiving adjuvant Let therapy. In addition, these findings add to the growing body of evidence that ZA possesses antitumor activity and can improve BC outcomes. Eidtmann H, et al. Cancer Res. 2009;69(Suppl 2): Abstract 44.
The Oncotype DX recurrence score (RS) has been validated for estimating residual risk of distant recurrence (DR) in patients with ER+ node-negative (N-) primary BC receiving adjuvant treatment with Tam. While adjuvant treatment with AIs is widely used in postmenopausal women with ER+ disease, the RS has not been evaluated in patients treated with an AI. Tumor blocks were collected retrospectively from patient in the monotherapy arms of the ATAC trial under the TransATAC protocol, yielding 1308 HR+ blocks in UK patients (J Clin Oncol. 2008;26(7):1059-1065). Results: There were 1231 evaluable patients, of which 872 were N-, 306 N+, and 53 N unknown in whom there were 72, 74, and 6 DRs, respectively. In the prospectively-defined primary multivariate analysis, tumor size, grade, and RS were each separately statistically significant in predicting time to DR in patients with N- disease (P<.001, P = .003, and P<.001 group, respectively). Similar results were seen in patients with N+ disease. For N- patients with a low-risk RS, 4% developed DR, as did 12% of those in the intermediate-risk group and 25% with a high-risk RS. Higher DR rates, regardless of the RS result, were observed for N+ patients: 17% in the low-risk group, 28% in the intermediate-risk group, and 49% in the high-risk group. Recurrence score showed statistically significant prognostic value beyond that provided by Adjuvant! Online in both N- (P<.001) and N+ patients (P = .003). Conclusions: In patients with N- or N+ HR+ disease treated with anastrozole or Tam, the Oncotype DX® RS is an independent predictor of the risk of distant recurrence. However, the data from this study are not predictive of a differential benefit between anastrozole and Tam.
Dowsett M, et al. Cancer Res. 2009;69(Suppl 2): Abstract 53.
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