FEBRUARY 2010 Issue

primeLINES CLINICAL OPINION POLL

PHARMACEUTICAL NEWS

Expanded Indication for Lapatinib

On January 29, 2010, and less than one month later on February 18, 2010, the US Food and Drug Administration (FDA) and European Medicines Agency (EMEA), respectively, approved GlaxoSmithKline’s lapatinib (Tykerb^®/Tyverb^®) in combination with letrozole (Femara^®) for the treatment of postmenopausal women with hormone receptor–positive, HER2-positive metastatic breast cancer for whom hormonal therapy is indicated. These new indications for lapatinib are based on results from EGF30008, a phase III trial that demonstrated a significant improvement in progression-free survival (PFS) and clinical benefit rate for lapatinib plus letrozole versus letrozole alone. Lapatinib was initially approved in combination with capecitabine (Xeloda^®) for the treatment of patients with metastatic HER2-positive breast cancer for whom prior trastuzumab-based therapy failed.

A New Treatment Option for Gastric Cancer

On December 17, 2009, Roche’s trastuzumab (Herceptin^®) received a positive recommendation from the European Medicines Agency (EMEA) for use in combination with standard chemotherapy for the treatment of previously untreated patients with HER2-positive metastatic adenocarcinoma of the stomach or gastroesophageal junction. The positive opinion for this new indication was issued in record time due to high unmet medical need and data from the ToGA trial, which demonstrated an increase in overall survival (OS) for patients with advanced HER2-positive gastric cancer who received trastuzumab plus chemotherapy (intravenous fluorouracil or capecitabine and cisplatin) compared to chemotherapy alone.

Denosumab for Osteoporosis and Bone Loss Associated with Hormone Ablation

On December 17, 2009, the EMEA granted approval of Amgen’s denosumab (Prolia^®), a novel human monoclonal antibody against RANK ligand (RANKL), for the treatment of osteoporosis in postmenopausal women at increased risk of fractures and for treatment of bone loss associated with hormone ablation in men with prostate cancer who also have increased risk of fractures. The positive opinion is based on data from six phase III trials demonstrating the ability of denosumab to increase bone mineral density at all skeletal sites measured. In addition, two pivotal phase III studies, FREEDOM (Fracture REduction Evaluation of Denosumab in Osteoporosis every six Months) in women with postmenopausal osteoporosis and HALT (Hormone AbLation Therapy) in men with nonmetastatic prostate cancer undergoing androgen deprivation therapy, demonstrated that denosumab administered as a subcutaneous injection twice yearly reduced the incidence of fractures in the osteoporosis and prostate cancer settings, respectively.

Oral Treatment for Chronic Idiopathic Thrombocytopenic Purpura Now Available in Europe

Almost a year after FDA approval, the EMEA granted approval on December 17, 2009, for GlaxoSmithKline’s eltrombopag (Revolade^®), a thrombopoietin (TPO) receptor agonist, for use in adult splenectomized patients with chronic immune (idiopathic) thrombocytopenic purpura (ITP) who are refractory to other treatments, such as corticosteroids or immunoglobulins. The indication also states that eltrombopag may be considered as a second-line therapy for adults who have not undergone splenectomy due to contraindication of surgery.

FROM THE LITERATURE

Clinical Validity versus Clinical Utility for Gene Expression Arrays in Breast Cancer

Many data have been published supporting the clinical validity of the 21-gene and 70-gene assays in regard to providing prognostic information about distant recurrence of breast cancer; however, there is a dearth of information about the clinical usefulness of these assays. In an editorial published in the January 11 issue of the Journal of Clinical Oncology, Joseph Sparano and Lawrence Solin attempt to address whether test results actually influence physicians’ clinical decisions and if patients benefit from a subsequent change in the choice of therapy. Current practice guidelines recommend adjuvant chemotherapy for the majority of patients with operable breast cancer, and many patients are willing to accept chemotherapy even if there is a low likelihood of benefit. The authors introduce the dilemma of chemotherapy in early-stage breast cancer by stating a quote by Yogi Berra, “When you come to a fork in the road, take it,” although it is unclear which path that should be. Indeed, in early breast cancer decisions must be made about adjuvant chemotherapy, but it is still unclear how to make the appropriate decision for each individual patient. Two reports published in the same issue of the Journal of Clinical Oncology are discussed by Sparano and Solin to clarify the issue of practical utility of the 21-gene recurrence score assay. These 2 reports are reviewed below.

J Clin Oncol. 2010 Jan 11. [Epub ahead of print]

A multicenter, prospective study by Shelly Lo et al examined whether results from the 21-gene recurrence score assay influenced adjuvant treatment selection by patients with node-negative, estrogen receptor (ER)–positive breast cancer and their physicians. Patients and physicians were asked to provide their treatment choice and recommendation, respectively, before and after obtaining the 21-gene recurrence score. The medical oncologists changed their treatment recommendation about one-third of the time, and approximately one-fourth of the patients changed their treatment decision. Most of the treatment changes were from a recommendation of chemotherapy plus hormonal therapy (CHT) to hormonal therapy (HT) only; thus, these patients benefited by being spared chemotherapy when it was not likely to beneficial.

J Clin Oncol. 2010 Jan 11. [Epub ahead of print]

Breast cancer locoregional recurrence (LRR) is a significant predictor of distant recurrence. The article by Eleftherios Mamounas and colleagues evaluated the relationship between the 21-gene recurrence score assay and LRR in patients with node-negative, ER-positive breast cancer from two National Surgical Adjuvant Breast and Bowel Project (NSABP) trials (NSABP B-14 and B-20). Results from this analysis demonstrated that the 21-gene recurrence score was a significant predictor of LRR, which was similar to the relationship between recurrence score and distant recurrence in the same group of patients. The authors conclude that these results have biologic, and potentially clinical, implications for locoregional therapy decisions in patients with node-negative and ER-positive breast cancer.

J Clin Oncol. 2010 Jan 11. [Epub ahead of print]

Editorial--Take home messages from the two articles include the following:

• Clinicians may be reassured that appropriate use of the recurrence score in selected patients with early stage, ER-positive breast cancer frequently impacts therapeutic decisions in a manner that benefits patients.
• The resulting reduction in chemotherapy use may result in cost savings.
• The development of multiparameter assays to include information about distant and local recurrence may provide a more precise estimate of the potential risks of breast cancer recurrence.

Though there is a known role for gene expression assays in node-negative, ER-positive breast patients, Kathy Albain et al evaluated the prognostic and predictive value of the 21-gene recurrence score assay in patients with node-positive, ER-positive disease. In this retrospective analysis of SWOG-8814, 376 specimens from postmenopausal women who were randomly assigned to receive tamoxifen alone or anthracycline-based chemotherapy (cyclophosphamide, doxorubicin, and fluorouracil; CAF) followed by tamoxifen were evaluated. Results demonstrated that the recurrence score was prognostic for tamoxifen-treated patients with positive nodes, and could also predict significant benefit of CAF in patients with a high recurrence score. In addition, a low recurrence score identified women who did not derive benefit from anthracycline-based chemotherapy, despite positive nodes. The authors state that these results challenge the current treatment standard of adjuvant chemotherapy for all women with positive axillary nodes and ER-positive breast cancer.

Lancet Oncol. 2010;11(1):55-65.

Response to Neoadjuvant Chemotherapy: Does Stage Matter?

The goals of neoadjuvant systemic treatment in patients with breast cancer include reducing the risk of recurrence, expanding surgical options, and providing early information on the response to treatment. Neoadjuvant chemotherapy followed by mastectomy is considered the treatment of choice in patients with locally advanced breast cancer (LABC) and inflammatory breast cancer (IBC), but neoadjuvant chemotherapy in these stages is considered less effective than in operable breast cancer (OBC). Inflammatory breast cancer and LABC have often been excluded from adjuvant and neoadjuvant clinical trials together with earlier stages because of their different biologic features and poor prognoses.

The prospectively randomized neoadjuvant phase III GeparTrio clinical trial evaluated the relationship between extended chemotherapy and pathologic complete response (pCR) at surgery in patients with untreated breast cancer. Patients in the GeparTrio trial were stratified by stage and received 2 initial cycles of docetaxel/doxorubicin/cyclophosphamide (TAC); after evaluation of response to this initial therapy, responders were randomized to an additional 4 or 6 cycles of TAC and nonresponders received 4 additional cycles of TAC or 4 cycles of vinorelbine and capecitabine (NX). Previously reported findings from this trial showed that nonresponders to the initial neoadjuvant TAC treatment achieved similar efficacy but better tolerability by switching to NX than continuing with TAC. Responders to initial therapy who received 6 additional cycles of TAC (eight total cycles) demonstrated statistically significantly higher sonographic response rates, but not pCR rates, than those receiving 6 total TAC cycles. One of the predefined objectives of the GeparTrio trial, which evaluated 2064 patients (93 with IBC, 194 with LABC and 1777 patients with OBC), was an analysis of the pCR in patients with IBC or LABC versus patients with OBC.

Overall, the pCR rate was not significantly different between IBC and LABC (8.6% versus 11.3%; P = .542), but when the two groups were analyzed together, the pCR rate was significantly lower compared to patients with OBC (10.5% versus 17.7%; P = .002). The overall response rate assessed by either sonographic or physical examination at surgery was 71.0% for patients with IBC versus 69.6% for patients with LABC, which when combined was significantly lower than the 83.4% response for patients with OBC (P<.001). In the group of patients with IBC or LABC, breast-conserving surgery (BCS) was performed in 26.5% of the patients compared to 69.9% of patients with OBC (P<.001). A multivariable analysis was performed to identify markers predicting pCR in patients with IBC or LABC and in the whole study population. Grade was found to be the only statistically independent predictor of pCR in patients with IBC or LABC; however, when all patients were included in the analysis, young age, nonlobular histologic type, grade 3, and negative hormone receptor status were found to be independent predictors of pCR. Tumor stage itself was not a significant independent predictor. Based on these analyses, the authors concluded that there is no significantly different response to neoadjuvant chemotherapy in patients with IBC and LABC compared to OBC and, thus, these patients can be included in the same neoadjuvant clinical trials of systemic therapy. In addition, they suggested further research to identify subgroups of patients for whom less aggressive surgery provides sufficient local control without compromising long-term outcome.

J Clin Oncol. 2010;28(1):83-91.

Long-Term Survival Benefit for Non-Small Cell Lung Cancer with Adjuvant Chemotherapy? The Jury’s Still Out

Updated survival data from JBR-10, a phase III randomized trial evaluating adjuvant cisplatin and vinorelbine versus observation in patients with completely resected stage IB or II non-small cell lung cancer (NSCLC), and the long-term results of the International Adjuvant Lung Cancer Trial (IALT) study, which evaluated adjuvant cisplatin-based chemotherapy in patients with completely resected stage I-III NSCLC, as well as an accompanying editorial were published in the January 1 issue of the Journal of Clinical Oncology.

With a median follow-up of 9.3 years in the JBR-10 trial, the 5-year survival benefit of adjuvant cisplatin and vinorelbine was maintained with an overall 11% improvement in survival (HR 0.78, P = .04); this benefit was also observed for cancer-specific survival. In comparison, updated IALT results based on a median follow-up of 7.5 years showed a fading effect of adjuvant chemotherapy on survival. Although the initial benefit during the first 5 years (reduction of the risk of death) was 14%, after 5 years, the risk of death was reduced by only 9% with adjuvant chemotherapy and this difference was no longer statistically significant.

In the editorial based on the updated analyses of JBR-10 and IALT, Jean-Yves Douillard commented on the opposite outcomes of adjuvant chemotherapy in the two trials after longer follow-up. He stated that differences in the type of chemotherapy used, varied patient populations, use of postoperative radiation (PORT), and the potential usefulness of prognostic or predictive biomarkers may explain differences in the long-term outcomes of IALT and JBR-10. It was noted that longer follow-up is needed in the adjuvant setting for lung cancer to assess cure, and the cause of death should be reported in such trials. Indeed, the definitions of lung cancer– and non-lung cancer–related death differed between the two trials. In IALT, treatment-related death and second malignancies were considered non-lung cancer deaths, while all other deaths were considered lung-cancer related; the JBR-10 authors denoted treatment-related deaths and lung cancer progression as lung-cancer related and all other causes as non-lung cancer-related. These definitions should be standardized to evaluate cancer-specific survival in future trials.

J Clin Oncol. 2010;28(1):29-34.
J Clin Oncol. 2010;28(1):35-42.
J Clin Oncol. 2010;28(1):3-5.

Cetuximab Improves Survival in Head and Neck Cancer

The standard of care for locally advanced squamous-cell carcinoma of the head and neck (LASCCHN) continues to evolve and varies with the stage of disease. It has been shown that the addition of concurrent chemotherapy to radiotherapy results in improved clinical outcome in terms of both locoregional control and OS; however, chemoradiotherapy is associated with severe, dose-limiting acute toxicities and, in some patients a higher proportion of late toxicities. Recent results from a phase III randomized study demonstrated that the epidermal growth factor receptor (EGFR) inhibitor cetuximab (Erbitux^®) given concomitantly with radiotherapy yields a significant improvement in PFS (HR = 0.70; P = .006) and OS (HR = 0.74; P = .03) over radiotherapy alone without any increase in radiotherapy-associated toxicity.

In the January issue of The Lancet Oncology, James Bonner et al report 5-year survival data from this phase III trial, and investigate the relationship between cetuximab-induced rash and survival. The current analysis demonstrated a 5-year OS rate of 36.4% in patients receiving radiotherapy alone and 45.6% in patients receiving radiotherapy plus cetuximab respectively (HR = 0.73; P = .018). Though the trial was not powered for subgroup analysis, as cautioned by the authors, data demonstrated that oropharyngeal tumors, T1-3 tumors, treatment in the United States, concomitant boost, advanced nodal stage (N1-N3), high Karnofsky performance score (90-100), male sex, and age less than 65 years were factors associated with a potential increased benefit from the addition of cetuximab to radiotherapy. It was also found that, among patients who received cetuximab, patients experiencing a prominent rash had significantly longer OS compared to those with mild rash (68.8 months versus 25.6 months; P = .002). In summary, these data confirm the use of cetuximab plus radiotherapy in patients with LASCCHN, and the authors suggest that acneiform rash is a possible biomarker of an immunologic response that leads to optimal outcome in patients treated with cetuximab.

It was also noted that a phase III trial, RTOG 0522, assessing concurrent accelerated radiation and cisplatin versus concurrent accelerated radiation, cisplatin, and cetuximab for advanced head and neck cancer recently closed to patient enrolment, and it is hoped that data from this trial will provide more information regarding role of cetuximab in combination with chemoradiation in the locally advanced setting, as well as provide the rationale for further investigation of cetuximab in earlier stages of disease.

Lancet Oncol. 2010;11(1):21-28.

Is There Still a Role for Post-Chemotherapy Retroperitoneal Lymph Node Dissection for Nonseminomatous Germ Cell Tumors?

The use of chemotherapy for patients with metastatic testicular tumors has substantially changed treatment outcomes for these patients and enabled cure for almost all patients with disseminated disease. The role of adjuvant regional surgery for patients with disseminated nonseminomatous germ cell tumors who achieve serologic complete response and minimal/no radiologic residual is unclear. Active surveillance of such patients represents a reasonable alternative and may spare them unnecessary major surgery if remission is sustained.

In the February 1 issue of the Journal of Clinical Oncology, Christian Kollmannsberger and colleagues reported results from a population-based study evaluating outcomes in 276 patients with disseminated germ cell tumors who received cisplatin-based combination chemotherapy. Patients achieving a complete remission (CR) or a tumor marker-negative partial remission (PR) with residual tumor <1 cm were managed with surveillance if permitted by institutional policy. Those with residual disease (>1 cm) underwent surgical resection. A main focus of the study was management and outcomes in patients with a complete serologic and radiologic response. Overall, 161 patients (59%) achieved a CR (115 of 161; 71%) or PR (29%) after chemotherapy with no further need for surgery. The majority of these patients (94%) were classified as having good risk disease according to International Germ Cell Cancer Collaborative Group (IGCCCG) criteria. Of these 161 patients, 10 patients (6%) relapsed, but there were no disease-specific deaths at a median follow-up 52 months. Two of the total 10 relapses occurred beyond 2 years, and 8 of the ten relapses were teratoma in nature and were treated with a delayed RPLND. The authors conclude that the results of this study support the use of cisplatin-based chemotherapy followed by active surveillance in patients with disseminated germ cell tumors who achieve serologic and radiographic CR. For patients with residual disease >1 cm, primary RPLND is warranted.

J Clin Oncol. 2010;28(4):537-542.

An accompanying editorial acknowledges the fact that this study provides some guidance regarding the decision-making process for patients with nonseminomatous germ cell tumors, but it is still difficult to define the role of post-chemotherapy RPLND in this patient population. After discussing the risks and benefits of each, the authors state that surveillance and RPLND are both standard options for patients with nonseminomatous germ cell tumors who achieve a clinical CR in the retroperitoneum. However, physicians should take into account short-term, intermediate-term, and long-term outcomes when making treatment decisions, including the emerging concern of second malignant neoplasms resulting from cumulative radiation exposure from CT scanning.

J Clin Oncol. 2010;28(4):519-521.

ADDITIONAL PUBLICATIONS WORTH READING

• Gluz O, Liedtke C, Gottschalk N, et al. Triple-negative breast cancer--current status and future directions. Ann Oncol. 2009;20(12):1913-1927. This comprehensive overview describes the molecular biology and outcome of triple-negative breast cancer, and discusses current and emerging therapeutic strategies for management of this heterogeneous breast cancer subtype.
• Azzoli CG, Baker S Jr, Temin S, et al. American Society of Clinical Oncology Clinical Practice Guideline update on chemotherapy for stage IV non-small-cell lung cancer. J Clin Oncol. 2009;27(36):6251-6266. This article provides updated recommendations for the first-line, second-line, and third-line treatment of patients with stage IV non-small-cell lung cancer.
• Provan D, Stasi R, Newland AC, et al. International consensus report on the investigation and management of primary immune thrombocytopenia. Blood. 2010;115(2):168-186. This publication aims to present new data and provide consensus-based recommendations relating to the diagnosis and treatment of primary immune thrombocytopenia in adults, in children, and during pregnancy.
• Gribben JG. How I treat CLL up front. Blood. 2010;115(2):187-197. Based on 25 years of clinical practice in oncology, research, and review of the literature, John Gribben provides a practical management approach for patients with previously untreated chronic lymphocytic leukemia (CLL).

UPCOMING prIME EVENTS

OTHER prIME ACTIVITIES